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IN THIS ISSUE:
September 2007

Antidepressants Can Help Prevent Depression after Stroke
Antidepressant drugs may provide relief for many patients suffering from depression following stroke.

Prazosin for PTSD Nightmares
Adjunctive treatment with the α1-blocker prazosin (Minipress and others) reduces trauma nightmares and sleep disturbance in patients with posttraumatic stress disorder.

Treating Bipolar Depression
Antidepressants add little benefit in treating bipolar depression, but the risk of inducing mania appears small.

Are SSRIs Teratogens?
There is a small risk of congenital malformations with fetal exposure to selective serotonin reuptake inhibitors, particularly paroxetine (Paxil and others), during the first trimester.

In Brief
Benefits of Antidepressants versus Suicide Risk; Rivastigmine Does Not Slow Progression to Alzheimer's Disease

Treating Bipolar Depression

September 2007

Recurrent episodes of depression are a defining characteristic of bipolar disorder.1 Family members, clinicians, and others are often bothered more by episodes of hypomania and mania, but depression levies the greatest toll on patients themselves.

When a patient with bipolar disorder becomes depressed, a conservative approach to treatment is to start a mood stabilizer or, if the patient is already taking one, to increase the dose or add a second mood stabilizer.1 A more aggressive approach would be to add an antidepressant.

Clinicians fear that adding an antidepressant to the treatment regimen of a patient with this condition could trigger a switch into mania or hypomania. Few studies have addressed optimal treatment for bipolar depression, but data suggest that venlafaxine (Effexor), along with tricyclic antidepressants, may carry a greater risk of causing a switch—especially for patients with rapid cycling (BTP 2007;30:10-11). In a report from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), funded by the National Institute of Mental Health, Sachs et al describe the use of adjunctive antidepressant medication in treating bipolar depression.2

STEP-BD involved 4360 patients with bipolar disorder. Of those, 2689 had had at least one episode of major depression. A small subset, 366 patients, entered a random-assignment study. For up to 26 weeks, in addition to their mood stabilizer, patients with bipolar depression received either placebo or one of two adjunctive antidepressants—bupropion (Wellbutrin and others) or paroxetine (Paxil and others).

Addition of an antidepressant provided no statistically significant benefit. In fact, there were modest nonsignificant trends that favored adjunctive placebo over adjunctive antidepressant therapy. There was no increased risk of a treatment-emergent switch into hypomania or mania.

In an accompanying editorial, Belmaker cautions that patients with bipolar disorder may be at increased risk of switching into mania if an antidepressant is initiated in the absence of a mood stabilizer.1 He notes that lamotrigine (Lamictal) is efficacious as a prophylactic treatment against bipolar depression, but that its status in treating acute bipolar depression is unclear. He mentions a role for electroconvulsive therapy and calls for additional studies of inositol and omega-3 fatty acids.

An independent study also examined two medications as treatment options for patients with bipolar depression. Nolen and coauthors selected patients with bipolar depression who were not responding to or not tolerating conventional antidepressants.3 Subjects were randomized on an open-label basis to tranylcypromine (Parnate), up to 100 mg/day, or lamotrigine, up to 40 mg/day, as an adjunct to ongoing treatment with a mood stabilizer for 10 weeks.

Because of the small number of patients who were recruited and randomized, results did not reach statistical significance. Nonetheless, responses did appear to favor tranylcypromine over lamotrigine. Five of eight patients who took tranylcypromine responded favorably, and none switched into mania. Only 4 of 11 on lamotrigine therapy responded, and 2 of the 11 experienced switches.

Patients who did not respond were given the option of taking the other drug. Between the two treatment phases, 8 of 10 patients who took tranylcypromine completed the study, but only 5 of 13 who took lamotrigine. The authors call for more systematic study.

At this moment, we are left with a disappointing result from the randomized trial in the STEP-BD program: namely, that adjunctive use of an antidepressant adds little benefit in treating bipolar depression. However, the risk of inducing mania—at least with bupropion or paroxetine—appears small. Today, only two medicines have been awarded the imprimatur of the US Food and Drug Administration to treat bipolar depression: the antipsychotic quetiapine (Seroquel) and the fixed-dose combination of olanzapine and fluoxetine (Symbyax). The treatment of bipolar depression is a substantial problem in need of much more research.

1Belmaker RH: Treatment of bipolar depression. N Engl J Med 2007;356:1771-1773.

2Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D, Martinez JM, Allen MH, Miklowitz DJ, Otto MW, Dennehy EB, Thase ME: Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007;356:1711-1722.

3Nolen WA, Kupka RW, Hellemann G, Frye MA, Altshuler LL, Leverich GS, Suppes T, Keck PE Jr, McElroy S, Grunze H, Mintz J, Post RM: Tranylcypromine vs. lamotrigine in the treatment of refractory bipolar depression: A failed but clinically useful study. Acta Psychiatr Scand 2007;115:360-365.