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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
RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*
| Acute treatment (10 wks) | Continuation treatment (52 wks)‡ | |||||
|---|---|---|---|---|---|---|
| Type of switch | Open (n=27) | Blind (n=100) | Total (n=127) | Open (n=12) | Blind (n=55) | Total (n=67) |
| Brief hypomania | 3.7% | 6% | 5.5% | – | 3.6% | 3% |
| Recurrent brief hypomania | 11 | 12 | 11.8 | 8.3% | 18.2 | 16.4 |
| Hypomania | 11 | 13 | 12.6 | 8.3 | 23.6 | 20.9 |
| Mania | 14.8 | 12 | 12.6 | 33.3 | 14.5 | 17.9 |
| Total | 25.8 | 25 | 25.2 | 41.6 | 38.1 | 38.8 |
| * 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
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
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
Table 4
STUDIES IN PROGRESS BY SFBN INVESTIGATORS
| Study (authors) | Randomized | Design | Number enrolled* | Notes |
|---|---|---|---|---|
| Topiramate vs. sibutramine | Yes | Open | 42 | Relative weight loss and mood stabilization |
| Omega-3 fatty acids (6 grams EPA vs. placebo) (for depression cycling) (Keck et al) | Yes Yes | Double-blind Double-blind | 62 60 | Data from both studies being analyzed |
| Acamprosate (for alcohol craving) (Grunze et al) | No | Open | 23 | Goal: 60 patients |
| Levetiracetam (Post et al) | No | Open | 13 | Goal: 30 patients |
| Zonisamide (McElroy et al) | No | Open | 45 | Goal: 60 patients European sites only |
| Tranylcypromine vs. lamotrigine (for refractory depression) (Nolen et al) | Yes | Open | 17 | Single-site study |
| Quetiapine (McElroy et al) | No | Open | 48 | Apparent superior antidepressant effects compared with risperidone or clozapine |
| Risperidone (Grunze et al) | No | Open | 37 | No significant effect on IDS‡ depression ratings |
| Clozapine (Suppes et al) | No | Open | 19 | No significant effect on IDS depression ratings |
| Modafinil vs. placebo (Frye et al) | Yes | Double-blind | Started 4/02 | |
| * Enrollment as of April 2002 n = 696 total patients in tables 3 and 4 | ||||
| ‡ 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.
In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).19 Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).
We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.21 This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.
We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.
Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.22 As monotherapy, however, gabapentin was not more effective than a placebo17 and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,23 although other double-blind, controlled studies have indicated positive effects in anxiety disorders24 and social phobias.25 Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.
Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.
Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.26 Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.27
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.
1. Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990.
2. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000;57:481-9.
3. Denicoff KD, Smith-Jackson EE, Disney ER, et al. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry 1997a;58:470-8.
4. Greil W, Kleindienst N. The comparative prophylactic efficacy of lithium and carbamazepine in patients with bipolar I disorder. Int Clin Psychopharmacol 1999;14:277-81.
5. Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for one year with daily prospective ratings on the NIMH-LCM (submitted for publication, 2002).
6. Calabrese JR, Rapport DJ. Mood stabilizers and the evolution of maintenance study designs in bipolar I disorder. J Clin Psychiatry 1999;60(suppl 5):5-13.
7. McElroy SL, Frye M, Denicoff K, et al. Olanzapine in treatment-resistant bipolar disorder. J Affect Disord 1998;49:119-22.
8. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158:131-4.
9. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002;59:62-9.
10. Keck PE, Jr. New antiepileptics in the treatment of bipolar disorder. Syllabus and Proceedings Summary of the 2001 American Psychiatric Association Meeting, New Orleans, May 5-10, 2001. Abstract 34E, 93.
11. Post RM, Altshuler LL, Frye MA, et al. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disord 2001;3:259-65.
12. Post RM, Leverich GS, Nolen WA, et al. A reevaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Bipolar Treatment Network. Bipolar Disord 2002 (in press).
13. Altshuler L, Kiriakos L, Calcagno J, et al. The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry 2001;62:612-6.
14. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute remission from bipolar depression on rates of depressive relapse at one-year follow-up (submitted for publication 2002).
15. Suppes T, Brown ES, McElroy SL, et al. Lamotrigine for the treatment of bipolar disorder: a clinical case series. J Affective Disord 1999;53:95-8.
16. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999;60:79-88.
17. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000;20:607-14.
18. Obrocea GV, Dunn RM, Frye MA, et al. Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Biolog Psychiatry 2002;51:253-60.
19. McElroy SL, Suppes T, Keck PE, et al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biolog Psychiatry 2000;47:1025-33.
20. McIntyre RS, Mancini DA, McCann SM, et al. Topiramiate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord 2002;4:207-13.
21. Reife R, Pledger G, Wu SC. Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults. Epilepsia 2000;41(suppl 1):S66-S71.
22. Altshuler LL, Keck PE, Jr, McElroy SL, et al. Gabapentin in the acute treatment of refractory bipolar disorder. Bipolar Disord 1999;1:61-5.
23. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord 2000;2:249-55.
24. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol 2000;20:467-71.
25. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol 1999;19:341-8.
26. Suppes T, Chisholm K, Dhvule D, et al. Tiagabine in bipolar disorder: adverse events in an open case series (submitted for publication, 2002).
27. Grunze H, Erfurth A, Marcuse A, et al. Tiagabine appears not to be efficacious in the treatment of acute mania. J Clin Psychiatry 1999;60:759-62.
28. Stoll AL, Severus WE, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-12.
29. Horrobin DF, Peet M. A dose-ranging study of ethyl-eicosapentaenoate in treatment-unresponsive depression. Biolog Psychiatry 2001;49:37S.-
30. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477-9.
31. Bauer MS, Williford WO, Dawson EE, et al. Principles of effectiveness trials and their implementation in VA Cooperative Study #430: Reducing the efficacy-effectiveness gap in bipolar disorder. J Affect Disord 2001;67:61-78.
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
RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*
| Acute treatment (10 wks) | Continuation treatment (52 wks)‡ | |||||
|---|---|---|---|---|---|---|
| Type of switch | Open (n=27) | Blind (n=100) | Total (n=127) | Open (n=12) | Blind (n=55) | Total (n=67) |
| Brief hypomania | 3.7% | 6% | 5.5% | – | 3.6% | 3% |
| Recurrent brief hypomania | 11 | 12 | 11.8 | 8.3% | 18.2 | 16.4 |
| Hypomania | 11 | 13 | 12.6 | 8.3 | 23.6 | 20.9 |
| Mania | 14.8 | 12 | 12.6 | 33.3 | 14.5 | 17.9 |
| Total | 25.8 | 25 | 25.2 | 41.6 | 38.1 | 38.8 |
| * 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
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
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
Table 4
STUDIES IN PROGRESS BY SFBN INVESTIGATORS
| Study (authors) | Randomized | Design | Number enrolled* | Notes |
|---|---|---|---|---|
| Topiramate vs. sibutramine | Yes | Open | 42 | Relative weight loss and mood stabilization |
| Omega-3 fatty acids (6 grams EPA vs. placebo) (for depression cycling) (Keck et al) | Yes Yes | Double-blind Double-blind | 62 60 | Data from both studies being analyzed |
| Acamprosate (for alcohol craving) (Grunze et al) | No | Open | 23 | Goal: 60 patients |
| Levetiracetam (Post et al) | No | Open | 13 | Goal: 30 patients |
| Zonisamide (McElroy et al) | No | Open | 45 | Goal: 60 patients European sites only |
| Tranylcypromine vs. lamotrigine (for refractory depression) (Nolen et al) | Yes | Open | 17 | Single-site study |
| Quetiapine (McElroy et al) | No | Open | 48 | Apparent superior antidepressant effects compared with risperidone or clozapine |
| Risperidone (Grunze et al) | No | Open | 37 | No significant effect on IDS‡ depression ratings |
| Clozapine (Suppes et al) | No | Open | 19 | No significant effect on IDS depression ratings |
| Modafinil vs. placebo (Frye et al) | Yes | Double-blind | Started 4/02 | |
| * Enrollment as of April 2002 n = 696 total patients in tables 3 and 4 | ||||
| ‡ 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.
In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).19 Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).
We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.21 This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.
We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.
Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.22 As monotherapy, however, gabapentin was not more effective than a placebo17 and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,23 although other double-blind, controlled studies have indicated positive effects in anxiety disorders24 and social phobias.25 Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.
Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.
Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.26 Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.27
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.
