I recently had the privilege of treating a family who spoke my first language, Hindi. My patient, Ms. M, was 16 years old and struggling to adjust to her new life in the United States, having recently come from India. America’s schooling, culture, and “open society” was a contrast to her life in a semi-rural town, especially her close-knit family structure in which her parents and siblings are everything. Due to their cultural beliefs and religious faith in Islam, both Ms. M and her father were initially resistant to begin treatment for her depression and anxiety. “Let’s give it a trial” was the attitude I finally got from the father. But to me, there was a clear discordance in the communication among the family members in addition to the primary mental illness that led them to come for treatment. I was attracted to work with this family because I had a reasonable understanding of their faith, their culture, and their family system, and I have an inclination toward spirituality. Even though I recognized this family’s social isolation, I wondered why they were still in a state of unrest, given their deep commitment to their faith.

Ms. M was isolating herself at home, in an environment that wasn’t supportive of talking about her concerns. These included being bullied for being “different,” for how she dressed, and for having home-cooked traditional meals for lunch, and being unable to socialize with most of her male peers, except for those from her same community. This led her to dream of returning to India.

The family did not have a social life. Ms. M told me, “I wanted to socialize, but I cannot because of my faith and religion.” So she chose to wear attire to identify with her mother and her culture of origin. She also did this to hide her emotional pain from enduring trauma related to bullying at her school. It was a challenge to understand how faith, resilience, and trauma were intermingled in Ms. M and her family.

I saw Ms. M and her family for 12 one-hour family psychotherapy sessions. The initial session unfolded uneasily. It was a challenge to build rapport and help them understand how family therapy works. Circular inquiries to each family member, specifically to get the mother’s point of view, brought mourning, shame, and guilt to this family. The importance of marriage, education, and immigration were processed in reference to their culture and their incomplete acculturation to life in the United States.

I wondered if there were other families with different cultural backgrounds who struggled with similar conflicts. I also wondered if those families understood the value of family therapy or had ever experienced this therapeutic process.

The 3 key signs that made me believe that this family was making progress through our work together included:

• They complied with treatment; the family never missed a session.
• The parents acknowledged that their daughter was doing better.
• The mother brought me a dinner as a gesture of gratitude in our last session. This is a particularly meaningful gesture on the part of people with their cultural background.

I clearly remember our first meeting, when Ms. M asked me disapprovingly about family therapy, “Why do we need to come here? Can’t we do it at home?” The question itself gave me the answer, for our goal for family therapy was to get her to function better at home and school. Although we ended our work together after 12 sessions, I hope this family continues to participate in therapy, to resolve the difficulties they are now aware of as a result of our family work.

I recently had the privilege of treating a family who spoke my first language, Hindi. My patient, Ms. M, was 16 years old and struggling to adjust to her new life in the United States, having recently come from India. America’s schooling, culture, and “open society” was a contrast to her life in a semi-rural town, especially her close-knit family structure in which her parents and siblings are everything. Due to their cultural beliefs and religious faith in Islam, both Ms. M and her father were initially resistant to begin treatment for her depression and anxiety. “Let’s give it a trial” was the attitude I finally got from the father. But to me, there was a clear discordance in the communication among the family members in addition to the primary mental illness that led them to come for treatment. I was attracted to work with this family because I had a reasonable understanding of their faith, their culture, and their family system, and I have an inclination toward spirituality. Even though I recognized this family’s social isolation, I wondered why they were still in a state of unrest, given their deep commitment to their faith.

Ms. M was isolating herself at home, in an environment that wasn’t supportive of talking about her concerns. These included being bullied for being “different,” for how she dressed, and for having home-cooked traditional meals for lunch, and being unable to socialize with most of her male peers, except for those from her same community. This led her to dream of returning to India.

The family did not have a social life. Ms. M told me, “I wanted to socialize, but I cannot because of my faith and religion.” So she chose to wear attire to identify with her mother and her culture of origin. She also did this to hide her emotional pain from enduring trauma related to bullying at her school. It was a challenge to understand how faith, resilience, and trauma were intermingled in Ms. M and her family.

I saw Ms. M and her family for 12 one-hour family psychotherapy sessions. The initial session unfolded uneasily. It was a challenge to build rapport and help them understand how family therapy works. Circular inquiries to each family member, specifically to get the mother’s point of view, brought mourning, shame, and guilt to this family. The importance of marriage, education, and immigration were processed in reference to their culture and their incomplete acculturation to life in the United States.

I wondered if there were other families with different cultural backgrounds who struggled with similar conflicts. I also wondered if those families understood the value of family therapy or had ever experienced this therapeutic process.

The 3 key signs that made me believe that this family was making progress through our work together included:

• They complied with treatment; the family never missed a session.
• The parents acknowledged that their daughter was doing better.
• The mother brought me a dinner as a gesture of gratitude in our last session. This is a particularly meaningful gesture on the part of people with their cultural background.

I clearly remember our first meeting, when Ms. M asked me disapprovingly about family therapy, “Why do we need to come here? Can’t we do it at home?” The question itself gave me the answer, for our goal for family therapy was to get her to function better at home and school. Although we ended our work together after 12 sessions, I hope this family continues to participate in therapy, to resolve the difficulties they are now aware of as a result of our family work.

I recently had the privilege of treating a family who spoke my first language, Hindi. My patient, Ms. M, was 16 years old and struggling to adjust to her new life in the United States, having recently come from India. America’s schooling, culture, and “open society” was a contrast to her life in a semi-rural town, especially her close-knit family structure in which her parents and siblings are everything. Due to their cultural beliefs and religious faith in Islam, both Ms. M and her father were initially resistant to begin treatment for her depression and anxiety. “Let’s give it a trial” was the attitude I finally got from the father. But to me, there was a clear discordance in the communication among the family members in addition to the primary mental illness that led them to come for treatment. I was attracted to work with this family because I had a reasonable understanding of their faith, their culture, and their family system, and I have an inclination toward spirituality. Even though I recognized this family’s social isolation, I wondered why they were still in a state of unrest, given their deep commitment to their faith.

Ms. M was isolating herself at home, in an environment that wasn’t supportive of talking about her concerns. These included being bullied for being “different,” for how she dressed, and for having home-cooked traditional meals for lunch, and being unable to socialize with most of her male peers, except for those from her same community. This led her to dream of returning to India.

The family did not have a social life. Ms. M told me, “I wanted to socialize, but I cannot because of my faith and religion.” So she chose to wear attire to identify with her mother and her culture of origin. She also did this to hide her emotional pain from enduring trauma related to bullying at her school. It was a challenge to understand how faith, resilience, and trauma were intermingled in Ms. M and her family.

I saw Ms. M and her family for 12 one-hour family psychotherapy sessions. The initial session unfolded uneasily. It was a challenge to build rapport and help them understand how family therapy works. Circular inquiries to each family member, specifically to get the mother’s point of view, brought mourning, shame, and guilt to this family. The importance of marriage, education, and immigration were processed in reference to their culture and their incomplete acculturation to life in the United States.

I wondered if there were other families with different cultural backgrounds who struggled with similar conflicts. I also wondered if those families understood the value of family therapy or had ever experienced this therapeutic process.

The 3 key signs that made me believe that this family was making progress through our work together included:

• They complied with treatment; the family never missed a session.
• The parents acknowledged that their daughter was doing better.
• The mother brought me a dinner as a gesture of gratitude in our last session. This is a particularly meaningful gesture on the part of people with their cultural background.

I clearly remember our first meeting, when Ms. M asked me disapprovingly about family therapy, “Why do we need to come here? Can’t we do it at home?” The question itself gave me the answer, for our goal for family therapy was to get her to function better at home and school. Although we ended our work together after 12 sessions, I hope this family continues to participate in therapy, to resolve the difficulties they are now aware of as a result of our family work.

As psychiatrists treating an aging population, we frequently face the daunting challenges of managing medically complex and behaviorally unstable patients whose fragile condition tests the brightest among us. As our population enters late life, not only are physicians confronted with aging patients whose bodies have decreased renal and hepatic function, but we also face the challenges of the aging brain, severed neuronal networks, and neurotransmitter diminution. These physiological changes can alter treatment response, increase the frequency of adverse effects, and increase the likelihood of emergence of behavioral and psychological symptoms.

During the past decade, the number of people reaching age 65 has dramatically increased. As life expectancy improves, the “oldest old”—those age 85 and older—are the fastest-growing segment of the population. The prevalence of cognitive impairment, including mild cognitive impairment and dementia, in this cohort is >40%.¹ Roughly 90% of patients with dementia will develop clinically significant behavioral problems at some point in the course of their illness.²

Behavioral and psychological symptoms of dementia (BPSD) have a tremendous impact on the quality of life for both patients and their caregivers. We are experts in understanding these behaviors and crafting nonpharmacologic treatment plans to manage them. Understanding the context in which behaviors emerge allows us to modify the environment, communication strategies, and other potential triggers, in turn reducing the need for pharmacologic intervention.

However, when nonpharmacologic interventions have been exhausted, what are the options? Antipsychotics have been one of the approaches used to address the challenges of behavioral disturbances and psychosis occurring in dementia. Unfortunately, there is conflicting evidence regarding the risks and benefits associated with the use of antipsychotics in this population. In this article, we provide a roadmap for the judicious use of antipsychotics for patients with dementia.

Weighing the risks and benefits of antipsychotics

Until better treatment options become available, second-generation antipsychotics (SGAs) continue to have an important but limited role in the treatment of behavioral disturbances in dementia. Although safety risks exist, they can be minimized through the careful selection of appropriate patients for treatment, close monitoring, and effective communication with patients and caregivers before and during treatment.

Several studies examining the efficacy of antipsychotics in the treatment of BPSD have demonstrated an increased risk of cerebrovascular events, including stroke and death due to any cause.³ This evidence prompted the FDA to issue a “black-box” warning in 2005 to highlight the increased risk of mortality for patients with dementia who are treated with SGAs.⁴ Both first-generation antipsychotics (FGAs) and SGAs have been associated with higher rates of mortality than most other psychotropic classes, except anticonvulsants. This increased mortality risk has been shown to persist for at least 6 to 12 months.^5,6 FGAs appear to be associated with a greater mortality risk compared with SGAs. As a result, if antipsychotic treatment is necessary, the use of FGAs in this population is not recommended.

The potential mechanisms leading to stroke and death remain unclear. They could include orthostatic hypotension, anticholinergic adverse effects, QT prolongation, platelet aggregation effects, and venous thromboembolism. The presence of cardiovascular and vascular risk factors, electrolyte imbalances, cardiac arrhythmias, and concomitant use of medications that prolong the QTc interval may confer additional risks.

Continued to: Although the use of antipsychotics for patients with dementia...

Although the use of antipsychotics for patients with dementia may increase the risk of mortality, the absolute increased risk to a given individual, at least with short-term treatment, is likely small. The risk may also vary depending on the choice of SGA. Patients who were treated with quetiapine had a slightly lower risk of death than those who were treated risperidone.⁵ Death rates among patients prescribed aripiprazole, olanzapine, and ziprasidone were similar to the death rates of patients who were treated with risperidone. Compared with patients who were treated with risperidone, patients who were treated with the FGA haloperidol were twice as likely to die during a subsequent 6-month observation period. The largest number of deaths occurred during the first 40 days of treatment.⁵

While this increased risk of mortality is an important factor to discuss with patients and caregivers when deciding whether to initiate antipsychotic treatment, it is also important to put it into perspective. For example, the risk of suddenly dying from a stroke or heart attack for a person with dementia who is not taking an antipsychotic is approximately 2%. When an individual is started on one of these agents, that risk increases to approximately 4%. While the mortality risk is doubled, it remains relatively small.⁴ When faced with verbal or physical assaults, hostility, paranoid ideations, or other psychotic symptoms, many families feel that this relatively low risk does not outweigh the potential benefits of reducing caregiver and patient distress. If nonpharmacologic and/or other pharmacologic interventions have failed, the treatment has reached a point of no good alternatives and therapy should then focus on minimizing risk.

Informed consent is essential. A discussion of risks and benefits with the patient, family, or other decision-makers should focus on the risk of stroke, potential metabolic effects, and mortality, as well as potential worsening of cognitive decline associated with antipsychotic treatment. This should be weighed together with the evidence that suggests psychosis and agitation are associated with earlier nursing home admission and death.^7,8 Families should be given ample time and opportunity to ask questions. Alternatives to immediate initiation of antipsychotics should be thoroughly reviewed.

Despite the above-noted risks, expert consensus suggests that the use of antipsychotics in the treatment of individuals with dementia can be appropriate, particularly in individuals with dangerous agitation or psychosis.⁹ These agents can minimize the risk of violence, reduce patient distress, improve the patient’s quality of life, and reduce caregiver burden. In clinical trials, the benefits of antipsychotics have been modest. Nevertheless, evidence has shown that these agents can reduce psychosis, agitation, aggression, hostility, and suspiciousness, which makes them a valid option when other interventions have proven insufficient.

Target specific symptoms

Despite this article’s focus on the appropriate use of antipsychotics for patients with BPSD, it is important to emphasize that the first-line approach to the management of BPSD in this population should always be a person-centered, psychosocial, multidisciplinary, nonpharmacologic approach that focuses on identifying triggers and treating potentially modifiable contributors to behavioral symptoms. Table 1¹⁰ outlines common underlying causes of BPSD in dementia that should be assessed before prescribing an antipsychotic.

Continued to: Alternative psychopharmacologic treatments...

Alternative psychopharmacologic treatments based on a psychobehavioral metaphor should also be considered (Table 2¹¹). This approach matches the dominant target symptoms to the most relevant medication class.¹¹ For example, in the case of a verbally and physically agitated patient who is also irritable, negative, socially withdrawn, and appears dysphoric, we might first undertake a trial of an antidepressant. Conversely, if the patient shows agitation in the context of increased motor activity, loud and rapid speech, and affective lability, we might consider the use of a mood stabilizer. Pharmacologic treatment should be aimed at the modification of clearly identified and documented target behaviors.

• severe agitation and aggression associated with risk of harm
• delusions and hallucinations
• comorbid preexisting mental health conditions (eg, bipolar disorder, schizophrenia, treatment-resistant depression, etc.).

Symptoms that do not usually respond to an antipsychotic include wandering, social withdrawal, shouting, pacing, touching, cognitive defects, and incontinence.¹² These symptoms may respond to interventions such as changes to the environment.

Continued to: Choosing an antipsychotic

Choosing an antipsychotic

Once you have identified that an antipsychotic is truly indicated, the choice of an agent will focus on patient-related factors. Considerations such as frailty, comorbid medical conditions including diabetes, history of falls, hepatic insufficiency, cardiac arrhythmias, and cerebrovascular risk factors, should all be analyzed prior to initiating an antipsychotic. The presence of these conditions will increase the likelihood that adverse effects may occur. It will also guide the dose trajectory and the target dose for discontinuation. Antipsychotics differ with respect to their efficacy and adverse effect profile. For practical purposes, adverse effects typically guide the selection of these agents when used for patients with dementia.

Continued to: Gradual structural changes occur...

Gradual structural changes occur in the dopaminergic system with age and increase the propensity for antipsychotic adverse effects. The number of dopaminergic neurons and D2 receptors decreases approximately 10% per decade. In order to avoid the development of adverse effects related to extrapyramidal symptoms, approximately 20% of receptors need to be free. FGAs tend to block approximately 90% of D2 receptors, whereas SGAs block less than 70% to 80% and dissociate more rapidly from D2 receptors.¹³ FGAs should therefore be avoided, as they have been associated with numerous adverse effects, including parkinsonism, tardive dyskinesia, akathisia, sedation, peripheral and central anticholinergic effects, postural hypotension, cardiac conduction defects, and falls. As noted above, they have been linked to a greater risk of mortality (Figure¹⁴ ).

Dosing considerations

When beginning treatment with an antipsychotic, the starting dose should be as low as possible. This is particularly important for patients who are older, frail, cognitively impaired, or who carry a specific, significant risk that the antipsychotic may increase, such as a risk for falling. The starting dose can be divided or scheduled according to the behavior. For example, a lunchtime dose may be appropriate for patients exhibiting increased agitation towards the end of the day (“sundowning”). A good rule of thumb is to administer a dose approximately 2 hours before the behaviors typically occur. While there is no formal evidence from clinical trials to support this type of dosing schedule, clinical experience has shown it to have merit.

Dose increments should be modest and, in a nonemergent setting, may be adjusted at weekly intervals depending on response. Prior to starting a treatment trial, it is advisable to estimate what will constitute a worthwhile clinical response, the duration of treatment, and the maximum dose. Avoid high doses or prolonged use of antipsychotics that have not significantly improved the target behavior.

When the decision to use a SGA is made, choosing the initial starting dose is challenging given that none of these medications has an indication for use in this population. We propose doses that have been used in completed randomized trials that reflect the best information available about the dose likely to maximize benefit and minimize risk. On the basis of those trials, reasonable starting doses would be^15-22:

• quetiapine 25 to 50 mg/d
• risperidone 0.5 to 1 mg/d
• aripiprazole 2 to 10 mg/d
• olanzapine 2.5 to 5 mg/d
• ziprasidone 20 mg/d

Continued to: The highest doses tested...

The highest doses tested for each of these compounds in randomized clinical trials for this population were: risperidone 2 mg/d, olanzapine 10 mg/d, and aripiprazole 15 mg/d. A wide variety of maximum doses of quetiapine were studied in clinical trials, with a top dose of 200 mg being most common. It is worth noting that doses higher than these have been used for other indications.^15-22

Quetiapine. One of the most commonly prescribed antipsychotics for the treatment of BPSD in individuals with memory disorders is quetiapine. The reasons for this preference include a low risk of extrapyramidal adverse effects, flexibility of dosing, ability to use lower dosages, and evidence of the lower risk of mortality when compared with other second-generation agents.^5,15 If an antipsychotic is indicated, quetiapine should be considered as a first-line antipsychotic therapy. Quetiapine has well-established effects on mood, anxiety, and sleep, all of which can be disrupted in dementia and can act as drivers for agitation.^5,15 Starting quetiapine may mitigate the need for separate agents to treat insomnia, loss of appetite, or anxiety, although it is not FDA-indicated for these comorbid conditions. Quetiapine is also less likely to exacerbate motor symptoms compared with other SGAs but has the potential to increase the risk of falls, and orthostasis, and carries a considerable anticholinergic burden.^5,15

Risperidone has been shown to provide modest improvements in some people exhibiting symptoms of aggression, agitation, and psychosis.^5,15 There is no evidence that risperidone is any more effective than other SGAs, but it has been tested on more geriatric patients than other SGAs. The fact that it is also available in an orally disintegrating tablet makes it a practical treatment in certain populations of patients, such as those who have difficulty swallowing. Risperidone carries the highest extrapyramidal symptom burden among the SGAs due to its potent D2 receptor binding. ^5,15

Aripiprazole. There have been several studies of aripiprazole for the treatment of psychosis and agitation in Alzheimer’s dementia.¹⁵ This medication showed modest effect and was generally well tolerated. Aripiprazole appears to have less associated weight gain, which may be pertinent for some patients. It also appears to be less sedating than many of the other SGAs. However, some patients may experience activation or insomnia with this agent, particularly with doses <15 mg/d. This activating effect may be beneficial for treating comorbid depressive symptoms, although lower doses could theoretically worsen psychosis due to the activating effects.

