THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

25. Psychiatric Disease - Jason Carter, PharmD

25-1. Axis Diagnosis

The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) of the American Psychiatric Association organizes psychiatric diagnoses into five axes:

I. Clinical disorders

II. Personality disorders and mental retardation

III. General medical conditions

IV. Psychosocial and environmental problems

V. Global assessment of functioning

25-2. Schizophrenia

Introduction

Schizophrenia is a psychiatric disorder characterized by a profound disruption in perception, cognition, and emotion.

Epidemiology

Approximately 1% of the U.S. adult population has schizophrenia. There are 200,000 new cases reported yearly.

No gender or racial differences exist. Onset is earlier in males (average age, 18-24 years) than in females (average age, late 20s to early 40s).

Types and Classifications

Paranoid

Paranoid schizophrenia is characterized by prominent preoccupation with hallucinations (usually auditory) and one or more delusions.

Disorganized

Disorganized schizophrenia is characterized by disorganized speech and behavior, as well as blunted, flat, or inappropriate affect.

Catatonic

With catatonic schizophrenia, psychomotor disturbances are present that may involve catalepsy or stupor, excessive motor activity, rigid posture, mutism, peculiar or repetitive movements, and echolalia or echopraxia.

Undifferentiated

With undifferentiated schizophrenia, hallucinations or delusions are present but without prominent paranoid, disorganized, or catatonic symptoms.

Residual

With residual schizophrenia, hallucinations and delusions are not prominent, but there is continued evidence of an ongoing disturbance (flat affect, poverty of speech, or avolition).

Clinical Presentation

The onset of schizophrenia is typically characterized by deterioration in occupational and social situations over a period of 6 months or more.

Symptoms

Symptoms include the following:

• Hallucinations (auditory, visual, tactile, olfactory, or gustatory)

• Delusions (usually persecutory or grandiose)

• Disorganized thoughts or speech

• Impaired cognition, attention, concentration, judgment, and motivation

Symptoms are commonly referred to as positive (hallucinations or delusions); negative (flat affect, avolition, anhedonia, and poverty of thought); or disorganized (disorganized speech or behavior).

Most patients fluctuate between acute episodes and remission, but complete remission without any symptoms is uncommon.

Associated features

Morbidity

There are many comorbid disease states (mental and medical); for example, substance abuse is found in 60-70% of persons with schizophrenia.

Mortality

Shortened life expectancy is a feature of schizophrenia. Patients with schizophrenia are at increased risk of suicide (10% commit suicide). Risk factors for suicide are as follows:

• Male

• Socially isolated

• Comorbid psychiatric disorders

• Unemployed

• < 30 years of age

Etiology

The etiology is most likely multifactorial:

• Genetic

• Neurobiologic

• Developmental (season of birth, viral illness, traumatic injury)

DSM-IV Diagnostic Criteria

Two or more of the following symptoms prevail for at least 1 month:

• Hallucinations

• Delusions

• Disorganized speech

• Grossly disorganized or catatonic behavior

• Negative symptoms

• Anhedonia

• Flat affect

• Avolition

Significant social dysfunction exists:

• Signs of the disturbance are continuous and persist for 6 months.

• Schizoaffective disorders and mood disorders, mental retardation, substance abuse, and other causative medical disorders have been ruled out.

Treatment Principles and Goals

• All antipsychotics are equally effective if used properly.

• Clozapine is the only agent proven effective in treating refractory schizophrenia.

• The basis for choosing an antipsychotic medication is the following:

• Past history of response (patient's response or a family member's response to a medication)

• Side-effect profile of the antipsychotic

• Administer therapy with a trial of antipsychotics (at least 4-6 weeks at recommended doses).

• Do everything possible to simplify the drug regimen.

• Consider long-acting injectable preparations in situations of poor compliance.

Drug Therapy

Tables 25-1 and

25-2 provide an overview of drug therapy alternatives.

Mechanism of action

These drugs block postsynaptic dopamine-2 receptors. They share anticholinergic, antihistaminic, and α-blocking properties.

Other conventional agents

Though not commonly used, perphenazine (Trilafon), thiothixene (Navane), trifluoperazine (Stelazine), and loxapine (Loxitane) are conventional agents used to treat schizophrenia.

Management of adverse effects

Sedation

The level of sedation depends on the drug used. Low-potency drugs in this class are more sedating than high-potency drugs.

Sedation effects are worse initially, but become more tolerable over time.

[Table 25-1. Typical (Conventional or Older) Antipsychotics]

[Table 25-2. Adverse Effects of Typical Antipsychotic Medications]

Orthostasis

Severity depends on the drug used. Low-potency formulations promote more orthostasis than do high potency formulations.

This condition is especially problematic in elderly patients.

Weight gain

Weight gain is very prominent in patients taking these medications. Low doses should be used. Appropriate diet and exercise should be encouraged to offset weight gain.

Anticholinergic effect

Severity depends on the drug used. Low-potency drugs of this type are more sedating than high-potency ones.

Dry mouth, blurred vision, constipation, and urinary hesitancy may occur. Use high-potency agents in patients bothered by anticholinergic side effects.

Extrapyramidal symptoms

Extrapyramidal symptoms (EPSs) are most likely attributed to an imbalance in dopamine and acetylcholine. Antipsychotics cause a hypodopaminergic state.

Dystonic reactions

Reactions usually occur within 24-96 hours of initiating or changing dose. They present as painful, involuntary muscle spasms in skeletal muscles (most commonly in the facial or neck muscles, but sometimes in the back, arm, and leg muscles).

Treatment is benztropine (Cogentin) 1-2 mg intramuscular (IM) or diphenhydramine (Benadryl) 25-50 mg IM every 30 minutes until the reaction is relieved. Prophylaxis with oral therapy is usually initiated.

Akathisia

Akathisia usually occurs within a few weeks of initiating antipsychotic therapy. It is described as a subjective feeling of discomfort, usually seen as motor restlessness of the legs (inability to stand still or sit still).

Akathisia is treated with lipophilic β-blockers (e.g., propranolol), benzodiazepines, clonidine, and anticholinergics.

Pseudoparkinsonism

Pseudoparkinsonism usually occurs after months or years of therapy. This condition resembles Parkinson's symptoms (e.g., cogwheel rigidity, bradykinesia, tremor, shuffling gait).

It is treated with amantadine (Symmetrel) 100 mg bid or anticholinergics.

Other adverse effects

Tardive dyskinesia

Tardive dyskinesia (TD) is an irreversible drug-induced movement disorder that occurs after years of antipsychotic therapy. It is caused by long-term suppression of dopamine.

A triad of symptoms characterize TD:

• Choreoathetosis (splayed, writhing fingers)

• Oral or buccal movements (grimacing, bruxism, lip-smacking)

• Protrusion of the tongue

The only treatment is prevention (i.e., use the lowest effective dose of antipsychotic). However, various therapies (vitamin E, lecithin, vitamin B6) may help alleviate symptoms.

Monitor for TD by administering the Abnormal Involuntary Movement Scale (AIMS) to all patients taking antipsychotics.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) has a low incidence and high mortality. It is thought to be due to dopamine blockade. Clinical presentation of NMS is as follows:

• Rapid progression (<24 hours)

• Body temperature > 104°F

• Lead-pipe rigidity

• Hypertension

• Diaphoresis

• Increased heart rate

• Incontinence

• Increased liver function test (LFT), creatinine phosphokinase (CPK), and white blood count (WBC)

Treatment is as follows:

• Transport patient to an emergency room immediately (STAT).

• Discontinue antipsychotic medication.

• Administer supportive therapy (cooling blankets, hydration); the dopamine agonist bromocriptine (Parlodel); and the smooth muscle relaxant dantrolene (Dantrium).

Endocrine and metabolic effects

Such effects include amenorrhea, galactorrhea, and gynecomastia caused by hyperprolactinemia.

Dopamine regulates prolactin release. When dopamine is blocked, prolactin is elevated.

Other effects include weight gain and decreased glucose tolerance.

Dermatologic effects (especially in long-term therapy)

Allergy to medication, photosensitivity, and pigmentation problems may occur.

Hypothalamic effects

Temperature dysregulation (i.e., sensitivity to extreme temperatures) is possible.

Cardiac effects

QT prolongation is possible. Effects are more common with thioridazine (black box warning).

The recommendation is to obtain an electrocardiogram (ECG) for all patients on antipsychotics.

Ophthalmologic effects

Pigmentary retinopathy is associated with daily thioridazine doses > 800 mg. Melanin deposits occur on the cornea and may lead to blindness.

Atypical (newer) antipsychotics

See

Table 25-3 for an overview of these drugs.

No universally accepted definition of atypical exists, but these drugs generally have the following features.

• Side effects are less severe (little or no EPS, minimal to no prolactin increase, less risk of TD).

