Update On Bipolar Disorder

Educational Objectives

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

1. Choose the most effective drug for a patient with
mixed mania.

2. Identify patients with bipolar disorder who may be
poor candidates for lithium.

3. Guide the primary care clinician who is concerned about the emergence of mania in a patient taking an
antidepressant drug.

4. Select appropriate drugs for maintenance in patients with bipolar disorder.

5. Treat patients who develop a rash while taking lamotrigine.

Summary

Diagnosis: bipolar disorder on spectrum; recognizing frank mania uncomplicated, but distinguishing more subtle manifestations from normal variations in affect, intensity, and mood challenging (behavioral norms vary among cultures)

Hypomania: definition not optimal; controversial criteria include 4 days of symptoms (number of days arbitrary), unequivocal change in functioning uncharacteristic of patient, and change observable by others (patient with good insight may recognize onset of hypomania when others do not); generally agreed on criterion for mania — impairments that affect life (eg, being fired from job, ruining relationship, spending life savings, being psychotic, being hospitalized)

Bipolar II disorder: milder form associated with hypomania; family history of bipolar II or bipolar I disorder present; in patient with recurrent hypomania without mania (eg, 3 episodes), risk for development of mania low

Mixed mania: Diagnostic and Statistical Manual of Mental Disorders, (Fourth Edition; DSM-4), required simultaneous full manic and full depressive syndrome for diagnosis; defined by DSM-5 as manic syndrome with ≥3 depressive features; may resemble agitated depression; treated like mania (avoid antidepressant drugs; valproate or antipsychotic agents appropriate); mixed features predictive for poor response to lithium

Rapid cycling: DSM-5 requires ≥4 episodes per year with full criteria for time; term sometimes used to describe ultrarapid cycling (≥4 episodes per month) or ultradian cycling (within-day cycling); most prevalent cause of ultradian cycling cluster B personality disorders (eg, borderline personality disorder); drug abuse withdrawal syndrome also in differential diagnosis

Bipolar spectrum: may include patients with affective lability who do not have cluster B personality disorder but do not meet other diagnostic criteria

Hypomanic or manic episodes that occur only when patient takes antidepressant drugs: in DSM-3, patient who became symptomatic while taking antidepressant drug considered to have bipolar disorder; in DSM-4, manic or hypomanic episode caused by antidepressant drug not considered bipolar disorder; patient considered to have major depression plus substance-induced mood disorder; in DSM-5, if hypomanic or manic episode emerges during antidepressant therapy and persists at fully syndromal level beyond physiologic effect of treatment, patient may be diagnosed with mania (eg, patient with hypomania that resolves after stopping antidepressant drugs experiencing drug effect; persistent symptoms after drug stopped indicate bipolar disorder); however, if antidepressant drugs stopped in these patients, another agent usually started (eg, lithium, valproate, antipsychotic drug); in these cases, improvement cannot be attributed to stopping antidepressant agent or starting new drug

Pharmacotherapy: phases of treatment acute, maintenance (to prevent future episodes after recurrent or chronic illness), and continuation (following single episode); risk for nonadherence to mood-stabilizer drugs high in young men who had euphoric grandiose episode (patients typically attribute event to external factor or person rather than underlying illness and may not perceive need for lifetime treatment)

Managing acute mania: effective agents include all D2 agonists (including those without indication for acute mania), lithium, and valproate; meta-analysis found that gabapentin, lamotrigine, and topiramate ineffective

Canadian study of continuation treatment: included acutely manic patients treated with lithium or divalproex (Depakote), plus risperidone or olanzapine; antipsychotic agent stopped on remission, after 24 wk, or after 1 yr, and patients continued taking lithium or divalproex; found fewer relapses in patients who continued taking antipsychotic agent for 24 wk; treatment for 52 wk conferred no advantage over 24 wk

Maintenance treatment: rate of relapse during 10 yr in treated patients with bipolar disorder 90%; efficacy of available drugs suboptimal; focus on having fewer episodes per year rather than no episodes may be appropriate

