Current Psychiatry

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor

While some classes of medications used to treat psychi­atric disorders, such as stimulants and benzodiazepines, are well-recognized as controlled substances and drugs of abuse, clinicians may be less familiar with the potential misuse/abuse of other psychiatric medications. This article reviews the evidence related to the misuse/abuse of anticholinergics, antidepressants, antipsychotics, and gabapentinoids.

The terms “misuse,” “abuse,” and “addiction” are used variably in the literature without standardized definitions. For this review, “misuse/abuse (M/A)” will be used to collectively describe self-administration that is recreational or otherwise inconsistent with legal or medical guidelines, unless a specific distinction is made. Whether or not the medications reviewed are truly “addictive” will be briefly discussed for each drug class, but the focus will be on clinically relevant aspects of M/A, including:

• excessive self-administration
• self-administration by non-oral routes
• co-administration with other drugs of abuse
• malingering of psychiatric symptoms to obtain prescriptions
• diversion for sale to third parties
• toxicity from overdose.

Anticholinergic medications

The first case describing the deliberate M/A of an anticholinergic medication for its euphoric effects was published in 1960.Further reportsfollowed in Europe before the M/A potential of prescription anticholinergic medications among psychiatric patients with an overdose syndrome characterized by atropinism and toxic psychosis was more widely recognized in the United States in the 1970s. Most reported cases of M/A to date have occurred among patients with psychiatric illness because anticholinergic medications, including trihexyphenidyl, benztropine, biperiden, procyclidine, and orphenadrine, were commonly prescribed for the management of first-generation and high dopamine D2-affinity antipsychotic-induced extrapyramidal symptoms (EPS). For example, one study of 234 consecutively hospitalized patients with schizophrenia noted an anticholinergic M/A incidence of 6.5%.¹

However, anticholinergic M/A is not limited to individuals with psychotic disorders. A UK study of 154 admissions to an inpatient unit specializing in behavioral disturbances found a 12-month trihexyphenidyl M/A incidence of 17%; the most common diagnosis among abusers was antisocial personality disorder.² Anticholinergic M/A has also been reported among patients with a primary diagnosis of substance use disorders (SUDs)³ as well as more indiscriminately in prison settings,⁴ with some inmates exchanging trihexyphenidyl as currency and using it recreationally by crushing it into powder and smoking it with tobacco.⁵ Others have noted that abusers sometimes take anticholinergics with alcohol in order to “potentiate” the effects of each substance.^6,7 Pullen et al⁸ described individuals with and without psychiatric illness who stole anticholinergic medications, purchased them from other patients, or bought them “on the street.” Malingering EPS in order to obtain anticholinergic medications has also been well documented.⁹ Clearly, anticholinergic M/A can occur in psychiatric and non-psychiatric populations, both within and outside of clinical settings. Although anticholinergic M/A appears to be less frequent in the United States now that second-generation antipsychotics (SGAs) are more frequently prescribed, M/A remains common in some settings outside of the United States.⁷

Among the various anticholinergic medications prescribed for EPS, trihexyphenidyl has been reported to have the greatest M/A potential, which has been attributed to its potency,¹⁰ its stimulating effects (whereas benztropine is more sedating),¹¹ and its former popularity among prescribers.⁸ Marken et al¹¹ published a review of 110 reports of M/A occurring in patients receiving anticholinergic medications as part of psychiatric treatment in which 69% of cases involved taking trihexyphenidyl 15 to 60 mg at a time (recommended dosing is 6 to 10 mg/d in divided doses).Most of these patients were prescribed anticholinergic medications for diagnostically appropriate reasons—only 7% were described as “true abusers” with no medical indication. Anticholinergic M/A was typically driven by a desire for euphoric and psychedelic/hallucinogenic effects, although in some cases, anticholinergic M/A was attributed to self-medication of EPS and depressive symptoms. These findings illustrate the blurred distinction between recreational use and perceived subjective benefit, and match those of a subsequent study of 50 psychiatric patients who reported anticholinergic M/A not only to “get high,” but to “decrease depression,” “increase energy,” and decrease antipsychotic adverse effects.¹² Once again, trihexyphenidyl was the most frequently misused anticholinergic in this sample.

Table 1^{2,3,7,8,10-15} outlines the subjective effects sought and experienced by anticholinergic abusers as well as potential toxic effects; there is the potential for overlap. Several authors have also described physiologic dependence with long-term trihexyphenidyl use, including tolerance and a withdrawal/abstinence syndrome.^7,16 In addition, there have been several reports of coma¹³ and death in the setting of intended suicide by overdose of anticholinergic medications.^14,15

Although anticholinergic M/A in the United States now appears to be less common, clinicians should remain aware of the M/A potential of anticholinergic medications prescribed for EPS. Management of M/A involves:

• detection
• reducing anticholinergic exposure by managing EPS with alternative strategies, such as switching or reducing the dose of the antipsychotic medication
• gradual tapering of anticholinergic medications to minimize withdrawal.¹¹

Continue to: Antidepressants

Haddad¹⁷ published a review of 21 English-language case reports from 1966 to 1998 describing antidepressant use in which individuals met DSM-IV criteria for substance dependence to the medication. An additional 14 cases of antidepressant M/A were excluded based on insufficient details to support a diagnosis of dependence. The 21 reported cases involved:

• tranylcypromine (a monoamine oxidase inhibitor [MAOI])
• amitriptyline (a tricyclic antidepressant [TCA])
• fluoxetine (a selective serotonin reuptake inhibitor [SSRI])
• amineptine (a TCA previously available in France but removed from the market in 1999 in part due to its abuse potential)
• nomifensine (a norepinephrine/dopamine reuptake inhibitor previously available in the United Kingdom but removed in 1986 due to hemolytic anemia).

In 95% of cases, the antidepressants were prescribed for treatment of an affective disorder but were abused for stimulant effects or the perceived ability to lift mood, cause euphoria or a “high,” or to improve functioning. Two-thirds of cases involved patients with preexisting substance misuse. Placing the case reports in the context of the millions of patients prescribed antidepressants during this period, Haddad concluded the “incidence of [antidepressant] addiction [is] so low as to be clinically irrelevant.”¹⁷

Despite this conclusion, Haddad singled out amineptine and tranylcypromine as antidepressants with some evidence of true addictive potential.^17,18 A more recent case series described 14 patients who met DSM-IV criteria for substance abuse of tertiary amine TCAs (which have strong anticholinergic activity) and concluded that “misuse of [TCAs] is more common than generally appreciated.”¹⁹ In keeping with that claim, a study of 54 outpatients taking unspecified antidepressants found that up to 15% met DSM-III-R criteria for substance dependence (for the antidepressant) in the past year, although that rate was much lower than the rate of benzodiazepine dependence (47%) in a comparative sample.²⁰ Finally, a comprehensive review by Evans and Sullivan²¹ found anecdotal reports published before 2014 that detailed misuse, abuse, and dependence with MAOIs, TCAs, fluoxetine, venlafaxine, bupropion, tianeptine, and amineptine. Taken together, existing evidence indicates that select individuals—typically those with other SUD comorbidity—sometimes misuse antidepressants in a way that suggests addiction.

Still, while it is well known that abrupt cessation of antidepressants can result in a discontinuation syndrome characterized by flu-like symptoms, nausea, and dizziness,²² physiologic withdrawal effects must be distinguished from historical definitions of substance “abuse” and the broader concept of psychological “addiction” or drug dependence^18,23 now incorporated into the DSM-5 definition of SUDs.²⁴ Indeed, although withdrawal symptoms were reported by more than half of those who took antidepressants and responded to a recent online survey,²⁵ evidence to support the existence of significant antidepressant tolerance, craving, or compulsive use is lacking.^17,18 Antidepressants as a class do not appear to be significantly rewarding or reinforcing and, on the contrary, discontinuation by patients is common in clinical practice.²⁶ The popular claim that some individuals taking antidepressants “can’t quit”²⁷ must also be disentangled from loss of therapeutic effects upon cessation.

Bupropion. A more convincing argument for antidepressant addiction can be made for bupropion, a weak norepinephrine and dopamine reuptake inhibitor with an otherwise unclear mechanism of action.²⁸ In 2002, the first report of recreational bupropion M/A described a 13-year-old girl who took 2,400 mg orally (recommended maximum dose is 450 mg/d in divided doses) after being told it would give her “a better high than amphetamine.”²⁹ This was followed in the same year by the first report of recreational M/A of bupropion via nasal insufflation (snorting), resulting in a seizure,³⁰ and in 2013 by the first published case of M/A by IV self-administration.³¹

Continue to: The M/A potential of bupropion...

The M/A potential of bupropion, most commonly via intranasal administration, is now broadly recognized based on several case reports describing desired effects that include a euphoric high and a stimulating “buzz” similar to that of cocaine or methamphetamine but less intense.^29-36 Among recreational users, bupropion tablets are referred to as “welbys,” “wellies,” “dubs,” or “barnies.”³⁷ Media coverage of a 2013 outbreak of bupropion M/A in Toronto detailed administration by snorting, smoking, and injection, and described bupropion as “poor man’s cocaine.”³⁸ Between 2003 and 2016, 2,232 cases of bupropion misuse/abuse/dependence adverse drug reactions were reported to the European Monitoring Agency.³⁷ A review of intentional bupropion M/A reported to US Poison Control Centers between 2000 to 2013 found 975 such cases, with the yearly number tripling between 2000 and 2012.³⁹ In this sample, nearly half (45%) of the users were age 13 to 19, and 76% of cases involved oral ingestion. In addition to bupropion M/A among younger people, individuals who misuse bupropion often include those with existing SUDs but limited access to illicit stimulants and those trying to evade detection by urine toxicology screening.³³ For example, widespread use and diversion has been well documented within correctional settings, and as a result, many facilities have removed bupropion from their formularies.^{21,28,33,34,40}

Beyond desired effects, the most common adverse events associated with bupropion M/A are listed in Table 2,^{28,30,32-34,36,39} along with their incidence based on cases brought to the attention of US Poison Control Centers.³⁹ With relatively little evidence of a significant bupropion withdrawal syndrome,³⁷ the argument in favor of modeling bupropion as a truly addictive drug is limited to anecdotal reports of cravings and compulsive self-administration³⁵ and pro-dopaminergic activity (reuptake inhibition) that might provide a mechanism for potential rewarding and reinforcing effects.⁴⁰ While early preclinical studies of bupropion failed to provide evidence of amphetamine-like abuse potential,^41,42 non-oral administration in amounts well beyond therapeutic dosing could account for euphoric effects and a greater risk of psychological dependence and addiction.^21,28,40

Bupropion also has an FDA indication as an aid to smoking cessation treatment, and the medication demonstrated early promise in the pharmacologic treatment of psycho­stimulant use disorders, with reported improvements in cravings and other SUD outcomes.^43-45 However, subsequent randomized controlled trials (RCTs) failed to demonstrate a clear therapeutic role for bupropion in the treatment of cocaine^46,47 and methamphetamine use disorders (although some secondary analyses suggest possible therapeutic effects among non-daily stimulant users who are able to maintain good adherence with bupropion).^48-51 Given these overall discouraging results, the additive seizure risk of bupropion use with concomitant psychostimulant use, and the potential for M/A and diversion of bupropion (particularly among those with existing SUDs), the use of bupropion for the off-label treatment of stimulant use disorders is not advised.

Antipsychotics

As dopamine antagonists, antipsychotics are typically considered to have low potential for rewarding or reinforcing effects. Indeed, misuse of antipsychotics was a rarity in the first-generation era, with only a few published reports of haloperidol M/A within a small cluster of naïve young people who developed acute EPS,⁵² and a report of diversion in a prison with the “sadistic” intent of inflicting dystonic reactions on others.⁵³ A more recent report described 2additional cases of M/A involving haloperidol and trifluoperazine.⁵⁴ Some authors have described occasional drug-seeking behavior for low-potency D2 blockers such as chlorpromazine, presumably based on their M/A as anticholinergic medications.⁵⁵

The potential for antipsychotic M/A has gained wider recognition since the advent of the SGAs. Three cases of prescription olanzapine M/A have been published to date. One involved a man who malingered manic symptoms to obtain olanzapine, taking ≥40 mg at a time (beyond his prescribed dose of 20 mg twice daily) to get a “buzz,” and combining it with alcohol and benzodiazepines for additive effects or to “come down” from cocaine.⁵⁶ This patient noted that olanzapine was “a popular drug at parties” and was bought, sold, or traded among users, and occasionally administered intravenously. Two other cases described women who self-administered olanzapine, 40 to 50 mg/d, for euphoric and anxiolytic effects.^57,58 James et al⁵⁹ detailed a sample of 28 adults who reported “non-medical use” of olanzapine for anxiolytic effects, as a sleep aid, or to “escape from worries.”

Continue to: Quetiapine

Quetiapine. In contrast to some reports of olanzapine M/A in which the line between M/A and “self-medication” was blurred, quetiapine has become a more convincing example of clear recreational antipsychotic M/A. Since the first report of oral and intranasal quetiapine M/A in the Los Angeles County Jail published in 2004,⁵⁵ subsequent cases have detailed other novel methods of recreational self-administration^60-68 (Table 3^55,60-68), and additional reports have been published in non-English language journals.^69,70 Collectively, these case reports have detailed that quetiapine is:

• misused for primary subjective effects as well as to mitigate the unpleasant effects of other drugs^60,67
• referred to as “quell,”“Q,” “Susie-Q,” “squirrel,” and “baby heroin”^55,71,72
• often obtained by malingering psychiatric symptoms^55,61,63,65
• diverted/sold with “street value” both within and outside of psychiatric facilities and correctional settings.^{55,60-62,67,68,73}

These anecdotal accounts of quetiapine M/A have since been corroborated on a larger scale based on several retrospective studies. Although early reports of quetiapine M/A occurring in correctional settings have resulted in formulary removal,^71,74 quetiapine M/A is by no means limited to forensic populations and is especially common among those with comorbid SUDs. A survey of 74 patients enrolled in a Canadian methadone program reported that nearly 60% had misused quetiapine at some point.⁷⁵ Among an Australian sample of 868 individuals with active IV drug abuse, 31% reported having misused quetiapine.⁷⁶ Finally, within a small sample of patients with SUDs admitted to a detoxification unit in New York City, 17% reported M/A of SGAs.⁷⁷ In this study, SGAs were often taken in conjunction with other drugs of abuse in order to “recover” from or “enhance” the effects of other drugs or to “experiment.” Quetiapine was by far the most frequently abused SGA, reported in 96% of the sample; the most frequently reported SGA/drug combinations were quetiapine/alcohol/opioids, quetiapine/cocaine, and quetiapine/opioids.

Looking more broadly at poison center data, reports to the US National Poison Data System (NPDS) from 2005 to 2011 included 3,116 cases of quetiapine abuse (37.5%, defined as intentional recreational use in order to obtain a “high”) or misuse (62.5%, defined as improper use or dosing for non-recreational purposes).⁷⁸ A more recent analysis of NPDS reports from 2003 to 2013 found 2,118 cases of quetiapine abuse, representing 61% of all cases of reported SGA abuse.⁷⁹ An analysis of the European Medicines Agency Adverse Drug Database yielded 18,112 reports of quetia­pine misuse, abuse, dependence, and withdrawal for quetiapine (from 2005 to 2016) compared with 4,178 for olanzapine (from 2004 to 2016).⁸⁰ These reports identified 368 fatalities associated with quetiapine.

The rate of quetiapine M/A appears to be increasing sharply. Reports of quetiapine M/A to poison centers in Australia increased nearly 7-fold from 2006 to 2016.⁸¹ Based on reports to the Drug Abuse Warning System, US emergency department visits for M/A of quetiapine increased from 19,195 in 2005 to 32,024 in 2011 (an average of 27,114 visits/year), with 75% of cases involving quetiapine taken in combination with other prescription drugs, alcohol, or illicit drugs.⁸² Consistent with poison center data, M/A was reported for other antipsychotics, but none nearly as frequently as for quetiapine.

With increasingly frequent quetiapine M/A, clinicians should be vigilant in monitoring for medical morbidity related to quetiapine and cumulative toxicity with other drugs. The most frequent adverse events associated with quetiapine M/A reported to US Poison Control Centers are presented in Table 4.^78,79

Continue to: Unlike bupropion...

Unlike bupropion, quetiapine’s dopamine antagonism makes it unlikely to be a truly addictive drug, although this mechanism of action could mediate an increase in concurrent psychostimulant use.⁸³ A few case reports have described a quetiapine discontinuation syndrome similar to that of antidepressants,^60,65,84-88 but withdrawal symptoms suggestive of physiologic dependence may be mediated by non-dopaminergic effects through histamine and serotonin receptors.^84,89 Evidence for quetiapine misuse being associated with craving and compulsive use is lacking, and true quetiapine addiction is probably rare.

Similar to bupropion, preliminary findings have suggested promise for quetiapine as a putative therapy for other SUDs.^90-93 However, subsequent RCTs have failed to demonstrate a therapeutic effect for alcohol and cocaine use disorders.^94-96 Given these negative results and the clear M/A potential of quetiapine, off-label use of quetiapine for the treatment of SUDs and psychiatric symptoms among those with SUDs must be considered judiciously, with an eye towards possible diversion and avoiding the substitution of one drug of abuse for another.

Gabapentinoids

In 1997, the first published case report of gabapentin M/A described a woman who self-administered her husband’s gabapentin to reduce cravings for and withdrawal from cocaine.⁹⁷ The authors highlighted the possible therapeutic benefit of gabapentin in this regard rather than raising concerns about diversion and M/A. By 2004, however, reports of recreational gabapentin M/A emerged among inmates incarcerated within Florida correctional facilities who self-administered intranasal gabapentin to achieve a “high” that was “reminiscent of prior effects from intranasal ingestion of cocaine powder.”⁹⁸ In 2007, a single case of gabapentin misuse up to 7,200 mg/d (recommended dosing is ≤3,600 mg/d) was reported, with documentation of both tolerance and withdrawal symptoms.⁹⁹ As of 2017, a total of 36 cases of gabapentin M/A and 19 cases of pregabalin M/A have been published.¹⁰⁰

In the past decade, anecdotal reports have given way to larger-scale epidemiologic data painting a clear picture of the now-widespread M/A of gabapentin and other gabapentinoids. For example, a study of online descriptions of gabapentin and pregabalin M/A from 2008 to 2010 documented:

• oral and IM use (gabapentin)
• IV and rectal (“plugging”) use (pregabalin)
• “parachuting” (emptying the contents of capsules for a larger dose) (pregabalin)
• euphoric, entactogenic, stimulant, calming/anxiolytic, and dissociative subjective effects (gabapentin/pregabalin)
• rapid development of tolerance to euphoric effects leading to self-administration of increasing doses (gabapentin/pregabalin)
• frequent co-administration with other drugs of abuse, including alcohol, benzodiazepines, cannabis, stimulants, opiates, hallucinogens, gamma-hydroxybutyrate, mephedrone, and Salvia divinorum (gabapentin/pregabalin)¹⁰¹

Several systematic reviews of both anecdotal reports and epidemiologic studies published in the past few years provide additional evidence of the above, such as:

• excessive dosing with self-administration
• intranasal and inhaled routes of administration
• diversion and “street value”
• greater M/A potential of pregabalin than gabapentin
• the presence of gabapentinoids in postmortem toxicology analyses, suggesting a role in overdose fatalities when combined with other drugs.^100,102,103

Continue to: The European Medicine Agency's EudraVigilance database...

