Am Fam Physician. 2004 Apr 1;69(7):1715-1717.
This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available at http://www.clinicalevidence.com.
What are the effects of treatments in mania?
One randomized controlled trial (RCT) in people with bipolar type I disorder experiencing a manic episode found that lithium increased the proportion of people who responded after three to four weeks compared with placebo. One systematic review found that lithium increased the proportion of people who had remission of manic symptoms at three weeks compared with chlorpromazine, and found no significant difference in symptoms at three to six weeks between lithium and haloperidol, olanzapine, valproate, lamotrigine, or clonazepam. One RCT found that lithium was less effective than risperidone in reducing manic symptoms at four weeks. Lithium can cause a range of adverse effects. The RCTs provided insufficient evidence about how the adverse effects of lithium compared with those of other antipsychotic drugs.
One systematic review in people with bipolar type I disorder found that olanzapine increased the proportion of people who responded at three to six weeks compared with placebo, as monotherapy and as add-on therapy to lithium or valproate, and found no significant difference in symptoms at 28 days between olanzapine and lithium. RCTs found that olanzapine was more effective in reducing symptoms than valproate, but it also was more likely to cause adverse effects such as sedation and weight gain. The acceptability of olanzapine may be limited because of weight gain.
One systematic review in people with bipolar type I disorder experiencing a manic episode found that valproate increased the proportion of people who responded over three weeks compared with placebo. It found no significant difference in response at one to six weeks between valproate and lithium, haloperidol, or carbamazepine. It found that valproate was less effective in reducing manic symptoms than olanzapine, but also was less likely to cause adverse effects such as sedation and weight gain.
LIKELY TO BE BENEFICIAL
RCTs in people with bipolar type I disorder experiencing a manic episode found no significant difference in manic symptoms at four to six weeks between carbamazepine and lithium or valproate.
We found no RCTs comparing clonazepam versus placebo in people with bipolar mania. RCTs in people with bipolar type I disorder experiencing a manic episode suggest that clonazepam may be as effective as lithium in improving manic symptoms at one to four weeks.
We found no RCTs comparing haloperidol versus placebo in people with bipolar mania. RCTs in people with bipolar type I disorder experiencing a manic episode found no significant difference in manic symptoms at one to three weeks between haloperidol and lithium or valproate, although haloperidol was associated with more extrapyramidal adverse effects and sedation than valproate.
We found no RCTs comparing risperidone versus placebo in people with bipolar mania. One RCT in people with bipolar type I disorder experiencing a manic episode found that risperidone reduced manic symptoms at four weeks compared with lithium. It gave no information on adverse effects.
One very small RCT in people with mania found limited evidence that chlorpromazine may improve manic symptoms over seven weeks more than placebo or imipramine. One systematic review found that fewer people had remission of symptoms at three weeks with chlorpromazine than with lithium.
We found no RCTs comparing lamotrigine versus placebo in people with bipolar mania. One RCT in people with bipolar type I disorder experiencing a manic episode found no significant difference in manic symptoms at four weeks between lamotrigine and lithium.
What are the effects of treatments in bipolar depression?
LIKELY TO BE BENEFICIAL
One RCT in people with bipolar type I disorder experiencing a major depressive episode found that lamotrigine increased the proportion of people who responded over seven weeks compared with placebo.
TRADE OFF BETWEEN BENEFITS AND HARMS
Systematic reviews found that antidepressant drugs improved depressive symptoms at the end of the trial (unspecified) compared with placebo. They found limited evidence that selective serotonin reuptake inhibitors (SSRIs) were more effective than tricyclic antidepressants, and found no significant difference in symptoms between monoamine oxidase inhibitors and tricyclic antidepressants or between SSRIs and serotonin noradrenaline reuptake inhibitors. The reviews provided insufficient evidence to assess whether antidepressant drugs induce bipolar mania.
One systematic review identified no RCTs of sufficient quality to assess these treatments in people with bipolar depression.
Psychologic Treatments; Valproate
We found no RCTs of these treatments in people with bipolar depression.
What are the effects of interventions to prevent relapse of mania or bipolar depression?
RCTs have found that lithium reduces relapse over two years compared with placebo, and have found no significant difference in relapse between lithium and valproate, carbamazepine, or lamotrigine.
LIKELY TO BE BENEFICIAL
We found no RCTs comparing carbamazepine versus placebo in preventing relapse. One systematic review found no significant difference between carbamazepine and lithium in the proportion of people who relapsed over one to three years.
