Current Psychiatry

As this nation’s population becomes increasingly diverse, tailoring your practice to your area’s demographics is crucial to providing effective treatment.

Here’s how to improve your “cultural competence.”

1. Recognize that culture extends beyond skin color. Although darker-skinned persons are commonly identified as “black” or African-American, some identify themselves as Hispanic, Jamaican, or white. Others may identify with their religion, gender, sexual preference, age, geography, socioeconomic status, or occupation. For example, the “tough-it-out” ethos of firefighters can breed denial of depression or trauma that limits their desire to seek or stay in treatment.
2. Find out each patient’s cultural background. On your intake forms, include questions about race, ethnicity, language(s), religion, and age, or ask the patient to discuss his or her cultural background during the initial interview.
3. Determine your cultural effectiveness. A sample breakdown of your patients can help you analyze treatment, compliance, progress, and outcomes among cultural groups.
4. Make your patients feel “at home.” If possible, your staff should reflect your area’s cultural makeup.
5. Conduct culturally sensitive evaluations. Cultural identification often leads to misdiagnosis.¹ For example, African-American men tend to be over-diagnosed with paranoid schizophrenia or antisocial personality disorder.²
6. Elicit patient expectations and preferences. Some cultures distrust modern drug therapy, while some patients think medication should magically resolve their disorders. Still others think psychotherapy works only for whites.
7. Understand your cultural identity. Do a “cultural self-analysis” and see how your values apply to psychiatry. For example, if your culture values independence and individuality, you may underestimate the effectiveness of family therapy for patients whose cultures value interdependence.

As this nation’s population becomes increasingly diverse, tailoring your practice to your area’s demographics is crucial to providing effective treatment.

Here’s how to improve your “cultural competence.”

1. Recognize that culture extends beyond skin color. Although darker-skinned persons are commonly identified as “black” or African-American, some identify themselves as Hispanic, Jamaican, or white. Others may identify with their religion, gender, sexual preference, age, geography, socioeconomic status, or occupation. For example, the “tough-it-out” ethos of firefighters can breed denial of depression or trauma that limits their desire to seek or stay in treatment.
2. Find out each patient’s cultural background. On your intake forms, include questions about race, ethnicity, language(s), religion, and age, or ask the patient to discuss his or her cultural background during the initial interview.
3. Determine your cultural effectiveness. A sample breakdown of your patients can help you analyze treatment, compliance, progress, and outcomes among cultural groups.
4. Make your patients feel “at home.” If possible, your staff should reflect your area’s cultural makeup.
5. Conduct culturally sensitive evaluations. Cultural identification often leads to misdiagnosis.¹ For example, African-American men tend to be over-diagnosed with paranoid schizophrenia or antisocial personality disorder.²
6. Elicit patient expectations and preferences. Some cultures distrust modern drug therapy, while some patients think medication should magically resolve their disorders. Still others think psychotherapy works only for whites.
7. Understand your cultural identity. Do a “cultural self-analysis” and see how your values apply to psychiatry. For example, if your culture values independence and individuality, you may underestimate the effectiveness of family therapy for patients whose cultures value interdependence.

As this nation’s population becomes increasingly diverse, tailoring your practice to your area’s demographics is crucial to providing effective treatment.

Here’s how to improve your “cultural competence.”

1. Recognize that culture extends beyond skin color. Although darker-skinned persons are commonly identified as “black” or African-American, some identify themselves as Hispanic, Jamaican, or white. Others may identify with their religion, gender, sexual preference, age, geography, socioeconomic status, or occupation. For example, the “tough-it-out” ethos of firefighters can breed denial of depression or trauma that limits their desire to seek or stay in treatment.
2. Find out each patient’s cultural background. On your intake forms, include questions about race, ethnicity, language(s), religion, and age, or ask the patient to discuss his or her cultural background during the initial interview.
3. Determine your cultural effectiveness. A sample breakdown of your patients can help you analyze treatment, compliance, progress, and outcomes among cultural groups.
4. Make your patients feel “at home.” If possible, your staff should reflect your area’s cultural makeup.
5. Conduct culturally sensitive evaluations. Cultural identification often leads to misdiagnosis.¹ For example, African-American men tend to be over-diagnosed with paranoid schizophrenia or antisocial personality disorder.²
6. Elicit patient expectations and preferences. Some cultures distrust modern drug therapy, while some patients think medication should magically resolve their disorders. Still others think psychotherapy works only for whites.
7. Understand your cultural identity. Do a “cultural self-analysis” and see how your values apply to psychiatry. For example, if your culture values independence and individuality, you may underestimate the effectiveness of family therapy for patients whose cultures value interdependence.

I’m sure we’ve all asked ourselves that question. Psychiatrists spend a lot of time observing hospitals. Our training requires us to work in hospitals, and many of us practice in hospitals after training.

You probably have ideas that could save your hospital thousands—even millions—of dollars, but the powers that be are not interested. You also, undoubtedly, have ideas to improve patient safety and satisfaction, but they are not interested in those, either.

Before anyone takes offense, I want to distinguish between hospitals—which tend to be stupid—and hospital administrators—who tend to be bright. I would guess that hospital administrators are even more frustrated than we are about how difficult it is for hospitals to make good decisions. Hospitals have this problem because they are big, complex systems with nobody in charge.

Years of “cost-based pricing”—when insurers paid whatever hospitals reported as t heir costs—contributed to hospital stupidity. This free-lunch reimbursement system may well have caused hospitals irreversible brain damage. It certainly made it difficult for them to adjust to “price-based costing”—having to bring costs in line with predetermined prices dictated by the payer.

I think, though, that the main reason hospitals became stupid was because they could get away with it. Hospitals had so much money and power that they did not need to be rational or responsive. Increased competition has eroded hospitals’ supremacy in the health-care market, but old habits die hard.

What can psychiatry learn from hospitals’ mistakes? If our profession could become more powerful without becoming stupid, we could rule the world—or, at least, the mental health care delivery system.

I’m sure we’ve all asked ourselves that question. Psychiatrists spend a lot of time observing hospitals. Our training requires us to work in hospitals, and many of us practice in hospitals after training.

You probably have ideas that could save your hospital thousands—even millions—of dollars, but the powers that be are not interested. You also, undoubtedly, have ideas to improve patient safety and satisfaction, but they are not interested in those, either.

Before anyone takes offense, I want to distinguish between hospitals—which tend to be stupid—and hospital administrators—who tend to be bright. I would guess that hospital administrators are even more frustrated than we are about how difficult it is for hospitals to make good decisions. Hospitals have this problem because they are big, complex systems with nobody in charge.

Years of “cost-based pricing”—when insurers paid whatever hospitals reported as t heir costs—contributed to hospital stupidity. This free-lunch reimbursement system may well have caused hospitals irreversible brain damage. It certainly made it difficult for them to adjust to “price-based costing”—having to bring costs in line with predetermined prices dictated by the payer.

I think, though, that the main reason hospitals became stupid was because they could get away with it. Hospitals had so much money and power that they did not need to be rational or responsive. Increased competition has eroded hospitals’ supremacy in the health-care market, but old habits die hard.

What can psychiatry learn from hospitals’ mistakes? If our profession could become more powerful without becoming stupid, we could rule the world—or, at least, the mental health care delivery system.

I’m sure we’ve all asked ourselves that question. Psychiatrists spend a lot of time observing hospitals. Our training requires us to work in hospitals, and many of us practice in hospitals after training.

You probably have ideas that could save your hospital thousands—even millions—of dollars, but the powers that be are not interested. You also, undoubtedly, have ideas to improve patient safety and satisfaction, but they are not interested in those, either.

Before anyone takes offense, I want to distinguish between hospitals—which tend to be stupid—and hospital administrators—who tend to be bright. I would guess that hospital administrators are even more frustrated than we are about how difficult it is for hospitals to make good decisions. Hospitals have this problem because they are big, complex systems with nobody in charge.

Years of “cost-based pricing”—when insurers paid whatever hospitals reported as t heir costs—contributed to hospital stupidity. This free-lunch reimbursement system may well have caused hospitals irreversible brain damage. It certainly made it difficult for them to adjust to “price-based costing”—having to bring costs in line with predetermined prices dictated by the payer.

I think, though, that the main reason hospitals became stupid was because they could get away with it. Hospitals had so much money and power that they did not need to be rational or responsive. Increased competition has eroded hospitals’ supremacy in the health-care market, but old habits die hard.

What can psychiatry learn from hospitals’ mistakes? If our profession could become more powerful without becoming stupid, we could rule the world—or, at least, the mental health care delivery system.

A first psychotic episode offers the opportunity to build a therapeutic alliance at a teachable moment—while patients and their families are dealing with a devastating diagnosis. With a proactive approach, you can influence how patients view themselves and their experience, including psychotic illness, your efforts to treat its symptoms, and the costs and benefits of interventions.

Unfortunately, the typical first psychotic episode goes undiagnosed and untreated for 1 to 2 years, which some studies suggest may allow schizophrenia to progress. Although controversial, evidence links a prolonged duration of untreated psychosis to poorer outcome.¹ Interventions during a prodromal (ie, pre-psychotic but already symptomatic) phase of schizophrenia also is being investigated, with the goal of attenuating—or perhaps even preventing—progression to frank psychosis.^2-6

The implication for clinicians: timely identification and treatment may improve response, reduce relapse rates, and ultimately improve schizophrenic patients’ quality of life.

High rates of response—and relapse

Patients with a first psychotic episode show a higher response rate to antipsychotics—up to 87% within 1 year⁷ —and are more sensitive to side effects than are multi-episode patients.⁸ Yet despite their high response rate, new-onset patients often suffer from residual symptoms, even when treated in controlled settings. They also have a high rate of relapse—82% within 5 years.⁹

The strongest modifiable predictor of relapse is medication non-adherence, which has been shown to increase the risk of relapse five-fold.⁷ The first treatment experience provides a window of opportunity to help the patient accept taking medications as a normal part of life.

Box

Therapeutic alliance. Your approach is key to building a therapeutic alliance with a person whose reality often is clouded by paranoia and referential thinking. Trust begins with the first clinical contact—during history-taking, ordering of tests, answering questions about the diagnosis, and discussing treatment options. Patients and their families must be informed about:

• target symptoms
• medication side effects
• predictors of response and relapse
• lack of certainty about how or when a patient will respond to any antipsychotic
• and the importance of rapid and uninterrupted treatment.

Supportive therapy. Support groups for the patient and family can help destigmatize the illness and reduce stress. Information about schizophrenia’s nature and course is available from the National Alliance for the Mentally Ill, National Mental Health Association, and other sources (see “Related resources”).¹⁰

CBT. Adjunctive cognitive-behavioral therapy (CBT) may speed up acute symptom response,^11,12 reduce rates of nonresponse, and shorten hospital stays¹³ by helping patients deal with uncertainty about outer and inner realities. CBT approaches are understudied but so far have not been found to reduce relapse rates.

A moving target. As treatment moves from acute to consolidation and maintenance, target symptoms may change, side effects can limit the preferred approach, and partial or nonresponse may require drug or dosing adjustments. It is prudent to be prepared to re-evaluate the initial diagnosis as new symptoms emerge, response patterns develop, additional test or historical data become available, or as the illness’ course becomes more clear. To improve outcome, address comorbid or concurrent diseases—such as substance abuse or dependence, mood disorders, anxiety and obsessive-compulsive symptoms, or eating disorders.

Diagnostic work-up

As in Mr. C’s case (Box), a first psychotic episode is characterized by DSM-IV diagnostic criteria for schizophrenia, including hallucinations, delusions, disorganized thoughts or speech, disorganized behavior(s), or negative symptoms (such as anhedonia, amotivation, asociality, alogia, or affective flattening). The work-up is more comprehensive than that for subsequent episodes and includes a thorough history, complete physical examination, and brain imaging (Table 1) to explore other possible medical and psychiatric diagnoses (Table 2).

Table 1

WORK-UP OF PATIENTS PRESENTING WITHA FIRST EPISODE OF PSYCHOSIS

The history—ideally gathered from the patient and others—includes:

• medical and psychiatric diagnoses
• medications (prescribed and over-the-counter remedies)
• presence of stressors/triggers
• chronology of symptoms
• potential for the episode to endanger the patient or others.

Imaging. Despite a relatively low yield, we recommend that every patient with a first psychotic episode undergo a brain CT or MRI to rule out a potentially treatable organic cause for the psychosis.¹⁴

Other tests. Because of the increased risk of hyperglycemia, dyslipidemia, and possible cardiac conduction abnormalities with atypical antipsychotics, obtain a baseline fasting blood glucose, lipid profile, and ECG. A sleep-deprived EEG is recommended for patients with unclear motor movements or family history of epilepsy.

Choosing medications

Medication choices for the patient with first-episode schizophrenia are influenced by:

• target symptoms
• whether the symptoms endanger the patient or others
• the patient’s personal or family history of medication response or side effects
• a generally increased sensitivity to side effects in patients who have never been exposed to antipsychotics
• concurrent medical and/or psychiatric disorders
• prescriber, patient, and family preferences.

Psychiatrists generally select psychotropic classes by symptom domains (Table 3) and individual agents in each class by side effect profile. Except for clozapine’s superior effectiveness in patients with refractory psychosis, controlled studies have shown no clinically significant differences in efficacy among the drugs in each class—including the antipsychotics. Individual patients, however, may respond differently to different agents.

Principles of prescribing antipsychotics

Antipsychotics are effective in treating most psychotic core symptoms, such as hallucinations, delusions, agitation, aggression, and disorganized thinking and behavior. Other medications can be added to speed up or enhance treatment response or to target other domains.

Dosages. First-episode patients often require lower dosages and slower titration than multi-episode patients. As a rule, antipsychotics are started at about one-half the dosage given to patients with a chronic treatment history, although symptom severity and absence of side effects at lower dosages can help individualize titration.

Side effects. Atypical antipsychotics are preferred because of their reduced risk of extrapyramidal symptoms (EPS), positive effects on depressive and cognitive symptoms, and improved patient satisfaction and adherence, compared with the older antipsychotics.^15-17 Atypicals’ potential side effects include weight gain, hyperglycemia, and dyslipidemia,¹⁸ as well as often-overlooked sexual side effects.¹⁹

Table 2

DIFFERENTIAL DIAGNOSIS OF FIRST-EPISODE PSYCHOSIS

Consider the patient’s risk for side effects when choosing an atypical antipsychotic, as each drug has strengths and weaknesses. For example, it may be reasonable to consider:

• risperidone, ziprasidone, or aripiprazole—rather than olanzapine or quetiapine—for patients at high risk for weight gain or with a family history of diabetes
• avoiding risperidone for patients with an early indication of sensitivity to EPS or prolactin-related side effects
• an agent that can be loaded rapidly, such as olanzapine or aripiprazole—rather than an agent that requires titration, such as quetiapine—for a patient presenting with severe agitation.

Clozapine—because of its side effect potential—is generally reserved for patients who have not responded to at least two antipsychotic trials of at least 4 to 6 weeks duration and have a steady-state clozapine level >350 ng/dl.

Acute agitation. Short-acting IM formulations can be used effectively for acute agitation and impulsivity or for patients who refuse oral antipsychotics. Until recently, only first-generation antipsychotics such as haloperidol and fluphenazine were available in IM formulations. Injectable ziprasidone mesylate is now available for acute agitation and has been found to be as safe and effective as haloperidol. Lorazepam may be used to treat agitation or as an adjunct to a patient’s antipsychotic agent.

Adjunctive therapies

When antipsychotic monotherapy is inadequate, adjunctive medications may be considered:

• to treat catatonia, obsessive-compulsive disorder, or depression
• to resolve agitation or mania more quickly
• to control agitation or anxiety while an antipsychotic dosage is being titrated
• when side effects emerge or residual symptoms remain despite adequate dosage and duration of antipsychotic treatment.

Deciding if and when to add another drug depends on the nature and severity of target symptoms, the degree and time course of response, and whether side effects appear. If you use adjunctive therapies during acute stabilization, attempt to taper and discontinue them after the patient’s symptoms have improved. Avoid combining antipsychotics, as no clinical data support the effectiveness and safety of this practice.²⁰

Benzodiazepines are often used adjunctively for agitation, anxiety, or temporary insomnia in patients with schizophrenia. Common dosages are:

• for agitation or anxiety, lorazepam, 0.5 to 2 mg bid or tid, or clonazepam, 0.5 mg bid to 2 mg tid
• for insomnia, lorazepam or clonazepam, 1 to 2 mg at bedtime, or zolpidem, 5 to 10 mg at bedtime.

Benzodiazepines also are effective for catatonia, which may be misdiagnosed as negative symptoms or depression when it presents as marked psychomotor retardation, staring, selective mutism, negativism, mild posturing, or stereotypies. If undiagnosed, catatonia may worsen during antipsychotic titration. Symptoms usually respond to high-dose lorazepam, 1 mg bid or tid, with increases up to a maximum dosage of 12 mg/d.

Mood stabilizers are often used adjunctively to treat acute agitation and disinhibition²¹ or as add-on agents for residual psychotic or affective symptoms. Recommended dosages and blood levels, as tolerated, are:

• valproic acid, starting at 10 to 20 mg/kg bid, with a target serum level of 60 to 120 μg/ml. A once-daily, extended-release formulation may improve compliance.
• lithium, starting at 300 mg bid to tid, aiming for a serum level of 0.8 to 1.2 mEq/L.

Manic symptoms in a schizoaffective presentation may require one or even two mood stabilizers.

Lamotrigine may be the treatment of choice for depressed patients with schizoaffective disorder, bipolar type.²² However, it must be started at 25 mg/d and titrated extremely slowly—by 25 mg every other week, up to a target 200 to 400 mg/d—to avoid the risk of potentially fatal Stevens-Johnson syndrome.

Gabapentin, 300 mg tid to 1,500 mg tid, may help treat anxiety—particularly in patients with comorbid substance abuse, in whom benzodiazepines should be used sparingly after stabilization.