The European Medicine Agency’s EudraVigilance database included 4,301 reports of gabapentin misuse, abuse, or dependence, and 7,639 such reports for pregabalin, from 2006 to 2015 (rising sharply after 2012), with 86 gabapentin-related and 27 pregabalin-related fatalities.¹⁰⁴ Data from the Drug Diversion Program of the Researched Abuse, Diversion, and Addiction-Related Surveillance System from 2002 to 2015 have likewise revealed that gabapentin diversion increased significantly in 2013.¹⁰⁵

While the prevalence of gabapentinoid M/A is not known, rates appear to be significantly lower than for traditional drugs of abuse such as cannabis, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and opioids.^106,107 However, gabapentin and pregabalin M/A appears to be increasingly common among individuals with SUDs and in particular among those with opioid use disorders (OUDs). For example, a 2015 report indicated that 15% of an adult cohort in Appalachian Kentucky with nonmedical use of diverted prescription opioids reported gabapentin M/A, an increase of nearly 3,000% since 2008.¹⁰⁸ Based on data from a US insurance enrollment and claims database, researchers found that the rate of gabapentin overuse among those also overusing opioids was 12% compared with only 2% for those using gabapentin alone.¹⁰⁹ It has also been reported that gabapentin is sometimes used as a “cutting agent” for heroin.¹¹⁰

Those who use gabapentinoids together with opioids report that gabapentin and pregabalin potentiate the euphoric effects of methadone¹¹¹ and endorse specific beliefs that pregabalin increases both the desired effects of heroin as well as negative effects such as “blackouts,” loss of control, and risk of overdose.¹¹² Indeed, sustained M/A of gabapentin and opioids together has been found to increase emergency department utilization, drug-related hospitalization, and respiratory depression.¹¹³ Based on a case-control study of opioid users in Canada, co-prescription of gabapentin and opioids was associated with a 50% increase in death from opioid-related causes compared with prescription of opioids alone.¹¹⁴

Case reports documenting tolerance, withdrawal, craving, and loss of control suggest a true addictive potential for gabapentinoids, but Bonnet and Sherbaum¹⁰⁰ concluded that while there is robust evidence of abusers “liking” gabapentin and pregabalin (eg, reward), evidence of “wanting” them (eg, psychological dependence) in the absence of other SUDs has been limited to only a few anecdotal reports with pregabalin. Accordingly, the risk of true addiction to gabapentinoids by those without preexisting SUDs appears to be low. Nonetheless, the M/A potential of both gabapentin and pregabalin is clear and in the context of a nationwide opioid epidemic, the increased morbidity/mortality risk related to combined use of gabapentinoids and opioids is both striking and concerning. Consequently, the state of Kentucky recently recognized the M/A potential of gabapentin by designating it a Schedule V controlled substance (pregabalin is already a Schedule V drug according to the US Drug Enforcement Agency),^103,113 and several other states now mandate the reporting of gabapentin prescriptions to prescription drug monitoring programs.¹¹⁵

Following a similar pattern to antidepressants and antipsychotics, a potential role for gabapentin in the treatment of cocaine use disorders was supported in preliminary studies,^116-118 but not in subsequent RCTs.^119-121 However, there is evidence from RCTs to support the use of gabapentin and pregabalin in the treatment of alcohol use disorders.^122-124 Gabapentin was also found to significantly reduce cannabis use and withdrawal symptoms in patients compared with placebo in an RCT of individuals with cannabis use disorders.¹²⁵ The perceived safety of gabapentinoids by clinicians, their subjective desirability by patients with SUDs, and efficacy data supporting a therapeutic role in SUDs must be balanced with recognition that approximately 80% of gabapentin prescriptions are written for off-label indications for which there is little supporting evidence,¹⁰⁹ such as low back pain.¹²⁶ Clinicians considering prescribing gabapentinoids to manage psychiatric symptoms, such as anxiety and insomnia, should carefully consider the risk of M/A and other potential morbidities, especially in the setting of SUDs and OUD in particular.

Continue to: Problematic, even if not addictive

Problematic, even if not addictive

It is sometimes claimed that “addiction” to psychiatric medications is not limited to stimulants and benzodiazepines.^27,127 Although anticholinergics, antidepressants, antipsychotics, and gabapentinoids can be drugs of abuse, with some users reporting physiologic withdrawal upon discontinuation, there is only limited evidence that the M/A of these psychiatric medications is associated with the characteristic features of a more complete definition of “addiction,” which may include:

• inability to consistently abstain
• impairment in behavioral control
• diminished recognition of significant problems associated with use
• a dysfunctional emotional response to chronic use.¹²⁸

Nonetheless, the literature documenting anticholinergic, antidepressant, antipsychotic, and gabapentinoid M/A includes several common features, including:

• initial reports among those with limited access to illicit drugs (eg, young people and incarcerated individuals) and subsequent spread to a wider population with more unconventional routes of administration
• use for recreational purposes and other subjective pseudo-therapeutic effects, often in combination with alcohol and illicit drugs
• greater M/A potential of certain medications within each of these drug classes (eg, trihexyphenidyl, bupropion, quetiapine)
• malingering psychiatric symptoms in order to obtain medications from prescribers and diversion for black market sale
• observations that medications might constitute therapy for SUDs that were not supported in subsequent RCTs (with the exception of gabapentin for alcohol and cannabis use disorders)
• increasing evidence of toxicity related to M/A, which suggests that prescription by clinicians has limited benefit and high risk for patients with SUDs.

Bottom Line

Some psychiatric medications are taken as drugs of abuse. Clinicians should be particularly aware of the misuse/abuse potential of anticholinergics, antidepressants, antipsychotics, and gabapentinoids, and use them cautiously, if at all, when treating patients with existing substance use disorders.

Related Resources

• Substance Abuse and Mental Health Services Administration. Prescription drug misuse and abuse. https://www.samhsa.gov/topics/prescription-drug-misuse-abuse.
• Substance Abuse and Mental Health Services Administration. Types of commonly misused or abused drugs. https://www.samhsa.gov/prescription-drug-misuse-abuse/types.
• National Institute on Drug Abuse. Misuse of prescription drugs. https://www.drugabuse.gov/publications/research-reports/misuse-prescription-drugs/summary.
• National Institute on Drug Abuse. New clinician screening tool available for substance use. https://www.drugabuse.gov/news-events/news-releases/2018/06/newclinician-screening-tool-available-substance-use.

Drug Brand Names

Amitriptyline • Elavil, Endep
Benztropine • Cogentin
Biperiden • Akineton
Bupropion • Wellbutrin, Zyban
Chlorpromazine • Thorzine
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Orphenadrine • Disipal, Norflex
Pregabalin • Lyrica, Lyrica CR
Procyclidine • Kemadrin
Quetiapine • Seroquel
Tianeptine • Coaxil, Stablon
Tranylcypromine • Parnate
Trifluoperazine • Stelazine
Trihexyphenidyl • Artane, Tremin
Venlafaxine • Effexor

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

In schizophrenia, negative symptoms such as social withdrawal, avoidance, lack of spontaneity and flow of conversation, reduced initiative, anhedonia, and blunted affect are among the most challenging to treat. These symptoms commonly persist after positive symptoms such as hallucinations, delusions, and paranoia have subsided. In an analysis of 20 pivotal placebo-controlled trials of second-generation antipsychotics (SGAs), almost 45% of patients who completed 6 weeks of treatment still had at least 1 residual negative symptom of at least moderate severity, and approximately 25% had 2 or more.¹ Negative symptoms are viewed as being intrinsic to schizophrenia, and also as the result of extrapyramidal symptoms, depression, and psychosis.

Nearly a decade ago, the Schizophrenia Patient Outcomes Research Team (PORT) published its recommendations for psychopharmacologic and psycho­social treatments of schizophrenia. Unfortunately, due to insufficient evidence, there is still no proven treatment for negative symptoms.^2-4 This is particularly problematic because negative symptoms are a major determinant of the poor social and vocational abilities of patients with schizophrenia.

This review focuses on treatments for negative symptoms of schizophrenia that have been evaluated since the PORT treatment recommendations were published and highlights those approaches that show promise.

_

The limitations of antipsychotics

Antipsychotics can both worsen and alleviate negative symptoms by reducing psychotic symptoms. Double-blind, placebo-controlled trials have found that most, if not all, antipsychotics are superior to placebo for treating negative symptoms in patients with acute psychosis.⁴ However, because these improvements occur in the early stages of treatment, concomitantly with improvement of psychotic symptoms, antipsychotics generally are not viewed as being very effective in the treatment of primary negative symptoms.⁴ Indeed, an examination of patients with prominent negative symptoms without prominent positive symptoms in the NEWMEDS cohort, which was extracted from 20 pivotal placebo-controlled trials of SGAs, revealed no clinically meaningful treatment effect on negative symptoms.¹

There is evidence that antipsychotics can contribute to the development of apathy, flat affect, and other negative symptoms.⁵ Dopamine (D2)-blocking antipsychotics produce secondary negative symptoms that are not always easy to distinguish from primary negative symptoms.⁶ In a double-blind, placebo-controlled trial of single doses of risperidone, haloperidol, or placebo in healthy participants, the antipsychotics increased negative symptoms, particularly avolition/apathy.⁷ Another study found that chronic treatment with antipsychotics did not necessarily affect motivation in patients with schizophrenia.⁸

Adverse effects, such as anhedonia, often produce and enhance negative symptoms and therefore can limit the use of pharmacologic treatment options. Other adverse effects associated with specific antipsycho­tics include extrapyramidal symptoms, sedation, increased prolactin secretion, weight gain, and other metabolic abnormalities.

Continue to: Seeking new pharmacologic options

The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.


Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box^9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.

Box

Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:

• MIN-101 is a novel cyclic amide derivative.¹⁸ In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.¹⁸
• Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor¹⁹
• Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties^18,20,21
• Raloxifene is a selective estrogen receptor modulator for postmenopausal women^22,23
• Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.²⁴

All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).

Continue to: Nonpharmacologic treatments

Recent studies of nonpharmacologic treatments for negative symptoms, including psychosocial approaches and noninvasive electromagnetic neurostimulation, have also been performed. The major psychosocial approaches that have been studied include social skills training (SST), cognitive-behavioral therapy (CBT) for psychosis, cognitive remediation, and family intervention. Some positive findings have been reported. A recent review of psychosocial treatments for negative symptoms in schizophrenia concluded that CBT and SST have the most empirical support, with some evidence even suggesting that gains from CBT are maintained as long as 6 months after treatment.²⁵ Another review found that CBT was significantly more efficacious for reducing positive symptoms and SST in reducing negative symptoms.²⁶

It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Motivation and Enhancement therapy (MOVE) is a potentially promising approach that combines environmental support, CBT, skills training, and other components in an attempt to address all domains of negative symptoms.²⁷ Preliminary results from a randomized controlled trial examining 51 patients with clinically meaningful negative symptoms suggested that MOVE improves negative symptoms. However, the group differences were not significant until after 9 months of treatment and not for all negative symptom scales. A follow-up study has been completed, but the results are not yet available.²⁸

Some small studies have suggested improvement of negative symptoms after noninvasive electromagnetic neurostimulation,^29-31 but this has not been replicated in larger studies.³² In the last few years, there were several studies underway that could help clarify if there is a role for noninvasive electromagnetic neurostimulation in the treatment of negative symptoms in schizophrenia; however, results have not been reported at this time.^33-35

_

Social skills training and combined interventions

Taken together, the data suggest that treating negative symptoms in schizophrenia remains a major challenge. Patients with negative symptoms are difficult to engage and motivate for treatment and there are no well-supported treatment options. Given the lack of evidence, it is not possible to synthesize this data into clear treatment recommendations. Because many of the negative symptoms are social in nature, it is perhaps not surprising that some evidence has emerged supporting the role of psycho­social approaches. Studies have pointed to the potential role of SST. It is believed to be beneficial as it targets participants’ social functioning by training verbal and nonverbal communication alongside perception and responses to social cues.³⁶ Some evidence suggests that treatment packages that combine several psychosocial interventions (eg, family psychoeducation and skill training) achieve better outcomes than standalone interventions.³⁷ Thus, psychosocial approaches appear to be potentially effective for the treatment of negative symptoms in patients with schizophrenia. In addition, because some antipsychotics has been shown to be associated with fewer negative symptoms than others, another treatment strategy could be to attempt the use of a different antipsychotic, or to revisit whether continued antipsychotic treatment is needed in the absence of positive symptoms.

Bottom Line

Treating negative symptoms in schizophrenia remains a major challenge. There is a lack of evidence for pharmacologic treatments; psychosocial approaches may be beneficial due to the social nature of many negative symptoms. Further, some evidence suggests that treatment packages that combine several psychosocial interventions may achieve better outcomes than standalone interventions.

Related Resource

Tandon R, Jibson M. Negative symptoms of schizophrenia: How to treat them most effectively. Current Psychiatry. 2002;1(9):36-42.

Drug Brand Names

Cariprazine • Vraylar
Haloperidol • Haldol
Minocycline • Dynacin, Minocin
Pimavanserin • Nuplazid
Raloxifene • Evista
Risperidone • Risperdal

In schizophrenia, negative symptoms such as social withdrawal, avoidance, lack of spontaneity and flow of conversation, reduced initiative, anhedonia, and blunted affect are among the most challenging to treat. These symptoms commonly persist after positive symptoms such as hallucinations, delusions, and paranoia have subsided. In an analysis of 20 pivotal placebo-controlled trials of second-generation antipsychotics (SGAs), almost 45% of patients who completed 6 weeks of treatment still had at least 1 residual negative symptom of at least moderate severity, and approximately 25% had 2 or more.¹ Negative symptoms are viewed as being intrinsic to schizophrenia, and also as the result of extrapyramidal symptoms, depression, and psychosis.

Nearly a decade ago, the Schizophrenia Patient Outcomes Research Team (PORT) published its recommendations for psychopharmacologic and psycho­social treatments of schizophrenia. Unfortunately, due to insufficient evidence, there is still no proven treatment for negative symptoms.^2-4 This is particularly problematic because negative symptoms are a major determinant of the poor social and vocational abilities of patients with schizophrenia.

This review focuses on treatments for negative symptoms of schizophrenia that have been evaluated since the PORT treatment recommendations were published and highlights those approaches that show promise.

_

The limitations of antipsychotics

Antipsychotics can both worsen and alleviate negative symptoms by reducing psychotic symptoms. Double-blind, placebo-controlled trials have found that most, if not all, antipsychotics are superior to placebo for treating negative symptoms in patients with acute psychosis.⁴ However, because these improvements occur in the early stages of treatment, concomitantly with improvement of psychotic symptoms, antipsychotics generally are not viewed as being very effective in the treatment of primary negative symptoms.⁴ Indeed, an examination of patients with prominent negative symptoms without prominent positive symptoms in the NEWMEDS cohort, which was extracted from 20 pivotal placebo-controlled trials of SGAs, revealed no clinically meaningful treatment effect on negative symptoms.¹

There is evidence that antipsychotics can contribute to the development of apathy, flat affect, and other negative symptoms.⁵ Dopamine (D2)-blocking antipsychotics produce secondary negative symptoms that are not always easy to distinguish from primary negative symptoms.⁶ In a double-blind, placebo-controlled trial of single doses of risperidone, haloperidol, or placebo in healthy participants, the antipsychotics increased negative symptoms, particularly avolition/apathy.⁷ Another study found that chronic treatment with antipsychotics did not necessarily affect motivation in patients with schizophrenia.⁸

Adverse effects, such as anhedonia, often produce and enhance negative symptoms and therefore can limit the use of pharmacologic treatment options. Other adverse effects associated with specific antipsycho­tics include extrapyramidal symptoms, sedation, increased prolactin secretion, weight gain, and other metabolic abnormalities.

Continue to: Seeking new pharmacologic options

The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.


Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box^9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.

Box

Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:

• MIN-101 is a novel cyclic amide derivative.¹⁸ In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.¹⁸
• Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor¹⁹
• Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties^18,20,21
• Raloxifene is a selective estrogen receptor modulator for postmenopausal women^22,23
• Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.²⁴

All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).

Continue to: Nonpharmacologic treatments

Recent studies of nonpharmacologic treatments for negative symptoms, including psychosocial approaches and noninvasive electromagnetic neurostimulation, have also been performed. The major psychosocial approaches that have been studied include social skills training (SST), cognitive-behavioral therapy (CBT) for psychosis, cognitive remediation, and family intervention. Some positive findings have been reported. A recent review of psychosocial treatments for negative symptoms in schizophrenia concluded that CBT and SST have the most empirical support, with some evidence even suggesting that gains from CBT are maintained as long as 6 months after treatment.²⁵ Another review found that CBT was significantly more efficacious for reducing positive symptoms and SST in reducing negative symptoms.²⁶

It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Motivation and Enhancement therapy (MOVE) is a potentially promising approach that combines environmental support, CBT, skills training, and other components in an attempt to address all domains of negative symptoms.²⁷ Preliminary results from a randomized controlled trial examining 51 patients with clinically meaningful negative symptoms suggested that MOVE improves negative symptoms. However, the group differences were not significant until after 9 months of treatment and not for all negative symptom scales. A follow-up study has been completed, but the results are not yet available.²⁸

Some small studies have suggested improvement of negative symptoms after noninvasive electromagnetic neurostimulation,^29-31 but this has not been replicated in larger studies.³² In the last few years, there were several studies underway that could help clarify if there is a role for noninvasive electromagnetic neurostimulation in the treatment of negative symptoms in schizophrenia; however, results have not been reported at this time.^33-35

_

Social skills training and combined interventions

Taken together, the data suggest that treating negative symptoms in schizophrenia remains a major challenge. Patients with negative symptoms are difficult to engage and motivate for treatment and there are no well-supported treatment options. Given the lack of evidence, it is not possible to synthesize this data into clear treatment recommendations. Because many of the negative symptoms are social in nature, it is perhaps not surprising that some evidence has emerged supporting the role of psycho­social approaches. Studies have pointed to the potential role of SST. It is believed to be beneficial as it targets participants’ social functioning by training verbal and nonverbal communication alongside perception and responses to social cues.³⁶ Some evidence suggests that treatment packages that combine several psychosocial interventions (eg, family psychoeducation and skill training) achieve better outcomes than standalone interventions.³⁷ Thus, psychosocial approaches appear to be potentially effective for the treatment of negative symptoms in patients with schizophrenia. In addition, because some antipsychotics has been shown to be associated with fewer negative symptoms than others, another treatment strategy could be to attempt the use of a different antipsychotic, or to revisit whether continued antipsychotic treatment is needed in the absence of positive symptoms.

Bottom Line

Treating negative symptoms in schizophrenia remains a major challenge. There is a lack of evidence for pharmacologic treatments; psychosocial approaches may be beneficial due to the social nature of many negative symptoms. Further, some evidence suggests that treatment packages that combine several psychosocial interventions may achieve better outcomes than standalone interventions.

Related Resource

Tandon R, Jibson M. Negative symptoms of schizophrenia: How to treat them most effectively. Current Psychiatry. 2002;1(9):36-42.

Drug Brand Names

Cariprazine • Vraylar
Haloperidol • Haldol
Minocycline • Dynacin, Minocin
Pimavanserin • Nuplazid
Raloxifene • Evista
Risperidone • Risperdal

In schizophrenia, negative symptoms such as social withdrawal, avoidance, lack of spontaneity and flow of conversation, reduced initiative, anhedonia, and blunted affect are among the most challenging to treat. These symptoms commonly persist after positive symptoms such as hallucinations, delusions, and paranoia have subsided. In an analysis of 20 pivotal placebo-controlled trials of second-generation antipsychotics (SGAs), almost 45% of patients who completed 6 weeks of treatment still had at least 1 residual negative symptom of at least moderate severity, and approximately 25% had 2 or more.¹ Negative symptoms are viewed as being intrinsic to schizophrenia, and also as the result of extrapyramidal symptoms, depression, and psychosis.

Nearly a decade ago, the Schizophrenia Patient Outcomes Research Team (PORT) published its recommendations for psychopharmacologic and psycho­social treatments of schizophrenia. Unfortunately, due to insufficient evidence, there is still no proven treatment for negative symptoms.^2-4 This is particularly problematic because negative symptoms are a major determinant of the poor social and vocational abilities of patients with schizophrenia.

