MANIC-DEPRESSIVE ILLNESS AND THE BIPOLAR SPECTRUM
From Biopsychiatric Brillance Bestowed by Brobdingnagian Bellwethers, sponsored by the University of Wisconsin Medical School and the Madison Institute of Medicine, Inc
Frederick K. Goodwin, MD, Professor of Psychiatry and Director, Psychopharmacology Research Center, Department of Psychiatry, George Washington University Medical Center, Washington, DC
| Historical evolution of concept of bipolar disorder: Aretaeus of Cappadocia (150 AD) described mania and melancholia in same patient; Kraepelin (1913) formulated concept of “manic-depressive insanity” (which included recurrent affective disorders); Leonhard (1957) elaborated concept of polarity; in early 1970s, speaker et al identified type II bipolar disorder; Akiskal (1980) broadened concept of illness to “bipolar spectrum”; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; 1994) included bipolar II (BPII), cyclothymia, and rapid cycling in category of bipolar disorders |
| DSM-IV classification of bipolar disorders: bipolar I (BPI); BPII; cyclothymia; bipolar disorder not otherwise specified (operational definitions; not clear whether they have clinical or biologic significance) |
| Impact of disorder classification on prevalence rates: BPI appears to show least variability, however, several studies have found substantial underdiagnosis of bipolar illness due to difficulty of establishing history of mania in patients who present for treatment of depression; BPII and bipolar spectrum disorders show much greater viability in prevalence rates |
| DSM-IV classification of mood disorders: first separates bipolar subtype of disorders from depressive disorders as distinct illness; by doing this, DSM-IV puts primary emphasis on polarity (ie, history of mania/hypomania) at expense of cyclicity or recurrence; result is that “depressive disorders” almost meaningless category of illness (only indicates “not bipolar”; contains tremendous amount of heterogeneity, eg, tertiary category of recurrent major depressive disorder may be used to classify patient with just 2 depressive episodes in his or her lifetime, as well as one who has an episode every 12-24 mo); speaker believes fifth edition of DSM (DSM-V) should first classify affective disorders as recurrent or nonrecurrent, then subdivide illnesses into categories of unipolar and bipolar |
| Characteristics of highly recurrent unipolar (cyclic) depression: family history of bipolar disorder; bipolar- like age of onset (teens and 20s); high episode frequency (matches bipolar disorder, ie, on average every 18-24 mo); represents 25% to 35% of cases of unipolar depression; patients may convert to bipolar disorder (but many never do unless treated with antidepressants [ADs] in absence of mood stabilizer); patients respond better to lithium prophylaxis than to maintenance therapy with imipramine; no category for these patients in DSM-IV |
| Unipolar misdiagnosis may lead to inappropriate treatment: separating bipolar from depressive disorders obscured relationship between bipolar and some forms of unipolar depression; this has contributed to misdiagnosis of depression as unipolar and underdiagnosis of bipolar illness; study by speaker and Ghaemi looked at 85 patients referred to their institution and found to have bipolar disorder; 56% previously misdiagnosed as unipolar depression; many of these patients developed mania/hypomania or rapid cycling when placed on AD therapy |
| Importance of input from family members: assessment and treatment of patients with depression must include input from family members on patient’s history of mania/hypomania (studies have show that, when family members not included in patient evaluation, clinicians miss 50% of cases of bipolar illness); “worst mistake” clinician can make is to manage patient with depression as unipolar when he or she truly is bipolar (because of negative consequences of treatment) |
| Extended bipolar spectrum of Akiskal: includes highly recurrent unipolar depression; speaker’s difficulty with this is that, while similar in age of onset, family history, and frequency of recurrence (and while some patients may have symptoms analogous to mania or hypomania), as a group, these patients not bipolar |
| Signs of potential bipolar diathesis: recurrent major depressive episodes; early age of onset (recent data show that 40% of patients with initial depressive episode before 20 yr of age turn out to have bipolar disorder; of remaining 60%, most have highly recurrent unipolar depression; thus, when dealing with teenagers, clinicians first should consider mood stabilizers before prescribing ADs); family history of bipolar disorder; atypical depressive symptoms (eg, hypophagia, hypersomnia); brief depressive episodes; episodes of psychotic depression; postpartum depression; AD-induced mania/hypomania; AD wear-off; lack of response to ADs |