Table 3

SYMPTOM-BASED DRUG TREATMENT OF FIRST-EPISODE SCHIZOPHRENIA

Antidepressants. Patients with schizophrenia can develop depression, even if they do not meet diagnostic criteria for schizoaffective disorder. Untreated depression can lead to non-adherence, self-medication with alcohol or illicit substances, and increased risk of suicide.

Differentiating depression from negative symptoms may be difficult, but there are subtle distinctions:

• Patients with negative symptoms appear more emotionally flat and unconcerned about their lack of motivation and diminished social and role functioning.
• Depressed persons often verbalize their demoralization, hopelessness, and desire to feel and behave differently.

Treat depression with any selective serotonin reuptake inhibitor or other newer-generation antidepressant such as mirtazapine, nefazodone, or venlafaxine at usual doses, as tolerated.

Miscellaneous medications. Use anticholinergic medications such as benztropine, 0.5 to 2 mg bid, or trihexyphenidyl, 1 to 5 mg bid, if parkinsonian symptoms occur and changing to an antipsychotic with a lower EPS potential is not feasible.

For akathisia, propranolol (10 mg bid or tid; titrate up to 160 mg/d if pulse rate and blood pressure remain stable) or benzodiazepines may be useful. Amantadine may also be used at dosages between 50 and 150 mg bid.

Insomnia may be treated with low dosages of sedating antidepressants, such as trazodone, 50 to 200 mg HS, or mirtazapine, 7.5 to 15 mg HS.

Preventing relapse during maintenance

Medication adherence depends on patient insight and attitude towards medications.²³ Once you start a first-episode patient on drug therapy, encourage adherence by monitoring symptoms and anticipating side effects. Every 3 months after the acute phase:

• Use a structured evaluation, such as the Brief Psychiatric Rating Scale,²⁴ to plot symptom severity, response, and risk for relapse.
• Rate EPS with the Simpson-Angus Scale²⁵ and tardive dyskinesia (TD) with the Abnormal Involuntary Movement Scale²⁶ because EPS and TD are associated with poor symptom response, adherence, and outcome.⁷

Reinforce information about the chronic nature of schizophrenia, especially when the patient or family question why treatment is needed if symptoms have resolved. Continue to counsel them about the patient’s need for:

• regular sleep of sufficient duration and without sleep-wake reversal
• gradual return to premorbid social, educational, and vocational activities/responsibilities
• ongoing treatment.

Encourage vigilance for relapse warning signs, including insomnia, social withdrawal, anxiety, refusal to eat or take medications, suspiciousness, agitation, disorganization, preoccupation with overvalued ideas, or responses to internal stimuli.

If the patient is noncompliant with antipsychotics in tablets or capsules, options include:

• liquid risperidone or olanzapine in a rapidly dissolving form that the patient cannot hide and spit out later
• long-acting depot formulations if the patient cannot be supervised and monitored daily. Older antipsychotics (such as haloperidol decanoate and fluphenazine decanoate) are available in depot formulations, and the FDA is considering risperidone in a microsphere formulation that would allow biweekly injections.

Medication withdrawal

Although the ideal duration of maintenance treatment after a first psychotic episode is debatable, we recommend that antipsychotics be continued at the full dosage that achieved symptom remission for at least 1 year.²⁷ Then, if the patient has returned to the premorbid baseline, you can attempt a gradual medication withdrawal across 2 to 4 months, ideally when the patient’s environment is stable.

Be cautious when withdrawing antipsychotics from patients with a family history of psychosis. Consider a more gradual dose reduction, ongoing group and/or individual psychotherapy, and at least monthly monitoring. When possible, involve people who are significant in the patient’s life and educate them to look for deterioration’s warning signs, such as insomnia, irritability, anxiety, social withdrawal, preoccupation with overvalued ideas, or pacing.

If relapse occurs, carefully assess how well the patient has adhered to medication. Once a second psychotic episode occurs, his or her medication probably should be continued indefinitely.

Related resources

• National Alliance for the Mentally Ill (800) 950-NAMI (6264); www.nami.org
• National Mental Health Association (800) 969-NMHA (6642); www.nmha.org
• National Alliance for Research on Schizophrenia and Depression (516) 829-0091; www.narsad.org/index.html
• Miller R, Mason SE. Diagnosis schizophrenia. A comprehensive resource. New York: Columbia University Press, 2002.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Clozapine • Clozaril
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor
• Ziprasidone • Geodon
• Zolpidem • Ambien

Disclosure

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

Dr. Mendelowitz receives grant/research support from, is a consultant to, and/or is a speaker for Pfizer Inc., Bristol-Myers Squibb Co.; and AstraZeneca Pharmaceuticals.

Acknowledgments

Research for this article was supported by grant 5P30MH60575 to The Zucker Hillside Hospital Intervention Research Center for Schizophrenia from the National Institute of Mental Health, Bethesda, MD.

A first psychotic episode offers the opportunity to build a therapeutic alliance at a teachable moment—while patients and their families are dealing with a devastating diagnosis. With a proactive approach, you can influence how patients view themselves and their experience, including psychotic illness, your efforts to treat its symptoms, and the costs and benefits of interventions.

Unfortunately, the typical first psychotic episode goes undiagnosed and untreated for 1 to 2 years, which some studies suggest may allow schizophrenia to progress. Although controversial, evidence links a prolonged duration of untreated psychosis to poorer outcome.¹ Interventions during a prodromal (ie, pre-psychotic but already symptomatic) phase of schizophrenia also is being investigated, with the goal of attenuating—or perhaps even preventing—progression to frank psychosis.^2-6

The implication for clinicians: timely identification and treatment may improve response, reduce relapse rates, and ultimately improve schizophrenic patients’ quality of life.

High rates of response—and relapse

Patients with a first psychotic episode show a higher response rate to antipsychotics—up to 87% within 1 year⁷ —and are more sensitive to side effects than are multi-episode patients.⁸ Yet despite their high response rate, new-onset patients often suffer from residual symptoms, even when treated in controlled settings. They also have a high rate of relapse—82% within 5 years.⁹

The strongest modifiable predictor of relapse is medication non-adherence, which has been shown to increase the risk of relapse five-fold.⁷ The first treatment experience provides a window of opportunity to help the patient accept taking medications as a normal part of life.

Box

Therapeutic alliance. Your approach is key to building a therapeutic alliance with a person whose reality often is clouded by paranoia and referential thinking. Trust begins with the first clinical contact—during history-taking, ordering of tests, answering questions about the diagnosis, and discussing treatment options. Patients and their families must be informed about:

• target symptoms
• medication side effects
• predictors of response and relapse
• lack of certainty about how or when a patient will respond to any antipsychotic
• and the importance of rapid and uninterrupted treatment.

Supportive therapy. Support groups for the patient and family can help destigmatize the illness and reduce stress. Information about schizophrenia’s nature and course is available from the National Alliance for the Mentally Ill, National Mental Health Association, and other sources (see “Related resources”).¹⁰

CBT. Adjunctive cognitive-behavioral therapy (CBT) may speed up acute symptom response,^11,12 reduce rates of nonresponse, and shorten hospital stays¹³ by helping patients deal with uncertainty about outer and inner realities. CBT approaches are understudied but so far have not been found to reduce relapse rates.

A moving target. As treatment moves from acute to consolidation and maintenance, target symptoms may change, side effects can limit the preferred approach, and partial or nonresponse may require drug or dosing adjustments. It is prudent to be prepared to re-evaluate the initial diagnosis as new symptoms emerge, response patterns develop, additional test or historical data become available, or as the illness’ course becomes more clear. To improve outcome, address comorbid or concurrent diseases—such as substance abuse or dependence, mood disorders, anxiety and obsessive-compulsive symptoms, or eating disorders.

Diagnostic work-up

As in Mr. C’s case (Box), a first psychotic episode is characterized by DSM-IV diagnostic criteria for schizophrenia, including hallucinations, delusions, disorganized thoughts or speech, disorganized behavior(s), or negative symptoms (such as anhedonia, amotivation, asociality, alogia, or affective flattening). The work-up is more comprehensive than that for subsequent episodes and includes a thorough history, complete physical examination, and brain imaging (Table 1) to explore other possible medical and psychiatric diagnoses (Table 2).

Table 1

WORK-UP OF PATIENTS PRESENTING WITHA FIRST EPISODE OF PSYCHOSIS

The history—ideally gathered from the patient and others—includes:

• medical and psychiatric diagnoses
• medications (prescribed and over-the-counter remedies)
• presence of stressors/triggers
• chronology of symptoms
• potential for the episode to endanger the patient or others.

Imaging. Despite a relatively low yield, we recommend that every patient with a first psychotic episode undergo a brain CT or MRI to rule out a potentially treatable organic cause for the psychosis.¹⁴

Other tests. Because of the increased risk of hyperglycemia, dyslipidemia, and possible cardiac conduction abnormalities with atypical antipsychotics, obtain a baseline fasting blood glucose, lipid profile, and ECG. A sleep-deprived EEG is recommended for patients with unclear motor movements or family history of epilepsy.

Choosing medications

Medication choices for the patient with first-episode schizophrenia are influenced by:

• target symptoms
• whether the symptoms endanger the patient or others
• the patient’s personal or family history of medication response or side effects
• a generally increased sensitivity to side effects in patients who have never been exposed to antipsychotics
• concurrent medical and/or psychiatric disorders
• prescriber, patient, and family preferences.

Psychiatrists generally select psychotropic classes by symptom domains (Table 3) and individual agents in each class by side effect profile. Except for clozapine’s superior effectiveness in patients with refractory psychosis, controlled studies have shown no clinically significant differences in efficacy among the drugs in each class—including the antipsychotics. Individual patients, however, may respond differently to different agents.

Principles of prescribing antipsychotics

Antipsychotics are effective in treating most psychotic core symptoms, such as hallucinations, delusions, agitation, aggression, and disorganized thinking and behavior. Other medications can be added to speed up or enhance treatment response or to target other domains.

Dosages. First-episode patients often require lower dosages and slower titration than multi-episode patients. As a rule, antipsychotics are started at about one-half the dosage given to patients with a chronic treatment history, although symptom severity and absence of side effects at lower dosages can help individualize titration.

Side effects. Atypical antipsychotics are preferred because of their reduced risk of extrapyramidal symptoms (EPS), positive effects on depressive and cognitive symptoms, and improved patient satisfaction and adherence, compared with the older antipsychotics.^15-17 Atypicals’ potential side effects include weight gain, hyperglycemia, and dyslipidemia,¹⁸ as well as often-overlooked sexual side effects.¹⁹

Table 2

DIFFERENTIAL DIAGNOSIS OF FIRST-EPISODE PSYCHOSIS

Consider the patient’s risk for side effects when choosing an atypical antipsychotic, as each drug has strengths and weaknesses. For example, it may be reasonable to consider:

• risperidone, ziprasidone, or aripiprazole—rather than olanzapine or quetiapine—for patients at high risk for weight gain or with a family history of diabetes
• avoiding risperidone for patients with an early indication of sensitivity to EPS or prolactin-related side effects
• an agent that can be loaded rapidly, such as olanzapine or aripiprazole—rather than an agent that requires titration, such as quetiapine—for a patient presenting with severe agitation.

Clozapine—because of its side effect potential—is generally reserved for patients who have not responded to at least two antipsychotic trials of at least 4 to 6 weeks duration and have a steady-state clozapine level >350 ng/dl.

Acute agitation. Short-acting IM formulations can be used effectively for acute agitation and impulsivity or for patients who refuse oral antipsychotics. Until recently, only first-generation antipsychotics such as haloperidol and fluphenazine were available in IM formulations. Injectable ziprasidone mesylate is now available for acute agitation and has been found to be as safe and effective as haloperidol. Lorazepam may be used to treat agitation or as an adjunct to a patient’s antipsychotic agent.

Adjunctive therapies

When antipsychotic monotherapy is inadequate, adjunctive medications may be considered:

• to treat catatonia, obsessive-compulsive disorder, or depression
• to resolve agitation or mania more quickly
• to control agitation or anxiety while an antipsychotic dosage is being titrated
• when side effects emerge or residual symptoms remain despite adequate dosage and duration of antipsychotic treatment.

Deciding if and when to add another drug depends on the nature and severity of target symptoms, the degree and time course of response, and whether side effects appear. If you use adjunctive therapies during acute stabilization, attempt to taper and discontinue them after the patient’s symptoms have improved. Avoid combining antipsychotics, as no clinical data support the effectiveness and safety of this practice.²⁰

Benzodiazepines are often used adjunctively for agitation, anxiety, or temporary insomnia in patients with schizophrenia. Common dosages are:

• for agitation or anxiety, lorazepam, 0.5 to 2 mg bid or tid, or clonazepam, 0.5 mg bid to 2 mg tid
• for insomnia, lorazepam or clonazepam, 1 to 2 mg at bedtime, or zolpidem, 5 to 10 mg at bedtime.

Benzodiazepines also are effective for catatonia, which may be misdiagnosed as negative symptoms or depression when it presents as marked psychomotor retardation, staring, selective mutism, negativism, mild posturing, or stereotypies. If undiagnosed, catatonia may worsen during antipsychotic titration. Symptoms usually respond to high-dose lorazepam, 1 mg bid or tid, with increases up to a maximum dosage of 12 mg/d.

Mood stabilizers are often used adjunctively to treat acute agitation and disinhibition²¹ or as add-on agents for residual psychotic or affective symptoms. Recommended dosages and blood levels, as tolerated, are:

• valproic acid, starting at 10 to 20 mg/kg bid, with a target serum level of 60 to 120 μg/ml. A once-daily, extended-release formulation may improve compliance.
• lithium, starting at 300 mg bid to tid, aiming for a serum level of 0.8 to 1.2 mEq/L.

Manic symptoms in a schizoaffective presentation may require one or even two mood stabilizers.

Lamotrigine may be the treatment of choice for depressed patients with schizoaffective disorder, bipolar type.²² However, it must be started at 25 mg/d and titrated extremely slowly—by 25 mg every other week, up to a target 200 to 400 mg/d—to avoid the risk of potentially fatal Stevens-Johnson syndrome.

Gabapentin, 300 mg tid to 1,500 mg tid, may help treat anxiety—particularly in patients with comorbid substance abuse, in whom benzodiazepines should be used sparingly after stabilization.

Table 3

SYMPTOM-BASED DRUG TREATMENT OF FIRST-EPISODE SCHIZOPHRENIA

Antidepressants. Patients with schizophrenia can develop depression, even if they do not meet diagnostic criteria for schizoaffective disorder. Untreated depression can lead to non-adherence, self-medication with alcohol or illicit substances, and increased risk of suicide.

Differentiating depression from negative symptoms may be difficult, but there are subtle distinctions:

• Patients with negative symptoms appear more emotionally flat and unconcerned about their lack of motivation and diminished social and role functioning.
• Depressed persons often verbalize their demoralization, hopelessness, and desire to feel and behave differently.

Treat depression with any selective serotonin reuptake inhibitor or other newer-generation antidepressant such as mirtazapine, nefazodone, or venlafaxine at usual doses, as tolerated.

Miscellaneous medications. Use anticholinergic medications such as benztropine, 0.5 to 2 mg bid, or trihexyphenidyl, 1 to 5 mg bid, if parkinsonian symptoms occur and changing to an antipsychotic with a lower EPS potential is not feasible.

For akathisia, propranolol (10 mg bid or tid; titrate up to 160 mg/d if pulse rate and blood pressure remain stable) or benzodiazepines may be useful. Amantadine may also be used at dosages between 50 and 150 mg bid.

Insomnia may be treated with low dosages of sedating antidepressants, such as trazodone, 50 to 200 mg HS, or mirtazapine, 7.5 to 15 mg HS.

Preventing relapse during maintenance

Medication adherence depends on patient insight and attitude towards medications.²³ Once you start a first-episode patient on drug therapy, encourage adherence by monitoring symptoms and anticipating side effects. Every 3 months after the acute phase:

• Use a structured evaluation, such as the Brief Psychiatric Rating Scale,²⁴ to plot symptom severity, response, and risk for relapse.
• Rate EPS with the Simpson-Angus Scale²⁵ and tardive dyskinesia (TD) with the Abnormal Involuntary Movement Scale²⁶ because EPS and TD are associated with poor symptom response, adherence, and outcome.⁷

Reinforce information about the chronic nature of schizophrenia, especially when the patient or family question why treatment is needed if symptoms have resolved. Continue to counsel them about the patient’s need for:

• regular sleep of sufficient duration and without sleep-wake reversal
• gradual return to premorbid social, educational, and vocational activities/responsibilities
• ongoing treatment.

Encourage vigilance for relapse warning signs, including insomnia, social withdrawal, anxiety, refusal to eat or take medications, suspiciousness, agitation, disorganization, preoccupation with overvalued ideas, or responses to internal stimuli.

If the patient is noncompliant with antipsychotics in tablets or capsules, options include:

• liquid risperidone or olanzapine in a rapidly dissolving form that the patient cannot hide and spit out later
• long-acting depot formulations if the patient cannot be supervised and monitored daily. Older antipsychotics (such as haloperidol decanoate and fluphenazine decanoate) are available in depot formulations, and the FDA is considering risperidone in a microsphere formulation that would allow biweekly injections.

Medication withdrawal

Although the ideal duration of maintenance treatment after a first psychotic episode is debatable, we recommend that antipsychotics be continued at the full dosage that achieved symptom remission for at least 1 year.²⁷ Then, if the patient has returned to the premorbid baseline, you can attempt a gradual medication withdrawal across 2 to 4 months, ideally when the patient’s environment is stable.

Be cautious when withdrawing antipsychotics from patients with a family history of psychosis. Consider a more gradual dose reduction, ongoing group and/or individual psychotherapy, and at least monthly monitoring. When possible, involve people who are significant in the patient’s life and educate them to look for deterioration’s warning signs, such as insomnia, irritability, anxiety, social withdrawal, preoccupation with overvalued ideas, or pacing.