This review focuses on treatments for negative symptoms of schizophrenia that have been evaluated since the PORT treatment recommendations were published and highlights those approaches that show promise.

_

The limitations of antipsychotics

Antipsychotics can both worsen and alleviate negative symptoms by reducing psychotic symptoms. Double-blind, placebo-controlled trials have found that most, if not all, antipsychotics are superior to placebo for treating negative symptoms in patients with acute psychosis.⁴ However, because these improvements occur in the early stages of treatment, concomitantly with improvement of psychotic symptoms, antipsychotics generally are not viewed as being very effective in the treatment of primary negative symptoms.⁴ Indeed, an examination of patients with prominent negative symptoms without prominent positive symptoms in the NEWMEDS cohort, which was extracted from 20 pivotal placebo-controlled trials of SGAs, revealed no clinically meaningful treatment effect on negative symptoms.¹

There is evidence that antipsychotics can contribute to the development of apathy, flat affect, and other negative symptoms.⁵ Dopamine (D2)-blocking antipsychotics produce secondary negative symptoms that are not always easy to distinguish from primary negative symptoms.⁶ In a double-blind, placebo-controlled trial of single doses of risperidone, haloperidol, or placebo in healthy participants, the antipsychotics increased negative symptoms, particularly avolition/apathy.⁷ Another study found that chronic treatment with antipsychotics did not necessarily affect motivation in patients with schizophrenia.⁸

Adverse effects, such as anhedonia, often produce and enhance negative symptoms and therefore can limit the use of pharmacologic treatment options. Other adverse effects associated with specific antipsycho­tics include extrapyramidal symptoms, sedation, increased prolactin secretion, weight gain, and other metabolic abnormalities.

Continue to: Seeking new pharmacologic options

The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.


Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box^9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.

Box

Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:

• MIN-101 is a novel cyclic amide derivative.¹⁸ In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.¹⁸
• Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor¹⁹
• Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties^18,20,21
• Raloxifene is a selective estrogen receptor modulator for postmenopausal women^22,23
• Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.²⁴

All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).

Continue to: Nonpharmacologic treatments

Recent studies of nonpharmacologic treatments for negative symptoms, including psychosocial approaches and noninvasive electromagnetic neurostimulation, have also been performed. The major psychosocial approaches that have been studied include social skills training (SST), cognitive-behavioral therapy (CBT) for psychosis, cognitive remediation, and family intervention. Some positive findings have been reported. A recent review of psychosocial treatments for negative symptoms in schizophrenia concluded that CBT and SST have the most empirical support, with some evidence even suggesting that gains from CBT are maintained as long as 6 months after treatment.²⁵ Another review found that CBT was significantly more efficacious for reducing positive symptoms and SST in reducing negative symptoms.²⁶

It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Motivation and Enhancement therapy (MOVE) is a potentially promising approach that combines environmental support, CBT, skills training, and other components in an attempt to address all domains of negative symptoms.²⁷ Preliminary results from a randomized controlled trial examining 51 patients with clinically meaningful negative symptoms suggested that MOVE improves negative symptoms. However, the group differences were not significant until after 9 months of treatment and not for all negative symptom scales. A follow-up study has been completed, but the results are not yet available.²⁸

Some small studies have suggested improvement of negative symptoms after noninvasive electromagnetic neurostimulation,^29-31 but this has not been replicated in larger studies.³² In the last few years, there were several studies underway that could help clarify if there is a role for noninvasive electromagnetic neurostimulation in the treatment of negative symptoms in schizophrenia; however, results have not been reported at this time.^33-35

_

Social skills training and combined interventions

Taken together, the data suggest that treating negative symptoms in schizophrenia remains a major challenge. Patients with negative symptoms are difficult to engage and motivate for treatment and there are no well-supported treatment options. Given the lack of evidence, it is not possible to synthesize this data into clear treatment recommendations. Because many of the negative symptoms are social in nature, it is perhaps not surprising that some evidence has emerged supporting the role of psycho­social approaches. Studies have pointed to the potential role of SST. It is believed to be beneficial as it targets participants’ social functioning by training verbal and nonverbal communication alongside perception and responses to social cues.³⁶ Some evidence suggests that treatment packages that combine several psychosocial interventions (eg, family psychoeducation and skill training) achieve better outcomes than standalone interventions.³⁷ Thus, psychosocial approaches appear to be potentially effective for the treatment of negative symptoms in patients with schizophrenia. In addition, because some antipsychotics has been shown to be associated with fewer negative symptoms than others, another treatment strategy could be to attempt the use of a different antipsychotic, or to revisit whether continued antipsychotic treatment is needed in the absence of positive symptoms.

Bottom Line

Treating negative symptoms in schizophrenia remains a major challenge. There is a lack of evidence for pharmacologic treatments; psychosocial approaches may be beneficial due to the social nature of many negative symptoms. Further, some evidence suggests that treatment packages that combine several psychosocial interventions may achieve better outcomes than standalone interventions.

Related Resource

Tandon R, Jibson M. Negative symptoms of schizophrenia: How to treat them most effectively. Current Psychiatry. 2002;1(9):36-42.

Drug Brand Names

Cariprazine • Vraylar
Haloperidol • Haldol
Minocycline • Dynacin, Minocin
Pimavanserin • Nuplazid
Raloxifene • Evista
Risperidone • Risperdal

Islands of knowledge in an ocean of ignorance. That summarizes the advances in unraveling the enigma of schizophrenia, arguably the most complex psychiatric brain disorder. The more breakthroughs are made, the more questions emerge.

Progress is definitely being made and the published literature, replete with new findings, is growing logarithmically. Particularly exciting are the recent advances in the etiology of schizophrenia, both genetic and environmental. Collaboration among geneticists around the world has enabled genome-wide association studies on almost 50,000 DNA samples and has revealed 3 genetic pathways to disrupted brain development, which lead to schizophrenia in early adulthood. Those genetic pathways include:

1. Susceptibility genes—more than 340 of them—are found significantly more often in patients with schizophrenia compared with the general population. These risk genes are scattered across all 23 pairs of chromosomes. They influence neurotransmitter functions, neuroplasticity, and immune regulation. The huge task that lies ahead is identifying what each of the risk genes disrupts in brain structure and/or function.

2. Copy number variants (CNVs), such as deletions (1 allele instead of the normal 2) or duplications (3 alleles), are much more frequent in patients with schizophrenia compared with the general population. That means too little or too much protein is made, which can disrupt the 4 stages of brain development (proliferation, migration, differentiation, and elimination).

3. de novo nonsense mutations, leading to complete absence of protein coding by the affected genes, with adverse ripple effects on brain development.

Approximately 10,000 genes (close to 50% of all 22,000 coding genes in the human genome) are involved in constructing the human brain. The latest estimate is that 79% of the hundreds of biotypes of schizophrenia are genetic in etiology.

In addition, multiple environmental factors can disrupt brain development and lead to schizophrenia. These include older paternal age (>45 years) at the time of conception, pregnancy complications (infections, gestational diabetes, vitamin D deficiency, hypoxia during delivery), childhood maltreatment (sexual or physical abuse or neglect) in the first 5 to 6 years of life, as well as migration and urbanicity (being born and raised in a large metropolitan area).

The bottom line: Schizophrenia is not only very complex, but also an extremely heterogeneous brain syndrome, both biologically and clinically. Psychiatric practitioners are fully cognizant of the extensive clinical variability in patients with schizophrenia, including the presence, absence, or severity of various signs and symptoms, such as insight, delusions, hallucinations, conceptual disorganization, bizarre behaviors, emotional withdrawal, agitation, depression, suicidality, anxiety, substance use, somatic concerns, hostility, idiosyncratic mannerisms, blunted affect, apathy, avolition, self-neglect, poor attention, memory impairment, and problems with decision-making, planning ahead, or organizing one’s life.

In addition, heterogeneity is encountered in such variables as age of onset, minor physical anomalies, soft neurologic signs, naturally occurring movement disorders, premorbid functioning, family history, general medical comorbidities, psychiatry comorbidities, structural brain abnormalities on neuroimaging, neurophysiological deviations (pre-pulse inhibition, p50, p300, N100, mismatch negativity, smooth pursuit eye movements), pituitary volume, rapidity and extent of response to antipsychotics, type and frequency of adverse effects, and functional disability or restoration of vocational functioning.

No wonder, then, given the daunting biologic and clinical heterogeneity of this complex brain syndrome, that myriad hypotheses have been proposed over the past century. The Table lists approximately 50 hypotheses, some discredited but others plausible and still viable. The most absurd hypotheses are the double bind theory of schizophrenia in the 1950s by Gregory Bateson et al, or the latent homosexuality theory of Freud. Some hypotheses may be related to a specific biotype within the schizophrenia syndrome (such as the megavitamin theory) that do not apply to other biotypes. Some of the hypotheses seem to be the product of the rich imagination of an enthusiastic researcher based on limited data.

To comment on this editorial or other topics of interest: [email protected].

Islands of knowledge in an ocean of ignorance. That summarizes the advances in unraveling the enigma of schizophrenia, arguably the most complex psychiatric brain disorder. The more breakthroughs are made, the more questions emerge.

Progress is definitely being made and the published literature, replete with new findings, is growing logarithmically. Particularly exciting are the recent advances in the etiology of schizophrenia, both genetic and environmental. Collaboration among geneticists around the world has enabled genome-wide association studies on almost 50,000 DNA samples and has revealed 3 genetic pathways to disrupted brain development, which lead to schizophrenia in early adulthood. Those genetic pathways include:

1. Susceptibility genes—more than 340 of them—are found significantly more often in patients with schizophrenia compared with the general population. These risk genes are scattered across all 23 pairs of chromosomes. They influence neurotransmitter functions, neuroplasticity, and immune regulation. The huge task that lies ahead is identifying what each of the risk genes disrupts in brain structure and/or function.

2. Copy number variants (CNVs), such as deletions (1 allele instead of the normal 2) or duplications (3 alleles), are much more frequent in patients with schizophrenia compared with the general population. That means too little or too much protein is made, which can disrupt the 4 stages of brain development (proliferation, migration, differentiation, and elimination).

3. de novo nonsense mutations, leading to complete absence of protein coding by the affected genes, with adverse ripple effects on brain development.

Approximately 10,000 genes (close to 50% of all 22,000 coding genes in the human genome) are involved in constructing the human brain. The latest estimate is that 79% of the hundreds of biotypes of schizophrenia are genetic in etiology.

In addition, multiple environmental factors can disrupt brain development and lead to schizophrenia. These include older paternal age (>45 years) at the time of conception, pregnancy complications (infections, gestational diabetes, vitamin D deficiency, hypoxia during delivery), childhood maltreatment (sexual or physical abuse or neglect) in the first 5 to 6 years of life, as well as migration and urbanicity (being born and raised in a large metropolitan area).

The bottom line: Schizophrenia is not only very complex, but also an extremely heterogeneous brain syndrome, both biologically and clinically. Psychiatric practitioners are fully cognizant of the extensive clinical variability in patients with schizophrenia, including the presence, absence, or severity of various signs and symptoms, such as insight, delusions, hallucinations, conceptual disorganization, bizarre behaviors, emotional withdrawal, agitation, depression, suicidality, anxiety, substance use, somatic concerns, hostility, idiosyncratic mannerisms, blunted affect, apathy, avolition, self-neglect, poor attention, memory impairment, and problems with decision-making, planning ahead, or organizing one’s life.

In addition, heterogeneity is encountered in such variables as age of onset, minor physical anomalies, soft neurologic signs, naturally occurring movement disorders, premorbid functioning, family history, general medical comorbidities, psychiatry comorbidities, structural brain abnormalities on neuroimaging, neurophysiological deviations (pre-pulse inhibition, p50, p300, N100, mismatch negativity, smooth pursuit eye movements), pituitary volume, rapidity and extent of response to antipsychotics, type and frequency of adverse effects, and functional disability or restoration of vocational functioning.

No wonder, then, given the daunting biologic and clinical heterogeneity of this complex brain syndrome, that myriad hypotheses have been proposed over the past century. The Table lists approximately 50 hypotheses, some discredited but others plausible and still viable. The most absurd hypotheses are the double bind theory of schizophrenia in the 1950s by Gregory Bateson et al, or the latent homosexuality theory of Freud. Some hypotheses may be related to a specific biotype within the schizophrenia syndrome (such as the megavitamin theory) that do not apply to other biotypes. Some of the hypotheses seem to be the product of the rich imagination of an enthusiastic researcher based on limited data.

To comment on this editorial or other topics of interest: [email protected].

Islands of knowledge in an ocean of ignorance. That summarizes the advances in unraveling the enigma of schizophrenia, arguably the most complex psychiatric brain disorder. The more breakthroughs are made, the more questions emerge.

Progress is definitely being made and the published literature, replete with new findings, is growing logarithmically. Particularly exciting are the recent advances in the etiology of schizophrenia, both genetic and environmental. Collaboration among geneticists around the world has enabled genome-wide association studies on almost 50,000 DNA samples and has revealed 3 genetic pathways to disrupted brain development, which lead to schizophrenia in early adulthood. Those genetic pathways include:

1. Susceptibility genes—more than 340 of them—are found significantly more often in patients with schizophrenia compared with the general population. These risk genes are scattered across all 23 pairs of chromosomes. They influence neurotransmitter functions, neuroplasticity, and immune regulation. The huge task that lies ahead is identifying what each of the risk genes disrupts in brain structure and/or function.

2. Copy number variants (CNVs), such as deletions (1 allele instead of the normal 2) or duplications (3 alleles), are much more frequent in patients with schizophrenia compared with the general population. That means too little or too much protein is made, which can disrupt the 4 stages of brain development (proliferation, migration, differentiation, and elimination).

3. de novo nonsense mutations, leading to complete absence of protein coding by the affected genes, with adverse ripple effects on brain development.

Approximately 10,000 genes (close to 50% of all 22,000 coding genes in the human genome) are involved in constructing the human brain. The latest estimate is that 79% of the hundreds of biotypes of schizophrenia are genetic in etiology.

In addition, multiple environmental factors can disrupt brain development and lead to schizophrenia. These include older paternal age (>45 years) at the time of conception, pregnancy complications (infections, gestational diabetes, vitamin D deficiency, hypoxia during delivery), childhood maltreatment (sexual or physical abuse or neglect) in the first 5 to 6 years of life, as well as migration and urbanicity (being born and raised in a large metropolitan area).

The bottom line: Schizophrenia is not only very complex, but also an extremely heterogeneous brain syndrome, both biologically and clinically. Psychiatric practitioners are fully cognizant of the extensive clinical variability in patients with schizophrenia, including the presence, absence, or severity of various signs and symptoms, such as insight, delusions, hallucinations, conceptual disorganization, bizarre behaviors, emotional withdrawal, agitation, depression, suicidality, anxiety, substance use, somatic concerns, hostility, idiosyncratic mannerisms, blunted affect, apathy, avolition, self-neglect, poor attention, memory impairment, and problems with decision-making, planning ahead, or organizing one’s life.

In addition, heterogeneity is encountered in such variables as age of onset, minor physical anomalies, soft neurologic signs, naturally occurring movement disorders, premorbid functioning, family history, general medical comorbidities, psychiatry comorbidities, structural brain abnormalities on neuroimaging, neurophysiological deviations (pre-pulse inhibition, p50, p300, N100, mismatch negativity, smooth pursuit eye movements), pituitary volume, rapidity and extent of response to antipsychotics, type and frequency of adverse effects, and functional disability or restoration of vocational functioning.

No wonder, then, given the daunting biologic and clinical heterogeneity of this complex brain syndrome, that myriad hypotheses have been proposed over the past century. The Table lists approximately 50 hypotheses, some discredited but others plausible and still viable. The most absurd hypotheses are the double bind theory of schizophrenia in the 1950s by Gregory Bateson et al, or the latent homosexuality theory of Freud. Some hypotheses may be related to a specific biotype within the schizophrenia syndrome (such as the megavitamin theory) that do not apply to other biotypes. Some of the hypotheses seem to be the product of the rich imagination of an enthusiastic researcher based on limited data.

To comment on this editorial or other topics of interest: [email protected].

X, a 17-year-old Mexican-American transgender male (assigned female at birth) experienced a traumatic brain injury (TBI) 4 years ago and subsequently developed posttraumatic stress disorder (PTSD). I came to treat X at a pediatric outpatient psychiatric clinic after he developed physiologic dysregulation of his nervous system and began to experience panic attacks, major depressive disorder, and auditory hallucinations. X also developed chronic widespread pain during the next few years, including migraines, abdominal pain, and back pain, which significantly impaired his ability to function socially and academically. X was treated by a child and adolescent psychiatrist who used an integrative approach of traditional and complementary medical practices in a pediatric chronic pain clinic.

X’s treatment course at the pediatric psychiatric clinic included 2 years of field capable mental health services. During this time, fluoxetine was started and titrated up to 40 mg/d to target anxiety and depressive symptoms such as pervasive sadness, poor self-esteem, poor concentration, physiologic arousal, and sleep disruption. Risperidone, 2 mg/d, was temporarily added to address residual mood symptoms and the auditory hallucinations X experienced at school. Neuropsychological testing did not indicate that X had cognitive impairments from the TBI. In the pain clinic, X was encouraged to continue with psychotherapy and the selective serotonin reuptake inhibitor. Another recommendation was to seek out acupuncture and yoga. Over the course of 1 year, X’s pain symptoms began to resolve, and his functioning improved significantly. It was during this year that X came out as transgender, first to his friends, and then to his family and his physicians.

The link between PTSD and chronic pain

X’s PTSD presented as nightmares, hypervigilance, and anxiety, especially when he was in school. He would often describe how his chronic pain symptoms prevented him from functioning academically and socially. I wondered if X’s presentation of PTSD indicated a predisposition for chronic widespread pain symptoms or pain syndromes. This theory could be approximated by an association, but research suggests there is a significant temporal relationship between PTSD and widespread pain symptoms, such as in fibromyalgia.

One multicenter study of patients with fibromyalgia found that the prevalence of comorbid PTSD was 45%.¹ In two-thirds of patients with fibromyalgia, traumatic life events and PTSD symptoms preceded the onset of chronic widespread pain, while in roughly one-third, traumatic life events and PTSD symptoms followed the onset of chronic widespread pain.¹ This study suggests that PTSD could be viewed as a marker of stress vulnerability in which individuals susceptible to stress are more likely to develop chronic widespread pain and other health problems, including fibromyalgia, when a traumatic event occurs.

Benefits of transgender-specific care

During the course of X’s psychiatric treatment, he eventually revealed that he had been experiencing gender dysphoria for many years. His gender transition was occurring during adolescence; during this time, identity formation is a central developmental task.² X was not comfortable asking others to use his preferred pronouns until he had physiologically transitioned. Any further delay to accessing transgender-specific services would increase the likelihood of a poor prognosis, both behaviorally and medically, because sexual minority adolescents are 3 to 4 times more likely to meet criteria for an internalizing disorder and 2 to 5 times more likely to meet criteria for externalizing disorders.³ My understanding of the minority stress model raised concerns that if X did not get appropriate treatment, the interdependence of stressors of being a sexual minority as well as an ethnic minority would further burden his mental health.

Now that X had access to transgender-specific care, how would management affect his pain symptoms or response to treatment? While some of his pain symptoms began to remit before he came out as transgender, I considered whether hormone therapy might improve his subjective pain. Little research has been conducted in transgender patients to determine whether sex-steroid administration might alter nociception. One study that examined daily fluctuations of sex hormones in 8 women with fibromyalgia found trends suggesting progesterone and testosterone are inversely associated with pain, with peaks of those hormones occurring on days with lower reported pain.⁴ A small study of female-to-male transgender patients found that administration of sex steroids was associated with relief from chronic painful conditions (headaches, musculoskeletal pain) in 6 of 16 patients who received testosterone injections.⁵ What little evidence I found in regards to an association between gender-affirming hormone therapy and chronic pain left me feeling optimistic that hormone therapy would not negatively affect the prognosis of X’s chronic pain.