Education to Recognize Symptoms of Relapse
One RCT found limited evidence that an educational program to recognize symptoms of relapse reduces manic relapse over 18 months, but that it may increase depressive episodes.
Lamotrigine (Bipolar Depressive Episodes)
Three RCTs have found that lamotrigine reduces relapse compared with placebo. However, secondary analyses in two of the RCTs suggested that lamotrigine protected against depressive relapse, but not manic relapse. RCTs have found no significant difference between lamotrigine and lithium in the proportion of people who relapse.
One RCT found that valproate reduced relapse over 12 months compared with placebo. One systematic review found no significant difference between lithium and valproate in relapse over 12 months.
One systematic review provided insufficient evidence to assess antidepressants in preventing relapse of bipolar disorder.
One RCT found that 21 sessions of family-focused psychoeducation reduced relapse over 12 months compared with two family sessions plus crisis management.
Bipolar disorder (bipolar affective disorder, manic depressive disorder) is characterized by marked mood swings between mania (mood elevation) and bipolar depression that cause significant personal distress or social dysfunction, and are not caused by drugs or known physical disorder. Bipolar type I disorder is diagnosed when episodes of depression are interspersed with mania or mixed episodes. Bipolar type II disorder is diagnosed when depression is interspersed with less severe episodes of elevated mood that do not lead to dysfunction or disability (hypomania). Bipolar disorder has been subdivided in several further ways.1
One 1996 cross-national community-based study (38,000 people) found lifetime prevalence rates of bipolar disorder ranging from 0.3 percent in Taiwan to 1.5 percent in New Zealand.2 It found that men and women were at similar risk, and that the age at first onset ranged from 19 to 29 years (average of six years earlier than first onset of major depression).
The cause of bipolar disorder is uncertain, although family and twin studies suggest a genetic basis.3 The lifetime risk of bipolar disorder is increased in first-degree relatives of a person with bipolar disorder (40 to 70 percent for a monozygotic twin; 5 to 10 percent for other first-degree relatives). If the first episode of mania occurs in an older adult, it may be secondary mania caused by underlying medical or substance-induced factors.4
Bipolar disorder is a recurring illness and is one of the leading causes of worldwide disability, especially in people 15 to 44 years of age.5 One four-year inception cohort study (173 people treated for a first episode of mania or mixed affective disorder) found that 93 percent of people no longer met criteria for mania at two years (median time to recover from a syndrome: 4.6 weeks), but that only 36 percent had recovered to premorbid function.6 The study found that 40 percent of people had a recurrent manic (20 percent) or depressive (20 percent) episode within two years of recovering from the first episode. A meta-analysis comparing observed suicide versus expected rates of suicide in an age- and sex-matched sample of the general population found that the lifetime prevalence of suicide was about 2 percent, or 15 times greater than expected, in people with bipolar disorder.7
search date:April 2002
Adapted with permission from Geddes JR. Bipolar disorder. Clin Evid Concise 2003;10:206–9.
The BALANCE trial, of which John Geddes is the principal investigator, received supplies of Depakote from Sanofi-Synthelabo.
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, D.C.: American Psychiatric Association, 1994.
2. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA. 1996;276:293–9.
3. Müller-Oerlinghausen B, Berghöfer A, Bauer M. Bipolar disorder. Lancet. 2002;359:241–7.
4. Tohen M, Shulman KI, Satlin A. First-episode mania in late life. Am J Psychiatry. 1994;151:130–2.
5. Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997;349:1436–42.
6. Tohen M, Hennen J, Zarate C, et al. Harvard first episodes project: predictors of recovery and relapse. Bipolar Disord. 2002;4suppl 1:135–6.
7. Harris EC, Barraclough B. Suicide as an outcome for mental disorders. A meta-analysis. Br J Psychiatry. 1997;170:205–8.
This is one in a series of chapters excerpted from Clinical Evidence Concise, published by the BMJ Publishing Group, Tavistock Square, London, United Kingdom. Clinical Evidence Concise is published in print twice a year and is updated monthly online. Each topic is revised every eight months, and subscribers should view the most up-to-date version at http://www.clinicalevidence.com. If you are interested in contributing to Clinical Evidence, please contact Claire Folkes ( firstname.lastname@example.org). This series is part of the AFP's CME. See “Clinical Quiz” on page 1603.
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