If relapse occurs, carefully assess how well the patient has adhered to medication. Once a second psychotic episode occurs, his or her medication probably should be continued indefinitely.

Related resources

• National Alliance for the Mentally Ill (800) 950-NAMI (6264); www.nami.org
• National Mental Health Association (800) 969-NMHA (6642); www.nmha.org
• National Alliance for Research on Schizophrenia and Depression (516) 829-0091; www.narsad.org/index.html
• Miller R, Mason SE. Diagnosis schizophrenia. A comprehensive resource. New York: Columbia University Press, 2002.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Clozapine • Clozaril
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor
• Ziprasidone • Geodon
• Zolpidem • Ambien

Disclosure

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

Dr. Mendelowitz receives grant/research support from, is a consultant to, and/or is a speaker for Pfizer Inc., Bristol-Myers Squibb Co.; and AstraZeneca Pharmaceuticals.

Acknowledgments

Research for this article was supported by grant 5P30MH60575 to The Zucker Hillside Hospital Intervention Research Center for Schizophrenia from the National Institute of Mental Health, Bethesda, MD.

A first psychotic episode offers the opportunity to build a therapeutic alliance at a teachable moment—while patients and their families are dealing with a devastating diagnosis. With a proactive approach, you can influence how patients view themselves and their experience, including psychotic illness, your efforts to treat its symptoms, and the costs and benefits of interventions.

Unfortunately, the typical first psychotic episode goes undiagnosed and untreated for 1 to 2 years, which some studies suggest may allow schizophrenia to progress. Although controversial, evidence links a prolonged duration of untreated psychosis to poorer outcome.¹ Interventions during a prodromal (ie, pre-psychotic but already symptomatic) phase of schizophrenia also is being investigated, with the goal of attenuating—or perhaps even preventing—progression to frank psychosis.^2-6

The implication for clinicians: timely identification and treatment may improve response, reduce relapse rates, and ultimately improve schizophrenic patients’ quality of life.

High rates of response—and relapse

Patients with a first psychotic episode show a higher response rate to antipsychotics—up to 87% within 1 year⁷ —and are more sensitive to side effects than are multi-episode patients.⁸ Yet despite their high response rate, new-onset patients often suffer from residual symptoms, even when treated in controlled settings. They also have a high rate of relapse—82% within 5 years.⁹

The strongest modifiable predictor of relapse is medication non-adherence, which has been shown to increase the risk of relapse five-fold.⁷ The first treatment experience provides a window of opportunity to help the patient accept taking medications as a normal part of life.

Box

Therapeutic alliance. Your approach is key to building a therapeutic alliance with a person whose reality often is clouded by paranoia and referential thinking. Trust begins with the first clinical contact—during history-taking, ordering of tests, answering questions about the diagnosis, and discussing treatment options. Patients and their families must be informed about:

• target symptoms
• medication side effects
• predictors of response and relapse
• lack of certainty about how or when a patient will respond to any antipsychotic
• and the importance of rapid and uninterrupted treatment.

Supportive therapy. Support groups for the patient and family can help destigmatize the illness and reduce stress. Information about schizophrenia’s nature and course is available from the National Alliance for the Mentally Ill, National Mental Health Association, and other sources (see “Related resources”).¹⁰

CBT. Adjunctive cognitive-behavioral therapy (CBT) may speed up acute symptom response,^11,12 reduce rates of nonresponse, and shorten hospital stays¹³ by helping patients deal with uncertainty about outer and inner realities. CBT approaches are understudied but so far have not been found to reduce relapse rates.

A moving target. As treatment moves from acute to consolidation and maintenance, target symptoms may change, side effects can limit the preferred approach, and partial or nonresponse may require drug or dosing adjustments. It is prudent to be prepared to re-evaluate the initial diagnosis as new symptoms emerge, response patterns develop, additional test or historical data become available, or as the illness’ course becomes more clear. To improve outcome, address comorbid or concurrent diseases—such as substance abuse or dependence, mood disorders, anxiety and obsessive-compulsive symptoms, or eating disorders.

Diagnostic work-up

As in Mr. C’s case (Box), a first psychotic episode is characterized by DSM-IV diagnostic criteria for schizophrenia, including hallucinations, delusions, disorganized thoughts or speech, disorganized behavior(s), or negative symptoms (such as anhedonia, amotivation, asociality, alogia, or affective flattening). The work-up is more comprehensive than that for subsequent episodes and includes a thorough history, complete physical examination, and brain imaging (Table 1) to explore other possible medical and psychiatric diagnoses (Table 2).

Table 1

WORK-UP OF PATIENTS PRESENTING WITHA FIRST EPISODE OF PSYCHOSIS

The history—ideally gathered from the patient and others—includes:

• medical and psychiatric diagnoses
• medications (prescribed and over-the-counter remedies)
• presence of stressors/triggers
• chronology of symptoms
• potential for the episode to endanger the patient or others.

Imaging. Despite a relatively low yield, we recommend that every patient with a first psychotic episode undergo a brain CT or MRI to rule out a potentially treatable organic cause for the psychosis.¹⁴

Other tests. Because of the increased risk of hyperglycemia, dyslipidemia, and possible cardiac conduction abnormalities with atypical antipsychotics, obtain a baseline fasting blood glucose, lipid profile, and ECG. A sleep-deprived EEG is recommended for patients with unclear motor movements or family history of epilepsy.

Choosing medications

Medication choices for the patient with first-episode schizophrenia are influenced by:

• target symptoms
• whether the symptoms endanger the patient or others
• the patient’s personal or family history of medication response or side effects
• a generally increased sensitivity to side effects in patients who have never been exposed to antipsychotics
• concurrent medical and/or psychiatric disorders
• prescriber, patient, and family preferences.

Psychiatrists generally select psychotropic classes by symptom domains (Table 3) and individual agents in each class by side effect profile. Except for clozapine’s superior effectiveness in patients with refractory psychosis, controlled studies have shown no clinically significant differences in efficacy among the drugs in each class—including the antipsychotics. Individual patients, however, may respond differently to different agents.

Principles of prescribing antipsychotics

Antipsychotics are effective in treating most psychotic core symptoms, such as hallucinations, delusions, agitation, aggression, and disorganized thinking and behavior. Other medications can be added to speed up or enhance treatment response or to target other domains.

Dosages. First-episode patients often require lower dosages and slower titration than multi-episode patients. As a rule, antipsychotics are started at about one-half the dosage given to patients with a chronic treatment history, although symptom severity and absence of side effects at lower dosages can help individualize titration.

Side effects. Atypical antipsychotics are preferred because of their reduced risk of extrapyramidal symptoms (EPS), positive effects on depressive and cognitive symptoms, and improved patient satisfaction and adherence, compared with the older antipsychotics.^15-17 Atypicals’ potential side effects include weight gain, hyperglycemia, and dyslipidemia,¹⁸ as well as often-overlooked sexual side effects.¹⁹

Table 2

DIFFERENTIAL DIAGNOSIS OF FIRST-EPISODE PSYCHOSIS

Consider the patient’s risk for side effects when choosing an atypical antipsychotic, as each drug has strengths and weaknesses. For example, it may be reasonable to consider:

• risperidone, ziprasidone, or aripiprazole—rather than olanzapine or quetiapine—for patients at high risk for weight gain or with a family history of diabetes
• avoiding risperidone for patients with an early indication of sensitivity to EPS or prolactin-related side effects
• an agent that can be loaded rapidly, such as olanzapine or aripiprazole—rather than an agent that requires titration, such as quetiapine—for a patient presenting with severe agitation.

Clozapine—because of its side effect potential—is generally reserved for patients who have not responded to at least two antipsychotic trials of at least 4 to 6 weeks duration and have a steady-state clozapine level >350 ng/dl.

Acute agitation. Short-acting IM formulations can be used effectively for acute agitation and impulsivity or for patients who refuse oral antipsychotics. Until recently, only first-generation antipsychotics such as haloperidol and fluphenazine were available in IM formulations. Injectable ziprasidone mesylate is now available for acute agitation and has been found to be as safe and effective as haloperidol. Lorazepam may be used to treat agitation or as an adjunct to a patient’s antipsychotic agent.

Adjunctive therapies

When antipsychotic monotherapy is inadequate, adjunctive medications may be considered:

• to treat catatonia, obsessive-compulsive disorder, or depression
• to resolve agitation or mania more quickly
• to control agitation or anxiety while an antipsychotic dosage is being titrated
• when side effects emerge or residual symptoms remain despite adequate dosage and duration of antipsychotic treatment.

Deciding if and when to add another drug depends on the nature and severity of target symptoms, the degree and time course of response, and whether side effects appear. If you use adjunctive therapies during acute stabilization, attempt to taper and discontinue them after the patient’s symptoms have improved. Avoid combining antipsychotics, as no clinical data support the effectiveness and safety of this practice.²⁰

Benzodiazepines are often used adjunctively for agitation, anxiety, or temporary insomnia in patients with schizophrenia. Common dosages are:

• for agitation or anxiety, lorazepam, 0.5 to 2 mg bid or tid, or clonazepam, 0.5 mg bid to 2 mg tid
• for insomnia, lorazepam or clonazepam, 1 to 2 mg at bedtime, or zolpidem, 5 to 10 mg at bedtime.

Benzodiazepines also are effective for catatonia, which may be misdiagnosed as negative symptoms or depression when it presents as marked psychomotor retardation, staring, selective mutism, negativism, mild posturing, or stereotypies. If undiagnosed, catatonia may worsen during antipsychotic titration. Symptoms usually respond to high-dose lorazepam, 1 mg bid or tid, with increases up to a maximum dosage of 12 mg/d.

Mood stabilizers are often used adjunctively to treat acute agitation and disinhibition²¹ or as add-on agents for residual psychotic or affective symptoms. Recommended dosages and blood levels, as tolerated, are:

• valproic acid, starting at 10 to 20 mg/kg bid, with a target serum level of 60 to 120 μg/ml. A once-daily, extended-release formulation may improve compliance.
• lithium, starting at 300 mg bid to tid, aiming for a serum level of 0.8 to 1.2 mEq/L.

Manic symptoms in a schizoaffective presentation may require one or even two mood stabilizers.

Lamotrigine may be the treatment of choice for depressed patients with schizoaffective disorder, bipolar type.²² However, it must be started at 25 mg/d and titrated extremely slowly—by 25 mg every other week, up to a target 200 to 400 mg/d—to avoid the risk of potentially fatal Stevens-Johnson syndrome.

Gabapentin, 300 mg tid to 1,500 mg tid, may help treat anxiety—particularly in patients with comorbid substance abuse, in whom benzodiazepines should be used sparingly after stabilization.

Table 3

SYMPTOM-BASED DRUG TREATMENT OF FIRST-EPISODE SCHIZOPHRENIA

Antidepressants. Patients with schizophrenia can develop depression, even if they do not meet diagnostic criteria for schizoaffective disorder. Untreated depression can lead to non-adherence, self-medication with alcohol or illicit substances, and increased risk of suicide.

Differentiating depression from negative symptoms may be difficult, but there are subtle distinctions:

• Patients with negative symptoms appear more emotionally flat and unconcerned about their lack of motivation and diminished social and role functioning.
• Depressed persons often verbalize their demoralization, hopelessness, and desire to feel and behave differently.

Treat depression with any selective serotonin reuptake inhibitor or other newer-generation antidepressant such as mirtazapine, nefazodone, or venlafaxine at usual doses, as tolerated.

Miscellaneous medications. Use anticholinergic medications such as benztropine, 0.5 to 2 mg bid, or trihexyphenidyl, 1 to 5 mg bid, if parkinsonian symptoms occur and changing to an antipsychotic with a lower EPS potential is not feasible.

For akathisia, propranolol (10 mg bid or tid; titrate up to 160 mg/d if pulse rate and blood pressure remain stable) or benzodiazepines may be useful. Amantadine may also be used at dosages between 50 and 150 mg bid.

Insomnia may be treated with low dosages of sedating antidepressants, such as trazodone, 50 to 200 mg HS, or mirtazapine, 7.5 to 15 mg HS.

Preventing relapse during maintenance

Medication adherence depends on patient insight and attitude towards medications.²³ Once you start a first-episode patient on drug therapy, encourage adherence by monitoring symptoms and anticipating side effects. Every 3 months after the acute phase:

• Use a structured evaluation, such as the Brief Psychiatric Rating Scale,²⁴ to plot symptom severity, response, and risk for relapse.
• Rate EPS with the Simpson-Angus Scale²⁵ and tardive dyskinesia (TD) with the Abnormal Involuntary Movement Scale²⁶ because EPS and TD are associated with poor symptom response, adherence, and outcome.⁷

Reinforce information about the chronic nature of schizophrenia, especially when the patient or family question why treatment is needed if symptoms have resolved. Continue to counsel them about the patient’s need for:

• regular sleep of sufficient duration and without sleep-wake reversal
• gradual return to premorbid social, educational, and vocational activities/responsibilities
• ongoing treatment.

Encourage vigilance for relapse warning signs, including insomnia, social withdrawal, anxiety, refusal to eat or take medications, suspiciousness, agitation, disorganization, preoccupation with overvalued ideas, or responses to internal stimuli.

If the patient is noncompliant with antipsychotics in tablets or capsules, options include:

• liquid risperidone or olanzapine in a rapidly dissolving form that the patient cannot hide and spit out later
• long-acting depot formulations if the patient cannot be supervised and monitored daily. Older antipsychotics (such as haloperidol decanoate and fluphenazine decanoate) are available in depot formulations, and the FDA is considering risperidone in a microsphere formulation that would allow biweekly injections.

Medication withdrawal

Although the ideal duration of maintenance treatment after a first psychotic episode is debatable, we recommend that antipsychotics be continued at the full dosage that achieved symptom remission for at least 1 year.²⁷ Then, if the patient has returned to the premorbid baseline, you can attempt a gradual medication withdrawal across 2 to 4 months, ideally when the patient’s environment is stable.

Be cautious when withdrawing antipsychotics from patients with a family history of psychosis. Consider a more gradual dose reduction, ongoing group and/or individual psychotherapy, and at least monthly monitoring. When possible, involve people who are significant in the patient’s life and educate them to look for deterioration’s warning signs, such as insomnia, irritability, anxiety, social withdrawal, preoccupation with overvalued ideas, or pacing.

If relapse occurs, carefully assess how well the patient has adhered to medication. Once a second psychotic episode occurs, his or her medication probably should be continued indefinitely.

Related resources

• National Alliance for the Mentally Ill (800) 950-NAMI (6264); www.nami.org
• National Mental Health Association (800) 969-NMHA (6642); www.nmha.org
• National Alliance for Research on Schizophrenia and Depression (516) 829-0091; www.narsad.org/index.html
• Miller R, Mason SE. Diagnosis schizophrenia. A comprehensive resource. New York: Columbia University Press, 2002.

Drug brand names

• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Clozapine • Clozaril
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Gabapentin • Neurontin
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor
• Ziprasidone • Geodon
• Zolpidem • Ambien

Disclosure

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

Dr. Mendelowitz receives grant/research support from, is a consultant to, and/or is a speaker for Pfizer Inc., Bristol-Myers Squibb Co.; and AstraZeneca Pharmaceuticals.

Acknowledgments

Research for this article was supported by grant 5P30MH60575 to The Zucker Hillside Hospital Intervention Research Center for Schizophrenia from the National Institute of Mental Health, Bethesda, MD.

When a patient revisits past trauma during psychotherapy, strong reactions may surface. There is no single best way to confront emotions such as anger or despair, nor does the patient warn you before an outburst happens. The emotional reaction could be part of the healing process or could signal the need for additional treatment. You must decide on the spot whether to move up the next session, check on the patient the next day, or hospitalize the patient for his or her protection.

Keys to assessment

Before gauging a distraught patient’s needs, consider:

• How well do you know the patient? An established patient can be appraised fairly quickly. Assessing a new patient with confidence may take more time, however.
• Can the patient set emotional boundaries? Can he or she make sound choices and consider their consequences?
• Does the patient have adequate support? Is the patient going home to an empty room, a loving family or significant other, or a situation between the two?
• What therapy model are you employing? For example, cognitive therapy might address the meaning a patient places on a situation or reaction.

Dealing with emotional reaction

When a patient becomes overwrought:

• Encourage the patient to talk about the issue. This allows the patient to problem-solve and gives you time to think and plan.
• Extend the therapy session, especially if you fear a prompt discharge would endanger the patient. Consider the patient’s cognitive and emotional state. If you are uneasy with his or her degree of self-control, don’t discharge that patient.
• Formulate a plan to address the trauma. You might say: “It seems clear that this is troubling you. How can we work together to ease the burden? Can you comfortably think it through so that we can work it out next week? Would writing down your feelings and thoughts help?”
• Move up the patient’s next appointment. If the patient typically reacts badly to a certain issue or cannot handle feeling distraught, bringing him or her back sooner can be reassuring.
• Call the patient that evening or the next day. A distraught patient who does not need immediate hospitalization may benefit from extra contact. Decide whether to call the patient at a set time or to arrange for the patient to contact you. These usually brief calls reassure you that the patient has gained some perspective toward the problem and convey to the patient that you care.

Arrange to admit the patient to the hospital until the acute situation is resolved or perspective restored. Consider a brief hospitalization:

• when a situation or issue seriously challenges the patient’s coping mechanisms
• for patients with a history of self-harm when stressed
• for a patient who is psychotic and whose response to the emotional state is unpredictable
• when drugs or alcohol cloud the patient’s sensorium
• for a patient who lives alone.

When a patient revisits past trauma during psychotherapy, strong reactions may surface. There is no single best way to confront emotions such as anger or despair, nor does the patient warn you before an outburst happens. The emotional reaction could be part of the healing process or could signal the need for additional treatment. You must decide on the spot whether to move up the next session, check on the patient the next day, or hospitalize the patient for his or her protection.