| General principles of management of bipolar disorder: use life charts to monitor course of patient’s illness (clinical case example from speaker’s practice); bipolar disorder basically depressive disorder (depression accounts for two thirds of morbidity), yet almost all medications introduced for treatment have been antimanic agents; issue in treatment not how to manage mania (plenty of effective agents available), but how to prevent recurrences (particularly of depression) and how to manage breakthrough episodes of depression, which are much more common than breakthrough manias in patients adequately treated with mood stabilizers; ADs have potential to induce mania and/or cycling; keep in mind high suicide risk associated with bipolar disorder |
| Prophylactic treatment with mood stabilizers: data from randomized placebo-controlled trials established efficacy of lithium (12 studies), lamotrigine (2 studies), and olanzapine (1 study against placebo, 1 against lithium); divalproex not considered mood stabilizer by Food and Drug Administration (FDA) because in main trial, it did not separate from placebo on primary outcome variable (however, speaker believes failure due to design of trial) |
| Treatment of breakthrough depression: lithium (modest effect; demonstrated in 9 studies); lamotrigine (more robust effect; however, less supporting data from literature); olanzapine (very small effect, which many believe related more to reduction of insomnia, agitation, and anxiety); quetiapine (appears to have large effect, that, unlike olanzapine, is specific to elements of depression; however, study data not yet published or gone through peer review) |
| Lithium maintenance therapy for prevention of mania and depression: meta-analysis of 28 studies (author reviewed all trials in literature that had blinded raters, placebo controls, and transparent diagnostic criteria); results of all studies showed similar or same direction (with most finding significant difference over placebo); overall reduction in recurrence risk with lithium 3.2-fold (in 12 placebo-controlled, parallel group studies [gold standard], reduction averaged 3.6-fold); no difference seen in mean reduction of risk in those trials (50%) that involved previous lithium withdrawal |
| Review of literature on lithium monotherapy (double-blind, placebo-controlled trials): for overall relapse prevention, lithium much more effective than placebo; for prevention of depression, lithium provides statistically significant improvement over placebo (“about 50% difference”), but not as effective as in prevention of mania |
| Possible reasons for decline in lithium monotherapy response rates (as reported in recent literature): difficulty of patient selection and referral bias changes character of new studies (in general, the longer successful medication has been available, the more difficult for research centers to demonstrate continued efficacy); aside from this, speaker believes decline in efficacy largely due to changes in illness (atypical bipolar disorder more common than typical illness; age of onset much earlier [in mid-1960s, average 32 yr; currently <17 yr]; increase in substance abuse comorbidity [from 20% in 1960s to nearly 60%]; much more exposure to ADs; question of whether correlation exists between increases in substance abuse and AD use and earlier age of onset and/or increased incidence of bipolar disorder) |
| Characteristics of typical bipolar disorder: manic/hypomanic episodes with prominent euphoria and grandiosity; episodes clearly demarcated; little or no evidence of deterioration; extremely responsive to lithium |
| Characteristics of atypical bipolar disorder: mixed states; rapid cycling; psychotic symptoms; chronic subthreshold symptoms (incomplete recovery); less evidence of illness in family history; many comorbid disorders; less responsive to lithium (may be more responsive to anticonvulsants) |
| Efficacy of mood stabilizers in preventing recurrence of depression: lithium—meta-analysis looked at 5 studies comparing mood stabilizer to AD for prevention of depression in patients with bipolar disorder; in no study was AD more effective than lithium; in 3 of 5 studies, lithium proved significantly better than imipramine; divalproex—few control data; open data indicate prophylactic antimanic effect greater than AD effect (however, secondary analysis of randomized study found fewer rescue ADs needed by patients on divalproex, indicating modest efficacy in preventing depression); olanzapine—recent trial looked at >200 patients with BPI randomized to olanzapine or lithium maintenance therapy for >15 mo; olanzapine proved superior to lithium in prevention of mania, roughly equivalent in prevention of relapse to depression; other than olanzapine, no controlled monotherapy maintenance studies of atypical ADs (much promise in this class of drugs, but lack of longitudinal data) |