Another consideration in treating X was the practice of chest binding, the compression of chest tissue for masculine gender expression among people who were assigned female sex at birth. One study found that chest binding can improve mood; decrease suicidality, anxiety, and dysphoria; and increase self-esteem.⁶ However, 97.2% of participants reported at least one negative outcome they attributed to binding. The most common was back pain (53.8%), which X had been experiencing before he began chest binding. I found it notable that X’s primary doctors in the transgender clinic kept this adverse effect in mind when they recommended that he take breaks and limit daily hours of chest binding to minimize the risk of increased chronic back pain.

This particular case spanned several specialized services and required coordination and careful consideration to address X’s developmental and gender-related needs. X experienced significant symptoms incited by a TBI; however, the manifestation of his chronic pain symptoms were more than likely influenced by several overlapping stressors, including belonging to an ethnic minority, transitioning into adulthood, transitioning publicly as a male, and mood symptoms. While it pleased me to see how X responded positively to the integrative and holistic treatment he received, I remain concerned that simply not enough research exists that addresses how transgender individuals are affected, physically and affectively, by chronic levels of stress attributable to their minority status.

X, a 17-year-old Mexican-American transgender male (assigned female at birth) experienced a traumatic brain injury (TBI) 4 years ago and subsequently developed posttraumatic stress disorder (PTSD). I came to treat X at a pediatric outpatient psychiatric clinic after he developed physiologic dysregulation of his nervous system and began to experience panic attacks, major depressive disorder, and auditory hallucinations. X also developed chronic widespread pain during the next few years, including migraines, abdominal pain, and back pain, which significantly impaired his ability to function socially and academically. X was treated by a child and adolescent psychiatrist who used an integrative approach of traditional and complementary medical practices in a pediatric chronic pain clinic.

X’s treatment course at the pediatric psychiatric clinic included 2 years of field capable mental health services. During this time, fluoxetine was started and titrated up to 40 mg/d to target anxiety and depressive symptoms such as pervasive sadness, poor self-esteem, poor concentration, physiologic arousal, and sleep disruption. Risperidone, 2 mg/d, was temporarily added to address residual mood symptoms and the auditory hallucinations X experienced at school. Neuropsychological testing did not indicate that X had cognitive impairments from the TBI. In the pain clinic, X was encouraged to continue with psychotherapy and the selective serotonin reuptake inhibitor. Another recommendation was to seek out acupuncture and yoga. Over the course of 1 year, X’s pain symptoms began to resolve, and his functioning improved significantly. It was during this year that X came out as transgender, first to his friends, and then to his family and his physicians.

The link between PTSD and chronic pain

X’s PTSD presented as nightmares, hypervigilance, and anxiety, especially when he was in school. He would often describe how his chronic pain symptoms prevented him from functioning academically and socially. I wondered if X’s presentation of PTSD indicated a predisposition for chronic widespread pain symptoms or pain syndromes. This theory could be approximated by an association, but research suggests there is a significant temporal relationship between PTSD and widespread pain symptoms, such as in fibromyalgia.

One multicenter study of patients with fibromyalgia found that the prevalence of comorbid PTSD was 45%.¹ In two-thirds of patients with fibromyalgia, traumatic life events and PTSD symptoms preceded the onset of chronic widespread pain, while in roughly one-third, traumatic life events and PTSD symptoms followed the onset of chronic widespread pain.¹ This study suggests that PTSD could be viewed as a marker of stress vulnerability in which individuals susceptible to stress are more likely to develop chronic widespread pain and other health problems, including fibromyalgia, when a traumatic event occurs.

Benefits of transgender-specific care

During the course of X’s psychiatric treatment, he eventually revealed that he had been experiencing gender dysphoria for many years. His gender transition was occurring during adolescence; during this time, identity formation is a central developmental task.² X was not comfortable asking others to use his preferred pronouns until he had physiologically transitioned. Any further delay to accessing transgender-specific services would increase the likelihood of a poor prognosis, both behaviorally and medically, because sexual minority adolescents are 3 to 4 times more likely to meet criteria for an internalizing disorder and 2 to 5 times more likely to meet criteria for externalizing disorders.³ My understanding of the minority stress model raised concerns that if X did not get appropriate treatment, the interdependence of stressors of being a sexual minority as well as an ethnic minority would further burden his mental health.

Now that X had access to transgender-specific care, how would management affect his pain symptoms or response to treatment? While some of his pain symptoms began to remit before he came out as transgender, I considered whether hormone therapy might improve his subjective pain. Little research has been conducted in transgender patients to determine whether sex-steroid administration might alter nociception. One study that examined daily fluctuations of sex hormones in 8 women with fibromyalgia found trends suggesting progesterone and testosterone are inversely associated with pain, with peaks of those hormones occurring on days with lower reported pain.⁴ A small study of female-to-male transgender patients found that administration of sex steroids was associated with relief from chronic painful conditions (headaches, musculoskeletal pain) in 6 of 16 patients who received testosterone injections.⁵ What little evidence I found in regards to an association between gender-affirming hormone therapy and chronic pain left me feeling optimistic that hormone therapy would not negatively affect the prognosis of X’s chronic pain.

Another consideration in treating X was the practice of chest binding, the compression of chest tissue for masculine gender expression among people who were assigned female sex at birth. One study found that chest binding can improve mood; decrease suicidality, anxiety, and dysphoria; and increase self-esteem.⁶ However, 97.2% of participants reported at least one negative outcome they attributed to binding. The most common was back pain (53.8%), which X had been experiencing before he began chest binding. I found it notable that X’s primary doctors in the transgender clinic kept this adverse effect in mind when they recommended that he take breaks and limit daily hours of chest binding to minimize the risk of increased chronic back pain.

This particular case spanned several specialized services and required coordination and careful consideration to address X’s developmental and gender-related needs. X experienced significant symptoms incited by a TBI; however, the manifestation of his chronic pain symptoms were more than likely influenced by several overlapping stressors, including belonging to an ethnic minority, transitioning into adulthood, transitioning publicly as a male, and mood symptoms. While it pleased me to see how X responded positively to the integrative and holistic treatment he received, I remain concerned that simply not enough research exists that addresses how transgender individuals are affected, physically and affectively, by chronic levels of stress attributable to their minority status.

X, a 17-year-old Mexican-American transgender male (assigned female at birth) experienced a traumatic brain injury (TBI) 4 years ago and subsequently developed posttraumatic stress disorder (PTSD). I came to treat X at a pediatric outpatient psychiatric clinic after he developed physiologic dysregulation of his nervous system and began to experience panic attacks, major depressive disorder, and auditory hallucinations. X also developed chronic widespread pain during the next few years, including migraines, abdominal pain, and back pain, which significantly impaired his ability to function socially and academically. X was treated by a child and adolescent psychiatrist who used an integrative approach of traditional and complementary medical practices in a pediatric chronic pain clinic.

X’s treatment course at the pediatric psychiatric clinic included 2 years of field capable mental health services. During this time, fluoxetine was started and titrated up to 40 mg/d to target anxiety and depressive symptoms such as pervasive sadness, poor self-esteem, poor concentration, physiologic arousal, and sleep disruption. Risperidone, 2 mg/d, was temporarily added to address residual mood symptoms and the auditory hallucinations X experienced at school. Neuropsychological testing did not indicate that X had cognitive impairments from the TBI. In the pain clinic, X was encouraged to continue with psychotherapy and the selective serotonin reuptake inhibitor. Another recommendation was to seek out acupuncture and yoga. Over the course of 1 year, X’s pain symptoms began to resolve, and his functioning improved significantly. It was during this year that X came out as transgender, first to his friends, and then to his family and his physicians.

The link between PTSD and chronic pain

X’s PTSD presented as nightmares, hypervigilance, and anxiety, especially when he was in school. He would often describe how his chronic pain symptoms prevented him from functioning academically and socially. I wondered if X’s presentation of PTSD indicated a predisposition for chronic widespread pain symptoms or pain syndromes. This theory could be approximated by an association, but research suggests there is a significant temporal relationship between PTSD and widespread pain symptoms, such as in fibromyalgia.

One multicenter study of patients with fibromyalgia found that the prevalence of comorbid PTSD was 45%.¹ In two-thirds of patients with fibromyalgia, traumatic life events and PTSD symptoms preceded the onset of chronic widespread pain, while in roughly one-third, traumatic life events and PTSD symptoms followed the onset of chronic widespread pain.¹ This study suggests that PTSD could be viewed as a marker of stress vulnerability in which individuals susceptible to stress are more likely to develop chronic widespread pain and other health problems, including fibromyalgia, when a traumatic event occurs.

Benefits of transgender-specific care

During the course of X’s psychiatric treatment, he eventually revealed that he had been experiencing gender dysphoria for many years. His gender transition was occurring during adolescence; during this time, identity formation is a central developmental task.² X was not comfortable asking others to use his preferred pronouns until he had physiologically transitioned. Any further delay to accessing transgender-specific services would increase the likelihood of a poor prognosis, both behaviorally and medically, because sexual minority adolescents are 3 to 4 times more likely to meet criteria for an internalizing disorder and 2 to 5 times more likely to meet criteria for externalizing disorders.³ My understanding of the minority stress model raised concerns that if X did not get appropriate treatment, the interdependence of stressors of being a sexual minority as well as an ethnic minority would further burden his mental health.

Now that X had access to transgender-specific care, how would management affect his pain symptoms or response to treatment? While some of his pain symptoms began to remit before he came out as transgender, I considered whether hormone therapy might improve his subjective pain. Little research has been conducted in transgender patients to determine whether sex-steroid administration might alter nociception. One study that examined daily fluctuations of sex hormones in 8 women with fibromyalgia found trends suggesting progesterone and testosterone are inversely associated with pain, with peaks of those hormones occurring on days with lower reported pain.⁴ A small study of female-to-male transgender patients found that administration of sex steroids was associated with relief from chronic painful conditions (headaches, musculoskeletal pain) in 6 of 16 patients who received testosterone injections.⁵ What little evidence I found in regards to an association between gender-affirming hormone therapy and chronic pain left me feeling optimistic that hormone therapy would not negatively affect the prognosis of X’s chronic pain.

Another consideration in treating X was the practice of chest binding, the compression of chest tissue for masculine gender expression among people who were assigned female sex at birth. One study found that chest binding can improve mood; decrease suicidality, anxiety, and dysphoria; and increase self-esteem.⁶ However, 97.2% of participants reported at least one negative outcome they attributed to binding. The most common was back pain (53.8%), which X had been experiencing before he began chest binding. I found it notable that X’s primary doctors in the transgender clinic kept this adverse effect in mind when they recommended that he take breaks and limit daily hours of chest binding to minimize the risk of increased chronic back pain.

This particular case spanned several specialized services and required coordination and careful consideration to address X’s developmental and gender-related needs. X experienced significant symptoms incited by a TBI; however, the manifestation of his chronic pain symptoms were more than likely influenced by several overlapping stressors, including belonging to an ethnic minority, transitioning into adulthood, transitioning publicly as a male, and mood symptoms. While it pleased me to see how X responded positively to the integrative and holistic treatment he received, I remain concerned that simply not enough research exists that addresses how transgender individuals are affected, physically and affectively, by chronic levels of stress attributable to their minority status.

Resilience is like patience; we all wish we had more of it, but we hope to avoid getting it the hard way. This wasn’t really an area of interest for me, until it needed to be. When one academic year brings the suicide of one colleague and the murder of another, resilience becomes the only alternative to despair.

I realize that even though the particular pain or trauma we endured may be unique, it’s becoming increasingly common. The alarming studies of resident depression and suicide are too difficult for us to ignore. Now we must look in that evidence-based mirror and decide where we will go from here, as a profession and as trainees. The 2018 American Psychiatric Association annual meeting gave us a rude awakening that we may not have it figured out. Even during a year-long theme on wellness, and several sessions at the meeting focusing on the same, we all found ourselves mourning the loss of 2 colleagues to suicide that very weekend only a few miles away from the gathering of the world’s experts.

It brought an eerie element to the conversation.

The wellness “window dressing” will not get the job done. I recently had a candid discussion with a mentor in administrative leadership, and his words surprised as well as challenged me. He told me that the “system” will not save you. You must save yourself. I have decided to respectfully reject that. I think everyone should be involved, including the “system” that is entrusted with my training, and the least that it ought to ensure is that I get out alive.

Has that really become too much to ask of our profession?

We must hold our system to a higher standard. More mindfulness and better breathing will surely be helpful—but I hope we can begin to admit that this is not the answer. Unfortunately, the culture of “pay your dues” and “you know how much harder it was when I was a resident?” is still the norm. We now receive our training in an environment where the pressure is extraordinarily high, the margin for error very low, and the possibility of support is almost a fantasy. “Sure, you can get the help you need ... but don’t take time off or you will be off cycle and create extra work for all your colleagues, who are also equally stressed and will hate you. In the meantime … enjoy this free ice cream and breathing exercise to mindfully cope with the madness around you.”

The perfectly resilient resident may very well be a mythical figure, a clinical unicorn, that we continue chasing. This is the resident who remarkably discovers posttraumatic growth in every stressor. The vicarious trauma they experience from their patients only bolsters their deep compassion, and they thrive under pressure, so we can continue to pile it on. In our search for this “super resident,” we seem to continue to lose a few ordinary residents along the way.

Are we brave enough as a health care culture to take a closer look at the way we are training the next generation of healers? As I get to the end of this article, I wish I had more answers. I’m just a trainee. What do I know? My fear is that we’ve been avoiding this question altogether and have had our eyes closed to the real problem while pacifying ourselves with one “wellness” activity after another. My sincere hope is that this article will make you angry enough to be driven by a conviction that this is not OK anymore, and that we will do something about it.

Resilience is like patience; we all wish we had more of it, but we hope to avoid getting it the hard way. This wasn’t really an area of interest for me, until it needed to be. When one academic year brings the suicide of one colleague and the murder of another, resilience becomes the only alternative to despair.

I realize that even though the particular pain or trauma we endured may be unique, it’s becoming increasingly common. The alarming studies of resident depression and suicide are too difficult for us to ignore. Now we must look in that evidence-based mirror and decide where we will go from here, as a profession and as trainees. The 2018 American Psychiatric Association annual meeting gave us a rude awakening that we may not have it figured out. Even during a year-long theme on wellness, and several sessions at the meeting focusing on the same, we all found ourselves mourning the loss of 2 colleagues to suicide that very weekend only a few miles away from the gathering of the world’s experts.

It brought an eerie element to the conversation.

The wellness “window dressing” will not get the job done. I recently had a candid discussion with a mentor in administrative leadership, and his words surprised as well as challenged me. He told me that the “system” will not save you. You must save yourself. I have decided to respectfully reject that. I think everyone should be involved, including the “system” that is entrusted with my training, and the least that it ought to ensure is that I get out alive.

Has that really become too much to ask of our profession?

We must hold our system to a higher standard. More mindfulness and better breathing will surely be helpful—but I hope we can begin to admit that this is not the answer. Unfortunately, the culture of “pay your dues” and “you know how much harder it was when I was a resident?” is still the norm. We now receive our training in an environment where the pressure is extraordinarily high, the margin for error very low, and the possibility of support is almost a fantasy. “Sure, you can get the help you need ... but don’t take time off or you will be off cycle and create extra work for all your colleagues, who are also equally stressed and will hate you. In the meantime … enjoy this free ice cream and breathing exercise to mindfully cope with the madness around you.”

The perfectly resilient resident may very well be a mythical figure, a clinical unicorn, that we continue chasing. This is the resident who remarkably discovers posttraumatic growth in every stressor. The vicarious trauma they experience from their patients only bolsters their deep compassion, and they thrive under pressure, so we can continue to pile it on. In our search for this “super resident,” we seem to continue to lose a few ordinary residents along the way.

Are we brave enough as a health care culture to take a closer look at the way we are training the next generation of healers? As I get to the end of this article, I wish I had more answers. I’m just a trainee. What do I know? My fear is that we’ve been avoiding this question altogether and have had our eyes closed to the real problem while pacifying ourselves with one “wellness” activity after another. My sincere hope is that this article will make you angry enough to be driven by a conviction that this is not OK anymore, and that we will do something about it.

Resilience is like patience; we all wish we had more of it, but we hope to avoid getting it the hard way. This wasn’t really an area of interest for me, until it needed to be. When one academic year brings the suicide of one colleague and the murder of another, resilience becomes the only alternative to despair.

I realize that even though the particular pain or trauma we endured may be unique, it’s becoming increasingly common. The alarming studies of resident depression and suicide are too difficult for us to ignore. Now we must look in that evidence-based mirror and decide where we will go from here, as a profession and as trainees. The 2018 American Psychiatric Association annual meeting gave us a rude awakening that we may not have it figured out. Even during a year-long theme on wellness, and several sessions at the meeting focusing on the same, we all found ourselves mourning the loss of 2 colleagues to suicide that very weekend only a few miles away from the gathering of the world’s experts.

It brought an eerie element to the conversation.

The wellness “window dressing” will not get the job done. I recently had a candid discussion with a mentor in administrative leadership, and his words surprised as well as challenged me. He told me that the “system” will not save you. You must save yourself. I have decided to respectfully reject that. I think everyone should be involved, including the “system” that is entrusted with my training, and the least that it ought to ensure is that I get out alive.

Has that really become too much to ask of our profession?

We must hold our system to a higher standard. More mindfulness and better breathing will surely be helpful—but I hope we can begin to admit that this is not the answer. Unfortunately, the culture of “pay your dues” and “you know how much harder it was when I was a resident?” is still the norm. We now receive our training in an environment where the pressure is extraordinarily high, the margin for error very low, and the possibility of support is almost a fantasy. “Sure, you can get the help you need ... but don’t take time off or you will be off cycle and create extra work for all your colleagues, who are also equally stressed and will hate you. In the meantime … enjoy this free ice cream and breathing exercise to mindfully cope with the madness around you.”

The perfectly resilient resident may very well be a mythical figure, a clinical unicorn, that we continue chasing. This is the resident who remarkably discovers posttraumatic growth in every stressor. The vicarious trauma they experience from their patients only bolsters their deep compassion, and they thrive under pressure, so we can continue to pile it on. In our search for this “super resident,” we seem to continue to lose a few ordinary residents along the way.

Are we brave enough as a health care culture to take a closer look at the way we are training the next generation of healers? As I get to the end of this article, I wish I had more answers. I’m just a trainee. What do I know? My fear is that we’ve been avoiding this question altogether and have had our eyes closed to the real problem while pacifying ourselves with one “wellness” activity after another. My sincere hope is that this article will make you angry enough to be driven by a conviction that this is not OK anymore, and that we will do something about it.

Oral antipsychotic nonadherence is a significant contributor to relapse in patients with schizophrenia spectrum disorders. Long-acting injectable (LAI) antipsychotics have been developed to provide sustained antipsychotic exposure, with evidence that use of LAIs significantly reduces hospitalization rates.¹ One limiting factor in transitioning patients to certain LAIs is the need for prolonged oral coverage at the onset of treatment for agents that cannot be loaded. Nonadherence with this bridging oral therapy places the patient at risk for symptom exacerbation until effective antipsychotic plasma levels are achieved from the LAI.² Although risperidone is one of the more widely used antipsychotics for treating schizophrenia, until recently the only available LAI preparation, risperidone microspheres (Risperdal Consta), required 3 weeks of oral coverage upon initiation.³

Clinical implications

Oral medication nonadherence remains a significant public health issue for patients with schizophrenia, with an estimated 50% of patients failing to achieve 80% adherence even when enrolled in clinical trials specifically designed to track adherence.⁵ Although LAI atypical antipsychotics have been available since the approval of Risperdal Consta, the LAI form of risperidone, and both LAI forms of aripiprazole, were not designed to be loaded. A 1-day initiation regimen for aripiprazole lauroxil has been developed to avoid the need for 3 weeks of oral medication coverage,^6,7 but aripiprazole monohydrate and risperidone microspheres mandate oral bridging of 2 and 3 weeks, respectively.² Because one of the primary indications for LAI antipsychotic therapy is oral medication nonadherence, this prolonged period of oral coverage creates a risk for symptom exacerbation when the bridging period occurs outside of a controlled setting, as is common when patients are discharged from inpatient hospitalization.

