From the stanley foundation bipolar network: Efficacy of adjunctive therapies for treatment-resistant patients
First the researchers identified the unique clinical characteristics of patients enrolled in the Stanley Foundation Bipolar Network. Their next challenge: to find evidence through clinical trials for therapies that could help improve patients’ quality of life.
When choosing psychopharmacologic agents for patients with bipolar disorder, the clinician lacks guidance from controlled clinical trials at virtually every therapeutic step. To help remedy this problem, we in the Stanley Foundation Bipolar Network (SFBN) evaluated compounds with potentially important therapeutic profiles. We began by documenting the demographics and illness characteristics of patients with bipolar disorder. Then we assessed some 16 treatments in naturalistic or formal studies, some of which are complete and others ongoing.
In this second installment, we report our current information about the efficacy of second-generation antidepressants, atypical antipsychotics, and anticonvulsant agents.
As mood stabilizers, the anticonvulsants carbamazepine and valproate are well-accepted alternatives or adjuncts to lithium carbonate, which remains a mainstay treatment for acute episodes and long-term prophylaxis.1
Valproate is approved by the FDA for treatment of acute mania but not for long-term prevention. Open studies in rapid-cycling, treatment-refractory patients demonstrate substantial improvement for both manic and depressive phases with valproate. In the most recent controlled study, valproate did not prevent manic episodes to a statistically significant degree, but it did show greater antidepressant effects than placebo or lithium. 2
Carbamazepine has been widely studied in acute mania and compared with lithium for long-term prophylaxis. Most studies show nonsignificant differences between carbamazepine and lithium in preventing manic and depressive episodes, although several studies indicate less-robust antimanic effects of carbamazepine,3 particularly for patients with classic euphoric mania without psychosis, bipolar II, or associated substance abuse.4
In atypical patients, carbamazepine appeared to outperform lithium, suggesting clinical differences in these agents that have different mechanisms of action across neurotransmitter and peptide systems.
Low response rates Most randomized controlled trials and open adjunct studies suggest that 50% or more patients respond to lithium, valproate, or carbamazepine. Outcomes may be far less positive in clinical practice, however. Despite the use of mood stabilizers and a variety of antidepressants, benzodiazepines, and neuroleptics, our patients experienced substantial residual manic and depressive symptoms and functional impairment.
Similarly, clinician ratings on the National Institute of Mental Health Life Chart Method (NIMH-LCM) indicated a high rate of breakthrough episodes during carefully monitored and aggressive psychopharmacologic treatment.5 Two-thirds of the first 258 bipolar outpatients that we followed and rated daily for 1 year continued to be substantially impaired. One-quarter of them were ill for more than 75% of the year, despite using an average 4.1 psychopharmacologic agents per patient, including mood stabilizers, antidepressants, antipsychotics, and other agents.
Acute and long-term combination therapy appears more effective than monotherapy, particularly for treatment-refractory rapid cyclers.3 Even so, many patients do not respond to combination therapy. For example, in a 1-year prophylaxis study, 25% or fewer patients were rated “much improved” to “very much improved” on the Clinical Global Impressions (CGI) scale with lithium or carbamazepine as the baseline mood stabilizer and with antidepressants, neuroleptics, and benzodiazepines used as needed. In the third year of combination therapy, the overall response rate, including rapid cyclers, was roughly 50%. 3
A low rate of response is apparent for lithium and valproate. While treating rapidly cycling patients, Calabrese and associates found that less than one-quarter of them responded well enough to the two-drug combination that they could be enrolled in a randomized double-blind comparison of each drug in monotherapy. Of those who were eligible, almost all relapsed with either lithium or valproate monotherapy and again required combination therapy.6
RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*
Acute treatment (10 wks)
Continuation treatment (52 wks)‡
Type of switch
Recurrent brief hypomania
* When bupropion, sertraline, or venlafaxine were used as adjuncts to mood stabilizers
‡ Most patients (80%) dropped out of this phase because of lack of efficacy (depressive recurrences), intolerance, or for administrative reasons.
Source: Post RM et al. Bipolar Disord 2001;3:259-65, and unpublished data.