| Possible mood stabilizing effects of anticonvulsants: all anticonvulsants share certain actions on sodium channels and calcium channels (that presumably relate to their anticonvulsant activity); other than that, different in their impact on limbic system; agents such as carbamazepine, divalproex, oxcarbazepine, topiramate enhance activity of γ- aminobutyric acid (GABA) neurotransmitter systems; predicted effects antimanic, anxiolytic, sedative, and weight increasing; on other hand, activating drugs (eg, lamotrigine, zonisamide) antiglutamatergic; predicted effects antidepressant, anxiogenic, stimulant, and weight reducing |
| Efficacy of anticonvulsants in treatment of BPI: data from 2 studies (1 involved patients who had recovered from acute manic/hypomanic episode; second of patients who had recovered from acute depressive episode); studies similarly designed, so authors able to do combined analysis; patients first taken off whatever medication they had been placed on by their clinician and gradually placed on lamotrigine; then randomized to lamotrigine, lithium, or placebo for maintenance period of 18 mo |
 | Survival analysis of recently manic/hypomanic patients: looking at time to intervention for manic episode, lithium much more effective than placebo, lamotrigine about as effective as placebo; looking at time to intervention for depressive episode, >80% of patients on lamotrigine did not require intervention over course of trial; 50% on placebo required intervention by 20 wk; lithium showed trend toward separating from placebo, but not as effective as lamotrigine |
| Survival analysis of recently depressed patients: looking at time to intervention for any episode, lithium and lamotrigine both more effective than placebo |
| Combined analysis: combining results of studies to look at prevention of mania and depression, authors found lithium and lamotrigine both superior to placebo in preventing either state; however, lithium always superior to lamotrigine in preventing mania, and lamotrigine always superior to lithium against depression |
| Comments: lamotrigine less effective than lithium in prevention of mania, but more effective than placebo by about same degree; possible clinical significance of this is that, if treating patient with lamotrigine to prevent depression, may not need to use full dose of lithium or divalproex to protect from mania (which would avoid risk for adverse effects of lithium/divalproex canceling out extreme tolerability effect of lamotrigine); in this study, lamotrigine associated with numerically lower (although not significantly lower) switch rate than placebo (suggesting it does not induce switch to mania/cycling, even though it has antidepressant activity) |
| Lamotrigine rash: lamotrigine recognized to cause severe skin reactions, eg, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN); however, recent data from German Rash Registry show only 1 case in 10,000 exposures (almost all neurology patients); in addition, while some potential risk associated with drug, Registry lists many other agents (including 9 antibiotics, 4 anticonvulsants) associated with greater risk |
| Drawbacks to existing mood stabilizers: weight gain—lithium (associated with some weight gain); divalproex (maybe little more than lithium, but roughly same); lamotrigine (no weight gain, slight weight loss); olanzapine (weight gain major problem); neurocognitive side effects—lithium (side effects demonstrated in many studies; dose- related); divalproex (recent studies in neurology have documented substantial neurocognitive side effects; some have shown them slightly less than with lithium; others, at same levels); lamotrigine (no side effects at doses used in psychiatry [generally ≤200 mg]); olanzapine (no neurocognitive side effects); prevention of depression—lithium (modest effect); divalproex (modest effect demonstrated in 1 study, but only in secondary analysis); lamotrigine (robust effect); olanzapine (modest effect; by inference, roughly comparable to lithium) |
| Questions and answers: relapse vs recurrence in maintenance studies; how speaker would list mood disorders if in charge of DSM-V; whether FDA missed point about suicidality in children on ADs by not emphasizing possibility of bipolar disorder |
Educational Objectives
| The goal of this activity is to provide an update on manic-depressive illness and the bipolar spectrum, including the current classification of bipolar disorders and the status of maintenance treatment. After hearing and assimilating this program, the clinician will be better able to: |
