Evidence-Based Reviews

Mr. J, age 52, has a history of opioid dependence. Four weeks after starting interferon therapy for hepatitis C, he presents to the outpatient mental health clinic with depressed mood, irritability, decreased energy, poor concentration, insomnia, anhedonia, and suicidal ideation.

Because Mr. J has no history of depression, the psychiatrist diagnoses him with depressive disorder secondary to interferon. Interferon is stopped. Mr. J’s mood improves, but he wants to restart interferon.

The psychiatrist starts Mr. J on sertraline, 50 mg/d, then gradually increases the dose to 150 mg/d as Mr. J’s mood symptoms return. Subsequently, the patient continues interferon with a combination of sertraline and supportive psychotherapy.

Recognizing a medication as the possible cause of your patient’s psychiatric symptoms can avoid inaccurate diagnosis and nonindicated psychiatric treatment. Diligently evaluating patients for drug-related psychiatric side effects is critical because complications usually are reversed when the offending drug is discontinued. Unfortunately, a thin line separates available evidence from anecdotal myths about psychiatric complications of nonpsychotropics.

Almost two-thirds (65%) of drugs included in the Physicians’ Desk Reference list potential psychiatric side effects, according to a random sample review.¹ In some patients, such as Mr. J, these effects can exacerbate mood symptoms and result in perceptual, cognitive, or behavioral disturbances.

A wide range of drugs can cause psychosis, agitation, anxiety, depression, delirium, or insomnia (Table). On the other hand, certain psychiatric side effects of nonpsychotropics can be beneficial (Box 1).

Improve your assessments by examining the evidence linking psychiatric side effects to commonly prescribed and over-the-counter (OTC) compounds, including:

• cardiovascular medications
  
• steroids (prescription and illegal)
  
• hormones
  
• interferons
  
• antimicrobials.
  

Table

New-onset psychiatric symptoms? Check patient’s drug list

Symptom	Documented as a possible cause
Psychosis/agitation	Anabolic androgenic steroids, antihistamines, clonidine, corticosteroids, decongestants, didanosine, ethionamide, H2 blockers, isoniazid, nitrates, NSAIDs, opioids, proton pump inhibitors, quinolones, salbutamol, skeletal muscle relaxants, sulfonamides/trimethoprim
Anxiety	Acyclovir, anabolic androgenic steroids, clonidine, corticosteroids, cyclosporine, decongestants, didanosine, serotonin 5-HT1 agonists such as sumatriptan, foscarnet, ganciclovir, nitrates, ondansetron, penicillins, skeletal muscle relaxants
Depression	Anabolic androgenic steroids, beta blockers, chloramphenicol, clonidine, corticosteroids, didanosine, digoxin, efavirenz, foscarnet, GnRH agonists, H2 blockers, interferons, isoniazid, isotretinoin, NSAIDs, quinolones, statins, tetracyclines
Delirium	ACE inhibitors, anabolic androgenic steroids, antibiotics (most), anticholinergics, beta blockers, centrally acting antihypertensives such as methyldopa and reserpine, cimetidine, clonidine, corticosteroids, didanosine, digoxin, H2 blockers, lidocaine, naltrexone, nitrates, NSAIDs, opioids
Insomnia	Aminophylline, anabolic androgenic steroids, clonidine, corticosteroids, decongestants, didanosine, opioid antagonists, proton pump inhibitors, quinolone antibiotics, salbutamol, skeletal muscle relaxants, tetracyclines
NSAIDs: nonsteroidal anti-inflammatory drugs; ACE: angiotensin-converting enzyme; GnRH: gonadotropin-releasing hormone
Source: Prepared for Current Psychiatry by Drs. Sidhu and Balon from references cited in this article

Cardiovascular medications

Beta blockers have CNS effects—some of which cause psychiatric syndromes—that might depend on an ancillary property such as lipophilicity.² Unlike hydrophilic agents such as atenolol that are excreted unchanged by the kidneys, lipophilic drugs such as metoprolol and propranolol are metabolized by the liver and are believed to enter the brain. Metoprolol has a brain/plasma concentration ratio about 20 times higher than that of atenolol.³

Metoprolol and propranolol can induce delirium and psychosis.^4,5 Psychiatric side effects with metoprolol are frequent,⁴ and propranolol has been associated with:

• sedation (affecting >10% of patients)
  
• nightmares
  
• visual impairment
  
• hallucinations
  
• delirium
  
• depression.⁵
  

In 1967, it was reported that up to 50% of patients taking propranolol may experience dysphoria and at times severe depression.⁶ These effects may occur acutely or develop gradually. ⁵

The relationship between depressive symptoms and beta blockers has been increasingly questioned, however. One study did not find a higher prevalence of depression in patients receiving beta blockers vs those receiving other medications, although this trial had major methodologic limitations.⁷ One large study found no significant association between beta-blocker use and major depression, regardless of patient age, gender, or race.⁸

These studies stress the importance of carefully assessing the individual patient before assigning neurotoxicity to beta blockers, as these drugs have considerable benefits for cardiovascular disease.⁹

Angiotensin-converting enzyme (ACE) inhibitors also affect the CNS. About 4% to 8% of patients taking an ACE inhibitor experience altered mental status—typically increased arousal and psychomotor activity—although

• anxiety
  
• mania
  
• insomnia
  
• fatigue
  
• paresthesias
  
• hallucinations.⁵
  

Sedation occurs in about 5% of patients taking ACE inhibitors. Depression and suicide ideation as a result of ACE inhibition have been reported;¹³ however, ACE inhibitors have also been known to improve depression. Episodes of frank delirium have been reported.⁵

Clonidine is a centrally acting alpha-agonist. The alpha-adrenergic system regulates arousal and has an important role in major depression, anxiety states, and other arousal disorders.

 

More than one-third (35%) of patients taking clonidine experience sedation or lethargy; less commonly, the drug causes anxiety (3%), agitation (3%), depression (1%), and insomnia (1%).⁵ Acute confusion, delirium, hypomania, and psychosis related to clonidine use have long been recognized, occurring in 5

Box 1

Other cardiovascular drugs. Side effects of nitrates/nitrites include delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania.⁵ Digoxin can cause cardiac glycoside-induced encephalopathy, which may present as sedation, apathy, depression, and psychosis. Patients may develop delirium, even when digoxin/digitoxin serum levels are within a therapeutic range.

Cholesterol-lowering statins might be linked to an increased risk of depression and suicide, but the evidence is inconclusive. Some studies have supported this link,^10,11 whereas others have strongly refuted it^12,13 or had mixed results.¹⁴ A recent review¹⁵ recommends being vigilant for psychiatric side effects in patients taking these drugs.

Steroids: prescription and illegal

Corticosteroids are prescribed for a variety of immune system-related diseases, including asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease, and dermatologic disorders. Mood changes are the most common psychiatric symptoms caused by corticosteroid use; delirium is less common. Psychiatric side effects include:

• lethargy
  
• insomnia
  
• euphoria
  
• depression
  
• psychosis
  
• “personality changes”
  
• anxiety
  
• agitation.⁵
  

Multiple studies have linked corticosteroids and mood symptoms. The Boston Collaborative Drug Surveillance Program¹⁶ confirmed a direct relationship between corticosteroid dosage and psychiatric effects. More than 18% of patients had severe psychiatric symptoms at corticosteroid dosages >80 mg/d.

A prospective study of asthma patients found statistically significant changes in mood—primarily manic symptoms—during brief corticosteroid courses at modest dosages. Depressed persons did not become more depressed during prednisone therapy, however; in fact, some improved. Some patients with posttraumatic stress disorder reported increased depression and memories of the traumatic event during prednisone therapy.¹⁷

In a study of 50 ophthalmologic patients who did not have psychiatric illness receiving prednisolone (mean starting dose 119 mg/d) for 8 days, 26% developed mania and 10% depression.¹⁸ None reported psychotic symptoms.

The most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Long-term therapy tends to induce depressive symptoms.¹⁹ A review of 79 cases of psychiatric syndromes induced by corticosteroids found that 41% reported depression, 28% mania, 6% mixed symptoms, and 14% psychosis.²⁰

A group of 16 healthy volunteers receiving 80 mg/d of prednisone over 5 days exhibited depressed or elevated mood, irritability, lability, increased energy, anxiety, and depersonalization.²¹ Numerous case studies have reported anxiety, agitation, mania, and psychotic symptoms in children and adults taking inhaled corticosteroids.

In general, psychiatric side effects of corticosteroids occur within 2 weeks of starting therapy and resolve with dosage reduction or discontinuation. In severe cases or situations in which the dosage cannot be reduced, the patient may require antipsychotics or mood stabilizers.¹⁹

Female gender and past psychiatric history might be risk factors for developing psychiatric symptoms with corticosteroids,²² although not all studies have confirmed these findings.¹⁸

Anabolic androgenic steroids (AAS) have limited therapeutic benefits but are used illegally by some bodybuilders, wrestlers, and other amateur and professional athletes to increase muscle mass, enhance performance, and gain a competitive edge. AAS can cause acute paranoia, delirium, mania or hypomania, homicidal rage, aggression, and extreme mood swings, as well as a marked increase in libido, irritability, agitation, and anger.

In a large observational cohort study of 320 bodybuilding amateur and recreational athletes,²³ AAS use induced many of these psychiatric side effects. The extent intensified as the abuse escalated. A study that used the Structured Clinical Interview for DSM-III-R to compare 88 athletes using steroids with 68 nonusers found that 23% of the AAS users reported major mood syndromes, including mania, hypomania, and major depression.²⁴

 

In a 2-week, double-blind, fixed-order, placebo-controlled, crossover study of healthy male inpatient volunteers, AAS had both:

• mood-elevating effects—euphoria (“steroid rush”), increased energy, and increased sexual arousal and drive
  
• mood-dysphoric effects, such as irritability, mood swings, increasingly violent feelings, increased hostility, and cognitive impairments.²⁵
  

As with corticosteroids, psychiatric symptoms from AAS become more prevalent and severe as dosage increases. They usually resolve within a few weeks after users discontinue steroids but may persist for up to 1 month, even if adequately treated with antipsychotic medication.

Hormones

Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide and nafarelin are approved for treating endometriosis, advanced prostate cancer, precocious puberty, and uterine leiomyomata. Some studies and case reports suggest that these agents cause depressive symptoms.²⁶

Progestins have complex and variable psychiatric effects. Clinical trials have investigated the antidepressant effects of exogenous estrogens on psychiatric patients, but results have been inconsistent—possibly because of small numbers of subjects and design flaws.²⁶ Some studies suggest a link between estrogen and depression in premenopausal and menopausal women with and without psychiatric illness, but findings remain controversial because other studies have found that estrogens have positive effects on mood.^26,27

Interferon

Various forms of interferon are used to treat hepatitis C, melanoma, multiple sclerosis, chronic myelogenous leukemia, and other illnesses. Psychiatric complications—particularly depression—are the most frequent side effect of interferon therapy and mainly occur within the first 12 weeks of therapy.²⁸

In a prospective observational study of veterans undergoing interferon-alfa/ribavirin treatment for chronic hepatitis C:

• 48% of patients not receiving psychiatric care at baseline required treatment for neuropsychiatric side effects
  
• 23% developed symptoms of major depression.²⁹
  

Treatment with a selective serotonin reuptake inhibitor stabilized these symptoms and allowed patients to continue hepatitis treatment.

Because patients who receive interferon are far more likely to require psychiatric intervention if they have a family history of mood disorders, closely monitor them for depressive symptoms and treat such symptoms aggressively. Also closely monitor patients with multiple psychiatric diagnoses receiving interferon-alfa therapy.³⁰

Jeungling et al³¹ speculated that hypometabolism in the prefrontal cortex may predispose patients to interferon-associated neuropsychological syndromes. Neuropsychiatric symptoms may be a characteristic of hepatitis C, interferon treatment, or both.³²

Antimicrobial agents

Antibiotic and antiviral drugs can cause psychiatric side effects:

• directly by affecting neuronal functions
  
• indirectly by entering the brain rapidly, taking advantage of the compromised blood-brain barrier during sepsis or infection.
  

Delirium is the most common psychiatric complication associated with these agents.⁵

Antibiotics. Penicillin and its analogues are associated with sedation, anxiety, and hallucinations. Delirium has been reported as a side effect of most cephalosporins, especially in patients with compromised renal function. Quinolones such as ciprofloxacin and ofloxacin rarely cause restlessness, irritability, lethargy, tremors, insomnia, mania, depression, psychosis, delirium, seizures, or catatonia (incidence ≤1%).⁵ Though not commonly used, chloramphenicol may cause depression, confusion, and delirium. Many case reports have strongly associated clarithromycin with delirium.³³

Isoniazid is one of the most commonly used antibiotics that can cause psychiatric side effects; it has been linked to delirium, mania, depression, and psychosis. Ethionamide is associated with sedation, irritability, depression, restlessness, and psychosis. Tetracyclines have been known to cause depression, insomnia, and irritability at high dosages.

Sulfonamides can cause delirium. Psychosis and confusion also have been reported, especially when sulfa drugs are combined with trimethoprim.⁵

Antivirals. When used intravenously and at high doses, acyclovir and ganciclovir can cause lethargy, anxiety, hallucinations, and frank delirium.⁵ Foscarnet—an antiviral used to treat herpes viruses—can cause depression, anxiety, hallucinations, and aggressive irritability.

Didanosine—an antiretroviral agent to treat HIV infections—can cause lethargy (5% to 7% of patients), depression (2%), anxiety (2%), emotional lability (25%), delirium (2%), insomnia (1%), and psychotic delusions (1%).⁵ Efavirenz treatment may be associated with major depression and severe suicidal ideation.³⁴ Tenofovir, a nucleotide reverse transcriptase inhibitor, has not been associated with psychiatric side effects.²⁷

Antifungals. Psychiatric side effects are rare.

OTC and other agents

Many common nonprescription agents can cause psychiatric symptoms. The most frequently used classes include cold and allergy preparations, reflux medications, and analgesics (Box 2).^5,35

Cold preparations. Combined antihistamines and decongestants—such as phenylpropanolamine, azatadine, loratadine, ephedrine, phenylephrine, pseudoephedrine, and naphazoline—can cause an atropine-like psychosis that typically manifests as confusion, disorientation, agitation, hallucinations, and memory problems. Decongestants can cause dangerously high levels of norepinephrine when combined with monoamine oxidase inhibitors (MAOIs) and are contraindicated in patients taking MAOIs. Ephedrine can induce restlessness, dysphoria, irritability, anxiety, and insomnia.

 

Reflux medications. Two primary classes of reflux medications are proton pump inhibitors (omeprazole and lansoprazole) and H₂ receptor antagonists (famotidine, nizatidine, ranitidine, and cimetidine). Although generally considered to have a benign side-effect profile, these medications have been reported to cause serious neuropsychiatric complications—including mental confusion, agitation, depression, and hallucinations—mainly in geriatric patients with impaired hepatic-renal function.³⁶ These occur in only 37

Time to onset of psychiatric side effects from H₂ antagonists varies. Ranitidine can cause depression 4 to 8 weeks after treatment begins. Cimetidine has been reported to cause adverse events within 2 to 3 weeks and delirium within 24 to 48 hours.³⁸ These effects usually resolve within 3 days of discontinuing the drug. Cimetidine is also associated with sexual dysfunction.

Discontinuing ranitidine or cimetidine can induce a withdrawal syndrome that includes anxiety, insomnia, and irritability.³⁹ Cimetidine can increase the blood level and action of tricyclic antidepressants. Blood levels of these antidepressants can become toxic, resulting in tachycardia and other adverse effects.

Other medications. Ondansetron is a 5-hydroxytryptamine subclass 3 (5-HT₃) antagonist used for antiemetic therapy. In case reports, it has been strongly associated with anxiety.⁴⁰ This association is complex, however, and studies are evaluating 5-HT₃ receptor antagonists for the treatment of anxiety, depression, phobia, and schizophrenia.

Isotretinoin—a retinoid used for severe acne—can cause severe depression and suicidal behavior.⁴¹

Aminophylline and salbutamol are associated with agitation, insomnia, euphoria, and delirium. Methotrexate is known to cause personality changes, irritability, and delirium.²⁷

Box 2

Treating drug-related mood effects

If you suspect a nonpsychotropic medication is causing your patient’s psychiatric symptoms, discuss this with the patient and the prescribing physician. Switching to another similar agent may be an option. If this is not possible:

• work closely with the patient’s primary physician
  
• treat mood symptoms with appropriate psychotropics.
  

Related resources

• Turjanski N, Lloyd GG. Psychiatric side-effects of medications: recent developments. Advances in Psychiatric Treatment 2005;11:58-70.
  
• Brown TM, Stoudemire A. Psychiatric side effects of prescription and over-the-counter medications. Recognition and management. Washington, DC: American Psychiatric Publishing; 1998.
  
• Physicians’ Desk Reference. www.pdr.net.
  

Drug brand name

• Acyclovir • Zovirax
  
• Aminophylline • Phyllocontin, Truphylline
  
• Atenolol • Tenormin
  
• Azatadine • Optimine
  
• Baclofen • Lioresal
  
• Chloramphenicol • Chloromycetin
  
• Cimetidine • Tagamet
  
• Ciprofloxacin • Cipro
  
• Clarithromycin • Biaxin
  
• Clonidine • Catapres
  
• Cyclosporine • Neoral, Sandimmune, others
  
• Dantrolene • Dantrium
  
• Didanosine • Videx
  
• Efavirenz • Sustiva
  
• Ethionamide • Trecator
  
• Famotidine • Pepcid
  
• Foscarnet • Foscavir
  
• Ganciclovir • Cytovene
  
• Indomethacin • Indocin
  
• Interferon alfa • Intron, Roferon
  
• Isoniazid • Nydrazid
  
• Isotretinoin • Accutane
  
• Lansoprazole • Prevacid
  
• Leuprolide • Lupron
  
• Lidocaine • Xylocaine, Xylocard
  
• Loratadine • Claritin
  
• Methotrexate • Rheumatrex, Trexall
  
• Methyldopa • Aldomet
  
• Metoprolol • Lopressor
  
• Mirtazapine • Remeron
  
• Nafarelin • Synarel
  
• Naloxone • Suboxone
  
• Naltrexone • Vivitrol
  
• Naphazoline • Naphcon-A, Clearine
  
• Naproxen • Aleve, others
  
• Nizatidine • Axid
  
• Ofloxacin • Floxin
  
• Omeprazole • Prilosec
  
• Ondansetron • Zofran
  
• Paroxetine • Paxil
  
• Peginterferon alfa • PEG-Intron, Pegasys
  
• Phenylephrine • Neo-Synephrine
  
• Prednisolone • Blephamide, Pred Forte, others
  
• Propranolol • Inderal
  
• Pseudoephedrine • Actifed, Sudafed
  
• Ranitidine • Zantac
  
• Reserpine • Serpasi
  
• Ribavirin • Copegus, Rebetol
  
• Salbutamol • Aerolin, Airomir, others
  
• Sertraline • Zoloft
  
• Sumatriptan • Imitrex
  
• Tenofovir • Viread
  
• Trimethoprim • Proloprim
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. J, age 52, has a history of opioid dependence. Four weeks after starting interferon therapy for hepatitis C, he presents to the outpatient mental health clinic with depressed mood, irritability, decreased energy, poor concentration, insomnia, anhedonia, and suicidal ideation.

Because Mr. J has no history of depression, the psychiatrist diagnoses him with depressive disorder secondary to interferon. Interferon is stopped. Mr. J’s mood improves, but he wants to restart interferon.

The psychiatrist starts Mr. J on sertraline, 50 mg/d, then gradually increases the dose to 150 mg/d as Mr. J’s mood symptoms return. Subsequently, the patient continues interferon with a combination of sertraline and supportive psychotherapy.

Recognizing a medication as the possible cause of your patient’s psychiatric symptoms can avoid inaccurate diagnosis and nonindicated psychiatric treatment. Diligently evaluating patients for drug-related psychiatric side effects is critical because complications usually are reversed when the offending drug is discontinued. Unfortunately, a thin line separates available evidence from anecdotal myths about psychiatric complications of nonpsychotropics.

Almost two-thirds (65%) of drugs included in the Physicians’ Desk Reference list potential psychiatric side effects, according to a random sample review.¹ In some patients, such as Mr. J, these effects can exacerbate mood symptoms and result in perceptual, cognitive, or behavioral disturbances.

A wide range of drugs can cause psychosis, agitation, anxiety, depression, delirium, or insomnia (Table). On the other hand, certain psychiatric side effects of nonpsychotropics can be beneficial (Box 1).