Aripiprazole has also been studied in Parkinson’s disease. While some patients had favorable responses with improvement in psychosis and behavioral disturbances, this medication was also associated with worsening of motor symptoms. Certain individuals also experienced a worsening of their psychosis.²³ For this reason, it is unlikely to be a useful agent for patients displaying evidence of parkinsonism, Parkinson’s dementia, or dementia with Lewy bodies.

Olanzapine. Several studies have shown that low-dose olanzapine has been modestly effective in decreasing agitation and aggression in patients suffering from Alzheimer’s and vascular dementias.²⁴ The medication is also available in an orally disintegrating form, which may be beneficial when treating individuals whose swallowing abilities are compromised. Olanzapine also has been associated with significant weight gain and metabolic syndrome.²⁴

Continued to: Ziprasidone

Ziprasidone. There are no specific studies of ziprasidone for geriatric patients and none for patients with dementia. However, case reports have suggested both oral and injectable forms of the medication may be well tolerated and have some benefit in treating agitation in this population.²⁵ Based on evidence from younger populations, ziprasidone is less likely to be associated with weight gain or orthostatic hypotension. Medication has been associated with QTc prolongation and should be used with caution and monitored with an ECG.

The initial dosing and potential adverse effects of quetiapine, risperidone, aripiprazole, olanzapine, and ziprasidone are highlighted in Table 3.¹⁰

Other SGAs. Newer antipsychotics have recently become available and may serve as additional tools for managing BPSD in the future. Unfortunately, there are currently no available studies regarding their efficacy in the treatment of agitation and psychosis in dementia. One notable exception is pimavaserin, a serotonin 2A receptor inverse agonist. This medication has recently been FDA-approved for the treatment of Parkinson’s disease psychosis. The medication was extensively studied in older patients. It appeared to be effective in reducing delusions and hallucinations while not impairing motor function or causing sedation or hypotension.²³ Additional studies are currently ongoing for the treatment of Alzheimer’s dementia psychosis.

Monitor treatment, consider discontinuation

American Psychiatric Association guidelines on the use of antipsychotics to treat agitation or psychosis in patients with dementia currently recommend that clinicians use a quantitative measure to track symptoms and response to treatment.²⁶ These measures may be formal, such as an overall assessment of symptom severity on a Likert scale, or as simple as monitoring the changes in the frequency of periods of agitation.

After starting an antipsychotic, a follow-up appointment should typically take place within 1 month. If the patient is at high risk for developing adverse effects, or if the symptoms are severe, a follow-up appointment for monitoring the response to treatment and potential adverse effects should occur within 1 week. At a minimum, expert consensus suggests follow-up visits should occur every 3 months.

If there is no clinical response after 4 weeks of adequate dosing of an anti­psychotic, the medication should be tapered and withdrawn. Switching to an alternative agent may be appropriate.

Many patients will have only partial remission of target symptoms. Therefore, increasing the dose or switching to an alternative agent may be necessary. Concurrent use of multiple antipsychotic agents should be avoided.

Continued to: Maintenance treatment may be appropriate

How to approach discontinuation

Behavioral and psychological symptoms of dementia are frequently temporary. If the patient has been stable, gradual dose reduction and eventual discontinuation of antipsychotics should be attempted every 3 months. Studies have reported that most patients who were taken off antipsychotics for treating BPSD showed no worsening of behavioral symptoms.²⁷

Discontinuation of antipsychotics should be done gradually by reducing the dose by 50% every 2 weeks, and then stopping after 2 weeks on the minimum dose, with monitoring for recurrence of target symptoms or emergence of new ones. The longer a medication has been prescribed, the slower the withdrawal occurs. Thus, the possibility of emerging symptoms related to drug withdrawal will lessen.

A roadmap for judicious prescribing

When underlying treatable or reversible causes of BPSD in dementia have been ruled out or nonpharmacologic treatments have failed, a trial of an antipsychotic may be indicated. The choice of agent should focus on patient-related factors and on clearly identified target behaviors. Treatment should be started at a low dose and titrated cautiously to the lowest effective dose.

Behavioral and psychological symptoms of dementia are frequently temporary. Therefore, a gradual reduction and eventual withdrawal of antipsychotic medications should be attempted every 3 months. Studies indicate that most patients are able to tolerate elimination of antipsychotic medications with no worsening of behavioral symptoms.

Despite the limitations of treatment, SGAs remain a valid consideration when other interventions have proven insufficient. However, judicious use of these agents remains the cornerstone of therapy.

Bottom Line 

Until better treatment options become available, second-generation antipsychotics (SGAs) continue to have an important, albeit limited, role in the treatment of behavioral disturbances in dementia. Despite the limitations of treatment, SGAs remain a valid consideration when other interventions have proven insufficient. However, judicious use of these agents remains the cornerstone of therapy.

Related Resources

• Kales HC, Mulsant BH, Sajatovic MS. Prescribing antipsychotics in geriatric patients: Focus on dementia. Third of 3 parts. Current Psychiatry. 2017;16(12):24-30.
• Meeks TW, Jeste DV. Antipsychotics in dementia: Beyond ‘black-box’ warnings. Current Psychiatry. 2008;7(6):51-52, 55-58, 64-65.

Drug Brand Names

Aripiprazole • Abilify
Haloperidol • Haldol
Olanzapine • Zyprexa
Pimavanserin • Nuplazid
Risperidone • Risperdal
Quetiapine • Seroquel
Ziprasidone • Geodon

As psychiatrists treating an aging population, we frequently face the daunting challenges of managing medically complex and behaviorally unstable patients whose fragile condition tests the brightest among us. As our population enters late life, not only are physicians confronted with aging patients whose bodies have decreased renal and hepatic function, but we also face the challenges of the aging brain, severed neuronal networks, and neurotransmitter diminution. These physiological changes can alter treatment response, increase the frequency of adverse effects, and increase the likelihood of emergence of behavioral and psychological symptoms.

During the past decade, the number of people reaching age 65 has dramatically increased. As life expectancy improves, the “oldest old”—those age 85 and older—are the fastest-growing segment of the population. The prevalence of cognitive impairment, including mild cognitive impairment and dementia, in this cohort is >40%.¹ Roughly 90% of patients with dementia will develop clinically significant behavioral problems at some point in the course of their illness.²

Behavioral and psychological symptoms of dementia (BPSD) have a tremendous impact on the quality of life for both patients and their caregivers. We are experts in understanding these behaviors and crafting nonpharmacologic treatment plans to manage them. Understanding the context in which behaviors emerge allows us to modify the environment, communication strategies, and other potential triggers, in turn reducing the need for pharmacologic intervention.

However, when nonpharmacologic interventions have been exhausted, what are the options? Antipsychotics have been one of the approaches used to address the challenges of behavioral disturbances and psychosis occurring in dementia. Unfortunately, there is conflicting evidence regarding the risks and benefits associated with the use of antipsychotics in this population. In this article, we provide a roadmap for the judicious use of antipsychotics for patients with dementia.

Weighing the risks and benefits of antipsychotics

Until better treatment options become available, second-generation antipsychotics (SGAs) continue to have an important but limited role in the treatment of behavioral disturbances in dementia. Although safety risks exist, they can be minimized through the careful selection of appropriate patients for treatment, close monitoring, and effective communication with patients and caregivers before and during treatment.

Several studies examining the efficacy of antipsychotics in the treatment of BPSD have demonstrated an increased risk of cerebrovascular events, including stroke and death due to any cause.³ This evidence prompted the FDA to issue a “black-box” warning in 2005 to highlight the increased risk of mortality for patients with dementia who are treated with SGAs.⁴ Both first-generation antipsychotics (FGAs) and SGAs have been associated with higher rates of mortality than most other psychotropic classes, except anticonvulsants. This increased mortality risk has been shown to persist for at least 6 to 12 months.^5,6 FGAs appear to be associated with a greater mortality risk compared with SGAs. As a result, if antipsychotic treatment is necessary, the use of FGAs in this population is not recommended.

The potential mechanisms leading to stroke and death remain unclear. They could include orthostatic hypotension, anticholinergic adverse effects, QT prolongation, platelet aggregation effects, and venous thromboembolism. The presence of cardiovascular and vascular risk factors, electrolyte imbalances, cardiac arrhythmias, and concomitant use of medications that prolong the QTc interval may confer additional risks.

Continued to: Although the use of antipsychotics for patients with dementia...

Although the use of antipsychotics for patients with dementia may increase the risk of mortality, the absolute increased risk to a given individual, at least with short-term treatment, is likely small. The risk may also vary depending on the choice of SGA. Patients who were treated with quetiapine had a slightly lower risk of death than those who were treated risperidone.⁵ Death rates among patients prescribed aripiprazole, olanzapine, and ziprasidone were similar to the death rates of patients who were treated with risperidone. Compared with patients who were treated with risperidone, patients who were treated with the FGA haloperidol were twice as likely to die during a subsequent 6-month observation period. The largest number of deaths occurred during the first 40 days of treatment.⁵

While this increased risk of mortality is an important factor to discuss with patients and caregivers when deciding whether to initiate antipsychotic treatment, it is also important to put it into perspective. For example, the risk of suddenly dying from a stroke or heart attack for a person with dementia who is not taking an antipsychotic is approximately 2%. When an individual is started on one of these agents, that risk increases to approximately 4%. While the mortality risk is doubled, it remains relatively small.⁴ When faced with verbal or physical assaults, hostility, paranoid ideations, or other psychotic symptoms, many families feel that this relatively low risk does not outweigh the potential benefits of reducing caregiver and patient distress. If nonpharmacologic and/or other pharmacologic interventions have failed, the treatment has reached a point of no good alternatives and therapy should then focus on minimizing risk.

Informed consent is essential. A discussion of risks and benefits with the patient, family, or other decision-makers should focus on the risk of stroke, potential metabolic effects, and mortality, as well as potential worsening of cognitive decline associated with antipsychotic treatment. This should be weighed together with the evidence that suggests psychosis and agitation are associated with earlier nursing home admission and death.^7,8 Families should be given ample time and opportunity to ask questions. Alternatives to immediate initiation of antipsychotics should be thoroughly reviewed.

Despite the above-noted risks, expert consensus suggests that the use of antipsychotics in the treatment of individuals with dementia can be appropriate, particularly in individuals with dangerous agitation or psychosis.⁹ These agents can minimize the risk of violence, reduce patient distress, improve the patient’s quality of life, and reduce caregiver burden. In clinical trials, the benefits of antipsychotics have been modest. Nevertheless, evidence has shown that these agents can reduce psychosis, agitation, aggression, hostility, and suspiciousness, which makes them a valid option when other interventions have proven insufficient.

Target specific symptoms

Despite this article’s focus on the appropriate use of antipsychotics for patients with BPSD, it is important to emphasize that the first-line approach to the management of BPSD in this population should always be a person-centered, psychosocial, multidisciplinary, nonpharmacologic approach that focuses on identifying triggers and treating potentially modifiable contributors to behavioral symptoms. Table 1¹⁰ outlines common underlying causes of BPSD in dementia that should be assessed before prescribing an antipsychotic.

Continued to: Alternative psychopharmacologic treatments...

Alternative psychopharmacologic treatments based on a psychobehavioral metaphor should also be considered (Table 2¹¹). This approach matches the dominant target symptoms to the most relevant medication class.¹¹ For example, in the case of a verbally and physically agitated patient who is also irritable, negative, socially withdrawn, and appears dysphoric, we might first undertake a trial of an antidepressant. Conversely, if the patient shows agitation in the context of increased motor activity, loud and rapid speech, and affective lability, we might consider the use of a mood stabilizer. Pharmacologic treatment should be aimed at the modification of clearly identified and documented target behaviors.

• severe agitation and aggression associated with risk of harm
• delusions and hallucinations
• comorbid preexisting mental health conditions (eg, bipolar disorder, schizophrenia, treatment-resistant depression, etc.).

Symptoms that do not usually respond to an antipsychotic include wandering, social withdrawal, shouting, pacing, touching, cognitive defects, and incontinence.¹² These symptoms may respond to interventions such as changes to the environment.

Continued to: Choosing an antipsychotic

Choosing an antipsychotic

Once you have identified that an antipsychotic is truly indicated, the choice of an agent will focus on patient-related factors. Considerations such as frailty, comorbid medical conditions including diabetes, history of falls, hepatic insufficiency, cardiac arrhythmias, and cerebrovascular risk factors, should all be analyzed prior to initiating an antipsychotic. The presence of these conditions will increase the likelihood that adverse effects may occur. It will also guide the dose trajectory and the target dose for discontinuation. Antipsychotics differ with respect to their efficacy and adverse effect profile. For practical purposes, adverse effects typically guide the selection of these agents when used for patients with dementia.

Continued to: Gradual structural changes occur...

Gradual structural changes occur in the dopaminergic system with age and increase the propensity for antipsychotic adverse effects. The number of dopaminergic neurons and D2 receptors decreases approximately 10% per decade. In order to avoid the development of adverse effects related to extrapyramidal symptoms, approximately 20% of receptors need to be free. FGAs tend to block approximately 90% of D2 receptors, whereas SGAs block less than 70% to 80% and dissociate more rapidly from D2 receptors.¹³ FGAs should therefore be avoided, as they have been associated with numerous adverse effects, including parkinsonism, tardive dyskinesia, akathisia, sedation, peripheral and central anticholinergic effects, postural hypotension, cardiac conduction defects, and falls. As noted above, they have been linked to a greater risk of mortality (Figure¹⁴ ).

Dosing considerations

When beginning treatment with an antipsychotic, the starting dose should be as low as possible. This is particularly important for patients who are older, frail, cognitively impaired, or who carry a specific, significant risk that the antipsychotic may increase, such as a risk for falling. The starting dose can be divided or scheduled according to the behavior. For example, a lunchtime dose may be appropriate for patients exhibiting increased agitation towards the end of the day (“sundowning”). A good rule of thumb is to administer a dose approximately 2 hours before the behaviors typically occur. While there is no formal evidence from clinical trials to support this type of dosing schedule, clinical experience has shown it to have merit.

Dose increments should be modest and, in a nonemergent setting, may be adjusted at weekly intervals depending on response. Prior to starting a treatment trial, it is advisable to estimate what will constitute a worthwhile clinical response, the duration of treatment, and the maximum dose. Avoid high doses or prolonged use of antipsychotics that have not significantly improved the target behavior.

When the decision to use a SGA is made, choosing the initial starting dose is challenging given that none of these medications has an indication for use in this population. We propose doses that have been used in completed randomized trials that reflect the best information available about the dose likely to maximize benefit and minimize risk. On the basis of those trials, reasonable starting doses would be^15-22:

• quetiapine 25 to 50 mg/d
• risperidone 0.5 to 1 mg/d
• aripiprazole 2 to 10 mg/d
• olanzapine 2.5 to 5 mg/d
• ziprasidone 20 mg/d

Continued to: The highest doses tested...

The highest doses tested for each of these compounds in randomized clinical trials for this population were: risperidone 2 mg/d, olanzapine 10 mg/d, and aripiprazole 15 mg/d. A wide variety of maximum doses of quetiapine were studied in clinical trials, with a top dose of 200 mg being most common. It is worth noting that doses higher than these have been used for other indications.^15-22

Quetiapine. One of the most commonly prescribed antipsychotics for the treatment of BPSD in individuals with memory disorders is quetiapine. The reasons for this preference include a low risk of extrapyramidal adverse effects, flexibility of dosing, ability to use lower dosages, and evidence of the lower risk of mortality when compared with other second-generation agents.^5,15 If an antipsychotic is indicated, quetiapine should be considered as a first-line antipsychotic therapy. Quetiapine has well-established effects on mood, anxiety, and sleep, all of which can be disrupted in dementia and can act as drivers for agitation.^5,15 Starting quetiapine may mitigate the need for separate agents to treat insomnia, loss of appetite, or anxiety, although it is not FDA-indicated for these comorbid conditions. Quetiapine is also less likely to exacerbate motor symptoms compared with other SGAs but has the potential to increase the risk of falls, and orthostasis, and carries a considerable anticholinergic burden.^5,15

Risperidone has been shown to provide modest improvements in some people exhibiting symptoms of aggression, agitation, and psychosis.^5,15 There is no evidence that risperidone is any more effective than other SGAs, but it has been tested on more geriatric patients than other SGAs. The fact that it is also available in an orally disintegrating tablet makes it a practical treatment in certain populations of patients, such as those who have difficulty swallowing. Risperidone carries the highest extrapyramidal symptom burden among the SGAs due to its potent D2 receptor binding. ^5,15

Aripiprazole. There have been several studies of aripiprazole for the treatment of psychosis and agitation in Alzheimer’s dementia.¹⁵ This medication showed modest effect and was generally well tolerated. Aripiprazole appears to have less associated weight gain, which may be pertinent for some patients. It also appears to be less sedating than many of the other SGAs. However, some patients may experience activation or insomnia with this agent, particularly with doses <15 mg/d. This activating effect may be beneficial for treating comorbid depressive symptoms, although lower doses could theoretically worsen psychosis due to the activating effects.

Aripiprazole has also been studied in Parkinson’s disease. While some patients had favorable responses with improvement in psychosis and behavioral disturbances, this medication was also associated with worsening of motor symptoms. Certain individuals also experienced a worsening of their psychosis.²³ For this reason, it is unlikely to be a useful agent for patients displaying evidence of parkinsonism, Parkinson’s dementia, or dementia with Lewy bodies.

Olanzapine. Several studies have shown that low-dose olanzapine has been modestly effective in decreasing agitation and aggression in patients suffering from Alzheimer’s and vascular dementias.²⁴ The medication is also available in an orally disintegrating form, which may be beneficial when treating individuals whose swallowing abilities are compromised. Olanzapine also has been associated with significant weight gain and metabolic syndrome.²⁴

Continued to: Ziprasidone

Ziprasidone. There are no specific studies of ziprasidone for geriatric patients and none for patients with dementia. However, case reports have suggested both oral and injectable forms of the medication may be well tolerated and have some benefit in treating agitation in this population.²⁵ Based on evidence from younger populations, ziprasidone is less likely to be associated with weight gain or orthostatic hypotension. Medication has been associated with QTc prolongation and should be used with caution and monitored with an ECG.

The initial dosing and potential adverse effects of quetiapine, risperidone, aripiprazole, olanzapine, and ziprasidone are highlighted in Table 3.¹⁰

Other SGAs. Newer antipsychotics have recently become available and may serve as additional tools for managing BPSD in the future. Unfortunately, there are currently no available studies regarding their efficacy in the treatment of agitation and psychosis in dementia. One notable exception is pimavaserin, a serotonin 2A receptor inverse agonist. This medication has recently been FDA-approved for the treatment of Parkinson’s disease psychosis. The medication was extensively studied in older patients. It appeared to be effective in reducing delusions and hallucinations while not impairing motor function or causing sedation or hypotension.²³ Additional studies are currently ongoing for the treatment of Alzheimer’s dementia psychosis.

Monitor treatment, consider discontinuation

American Psychiatric Association guidelines on the use of antipsychotics to treat agitation or psychosis in patients with dementia currently recommend that clinicians use a quantitative measure to track symptoms and response to treatment.²⁶ These measures may be formal, such as an overall assessment of symptom severity on a Likert scale, or as simple as monitoring the changes in the frequency of periods of agitation.

After starting an antipsychotic, a follow-up appointment should typically take place within 1 month. If the patient is at high risk for developing adverse effects, or if the symptoms are severe, a follow-up appointment for monitoring the response to treatment and potential adverse effects should occur within 1 week. At a minimum, expert consensus suggests follow-up visits should occur every 3 months.

If there is no clinical response after 4 weeks of adequate dosing of an anti­psychotic, the medication should be tapered and withdrawn. Switching to an alternative agent may be appropriate.

Many patients will have only partial remission of target symptoms. Therefore, increasing the dose or switching to an alternative agent may be necessary. Concurrent use of multiple antipsychotic agents should be avoided.

Continued to: Maintenance treatment may be appropriate

How to approach discontinuation

Behavioral and psychological symptoms of dementia are frequently temporary. If the patient has been stable, gradual dose reduction and eventual discontinuation of antipsychotics should be attempted every 3 months. Studies have reported that most patients who were taken off antipsychotics for treating BPSD showed no worsening of behavioral symptoms.²⁷

Discontinuation of antipsychotics should be done gradually by reducing the dose by 50% every 2 weeks, and then stopping after 2 weeks on the minimum dose, with monitoring for recurrence of target symptoms or emergence of new ones. The longer a medication has been prescribed, the slower the withdrawal occurs. Thus, the possibility of emerging symptoms related to drug withdrawal will lessen.

A roadmap for judicious prescribing

When underlying treatable or reversible causes of BPSD in dementia have been ruled out or nonpharmacologic treatments have failed, a trial of an antipsychotic may be indicated. The choice of agent should focus on patient-related factors and on clearly identified target behaviors. Treatment should be started at a low dose and titrated cautiously to the lowest effective dose.

Behavioral and psychological symptoms of dementia are frequently temporary. Therefore, a gradual reduction and eventual withdrawal of antipsychotic medications should be attempted every 3 months. Studies indicate that most patients are able to tolerate elimination of antipsychotic medications with no worsening of behavioral symptoms.

Despite the limitations of treatment, SGAs remain a valid consideration when other interventions have proven insufficient. However, judicious use of these agents remains the cornerstone of therapy.

Bottom Line 

Until better treatment options become available, second-generation antipsychotics (SGAs) continue to have an important, albeit limited, role in the treatment of behavioral disturbances in dementia. Despite the limitations of treatment, SGAs remain a valid consideration when other interventions have proven insufficient. However, judicious use of these agents remains the cornerstone of therapy.

Related Resources

• Kales HC, Mulsant BH, Sajatovic MS. Prescribing antipsychotics in geriatric patients: Focus on dementia. Third of 3 parts. Current Psychiatry. 2017;16(12):24-30.
• Meeks TW, Jeste DV. Antipsychotics in dementia: Beyond ‘black-box’ warnings. Current Psychiatry. 2008;7(6):51-52, 55-58, 64-65.

Drug Brand Names

Aripiprazole • Abilify
Haloperidol • Haldol
Olanzapine • Zyprexa
Pimavanserin • Nuplazid
Risperidone • Risperdal
Quetiapine • Seroquel
Ziprasidone • Geodon

As psychiatrists treating an aging population, we frequently face the daunting challenges of managing medically complex and behaviorally unstable patients whose fragile condition tests the brightest among us. As our population enters late life, not only are physicians confronted with aging patients whose bodies have decreased renal and hepatic function, but we also face the challenges of the aging brain, severed neuronal networks, and neurotransmitter diminution. These physiological changes can alter treatment response, increase the frequency of adverse effects, and increase the likelihood of emergence of behavioral and psychological symptoms.

During the past decade, the number of people reaching age 65 has dramatically increased. As life expectancy improves, the “oldest old”—those age 85 and older—are the fastest-growing segment of the population. The prevalence of cognitive impairment, including mild cognitive impairment and dementia, in this cohort is >40%.¹ Roughly 90% of patients with dementia will develop clinically significant behavioral problems at some point in the course of their illness.²

Behavioral and psychological symptoms of dementia (BPSD) have a tremendous impact on the quality of life for both patients and their caregivers. We are experts in understanding these behaviors and crafting nonpharmacologic treatment plans to manage them. Understanding the context in which behaviors emerge allows us to modify the environment, communication strategies, and other potential triggers, in turn reducing the need for pharmacologic intervention.

However, when nonpharmacologic interventions have been exhausted, what are the options? Antipsychotics have been one of the approaches used to address the challenges of behavioral disturbances and psychosis occurring in dementia. Unfortunately, there is conflicting evidence regarding the risks and benefits associated with the use of antipsychotics in this population. In this article, we provide a roadmap for the judicious use of antipsychotics for patients with dementia.

Weighing the risks and benefits of antipsychotics

Until better treatment options become available, second-generation antipsychotics (SGAs) continue to have an important but limited role in the treatment of behavioral disturbances in dementia. Although safety risks exist, they can be minimized through the careful selection of appropriate patients for treatment, close monitoring, and effective communication with patients and caregivers before and during treatment.

Several studies examining the efficacy of antipsychotics in the treatment of BPSD have demonstrated an increased risk of cerebrovascular events, including stroke and death due to any cause.³ This evidence prompted the FDA to issue a “black-box” warning in 2005 to highlight the increased risk of mortality for patients with dementia who are treated with SGAs.⁴ Both first-generation antipsychotics (FGAs) and SGAs have been associated with higher rates of mortality than most other psychotropic classes, except anticonvulsants. This increased mortality risk has been shown to persist for at least 6 to 12 months.^5,6 FGAs appear to be associated with a greater mortality risk compared with SGAs. As a result, if antipsychotic treatment is necessary, the use of FGAs in this population is not recommended.

The potential mechanisms leading to stroke and death remain unclear. They could include orthostatic hypotension, anticholinergic adverse effects, QT prolongation, platelet aggregation effects, and venous thromboembolism. The presence of cardiovascular and vascular risk factors, electrolyte imbalances, cardiac arrhythmias, and concomitant use of medications that prolong the QTc interval may confer additional risks.

Continued to: Although the use of antipsychotics for patients with dementia...

Although the use of antipsychotics for patients with dementia may increase the risk of mortality, the absolute increased risk to a given individual, at least with short-term treatment, is likely small. The risk may also vary depending on the choice of SGA. Patients who were treated with quetiapine had a slightly lower risk of death than those who were treated risperidone.⁵ Death rates among patients prescribed aripiprazole, olanzapine, and ziprasidone were similar to the death rates of patients who were treated with risperidone. Compared with patients who were treated with risperidone, patients who were treated with the FGA haloperidol were twice as likely to die during a subsequent 6-month observation period. The largest number of deaths occurred during the first 40 days of treatment.⁵

While this increased risk of mortality is an important factor to discuss with patients and caregivers when deciding whether to initiate antipsychotic treatment, it is also important to put it into perspective. For example, the risk of suddenly dying from a stroke or heart attack for a person with dementia who is not taking an antipsychotic is approximately 2%. When an individual is started on one of these agents, that risk increases to approximately 4%. While the mortality risk is doubled, it remains relatively small.⁴ When faced with verbal or physical assaults, hostility, paranoid ideations, or other psychotic symptoms, many families feel that this relatively low risk does not outweigh the potential benefits of reducing caregiver and patient distress. If nonpharmacologic and/or other pharmacologic interventions have failed, the treatment has reached a point of no good alternatives and therapy should then focus on minimizing risk.

Informed consent is essential. A discussion of risks and benefits with the patient, family, or other decision-makers should focus on the risk of stroke, potential metabolic effects, and mortality, as well as potential worsening of cognitive decline associated with antipsychotic treatment. This should be weighed together with the evidence that suggests psychosis and agitation are associated with earlier nursing home admission and death.^7,8 Families should be given ample time and opportunity to ask questions. Alternatives to immediate initiation of antipsychotics should be thoroughly reviewed.

Despite the above-noted risks, expert consensus suggests that the use of antipsychotics in the treatment of individuals with dementia can be appropriate, particularly in individuals with dangerous agitation or psychosis.⁹ These agents can minimize the risk of violence, reduce patient distress, improve the patient’s quality of life, and reduce caregiver burden. In clinical trials, the benefits of antipsychotics have been modest. Nevertheless, evidence has shown that these agents can reduce psychosis, agitation, aggression, hostility, and suspiciousness, which makes them a valid option when other interventions have proven insufficient.

Target specific symptoms

Despite this article’s focus on the appropriate use of antipsychotics for patients with BPSD, it is important to emphasize that the first-line approach to the management of BPSD in this population should always be a person-centered, psychosocial, multidisciplinary, nonpharmacologic approach that focuses on identifying triggers and treating potentially modifiable contributors to behavioral symptoms. Table 1¹⁰ outlines common underlying causes of BPSD in dementia that should be assessed before prescribing an antipsychotic.

Continued to: Alternative psychopharmacologic treatments...

Alternative psychopharmacologic treatments based on a psychobehavioral metaphor should also be considered (Table 2¹¹). This approach matches the dominant target symptoms to the most relevant medication class.¹¹ For example, in the case of a verbally and physically agitated patient who is also irritable, negative, socially withdrawn, and appears dysphoric, we might first undertake a trial of an antidepressant. Conversely, if the patient shows agitation in the context of increased motor activity, loud and rapid speech, and affective lability, we might consider the use of a mood stabilizer. Pharmacologic treatment should be aimed at the modification of clearly identified and documented target behaviors.

• severe agitation and aggression associated with risk of harm
• delusions and hallucinations
• comorbid preexisting mental health conditions (eg, bipolar disorder, schizophrenia, treatment-resistant depression, etc.).

Symptoms that do not usually respond to an antipsychotic include wandering, social withdrawal, shouting, pacing, touching, cognitive defects, and incontinence.¹² These symptoms may respond to interventions such as changes to the environment.

Continued to: Choosing an antipsychotic

Choosing an antipsychotic

Once you have identified that an antipsychotic is truly indicated, the choice of an agent will focus on patient-related factors. Considerations such as frailty, comorbid medical conditions including diabetes, history of falls, hepatic insufficiency, cardiac arrhythmias, and cerebrovascular risk factors, should all be analyzed prior to initiating an antipsychotic. The presence of these conditions will increase the likelihood that adverse effects may occur. It will also guide the dose trajectory and the target dose for discontinuation. Antipsychotics differ with respect to their efficacy and adverse effect profile. For practical purposes, adverse effects typically guide the selection of these agents when used for patients with dementia.

Continued to: Gradual structural changes occur...

Gradual structural changes occur in the dopaminergic system with age and increase the propensity for antipsychotic adverse effects. The number of dopaminergic neurons and D2 receptors decreases approximately 10% per decade. In order to avoid the development of adverse effects related to extrapyramidal symptoms, approximately 20% of receptors need to be free. FGAs tend to block approximately 90% of D2 receptors, whereas SGAs block less than 70% to 80% and dissociate more rapidly from D2 receptors.¹³ FGAs should therefore be avoided, as they have been associated with numerous adverse effects, including parkinsonism, tardive dyskinesia, akathisia, sedation, peripheral and central anticholinergic effects, postural hypotension, cardiac conduction defects, and falls. As noted above, they have been linked to a greater risk of mortality (Figure¹⁴ ).

Dosing considerations

When beginning treatment with an antipsychotic, the starting dose should be as low as possible. This is particularly important for patients who are older, frail, cognitively impaired, or who carry a specific, significant risk that the antipsychotic may increase, such as a risk for falling. The starting dose can be divided or scheduled according to the behavior. For example, a lunchtime dose may be appropriate for patients exhibiting increased agitation towards the end of the day (“sundowning”). A good rule of thumb is to administer a dose approximately 2 hours before the behaviors typically occur. While there is no formal evidence from clinical trials to support this type of dosing schedule, clinical experience has shown it to have merit.

Dose increments should be modest and, in a nonemergent setting, may be adjusted at weekly intervals depending on response. Prior to starting a treatment trial, it is advisable to estimate what will constitute a worthwhile clinical response, the duration of treatment, and the maximum dose. Avoid high doses or prolonged use of antipsychotics that have not significantly improved the target behavior.

When the decision to use a SGA is made, choosing the initial starting dose is challenging given that none of these medications has an indication for use in this population. We propose doses that have been used in completed randomized trials that reflect the best information available about the dose likely to maximize benefit and minimize risk. On the basis of those trials, reasonable starting doses would be^15-22:

• quetiapine 25 to 50 mg/d
• risperidone 0.5 to 1 mg/d
• aripiprazole 2 to 10 mg/d
• olanzapine 2.5 to 5 mg/d
• ziprasidone 20 mg/d

Continued to: The highest doses tested...

The highest doses tested for each of these compounds in randomized clinical trials for this population were: risperidone 2 mg/d, olanzapine 10 mg/d, and aripiprazole 15 mg/d. A wide variety of maximum doses of quetiapine were studied in clinical trials, with a top dose of 200 mg being most common. It is worth noting that doses higher than these have been used for other indications.^15-22

Quetiapine. One of the most commonly prescribed antipsychotics for the treatment of BPSD in individuals with memory disorders is quetiapine. The reasons for this preference include a low risk of extrapyramidal adverse effects, flexibility of dosing, ability to use lower dosages, and evidence of the lower risk of mortality when compared with other second-generation agents.^5,15 If an antipsychotic is indicated, quetiapine should be considered as a first-line antipsychotic therapy. Quetiapine has well-established effects on mood, anxiety, and sleep, all of which can be disrupted in dementia and can act as drivers for agitation.^5,15 Starting quetiapine may mitigate the need for separate agents to treat insomnia, loss of appetite, or anxiety, although it is not FDA-indicated for these comorbid conditions. Quetiapine is also less likely to exacerbate motor symptoms compared with other SGAs but has the potential to increase the risk of falls, and orthostasis, and carries a considerable anticholinergic burden.^5,15

Risperidone has been shown to provide modest improvements in some people exhibiting symptoms of aggression, agitation, and psychosis.^5,15 There is no evidence that risperidone is any more effective than other SGAs, but it has been tested on more geriatric patients than other SGAs. The fact that it is also available in an orally disintegrating tablet makes it a practical treatment in certain populations of patients, such as those who have difficulty swallowing. Risperidone carries the highest extrapyramidal symptom burden among the SGAs due to its potent D2 receptor binding. ^5,15

Aripiprazole. There have been several studies of aripiprazole for the treatment of psychosis and agitation in Alzheimer’s dementia.¹⁵ This medication showed modest effect and was generally well tolerated. Aripiprazole appears to have less associated weight gain, which may be pertinent for some patients. It also appears to be less sedating than many of the other SGAs. However, some patients may experience activation or insomnia with this agent, particularly with doses <15 mg/d. This activating effect may be beneficial for treating comorbid depressive symptoms, although lower doses could theoretically worsen psychosis due to the activating effects.

Aripiprazole has also been studied in Parkinson’s disease. While some patients had favorable responses with improvement in psychosis and behavioral disturbances, this medication was also associated with worsening of motor symptoms. Certain individuals also experienced a worsening of their psychosis.²³ For this reason, it is unlikely to be a useful agent for patients displaying evidence of parkinsonism, Parkinson’s dementia, or dementia with Lewy bodies.

Olanzapine. Several studies have shown that low-dose olanzapine has been modestly effective in decreasing agitation and aggression in patients suffering from Alzheimer’s and vascular dementias.²⁴ The medication is also available in an orally disintegrating form, which may be beneficial when treating individuals whose swallowing abilities are compromised. Olanzapine also has been associated with significant weight gain and metabolic syndrome.²⁴

Continued to: Ziprasidone

Ziprasidone. There are no specific studies of ziprasidone for geriatric patients and none for patients with dementia. However, case reports have suggested both oral and injectable forms of the medication may be well tolerated and have some benefit in treating agitation in this population.²⁵ Based on evidence from younger populations, ziprasidone is less likely to be associated with weight gain or orthostatic hypotension. Medication has been associated with QTc prolongation and should be used with caution and monitored with an ECG.

The initial dosing and potential adverse effects of quetiapine, risperidone, aripiprazole, olanzapine, and ziprasidone are highlighted in Table 3.¹⁰

Other SGAs. Newer antipsychotics have recently become available and may serve as additional tools for managing BPSD in the future. Unfortunately, there are currently no available studies regarding their efficacy in the treatment of agitation and psychosis in dementia. One notable exception is pimavaserin, a serotonin 2A receptor inverse agonist. This medication has recently been FDA-approved for the treatment of Parkinson’s disease psychosis. The medication was extensively studied in older patients. It appeared to be effective in reducing delusions and hallucinations while not impairing motor function or causing sedation or hypotension.²³ Additional studies are currently ongoing for the treatment of Alzheimer’s dementia psychosis.

Monitor treatment, consider discontinuation

American Psychiatric Association guidelines on the use of antipsychotics to treat agitation or psychosis in patients with dementia currently recommend that clinicians use a quantitative measure to track symptoms and response to treatment.²⁶ These measures may be formal, such as an overall assessment of symptom severity on a Likert scale, or as simple as monitoring the changes in the frequency of periods of agitation.

After starting an antipsychotic, a follow-up appointment should typically take place within 1 month. If the patient is at high risk for developing adverse effects, or if the symptoms are severe, a follow-up appointment for monitoring the response to treatment and potential adverse effects should occur within 1 week. At a minimum, expert consensus suggests follow-up visits should occur every 3 months.

If there is no clinical response after 4 weeks of adequate dosing of an anti­psychotic, the medication should be tapered and withdrawn. Switching to an alternative agent may be appropriate.

Many patients will have only partial remission of target symptoms. Therefore, increasing the dose or switching to an alternative agent may be necessary. Concurrent use of multiple antipsychotic agents should be avoided.

Continued to: Maintenance treatment may be appropriate

How to approach discontinuation

Behavioral and psychological symptoms of dementia are frequently temporary. If the patient has been stable, gradual dose reduction and eventual discontinuation of antipsychotics should be attempted every 3 months. Studies have reported that most patients who were taken off antipsychotics for treating BPSD showed no worsening of behavioral symptoms.²⁷

Discontinuation of antipsychotics should be done gradually by reducing the dose by 50% every 2 weeks, and then stopping after 2 weeks on the minimum dose, with monitoring for recurrence of target symptoms or emergence of new ones. The longer a medication has been prescribed, the slower the withdrawal occurs. Thus, the possibility of emerging symptoms related to drug withdrawal will lessen.

A roadmap for judicious prescribing

When underlying treatable or reversible causes of BPSD in dementia have been ruled out or nonpharmacologic treatments have failed, a trial of an antipsychotic may be indicated. The choice of agent should focus on patient-related factors and on clearly identified target behaviors. Treatment should be started at a low dose and titrated cautiously to the lowest effective dose.

Behavioral and psychological symptoms of dementia are frequently temporary. Therefore, a gradual reduction and eventual withdrawal of antipsychotic medications should be attempted every 3 months. Studies indicate that most patients are able to tolerate elimination of antipsychotic medications with no worsening of behavioral symptoms.

Despite the limitations of treatment, SGAs remain a valid consideration when other interventions have proven insufficient. However, judicious use of these agents remains the cornerstone of therapy.

Bottom Line 

Until better treatment options become available, second-generation antipsychotics (SGAs) continue to have an important, albeit limited, role in the treatment of behavioral disturbances in dementia. Despite the limitations of treatment, SGAs remain a valid consideration when other interventions have proven insufficient. However, judicious use of these agents remains the cornerstone of therapy.

Related Resources

• Kales HC, Mulsant BH, Sajatovic MS. Prescribing antipsychotics in geriatric patients: Focus on dementia. Third of 3 parts. Current Psychiatry. 2017;16(12):24-30.
• Meeks TW, Jeste DV. Antipsychotics in dementia: Beyond ‘black-box’ warnings. Current Psychiatry. 2008;7(6):51-52, 55-58, 64-65.

Drug Brand Names

Aripiprazole • Abilify
Haloperidol • Haldol
Olanzapine • Zyprexa
Pimavanserin • Nuplazid
Risperidone • Risperdal
Quetiapine • Seroquel
Ziprasidone • Geodon

There is a well-established relationship between antipsychotic treatment and hyperprolactinemia. Most antipsychotics have been linked to increased prolactin levels, and the risk appears to be dose-related.¹ Antipsychotic-induced hyperprolactinemia can be asymptomatic, but it also has been associated with several adverse effects, including menstrual irregularity, osteoporosis, gynecomastia, and sexual dysfunction. Here I discuss what to do before starting a patient on an antipsychotic, and 5 treatment strategies for addressing antipsychotic-induced hyperprolactinemia.

Get a baseline prolactin level

Before starting a patient on an antipsychotic, obtain a baseline prolactin level measurement. If the patient later develops hyperprolactinemia, having a baseline measurement will make it easier to determine if the antipsychotic is a potential cause. Also, it is helpful to gather additional information regarding baseline psychosexual function and menstruation before starting an antipsychotic.

It is critical to determine if a temporal relationship exists between exposure to an antipsychotic and increase in prolactin levels.³ If the time course is unclear, laboratory tests need to be performed, including assessing liver, renal, and thyroid function or imaging of the pituitary gland. Also, hyperprolactinemia should not be diagnosed based on a single blood test result, because emotional and physical stress can elevate prolactin levels.

Continued to: 5 strategies for addressing hyperprolactinemia

1. Reduce the antipsychotic dose. Because the risk of hyperprolactinemia is dose-dependent, reducing the antipsychotic dose could be helpful for some patients.

2. Switch to a prolactin-sparing antipsychotic, such as clozapine, quetiapine, olanzapine, or ziprasidone. However, it is often difficult to predict positive outcomes because switching antipsychotics may cause new adverse effects or trigger a psychotic relapse.

3. Consider sex hormone replacement therapy. A combined oral contraceptive could prevent osteoporosis and help estrogen deficiency symptoms in women who require antipsychotic medication. However, this treatment approach may worsen galactorrhea.

4. Use a dopamine receptor agonist. Dopamine receptor agonists, such as cabergoline or bromocriptine, have been shown to suppress prolactin secretion. Clinicians should always proceed cautiously because these medications can potentially increase the risk of psychosis.

5. Examine the potential benefits of adding aripiprazole because it can be used for augmentation to reduce prolactin levels in patients receiving other antipsychotics. In some cases, dopamine receptors can be exposed to competition between a partial agonist (aripiprazole) and an antagonist (the current antipsychotic). This competition may decrease the effectiveness of the current antipsychotic.¹ Also, adding another antipsychotic could increase overall adverse effects.

There is a well-established relationship between antipsychotic treatment and hyperprolactinemia. Most antipsychotics have been linked to increased prolactin levels, and the risk appears to be dose-related.¹ Antipsychotic-induced hyperprolactinemia can be asymptomatic, but it also has been associated with several adverse effects, including menstrual irregularity, osteoporosis, gynecomastia, and sexual dysfunction. Here I discuss what to do before starting a patient on an antipsychotic, and 5 treatment strategies for addressing antipsychotic-induced hyperprolactinemia.

Get a baseline prolactin level

Before starting a patient on an antipsychotic, obtain a baseline prolactin level measurement. If the patient later develops hyperprolactinemia, having a baseline measurement will make it easier to determine if the antipsychotic is a potential cause. Also, it is helpful to gather additional information regarding baseline psychosexual function and menstruation before starting an antipsychotic.

It is critical to determine if a temporal relationship exists between exposure to an antipsychotic and increase in prolactin levels.³ If the time course is unclear, laboratory tests need to be performed, including assessing liver, renal, and thyroid function or imaging of the pituitary gland. Also, hyperprolactinemia should not be diagnosed based on a single blood test result, because emotional and physical stress can elevate prolactin levels.

Continued to: 5 strategies for addressing hyperprolactinemia

1. Reduce the antipsychotic dose. Because the risk of hyperprolactinemia is dose-dependent, reducing the antipsychotic dose could be helpful for some patients.

2. Switch to a prolactin-sparing antipsychotic, such as clozapine, quetiapine, olanzapine, or ziprasidone. However, it is often difficult to predict positive outcomes because switching antipsychotics may cause new adverse effects or trigger a psychotic relapse.

3. Consider sex hormone replacement therapy. A combined oral contraceptive could prevent osteoporosis and help estrogen deficiency symptoms in women who require antipsychotic medication. However, this treatment approach may worsen galactorrhea.

4. Use a dopamine receptor agonist. Dopamine receptor agonists, such as cabergoline or bromocriptine, have been shown to suppress prolactin secretion. Clinicians should always proceed cautiously because these medications can potentially increase the risk of psychosis.

5. Examine the potential benefits of adding aripiprazole because it can be used for augmentation to reduce prolactin levels in patients receiving other antipsychotics. In some cases, dopamine receptors can be exposed to competition between a partial agonist (aripiprazole) and an antagonist (the current antipsychotic). This competition may decrease the effectiveness of the current antipsychotic.¹ Also, adding another antipsychotic could increase overall adverse effects.

There is a well-established relationship between antipsychotic treatment and hyperprolactinemia. Most antipsychotics have been linked to increased prolactin levels, and the risk appears to be dose-related.¹ Antipsychotic-induced hyperprolactinemia can be asymptomatic, but it also has been associated with several adverse effects, including menstrual irregularity, osteoporosis, gynecomastia, and sexual dysfunction. Here I discuss what to do before starting a patient on an antipsychotic, and 5 treatment strategies for addressing antipsychotic-induced hyperprolactinemia.

Get a baseline prolactin level

Before starting a patient on an antipsychotic, obtain a baseline prolactin level measurement. If the patient later develops hyperprolactinemia, having a baseline measurement will make it easier to determine if the antipsychotic is a potential cause. Also, it is helpful to gather additional information regarding baseline psychosexual function and menstruation before starting an antipsychotic.

It is critical to determine if a temporal relationship exists between exposure to an antipsychotic and increase in prolactin levels.³ If the time course is unclear, laboratory tests need to be performed, including assessing liver, renal, and thyroid function or imaging of the pituitary gland. Also, hyperprolactinemia should not be diagnosed based on a single blood test result, because emotional and physical stress can elevate prolactin levels.

Continued to: 5 strategies for addressing hyperprolactinemia

1. Reduce the antipsychotic dose. Because the risk of hyperprolactinemia is dose-dependent, reducing the antipsychotic dose could be helpful for some patients.

2. Switch to a prolactin-sparing antipsychotic, such as clozapine, quetiapine, olanzapine, or ziprasidone. However, it is often difficult to predict positive outcomes because switching antipsychotics may cause new adverse effects or trigger a psychotic relapse.

3. Consider sex hormone replacement therapy. A combined oral contraceptive could prevent osteoporosis and help estrogen deficiency symptoms in women who require antipsychotic medication. However, this treatment approach may worsen galactorrhea.

4. Use a dopamine receptor agonist. Dopamine receptor agonists, such as cabergoline or bromocriptine, have been shown to suppress prolactin secretion. Clinicians should always proceed cautiously because these medications can potentially increase the risk of psychosis.

5. Examine the potential benefits of adding aripiprazole because it can be used for augmentation to reduce prolactin levels in patients receiving other antipsychotics. In some cases, dopamine receptors can be exposed to competition between a partial agonist (aripiprazole) and an antagonist (the current antipsychotic). This competition may decrease the effectiveness of the current antipsychotic.¹ Also, adding another antipsychotic could increase overall adverse effects.

Mrs. J, age 49, presents to your psychiatric clinic. For the last few years, she has been experiencing night sweats and hot flashes, which she has attributed to being perimenopausal. Over the last year, she has noticed that her mood has declined; however, she has suffered several life events that she feels have contributed. Her mother was diagnosed with Alzheimer’s disease and had to move into a nursing home, which Mrs. J found very stressful. At the same time, her daughter left home for college, and her son is exploring his college options. Recently, Mrs. J has not been able to work due to her mood, and she is afraid she may lose her job as a consequence. She has struggled to talk to her husband about how she is feeling, and feels increasingly isolated. Over the last month, she has had increased problems sleeping and less energy; some days she struggles to get out of bed. She is finding it difficult to concentrate and is more forgetful. She has lost interest in her hobbies and is no longer meeting with her friends. She has no history of depression or anxiety, although she recalls feeling very low in mood for months after the birth of each of her children.

Are Mrs. J’s symptoms related to menopause or depression? What further investigations are necessary? Would you modify your treatment plan because of her menopausal status?

Women are at elevated risk of developing psychiatric symptoms and disorders throughout their reproductive lives, including during menopause. Menopause is a time of life transition, when women may experience multiple physical symptoms, including vasomotor symptoms (night sweats and hot flashes), sexual symptoms, and sleep difficulties. Depressive symptoms occur more frequently during menopause, and symptoms of schizophrenia may worsen.

Estrogen plays a role in mental illness throughout a woman’s life. In menopause, decreasing estrogen levels may correlate with increased mood symptoms, physical symptoms, and psychotic symptoms. As such, psychiatrists should consider whether collaboration regarding adjunctive hormone replacement therapy would be beneficial, and whether the benefits outweigh the potential risks. Otherwise, treatment of depression in menopause is similar to treatment outside of the menopausal transition, though serotonergic antidepressants may help target vasomotor symptoms while therapy may focus on role transition and loss. In this article, we review why women are at increased risk for mental illness during menopause, the role of estrogen, and treatment of mood and psychotic disorders during this phase of a woman’s life.

Increased vulnerability across the lifespan

Continued to: Why menopause?

Why menopause?

Perimenopausal mood disorders

However, one should keep in mind that new-onset mania in menopause is rare and should trigger a medical work-up and a dementia evaluation.¹³ Table 4¹⁴ provides recommendations for evaluation of women undergoing menopause.

Menopause and serious mental illnesses

A study of 91 perimenopausal and postmenopausal women (age 45 to 55) who were diagnosed with schizophrenia/schizoaffective disorder, bipolar disorder, or major depressive disorder (MDD) found that women with severe mental illness experienced significant vasomotor, physical, sexual, and psychosocial symptoms related to menopause.¹⁵ Furthermore, on 7 of 29 items on the Menopause Specific Quality of Life Scale, including hot flashes, women diagnosed with MDD reported problems significantly more often than women with other serious mental illnesses.¹⁵

Women with serious mental illness often have deficits in their knowledge about menopause.³ More than half of the 91 women in the study diagnosed with schizophrenia/schizoaffective disorder, bipolar disorder, or MDD felt more stressed related to menopause, and reported that menopause had a negative effect on their mental health.³ These women rated their top 5 symptoms potentially related to menopause as feeling depressed, anxious, or tired; lacking energy; and experiencing poor memory.³

Continued to: Role of estrogen on mood and psychosis

Women are at higher risk throughout their reproductive life than are men for MDD, anxiety disorders, and trauma-related disorders.¹² Factors associated with depression during the menopause transition are reproductive hormonal changes (rise of follicle-stimulating hormone [FSH] and luteinizing hormone levels, and variability in estrogen [E2] and FSH levels); menopausal symptoms, particularly vasomotor symptoms; prior depression; psychosocial factors (adverse life events, financial strain, poor social supports); high body mass index, smoking, and poor physical health.^6,7 Decreasing estrogen in the menopause transition may increase susceptibility to depression in some women.¹⁶ The Box^17,18 provides more information on the relationship between estrogen and brain function.

Depressive disorders, including premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression, have been linked to changes in hormonal status in women. Symptomatic menopause transition occurs in at least 20% of women, and a retrospective cohort study suggests that symptomatic menopause transition might increase the risk of new-onset depressive disorders, bipolar disorders, anxiety disorders, and sleep disorders.¹⁹ Symptomatic menopause transition also is a vulnerable time for relapse of MDD. Among women experiencing menopausal symptoms, including hot flashes, one-third also report depression—which correlates with a poorer quality of life, less work productivity, and greater use of health care services.⁹

Women who undergo surgical menopause are at greater risk for depression.^8,10,11 This may be due to abrupt deprivation of estrogen—or related to a psychological reaction to the loss of fertility.

The observation that hormonal fluctuations related to women’s reproductive cycle have a significant impact on psychotic symptomatology has resulted in the “hypo-estrogenism hypothesis,” which proposes that gonadal dysfunction may increase vulnerability to schizophrenia, or that schizophrenia may lead to gonadal dysfunction.²⁰ The “estrogen protection hypothesis” proposes that estrogen may protect women from schizophrenia, and may be a factor in the delayed onset of schizophrenia compared with men, less severe psychopathology, better outcomes, and premenstrual and postmenopausal deterioration in women. Many women of reproductive age with schizophrenia experience improvement in symptoms during the high estrogen phase of their menstrual cycle.

Pope et al²¹ have suggested that a hormone sensitivity syndrome may underlie why some women experience physical, psychological, and emotional symptoms at times of hormonal shifts such as menopause. This may represent a critical window of vulnerability, and also an opportunity to consider E2 as a therapeutic intervention.

Continued to: Treating mental illness in menopause

Changes to drug pharmacokinetics occur because some metabolising enzymes are estrogen-dependent and their levels decline after menopause, which leads to greater variability in drug response, particularly for oral medications. Other factors that can contribute to variability in medication response are polypharmacy, alcohol, illicit drugs, liver mass, smoking, caffeine, and nutritional intake.

While antidepressants are the first-line treatment for MDD and anxiety disorders, some patients remain unresponsive or inadequately responsive to currently available medications. In perimenopausal women with MDD, there may be an indication for adjunctive therapy with transdermal E2 in refractory cases; estrogen may augment the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants as well as hasten the onset of antidepressant action.²² Estrogen also may be worth considering in women with mild depressive symptoms. For MDD, SSRIs plus estrogen may be more beneficial in improving mood than either agent alone. The effectiveness of E2 is less certain in postmenopausal depression.

Hormonal therapy for mental health disorders has equivocal evidence. The individual’s history and risk factors (eg, cardiovascular and osteoporosis risks) must be considered. A recent trial found that treatment with either venlafaxine or low-dose estrogen improved quality of life in menopausal women with vasomotor symptoms.²³ Venlafaxine improved the psychosocial domain, while estrogen improved quality of life in other domains. Escitalopram, duloxetine, and citalopram have also been identified as having a possible positive impact on menopausal symptoms.²² SSRIs and serotonin-norepinephrine reuptake inhibitors may help reduce hot flashes and improve sleep.¹¹

Regarding schizophrenia and estrogen, there may be improved symptoms during the high estrogen phase of the menstrual cycle, followed by a premenstrual aggravation of symptoms. Recall that women have a second peak of onset of schizophrenia after age 45, around the age of the onset of menopause.²⁴ In a study of geropsychiatric hospital admissions, women were overrepresented among those with schizophrenia and schizoaffective disorder, compared with other psychiatric disorders.²⁵ Postmenopausally, some women experience a decreased responsiveness to antipsychotics and worsening symptoms. In menopausal women with schizophrenia, check prolactin levels to help determine whether they are experiencing a natural menopause or medication-induced amenorrhea. Gender differences in pharmacotherapy responses and the decreasing response to antipsychotics in women older than age 50 have been observed²⁶ and have led to exploration of the role of estrogen for treating schizophrenia in menopausal women. There have been contradictory results regarding use of estrogen as an adjunct to antipsychotics, with some reports finding this approach is effective and results in lower average doses of antipsychotics. Kulkarni et al^27,28 have reported improvements in positive symptoms of treatment-resistant schizophrenia with transdermal use of E2, 200 mcg, as an adjunct to antipsychotics in women of childbearing age. However, they expressed caution regarding the health risks associated with prolonged use of E2. Long-term risks of high-dose estrogen therapies include thromboembolism, endometrial hyperplasia, and breast cancer, and individual factors should be considered before starting any form of hormone therapy. Selective estrogen receptor modulators (SERMs), such as raloxifene, which can cause activation of E2 receptors in a tissue-specific fashion and have less estrogen-related adverse effects, offer hope for future development in this field.^27,28 While the use of adjunctive hormone therapy to manage psychotic symptoms in menopause is not routinely advised, the dosages of previously effective antipsychotics may need to be reviewed, or long-acting depot routes considered.²⁹ Increased risk of prolonged QTc interval and tardive dyskinesia in geriatric women also should be considered in decisions regarding changes to antipsychotics or dosages.³⁰

There are no guidelines regarding change in dosage of either individual antidepressants or antipsychotics in women at the time of menopause for managing pre-existing conditions. This may be due to the high variability in the effect of menopause on mental health and recognition that menopause is also a time for deterioration in physical health, as well as psychosocial changes for women, and thus other forms of intervention need to be considered.

Continued to: The biopsychosocial approach to treatment...

Although there are overlapping symptoms with both MDD and the perimenopause, these are typically restricted to impaired energy, sleep, and concentration, or changes in libido and weight.³² Therefore, it is vital to obtain a clear history and explore these symptoms in greater depth, as well as collect further information related to additional criteria such as appetite, agitation, feelings of worthlessness or guilt, and suicidal ideation.

Starting an antidepressant

On evaluation, Mrs. J discloses that she had experienced thoughts of wanting to end her life by overdose, although she had not acted on these thoughts. She appears subdued with poor eye contact, latency of response, and a slowed thought process. Mrs. J has blood tests to rule out thyroid abnormality or anemia. FSH and LH levels also are measured; these could provide a useful reference for later.

After a discussion with Mrs. J, she agrees to start an antidepressant. She also plans to speak to her gynecologist about the possibility of hormone replacement therapy. She is referred for psychotherapy to help support her with current life stressors. Mrs. J is started on escitalopram, 10 mg/d, and, after a month, she notices some improvement in her mood, psychomotor symptoms, sleep, and energy levels.

Bottom Line

Menopause is an important transition in our patients’ lives—both biologically and psychosocially. Women’s symptom patterns and medication needs may change during menopause.

Related Resource

• The North American Menopause Society. Depression & menopause. https://www.menopause.org/for-women/menopauseflashes/mental-health-at-menopause/depressionmenopause.

Drug Brand Names
Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Raloxifene • Evista
Venlafaxine • Effexor

Mrs. J, age 49, presents to your psychiatric clinic. For the last few years, she has been experiencing night sweats and hot flashes, which she has attributed to being perimenopausal. Over the last year, she has noticed that her mood has declined; however, she has suffered several life events that she feels have contributed. Her mother was diagnosed with Alzheimer’s disease and had to move into a nursing home, which Mrs. J found very stressful. At the same time, her daughter left home for college, and her son is exploring his college options. Recently, Mrs. J has not been able to work due to her mood, and she is afraid she may lose her job as a consequence. She has struggled to talk to her husband about how she is feeling, and feels increasingly isolated. Over the last month, she has had increased problems sleeping and less energy; some days she struggles to get out of bed. She is finding it difficult to concentrate and is more forgetful. She has lost interest in her hobbies and is no longer meeting with her friends. She has no history of depression or anxiety, although she recalls feeling very low in mood for months after the birth of each of her children.

Are Mrs. J’s symptoms related to menopause or depression? What further investigations are necessary? Would you modify your treatment plan because of her menopausal status?

Women are at elevated risk of developing psychiatric symptoms and disorders throughout their reproductive lives, including during menopause. Menopause is a time of life transition, when women may experience multiple physical symptoms, including vasomotor symptoms (night sweats and hot flashes), sexual symptoms, and sleep difficulties. Depressive symptoms occur more frequently during menopause, and symptoms of schizophrenia may worsen.

Estrogen plays a role in mental illness throughout a woman’s life. In menopause, decreasing estrogen levels may correlate with increased mood symptoms, physical symptoms, and psychotic symptoms. As such, psychiatrists should consider whether collaboration regarding adjunctive hormone replacement therapy would be beneficial, and whether the benefits outweigh the potential risks. Otherwise, treatment of depression in menopause is similar to treatment outside of the menopausal transition, though serotonergic antidepressants may help target vasomotor symptoms while therapy may focus on role transition and loss. In this article, we review why women are at increased risk for mental illness during menopause, the role of estrogen, and treatment of mood and psychotic disorders during this phase of a woman’s life.

Increased vulnerability across the lifespan

Continued to: Why menopause?

Why menopause?

Perimenopausal mood disorders

However, one should keep in mind that new-onset mania in menopause is rare and should trigger a medical work-up and a dementia evaluation.¹³ Table 4¹⁴ provides recommendations for evaluation of women undergoing menopause.

Menopause and serious mental illnesses

A study of 91 perimenopausal and postmenopausal women (age 45 to 55) who were diagnosed with schizophrenia/schizoaffective disorder, bipolar disorder, or major depressive disorder (MDD) found that women with severe mental illness experienced significant vasomotor, physical, sexual, and psychosocial symptoms related to menopause.¹⁵ Furthermore, on 7 of 29 items on the Menopause Specific Quality of Life Scale, including hot flashes, women diagnosed with MDD reported problems significantly more often than women with other serious mental illnesses.¹⁵

Women with serious mental illness often have deficits in their knowledge about menopause.³ More than half of the 91 women in the study diagnosed with schizophrenia/schizoaffective disorder, bipolar disorder, or MDD felt more stressed related to menopause, and reported that menopause had a negative effect on their mental health.³ These women rated their top 5 symptoms potentially related to menopause as feeling depressed, anxious, or tired; lacking energy; and experiencing poor memory.³

Continued to: Role of estrogen on mood and psychosis

Women are at higher risk throughout their reproductive life than are men for MDD, anxiety disorders, and trauma-related disorders.¹² Factors associated with depression during the menopause transition are reproductive hormonal changes (rise of follicle-stimulating hormone [FSH] and luteinizing hormone levels, and variability in estrogen [E2] and FSH levels); menopausal symptoms, particularly vasomotor symptoms; prior depression; psychosocial factors (adverse life events, financial strain, poor social supports); high body mass index, smoking, and poor physical health.^6,7 Decreasing estrogen in the menopause transition may increase susceptibility to depression in some women.¹⁶ The Box^17,18 provides more information on the relationship between estrogen and brain function.

Depressive disorders, including premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression, have been linked to changes in hormonal status in women. Symptomatic menopause transition occurs in at least 20% of women, and a retrospective cohort study suggests that symptomatic menopause transition might increase the risk of new-onset depressive disorders, bipolar disorders, anxiety disorders, and sleep disorders.¹⁹ Symptomatic menopause transition also is a vulnerable time for relapse of MDD. Among women experiencing menopausal symptoms, including hot flashes, one-third also report depression—which correlates with a poorer quality of life, less work productivity, and greater use of health care services.⁹

Women who undergo surgical menopause are at greater risk for depression.^8,10,11 This may be due to abrupt deprivation of estrogen—or related to a psychological reaction to the loss of fertility.

The observation that hormonal fluctuations related to women’s reproductive cycle have a significant impact on psychotic symptomatology has resulted in the “hypo-estrogenism hypothesis,” which proposes that gonadal dysfunction may increase vulnerability to schizophrenia, or that schizophrenia may lead to gonadal dysfunction.²⁰ The “estrogen protection hypothesis” proposes that estrogen may protect women from schizophrenia, and may be a factor in the delayed onset of schizophrenia compared with men, less severe psychopathology, better outcomes, and premenstrual and postmenopausal deterioration in women. Many women of reproductive age with schizophrenia experience improvement in symptoms during the high estrogen phase of their menstrual cycle.

Pope et al²¹ have suggested that a hormone sensitivity syndrome may underlie why some women experience physical, psychological, and emotional symptoms at times of hormonal shifts such as menopause. This may represent a critical window of vulnerability, and also an opportunity to consider E2 as a therapeutic intervention.

Continued to: Treating mental illness in menopause

Changes to drug pharmacokinetics occur because some metabolising enzymes are estrogen-dependent and their levels decline after menopause, which leads to greater variability in drug response, particularly for oral medications. Other factors that can contribute to variability in medication response are polypharmacy, alcohol, illicit drugs, liver mass, smoking, caffeine, and nutritional intake.

While antidepressants are the first-line treatment for MDD and anxiety disorders, some patients remain unresponsive or inadequately responsive to currently available medications. In perimenopausal women with MDD, there may be an indication for adjunctive therapy with transdermal E2 in refractory cases; estrogen may augment the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants as well as hasten the onset of antidepressant action.²² Estrogen also may be worth considering in women with mild depressive symptoms. For MDD, SSRIs plus estrogen may be more beneficial in improving mood than either agent alone. The effectiveness of E2 is less certain in postmenopausal depression.

Hormonal therapy for mental health disorders has equivocal evidence. The individual’s history and risk factors (eg, cardiovascular and osteoporosis risks) must be considered. A recent trial found that treatment with either venlafaxine or low-dose estrogen improved quality of life in menopausal women with vasomotor symptoms.²³ Venlafaxine improved the psychosocial domain, while estrogen improved quality of life in other domains. Escitalopram, duloxetine, and citalopram have also been identified as having a possible positive impact on menopausal symptoms.²² SSRIs and serotonin-norepinephrine reuptake inhibitors may help reduce hot flashes and improve sleep.¹¹

Regarding schizophrenia and estrogen, there may be improved symptoms during the high estrogen phase of the menstrual cycle, followed by a premenstrual aggravation of symptoms. Recall that women have a second peak of onset of schizophrenia after age 45, around the age of the onset of menopause.²⁴ In a study of geropsychiatric hospital admissions, women were overrepresented among those with schizophrenia and schizoaffective disorder, compared with other psychiatric disorders.²⁵ Postmenopausally, some women experience a decreased responsiveness to antipsychotics and worsening symptoms. In menopausal women with schizophrenia, check prolactin levels to help determine whether they are experiencing a natural menopause or medication-induced amenorrhea. Gender differences in pharmacotherapy responses and the decreasing response to antipsychotics in women older than age 50 have been observed²⁶ and have led to exploration of the role of estrogen for treating schizophrenia in menopausal women. There have been contradictory results regarding use of estrogen as an adjunct to antipsychotics, with some reports finding this approach is effective and results in lower average doses of antipsychotics. Kulkarni et al^27,28 have reported improvements in positive symptoms of treatment-resistant schizophrenia with transdermal use of E2, 200 mcg, as an adjunct to antipsychotics in women of childbearing age. However, they expressed caution regarding the health risks associated with prolonged use of E2. Long-term risks of high-dose estrogen therapies include thromboembolism, endometrial hyperplasia, and breast cancer, and individual factors should be considered before starting any form of hormone therapy. Selective estrogen receptor modulators (SERMs), such as raloxifene, which can cause activation of E2 receptors in a tissue-specific fashion and have less estrogen-related adverse effects, offer hope for future development in this field.^27,28 While the use of adjunctive hormone therapy to manage psychotic symptoms in menopause is not routinely advised, the dosages of previously effective antipsychotics may need to be reviewed, or long-acting depot routes considered.²⁹ Increased risk of prolonged QTc interval and tardive dyskinesia in geriatric women also should be considered in decisions regarding changes to antipsychotics or dosages.³⁰

There are no guidelines regarding change in dosage of either individual antidepressants or antipsychotics in women at the time of menopause for managing pre-existing conditions. This may be due to the high variability in the effect of menopause on mental health and recognition that menopause is also a time for deterioration in physical health, as well as psychosocial changes for women, and thus other forms of intervention need to be considered.

Continued to: The biopsychosocial approach to treatment...

Although there are overlapping symptoms with both MDD and the perimenopause, these are typically restricted to impaired energy, sleep, and concentration, or changes in libido and weight.³² Therefore, it is vital to obtain a clear history and explore these symptoms in greater depth, as well as collect further information related to additional criteria such as appetite, agitation, feelings of worthlessness or guilt, and suicidal ideation.

Starting an antidepressant

On evaluation, Mrs. J discloses that she had experienced thoughts of wanting to end her life by overdose, although she had not acted on these thoughts. She appears subdued with poor eye contact, latency of response, and a slowed thought process. Mrs. J has blood tests to rule out thyroid abnormality or anemia. FSH and LH levels also are measured; these could provide a useful reference for later.

After a discussion with Mrs. J, she agrees to start an antidepressant. She also plans to speak to her gynecologist about the possibility of hormone replacement therapy. She is referred for psychotherapy to help support her with current life stressors. Mrs. J is started on escitalopram, 10 mg/d, and, after a month, she notices some improvement in her mood, psychomotor symptoms, sleep, and energy levels.

Bottom Line

Menopause is an important transition in our patients’ lives—both biologically and psychosocially. Women’s symptom patterns and medication needs may change during menopause.

Related Resource

• The North American Menopause Society. Depression & menopause. https://www.menopause.org/for-women/menopauseflashes/mental-health-at-menopause/depressionmenopause.

Drug Brand Names
Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Raloxifene • Evista
Venlafaxine • Effexor

Mrs. J, age 49, presents to your psychiatric clinic. For the last few years, she has been experiencing night sweats and hot flashes, which she has attributed to being perimenopausal. Over the last year, she has noticed that her mood has declined; however, she has suffered several life events that she feels have contributed. Her mother was diagnosed with Alzheimer’s disease and had to move into a nursing home, which Mrs. J found very stressful. At the same time, her daughter left home for college, and her son is exploring his college options. Recently, Mrs. J has not been able to work due to her mood, and she is afraid she may lose her job as a consequence. She has struggled to talk to her husband about how she is feeling, and feels increasingly isolated. Over the last month, she has had increased problems sleeping and less energy; some days she struggles to get out of bed. She is finding it difficult to concentrate and is more forgetful. She has lost interest in her hobbies and is no longer meeting with her friends. She has no history of depression or anxiety, although she recalls feeling very low in mood for months after the birth of each of her children.

Are Mrs. J’s symptoms related to menopause or depression? What further investigations are necessary? Would you modify your treatment plan because of her menopausal status?

Women are at elevated risk of developing psychiatric symptoms and disorders throughout their reproductive lives, including during menopause. Menopause is a time of life transition, when women may experience multiple physical symptoms, including vasomotor symptoms (night sweats and hot flashes), sexual symptoms, and sleep difficulties. Depressive symptoms occur more frequently during menopause, and symptoms of schizophrenia may worsen.

Estrogen plays a role in mental illness throughout a woman’s life. In menopause, decreasing estrogen levels may correlate with increased mood symptoms, physical symptoms, and psychotic symptoms. As such, psychiatrists should consider whether collaboration regarding adjunctive hormone replacement therapy would be beneficial, and whether the benefits outweigh the potential risks. Otherwise, treatment of depression in menopause is similar to treatment outside of the menopausal transition, though serotonergic antidepressants may help target vasomotor symptoms while therapy may focus on role transition and loss. In this article, we review why women are at increased risk for mental illness during menopause, the role of estrogen, and treatment of mood and psychotic disorders during this phase of a woman’s life.

Increased vulnerability across the lifespan

Continued to: Why menopause?

Why menopause?

Perimenopausal mood disorders

However, one should keep in mind that new-onset mania in menopause is rare and should trigger a medical work-up and a dementia evaluation.¹³ Table 4¹⁴ provides recommendations for evaluation of women undergoing menopause.

Menopause and serious mental illnesses

A study of 91 perimenopausal and postmenopausal women (age 45 to 55) who were diagnosed with schizophrenia/schizoaffective disorder, bipolar disorder, or major depressive disorder (MDD) found that women with severe mental illness experienced significant vasomotor, physical, sexual, and psychosocial symptoms related to menopause.¹⁵ Furthermore, on 7 of 29 items on the Menopause Specific Quality of Life Scale, including hot flashes, women diagnosed with MDD reported problems significantly more often than women with other serious mental illnesses.¹⁵

Women with serious mental illness often have deficits in their knowledge about menopause.³ More than half of the 91 women in the study diagnosed with schizophrenia/schizoaffective disorder, bipolar disorder, or MDD felt more stressed related to menopause, and reported that menopause had a negative effect on their mental health.³ These women rated their top 5 symptoms potentially related to menopause as feeling depressed, anxious, or tired; lacking energy; and experiencing poor memory.³

Continued to: Role of estrogen on mood and psychosis

Women are at higher risk throughout their reproductive life than are men for MDD, anxiety disorders, and trauma-related disorders.¹² Factors associated with depression during the menopause transition are reproductive hormonal changes (rise of follicle-stimulating hormone [FSH] and luteinizing hormone levels, and variability in estrogen [E2] and FSH levels); menopausal symptoms, particularly vasomotor symptoms; prior depression; psychosocial factors (adverse life events, financial strain, poor social supports); high body mass index, smoking, and poor physical health.^6,7 Decreasing estrogen in the menopause transition may increase susceptibility to depression in some women.¹⁶ The Box^17,18 provides more information on the relationship between estrogen and brain function.

Depressive disorders, including premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression, have been linked to changes in hormonal status in women. Symptomatic menopause transition occurs in at least 20% of women, and a retrospective cohort study suggests that symptomatic menopause transition might increase the risk of new-onset depressive disorders, bipolar disorders, anxiety disorders, and sleep disorders.¹⁹ Symptomatic menopause transition also is a vulnerable time for relapse of MDD. Among women experiencing menopausal symptoms, including hot flashes, one-third also report depression—which correlates with a poorer quality of life, less work productivity, and greater use of health care services.⁹

Women who undergo surgical menopause are at greater risk for depression.^8,10,11 This may be due to abrupt deprivation of estrogen—or related to a psychological reaction to the loss of fertility.

The observation that hormonal fluctuations related to women’s reproductive cycle have a significant impact on psychotic symptomatology has resulted in the “hypo-estrogenism hypothesis,” which proposes that gonadal dysfunction may increase vulnerability to schizophrenia, or that schizophrenia may lead to gonadal dysfunction.²⁰ The “estrogen protection hypothesis” proposes that estrogen may protect women from schizophrenia, and may be a factor in the delayed onset of schizophrenia compared with men, less severe psychopathology, better outcomes, and premenstrual and postmenopausal deterioration in women. Many women of reproductive age with schizophrenia experience improvement in symptoms during the high estrogen phase of their menstrual cycle.

Pope et al²¹ have suggested that a hormone sensitivity syndrome may underlie why some women experience physical, psychological, and emotional symptoms at times of hormonal shifts such as menopause. This may represent a critical window of vulnerability, and also an opportunity to consider E2 as a therapeutic intervention.

Continued to: Treating mental illness in menopause

Changes to drug pharmacokinetics occur because some metabolising enzymes are estrogen-dependent and their levels decline after menopause, which leads to greater variability in drug response, particularly for oral medications. Other factors that can contribute to variability in medication response are polypharmacy, alcohol, illicit drugs, liver mass, smoking, caffeine, and nutritional intake.

While antidepressants are the first-line treatment for MDD and anxiety disorders, some patients remain unresponsive or inadequately responsive to currently available medications. In perimenopausal women with MDD, there may be an indication for adjunctive therapy with transdermal E2 in refractory cases; estrogen may augment the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants as well as hasten the onset of antidepressant action.²² Estrogen also may be worth considering in women with mild depressive symptoms. For MDD, SSRIs plus estrogen may be more beneficial in improving mood than either agent alone. The effectiveness of E2 is less certain in postmenopausal depression.

Hormonal therapy for mental health disorders has equivocal evidence. The individual’s history and risk factors (eg, cardiovascular and osteoporosis risks) must be considered. A recent trial found that treatment with either venlafaxine or low-dose estrogen improved quality of life in menopausal women with vasomotor symptoms.²³ Venlafaxine improved the psychosocial domain, while estrogen improved quality of life in other domains. Escitalopram, duloxetine, and citalopram have also been identified as having a possible positive impact on menopausal symptoms.²² SSRIs and serotonin-norepinephrine reuptake inhibitors may help reduce hot flashes and improve sleep.¹¹

Regarding schizophrenia and estrogen, there may be improved symptoms during the high estrogen phase of the menstrual cycle, followed by a premenstrual aggravation of symptoms. Recall that women have a second peak of onset of schizophrenia after age 45, around the age of the onset of menopause.²⁴ In a study of geropsychiatric hospital admissions, women were overrepresented among those with schizophrenia and schizoaffective disorder, compared with other psychiatric disorders.²⁵ Postmenopausally, some women experience a decreased responsiveness to antipsychotics and worsening symptoms. In menopausal women with schizophrenia, check prolactin levels to help determine whether they are experiencing a natural menopause or medication-induced amenorrhea. Gender differences in pharmacotherapy responses and the decreasing response to antipsychotics in women older than age 50 have been observed²⁶ and have led to exploration of the role of estrogen for treating schizophrenia in menopausal women. There have been contradictory results regarding use of estrogen as an adjunct to antipsychotics, with some reports finding this approach is effective and results in lower average doses of antipsychotics. Kulkarni et al^27,28 have reported improvements in positive symptoms of treatment-resistant schizophrenia with transdermal use of E2, 200 mcg, as an adjunct to antipsychotics in women of childbearing age. However, they expressed caution regarding the health risks associated with prolonged use of E2. Long-term risks of high-dose estrogen therapies include thromboembolism, endometrial hyperplasia, and breast cancer, and individual factors should be considered before starting any form of hormone therapy. Selective estrogen receptor modulators (SERMs), such as raloxifene, which can cause activation of E2 receptors in a tissue-specific fashion and have less estrogen-related adverse effects, offer hope for future development in this field.^27,28 While the use of adjunctive hormone therapy to manage psychotic symptoms in menopause is not routinely advised, the dosages of previously effective antipsychotics may need to be reviewed, or long-acting depot routes considered.²⁹ Increased risk of prolonged QTc interval and tardive dyskinesia in geriatric women also should be considered in decisions regarding changes to antipsychotics or dosages.³⁰

There are no guidelines regarding change in dosage of either individual antidepressants or antipsychotics in women at the time of menopause for managing pre-existing conditions. This may be due to the high variability in the effect of menopause on mental health and recognition that menopause is also a time for deterioration in physical health, as well as psychosocial changes for women, and thus other forms of intervention need to be considered.

Continued to: The biopsychosocial approach to treatment...

Although there are overlapping symptoms with both MDD and the perimenopause, these are typically restricted to impaired energy, sleep, and concentration, or changes in libido and weight.³² Therefore, it is vital to obtain a clear history and explore these symptoms in greater depth, as well as collect further information related to additional criteria such as appetite, agitation, feelings of worthlessness or guilt, and suicidal ideation.

Starting an antidepressant

On evaluation, Mrs. J discloses that she had experienced thoughts of wanting to end her life by overdose, although she had not acted on these thoughts. She appears subdued with poor eye contact, latency of response, and a slowed thought process. Mrs. J has blood tests to rule out thyroid abnormality or anemia. FSH and LH levels also are measured; these could provide a useful reference for later.

After a discussion with Mrs. J, she agrees to start an antidepressant. She also plans to speak to her gynecologist about the possibility of hormone replacement therapy. She is referred for psychotherapy to help support her with current life stressors. Mrs. J is started on escitalopram, 10 mg/d, and, after a month, she notices some improvement in her mood, psychomotor symptoms, sleep, and energy levels.

Bottom Line

Menopause is an important transition in our patients’ lives—both biologically and psychosocially. Women’s symptom patterns and medication needs may change during menopause.

Related Resource

• The North American Menopause Society. Depression & menopause. https://www.menopause.org/for-women/menopauseflashes/mental-health-at-menopause/depressionmenopause.

Drug Brand Names
Citalopram • Celexa
Duloxetine • Cymbalta
Escitalopram • Lexapro
Raloxifene • Evista
Venlafaxine • Effexor

Autism spectrum disorder (ASD) is an umbrella term used to describe lifelong neurodevelopmental disorders characterized by impairment in social interactions and communication coupled with restricted, repetitive patterns of behaviors or interests that appear to share a common developmental course.¹ In this article, we examine psychiatric care of patients with ASD and the most common symptom clusters treated with pharmacotherapy: irritability, anxiety, and hyperactivity/inattention.

First step: Keep the diagnosis in mind

Prior to 2013, ASD was comprised of 3 separate disorders distinguished by language delay and overall severity: autistic disorder, Asperger’s disorder, and pervasive developmental disorder, not otherwise specified.² With the release of DSM-5 in 2013, these disorders were essentially collapsed into a single ASD.³ ASD prevalence is estimated to be 1 in 59 children,⁴ which represents a 20- to 30-fold increase since the 1960s.

In order to provide adequate psychiatric care for individuals with ASD, the first step is to remember the diagnosis; keep it in mind. This may be particularly important for clinicians who primarily care for adults, because such clinicians often receive limited training in disorders first manifesting in childhood and may not consider ASD in patients who have not been previously diagnosed. However, ASD diagnostic criteria have become broader, and public knowledge of the diagnosis has grown. DSM-5 acknowledges that although symptoms begin in early childhood, they may become more recognizable later in life with increasing social demand. The result is that many adults are likely undiagnosed. The estimated prevalence of ASD in adult psychiatric settings range from 1.5% to 4%.^5-7 These patients have different treatment needs and unfortunately are often misdiagnosed with other psychiatric conditions.

A recent study in a state psychiatric facility found that 10% of patients in this setting met criteria for ASD.⁸ Almost all of those patients had been misdiagnosed with some form of schizophrenia, including one patient who had been previously diagnosed with autism by the father of autism himself, Leo Kanner, MD. Through the years, this patient’s autism diagnosis had fallen away, and at the time of the study, the patient carried a diagnosis of undifferentiated schizophrenia and was prescribed 8 psychotropic medications. The patient had repeatedly denied auditory or visual hallucinations; however, his stereotypies and odd behaviors were taken as evidence that he was responding to internal stimuli. This case highlights the importance of keeping the ASD diagnosis in mind when evaluating and treating patients.

Addressing 3 key symptom clusters

Even for patients with an established ASD diagnosis, comprehensive treatment is complex. It typically involves a multimodal approach that includes speech therapy, occupational therapy, applied behavioral analysis (ABA), and vocational training and support as well as management of associated medical conditions. Because medical comorbidities may play an important role in exacerbation of severe behaviors in ASD, often leading to acute behavioral regression and psychiatric admission, it is essential that they not be overlooked during evaluations.^9,10

There are no effective pharmacologic treatments for the core social deficits seen in ASD. Novel pharmacotherapies to improve social impairment are in the early stages of research,^11,12 but currently social impairment is best addressed through behavioral therapy and social skills training. Our role as psychiatrists is most often to treat co-occurring psychiatric symptoms so that individuals with ASD can fully participate in behavioral and school-based treatments that lead to improved social skills, activities of daily living, and quality of life. Three of the most common of these symptoms are irritability, anxiety, and hyperactivity/inattention.

Irritability

Irritability, marked by aggression, self-injury, and severe tantrums, causes serious distress for both patients and families, and this behavior cluster is the most frequently reported comorbid symptom in ASD.^13-15 Nonpharmacologic treatment of irritability often involves ABA-based therapy and communication training.

Continued to: ABA includes an initial functional behavior assessment...

ABA includes an initial functional behavior assessment (FBA) of maladaptive behavior followed by the application of specific schedules of reinforcement for positive behavior. The FBA allows the therapist to determine what desirable consequences maintain a behavior. Without this knowledge, there is the risk of inadvertently rewarding a maladaptive behavior. For instance, if you are recommending a time-out for escape-motivated aggression, the result will likely be an increase rather than decrease in aggression.

Communication training teaches the patient to use communicative means to request a desired outcome to reduce inappropriate behaviors and improve independent functioning. Communication training can include speech therapy, teaching sign language, using picture exchange programs, or navigating communication devices. Consideration of nonpharmacologic management is vital in treatment planning. Continual inadvertent reward of behaviors will limit the effects of medications. Evidence suggests that pharmacotherapy is more effective when it occurs in the context of appropriate behavioral management techniques.¹⁶

Irritability has been the focus of significant pharmacotherapy research in ASD. Second-generation antipsychotics (SGAs) are first-line pharmacotherapy for severe irritability. Risperidone and aripiprazole are both FDA-approved for addressing irritability in youth with ASD. Their efficacy has been established in several large, placebo-controlled trials.^17-23

Given issues with tolerability and cases refractory to the use of first-line agents,²⁴ other SGAs are frequently used off-label for this indication with limited safety or efficacy data. Olanzapine demonstrated high response rates in early open-label studies,^25,26 followed by efficacy over an 8-week double-blind placebo-controlled trial, although with significant weight gain.²⁷ No other SGAs have been examined in double-blind placebo-controlled trials. Paliperidone demonstrated a particularly high response rate (84%) in a prospective open-label study of 25 adolescents and young adults with ASD.²⁸ In a retrospective study of ziprasidone in 42 youth with ASD and irritability, we reported a response rate of 40%, which is lower than that seen for some other SGAs; however, ziprasidone can be an appealing option for patients for whom SGA-associated weight gain has been significant, because it is much more likely to be weight-neutral.^29,30 Open-label studies with quetiapine in ASD have generally revealed only minimal efficacy for aggression,^31,32 although sleep improvement may be more substantial.³² The safety and tolerability of lurasidone in treating irritability in youth with ASD has yet to be established.³³ It is the only SGA with a published negative placebo-controlled trial in ASD.³⁴ Use of SGAs may be limited by adverse effects, including weight gain, increased appetite, sedation, enuresis, and elevated prolactin. Monitoring of body mass index and metabolic profiles is indicated with all SGAs.

Haloperidol is the only first-generation antipsychotic with significant evidence (from multiple studies dating back to 1978) to support its use for ASD-associated irritability.³⁵ However, due to the high incidence of dyskinesias and potential dystonias, use of haloperidol is reserved for severe treatment-refractory symptoms that have often not improved after multiple SGA trials.

Continued to: When severe self-inury and aggression fail to improve...

Anxiety

Anxiety is a significant issue for many individuals with ASD.⁴⁷ Anxiety symptoms and disorders, including specific phobias, obsessive-compulsive disorder (OCD), social anxiety, and generalized anxiety disorder, are commonly seen in persons with ASD.⁴⁸ Anxiety is often combined with restricted, repetitive behaviors (RBs) in ASD literature. Some evidence suggests that in individuals with ASD, sameness behaviors may limit sensory input and modulate anxiety.⁴⁹ However, the core RBs symptom domain may not be related solely to anxiety, but rather represents deficits in executive processes that include cognitive flexibility and inhibitory control seen across multiple disorders with prominent RBs.^50-54 Research indicates that anxiety is an independent and separable construct in ASD.⁵⁵

Studies of treatments for both RBs and anxiety have focused primarily on selective serotonin reuptake inhibitors (SSRIs), hoping that the promising results for anxiety and OCD behaviors seen in neurotypical patients would translate to patients with ASD.⁵⁶ Unfortunately, there is little evidence for effective pharmacologic management of ASD-associated anxiety.⁵⁷ Large, randomized controlled trials (RCTs) are lacking. A Cochrane Database review of SSRIs for ASD⁵⁸ examined 9 RCTs with a total of 320 patients. The authors concluded that there is no evidence to support the use of SSRIs for children with ASD, and limited evidence of utility in adults. Youth with ASD are particularly vulnerable to adverse effects from SSRIs, specifically impulsivity and agitation.^57,59 However, SSRIs are among the most commonly prescribed medications for youth with ASD. Because there is limited evidence supporting SSRIs’ efficacy for this indication and issues with tolerability, there is significant concern for the overprescribing of SSRIs to patients with ASD. In comparison, there is some compelling evidence of efficacy for modified cognitive-behavioral therapy (CBT) for patients with high-functioning ASD. Seven RCTs have shown that CBT is superior to treatment as usual and waiting list control groups, with most effect sizes >0.8 and with no treatment-associated adverse effects.⁵⁷

Risperidone has been shown to reduce RBs^17,60 and anxiety¹⁷ in patients with ASD. In young children with co-occurring irritability, risperidone monotherapy is likely best to address both symptoms. When anxiety occurs in isolation and is severe, clinical experience suggests that SSRIs can be effective in a limited percentage of cases, though we recommend starting at low doses with frequent monitoring for activation and irritability. Treatment of anxiety is further complicated by the significant challenges presented by the diagnosis of true anxiety in the context of ASD.

Continued to: Hyperactivity and impulsivity

Hyperactivity and impulsivity are common among patients with ASD, with rates estimated from 41% to 78%.⁶¹ Hyperactivity and inattention are treated with a variety of medications. Research examining methylphenidate in ASD has demonstrated modest effects compared with placebo, though with frequent adverse effects, such as increased irritability and insomnia^62,63 Other smaller studies have confirmed these results.^64-66 One additional study found improvements not only in hyperactivity but also in joint attention and self-regulation of affective state following stimulant treatment.⁶⁷ There is limited data on the efficacy and tolerability of amphetamine for treating hyperactivity and impulsivity in ASD. Stimulant medications often are avoided as the first-line treatment for hyperactivity because of concerns about increased irritability. Alpha-2 adrenergic receptor agonists often are used before stimulants because of their relatively benign adverse effect profile. Clonidine, guanfacine, and guanfacine ER all have demonstrated effectiveness in double-blind, placebo-controls trials in patients with ASD.^68-70 In these trails, sedation was the most common adverse effect, although some studies have reported increased irritability with guanfacine.^70,71

The Table provides a summary of the target symptoms and their treatment options for patients with ASD.

Improved diagnosis, but few evidence-based treatments

The rise in ASD cases observed over the past 20 years can be explained in part by a broader diagnostic algorithm and increased awareness. We are better at identifying ASD; however, there are still considerable gaps in identifying ASD in high-functioning patients and adults. One percent of the population has ASD,^72,73 and this group is overrepresented in psychiatric clinic and hospital settings.⁷⁴ Therefore, we must be aware of and understand the diagnosis.

Medication treatments are often less effective and less tolerable in patients with ASD than in patients without neurodevelop­mental disability. There are differences in pharmacotherapy response and tolerability across development in ASD and limited evidence to guide prescribing in adults with ASD. SGAs appear to be effective across multiple symptom domains, but carry the risk of significant adverse effects. For anxiety and irritability, there is compelling evidence supporting the use of nonpharmacologic treatments.

Bottom Line

A subset of patients seen in psychiatry will have undiagnosed autism spectrum disorder (ASD). When evaluating worsening behaviors, first rule out organic causes. Second-generation antipsychotics have the most evidence for efficacy in ASD across multiple symptom domains. To sustain improvement in symptoms, it is vital to incorporate nonpharmacologic treatments.

Related Resources

• National Institute of Mental Health. Autism spectrum disorder. https://www.nimh.nih.gov/health/publications/autismspectrum-disorder/index.shtml.
• Centers for Disease Control and Prevention. Autism spectrum disorder (ASD). https://www.cdc.gov/ncbddd/ autism/index.html.

Drug Brand Names
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Guanfacine • Tenex
Guanfacine Extended Release • Intuniv
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Paliperidone • Invega
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

Autism spectrum disorder (ASD) is an umbrella term used to describe lifelong neurodevelopmental disorders characterized by impairment in social interactions and communication coupled with restricted, repetitive patterns of behaviors or interests that appear to share a common developmental course.¹ In this article, we examine psychiatric care of patients with ASD and the most common symptom clusters treated with pharmacotherapy: irritability, anxiety, and hyperactivity/inattention.

First step: Keep the diagnosis in mind

Prior to 2013, ASD was comprised of 3 separate disorders distinguished by language delay and overall severity: autistic disorder, Asperger’s disorder, and pervasive developmental disorder, not otherwise specified.² With the release of DSM-5 in 2013, these disorders were essentially collapsed into a single ASD.³ ASD prevalence is estimated to be 1 in 59 children,⁴ which represents a 20- to 30-fold increase since the 1960s.

In order to provide adequate psychiatric care for individuals with ASD, the first step is to remember the diagnosis; keep it in mind. This may be particularly important for clinicians who primarily care for adults, because such clinicians often receive limited training in disorders first manifesting in childhood and may not consider ASD in patients who have not been previously diagnosed. However, ASD diagnostic criteria have become broader, and public knowledge of the diagnosis has grown. DSM-5 acknowledges that although symptoms begin in early childhood, they may become more recognizable later in life with increasing social demand. The result is that many adults are likely undiagnosed. The estimated prevalence of ASD in adult psychiatric settings range from 1.5% to 4%.^5-7 These patients have different treatment needs and unfortunately are often misdiagnosed with other psychiatric conditions.

A recent study in a state psychiatric facility found that 10% of patients in this setting met criteria for ASD.⁸ Almost all of those patients had been misdiagnosed with some form of schizophrenia, including one patient who had been previously diagnosed with autism by the father of autism himself, Leo Kanner, MD. Through the years, this patient’s autism diagnosis had fallen away, and at the time of the study, the patient carried a diagnosis of undifferentiated schizophrenia and was prescribed 8 psychotropic medications. The patient had repeatedly denied auditory or visual hallucinations; however, his stereotypies and odd behaviors were taken as evidence that he was responding to internal stimuli. This case highlights the importance of keeping the ASD diagnosis in mind when evaluating and treating patients.

Addressing 3 key symptom clusters

Even for patients with an established ASD diagnosis, comprehensive treatment is complex. It typically involves a multimodal approach that includes speech therapy, occupational therapy, applied behavioral analysis (ABA), and vocational training and support as well as management of associated medical conditions. Because medical comorbidities may play an important role in exacerbation of severe behaviors in ASD, often leading to acute behavioral regression and psychiatric admission, it is essential that they not be overlooked during evaluations.^9,10

There are no effective pharmacologic treatments for the core social deficits seen in ASD. Novel pharmacotherapies to improve social impairment are in the early stages of research,^11,12 but currently social impairment is best addressed through behavioral therapy and social skills training. Our role as psychiatrists is most often to treat co-occurring psychiatric symptoms so that individuals with ASD can fully participate in behavioral and school-based treatments that lead to improved social skills, activities of daily living, and quality of life. Three of the most common of these symptoms are irritability, anxiety, and hyperactivity/inattention.

Irritability

Irritability, marked by aggression, self-injury, and severe tantrums, causes serious distress for both patients and families, and this behavior cluster is the most frequently reported comorbid symptom in ASD.^13-15 Nonpharmacologic treatment of irritability often involves ABA-based therapy and communication training.

Continued to: ABA includes an initial functional behavior assessment...

ABA includes an initial functional behavior assessment (FBA) of maladaptive behavior followed by the application of specific schedules of reinforcement for positive behavior. The FBA allows the therapist to determine what desirable consequences maintain a behavior. Without this knowledge, there is the risk of inadvertently rewarding a maladaptive behavior. For instance, if you are recommending a time-out for escape-motivated aggression, the result will likely be an increase rather than decrease in aggression.

Communication training teaches the patient to use communicative means to request a desired outcome to reduce inappropriate behaviors and improve independent functioning. Communication training can include speech therapy, teaching sign language, using picture exchange programs, or navigating communication devices. Consideration of nonpharmacologic management is vital in treatment planning. Continual inadvertent reward of behaviors will limit the effects of medications. Evidence suggests that pharmacotherapy is more effective when it occurs in the context of appropriate behavioral management techniques.¹⁶

Irritability has been the focus of significant pharmacotherapy research in ASD. Second-generation antipsychotics (SGAs) are first-line pharmacotherapy for severe irritability. Risperidone and aripiprazole are both FDA-approved for addressing irritability in youth with ASD. Their efficacy has been established in several large, placebo-controlled trials.^17-23

Given issues with tolerability and cases refractory to the use of first-line agents,²⁴ other SGAs are frequently used off-label for this indication with limited safety or efficacy data. Olanzapine demonstrated high response rates in early open-label studies,^25,26 followed by efficacy over an 8-week double-blind placebo-controlled trial, although with significant weight gain.²⁷ No other SGAs have been examined in double-blind placebo-controlled trials. Paliperidone demonstrated a particularly high response rate (84%) in a prospective open-label study of 25 adolescents and young adults with ASD.²⁸ In a retrospective study of ziprasidone in 42 youth with ASD and irritability, we reported a response rate of 40%, which is lower than that seen for some other SGAs; however, ziprasidone can be an appealing option for patients for whom SGA-associated weight gain has been significant, because it is much more likely to be weight-neutral.^29,30 Open-label studies with quetiapine in ASD have generally revealed only minimal efficacy for aggression,^31,32 although sleep improvement may be more substantial.³² The safety and tolerability of lurasidone in treating irritability in youth with ASD has yet to be established.³³ It is the only SGA with a published negative placebo-controlled trial in ASD.³⁴ Use of SGAs may be limited by adverse effects, including weight gain, increased appetite, sedation, enuresis, and elevated prolactin. Monitoring of body mass index and metabolic profiles is indicated with all SGAs.

Haloperidol is the only first-generation antipsychotic with significant evidence (from multiple studies dating back to 1978) to support its use for ASD-associated irritability.³⁵ However, due to the high incidence of dyskinesias and potential dystonias, use of haloperidol is reserved for severe treatment-refractory symptoms that have often not improved after multiple SGA trials.

Continued to: When severe self-inury and aggression fail to improve...

Anxiety

Anxiety is a significant issue for many individuals with ASD.⁴⁷ Anxiety symptoms and disorders, including specific phobias, obsessive-compulsive disorder (OCD), social anxiety, and generalized anxiety disorder, are commonly seen in persons with ASD.⁴⁸ Anxiety is often combined with restricted, repetitive behaviors (RBs) in ASD literature. Some evidence suggests that in individuals with ASD, sameness behaviors may limit sensory input and modulate anxiety.⁴⁹ However, the core RBs symptom domain may not be related solely to anxiety, but rather represents deficits in executive processes that include cognitive flexibility and inhibitory control seen across multiple disorders with prominent RBs.^50-54 Research indicates that anxiety is an independent and separable construct in ASD.⁵⁵

Studies of treatments for both RBs and anxiety have focused primarily on selective serotonin reuptake inhibitors (SSRIs), hoping that the promising results for anxiety and OCD behaviors seen in neurotypical patients would translate to patients with ASD.⁵⁶ Unfortunately, there is little evidence for effective pharmacologic management of ASD-associated anxiety.⁵⁷ Large, randomized controlled trials (RCTs) are lacking. A Cochrane Database review of SSRIs for ASD⁵⁸ examined 9 RCTs with a total of 320 patients. The authors concluded that there is no evidence to support the use of SSRIs for children with ASD, and limited evidence of utility in adults. Youth with ASD are particularly vulnerable to adverse effects from SSRIs, specifically impulsivity and agitation.^57,59 However, SSRIs are among the most commonly prescribed medications for youth with ASD. Because there is limited evidence supporting SSRIs’ efficacy for this indication and issues with tolerability, there is significant concern for the overprescribing of SSRIs to patients with ASD. In comparison, there is some compelling evidence of efficacy for modified cognitive-behavioral therapy (CBT) for patients with high-functioning ASD. Seven RCTs have shown that CBT is superior to treatment as usual and waiting list control groups, with most effect sizes >0.8 and with no treatment-associated adverse effects.⁵⁷

Risperidone has been shown to reduce RBs^17,60 and anxiety¹⁷ in patients with ASD. In young children with co-occurring irritability, risperidone monotherapy is likely best to address both symptoms. When anxiety occurs in isolation and is severe, clinical experience suggests that SSRIs can be effective in a limited percentage of cases, though we recommend starting at low doses with frequent monitoring for activation and irritability. Treatment of anxiety is further complicated by the significant challenges presented by the diagnosis of true anxiety in the context of ASD.

Continued to: Hyperactivity and impulsivity

Hyperactivity and impulsivity are common among patients with ASD, with rates estimated from 41% to 78%.⁶¹ Hyperactivity and inattention are treated with a variety of medications. Research examining methylphenidate in ASD has demonstrated modest effects compared with placebo, though with frequent adverse effects, such as increased irritability and insomnia^62,63 Other smaller studies have confirmed these results.^64-66 One additional study found improvements not only in hyperactivity but also in joint attention and self-regulation of affective state following stimulant treatment.⁶⁷ There is limited data on the efficacy and tolerability of amphetamine for treating hyperactivity and impulsivity in ASD. Stimulant medications often are avoided as the first-line treatment for hyperactivity because of concerns about increased irritability. Alpha-2 adrenergic receptor agonists often are used before stimulants because of their relatively benign adverse effect profile. Clonidine, guanfacine, and guanfacine ER all have demonstrated effectiveness in double-blind, placebo-controls trials in patients with ASD.^68-70 In these trails, sedation was the most common adverse effect, although some studies have reported increased irritability with guanfacine.^70,71

The Table provides a summary of the target symptoms and their treatment options for patients with ASD.

Improved diagnosis, but few evidence-based treatments

The rise in ASD cases observed over the past 20 years can be explained in part by a broader diagnostic algorithm and increased awareness. We are better at identifying ASD; however, there are still considerable gaps in identifying ASD in high-functioning patients and adults. One percent of the population has ASD,^72,73 and this group is overrepresented in psychiatric clinic and hospital settings.⁷⁴ Therefore, we must be aware of and understand the diagnosis.

Medication treatments are often less effective and less tolerable in patients with ASD than in patients without neurodevelop­mental disability. There are differences in pharmacotherapy response and tolerability across development in ASD and limited evidence to guide prescribing in adults with ASD. SGAs appear to be effective across multiple symptom domains, but carry the risk of significant adverse effects. For anxiety and irritability, there is compelling evidence supporting the use of nonpharmacologic treatments.

Bottom Line

A subset of patients seen in psychiatry will have undiagnosed autism spectrum disorder (ASD). When evaluating worsening behaviors, first rule out organic causes. Second-generation antipsychotics have the most evidence for efficacy in ASD across multiple symptom domains. To sustain improvement in symptoms, it is vital to incorporate nonpharmacologic treatments.

Related Resources

• National Institute of Mental Health. Autism spectrum disorder. https://www.nimh.nih.gov/health/publications/autismspectrum-disorder/index.shtml.
• Centers for Disease Control and Prevention. Autism spectrum disorder (ASD). https://www.cdc.gov/ncbddd/ autism/index.html.

Drug Brand Names
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Guanfacine • Tenex
Guanfacine Extended Release • Intuniv
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Paliperidone • Invega
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

Autism spectrum disorder (ASD) is an umbrella term used to describe lifelong neurodevelopmental disorders characterized by impairment in social interactions and communication coupled with restricted, repetitive patterns of behaviors or interests that appear to share a common developmental course.¹ In this article, we examine psychiatric care of patients with ASD and the most common symptom clusters treated with pharmacotherapy: irritability, anxiety, and hyperactivity/inattention.

First step: Keep the diagnosis in mind

Prior to 2013, ASD was comprised of 3 separate disorders distinguished by language delay and overall severity: autistic disorder, Asperger’s disorder, and pervasive developmental disorder, not otherwise specified.² With the release of DSM-5 in 2013, these disorders were essentially collapsed into a single ASD.³ ASD prevalence is estimated to be 1 in 59 children,⁴ which represents a 20- to 30-fold increase since the 1960s.

In order to provide adequate psychiatric care for individuals with ASD, the first step is to remember the diagnosis; keep it in mind. This may be particularly important for clinicians who primarily care for adults, because such clinicians often receive limited training in disorders first manifesting in childhood and may not consider ASD in patients who have not been previously diagnosed. However, ASD diagnostic criteria have become broader, and public knowledge of the diagnosis has grown. DSM-5 acknowledges that although symptoms begin in early childhood, they may become more recognizable later in life with increasing social demand. The result is that many adults are likely undiagnosed. The estimated prevalence of ASD in adult psychiatric settings range from 1.5% to 4%.^5-7 These patients have different treatment needs and unfortunately are often misdiagnosed with other psychiatric conditions.

A recent study in a state psychiatric facility found that 10% of patients in this setting met criteria for ASD.⁸ Almost all of those patients had been misdiagnosed with some form of schizophrenia, including one patient who had been previously diagnosed with autism by the father of autism himself, Leo Kanner, MD. Through the years, this patient’s autism diagnosis had fallen away, and at the time of the study, the patient carried a diagnosis of undifferentiated schizophrenia and was prescribed 8 psychotropic medications. The patient had repeatedly denied auditory or visual hallucinations; however, his stereotypies and odd behaviors were taken as evidence that he was responding to internal stimuli. This case highlights the importance of keeping the ASD diagnosis in mind when evaluating and treating patients.

Addressing 3 key symptom clusters

Even for patients with an established ASD diagnosis, comprehensive treatment is complex. It typically involves a multimodal approach that includes speech therapy, occupational therapy, applied behavioral analysis (ABA), and vocational training and support as well as management of associated medical conditions. Because medical comorbidities may play an important role in exacerbation of severe behaviors in ASD, often leading to acute behavioral regression and psychiatric admission, it is essential that they not be overlooked during evaluations.^9,10

There are no effective pharmacologic treatments for the core social deficits seen in ASD. Novel pharmacotherapies to improve social impairment are in the early stages of research,^11,12 but currently social impairment is best addressed through behavioral therapy and social skills training. Our role as psychiatrists is most often to treat co-occurring psychiatric symptoms so that individuals with ASD can fully participate in behavioral and school-based treatments that lead to improved social skills, activities of daily living, and quality of life. Three of the most common of these symptoms are irritability, anxiety, and hyperactivity/inattention.

Irritability

Irritability, marked by aggression, self-injury, and severe tantrums, causes serious distress for both patients and families, and this behavior cluster is the most frequently reported comorbid symptom in ASD.^13-15 Nonpharmacologic treatment of irritability often involves ABA-based therapy and communication training.

Continued to: ABA includes an initial functional behavior assessment...

ABA includes an initial functional behavior assessment (FBA) of maladaptive behavior followed by the application of specific schedules of reinforcement for positive behavior. The FBA allows the therapist to determine what desirable consequences maintain a behavior. Without this knowledge, there is the risk of inadvertently rewarding a maladaptive behavior. For instance, if you are recommending a time-out for escape-motivated aggression, the result will likely be an increase rather than decrease in aggression.

Communication training teaches the patient to use communicative means to request a desired outcome to reduce inappropriate behaviors and improve independent functioning. Communication training can include speech therapy, teaching sign language, using picture exchange programs, or navigating communication devices. Consideration of nonpharmacologic management is vital in treatment planning. Continual inadvertent reward of behaviors will limit the effects of medications. Evidence suggests that pharmacotherapy is more effective when it occurs in the context of appropriate behavioral management techniques.¹⁶

Irritability has been the focus of significant pharmacotherapy research in ASD. Second-generation antipsychotics (SGAs) are first-line pharmacotherapy for severe irritability. Risperidone and aripiprazole are both FDA-approved for addressing irritability in youth with ASD. Their efficacy has been established in several large, placebo-controlled trials.^17-23

Given issues with tolerability and cases refractory to the use of first-line agents,²⁴ other SGAs are frequently used off-label for this indication with limited safety or efficacy data. Olanzapine demonstrated high response rates in early open-label studies,^25,26 followed by efficacy over an 8-week double-blind placebo-controlled trial, although with significant weight gain.²⁷ No other SGAs have been examined in double-blind placebo-controlled trials. Paliperidone demonstrated a particularly high response rate (84%) in a prospective open-label study of 25 adolescents and young adults with ASD.²⁸ In a retrospective study of ziprasidone in 42 youth with ASD and irritability, we reported a response rate of 40%, which is lower than that seen for some other SGAs; however, ziprasidone can be an appealing option for patients for whom SGA-associated weight gain has been significant, because it is much more likely to be weight-neutral.^29,30 Open-label studies with quetiapine in ASD have generally revealed only minimal efficacy for aggression,^31,32 although sleep improvement may be more substantial.³² The safety and tolerability of lurasidone in treating irritability in youth with ASD has yet to be established.³³ It is the only SGA with a published negative placebo-controlled trial in ASD.³⁴ Use of SGAs may be limited by adverse effects, including weight gain, increased appetite, sedation, enuresis, and elevated prolactin. Monitoring of body mass index and metabolic profiles is indicated with all SGAs.

Haloperidol is the only first-generation antipsychotic with significant evidence (from multiple studies dating back to 1978) to support its use for ASD-associated irritability.³⁵ However, due to the high incidence of dyskinesias and potential dystonias, use of haloperidol is reserved for severe treatment-refractory symptoms that have often not improved after multiple SGA trials.

Continued to: When severe self-inury and aggression fail to improve...

Anxiety

Anxiety is a significant issue for many individuals with ASD.⁴⁷ Anxiety symptoms and disorders, including specific phobias, obsessive-compulsive disorder (OCD), social anxiety, and generalized anxiety disorder, are commonly seen in persons with ASD.⁴⁸ Anxiety is often combined with restricted, repetitive behaviors (RBs) in ASD literature. Some evidence suggests that in individuals with ASD, sameness behaviors may limit sensory input and modulate anxiety.⁴⁹ However, the core RBs symptom domain may not be related solely to anxiety, but rather represents deficits in executive processes that include cognitive flexibility and inhibitory control seen across multiple disorders with prominent RBs.^50-54 Research indicates that anxiety is an independent and separable construct in ASD.⁵⁵

Studies of treatments for both RBs and anxiety have focused primarily on selective serotonin reuptake inhibitors (SSRIs), hoping that the promising results for anxiety and OCD behaviors seen in neurotypical patients would translate to patients with ASD.⁵⁶ Unfortunately, there is little evidence for effective pharmacologic management of ASD-associated anxiety.⁵⁷ Large, randomized controlled trials (RCTs) are lacking. A Cochrane Database review of SSRIs for ASD⁵⁸ examined 9 RCTs with a total of 320 patients. The authors concluded that there is no evidence to support the use of SSRIs for children with ASD, and limited evidence of utility in adults. Youth with ASD are particularly vulnerable to adverse effects from SSRIs, specifically impulsivity and agitation.^57,59 However, SSRIs are among the most commonly prescribed medications for youth with ASD. Because there is limited evidence supporting SSRIs’ efficacy for this indication and issues with tolerability, there is significant concern for the overprescribing of SSRIs to patients with ASD. In comparison, there is some compelling evidence of efficacy for modified cognitive-behavioral therapy (CBT) for patients with high-functioning ASD. Seven RCTs have shown that CBT is superior to treatment as usual and waiting list control groups, with most effect sizes >0.8 and with no treatment-associated adverse effects.⁵⁷

Risperidone has been shown to reduce RBs^17,60 and anxiety¹⁷ in patients with ASD. In young children with co-occurring irritability, risperidone monotherapy is likely best to address both symptoms. When anxiety occurs in isolation and is severe, clinical experience suggests that SSRIs can be effective in a limited percentage of cases, though we recommend starting at low doses with frequent monitoring for activation and irritability. Treatment of anxiety is further complicated by the significant challenges presented by the diagnosis of true anxiety in the context of ASD.

Continued to: Hyperactivity and impulsivity

Hyperactivity and impulsivity are common among patients with ASD, with rates estimated from 41% to 78%.⁶¹ Hyperactivity and inattention are treated with a variety of medications. Research examining methylphenidate in ASD has demonstrated modest effects compared with placebo, though with frequent adverse effects, such as increased irritability and insomnia^62,63 Other smaller studies have confirmed these results.^64-66 One additional study found improvements not only in hyperactivity but also in joint attention and self-regulation of affective state following stimulant treatment.⁶⁷ There is limited data on the efficacy and tolerability of amphetamine for treating hyperactivity and impulsivity in ASD. Stimulant medications often are avoided as the first-line treatment for hyperactivity because of concerns about increased irritability. Alpha-2 adrenergic receptor agonists often are used before stimulants because of their relatively benign adverse effect profile. Clonidine, guanfacine, and guanfacine ER all have demonstrated effectiveness in double-blind, placebo-controls trials in patients with ASD.^68-70 In these trails, sedation was the most common adverse effect, although some studies have reported increased irritability with guanfacine.^70,71

The Table provides a summary of the target symptoms and their treatment options for patients with ASD.

Improved diagnosis, but few evidence-based treatments

The rise in ASD cases observed over the past 20 years can be explained in part by a broader diagnostic algorithm and increased awareness. We are better at identifying ASD; however, there are still considerable gaps in identifying ASD in high-functioning patients and adults. One percent of the population has ASD,^72,73 and this group is overrepresented in psychiatric clinic and hospital settings.⁷⁴ Therefore, we must be aware of and understand the diagnosis.

Medication treatments are often less effective and less tolerable in patients with ASD than in patients without neurodevelop­mental disability. There are differences in pharmacotherapy response and tolerability across development in ASD and limited evidence to guide prescribing in adults with ASD. SGAs appear to be effective across multiple symptom domains, but carry the risk of significant adverse effects. For anxiety and irritability, there is compelling evidence supporting the use of nonpharmacologic treatments.

Bottom Line

A subset of patients seen in psychiatry will have undiagnosed autism spectrum disorder (ASD). When evaluating worsening behaviors, first rule out organic causes. Second-generation antipsychotics have the most evidence for efficacy in ASD across multiple symptom domains. To sustain improvement in symptoms, it is vital to incorporate nonpharmacologic treatments.

Related Resources

• National Institute of Mental Health. Autism spectrum disorder. https://www.nimh.nih.gov/health/publications/autismspectrum-disorder/index.shtml.
• Centers for Disease Control and Prevention. Autism spectrum disorder (ASD). https://www.cdc.gov/ncbddd/ autism/index.html.

Drug Brand Names
Aripiprazole • Abilify
Clonidine • Catapres
Clozapine • Clozaril
Guanfacine • Tenex
Guanfacine Extended Release • Intuniv
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lurasidone • Latuda
Methylphenidate • Ritalin
Olanzapine • Zyprexa
Paliperidone • Invega
Quetiapine • Seroquel
Risperidone • Risperdal
Ziprasidone • Geodon

We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.

We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.

But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.

Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.

This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.

Continued to: I think I sensed this odious scenario coming...

Henry A. Nasrallah, MD
Editor-in-Chief

We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.

We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.

But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.

Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.

This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.

Continued to: I think I sensed this odious scenario coming...

Henry A. Nasrallah, MD
Editor-in-Chief

We psychiatrists encounter a wide variety of intense negative emotions in our patients on a daily basis, whether in the clinic or on an inpatient unit. These include rage, irritability, hostility, paranoia, loathing, and unadulterated hatred.

We evaluate, diagnose, and treat the underlying psychiatric brain disorders that generate such maladaptive emotions, and have our patients regain their baseline functioning by resolving the psychopathology that ignited their amygdala and their limbic circuitry.

But while we can manage the microcosm of one patient’s mental state, we are unable to intervene in the macrocosm of an entire society ravaged by extreme hyper-partisanship and naked bidirectional hatred. It is literally impossible for even the most skillful psychiatrists to repair a nation caught up in poisonous emotional turmoil, irreconcilable political differences, and a veritable war of belief systems that mimic religious fanaticism, which history tells us led to so many tragic wars over the centuries and millennia.

Ideally, politics is supposed to be an elegant cerebral process, a debate of ideas across disparate ideologies, the product of which is expected to be the advancement of the welfare of the nation and its citizens. But what we are currently witnessing is a distressing degeneration of politics into personal hatred and ad hominem attacks, with partisans frothing at the mouth as they describe the utter stupidity and dangerousness of their despised political opponents-cum-bitter enemies. They even declare each other “mentally ill,” which is an absurd explanation of why other people do not agree with their belief system. Neither side can find an iota of redeeming value in the political views of the “other side” and hurl insults and epithets verbally and in writing via dueling books that become instant best sellers among the partisan aficionados on both sides.

This disastrous political “climate change” may have ominous repercussions for the brains of the political combatants themselves, and even for those on the sidelines who are subjected to the relentless stress of witnessing a social train wreck in the making. As a neuropsychiatrist, I wonder if the collective national amygdala of the country is on fire, and the national prefrontal cortex is being corroded by the pervasive and ugly negativity that engulfs us all, with social media that incites its users night and day, adding gasoline to the fire. Chronic stress and its associated hypercortisolemia are known to be neurotoxic to the hippocampus and eventuate in clinical depression and its grave consequences.

Continued to: I think I sensed this odious scenario coming...

Henry A. Nasrallah, MD
Editor-in-Chief

I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center 
Clinical Assistant Professor of Psychiatry 
Rosalind Franklin University
Chicago, Illinois

Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.

Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland

Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.

Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.^1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.

Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.³ Clemastine reverses acute leukoencephalopathy.⁴

If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.

The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.

Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico

References

1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.

Continue to: Dr. Nasrallah responds

Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.

To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.

Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.

To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.

As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.¹ This is also true for bipolar disorder recurrences.² A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.³ Another 7-year study showed the same thing.⁴ It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.

To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”⁵ in which I mentioned all the above. I also pointed out the many neuro­protective effects of atypical antipsychotics in another editorial.⁶ Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References

1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of anti­psychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuro­protection. Current Psychiatry. 2015;14(2):19-21.

I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center 
Clinical Assistant Professor of Psychiatry 
Rosalind Franklin University
Chicago, Illinois

Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.

Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland

Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.

Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.^1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.

Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.³ Clemastine reverses acute leukoencephalopathy.⁴

If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.

The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.

Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico

References

1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.

Continue to: Dr. Nasrallah responds

Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.

To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.

Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.

To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.

As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.¹ This is also true for bipolar disorder recurrences.² A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.³ Another 7-year study showed the same thing.⁴ It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.

To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”⁵ in which I mentioned all the above. I also pointed out the many neuro­protective effects of atypical antipsychotics in another editorial.⁶ Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References

1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of anti­psychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuro­protection. Current Psychiatry. 2015;14(2):19-21.