Taken together, these studies indicate that even with our most effective and most studied agents, many patients respond inadequately. On the basis of this clinical reality, we began to explore additional options that might enhance clinical effectiveness.
We assessed the addition of the atypical antipsychotic olanzapine in patients with treatment-refractory bipolar disorder7 and saw improvement in 57% of subjects with manic, mixed, and depressive components. These data foreshadowed more recent controlled findings of olanzapine’s usefulness in depression and mania.8,9 Our preliminary open clinical trial experience allowed for more controlled studies and subsequent approval and wider clinical use of olanzapine in bipolar illness.
Our initial assessment of other atypical antipsychotics found that quetiapine was associated with significantly fewer depressive symptoms on the Inventory of Depressive Symptomatology (IDS) when used as part of the regular treatment regimen. This improvement, which was seen in the first month, was maintained over 4 months of treatment, whereas no significant improvement in depression severity was seen with the use of risperidone or clozapine.10
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.
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
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)
Study #2 (n=41)
Study #1 (n=25)
Study #2 (n=43)
* 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.
SIX STUDIES COMPLETED BY SFBN INVESTIGATORS
vs. sertraline vs. venlafaxine (Post et al, 2001)
Total = 200
Olanzapine (McElroy et al, 1998)
Lamotrigine (Suppes et al, 1999)
Gabapentin (Altshuler et al, 1999)
78% (14/18) for mania or hypomania 100% (n = 5) for depression 20% (1/5) for cycling
Topiramate (McElroy et al, 2000)
63% for mania or cycling 27% for acute depression (weight loss observed)
Tiagabine (Suppes et al, 2002)
18% (3/17) (3 possible seizures)
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
In two recent industry-sponsored controlled trials of long-term prophylaxis (following a recent manic or depressive episode), lamotrigine was significantly more effective than a placebo (Bowden et al and Calabrese et al, unpublished data). Lamotrigine was more effective than lithium in preventing depressive episodes, whereas lithium was more effective than lamotrigine for manic episodes, although lamotrigine was significantly better than the placebo.
These data suggest that lamotrigine may differ from valproate, carbamazepine, and lithium in being a more effective antidepressant than antimanic agent.
Topiramate Adjunctive use of topiramate in rapid-cycling and treatment-resistant patients has been examined in open studies, but controlled studies have not yet been published. In our open-label case series observations, 19 of 30 (63%) patients taking topiramate for mania or cycling were “much” or “very much” improved after 10 weeks, whereas only 3 of 11 (27%) patients taking topiramate for acute depression were so improved.19
STUDIES IN PROGRESS BY SFBN INVESTIGATORS
Topiramate vs. sibutramine
Relative weight loss and mood stabilization
Omega-3 fatty acids (6 grams EPA vs. placebo) (for depression cycling) (Keck et al)
Data from both studies being analyzed
Acamprosate (for alcohol craving) (Grunze et al)
Goal: 60 patients
Levetiracetam (Post et al)
Goal: 30 patients
Zonisamide (McElroy et al)
Goal: 60 patients European sites only
Tranylcypromine vs. lamotrigine (for refractory depression) (Nolen et al)
Quetiapine (McElroy et al)
Apparent superior antidepressant effects compared with risperidone or clozapine
Risperidone (Grunze et al)
No significant effect on IDS‡ depression ratings
Clozapine (Suppes et al)
No significant effect on IDS depression ratings
Modafinil vs. placebo (Frye et al)
‡ IDS = Inventory of Depressive Symptomatology
An industry-sponsored double-blind, randomized trial of topiramate in acute mania looked promising in the first 67 patients, but not as encouraging in subsequent subjects. A positive drug effect re-emerged if one eliminated patients whose manic episodes were precipitated by antidepressants.
The acute antidepressant effects of topiramate did not appear promising in our study. On the other hand, a single-blind, randomized study of topiramate versus bupropion as adjunctive therapy for breakthrough bipolar depression suggested excellent acute response (approximately 56%) to both agents. 20 These data leave the potential antidepressant effects of topiramate undetermined.