Improve your assessments by examining the evidence linking psychiatric side effects to commonly prescribed and over-the-counter (OTC) compounds, including:

• cardiovascular medications
  
• steroids (prescription and illegal)
  
• hormones
  
• interferons
  
• antimicrobials.
  

Table

New-onset psychiatric symptoms? Check patient’s drug list

Symptom	Documented as a possible cause
Psychosis/agitation	Anabolic androgenic steroids, antihistamines, clonidine, corticosteroids, decongestants, didanosine, ethionamide, H2 blockers, isoniazid, nitrates, NSAIDs, opioids, proton pump inhibitors, quinolones, salbutamol, skeletal muscle relaxants, sulfonamides/trimethoprim
Anxiety	Acyclovir, anabolic androgenic steroids, clonidine, corticosteroids, cyclosporine, decongestants, didanosine, serotonin 5-HT1 agonists such as sumatriptan, foscarnet, ganciclovir, nitrates, ondansetron, penicillins, skeletal muscle relaxants
Depression	Anabolic androgenic steroids, beta blockers, chloramphenicol, clonidine, corticosteroids, didanosine, digoxin, efavirenz, foscarnet, GnRH agonists, H2 blockers, interferons, isoniazid, isotretinoin, NSAIDs, quinolones, statins, tetracyclines
Delirium	ACE inhibitors, anabolic androgenic steroids, antibiotics (most), anticholinergics, beta blockers, centrally acting antihypertensives such as methyldopa and reserpine, cimetidine, clonidine, corticosteroids, didanosine, digoxin, H2 blockers, lidocaine, naltrexone, nitrates, NSAIDs, opioids
Insomnia	Aminophylline, anabolic androgenic steroids, clonidine, corticosteroids, decongestants, didanosine, opioid antagonists, proton pump inhibitors, quinolone antibiotics, salbutamol, skeletal muscle relaxants, tetracyclines
NSAIDs: nonsteroidal anti-inflammatory drugs; ACE: angiotensin-converting enzyme; GnRH: gonadotropin-releasing hormone
Source: Prepared for Current Psychiatry by Drs. Sidhu and Balon from references cited in this article

Cardiovascular medications

Beta blockers have CNS effects—some of which cause psychiatric syndromes—that might depend on an ancillary property such as lipophilicity.² Unlike hydrophilic agents such as atenolol that are excreted unchanged by the kidneys, lipophilic drugs such as metoprolol and propranolol are metabolized by the liver and are believed to enter the brain. Metoprolol has a brain/plasma concentration ratio about 20 times higher than that of atenolol.³

Metoprolol and propranolol can induce delirium and psychosis.^4,5 Psychiatric side effects with metoprolol are frequent,⁴ and propranolol has been associated with:

• sedation (affecting >10% of patients)
  
• nightmares
  
• visual impairment
  
• hallucinations
  
• delirium
  
• depression.⁵
  

In 1967, it was reported that up to 50% of patients taking propranolol may experience dysphoria and at times severe depression.⁶ These effects may occur acutely or develop gradually. ⁵

The relationship between depressive symptoms and beta blockers has been increasingly questioned, however. One study did not find a higher prevalence of depression in patients receiving beta blockers vs those receiving other medications, although this trial had major methodologic limitations.⁷ One large study found no significant association between beta-blocker use and major depression, regardless of patient age, gender, or race.⁸

These studies stress the importance of carefully assessing the individual patient before assigning neurotoxicity to beta blockers, as these drugs have considerable benefits for cardiovascular disease.⁹

Angiotensin-converting enzyme (ACE) inhibitors also affect the CNS. About 4% to 8% of patients taking an ACE inhibitor experience altered mental status—typically increased arousal and psychomotor activity—although

• anxiety
  
• mania
  
• insomnia
  
• fatigue
  
• paresthesias
  
• hallucinations.⁵
  

Sedation occurs in about 5% of patients taking ACE inhibitors. Depression and suicide ideation as a result of ACE inhibition have been reported;¹³ however, ACE inhibitors have also been known to improve depression. Episodes of frank delirium have been reported.⁵

Clonidine is a centrally acting alpha-agonist. The alpha-adrenergic system regulates arousal and has an important role in major depression, anxiety states, and other arousal disorders.

 

More than one-third (35%) of patients taking clonidine experience sedation or lethargy; less commonly, the drug causes anxiety (3%), agitation (3%), depression (1%), and insomnia (1%).⁵ Acute confusion, delirium, hypomania, and psychosis related to clonidine use have long been recognized, occurring in 5

Box 1

Other cardiovascular drugs. Side effects of nitrates/nitrites include delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania.⁵ Digoxin can cause cardiac glycoside-induced encephalopathy, which may present as sedation, apathy, depression, and psychosis. Patients may develop delirium, even when digoxin/digitoxin serum levels are within a therapeutic range.

Cholesterol-lowering statins might be linked to an increased risk of depression and suicide, but the evidence is inconclusive. Some studies have supported this link,^10,11 whereas others have strongly refuted it^12,13 or had mixed results.¹⁴ A recent review¹⁵ recommends being vigilant for psychiatric side effects in patients taking these drugs.

Steroids: prescription and illegal

Corticosteroids are prescribed for a variety of immune system-related diseases, including asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease, and dermatologic disorders. Mood changes are the most common psychiatric symptoms caused by corticosteroid use; delirium is less common. Psychiatric side effects include:

• lethargy
  
• insomnia
  
• euphoria
  
• depression
  
• psychosis
  
• “personality changes”
  
• anxiety
  
• agitation.⁵
  

Multiple studies have linked corticosteroids and mood symptoms. The Boston Collaborative Drug Surveillance Program¹⁶ confirmed a direct relationship between corticosteroid dosage and psychiatric effects. More than 18% of patients had severe psychiatric symptoms at corticosteroid dosages >80 mg/d.

A prospective study of asthma patients found statistically significant changes in mood—primarily manic symptoms—during brief corticosteroid courses at modest dosages. Depressed persons did not become more depressed during prednisone therapy, however; in fact, some improved. Some patients with posttraumatic stress disorder reported increased depression and memories of the traumatic event during prednisone therapy.¹⁷

In a study of 50 ophthalmologic patients who did not have psychiatric illness receiving prednisolone (mean starting dose 119 mg/d) for 8 days, 26% developed mania and 10% depression.¹⁸ None reported psychotic symptoms.

The most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Long-term therapy tends to induce depressive symptoms.¹⁹ A review of 79 cases of psychiatric syndromes induced by corticosteroids found that 41% reported depression, 28% mania, 6% mixed symptoms, and 14% psychosis.²⁰

A group of 16 healthy volunteers receiving 80 mg/d of prednisone over 5 days exhibited depressed or elevated mood, irritability, lability, increased energy, anxiety, and depersonalization.²¹ Numerous case studies have reported anxiety, agitation, mania, and psychotic symptoms in children and adults taking inhaled corticosteroids.

In general, psychiatric side effects of corticosteroids occur within 2 weeks of starting therapy and resolve with dosage reduction or discontinuation. In severe cases or situations in which the dosage cannot be reduced, the patient may require antipsychotics or mood stabilizers.¹⁹

Female gender and past psychiatric history might be risk factors for developing psychiatric symptoms with corticosteroids,²² although not all studies have confirmed these findings.¹⁸

Anabolic androgenic steroids (AAS) have limited therapeutic benefits but are used illegally by some bodybuilders, wrestlers, and other amateur and professional athletes to increase muscle mass, enhance performance, and gain a competitive edge. AAS can cause acute paranoia, delirium, mania or hypomania, homicidal rage, aggression, and extreme mood swings, as well as a marked increase in libido, irritability, agitation, and anger.

In a large observational cohort study of 320 bodybuilding amateur and recreational athletes,²³ AAS use induced many of these psychiatric side effects. The extent intensified as the abuse escalated. A study that used the Structured Clinical Interview for DSM-III-R to compare 88 athletes using steroids with 68 nonusers found that 23% of the AAS users reported major mood syndromes, including mania, hypomania, and major depression.²⁴

 

In a 2-week, double-blind, fixed-order, placebo-controlled, crossover study of healthy male inpatient volunteers, AAS had both:

• mood-elevating effects—euphoria (“steroid rush”), increased energy, and increased sexual arousal and drive
  
• mood-dysphoric effects, such as irritability, mood swings, increasingly violent feelings, increased hostility, and cognitive impairments.²⁵
  

As with corticosteroids, psychiatric symptoms from AAS become more prevalent and severe as dosage increases. They usually resolve within a few weeks after users discontinue steroids but may persist for up to 1 month, even if adequately treated with antipsychotic medication.

Hormones

Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide and nafarelin are approved for treating endometriosis, advanced prostate cancer, precocious puberty, and uterine leiomyomata. Some studies and case reports suggest that these agents cause depressive symptoms.²⁶

Progestins have complex and variable psychiatric effects. Clinical trials have investigated the antidepressant effects of exogenous estrogens on psychiatric patients, but results have been inconsistent—possibly because of small numbers of subjects and design flaws.²⁶ Some studies suggest a link between estrogen and depression in premenopausal and menopausal women with and without psychiatric illness, but findings remain controversial because other studies have found that estrogens have positive effects on mood.^26,27

Interferon

Various forms of interferon are used to treat hepatitis C, melanoma, multiple sclerosis, chronic myelogenous leukemia, and other illnesses. Psychiatric complications—particularly depression—are the most frequent side effect of interferon therapy and mainly occur within the first 12 weeks of therapy.²⁸

In a prospective observational study of veterans undergoing interferon-alfa/ribavirin treatment for chronic hepatitis C:

• 48% of patients not receiving psychiatric care at baseline required treatment for neuropsychiatric side effects
  
• 23% developed symptoms of major depression.²⁹
  

Treatment with a selective serotonin reuptake inhibitor stabilized these symptoms and allowed patients to continue hepatitis treatment.

Because patients who receive interferon are far more likely to require psychiatric intervention if they have a family history of mood disorders, closely monitor them for depressive symptoms and treat such symptoms aggressively. Also closely monitor patients with multiple psychiatric diagnoses receiving interferon-alfa therapy.³⁰

Jeungling et al³¹ speculated that hypometabolism in the prefrontal cortex may predispose patients to interferon-associated neuropsychological syndromes. Neuropsychiatric symptoms may be a characteristic of hepatitis C, interferon treatment, or both.³²

Antimicrobial agents

Antibiotic and antiviral drugs can cause psychiatric side effects:

• directly by affecting neuronal functions
  
• indirectly by entering the brain rapidly, taking advantage of the compromised blood-brain barrier during sepsis or infection.
  

Delirium is the most common psychiatric complication associated with these agents.⁵

Antibiotics. Penicillin and its analogues are associated with sedation, anxiety, and hallucinations. Delirium has been reported as a side effect of most cephalosporins, especially in patients with compromised renal function. Quinolones such as ciprofloxacin and ofloxacin rarely cause restlessness, irritability, lethargy, tremors, insomnia, mania, depression, psychosis, delirium, seizures, or catatonia (incidence ≤1%).⁵ Though not commonly used, chloramphenicol may cause depression, confusion, and delirium. Many case reports have strongly associated clarithromycin with delirium.³³

Isoniazid is one of the most commonly used antibiotics that can cause psychiatric side effects; it has been linked to delirium, mania, depression, and psychosis. Ethionamide is associated with sedation, irritability, depression, restlessness, and psychosis. Tetracyclines have been known to cause depression, insomnia, and irritability at high dosages.

Sulfonamides can cause delirium. Psychosis and confusion also have been reported, especially when sulfa drugs are combined with trimethoprim.⁵

Antivirals. When used intravenously and at high doses, acyclovir and ganciclovir can cause lethargy, anxiety, hallucinations, and frank delirium.⁵ Foscarnet—an antiviral used to treat herpes viruses—can cause depression, anxiety, hallucinations, and aggressive irritability.

Didanosine—an antiretroviral agent to treat HIV infections—can cause lethargy (5% to 7% of patients), depression (2%), anxiety (2%), emotional lability (25%), delirium (2%), insomnia (1%), and psychotic delusions (1%).⁵ Efavirenz treatment may be associated with major depression and severe suicidal ideation.³⁴ Tenofovir, a nucleotide reverse transcriptase inhibitor, has not been associated with psychiatric side effects.²⁷

Antifungals. Psychiatric side effects are rare.

OTC and other agents

Many common nonprescription agents can cause psychiatric symptoms. The most frequently used classes include cold and allergy preparations, reflux medications, and analgesics (Box 2).^5,35

Cold preparations. Combined antihistamines and decongestants—such as phenylpropanolamine, azatadine, loratadine, ephedrine, phenylephrine, pseudoephedrine, and naphazoline—can cause an atropine-like psychosis that typically manifests as confusion, disorientation, agitation, hallucinations, and memory problems. Decongestants can cause dangerously high levels of norepinephrine when combined with monoamine oxidase inhibitors (MAOIs) and are contraindicated in patients taking MAOIs. Ephedrine can induce restlessness, dysphoria, irritability, anxiety, and insomnia.

 

Reflux medications. Two primary classes of reflux medications are proton pump inhibitors (omeprazole and lansoprazole) and H₂ receptor antagonists (famotidine, nizatidine, ranitidine, and cimetidine). Although generally considered to have a benign side-effect profile, these medications have been reported to cause serious neuropsychiatric complications—including mental confusion, agitation, depression, and hallucinations—mainly in geriatric patients with impaired hepatic-renal function.³⁶ These occur in only 37

Time to onset of psychiatric side effects from H₂ antagonists varies. Ranitidine can cause depression 4 to 8 weeks after treatment begins. Cimetidine has been reported to cause adverse events within 2 to 3 weeks and delirium within 24 to 48 hours.³⁸ These effects usually resolve within 3 days of discontinuing the drug. Cimetidine is also associated with sexual dysfunction.

Discontinuing ranitidine or cimetidine can induce a withdrawal syndrome that includes anxiety, insomnia, and irritability.³⁹ Cimetidine can increase the blood level and action of tricyclic antidepressants. Blood levels of these antidepressants can become toxic, resulting in tachycardia and other adverse effects.

Other medications. Ondansetron is a 5-hydroxytryptamine subclass 3 (5-HT₃) antagonist used for antiemetic therapy. In case reports, it has been strongly associated with anxiety.⁴⁰ This association is complex, however, and studies are evaluating 5-HT₃ receptor antagonists for the treatment of anxiety, depression, phobia, and schizophrenia.

Isotretinoin—a retinoid used for severe acne—can cause severe depression and suicidal behavior.⁴¹

Aminophylline and salbutamol are associated with agitation, insomnia, euphoria, and delirium. Methotrexate is known to cause personality changes, irritability, and delirium.²⁷

Box 2

Treating drug-related mood effects

If you suspect a nonpsychotropic medication is causing your patient’s psychiatric symptoms, discuss this with the patient and the prescribing physician. Switching to another similar agent may be an option. If this is not possible:

• work closely with the patient’s primary physician
  
• treat mood symptoms with appropriate psychotropics.
  

Related resources

• Turjanski N, Lloyd GG. Psychiatric side-effects of medications: recent developments. Advances in Psychiatric Treatment 2005;11:58-70.
  
• Brown TM, Stoudemire A. Psychiatric side effects of prescription and over-the-counter medications. Recognition and management. Washington, DC: American Psychiatric Publishing; 1998.
  
• Physicians’ Desk Reference. www.pdr.net.
  

Drug brand name

• Acyclovir • Zovirax
  
• Aminophylline • Phyllocontin, Truphylline
  
• Atenolol • Tenormin
  
• Azatadine • Optimine
  
• Baclofen • Lioresal
  
• Chloramphenicol • Chloromycetin
  
• Cimetidine • Tagamet
  
• Ciprofloxacin • Cipro
  
• Clarithromycin • Biaxin
  
• Clonidine • Catapres
  
• Cyclosporine • Neoral, Sandimmune, others
  
• Dantrolene • Dantrium
  
• Didanosine • Videx
  
• Efavirenz • Sustiva
  
• Ethionamide • Trecator
  
• Famotidine • Pepcid
  
• Foscarnet • Foscavir
  
• Ganciclovir • Cytovene
  
• Indomethacin • Indocin
  
• Interferon alfa • Intron, Roferon
  
• Isoniazid • Nydrazid
  
• Isotretinoin • Accutane
  
• Lansoprazole • Prevacid
  
• Leuprolide • Lupron
  
• Lidocaine • Xylocaine, Xylocard
  
• Loratadine • Claritin
  
• Methotrexate • Rheumatrex, Trexall
  
• Methyldopa • Aldomet
  
• Metoprolol • Lopressor
  
• Mirtazapine • Remeron
  
• Nafarelin • Synarel
  
• Naloxone • Suboxone
  
• Naltrexone • Vivitrol
  
• Naphazoline • Naphcon-A, Clearine
  
• Naproxen • Aleve, others
  
• Nizatidine • Axid
  
• Ofloxacin • Floxin
  
• Omeprazole • Prilosec
  
• Ondansetron • Zofran
  
• Paroxetine • Paxil
  
• Peginterferon alfa • PEG-Intron, Pegasys
  
• Phenylephrine • Neo-Synephrine
  
• Prednisolone • Blephamide, Pred Forte, others
  
• Propranolol • Inderal
  
• Pseudoephedrine • Actifed, Sudafed
  
• Ranitidine • Zantac
  
• Reserpine • Serpasi
  
• Ribavirin • Copegus, Rebetol
  
• Salbutamol • Aerolin, Airomir, others
  
• Sertraline • Zoloft
  
• Sumatriptan • Imitrex
  
• Tenofovir • Viread
  
• Trimethoprim • Proloprim
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. J, age 52, has a history of opioid dependence. Four weeks after starting interferon therapy for hepatitis C, he presents to the outpatient mental health clinic with depressed mood, irritability, decreased energy, poor concentration, insomnia, anhedonia, and suicidal ideation.

Because Mr. J has no history of depression, the psychiatrist diagnoses him with depressive disorder secondary to interferon. Interferon is stopped. Mr. J’s mood improves, but he wants to restart interferon.

The psychiatrist starts Mr. J on sertraline, 50 mg/d, then gradually increases the dose to 150 mg/d as Mr. J’s mood symptoms return. Subsequently, the patient continues interferon with a combination of sertraline and supportive psychotherapy.

Recognizing a medication as the possible cause of your patient’s psychiatric symptoms can avoid inaccurate diagnosis and nonindicated psychiatric treatment. Diligently evaluating patients for drug-related psychiatric side effects is critical because complications usually are reversed when the offending drug is discontinued. Unfortunately, a thin line separates available evidence from anecdotal myths about psychiatric complications of nonpsychotropics.

Almost two-thirds (65%) of drugs included in the Physicians’ Desk Reference list potential psychiatric side effects, according to a random sample review.¹ In some patients, such as Mr. J, these effects can exacerbate mood symptoms and result in perceptual, cognitive, or behavioral disturbances.

A wide range of drugs can cause psychosis, agitation, anxiety, depression, delirium, or insomnia (Table). On the other hand, certain psychiatric side effects of nonpsychotropics can be beneficial (Box 1).

Improve your assessments by examining the evidence linking psychiatric side effects to commonly prescribed and over-the-counter (OTC) compounds, including:

• cardiovascular medications
  
• steroids (prescription and illegal)
  
• hormones
  
• interferons
  
• antimicrobials.
  