One solution to this problem has its antecedents in the development of the Atrigel biodegradable injectable polymer, which was designed to deliver prolonged medication exposure after subcutaneous injection.⁸ This biodegradable polymer drug delivery system suspends and dissolves the medication of interest (in this case, risperidone) in a poly DL-lactide-coglycolide gel and its biocompatible carrier.⁹ The viscous liquid undergoes a phase transition upon contact with tissue fluids after subcutaneous injection, resulting in an implant that releases risperidone in a controlled manner as it is resorbed. Importantly, the kinetic parameters of RBP-7000 are such that effective drug levels are seen within the first week without the need for oral coverage.¹⁰

Use in adults with schizophrenia. After establishing tolerability with oral risperidone, the recommended doses are 90 mg or 120 mg monthly, which correspond to oral daily risperidone doses of 3 mg or 4 mg. RBP-7000 must be administered as a subcutaneous abdominal injection by a health care professional. It is recommended that the patient be in the supine position for the injection and that the injection sites be rotated monthly among 4 quadrants in the abdominal region. The injection volumes for the 90 mg and 120 mg doses are 0.6 mL and 0.8 mL, respectively.¹⁰ As the gel implant becomes firmer, the patient will notice a lump for several weeks that will decrease in size over time. Patients should be advised not to rub or massage the injection site, and to be aware of the placement of any belts or clothing with waistbands.¹⁰

Pharmacologic profile, adverse reactions

Risperidone is an atypical antipsychotic that has been commercially available in the U.S. since December 29, 1993, and its adverse effect profile is well characterized. The most common adverse effects associated with risperidone include those related to dopamine D2 antagonism, metabolic adverse effects, and an increase in serum prolactin. In the 12-month long-term safety study of RBP-7000, 1-minute post-dose injection site pain scores (on a 100-point scale) were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following the last injection).¹⁰

Continue to: How the Atrigel system works

The kinetics for RBP-7000 are markedly different than those for oral risperidone (Figure 2¹⁵). After a single subcutaneous injection, RBP-7000 shows 2 absorption peaks for risperidone. The first lower peak occurs with a T_max of 4 to 6 hours due to initial release of risperidone during the implant formation process; a second risperidone peak occurs after 10 to 14 days and is associated with slow release from the subcutaneous depot.^9,16,17 For both 9-OH risperidone levels and the total active moiety (risperidone plus 9-OH risperidone levels), the median T_max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Following a single subcutaneous injection of RBP-7000, the apparent terminal half-life of risperidone ranges from 9 to 11 days, on average. The mean apparent terminal half-life of the active moiety ranges from 8 to 9 days.^9,16,17 Based on population pharmacokinetic modeling, the 90 mg and 120 mg doses of RBP-7000 are estimated to provide drug exposure equivalent to 3 mg/d and 4 mg/d of oral risperidone, respectively.^9,16,17

Continue to: Efficacy of RBP-7000

Efficacy of RBP-7000 was established in an 8-week, double-blind, placebo-controlled trial of adult patients experiencing an acute exacerbation of schizo­phrenia (age 18 to 55).⁴ Eligible participants had:

• An acute exacerbation of schizophrenia that occurred ≤8 weeks before the screening visit and would have benefited from psychiatric hospitalization or continued hospitalization
• Positive and Negative Syndrome Scale (PANSS) total score between 80 and 120 at visit 1 and a score of >4 on at least 2 of the following 4 items: hallucinatory behavior, delusions, conceptual disorganization, or suspiciousness/persecution
• The diagnosis of acute exacerbation of schizophrenia and PANSS total score were confirmed through an independent video-conference interview conducted by an experienced rater.

Participants were excluded if they:

• Experienced a ≥20% improvement in PANSS total score between the initial screening visit and the first injection
• had been treated at any time with clozapine for treatment-resistant schizophrenia
• had met DSM-IV-TR criteria for substance dependence (with the exception of nicotine or caffeine) before screening.

During the initial screening visit, participants received a 0.25-mg tablet of oral risperidone on 2 consecutive days to assess the tolerability of risperidone.

Outcome. Participants were randomized in a 1:1:1 manner to placebo (n = 112) or 1 of 2 monthly doses of RBP-7000: 90 mg (n = 111) or 120 mg (n = 114). Using the least squares means of repeated-measures changes from baseline in PANSS total scores, there was a significant improvement in the difference in PANSS total scores from baseline to the end of the study compared with placebo: 90-mg RBP-7000, -6.148 points (95% confidence interval [CI], -9.982 to -2.314, P = .0004); 120-mg RBP-7000, -7.237 points (95% CI, -11.045 to -3.429, P < .0001). The absolute change from baseline in PANSS total score was -15.367 points for the 90-mg dose and -16.456 points for the 120-mg dose.⁴ Completion rates across all 3 arms were comparable: placebo 70.6%, RBP-7000 90 mg 77.6%, and RBP-7000 120 mg 71.4%.

Tolerability. In the 8-week phase III efficacy trial of RBP-7000, adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo were weight gain (placebo 3.4%, 90 mg 13.0%, 120 mg 12.8%) and sedation (placebo 0%, 90 mg 7.0%, 120 mg 7.7%).¹⁰ Compared with baseline, participants had a mean weight gain at the end of the study of 2.83 kg in the placebo group, 5.15 kg in the 90-mg RBP-7000 group, and 4.69 kg in the 120-mg RBP-7000 group. There were no clinically significant differences at study endpoint in glucose and lipid parameters. Consistent with the known effects of risperidone, there were increases in mean prolactin levels during the 8-week study, the effects of which were greater for women. For men, mean prolactin levels from baseline to study end were: placebo: 9.8 ± 7.9 vs 9.9 ± 8.0 ng/mL; 90 mg: 8.9 ± 6.9 vs 22.4 ± 11.2 ng/mL; and 120 mg: 8.2 ± 5.2 vs 31.3 ± 14.8 ng/mL. For women, mean prolactin levels from baseline to study end were: placebo: 12.8 ± 11.7 vs 10.4 ± 8.0 ng/mL; 90 mg: 7.7 ± 5.3 vs 60.3 ± 46.9 ng/mL; and 120 mg: 10.9 ± 8.6 vs 85.5 ± 55.1 ng/mL. In the pivotal study, discontinuations due to adverse events were low across all treatment groups: 2.5% for placebo vs 0% for 90 mg and 1.7% for 120 mg.⁴ There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥2% and greater than placebo in patients treated with RBP-7000.¹⁰ There were no clinically relevant differences in mean changes from baseline in corrected QT, QRS, and PR intervals, and in heart rate. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean electrocardiography interval values from baseline to post-dose assessments.¹⁰

Using a 100-point visual analog scale (VAS), injection site pain scores 1 minute after the first dose decreased from a mean of 27 to the range of 3 to 7 for scores obtained 30 to 60 minutes post-dose. In the 12-month long-term safety study, 1-minute post-dose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection).¹⁰

Clinical considerations

Unique properties. RBP-7000 uses the established Atrigel system to provide effective antipsychotic levels in the first week of treatment, without the need for bridging oral coverage or a second loading injection. The abdominal subcutaneous injection volume is relatively small (0.6 mL or 0.8 mL).

Why Rx? The reasons to prescribe RBP-7000 for adult patients with schizophrenia include:

• no oral coverage required at the initiation of treatment
• effective plasma active moiety levels are seen within the first week without the need for a second loading injection
• monthly injection schedule.

Dosing. The recommended dosage of RBP-7000 is 90 mg or 120 mg once monthly, equivalent to 3 mg/d or 4 mg/d of oral risperidone, respectively. Oral risperidone tolerability should be established before the first injection. No oral risperidone coverage is required. RBP-7000 has not been studied in patients with renal or hepatic impairment and should be used with caution in these patients. Prior to initiating treatment in these patients, it is advised to carefully titrate up to at least 3 mg/d of oral risperidone. If a patient can tolerate 3 mg/d of oral risperidone and is psychiatrically stable, then the 90-mg dose of RBP-7000 can be considered.¹⁰ 

Contraindications. The only contraindications for RBP-7000 are known hypersensitivity to risperidone, paliperidone (9-OH risperidone), or other components of the injection.

Bottom Line

RBP-7000 (Perseris) is the second long-acting injectable (LAI) form of risperidone approved in the U.S. Unlike risperidone microspheres (Consta), RBP-7000 does not require any oral risperidone coverage at the beginning of therapy, provides effective drug levels within the first week of treatment with a single injection, and uses a monthly dosing interval. RBP-7000 does not require loading upon initiation. The monthly injection is <1 mL, is administered in abdominal subcutaneous tissue, and uses the Atrigel system.

Related Resource

• Carpenter J, Wong KK. Long-acting injectable antipsychotics: What to do about missed doses. Current Psychiatry. 2018;17(7):10-12,14-19,56.
   

Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Carbatrol, Tegretol
Doxycycline • Atridox
Leuprolide acetate injectable suspension • Eligard
Paliperidone palmitate • Invega Sustenna
Risperidone • Risperdal
Risperidone extended-release injectable suspension • Perseris
Risperidone long-acting injection • Risperdal Consta

Oral antipsychotic nonadherence is a significant contributor to relapse in patients with schizophrenia spectrum disorders. Long-acting injectable (LAI) antipsychotics have been developed to provide sustained antipsychotic exposure, with evidence that use of LAIs significantly reduces hospitalization rates.¹ One limiting factor in transitioning patients to certain LAIs is the need for prolonged oral coverage at the onset of treatment for agents that cannot be loaded. Nonadherence with this bridging oral therapy places the patient at risk for symptom exacerbation until effective antipsychotic plasma levels are achieved from the LAI.² Although risperidone is one of the more widely used antipsychotics for treating schizophrenia, until recently the only available LAI preparation, risperidone microspheres (Risperdal Consta), required 3 weeks of oral coverage upon initiation.³

Clinical implications

Oral medication nonadherence remains a significant public health issue for patients with schizophrenia, with an estimated 50% of patients failing to achieve 80% adherence even when enrolled in clinical trials specifically designed to track adherence.⁵ Although LAI atypical antipsychotics have been available since the approval of Risperdal Consta, the LAI form of risperidone, and both LAI forms of aripiprazole, were not designed to be loaded. A 1-day initiation regimen for aripiprazole lauroxil has been developed to avoid the need for 3 weeks of oral medication coverage,^6,7 but aripiprazole monohydrate and risperidone microspheres mandate oral bridging of 2 and 3 weeks, respectively.² Because one of the primary indications for LAI antipsychotic therapy is oral medication nonadherence, this prolonged period of oral coverage creates a risk for symptom exacerbation when the bridging period occurs outside of a controlled setting, as is common when patients are discharged from inpatient hospitalization.

One solution to this problem has its antecedents in the development of the Atrigel biodegradable injectable polymer, which was designed to deliver prolonged medication exposure after subcutaneous injection.⁸ This biodegradable polymer drug delivery system suspends and dissolves the medication of interest (in this case, risperidone) in a poly DL-lactide-coglycolide gel and its biocompatible carrier.⁹ The viscous liquid undergoes a phase transition upon contact with tissue fluids after subcutaneous injection, resulting in an implant that releases risperidone in a controlled manner as it is resorbed. Importantly, the kinetic parameters of RBP-7000 are such that effective drug levels are seen within the first week without the need for oral coverage.¹⁰

Use in adults with schizophrenia. After establishing tolerability with oral risperidone, the recommended doses are 90 mg or 120 mg monthly, which correspond to oral daily risperidone doses of 3 mg or 4 mg. RBP-7000 must be administered as a subcutaneous abdominal injection by a health care professional. It is recommended that the patient be in the supine position for the injection and that the injection sites be rotated monthly among 4 quadrants in the abdominal region. The injection volumes for the 90 mg and 120 mg doses are 0.6 mL and 0.8 mL, respectively.¹⁰ As the gel implant becomes firmer, the patient will notice a lump for several weeks that will decrease in size over time. Patients should be advised not to rub or massage the injection site, and to be aware of the placement of any belts or clothing with waistbands.¹⁰

Pharmacologic profile, adverse reactions

Risperidone is an atypical antipsychotic that has been commercially available in the U.S. since December 29, 1993, and its adverse effect profile is well characterized. The most common adverse effects associated with risperidone include those related to dopamine D2 antagonism, metabolic adverse effects, and an increase in serum prolactin. In the 12-month long-term safety study of RBP-7000, 1-minute post-dose injection site pain scores (on a 100-point scale) were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following the last injection).¹⁰

Continue to: How the Atrigel system works

The kinetics for RBP-7000 are markedly different than those for oral risperidone (Figure 2¹⁵). After a single subcutaneous injection, RBP-7000 shows 2 absorption peaks for risperidone. The first lower peak occurs with a T_max of 4 to 6 hours due to initial release of risperidone during the implant formation process; a second risperidone peak occurs after 10 to 14 days and is associated with slow release from the subcutaneous depot.^9,16,17 For both 9-OH risperidone levels and the total active moiety (risperidone plus 9-OH risperidone levels), the median T_max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Following a single subcutaneous injection of RBP-7000, the apparent terminal half-life of risperidone ranges from 9 to 11 days, on average. The mean apparent terminal half-life of the active moiety ranges from 8 to 9 days.^9,16,17 Based on population pharmacokinetic modeling, the 90 mg and 120 mg doses of RBP-7000 are estimated to provide drug exposure equivalent to 3 mg/d and 4 mg/d of oral risperidone, respectively.^9,16,17

Continue to: Efficacy of RBP-7000

Efficacy of RBP-7000 was established in an 8-week, double-blind, placebo-controlled trial of adult patients experiencing an acute exacerbation of schizo­phrenia (age 18 to 55).⁴ Eligible participants had:

• An acute exacerbation of schizophrenia that occurred ≤8 weeks before the screening visit and would have benefited from psychiatric hospitalization or continued hospitalization
• Positive and Negative Syndrome Scale (PANSS) total score between 80 and 120 at visit 1 and a score of >4 on at least 2 of the following 4 items: hallucinatory behavior, delusions, conceptual disorganization, or suspiciousness/persecution
• The diagnosis of acute exacerbation of schizophrenia and PANSS total score were confirmed through an independent video-conference interview conducted by an experienced rater.

Participants were excluded if they:

• Experienced a ≥20% improvement in PANSS total score between the initial screening visit and the first injection
• had been treated at any time with clozapine for treatment-resistant schizophrenia
• had met DSM-IV-TR criteria for substance dependence (with the exception of nicotine or caffeine) before screening.

During the initial screening visit, participants received a 0.25-mg tablet of oral risperidone on 2 consecutive days to assess the tolerability of risperidone.

Outcome. Participants were randomized in a 1:1:1 manner to placebo (n = 112) or 1 of 2 monthly doses of RBP-7000: 90 mg (n = 111) or 120 mg (n = 114). Using the least squares means of repeated-measures changes from baseline in PANSS total scores, there was a significant improvement in the difference in PANSS total scores from baseline to the end of the study compared with placebo: 90-mg RBP-7000, -6.148 points (95% confidence interval [CI], -9.982 to -2.314, P = .0004); 120-mg RBP-7000, -7.237 points (95% CI, -11.045 to -3.429, P < .0001). The absolute change from baseline in PANSS total score was -15.367 points for the 90-mg dose and -16.456 points for the 120-mg dose.⁴ Completion rates across all 3 arms were comparable: placebo 70.6%, RBP-7000 90 mg 77.6%, and RBP-7000 120 mg 71.4%.

Tolerability. In the 8-week phase III efficacy trial of RBP-7000, adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo were weight gain (placebo 3.4%, 90 mg 13.0%, 120 mg 12.8%) and sedation (placebo 0%, 90 mg 7.0%, 120 mg 7.7%).¹⁰ Compared with baseline, participants had a mean weight gain at the end of the study of 2.83 kg in the placebo group, 5.15 kg in the 90-mg RBP-7000 group, and 4.69 kg in the 120-mg RBP-7000 group. There were no clinically significant differences at study endpoint in glucose and lipid parameters. Consistent with the known effects of risperidone, there were increases in mean prolactin levels during the 8-week study, the effects of which were greater for women. For men, mean prolactin levels from baseline to study end were: placebo: 9.8 ± 7.9 vs 9.9 ± 8.0 ng/mL; 90 mg: 8.9 ± 6.9 vs 22.4 ± 11.2 ng/mL; and 120 mg: 8.2 ± 5.2 vs 31.3 ± 14.8 ng/mL. For women, mean prolactin levels from baseline to study end were: placebo: 12.8 ± 11.7 vs 10.4 ± 8.0 ng/mL; 90 mg: 7.7 ± 5.3 vs 60.3 ± 46.9 ng/mL; and 120 mg: 10.9 ± 8.6 vs 85.5 ± 55.1 ng/mL. In the pivotal study, discontinuations due to adverse events were low across all treatment groups: 2.5% for placebo vs 0% for 90 mg and 1.7% for 120 mg.⁴ There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥2% and greater than placebo in patients treated with RBP-7000.¹⁰ There were no clinically relevant differences in mean changes from baseline in corrected QT, QRS, and PR intervals, and in heart rate. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean electrocardiography interval values from baseline to post-dose assessments.¹⁰

Using a 100-point visual analog scale (VAS), injection site pain scores 1 minute after the first dose decreased from a mean of 27 to the range of 3 to 7 for scores obtained 30 to 60 minutes post-dose. In the 12-month long-term safety study, 1-minute post-dose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection).¹⁰

Clinical considerations

Unique properties. RBP-7000 uses the established Atrigel system to provide effective antipsychotic levels in the first week of treatment, without the need for bridging oral coverage or a second loading injection. The abdominal subcutaneous injection volume is relatively small (0.6 mL or 0.8 mL).

Why Rx? The reasons to prescribe RBP-7000 for adult patients with schizophrenia include:

• no oral coverage required at the initiation of treatment
• effective plasma active moiety levels are seen within the first week without the need for a second loading injection
• monthly injection schedule.

Dosing. The recommended dosage of RBP-7000 is 90 mg or 120 mg once monthly, equivalent to 3 mg/d or 4 mg/d of oral risperidone, respectively. Oral risperidone tolerability should be established before the first injection. No oral risperidone coverage is required. RBP-7000 has not been studied in patients with renal or hepatic impairment and should be used with caution in these patients. Prior to initiating treatment in these patients, it is advised to carefully titrate up to at least 3 mg/d of oral risperidone. If a patient can tolerate 3 mg/d of oral risperidone and is psychiatrically stable, then the 90-mg dose of RBP-7000 can be considered.¹⁰ 

Contraindications. The only contraindications for RBP-7000 are known hypersensitivity to risperidone, paliperidone (9-OH risperidone), or other components of the injection.

Bottom Line

RBP-7000 (Perseris) is the second long-acting injectable (LAI) form of risperidone approved in the U.S. Unlike risperidone microspheres (Consta), RBP-7000 does not require any oral risperidone coverage at the beginning of therapy, provides effective drug levels within the first week of treatment with a single injection, and uses a monthly dosing interval. RBP-7000 does not require loading upon initiation. The monthly injection is <1 mL, is administered in abdominal subcutaneous tissue, and uses the Atrigel system.

Related Resource

• Carpenter J, Wong KK. Long-acting injectable antipsychotics: What to do about missed doses. Current Psychiatry. 2018;17(7):10-12,14-19,56.
   

Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Carbatrol, Tegretol
Doxycycline • Atridox
Leuprolide acetate injectable suspension • Eligard
Paliperidone palmitate • Invega Sustenna
Risperidone • Risperdal
Risperidone extended-release injectable suspension • Perseris
Risperidone long-acting injection • Risperdal Consta

Oral antipsychotic nonadherence is a significant contributor to relapse in patients with schizophrenia spectrum disorders. Long-acting injectable (LAI) antipsychotics have been developed to provide sustained antipsychotic exposure, with evidence that use of LAIs significantly reduces hospitalization rates.¹ One limiting factor in transitioning patients to certain LAIs is the need for prolonged oral coverage at the onset of treatment for agents that cannot be loaded. Nonadherence with this bridging oral therapy places the patient at risk for symptom exacerbation until effective antipsychotic plasma levels are achieved from the LAI.² Although risperidone is one of the more widely used antipsychotics for treating schizophrenia, until recently the only available LAI preparation, risperidone microspheres (Risperdal Consta), required 3 weeks of oral coverage upon initiation.³

Clinical implications

Oral medication nonadherence remains a significant public health issue for patients with schizophrenia, with an estimated 50% of patients failing to achieve 80% adherence even when enrolled in clinical trials specifically designed to track adherence.⁵ Although LAI atypical antipsychotics have been available since the approval of Risperdal Consta, the LAI form of risperidone, and both LAI forms of aripiprazole, were not designed to be loaded. A 1-day initiation regimen for aripiprazole lauroxil has been developed to avoid the need for 3 weeks of oral medication coverage,^6,7 but aripiprazole monohydrate and risperidone microspheres mandate oral bridging of 2 and 3 weeks, respectively.² Because one of the primary indications for LAI antipsychotic therapy is oral medication nonadherence, this prolonged period of oral coverage creates a risk for symptom exacerbation when the bridging period occurs outside of a controlled setting, as is common when patients are discharged from inpatient hospitalization.

One solution to this problem has its antecedents in the development of the Atrigel biodegradable injectable polymer, which was designed to deliver prolonged medication exposure after subcutaneous injection.⁸ This biodegradable polymer drug delivery system suspends and dissolves the medication of interest (in this case, risperidone) in a poly DL-lactide-coglycolide gel and its biocompatible carrier.⁹ The viscous liquid undergoes a phase transition upon contact with tissue fluids after subcutaneous injection, resulting in an implant that releases risperidone in a controlled manner as it is resorbed. Importantly, the kinetic parameters of RBP-7000 are such that effective drug levels are seen within the first week without the need for oral coverage.¹⁰

Use in adults with schizophrenia. After establishing tolerability with oral risperidone, the recommended doses are 90 mg or 120 mg monthly, which correspond to oral daily risperidone doses of 3 mg or 4 mg. RBP-7000 must be administered as a subcutaneous abdominal injection by a health care professional. It is recommended that the patient be in the supine position for the injection and that the injection sites be rotated monthly among 4 quadrants in the abdominal region. The injection volumes for the 90 mg and 120 mg doses are 0.6 mL and 0.8 mL, respectively.¹⁰ As the gel implant becomes firmer, the patient will notice a lump for several weeks that will decrease in size over time. Patients should be advised not to rub or massage the injection site, and to be aware of the placement of any belts or clothing with waistbands.¹⁰

Pharmacologic profile, adverse reactions

Risperidone is an atypical antipsychotic that has been commercially available in the U.S. since December 29, 1993, and its adverse effect profile is well characterized. The most common adverse effects associated with risperidone include those related to dopamine D2 antagonism, metabolic adverse effects, and an increase in serum prolactin. In the 12-month long-term safety study of RBP-7000, 1-minute post-dose injection site pain scores (on a 100-point scale) were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following the last injection).¹⁰

Continue to: How the Atrigel system works

The kinetics for RBP-7000 are markedly different than those for oral risperidone (Figure 2¹⁵). After a single subcutaneous injection, RBP-7000 shows 2 absorption peaks for risperidone. The first lower peak occurs with a T_max of 4 to 6 hours due to initial release of risperidone during the implant formation process; a second risperidone peak occurs after 10 to 14 days and is associated with slow release from the subcutaneous depot.^9,16,17 For both 9-OH risperidone levels and the total active moiety (risperidone plus 9-OH risperidone levels), the median T_max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Following a single subcutaneous injection of RBP-7000, the apparent terminal half-life of risperidone ranges from 9 to 11 days, on average. The mean apparent terminal half-life of the active moiety ranges from 8 to 9 days.^9,16,17 Based on population pharmacokinetic modeling, the 90 mg and 120 mg doses of RBP-7000 are estimated to provide drug exposure equivalent to 3 mg/d and 4 mg/d of oral risperidone, respectively.^9,16,17

Continue to: Efficacy of RBP-7000

Efficacy of RBP-7000 was established in an 8-week, double-blind, placebo-controlled trial of adult patients experiencing an acute exacerbation of schizo­phrenia (age 18 to 55).⁴ Eligible participants had:

• An acute exacerbation of schizophrenia that occurred ≤8 weeks before the screening visit and would have benefited from psychiatric hospitalization or continued hospitalization
• Positive and Negative Syndrome Scale (PANSS) total score between 80 and 120 at visit 1 and a score of >4 on at least 2 of the following 4 items: hallucinatory behavior, delusions, conceptual disorganization, or suspiciousness/persecution
• The diagnosis of acute exacerbation of schizophrenia and PANSS total score were confirmed through an independent video-conference interview conducted by an experienced rater.

Participants were excluded if they:

• Experienced a ≥20% improvement in PANSS total score between the initial screening visit and the first injection
• had been treated at any time with clozapine for treatment-resistant schizophrenia
• had met DSM-IV-TR criteria for substance dependence (with the exception of nicotine or caffeine) before screening.

During the initial screening visit, participants received a 0.25-mg tablet of oral risperidone on 2 consecutive days to assess the tolerability of risperidone.

Outcome. Participants were randomized in a 1:1:1 manner to placebo (n = 112) or 1 of 2 monthly doses of RBP-7000: 90 mg (n = 111) or 120 mg (n = 114). Using the least squares means of repeated-measures changes from baseline in PANSS total scores, there was a significant improvement in the difference in PANSS total scores from baseline to the end of the study compared with placebo: 90-mg RBP-7000, -6.148 points (95% confidence interval [CI], -9.982 to -2.314, P = .0004); 120-mg RBP-7000, -7.237 points (95% CI, -11.045 to -3.429, P < .0001). The absolute change from baseline in PANSS total score was -15.367 points for the 90-mg dose and -16.456 points for the 120-mg dose.⁴ Completion rates across all 3 arms were comparable: placebo 70.6%, RBP-7000 90 mg 77.6%, and RBP-7000 120 mg 71.4%.

Tolerability. In the 8-week phase III efficacy trial of RBP-7000, adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo were weight gain (placebo 3.4%, 90 mg 13.0%, 120 mg 12.8%) and sedation (placebo 0%, 90 mg 7.0%, 120 mg 7.7%).¹⁰ Compared with baseline, participants had a mean weight gain at the end of the study of 2.83 kg in the placebo group, 5.15 kg in the 90-mg RBP-7000 group, and 4.69 kg in the 120-mg RBP-7000 group. There were no clinically significant differences at study endpoint in glucose and lipid parameters. Consistent with the known effects of risperidone, there were increases in mean prolactin levels during the 8-week study, the effects of which were greater for women. For men, mean prolactin levels from baseline to study end were: placebo: 9.8 ± 7.9 vs 9.9 ± 8.0 ng/mL; 90 mg: 8.9 ± 6.9 vs 22.4 ± 11.2 ng/mL; and 120 mg: 8.2 ± 5.2 vs 31.3 ± 14.8 ng/mL. For women, mean prolactin levels from baseline to study end were: placebo: 12.8 ± 11.7 vs 10.4 ± 8.0 ng/mL; 90 mg: 7.7 ± 5.3 vs 60.3 ± 46.9 ng/mL; and 120 mg: 10.9 ± 8.6 vs 85.5 ± 55.1 ng/mL. In the pivotal study, discontinuations due to adverse events were low across all treatment groups: 2.5% for placebo vs 0% for 90 mg and 1.7% for 120 mg.⁴ There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥2% and greater than placebo in patients treated with RBP-7000.¹⁰ There were no clinically relevant differences in mean changes from baseline in corrected QT, QRS, and PR intervals, and in heart rate. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean electrocardiography interval values from baseline to post-dose assessments.¹⁰

Using a 100-point visual analog scale (VAS), injection site pain scores 1 minute after the first dose decreased from a mean of 27 to the range of 3 to 7 for scores obtained 30 to 60 minutes post-dose. In the 12-month long-term safety study, 1-minute post-dose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection).¹⁰

Clinical considerations

Unique properties. RBP-7000 uses the established Atrigel system to provide effective antipsychotic levels in the first week of treatment, without the need for bridging oral coverage or a second loading injection. The abdominal subcutaneous injection volume is relatively small (0.6 mL or 0.8 mL).

Why Rx? The reasons to prescribe RBP-7000 for adult patients with schizophrenia include:

• no oral coverage required at the initiation of treatment
• effective plasma active moiety levels are seen within the first week without the need for a second loading injection
• monthly injection schedule.

Dosing. The recommended dosage of RBP-7000 is 90 mg or 120 mg once monthly, equivalent to 3 mg/d or 4 mg/d of oral risperidone, respectively. Oral risperidone tolerability should be established before the first injection. No oral risperidone coverage is required. RBP-7000 has not been studied in patients with renal or hepatic impairment and should be used with caution in these patients. Prior to initiating treatment in these patients, it is advised to carefully titrate up to at least 3 mg/d of oral risperidone. If a patient can tolerate 3 mg/d of oral risperidone and is psychiatrically stable, then the 90-mg dose of RBP-7000 can be considered.¹⁰ 

Contraindications. The only contraindications for RBP-7000 are known hypersensitivity to risperidone, paliperidone (9-OH risperidone), or other components of the injection.

Bottom Line

RBP-7000 (Perseris) is the second long-acting injectable (LAI) form of risperidone approved in the U.S. Unlike risperidone microspheres (Consta), RBP-7000 does not require any oral risperidone coverage at the beginning of therapy, provides effective drug levels within the first week of treatment with a single injection, and uses a monthly dosing interval. RBP-7000 does not require loading upon initiation. The monthly injection is <1 mL, is administered in abdominal subcutaneous tissue, and uses the Atrigel system.

Related Resource

• Carpenter J, Wong KK. Long-acting injectable antipsychotics: What to do about missed doses. Current Psychiatry. 2018;17(7):10-12,14-19,56.
   

Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Carbatrol, Tegretol
Doxycycline • Atridox
Leuprolide acetate injectable suspension • Eligard
Paliperidone palmitate • Invega Sustenna
Risperidone • Risperdal
Risperidone extended-release injectable suspension • Perseris
Risperidone long-acting injection • Risperdal Consta

Mr. W, age 50, who has been diagnosed with hypertension and catatonia associated with schizophrenia, is brought to the emergency department by his case manager for evaluation of increasing disorganization, inability to function, and nonadherence to medications. He has not been bathing, eating, or drinking. During the admission interview, he is mute, and is noted to have purposeless activity, alternating between rocking from leg to leg to pacing in circles. At times Mr. W holds a rigid, prayer-type posture with his arms. Negativism is present, primarily opposition to interviewer requests.

Previously stable on paliperidone palmitate, 234 mg IM monthly, Mr. W has refused his past 3 injections. Past psychotropics include clozapine, 250 mg at bedtime (discontinued because Mr. W was repeatedly nonadherent to blood draws), risperidone long-acting injection, 25 mg every 2 weeks, as well as olanzapine, quetiapine, lurasidone, asenapine, lithium, fluoxetine, citalopram, mirtazapine (doses unknown). Previously, electroconvulsive therapy (ECT) was used to successfully treat his catatonia.

On the inpatient psychiatry unit, Mr. W continues to be mute, staying in bed except to use the bathroom. He refuses all food and fluids. The team initiates subcutaneous enoxaparin for deep vein thrombosis (DVT) prophylaxis and IV fluids for hydration. Mr. W receives a benzodiazepine challenge with lorazepam, 2 mg IM. Within 1 hour of receiving lorazepam, he is walking in the hall, speaking to staff, and eating. Therefore, lorazepam, 2 mg IM, 3 times a day, is continued, but the response is unsustained. Ultimately, ECT is initiated.

Continue to: Medical complications can be fatal

Treatment usually starts with lorazepam

Benzodiazepines are a first-line option for the management of catatonia.^2,5 Controversy exists as to effectiveness of different routes of administration. Generally, IV lorazepam is preferred due to its ease of administration, fast onset, and longer duration of action.¹ Some inpatient psychiatric units are unable to administer IV benzodiazepines; in these scenarios, IM administration is preferred to oral benzodiazepines.

The initial lorazepam challenge dose should be 2 mg. A positive response to the lorazepam challenge often confirms the catatonia diagnosis.^2,7 This challenge should be followed by maintenance doses ranging from 6 to 8 mg/d in divided doses (3 or 4 times a day). Higher doses (up to 24 mg/d) are sometimes used.^2,5,8 A recent case report described catatonia remission using lorazepam, 28 mg/d, after unsuccessful ECT.⁹ The lorazepam dose prior to ECT was 8 mg/d.⁹ Response is usually seen within 3 to 7 days of an adequate dose.^2,8 Parenteral lorazepam typically is continued for several days before converting to oral lorazepam.¹ Approximately 70% to 80% of patients with catatonia will show improvement in symptoms with lorazepam.^2,7,8

The optimal duration of benzodiazepine treatment is unclear.² In some cases, once remission of the underlying illness is achieved, benzodiazepines are discontinued.² However, in other cases, symptoms of catatonia may emerge when lorazepam is tapered, therefore suggesting the need for a longer duration of treatment.² Despite this high rate of improvement, many patients ultimately receive ECT due to unsustained response or to prevent future episodes of catatonia.

A recent review of 60 Turkish patients with catatonia found 91.7% (n = 55) received oral lorazepam (up to 15 mg/d) as the first-line therapy.⁷ Improvement was seen in 23.7% (n = 13) of patients treated with lorazepam, yet 70% (n = 42) showed either no response or partial response, and ultimately received ECT in combination with lorazepam.⁷ The lower improvement rate seen in this review may be secondary to the use of oral lorazepam instead of parenteral, or may highlight the frequency in which patients ultimately go on to receive ECT.

Continue to: ECT

ECT. If high doses of benzodiazepines are not effective within 48 to 72 hours, ECT should be considered.^1,7 ECT should be considered sooner for patients with life-threatening catatonia or those who present with excited features or malignant catatonia.^1,2,7 In patients with catatonia, ECT response rates range from 80% to 100%.^2,7 Unal et al⁷ reported a 100% response rate if ECT was used as the first-line treatment (n = 5), and a 92.9% (n = 39) response rate after adding ECT to lorazepam. Lorazepam may interfere with the seizure threshold, but if indicated, this medication can be continued.² A minimum of 6 ECT treatments are suggested; however, as many as 20 treatments have been needed.¹ Mr. W required a total of 18 ECT treatments. In some cases, maintenance ECT may be required.²

Antipsychotics. Discontinuation of antipsychotics is generally encouraged in patients presenting with catatonia.^2,7,8 Antipsychotics carry a risk of potentially worsening catatonia, conversion to malignant catatonia, or precipitation of NMS; therefore, carefully weigh the risks vs benefits.^1,2 If catatonia is secondary to psychosis, as in Mr. W’s case, antipsychotics may be considered once catatonia improves.² If an antipsychotic is warranted, consider aripiprazole (because of its D2 partial agonist activity) or low-dose olanzapine.^1,2 If catatonia is secondary to clozapine withdrawal, the initial therapy should be clozapine re-initiation.¹ Although high-potency agents, such as haloperidol and risperidone, typically are not preferred, risperidone was restarted for Mr. W because of his history of response to and tolerability of this medication during a previous catatonic episode.

Other treatments. In a recent review, Beach et al¹ described the use of additional agents, mostly in a small number of positive case reports, for managing catatonia. These included:

• zolpidem (zolpidem 10 mg as a challenge test, and doses of ≤40 mg/d)
• the N-methyl-D-aspartic acid antagonists amantadine (100 to 600 mg/d) or memantine (5 to 20 mg/d)
• carbidopa/levodopa
• methylphenidate
• antiepileptics (eg, carbamazepine, topiramate, and divalproex sodium)
• anticholinergics.^1,2

Lithium has been used in attempts to prevent recurrent catatonia with limited success.² There are also a few reports of using transcranial magnetic stimulation (TMS) to manage catatonia.¹

Beach et al¹ proposed a treatment algorithm in which IV lorazepam (Step 1) and ECT (Step 2) remain the preferred treatments. Next, for Step 3 consider a glutamate antagonist (amantadine or memantine), followed by an antiepileptic (Step 4), and lastly an atypical antipsychotic (aripiprazole, olanzapine, or clozapine) in combination with lorazepam (Step 5).

When indicated, don’t delay ECT

Initial management of catatonia is with a benzodiazepine challenge. Ultimately, the gold-standard treatment of catatonia that does not improve with benzodiazepines is ECT, and ECT should be implemented as soon as it is clear that pharmaco­therapy is less than fully effective. Consider ECT initially in life-threatening cases and for patients with malignant catatonia. Although additional agents and TMS have been explored, these should be reserved for patients who fail to respond to, or who are not candidates for, benzodiazepines or ECT.

CASE CONTINUED

After 5 ECT treatments, Mr. W says a few words, but he communicates primarily with gestures (primarily waving people away). After 10 to 12 ECT treatments, Mr. W becomes more interactive and conversant, and his nutrition improves; however, he still exhibits symptoms of catatonia and is not at baseline. He undergoes a total of 18 ECT treatments. Antipsychotics were initially discontinued; however, given Mr. W’s improvement with ECT and the presence of auditory hallucinations, oral risperidone is restarted and titrated to 2 mg, 2 times a day, and he is transitioned back to paliperidone palmitate before he is discharged. Lorazepam is tapered and discontinued. Mr. W is discharged back to his nursing home and is interactive (laughing and joking with family) and attending to his activities of daily living. Unfortunately, Mr. W did not followup with the recommendation for maintenance ECT, and adherence to paliperidone palmitate injections is unknown. Mr. W presented to our facility again 6 months later with symptoms of catatonia and ultimately transferred to a state hospital.

Related Resources

• Fink M, Taylor MA. Catatonia: A clinician’s guide to diagnosis and treatment. New York, NY: Cambridge University Press; 2006. • Carroll BT, Spiegel DR. Catatonia on the consultation liaison service and other clinical settings. Hauppauge, NY: Nova Science Pub Inc.; 2016.
• Benarous X, Raffin M, Ferrafiat V, et al. Catatonia in children and adolescents: new perspectives. Schizophr Res. 2018;200:56-67.
• Malignant Hyperthermia Association of the United States. What is NMSIS? http://www.mhaus.org/nmsis/about-us/ what-is-nmsis/.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Asenapine • Saphris
Carbamazepine • Carbatrol, Tegretol
Carbidopa/Levodopa • Sinemet
Citalopram • Celexa
Clozapine • Clozaril
Divalproex Sodium • Depakote
Enoxaparin • Lovenox
Fluoxetine • Prozac
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Lurasidone • Latuda
Memantine • Namenda
Methylphenidate • Concerta, Ritalin
Mirtazapine • Remeron
Olanzapine • Zyprexa
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone long-acting injection • Risperdal Consta
Topiramate • Topamax
Zolpidem • Ambien

Mr. W, age 50, who has been diagnosed with hypertension and catatonia associated with schizophrenia, is brought to the emergency department by his case manager for evaluation of increasing disorganization, inability to function, and nonadherence to medications. He has not been bathing, eating, or drinking. During the admission interview, he is mute, and is noted to have purposeless activity, alternating between rocking from leg to leg to pacing in circles. At times Mr. W holds a rigid, prayer-type posture with his arms. Negativism is present, primarily opposition to interviewer requests.