• More weight gain, more lipid abnormalities, and a greater risk of diabetes are seen with these drugs.

• A dose-dependent increased risk of ventricular arrhythmias and sudden cardiac death is seen, possibly because of prolongation of the QT interval similar to typical antipsychotics.

[Table 25-3. Atypical Antipsychotics]

• Decreased affinity for the dopamine receptor is present.

• Results from the CATIE (Clinical Antipsychotic Trials in Intervention Effectiveness) showed very high discontinuation rates for all antipsychotics secondary to inefficacy or intolerable side effects. No difference was seen between perphenazine and atypicals (except olanzapine).

• There is a black box warning for increase in mortality with atypical antipsychotics in elderly patients with dementia, and atypical antipsychotics are not approved for the treatment of patients with dementia-related psychosis.

Mechanism of action

These drugs are weak dopamine and dopamine-2 receptor blockers that block serotonin and α-adrenergic, histaminic, and muscarinic receptors in the central nervous system.

Treatment Strategies

Acute schizophrenia

• Decrease danger to self and others.

• Haloperidol or fluphenazine (immediate release) 5-10 mg IM and lorazepam 2 mg IM q4h prn may be used for psychosis or agitation. An anticholinergic may also be needed (e.g., benztropine or diphenhydramine for EPSs).

• Olanzapine 10 mg IM may be used and can be repeated in 2 hours and again 4 hours later, for a maximum of 30 mg/d for psychosis or agitation.

• Patients may use ziprasidone 10 mg IM administered every 2 hours or 20 mg IM administered every 4 hours, for a maximum of 40 mg/d for psychosis or agitation.

Maintenance

• Start an atypical antipsychotic at a recommended dose or continue a conventional agent (if it was effective for patient before hospital admission).

• Positive symptoms will respond first.

• Monitor for side effects and emphasize compliance.

• Lifelong therapy is usually needed.

• Use lowest effective dose to decrease risk of side effects (e.g., TD).

Recommended monitoring for patients on atypical antipsychotics

• Fasting glucose and lipids and blood pressure at baseline and at 12 weeks

• Weight (body mass index) at baseline, 4 weeks, 8 weeks, and 12 weeks, and then quarterly

• Waist circumference at baseline and then annually

Noncompliance and alternative dosing

Haloperidol decanoate (Haldol-D)

The dosage conversion from po to IM is as follows: po daily dose × 10 = IM dose every 4 weeks. For example, 20 mg daily dose × 10 = 200 mg every 4 weeks.

Steady state is reached in 8-12 weeks.

Fluphenazine decanoate (Prolixin-D)

The dosage conversion from po to IM is as follows: 1 mg po = 1.25 mg IM. For example, 20 mg daily dose × 1.25 mg = 25 mg IM every 2 weeks.

Steady state is reached in approximately 6 weeks.

Depot administration technique

Both medications are suspended in sesame seed oil. They are very viscous. Ensure that the patient has no allergy to sesame seed oil.

Administer in gluteal or deltoid muscle with a 16-or 18-gauge needle.

Risperidone long-acting injection (Risperdal Consta)

Overlap with po medication for 3 weeks.

The recommended dose is 25 mg every 2 weeks. The maximum dose is 50 mg every 2 weeks. Alternate IM administration between two buttocks.

Steady state is reached in approximately 8 weeks.

Use the diluent and needle supplied in the pack to reconstitute and administer injection.

25-3. Bipolar Disorder

Introduction

Bipolar disorder (manic-depressive illness) is a recurrent mood disorder with a lifetime prevalence of 0.8%-1.6%. This disorder is associated with significant morbidity and mortality.

Incidence is equal in females and males. Onset is usually between ages 8 and 44. The first episode for females is usually marked by a depressive episode. For males, it is usually marked by a manic episode.

Types and Classifications

• Bipolar I: This type is characterized by the occurrence of manic episodes and major depressive episodes.

• Bipolar II: This type is characterized by the occurrence of hypomanic episodes and major depressive episodes.

• Cyclothymia: This type is defined as numerous episodes of hypomania and depressive episodes that cannot be classified as major depressive episodes. Diagnosis requires that cyclothymia occur for at least a 2-year period.

Clinical Presentation

See DSM-IV for complete diagnostic criteria.

Mania

Mania is characterized by heightened mood (euphoria), flight of ideas, rapid or pressured speech, grandiosity, increased energy, decreased need for sleep, irritability, and impulsivity. Judgment is significantly impaired (e.g., increased risk-taking behavior). Marked impairment also exists in social or occupational functioning.

Psychotic features are usually present. Hospitalization is needed.

Changes in sleeping patterns (especially insomnia) commonly initiate manic episodes.

Drug-induced causes include antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors); bronchodilators (albuterol, salmeterol); stimulants; xanthines (caffeine, theophylline); dopamine agonists (bromocriptine, amantadine); and sympathomimetics.

Note: The STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) trial showed that antidepressants used in combination with mood stabilizers did not increase the risk of inducing mania in bipolar depression. However, this combination was not associated with increased efficacy.

Hypomania

Hypomania is a less severe form of mania. This disorder usually does not cause marked impairment in social or occupational functioning.

Many patients find this state highly desirable because they experience a great sense of well-being and feel productive, creative, and confident.

Dysphoric (mixed) mania

Dysphoric mania is characterized by manic and depressive features, mood variability, and mood lability. Symptoms usually include agitation, insomnia, suicidal ideation, psychosis, and appetite disturbances.

Major depression

See Section 25-4.

Rapid cycling

In rapid cycling, the patient experiences > 4 mood episodes in a year. Mood episodes may occur in any combination.

Rapid cycling primarily occurs in women (70-90%). The prognosis is usually poor.

Etiology

The etiology is unknown; however, the leading hypothesis supports genetic etiology. Other theories include neurotransmitter involvement, circadian rhythm, and kindling hypothesis.

Clinical Course

The mean age of onset is 21 years. The first episode for females is usually depression. For males, it is mania.

Untreated episodes may last from weeks to months. A high mortality rate exists because of suicide. Comorbid substance abuse is very common (60-70%).

Treatment Principles and Goals

Acute

In acute cases, the goal is to control the current episode (i.e., slow down the patient and reduce harm to self and others).

Maintenance

Maintenance goals are as follows:

• Prevent or minimize future episodes.

• Maintain drug therapy, and reduce adverse effects.

• Prevent drug interactions.

• Educate the patient and family about the disorder.

• Provide adequate follow-up services (including substance abuse treatment).

• Maximize the patient's functional status and quality of life.

Drug Therapy

Table 25-4 provides information about mood stabilizers.

Lithium

Indications

Lithium is indicated for acute treatment and prophylaxis of manic episodes associated with bipolar disorders. It is effective for both the manic and depressive components.

Mechanism of action

The mechanism of action is unknown. Various theories suggest that lithium facilitates γ-aminobutyric acid (GABA) function, alters cation transport across cell membranes in nerve and muscle cells, or influences reuptake of 5-hydroxytryptamine (5-HT) or norepinephrine (NE).

[Table 25-4. Mood Stabilizers]

Contraindications

Contraindications include renal disease, severe cardiovascular disease, history of leukemia, first trimester of pregnancy, and hypersensitivity to lithium.

Precautions

Use with caution in patients who have thyroid disease, patients who have sodium depletion, patients who are receiving diuretics, or dehydrated patients.

Monitoring (baseline and follow-up)

• Thyroid panel: Lithium may cause hypothyroidism. Test baseline and thyroid-stimulating hormone (TSH) every 6-12 months or as clinically indicated.

• Serum creatinine (SCr) and blood urea nitrogen (BUN): Lithium is 100% renally eliminated. Test baseline and every 3 months for patients with renal dysfunction and every 12 months otherwise or as clinically indicated.

• Complete blood count (CBC) with differential: Lithium may cause leukocytosis and may reactivate leukemia. Test baseline and every month for 3 months; then test as clinically indicated.

• Electrolytes: In the event of hyponatremia, lithium toxicity may occur.

• ECG: Lithium causes flattened or inverted T waves. This condition is reversible. Test baseline and every 6-12 months or as clinically indicated.

• Urinalysis: Lithium may decrease specific gravity.

• Pregnancy test: Lithium may cause cardiovascular defects (e.g., Ebstein's anomaly).

• Lithium level: Lithium reaches steady-state levels in 4-5 days (half-life = ~24 h). Obtain the level 2-8 hours after the dose (acute: 0.6-1.2 mEq/L; maintenance: 0.8-1.0 mEq/L). Draw the level weekly for 4 weeks and then monthly for 3 months or as clinically indicated.

Drug interactions

Table 25-5 summarizes the drug interactions associated with lithium.

[Table 25-5. Drug Interactions with Lithium]

In addition, several toxicity concerns are associated with the drug:

• Mild toxicity (serum levels 1.5-2.0 mEq/L): Gastrointestinal (GI) upset (nausea, vomiting, diarrhea); muscle weakness; fatigue; fine hand tremor; difficulty with concentration and memory

• Moderate toxicity (serum levels 2.0-2.5 mEq/L): Ataxia, lethargy, nystagmus, worsening confusion, severe GI upset, coarse tremors, increased deep tendon reflexes

• Severe toxicity (serum levels > 3.0 mEq/L): Severely impaired consciousness, coma, seizures, respiratory complications, death

Toxicity is treated as follows:

• Discontinue lithium and initiate gastric lavage.

• Correct electrolyte and fluid imbalances.

• Monitor neurologic changes.

• Give supportive care.

• Give dialysis if indicated.

Patient information

• Monitoring serum lithium levels routinely is important.

• Maintain a steady salt and fluid intake.

• Do not crush or chew extended- or slow-release dosage forms.

Divalproex sodium

Divalproex sodium is indicated for bipolar disorder. It is considered first-line treatment for acute manic episodes. It has unlabeled use for prophylaxis of manic episodes, is effective for rapid cyclers and patients with dysphoric mood, and is helpful in the management of agitation and aggression.

Mechanism of action

Its mechanism of action is unknown, but divalproex sodium is thought to increase GABA or mimic its action at the postsynaptic receptor site.

Contraindications

Contraindications include

• Hepatic dysfunction

• Hypersensitivity to divalproex sodium

• Patients < 2 years old

• Pregnancy

With respect to pregnancy, valproic acid (VPA) may cause neural tube defects. If the benefit outweighs the risk, supplement with 4-5 mg/d of folic acid to decrease risk of fetal damage.

Monitoring

VPA

• VPA level reaches steady state in 3-5 days (half-life = 9-16 h); 50-125 mcg/mL is optimal.

• Draw level weekly for 2-3 weeks, then every 3 months or as clinically indicated.

LFTs

• Test baseline and every month for 6 months, and then every 6 months or as clinically indicated.

• Divalproex sodium is hepatically eliminated; it carries a black box warning for hepatotoxicity.

CBC with differential

• Test baseline and every month for 6 months, and then every 6 months or as clinically indicated.

• VPA may cause thrombocytopenia.

Drug interactions

• Divalproex sodium is a cytochrome P450 (CYP450) 2C19 enzyme substrate, a CYP450 2C9 and 2D6 inhibitor, and a weak CYP450 3A3/4 inhibitor.

• Interactions occur with carbamazepine, lamotrigine, and phenytoin. Increased sedative effects occur with phenobarbital and benzodiazepines.

Patient information

• Take with food to avoid GI upset.

• Take a multivitamin with selenium and zinc if alopecia (hair loss) occurs.

• It is important to monitor VPA levels routinely.

Carbamazepine

Carbamazepine (CBZ) is considered second-line therapy for acute and prophylactic treatment of bipolar disorder.

Mechanism of action

The mechanism of action is unknown.

Monitoring

Monitor CBC with differential, electrolytes, LFTs, SCr or BUN, and ECG (if the patient is > 40 years old or has a preexisting heart disease).

CBZ is an autoinducer. Monitor levels routinely, especially during first few months of therapy. The optimal level is 4-12 mcg/mL.

Contraindications

Contraindications include history of previous bone marrow depression and hypersensitivity to CBZ.

Drug interactions

• CBZ is a CYP450 2C8 and 3A3/4 enzyme substrate.

• It is a CYP450 1A2, 2C, and 3A3/4 inducer.

• CBZ may induce the metabolism of benzodiazepines, clozapine, corticosteroids, oral contraceptives, VPA, warfarin, phenytoin, and tricyclic antidepressants (plus others).

• Cimetidine, clarithromycin, diltiazem, propoxyphene, verapamil, metronidazole, and lamotrigine (plus others) inhibit CBZ.

Lamotrigine (Lamictal)

Lamotrigine is approved for maintenance treatment of Bipolar I disorder. Titration of the dose is required to monitor for signs and symptoms of severe and potentially life-threatening skin rashes (

Table 25-6). Coadministration with VPA increases the risk.

Drug interactions and effects

• CBZ, phenytoin, oral contraceptives, rifampin, and phenobarbital decrease lamotrigine concentrations.

• VPA increases lamotrigine concentrations.

• Adverse effects include nausea, headache, tremor or anxiety, and sedation.

Other therapies

Atypical antipsychotics

These agents are approved for treatment of bipolar disorder. Olanzapine or fluoxetine (Symbyax) is indicated for the treatment of depressive episodes associated with bipolar disorder.

Gabapentin (Neurontin)

This agent may be useful as adjunctive therapy for bipolar disorder. No significant drug interactions exist. No drug serum level monitoring is required.

Gabapentin is renally eliminated. It has mild sedative effects (sedation, ataxia, and fatigue).

Oxcarbazepine (Trileptal)

This agent is structurally similar to CBZ (ketoanalogue of CBZ). It is sometimes used as a mood stabilizer in patients with bipolar disorder, but further studies are needed.

No autoinduction problems exist, and there are no drug serum levels to monitor. It appears to have fewer drug-drug interactions than CBZ.

[Table 25-6. Lamotrigine Dose Titration]

Topiramate (Topamax)

This agent may be useful for treatment of bipolar disorder, but further studies are needed. Doses are usually lower than those indicated for treating seizure disorders.

Topiramate may cause weight loss.

Calcium channel blockers

These agents are usually reserved as last-line therapy. Data in the literature are inconsistent about using verapamil for mania (other calcium channel blockers may be effective).

Although these agents are not routinely used, they could possibly be used in pregnancy.

25-4. Major Depression

Introduction

Major depression is a prevalent and serious illness in the United States. It affects 10 million to 14 million people of all ages.

The condition is treatable but grossly undertreated. Most cases go unrecognized, which may be due to the social stigma surrounding depression. Several myths contribute to the problem of undertreatment (e.g., major depression is due to personal weakness or an inability to handle life's problems).

Epidemiology

The lifetime prevalence rate is 17%. One out of four females (10-24%) is affected. One out of 8 males (5%-12%) is affected.

Major depression is most common between the ages of 25 and 44.

Risk factors include the following:

• Family history

• Female

• Previous depressive episode

• Previous suicide attempt

• Comorbid medical or substance abuse disorder

Etiology

The etiology is unknown; however, there are many hypotheses, including the following:

• Dysregulation of neurotransmitters

• Decreased concentration of certain neurotransmitters

• Genetic basis for the disorder

Clinical Presentation

Physical findings

• Fatigue

• Pain (i.e., headaches, back pain, GI upset)

• Sleep disturbances (usually insomnia)

• Appetite disturbances (usually decreased appetite)

• Psychomotor retardation or agitation

Emotional symptoms

• Anhedonia

• Depressed mood for most of the day

• Hopelessness or helplessness

• Inappropriate feelings of guilt and worthlessness

• Anxiety or worry

• Suicidal ideation

Cognitive symptoms

• Decreased ability to concentrate

• Indecisiveness

Laboratory studies

There are no diagnostic laboratory tests for depression, but the following lab work should be conducted to rule out other medical illnesses that may manifest as depressive symptoms:

• CBC with differential

• Thyroid function tests

• Rapid plasma reagin (test for syphilis)

• Urine drug screen

Medical conditions that may contribute to the development or worsening of depression include the following:

• Myocardial infarction (MI)

• Cerebrovascular accident

• Parkinson's disease

• Multiple sclerosis

• Systemic lupus erythematosus

• Human immunodeficiency virus

• Rheumatoid arthritis

• Thyroid abnormalities

• Diabetes mellitus

• Cancer

• Vitamin deficiency

Possible drug-induced causes of depression should also be ruled out, including corticosteroids, oral contraceptives, propranolol, clonidine, and methyldopa.

Prognosis

Seventy percent of patients are responsive to antidepressant therapy. Following the first episode, 50-60% of patients will have another episode; following the second episode, 70-80% will have a third; and following the third, 90% will have another.

If untreated, an episode may resolve spontaneously within 6 to 24 months.

Approximately 15% of patients will commit suicide. Risk factors for suicide include being male, >50 years old, or unemployed; having recently lost a job or spouse; being socially isolated; having access to a weapon; and experiencing comorbid substance abuse.

Males are more likely to commit suicide, but females are more likely to attempt suicide. Males commonly use more violent means of suicide (e.g., firearms and hanging) than do females (e.g., slashing of wrists and drug overdoses).

DSM-IV Diagnostic Criteria

At least five symptoms (see previous discussion of clinical presentation) must be present mostly every day for a 2-week period and represent a change from previous functioning. At least one of the symptoms must be depressed mood or anhedonia.

Treatment Principles and Goals

Goals are as follows:

• Improve patient's ability to function and quality of life.

• Reduce or eliminate target symptoms with an antidepressant.

• Optimally, incorporate psychotherapy.

• Prevent relapse.

All antidepressants are equally effective in a given population:

Response varies from person to person.

• Each differs in side-effect and drug-interaction profiles.

• None are "speed" or "uppers."

Note: The U.S. Food and Drug Administration now requires all antidepressant drugs to include boxed warnings about increased risk of suicidal ideation and behavior in children and adolescents and in young adults (up to age 24), and a medication guide highlighting these risks is to be distributed with each new or refilled prescription for antidepressants in this population.

Basis for choosing an agent

• Past history of a patient's response or a family member's response to certain agents

• Side-effect profile and how it relates to any given patient's situation

Monitoring parameters

In the first week, the following should be noted:

• Decreased anxiety

• Trend toward normalization of appetite and sleep pattern

In the second to third week, the following should be noted:

• Increased energy

• Improved concentration and memory

• Improved somatic symptoms

Note: There is an increased risk for suicide at this time because the patient has the energy to carry out any ideations.

At 4-6 weeks, the following should be evident:

• Improved mood

• Decreased suicidal ideation

• Increased libido

Duration of therapy

Acute phase

The acute phase is usually 6-12 weeks or the length of time needed to stabilize depressive symptoms.

Maintenance phase

During this phase, maintain therapeutic doses of antidepressant. The duration is usually 1 year; you may taper antidepressant for a period of time and monitor for signs of relapse. The goal is to prevent relapse.

Prophylaxis

Chronic antidepressant therapy may be necessary for certain patients experiencing the following:

• A first-degree relative with bipolar disorder or recurrent depression

• Onset of depression before age 20 or after age 60

• Recurrence of depression within 1 year after medication discontinuation

• Severe, sudden, or life-threatening depression

Drug Therapy

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) are described in

Table 25-7.

Mechanism of action

TCAs increase the synaptic concentration of 5-HT or NE in the central nervous system (i.e., TCAs inhibit the presynaptic neuronal membrane's reuptake of 5-HT or NE).

Other information about TCAs

• Doses may be titrated to full dose range over 1-3 weeks.

• Many patients are dosed half-strength because of sedative effects; however, for patients with insomnia, the sedating effects may be helpful.

• These agents are deadly in overdose (blocks sinoatrial node in the heart).

• Drug serum levels are not commonly used in guiding therapy, but monitoring may be useful in patients taking amitriptyline, desipramine, imipramine, or nortriptyline.

Adverse effects

Effects include orthostatic hypotension, tachycardia, sedation, anticholinergic effects, arrhythmias (prolonged QT interval), weight gain, and sexual dysfunction.

Tertiary amines (e.g., amitriptyline, imipramine, doxepin, clomipramine) have more intense adverse effects compared to secondary amines (e.g., nortriptyline, desipramine).

Contraindications

Concomitant use of a monoamine oxidase inhibitor (MAOI) within the past 14 days, during pregnancy or lactation, and with narrow-angle glaucoma is contraindicated.

[Table 25-7. Tricyclic Antidepressants]

Precautions

Use with caution in patients with cardiac conduction disturbances, seizure disorders, hyperthyroidism, and renal or hepatic impairment. Avoid abrupt withdrawal in patients with prolonged use.

Drug interactions

• Increase in TCA level increases the levels of selective serotonin reuptake inhibitors (SSRIs), cimetidine, diltiazem, verapamil, labetalol, propoxyphene, quinidine, haloperidol, and methylphenidate.

• Decrease in TCA level affects CBZ, phenytoin, and barbiturate metabolism.

• Administration with MAOIs may cause serotonin syndrome.

• Monitoring blood pressure, pulse, ECG changes, and mental status changes is prudent; drug serum monitoring may be useful for amitriptyline, desipramine, imipramine, and nortriptyline.

Monoamine oxidase inhibitors

Table 25-8 summarizes information about MAOIs.

Mechanism of action

MAOIs increase the synaptic concentration of NE, 5-HT, and dopamine (DA) by inhibiting the breakdown enzyme—monoamine oxidase.

Note: MAOIs may be useful for patients who do not respond to other antidepressants or for treatment of atypical depression; however, they are rarely used because of the need for dietary restrictions, their side effect profile, and their potentially dangerous interactions with other medications.

Adverse effects

Effects include orthostatic hypotension, weight gain, sexual dysfunction, anticholinergic effects, and hypertensive crisis.

Contraindications

Be alert for renal or hepatic dysfunction, cardiovascular disease, and concomitant sympathomimetic therapy (e.g., pseudoephedrine, ephedra).

When a patient is switched from MAOIs to SSRIs, the MAOI must be discontinued 2 weeks prior to initiation of SSRI to prevent serotonin syndrome. When a patient is switched from SSRIs to MAOIs, the SSRI must be discontinued 2 weeks prior to initiation of MAOI, with the exception of fluoxetine, which requires 5 weeks because of its long half-life.

Precautions

Be aware of drug-food interaction with tyramine-containing foods (e.g., red wine, aged cheeses, and marmite).

Drug interactions

• TCAs

• SSRIs

• Sympathomimetics

• Meperidine

Selective serotonin reuptake inhibitors

See

Table 25-9 for information about SSRIs.

Mechanism of action

These agents selectively inhibit the reuptake of 5-HT.

All SSRIs should be tapered upon discontinuation of treatment (over 2-4 weeks), except fluoxetine. Side effects with abrupt withdrawal include flu-like symptoms, dizziness, nausea, tremor, anxiety, and palpitations.

Adverse effects

Effects include GI complaints, nervousness, insomnia, headache, fatigue, and sexual dysfunction, but SSRIs are safer in overdose than TCAs.

[Table 25-8. Monoamine Oxidase Inhibitors]

[Table 25-9. Selective Serotonin Reuptake Inhibitors]

Drug interactions

Drug interactions exist with TCAs, MAOIs, and SSRIs. Interactions are variable depending on the SSRI. Reportedly there are fewer drug interactions with escitalopram and citalopram.

Serotonin-norepinephrine reuptake inhibitors

See

Table 25-10 for information about serotonin-norepinephrine reuptake inhibitors (SNRIs).

Venlafaxine (Effexor, Effexor XR)

Mechanism of action

This agent inhibits the reuptake of 5-HT and NE (and also DA at higher doses). It is frequently referred to as an SNRI. Anticholinergic and antihistaminic effects are negligible. As the dose increases, NE and DA reuptake are more pronounced.

Adverse effects

Effects include GI upset, anxiety, insomnia, and headache. Elevation in blood pressure is possible; use with

[Table 25-10. Serotonin-Norepinephrine Reuptake Inhibitors]

caution in patients with uncontrolled hypertension. An extended release formulation is available to minimize GI upset. Other side effects are similar to those of SSRIs. Withdrawal symptoms may occur if the medication is abruptly discontinued.

Drug interactions

Cimetidine inhibits venlafaxine metabolism. Cyproheptadine induces venlafaxine metabolism. Serotonin syndrome is seen in combination with sibutramine, sumatriptan, tramadol, and trazodone. PT/INR (prothrombin time per international ratio) elevations have been seen when venlafaxine is added to patients taking warfarin.

Other aspects

Venlafaxine is indicated for both generalized anxiety disorder and major depression. It is not recommended in patients with uncontrolled hypertension or recent MI or cerebrovascular disorders.

Desvenlafaxine (Pristiq)

Mechanism of action

The mechanism of action of desvenlafaxine is similar to that of venlafaxine.

Adverse effects

Common effects include GI upset, increased serum cholesterol and triglycerides, xerostomia, sleep disturbances, and erectile dysfunction. Serious effects include hypertension, hyponatremia, and abnormal bleeding.

Withdrawal symptoms may occur if the drug is abruptly discontinued.

Drug interactions

The primary metabolic pathway is conjugation; therefore, desvenlafaxine has fewer drug interactions than venlafaxine.

Serotonin syndrome is seen in combination with MAOIs, SSRIs, sibutramine, tramadol, triptans, and linezolid.

Use in combination with unfractionated heparin, glycoprotein IIb or IIIa receptor inhibitors, warfarin, and nonsteroidal anti-inflammatory drugs may increase the risk of bleeding.

Duloxetine (Cymbalta)

Mechanism of action

The mechanism of action of duloxetine is similar to that of venlafaxine. It is a potent inhibitor of 5-HT and NE, and it has no significant affinity for dopaminergic, adrenergic, cholinergic, or histaminergic receptors.

Adverse effects

Effects include GI upset, dry mouth, dizziness, decreased appetite, elevation in blood pressure, and other side effects similar to those of SSRIs. Urinary hesitation may occur. The patient may have withdrawal symptoms with abrupt discontinuation.

Drug interactions

CYP1A2 inhibitors (e.g., cimetidine, quinolone antibiotics) and CYP2D6 inhibitors (e.g., fluoxetine, quinidine) increase duloxetine levels. The combination of duloxetine with triptans and serotonergic drugs may cause serotonin syndrome.

Other aspects

Duloxetine is indicated for both major depression (20 or 30 mg bid or 60 mg qd) and diabetic peripheral neuropathic pain (60 mg qd). It is metabolized by CYP450 1A2 and 2D6; these inhibitors may increase plasma levels of duloxetine, causing increased side effects. Duloxetine is contraindicated in uncontrolled narrow-angle glaucoma.

Other classes of antidepressant medication

Bupropion (Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban)

Mechanism of action

Bupropion, an inhibitor of NE and DA reuptake (effects on 5-HT reuptake are minimal), is referred to as a norepinephrine-dopamine reuptake inhibitor (NDRI).

Adverse effects

Effects include GI upset, insomnia, anxiety, headache, and psychosis (rare). Buproprion is less associated with sexual dysfunction than are SSRIs and other classes. It also decreases the seizure threshold.

Drug interactions

Cimetidine and ritonavir inhibit bupropion metabolism, and CBZ induces bupropion metabolism.

Other aspects

There is an increased risk of seizure with bupropion, especially in patients with a seizure disorder, eating disorder, or electrolyte imbalance. The maximum daily dose is 450 mg (400 mg SR). Titrate the dose slowly to minimize seizure risk. Bupropion is marketed as Zyban for smoking cessation.

Trazodone (Desyrel)

Mechanism of action

This agent inhibits 5-HT reuptake and blocks 5-HT2A receptors.

Adverse effects

Effects include extreme sedation, orthostatic hypotension, and priapism. There are no anticholinergic or cardiotoxic effects.

Drug interactions

Fluoxetine and ritonavir inhibit trazodone metabolism.

Other aspects

Because it causes excessive sedation, trazodone is not clinically used as an antidepressant; rather, it is commonly used to treat insomnia (usually dosed 25-150 mg qhs).

Nefazodone (Serzone)

Mechanism of action

This agent inhibits 5-HT and NE uptake and blocks 5-HT2A receptors.

Adverse effects

Effects include GI upset, sedation, dry mouth, constipation, and lightheadedness. Nefazodone is associated with minimal sexual dysfunction and orthostatic hypotension.

Drug interactions

Nefazodone is a potent inhibitor of CYP3A4 isoenzyme; use with caution with drugs metabolized through this enzyme (e.g., buspirone, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, alprazolam, triazolam, digoxin). Ritonavir inhibits nefazodone metabolism.

Other aspects

Nefazodone is usually dosed bid because of its short half-life. There is a black box warning for hepatotoxicity.

Mirtazapine (Remeron and Remeron Soltab)

Mirtazapine is available in 7.5, 15.0, 30.0, and 45.0 mg tablets.

Mechanism of action

This agent antagonizes presynaptic α2 autoreceptors and heteroreceptors that prevent the release of 5-HT and NE (resulting in increased 5-HT and NE in the synapses). It antagonizes 5-HT2A and 5-HT3 receptors, thereby resulting in less GI upset and less anxiety.

Adverse effects

Effects include sedation, increased appetite, weight gain, and constipation. Elevation in LFTs and increase in triglycerides may occur. There is also a small risk of agranulocytosis or neutropenia.

Other aspects

Mirtazapine may be useful in geriatric patients because it causes increased appetite, is sedating, and has no significant drug interactions.

Aripiprazole (Abilify)

Aripiprazole is approved for adjunct treatment of major depressive disorders. It is available in 2, 5, 10, 15, 20, and 30 mg tabs and in a 1 mg/mL concentrate. The maximum dose is 15 mg/d.

Mechanism of action

This agent's action is not fully understood; it partially antagonizes D2 and 5-HT1A receptors and antagonizes 5-HT2A receptors.

Adverse effects

See Section 25-2 on schizophrenia.

Selegiline (Emsam)

Selegiline is available in 6, 9, and 12 mg/24 hour patches.

Mechanism of action

This agent's mechanism of action is not fully understood; however, it is believed to be linked to selegiline's irreversible inhibition of monoamine oxidase.

Adverse effects

Effects include headache, insomnia, application-site reaction, diarrhea, and dry mouth.

Other aspects

There are no dietary restrictions for the 6 mg dose.

Psychostimulants

Methylphenidate has been used to treat depression (especially in the geriatric population) and has been shown to increase activity level as well as improve mood symptoms. It may cause GI upset, insomnia, and cardiovascular effects. It should be used with caution in anxious or psychotic patients. It inhibits TCA metabolism.

Nonpharmacologic Treatments

Psychotherapy

Psychotherapy is especially useful combined with drug therapy.

Electroconvulsive therapy

Electroconvulsive therapy (ECT) is very safe and effective for treating depression. It is believed to physically "reset" receptors in the brain. ECT is usually reserved for refractory or psychotic patients.

Procedure

The patient is anesthetized and paralyzed in an outpatient setting. The patient is monitored through an electroencephalogram (EEG) during the procedure, and a seizure is induced for 30-90 seconds.

Acute and maintenance treatment

The procedure is administered every other day for 6-9 treatments. Maintenance treatment is variable for each patient, but ECT is usually administered monthly after acute treatment.

Adverse effects

Effects include short-term memory loss and confusion on the day of treatment.

Relative contraindications

ECT increases intracranial pressure and, therefore, is not recommended in patients with recent MI, intracerebral hemorrhage, or cerebral lesions.

25-5. Anxiety Disorders

Introduction

Anxiety disorders are serious, debilitating mental illnesses that include a group of conditions that share extreme anxiety as the primary mood disturbance.

Epidemiology

Anxiety disorders affect approximately 19 million adults in the United States. There are no racial or cultural differences, and gender differences depend on the specific anxiety disorder.

There is significant comorbidity with other psychiatric illnesses (e.g., substance abuse).

Types and Classifications

Generalized anxiety disorder

Generalized anxiety disorder (GAD) is characterized by unprovoked excessive worry and tension. Anxiety usually consumes the patient's day, thereby affecting social and occupational functioning. Physical complaints (e.g., GI upset, headache, muscle tension, tremors, insomnia, fatigue) are common. Incidence of GAD is higher in females than in males.

Panic disorder

Panic disorder (PD), with or without agoraphobia, is characterized by feelings of terror that suddenly strike without warning and usually last for approximately 10-15 minutes.

Physical symptoms include increased heart rate, sweating, tremors, shortness of breath, chest pain, and dizziness. The patient feels as if death is imminent.

Agoraphobia (fear of open or public places) usually develops later in the illness, especially if PD is not treated. Agoraphobic patients associate panic attacks with certain places and occasions, so they avoid going out and remain at home. Agoraphobia is more prevalent in females than in males.

Obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is characterized by intrusive, recurrent, and repetitive thoughts that severely interfere with the patient's social and occupational functioning (e.g., preoccupation with contamination, order, counting, cleanliness, safety).

Compulsions (e.g., repetitive washing of hands and checking and rechecking) are acts that must be performed in an attempt to decrease the anxiety felt about the obsessions. Prevalence of OCD is equal in males and females.

Social anxiety disorder

Social anxiety disorder (SAD) is characterized by feelings of anxiety in social situations (e.g., speaking in front of others and attending social gatherings). Patients feel as though everyone is staring and judging them. People affected by SAD usually do not seek treatment and will, instead, self-medicate with alcohol. There is equal male and female prevalence.

Simple or specific phobias

Simple phobias are defined as specific fears (e.g., heights, dogs, mice, spiders, needles) that cause an extreme anxiety response. Affected persons usually do not seek treatment and will, instead, avoid situations that involve the phobia.

Exposure therapy to the perceived threat is common therapy. Incidence in females is greater than in males.

Post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is characterized by severe anxiety that is caused by an event outside of normal human experience (e.g., war, rape, natural disasters). Symptoms include vividly reliving the event to the extent that anxiety symptoms (i.e., flashbacks, nightmares or night terrors, extreme mood changes, feelings of fright) commonly occur. PTSD is often associated with strong guilt feelings, impaired relationships, social withdrawal, and personality changes. There is a greater prevalence in females than in males.

Anxiety due to a medical disorder

Anxiety is likely to be related to evidence of a medical condition (e.g., congestive heart failure, hyperthyroidism, chronic obstructive pulmonary disease [COPD]).

Substance-induced anxiety disorder

Anxiety symptoms are likely to be a direct result of use of an agent (e.g., amphetamines, toxin, medication). Symptoms may also occur with intoxication or withdrawal.

Associated features

High comorbidity exists with other psychiatric illnesses, especially depression. High comorbidity also exists with alcohol or substance abuse.

This disorder is associated with chronic medical illnesses (e.g., chronic pain syndromes, long-term illnesses, GI distress, headaches).

Etiology

This disorder's etiology is presently unknown. Most current evidence suggests the cause is primarily biologic (imbalance of GABA, 5-HT, and NE) with genetic predisposition.

Drug Therapy

Benzodiazepines

Benzodiazepines (BZDs), the most commonly used anxiolytics, are described in

Table 25-11.

Mechanism of action

BZDs potentiate the actions of GABA by increasing the influx of chloride ions into neurons. It is hypothesized that, through their effects on neurons mediated by receptor complexes, BZDs reduce neuronal firing and, thus, the symptoms of anxiety.

Note: The rate of absorption varies with BZDs. The more lipophilic compounds (i.e., alprazolam, diazepam, clorazepate, flurazepam) are rapidly absorbed and result in quicker onset of action. The less lipophilic BZDs are chlordiazepoxide, clonazepam, and lorazepam.

Adverse effects

Effects include sedation, dizziness, confusion, blurred vision, diplopia, syncope, residual daytime sedation, and reduced psychomotor and cognitive dysfunction.

Metabolism

Lorazepam, oxazepam, and temazepam (LOT) are conjugated and are preferred in patients with hepatic dysfunction and elderly patients.

[Table 25-11. Benzodiazepines]

Drug interactions

BZDs metabolized by CYP3A4 (e.g., alprazolam, diazepam, and triazolam) have decreased clearance if taken concomitantly with CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, nefazodone). BZDs are deadly in overdose if taken concomitantly with alcohol.

Clinical pearls

• BZDs may cause a paradoxical reaction in children, cognitively impaired elderly patients, mentally retarded patients, and post-head injury patients.

• Never abruptly discontinue BZDs because doing so may precipitate status epilepticus. Always taper the dose to avoid seizure risk and withdrawal symptoms.

• In elderly patients, the BZDs of choice are those that are conjugated (LOT). There is an increased risk of falls in this population.

• It is best to avoid use of BZDs in pregnancy (especially first trimester) because of risk of cleft palate. BZDs are also present in breast milk and should be avoided in nursing females.

• The abuse potential is great; BZDs are not recommended for patients with substance abuse issues.

• Tolerance is common, and increasing doses are needed to control anxiety levels.

• Alprazolam extended-release (Xanax XR) is dosed once daily; do not crush, chew, or break doses. It is also available as an orally disintegrating tablet (Niravam).

Buspirone (BuSpar)

Mechanism of action

The mechanism of action is poorly understood; 5-HT1A is a partial agonist, and buspirone reportedly stimulates presynaptic 5-HT1A receptors. In addition, the agent has a moderate affinity for D2 receptors.

Buspirone does not interact with the BZD-GABA receptor complex.

Onset of anxiolytic effect is longer for buspirone than for BZD (2-3 weeks).

Adverse effects

Effects include GI upset, headache, and nervousness.

Benefits

Possible benefits over BZDs include the following:

• Usually less sedating than BZDs

• Little to no psychomotor or cognitive impairment

• No association with withdrawal symptoms, abuse, or physical dependence

• Not cross-tolerant with BZDs or alcohol

Antidepressants as treatment for anxiety disorders

TCAs are usually a third-line treatment because of side effects and the danger of overdose. Clomipramine is effective for OCD.

MAOIs are usually a third-line treatment because of side effects and drug-food interactions.

SSRIs and SNRIs are a first-line treatment for many anxiety disorders, especially in patients with comorbid depression and substance abuse problems.

Titrate doses of antidepressants slowly to decrease risk of initial anxiety symptoms. Ultimately, higher doses are commonly used for anxiety disorders.

Other classes of drugs used to treat anxiety disorders

β-blockers (e.g., propranolol and atenolol) ease peripheral symptoms of anxiety and may be useful for panic disorders and SAD.

Hydroxyzine reduces anxiety and is often used in patients with substance abuse issues.

Nonpharmacologic Treatment

• Supportive psychotherapy (individual, group, family)

• Cognitive behavioral therapy

• Focus on coping with the fear of the symptoms of anxiety

• Relaxation techniques

• Exercise and lifestyle modifications (reduce caffeine and simple sugars)

25-6. Eating Disorders

Anorexia Nervosa

Characteristics

Patients suffering from anorexia nervosa refuse to maintain body weight at or above a minimal, normal weight for their age and height (85% or less of expected body weight). They experience intense fear of gaining weight or becoming fat, although they are underweight. There is a disturbance in self-perception of body weight, size, proportion, and attractiveness.

A female patient experiences amenorrhea for at least three consecutive cycles.

Types

• Restricting

• Binge eating and purging

Bulimia Nervosa

Characteristics

Recurrent episodes of binge eating occur (often followed by intense feelings of guilt). The patient may consume as much as 5,000-20,000 calories over 2-8 hours. Recurrent and inappropriate compensatory behavior occurs in order to prevent weight gain.

A person averages 2 binges per week for 3 months. Self-evaluation is primarily influenced by body shape and weight.

Types

• Purging (vomiting, abuse of laxatives or diuretics)

• Nonpurging (excessive exercise, fasting)

Binge Eating Disorder

Characteristics

Recurrent episodes of binge eating occur (patients are usually obese). The patient eats when not physically hungry, eats more rapidly than normal, and feels disgusted with himself or herself. Marked distress is present regarding binge eating.

Binge eating episodes occur, on average, at least 2 days per week for 6 months.

Etiology and Prevalence

The etiology of eating disorders is essentially unknown, but various theories have been proposed (genetic predisposition, environmental and societal issues, chemical imbalance in the brain). There is usually a defined event or situation that begins the disorder (e.g., a significant stressor such as starting college, divorce, or death of a loved one).

Eating disorders are most commonly seen in Caucasian, middle- to upper-class females.

The age of onset for anorexia nervosa is 13-20 years old. The male-to-female ratio is 1:10-20. For bulimia nervosa, the age of onset is 16-18 years old, and the male-to-female ratio is 1:10.

Medical Complications and Signs of Disease

• Eating disorders produce states of semistarvation and noticeable malnutrition, especially in anorexia.

• In bulimia, patients are more difficult to identify because they are commonly of normal body weight.

• Dehydration occurs.

• There is a high incidence of comorbid anxiety, depression, OCD, and substance abuse.

• Dental caries and enamel erosion occur because of stomach acid exposure.

• Calluses on the dorsum of the hand or fingers develop because of induction of vomiting.

• Mortality rate is about 10% from starvation (primarily because of electrolyte imbalances), arrhythmia, or suicide.

• Long-term complications include endocrine or metabolic, cardiovascular, renal, gastroenterologic, hematologic, pulmonary, musculoskeletal, immunologic, and dermatologic issues.

Treatment

Psychotherapy is the mainstay of treatment. Therapy can be individual, group, family, supportive, cognitive behavioral, or insight oriented. Primary objectives are to define and examine extent of problem. The patient learns to accept the condition, and treatment results in a reconstruction of self-identity and self-confidence.

Dietary intake is slowly normalized with the goal of restoring normal body weight. Nutritional counseling is used. Distorted ideas about caloric intake and body shape are corrected.

Relapse prevention focuses on developing and using coping mechanisms and avoiding high-risk situations.

Drug Therapy

SSRIs are primarily used and may be more effective for patients with bulimia. Antidepressants do not appear to be beneficial in helping severely malnourished anorexia nervosa patients gain weight, but they may help patients maintain weight after it has been gained.

Fluoxetine (Prozac) is indicated for the treatment of bulimia nervosa. Higher doses are used; titrate to 60 mg/d every morning.

Topiramate (Topamax) and zonisamide (Zonegran) may be beneficial in binge-eating disorder and bulimia nervosa.

Ideally, treatment of eating disorders includes both psychotherapy and pharmacotherapy.

25-7. Key Points

Schizophrenia

• Patients with schizophrenia have positive (hallucinations and delusions), negative (flat affect, avolition, anhedonia, poverty of thought), and disorganized speech and behavior symptoms. Positive symptoms usually respond to drug therapy first.

• Antipsychotics (conventional or atypical) are essential treatment for schizophrenia; atypical medications (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, and paliperidone) have been considered first-line medical treatment because they lower risk of EPSs and TD more than conventional medications and they appear to be more beneficial for negative symptoms.

• Recent evidence has shown that schizophrenic patients discontinue medications frequently regardless of whether they are taking second-generation or first-generation antipsychotics. Such research questions whether the atypical antipsychotics are more effective at treating negative symptoms than are the typical medications.

• Atypical antipsychotics (especially olanzapine) are associated with weight gain and with lipid and glucose abnormalities (ziprasidone and aripiprazole do not appear to have the weight gain and metabolic abnormalities).

• Low-potency conventional agents (chlorpromazine, thioridazine) are used more often than high-potency agents (haloperidol, fluphenazine).

• Low-potency agents have more sedation, orthostatic hypotension, and anticholinergic side effects and fewer EPS than high-potency agents. High-potency agents have more EPS and less sedation, orthostatic hypotension, and anticholinergic effects.

• EPS consist of dystonic reactions (to be remedied by diphenhydramine 25-50 mg IM or benztropine 1-2 mg IM every 30 minutes until resolution); akathisia (to be treated with lorazepam, clonidine, or propranolol); and pseudoparkinsonism (ameliorated by amantadine or benztropine).

• Clozapine is the only agent proven effective for refractory schizophrenia.

• Consider long-acting injectable preparations in situations of poor compliance.

Bipolar Disorder

• The acute treatment for bipolar disorder focuses on slowing down the patient and reducing harm to himself or herself and others

• Maintenance treatment focuses on preventing or reducing the number of future episodes.

• A mood stabilizer is an essential component in the treatment of bipolar disorder. First-line mood stabilizers include lithium and divalproex sodium (or valproic acid).

• The risk of lithium side effects and toxicity can be prevented by monitoring the patient for signs and symptoms of problems and by obtaining regular blood-level readings.

• Other drug therapies that may be used to treat the patient with bipolar disorder include atypical antipsychotics, gabapentin, carbamazepine, oxcarbazepine, topiramate, and lamotrigine (especially if the patient is depressed).

Major Depression

• All antidepressants are equally effective in a given population.

• Response varies from person to person. Antidepressants differ in side-effect and drug-interaction profiles, and none are "speed" or "uppers."

• Choice of agent depends on the history of response of other family members to certain antidepressants (if available) and the particular side-effect profile (as it relates to any given patient).

• First-line agents include SSRIs, bupropion, venlafaxine, and duloxetine; second-line agents may include mirtazapine and nefazodone; third-line agents may include TCAs and MAOIs.

• The goal is to reduce or eliminate target symptoms with an antidepressant; incorporating psychotherapy is optimal.

• The goal of treatment of depression is to improve the patient's ability to function and his or her quality of life.

Anxiety Disorders

• Anxiety disorders are serious, debilitating mental illnesses that have extreme anxiety as the primary mood disturbance.

• Various drug therapies include benzodiazepines, buspirone, antidepressants (especially SSRIs and venlafaxine), β-blockers, and hydroxyzine.

• Nonpharmacologic therapy of anxiety disorders is an important aspect of care (e.g., supportive therapy, cognitive behavioral therapy, relaxation techniques, and exercise and lifestyle modifications).

Eating disorders

• Anorexia nervosa is characterized by a refusal to maintain body weight (at or above a minimal normal weight for age and height), an intense fear of gaining weight, a disturbance in self-perception of body weight, and amenorrhea for at least three consecutive cycles.

• Bulimia nervosa is characterized by recurrent episodes of binge eating, recurrent and inappropriate compensatory behavior to prevent weight gain, an average of two binges per week for 3 months, and self-evaluation that is primarily influenced by body shape and weight.

• Eating disorders most commonly occur in young, Caucasian, middle- to upper-class females.

• Medical complications and comorbid psychiatric disorders (e.g., anxiety, depression, and substance abuse) are extremely common in this population.

• Medications such as antidepressants may be helpful in treating eating disorders (especially bulimia); optimal therapy should include psychotherapy in combination with drug therapy.

25-8. Questions

Select the single best response for questions 1-4.

1.

S. J. is a 30-year-old white female with a 10-year history of schizophrenia. Her current therapy includes haloperidol 10 mg po bid. The psychiatrist wants to convert her to haloperidol decanoate. What would be the appropriate equivalent monthly dose of haloperidol decanoate?

A. 100 mg

B. 10 mg

C. 500 mg

D. 200 mg

E. 12.5 mg

 

2.

B. T. reports to the nursing station with his head pulled sharply to the side and rear. He complains of severe pain in his neck and back area. The most appropriate diagnosis and treatment would be which of the following?

A. Akathisia; propranolol 20 mg IM until resolution

B. Dystonic reaction; diphenhydramine 50 mg IM every 30 minutes until resolution

C. Tardive dyskinesia; physical therapy

D. Dystonic reaction; lorazepam 2 mg IM every 30 minutes until resolution

E. None of the above

 

3.

Negative symptoms in schizophrenia could include all of the following except

A. flat affect.

B. anhedonia.

C. avolition.

D. persecutory delusions.

E. poverty of thought.

 

4.

A 48-year-old black male arrives at the emergency department seeking his "nerve pill." He has a 27-year history of paranoid schizophrenia with multiple hospitalizations. In recent years, he has been effectively maintained on fluphenazine 10 mg po bid. He now states that he feels "really bad today." His arms and jaws are stiff, his temperature is 104°F, his blood pressure is 176/110, and his WBC is 19,000. LFTs and CPK are ordered STAT. While you await the test results, you should do which of the following?

A. Discontinue oral fluphenazine and begin quetiapine.

B. Discontinue oral fluphenazine.

C. Continue oral fluphenazine and add bromocriptine.

D. Discontinue oral fluphenazine and give fluphenazine decanoate 25 mg IM STAT.

E. Do nothing; labs need to be evaluated first.

 

For questions 5-8, one or more of the answers given may be correct. Answer each question as follows:

A. I only

B. II only

C. I and III only

D. II and III only

E. I, II, and III

A 25-year-old white male has been increasingly disruptive at home. He has been claiming that he is the president of the United States and has been staying awake all night planning bills for Congress. He has been argumentative and threatening with his friends and family. Though he appears extremely tired physically, he is constantly active.

5.

The psychiatrist has decided to initiate Eskalith CR 450 mg bid in this patient. Which of the following lab tests will need to be performed for this patient before starting this drug therapy regimen?

I. Pregnancy test

II. Thyroid function tests

III. SCr

 

6.

As the pharmacist on the treatment team, you alert the patient's family to the common side effects of lithium, which include

I. polyuria.

II. alopecia.

III. elevated hepatic enzymes.

 

7.

Which of the following statements are correct regarding the treatment of bipolar disorder?

I. Lithium and divalproex sodium are considered first-line therapy options for mood stabilization.

II. When treating a patient with lithium, one must monitor the WBC and ANC because of lithium's propensity to cause agranulocytosis.

III. Patients diagnosed with bipolar I disorder exhibit intermittent cycles of mania and major depression.

 

8.

Which of the following therapies have been used for the treatment of bipolar disorder?

I. Olanzapine

II. Topiramate

III. Calcium channel blockers

 

Select the single best response for questions 9-11.

9.

Insomnia, GI upset, and headache are common side effects of which of the following antidepressants?

A. Phenelzine

B. Amitriptyline

C. Fluoxetine

D. Trazodone

E. Both B and C

 

10.

A 29-year-old depressed black female has shown little improvement with fluoxetine treatment, so the psychiatrist decides to change her medication to tranylcypromine. What is your recommendation for the switch?

A. Gradually decrease fluoxetine dosage over a 4-week period, and then start tranylcypromine.

B. Wait 2 weeks after stopping fluoxetine, and then begin tranylcypromine.

C. Over 6 weeks, gradually decrease fluoxetine dosage as you gradually increase the tranylcypromine dosage.

D. Wait 5 weeks after stopping fluoxetine before initiating tranylcypromine.

E. Maintain fluoxetine dosage, and start tranylcypromine; stop the fluoxetine when the tranylcypromine has achieved a therapeutic level.

 

11.

Which of the following has been shown to induce or worsen depression?

A. Oral contraceptives

B. Amoxicillin

C. Thiamine

D. Methylphenidate

E. Phenelzine

 

The following case should be used to answer questions 12 and 13.

K. Y. is a 36-year-old female admitted to your mental health facility for the fifth time in the past 3 years for major depressive disorder. She presents with lack of appetite, avolition, anhedonia, and suicidal ideations with a plan. Vitals include BP 127/76, P 82, R 18, T 98.6°F. Labs include TSH 4, FBG 135, (-) UDS, BAL 0. Her current medications are fluoxetine 40 mg daily, metformin 1,000 mg bid, and hydroxyzine 25 mg tid. K. Y. states compliance and denies side effects. Past medications include citalopram and venlafaxine.

12.

What axis diagnosis is major depressive disorder?

A. I

B. II

C. III

D. IV

E. V

 

13.

The psychiatrist asks for your recommendation for this patient with refractory depression. What is the best option?

A. Discontinue fluoxetine, and initiate Pristiq.

B. Discontinue fluoxetine, wait 2 weeks, and start Selegiline.

C. Add Abilify to current regimen.

D. Discontinue fluoxetine, and start Lexapro.

E. Add Serax to current regimen.

 

14.

Which of the following is correct regarding electroconvulsive therapy (ECT)?

A. For maximum effectiveness, seizures should last 5-10 minutes.

B. ECT is contraindicated in patients with COPD.

C. ECT is effective treatment for pregnant females with major depression.

D. Memory loss lasting 1-2 weeks is common.

E. ECT may cause amenorrhea in female patients.

 

15.

A 33-year-old waitress is experiencing symptoms of anxiety, including night terrors and mood lability. She reports no past psychiatric history but admits that these symptoms started about 2 weeks after armed and masked gunmen robbed her restaurant. She is most likely experiencing which of the following?

A. LSD

B. PTSD

C. GAD

D. OCD

 

16.

A new patient presents to your clinic. He reports that it took him 3 hours to get ready for this appointment and that he returned home several times to check to see if the door was locked. During the interview, he straightens up your desk, making sure all square items are at right angles to each other. He would most likely be diagnosed with which of the following?

A. PTSD

B. PCP

C. OCD

D. GAD

 

17.

Which of the following statements regarding the use of SSRIs in anxiety disorders is most accurate?

A. SSRIs are not usually effective in the treatment of anxiety.

B. SSRI doses for anxiety should be started lower than initial doses for depression.

C. SSRIs should be used only after a failed treatment trial with benzodiazepines.

D. SSRIs may be used on a prn basis when anxiety symptoms emerge.

 

18.

Which of the following characteristics is not correct regarding benzodiazepines?

A. They potentiate the effect of γ-aminobutyric acid.

B. They are highly lipophilic.

C. They are cross-tolerant with alcohol.

D. Their pharmacologic action is similar to that of buspirone.

E. There is risk of seizure if they are abruptly discontinued.

 

For questions 19-22, one or more of the following answers given are correct. Answer each question as follows:

A. I only

B. II only

C. I and III only

D. II and III only

E. I, II, and III

19.

Which of the following is true regarding anorexia nervosa (AN)?

I. AN is characterized by recurrent and inappropriate compensatory behavior to prevent weight gain.

II. Patients with AN generally appear to be of normal weight for age and height.

III. AN patients have an intense fear of gaining weight or becoming fat, although they are underweight.

 

20.

What DSM-IV criteria for AN are diagnostic for this type of eating disorder?

I. Absence of at least three consecutive menstrual cycles

II. Sunken eyes with dark circles underneath

III. A binge eating-purging episode that occurs at least once in the past 6 months

 

21.

Which of the following is true regarding bulimia nervosa?

I. The individual may consume 5,000-20,000 calories in a single binge episode that may last as long as 2-8 hours.

II. The two specific types of bulimic patients are purging type and nonpurging type.

III. There is an average of two binges per week for 3 consecutive months.

 

22.

Patients with AN may demonstrate which of the following characteristics?

I. Kleptomania

II. Laxative or diuretic abuse

III. Amenorrhea

 

23.

Which of the following is the most appropriate treatment for bulimia nervosa?

A. Insight-oriented therapy

B. Fluoxetine 20 mg qd

C. Fluoxetine 60 mg qam + cognitive behavioral therapy

D. Olanzapine 10 mg qhs

E. Olanzapine 20 mg qhs + family therapy

 

25-9. Answers

1.

D. The patient is on haloperidol 10 mg bid. Therefore, to convert to the decanoate injection, the total oral daily dose is multiplied by 10. The dose would be Haldol-D 200 mg IM every 4 weeks.

 

2.

B. The patient is experiencing a dystonic reaction, which can be treated with either benztropine 1-2 mg IM or diphenhydramine 25-50 mg IM every 30 minutes until resolved. The dystonic reaction is thought to occur because of an imbalance in dopamine and acetylcholine in the nigrostriatal region of the brain.

 

3.

D. Delusions are false beliefs or wrong judgments held with conviction despite incontrovertible evidence to the contrary. Such symptoms are referred to as positive for patients with schizophrenia.

 

4.

B. The symptoms that the patient is displaying appear to be the result of neuroleptic malignant syndrome. All neuroleptics have the propensity to cause this rare but deadly adverse effect. The first steps in treating NMS are to discontinue the offending agent, offer supportive therapy, and prescribe a dopamine agonist and (commonly) a skeletal muscle relaxant.

 

5.

D. Initiation of lithium requires several baseline lab tests: pregnancy test (if patient is female and of childbearing age), ECG and BP to assess cardiovascular status, thyroid function tests to rule out euthyroid goiter or hypothyroidism, SCr/BUN (lithium is 100% renally eliminated), and CBC with differential to evaluate for leukocytosis. Electrolytes should also be evaluated (decreased sodium can increase lithium levels). Hence, only the pregnancy test should not be performed, because the patient is male.

 

6.

A. Common side effects that occur with the initiation of lithium include polyuria, polydipsia, tremor, and GI upset. Common side effects that may occur later in therapy include weight gain and mental dulling. Elevated hepatic enzymes and alopecia are side effects that may occur with divalproex sodium.

 

7.

C. Agranulocytosis is a side effect that is monitored weekly with clozapine therapy for 6 months. After 6 months, monitoring can be done every 2 weeks for the duration of therapy.

 

8.

E. All of the therapies listed have been used for mood stabilization in bipolar disorder.

 

9.

C. SSRIs commonly cause insomnia, GI upset, anxiety, headache, and sexual dysfunction. Phenelzine, amitriptyline, and trazodone cause sedative effects.

 

10.

D. Because of fluoxetine's long half-life, 5 weeks should pass before initiating MAOI therapy. If fluoxetine is not cleared from the body by the time the MAOI is started, there is a risk of developing serotonin syndrome.

 

11.

A. Many medications can cause or worsen depression, such as antihypertensives (reserpine, methyldopa, propranolol, clonidine); antiparkinsonian agents (levodopa, carbidopa, amantadine); hormonal agents (estrogens, progesterone); corticosteroids; cycloserine; and the anticancer agents vinblastine and vincristine.

 

12.

A. Axis I is for clinical disorders.

 

13.

C. Abilify (aripiprazole) is approved as adjunct treatment for refractory depression. The patient has already failed a trial with venlafaxine; therefore, initiating therapy with its isomer Pristiq (desvenlafaxine) may not be the best option. MAOIs are a viable fourth-line treatment option. However, you would wait 5 weeks after discontinuing fluoxetine before initiating an MAOI. Lexapro (escitalopram) is an isomer of citalopram, which the patient had already failed. Benzodiazepines are not recommended for treatment of depression.

 

14.

C. ECT is a safe and effective therapy for pregnant females and patients with COPD. Relative contraindications include increased intracranial pressure, recent MI, recent intracerebral hemorrhage, and cerebral lesions. Memory loss is a common side effect, but it usually occurs only on the day of treatment and perhaps the following day. The induced seizure lasts 30-90 seconds and is monitored by an EEG. Additionally, ECT does not cause amenorrhea in female patients.

 

15.

B. The patient experienced a violent and frightening episode 2 weeks before her symptoms appeared. The symptoms of reexperiencing of the event, night terrors, and mood lability are common in patients with PTSD.

 

16.

C. The patient is displaying signs and symptoms of OCD (e.g., a long time is spent getting ready, and there is repeated checking behavior and preoccupation with rearranging items to 90-degree angles). These activities are time consuming and limit his social and occupational functioning.

 

17.

B. Because SSRIs can be activating and may initially cause symptoms of anxiety, it is important to "start low and go slow" with these agents when used for anxiety disorders.

 

18.

D. Buspirone's mechanism of action is agonism of 5-HT1A receptors. Buspirone also possesses moderate affinity for D2 receptors. It does not interact with the BZD-GABA receptor complex like the BZDs do. The BZDs cross the blood-brain barrier and are cross-tolerant with alcohol. If BZDs are abruptly discontinued, seizures can result.

 

19.

C. Patients with AN refuse to maintain body weight at or above a minimal, normal weight for age and height (less than 15% of expected body weight). Patients with AN may respond to antidepressants, but psychotherapy is usually more effective. AN is most commonly seen in Caucasian, middle- to upper-class females.

 

20.

A. DSM-IV criteria list the refusal to maintain body weight at or above a minimal, normal weight for age and height (85% or less of expected body weight and an intense fear of gaining weight or becoming fat although underweight); disturbance in self-perception of body weight (i.e., size, proportion, attractiveness); and amenorrhea for at least three consecutive cycles.

 

21.

E. All of the answers are correct regarding bulimia nervosa.

 

22.

D. Patients with AN commonly reduce weight by reducing food intake. Many patients use other methods to lose weight such as excessive exercise, laxative or diuretic use, substance abuse, and self-induced vomiting. Amenorrhea ensues as a result of estrogen deficiency; it may occur before weight loss.

 

23.

C. Fluoxetine is approved for treating bulimia nervosa; 60 mg is the most common dose. A combination of psychotherapy and pharmacotherapy is preferred.

 

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