Management of Bipolar Disorder



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Am Fam Physician. 2000 Sep 15;62(6):1343-1353.

  See related patient information handout on bipolar disorder, written by the authors of this article.

ACF  This article exemplifies the AAFP 2000 Annual Clinical Focus on mental health.

Bipolar disorder most commonly is diagnosed in persons between 18 and 24 years of age. The clinical presentations of this disorder are broad and include mania, hypomania and psychosis. Frequently associated comorbid conditions include substance abuse and anxiety disorders. Patients with acute mania must be evaluated urgently. Effective mood stabilizers include lithium, valproic acid and carbamazepine. A comprehensive management program, including collaboration between the patient's family physician and psychiatrist, should be implemented to optimize medical care.

Bipolar disorder is characterized by variations in mood, from elation and/or irritability to depression. This disorder can cause major disruptions in family, social and occupational life. Bipolar I disorder is defined as episodes of full mania alternating with episodes of major depression. Patients with mania often exhibit disregard for danger and engage in high-risk behaviors such as promiscuous sexual activity, increased spending, violence, substance abuse and driving while intoxicated.

Bipolar II disorder is characterized by recurrent episodes of major depression and hypomania. Hypomania is manifested by an elevated and expansive mood. The behaviors characteristic of hypomania are similar to those of mania but without gross lapses of impulse and judgment. Hypomania does not cause impairment of function and may actually enhance function in the short term.

Bipolar I disorder is typically diagnosed when patients are in their early 20s. Manic symptoms can rapidly escalate over a period of days and frequently follow psychosocial stressors. Some patients initially seek treatment for depression. Other patients may appear irritable, disorganized or psychotic. Differentiating true mania from mania resulting from secondary causes can be challenging (Table 1).1,2

TABLE 1
Causes of Secondary Mania

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Bipolar II disorder typically is brought to medical attention when the patient is depressed. A careful history will usually illuminate the diagnosis. Some depressed patients exhibit hypomania when given antidepressants.3 This variation is sometimes referred to as bipolar III disorder. The criteria for major depressive episode and manic episode, as described in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), are summarized in Table 2.4

TABLE 2

Criteria for Major Depressive Episode and Manic Episode

Major depressive episode

Five or more of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood.

2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)

3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains.

4. Insomnia or hypersomnia nearly every day

5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)

6. Fatigue or loss of energy nearly every day

7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)

8. Diminished ability to think or concentrate, or indeciseveness, nearly every day (either by subjective account or as observed by others)

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

Manic episode

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary)

B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:

1. Inflated self-esteem or grandiosity

2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)

3. More talkative than usual or pressure to keep talking

4. Flight of ideas or subjective experience that thoughts are racing

5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)

6. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation

7. Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)


Reprinted with permission from American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, D.C.: American Psychiatric Association, 1994:327,332. Copyright 1994.

TABLE 2   Criteria for Major Depressive Episode and Manic Episode

View Table

TABLE 2

Criteria for Major Depressive Episode and Manic Episode

Major depressive episode

Five or more of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood.

2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)

3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains.

4. Insomnia or hypersomnia nearly every day

5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)

6. Fatigue or loss of energy nearly every day

7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)

8. Diminished ability to think or concentrate, or indeciseveness, nearly every day (either by subjective account or as observed by others)

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

Manic episode

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary)

B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:

1. Inflated self-esteem or grandiosity

2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)

3. More talkative than usual or pressure to keep talking

4. Flight of ideas or subjective experience that thoughts are racing

5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)

6. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation

7. Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)


Reprinted with permission from American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, D.C.: American Psychiatric Association, 1994:327,332. Copyright 1994.

Epidemiology

The lifetime prevalence of bipolar disorder is 1 percent, which compares to a lifetime prevalence of 6 percent for unipolar depression.5 The prevalence of bipolar disorder does not differ in males and females.6 The disorder affects persons of all ages. The epidemiologic catchment area study revealed the highest prevalence in the 18-to-24-year age group.7 In some patients, however, bipolar disorder does not become manifest until patients are older. One study reported new-onset bipolar disorder in patients older than 60 years.8

The incidence of bipolar disorder is increased in first-degree relatives of persons with the disorder, as is the incidence of other mood disorders.9 One study revealed a 13 percent risk of bipolar disorder among offspring of persons with the disorder.10 The risk of unipolar depression was 15 percent, and the risk of schizoaffective disorder was 1 percent.10 The mode of inheritance remains unclear, and no algorithm exists to predict the risk of bipolar disorder.11 Because of the familial association, genetic counseling should be offered to patients and their families as part of comprehensive educational and supportive approaches.

Clinical Presentations

Patients with symptoms of a mood disorder often do not meet the full criteria for bipolar disorder. Many patients with bipolar disorder are diagnosed as having depression. If agitation is prominent, hypomanic symptoms may be misunderstood as representing an anxiety state. Accurate diagnosis of bipolar disorder requires obtaining a comprehensive psychiatric history.

CHILDREN

Hyperactivity is the most common behavioral manifestation of mania in children.12 Manic children may exhibit irritability or temper tantrums.13 The differential psychiatric diagnoses include attention-deficit/hyperactivity disorder, conduct disorder and schizophrenia.14

ADOLESCENTS

Manic symptoms in adolescents are similar to those in adults. Florid psychosis can be a presentation of bipolar disorder in adolescents. Included in the differential diagnosis of mania in adolescents are substance abuse and schizophrenia, which may be challenging to distinguish from bipolar disorder. The normal risk-taking behavior in some adolescents must be distinguished from the reckless nature of manic symptoms.

DURING PREGNANCY

The course of bipolar disorder during pregnancy is variable. Management requires sustained collaboration between the patient's family physician and her psychiatrist. A patient with bipolar disorder should be encouraged to plan pregnancy so that the dosage of her psychiatric medication can be slowly tapered. The risk of relapse is increased with abrupt discontinuation.15

Relapse during pregnancy must be treated aggressively with mood stabilizers. The patient should be admitted to the hospital. If lithium therapy is required, the patient should be counseled regarding the increased risk of cardiovascular malformations in fetuses exposed to lithium. Breast-feeding during lithium therapy is discouraged because lithium is excreted in breast milk.16

During the postpartum period, worsening of affective symptoms may occur, including rapid cycling, which is sometimes refractory to drug therapy.17 Women who have worsening of symptoms postpartum may have an increased risk of recurrence.

Comorbid Conditions

Studies of primary care patients with major depressive disorders have demonstrated a tendency toward certain comorbid conditions. In one study,18 more than 42 percent of patients meeting the criteria for a major depressive disorder (including bipolar disorder) had lifetime histories of substance abuse. In another study,19 the frequency of substance abuse was 39 percent in adolescents who had symptoms of bipolar disorder. Another study20 revealed a high prevalence of moderate to severe anxiety disorders in association with bipolar disorder, as well as a high prevalence of psychosocial morbidity.

While many patients with bipolar disorder show gradual improvement in the first several years after diagnosis, a substantial subgroup experiences poor adjustment in one or more areas of functioning.21 In a study of psychiatric patients who were evaluated 30 to 40 years after the index hospitalization for mania, 24 percent of the sample was considered to be occupationally incapacitated.22

Treatment

URGENT AND EMERGENT

If a patient with symptoms of acute mania presents to the office, a psychiatrist should be consulted, and the patient should be evaluated urgently. The family physician must know the legal requirements in the community for transferring a patient with acute mania from the office to the hospital. Often, police must be involved. It is inappropriate to expect family members to transport the patient from the office to the hospital, because family members may not appreciate the irrationality of manic thinking and the unpredictability of manic behavior.

The family physician and psychiatrist have the responsibility to inform, educate and support family members in terms of the possible need for the family to petition the court for the patient's admission to a psychiatric unit. It is important to recognize, and to try to allay, the guilt and regret family members often feel in these circumstances.

Patients with newly diagnosed bipolar disorder require a medical evaluation along with a psychiatric evaluation. Table 323 lists the recommended laboratory tests for patients evaluated on an inpatient or an outpatient basis. Computed tomography or magnetic resonance imaging and electroencephalography are second-line options in the evaluation of treatment-resistant patients. These studies are not routinely required without a specific clinical reason. Similarly, the need for electrocardiography in patients younger than 40 years rests with the clinician's judgment.

If necessary, and if the patient has been in good general health, mood stabilizers, as well as other drugs used in the treatment of bipolar disorder, can be started before the test results are available. If the need to begin treatment is urgent, medication can be given even before laboratory specimens are obtained.

TABLE 3

Laboratory Evaluation of Patients Presenting with Bipolar Disorder

Inpatient

Complete physical examination

Serum levels of lithium, valproic acid (Depakene), carbamazepine (Tegretol) and selected tricyclic antidepressants (if relevant)

Thyroid function tests

Complete blood count and general chemistry screening

Urinalysis if lithium therapy is initiated

Electrocardiography in patients older than 40 years

Urine toxicology for substance abuse

Pregnancy test (if relevant)

Outpatient

Complete physical examination

Serum levels of lithium, valproic acid, carbamazepine and selected tricyclic antidepressants (if relevant)

Thyroid function tests

Complete blood count and general chemistry screening

Urinalysis if lithium therapy is initiated

Pregnancy test (if relevant)

Second-line tests: urine toxicology for substance abuse and electrocardiography in patients older than 40 years


Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

TABLE 3   Laboratory Evaluation of Patients Presenting with Bipolar Disorder

View Table

TABLE 3

Laboratory Evaluation of Patients Presenting with Bipolar Disorder

Inpatient

Complete physical examination

Serum levels of lithium, valproic acid (Depakene), carbamazepine (Tegretol) and selected tricyclic antidepressants (if relevant)

Thyroid function tests

Complete blood count and general chemistry screening

Urinalysis if lithium therapy is initiated

Electrocardiography in patients older than 40 years

Urine toxicology for substance abuse

Pregnancy test (if relevant)

Outpatient

Complete physical examination

Serum levels of lithium, valproic acid, carbamazepine and selected tricyclic antidepressants (if relevant)

Thyroid function tests

Complete blood count and general chemistry screening

Urinalysis if lithium therapy is initiated

Pregnancy test (if relevant)

Second-line tests: urine toxicology for substance abuse and electrocardiography in patients older than 40 years


Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

COLLABORATIVE ONGOING CARE

Given the chronic nature of bipolar disorder and its impact on the entire family, it is important for the patient's family physician and psychiatrist to develop an effective and collaborative relationship. Informed collaboration depends on an agreed method of communication in a frequency that meets the needs of each physician.24 A Canadian model brings psychiatrists and counselors into family practice offices for shared care.25

At the onset of bipolar disorder, the family physician might seek psychiatric consultation for differential diagnosis and treatment recommendations. Often, the psychiatrist assumes responsibility for initial management until the patient's clinical pattern is determined. During follow-up, both physicians should monitor the patient for signs of psychosis, mood swings, violence and self-harmful behaviors. As the patient's illness stabilizes and management becomes routine, the physicians can renegotiate, with each other and with the patient, responsibility for ongoing care.

When the patient's condition has become stable, the psychiatrist may not need to see the patient as often, although the frequency of follow-up psychiatric visits depends on the course of the illness, the patient's adherence to treatment, medication requirements, the need for ongoing psychotherapy and patterns of care in a particular geographic area. It is important for the patient's family physician and psychiatrist to coordinate medication prescriptions and follow-up laboratory tests such as determination of serum drug levels. In addition, counseling and family therapy are important components of management and may be rendered by the family physician, psychiatrist and/or psychologist.

MEDICATION

Recommendations for drug therapy in patients with bipolar disorder are summarized in Table 4.23

Medication is the key to stabilizing bipolar disorder. Initial treatment of mania consists of lithium or valproic acid (Depakene). If the patient is psychotic, a neuroleptic medication is also given. Long-acting benzodiazepines may be used for treating agitation. However, in patients with a substance-abuse history, benzodiazepines should be used with caution because of the addictive potential of these agents.

TABLE 4

Recommendations for Drug Therapy in Patients with Bipolar Disorder

Considerations for prescribing mood stabilizers

Lithium: For classic, euphoric mania; for mixed manic episode; when a mood stabilizer alone is used to treat depression; when the mood stabilizer must be given in a single evening dose; in patients with liver disease, excessive alcohol use or cocaine use; and in patients older than 65 years

Valproic acid (Depakene): For classic, euphoric mania; for mixed manic episode; for mania with rapid cycling; for long-term maintenance therapy in patients who do not tolerate lithium because of the “flat” feeling lithium causes; in patients with structural central nervous system disease, renal disease and cocaine use; and in patients older than 65 years

Carbamazepine (Tegretol): For mixed manic episode; for mania with rapid cycling; in patients with structural central nervous system disease or renal disease

An antipsychotic agent

High- or medium-potency antipsychotic agents are used as adjunctive treatment for mania with psychosis or psychotic depression.

A benzodiazepine

Sleep and sedation in mania or hypomania; insomnia in depression

The combination of a mood stabilizer, an antidepressant and an antipsychotic

Psychotic depression

The combination of a mood stabilizer and an antidepressant

Nonpsychotic depression

A mood stabilizer alone

Milder depression in bipolar I disorder

Bupropion (Wellbutrin)

Bipolar depression

Patient with high risk of manic switch or rapid cycling

A selective serotonin reuptake inhibitor

Bipolar depression


Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

TABLE 4   Recommendations for Drug Therapy in Patients with Bipolar Disorder

View Table

TABLE 4

Recommendations for Drug Therapy in Patients with Bipolar Disorder

Considerations for prescribing mood stabilizers

Lithium: For classic, euphoric mania; for mixed manic episode; when a mood stabilizer alone is used to treat depression; when the mood stabilizer must be given in a single evening dose; in patients with liver disease, excessive alcohol use or cocaine use; and in patients older than 65 years

Valproic acid (Depakene): For classic, euphoric mania; for mixed manic episode; for mania with rapid cycling; for long-term maintenance therapy in patients who do not tolerate lithium because of the “flat” feeling lithium causes; in patients with structural central nervous system disease, renal disease and cocaine use; and in patients older than 65 years

Carbamazepine (Tegretol): For mixed manic episode; for mania with rapid cycling; in patients with structural central nervous system disease or renal disease

An antipsychotic agent

High- or medium-potency antipsychotic agents are used as adjunctive treatment for mania with psychosis or psychotic depression.

A benzodiazepine

Sleep and sedation in mania or hypomania; insomnia in depression

The combination of a mood stabilizer, an antidepressant and an antipsychotic

Psychotic depression

The combination of a mood stabilizer and an antidepressant

Nonpsychotic depression

A mood stabilizer alone

Milder depression in bipolar I disorder

Bupropion (Wellbutrin)

Bipolar depression

Patient with high risk of manic switch or rapid cycling

A selective serotonin reuptake inhibitor

Bipolar depression


Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

When the patient with bipolar disorder becomes depressed, a selective serotonin reuptake inhibitor (SSRI) or bupropion (Wellbutrin) is recommended.26 The use of tricyclic antidepressants should be avoided because of the possibility of inducing rapid cycling of symptoms.

Drug interactions are an important consideration when prescribing lithium (Table 5),27  valproic acid (Table 6)27  and a selective serotonin reuptake inhibitor (Table 7).27  Information about starting and maintenance dosages for lithium, valproic acid and carbamazepine (Tegretol) is summarized in Table 8.23

TABLE 5

Drug Interactions with Lithium

Drug Effect on lithium level Management

Thiazide diuretics

Increased lithium level

Avoid this combination or reduce dosage; monitor lithium level

Loop diuretics

Increased or decreased lithium level

Avoid this combination or alter either dosage as needed; monitor lithium level

Potassium-sparing diuretics

Decreased lithium level

Monitor lithium level and adjust dosage

Nonsteroidal anti-inflammatory drugs

Increased lithium level

Use lower dosage of lithium; consider aspirin or sulindac

Angiotensin-converting enzyme inhibitors

Increased lithium level; toxicity reported

Use lower dosage of lithium; monitor lithium level closely

Calcium channel blockers

Increased or decreased lithium level

Monitor lithium level closely


Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

TABLE 5   Drug Interactions with Lithium

View Table

TABLE 5

Drug Interactions with Lithium

Drug Effect on lithium level Management

Thiazide diuretics

Increased lithium level

Avoid this combination or reduce dosage; monitor lithium level

Loop diuretics

Increased or decreased lithium level

Avoid this combination or alter either dosage as needed; monitor lithium level

Potassium-sparing diuretics

Decreased lithium level

Monitor lithium level and adjust dosage

Nonsteroidal anti-inflammatory drugs

Increased lithium level

Use lower dosage of lithium; consider aspirin or sulindac

Angiotensin-converting enzyme inhibitors

Increased lithium level; toxicity reported

Use lower dosage of lithium; monitor lithium level closely

Calcium channel blockers

Increased or decreased lithium level

Monitor lithium level closely


Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

TABLE 6

Drug Interactions with Valproic Acid (Depakene)

Drug Interaction Management

Phenobarbital

Increased phenobarbital level

Reduce dosage

Magnesium- and aluminum- containing antacids

Increased valproic acid level

Monitor valproic acid level; reduce dosage

Carbamazepine (Tegretol)

Decreased valproic acid level; possible increased carbamazepine level

Monitor valproic acid level; adjust dosage

Aspirin and naproxen (Naprosyn)

Increased valproic acid level

Avoid salicylates or other drugs bound to plasma albumin

Clonazepam (Klonopin)

Increased sedation

Use with caution


Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

TABLE 6   Drug Interactions with Valproic Acid (Depakene)

View Table

TABLE 6

Drug Interactions with Valproic Acid (Depakene)

Drug Interaction Management

Phenobarbital

Increased phenobarbital level

Reduce dosage

Magnesium- and aluminum- containing antacids

Increased valproic acid level

Monitor valproic acid level; reduce dosage

Carbamazepine (Tegretol)

Decreased valproic acid level; possible increased carbamazepine level

Monitor valproic acid level; adjust dosage

Aspirin and naproxen (Naprosyn)

Increased valproic acid level

Avoid salicylates or other drugs bound to plasma albumin

Clonazepam (Klonopin)

Increased sedation

Use with caution


Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

TABLE 7

Drug Interactions with Selective Serotonin Reuptake Inhibitors

Drug Interaction Management

Alprazolam (Xanax)

Increased alprazolam levels

Monitor; reduce dosage

TCAs

Increased TCA level

Monitor TCA level

Warfarin (Coumadin)

Increased warfarin level with fluvoxamine (Luvox)

Monitor prothrombin time (INR); reduce fluvoxamine dosage

MAOIs

Serotonin syndrome

Combination of MAOI and SSRI is contraindicated

Clozapine (Clozaril)

Increased clozapine level with fluvoxamine

Monitor clozapine level

l-Tryptophan

Serotonin syndrome

Combination of L-tryptophan and SSRI is contraindicated

Phenytoin (Dilantin)

Possible phenytoin toxicity

Monitor phenytoin level

Carbamazepine (Tegretol)

Increased carbamazepine level with fluvoxamine and fluoxetine (Prozac)

Monitor carbamazpine level

Tolbutamide

Possible increased hypoglycemia

Monitor blood glucose level

Theophylline

Increased theophylline level with fluvoxamine

Monitor theophylline level

Cimetidine (Tagamet)

Increased SSRI levels

Monitor clinically

Type Ic antiarrhythmics

Increased antiarrhythmic level with fluoxetine, paroxetine (Paxil) and sertraline (Zoloft)

Monitor antiarrhythmic drug levels

Beta-adrenergic blockers

Increased beta-blocker level and enhanced effects

Use lower beta-blocker dosage

Codeine

Inhibited metabolism from fluoxetine, paroxetine and sertraline

Use different SSRI

St. John's wort

Serotonin syndrome

Stop St. John's wort before beginning SSRI therapy


SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; INR = International Normalized Ratio; MAOI = monoamine oxidase inhibitor.

Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

TABLE 7   Drug Interactions with Selective Serotonin Reuptake Inhibitors

View Table

TABLE 7

Drug Interactions with Selective Serotonin Reuptake Inhibitors

Drug Interaction Management

Alprazolam (Xanax)

Increased alprazolam levels

Monitor; reduce dosage

TCAs

Increased TCA level

Monitor TCA level

Warfarin (Coumadin)

Increased warfarin level with fluvoxamine (Luvox)

Monitor prothrombin time (INR); reduce fluvoxamine dosage

MAOIs

Serotonin syndrome

Combination of MAOI and SSRI is contraindicated

Clozapine (Clozaril)

Increased clozapine level with fluvoxamine

Monitor clozapine level

l-Tryptophan

Serotonin syndrome

Combination of L-tryptophan and SSRI is contraindicated

Phenytoin (Dilantin)

Possible phenytoin toxicity

Monitor phenytoin level

Carbamazepine (Tegretol)

Increased carbamazepine level with fluvoxamine and fluoxetine (Prozac)

Monitor carbamazpine level

Tolbutamide

Possible increased hypoglycemia

Monitor blood glucose level

Theophylline

Increased theophylline level with fluvoxamine

Monitor theophylline level

Cimetidine (Tagamet)

Increased SSRI levels

Monitor clinically

Type Ic antiarrhythmics

Increased antiarrhythmic level with fluoxetine, paroxetine (Paxil) and sertraline (Zoloft)

Monitor antiarrhythmic drug levels

Beta-adrenergic blockers

Increased beta-blocker level and enhanced effects

Use lower beta-blocker dosage

Codeine

Inhibited metabolism from fluoxetine, paroxetine and sertraline

Use different SSRI

St. John's wort

Serotonin syndrome

Stop St. John's wort before beginning SSRI therapy


SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; INR = International Normalized Ratio; MAOI = monoamine oxidase inhibitor.

Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

TABLE 8

Starting and Maintenance Dosages of Lithium, Valproic Acid and Carbamazepine and Common Side Effects

Initial dosing strategy* Maintenance dosage Common side effects Cost (generic)§

Lithium

900 mg per day; increase by 300 to 600 mg every 2 to 3 days as tolerated

900 to 1,800 mg per day; 1,200 mg may be given as a single bedtime dose if tolerated; otherwise, prescribe twice-daily dosing Therapeutic blood level: 0.8 to 1.5 mEq per L

Thirst, polyuria, cognitive complaints, tremor,∥ weight gain, sedation, diarrhea, nausea (watch for dehydration, which can lead to toxicity), hypothyroidism (monitor TSH; give levothyroxine [Synthroid] if TSH is elevated)

One 300-mg capsule: $0.19 (0.06 to 0.10)

Valproic acid (Depakene)

20 mg per kg per day for mania; adjust dosage in 3 to 5 days An alternative is 500 to 750 mg daily; increase by 30 to 50 percent every 2 to 3 days as tolerated

1,000 to 3,000 mg per day. Lower dosages may be used in hypomania. Sometimes it is appropriate to give as a single bedtime dose; otherwise, prescribe twice-daily dosing Therapeutic blood level: 50 to 125 μg per mL

Tremor, ∥ sedation, diarrhea, nausea (use divalproex [Depakote]; give histamine H2-receptor blocker such as ranitidine [Zantac], 150 mg daily); weight gain, hair loss, mild elevation on liver function tests

One 250-mg capsule: $1.24

Carbamazepine (Tegretol)

200 to 400 per day; increase by 200 mg daily every 2 to 4 days

400 to 1,200 mg daily; in an occasional patient, it is appropriate to give a single bedtime dose; otherwise, prescribe twice-daily dosing Therapeutic blood level: 4 to 12 μg per mL; not well established

Headache, nystagmus, ataxia, sedation, rash, leukopenia (do not combine with clozapine [Clorazil]), mild elevation on liver function tests. Carbamazepine is associated with frequent drug–drug interactions related to induction of cytochrome P450 liver enzymes, resulting in lower drug levels of many other medications.

One 200-mg tablet: $0.44 (0.29 to 0.33)


TSH = thyroid-stimulating hormone.

*—When initiating therapy, consider lower dosages in patients with hypomania and in medically ill or elderly patients.

—Consolidate doses to twice daily or once daily at bedtime if tolerated and efficacious.

—Many of the side effects are dose related. Tolerance can be enhanced by tailoring the dosage to each patient's tolerance and response.

§ —Estimated cost to the pharmacist for one tablet or capsule based on average wholesale prices rounded to the nearest dollar in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee.

—Tremor may be relieved with a beta-adrenergic blocker such as atenolol (Tenormin), in a dosage of 50 mg daily.

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

TABLE 8   Starting and Maintenance Dosages of Lithium, Valproic Acid and Carbamazepine and Common Side Effects

View Table

TABLE 8

Starting and Maintenance Dosages of Lithium, Valproic Acid and Carbamazepine and Common Side Effects

Initial dosing strategy* Maintenance dosage Common side effects Cost (generic)§

Lithium

900 mg per day; increase by 300 to 600 mg every 2 to 3 days as tolerated

900 to 1,800 mg per day; 1,200 mg may be given as a single bedtime dose if tolerated; otherwise, prescribe twice-daily dosing Therapeutic blood level: 0.8 to 1.5 mEq per L

Thirst, polyuria, cognitive complaints, tremor,∥ weight gain, sedation, diarrhea, nausea (watch for dehydration, which can lead to toxicity), hypothyroidism (monitor TSH; give levothyroxine [Synthroid] if TSH is elevated)

One 300-mg capsule: $0.19 (0.06 to 0.10)

Valproic acid (Depakene)

20 mg per kg per day for mania; adjust dosage in 3 to 5 days An alternative is 500 to 750 mg daily; increase by 30 to 50 percent every 2 to 3 days as tolerated

1,000 to 3,000 mg per day. Lower dosages may be used in hypomania. Sometimes it is appropriate to give as a single bedtime dose; otherwise, prescribe twice-daily dosing Therapeutic blood level: 50 to 125 μg per mL

Tremor, ∥ sedation, diarrhea, nausea (use divalproex [Depakote]; give histamine H2-receptor blocker such as ranitidine [Zantac], 150 mg daily); weight gain, hair loss, mild elevation on liver function tests

One 250-mg capsule: $1.24

Carbamazepine (Tegretol)

200 to 400 per day; increase by 200 mg daily every 2 to 4 days

400 to 1,200 mg daily; in an occasional patient, it is appropriate to give a single bedtime dose; otherwise, prescribe twice-daily dosing Therapeutic blood level: 4 to 12 μg per mL; not well established

Headache, nystagmus, ataxia, sedation, rash, leukopenia (do not combine with clozapine [Clorazil]), mild elevation on liver function tests. Carbamazepine is associated with frequent drug–drug interactions related to induction of cytochrome P450 liver enzymes, resulting in lower drug levels of many other medications.

One 200-mg tablet: $0.44 (0.29 to 0.33)


TSH = thyroid-stimulating hormone.

*—When initiating therapy, consider lower dosages in patients with hypomania and in medically ill or elderly patients.

—Consolidate doses to twice daily or once daily at bedtime if tolerated and efficacious.

—Many of the side effects are dose related. Tolerance can be enhanced by tailoring the dosage to each patient's tolerance and response.

§ —Estimated cost to the pharmacist for one tablet or capsule based on average wholesale prices rounded to the nearest dollar in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee.

—Tremor may be relieved with a beta-adrenergic blocker such as atenolol (Tenormin), in a dosage of 50 mg daily.

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

MONITORING ISSUES

Treatment with mood stabilizers requires periodic laboratory tests to monitor the patient's response to the drug (Table 9).23 In addition, preventive care includes surveillance for possible comorbidities. Screening for substance abuse and other mental health problems should be conducted routinely. If prodromal symptoms of depression or mania are noted, interventions may include more frequent office visits, crisis telephone calls and intensive outpatient programs.23 It is important that patients regulate their sleep. Insufficient and irregular hours of sleep often precipitate mood disturbance.

TABLE 9

Recommended Laboratory Tests for Monitoring Response to Lithium, Valproic Acid and Carbamazepine

Lithium Valproic acid (Depakene) Carbamazepine (Tegretol)

First two months of therapy

Serum level every 1 to 2 weeks*†

Serum level every 1 to 2 weeks* CBC and liver function tests monthly

Serum level every 1 to 2 weeks* CBC and liver function tests monthly

Long-term therapy

Serum level every 3 to 6 months*† Thyroid function tests yearly (total T4, T4 uptake and TSH)† Renal function every 6 to 12 months (serum urea nitrogen, creatinine and electrolytes); 24-hour urine for volume and GFR only if specifically indicated, not routinely

Serum level every 3 to 6 months*† CBC and liver function tests every 6 to 12 months

Serum level every 3 to 6 months* CBC and liver function tests every 6 months


CBC = complete blood count; T4 = thyroxine; TSH = thyroid-stimulating hormone; GFR = glomerular filtration rate.

*—Serum levels of mood stabilizers should be obtained whenever the dosage or clinical situation changes.

—Tests are strongly recommended by the committee that formulated the guidelines for treatment of bipolar disorder.

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

TABLE 9   Recommended Laboratory Tests for Monitoring Response to Lithium, Valproic Acid and Carbamazepine

View Table

TABLE 9

Recommended Laboratory Tests for Monitoring Response to Lithium, Valproic Acid and Carbamazepine

Lithium Valproic acid (Depakene) Carbamazepine (Tegretol)

First two months of therapy

Serum level every 1 to 2 weeks*†

Serum level every 1 to 2 weeks* CBC and liver function tests monthly

Serum level every 1 to 2 weeks* CBC and liver function tests monthly

Long-term therapy

Serum level every 3 to 6 months*† Thyroid function tests yearly (total T4, T4 uptake and TSH)† Renal function every 6 to 12 months (serum urea nitrogen, creatinine and electrolytes); 24-hour urine for volume and GFR only if specifically indicated, not routinely

Serum level every 3 to 6 months*† CBC and liver function tests every 6 to 12 months

Serum level every 3 to 6 months* CBC and liver function tests every 6 months


CBC = complete blood count; T4 = thyroxine; TSH = thyroid-stimulating hormone; GFR = glomerular filtration rate.

*—Serum levels of mood stabilizers should be obtained whenever the dosage or clinical situation changes.

—Tests are strongly recommended by the committee that formulated the guidelines for treatment of bipolar disorder.

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

Family and Psychosocial Issues

Significant issues for the patient and family members include the stigma that is frequently associated with mental illness and the need for support and education. Because patients with bipolar disorder lose judgment early in the course of the illness and often engage in high-risk behavior, family members may be interacting with the legal system, the police and the health care system simultaneously. Guilt, anger, grief and ambivalence are frequent feelings among family members as they cope with the difficulties.

Family members must be educated about possible relapses, what to look for and how to handle different situations. The recklessness that accompanies mania can have devastating consequences—including sexually transmitted diseases, financial ruin, traumatic injuries and accidents. Risk-taking causes significant distress to patients and families, and such behavior is a problem for which family physicians, psychiatrists and mental health professionals can intervene with appropriate medical, preventive, educational and social strategies (Table 10).23 Initial intervention includes education for the patient and family, including informational pamphlets, videos and involvement in support and patient advocacy groups.

TABLE 10

Psychosocial Issues to Address in the Acute and Maintenance Phases of Bipolar Disorder

Acute phase

Monitor suicidality, mood, substance use, sleep patterns and medication compliance.

Educate patient and family members about features and biologic nature of the illness and the importance of compliance with therapy.

Encourage telephone contact and optimism regarding recovery. Set limits on impulsive behavior in patients with mania. Consider interpersonal or cognitive therapy for patients with depression. Hold family meetings to discuss issues.

Maintenance phase

Inquire about suicidality, mood, medication compliance, life events, substance use, sleep and activity.

Educate patient and family members about use of medication, warning signs of relapse, management of stress, sleep hygiene, eating and exercising regularly, limited caffeine and alcohol intake and management of work and leisure activities.

Long-range issues may include marital problems, employment and financial problems, peer relationships and modification of personality traits.


Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

TABLE 10   Psychosocial Issues to Address in the Acute and Maintenance Phases of Bipolar Disorder

View Table

TABLE 10

Psychosocial Issues to Address in the Acute and Maintenance Phases of Bipolar Disorder

Acute phase

Monitor suicidality, mood, substance use, sleep patterns and medication compliance.

Educate patient and family members about features and biologic nature of the illness and the importance of compliance with therapy.

Encourage telephone contact and optimism regarding recovery. Set limits on impulsive behavior in patients with mania. Consider interpersonal or cognitive therapy for patients with depression. Hold family meetings to discuss issues.

Maintenance phase

Inquire about suicidality, mood, medication compliance, life events, substance use, sleep and activity.

Educate patient and family members about use of medication, warning signs of relapse, management of stress, sleep hygiene, eating and exercising regularly, limited caffeine and alcohol intake and management of work and leisure activities.

Long-range issues may include marital problems, employment and financial problems, peer relationships and modification of personality traits.


Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

Patients who are manic or depressed may attempt suicide or homicide. The risk is increased in patients who are psychotic and have severe depressive symptoms concurrent with mania.28 The lifetime suicide risk is 15 percent in patients with bipolar disorder; patients at highest risk are young men in an early phase of illness who have made previous suicide attempts or who abuse alcohol.29 Family members must learn the warning signs of suicide and must be able to distinguish between the signs of mania and those of depression.

Substance use should be discouraged. Even modest social drinking can lead to mood disturbance. In addition, substances such as alcohol can interact with medications, disinhibit patients and contribute to risky behaviors.

Guns should be removed from the house. Easy access to firearms can supply a ready means of suicide or accidental injury in a patient with impaired insight and judgment.

If the patient or family has concerns about sexually transmitted diseases, testing and counseling can be offered and preventive strategies explained and encouraged.

Legal intervention may be required in patients who exhibit violent behavior. Spouses should be informed of their legal rights, given crisis intervention information and access to safe houses.

If a patient is out of control in spending money, several avenues should be explored. Patients and family members may need referral to social services and/or to legal counsel. Precautions might include putting the house in the spouse's name, limiting credit lines, creating trust funds and using financial planning services. Support groups are useful, as is family therapy.

Final Comment

Bipolar disorder can be well managed by family physicians in concert with psychiatrists. The consequences of the patient's behavior on the patient's life as well as the lives of family members must be explored. The family physician has a significant contribution to make in terms of education, support and follow-up. Both family physicians and psychiatrists have opportunities to intervene and help these patients and their families.

The Authors

KIM S. GRISWOLD, M.D., M.P.H., is assistant professor of family medicine and psychiatry in the Department of Family Medicine at the State University of New York (SUNY) at Buffalo School of Medicine and Biomedical Sciences. She received a master's degree in public health from Yale University, New Haven, Conn., and completed a faculty development fellowship in primary care at Michigan State University College of Human Medicine, East Lansing. After graduating from the SUNY–Buffalo School of Medicine and Biomedical Sciences, she completed a family practice residency at Buffalo (N.Y.) General Hospital.

LINDA F. PESSAR, M.D., is a psychiatrist and associate professor of clinical psychiatry and family medicine at SUNY–Buffalo School of Medicine and Biomedical Sciences, where she is also director of medical student education in psychiatry. She received a medical degree from Columbia University College of Physicians and Surgeons, New York City, and completed a psychiatry residency at New York State Psychiatric Institute/Columbia Presbyterian Medical Center, New York City.

Address correspondence to Kim S. Griswold, M.D., M.P.H., Department of Family Medicine, State University of New York at Buffalo, Center for Urban Research in Primary Care, 135 Grant St., Buffalo, NY 14213. Reprints are not available from the authors.

The authors thank Carlos R. Jaen, M.D., Ph.D., Department of Family Medicine, State University of New York at Buffalo, for support in the preparation of the manuscript.

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