| 1. Explain how the classification of mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) has led to confusion in the classification of bipolar and depressive disorders. |
| 2. Discuss the underdiagnosis of bipolar disorder, including its frequency, reasons for misdiagnosis, and the consequences of treating bipolar as unipolar depression. |
| 3. Consider and cite research data on the use of lithium and other medications (specifically divalproex, lamotrigine, and olanzapine) as maintenance therapy for manic-depressive illness. |
| 4. Describe possible reasons for the recent decline in the efficacy of lithium monotherapy, plus some of the major drawbacks of the existing mood stabilizers. |
| 5. Prescribe long–term therapy for patients with bipolar illness that effectively prevents relapse to mania and/or depression. |
Discussed on This Program
Aripiprazole [Abilify] Bupropion HCl [Wellbutrin, Wellbutrin SR, Zyban] Carbamazepine [Atretol, Carbatrol, Epitol, Tegretol, Tegretol-XR] Divalproex sodium [Depakote, Depakote ER] Fluoxetine HCl [Prozac, Prozac Pulvules, Prozac Weekly, Sarafem, Sarafem Pulvules] Gabapentin [Neurontin] Haloperidol [Haldol, Haldol Decanoate 50, Haldol Decanoate 100] Imipramine HCl [Tofranil] Lamotrigine [Lamictal, Lamictal Chewable Dispersible] Lithium [Eskalith, Eskalith CR, Lithobid, Lithonate, Lithotabs] Olanzapine [Zyprexa, Zyprexa Intramuscular, Zyprexa Zydis] Oxcarbazepine (oxycarbamazepine) [Trileptal] Quetiapine fumarate [Seroquel] Zonisamide [Zonegran]
Suggested Reading
Angst J: The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 50:143, 1998; Angst J, Cassano G: The mood spectrum: improving the diagnosis of bipolar disorder. Bipolar Disord 7 Suppl 4:4, 2005; Angst J et al: Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J Affect Disord 84:149, 2005; Baldassano CF et al: Acute treatment of bipolar depression with adjunctive zonisamide: a retrospective chart review. Bipolar Disord 6:432, 2004; Bowden CL: A different depression: clinical distinctions between bipolar and unipolar depression. J Affect Disord 84:117, 2005; Bowden CL et al: Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 60:392, 2003; Calabrese JR et al: Lamictal 605 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 64:1013, 2003; Calabrese JR et al: Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J Clin Psychiatry 63:1012, 2002; Ghaemi SN et al: Antidepressants in bipolar disorder: the case for caution. Bipolar Disord 5:421, 2003; Ghaemi SN et al: Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatry 161:163, 2004; Ghaemi SN, Pardo TB, Hsu DJ: Strategies for preventing the recurrence of bipolar disorder. J Clin Psychiatry 65 Suppl 10:16, 2004; Ghaemi SN, Sachs GS, Goodwin FK: What is to be done? Controversies in the diagnosis and treatment of manic-depressive illness. World J Biol Psychiatry 1:65, 2000; Goodwin FK: Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment. J Clin Psychiatry 63 Suppl 10:5, 2002; Goodwin FK, Goldstein MA: Optimizing lithium treatment in bipolar disorder: a review of the literature and clinical recommendations. J Psychiatr Pract 9:333, 2003; Goodwin FK, Ghaemi SN: Understanding manic-depressive illness. Arch Gen Psychiatry 55:23, 1998; Goodwin FK, Jamison KR: Manic-Depressive Illness (1st ed). New York: Oxford University Press, 1990; Lieberman DZ, Goodwin FK: Separate and concomitant use of lamotrigine, lithium, and divalproex in bipolar disorders. Curr Psychiatry Rep 6:459, 2004; Rzany B et al: Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet 353:2190, 1999; Soldani F, Ghaemi SN: Lamotrigine and lithium are effective maintenance treatments in recently depressed people with bipolar I disorder. Evid Based Ment Health 7:48, 2004; Tohen M et al: Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry 184:337, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed: Dr. Goodwin has received research support from, served as a consultant for, or served on the Speaker’s Bureau of Abbott Laboratories, Bristol-Myers Squibb Co., Forest Laboratories, Inc., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Co., Novartis Pharmaceuticals USA, Pfizer Inc., Solvay Pharmaceuticals, Inc., and Sanofi-Synthélabo Inc.
Dr. Goodwin spoke at Biopsychiatric Brillance Bestowed by Brobdingnagian Bellwethers, held March 4-5, 2005, in Madison, Wisconsin and sponsored by the University of Wisconsin Medical School and the Madison Institute of Medicine, Inc. The Audio-Digest Foundation thanks Dr. Goodwin, the University of Wisconsin Medical School, and the Madison Institute of Medicine for their cooperation in the production of this program.
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