It would be highly preliminary to conclude from these uncontrolled data that quetiapine had greater effects on bipolar depressive symptoms than did risperidone or clozapine. We cannot rule out the possibility that patients with different degrees of treatment resistance were enrolled and treated with the different concomitant drugs. However, patients did not differ at baseline in severity of their depression.
In this initial look at the atypicals, the severity of depressive symptoms on the IDS was much greater than that of mania, as measured by the Young Mania Rating Scale (YMRS). Thus, the precise patterns of illness being treated and the impact of these antipsychotics on depressive cyclicity and duration await closer examination. We intend to look at the relative efficacy and side-effect profiles of each of the atypical antipsychotics as used in clinical practice.
Second-generation antidepressants
Bupropion, sertraline, and venlafaxine have different mechanisms of action but appear to be of value as adjuncts to bipolar disorder treatment. When we used them as adjuncts to mood stabilizers in a prospective study, we found a 40 to 50% acute response rate and some switching into hypomania and mania (Table 1).11 Many switches appeared to involve only isolated brief bursts of hypomania or recurrent brief hypomanias, but more sustained episodes of hypomania (7 days) could be more clinically problematic. Only 13% of patients treated acutely with these antidepressants had more full-blown manic symptoms (i.e., those associated with moderate or greater dysfunction on the NIMH-LCM).
During the next year, when apparent acute antidepressant responders were offered continuation treatment, 18% switched into mania. However, most patients (about 80%) dropped out because of lack of efficacy (depressive recurrences), intolerance, or for administrative reasons. The 127 patients who were randomized received 175 acute antidepressant trials. Only 9% were associated with a switch into mania with moderate dysfunction, whereas another 9% showed periods of hypomania lasting longer than 1 week.12
Table 2
RELAPSE INTO DEPRESSION IN BIPOLAR PATIENTS AFTER 1 YEAR WITH OR WITHOUT ADJUNCTIVE ANTIDEPRESSANT TREATMENT*
| Rate of relapse | |
|---|---|
| Continued on antidepressants | |
| Study #1 (n=19) | 35% |
| Study #2 (n=41) | 41% |
| Discontinued antidepressants | |
| Study #1 (n=25) | 68% |
| Study #2 (n=43) | 71% |
| * When bupropion, sertraline, or venlafaxine were used as adjuncts to mood stabilizers | |
| Study #1: Altshuler et al. J Clin Psychiatry 2001;62:612-6. | |
| Study #2: Altshuler et al. (submitted for publication 2002). | |
We have entered 176 patients into this double-blind, randomized comparison of bupropion, sertraline, and venlafaxine, with another 27 randomized openly. The study will attempt to examine any possible between-drug differences. Even without the blind being broken, it appears that these antidepressants are associated with a somewhat lower-than-expected rate of switching into mania with dysfunction, but a direct comparison with a placebo is not available.
In two other series, patients who remained well for 2 months on antidepressants plus mood stabilizers and then continued on their antidepressants had a much lower incidence of depressive relapses over the following year than those who discontinued their antidepressants (Table 2).13,14 Surprisingly, continuing the antidepressant was not associated with an increased rate of switching into mania.
Prospective randomized, controlled studies are required to confirm these findings. Even so, our studies appear to challenge conventional wisdom for the first time. Stopping antidepressant treatment in bipolar patients as soon as possible for fear of inducing a manic episode may not be the optimal recommendation in the admittedly small subgroup (about 15%) of patients who have responded well to an antidepressant for at least 2 months.
Table 3
SIX STUDIES COMPLETED BY SFBN INVESTIGATORS
| Study (authors) | Randomized | Design | Number studied | Response rate |
|---|---|---|---|---|
| Antidepressants bupropion | Yes | Double-blind | 173 | ~ 47% |
| vs. sertraline vs. venlafaxine (Post et al, 2001) | Yes | Open | 27 | |
| Total = 200 | ||||
| Olanzapine (McElroy et al, 1998) | No | Open | 14 | ~ 57% |
| Lamotrigine (Suppes et al, 1999) | No | Open | 17 | ~ 65% |
| Gabapentin (Altshuler et al, 1999) | No | Open | 28 | 78% (14/18) for mania or hypomania 100% (n = 5) for depression 20% (1/5) for cycling |
| Topiramate (McElroy et al, 2000) | No | Open | 54 | 63% for mania or cycling 27% for acute depression (weight loss observed) |
| Tiagabine (Suppes et al, 2002) | No | Open | 17 | 18% (3/17) (3 possible seizures) |
Second-generation anticonvulsants
Based on our patients’ substantial residual symptoms, we explored a series of newly approved anticonvulsants for potential use as mood stabilizers.
Lamotrigine Consistent with other open and double-blind, placebo-controlled studies, lamotrigine showed promise as an adjunctive treatment, with improvement in depressive symptoms and cycling.15 One such study showed acute antidepressant effects of lamotrigine monotherapy compared with a placebo at dosages of 50 or 200 mg/d.16
Another double-blind, randomized, placebo-controlled NIMH study (partially funded by the Stanley Foundation) compared lamotrigine with gabapentin and a placebo in patients for whom lithium, carbamazepine, and valproate had failed.17 Most of these treatment-refractory patients received all three agents through three 6-week randomizations. Lamotrigine was much more effective in depression and overall illness than either a placebo or gabapentin. Men with bipolar compared with unipolar illness and patients with fewer unsuccessful clinical trials and hospitalizations for depression showed the greatest response.18