Previously stable on paliperidone palmitate, 234 mg IM monthly, Mr. W has refused his past 3 injections. Past psychotropics include clozapine, 250 mg at bedtime (discontinued because Mr. W was repeatedly nonadherent to blood draws), risperidone long-acting injection, 25 mg every 2 weeks, as well as olanzapine, quetiapine, lurasidone, asenapine, lithium, fluoxetine, citalopram, mirtazapine (doses unknown). Previously, electroconvulsive therapy (ECT) was used to successfully treat his catatonia.

On the inpatient psychiatry unit, Mr. W continues to be mute, staying in bed except to use the bathroom. He refuses all food and fluids. The team initiates subcutaneous enoxaparin for deep vein thrombosis (DVT) prophylaxis and IV fluids for hydration. Mr. W receives a benzodiazepine challenge with lorazepam, 2 mg IM. Within 1 hour of receiving lorazepam, he is walking in the hall, speaking to staff, and eating. Therefore, lorazepam, 2 mg IM, 3 times a day, is continued, but the response is unsustained. Ultimately, ECT is initiated.

Continue to: Medical complications can be fatal

Treatment usually starts with lorazepam

Benzodiazepines are a first-line option for the management of catatonia.^2,5 Controversy exists as to effectiveness of different routes of administration. Generally, IV lorazepam is preferred due to its ease of administration, fast onset, and longer duration of action.¹ Some inpatient psychiatric units are unable to administer IV benzodiazepines; in these scenarios, IM administration is preferred to oral benzodiazepines.

The initial lorazepam challenge dose should be 2 mg. A positive response to the lorazepam challenge often confirms the catatonia diagnosis.^2,7 This challenge should be followed by maintenance doses ranging from 6 to 8 mg/d in divided doses (3 or 4 times a day). Higher doses (up to 24 mg/d) are sometimes used.^2,5,8 A recent case report described catatonia remission using lorazepam, 28 mg/d, after unsuccessful ECT.⁹ The lorazepam dose prior to ECT was 8 mg/d.⁹ Response is usually seen within 3 to 7 days of an adequate dose.^2,8 Parenteral lorazepam typically is continued for several days before converting to oral lorazepam.¹ Approximately 70% to 80% of patients with catatonia will show improvement in symptoms with lorazepam.^2,7,8

The optimal duration of benzodiazepine treatment is unclear.² In some cases, once remission of the underlying illness is achieved, benzodiazepines are discontinued.² However, in other cases, symptoms of catatonia may emerge when lorazepam is tapered, therefore suggesting the need for a longer duration of treatment.² Despite this high rate of improvement, many patients ultimately receive ECT due to unsustained response or to prevent future episodes of catatonia.

A recent review of 60 Turkish patients with catatonia found 91.7% (n = 55) received oral lorazepam (up to 15 mg/d) as the first-line therapy.⁷ Improvement was seen in 23.7% (n = 13) of patients treated with lorazepam, yet 70% (n = 42) showed either no response or partial response, and ultimately received ECT in combination with lorazepam.⁷ The lower improvement rate seen in this review may be secondary to the use of oral lorazepam instead of parenteral, or may highlight the frequency in which patients ultimately go on to receive ECT.

Continue to: ECT

ECT. If high doses of benzodiazepines are not effective within 48 to 72 hours, ECT should be considered.^1,7 ECT should be considered sooner for patients with life-threatening catatonia or those who present with excited features or malignant catatonia.^1,2,7 In patients with catatonia, ECT response rates range from 80% to 100%.^2,7 Unal et al⁷ reported a 100% response rate if ECT was used as the first-line treatment (n = 5), and a 92.9% (n = 39) response rate after adding ECT to lorazepam. Lorazepam may interfere with the seizure threshold, but if indicated, this medication can be continued.² A minimum of 6 ECT treatments are suggested; however, as many as 20 treatments have been needed.¹ Mr. W required a total of 18 ECT treatments. In some cases, maintenance ECT may be required.²

Antipsychotics. Discontinuation of antipsychotics is generally encouraged in patients presenting with catatonia.^2,7,8 Antipsychotics carry a risk of potentially worsening catatonia, conversion to malignant catatonia, or precipitation of NMS; therefore, carefully weigh the risks vs benefits.^1,2 If catatonia is secondary to psychosis, as in Mr. W’s case, antipsychotics may be considered once catatonia improves.² If an antipsychotic is warranted, consider aripiprazole (because of its D2 partial agonist activity) or low-dose olanzapine.^1,2 If catatonia is secondary to clozapine withdrawal, the initial therapy should be clozapine re-initiation.¹ Although high-potency agents, such as haloperidol and risperidone, typically are not preferred, risperidone was restarted for Mr. W because of his history of response to and tolerability of this medication during a previous catatonic episode.

Other treatments. In a recent review, Beach et al¹ described the use of additional agents, mostly in a small number of positive case reports, for managing catatonia. These included:

• zolpidem (zolpidem 10 mg as a challenge test, and doses of ≤40 mg/d)
• the N-methyl-D-aspartic acid antagonists amantadine (100 to 600 mg/d) or memantine (5 to 20 mg/d)
• carbidopa/levodopa
• methylphenidate
• antiepileptics (eg, carbamazepine, topiramate, and divalproex sodium)
• anticholinergics.^1,2

Lithium has been used in attempts to prevent recurrent catatonia with limited success.² There are also a few reports of using transcranial magnetic stimulation (TMS) to manage catatonia.¹

Beach et al¹ proposed a treatment algorithm in which IV lorazepam (Step 1) and ECT (Step 2) remain the preferred treatments. Next, for Step 3 consider a glutamate antagonist (amantadine or memantine), followed by an antiepileptic (Step 4), and lastly an atypical antipsychotic (aripiprazole, olanzapine, or clozapine) in combination with lorazepam (Step 5).

When indicated, don’t delay ECT

Initial management of catatonia is with a benzodiazepine challenge. Ultimately, the gold-standard treatment of catatonia that does not improve with benzodiazepines is ECT, and ECT should be implemented as soon as it is clear that pharmaco­therapy is less than fully effective. Consider ECT initially in life-threatening cases and for patients with malignant catatonia. Although additional agents and TMS have been explored, these should be reserved for patients who fail to respond to, or who are not candidates for, benzodiazepines or ECT.

CASE CONTINUED

After 5 ECT treatments, Mr. W says a few words, but he communicates primarily with gestures (primarily waving people away). After 10 to 12 ECT treatments, Mr. W becomes more interactive and conversant, and his nutrition improves; however, he still exhibits symptoms of catatonia and is not at baseline. He undergoes a total of 18 ECT treatments. Antipsychotics were initially discontinued; however, given Mr. W’s improvement with ECT and the presence of auditory hallucinations, oral risperidone is restarted and titrated to 2 mg, 2 times a day, and he is transitioned back to paliperidone palmitate before he is discharged. Lorazepam is tapered and discontinued. Mr. W is discharged back to his nursing home and is interactive (laughing and joking with family) and attending to his activities of daily living. Unfortunately, Mr. W did not followup with the recommendation for maintenance ECT, and adherence to paliperidone palmitate injections is unknown. Mr. W presented to our facility again 6 months later with symptoms of catatonia and ultimately transferred to a state hospital.

Related Resources

• Fink M, Taylor MA. Catatonia: A clinician’s guide to diagnosis and treatment. New York, NY: Cambridge University Press; 2006. • Carroll BT, Spiegel DR. Catatonia on the consultation liaison service and other clinical settings. Hauppauge, NY: Nova Science Pub Inc.; 2016.
• Benarous X, Raffin M, Ferrafiat V, et al. Catatonia in children and adolescents: new perspectives. Schizophr Res. 2018;200:56-67.
• Malignant Hyperthermia Association of the United States. What is NMSIS? http://www.mhaus.org/nmsis/about-us/ what-is-nmsis/.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Asenapine • Saphris
Carbamazepine • Carbatrol, Tegretol
Carbidopa/Levodopa • Sinemet
Citalopram • Celexa
Clozapine • Clozaril
Divalproex Sodium • Depakote
Enoxaparin • Lovenox
Fluoxetine • Prozac
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Lurasidone • Latuda
Memantine • Namenda
Methylphenidate • Concerta, Ritalin
Mirtazapine • Remeron
Olanzapine • Zyprexa
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone long-acting injection • Risperdal Consta
Topiramate • Topamax
Zolpidem • Ambien

Mr. W, age 50, who has been diagnosed with hypertension and catatonia associated with schizophrenia, is brought to the emergency department by his case manager for evaluation of increasing disorganization, inability to function, and nonadherence to medications. He has not been bathing, eating, or drinking. During the admission interview, he is mute, and is noted to have purposeless activity, alternating between rocking from leg to leg to pacing in circles. At times Mr. W holds a rigid, prayer-type posture with his arms. Negativism is present, primarily opposition to interviewer requests.

Previously stable on paliperidone palmitate, 234 mg IM monthly, Mr. W has refused his past 3 injections. Past psychotropics include clozapine, 250 mg at bedtime (discontinued because Mr. W was repeatedly nonadherent to blood draws), risperidone long-acting injection, 25 mg every 2 weeks, as well as olanzapine, quetiapine, lurasidone, asenapine, lithium, fluoxetine, citalopram, mirtazapine (doses unknown). Previously, electroconvulsive therapy (ECT) was used to successfully treat his catatonia.

On the inpatient psychiatry unit, Mr. W continues to be mute, staying in bed except to use the bathroom. He refuses all food and fluids. The team initiates subcutaneous enoxaparin for deep vein thrombosis (DVT) prophylaxis and IV fluids for hydration. Mr. W receives a benzodiazepine challenge with lorazepam, 2 mg IM. Within 1 hour of receiving lorazepam, he is walking in the hall, speaking to staff, and eating. Therefore, lorazepam, 2 mg IM, 3 times a day, is continued, but the response is unsustained. Ultimately, ECT is initiated.

Continue to: Medical complications can be fatal

Treatment usually starts with lorazepam

Benzodiazepines are a first-line option for the management of catatonia.^2,5 Controversy exists as to effectiveness of different routes of administration. Generally, IV lorazepam is preferred due to its ease of administration, fast onset, and longer duration of action.¹ Some inpatient psychiatric units are unable to administer IV benzodiazepines; in these scenarios, IM administration is preferred to oral benzodiazepines.

The initial lorazepam challenge dose should be 2 mg. A positive response to the lorazepam challenge often confirms the catatonia diagnosis.^2,7 This challenge should be followed by maintenance doses ranging from 6 to 8 mg/d in divided doses (3 or 4 times a day). Higher doses (up to 24 mg/d) are sometimes used.^2,5,8 A recent case report described catatonia remission using lorazepam, 28 mg/d, after unsuccessful ECT.⁹ The lorazepam dose prior to ECT was 8 mg/d.⁹ Response is usually seen within 3 to 7 days of an adequate dose.^2,8 Parenteral lorazepam typically is continued for several days before converting to oral lorazepam.¹ Approximately 70% to 80% of patients with catatonia will show improvement in symptoms with lorazepam.^2,7,8

The optimal duration of benzodiazepine treatment is unclear.² In some cases, once remission of the underlying illness is achieved, benzodiazepines are discontinued.² However, in other cases, symptoms of catatonia may emerge when lorazepam is tapered, therefore suggesting the need for a longer duration of treatment.² Despite this high rate of improvement, many patients ultimately receive ECT due to unsustained response or to prevent future episodes of catatonia.

A recent review of 60 Turkish patients with catatonia found 91.7% (n = 55) received oral lorazepam (up to 15 mg/d) as the first-line therapy.⁷ Improvement was seen in 23.7% (n = 13) of patients treated with lorazepam, yet 70% (n = 42) showed either no response or partial response, and ultimately received ECT in combination with lorazepam.⁷ The lower improvement rate seen in this review may be secondary to the use of oral lorazepam instead of parenteral, or may highlight the frequency in which patients ultimately go on to receive ECT.

Continue to: ECT

ECT. If high doses of benzodiazepines are not effective within 48 to 72 hours, ECT should be considered.^1,7 ECT should be considered sooner for patients with life-threatening catatonia or those who present with excited features or malignant catatonia.^1,2,7 In patients with catatonia, ECT response rates range from 80% to 100%.^2,7 Unal et al⁷ reported a 100% response rate if ECT was used as the first-line treatment (n = 5), and a 92.9% (n = 39) response rate after adding ECT to lorazepam. Lorazepam may interfere with the seizure threshold, but if indicated, this medication can be continued.² A minimum of 6 ECT treatments are suggested; however, as many as 20 treatments have been needed.¹ Mr. W required a total of 18 ECT treatments. In some cases, maintenance ECT may be required.²

Antipsychotics. Discontinuation of antipsychotics is generally encouraged in patients presenting with catatonia.^2,7,8 Antipsychotics carry a risk of potentially worsening catatonia, conversion to malignant catatonia, or precipitation of NMS; therefore, carefully weigh the risks vs benefits.^1,2 If catatonia is secondary to psychosis, as in Mr. W’s case, antipsychotics may be considered once catatonia improves.² If an antipsychotic is warranted, consider aripiprazole (because of its D2 partial agonist activity) or low-dose olanzapine.^1,2 If catatonia is secondary to clozapine withdrawal, the initial therapy should be clozapine re-initiation.¹ Although high-potency agents, such as haloperidol and risperidone, typically are not preferred, risperidone was restarted for Mr. W because of his history of response to and tolerability of this medication during a previous catatonic episode.

Other treatments. In a recent review, Beach et al¹ described the use of additional agents, mostly in a small number of positive case reports, for managing catatonia. These included:

• zolpidem (zolpidem 10 mg as a challenge test, and doses of ≤40 mg/d)
• the N-methyl-D-aspartic acid antagonists amantadine (100 to 600 mg/d) or memantine (5 to 20 mg/d)
• carbidopa/levodopa
• methylphenidate
• antiepileptics (eg, carbamazepine, topiramate, and divalproex sodium)
• anticholinergics.^1,2

Lithium has been used in attempts to prevent recurrent catatonia with limited success.² There are also a few reports of using transcranial magnetic stimulation (TMS) to manage catatonia.¹

Beach et al¹ proposed a treatment algorithm in which IV lorazepam (Step 1) and ECT (Step 2) remain the preferred treatments. Next, for Step 3 consider a glutamate antagonist (amantadine or memantine), followed by an antiepileptic (Step 4), and lastly an atypical antipsychotic (aripiprazole, olanzapine, or clozapine) in combination with lorazepam (Step 5).

When indicated, don’t delay ECT

Initial management of catatonia is with a benzodiazepine challenge. Ultimately, the gold-standard treatment of catatonia that does not improve with benzodiazepines is ECT, and ECT should be implemented as soon as it is clear that pharmaco­therapy is less than fully effective. Consider ECT initially in life-threatening cases and for patients with malignant catatonia. Although additional agents and TMS have been explored, these should be reserved for patients who fail to respond to, or who are not candidates for, benzodiazepines or ECT.

CASE CONTINUED

After 5 ECT treatments, Mr. W says a few words, but he communicates primarily with gestures (primarily waving people away). After 10 to 12 ECT treatments, Mr. W becomes more interactive and conversant, and his nutrition improves; however, he still exhibits symptoms of catatonia and is not at baseline. He undergoes a total of 18 ECT treatments. Antipsychotics were initially discontinued; however, given Mr. W’s improvement with ECT and the presence of auditory hallucinations, oral risperidone is restarted and titrated to 2 mg, 2 times a day, and he is transitioned back to paliperidone palmitate before he is discharged. Lorazepam is tapered and discontinued. Mr. W is discharged back to his nursing home and is interactive (laughing and joking with family) and attending to his activities of daily living. Unfortunately, Mr. W did not followup with the recommendation for maintenance ECT, and adherence to paliperidone palmitate injections is unknown. Mr. W presented to our facility again 6 months later with symptoms of catatonia and ultimately transferred to a state hospital.

Related Resources

• Fink M, Taylor MA. Catatonia: A clinician’s guide to diagnosis and treatment. New York, NY: Cambridge University Press; 2006. • Carroll BT, Spiegel DR. Catatonia on the consultation liaison service and other clinical settings. Hauppauge, NY: Nova Science Pub Inc.; 2016.
• Benarous X, Raffin M, Ferrafiat V, et al. Catatonia in children and adolescents: new perspectives. Schizophr Res. 2018;200:56-67.
• Malignant Hyperthermia Association of the United States. What is NMSIS? http://www.mhaus.org/nmsis/about-us/ what-is-nmsis/.

Drug Brand Names

Amantadine • Symmetrel
Aripiprazole • Abilify
Asenapine • Saphris
Carbamazepine • Carbatrol, Tegretol
Carbidopa/Levodopa • Sinemet
Citalopram • Celexa
Clozapine • Clozaril
Divalproex Sodium • Depakote
Enoxaparin • Lovenox
Fluoxetine • Prozac
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Lurasidone • Latuda
Memantine • Namenda
Methylphenidate • Concerta, Ritalin
Mirtazapine • Remeron
Olanzapine • Zyprexa
Paliperidone palmitate • Invega Sustenna
Quetiapine • Seroquel
Risperidone • Risperdal
Risperidone long-acting injection • Risperdal Consta
Topiramate • Topamax
Zolpidem • Ambien

Performance enhancement in sports (“doping”) dates back to Ancient Greece. This was an era when Olympic athletes would attempt to improve their physical performance by consuming magic potions, herbal medications, and even exotic meats such as sheep testicles—a delicacy high in testosterone. Advances in medical and pharmaceutical technologies have increased both the range of enhancement agents available and their efficacy, leading to the development of anti-doping agencies and routine screening for doping in athletics. This has led to the renouncement of titles, medals, and financial sponsorship of athletes found to have been using prohibited substances during competition.

While doping in elite athletes often forms the nidus of media attention, the pressure to compete and perform at, or even beyond, one’s potential extends into many facets of today’s achievementfocused society. In the face of these pressures, individuals are increasingly seeking medications to enhance their performance across numerous domains, including cognitive, athletic, and artistic endeavors. Medication classes used to enhance performance include stimulants, which increase attention, executive function, and energy; cholinesterase inhibitors, which may ameliorate age-related memory decline; and beta-blockers, which decrease physiologic symptoms of anxiety and have been demonstrated to be beneficial for musical performance.¹ Fifty-three percent of college athletes report using prescription medications to enhance athletic performance,² and most college students who take stimulants without a prescription use them to study (84%) or stay awake (51%).³

Pharmacologic performance enhancement is the use of medications by healthy individuals to improve function in the absence of mental illness. Psychiatrists are increasingly finding themselves in the controversial position of “gatekeeper” of these medications for enhancement purposes. In this article we:

• outline arguments that support the use of psychopharmacology for performance enhancement, as well as some serious concerns with this practice
• discuss special considerations for pediatric populations and the risk of malpractice when prescribing for performance enhancement
• offer practice guidelines for approaching requests for psychopharmacologic performance enhancement.

Performance enhancement: The wave of the future?

The ethical principle that supports providing medication for performance enhancement is beneficence, the promotion of the patient’s well-being. In other words, it is a physician’s duty to help his or her patient in need. Individuals seeking performance enhancement typically present with suffering, and the principle of beneficence would call upon the psychiatrist to help ameliorate that suffering. Furthermore, patients who seek performance enhancement may present with impairing “subsyndromal” psychiatric symptoms (for example, low-grade attentional difficulty that occurs only in one setting), which, even if they do not rise to the threshold of a DSM diagnosis, may improve with psychiatric medications.

Using medical knowledge and skills beyond the traditional physician duty to diagnose and treat medical conditions is not unprecedented (eg, when surgeons perform cosmetic enhancement). Might elective enhancement of cognition and psychological performance through the judicious use of medication be part of the future of psychiatry? If cognitive and emotional enhancement becomes a more widely accepted standard of care, might this increase both individual and societal innovation and productivity?

