Evidence-Based Reviews

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

Current Psychiatry. 2002 August;1(8):36-44

References

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Thus, our initial observations led us to discontinue use of tiagabine and suggest any further clinical consideration of this agent for treatment-resistant affective disorders would require great care. This perspective contrasts with several previous positive case reports. It is unknown whether selected patients or those treated with lower dosages would be more responsive to this agent.

Like valproate, gabapentin and tiagabine increase brain GABA, but their apparent lack of antimanic efficacy strongly suggests that raising brain GABA alone does little to counter mania. These data further support the viewpoint already offered that all anticonvulsants are not alike and that anticonvulsants as a class are not necessarily mood stabilizers.

Zonisamide and levetiracetam Open studies of these two other anticonvulsants are near completion. Each has an interesting mechanistic profile, good tolerability, and the (potentially positive) side effect of inducing some weight loss, based on studies of neurologic patients.

Omega-3 fatty acids Based on positive reports of antidepressant effects of omega-3 fatty acids,^28-30 we recently recruited more than 120 patients with bipolar disorder for two double-blind, randomized, controlled trials. Those patients with either an acute depression or a cyclic course will receive 6 grams of omega-3 fatty acid (the eicosapentaenoate form) or a placebo for 4 months of double-blind treatment, followed by an 8-month open, active continuation phase.

If results are positive, omega-3 fatty acids would represent the much-needed addition of a well-tolerated dietary agent to the therapeutic armamentarium directed at bipolar illness.

Conclusion

The Stanley Foundation Bipolar Network has begun to evaluate the usefulness of numerous older and new compounds for patients with bipolar disorder, including second-generation antidepressants, anticonvulsants, atypical antipsychotic agents, and omega-3 fatty acids. Based on initial observations from 16 treatment studies (Table 3), we have drawn these conclusions:

Second-generation antidepressants such as bupropion, sertraline, and venlafaxine appear to have a lower-than-expected switch rate into mania, compared with the use of the older tricyclic antidepressants.
If the addition of a second-generation antidepressant results in good antidepressant response for 2 months and no switches into mania, one should consider continuing the antidepressant in this small minority of patients, rather than stopping it as soon as possible as previously recommended.
Adjunctive use of lamotrigine appears to be of value, particularly for acute depression and prophylaxis, for many patients who have not responded to other treatments.
While our group and others have reported improvement with adjunctive gabapentin in bipolar patients in uncontrolled case series, its primary antimanic or mood-stabilizing utility (as well as that of tiagabine) does not appear promising.
Topiramate’s ability to induce substantial weight loss may emerge as clinically therapeutic for patients with problematic weight gain related to other psychotropic drugs, independent of its ultimate utility as a possible mood stabilizer.

We are preparing to analyze other open case series assessing acute and long-term treatment outcomes as well as randomized, double-blind clinical trials. Even though the funding of this unique collaborative network is ending, we look forward to more effective treatment of bipolar disorder in the future with continued development of new psychotropic agents and data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) and the VA Cooperative studies.³¹

Related resources

National Alliance for the Mentally Ill (NAMI). www.nami.org
National Depressive and Manic-Depressive Association (NDMDA). www.ndmda.org

Drug brand names

Bupropion • Wellbutrin
Carbamazepine • Tegretol
Clozapine • Clozaril
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levetiracetam • Keppra
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Sibutramine • Meridia
Tiagabine • Gabitril
Topiramate • Topamax
Valproate • Depakote
Venlafaxine • Effexor
Zonisamide • Zonegran

Acknowledgement

The authors are particularly indebted to the generosity of The Stanley Foundation in making funds available for this series of studies and several about to be completed.

Disclosure

Financial disclosure statements have been provided by all authors and are available upon request at current.psychiatry@dowdenhealth.com.