Lithium: patients with nonclassic presentation less likely to respond to lithium; predictors of poor response include pronounced psychotic features outside mood episodes, mixed features, and rapid cycling; meta-analysis of 7 placebo-controlled studies found lithium superior to placebo, especially in preventing mania; adverse effects include destruction of renal tubules and polyuria; prevalence of end-stage renal disease low; creatinine level and estimated glomerular filtration rate should be monitored; other adverse effects include hypothyroidism and increased levels of calcium and parathyroid hormone; future guidelines may recommend monitoring calcium, parathyroid hormone, and TSH (thyrotropin)

Valproate: study that compared valproate with lithium and placebo in patients with acute mania found efficacy of valproate and lithium equivalent; target level in blood ≥95 μg/mL; appropriate level for maintenance treatment unknown (target for majority of clinicians 70-100 μg/mL); US Food and Drug Administration (FDA) indication for maintenance treatment lacking because of study that found drug ineffective (same study also found lithium ineffective); negative findings probably attributable to enrollment of relatively stable patients unlikely to relapse when taking placebo

Lamotrigine: appropriate in patients with predominant symptoms of depression (eg, bipolar II disorder); study that led to approval of drug for maintenance treatment found efficacy of lithium and lamotrigine (eg, Lamictal, Subvenite) similar and superior to that of placebo; efficacy of lamotrigine higher than lithium for preventing depression; efficacy of lithium significantly higher than lamotrigine for preventing mania; combining lamotrigine and lithium common

Second-generation antipsychotic drugs: efficacy in treating and preventing mania high (eg, clozapine, risperidone); some also effective as antidepressant drugs, but more effective in preventing mania (quetiapine exception [efficacy in preventing mania and depression equal]); long-acting risperidone (Risperdal Consta) available in injectable form

Bipolar Depression

Clinical considerations: consider efficacy of drug and possibility that patient’s condition may worsen during treatment because of change in drugs (eg, patient who begins taking antidepressant drugs develops mania or hypomania) or affective lability caused by antidepressant drug

Mood-stabilizer drugs: 4 double-blind studies confirmed efficacy of valproate for treating bipolar depression; 4 of 5 double-blind studies evaluating lamotrigine negative, but pooled analysis suggested that lamotrigine weakly effective (number needed to treat [NNT] 11 [>10 suggests drug not clinically effective]); when patients dichotomized by severity of depression, lamotrigine found superior to placebo in more depressed patients (NNT 7); severity of depression (score on Hamilton Depression Rating Scale ≥24) best predictor of which patients with acute bipolar depression likely to improve while taking lamotrigine; few data available on efficacy of other mood-stabilizer drugs

Antipsychotic drugs: quetiapine (Seroquel) — found superior to placebo in 5 double-blind studies; efficacy of 300 mg and 600 mg equal; lurasidone (Latuda) — has FDA indication; evaluated as monotherapy or add-on therapy to lithium or divalproex; efficacy of 20 to 60 mg and 80 to 120 mg equal for bipolar depression; cariprazine (Vraylar) — findings of one study support efficacy; low dose adequate in bipolar depression

Antidepressant drugs: conclusions of meta-analyses looking at same data differ, depending on which studies included; meta-analysis by Sidor and MacQueen of 6 placebo-controlled studies did not confirm superiority of antidepressant drugs for treating bipolar depression; however, recent meta-analysis found that efficacy of antidepressant drugs similar in patients with bipolar and unipolar depression; Sidor and MacQueen reported that antidepressant drugs no more likely to cause affective “switching” than placebo; however, these studies short (6-10 wk) and did not address risk factors for switching; future studies should identify which patients likely to benefit from, or be harmed by, antidepressant drugs; recent meta-analysis of 6 studies — evaluated selective serotonin reuptake inhibitors (SSRIs), agomelatine (melatonin agonist drug not marketed in United States), and bupropion (Wellbutrin); found no evidence of efficacy in full group of patients (who also took mood- stabilizer drugs); however, when patients analyzed by type of mood-stabilizer drug taken, antidepressant drugs found effective in those taking second-generation antipsychotic drugs (olanzapine, quetiapine, or aripiprazole) but not in those taking lithium or divalproex; found no difference in treatment-emergent mania between these groups over short term; in 2 studies that included 52-wk extension, switching observed in patients taking antidepressant drugs (association weak; number needed to harm 19)