Keys to assessment

Before gauging a distraught patient’s needs, consider:

• How well do you know the patient? An established patient can be appraised fairly quickly. Assessing a new patient with confidence may take more time, however.
• Can the patient set emotional boundaries? Can he or she make sound choices and consider their consequences?
• Does the patient have adequate support? Is the patient going home to an empty room, a loving family or significant other, or a situation between the two?
• What therapy model are you employing? For example, cognitive therapy might address the meaning a patient places on a situation or reaction.

Dealing with emotional reaction

When a patient becomes overwrought:

• Encourage the patient to talk about the issue. This allows the patient to problem-solve and gives you time to think and plan.
• Extend the therapy session, especially if you fear a prompt discharge would endanger the patient. Consider the patient’s cognitive and emotional state. If you are uneasy with his or her degree of self-control, don’t discharge that patient.
• Formulate a plan to address the trauma. You might say: “It seems clear that this is troubling you. How can we work together to ease the burden? Can you comfortably think it through so that we can work it out next week? Would writing down your feelings and thoughts help?”
• Move up the patient’s next appointment. If the patient typically reacts badly to a certain issue or cannot handle feeling distraught, bringing him or her back sooner can be reassuring.
• Call the patient that evening or the next day. A distraught patient who does not need immediate hospitalization may benefit from extra contact. Decide whether to call the patient at a set time or to arrange for the patient to contact you. These usually brief calls reassure you that the patient has gained some perspective toward the problem and convey to the patient that you care.

Arrange to admit the patient to the hospital until the acute situation is resolved or perspective restored. Consider a brief hospitalization:

• when a situation or issue seriously challenges the patient’s coping mechanisms
• for patients with a history of self-harm when stressed
• for a patient who is psychotic and whose response to the emotional state is unpredictable
• when drugs or alcohol cloud the patient’s sensorium
• for a patient who lives alone.

When a patient revisits past trauma during psychotherapy, strong reactions may surface. There is no single best way to confront emotions such as anger or despair, nor does the patient warn you before an outburst happens. The emotional reaction could be part of the healing process or could signal the need for additional treatment. You must decide on the spot whether to move up the next session, check on the patient the next day, or hospitalize the patient for his or her protection.

Keys to assessment

Before gauging a distraught patient’s needs, consider:

• How well do you know the patient? An established patient can be appraised fairly quickly. Assessing a new patient with confidence may take more time, however.
• Can the patient set emotional boundaries? Can he or she make sound choices and consider their consequences?
• Does the patient have adequate support? Is the patient going home to an empty room, a loving family or significant other, or a situation between the two?
• What therapy model are you employing? For example, cognitive therapy might address the meaning a patient places on a situation or reaction.

Dealing with emotional reaction

When a patient becomes overwrought:

• Encourage the patient to talk about the issue. This allows the patient to problem-solve and gives you time to think and plan.
• Extend the therapy session, especially if you fear a prompt discharge would endanger the patient. Consider the patient’s cognitive and emotional state. If you are uneasy with his or her degree of self-control, don’t discharge that patient.
• Formulate a plan to address the trauma. You might say: “It seems clear that this is troubling you. How can we work together to ease the burden? Can you comfortably think it through so that we can work it out next week? Would writing down your feelings and thoughts help?”
• Move up the patient’s next appointment. If the patient typically reacts badly to a certain issue or cannot handle feeling distraught, bringing him or her back sooner can be reassuring.
• Call the patient that evening or the next day. A distraught patient who does not need immediate hospitalization may benefit from extra contact. Decide whether to call the patient at a set time or to arrange for the patient to contact you. These usually brief calls reassure you that the patient has gained some perspective toward the problem and convey to the patient that you care.

Arrange to admit the patient to the hospital until the acute situation is resolved or perspective restored. Consider a brief hospitalization:

• when a situation or issue seriously challenges the patient’s coping mechanisms
• for patients with a history of self-harm when stressed
• for a patient who is psychotic and whose response to the emotional state is unpredictable
• when drugs or alcohol cloud the patient’s sensorium
• for a patient who lives alone.

A typical antipsychotics have enhanced outcomes in schizophrenia while helping patients avert the troublesome motor effects associated with older agents. Some side effects, such as weight gain and prolactin elevation, have remained a concern, however.

Aripiprazole, a novel antipsychotic recently FDA-approved for treating schizophrenia, exhibited efficacy and tolerability in preclinical and clinical trials.

How aripiprazole works

Aripiprazole’s mechanism of action is important to our understanding of the dopamine hypothesis of antipsychotic effect.¹

The dopamine hypothesis remains the predominant explanation of how antipsychotics work.² However, the evolution of antipsychotic therapy has led to further refinement of the dopamine hypothesis, including selective dopamine (D4) antagonism, rapid dissociation from dopamine receptors, dopamine-serotonin receptor system interactions, dopamine-GABA system interactions, and now (with aripiprazole) partial agonist effects at dopamine (and selective serotonin) receptors.^1,2

Table

ARIPIPRAZOLE: FASTFACTS

Table 1

ARIPIPRAZOLE’S RECEPTOR-BINDING PROFILE

Table 2

POTENTIAL DRUG-DRUG INTERACTIONS WITH ARIPIPRAZOLE

Unlike other antipsychotics, which appear to act through dopamine receptor antagonism, aripiprazole is a potent partial agonist at both the dopamine (D2) and serotonin (5HT1A) receptors.^1,2Table 1 describes the agent’s receptor-binding profile.

The agent offers 78% bioavailability. It is metabolized through the hepatic microenzyme system, specifically the cytochrome P450 enzymes 2D6 and 3A4. Use of nicotine does not alter the agent’s plasma levels. Its active moiety is aripiprazole with minor contributions from the derivative dehydro-aripiprazole.

Aripiprazole therapy can be started at 10 or 15 mg/d; the starting dosage—15 mg/d in most cases—may also suffice as maintenance therapy for many patients. If the patient does not respond, it is prudent to wait several weeks before increasing the dosage beyond 15 mg/d.

The FDA-approved maximum dosage for aripiprazole is 30 mg/d. However, information from clinical trials indicates that increasing the dosage from 15 to 30 mg/d does not enhance the antipsychotic’s efficacy.^3,4 Because of its absorption properties, the agent can be taken with or without food.

Aripiprazole has a relatively long half-life (75 hours), so it can be administered once daily. This provides an advantage when switching treatments. Some information suggests that patients may be switched directly to aripiprazole,⁵ although cross-titration is recommended.³

Although data in clinical populations are insufficient, studies in normal volunteers suggest that aripiprazole can be given at regular dosages to older patients and to those with renal or hepatic impairment.³Table 2 highlights potential drug-drug interactions with agents that can influence the hepatic microenzyme system.

Efficacy

Aripiprazole has demonstrated efficacy in clinical studies of patients with schizophrenia and schizoaffective disorder.^3-8

• In a placebo-controlled, 4-week trial, patients who received aripiprazole, 15 to 30 mg/d, or haloperidol, 10 mg/d, reported similar improvements in positive and negative symptoms, psychopathology, and overall function.⁶
• A placebo-controlled, 4-week trial of aripiprazole, 20 and 30 mg/d, compared with risperidone, 6 mg/d, revealed similar efficacy with respect to symptom improvement and overall functioning.⁷
• Aripiprazole and olanzapine demonstrated comparable efficacy in a 28-week study. However, patients in the aripiprazole group showed greater improvement at 8 weeks and sustained improvement through 28 weeks in a measure of verbal memory.⁸

Researchers have not yet compared aripiprazole with clozapine, quetiapine, or ziprasidone. Also, information on the dosing, efficacy, and tolerability of aripiprazole in patients with first-episode or treatment-refractory schizophrenia is limited. According to the manufacturers’ prescription information, aripiprazole’s long-term efficacy in schizophrenia treatment has not been established. Data on 1-year treatment with aripiprazole appear encouraging.³

Preliminary data suggest that aripiprazole may help treat nonpsychotic conditions, although which ones has yet to be determined. A 3-week, placebo-controlled study demonstrated that aripiprazole, 30 mg/d, helped ameliorate symptoms of mania.⁹

Tolerability

Aripiprazole’s side-effect profile, revealed in preclinical and clinical trials, suggests that the drug could be well tolerated among a broad range of patients.¹⁰

In the 4-week, placebo-controlled comparison with haloperidol, rates of extrapyramidal symptoms (EPS) among aripiprazole-treated patients were much lower than those in the haloperidol group and similar to those in the placebo group.⁶ There is no evidence that higher dosages of aripiprazole lead to increased EPS. It is also not known whether aripiprazole will cause EPS in children and in patients older than 65, who are more susceptible than other age groups to antipsychotic-induced motor side effects.

Aripiprazole is believed to be less likely than typical antipsychotics to induce tardive dyskinesia, but more long-term information is needed.³

Studies have associated aripiprazole use with some weight gain, but (marginally) less than risperidone,⁷ less than haloperidol,⁶ and substantially less than olanzapine.⁸ Direct comparisons with other atypicals are not yet available.

Aripiprazole’s effect on glucose metabolism has not been determined, but early information suggests a favorable profile with respect to metabolic indices. Aripiprazole does not appear to elevate prolactin or cause cardiac QTc prolongation. Sedation appears to be the most pronounced side effect; this effect also appears to increase with higher dosages.

As has happened with the other atypicals, the pattern of use for aripiprazole will unfold over time as clinicians gain experience with using this agent in distinct patient groups.

Related resources

• Jordan S, Koprivica V, Chen R, et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5HT(1A) receptor. Eur J Pharmacol 2002;50:873-83.
• Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-71.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Buckley receives grant support from, is a consultant to, and is a speaker for AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Dr. Sinha is a consultant to Bristol-Myers Squibb Co.

Dr. Sebastian is a consultant to Eli Lilly and Co.

Ms. Stirewalt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

A typical antipsychotics have enhanced outcomes in schizophrenia while helping patients avert the troublesome motor effects associated with older agents. Some side effects, such as weight gain and prolactin elevation, have remained a concern, however.

Aripiprazole, a novel antipsychotic recently FDA-approved for treating schizophrenia, exhibited efficacy and tolerability in preclinical and clinical trials.

How aripiprazole works

Aripiprazole’s mechanism of action is important to our understanding of the dopamine hypothesis of antipsychotic effect.¹

The dopamine hypothesis remains the predominant explanation of how antipsychotics work.² However, the evolution of antipsychotic therapy has led to further refinement of the dopamine hypothesis, including selective dopamine (D4) antagonism, rapid dissociation from dopamine receptors, dopamine-serotonin receptor system interactions, dopamine-GABA system interactions, and now (with aripiprazole) partial agonist effects at dopamine (and selective serotonin) receptors.^1,2

Table

ARIPIPRAZOLE: FASTFACTS

Table 1

ARIPIPRAZOLE’S RECEPTOR-BINDING PROFILE

Table 2

POTENTIAL DRUG-DRUG INTERACTIONS WITH ARIPIPRAZOLE

Unlike other antipsychotics, which appear to act through dopamine receptor antagonism, aripiprazole is a potent partial agonist at both the dopamine (D2) and serotonin (5HT1A) receptors.^1,2Table 1 describes the agent’s receptor-binding profile.

The agent offers 78% bioavailability. It is metabolized through the hepatic microenzyme system, specifically the cytochrome P450 enzymes 2D6 and 3A4. Use of nicotine does not alter the agent’s plasma levels. Its active moiety is aripiprazole with minor contributions from the derivative dehydro-aripiprazole.

Aripiprazole therapy can be started at 10 or 15 mg/d; the starting dosage—15 mg/d in most cases—may also suffice as maintenance therapy for many patients. If the patient does not respond, it is prudent to wait several weeks before increasing the dosage beyond 15 mg/d.

The FDA-approved maximum dosage for aripiprazole is 30 mg/d. However, information from clinical trials indicates that increasing the dosage from 15 to 30 mg/d does not enhance the antipsychotic’s efficacy.^3,4 Because of its absorption properties, the agent can be taken with or without food.

Aripiprazole has a relatively long half-life (75 hours), so it can be administered once daily. This provides an advantage when switching treatments. Some information suggests that patients may be switched directly to aripiprazole,⁵ although cross-titration is recommended.³

Although data in clinical populations are insufficient, studies in normal volunteers suggest that aripiprazole can be given at regular dosages to older patients and to those with renal or hepatic impairment.³Table 2 highlights potential drug-drug interactions with agents that can influence the hepatic microenzyme system.

Efficacy

Aripiprazole has demonstrated efficacy in clinical studies of patients with schizophrenia and schizoaffective disorder.^3-8

• In a placebo-controlled, 4-week trial, patients who received aripiprazole, 15 to 30 mg/d, or haloperidol, 10 mg/d, reported similar improvements in positive and negative symptoms, psychopathology, and overall function.⁶
• A placebo-controlled, 4-week trial of aripiprazole, 20 and 30 mg/d, compared with risperidone, 6 mg/d, revealed similar efficacy with respect to symptom improvement and overall functioning.⁷
• Aripiprazole and olanzapine demonstrated comparable efficacy in a 28-week study. However, patients in the aripiprazole group showed greater improvement at 8 weeks and sustained improvement through 28 weeks in a measure of verbal memory.⁸

Researchers have not yet compared aripiprazole with clozapine, quetiapine, or ziprasidone. Also, information on the dosing, efficacy, and tolerability of aripiprazole in patients with first-episode or treatment-refractory schizophrenia is limited. According to the manufacturers’ prescription information, aripiprazole’s long-term efficacy in schizophrenia treatment has not been established. Data on 1-year treatment with aripiprazole appear encouraging.³

Preliminary data suggest that aripiprazole may help treat nonpsychotic conditions, although which ones has yet to be determined. A 3-week, placebo-controlled study demonstrated that aripiprazole, 30 mg/d, helped ameliorate symptoms of mania.⁹

Tolerability

Aripiprazole’s side-effect profile, revealed in preclinical and clinical trials, suggests that the drug could be well tolerated among a broad range of patients.¹⁰

In the 4-week, placebo-controlled comparison with haloperidol, rates of extrapyramidal symptoms (EPS) among aripiprazole-treated patients were much lower than those in the haloperidol group and similar to those in the placebo group.⁶ There is no evidence that higher dosages of aripiprazole lead to increased EPS. It is also not known whether aripiprazole will cause EPS in children and in patients older than 65, who are more susceptible than other age groups to antipsychotic-induced motor side effects.

Aripiprazole is believed to be less likely than typical antipsychotics to induce tardive dyskinesia, but more long-term information is needed.³

Studies have associated aripiprazole use with some weight gain, but (marginally) less than risperidone,⁷ less than haloperidol,⁶ and substantially less than olanzapine.⁸ Direct comparisons with other atypicals are not yet available.

Aripiprazole’s effect on glucose metabolism has not been determined, but early information suggests a favorable profile with respect to metabolic indices. Aripiprazole does not appear to elevate prolactin or cause cardiac QTc prolongation. Sedation appears to be the most pronounced side effect; this effect also appears to increase with higher dosages.

As has happened with the other atypicals, the pattern of use for aripiprazole will unfold over time as clinicians gain experience with using this agent in distinct patient groups.

Related resources

• Jordan S, Koprivica V, Chen R, et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5HT(1A) receptor. Eur J Pharmacol 2002;50:873-83.
• Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-71.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Buckley receives grant support from, is a consultant to, and is a speaker for AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Dr. Sinha is a consultant to Bristol-Myers Squibb Co.

Dr. Sebastian is a consultant to Eli Lilly and Co.

Ms. Stirewalt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

A typical antipsychotics have enhanced outcomes in schizophrenia while helping patients avert the troublesome motor effects associated with older agents. Some side effects, such as weight gain and prolactin elevation, have remained a concern, however.

Aripiprazole, a novel antipsychotic recently FDA-approved for treating schizophrenia, exhibited efficacy and tolerability in preclinical and clinical trials.

How aripiprazole works

Aripiprazole’s mechanism of action is important to our understanding of the dopamine hypothesis of antipsychotic effect.¹

The dopamine hypothesis remains the predominant explanation of how antipsychotics work.² However, the evolution of antipsychotic therapy has led to further refinement of the dopamine hypothesis, including selective dopamine (D4) antagonism, rapid dissociation from dopamine receptors, dopamine-serotonin receptor system interactions, dopamine-GABA system interactions, and now (with aripiprazole) partial agonist effects at dopamine (and selective serotonin) receptors.^1,2

Table

ARIPIPRAZOLE: FASTFACTS

Table 1

ARIPIPRAZOLE’S RECEPTOR-BINDING PROFILE

Table 2

POTENTIAL DRUG-DRUG INTERACTIONS WITH ARIPIPRAZOLE

Unlike other antipsychotics, which appear to act through dopamine receptor antagonism, aripiprazole is a potent partial agonist at both the dopamine (D2) and serotonin (5HT1A) receptors.^1,2Table 1 describes the agent’s receptor-binding profile.

The agent offers 78% bioavailability. It is metabolized through the hepatic microenzyme system, specifically the cytochrome P450 enzymes 2D6 and 3A4. Use of nicotine does not alter the agent’s plasma levels. Its active moiety is aripiprazole with minor contributions from the derivative dehydro-aripiprazole.

Aripiprazole therapy can be started at 10 or 15 mg/d; the starting dosage—15 mg/d in most cases—may also suffice as maintenance therapy for many patients. If the patient does not respond, it is prudent to wait several weeks before increasing the dosage beyond 15 mg/d.

The FDA-approved maximum dosage for aripiprazole is 30 mg/d. However, information from clinical trials indicates that increasing the dosage from 15 to 30 mg/d does not enhance the antipsychotic’s efficacy.^3,4 Because of its absorption properties, the agent can be taken with or without food.

Aripiprazole has a relatively long half-life (75 hours), so it can be administered once daily. This provides an advantage when switching treatments. Some information suggests that patients may be switched directly to aripiprazole,⁵ although cross-titration is recommended.³

Although data in clinical populations are insufficient, studies in normal volunteers suggest that aripiprazole can be given at regular dosages to older patients and to those with renal or hepatic impairment.³Table 2 highlights potential drug-drug interactions with agents that can influence the hepatic microenzyme system.

Efficacy

Aripiprazole has demonstrated efficacy in clinical studies of patients with schizophrenia and schizoaffective disorder.^3-8

• In a placebo-controlled, 4-week trial, patients who received aripiprazole, 15 to 30 mg/d, or haloperidol, 10 mg/d, reported similar improvements in positive and negative symptoms, psychopathology, and overall function.⁶
• A placebo-controlled, 4-week trial of aripiprazole, 20 and 30 mg/d, compared with risperidone, 6 mg/d, revealed similar efficacy with respect to symptom improvement and overall functioning.⁷
• Aripiprazole and olanzapine demonstrated comparable efficacy in a 28-week study. However, patients in the aripiprazole group showed greater improvement at 8 weeks and sustained improvement through 28 weeks in a measure of verbal memory.⁸

Researchers have not yet compared aripiprazole with clozapine, quetiapine, or ziprasidone. Also, information on the dosing, efficacy, and tolerability of aripiprazole in patients with first-episode or treatment-refractory schizophrenia is limited. According to the manufacturers’ prescription information, aripiprazole’s long-term efficacy in schizophrenia treatment has not been established. Data on 1-year treatment with aripiprazole appear encouraging.³

Preliminary data suggest that aripiprazole may help treat nonpsychotic conditions, although which ones has yet to be determined. A 3-week, placebo-controlled study demonstrated that aripiprazole, 30 mg/d, helped ameliorate symptoms of mania.⁹

Tolerability

Aripiprazole’s side-effect profile, revealed in preclinical and clinical trials, suggests that the drug could be well tolerated among a broad range of patients.¹⁰

In the 4-week, placebo-controlled comparison with haloperidol, rates of extrapyramidal symptoms (EPS) among aripiprazole-treated patients were much lower than those in the haloperidol group and similar to those in the placebo group.⁶ There is no evidence that higher dosages of aripiprazole lead to increased EPS. It is also not known whether aripiprazole will cause EPS in children and in patients older than 65, who are more susceptible than other age groups to antipsychotic-induced motor side effects.

Aripiprazole is believed to be less likely than typical antipsychotics to induce tardive dyskinesia, but more long-term information is needed.³

Studies have associated aripiprazole use with some weight gain, but (marginally) less than risperidone,⁷ less than haloperidol,⁶ and substantially less than olanzapine.⁸ Direct comparisons with other atypicals are not yet available.

Aripiprazole’s effect on glucose metabolism has not been determined, but early information suggests a favorable profile with respect to metabolic indices. Aripiprazole does not appear to elevate prolactin or cause cardiac QTc prolongation. Sedation appears to be the most pronounced side effect; this effect also appears to increase with higher dosages.

As has happened with the other atypicals, the pattern of use for aripiprazole will unfold over time as clinicians gain experience with using this agent in distinct patient groups.

Related resources

• Jordan S, Koprivica V, Chen R, et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5HT(1A) receptor. Eur J Pharmacol 2002;50:873-83.
• Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763-71.

Drug brand names

• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Buckley receives grant support from, is a consultant to, and is a speaker for AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Eli Lilly and Co., Janssen Pharmaceutica, and Novartis Pharmaceuticals Corp.

Dr. Sinha is a consultant to Bristol-Myers Squibb Co.

Dr. Sebastian is a consultant to Eli Lilly and Co.

Ms. Stirewalt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Hillard states that “light therapy should not be used without pharmacotherapy to treat a major depressive episode” in seasonal affective disorder, or SAD (Current Psychiatry, December 2002).

It is well supported that both full syndromal and sub-syndromal winter depression can be successfully treated with light therapy alone.^1,2 Response rates have varied between 60 and 90%. Many—if not most—SAD specialists consider light therapy the treatment of choice.¹ Antidepressant medication can be added later if light therapy does not achieve an optimal result.

Figure 1 Antimanic efficacy of olanzapine, 15 mg/d, in acute bipolar mania and mixed episodes

Patients with acute bipolar mania or a mixed episode were treated with olanzapine or placebo for 4 weeks in a randomized, double-blind trial. Compared with placebo, olanzapine at a starting dosage of 15 mg/d was associated with significant symptom improvement in the first week (50% change from baseline in Young Mania Rating Scale total score). This trend continued throughout the trial.

Source: Reprinted with permission from Tohen M et al. Arch Gen Psychiatry 2002; 57(9):841-9. Copyright 2002. American Medical Association

Psychotropics are first-line therapy only for severely depressed inpatients with SAD.² This occurs infrequently, however, and even in these rare cases the efficacy of drug vs. light therapy or combined treatment has not been definitively studied.

J. Daniel Kanofsky MD, MPH; Assistant professor of psychiatry
Albert Einstein College of Medicine of Yeshiva University; Bronx, NY
Brenda Byrne, PhD; Margolis Berman Byrne Health Psychology Philadelphia, PA

References

1. Wirz-Justice A. Beginning to see the light. Arch Gen Psychiatry 1998;55(10):861–2.
2. Lam RW. Seasonal affective disorder: diagnosis and management. Primary Care Psychiatry 1998;4:63-74.

Your article on SAD indicates that “Light therapy can be used alone or in addition to pharmacotherapy in patients whose previously well-controlled depressive symptoms worsen in the fall or winter.”

However, Philips Electronics states on its Web site: “Do not take antidepressants in combination with light therapy—this may damage your eyes.”¹

I would like an authoritative, reliable resolution. Can light therapy be used concurrently with antidepressants without resulting in eye damage?

Martin Schwartz; New York, NY

Reference

1. Philips Bright Light Energy: Alternatives to light baths. Available at: www.brightlight.philips.co.uk/b/4.html. Accessed Feb. 25, 2003.

Dr. Hillard responds

I thank Drs. Kanofsky and Byrne and Mr. Schwartz for their insights.

After an extensive search of the literature and the Philips Electronics Web site, we can find no justification for not using drug therapy in SAD.

J. Randolph Hillard, MD
Editor-in-chief

Dr. Hillard states that “light therapy should not be used without pharmacotherapy to treat a major depressive episode” in seasonal affective disorder, or SAD (Current Psychiatry, December 2002).

It is well supported that both full syndromal and sub-syndromal winter depression can be successfully treated with light therapy alone.^1,2 Response rates have varied between 60 and 90%. Many—if not most—SAD specialists consider light therapy the treatment of choice.¹ Antidepressant medication can be added later if light therapy does not achieve an optimal result.

Figure 1 Antimanic efficacy of olanzapine, 15 mg/d, in acute bipolar mania and mixed episodes

Patients with acute bipolar mania or a mixed episode were treated with olanzapine or placebo for 4 weeks in a randomized, double-blind trial. Compared with placebo, olanzapine at a starting dosage of 15 mg/d was associated with significant symptom improvement in the first week (50% change from baseline in Young Mania Rating Scale total score). This trend continued throughout the trial.

Source: Reprinted with permission from Tohen M et al. Arch Gen Psychiatry 2002; 57(9):841-9. Copyright 2002. American Medical Association

Psychotropics are first-line therapy only for severely depressed inpatients with SAD.² This occurs infrequently, however, and even in these rare cases the efficacy of drug vs. light therapy or combined treatment has not been definitively studied.

J. Daniel Kanofsky MD, MPH; Assistant professor of psychiatry
Albert Einstein College of Medicine of Yeshiva University; Bronx, NY
Brenda Byrne, PhD; Margolis Berman Byrne Health Psychology Philadelphia, PA

References

1. Wirz-Justice A. Beginning to see the light. Arch Gen Psychiatry 1998;55(10):861–2.
2. Lam RW. Seasonal affective disorder: diagnosis and management. Primary Care Psychiatry 1998;4:63-74.

Your article on SAD indicates that “Light therapy can be used alone or in addition to pharmacotherapy in patients whose previously well-controlled depressive symptoms worsen in the fall or winter.”

However, Philips Electronics states on its Web site: “Do not take antidepressants in combination with light therapy—this may damage your eyes.”¹

I would like an authoritative, reliable resolution. Can light therapy be used concurrently with antidepressants without resulting in eye damage?

Martin Schwartz; New York, NY

Reference

1. Philips Bright Light Energy: Alternatives to light baths. Available at: www.brightlight.philips.co.uk/b/4.html. Accessed Feb. 25, 2003.

Dr. Hillard responds

I thank Drs. Kanofsky and Byrne and Mr. Schwartz for their insights.

After an extensive search of the literature and the Philips Electronics Web site, we can find no justification for not using drug therapy in SAD.

J. Randolph Hillard, MD
Editor-in-chief

Dr. Hillard states that “light therapy should not be used without pharmacotherapy to treat a major depressive episode” in seasonal affective disorder, or SAD (Current Psychiatry, December 2002).

It is well supported that both full syndromal and sub-syndromal winter depression can be successfully treated with light therapy alone.^1,2 Response rates have varied between 60 and 90%. Many—if not most—SAD specialists consider light therapy the treatment of choice.¹ Antidepressant medication can be added later if light therapy does not achieve an optimal result.

Figure 1 Antimanic efficacy of olanzapine, 15 mg/d, in acute bipolar mania and mixed episodes

Patients with acute bipolar mania or a mixed episode were treated with olanzapine or placebo for 4 weeks in a randomized, double-blind trial. Compared with placebo, olanzapine at a starting dosage of 15 mg/d was associated with significant symptom improvement in the first week (50% change from baseline in Young Mania Rating Scale total score). This trend continued throughout the trial.

Source: Reprinted with permission from Tohen M et al. Arch Gen Psychiatry 2002; 57(9):841-9. Copyright 2002. American Medical Association

Psychotropics are first-line therapy only for severely depressed inpatients with SAD.² This occurs infrequently, however, and even in these rare cases the efficacy of drug vs. light therapy or combined treatment has not been definitively studied.

J. Daniel Kanofsky MD, MPH; Assistant professor of psychiatry
Albert Einstein College of Medicine of Yeshiva University; Bronx, NY
Brenda Byrne, PhD; Margolis Berman Byrne Health Psychology Philadelphia, PA

References

1. Wirz-Justice A. Beginning to see the light. Arch Gen Psychiatry 1998;55(10):861–2.
2. Lam RW. Seasonal affective disorder: diagnosis and management. Primary Care Psychiatry 1998;4:63-74.

Your article on SAD indicates that “Light therapy can be used alone or in addition to pharmacotherapy in patients whose previously well-controlled depressive symptoms worsen in the fall or winter.”

However, Philips Electronics states on its Web site: “Do not take antidepressants in combination with light therapy—this may damage your eyes.”¹

I would like an authoritative, reliable resolution. Can light therapy be used concurrently with antidepressants without resulting in eye damage?

Martin Schwartz; New York, NY

Reference

1. Philips Bright Light Energy: Alternatives to light baths. Available at: www.brightlight.philips.co.uk/b/4.html. Accessed Feb. 25, 2003.

Dr. Hillard responds

I thank Drs. Kanofsky and Byrne and Mr. Schwartz for their insights.

After an extensive search of the literature and the Philips Electronics Web site, we can find no justification for not using drug therapy in SAD.

J. Randolph Hillard, MD
Editor-in-chief

“If I’m ever angry at a psychiatrist, I will refer that doctor a patient with a first episode of psychosis.”

A psychiatrist whose brother suffers from a psychotic disorder once said this to me. She was joking, but—in a way—she was totally serious. The serious part relates to her experience as the loving family member of someone who suddenly and inexplicably became devastatingly ill. She and her family wanted to know the diagnosis, yet were afraid to find out. They alternately wanted to—and didn’t want to—discover a physical cause behind the illness. They blamed themselves, then resolved not to blame themselves.

They were educated and reasonably well informed; they thought they understood what serious mental illness was about. But when it came to confronting it in a loved one, they ultimately realized they knew nothing. In retrospect, they viewed their psychiatrist as pretty good, but at the time they had nothing good to say about him. Patients and their families often feel unhappy with the psychiatrist who treats a first episode of psychosis.

All physicians have the burden of helping patients and families come to terms with terrible, unexpected, and incomprehensible illnesses. That task is doubly difficult for psychiatrists, because of:

• the stigma attached to the illnesses we treat
• the subtlety of some early symptoms
• and peoples’ belief that a psychiatric illness cannot happen to them or to their loved ones.

First-episode psychoses may pose our greatest challenge as clinicians. In “First psychotic episode—a window of opportunity”, Christoph Correll, MD, and Alan Mendelowitz, MD, adeptly describe the many challenges we face in this clinical scenario: differential diagnosis, communicating the diagnosis, encouraging the family and patient to engage constructively in treatment, and getting the patient, attendants, and externals on the same page.

Nowhere in medicine is Hippocrates’ first aphorism more relevant: “Life is short, the art is long; the occasion is fleeting; experience fallacious, and judgment difficult.” I would probably say “help the patient … cooperate,” rather than “make the patient … cooperate,” but other than that, despite everything we have learned in medicine in the last few millennia, I would not change a thing.

“If I’m ever angry at a psychiatrist, I will refer that doctor a patient with a first episode of psychosis.”

A psychiatrist whose brother suffers from a psychotic disorder once said this to me. She was joking, but—in a way—she was totally serious. The serious part relates to her experience as the loving family member of someone who suddenly and inexplicably became devastatingly ill. She and her family wanted to know the diagnosis, yet were afraid to find out. They alternately wanted to—and didn’t want to—discover a physical cause behind the illness. They blamed themselves, then resolved not to blame themselves.

They were educated and reasonably well informed; they thought they understood what serious mental illness was about. But when it came to confronting it in a loved one, they ultimately realized they knew nothing. In retrospect, they viewed their psychiatrist as pretty good, but at the time they had nothing good to say about him. Patients and their families often feel unhappy with the psychiatrist who treats a first episode of psychosis.

All physicians have the burden of helping patients and families come to terms with terrible, unexpected, and incomprehensible illnesses. That task is doubly difficult for psychiatrists, because of:

• the stigma attached to the illnesses we treat
• the subtlety of some early symptoms
• and peoples’ belief that a psychiatric illness cannot happen to them or to their loved ones.

First-episode psychoses may pose our greatest challenge as clinicians. In “First psychotic episode—a window of opportunity”, Christoph Correll, MD, and Alan Mendelowitz, MD, adeptly describe the many challenges we face in this clinical scenario: differential diagnosis, communicating the diagnosis, encouraging the family and patient to engage constructively in treatment, and getting the patient, attendants, and externals on the same page.

Nowhere in medicine is Hippocrates’ first aphorism more relevant: “Life is short, the art is long; the occasion is fleeting; experience fallacious, and judgment difficult.” I would probably say “help the patient … cooperate,” rather than “make the patient … cooperate,” but other than that, despite everything we have learned in medicine in the last few millennia, I would not change a thing.

“If I’m ever angry at a psychiatrist, I will refer that doctor a patient with a first episode of psychosis.”

A psychiatrist whose brother suffers from a psychotic disorder once said this to me. She was joking, but—in a way—she was totally serious. The serious part relates to her experience as the loving family member of someone who suddenly and inexplicably became devastatingly ill. She and her family wanted to know the diagnosis, yet were afraid to find out. They alternately wanted to—and didn’t want to—discover a physical cause behind the illness. They blamed themselves, then resolved not to blame themselves.

They were educated and reasonably well informed; they thought they understood what serious mental illness was about. But when it came to confronting it in a loved one, they ultimately realized they knew nothing. In retrospect, they viewed their psychiatrist as pretty good, but at the time they had nothing good to say about him. Patients and their families often feel unhappy with the psychiatrist who treats a first episode of psychosis.

All physicians have the burden of helping patients and families come to terms with terrible, unexpected, and incomprehensible illnesses. That task is doubly difficult for psychiatrists, because of:

• the stigma attached to the illnesses we treat
• the subtlety of some early symptoms
• and peoples’ belief that a psychiatric illness cannot happen to them or to their loved ones.

First-episode psychoses may pose our greatest challenge as clinicians. In “First psychotic episode—a window of opportunity”, Christoph Correll, MD, and Alan Mendelowitz, MD, adeptly describe the many challenges we face in this clinical scenario: differential diagnosis, communicating the diagnosis, encouraging the family and patient to engage constructively in treatment, and getting the patient, attendants, and externals on the same page.

Nowhere in medicine is Hippocrates’ first aphorism more relevant: “Life is short, the art is long; the occasion is fleeting; experience fallacious, and judgment difficult.” I would probably say “help the patient … cooperate,” rather than “make the patient … cooperate,” but other than that, despite everything we have learned in medicine in the last few millennia, I would not change a thing.

Deciding if a patient’s depressive episodes are “atypical” can be difficult because key pieces of the diagnostic puzzle are missing. Notwithstanding DSM-IV criteria, atypical depression’s definition remains unclear. This creates a therapeutic dilemma because we know that patients with atypical depression respond differently to antidepressants:

• Monoamine oxidase inhibitors (MAOIs) may be most effective, but their side effects can be troublesome.
• Tricyclics are clearly less effective than MAOIs, but the newer antidepressants’ role in treating atypical depressive symptoms has not been adequately explored.

We offer recommendations for diagnosing and treating atypical depression and address issues that may affect your clinical approach. These include possible overemphasis on mood reactivity in DSM-IV, shortcomings in studies defining the atypical depressive syndrome, and the potential role of biological markers in clarifying this challenging diagnosis.