Table

New-onset psychiatric symptoms? Check patient’s drug list

Symptom	Documented as a possible cause
Psychosis/agitation	Anabolic androgenic steroids, antihistamines, clonidine, corticosteroids, decongestants, didanosine, ethionamide, H2 blockers, isoniazid, nitrates, NSAIDs, opioids, proton pump inhibitors, quinolones, salbutamol, skeletal muscle relaxants, sulfonamides/trimethoprim
Anxiety	Acyclovir, anabolic androgenic steroids, clonidine, corticosteroids, cyclosporine, decongestants, didanosine, serotonin 5-HT1 agonists such as sumatriptan, foscarnet, ganciclovir, nitrates, ondansetron, penicillins, skeletal muscle relaxants
Depression	Anabolic androgenic steroids, beta blockers, chloramphenicol, clonidine, corticosteroids, didanosine, digoxin, efavirenz, foscarnet, GnRH agonists, H2 blockers, interferons, isoniazid, isotretinoin, NSAIDs, quinolones, statins, tetracyclines
Delirium	ACE inhibitors, anabolic androgenic steroids, antibiotics (most), anticholinergics, beta blockers, centrally acting antihypertensives such as methyldopa and reserpine, cimetidine, clonidine, corticosteroids, didanosine, digoxin, H2 blockers, lidocaine, naltrexone, nitrates, NSAIDs, opioids
Insomnia	Aminophylline, anabolic androgenic steroids, clonidine, corticosteroids, decongestants, didanosine, opioid antagonists, proton pump inhibitors, quinolone antibiotics, salbutamol, skeletal muscle relaxants, tetracyclines
NSAIDs: nonsteroidal anti-inflammatory drugs; ACE: angiotensin-converting enzyme; GnRH: gonadotropin-releasing hormone
Source: Prepared for Current Psychiatry by Drs. Sidhu and Balon from references cited in this article

Cardiovascular medications

Beta blockers have CNS effects—some of which cause psychiatric syndromes—that might depend on an ancillary property such as lipophilicity.² Unlike hydrophilic agents such as atenolol that are excreted unchanged by the kidneys, lipophilic drugs such as metoprolol and propranolol are metabolized by the liver and are believed to enter the brain. Metoprolol has a brain/plasma concentration ratio about 20 times higher than that of atenolol.³

Metoprolol and propranolol can induce delirium and psychosis.^4,5 Psychiatric side effects with metoprolol are frequent,⁴ and propranolol has been associated with:

• sedation (affecting >10% of patients)
  
• nightmares
  
• visual impairment
  
• hallucinations
  
• delirium
  
• depression.⁵
  

In 1967, it was reported that up to 50% of patients taking propranolol may experience dysphoria and at times severe depression.⁶ These effects may occur acutely or develop gradually. ⁵

The relationship between depressive symptoms and beta blockers has been increasingly questioned, however. One study did not find a higher prevalence of depression in patients receiving beta blockers vs those receiving other medications, although this trial had major methodologic limitations.⁷ One large study found no significant association between beta-blocker use and major depression, regardless of patient age, gender, or race.⁸

These studies stress the importance of carefully assessing the individual patient before assigning neurotoxicity to beta blockers, as these drugs have considerable benefits for cardiovascular disease.⁹

Angiotensin-converting enzyme (ACE) inhibitors also affect the CNS. About 4% to 8% of patients taking an ACE inhibitor experience altered mental status—typically increased arousal and psychomotor activity—although

• anxiety
  
• mania
  
• insomnia
  
• fatigue
  
• paresthesias
  
• hallucinations.⁵
  

Sedation occurs in about 5% of patients taking ACE inhibitors. Depression and suicide ideation as a result of ACE inhibition have been reported;¹³ however, ACE inhibitors have also been known to improve depression. Episodes of frank delirium have been reported.⁵

Clonidine is a centrally acting alpha-agonist. The alpha-adrenergic system regulates arousal and has an important role in major depression, anxiety states, and other arousal disorders.

 

More than one-third (35%) of patients taking clonidine experience sedation or lethargy; less commonly, the drug causes anxiety (3%), agitation (3%), depression (1%), and insomnia (1%).⁵ Acute confusion, delirium, hypomania, and psychosis related to clonidine use have long been recognized, occurring in 5

Box 1

Other cardiovascular drugs. Side effects of nitrates/nitrites include delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania.⁵ Digoxin can cause cardiac glycoside-induced encephalopathy, which may present as sedation, apathy, depression, and psychosis. Patients may develop delirium, even when digoxin/digitoxin serum levels are within a therapeutic range.

Cholesterol-lowering statins might be linked to an increased risk of depression and suicide, but the evidence is inconclusive. Some studies have supported this link,^10,11 whereas others have strongly refuted it^12,13 or had mixed results.¹⁴ A recent review¹⁵ recommends being vigilant for psychiatric side effects in patients taking these drugs.

Steroids: prescription and illegal

Corticosteroids are prescribed for a variety of immune system-related diseases, including asthma, allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease, and dermatologic disorders. Mood changes are the most common psychiatric symptoms caused by corticosteroid use; delirium is less common. Psychiatric side effects include:

• lethargy
  
• insomnia
  
• euphoria
  
• depression
  
• psychosis
  
• “personality changes”
  
• anxiety
  
• agitation.⁵
  

Multiple studies have linked corticosteroids and mood symptoms. The Boston Collaborative Drug Surveillance Program¹⁶ confirmed a direct relationship between corticosteroid dosage and psychiatric effects. More than 18% of patients had severe psychiatric symptoms at corticosteroid dosages >80 mg/d.

A prospective study of asthma patients found statistically significant changes in mood—primarily manic symptoms—during brief corticosteroid courses at modest dosages. Depressed persons did not become more depressed during prednisone therapy, however; in fact, some improved. Some patients with posttraumatic stress disorder reported increased depression and memories of the traumatic event during prednisone therapy.¹⁷

In a study of 50 ophthalmologic patients who did not have psychiatric illness receiving prednisolone (mean starting dose 119 mg/d) for 8 days, 26% developed mania and 10% depression.¹⁸ None reported psychotic symptoms.

The most common adverse effects of short-term corticosteroid therapy are euphoria and hypomania. Long-term therapy tends to induce depressive symptoms.¹⁹ A review of 79 cases of psychiatric syndromes induced by corticosteroids found that 41% reported depression, 28% mania, 6% mixed symptoms, and 14% psychosis.²⁰

A group of 16 healthy volunteers receiving 80 mg/d of prednisone over 5 days exhibited depressed or elevated mood, irritability, lability, increased energy, anxiety, and depersonalization.²¹ Numerous case studies have reported anxiety, agitation, mania, and psychotic symptoms in children and adults taking inhaled corticosteroids.

In general, psychiatric side effects of corticosteroids occur within 2 weeks of starting therapy and resolve with dosage reduction or discontinuation. In severe cases or situations in which the dosage cannot be reduced, the patient may require antipsychotics or mood stabilizers.¹⁹

Female gender and past psychiatric history might be risk factors for developing psychiatric symptoms with corticosteroids,²² although not all studies have confirmed these findings.¹⁸

Anabolic androgenic steroids (AAS) have limited therapeutic benefits but are used illegally by some bodybuilders, wrestlers, and other amateur and professional athletes to increase muscle mass, enhance performance, and gain a competitive edge. AAS can cause acute paranoia, delirium, mania or hypomania, homicidal rage, aggression, and extreme mood swings, as well as a marked increase in libido, irritability, agitation, and anger.

In a large observational cohort study of 320 bodybuilding amateur and recreational athletes,²³ AAS use induced many of these psychiatric side effects. The extent intensified as the abuse escalated. A study that used the Structured Clinical Interview for DSM-III-R to compare 88 athletes using steroids with 68 nonusers found that 23% of the AAS users reported major mood syndromes, including mania, hypomania, and major depression.²⁴

 

In a 2-week, double-blind, fixed-order, placebo-controlled, crossover study of healthy male inpatient volunteers, AAS had both:

• mood-elevating effects—euphoria (“steroid rush”), increased energy, and increased sexual arousal and drive
  
• mood-dysphoric effects, such as irritability, mood swings, increasingly violent feelings, increased hostility, and cognitive impairments.²⁵
  

As with corticosteroids, psychiatric symptoms from AAS become more prevalent and severe as dosage increases. They usually resolve within a few weeks after users discontinue steroids but may persist for up to 1 month, even if adequately treated with antipsychotic medication.

Hormones

Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide and nafarelin are approved for treating endometriosis, advanced prostate cancer, precocious puberty, and uterine leiomyomata. Some studies and case reports suggest that these agents cause depressive symptoms.²⁶

Progestins have complex and variable psychiatric effects. Clinical trials have investigated the antidepressant effects of exogenous estrogens on psychiatric patients, but results have been inconsistent—possibly because of small numbers of subjects and design flaws.²⁶ Some studies suggest a link between estrogen and depression in premenopausal and menopausal women with and without psychiatric illness, but findings remain controversial because other studies have found that estrogens have positive effects on mood.^26,27

Interferon

Various forms of interferon are used to treat hepatitis C, melanoma, multiple sclerosis, chronic myelogenous leukemia, and other illnesses. Psychiatric complications—particularly depression—are the most frequent side effect of interferon therapy and mainly occur within the first 12 weeks of therapy.²⁸

In a prospective observational study of veterans undergoing interferon-alfa/ribavirin treatment for chronic hepatitis C:

• 48% of patients not receiving psychiatric care at baseline required treatment for neuropsychiatric side effects
  
• 23% developed symptoms of major depression.²⁹
  

Treatment with a selective serotonin reuptake inhibitor stabilized these symptoms and allowed patients to continue hepatitis treatment.

Because patients who receive interferon are far more likely to require psychiatric intervention if they have a family history of mood disorders, closely monitor them for depressive symptoms and treat such symptoms aggressively. Also closely monitor patients with multiple psychiatric diagnoses receiving interferon-alfa therapy.³⁰

Jeungling et al³¹ speculated that hypometabolism in the prefrontal cortex may predispose patients to interferon-associated neuropsychological syndromes. Neuropsychiatric symptoms may be a characteristic of hepatitis C, interferon treatment, or both.³²

Antimicrobial agents

Antibiotic and antiviral drugs can cause psychiatric side effects:

• directly by affecting neuronal functions
  
• indirectly by entering the brain rapidly, taking advantage of the compromised blood-brain barrier during sepsis or infection.
  

Delirium is the most common psychiatric complication associated with these agents.⁵

Antibiotics. Penicillin and its analogues are associated with sedation, anxiety, and hallucinations. Delirium has been reported as a side effect of most cephalosporins, especially in patients with compromised renal function. Quinolones such as ciprofloxacin and ofloxacin rarely cause restlessness, irritability, lethargy, tremors, insomnia, mania, depression, psychosis, delirium, seizures, or catatonia (incidence ≤1%).⁵ Though not commonly used, chloramphenicol may cause depression, confusion, and delirium. Many case reports have strongly associated clarithromycin with delirium.³³

Isoniazid is one of the most commonly used antibiotics that can cause psychiatric side effects; it has been linked to delirium, mania, depression, and psychosis. Ethionamide is associated with sedation, irritability, depression, restlessness, and psychosis. Tetracyclines have been known to cause depression, insomnia, and irritability at high dosages.

Sulfonamides can cause delirium. Psychosis and confusion also have been reported, especially when sulfa drugs are combined with trimethoprim.⁵

Antivirals. When used intravenously and at high doses, acyclovir and ganciclovir can cause lethargy, anxiety, hallucinations, and frank delirium.⁵ Foscarnet—an antiviral used to treat herpes viruses—can cause depression, anxiety, hallucinations, and aggressive irritability.

Didanosine—an antiretroviral agent to treat HIV infections—can cause lethargy (5% to 7% of patients), depression (2%), anxiety (2%), emotional lability (25%), delirium (2%), insomnia (1%), and psychotic delusions (1%).⁵ Efavirenz treatment may be associated with major depression and severe suicidal ideation.³⁴ Tenofovir, a nucleotide reverse transcriptase inhibitor, has not been associated with psychiatric side effects.²⁷

Antifungals. Psychiatric side effects are rare.

OTC and other agents

Many common nonprescription agents can cause psychiatric symptoms. The most frequently used classes include cold and allergy preparations, reflux medications, and analgesics (Box 2).^5,35

Cold preparations. Combined antihistamines and decongestants—such as phenylpropanolamine, azatadine, loratadine, ephedrine, phenylephrine, pseudoephedrine, and naphazoline—can cause an atropine-like psychosis that typically manifests as confusion, disorientation, agitation, hallucinations, and memory problems. Decongestants can cause dangerously high levels of norepinephrine when combined with monoamine oxidase inhibitors (MAOIs) and are contraindicated in patients taking MAOIs. Ephedrine can induce restlessness, dysphoria, irritability, anxiety, and insomnia.

 

Reflux medications. Two primary classes of reflux medications are proton pump inhibitors (omeprazole and lansoprazole) and H₂ receptor antagonists (famotidine, nizatidine, ranitidine, and cimetidine). Although generally considered to have a benign side-effect profile, these medications have been reported to cause serious neuropsychiatric complications—including mental confusion, agitation, depression, and hallucinations—mainly in geriatric patients with impaired hepatic-renal function.³⁶ These occur in only 37

Time to onset of psychiatric side effects from H₂ antagonists varies. Ranitidine can cause depression 4 to 8 weeks after treatment begins. Cimetidine has been reported to cause adverse events within 2 to 3 weeks and delirium within 24 to 48 hours.³⁸ These effects usually resolve within 3 days of discontinuing the drug. Cimetidine is also associated with sexual dysfunction.

Discontinuing ranitidine or cimetidine can induce a withdrawal syndrome that includes anxiety, insomnia, and irritability.³⁹ Cimetidine can increase the blood level and action of tricyclic antidepressants. Blood levels of these antidepressants can become toxic, resulting in tachycardia and other adverse effects.

Other medications. Ondansetron is a 5-hydroxytryptamine subclass 3 (5-HT₃) antagonist used for antiemetic therapy. In case reports, it has been strongly associated with anxiety.⁴⁰ This association is complex, however, and studies are evaluating 5-HT₃ receptor antagonists for the treatment of anxiety, depression, phobia, and schizophrenia.

Isotretinoin—a retinoid used for severe acne—can cause severe depression and suicidal behavior.⁴¹

Aminophylline and salbutamol are associated with agitation, insomnia, euphoria, and delirium. Methotrexate is known to cause personality changes, irritability, and delirium.²⁷

Box 2

Treating drug-related mood effects

If you suspect a nonpsychotropic medication is causing your patient’s psychiatric symptoms, discuss this with the patient and the prescribing physician. Switching to another similar agent may be an option. If this is not possible:

• work closely with the patient’s primary physician
  
• treat mood symptoms with appropriate psychotropics.
  

Related resources

• Turjanski N, Lloyd GG. Psychiatric side-effects of medications: recent developments. Advances in Psychiatric Treatment 2005;11:58-70.
  
• Brown TM, Stoudemire A. Psychiatric side effects of prescription and over-the-counter medications. Recognition and management. Washington, DC: American Psychiatric Publishing; 1998.
  
• Physicians’ Desk Reference. www.pdr.net.
  

Drug brand name

• Acyclovir • Zovirax
  
• Aminophylline • Phyllocontin, Truphylline
  
• Atenolol • Tenormin
  
• Azatadine • Optimine
  
• Baclofen • Lioresal
  
• Chloramphenicol • Chloromycetin
  
• Cimetidine • Tagamet
  
• Ciprofloxacin • Cipro
  
• Clarithromycin • Biaxin
  
• Clonidine • Catapres
  
• Cyclosporine • Neoral, Sandimmune, others
  
• Dantrolene • Dantrium
  
• Didanosine • Videx
  
• Efavirenz • Sustiva
  
• Ethionamide • Trecator
  
• Famotidine • Pepcid
  
• Foscarnet • Foscavir
  
• Ganciclovir • Cytovene
  
• Indomethacin • Indocin
  
• Interferon alfa • Intron, Roferon
  
• Isoniazid • Nydrazid
  
• Isotretinoin • Accutane
  
• Lansoprazole • Prevacid
  
• Leuprolide • Lupron
  
• Lidocaine • Xylocaine, Xylocard
  
• Loratadine • Claritin
  
• Methotrexate • Rheumatrex, Trexall
  
• Methyldopa • Aldomet
  
• Metoprolol • Lopressor
  
• Mirtazapine • Remeron
  
• Nafarelin • Synarel
  
• Naloxone • Suboxone
  
• Naltrexone • Vivitrol
  
• Naphazoline • Naphcon-A, Clearine
  
• Naproxen • Aleve, others
  
• Nizatidine • Axid
  
• Ofloxacin • Floxin
  
• Omeprazole • Prilosec
  
• Ondansetron • Zofran
  
• Paroxetine • Paxil
  
• Peginterferon alfa • PEG-Intron, Pegasys
  
• Phenylephrine • Neo-Synephrine
  
• Prednisolone • Blephamide, Pred Forte, others
  
• Propranolol • Inderal
  
• Pseudoephedrine • Actifed, Sudafed
  
• Ranitidine • Zantac
  
• Reserpine • Serpasi
  
• Ribavirin • Copegus, Rebetol
  
• Salbutamol • Aerolin, Airomir, others
  
• Sertraline • Zoloft
  
• Sumatriptan • Imitrex
  
• Tenofovir • Viread
  
• Trimethoprim • Proloprim
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. R, age 67, presents with what he describes as uncharacteristic “memory loss” that is affecting his ability to run his accounting business. He and his wife relate that he was doing well until approximately 9 months ago, when he started showing difficulties remembering clients’ names and addresses.

His wife became extremely concerned when he made serious accounting errors in a 1-month period that resulted in the loss of a longtime customer. Mr. R has become easily distracted and absentminded as well, and his wife reports he is misplacing things around the house.

Screening for mild cognitive impairment (MCI) is not recommended for asymptomatic, cognitively healthy older persons, but memory complaints in individuals age >50—especially when corroborated by a reliable informant—warrant further assessment. Your challenge is to determine whether subtle cognitive changes in patients such as Mr. R are part of normal aging, caused by medical or mental illnesses, or a harbinger of Alzheimer’s disease (AD) or another dementia.

Although no treatments can yet prevent dementia, substantial new research is defining the MCI diagnosis for clinicians. This article describes:

• the evolving understanding of MCI and its subtypes
  
• risk factors for converting from MCI to AD
  
• an evidence-based work-up (including functional, cognitive, and neuropsychological testing)
  
• neuroprotective strategies for patients with an MCI diagnosis, including evidence on cholinesterase inhibitors, vitamin E, and anti-inflammatory agents.
  

MCI’s evolving definition

MCI is characterized by subjective and objective cognitive decline greater than expected for an individual’s age and education but less than the functional deficit required for a dementia diagnosis. MCI is proposed to identify persons with early but pathologic cognitive impairment that has a high risk to progress to AD and possibly other dementias.

MCI is thought to be a transitional state between normal aging and dementia.¹ Its estimated prevalence in the general population is 19% among individuals age 85.²

MCI subtypes. Some experts view MCI as a single entity, whereas others suggest amnestic (aMCI) and nonamnestic (nMCI) subtypes.^1,3 Each subtype is further divided into single and multiple cognitive domains. So, for example, the diagnosis would be:

• aMCI-single cognitive domain for memory impairment only
  
• aMCI-multiple cognitive domains for memory impairment plus nonmemory deficits, such as in language, executive function, or visuospatial function
  
• nMCI-single or multiple cognitive domains for nonmemory deficits without memory impairment.
  

MCI subtypes may have different outcomes for progression to dementia, and all progressive dementias may have their own predementia states.⁴ Vascular MCI, for instance, is thought to result from cerebrovascular disease and is proposed to describe a prodrome of vascular dementia.⁵

Determining a patient’s MCI subtype is still a research activity and calls for comprehensive neuropsychological testing. MCI patients perform at least 1.5 standard deviations below the average for age- and education-matched healthy individuals on objective measures of memory.¹

Conversion to dementia

In longitudinal population studies patients with MCI have shown an 11% to 33% risk of developing dementia within 2 years, whereas 44% reverted to normal 1 year later. Reasons for reversibility may include variable definitions of MCI among the longitudinal studies and the possibility that patients who recovered or improved may have had reversible causes of dementia.¹

When patients with MCI are followed over time, they progress not only to AD but also to non-AD dementias. For example, patients with Parkinson’s disease (PD) and MCI may be at higher risk of progressing to dementia than cognitively intact PD patients.⁶ MCI patients with the e4 allele of the apolipoprotein E gene (ApoE e4) are at increased risk to convert from MCI to AD.⁷

Individuals with aMCI (Table 1)⁸ progress to AD at a rate of 10% to 15% per year, compared with 1% to 2% per year in normal elderly persons. The Mayo AD research center studies reported a conversion rate of up to 80% from aMCI to AD within 6 years.⁹

Research focuses on identifying preclinical AD states and potential targets for intervention using disease-modifying therapies. Some experts consider MCI to be the earliest clinical manifestation of AD, at least in a subgroup of patients.

Identifying markers to predict which patients are likely to convert from MCI to dementia also is a major research objective. In addition to ApoE status (Table 2),^7,9-15 predictors of conversion may include:

 

• hippocampal atrophy¹³
  
• reduced metabolism in the temporoparietal cortex and posterior cingulum¹⁴
  
• elevated CSF tau and the 42 amino acid form of ß-amyloid (Aß 42).¹⁵
  

Research techniques such as structural neuroimaging, positron-emission tomography, functional magnetic resonance imaging (fMRI), and cerebrospinal fluid biomarkers have not been defined for clinical use, however.

