Evidence-Based Reviews

From the Stanley Foundation Bipolar Network: Efficacy of adjunctive therapies for treatment-resistant patients

Author and Disclosure Information

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.

Mood stabilizers

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

Table 1


Acute treatment (10 wks)Continuation treatment (52 wks)
Type of switchOpen (n=27)Blind (n=100)Total (n=127)Open (n=12)Blind (n=55)Total (n=67)
Brief hypomania3.7%6%5.5%3.6%3%
Recurrent brief hypomania111211.88.3%18.216.4
* 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.

Atypical antipsychotics

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


Next Article: