Psychopharmacology and Bipolar Disorder

From the 40th Review Course for the Family Physician and the First Joint Family Medicine/Psychiatry CME Conference, presented June 18-20, 2008

James R. Woods, MD, Clinical Assistant Professor of Psychiatry,
University of Tennessee College of Medicine, Memphis

Educational Objectives

The goal of this program is to improve the psychopharmacologic management of bipolar disorder in the primary care setting. After hearing and assimilating this program, the clinician will be better able to:

Select appropriate agents to avoid treatment-emergent manic episodes.

Discuss efficacy of antidepressants in patients with bipolar disorder.

Describe effects of lamotrigine, lithium, and atypical antipsychotic agents.

List side effects of atypical antipsychotic agents used to treat bipolar disorder.

Address safety concerns associated with treatment of bipolar disorder.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Woods is a consultant to and/or serves on the Speakers’ Bureaus for Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Labor-atories, GlaxoSmithKline, Pfizer, Sepracor, Solvay, and Wyeth-Ayerst. The planning committee reported nothing to disclose.

Acknowledgements

Dr. Woods was recorded on June 20, 2008, in Memphis, TN, at the 40th Review Course for the Family Physician and the First Joint Family Medicine/Psychiatry CME Conference, sponsored by the University of Tennessee College of Medicine. The Audio-Digest Foundation thanks Dr. Woods and the University of Tennessee College of Medicine for their cooperation in the production of this program.

Bipolar disorder: prevalence in United States, »4%; 7 in 10 patients initially misdiagnosed with, eg, major depres­sive disorder, schizophrenia, borderline personality disorder; 1 in 5 patients who presents to primary care office with depressive symptoms diagnosed within 1 to 2 yr; patients with bipolar disorder 29 times more likely to com­mit suicide when depressed; bipolar disorder increases risk for suicide 30-fold; most patients with bipolar disorder treated by primary care physicians (PCPs); increases risk for death by automobile accident, HIV, multiple failed re­lationships and jobs, and comorbid substance abuse disorder; common complaints  —depressed mood; decreased in­terest; avolition; anhedonia; apathy; feelings of worthlessness, helplessness, and hopelessness; difficulty concentrating; feelings of guilt; sleep difficulties; disease of depression interspersed by periods of mania and hypo­mania, and sometimes euthymia; often difficult to diagnose and treat (antidepressants in depressed bipolar patients can destabilize mood or result in treatment-emergent manic episode [“switching”])

Case example (Tim): history  —  first depressive episode at age 13 yr (50% of adolescents who present with first de­pressive episode at age 13 yr diagnosed with bipolar disorder by end of teenage years); in adulthood, Tim placed on several medications (paroxetine [eg, Paxil], fluoxetine [eg, Prozac], and amitriptyline [Elavil; no longer on market]) with limited success; for weeks or months, patients with unipolar depression may not be recognized as depressed; sudden onset of depression sometimes characteristic of bipolar disorder; important to ask about family psychiatric history (Tim’s aunt and uncle had manic depressive illness; aunt committed suicide); November 2001  —  Tim pre­sented to new PCP and placed on 300 mg/day of venlafaxine (Effexor) and 400 mg/day of bupropion (eg, Well­butrin); by end of month, Tim highly paranoid, hearing voices (of, eg, Federal Bureau of Investigation [FBI] agents), desperate, and unable to sleep; December 2001  —  paranoia leads to Tim's plans to flee country; Tim pur­chases one-way ticket to Jamaica; from airport, Tim calls FBI, warning FBI agents not to follow him (threatens to blow up airplane); Tim arrested, tried, and convicted of felony; sentenced to 1 yr in FBI penal camp; on third night of incarceration, nurse noted pressured speech, flight of ideas, psychomotor agitation, profound insomnia, and re­sponses to unseen people; at age 35 yr, after psychiatric consultation, Tim diagnosed with treatment-emergent manic episode; anti-depressants discontinued; Tim placed on mood-stabilizing medication; mixed mania quickly resolved

Mood Disorder Questionnaire (MDQ): helps diagnose bipolar disorder; 13-item self-reporting tool; sensitivity, 70%; specificity, 90%; 7 of 10 questions answered positively indicates high likelihood of bipolar disorder; takes <5 min to complete; if <7 of 10 questions answered positively, choose selective serotonin reuptake inhibitor (SSRI); if >7 questions answered positively, consider mood stabilizer for treatment of depression; MDQ available on Internet

Treatment strategies: medications for mania, maintenance, and acute depression; anticonvulsants (eg, lamotrigine) commonly used; atypical antipsychotic agents (eg, low-dose aripiprazole; ziprasidone [Geodon] undergoing stud­ies); antidepressants

Antidepressants: dual-mechanism agents  —  more likely than single-mechanism agents to precipitate mania; tricy­clic antidepressants (eg, amitriptyline, imipramine, desipramine, clomipramine [Anafranil], nortriptyline); venla­faxine; duloxetine (Cymbalta); study showed rapid cycling between mania and depression with desipramine; uncertain whether starting antidepressants changes pathophysiology of illness; study  —  bipolar depressed patients placed on antidepressant and followed for 1 yr; looked at chance for cycling into mania; compared to patients given no antidepressants (who had »15% chance for cycling), patients given bupropion had nearly 30% chance, patients given sertraline (Zoloft) had slightly >30% chance, and patients taking venlafaxine had nearly 50% chance; con­cluded that all effective in treating depression, but switching and mania concerning; study from Systematic Treat­ment Enhancement Program for Bipolar Disorder (STEP-BD) research collaborative  —  large multicenter study; looked at patients continued on mood stabilizer (eg, lithium, divalproex [eg, Depakote], carbamazepine [eg, Tegre­tol]) and patients who added antidepressant (bupropion or paroxetine); found adding bupropion or paroxetine achieved remission lasting ³8 wk in slightly >20%; patients who remained on mood stabilizer alone did just as well as patients who added antidepressant; adding mood stabilizer to tricyclic antidepressant, SSRI, or other agent (eg, amphetamine plus dextroamphetamine [Adderall]) lowers risk for treatment-emergent affective switch

Lithium: adequate doses of lithium alone as effective as combination of lithium and antidepressant; partial doses of lithium not as effective as lithium and imipramine or lithium and paroxetine; when full dose used, effective antide­pressant in bipolar depression; antidepressant efficacy reduced when serum lithium level <0.8 mEq/L (may need to augment with other agent); therapeutic index narrow (serum lithium level of 0.8-1.2 mEq/L; tolerability decreases; patients may develop tremor or cognitive deficits); reasonably effective in treating bipolar depression; may be more effective at preventing relapse into depression than pulling patient out of depression; inexpensive; should not be given with thiazide diuretics, high doses of nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-convert­ing enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs); associated with 5-fold risk reduction in suicide

Divalproex: mood stabilizer; “quite good” for bipolar mania; no large double-blind placebo-controlled trials; con­flicting findings in small studies; generally considered better for mania than for depression; may be effective in manic patients with anxiety symptoms; works as g-aminobutyric acid (GABA) agonist

Carbamazepine: antiepileptic drug; limited data on bipolar depression; study of 27 patients showed some efficacy, but “nothing really to hang your hat on”

Lamotrigine (Lamictal): antiepileptic drug; 5 failed studies in bipolar I depression, 2 failed studies in bipolar II de­pression, and 2 failed studies in major depressive disorder; however, speaker notes that “in our office, we’ve seen it work” (most trials for depression last »8 wk; lamotrigine takes 5-6 wk to reach therapeutic dose); in office setting, drug appears to alleviate depression after 9 to 11 wk (uncertain whether drug alleviates depression or whether pa­tients cycle out of depression; when bipolar depression untreated, patients tend to cycle out after 3 mo); good alter­native; well tolerated; few side effects; risk for skin rash (Stevens-Johnson syndrome; occurs in 1 in 1000 patients); do not use in combination with divalproex; on secondary outcome measure, 50 mg/day and 200 mg/day more effec­tive than placebo; in study comparing olanzapine plus fluoxetine (Symbyax) to lamotrigine for bipolar depression, both did well on primary outcome measure (lamotrigine appeared as effective as olanzapine plus fluoxetine at treat­ing depression); treatment-resistant bipolar depression  —23% of patients with no remission history entered remis­sion after treatment with lamotrigine; 1 in 6 patients treated with inositol (sugar converted into inositol triphosphate) improved with no side effects; inositol can be purchased over-the-counter at vitamin supplement stores; risperidone (Risperdal) associated with poor efficacy (increases dopamine levels, but with high D₂-receptor occupancy); study comparing lamotrigine to lithium found both highly effective at treating bipolar II depression

Atypical antipsychotic agents: data limited; more studies needed on aripiprazole, quetiapine (Seroquel), olanza-pine, and risperidone; 4 mg of risperidone blocks 80% of D₂-receptors

Ziprasidone: no large studies presented or published; currently undergoing studies; monoamine reuptake inhibitor

Aripiprazole: studies found 15 mg/day and 17 mg/day separated initially from placebo, but statistical separation later lost; high doses not recommended; lower doses (5-7 mg/day) may be more effective; indicated as adjunctive treatment for major depressive disorder (average dose in studies, 11 mg/day); associated with akathisia (ie, over­whelming feeling of restlessness) and insomnia; shown to decrease prolactin levels; glucose- and weight-neutral medication; no difference in QTC prolongation, compared to placebo; correct doses important

Olanzapine plus fluoxetine: indicated for bipolar depression; nonstandard analysis of 2 studies showed olanzapine alone statistically separated from placebo at every week; under standard analysis, olanzapine alone not better than placebo; olanzapine plus fluoxetine efficacious in treating bipolar depression; side effect burden for signifi­cant adverse event higher with olanzapine plus fluoxetine than with lamotrigine; olanzapine plus fluoxetine raised cholesterol (lamotrigine lowered cholesterol); olanzapine plus fluoxetine increased weight and prolactin level; effective at preventing switching into mania

Quetiapine:  BipOLar DEpRession (BOLDER) I and BOLDER II studies found quetiapine 300 mg/day and 600 mg/day significantly better at treating bipolar depression than placebo (600 mg/day not more effective than 300 mg/day); reduced suicidal ideation; effective for bipolar I and bipolar II disorders; approved by Food and Drug Administration (FDA) for manic and depressive episodes in bipolar disorder; 600 mg/day twice as effective at treating bipolar depression than treatment of major depression with fluoxetine; norquetiapine (demethylated me­tabolite of quetiapine) »250 times more powerful at binding to norepinephrine transporter and inhibiting norepi­nephrine reuptake than venlafaxine; liberates prefrontal dopamine

Modafinil (Provigil): expensive ($200-$250 for 30-day supply); effective for attention-deficit/hyperactivity disorder or as augmentation for depression or bipolar depression; study showed low dose (200 mg/day) could be effective for treating bipolar depression with no associated manic switch

Pramipexole (Mirapex): dopamine agonist; used to treat restless legs syndrome; may be effective in treating bipolar II depression

Safety and tolerability: lithium overdoses fatal; divalproex teratogenic; cardiac problems associated with lithium and may be associated with ziprasidone; carbamazepine and divalproex can lead to bone marrow suppression, neu­tropenia, or thrombocytopenia; hepatic necrosis can occur with divalproex (rare); metabolic disorders associated with olanzapine, clozapine (Clozaril), and possibly risperidone and quetiapine; neurologic problems associated with lithium and carbamazepine; lithium problematic when serum creatinine level ³6.5 mg/dL (give lithium once very 2 wk); weight gain associated with olanzapine; akathisia associated with risperidone and high doses of olan­zapine; 1 in 4 to 5 patients on aripiprazole experience akathisia, but not extrapyramidal side effects (EPS); prolactin elevation associated with risperidone; quetiapine and aripiprazole lower prolactin levels; dermatologic effects seen with carbamazepine; Stevens-Johnson syndrome with lamotrigine rare; acne with lithium; akathisia predictor of suicidality (discuss with patients); worst EPS occurred with risperidone (seen in 50% of patients in bipolar trials); diabetes  —  conflicting studies; aripiprazole and ziprasidone metabolically neutral; discuss metabolic syndrome and weight gain; recommend lifestyle modifications (eg, exercise 5 days/wk); encourage patients to be nutritionally in­formed, to reduce fat intake, and to increase protein intake

Suggested Reading

Bond DJ et al: Antidepressant-associated mood elevations in bipolar II disorder compared with bipolar I disorder and major depressive disorder: a systematic review and meta-analysis. J Clin Psychiatry 69:1589, 2008; Frye MA et al: Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psy­chiatry 166:164, 2009; Geller B et al: Proposed definitions of bipolar I disorder episodes and daily rapid cycling phe­nomena in preschoolers, school-aged children, adolescents, and adults. J Child Adolesc Psychopharmacol 17:217, 2007; Goldberg JF et al: Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD. J Clin Psychiatry 70:155, 2009; Judd LL et al: Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence. Arch Gen Psychiatry 65:386, 2008; Leverich GS et al: Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry 163:232, 2006; Liebowitz MR et al: Ziprasidone monotherapy in bipolar II depression: An open trial. J Affect Disord 14 Suppl 2:55, 2009; Nemeroff CB et al: Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 158:906, 2001; Nierenberg AA et al: Treat­ment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmenta­tion with lamotrigine, inositol, or risperidone. Am J Psychiatry 163:210, 2006; Nierenberg AA: Effective agents in treating bipolar depression. J Clin Psychiatry 69:e29, 2008; Nierenberg AA: Lessons from STEP-BD for the treat­ment of bipolar depression. Depress Anxiety 26:106, 2009; Shelton RC et al: Risperidone and paroxetine given sin­gly and in combination for bipolar depression. J Clin Psychiatry 65:1715, 2004.