Neuropsychiatric symptoms. Individuals with MCI and neuropsychiatric symptoms may be at particular risk for progressing to dementia. Agitation or depression are more prevalent in persons with MCI than in normal elderly but less prevalent than in those with dementia (Table 3).^10,16

The cross-sectional, community-based Cardiovascular Health Study showed one or more neuropsychiatric symptom in:

• 16% of normal healthy elderly
  
• 43% of MCI patients
  
• 75% of dementia patients.¹⁶
  

Depression (20%), apathy (15%), and irritability (15%) were the neuropsychiatric symptoms reported most frequently in MCI patients, compared with apathy (36%), depression (32%), and agitation/aggression (30%) in dementia patients.

Sleep disturbances and anxiety in persons with MCI may predict progression to AD.¹⁰ A baseline high frequency of apathy in aMCI patients has been associated with progression to AD within 1 year.¹¹

Table 1

Amnestic MCI: Proposed diagnostic criteria

Subjective memory impairment, preferably corroborated by a reliable informant
Reduced performance on objective memory tests, compared with persons of similar age and educational background
Typical general cognitive function
Intact basic activities of daily living and intact or minimally impaired instrumental activities of daily living
Absence of dementia
MCI: mild cognitive impairment
Source: Reference 8

Table 2

Factors shown to predict conversion from MCI to dementia

Category	Predictors of conversion
Clinical	Cognitive: Amnestic MCI Neuropsychiatric: Depression, apathy, and possibly nighttime behaviors and anxiety
Neuropsychological tests	Clock-drawing test, Trail-Making Test B, Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), ADAS-Cog total score
Neuroimaging	MRI: Entorhinal cortex and hippocampal atrophy PET: Medial temporal region, parietotemporal association cortex, and posterior cingulate hypometabolism fMRI: Abnormal hippocampal, posterior cingulate, and medial temporal region activation on memory tasks
CSF markers	Increase: t-tau, p-tau Decrease: Aß 42
Genetic markers	ApoE e4 carriers
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ApoE e4: apolipoprotein E gene, e4 allele; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; fMRI: functional MRI; PET: positron-emission tomography
Source: References 7,9-15

Table 3

Neuropsychiatric symptoms: Rising prevalence mirrors cognitive deterioration in elderly patients*

Neuropsychiatric symptoms	Normal elderly	MCI	Mild AD
Depressed mood/dysphoria	+	++	+++
Nighttime behaviors/sleep	+	++	+++
Irritability	+	++	+++
Anxiety	+/-	++	+++
Apathy/indifference	+/-	++	+++
Agitation/aggression	+/-	+/++	+++
Eating/appetite disturbance	+/-	+	++
Disinhibition	+/-	+/-	++
Aberrant motor behavior	0	+	++
Delusions	0	+/-	++
Euphoria	0	+/-	+/-
Hallucinations	0	0	+
* 0 = 0%; +/- = 1% to 5%; + = 6% to 10%; ++ = 11% to 20%; +++ = 21% to 40%
MCI: mild cognitive impairment; AD: Alzheimer’s disease
Source: References 10,16

Depression and MCI

Depression and cognitive complaints overlap considerably in older adults. Depressed patients without dementia show persistent cognitive deficits even after depression remits. In some patients, new-onset geriatric depression is considered a prodrome of MCI and AD. Given that AD neuropathologic changes precede clinical symptoms by many years, depression and AD have been proposed as different clinical manifestations of AD pathology.¹⁷

Among patients with MCI, 20% meet criteria for major depression and 26% for minor depression. Symptoms often include sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and insomnia.¹⁸

Depressed MCI patients are at higher risk of developing dementia than those without depression, especially if cognitive measures do not improve after depression is treated.¹² Similarly, cognitively intact older persons who develop depression are at increased risk for MCI, particularly if they carry the ApoE e4 genotype.¹⁹

In the only study in which MCI patients’ neuropsychiatric symptoms have been treated, 39 elderly patients with depression and MCI received open-label sertraline, ≤200 mg/d, for 12 weeks. Among the 26 patients who completed the trial, 17 showed moderate improvement in depressive symptoms, attention, and executive function, and 9 showed no response.²⁰

Recommendation. In clinical practice, antidepressant treatment—usually a selective serotonin reuptake inhibitor (SSRI), with or without psychotherapy—is recommended for the MCI patient with comorbid major depression.

CASE CONTINUED: No signs of depression

Mr. R’s medical, neurologic, and substance use history is unremarkable. Family history includes AD in a paternal aunt diagnosed at age 82. Mr. R reports no history of mood, sleep, or appetite changes and no psychotic symptoms. He shows no deficits in activities of daily living (ADL), although his wife recently took over paying household bills after he forgot to make a payment.

Evidence-based workup

Functional assessment. In the differential diagnosis of MCI, give special attention to functional impairment, which points toward dementia. ADL generally are preserved in MCI, and minimal deterioration is seen in instrumental activities of daily living (IADL). A relatively easy way to assess function is to use the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), which is based on 16 ADL and IADL items (Table 4).²¹

 

A substantial functional decline precludes an MCI diagnosis, although the degree of functional decline can be difficult to assess in older adults with physical limitations caused by medical comorbidities.

Cognitive assessment. Because most individuals with MCI score in the normal range on the Folstein Mini-Mental State Examination (MMSE), the modified MMSE (3MS)²² may be more sensitive for detecting MCI. The 3MS retains the MMSE’s brevity (≤10 minutes to administer) but incorporates 4 additional items, has more graded scoring responses, and broadens the score range to 0 to 100. The clock-drawing test also is sensitive for MCI, especially in detecting early visuoconstructional dysfunction.

The Montreal Cognitive Assessment (MoCA) is a 10-minute, 30-point scale designed to help clinicians detect MCI (see Related Resources). The MoCA usually is given with the modified MMSE for a comprehensive cognitive assessment.

Nasreddine et al²³ administered the MoCA and MMSE to 94 patients who met clinical criteria for MCI, 93 patients with mild AD, and 90 healthy cognitively normal elderly persons, using a cutoff score of 26. MoCA showed:

• 90% sensitivity for detecting MCI (compared with 18% for the MMSE)
  
• 87% specificity to exclude normal elderly persons.
  

The average MoCA score in patients with AD was much lower than in individuals with MCI, but score ranges of these 2 groups overlapped. Therefore, a score

Neuropsychological testing can be more sensitive than office-based screening tools in defining MCI subtypes. In the Alzheimer’s Disease Cooperative Study (ADCS), the neuropsychological measures that most accurately predicted progression of patients with aMCI to AD within 36 months were the:

• Symbol Digit Modalities Test
  
• New York University Paragraph Recall Test (Delayed)
  
• Delayed 10-Word List Recall
  
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.²⁴
  

Laboratory tests, imaging. Use laboratory studies (Table 5) to rule out reversible causes of MCI symptoms.⁸ Reserve CSF studies for suspected CNS infection (such as meningitis, human immunodeficiency virus, or neurosyphilis) and brain imaging for suspected cerebral pathology (such as infarct, subdural hematoma, normal pressure hydrocephalus, or tumor).

Table 4

Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS)

Basic ADL	Instrumental ADL (IADL)
Toileting	Use of telephone
Feeding	Household tasks
Dressing	Using household appliances
Personal hygiene and grooming	Managing money
	Shopping
Bathing	Food preparation
Walking	Ability to get around inside and outside home
	Hobbies and leisure activities
	Handling personal mail
	Grasp of situations and explanations
The 16-item ADFACS total score ranges from 0 to 54 (best to worst): Rate basic ADLs from 0 (no impairment) to 4 (very severe impairment), for a total score range of 0 to 24. Rate IADLs from 0 (no impairment) to 3 (severe impairment), for a total score range of 0 to 30.
Use total scores to assess for functional decline from baseline. A decline from 0 to 1 on individual ADL and IADL items is not considered clinically significant.
ADL: activities of daily living
Source: Reprinted with permission from reference 21

Table 5

Lab studies to rule out reversible causes of MCI

Complete blood count with differential
Basic metabolic panel
Liver function tests
Serum calcium
Serum vitamin B12 and folate
Thyroid function tests
Rapid plasma reagin
HIV in high-risk individuals
CSF studies if CNS infection is suspected
CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; MCI: mild cognitive impairment
Source: Reference 8

CASE CONTINUED: Subtle cognitive deficits

Mr. R scores 27/30 on the MMSE (losing 3 points on recall) and 25/30 on the MoCA (losing points on visuospatial/executive function, fluency, and delayed recall). Thyroid stimulating hormone, vitamin B12, folate, and rapid plasma reagin tests are unremarkable; brain MRI shows no significant abnormalities.

You refer Mr. R for neuropsychological testing, and most cognitive domains are normal. Exceptions include moderate impairment in immediate and delayed verbal and visual memory and mild executive dysfunction.

Based on your clinical evaluation and neuropsychological testing, you diagnose amnestic MCI. Mr. R shows abnormalities in memory and executive functioning without significant decline in basic and instrumental ADLs, is not taking medications, and has no other medical or psychiatric condition that could explain his cognitive deficits.

You discuss the diagnosis with him and his wife, including evidence on his risk for progression to dementia, neuroprotective strategies, and medications.

After an MCI diagnosis

Neuroprotection. Eliminate medications with anticholinergic effects, including:

• tricyclic antidepressants
  
• conventional antipsychotics
  
• antihistamines
  
• drugs used to treat urinary incontinence, such as oxybutynin
  
• muscle relaxants, such as cyclobenzaprine
  
• certain antiparkinsonian drugs, such as benztropine.
  

Encourage patients to avoid alcohol and sedatives. Collaborate with primary care providers to control cerebrovascular risk factors such as hyperlipidemia, diabetes mellitus, hypertension, and obesity. Treat depression, which may be a risk factor for developing dementia.

 

Monitoring. The American Academy of Neurology recommends monitoring patients diagnosed with MCI every 6 to 12 months for cognitive and functional decline.

In these visits, include:

• repeat office-based cognitive assessment, especially the modified MMSE, clock-drawing test, and MoCA
  
• careful history-taking from the patient and reliable informant
  
• repeat neuropsychological testing annually or when dementia is suspected
  
• assessment of the caregiver for distress.
  

Compensating for memory loss. Many individuals with MCI have insight into their cognitive deficits and are interested in making lifestyle changes. Experts recommend:

• moderate exercise (at least 30 minutes per session, 3 times a week)
  
• cognitively stimulating activities that involve language and psychomotor coordination, such as dancing, crossword puzzles, and volunteer work.
  

Potentially helpful tools include calendars, reminder notes, electronic cuing devices, pill boxes, and “speed-dial” telephones. Encourage patients to participate in local senior organizations and to use community resources.¹

Medications—yes or no? Cholinesterase inhibitors, rofecoxib, and vitamin E have not been shown to prevent MCI from progressing to AD. Thus, insufficient evidence exists to recommend medications for patients with MCI.

Donepezil has shown possible short-term benefits, however, and patients may choose to try this medication. Some find comfort in seeking this “extra time” to make decisions about advanced directives, attend to estate and will issues, and optimize relationships while they have only mild cognitive deficits and possess decision-making capacity.

Donepezil. The Alzheimer’s Disease Cooperative Study—supported by the National Institute on Aging—was designed to determine whether daily doses of donepezil or vitamin E can delay or prevent progression of aMCI to AD.²⁵ In the double-blind, placebo-controlled, parallel group study, 769 patients with aMCI were randomly assigned to receive donepezil, 10 mg/d; vitamin E, 1,000 IU bid; or placebo for 3 years.

Overall progression to AD was 16% per year, and the 3-year risk of progression was the same in all 3 groups. Donepezil therapy was associated with a reduced rate of progression to AD compared with placebo during the first year of treatment. Donepezil’s benefit was evident among ApoE e4 carriers at 2-year follow-up, but none of the 3 groups showed statistically significant differences after 3 years. Vitamin E showed no effect on AD progression throughout the study.

Rivastigmine. A randomized, placebo-controlled trial in which 1,018 MCI patients received rivastigmine or placebo for 4 years found no statistically significant benefit of rivastigmine on AD progression.²⁶

Galantamine. Two international randomized, double-blind, placebo-controlled trials failed to show a statistically significant benefit of galantamine in slowing progression from aMCI to AD. MRI data from one of these studies suggested that galantamine may have reduced the rate of brain atrophy over a 2-year period.²⁷

Rofecoxib. Epidemiologic studies indicate that anti-inflammatory drugs may reduce the risk of developing AD, but the COX-2 inhibitor rofecoxib did not delay progression to AD among aMCI patients in a large, placebo-controlled trial.²⁸

Educate patients and family members about supportive nonpharmacologic treatments and cholinesterase inhibitors. The Alzheimer’s Association, National Institute on Aging, and local department of aging agencies offer useful resources (see Related Resources).

CASE CONTINUED: Dealing with uncertainty

Mr. R and his wife are unsettled by his MCI diagnosis. They prefer to take a “wait and watch” approach, decline initiation of a cholinesterase inhibitor, and agree to adhere to nonpharmacologic interventions you discussed. You schedule a follow-up visit in 6 months and encourage them to call you with questions.

Related resources

• Rosenberg PB, Johnston D, Lyketsos CG. A clinical approach to mild cognitive impairment. Am J Psychiatry 2006;163: 1884-90.
  
• Montreal Cognitive Assessment (MoCA). 10-minute screening test designed to help clinicians detect mild cognitive impairment. www.mocatest.org.
  
• Alzheimer’s Association. www.alz.org.
  
• National Institute on Aging. www.nia.nih.gov.
  

Drug brand name

• Benztropine • Cogentin
  
• Cyclobenzaprine • Flexeril
  
• Donepezil • Aricept
  
• Galantamine • Razadyne
  
• Oxybutynin • Ditropan
  
• Rivastigmine • Exelon
  
• Rofecoxib • Vioxx
  
• Sertraline • Zoloft
  

Disclosure

Dr. Goveas and Dr. Dixon-Holbrook report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kerwin is a consultant to Pfizer and a speaker for Pfizer and Novartis.

Dr. Antuono receives research support from Eisai, Pfizer, and Elan and is a speaker for Pfizer and Forest Pharmaceuticals.

Mr. R, age 67, presents with what he describes as uncharacteristic “memory loss” that is affecting his ability to run his accounting business. He and his wife relate that he was doing well until approximately 9 months ago, when he started showing difficulties remembering clients’ names and addresses.

His wife became extremely concerned when he made serious accounting errors in a 1-month period that resulted in the loss of a longtime customer. Mr. R has become easily distracted and absentminded as well, and his wife reports he is misplacing things around the house.

Screening for mild cognitive impairment (MCI) is not recommended for asymptomatic, cognitively healthy older persons, but memory complaints in individuals age >50—especially when corroborated by a reliable informant—warrant further assessment. Your challenge is to determine whether subtle cognitive changes in patients such as Mr. R are part of normal aging, caused by medical or mental illnesses, or a harbinger of Alzheimer’s disease (AD) or another dementia.

Although no treatments can yet prevent dementia, substantial new research is defining the MCI diagnosis for clinicians. This article describes:

• the evolving understanding of MCI and its subtypes
  
• risk factors for converting from MCI to AD
  
• an evidence-based work-up (including functional, cognitive, and neuropsychological testing)
  
• neuroprotective strategies for patients with an MCI diagnosis, including evidence on cholinesterase inhibitors, vitamin E, and anti-inflammatory agents.
  

MCI’s evolving definition

MCI is characterized by subjective and objective cognitive decline greater than expected for an individual’s age and education but less than the functional deficit required for a dementia diagnosis. MCI is proposed to identify persons with early but pathologic cognitive impairment that has a high risk to progress to AD and possibly other dementias.

MCI is thought to be a transitional state between normal aging and dementia.¹ Its estimated prevalence in the general population is 19% among individuals age 85.²

MCI subtypes. Some experts view MCI as a single entity, whereas others suggest amnestic (aMCI) and nonamnestic (nMCI) subtypes.^1,3 Each subtype is further divided into single and multiple cognitive domains. So, for example, the diagnosis would be:

• aMCI-single cognitive domain for memory impairment only
  
• aMCI-multiple cognitive domains for memory impairment plus nonmemory deficits, such as in language, executive function, or visuospatial function
  
• nMCI-single or multiple cognitive domains for nonmemory deficits without memory impairment.
  

MCI subtypes may have different outcomes for progression to dementia, and all progressive dementias may have their own predementia states.⁴ Vascular MCI, for instance, is thought to result from cerebrovascular disease and is proposed to describe a prodrome of vascular dementia.⁵

Determining a patient’s MCI subtype is still a research activity and calls for comprehensive neuropsychological testing. MCI patients perform at least 1.5 standard deviations below the average for age- and education-matched healthy individuals on objective measures of memory.¹

Conversion to dementia

In longitudinal population studies patients with MCI have shown an 11% to 33% risk of developing dementia within 2 years, whereas 44% reverted to normal 1 year later. Reasons for reversibility may include variable definitions of MCI among the longitudinal studies and the possibility that patients who recovered or improved may have had reversible causes of dementia.¹

When patients with MCI are followed over time, they progress not only to AD but also to non-AD dementias. For example, patients with Parkinson’s disease (PD) and MCI may be at higher risk of progressing to dementia than cognitively intact PD patients.⁶ MCI patients with the e4 allele of the apolipoprotein E gene (ApoE e4) are at increased risk to convert from MCI to AD.⁷

Individuals with aMCI (Table 1)⁸ progress to AD at a rate of 10% to 15% per year, compared with 1% to 2% per year in normal elderly persons. The Mayo AD research center studies reported a conversion rate of up to 80% from aMCI to AD within 6 years.⁹

Research focuses on identifying preclinical AD states and potential targets for intervention using disease-modifying therapies. Some experts consider MCI to be the earliest clinical manifestation of AD, at least in a subgroup of patients.

Identifying markers to predict which patients are likely to convert from MCI to dementia also is a major research objective. In addition to ApoE status (Table 2),^7,9-15 predictors of conversion may include:

 

• hippocampal atrophy¹³
  
• reduced metabolism in the temporoparietal cortex and posterior cingulum¹⁴
  
• elevated CSF tau and the 42 amino acid form of ß-amyloid (Aß 42).¹⁵
  

Research techniques such as structural neuroimaging, positron-emission tomography, functional magnetic resonance imaging (fMRI), and cerebrospinal fluid biomarkers have not been defined for clinical use, however.

Neuropsychiatric symptoms. Individuals with MCI and neuropsychiatric symptoms may be at particular risk for progressing to dementia. Agitation or depression are more prevalent in persons with MCI than in normal elderly but less prevalent than in those with dementia (Table 3).^10,16

The cross-sectional, community-based Cardiovascular Health Study showed one or more neuropsychiatric symptom in:

• 16% of normal healthy elderly
  
• 43% of MCI patients
  
• 75% of dementia patients.¹⁶
  

Depression (20%), apathy (15%), and irritability (15%) were the neuropsychiatric symptoms reported most frequently in MCI patients, compared with apathy (36%), depression (32%), and agitation/aggression (30%) in dementia patients.

Sleep disturbances and anxiety in persons with MCI may predict progression to AD.¹⁰ A baseline high frequency of apathy in aMCI patients has been associated with progression to AD within 1 year.¹¹

Table 1

Amnestic MCI: Proposed diagnostic criteria

Subjective memory impairment, preferably corroborated by a reliable informant
Reduced performance on objective memory tests, compared with persons of similar age and educational background
Typical general cognitive function
Intact basic activities of daily living and intact or minimally impaired instrumental activities of daily living
Absence of dementia
MCI: mild cognitive impairment
Source: Reference 8

Table 2

Factors shown to predict conversion from MCI to dementia

Category	Predictors of conversion
Clinical	Cognitive: Amnestic MCI Neuropsychiatric: Depression, apathy, and possibly nighttime behaviors and anxiety
Neuropsychological tests	Clock-drawing test, Trail-Making Test B, Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), ADAS-Cog total score
Neuroimaging	MRI: Entorhinal cortex and hippocampal atrophy PET: Medial temporal region, parietotemporal association cortex, and posterior cingulate hypometabolism fMRI: Abnormal hippocampal, posterior cingulate, and medial temporal region activation on memory tasks
CSF markers	Increase: t-tau, p-tau Decrease: Aß 42
Genetic markers	ApoE e4 carriers
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ApoE e4: apolipoprotein E gene, e4 allele; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; fMRI: functional MRI; PET: positron-emission tomography
Source: References 7,9-15

Table 3

Neuropsychiatric symptoms: Rising prevalence mirrors cognitive deterioration in elderly patients*

Neuropsychiatric symptoms	Normal elderly	MCI	Mild AD
Depressed mood/dysphoria	+	++	+++
Nighttime behaviors/sleep	+	++	+++
Irritability	+	++	+++
Anxiety	+/-	++	+++
Apathy/indifference	+/-	++	+++
Agitation/aggression	+/-	+/++	+++
Eating/appetite disturbance	+/-	+	++
Disinhibition	+/-	+/-	++
Aberrant motor behavior	0	+	++
Delusions	0	+/-	++
Euphoria	0	+/-	+/-
Hallucinations	0	0	+
* 0 = 0%; +/- = 1% to 5%; + = 6% to 10%; ++ = 11% to 20%; +++ = 21% to 40%
MCI: mild cognitive impairment; AD: Alzheimer’s disease
Source: References 10,16

Depression and MCI

Depression and cognitive complaints overlap considerably in older adults. Depressed patients without dementia show persistent cognitive deficits even after depression remits. In some patients, new-onset geriatric depression is considered a prodrome of MCI and AD. Given that AD neuropathologic changes precede clinical symptoms by many years, depression and AD have been proposed as different clinical manifestations of AD pathology.¹⁷

Among patients with MCI, 20% meet criteria for major depression and 26% for minor depression. Symptoms often include sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and insomnia.¹⁸

Depressed MCI patients are at higher risk of developing dementia than those without depression, especially if cognitive measures do not improve after depression is treated.¹² Similarly, cognitively intact older persons who develop depression are at increased risk for MCI, particularly if they carry the ApoE e4 genotype.¹⁹

In the only study in which MCI patients’ neuropsychiatric symptoms have been treated, 39 elderly patients with depression and MCI received open-label sertraline, ≤200 mg/d, for 12 weeks. Among the 26 patients who completed the trial, 17 showed moderate improvement in depressive symptoms, attention, and executive function, and 9 showed no response.²⁰

Recommendation. In clinical practice, antidepressant treatment—usually a selective serotonin reuptake inhibitor (SSRI), with or without psychotherapy—is recommended for the MCI patient with comorbid major depression.