Antidepressant drugs for bipolar II disorder: some patients with hypomania desire to take antidepressant drugs but not mood-stabilizer drugs; Amsterdam and Shults (2010) — studied 81 patients with bipolar II disorder and depression; patients first treated with 20 mg fluoxetine (Prozac); responders then randomized to blinded treatment with fluoxetine, lithium, or placebo for 1 yr; found risk for relapse lowest in patients in fluoxetine arm (no difference found between lithium and placebo arms); patients with bipolar II disorder who respond to antidepressant drug should not be switched to lithium; over year of treatment, incidence of hypomania no higher in fluoxetine arm than in other arms, but scores on Young Mania Rating Scale suggest that degree of affective lability highest in patients who take fluoxetine; Altshuler et al (2017) — multicenter study included 142 patients with bipolar II disorder and depression; patients randomized to lithium, sertraline (Zoloft), or combination; found no differences in efficacy over 4 mo; burden of adverse effects highest in combination arm; rates of switching similar in each arm; study suggests that monotherapy with antidepressant drug reasonable in patients with bipolar II disorder, at least in short term; switching polarity — rates of switching lowest in patients who take SSRIs and bupropion; rate twice as high in those treated with serotonin-norepinephrine reuptake inhibitors; predictors of switching include low level of lithium and history of abuse of stimulant drugs

Stimulant drugs: used as adjunctive medications in patients with bipolar disorder who take mood-stabilizer drugs; dopaminergic stimulant agents (eg, dextroamphetamine-amphetamine [Adderall], lisdexamfetamine [Vyvanse], methylphenidate [Ritalin], dextroamphetamine [Dexedrine]) do not cause switching as long as patient taking mood-stabilizer drug; modafinil (Provigil) and armodafinil (Nuvigil) used, but FDA indication for bipolar depression lacking; studies evaluating these drugs only weakly positive, but clinical experience favorable

Questions and Answers

Carbamazepine (eg, Epitol, Equetro, Tegretol) and oxcarbazepine (eg, Oxtellar, Trileptal): efficacy in bipolar depression lacking; studies suggest mood-stabilizing properties for carbamazepine (efficacy lower than lithium); only few data on oxcarbazepine available; oxcarbazepine associated with greater degree of hyponatremia than carbamazepine; number of adverse effects higher for carbamazepine; speaker typically gives oxcarbazepine only as adjunctive agent

Lactating women with bipolar II disorder and depression: majority of medications safe; lithium contraindicated (level in breast milk ≈40% of that in serum); SSRIs safe; valproate and carbamazepine should be avoided during pregnancy, but may be used during breastfeeding; antipsychotic drugs likely safe

Valproate in premenopausal women: risk for neural tube defects 3% to 4% in fetus exposed to valproate during first trimester; drug no longer problematic at >15 wk gestation; may be appropriate in select women, but risks should be discussed with patient; associated with polycystic ovary syndrome; risk for sedation high, but risk for major depression low

Rash in patients taking lamotrigine: 2 types of rash found; pruritic maculopapular rash — develops in 5% to 9%; not significant; responds to topical steroids and antihistamines; immunologic rash — represents systemic response affecting skin, liver, and other organs; rate 1 in 6000 patients; recommendations — patients with erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis critically ill and should not take lamotrigine again; in those with maculopapular rash, rechallenge appropriate after few weeks (beginning at 50% of original dose)