I read with great interest Dr. Nasrallah’s editorial, “FAST and RAPID: Acronyms to prevent brain damage in stroke and psychosis” (From the Editor, Current Psychiatry, August 2018, p. 6-8). It makes me wonder about the ethics of allowing patients with active psychosis to participate in placebo-controlled studies. If a patient’s brain undergoes damage while psychotic, allowing the psychosis to continue without active treatment sounds possibly at odds with a physician’s oath. If a patient is in the placebo arm, then they are not receiving treatment for their psychotic symptoms. I wonder about his opinion on this.

Mitchell L. Glaser, MD
Board-Certified Child/Adolescent and General Psychiatrist
Assistant Professor of Psychiatry
Rush University Medical Center
Chairman
Department of Psychiatry
Medical Director of Child/Adolescent Psychiatry
St. Mary/Elizabeth Medical Center 
Clinical Assistant Professor of Psychiatry 
Rosalind Franklin University
Chicago, Illinois

Thank you, Dr. Nasrallah, for your incisive thinking and for bringing our attention as psychiatrists to the crucial issues of our clinical practice. I’d like to offer some nuance on the RAPID acronym. First, I’d like to counterpropose DASH: Delusions, Auditory hallucinations, Strange behavior, Hospital now. This is more in line with getting physicians to tune in to the symptoms that should alarm them and bring them to action. I agree that neurodegeneration and illness recurrence are the problems to address. One unsettled issue remains: With early intervention, can we eventually taper patients off antipsychotics to spare them the metabolic and immune morbidity associated with these medications? There is some evidence that this is possible, but it is difficult to collect data. One of the factors delaying treatment, other than lack of recognition, is the general public’s belief that the treatment is sometimes worse than the disease. If we can address this issue in a nuanced fashion, we may get more “early adopters” of these neuron-sparing treatments.

Michael S. Diamond, MD
Private psychiatric practice
Chevy Chase, Maryland

Dr. Nasrallah is right to focus on brain injury patterns, including inflammation and de-myelination, during psychotic episodes. He and Dr. Roque note that starting a patient on a long-acting injectable antipsychotic as soon as possible may prevent subsequent relapse and further brain damage. However, their editorial omits 2 treatments—minocycline and clemastine—that can help stop CNS inflammation, reduce brain damage, and promote remyelination.

Minocycline has been shown to reduce stroke infarct penumbra size and improve outcomes in functional recovery from stroke.^1,2 Minocycline’s effects as a potent CNS anti-inflammatory and antiapoptotic agent are well established.

Clemastine has been shown to improve function in multiple sclerosis by activating oligodendrocyte precursor cells into active agents of myelination and fiber bundle stabilization.³ Clemastine reverses acute leukoencephalopathy.⁴

If we are to treat acute psychosis as a neurologic emergency, we cannot rely on long-acting injectable antipsychotics as the sole treatment. Psychiatric medication alone is not sufficient across every neuropsychiatric condition in which inflammation and white matter damage are part of the etiology, destruction, and pattern of relapse.

The adverse effects risk of adjunctive minocycline and clemastine is low compared with the potential benefits of stopping inflammation, reducing apoptosis, and jump-starting white matter repair. Doses of oral minocycline in the 50- to 100-mg/d range and oral clemastine in the 1.34- to 2.68-mg/d range together can lead to reduced cranial heat, improved cranial suture mobility, and improved elasticity of white matter bundle tracts palpable on physical examination. Both medications show clinical results in improved emotional self-regulation, according to family reports and clinical observations in the outpatient setting. There is no reason to delay neurologic-based adjunctive treatment when our goal is to prevent and reverse brain damage.

Daniel Kerlinsky, MD
Child Psychiatrist
Clinical Assistant Professor
Burrell College of Osteopathic Medicine
Albuquerque, New Mexico

References

1. Hess DH, Fagan SC. Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. Rev Neurol Dis. 2010;30(7 pt 2):55S-61S.
2. Vedantam S, Moller AR. Minocycline: a novel stroke therapy. J Neurol Stroke. 2015;2(6):00073. doi: 10.15406/jnsk.2015.02.00073.
3. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. 2017;390(10111):2481-2489.
4. Cree BAC, Niu J, Hoi KK, et al. Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2018;141(1):85-98.

Continue to: Dr. Nasrallah responds

Thanks to my colleagues, Drs. Diamond, Glaser, and Kerlinsky, for their cogent letters about my editorial.

To Dr. Glaser: The “ethics” of conducting placebo-controlled studies when developing a new antipsychotic has been raging for some time. For decades, the FDA has insisted on using a placebo group because around 25% to 30% of research participants respond to placebo, and because participants receiving placebo also complain of many adverse effects. So a new drug has to demonstrate a statistically higher efficacy than a placebo, and the adverse effect profile of the placebo group will put the safety and tolerability profile of a new drug in proper perspective. However, in Europe, they do not conduct placebo-controlled studies; instead, they conduct what is called a “non-inferiority” trial of a new antipsychotic compared with a well-established antipsychotic.

Interestingly, even though the discovery of the neurodegenerative effects of untreated psychosis was only 20 years ago (in 1997 after serial MRI scans revealed progressive atrophy), in the 1960s, the first antipsychotic, chlorpromazine, was compared with placebo in a large national study for 6 months. This study showed without a doubt that chlorpromazine has a higher efficacy than placebo. After the study was done, Dr. Philip May at University of California, Los Angeles looked at what happened to the psychotic patients who received placebo for 6 months and found that they became less responsive to treatment, were re-hospitalized more often, and had more negative symptoms and a poorer overall outcome. That was a clue that untreated psychosis can be harmful, and it supports your point about the ethics of using placebo. In contemporary studies, a trial of oral antipsychotics is 6 weeks, not 6 months. In the year-long, placebo-controlled studies of injectable antipsychotics in stable patients, those who show the slightest increase in delusions, hallucinations, or suicidal/homicidal behavior were promptly taken out of the study and treated. This reduced the “harm,” although not completely. Perhaps the FDA will change its policies and adopt the non-inferiority model. That’s what is done with nonpsychiatric disorders such as pneumonia, stroke, or diabetes. But one last fact has to be stated: The placebo response in anxiety, depression, or psychosis is much higher (25% to 35%) than the 1% placebo response in pneumonia.

To Dr. Diamond: I really like DASH, and it is an acronym for quick symptomatic diagnosis. Speedy treatment then follows with the acronym RAPID to prevent brain damage that gets worse with delay.

As for the second issue of tapering off the antipsychotic medication, the evidence is overwhelming in favor of continuous pharmacotherapy. Just as hypertension and diabetes will return if medications are tapered or stopped, so will psychosis, and vengefully so because treatment resistance increases with each relapse.¹ This is also true for bipolar disorder recurrences.² A recent 20-year follow-up study showed that stopping antipsychotic treatment is associated with a much higher mortality rate than continuation therapy.³ Another 7-year study showed the same thing.⁴ It is literally deadly, and not just neurodegenerative, for persons with schizophrenia to stop their medications.

To Dr. Kerlinsky: I agree with you about using certain adjunctive pharmacotherapies for acute psychosis, which is associated with neuroinflammation, oxidative stress, and neuropil and myelin damage. I support using agents with anti-inflammatory effects (such as minocycline and omega-3 fatty acid), antioxidant effects (such as N-acetylcysteine), and neuroprotective effects (such as minocycline, clemastine, lithium, vitamin D, erythropoietin, etc.). I refer you to my past editorial, “Are you neuroprotecting your patients? 10 Adjunctive therapies to consider,”⁵ in which I mentioned all the above. I also pointed out the many neuro­protective effects of atypical antipsychotics in another editorial.⁶ Although off-label, those supplements can be useful interventions that can ameliorate the gray and white matter damage associated with acute psychotic relapses in patients with schizophrenia.

Henry A. Nasrallah, MD
Editor-in-Chief
The Sydney W. Souers Endowed Chair
Professor and Chairman
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

References

1. Emsley R, Oosthuizen P, Koen L, et al. Comparison of treatment response in second-episode versus first-episode schizophrenia. J Clin Psychopharmacol. 2013;33(1):80-83.
2. Post RM. Preventing the malignant transformation of bipolar disorder. JAMA. 2018;E1-E2.
3. Tiihonen J, Tanskanen A, Taipale H. 20-year nationwide follow-up study on discontinuation of anti­psychotic treatment in first-episode schizophrenia. Am J Psychiatry. 2018;175(8):765-773.
4. Taipale H, Mittendorfer-Rutz E, Alexanderson K, et al. Antipsychotics and mortality in a nationwide cohort of 29,823 patients with schizophrenia. Schizophr Res. 2018;197:274-280.
5. Nasrallah HA. Are you neuroprotecting your patients? 10 Adjunctive therapies to consider. Current Psychiatry. 2016;15(12):12-14.
6. Nasrallah HA. A decade after the CATIE study, the focus has shifted from effectiveness to neuro­protection. Current Psychiatry. 2015;14(2):19-21.

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

Mr. S, age 47, weighs 209 lb and has a history of seizure disorder, bipolar disorder not otherwise specified, hypertension, and type 2 diabetes mellitus. He presents to the emergency department after not taking his medications for 2 days while on vacation. He has increased energy, decreased sleep, and pressured speech, and insists on walking for up to 10 hours per day “in preparation for a marathon,” even though he has a 4-cm foot ulcer. His family reports that he had been compliant with his medications until the present incident.

Mr. S has no known drug allergies. His medications include oral divalproex sodium delayed release (valproic acid [VPA]), 1,000 mg twice a day, oral lisinopril, 20 mg every morning, and insulin glargine, 22 units subcutaneously every evening.

A complete blood count, basic metabolic panel, creatine kinase level, VPA level, and urine drug screen are ordered. Relevant results include a serum creatinine level of 1.4 mg/dL (normal range: 0.6 to 1.2 mg/dL), a glucose serum level of 188 mg/dL (normal range: 70 to 100 mg/dL), and a VPA level of 23 mcg/mL (therapeutic range: 50 to 125 mcg/mL). A liver function panel is within normal limits: albumin level of 3.9 g/dL, aspartate aminotransferase level of 18 IU/L, and alanine aminotransferase level of 14 IU/L. In light of Mr. S’s seizure history, neurology is consulted and the decision is made to continue treating him with VPA because he has been seizure-free for 4.5 years and this medication has also helped with his bipolar disorder.

Mr. S is admitted to the hospital and his home medications are resumed at the current doses. On hospital Day 3, Mr. S’s VPA level is 62 mcg/mL, his obsession with a marathon has remitted, and his sleep pattern has normalized. Infectious disease and podiatry services are consulted for his diabetic foot infection, which has ulcerated down to the bone. IV ertapenem, 1,000 mg/d, is initiated with plans for debridement the following week. Two days later, Mr. S has a witnessed seizure; his VPA level is 9 mcg/mL.

A common question asked of pharmacists is, “Will protein binding changes affect drug dosages?” In this article, I describe how protein binding changes may occur, and the complexity of the dynamic. Being highly bound to a protein typically does not mean all medications will interact, but some interactions can be important. This article does not cover medications that bind to hormones.

Why is protein binding important? When a medication is bound to plasma protein, it is not free to act. There can be a delay in therapeutic effect (because no drug is available to react), delayed elimination, or possibly displacement of another protein-bound medication. Additionally, medications tend not to cross the blood-brain barrier or be eliminated when bound. For example, if a drug is 99% bound (leaving 1% free) and displacement now leaves 2% of the drug free, this event has doubled the amount of free drug. As the unbound medication is eliminated, the drug that is bound to the protein can act as a reservoir. A dynamic relationship exists between bound drug, unbound drug, and rate of elimination.

Which proteins do drugs commonly bind to? The proteins often associated with binding include albumin, alpha-1-acid glycoprotein (AAG), and lipoproteins. Albumin comprises 60% of total plasma protein in the plasma. Lipoproteins include very high-density lipoprotein (VHDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL).¹ Medications that bind to lipoproteins include cyclosporine, tacrolimus, and propofol.²

Continued to: What common disease states can cause hypoalbuminemia?

• free vs protein-bound drug in the plasma or tissue
• volume of distribution
• organs affected
• hepatic bioavailability
• drug clearance.

For example, VPA is 93% protein-bound and phenytoin is 91% protein-bound.¹ However, this interaction is affected by more than just protein binding. VPA not only displaces the protein-bound phenytoin, but also inhibits its metabolism, which together result in increased free phenytoin levels.

Continued to: Another area of concern is a critically ill patient...

What happened to Mr. S? Mr. S likely experienced a drug–drug interaction that resulted in a subtherapeutic VPA level and subsequent seizure. Case reports have shown evidence that the carbapenem class of antibiotics, which includes ertapenem, interacts with VPA.⁷ Proposed mechanisms include a lowering of VPA serum levels due to a redistribution of the VPA onto the RBCs due to carbapenem. Other theories include the possibility that carbapenems may limit oral VPA absorption, decrease VPA enterohepatic recirculation, and increase VPA metabolism.⁷ Using VPA and ertapenem together is discouraged because seizures have been reported among patients receiving this combination. If it is medically necessary to administer VPA and ertapenem, closely monitor VPA levels. In Mr. S’s case, another broad-spectrum antibiotic, such as piperacillin-tazobactam, could have been used, for his diabetic foot infection.

While many medications may have high protein binding, there are few clinically important known interactions. However, our understanding of the relationship between protein binding and drug interactions may improve with additional research.

CASE CONTINUED

Under neurology’s care, lacosamide is added for treatment of Mr. S’s seizures. No more seizures are noted during the remainder of his hospitalization. Infectious disease services change his antibiotic to piperacillin-tazobactam. Mr. S continues to progress well and is discharged to a rehabilitation center 2 days later.

Related Resource

• DrugBank. www.drugbank.ca. Canadian Institutes of Health Research.

Drug Brand Names
Amiodarone • Cordarone, Pacerone
Bumetanide • Bumex
Bupivacaine • Marcaine, Sensorcaine
Buprenorphine • Belbuca, Subutex
Ceftriaxone • Rocephin
Chlordiazepoxide • Librium
Chlorpromazine • Thorazine
Clozapine • Clozaril
Cyclosporine • Gengraf, Neoral
Diazepam • Valium
Doxycycline • Acticlate, Doryx
Duloxetine • Cymbalta
Ertapenem • Invanz
Fluoxetine • Prozac, Sarafem
Furosemide • Lasix
Glargine (Insulin) • Lantus, Toujeo
Glipizide • Glucotrol
Haloperidol • Haldol
Ibuprofen • Advil, Motrin
Imipramine • Tofranil
Lacosamide • Vimpat
Lisinopril • Prinivil, Zestril
Lorazepam • Ativan
Nicardipine • Cardene
Nortriptyline • Pamelor
Paclitaxel • Abraxane, Taxol
Phenytoin • Dilantin, Phenytek
Piperacillin-tazobactam • Zosyn
Propofol • Diprivan
Sertraline • Zoloft
Tacrolimus • Prograf
Tamoxifen • Soltamox
Valproic acid • Depakene, Depakote
Verapamil • Calan, Verelan
Warfarin • Coumadin, Jantoven

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴

Although antipsychotics have revolutionized the treatment of severe mental illnesses, adverse effects often present a substantial obstacle to adherence. One of the most tenacious and difficult-to-treat adverse effects is tardive dyskinesia (TD), a neuromotor syndrome with characteristic involuntary repetitive movements, typically of the muscles of the jaw, lips, and tongue. In addition to spasms and grimacing, patients can have choreoathetoid movements of the neck. In more extreme presentations, some patients can have difficulty breathing. TD is a largely irreversible condition. It is often a disfiguring lifelong disability that can further stigmatize patients who already suffer scorn and derision. TD usually has a delayed onset after a patient is started on an antipsychotic.¹ The syndrome is more commonly associated with first-generation antipsychotics, but affects up to 20% of patients who are treated with second-generation antipsychotics.¹ In the United States, TD affects as many as 500,000 patients.¹

There are several palliative interventions for TD, but the evidence for a consistently reliable treatment is weak. Branched-chain amino acids, ginkgo biloba, melatonin, and vitamin E have been investigated as interventions. Other approaches include switching to an alternate antipsychotic such as clozapine, adjusting the antipsychotic dose, using anticholinergic medications, adjunctive amantadine, gamma aminobutyric acid agonists, or adding tetrabenazine.

The FDA recently approved two vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for addressing symptoms of TD. However, these medications can cost tens of thousands of dollars per year, and also carry the risk of adverse effects such as sedation, akathisia, urinary retention, constipation, and muscle pain.² When treating a patient who develops TD, one might consider other potentially effective therapies with low adverse effect profiles that may be more cost-effective than existing treatments. The bioactive form of vitamin B6 (pyridoxine), pyridoxal-5-phosphate, has been used to treat various antipsychotic-induced movement disorders. Preliminary evidence suggests that vitamin B6 may help reduce the symptoms of TD.

A recent Cochrane Database Review (2015)³ of pyridoxal-5-phosphate treatment for TD found a significant improvement in symptoms compared with placebo. Although the studies included in this review were limited by modest sample sizes and short follow-up periods, 2 of the investigations revealed improvements of >40% in extrapyramidal symptoms with vitamin B6 compared with placebo. Lerner et al (2001)⁴ conducted a randomized, double-blind, placebo-controlled crossover trial in which 15 inpatients with schizophrenia who met the criteria for TD were assigned to vitamin B6, 400 mg/d, or placebo for 4 weeks. After a 2-week washout period, the placebo group was given vitamin B6 and vice versa. Compared with placebo, mean scores on the parkinsonism and dyskinetic movement subscales of the Extrapyramidal Symptom Rating Scale were significantly better in the third week of treatment with vitamin B6.

Lerner et al (2007)⁵ later conducted a separate crossover study using the same design with a washout period. This trial included a larger sample size (50 inpatients with DSM-IV diagnoses of schizophrenia or schizoaffective disorder and TD) and the dosage of vitamin B6 was increased to 1,200 mg/d over 26 weeks. Patients who received vitamin B6 experienced a significantly greater decrease in Extrapyramidal Symptom Rating Scale scores compared with those in the placebo group.

Continued to: A 29-year-old woman with treatment-resistant schizophrenia...

Vitamin B6 has been known to improve other psychotropic-induced movement disorders. In a study of lithium-induced tremors, treatment with pyridoxine, 900 to 1,200 mg/d, resulted in “impressive improvement until total disappearance of tremor.”⁸ Lerner et al (2004)⁹ also reported significant improvement for patients with neuroleptic-induced akathisia who were treated with vitamin B6.

Some proposed mechanisms of action

Pyridoxal-5-phosphate is a coenzyme in the synthesis of dopamine and other neuro­transmitters. This might explain in part the biochemical mechanism of vitamin B6 in attenuating motor symptoms following long-term dopamine blockade. Chronic neurotransmitter antagonism may result in an upregulation of dopamine receptors in response. This compensatory reaction might create a dopamine receptor super-sensitivity in the nigrostriatal pathways.¹⁰

Another potential mechanism of action might be vitamin B6’s potent antioxidant properties and its scavenging of free radicals. The neurotoxicity of oxidative stress has been implicated in various movement disorders and psychiatric conditions.

In all of the studies described here, patients continued to receive daily antipsychotic treatment. In these trials, the adverse effects of vitamin B6 were minimal or negligible. In one study, vitamin B6 was reported to have had a better adverse effect profile than placebo.⁴