CASE CONTINUED: No signs of depression

Mr. R’s medical, neurologic, and substance use history is unremarkable. Family history includes AD in a paternal aunt diagnosed at age 82. Mr. R reports no history of mood, sleep, or appetite changes and no psychotic symptoms. He shows no deficits in activities of daily living (ADL), although his wife recently took over paying household bills after he forgot to make a payment.

Evidence-based workup

Functional assessment. In the differential diagnosis of MCI, give special attention to functional impairment, which points toward dementia. ADL generally are preserved in MCI, and minimal deterioration is seen in instrumental activities of daily living (IADL). A relatively easy way to assess function is to use the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), which is based on 16 ADL and IADL items (Table 4).²¹

 

A substantial functional decline precludes an MCI diagnosis, although the degree of functional decline can be difficult to assess in older adults with physical limitations caused by medical comorbidities.

Cognitive assessment. Because most individuals with MCI score in the normal range on the Folstein Mini-Mental State Examination (MMSE), the modified MMSE (3MS)²² may be more sensitive for detecting MCI. The 3MS retains the MMSE’s brevity (≤10 minutes to administer) but incorporates 4 additional items, has more graded scoring responses, and broadens the score range to 0 to 100. The clock-drawing test also is sensitive for MCI, especially in detecting early visuoconstructional dysfunction.

The Montreal Cognitive Assessment (MoCA) is a 10-minute, 30-point scale designed to help clinicians detect MCI (see Related Resources). The MoCA usually is given with the modified MMSE for a comprehensive cognitive assessment.

Nasreddine et al²³ administered the MoCA and MMSE to 94 patients who met clinical criteria for MCI, 93 patients with mild AD, and 90 healthy cognitively normal elderly persons, using a cutoff score of 26. MoCA showed:

• 90% sensitivity for detecting MCI (compared with 18% for the MMSE)
  
• 87% specificity to exclude normal elderly persons.
  

The average MoCA score in patients with AD was much lower than in individuals with MCI, but score ranges of these 2 groups overlapped. Therefore, a score

Neuropsychological testing can be more sensitive than office-based screening tools in defining MCI subtypes. In the Alzheimer’s Disease Cooperative Study (ADCS), the neuropsychological measures that most accurately predicted progression of patients with aMCI to AD within 36 months were the:

• Symbol Digit Modalities Test
  
• New York University Paragraph Recall Test (Delayed)
  
• Delayed 10-Word List Recall
  
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.²⁴
  

Laboratory tests, imaging. Use laboratory studies (Table 5) to rule out reversible causes of MCI symptoms.⁸ Reserve CSF studies for suspected CNS infection (such as meningitis, human immunodeficiency virus, or neurosyphilis) and brain imaging for suspected cerebral pathology (such as infarct, subdural hematoma, normal pressure hydrocephalus, or tumor).

Table 4

Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS)

Basic ADL	Instrumental ADL (IADL)
Toileting	Use of telephone
Feeding	Household tasks
Dressing	Using household appliances
Personal hygiene and grooming	Managing money
	Shopping
Bathing	Food preparation
Walking	Ability to get around inside and outside home
	Hobbies and leisure activities
	Handling personal mail
	Grasp of situations and explanations
The 16-item ADFACS total score ranges from 0 to 54 (best to worst): Rate basic ADLs from 0 (no impairment) to 4 (very severe impairment), for a total score range of 0 to 24. Rate IADLs from 0 (no impairment) to 3 (severe impairment), for a total score range of 0 to 30.
Use total scores to assess for functional decline from baseline. A decline from 0 to 1 on individual ADL and IADL items is not considered clinically significant.
ADL: activities of daily living
Source: Reprinted with permission from reference 21

Table 5

Lab studies to rule out reversible causes of MCI

Complete blood count with differential
Basic metabolic panel
Liver function tests
Serum calcium
Serum vitamin B12 and folate
Thyroid function tests
Rapid plasma reagin
HIV in high-risk individuals
CSF studies if CNS infection is suspected
CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; MCI: mild cognitive impairment
Source: Reference 8

CASE CONTINUED: Subtle cognitive deficits

Mr. R scores 27/30 on the MMSE (losing 3 points on recall) and 25/30 on the MoCA (losing points on visuospatial/executive function, fluency, and delayed recall). Thyroid stimulating hormone, vitamin B12, folate, and rapid plasma reagin tests are unremarkable; brain MRI shows no significant abnormalities.

You refer Mr. R for neuropsychological testing, and most cognitive domains are normal. Exceptions include moderate impairment in immediate and delayed verbal and visual memory and mild executive dysfunction.

Based on your clinical evaluation and neuropsychological testing, you diagnose amnestic MCI. Mr. R shows abnormalities in memory and executive functioning without significant decline in basic and instrumental ADLs, is not taking medications, and has no other medical or psychiatric condition that could explain his cognitive deficits.

You discuss the diagnosis with him and his wife, including evidence on his risk for progression to dementia, neuroprotective strategies, and medications.

After an MCI diagnosis

Neuroprotection. Eliminate medications with anticholinergic effects, including:

• tricyclic antidepressants
  
• conventional antipsychotics
  
• antihistamines
  
• drugs used to treat urinary incontinence, such as oxybutynin
  
• muscle relaxants, such as cyclobenzaprine
  
• certain antiparkinsonian drugs, such as benztropine.
  

Encourage patients to avoid alcohol and sedatives. Collaborate with primary care providers to control cerebrovascular risk factors such as hyperlipidemia, diabetes mellitus, hypertension, and obesity. Treat depression, which may be a risk factor for developing dementia.

 

Monitoring. The American Academy of Neurology recommends monitoring patients diagnosed with MCI every 6 to 12 months for cognitive and functional decline.

In these visits, include:

• repeat office-based cognitive assessment, especially the modified MMSE, clock-drawing test, and MoCA
  
• careful history-taking from the patient and reliable informant
  
• repeat neuropsychological testing annually or when dementia is suspected
  
• assessment of the caregiver for distress.
  

Compensating for memory loss. Many individuals with MCI have insight into their cognitive deficits and are interested in making lifestyle changes. Experts recommend:

• moderate exercise (at least 30 minutes per session, 3 times a week)
  
• cognitively stimulating activities that involve language and psychomotor coordination, such as dancing, crossword puzzles, and volunteer work.
  

Potentially helpful tools include calendars, reminder notes, electronic cuing devices, pill boxes, and “speed-dial” telephones. Encourage patients to participate in local senior organizations and to use community resources.¹

Medications—yes or no? Cholinesterase inhibitors, rofecoxib, and vitamin E have not been shown to prevent MCI from progressing to AD. Thus, insufficient evidence exists to recommend medications for patients with MCI.

Donepezil has shown possible short-term benefits, however, and patients may choose to try this medication. Some find comfort in seeking this “extra time” to make decisions about advanced directives, attend to estate and will issues, and optimize relationships while they have only mild cognitive deficits and possess decision-making capacity.

Donepezil. The Alzheimer’s Disease Cooperative Study—supported by the National Institute on Aging—was designed to determine whether daily doses of donepezil or vitamin E can delay or prevent progression of aMCI to AD.²⁵ In the double-blind, placebo-controlled, parallel group study, 769 patients with aMCI were randomly assigned to receive donepezil, 10 mg/d; vitamin E, 1,000 IU bid; or placebo for 3 years.

Overall progression to AD was 16% per year, and the 3-year risk of progression was the same in all 3 groups. Donepezil therapy was associated with a reduced rate of progression to AD compared with placebo during the first year of treatment. Donepezil’s benefit was evident among ApoE e4 carriers at 2-year follow-up, but none of the 3 groups showed statistically significant differences after 3 years. Vitamin E showed no effect on AD progression throughout the study.

Rivastigmine. A randomized, placebo-controlled trial in which 1,018 MCI patients received rivastigmine or placebo for 4 years found no statistically significant benefit of rivastigmine on AD progression.²⁶

Galantamine. Two international randomized, double-blind, placebo-controlled trials failed to show a statistically significant benefit of galantamine in slowing progression from aMCI to AD. MRI data from one of these studies suggested that galantamine may have reduced the rate of brain atrophy over a 2-year period.²⁷

Rofecoxib. Epidemiologic studies indicate that anti-inflammatory drugs may reduce the risk of developing AD, but the COX-2 inhibitor rofecoxib did not delay progression to AD among aMCI patients in a large, placebo-controlled trial.²⁸

Educate patients and family members about supportive nonpharmacologic treatments and cholinesterase inhibitors. The Alzheimer’s Association, National Institute on Aging, and local department of aging agencies offer useful resources (see Related Resources).

CASE CONTINUED: Dealing with uncertainty

Mr. R and his wife are unsettled by his MCI diagnosis. They prefer to take a “wait and watch” approach, decline initiation of a cholinesterase inhibitor, and agree to adhere to nonpharmacologic interventions you discussed. You schedule a follow-up visit in 6 months and encourage them to call you with questions.

Related resources

• Rosenberg PB, Johnston D, Lyketsos CG. A clinical approach to mild cognitive impairment. Am J Psychiatry 2006;163: 1884-90.
  
• Montreal Cognitive Assessment (MoCA). 10-minute screening test designed to help clinicians detect mild cognitive impairment. www.mocatest.org.
  
• Alzheimer’s Association. www.alz.org.
  
• National Institute on Aging. www.nia.nih.gov.
  

Drug brand name

• Benztropine • Cogentin
  
• Cyclobenzaprine • Flexeril
  
• Donepezil • Aricept
  
• Galantamine • Razadyne
  
• Oxybutynin • Ditropan
  
• Rivastigmine • Exelon
  
• Rofecoxib • Vioxx
  
• Sertraline • Zoloft
  

Disclosure

Dr. Goveas and Dr. Dixon-Holbrook report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kerwin is a consultant to Pfizer and a speaker for Pfizer and Novartis.

Dr. Antuono receives research support from Eisai, Pfizer, and Elan and is a speaker for Pfizer and Forest Pharmaceuticals.

Mr. R, age 67, presents with what he describes as uncharacteristic “memory loss” that is affecting his ability to run his accounting business. He and his wife relate that he was doing well until approximately 9 months ago, when he started showing difficulties remembering clients’ names and addresses.

His wife became extremely concerned when he made serious accounting errors in a 1-month period that resulted in the loss of a longtime customer. Mr. R has become easily distracted and absentminded as well, and his wife reports he is misplacing things around the house.

Screening for mild cognitive impairment (MCI) is not recommended for asymptomatic, cognitively healthy older persons, but memory complaints in individuals age >50—especially when corroborated by a reliable informant—warrant further assessment. Your challenge is to determine whether subtle cognitive changes in patients such as Mr. R are part of normal aging, caused by medical or mental illnesses, or a harbinger of Alzheimer’s disease (AD) or another dementia.

Although no treatments can yet prevent dementia, substantial new research is defining the MCI diagnosis for clinicians. This article describes:

• the evolving understanding of MCI and its subtypes
  
• risk factors for converting from MCI to AD
  
• an evidence-based work-up (including functional, cognitive, and neuropsychological testing)
  
• neuroprotective strategies for patients with an MCI diagnosis, including evidence on cholinesterase inhibitors, vitamin E, and anti-inflammatory agents.
  

MCI’s evolving definition

MCI is characterized by subjective and objective cognitive decline greater than expected for an individual’s age and education but less than the functional deficit required for a dementia diagnosis. MCI is proposed to identify persons with early but pathologic cognitive impairment that has a high risk to progress to AD and possibly other dementias.

MCI is thought to be a transitional state between normal aging and dementia.¹ Its estimated prevalence in the general population is 19% among individuals age 85.²

MCI subtypes. Some experts view MCI as a single entity, whereas others suggest amnestic (aMCI) and nonamnestic (nMCI) subtypes.^1,3 Each subtype is further divided into single and multiple cognitive domains. So, for example, the diagnosis would be:

• aMCI-single cognitive domain for memory impairment only
  
• aMCI-multiple cognitive domains for memory impairment plus nonmemory deficits, such as in language, executive function, or visuospatial function
  
• nMCI-single or multiple cognitive domains for nonmemory deficits without memory impairment.
  

MCI subtypes may have different outcomes for progression to dementia, and all progressive dementias may have their own predementia states.⁴ Vascular MCI, for instance, is thought to result from cerebrovascular disease and is proposed to describe a prodrome of vascular dementia.⁵

Determining a patient’s MCI subtype is still a research activity and calls for comprehensive neuropsychological testing. MCI patients perform at least 1.5 standard deviations below the average for age- and education-matched healthy individuals on objective measures of memory.¹

Conversion to dementia

In longitudinal population studies patients with MCI have shown an 11% to 33% risk of developing dementia within 2 years, whereas 44% reverted to normal 1 year later. Reasons for reversibility may include variable definitions of MCI among the longitudinal studies and the possibility that patients who recovered or improved may have had reversible causes of dementia.¹

When patients with MCI are followed over time, they progress not only to AD but also to non-AD dementias. For example, patients with Parkinson’s disease (PD) and MCI may be at higher risk of progressing to dementia than cognitively intact PD patients.⁶ MCI patients with the e4 allele of the apolipoprotein E gene (ApoE e4) are at increased risk to convert from MCI to AD.⁷

Individuals with aMCI (Table 1)⁸ progress to AD at a rate of 10% to 15% per year, compared with 1% to 2% per year in normal elderly persons. The Mayo AD research center studies reported a conversion rate of up to 80% from aMCI to AD within 6 years.⁹

Research focuses on identifying preclinical AD states and potential targets for intervention using disease-modifying therapies. Some experts consider MCI to be the earliest clinical manifestation of AD, at least in a subgroup of patients.

Identifying markers to predict which patients are likely to convert from MCI to dementia also is a major research objective. In addition to ApoE status (Table 2),^7,9-15 predictors of conversion may include:

 

• hippocampal atrophy¹³
  
• reduced metabolism in the temporoparietal cortex and posterior cingulum¹⁴
  
• elevated CSF tau and the 42 amino acid form of ß-amyloid (Aß 42).¹⁵
  

Research techniques such as structural neuroimaging, positron-emission tomography, functional magnetic resonance imaging (fMRI), and cerebrospinal fluid biomarkers have not been defined for clinical use, however.

Neuropsychiatric symptoms. Individuals with MCI and neuropsychiatric symptoms may be at particular risk for progressing to dementia. Agitation or depression are more prevalent in persons with MCI than in normal elderly but less prevalent than in those with dementia (Table 3).^10,16

The cross-sectional, community-based Cardiovascular Health Study showed one or more neuropsychiatric symptom in:

• 16% of normal healthy elderly
  
• 43% of MCI patients
  
• 75% of dementia patients.¹⁶
  

Depression (20%), apathy (15%), and irritability (15%) were the neuropsychiatric symptoms reported most frequently in MCI patients, compared with apathy (36%), depression (32%), and agitation/aggression (30%) in dementia patients.

Sleep disturbances and anxiety in persons with MCI may predict progression to AD.¹⁰ A baseline high frequency of apathy in aMCI patients has been associated with progression to AD within 1 year.¹¹

Table 1

Amnestic MCI: Proposed diagnostic criteria

Subjective memory impairment, preferably corroborated by a reliable informant
Reduced performance on objective memory tests, compared with persons of similar age and educational background
Typical general cognitive function
Intact basic activities of daily living and intact or minimally impaired instrumental activities of daily living
Absence of dementia
MCI: mild cognitive impairment
Source: Reference 8

Table 2

Factors shown to predict conversion from MCI to dementia

Category	Predictors of conversion
Clinical	Cognitive: Amnestic MCI Neuropsychiatric: Depression, apathy, and possibly nighttime behaviors and anxiety
Neuropsychological tests	Clock-drawing test, Trail-Making Test B, Symbol Digit Modalities Test, Delayed 10-Word List Recall, New York University Paragraph Recall Test (Delayed), ADAS-Cog total score
Neuroimaging	MRI: Entorhinal cortex and hippocampal atrophy PET: Medial temporal region, parietotemporal association cortex, and posterior cingulate hypometabolism fMRI: Abnormal hippocampal, posterior cingulate, and medial temporal region activation on memory tasks
CSF markers	Increase: t-tau, p-tau Decrease: Aß 42
Genetic markers	ApoE e4 carriers
ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ApoE e4: apolipoprotein E gene, e4 allele; CSF: cerebrospinal fluid; MCI: mild cognitive impairment; MRI: magnetic resonance imaging; fMRI: functional MRI; PET: positron-emission tomography
Source: References 7,9-15

Table 3

Neuropsychiatric symptoms: Rising prevalence mirrors cognitive deterioration in elderly patients*

Neuropsychiatric symptoms	Normal elderly	MCI	Mild AD
Depressed mood/dysphoria	+	++	+++
Nighttime behaviors/sleep	+	++	+++
Irritability	+	++	+++
Anxiety	+/-	++	+++
Apathy/indifference	+/-	++	+++
Agitation/aggression	+/-	+/++	+++
Eating/appetite disturbance	+/-	+	++
Disinhibition	+/-	+/-	++
Aberrant motor behavior	0	+	++
Delusions	0	+/-	++
Euphoria	0	+/-	+/-
Hallucinations	0	0	+
* 0 = 0%; +/- = 1% to 5%; + = 6% to 10%; ++ = 11% to 20%; +++ = 21% to 40%
MCI: mild cognitive impairment; AD: Alzheimer’s disease
Source: References 10,16

Depression and MCI

Depression and cognitive complaints overlap considerably in older adults. Depressed patients without dementia show persistent cognitive deficits even after depression remits. In some patients, new-onset geriatric depression is considered a prodrome of MCI and AD. Given that AD neuropathologic changes precede clinical symptoms by many years, depression and AD have been proposed as different clinical manifestations of AD pathology.¹⁷

Among patients with MCI, 20% meet criteria for major depression and 26% for minor depression. Symptoms often include sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and insomnia.¹⁸

Depressed MCI patients are at higher risk of developing dementia than those without depression, especially if cognitive measures do not improve after depression is treated.¹² Similarly, cognitively intact older persons who develop depression are at increased risk for MCI, particularly if they carry the ApoE e4 genotype.¹⁹

In the only study in which MCI patients’ neuropsychiatric symptoms have been treated, 39 elderly patients with depression and MCI received open-label sertraline, ≤200 mg/d, for 12 weeks. Among the 26 patients who completed the trial, 17 showed moderate improvement in depressive symptoms, attention, and executive function, and 9 showed no response.²⁰

Recommendation. In clinical practice, antidepressant treatment—usually a selective serotonin reuptake inhibitor (SSRI), with or without psychotherapy—is recommended for the MCI patient with comorbid major depression.

CASE CONTINUED: No signs of depression

Mr. R’s medical, neurologic, and substance use history is unremarkable. Family history includes AD in a paternal aunt diagnosed at age 82. Mr. R reports no history of mood, sleep, or appetite changes and no psychotic symptoms. He shows no deficits in activities of daily living (ADL), although his wife recently took over paying household bills after he forgot to make a payment.