Dose of lamotrigine: speaker typically gives 200 mg, but ≤400 mg may be given; optimal dose for maintenance treatment not studied; 800 to 900 mg/day sometimes used in patients with neurologic disorders; clinician may consider obtaining serum lamotrigine level in nonresponder; therapeutic range in patients with mood disorder unknown; serum lamotrigine level 2 to 10 μg/mL considered adequate in patients with neurologic disorders (rough guideline)

Lithium: renal function — serum creatinine should be measured annually in patients who take lithium; more intensive monitoring indicated at creatinine level 1.2 to 1.3 mg/dL; 1.4 to 1.6 mg/dL should trigger consultation with nephrologist and discussion with patient about continuation; at ≥2.5 mg/dL, risk for transplantation or dialysis high; if lithium stopped when creatinine level ≤1.6 mg/dL, renal function does not recover, but it may not worsen; renal neoplasm — whether lithium increases relative risk for renal neoplasm not determined, but absolute risk low; level in maintenance treatment — except in geriatric patients, recommended 12-hr dose 0.6 to 0.8 mmol/L; adverse effects more prevalent when target 0.9 mmol/L; in older patients, lower levels may be adequate (eg, 0.35 mmol/L); frequency of dosing — early studies used twice-daily regimens, but renal toxicity may be lower if lithium given once daily; once-daily dosing results in few hours per day of minimal lithium levels (allows regeneration of kidney cells); however, switching to daily regimen may not confer benefits to kidney in patient who has taken lithium twice daily for years; unipolar depression — why lithium effective as adjunctive agent for unipolar but not bipolar depression not known; restarting lithium after noncompliance — effective in majority of patients

Readings

Altshuler LL et al: Switch rates during acute treatment for bipolar II depression with lithium, sertraline, or the two combined: a randomized double-blind comparison. Am J Psychiatry 2017 Mar 1;174(3):266-276; Amsterdam JD, Shults J: Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Am J Psychiatry 2010 Jul;167(7):792-800; Calabrese JR et al: Lamotrigine in the acute treatment of bipolar depression: results of five double-blind, placebo-controlled clinical trials. Bipolar Disord 2008 Mar;10(2):323-33; Cipriani A et al: Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet 2011 Oct 8;378(9799):1306-15; Durgam S et al: An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression. Am J Psychiatry 2016 Mar 1;173(3):271-81; Geddes JR et al: Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. Br J Psychiatry 2009 Jan;194(1):4-9; McGirr A et al: Safety and efficacy of adjunctive second-generation antidepressant therapy with a mood stabiliser or an atypical antipsychotic in acute bipolar depression: a systematic review and meta-analysis of randomised placebo-controlled trials. Lancet Psychiatry 2016 Dec;3(12):1138-1146; McIntyre RS et al: Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo-controlled trial. J Clin Psychiatry 2015 Apr;76(4):398-405; Novick DM et al: Suicide attempts in bipolar I and bipolar II disorder: a review and meta-analysis of the evidence. Bipolar Disord 2010 Feb;12(1):1-9; Severus E et al: Lithium for prevention of mood episodes in bipolar disorders: systematic review and meta-analysis. Int J Bipolar Disord 2014 Dec 20;2:15; Sidor MM, MacQueen GM: An update on antidepressant use in bipolar depression. Curr Psychiatry Rep 2012 Dec;14(6):696-704; Vázquez G et al: Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: a meta-analytic review. Pharmacopsychiatry 2011 Jan;44(1):21-6; Yatham LN et al: Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial. Br J Psychiatry 2016 Jan;208(1):78-86; Yildiz A et al: Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology 2011 Jan;36(2):375-89.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Gitlin presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Gitlin was recorded at the 23rd Annual National Psychopharmacology Update, presented by the Nevada Psychiatric Association and held February 14-17, 2018, in Las Vegas, NV. For information on the 24th Annual National Psychopharmacology Update, scheduled for February 13-16, 2019, in Las Vegas, NV, please visit nvpsychiatry.org. The Audio Digest Foundation thanks Dr. Gitlin and the Nevada Psychiatric Association for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PS472101

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.