Features of atypical depression

Atypical depression, as defined in DSM-IV,¹ is characterized by mood reactivity and two or more of the following criteria:

• hypersomnia
• increased appetite or weight gain
• leaden paralysis (heavy, leaden feeling in arms or legs)
• longstanding sensitivity to interpersonal rejection that results in significant social or occupational impairment (Table 1 ).

An estimated 16 to 23% of patients with unipolar depression present with atypical features.² These rates are higher among patients with bipolar disorder.^2,3

Distinctive features. Studies comparing atypical depression with typical or melancholic depression suggest that atypical depression may be distinct in epidemiology, family history, comorbidity, and course of illness (Table 2). Specifically, atypical depression has a higher female-to-male ratio and earlier age of onset.⁴ Patients with atypical depression have higher rates of comorbid panic disorder,^4,5 social phobia,^4,5 bipolar II disorder,⁵ and bulimia⁶ than do those with typical depression.

Family members of patients with atypical depression are more likely to have atypical features during a depressive episode than are family members of patients with melancholic depression.⁷ These findings suggest a genetic component to atypical depression. Atypical depressive episodes also may be more likely to become chronic.^4,8

Not all patients are alike. Studies of the diagnostic stability of atypical depression over time suggest that patients exhibiting atypical features are heterogeneous.⁹ Some longitudinal studies report reasonable diagnostic stability, with 59% to 100% of patients with an index episode of atypical depression exhibiting atypical features 12 to 24 months later.^9,10 In a follow-up study of patients in remission from an episode of atypical depression, 64% of patients suffering a relapse were again found to have atypical features.¹¹

Table 1

MOOD EPISODES: DSM-IV CRITERIA FOR ATYPICAL FEATURES SPECIFIER

Although numerous studies have failed to replicate one or more of these findings,^4,8 several investigators have concluded that atypical depression is a distinct and valid sub-type of major depression.^4,7,8

Antidepressant dilemmas

Unlike typical or melancholic depression, atypical depression responds more robustly to MAOIs than to tricyclic antidepressants (TCAs).¹² MAOIs are roughly twice as effective as TCAs (response rate 72% vs. 44%, respectively), according to a meta-analysis of six studies comparing MAOIs and TCAs in patients with atypical depression.¹³

Clinicians rarely use MAOIs as first-line antidepressants, however, because of side effects and potential dietary and drug interactions. A depressed patient is thus unlikely to receive MAOIs unless the clinician strongly suspects that the presentation is atypical.

SSRIs. Few studies have evaluated how patients with atypical depression respond to newer antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). This lack of evidence creates a dilemma when treating atypical depression, as SSRIs are widely used in depressed patients, including those with atypical features.

One study found fluoxetine and phenelzine comparably effective in atypical depression,¹⁴ while another found sertraline works as well as moclobe-mide.¹⁵ However, the fluoxetine study was limited by a relatively small sample size (n=42), and both studies lacked placebo controls.

Some studies have suggested that SSRIs are less effective than MAOIs¹⁶ or as effective as TCAs in depressed patients with atypical features.^17,18 However, one of these trials was limited by a small sample size (n=28),¹⁸ and only one was placebo-controlled.¹⁷

Bupropion. Studies of other antidepressants in atypical depression also are limited. In two separate trials, depressed patients with atypical features showed a greater response to bupropion than did depressed patients with typical features.^19,20

Bupropion—a combined dopaminergic-noradrenergic antidepressant—appears to have stimulating properties that may help patients with hypersomnia and hyperphagia. Like MAOIs, bupropion also appears to have a greater effect on dopaminergic systems than either TCAs or SSRIs.

Recommendation. The most prudent approach appears to be using SSRIs or bupropion as first-line treatment for atypical depression and reserving MAOIs for patients who do not respond.

Attempts to define atypical depression

Although atypical depression responds differently to MAOIs than to TCAs, it is unclear which patients will respond preferentially to MAOIs. Early attempts to classify this subgroup recognized that these patients display symptom clusters, including:

• anxious depression (prominent anxiety symptoms)
• anergic depression (prominent fatigue and/or psychomotor retardation)
• and depression with reversed vegetative symptoms (hypersomnia and increased weight/appetite).^7,21

Researchers have focused on patients with different combinations of these symptom profiles when defining the atypical depressive syndrome. Some have defined atypical depression as anxious temperament and reactive mood; others, as depression with reversed vegetative symptoms and severe fatigue; still others employ aspects of both profiles, as does DSM-IV.²¹ As a result of this confusion, investigators have demonstrated the preferential response to MAOIs in groups that exhibit different “atypical” symptoms.

Mood reactivity. The importance of mood reactivity in the diagnosis of atypical depression has been debated. DSM-IV requires mood reactivity for the diagnosis, perhaps to clearly differentiate melancholia from atypical depression.⁷ Yet some studies have demonstrated the preferential MAOI response in patients without this symptom.

Table 2

HOW ATYPICAL DEPRESSION COMPARES WITH MELANCHOLIC OR ‘TYPICAL’ DEPRESSION

The Columbia group, from whose work the DSM-IV definition was adopted, performed several convincing studies showing clear superiority of MAOIs in patients who had reactive mood and displayed at least two additional atypical features, such as reversed vegetative symptoms and anergia.²² Patients with reactive mood and only one additional atypical symptom (classified as “probable” atypical depression) also displayed the preferential response to MAOIs, whereas patients who displayed mood reactivity alone did not.¹²

Thase et al,²³ however, reported that reversed vegetative symptoms were more common with nonreactive mood (48%) than with reactive mood (16%) in patients with highly recurrent depression. Moreover, patients who displayed reversed vegetative symptoms without mood reactivity showed the same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Table 3

HOW ANTIDEPRESSANTS COMPARE IN CLINICAL TRIALS OF ATYPICAL DEPRESSION

More evidence suggests that mood reactivity should not be given the hierarchical importance it holds in the DSM-IV definition of atypical depression. In studies using latent class and cluster analyses, mood reactivity did not correlate with any other atypical feature,^4,21 whereas hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity appear to be associated with one another.

Recommendation. Mood reactivity’s uncertain status in atypical depression’s definition makes it difficult to predict which patients may respond preferentially to MAOIs, as many patients present with other atypical features and nonreactive mood. Most recently, it has been suggested that atypical depression’s diagnostic criteria should be modified so that mood reactivity is not required but is one of five atypical features, of which three must be present for the diagnosis.²⁴

Biological markers of depression

Atypical depression’s definition might be clarified if specific depressive symptoms could be linked to any biological markers. One proposed marker is decreased HPA axis activity, possibly caused by a central deficiency of corticotropin-releasing hormone (CRH),²⁵ a potent HPA axis stimulator.

• HPA axis hyperactivity—presumably caused by increased CRH activity in the central nervous system—has been linked to melancholic depressive symptoms—particularly insomnia and reduced appetite.²⁶
• Normal or diminished HPA axis activity—suggested by normal cortisol levels, low levels of CRH in cerebrospinal fluid, and increased frequency of dexamethasone suppression—has been associated with some atypical depressive features—specifically reversed vegetative symptoms.^27-29

However, no studies have examined whether low HPA axis activity is associated with other atypical symptoms listed in DSM-IV. Research is needed to determine whether HPA axis hypoactivity is associated only with reversed vegetative symptoms or with atypical depression per se.

Obesity and eating disorders. Depressed patients who are obese or present with eating disorders may overlap with the atypical subtype and may respond better to some drug interventions than to others. Evidence suggests that depression—particularly the atypical subtype—is associated with increased rates of obesity^8,29 and eating disorders.^8,30

In our clinical experience, the combination of venlafaxine and bupropion can be effective for both depression and excessive eating in these patients, many of whom also exhibit other atypical features. A possible explanation is that the combined pharmacologic effect of venlafaxine and bupropion resembles that of the MAOIs (increased synaptic availability of serotonin, norepinephrine, and dopamine) without many MAOI side effects, such as weight gain.

We have, however, also observed treatment-emergent hypomania when using this drug combination, which is consistent with:

• the idea that mood reactivity and rejection sensitivity may be markers for bipolar disorder
• the often-reported high rate of bipolar II disorder among patients with atypical depression.⁵

In obese patients with bipolar II disorder, we have found that adding topiramate to mood stabilizer therapy can help treat both mood instability and overeating.^31,32 same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Related resources

• Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry 2002;159(9):1470-9.
• Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7(3):254-75.
• Nierenberg AA, Alpert JE, Pava J, Rosenbaum JF, Fava M. Course and treatment of atypical depression. J Clin Psychiatry 1998;59(suppl 18):5-9.

Drug brand names

• Bupropion • Wellbutrin
• Fluoxetine • Prozac
• Moclobemide • Manerix
• Phenelzine • Nardil
• Sertraline • Zoloft
• Topiramate • Topamax
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives grant/research support from Eli Lilly & Co. and Wyeth Pharmaceuticals and is on the speakers bureau of Wyeth Pharmaceuticals.

Dr. McElroy is a consultant or scientific advisor to Abbott Laboratories, Bristol-Myers Squibb Co., Elan Corp., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Ortho-McNeil Pharmaceutical, UCB Pharma, and Wyeth Pharmaceuticals. She receives research support from Forest Laboratories, GlaxoSmithKline, Elan Corp., Eli Lilly & Co., Merck & Co., Ortho-McNeil Pharmaceutical, Pfizer Inc., Sanofi-Synthelabo, and UCB Pharma.

Deciding if a patient’s depressive episodes are “atypical” can be difficult because key pieces of the diagnostic puzzle are missing. Notwithstanding DSM-IV criteria, atypical depression’s definition remains unclear. This creates a therapeutic dilemma because we know that patients with atypical depression respond differently to antidepressants:

• Monoamine oxidase inhibitors (MAOIs) may be most effective, but their side effects can be troublesome.
• Tricyclics are clearly less effective than MAOIs, but the newer antidepressants’ role in treating atypical depressive symptoms has not been adequately explored.

We offer recommendations for diagnosing and treating atypical depression and address issues that may affect your clinical approach. These include possible overemphasis on mood reactivity in DSM-IV, shortcomings in studies defining the atypical depressive syndrome, and the potential role of biological markers in clarifying this challenging diagnosis.

Features of atypical depression

Atypical depression, as defined in DSM-IV,¹ is characterized by mood reactivity and two or more of the following criteria:

• hypersomnia
• increased appetite or weight gain
• leaden paralysis (heavy, leaden feeling in arms or legs)
• longstanding sensitivity to interpersonal rejection that results in significant social or occupational impairment (Table 1 ).

An estimated 16 to 23% of patients with unipolar depression present with atypical features.² These rates are higher among patients with bipolar disorder.^2,3

Distinctive features. Studies comparing atypical depression with typical or melancholic depression suggest that atypical depression may be distinct in epidemiology, family history, comorbidity, and course of illness (Table 2). Specifically, atypical depression has a higher female-to-male ratio and earlier age of onset.⁴ Patients with atypical depression have higher rates of comorbid panic disorder,^4,5 social phobia,^4,5 bipolar II disorder,⁵ and bulimia⁶ than do those with typical depression.

Family members of patients with atypical depression are more likely to have atypical features during a depressive episode than are family members of patients with melancholic depression.⁷ These findings suggest a genetic component to atypical depression. Atypical depressive episodes also may be more likely to become chronic.^4,8

Not all patients are alike. Studies of the diagnostic stability of atypical depression over time suggest that patients exhibiting atypical features are heterogeneous.⁹ Some longitudinal studies report reasonable diagnostic stability, with 59% to 100% of patients with an index episode of atypical depression exhibiting atypical features 12 to 24 months later.^9,10 In a follow-up study of patients in remission from an episode of atypical depression, 64% of patients suffering a relapse were again found to have atypical features.¹¹

Table 1

MOOD EPISODES: DSM-IV CRITERIA FOR ATYPICAL FEATURES SPECIFIER

Although numerous studies have failed to replicate one or more of these findings,^4,8 several investigators have concluded that atypical depression is a distinct and valid sub-type of major depression.^4,7,8

Antidepressant dilemmas

Unlike typical or melancholic depression, atypical depression responds more robustly to MAOIs than to tricyclic antidepressants (TCAs).¹² MAOIs are roughly twice as effective as TCAs (response rate 72% vs. 44%, respectively), according to a meta-analysis of six studies comparing MAOIs and TCAs in patients with atypical depression.¹³

Clinicians rarely use MAOIs as first-line antidepressants, however, because of side effects and potential dietary and drug interactions. A depressed patient is thus unlikely to receive MAOIs unless the clinician strongly suspects that the presentation is atypical.

SSRIs. Few studies have evaluated how patients with atypical depression respond to newer antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). This lack of evidence creates a dilemma when treating atypical depression, as SSRIs are widely used in depressed patients, including those with atypical features.

One study found fluoxetine and phenelzine comparably effective in atypical depression,¹⁴ while another found sertraline works as well as moclobe-mide.¹⁵ However, the fluoxetine study was limited by a relatively small sample size (n=42), and both studies lacked placebo controls.

Some studies have suggested that SSRIs are less effective than MAOIs¹⁶ or as effective as TCAs in depressed patients with atypical features.^17,18 However, one of these trials was limited by a small sample size (n=28),¹⁸ and only one was placebo-controlled.¹⁷

Bupropion. Studies of other antidepressants in atypical depression also are limited. In two separate trials, depressed patients with atypical features showed a greater response to bupropion than did depressed patients with typical features.^19,20

Bupropion—a combined dopaminergic-noradrenergic antidepressant—appears to have stimulating properties that may help patients with hypersomnia and hyperphagia. Like MAOIs, bupropion also appears to have a greater effect on dopaminergic systems than either TCAs or SSRIs.

Recommendation. The most prudent approach appears to be using SSRIs or bupropion as first-line treatment for atypical depression and reserving MAOIs for patients who do not respond.

Attempts to define atypical depression

Although atypical depression responds differently to MAOIs than to TCAs, it is unclear which patients will respond preferentially to MAOIs. Early attempts to classify this subgroup recognized that these patients display symptom clusters, including:

• anxious depression (prominent anxiety symptoms)
• anergic depression (prominent fatigue and/or psychomotor retardation)
• and depression with reversed vegetative symptoms (hypersomnia and increased weight/appetite).^7,21

Researchers have focused on patients with different combinations of these symptom profiles when defining the atypical depressive syndrome. Some have defined atypical depression as anxious temperament and reactive mood; others, as depression with reversed vegetative symptoms and severe fatigue; still others employ aspects of both profiles, as does DSM-IV.²¹ As a result of this confusion, investigators have demonstrated the preferential response to MAOIs in groups that exhibit different “atypical” symptoms.

Mood reactivity. The importance of mood reactivity in the diagnosis of atypical depression has been debated. DSM-IV requires mood reactivity for the diagnosis, perhaps to clearly differentiate melancholia from atypical depression.⁷ Yet some studies have demonstrated the preferential MAOI response in patients without this symptom.

Table 2

HOW ATYPICAL DEPRESSION COMPARES WITH MELANCHOLIC OR ‘TYPICAL’ DEPRESSION

The Columbia group, from whose work the DSM-IV definition was adopted, performed several convincing studies showing clear superiority of MAOIs in patients who had reactive mood and displayed at least two additional atypical features, such as reversed vegetative symptoms and anergia.²² Patients with reactive mood and only one additional atypical symptom (classified as “probable” atypical depression) also displayed the preferential response to MAOIs, whereas patients who displayed mood reactivity alone did not.¹²

Thase et al,²³ however, reported that reversed vegetative symptoms were more common with nonreactive mood (48%) than with reactive mood (16%) in patients with highly recurrent depression. Moreover, patients who displayed reversed vegetative symptoms without mood reactivity showed the same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Table 3

HOW ANTIDEPRESSANTS COMPARE IN CLINICAL TRIALS OF ATYPICAL DEPRESSION

More evidence suggests that mood reactivity should not be given the hierarchical importance it holds in the DSM-IV definition of atypical depression. In studies using latent class and cluster analyses, mood reactivity did not correlate with any other atypical feature,^4,21 whereas hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity appear to be associated with one another.

Recommendation. Mood reactivity’s uncertain status in atypical depression’s definition makes it difficult to predict which patients may respond preferentially to MAOIs, as many patients present with other atypical features and nonreactive mood. Most recently, it has been suggested that atypical depression’s diagnostic criteria should be modified so that mood reactivity is not required but is one of five atypical features, of which three must be present for the diagnosis.²⁴

Biological markers of depression

Atypical depression’s definition might be clarified if specific depressive symptoms could be linked to any biological markers. One proposed marker is decreased HPA axis activity, possibly caused by a central deficiency of corticotropin-releasing hormone (CRH),²⁵ a potent HPA axis stimulator.

• HPA axis hyperactivity—presumably caused by increased CRH activity in the central nervous system—has been linked to melancholic depressive symptoms—particularly insomnia and reduced appetite.²⁶
• Normal or diminished HPA axis activity—suggested by normal cortisol levels, low levels of CRH in cerebrospinal fluid, and increased frequency of dexamethasone suppression—has been associated with some atypical depressive features—specifically reversed vegetative symptoms.^27-29

However, no studies have examined whether low HPA axis activity is associated with other atypical symptoms listed in DSM-IV. Research is needed to determine whether HPA axis hypoactivity is associated only with reversed vegetative symptoms or with atypical depression per se.

Obesity and eating disorders. Depressed patients who are obese or present with eating disorders may overlap with the atypical subtype and may respond better to some drug interventions than to others. Evidence suggests that depression—particularly the atypical subtype—is associated with increased rates of obesity^8,29 and eating disorders.^8,30

In our clinical experience, the combination of venlafaxine and bupropion can be effective for both depression and excessive eating in these patients, many of whom also exhibit other atypical features. A possible explanation is that the combined pharmacologic effect of venlafaxine and bupropion resembles that of the MAOIs (increased synaptic availability of serotonin, norepinephrine, and dopamine) without many MAOI side effects, such as weight gain.

We have, however, also observed treatment-emergent hypomania when using this drug combination, which is consistent with:

• the idea that mood reactivity and rejection sensitivity may be markers for bipolar disorder
• the often-reported high rate of bipolar II disorder among patients with atypical depression.⁵

In obese patients with bipolar II disorder, we have found that adding topiramate to mood stabilizer therapy can help treat both mood instability and overeating.^31,32 same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Related resources

• Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry 2002;159(9):1470-9.
• Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7(3):254-75.
• Nierenberg AA, Alpert JE, Pava J, Rosenbaum JF, Fava M. Course and treatment of atypical depression. J Clin Psychiatry 1998;59(suppl 18):5-9.

Drug brand names

• Bupropion • Wellbutrin
• Fluoxetine • Prozac
• Moclobemide • Manerix
• Phenelzine • Nardil
• Sertraline • Zoloft
• Topiramate • Topamax
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives grant/research support from Eli Lilly & Co. and Wyeth Pharmaceuticals and is on the speakers bureau of Wyeth Pharmaceuticals.

Dr. McElroy is a consultant or scientific advisor to Abbott Laboratories, Bristol-Myers Squibb Co., Elan Corp., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Ortho-McNeil Pharmaceutical, UCB Pharma, and Wyeth Pharmaceuticals. She receives research support from Forest Laboratories, GlaxoSmithKline, Elan Corp., Eli Lilly & Co., Merck & Co., Ortho-McNeil Pharmaceutical, Pfizer Inc., Sanofi-Synthelabo, and UCB Pharma.

Deciding if a patient’s depressive episodes are “atypical” can be difficult because key pieces of the diagnostic puzzle are missing. Notwithstanding DSM-IV criteria, atypical depression’s definition remains unclear. This creates a therapeutic dilemma because we know that patients with atypical depression respond differently to antidepressants:

• Monoamine oxidase inhibitors (MAOIs) may be most effective, but their side effects can be troublesome.
• Tricyclics are clearly less effective than MAOIs, but the newer antidepressants’ role in treating atypical depressive symptoms has not been adequately explored.

We offer recommendations for diagnosing and treating atypical depression and address issues that may affect your clinical approach. These include possible overemphasis on mood reactivity in DSM-IV, shortcomings in studies defining the atypical depressive syndrome, and the potential role of biological markers in clarifying this challenging diagnosis.

Features of atypical depression

Atypical depression, as defined in DSM-IV,¹ is characterized by mood reactivity and two or more of the following criteria:

• hypersomnia
• increased appetite or weight gain
• leaden paralysis (heavy, leaden feeling in arms or legs)
• longstanding sensitivity to interpersonal rejection that results in significant social or occupational impairment (Table 1 ).

An estimated 16 to 23% of patients with unipolar depression present with atypical features.² These rates are higher among patients with bipolar disorder.^2,3

Distinctive features. Studies comparing atypical depression with typical or melancholic depression suggest that atypical depression may be distinct in epidemiology, family history, comorbidity, and course of illness (Table 2). Specifically, atypical depression has a higher female-to-male ratio and earlier age of onset.⁴ Patients with atypical depression have higher rates of comorbid panic disorder,^4,5 social phobia,^4,5 bipolar II disorder,⁵ and bulimia⁶ than do those with typical depression.

Family members of patients with atypical depression are more likely to have atypical features during a depressive episode than are family members of patients with melancholic depression.⁷ These findings suggest a genetic component to atypical depression. Atypical depressive episodes also may be more likely to become chronic.^4,8

Not all patients are alike. Studies of the diagnostic stability of atypical depression over time suggest that patients exhibiting atypical features are heterogeneous.⁹ Some longitudinal studies report reasonable diagnostic stability, with 59% to 100% of patients with an index episode of atypical depression exhibiting atypical features 12 to 24 months later.^9,10 In a follow-up study of patients in remission from an episode of atypical depression, 64% of patients suffering a relapse were again found to have atypical features.¹¹

Table 1

MOOD EPISODES: DSM-IV CRITERIA FOR ATYPICAL FEATURES SPECIFIER

Although numerous studies have failed to replicate one or more of these findings,^4,8 several investigators have concluded that atypical depression is a distinct and valid sub-type of major depression.^4,7,8

Antidepressant dilemmas

Unlike typical or melancholic depression, atypical depression responds more robustly to MAOIs than to tricyclic antidepressants (TCAs).¹² MAOIs are roughly twice as effective as TCAs (response rate 72% vs. 44%, respectively), according to a meta-analysis of six studies comparing MAOIs and TCAs in patients with atypical depression.¹³

Clinicians rarely use MAOIs as first-line antidepressants, however, because of side effects and potential dietary and drug interactions. A depressed patient is thus unlikely to receive MAOIs unless the clinician strongly suspects that the presentation is atypical.

SSRIs. Few studies have evaluated how patients with atypical depression respond to newer antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs). This lack of evidence creates a dilemma when treating atypical depression, as SSRIs are widely used in depressed patients, including those with atypical features.

One study found fluoxetine and phenelzine comparably effective in atypical depression,¹⁴ while another found sertraline works as well as moclobe-mide.¹⁵ However, the fluoxetine study was limited by a relatively small sample size (n=42), and both studies lacked placebo controls.

Some studies have suggested that SSRIs are less effective than MAOIs¹⁶ or as effective as TCAs in depressed patients with atypical features.^17,18 However, one of these trials was limited by a small sample size (n=28),¹⁸ and only one was placebo-controlled.¹⁷

Bupropion. Studies of other antidepressants in atypical depression also are limited. In two separate trials, depressed patients with atypical features showed a greater response to bupropion than did depressed patients with typical features.^19,20

Bupropion—a combined dopaminergic-noradrenergic antidepressant—appears to have stimulating properties that may help patients with hypersomnia and hyperphagia. Like MAOIs, bupropion also appears to have a greater effect on dopaminergic systems than either TCAs or SSRIs.

Recommendation. The most prudent approach appears to be using SSRIs or bupropion as first-line treatment for atypical depression and reserving MAOIs for patients who do not respond.

Attempts to define atypical depression

Although atypical depression responds differently to MAOIs than to TCAs, it is unclear which patients will respond preferentially to MAOIs. Early attempts to classify this subgroup recognized that these patients display symptom clusters, including:

• anxious depression (prominent anxiety symptoms)
• anergic depression (prominent fatigue and/or psychomotor retardation)
• and depression with reversed vegetative symptoms (hypersomnia and increased weight/appetite).^7,21

Researchers have focused on patients with different combinations of these symptom profiles when defining the atypical depressive syndrome. Some have defined atypical depression as anxious temperament and reactive mood; others, as depression with reversed vegetative symptoms and severe fatigue; still others employ aspects of both profiles, as does DSM-IV.²¹ As a result of this confusion, investigators have demonstrated the preferential response to MAOIs in groups that exhibit different “atypical” symptoms.

Mood reactivity. The importance of mood reactivity in the diagnosis of atypical depression has been debated. DSM-IV requires mood reactivity for the diagnosis, perhaps to clearly differentiate melancholia from atypical depression.⁷ Yet some studies have demonstrated the preferential MAOI response in patients without this symptom.

Table 2

HOW ATYPICAL DEPRESSION COMPARES WITH MELANCHOLIC OR ‘TYPICAL’ DEPRESSION

The Columbia group, from whose work the DSM-IV definition was adopted, performed several convincing studies showing clear superiority of MAOIs in patients who had reactive mood and displayed at least two additional atypical features, such as reversed vegetative symptoms and anergia.²² Patients with reactive mood and only one additional atypical symptom (classified as “probable” atypical depression) also displayed the preferential response to MAOIs, whereas patients who displayed mood reactivity alone did not.¹²

Thase et al,²³ however, reported that reversed vegetative symptoms were more common with nonreactive mood (48%) than with reactive mood (16%) in patients with highly recurrent depression. Moreover, patients who displayed reversed vegetative symptoms without mood reactivity showed the same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Table 3

HOW ANTIDEPRESSANTS COMPARE IN CLINICAL TRIALS OF ATYPICAL DEPRESSION

More evidence suggests that mood reactivity should not be given the hierarchical importance it holds in the DSM-IV definition of atypical depression. In studies using latent class and cluster analyses, mood reactivity did not correlate with any other atypical feature,^4,21 whereas hyperphagia, hypersomnia, leaden paralysis, and rejection sensitivity appear to be associated with one another.

Recommendation. Mood reactivity’s uncertain status in atypical depression’s definition makes it difficult to predict which patients may respond preferentially to MAOIs, as many patients present with other atypical features and nonreactive mood. Most recently, it has been suggested that atypical depression’s diagnostic criteria should be modified so that mood reactivity is not required but is one of five atypical features, of which three must be present for the diagnosis.²⁴

Biological markers of depression

Atypical depression’s definition might be clarified if specific depressive symptoms could be linked to any biological markers. One proposed marker is decreased HPA axis activity, possibly caused by a central deficiency of corticotropin-releasing hormone (CRH),²⁵ a potent HPA axis stimulator.

• HPA axis hyperactivity—presumably caused by increased CRH activity in the central nervous system—has been linked to melancholic depressive symptoms—particularly insomnia and reduced appetite.²⁶
• Normal or diminished HPA axis activity—suggested by normal cortisol levels, low levels of CRH in cerebrospinal fluid, and increased frequency of dexamethasone suppression—has been associated with some atypical depressive features—specifically reversed vegetative symptoms.^27-29

However, no studies have examined whether low HPA axis activity is associated with other atypical symptoms listed in DSM-IV. Research is needed to determine whether HPA axis hypoactivity is associated only with reversed vegetative symptoms or with atypical depression per se.

Obesity and eating disorders. Depressed patients who are obese or present with eating disorders may overlap with the atypical subtype and may respond better to some drug interventions than to others. Evidence suggests that depression—particularly the atypical subtype—is associated with increased rates of obesity^8,29 and eating disorders.^8,30

In our clinical experience, the combination of venlafaxine and bupropion can be effective for both depression and excessive eating in these patients, many of whom also exhibit other atypical features. A possible explanation is that the combined pharmacologic effect of venlafaxine and bupropion resembles that of the MAOIs (increased synaptic availability of serotonin, norepinephrine, and dopamine) without many MAOI side effects, such as weight gain.

We have, however, also observed treatment-emergent hypomania when using this drug combination, which is consistent with:

• the idea that mood reactivity and rejection sensitivity may be markers for bipolar disorder
• the often-reported high rate of bipolar II disorder among patients with atypical depression.⁵

In obese patients with bipolar II disorder, we have found that adding topiramate to mood stabilizer therapy can help treat both mood instability and overeating.^31,32 same preferential response to MAOIs as the mood-reactive group. Patients with typical vegetative symptoms did not show this differential response.

Related resources

• Parker G, Roy K, Mitchell P, Wilhelm K, Malhi G, Hadzi-Pavlovic D. Atypical depression: a reappraisal. Am J Psychiatry 2002;159(9):1470-9.
• Gold PW, Chrousos GP. Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs. low CRH/NE states. Mol Psychiatry 2002;7(3):254-75.
• Nierenberg AA, Alpert JE, Pava J, Rosenbaum JF, Fava M. Course and treatment of atypical depression. J Clin Psychiatry 1998;59(suppl 18):5-9.

Drug brand names

• Bupropion • Wellbutrin
• Fluoxetine • Prozac
• Moclobemide • Manerix
• Phenelzine • Nardil
• Sertraline • Zoloft
• Topiramate • Topamax
• Venlafaxine • Effexor

Disclosure

Dr. Nelson receives grant/research support from Eli Lilly & Co. and Wyeth Pharmaceuticals and is on the speakers bureau of Wyeth Pharmaceuticals.

Dr. McElroy is a consultant or scientific advisor to Abbott Laboratories, Bristol-Myers Squibb Co., Elan Corp., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co., Novartis Pharmaceuticals Corp., Ortho-McNeil Pharmaceutical, UCB Pharma, and Wyeth Pharmaceuticals. She receives research support from Forest Laboratories, GlaxoSmithKline, Elan Corp., Eli Lilly & Co., Merck & Co., Ortho-McNeil Pharmaceutical, Pfizer Inc., Sanofi-Synthelabo, and UCB Pharma.

History: Initial symptoms

Ms. G, 17, has battled attention-deficit/hyperactivity disorder (ADHD) since age 6, and within the past 2 years was also diagnosed as having schizoaffective disorder, bipolar type. An outpatient child psychiatrist and a therapist have helped keep her symptoms in control through much of her life.

During one recent visit to her psychiatrist, however, she complained of decreased energy, increased crying spells, broken sleep, and a depressed mood. She reported that these symptoms began approximately 2 months before the visit, and neither she nor her parents could identify a clear-cut cause.

Throughout her life she has complied with her drug regimens. For 2 years she has been taking divalproex sodium, 500 mg twice daily to manage her manic and depressive episodes, dextroamphetamine sulfate, 30 mg in the morning for her ADHD; risperidone, 2 mg at bedtime for her psychotic symptoms; and mestranol, 60 mcg/d, plus norethindrone, 1 mg/d, for contraception. A recent valproic acid reading of 62 μg/ml is consistent with levels over the last 2 years.

During previous psychotic episodes, Ms. G often became delusional and paranoid with command-type hallucinations. She destroyed her room during her most recent episode.

Ms. G’s adoptive mother accompanied her during this visit. She is concerned for her daughter, especially with the start of school about 1 month away.

Which would you address first: the depression or the psychosis? Would you change Ms. G’s medication and if so, how?

Figure 1 DEPRESSION IN SCHIZOPHRENIA: IMPROVING OUTCOMES

Drs. Yu’s and Maguire’s observations

Complaints of depression in a patient with schizoaffective disorder are especially concerning because multiple domains could be affected (Figure 1). For patients with schizophrenia, the 60% lifetime incidence of major depressive disorder substantially exceeds the 8 to 26% risk in the general population. Ms. G’s comorbid depression also may predispose her to an increased rate of relapse into schizoaffective psychosis, poor treatment response, and a longer duration of psychotic illness that could require hospitalization.¹

Although Ms. G’s divalproex level was therapeutic (between 50 and 100 μg/ml), some data indicate that valproic acid may be less effective in schizoaffective disorder than in bipolar I disorder. Still, treatment of schizoaffective disorder often follows antimanic and antidepressant protocols.²

Treatment: An agent is added

The outpatient psychiatrist adds fluoxetine, 20 mg each morning, to address Ms. G’s depressive symptoms. She reports no improvement after 1 month, and her fluoxetine is increased to 30 mg/d.

Three weeks later, Ms. G’s parents bring her to the psychiatrist for an emergency visit. She reports suicidal ideation over the previous month. Rolling up both sleeves, she reveals several superficial cuts on her forearms and wrists that she inflicted after breaking up with her boyfriend.

Her mother, appearing anxious and overwhelmed, reports that her daughter pushed her because she had refused to give Ms. G her calling card. She had told her mother that she wanted to call a boy in Utah that she had met over the Internet.

Ms. G’s speech is noticeably pressured and she is extremely distractible. Her mother notes that her daughter is sleeping only 2 to 3 hours a night, yet exhibits no decrease in energy. Still depressed, her affect is markedly labile, crying at one moment when discussing her suicidality, then railing at her mother when she tries to explain Ms. G’s aggressiveness. When the psychiatrist recommends hospitalization to stabilize her symptoms, she vehemently demands to be let out so that she can run in front of a moving car. The police are called, and she is restrained and brought into the hospital.

What caused Ms. G’s sudden decline? How would you address it?

Drs. Yu’s and Maguire’s observations

Although antidepressants can effectively treat depression in schizoaffective disorder, many of these medications can trigger a manic episode,³ which can include mania, mixed mania with depression, or rapid cycling every few days or hours. In Ms. G’s case, an increase in serotonin due to the fluoxetine may have caused her mania.

We would stop the fluoxetine and see if her manic symptoms resolve. Fluoxetine’s long half-life (4 to 16 days) cuts down the odds of a serotonin-discontinuation syndrome, making immediate discontinuation feasible.

Still, the cause of Ms. G’s depressive symptoms remains unknown. At this stage, observation in the adolescent inpatient ward holds our best hope of reaching a definitive diagnosis.

Treatment: A diagnostic clue surfaces

Blood tests on admission (including a negative drug screen for narcotics or other depressogenic substances) are normal, and her valproic acid level is 61 μg/ml. Her divalproex is increased to 500 mg in the morning and 750 mg at bedtime, and she is tapered off fluoxetine. Her symptoms gradually improve with the change in the medications and her attendance in milieu and group therapy on the ward. A second valproic acid reading on day three of hospitalization is 67 μg/ml.

That day, a nurse informs the inpatient child/adolescent psychiatrist that Ms. G has requested extra hospital gowns. Ms. G later reveals that for about 4 months she has been producing a milky discharge from both breasts, and that the flow has been increasing in frequency and quantity. She adds that she has not menstruated for almost 5 months and complains of breast tenderness.

What do Ms. G’s latest symptoms suggest? How will your response to these symptoms affect treatment?

Drs. Yu’s and Maguire’s observations

Complaints of menstrual irregularities, breast tenderness, and galactorrhea should arouse suspicions of hyperprolactinemia. Because tumors that raise prolactin levels are rare, medications are the most likely culprit in Ms. G’s case. Dopamine blockade within the tuberoinfundibular tract is the mechanism of action behind prolactin elevation.⁴

Prolactin levels in patients with schizophrenia are generally normal (1 to 25 mg/L) prior to treatment,⁵ but have been known to increase with use of typical antipsychotics. The atypical antipsychotic risperidone has been associated with dose-related increases in plasma prolactin concentration, although Kleinberg et al found no correlation between risperidone-induced plasma prolactin concentrations and adverse events.⁶

Figure 2 POSSIBLE ADVERSE EFFECTS OF HYPERPROLACTINEMIA⁸

Prolactin elevation in women may lead to an estrogen deficiency, causing changes in mood and cognition and psychopathology⁹ that can manifest as increased depression, anxiety, and hostility.¹⁰ Hyperprolactinemia can also cause depression in men, though the mechanism of action is unknown.