Evidence-based workup

Functional assessment. In the differential diagnosis of MCI, give special attention to functional impairment, which points toward dementia. ADL generally are preserved in MCI, and minimal deterioration is seen in instrumental activities of daily living (IADL). A relatively easy way to assess function is to use the Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS), which is based on 16 ADL and IADL items (Table 4).²¹

 

A substantial functional decline precludes an MCI diagnosis, although the degree of functional decline can be difficult to assess in older adults with physical limitations caused by medical comorbidities.

Cognitive assessment. Because most individuals with MCI score in the normal range on the Folstein Mini-Mental State Examination (MMSE), the modified MMSE (3MS)²² may be more sensitive for detecting MCI. The 3MS retains the MMSE’s brevity (≤10 minutes to administer) but incorporates 4 additional items, has more graded scoring responses, and broadens the score range to 0 to 100. The clock-drawing test also is sensitive for MCI, especially in detecting early visuoconstructional dysfunction.

The Montreal Cognitive Assessment (MoCA) is a 10-minute, 30-point scale designed to help clinicians detect MCI (see Related Resources). The MoCA usually is given with the modified MMSE for a comprehensive cognitive assessment.

Nasreddine et al²³ administered the MoCA and MMSE to 94 patients who met clinical criteria for MCI, 93 patients with mild AD, and 90 healthy cognitively normal elderly persons, using a cutoff score of 26. MoCA showed:

• 90% sensitivity for detecting MCI (compared with 18% for the MMSE)
  
• 87% specificity to exclude normal elderly persons.
  

The average MoCA score in patients with AD was much lower than in individuals with MCI, but score ranges of these 2 groups overlapped. Therefore, a score

Neuropsychological testing can be more sensitive than office-based screening tools in defining MCI subtypes. In the Alzheimer’s Disease Cooperative Study (ADCS), the neuropsychological measures that most accurately predicted progression of patients with aMCI to AD within 36 months were the:

• Symbol Digit Modalities Test
  
• New York University Paragraph Recall Test (Delayed)
  
• Delayed 10-Word List Recall
  
• Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) total score.²⁴
  

Laboratory tests, imaging. Use laboratory studies (Table 5) to rule out reversible causes of MCI symptoms.⁸ Reserve CSF studies for suspected CNS infection (such as meningitis, human immunodeficiency virus, or neurosyphilis) and brain imaging for suspected cerebral pathology (such as infarct, subdural hematoma, normal pressure hydrocephalus, or tumor).

Table 4

Alzheimer’s Disease Functional Assessment and Change Scale (ADFACS)

Basic ADL	Instrumental ADL (IADL)
Toileting	Use of telephone
Feeding	Household tasks
Dressing	Using household appliances
Personal hygiene and grooming	Managing money
	Shopping
Bathing	Food preparation
Walking	Ability to get around inside and outside home
	Hobbies and leisure activities
	Handling personal mail
	Grasp of situations and explanations
The 16-item ADFACS total score ranges from 0 to 54 (best to worst): Rate basic ADLs from 0 (no impairment) to 4 (very severe impairment), for a total score range of 0 to 24. Rate IADLs from 0 (no impairment) to 3 (severe impairment), for a total score range of 0 to 30.
Use total scores to assess for functional decline from baseline. A decline from 0 to 1 on individual ADL and IADL items is not considered clinically significant.
ADL: activities of daily living
Source: Reprinted with permission from reference 21

Table 5

Lab studies to rule out reversible causes of MCI

Complete blood count with differential
Basic metabolic panel
Liver function tests
Serum calcium
Serum vitamin B12 and folate
Thyroid function tests
Rapid plasma reagin
HIV in high-risk individuals
CSF studies if CNS infection is suspected
CSF: cerebrospinal fluid; HIV: human immunodeficiency virus; MCI: mild cognitive impairment
Source: Reference 8

CASE CONTINUED: Subtle cognitive deficits

Mr. R scores 27/30 on the MMSE (losing 3 points on recall) and 25/30 on the MoCA (losing points on visuospatial/executive function, fluency, and delayed recall). Thyroid stimulating hormone, vitamin B12, folate, and rapid plasma reagin tests are unremarkable; brain MRI shows no significant abnormalities.

You refer Mr. R for neuropsychological testing, and most cognitive domains are normal. Exceptions include moderate impairment in immediate and delayed verbal and visual memory and mild executive dysfunction.

Based on your clinical evaluation and neuropsychological testing, you diagnose amnestic MCI. Mr. R shows abnormalities in memory and executive functioning without significant decline in basic and instrumental ADLs, is not taking medications, and has no other medical or psychiatric condition that could explain his cognitive deficits.

You discuss the diagnosis with him and his wife, including evidence on his risk for progression to dementia, neuroprotective strategies, and medications.

After an MCI diagnosis

Neuroprotection. Eliminate medications with anticholinergic effects, including:

• tricyclic antidepressants
  
• conventional antipsychotics
  
• antihistamines
  
• drugs used to treat urinary incontinence, such as oxybutynin
  
• muscle relaxants, such as cyclobenzaprine
  
• certain antiparkinsonian drugs, such as benztropine.
  

Encourage patients to avoid alcohol and sedatives. Collaborate with primary care providers to control cerebrovascular risk factors such as hyperlipidemia, diabetes mellitus, hypertension, and obesity. Treat depression, which may be a risk factor for developing dementia.

 

Monitoring. The American Academy of Neurology recommends monitoring patients diagnosed with MCI every 6 to 12 months for cognitive and functional decline.

In these visits, include:

• repeat office-based cognitive assessment, especially the modified MMSE, clock-drawing test, and MoCA
  
• careful history-taking from the patient and reliable informant
  
• repeat neuropsychological testing annually or when dementia is suspected
  
• assessment of the caregiver for distress.
  

Compensating for memory loss. Many individuals with MCI have insight into their cognitive deficits and are interested in making lifestyle changes. Experts recommend:

• moderate exercise (at least 30 minutes per session, 3 times a week)
  
• cognitively stimulating activities that involve language and psychomotor coordination, such as dancing, crossword puzzles, and volunteer work.
  

Potentially helpful tools include calendars, reminder notes, electronic cuing devices, pill boxes, and “speed-dial” telephones. Encourage patients to participate in local senior organizations and to use community resources.¹

Medications—yes or no? Cholinesterase inhibitors, rofecoxib, and vitamin E have not been shown to prevent MCI from progressing to AD. Thus, insufficient evidence exists to recommend medications for patients with MCI.

Donepezil has shown possible short-term benefits, however, and patients may choose to try this medication. Some find comfort in seeking this “extra time” to make decisions about advanced directives, attend to estate and will issues, and optimize relationships while they have only mild cognitive deficits and possess decision-making capacity.

Donepezil. The Alzheimer’s Disease Cooperative Study—supported by the National Institute on Aging—was designed to determine whether daily doses of donepezil or vitamin E can delay or prevent progression of aMCI to AD.²⁵ In the double-blind, placebo-controlled, parallel group study, 769 patients with aMCI were randomly assigned to receive donepezil, 10 mg/d; vitamin E, 1,000 IU bid; or placebo for 3 years.

Overall progression to AD was 16% per year, and the 3-year risk of progression was the same in all 3 groups. Donepezil therapy was associated with a reduced rate of progression to AD compared with placebo during the first year of treatment. Donepezil’s benefit was evident among ApoE e4 carriers at 2-year follow-up, but none of the 3 groups showed statistically significant differences after 3 years. Vitamin E showed no effect on AD progression throughout the study.

Rivastigmine. A randomized, placebo-controlled trial in which 1,018 MCI patients received rivastigmine or placebo for 4 years found no statistically significant benefit of rivastigmine on AD progression.²⁶

Galantamine. Two international randomized, double-blind, placebo-controlled trials failed to show a statistically significant benefit of galantamine in slowing progression from aMCI to AD. MRI data from one of these studies suggested that galantamine may have reduced the rate of brain atrophy over a 2-year period.²⁷

Rofecoxib. Epidemiologic studies indicate that anti-inflammatory drugs may reduce the risk of developing AD, but the COX-2 inhibitor rofecoxib did not delay progression to AD among aMCI patients in a large, placebo-controlled trial.²⁸

Educate patients and family members about supportive nonpharmacologic treatments and cholinesterase inhibitors. The Alzheimer’s Association, National Institute on Aging, and local department of aging agencies offer useful resources (see Related Resources).

CASE CONTINUED: Dealing with uncertainty

Mr. R and his wife are unsettled by his MCI diagnosis. They prefer to take a “wait and watch” approach, decline initiation of a cholinesterase inhibitor, and agree to adhere to nonpharmacologic interventions you discussed. You schedule a follow-up visit in 6 months and encourage them to call you with questions.

Related resources

• Rosenberg PB, Johnston D, Lyketsos CG. A clinical approach to mild cognitive impairment. Am J Psychiatry 2006;163: 1884-90.
  
• Montreal Cognitive Assessment (MoCA). 10-minute screening test designed to help clinicians detect mild cognitive impairment. www.mocatest.org.
  
• Alzheimer’s Association. www.alz.org.
  
• National Institute on Aging. www.nia.nih.gov.
  

Drug brand name

• Benztropine • Cogentin
  
• Cyclobenzaprine • Flexeril
  
• Donepezil • Aricept
  
• Galantamine • Razadyne
  
• Oxybutynin • Ditropan
  
• Rivastigmine • Exelon
  
• Rofecoxib • Vioxx
  
• Sertraline • Zoloft
  

Disclosure

Dr. Goveas and Dr. Dixon-Holbrook report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Kerwin is a consultant to Pfizer and a speaker for Pfizer and Novartis.

Dr. Antuono receives research support from Eisai, Pfizer, and Elan and is a speaker for Pfizer and Forest Pharmaceuticals.

On April 16, 2007, Seung Hui Cho shot and killed 32 students and faculty on the Virginia Tech campus and wounded 25 others before killing himself. A judge had declared Cho mentally ill in 2005 and placed him on involuntary outpatient commitment (OPC). Cho apparently never sought treatment, and no one made sure that he did (Box 1).¹

Much second-guessing has occurred about whether enforcing Cho’s OPC could have prevented the Virginia Tech tragedy. Most states authorize OPC, but few make much use of OPC statues that require patients to adhere to prescribed treatment in the community. Virginia was typical; an OPC statute was on the books but rarely enforced.

This article discusses the evidence on OPC laws’ effectiveness and offers recommendations on how to use these tools in psychiatric practice.

Mandating needed treatment

OPC—also called “assisted outpatient treatment” or “mandated outpatient treatment”—is a civil court procedure whereby a judge can order a noncompliant mentally ill patient to adhere to needed treatment. OPC statutes exist in 42 states and the District of Columbia, although judges use these powers erratically.^2,3

Most states have set identical thresholds for inpatient and outpatient commitment, such as when the patient is considered dangerous to self or others or (in some statutes) so gravely impaired that he is unable to safely care for himself in the community. These high thresholds have dramatically reduced inpatient commitment eligibility and yet may flag the patient as too dangerous for outpatient commitment.

Box 1

OPC orders usually cannot force medication. Periods of initial and subsequent commitment vary across states but not dramatically. In North Carolina, for example, initial OPC may be ≤90 days, after which a hearing must be held to renew the order for ≤180 days. Depending on individual states’ statutes, OPC can be used as:

• an alternative to hospitalization for patients who meet inpatient commitment criteria
  
• a form of conditional release for patients completing an involuntary inpatient commitment
  
• an alternative to hospitalization for noncompliant patients at risk for relapse and involuntary inpatient commitment.²
  

Few states have lowered the threshold to the last variant, allowing OPC use to avert relapse and hospitalization. Newer statutes in New York, North Carolina, and elsewhere have incorporated these preventative outpatient commitment criteria.^4,5

Enforcement. Courts typically can request that law officers transport patients who fail to comply with OPC to a treatment facility. There, patients will be encouraged to comply with treatment or evaluated for inpatient commitment.² This relatively weak enforcement authority has led some to argue that OPC has no teeth.

Without clearly defined steps for implementation, an outpatient commitment order can be likened to a message in a bottle—a cry for help at risk for nondelivery. In the Virginia Tech case, the judge issued an outpatient commitment order for Cho, but how the local clinic understood its responsibilities and what resources and enforcement power it had were unclear.

Noncontrolled studies

Evidence from noncontrolled OPC studies is difficult to interpret because of:

• lack of comparable committed and noncommitted groups
  
• difficulty in comparing treatment across comparison groups
  
• selection effects, whereby clinicians and courts select patients for a predicted good outcome.²
  

 

Most noncontrolled studies have concluded that OPC improves treatment outcomes and decreases hospital readmission rates and lengths of stay under some circumstances.^6-12 The largest study reported on New York’s initial 5 years’ experience with more than 3,000 patients under its OPC statute, known as “Kendra’s Law” (Box 2).¹² Under this law—the most intensively implemented OPC statute in the United States—the court’s order specifies a detailed plan of medications and psychosocial treatment.

Most of New York’s OPC recipients stayed in assisted outpatient treatment longer than the court-mandated 6 months (average 16 months). The incidence of hospitalizations, homelessness, arrests, and incarcerations was far lower while patients participated in OPC, compared with the previous 3 years of their lives (Table). Medication adherence improved from 34% before OPC to 69% after commitment, and engagement with treatment improved from 41% to 62%, respectively.¹²

Table

Change in adverse events among OPC patients in New York

Event	Incidence during 3 years prior to OPC*	Incidence during OPC treatment	Rate of decline
Incarceration	23%	3%	87%
Arrest	30%	5%	83%
Psychiatric hospitalization	97%	22%	77%
Homelessness	19%	5%	74%
* Adverse events reported as occurring at least once
OPC: outpatient commitment
Source: Reprinted from reference 12, table 10

Conflicting controlled trials

Duke Mental Health Study. In the first controlled study of OPC, the Duke Mental Health Study (DMHS) enrolled 331 seriously mentally ill inpatients being discharged from involuntarily hospitalization to court-ordered outpatient treatment between 1993 and 1996. Patients with a history of violent behavior in the previous year were placed in a nonrandomized comparison group and remained on OPC for at least 90 days. The remaining 264 patients were randomly assigned to:

• an experimental group that received OPC for ≤90 days (could be renewed for ≤180 days) plus consistent community mental health services
  
• a control group that was released from OPC but received the same community mental health services as the experimental group.¹³
  

Community services included psychiatric appointments and case management. During 12-month follow-up, researchers interviewed patients, families, and clinicians to gather data on OPC’s effectiveness.

Patients ordered to OPC had fewer hospital readmissions and spent fewer days in the hospital only if they received OPC plus consistent community services for ≥6 months.¹⁴ Patients who received this model of care were:

• less likely to be homeless,¹⁵ criminally victimized,¹⁶ arrested if they had past arrests,¹⁷ or violent¹⁸
  
• more likely than the control group to comply with recommended treatment.¹⁹
  

Patients received no benefit from OPC

Study limitations. Length of time on OPC could not be randomly assigned, even though this was a key variable in the intervention. If lower-risk subjects had been selected for longer periods of commitment, positive findings could have been overstated. Legal criteria for renewing OPC also prevented us from selecting lower-risk subjects for longer exposure to court-ordered treatment. Higher-risk subjects appeared in preliminary analyses to have received longer periods of commitment, but unknown selection factors could have affected OPC duration.

Outpatient service intensity was not controlled but varied according to clinical need and other unknown factors. As a result, selectively providing services could have influenced outcomes, although other analyses argue that this factor was not important.⁴

New York. In 1994, the state legislature established a 3-year pilot program to evaluate OPC in New York City’s Bellevue Hospital as a first step toward considering permanent OPC legislation.²⁰ The randomized, controlled study compared a court-ordered group (N=78) and a control group (N=64) during 1 year after hospital discharge. Both groups received enhanced outpatient services, such as psychiatrist appointments, intensive case management, and treatment for co-occurring substance abuse as needed.

Box 2

 

Control and experimental groups showed no statistically significant differences in hospitalizations, arrests, quality of life, symptoms, homelessness, or other outcomes. The authors interpreted these findings to suggest that in this study intensive services—and not OPC court orders—reduced hospital recidivism and other poor outcomes in seriously mentally ill patients.

Study limitations. Statute implementation and OPC enforcement were haphazard, and in most cases sanctions for noncompliance—such as orders to law enforcement to detain noncompliant patients—were not put into effect. Patients and providers often did not clearly distinguish between the control and experimental groups. And finally, the study likely was too small to demonstrate a positive effect for OPC. Nevertheless, the findings suggest that OPC might provide no added benefit if persons with serious mental illnesses have access to enhanced outpatient services.⁴

Do OPC laws prevent violence?

The North Carolina and New York controlled studies of OPC yielded contradictory findings and are difficult to compare. Even within North Carolina—where OPC has been shown most consistently to be effective—OPC orders’ duration (the “dose”) varies widely, as do the services patients receive.

No further randomized, controlled trials of OPC are underway. Our group is participating in a study supported by the MacArthur Foundation Research Network on Mandated Community Treatment and New York State Office of Mental Health to intensively review patient outcomes under New York’s OPC statute.

Rare, violent acts such Seung Hui Cho’s rampage at Virginia Tech have motivated many states to propose OPC statutes. OPC statutes are designed more to improve treatment adherence and reduce rehospitalization than to prevent violence, however. Although the North Carolina study suggests OPC can prevent relatively minor acts of violence,¹⁸ the desired benefit of preventing potentially lethal violence is exceedingly difficult to realize or document.

Given that most states permit OPC, attempts to standardize and implement OPC are needed. To make OPC effective, evidence indicates that states also must provide intensive community services to keep patients in treatment.

Strategies for using OPC

OPC is controversial in society and among clinicians. Some mental health organizations oppose outpatient commitment orders as coercive and intrusive, and some mental health professionals have concerns about legal or malpractice liability, increased paperwork, and administrative burden. Others may view OPC as:

• ineffective —providing weak sanctions that are impractical to enforce
  
• detrimental to the therapeutic alliance
  
• a less-desirable substitute for making high-quality voluntary treatment more widely available for the seriously mentally ill.
  

Reach a consensus. If your team is considering OPC for a patient, you must all agree on its use. Because most court orders are initiated on an inpatient unit as part of a discharge plan, clinicians across inpatient and outpatient settings must agree on how you will apply OPC to this patient.

Select appropriate candidates. Our group’s experience suggests that patients with severe mental illness—especially schizophrenia spectrum disorders—are those most likely to benefit from OPC. There is no evidence that outpatient commitment helps patients with personality disorders or substance abuse without comorbid severe mental illness.

Maximize effectiveness. Evidence from the North Carolina studies suggests keeping OPC in place for ≥6 months and providing relatively intensive outpatient services. For schizophrenia-spectrum patients, combining OPC with depot antipsychotics may be more effective than oral agents for ensuring adherence and improving function.¹⁹

Plan enforcement. To enforce OPC orders, you need a mechanism to plan and coordinate law enforcement transport of patients to treatment in cases of nonadherence. Because transport can be a burden to law enforcement officers, at least one North Carolina county developed a legal agreement to allow its mental health clinicians to enforce orders and pick up patients.

Decide when to terminate. OPC orders probably should last at least 6 months, but little evidence exists to guide discontinuing an order after 6 months. This dilemma is similar to deciding when a depot antipsychotic can or should be converted to an oral agent in previously nonadherent patients.

Our approach is to consider terminating the order in patients with restored insight who have ≥6 months of consistent treatment compliance without a need for or threat of OPC enforcement. In some cases, other leverage may preempt the need for continuing an order, such as:

 

• financial contingencies from family or others
  
• treatment required as a condition of probation or parole
  
• housing conditioned on treatment adherence.
  

Related resources

• Treatment Advocacy Center. Nonprofit organization dedicated to eliminating barriers to timely, effective treatment of severe mental illnesses. www.psychlaws.org.
  
• MacArthur Foundation Research Network on Mandated Community Treatment. www.macarthur.virginia.edu/researchnetwork.html.
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

This work was supported by NIMH Grants MH 48103 and MH 51410 and the MacArthur Foundation Research Network on Mandated Community Treatment.

On April 16, 2007, Seung Hui Cho shot and killed 32 students and faculty on the Virginia Tech campus and wounded 25 others before killing himself. A judge had declared Cho mentally ill in 2005 and placed him on involuntary outpatient commitment (OPC). Cho apparently never sought treatment, and no one made sure that he did (Box 1).¹

Much second-guessing has occurred about whether enforcing Cho’s OPC could have prevented the Virginia Tech tragedy. Most states authorize OPC, but few make much use of OPC statues that require patients to adhere to prescribed treatment in the community. Virginia was typical; an OPC statute was on the books but rarely enforced.