Dilemma: Cautions against performance enhancement

One of the major cautions against prescribing psychotropics for the purpose of performance enhancement is the lack of clearly supported efficacy. Psychiatric medications generally are studied in individuals who meet criteria for mental illness, and they are FDA-approved for use in ill persons. It may be erroneous to extrapolate that a medication that improves symptoms in a patient with an illness would achieve the same target effect in a healthy individual. For example, data on whether stimulants provide neurocognitive enhancement in healthy individuals without attention-deficit/hyperactivity disorder is mixed, and these agents may even promote risky behavior in healthy controls.⁴ Furthermore, dopamine agonism may compress cognitive performance in both directions,⁵ as it has been observed that methylphenidate improves executive function in healthy controls, but is less beneficial for those with strong executive function at baseline.⁶

In the face of unclear benefit, it is particularly important to consider the risk of medications used for performance enhancement. Pharmacologic performance enhancement in individuals without psychopathology can be considered an “elective” intervention, for which individuals typically tolerate less risk. Physical risks, including medication-related adverse effects, must be considered, particularly in settings where there may be temptation to use more than prescribed, or to divert medication to others who may use it without medical monitoring. In addition to physical harm, there may be psychological harm associated with prescribing performance enhancers, such as pathologizing variants of “normal,” diminishing one’s sense of self-efficacy, or decreasing one’s ability to bear failure.

Continue to: Finally, there are ethical quandaries

Finally, there are ethical quandaries regarding using medications for performance enhancement. Widespread adoption of pharmacologic performance enhancement may lead to implicit coercion for all individuals to enhance their abilities. As a greater proportion of society receives pharmacologic enhancement, society as a whole faces stronger pressures to seek pharmacologic enhancement, ultimately constricting an individual’s freedom of choice to enhance.⁶ In this setting, distributive justice would become a consideration, because insurance companies are unlikely to reimburse for medications used for enhancement,⁷ which would give an advantage to individuals with higher socioeconomic status. Research shows that children from higher socioeconomic communities and from states with higher academic standards are more likely to use stimulants.⁸

Areas of controversy

Pediatric populations. There are special considerations when prescribing performance-enhancing medications for children and adolescents. First, such prescribing may inhibit normal child development, shifting the focus away from the normative tasks of social and emotional development that occur through leisure and creativity, experimentation, and play to an emphasis on performance and outcomes-based achievement.⁹ Second, during childhood and adolescence, one develops a sense of his or her identity, morals, and values. Taking a medication during childhood to enhance performance may inhibit the process of learning to tolerate failure, become aware of one’s weaknesses, and value effort in addition to outcome.

Malpractice risk. Practicing medicine beyond the scope of one’s expertise is unethical and unlawful. In the past 30 years, medical malpractice has become one of the most difficult health care issues in the U.S.¹⁰ In addition to billions of dollars in legal fees and court costs, medical malpractice premiums in the U.S. total more than $5 billion annually,¹¹ and “defensive medicine”— procedures performed to protect against litigation—is estimated to cost more than $14 billion a year.¹²

When considering performance-enhancing treatment, it is the physician’s duty to conduct a diagnostic assessment, including noting target symptoms that are interfering with the patient’s function, and to tailor such treatment toward measurable goals and outcomes. Aside from medication, this could include a therapeutic approach to improving performance that might include cognitive-behavioral therapy and promotion of a healthy diet and exercise.

Treatment rises to the level of malpractice when there is a dereliction of duty that directly leads to damages.¹³ Part of a physician’s duty is to educate patients about the pros and cons of different treatment options. For performance-enhancing medications, the risks of addiction and dependence are adverse effects that require discussion. And for a pediatric patient, this would require the guardian’s engagement and understanding.

Continue to: What to do if you decide to prescribe

Inevitably, the decision to prescribe psychotropic medications for performance enhancement is a physician-specific one. Certainly, psychiatrists should not feel obligated to prescribe performance enhancers. Given our current state of pharmacology, it is unclear whether medications would be helpful in the absence of psychopathology. When deciding whether to prescribe for performance enhancement in the absence of psychopathology, we suggest first carefully considering how to maintain the ethical value of nonmaleficence by weighing both the potential physical and psychologic harms of prescribing as well as the legal risks and rules of applicable sport governing bodies.

For a psychiatrist who chooses to prescribe for performance enhancement, we recommend conducting a thorough psychiatric assessment to determine whether the patient has a treatable mental illness. If so, then effective treatment of that illness should take priority. Before prescribing, the psychiatrist and patient should discuss the patient’s specific performance goals and how to measure them.

Any prescription for a performance-enhancing medication should be given in conjunction with nonpharmacologic approaches, including optimizing diet, exercise, and sleep. Therapy to address problem-solving techniques and skills to cope with stress may also be appropriate. The patient and psychiatrist should engage in regular follow-up to assess the efficacy of the medication, as well as its safety and tolerability. Finally, if a medication is not efficacious as a performance enhancer, then both the patient and psychiatrist should be open to re-evaluating the treatment plan, and when appropriate, stopping the medication.

Performance enhancement in sports (“doping”) dates back to Ancient Greece. This was an era when Olympic athletes would attempt to improve their physical performance by consuming magic potions, herbal medications, and even exotic meats such as sheep testicles—a delicacy high in testosterone. Advances in medical and pharmaceutical technologies have increased both the range of enhancement agents available and their efficacy, leading to the development of anti-doping agencies and routine screening for doping in athletics. This has led to the renouncement of titles, medals, and financial sponsorship of athletes found to have been using prohibited substances during competition.

While doping in elite athletes often forms the nidus of media attention, the pressure to compete and perform at, or even beyond, one’s potential extends into many facets of today’s achievementfocused society. In the face of these pressures, individuals are increasingly seeking medications to enhance their performance across numerous domains, including cognitive, athletic, and artistic endeavors. Medication classes used to enhance performance include stimulants, which increase attention, executive function, and energy; cholinesterase inhibitors, which may ameliorate age-related memory decline; and beta-blockers, which decrease physiologic symptoms of anxiety and have been demonstrated to be beneficial for musical performance.¹ Fifty-three percent of college athletes report using prescription medications to enhance athletic performance,² and most college students who take stimulants without a prescription use them to study (84%) or stay awake (51%).³

Pharmacologic performance enhancement is the use of medications by healthy individuals to improve function in the absence of mental illness. Psychiatrists are increasingly finding themselves in the controversial position of “gatekeeper” of these medications for enhancement purposes. In this article we:

• outline arguments that support the use of psychopharmacology for performance enhancement, as well as some serious concerns with this practice
• discuss special considerations for pediatric populations and the risk of malpractice when prescribing for performance enhancement
• offer practice guidelines for approaching requests for psychopharmacologic performance enhancement.

Performance enhancement: The wave of the future?

The ethical principle that supports providing medication for performance enhancement is beneficence, the promotion of the patient’s well-being. In other words, it is a physician’s duty to help his or her patient in need. Individuals seeking performance enhancement typically present with suffering, and the principle of beneficence would call upon the psychiatrist to help ameliorate that suffering. Furthermore, patients who seek performance enhancement may present with impairing “subsyndromal” psychiatric symptoms (for example, low-grade attentional difficulty that occurs only in one setting), which, even if they do not rise to the threshold of a DSM diagnosis, may improve with psychiatric medications.

Using medical knowledge and skills beyond the traditional physician duty to diagnose and treat medical conditions is not unprecedented (eg, when surgeons perform cosmetic enhancement). Might elective enhancement of cognition and psychological performance through the judicious use of medication be part of the future of psychiatry? If cognitive and emotional enhancement becomes a more widely accepted standard of care, might this increase both individual and societal innovation and productivity?

Dilemma: Cautions against performance enhancement

One of the major cautions against prescribing psychotropics for the purpose of performance enhancement is the lack of clearly supported efficacy. Psychiatric medications generally are studied in individuals who meet criteria for mental illness, and they are FDA-approved for use in ill persons. It may be erroneous to extrapolate that a medication that improves symptoms in a patient with an illness would achieve the same target effect in a healthy individual. For example, data on whether stimulants provide neurocognitive enhancement in healthy individuals without attention-deficit/hyperactivity disorder is mixed, and these agents may even promote risky behavior in healthy controls.⁴ Furthermore, dopamine agonism may compress cognitive performance in both directions,⁵ as it has been observed that methylphenidate improves executive function in healthy controls, but is less beneficial for those with strong executive function at baseline.⁶

In the face of unclear benefit, it is particularly important to consider the risk of medications used for performance enhancement. Pharmacologic performance enhancement in individuals without psychopathology can be considered an “elective” intervention, for which individuals typically tolerate less risk. Physical risks, including medication-related adverse effects, must be considered, particularly in settings where there may be temptation to use more than prescribed, or to divert medication to others who may use it without medical monitoring. In addition to physical harm, there may be psychological harm associated with prescribing performance enhancers, such as pathologizing variants of “normal,” diminishing one’s sense of self-efficacy, or decreasing one’s ability to bear failure.

Continue to: Finally, there are ethical quandaries

Finally, there are ethical quandaries regarding using medications for performance enhancement. Widespread adoption of pharmacologic performance enhancement may lead to implicit coercion for all individuals to enhance their abilities. As a greater proportion of society receives pharmacologic enhancement, society as a whole faces stronger pressures to seek pharmacologic enhancement, ultimately constricting an individual’s freedom of choice to enhance.⁶ In this setting, distributive justice would become a consideration, because insurance companies are unlikely to reimburse for medications used for enhancement,⁷ which would give an advantage to individuals with higher socioeconomic status. Research shows that children from higher socioeconomic communities and from states with higher academic standards are more likely to use stimulants.⁸

Areas of controversy

Pediatric populations. There are special considerations when prescribing performance-enhancing medications for children and adolescents. First, such prescribing may inhibit normal child development, shifting the focus away from the normative tasks of social and emotional development that occur through leisure and creativity, experimentation, and play to an emphasis on performance and outcomes-based achievement.⁹ Second, during childhood and adolescence, one develops a sense of his or her identity, morals, and values. Taking a medication during childhood to enhance performance may inhibit the process of learning to tolerate failure, become aware of one’s weaknesses, and value effort in addition to outcome.

Malpractice risk. Practicing medicine beyond the scope of one’s expertise is unethical and unlawful. In the past 30 years, medical malpractice has become one of the most difficult health care issues in the U.S.¹⁰ In addition to billions of dollars in legal fees and court costs, medical malpractice premiums in the U.S. total more than $5 billion annually,¹¹ and “defensive medicine”— procedures performed to protect against litigation—is estimated to cost more than $14 billion a year.¹²

When considering performance-enhancing treatment, it is the physician’s duty to conduct a diagnostic assessment, including noting target symptoms that are interfering with the patient’s function, and to tailor such treatment toward measurable goals and outcomes. Aside from medication, this could include a therapeutic approach to improving performance that might include cognitive-behavioral therapy and promotion of a healthy diet and exercise.

Treatment rises to the level of malpractice when there is a dereliction of duty that directly leads to damages.¹³ Part of a physician’s duty is to educate patients about the pros and cons of different treatment options. For performance-enhancing medications, the risks of addiction and dependence are adverse effects that require discussion. And for a pediatric patient, this would require the guardian’s engagement and understanding.

Continue to: What to do if you decide to prescribe

Inevitably, the decision to prescribe psychotropic medications for performance enhancement is a physician-specific one. Certainly, psychiatrists should not feel obligated to prescribe performance enhancers. Given our current state of pharmacology, it is unclear whether medications would be helpful in the absence of psychopathology. When deciding whether to prescribe for performance enhancement in the absence of psychopathology, we suggest first carefully considering how to maintain the ethical value of nonmaleficence by weighing both the potential physical and psychologic harms of prescribing as well as the legal risks and rules of applicable sport governing bodies.

For a psychiatrist who chooses to prescribe for performance enhancement, we recommend conducting a thorough psychiatric assessment to determine whether the patient has a treatable mental illness. If so, then effective treatment of that illness should take priority. Before prescribing, the psychiatrist and patient should discuss the patient’s specific performance goals and how to measure them.

Any prescription for a performance-enhancing medication should be given in conjunction with nonpharmacologic approaches, including optimizing diet, exercise, and sleep. Therapy to address problem-solving techniques and skills to cope with stress may also be appropriate. The patient and psychiatrist should engage in regular follow-up to assess the efficacy of the medication, as well as its safety and tolerability. Finally, if a medication is not efficacious as a performance enhancer, then both the patient and psychiatrist should be open to re-evaluating the treatment plan, and when appropriate, stopping the medication.

Performance enhancement in sports (“doping”) dates back to Ancient Greece. This was an era when Olympic athletes would attempt to improve their physical performance by consuming magic potions, herbal medications, and even exotic meats such as sheep testicles—a delicacy high in testosterone. Advances in medical and pharmaceutical technologies have increased both the range of enhancement agents available and their efficacy, leading to the development of anti-doping agencies and routine screening for doping in athletics. This has led to the renouncement of titles, medals, and financial sponsorship of athletes found to have been using prohibited substances during competition.

While doping in elite athletes often forms the nidus of media attention, the pressure to compete and perform at, or even beyond, one’s potential extends into many facets of today’s achievementfocused society. In the face of these pressures, individuals are increasingly seeking medications to enhance their performance across numerous domains, including cognitive, athletic, and artistic endeavors. Medication classes used to enhance performance include stimulants, which increase attention, executive function, and energy; cholinesterase inhibitors, which may ameliorate age-related memory decline; and beta-blockers, which decrease physiologic symptoms of anxiety and have been demonstrated to be beneficial for musical performance.¹ Fifty-three percent of college athletes report using prescription medications to enhance athletic performance,² and most college students who take stimulants without a prescription use them to study (84%) or stay awake (51%).³

Pharmacologic performance enhancement is the use of medications by healthy individuals to improve function in the absence of mental illness. Psychiatrists are increasingly finding themselves in the controversial position of “gatekeeper” of these medications for enhancement purposes. In this article we:

• outline arguments that support the use of psychopharmacology for performance enhancement, as well as some serious concerns with this practice
• discuss special considerations for pediatric populations and the risk of malpractice when prescribing for performance enhancement
• offer practice guidelines for approaching requests for psychopharmacologic performance enhancement.

Performance enhancement: The wave of the future?

The ethical principle that supports providing medication for performance enhancement is beneficence, the promotion of the patient’s well-being. In other words, it is a physician’s duty to help his or her patient in need. Individuals seeking performance enhancement typically present with suffering, and the principle of beneficence would call upon the psychiatrist to help ameliorate that suffering. Furthermore, patients who seek performance enhancement may present with impairing “subsyndromal” psychiatric symptoms (for example, low-grade attentional difficulty that occurs only in one setting), which, even if they do not rise to the threshold of a DSM diagnosis, may improve with psychiatric medications.

Using medical knowledge and skills beyond the traditional physician duty to diagnose and treat medical conditions is not unprecedented (eg, when surgeons perform cosmetic enhancement). Might elective enhancement of cognition and psychological performance through the judicious use of medication be part of the future of psychiatry? If cognitive and emotional enhancement becomes a more widely accepted standard of care, might this increase both individual and societal innovation and productivity?

Dilemma: Cautions against performance enhancement

One of the major cautions against prescribing psychotropics for the purpose of performance enhancement is the lack of clearly supported efficacy. Psychiatric medications generally are studied in individuals who meet criteria for mental illness, and they are FDA-approved for use in ill persons. It may be erroneous to extrapolate that a medication that improves symptoms in a patient with an illness would achieve the same target effect in a healthy individual. For example, data on whether stimulants provide neurocognitive enhancement in healthy individuals without attention-deficit/hyperactivity disorder is mixed, and these agents may even promote risky behavior in healthy controls.⁴ Furthermore, dopamine agonism may compress cognitive performance in both directions,⁵ as it has been observed that methylphenidate improves executive function in healthy controls, but is less beneficial for those with strong executive function at baseline.⁶

In the face of unclear benefit, it is particularly important to consider the risk of medications used for performance enhancement. Pharmacologic performance enhancement in individuals without psychopathology can be considered an “elective” intervention, for which individuals typically tolerate less risk. Physical risks, including medication-related adverse effects, must be considered, particularly in settings where there may be temptation to use more than prescribed, or to divert medication to others who may use it without medical monitoring. In addition to physical harm, there may be psychological harm associated with prescribing performance enhancers, such as pathologizing variants of “normal,” diminishing one’s sense of self-efficacy, or decreasing one’s ability to bear failure.

Continue to: Finally, there are ethical quandaries

Finally, there are ethical quandaries regarding using medications for performance enhancement. Widespread adoption of pharmacologic performance enhancement may lead to implicit coercion for all individuals to enhance their abilities. As a greater proportion of society receives pharmacologic enhancement, society as a whole faces stronger pressures to seek pharmacologic enhancement, ultimately constricting an individual’s freedom of choice to enhance.⁶ In this setting, distributive justice would become a consideration, because insurance companies are unlikely to reimburse for medications used for enhancement,⁷ which would give an advantage to individuals with higher socioeconomic status. Research shows that children from higher socioeconomic communities and from states with higher academic standards are more likely to use stimulants.⁸

Areas of controversy

Pediatric populations. There are special considerations when prescribing performance-enhancing medications for children and adolescents. First, such prescribing may inhibit normal child development, shifting the focus away from the normative tasks of social and emotional development that occur through leisure and creativity, experimentation, and play to an emphasis on performance and outcomes-based achievement.⁹ Second, during childhood and adolescence, one develops a sense of his or her identity, morals, and values. Taking a medication during childhood to enhance performance may inhibit the process of learning to tolerate failure, become aware of one’s weaknesses, and value effort in addition to outcome.

Malpractice risk. Practicing medicine beyond the scope of one’s expertise is unethical and unlawful. In the past 30 years, medical malpractice has become one of the most difficult health care issues in the U.S.¹⁰ In addition to billions of dollars in legal fees and court costs, medical malpractice premiums in the U.S. total more than $5 billion annually,¹¹ and “defensive medicine”— procedures performed to protect against litigation—is estimated to cost more than $14 billion a year.¹²

When considering performance-enhancing treatment, it is the physician’s duty to conduct a diagnostic assessment, including noting target symptoms that are interfering with the patient’s function, and to tailor such treatment toward measurable goals and outcomes. Aside from medication, this could include a therapeutic approach to improving performance that might include cognitive-behavioral therapy and promotion of a healthy diet and exercise.

Treatment rises to the level of malpractice when there is a dereliction of duty that directly leads to damages.¹³ Part of a physician’s duty is to educate patients about the pros and cons of different treatment options. For performance-enhancing medications, the risks of addiction and dependence are adverse effects that require discussion. And for a pediatric patient, this would require the guardian’s engagement and understanding.

Continue to: What to do if you decide to prescribe

Inevitably, the decision to prescribe psychotropic medications for performance enhancement is a physician-specific one. Certainly, psychiatrists should not feel obligated to prescribe performance enhancers. Given our current state of pharmacology, it is unclear whether medications would be helpful in the absence of psychopathology. When deciding whether to prescribe for performance enhancement in the absence of psychopathology, we suggest first carefully considering how to maintain the ethical value of nonmaleficence by weighing both the potential physical and psychologic harms of prescribing as well as the legal risks and rules of applicable sport governing bodies.

For a psychiatrist who chooses to prescribe for performance enhancement, we recommend conducting a thorough psychiatric assessment to determine whether the patient has a treatable mental illness. If so, then effective treatment of that illness should take priority. Before prescribing, the psychiatrist and patient should discuss the patient’s specific performance goals and how to measure them.

Any prescription for a performance-enhancing medication should be given in conjunction with nonpharmacologic approaches, including optimizing diet, exercise, and sleep. Therapy to address problem-solving techniques and skills to cope with stress may also be appropriate. The patient and psychiatrist should engage in regular follow-up to assess the efficacy of the medication, as well as its safety and tolerability. Finally, if a medication is not efficacious as a performance enhancer, then both the patient and psychiatrist should be open to re-evaluating the treatment plan, and when appropriate, stopping the medication.