Prolactin elevation can lead to numerous other health disturbances (Figure 2). When screening women who are taking antipsychotics, ask about menstrual irregularities, sexual dysfunction, breast tenderness, and galactorrhea. Ask male patients about a loss of libido, erectile dysfunction, ejaculatory dysfunction, and gynecomastia.

When hyperprolactinemia becomes apparent, we suggest discontinuing the offending drug and, if necessary:

• switching to a prolactin-sparing atypical antipsychotic
• or trying another agent, such as bromocriptine or pergolide, if switching to another antipsychotic is infeasible.^10,11

Baseline prolactin levels should be measured before starting any prolactin-elevating antipsychotic. Because prolactin levels may not correlate with severity of clinical symptoms, the net change in these levels may be a better indicator.⁴ If prolactin levels exceed 100 mg/L, consider an MRI with fine cuts though the sellae to check for a primary adenoma.⁴

Conclusion: A cause is found

An MRI of Ms. G’s head is normal, but her serum prolactin level is 125 μg/L. Her risperidone is tapered off, and olanzapine, 10 mg at bedtime, is started with her mother’s consent. Two days later, her prolactin level drops to 85 μg/L. Notable improvement is reported on day seven of hospitalization; she is sleeping and eating well with no suicidal or homicidal ideations and notes no psychotic symptoms. She is discharged that day.

Two weeks later, Ms. G’s improvement continues. Lab tests reveal normal prolactin levels. Over the next few months, she remains stable, attends school, and takes her medications with no adverse effects.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002; 63(suppl 4):56-62. Available at: www.psychiatrist.com/supplenet/v63s04/v63s0408.pdf. Accessed March 11, 2003.

Drug brand names

• Aripiprazole • Abilify
• Dextroamphetamine sulfate • Dexadrine
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Mestranol • Necon 1/50
• Norethindrone • Activella
• Pergolide • Permax
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Yu receives research/grant support from, is a consultant to, and/or is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.

Dr. Maguire receives research/grant support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.

History: Initial symptoms

Ms. G, 17, has battled attention-deficit/hyperactivity disorder (ADHD) since age 6, and within the past 2 years was also diagnosed as having schizoaffective disorder, bipolar type. An outpatient child psychiatrist and a therapist have helped keep her symptoms in control through much of her life.

During one recent visit to her psychiatrist, however, she complained of decreased energy, increased crying spells, broken sleep, and a depressed mood. She reported that these symptoms began approximately 2 months before the visit, and neither she nor her parents could identify a clear-cut cause.

Throughout her life she has complied with her drug regimens. For 2 years she has been taking divalproex sodium, 500 mg twice daily to manage her manic and depressive episodes, dextroamphetamine sulfate, 30 mg in the morning for her ADHD; risperidone, 2 mg at bedtime for her psychotic symptoms; and mestranol, 60 mcg/d, plus norethindrone, 1 mg/d, for contraception. A recent valproic acid reading of 62 μg/ml is consistent with levels over the last 2 years.

During previous psychotic episodes, Ms. G often became delusional and paranoid with command-type hallucinations. She destroyed her room during her most recent episode.

Ms. G’s adoptive mother accompanied her during this visit. She is concerned for her daughter, especially with the start of school about 1 month away.

Which would you address first: the depression or the psychosis? Would you change Ms. G’s medication and if so, how?

Figure 1 DEPRESSION IN SCHIZOPHRENIA: IMPROVING OUTCOMES

Drs. Yu’s and Maguire’s observations

Complaints of depression in a patient with schizoaffective disorder are especially concerning because multiple domains could be affected (Figure 1). For patients with schizophrenia, the 60% lifetime incidence of major depressive disorder substantially exceeds the 8 to 26% risk in the general population. Ms. G’s comorbid depression also may predispose her to an increased rate of relapse into schizoaffective psychosis, poor treatment response, and a longer duration of psychotic illness that could require hospitalization.¹

Although Ms. G’s divalproex level was therapeutic (between 50 and 100 μg/ml), some data indicate that valproic acid may be less effective in schizoaffective disorder than in bipolar I disorder. Still, treatment of schizoaffective disorder often follows antimanic and antidepressant protocols.²

Treatment: An agent is added

The outpatient psychiatrist adds fluoxetine, 20 mg each morning, to address Ms. G’s depressive symptoms. She reports no improvement after 1 month, and her fluoxetine is increased to 30 mg/d.

Three weeks later, Ms. G’s parents bring her to the psychiatrist for an emergency visit. She reports suicidal ideation over the previous month. Rolling up both sleeves, she reveals several superficial cuts on her forearms and wrists that she inflicted after breaking up with her boyfriend.

Her mother, appearing anxious and overwhelmed, reports that her daughter pushed her because she had refused to give Ms. G her calling card. She had told her mother that she wanted to call a boy in Utah that she had met over the Internet.

Ms. G’s speech is noticeably pressured and she is extremely distractible. Her mother notes that her daughter is sleeping only 2 to 3 hours a night, yet exhibits no decrease in energy. Still depressed, her affect is markedly labile, crying at one moment when discussing her suicidality, then railing at her mother when she tries to explain Ms. G’s aggressiveness. When the psychiatrist recommends hospitalization to stabilize her symptoms, she vehemently demands to be let out so that she can run in front of a moving car. The police are called, and she is restrained and brought into the hospital.

What caused Ms. G’s sudden decline? How would you address it?

Drs. Yu’s and Maguire’s observations

Although antidepressants can effectively treat depression in schizoaffective disorder, many of these medications can trigger a manic episode,³ which can include mania, mixed mania with depression, or rapid cycling every few days or hours. In Ms. G’s case, an increase in serotonin due to the fluoxetine may have caused her mania.

We would stop the fluoxetine and see if her manic symptoms resolve. Fluoxetine’s long half-life (4 to 16 days) cuts down the odds of a serotonin-discontinuation syndrome, making immediate discontinuation feasible.

Still, the cause of Ms. G’s depressive symptoms remains unknown. At this stage, observation in the adolescent inpatient ward holds our best hope of reaching a definitive diagnosis.

Treatment: A diagnostic clue surfaces

Blood tests on admission (including a negative drug screen for narcotics or other depressogenic substances) are normal, and her valproic acid level is 61 μg/ml. Her divalproex is increased to 500 mg in the morning and 750 mg at bedtime, and she is tapered off fluoxetine. Her symptoms gradually improve with the change in the medications and her attendance in milieu and group therapy on the ward. A second valproic acid reading on day three of hospitalization is 67 μg/ml.

That day, a nurse informs the inpatient child/adolescent psychiatrist that Ms. G has requested extra hospital gowns. Ms. G later reveals that for about 4 months she has been producing a milky discharge from both breasts, and that the flow has been increasing in frequency and quantity. She adds that she has not menstruated for almost 5 months and complains of breast tenderness.

What do Ms. G’s latest symptoms suggest? How will your response to these symptoms affect treatment?

Drs. Yu’s and Maguire’s observations

Complaints of menstrual irregularities, breast tenderness, and galactorrhea should arouse suspicions of hyperprolactinemia. Because tumors that raise prolactin levels are rare, medications are the most likely culprit in Ms. G’s case. Dopamine blockade within the tuberoinfundibular tract is the mechanism of action behind prolactin elevation.⁴

Prolactin levels in patients with schizophrenia are generally normal (1 to 25 mg/L) prior to treatment,⁵ but have been known to increase with use of typical antipsychotics. The atypical antipsychotic risperidone has been associated with dose-related increases in plasma prolactin concentration, although Kleinberg et al found no correlation between risperidone-induced plasma prolactin concentrations and adverse events.⁶

Figure 2 POSSIBLE ADVERSE EFFECTS OF HYPERPROLACTINEMIA⁸

Prolactin elevation in women may lead to an estrogen deficiency, causing changes in mood and cognition and psychopathology⁹ that can manifest as increased depression, anxiety, and hostility.¹⁰ Hyperprolactinemia can also cause depression in men, though the mechanism of action is unknown.

Prolactin elevation can lead to numerous other health disturbances (Figure 2). When screening women who are taking antipsychotics, ask about menstrual irregularities, sexual dysfunction, breast tenderness, and galactorrhea. Ask male patients about a loss of libido, erectile dysfunction, ejaculatory dysfunction, and gynecomastia.

When hyperprolactinemia becomes apparent, we suggest discontinuing the offending drug and, if necessary:

• switching to a prolactin-sparing atypical antipsychotic
• or trying another agent, such as bromocriptine or pergolide, if switching to another antipsychotic is infeasible.^10,11

Baseline prolactin levels should be measured before starting any prolactin-elevating antipsychotic. Because prolactin levels may not correlate with severity of clinical symptoms, the net change in these levels may be a better indicator.⁴ If prolactin levels exceed 100 mg/L, consider an MRI with fine cuts though the sellae to check for a primary adenoma.⁴

Conclusion: A cause is found

An MRI of Ms. G’s head is normal, but her serum prolactin level is 125 μg/L. Her risperidone is tapered off, and olanzapine, 10 mg at bedtime, is started with her mother’s consent. Two days later, her prolactin level drops to 85 μg/L. Notable improvement is reported on day seven of hospitalization; she is sleeping and eating well with no suicidal or homicidal ideations and notes no psychotic symptoms. She is discharged that day.

Two weeks later, Ms. G’s improvement continues. Lab tests reveal normal prolactin levels. Over the next few months, she remains stable, attends school, and takes her medications with no adverse effects.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002; 63(suppl 4):56-62. Available at: www.psychiatrist.com/supplenet/v63s04/v63s0408.pdf. Accessed March 11, 2003.

Drug brand names

• Aripiprazole • Abilify
• Dextroamphetamine sulfate • Dexadrine
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Mestranol • Necon 1/50
• Norethindrone • Activella
• Pergolide • Permax
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Yu receives research/grant support from, is a consultant to, and/or is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.

Dr. Maguire receives research/grant support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.

History: Initial symptoms

Ms. G, 17, has battled attention-deficit/hyperactivity disorder (ADHD) since age 6, and within the past 2 years was also diagnosed as having schizoaffective disorder, bipolar type. An outpatient child psychiatrist and a therapist have helped keep her symptoms in control through much of her life.

During one recent visit to her psychiatrist, however, she complained of decreased energy, increased crying spells, broken sleep, and a depressed mood. She reported that these symptoms began approximately 2 months before the visit, and neither she nor her parents could identify a clear-cut cause.

Throughout her life she has complied with her drug regimens. For 2 years she has been taking divalproex sodium, 500 mg twice daily to manage her manic and depressive episodes, dextroamphetamine sulfate, 30 mg in the morning for her ADHD; risperidone, 2 mg at bedtime for her psychotic symptoms; and mestranol, 60 mcg/d, plus norethindrone, 1 mg/d, for contraception. A recent valproic acid reading of 62 μg/ml is consistent with levels over the last 2 years.

During previous psychotic episodes, Ms. G often became delusional and paranoid with command-type hallucinations. She destroyed her room during her most recent episode.

Ms. G’s adoptive mother accompanied her during this visit. She is concerned for her daughter, especially with the start of school about 1 month away.

Which would you address first: the depression or the psychosis? Would you change Ms. G’s medication and if so, how?

Figure 1 DEPRESSION IN SCHIZOPHRENIA: IMPROVING OUTCOMES

Drs. Yu’s and Maguire’s observations

Complaints of depression in a patient with schizoaffective disorder are especially concerning because multiple domains could be affected (Figure 1). For patients with schizophrenia, the 60% lifetime incidence of major depressive disorder substantially exceeds the 8 to 26% risk in the general population. Ms. G’s comorbid depression also may predispose her to an increased rate of relapse into schizoaffective psychosis, poor treatment response, and a longer duration of psychotic illness that could require hospitalization.¹

Although Ms. G’s divalproex level was therapeutic (between 50 and 100 μg/ml), some data indicate that valproic acid may be less effective in schizoaffective disorder than in bipolar I disorder. Still, treatment of schizoaffective disorder often follows antimanic and antidepressant protocols.²

Treatment: An agent is added

The outpatient psychiatrist adds fluoxetine, 20 mg each morning, to address Ms. G’s depressive symptoms. She reports no improvement after 1 month, and her fluoxetine is increased to 30 mg/d.

Three weeks later, Ms. G’s parents bring her to the psychiatrist for an emergency visit. She reports suicidal ideation over the previous month. Rolling up both sleeves, she reveals several superficial cuts on her forearms and wrists that she inflicted after breaking up with her boyfriend.

Her mother, appearing anxious and overwhelmed, reports that her daughter pushed her because she had refused to give Ms. G her calling card. She had told her mother that she wanted to call a boy in Utah that she had met over the Internet.

Ms. G’s speech is noticeably pressured and she is extremely distractible. Her mother notes that her daughter is sleeping only 2 to 3 hours a night, yet exhibits no decrease in energy. Still depressed, her affect is markedly labile, crying at one moment when discussing her suicidality, then railing at her mother when she tries to explain Ms. G’s aggressiveness. When the psychiatrist recommends hospitalization to stabilize her symptoms, she vehemently demands to be let out so that she can run in front of a moving car. The police are called, and she is restrained and brought into the hospital.

What caused Ms. G’s sudden decline? How would you address it?

Drs. Yu’s and Maguire’s observations

Although antidepressants can effectively treat depression in schizoaffective disorder, many of these medications can trigger a manic episode,³ which can include mania, mixed mania with depression, or rapid cycling every few days or hours. In Ms. G’s case, an increase in serotonin due to the fluoxetine may have caused her mania.

We would stop the fluoxetine and see if her manic symptoms resolve. Fluoxetine’s long half-life (4 to 16 days) cuts down the odds of a serotonin-discontinuation syndrome, making immediate discontinuation feasible.

Still, the cause of Ms. G’s depressive symptoms remains unknown. At this stage, observation in the adolescent inpatient ward holds our best hope of reaching a definitive diagnosis.

Treatment: A diagnostic clue surfaces

Blood tests on admission (including a negative drug screen for narcotics or other depressogenic substances) are normal, and her valproic acid level is 61 μg/ml. Her divalproex is increased to 500 mg in the morning and 750 mg at bedtime, and she is tapered off fluoxetine. Her symptoms gradually improve with the change in the medications and her attendance in milieu and group therapy on the ward. A second valproic acid reading on day three of hospitalization is 67 μg/ml.

That day, a nurse informs the inpatient child/adolescent psychiatrist that Ms. G has requested extra hospital gowns. Ms. G later reveals that for about 4 months she has been producing a milky discharge from both breasts, and that the flow has been increasing in frequency and quantity. She adds that she has not menstruated for almost 5 months and complains of breast tenderness.

What do Ms. G’s latest symptoms suggest? How will your response to these symptoms affect treatment?

Drs. Yu’s and Maguire’s observations

Complaints of menstrual irregularities, breast tenderness, and galactorrhea should arouse suspicions of hyperprolactinemia. Because tumors that raise prolactin levels are rare, medications are the most likely culprit in Ms. G’s case. Dopamine blockade within the tuberoinfundibular tract is the mechanism of action behind prolactin elevation.⁴

Prolactin levels in patients with schizophrenia are generally normal (1 to 25 mg/L) prior to treatment,⁵ but have been known to increase with use of typical antipsychotics. The atypical antipsychotic risperidone has been associated with dose-related increases in plasma prolactin concentration, although Kleinberg et al found no correlation between risperidone-induced plasma prolactin concentrations and adverse events.⁶

Figure 2 POSSIBLE ADVERSE EFFECTS OF HYPERPROLACTINEMIA⁸

Prolactin elevation in women may lead to an estrogen deficiency, causing changes in mood and cognition and psychopathology⁹ that can manifest as increased depression, anxiety, and hostility.¹⁰ Hyperprolactinemia can also cause depression in men, though the mechanism of action is unknown.

Prolactin elevation can lead to numerous other health disturbances (Figure 2). When screening women who are taking antipsychotics, ask about menstrual irregularities, sexual dysfunction, breast tenderness, and galactorrhea. Ask male patients about a loss of libido, erectile dysfunction, ejaculatory dysfunction, and gynecomastia.

When hyperprolactinemia becomes apparent, we suggest discontinuing the offending drug and, if necessary:

• switching to a prolactin-sparing atypical antipsychotic
• or trying another agent, such as bromocriptine or pergolide, if switching to another antipsychotic is infeasible.^10,11

Baseline prolactin levels should be measured before starting any prolactin-elevating antipsychotic. Because prolactin levels may not correlate with severity of clinical symptoms, the net change in these levels may be a better indicator.⁴ If prolactin levels exceed 100 mg/L, consider an MRI with fine cuts though the sellae to check for a primary adenoma.⁴

Conclusion: A cause is found

An MRI of Ms. G’s head is normal, but her serum prolactin level is 125 μg/L. Her risperidone is tapered off, and olanzapine, 10 mg at bedtime, is started with her mother’s consent. Two days later, her prolactin level drops to 85 μg/L. Notable improvement is reported on day seven of hospitalization; she is sleeping and eating well with no suicidal or homicidal ideations and notes no psychotic symptoms. She is discharged that day.

Two weeks later, Ms. G’s improvement continues. Lab tests reveal normal prolactin levels. Over the next few months, she remains stable, attends school, and takes her medications with no adverse effects.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002; 63(suppl 4):56-62. Available at: www.psychiatrist.com/supplenet/v63s04/v63s0408.pdf. Accessed March 11, 2003.

Drug brand names

• Aripiprazole • Abilify
• Dextroamphetamine sulfate • Dexadrine
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Mestranol • Necon 1/50
• Norethindrone • Activella
• Pergolide • Permax
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Yu receives research/grant support from, is a consultant to, and/or is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.

Dr. Maguire receives research/grant support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.