This article discusses the evidence on OPC laws’ effectiveness and offers recommendations on how to use these tools in psychiatric practice.

Mandating needed treatment

OPC—also called “assisted outpatient treatment” or “mandated outpatient treatment”—is a civil court procedure whereby a judge can order a noncompliant mentally ill patient to adhere to needed treatment. OPC statutes exist in 42 states and the District of Columbia, although judges use these powers erratically.^2,3

Most states have set identical thresholds for inpatient and outpatient commitment, such as when the patient is considered dangerous to self or others or (in some statutes) so gravely impaired that he is unable to safely care for himself in the community. These high thresholds have dramatically reduced inpatient commitment eligibility and yet may flag the patient as too dangerous for outpatient commitment.

Box 1

OPC orders usually cannot force medication. Periods of initial and subsequent commitment vary across states but not dramatically. In North Carolina, for example, initial OPC may be ≤90 days, after which a hearing must be held to renew the order for ≤180 days. Depending on individual states’ statutes, OPC can be used as:

• an alternative to hospitalization for patients who meet inpatient commitment criteria
  
• a form of conditional release for patients completing an involuntary inpatient commitment
  
• an alternative to hospitalization for noncompliant patients at risk for relapse and involuntary inpatient commitment.²
  

Few states have lowered the threshold to the last variant, allowing OPC use to avert relapse and hospitalization. Newer statutes in New York, North Carolina, and elsewhere have incorporated these preventative outpatient commitment criteria.^4,5

Enforcement. Courts typically can request that law officers transport patients who fail to comply with OPC to a treatment facility. There, patients will be encouraged to comply with treatment or evaluated for inpatient commitment.² This relatively weak enforcement authority has led some to argue that OPC has no teeth.

Without clearly defined steps for implementation, an outpatient commitment order can be likened to a message in a bottle—a cry for help at risk for nondelivery. In the Virginia Tech case, the judge issued an outpatient commitment order for Cho, but how the local clinic understood its responsibilities and what resources and enforcement power it had were unclear.

Noncontrolled studies

Evidence from noncontrolled OPC studies is difficult to interpret because of:

• lack of comparable committed and noncommitted groups
  
• difficulty in comparing treatment across comparison groups
  
• selection effects, whereby clinicians and courts select patients for a predicted good outcome.²
  

 

Most noncontrolled studies have concluded that OPC improves treatment outcomes and decreases hospital readmission rates and lengths of stay under some circumstances.^6-12 The largest study reported on New York’s initial 5 years’ experience with more than 3,000 patients under its OPC statute, known as “Kendra’s Law” (Box 2).¹² Under this law—the most intensively implemented OPC statute in the United States—the court’s order specifies a detailed plan of medications and psychosocial treatment.

Most of New York’s OPC recipients stayed in assisted outpatient treatment longer than the court-mandated 6 months (average 16 months). The incidence of hospitalizations, homelessness, arrests, and incarcerations was far lower while patients participated in OPC, compared with the previous 3 years of their lives (Table). Medication adherence improved from 34% before OPC to 69% after commitment, and engagement with treatment improved from 41% to 62%, respectively.¹²

Table

Change in adverse events among OPC patients in New York

Event	Incidence during 3 years prior to OPC*	Incidence during OPC treatment	Rate of decline
Incarceration	23%	3%	87%
Arrest	30%	5%	83%
Psychiatric hospitalization	97%	22%	77%
Homelessness	19%	5%	74%
* Adverse events reported as occurring at least once
OPC: outpatient commitment
Source: Reprinted from reference 12, table 10

Conflicting controlled trials

Duke Mental Health Study. In the first controlled study of OPC, the Duke Mental Health Study (DMHS) enrolled 331 seriously mentally ill inpatients being discharged from involuntarily hospitalization to court-ordered outpatient treatment between 1993 and 1996. Patients with a history of violent behavior in the previous year were placed in a nonrandomized comparison group and remained on OPC for at least 90 days. The remaining 264 patients were randomly assigned to:

• an experimental group that received OPC for ≤90 days (could be renewed for ≤180 days) plus consistent community mental health services
  
• a control group that was released from OPC but received the same community mental health services as the experimental group.¹³
  

Community services included psychiatric appointments and case management. During 12-month follow-up, researchers interviewed patients, families, and clinicians to gather data on OPC’s effectiveness.

Patients ordered to OPC had fewer hospital readmissions and spent fewer days in the hospital only if they received OPC plus consistent community services for ≥6 months.¹⁴ Patients who received this model of care were:

• less likely to be homeless,¹⁵ criminally victimized,¹⁶ arrested if they had past arrests,¹⁷ or violent¹⁸
  
• more likely than the control group to comply with recommended treatment.¹⁹
  

Patients received no benefit from OPC

Study limitations. Length of time on OPC could not be randomly assigned, even though this was a key variable in the intervention. If lower-risk subjects had been selected for longer periods of commitment, positive findings could have been overstated. Legal criteria for renewing OPC also prevented us from selecting lower-risk subjects for longer exposure to court-ordered treatment. Higher-risk subjects appeared in preliminary analyses to have received longer periods of commitment, but unknown selection factors could have affected OPC duration.

Outpatient service intensity was not controlled but varied according to clinical need and other unknown factors. As a result, selectively providing services could have influenced outcomes, although other analyses argue that this factor was not important.⁴

New York. In 1994, the state legislature established a 3-year pilot program to evaluate OPC in New York City’s Bellevue Hospital as a first step toward considering permanent OPC legislation.²⁰ The randomized, controlled study compared a court-ordered group (N=78) and a control group (N=64) during 1 year after hospital discharge. Both groups received enhanced outpatient services, such as psychiatrist appointments, intensive case management, and treatment for co-occurring substance abuse as needed.

Box 2

 

Control and experimental groups showed no statistically significant differences in hospitalizations, arrests, quality of life, symptoms, homelessness, or other outcomes. The authors interpreted these findings to suggest that in this study intensive services—and not OPC court orders—reduced hospital recidivism and other poor outcomes in seriously mentally ill patients.

Study limitations. Statute implementation and OPC enforcement were haphazard, and in most cases sanctions for noncompliance—such as orders to law enforcement to detain noncompliant patients—were not put into effect. Patients and providers often did not clearly distinguish between the control and experimental groups. And finally, the study likely was too small to demonstrate a positive effect for OPC. Nevertheless, the findings suggest that OPC might provide no added benefit if persons with serious mental illnesses have access to enhanced outpatient services.⁴

Do OPC laws prevent violence?

The North Carolina and New York controlled studies of OPC yielded contradictory findings and are difficult to compare. Even within North Carolina—where OPC has been shown most consistently to be effective—OPC orders’ duration (the “dose”) varies widely, as do the services patients receive.

No further randomized, controlled trials of OPC are underway. Our group is participating in a study supported by the MacArthur Foundation Research Network on Mandated Community Treatment and New York State Office of Mental Health to intensively review patient outcomes under New York’s OPC statute.

Rare, violent acts such Seung Hui Cho’s rampage at Virginia Tech have motivated many states to propose OPC statutes. OPC statutes are designed more to improve treatment adherence and reduce rehospitalization than to prevent violence, however. Although the North Carolina study suggests OPC can prevent relatively minor acts of violence,¹⁸ the desired benefit of preventing potentially lethal violence is exceedingly difficult to realize or document.

Given that most states permit OPC, attempts to standardize and implement OPC are needed. To make OPC effective, evidence indicates that states also must provide intensive community services to keep patients in treatment.

Strategies for using OPC

OPC is controversial in society and among clinicians. Some mental health organizations oppose outpatient commitment orders as coercive and intrusive, and some mental health professionals have concerns about legal or malpractice liability, increased paperwork, and administrative burden. Others may view OPC as:

• ineffective —providing weak sanctions that are impractical to enforce
  
• detrimental to the therapeutic alliance
  
• a less-desirable substitute for making high-quality voluntary treatment more widely available for the seriously mentally ill.
  

Reach a consensus. If your team is considering OPC for a patient, you must all agree on its use. Because most court orders are initiated on an inpatient unit as part of a discharge plan, clinicians across inpatient and outpatient settings must agree on how you will apply OPC to this patient.

Select appropriate candidates. Our group’s experience suggests that patients with severe mental illness—especially schizophrenia spectrum disorders—are those most likely to benefit from OPC. There is no evidence that outpatient commitment helps patients with personality disorders or substance abuse without comorbid severe mental illness.

Maximize effectiveness. Evidence from the North Carolina studies suggests keeping OPC in place for ≥6 months and providing relatively intensive outpatient services. For schizophrenia-spectrum patients, combining OPC with depot antipsychotics may be more effective than oral agents for ensuring adherence and improving function.¹⁹

Plan enforcement. To enforce OPC orders, you need a mechanism to plan and coordinate law enforcement transport of patients to treatment in cases of nonadherence. Because transport can be a burden to law enforcement officers, at least one North Carolina county developed a legal agreement to allow its mental health clinicians to enforce orders and pick up patients.

Decide when to terminate. OPC orders probably should last at least 6 months, but little evidence exists to guide discontinuing an order after 6 months. This dilemma is similar to deciding when a depot antipsychotic can or should be converted to an oral agent in previously nonadherent patients.

Our approach is to consider terminating the order in patients with restored insight who have ≥6 months of consistent treatment compliance without a need for or threat of OPC enforcement. In some cases, other leverage may preempt the need for continuing an order, such as:

 

• financial contingencies from family or others
  
• treatment required as a condition of probation or parole
  
• housing conditioned on treatment adherence.
  

Related resources

• Treatment Advocacy Center. Nonprofit organization dedicated to eliminating barriers to timely, effective treatment of severe mental illnesses. www.psychlaws.org.
  
• MacArthur Foundation Research Network on Mandated Community Treatment. www.macarthur.virginia.edu/researchnetwork.html.
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

This work was supported by NIMH Grants MH 48103 and MH 51410 and the MacArthur Foundation Research Network on Mandated Community Treatment.

On April 16, 2007, Seung Hui Cho shot and killed 32 students and faculty on the Virginia Tech campus and wounded 25 others before killing himself. A judge had declared Cho mentally ill in 2005 and placed him on involuntary outpatient commitment (OPC). Cho apparently never sought treatment, and no one made sure that he did (Box 1).¹

Much second-guessing has occurred about whether enforcing Cho’s OPC could have prevented the Virginia Tech tragedy. Most states authorize OPC, but few make much use of OPC statues that require patients to adhere to prescribed treatment in the community. Virginia was typical; an OPC statute was on the books but rarely enforced.

This article discusses the evidence on OPC laws’ effectiveness and offers recommendations on how to use these tools in psychiatric practice.

Mandating needed treatment

OPC—also called “assisted outpatient treatment” or “mandated outpatient treatment”—is a civil court procedure whereby a judge can order a noncompliant mentally ill patient to adhere to needed treatment. OPC statutes exist in 42 states and the District of Columbia, although judges use these powers erratically.^2,3

Most states have set identical thresholds for inpatient and outpatient commitment, such as when the patient is considered dangerous to self or others or (in some statutes) so gravely impaired that he is unable to safely care for himself in the community. These high thresholds have dramatically reduced inpatient commitment eligibility and yet may flag the patient as too dangerous for outpatient commitment.

Box 1

OPC orders usually cannot force medication. Periods of initial and subsequent commitment vary across states but not dramatically. In North Carolina, for example, initial OPC may be ≤90 days, after which a hearing must be held to renew the order for ≤180 days. Depending on individual states’ statutes, OPC can be used as:

• an alternative to hospitalization for patients who meet inpatient commitment criteria
  
• a form of conditional release for patients completing an involuntary inpatient commitment
  
• an alternative to hospitalization for noncompliant patients at risk for relapse and involuntary inpatient commitment.²
  

Few states have lowered the threshold to the last variant, allowing OPC use to avert relapse and hospitalization. Newer statutes in New York, North Carolina, and elsewhere have incorporated these preventative outpatient commitment criteria.^4,5

Enforcement. Courts typically can request that law officers transport patients who fail to comply with OPC to a treatment facility. There, patients will be encouraged to comply with treatment or evaluated for inpatient commitment.² This relatively weak enforcement authority has led some to argue that OPC has no teeth.

Without clearly defined steps for implementation, an outpatient commitment order can be likened to a message in a bottle—a cry for help at risk for nondelivery. In the Virginia Tech case, the judge issued an outpatient commitment order for Cho, but how the local clinic understood its responsibilities and what resources and enforcement power it had were unclear.

Noncontrolled studies

Evidence from noncontrolled OPC studies is difficult to interpret because of:

• lack of comparable committed and noncommitted groups
  
• difficulty in comparing treatment across comparison groups
  
• selection effects, whereby clinicians and courts select patients for a predicted good outcome.²
  

 

Most noncontrolled studies have concluded that OPC improves treatment outcomes and decreases hospital readmission rates and lengths of stay under some circumstances.^6-12 The largest study reported on New York’s initial 5 years’ experience with more than 3,000 patients under its OPC statute, known as “Kendra’s Law” (Box 2).¹² Under this law—the most intensively implemented OPC statute in the United States—the court’s order specifies a detailed plan of medications and psychosocial treatment.

Most of New York’s OPC recipients stayed in assisted outpatient treatment longer than the court-mandated 6 months (average 16 months). The incidence of hospitalizations, homelessness, arrests, and incarcerations was far lower while patients participated in OPC, compared with the previous 3 years of their lives (Table). Medication adherence improved from 34% before OPC to 69% after commitment, and engagement with treatment improved from 41% to 62%, respectively.¹²

Table

Change in adverse events among OPC patients in New York

Event	Incidence during 3 years prior to OPC*	Incidence during OPC treatment	Rate of decline
Incarceration	23%	3%	87%
Arrest	30%	5%	83%
Psychiatric hospitalization	97%	22%	77%
Homelessness	19%	5%	74%
* Adverse events reported as occurring at least once
OPC: outpatient commitment
Source: Reprinted from reference 12, table 10

Conflicting controlled trials

Duke Mental Health Study. In the first controlled study of OPC, the Duke Mental Health Study (DMHS) enrolled 331 seriously mentally ill inpatients being discharged from involuntarily hospitalization to court-ordered outpatient treatment between 1993 and 1996. Patients with a history of violent behavior in the previous year were placed in a nonrandomized comparison group and remained on OPC for at least 90 days. The remaining 264 patients were randomly assigned to:

• an experimental group that received OPC for ≤90 days (could be renewed for ≤180 days) plus consistent community mental health services
  
• a control group that was released from OPC but received the same community mental health services as the experimental group.¹³
  

Community services included psychiatric appointments and case management. During 12-month follow-up, researchers interviewed patients, families, and clinicians to gather data on OPC’s effectiveness.

Patients ordered to OPC had fewer hospital readmissions and spent fewer days in the hospital only if they received OPC plus consistent community services for ≥6 months.¹⁴ Patients who received this model of care were:

• less likely to be homeless,¹⁵ criminally victimized,¹⁶ arrested if they had past arrests,¹⁷ or violent¹⁸
  
• more likely than the control group to comply with recommended treatment.¹⁹
  

Patients received no benefit from OPC

Study limitations. Length of time on OPC could not be randomly assigned, even though this was a key variable in the intervention. If lower-risk subjects had been selected for longer periods of commitment, positive findings could have been overstated. Legal criteria for renewing OPC also prevented us from selecting lower-risk subjects for longer exposure to court-ordered treatment. Higher-risk subjects appeared in preliminary analyses to have received longer periods of commitment, but unknown selection factors could have affected OPC duration.

Outpatient service intensity was not controlled but varied according to clinical need and other unknown factors. As a result, selectively providing services could have influenced outcomes, although other analyses argue that this factor was not important.⁴

New York. In 1994, the state legislature established a 3-year pilot program to evaluate OPC in New York City’s Bellevue Hospital as a first step toward considering permanent OPC legislation.²⁰ The randomized, controlled study compared a court-ordered group (N=78) and a control group (N=64) during 1 year after hospital discharge. Both groups received enhanced outpatient services, such as psychiatrist appointments, intensive case management, and treatment for co-occurring substance abuse as needed.

Box 2

 

Control and experimental groups showed no statistically significant differences in hospitalizations, arrests, quality of life, symptoms, homelessness, or other outcomes. The authors interpreted these findings to suggest that in this study intensive services—and not OPC court orders—reduced hospital recidivism and other poor outcomes in seriously mentally ill patients.

Study limitations. Statute implementation and OPC enforcement were haphazard, and in most cases sanctions for noncompliance—such as orders to law enforcement to detain noncompliant patients—were not put into effect. Patients and providers often did not clearly distinguish between the control and experimental groups. And finally, the study likely was too small to demonstrate a positive effect for OPC. Nevertheless, the findings suggest that OPC might provide no added benefit if persons with serious mental illnesses have access to enhanced outpatient services.⁴

Do OPC laws prevent violence?

The North Carolina and New York controlled studies of OPC yielded contradictory findings and are difficult to compare. Even within North Carolina—where OPC has been shown most consistently to be effective—OPC orders’ duration (the “dose”) varies widely, as do the services patients receive.

No further randomized, controlled trials of OPC are underway. Our group is participating in a study supported by the MacArthur Foundation Research Network on Mandated Community Treatment and New York State Office of Mental Health to intensively review patient outcomes under New York’s OPC statute.

Rare, violent acts such Seung Hui Cho’s rampage at Virginia Tech have motivated many states to propose OPC statutes. OPC statutes are designed more to improve treatment adherence and reduce rehospitalization than to prevent violence, however. Although the North Carolina study suggests OPC can prevent relatively minor acts of violence,¹⁸ the desired benefit of preventing potentially lethal violence is exceedingly difficult to realize or document.

Given that most states permit OPC, attempts to standardize and implement OPC are needed. To make OPC effective, evidence indicates that states also must provide intensive community services to keep patients in treatment.

Strategies for using OPC

OPC is controversial in society and among clinicians. Some mental health organizations oppose outpatient commitment orders as coercive and intrusive, and some mental health professionals have concerns about legal or malpractice liability, increased paperwork, and administrative burden. Others may view OPC as:

• ineffective —providing weak sanctions that are impractical to enforce
  
• detrimental to the therapeutic alliance
  
• a less-desirable substitute for making high-quality voluntary treatment more widely available for the seriously mentally ill.
  

Reach a consensus. If your team is considering OPC for a patient, you must all agree on its use. Because most court orders are initiated on an inpatient unit as part of a discharge plan, clinicians across inpatient and outpatient settings must agree on how you will apply OPC to this patient.

Select appropriate candidates. Our group’s experience suggests that patients with severe mental illness—especially schizophrenia spectrum disorders—are those most likely to benefit from OPC. There is no evidence that outpatient commitment helps patients with personality disorders or substance abuse without comorbid severe mental illness.

Maximize effectiveness. Evidence from the North Carolina studies suggests keeping OPC in place for ≥6 months and providing relatively intensive outpatient services. For schizophrenia-spectrum patients, combining OPC with depot antipsychotics may be more effective than oral agents for ensuring adherence and improving function.¹⁹

Plan enforcement. To enforce OPC orders, you need a mechanism to plan and coordinate law enforcement transport of patients to treatment in cases of nonadherence. Because transport can be a burden to law enforcement officers, at least one North Carolina county developed a legal agreement to allow its mental health clinicians to enforce orders and pick up patients.

Decide when to terminate. OPC orders probably should last at least 6 months, but little evidence exists to guide discontinuing an order after 6 months. This dilemma is similar to deciding when a depot antipsychotic can or should be converted to an oral agent in previously nonadherent patients.

Our approach is to consider terminating the order in patients with restored insight who have ≥6 months of consistent treatment compliance without a need for or threat of OPC enforcement. In some cases, other leverage may preempt the need for continuing an order, such as:

 

• financial contingencies from family or others
  
• treatment required as a condition of probation or parole
  
• housing conditioned on treatment adherence.
  

Related resources

• Treatment Advocacy Center. Nonprofit organization dedicated to eliminating barriers to timely, effective treatment of severe mental illnesses. www.psychlaws.org.
  
• MacArthur Foundation Research Network on Mandated Community Treatment. www.macarthur.virginia.edu/researchnetwork.html.
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

This work was supported by NIMH Grants MH 48103 and MH 51410 and the MacArthur Foundation Research Network on Mandated Community Treatment.

Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”

Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.

Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:

• neurologic conditions that result in IEED
  
• underlying pathology
  
• diagnostic criteria
  
• effective treatments.
  

Brain dysfunction alters affect

IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.¹

IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.² IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.³

IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).^4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).⁷

Table 1

Neurologic conditions associated with IEED

Amyotrophic lateral sclerosis
Multiple sclerosis
Traumatic brain injury
Stroke
Alzheimer’s disease
Frontotemporal dementia
Parkinson’s disease
Progressive supranuclear palsy
Multiple systems atrophy
Wilson’s disease
Normal pressure hydrocephalus
Olivopontine cerebellar atrophy
Source: Reference 7

Diagnosis can be elusive

Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).¹ As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.

The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.

To be considered IEED, the patient’s symptoms must represent a change from his or her normal emotional reactivity. When interviewing patients and their families, compare the patient’s current emotional reactivity with that from when he or she was free of all disease symptoms. Such considerations are important because a patient may have a life-long condition in which he or she is prone to emotional displays—such as essential crying—that is distinct from IEED.⁸

Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.

IEED episodes have characteristic clinical features (Table 3). They are brief—lasting seconds to minutes—and sudden in onset and conclusion. Episodes are likely to be stereotyped in severity and presenting type within patients, as well as in the triggering stimulus or set of stimuli. For example, patients often experience episodes when asked about the syndrome.⁹ In severe cases, patients experience episodes with any interpersonal contact.¹⁰

Some characteristics support—but are not essential for—an IEED diagnosis:

• autonomic symptoms, such as flushing of the face and increased salivary production during episodes
  
• pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
  
• other emotional outbursts.
  

 

Table 2

Is it IEED? Diagnostic criteria

Presence of brain damage
Episodes of involuntary emotional motor output that: represent a change from normal emotional reactivity are independent or in excess of provoking stimuli result in clinically significant distress or social or functional impairment
Disorder is not: better accounted for by another neurologic or psychiatric disorder caused by a physiologic substance
Source: Reference 1

Table 3

Characteristics of IEED episodes

Paroxysmal, sudden onset with rapid offset
Brief (up to several minutes)
Stereotyped across patients (may manifest in similar fashion from patient to patient)
Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli)

Box 1

CASE CONTINUED: Reaching a diagnosis

After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.

Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:

• duration of crying
  
• associated mood state.
  

Major depressive disorder (MDD) is a persistent change in a patient’s mood lasting weeks to months, accompanied by feelings of guilt, helplessness, hopelessness, and worthlessness, apathy, and anhedonia.¹¹ IEED is paroxysmal, with uncontrollable changes in affect without a corresponding sudden mood change. Patients may report mood changes during episodes, but between episodes return to an euthymic affect.

Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.¹² Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.

Recommended treatment

Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.

Teach them to cope with IEED by:

• identifying and avoiding stimuli that provoke IEED episodes
  
• ignoring the episodes and continuing with usual activities.
  

Antidepressants are first-line pharmacotherapy for IEED. Studies and case reports have shown efficacy for tricyclic antidepressants (TCAs) such as nortriptyline and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Table 4).^2,12-16

These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.^2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.

Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.¹⁷ In another study, levodopa therapy resulted in improvement in 10 of 25 patients.¹⁸

Box 2

 

A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS¹⁹ and MS²⁰ and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.²¹

Table 4

IEED: Evidence for antidepressants

Drug	Study design/population	Dosage	Outcome
Tricyclics
Amitriptyline	Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients	Mean: 57.8 mg/d	8 patients showed significant improvement compared with placebo
Nortriptyline	Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients	≤100 mg/d	Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo
Selective serotonin reuptake inhibitors
Citalopram	Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients	10 to 20 mg/d	Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo
Fluoxetine	Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients	20 mg/d	Fluoxetine significantly improved measures of IEED and anger proneness but not depression
Paroxetine	Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke	10 to 40 mg/d	Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism
Sertraline	Burns et al;16 double-blind, placebo-controlled; 28 stroke patients	50 mg/d	Patients receiving sertraline had significant improvements in measures of emotionalism
IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale

CASE CONTINUED: Effective pharmacotherapy

After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.

Recommendations. We recommend using pharmacologic therapy for IEED. Because of the presence of underlying brain damage, IEED patients are likely to require treatment for other chronic or progressive conditions. Choose first-line therapy based on the patient’s medication regimen and comorbid conditions, as well as the drug’s side-effect profile.

Effective pharmacologic intervention can greatly improve patients’ quality of life.^19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).^{12,19,20,22-25} Because treatment failure is a realistic possibility,¹⁷ you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.

Related Resources

• Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
  
• Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
  
• Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Citalopram • Celexa
  
• Dextromethorphan/quinidine • Zenvia*
  
• Fluoxetine • Prozac
  
• Levodopa • Larodopa
  
• Mirtazapine • Remeron
  
• Nortriptyline • Aventyl
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• * IN PHASE III DEVELOPMENT
  

Disclosures

Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.

Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”

Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.

Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:

• neurologic conditions that result in IEED
  
• underlying pathology
  
• diagnostic criteria
  
• effective treatments.
  

Brain dysfunction alters affect

IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.¹

IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.² IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.³

IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).^4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).⁷

Table 1

Neurologic conditions associated with IEED

Amyotrophic lateral sclerosis
Multiple sclerosis
Traumatic brain injury
Stroke
Alzheimer’s disease
Frontotemporal dementia
Parkinson’s disease
Progressive supranuclear palsy
Multiple systems atrophy
Wilson’s disease
Normal pressure hydrocephalus
Olivopontine cerebellar atrophy
Source: Reference 7

Diagnosis can be elusive

Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).¹ As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.

The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.

To be considered IEED, the patient’s symptoms must represent a change from his or her normal emotional reactivity. When interviewing patients and their families, compare the patient’s current emotional reactivity with that from when he or she was free of all disease symptoms. Such considerations are important because a patient may have a life-long condition in which he or she is prone to emotional displays—such as essential crying—that is distinct from IEED.⁸

Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.

IEED episodes have characteristic clinical features (Table 3). They are brief—lasting seconds to minutes—and sudden in onset and conclusion. Episodes are likely to be stereotyped in severity and presenting type within patients, as well as in the triggering stimulus or set of stimuli. For example, patients often experience episodes when asked about the syndrome.⁹ In severe cases, patients experience episodes with any interpersonal contact.¹⁰

Some characteristics support—but are not essential for—an IEED diagnosis:

• autonomic symptoms, such as flushing of the face and increased salivary production during episodes
  
• pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
  
• other emotional outbursts.
  

 

Table 2

Is it IEED? Diagnostic criteria

Presence of brain damage
Episodes of involuntary emotional motor output that: represent a change from normal emotional reactivity are independent or in excess of provoking stimuli result in clinically significant distress or social or functional impairment
Disorder is not: better accounted for by another neurologic or psychiatric disorder caused by a physiologic substance
Source: Reference 1

Table 3

Characteristics of IEED episodes

Paroxysmal, sudden onset with rapid offset
Brief (up to several minutes)
Stereotyped across patients (may manifest in similar fashion from patient to patient)
Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli)

Box 1

CASE CONTINUED: Reaching a diagnosis

After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.

Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:

• duration of crying
  
• associated mood state.
  

Major depressive disorder (MDD) is a persistent change in a patient’s mood lasting weeks to months, accompanied by feelings of guilt, helplessness, hopelessness, and worthlessness, apathy, and anhedonia.¹¹ IEED is paroxysmal, with uncontrollable changes in affect without a corresponding sudden mood change. Patients may report mood changes during episodes, but between episodes return to an euthymic affect.

Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.¹² Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.

Recommended treatment

Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.

Teach them to cope with IEED by:

• identifying and avoiding stimuli that provoke IEED episodes
  
• ignoring the episodes and continuing with usual activities.
  

Antidepressants are first-line pharmacotherapy for IEED. Studies and case reports have shown efficacy for tricyclic antidepressants (TCAs) such as nortriptyline and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Table 4).^2,12-16

These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.^2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.

Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.¹⁷ In another study, levodopa therapy resulted in improvement in 10 of 25 patients.¹⁸

Box 2

 

A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS¹⁹ and MS²⁰ and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.²¹

Table 4

IEED: Evidence for antidepressants

Drug	Study design/population	Dosage	Outcome
Tricyclics
Amitriptyline	Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients	Mean: 57.8 mg/d	8 patients showed significant improvement compared with placebo
Nortriptyline	Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients	≤100 mg/d	Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo
Selective serotonin reuptake inhibitors
Citalopram	Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients	10 to 20 mg/d	Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo
Fluoxetine	Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients	20 mg/d	Fluoxetine significantly improved measures of IEED and anger proneness but not depression
Paroxetine	Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke	10 to 40 mg/d	Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism
Sertraline	Burns et al;16 double-blind, placebo-controlled; 28 stroke patients	50 mg/d	Patients receiving sertraline had significant improvements in measures of emotionalism
IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale

CASE CONTINUED: Effective pharmacotherapy

After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.

Recommendations. We recommend using pharmacologic therapy for IEED. Because of the presence of underlying brain damage, IEED patients are likely to require treatment for other chronic or progressive conditions. Choose first-line therapy based on the patient’s medication regimen and comorbid conditions, as well as the drug’s side-effect profile.

Effective pharmacologic intervention can greatly improve patients’ quality of life.^19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).^{12,19,20,22-25} Because treatment failure is a realistic possibility,¹⁷ you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.

Related Resources

• Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
  
• Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
  
• Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Citalopram • Celexa
  
• Dextromethorphan/quinidine • Zenvia*
  
• Fluoxetine • Prozac
  
• Levodopa • Larodopa
  
• Mirtazapine • Remeron
  
• Nortriptyline • Aventyl
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• * IN PHASE III DEVELOPMENT
  

Disclosures

Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.

Mrs. R, a 68-year-old retired teacher, is referred to you for suspected mania after a closed head injury from a car accident. The referring physician reports that Mrs. R experienced mild anterograde amnesia that has resolved, but she continues to suffer from “persistent mood swings as evidenced by substantial inappropriate laughter.”

Mrs. R is not manic. Her mood is normal, with a relatively euthymic affect. When asked about her accident or injury, however, she breaks into bouts of laughter that appear to be uncontrollable and last up to several minutes. These episodes include respiratory changes that make her laughter nearly indistinguishable from crying. Mrs. R explains that the episodes occur every time she discusses the accident—regardless of her efforts to prevent them—and complains they are extremely frustrating and embarrassing. She avoids situations that might trigger the episodes.

Patients with involuntary emotional expression disorder (IEED)—a neurologic disorder that manifests as brief bouts of uncontrollable crying, laughing, or both—may appear to have bipolar disorder, schizophrenia, depression, or another psychiatric disorder. Careful evaluation, however, can distinguish IEED from other conditions. Managing the disorder requires an understanding of IEED phenomenology, including:

• neurologic conditions that result in IEED
  
• underlying pathology
  
• diagnostic criteria
  
• effective treatments.
  

Brain dysfunction alters affect

IEED was introduced as an inclusive term, replacing previous nomenclature such as pathologic laughing and crying, pseudobulbar affect, affective lability, and emotional incontinence.¹

IEED can present as episodes of laughter, as in Mrs. R’s case, but more commonly manifests as bouts of crying. Other presentations include a combination of laughing and crying, but episodic outbursts of other emotions that are out of the patient’s control—such as anger—can be included in this syndrome.² IEED episodes can lead to embarrassment, frustration, and anger that eventually can affect mood and often cause patients to avoid social interaction.³

IEED can occur in any condition that damages and affects the brain areas critical to emotional motor output (Box 1).^4-6 The broad pattern of lesions that can result in IEED stems from many disease states. IEED is often observed in amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury. It also may occur in dementia, Parkinson’s disease, and other disorders (Table 1).⁷

Table 1

Neurologic conditions associated with IEED

Amyotrophic lateral sclerosis
Multiple sclerosis
Traumatic brain injury
Stroke
Alzheimer’s disease
Frontotemporal dementia
Parkinson’s disease
Progressive supranuclear palsy
Multiple systems atrophy
Wilson’s disease
Normal pressure hydrocephalus
Olivopontine cerebellar atrophy
Source: Reference 7

Diagnosis can be elusive

Although IEED is not included in DSM-IV-TR, recently developed diagnostic criteria can help distinguish it from other disorders (Table 2).¹ As with DSM-categorized disorders, IEED must result in clinically significant distress or impairment in social or occupational function and must not be better accounted for by another disorder or caused by a physiologic substance.

The patient must present with symptoms caused by brain dysfunction from brain injury or neurodegenerative disease. Underlying brain damage might not be apparent when the patient first presents, but to our knowledge no case of idiopathic IEED has been described. If a patient presents with symptoms thought to be IEED, first determine what underlying neurologic condition is causing the symptoms and optimally manage this disorder.

To be considered IEED, the patient’s symptoms must represent a change from his or her normal emotional reactivity. When interviewing patients and their families, compare the patient’s current emotional reactivity with that from when he or she was free of all disease symptoms. Such considerations are important because a patient may have a life-long condition in which he or she is prone to emotional displays—such as essential crying—that is distinct from IEED.⁸

Symptoms must be incongruent with or in excess of the person’s underlying mood and independent or in excess of the provoking stimulus. Inappropriateness of the emotional response is the hallmark of IEED.

IEED episodes have characteristic clinical features (Table 3). They are brief—lasting seconds to minutes—and sudden in onset and conclusion. Episodes are likely to be stereotyped in severity and presenting type within patients, as well as in the triggering stimulus or set of stimuli. For example, patients often experience episodes when asked about the syndrome.⁹ In severe cases, patients experience episodes with any interpersonal contact.¹⁰

Some characteristics support—but are not essential for—an IEED diagnosis:

• autonomic symptoms, such as flushing of the face and increased salivary production during episodes
  
• pseudobulbar signs, such as increased jaw jerk, exaggerated gag reflex, dysarthria, and dysphagia
  
• other emotional outbursts.
  

 

Table 2

Is it IEED? Diagnostic criteria

Presence of brain damage
Episodes of involuntary emotional motor output that: represent a change from normal emotional reactivity are independent or in excess of provoking stimuli result in clinically significant distress or social or functional impairment
Disorder is not: better accounted for by another neurologic or psychiatric disorder caused by a physiologic substance
Source: Reference 1

Table 3

Characteristics of IEED episodes

Paroxysmal, sudden onset with rapid offset
Brief (up to several minutes)
Stereotyped across patients (may manifest in similar fashion from patient to patient)
Stereotyped within patients (episodes often have similar type, severity, and eliciting stimuli)

Box 1

CASE CONTINUED: Reaching a diagnosis

After thoroughly interviewing Mrs. R, you exclude mood disorders such as depression or bipolar disorder. The paroxysmal, episodic nature of her emotional outbursts and the consistency of the eliciting stimulus, suggest IEED.

Distinguishing IEED from depression. Physicians may be quick to diagnose a patient with consistent, recurrent crying as having a depressive disorder. In IEED, the patient’s family commonly (and inappropriately) will confirm this misperception, even if the patient claims otherwise. The hallmark distinctions between depression and IEED are:

• duration of crying
  
• associated mood state.
  

Major depressive disorder (MDD) is a persistent change in a patient’s mood lasting weeks to months, accompanied by feelings of guilt, helplessness, hopelessness, and worthlessness, apathy, and anhedonia.¹¹ IEED is paroxysmal, with uncontrollable changes in affect without a corresponding sudden mood change. Patients may report mood changes during episodes, but between episodes return to an euthymic affect.

Patients who suffer from MDD, however, are not excluded from an IEED diagnosis. In 1 small study, almost one-half of patients with IEED also had major depression.¹² Differentiating these syndromes—even in patients who suffer from both—is important to ensure proper management and patient and family understanding of the condition. Lastly, although IEED is not a mood disorder, the embarrassment and frustration it causes can change a patient’s mood over time.

Recommended treatment

Education. In our experience, education is critical to help patients and family members understand IEED and deal with embarrassment and other normal reactions they may experience. Explain that these emotional displays are not manic or psychotic episodes but periods of motor dyscontrol caused by a neurologic condition.

Teach them to cope with IEED by:

• identifying and avoiding stimuli that provoke IEED episodes
  
• ignoring the episodes and continuing with usual activities.
  

Antidepressants are first-line pharmacotherapy for IEED. Studies and case reports have shown efficacy for tricyclic antidepressants (TCAs) such as nortriptyline and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Table 4).^2,12-16

These agents have IEED-specific therapeutic effects through a mechanism independent of their antidepressant action. In patients with IEED and depression, antidepressants may resolve IEED while depression remains refractory.^2,12 Potential drawbacks include anticholinergic effects with TCAs and sexual and gastrointestinal side effects with SSRIs. Nevertheless, these agents are the optimal first-line therapy for IEED among currently available options.

Other agents. Small studies have investigated other agents, but the data are insufficient to warrant recommendations for clinical practice. One study found that the novel antidepressant mirtazapine improved symptoms in 2 patients who did not respond to SSRIs.¹⁷ In another study, levodopa therapy resulted in improvement in 10 of 25 patients.¹⁸

Box 2

 

A combination dextromethorphan and quinidine (DM/Q) is being evaluated for IEED. This compound has demonstrated efficacy in IEED patients with ALS¹⁹ and MS²⁰ and is in Phase III clinical development. DM/Q is thought to be a potent activator of the sigma-1 receptor system as well as an N-methyl-D-aspartate antagonist.²¹

Table 4

IEED: Evidence for antidepressants

Drug	Study design/population	Dosage	Outcome
Tricyclics
Amitriptyline	Schiffer et al;13 double-blind crossover; 12 multiple sclerosis patients	Mean: 57.8 mg/d	8 patients showed significant improvement compared with placebo
Nortriptyline	Robinson et al;12 double-blind, placebo-controlled; 28 stroke patients	≤100 mg/d	Patients receiving nortriptyline reported significantly greater improvement on PLACS at 4 and 6 weeks compared with placebo
Selective serotonin reuptake inhibitors
Citalopram	Anderson et al;14 double-blind, placebo-controlled crossover; 16 stroke patients	10 to 20 mg/d	Citalopram decreased the number of daily crying episodes by ≥50% compared with placebo
Fluoxetine	Choi-Kwon et al;2 double-blind placebo-controlled; 152 patients	20 mg/d	Fluoxetine significantly improved measures of IEED and anger proneness but not depression
Paroxetine	Müller et al;15 consecutive case series, comparison with citalopram; 26 patients with traumatic brain injury or stroke	10 to 40 mg/d	Both paroxetine and citalopram resulted in significant improvements in measures of emotionalism
Sertraline	Burns et al;16 double-blind, placebo-controlled; 28 stroke patients	50 mg/d	Patients receiving sertraline had significant improvements in measures of emotionalism
IEED: involuntary emotional expression disorder; PLACS: Pathological Laughing and Crying Scale

CASE CONTINUED: Effective pharmacotherapy

After diagnosing IEED, you start Mrs. R on sertraline, 50 mg/d. She experiences a nearly immediate reduction in the number of daily IEED episodes. As a result, she feels more comfortable engaging in social activities.

Recommendations. We recommend using pharmacologic therapy for IEED. Because of the presence of underlying brain damage, IEED patients are likely to require treatment for other chronic or progressive conditions. Choose first-line therapy based on the patient’s medication regimen and comorbid conditions, as well as the drug’s side-effect profile.

Effective pharmacologic intervention can greatly improve patients’ quality of life.^19,20 Use scales that measure IEED severity to gauge treatment effectiveness (Box 2).^{12,19,20,22-25} Because treatment failure is a realistic possibility,¹⁷ you may need to try a variety of agents to determine which regimen provides the greatest efficacy and therapeutic effects.

Related Resources

• Involuntary emotional expressive disorder (for healthcare professionals). www.ieed.org/hp.
  
• Pathological laughing and crying scale (PLACS). Robinson RG, Parikh RM, Lipsey JR, et al. Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 1993;150:286-93.
  
• Center for neurologic study—lability scale (CNS-LS). Moore SR, Gresham LS, Bromberg MB, et al. A self report measure of affective lability. J Neurol Neurosurg Psychiatry 1997;63:89-93.
  

Drug brand names

• Amitriptyline • Elavil, Endep
  
• Citalopram • Celexa
  
• Dextromethorphan/quinidine • Zenvia*
  
• Fluoxetine • Prozac
  
• Levodopa • Larodopa
  
• Mirtazapine • Remeron
  
• Nortriptyline • Aventyl
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• * IN PHASE III DEVELOPMENT
  

Disclosures

Dr. Grill reports no financial relationship with any company whose products are mentioned in the article or with manufacturers of competing products.

Dr. Cummings is a consultant to Acadia Pharmaceuticals, Astellas Pharma, Avanir Pharmaceuticals, Cephalon, CoMentis, Eisai, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merck, Merz Pharma, Myriad, Neurochem, Novartis, Ono Pharmaceutical Co., Pfizer Inc., and sanofi-aventis. He is a speaker for Eisai, Forest Pharmaceuticals, Janssen, L.P., Lundbeck, Merz Pharma, Novartis, and Pfizer Inc.