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
RATE OF SWITCHING (%) INTO MANIA IN DEPRESSED BIPOLAR PATIENTS DURING ANTIDEPRESSANT TREATMENT*
| Acute treatment (10 wks) | Continuation treatment (52 wks)‡ | |||||
|---|---|---|---|---|---|---|
| Type of switch | Open (n=27) | Blind (n=100) | Total (n=127) | Open (n=12) | Blind (n=55) | Total (n=67) |
| Brief hypomania | 3.7% | 6% | 5.5% | – | 3.6% | 3% |
| Recurrent brief hypomania | 11 | 12 | 11.8 | 8.3% | 18.2 | 16.4 |
| Hypomania | 11 | 13 | 12.6 | 8.3 | 23.6 | 20.9 |
| Mania | 14.8 | 12 | 12.6 | 33.3 | 14.5 | 17.9 |
| Total | 25.8 | 25 | 25.2 | 41.6 | 38.1 | 38.8 |
| * 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
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
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
Table 4
STUDIES IN PROGRESS BY SFBN INVESTIGATORS
| Study (authors) | Randomized | Design | Number enrolled* | Notes |
|---|---|---|---|---|
| Topiramate vs. sibutramine | Yes | Open | 42 | Relative weight loss and mood stabilization |
| Omega-3 fatty acids (6 grams EPA vs. placebo) (for depression cycling) (Keck et al) | Yes Yes | Double-blind Double-blind | 62 60 | Data from both studies being analyzed |
| Acamprosate (for alcohol craving) (Grunze et al) | No | Open | 23 | Goal: 60 patients |
| Levetiracetam (Post et al) | No | Open | 13 | Goal: 30 patients |
| Zonisamide (McElroy et al) | No | Open | 45 | Goal: 60 patients European sites only |
| Tranylcypromine vs. lamotrigine (for refractory depression) (Nolen et al) | Yes | Open | 17 | Single-site study |
| Quetiapine (McElroy et al) | No | Open | 48 | Apparent superior antidepressant effects compared with risperidone or clozapine |
| Risperidone (Grunze et al) | No | Open | 37 | No significant effect on IDS‡ depression ratings |
| Clozapine (Suppes et al) | No | Open | 19 | No significant effect on IDS depression ratings |
| Modafinil vs. placebo (Frye et al) | Yes | Double-blind | Started 4/02 | |
| * Enrollment as of April 2002 n = 696 total patients in tables 3 and 4 | ||||
| ‡ 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.
In patients being treated with topiramate, we found significant weight loss (average –0.7 kg at 4 weeks, –1.6 kg at 10 weeks, –4.7 kg at 6 months, and –6.2 kg at 1 year).19 Average weight loss was 4.5±6.7 kg at the final evaluation (body mass index [BMI] change of –6.3% and –5% at 1 year and last evaluation, respectively).
We and others have thus seen substantial weight loss in one-third to one-half of patients taking topiramate for bipolar disorder.21 This weight loss is maintained over relatively long periods, which differentiates topiramate from other weight-loss regimens. Topiramate’s ability to decrease weight—even while it is in the early stages of evaluation as a mood stabilizer—is of considerable interest, given the substantial problem of overweight in the bipolar population and the fact that many drug therapies used in the illness are associated with weight gain.
We are proceeding with a randomized open comparison of the relative weight loss and psychotropic efficacy of topiramate versus the antiobesity agent sibutramine. Sibutramine has been reported to have antidepressant properties and is FDA-approved for weight loss.
Gabapentin and tiagabine Our group and many others have reported substantial overall clinical improvement when gabapentin was used as adjunctive therapy in an open study of patients with inadequate response to previous treatments.22 As monotherapy, however, gabapentin was not more effective than a placebo17 and was less effective than lamotrigine. Similarly, gabapentin was not an effective acute antimanic agent when compared with a placebo,23 although other double-blind, controlled studies have indicated positive effects in anxiety disorders24 and social phobias.25 Thus, the gabapentin literature appears to be divergent—i.e., positive studies support its adjunctive use in bipolar patients, but controlled studies suggest that it is not directly antimanic or mood-stabilizing.
Gabapentin’s effect on syndromes that are highly comorbid with bipolar illness could account for its apparent success as open adjunctive therapy. For example, in addition to its antianxiety effects, gabapentin shows positive effects in alcohol withdrawal, pain syndromes, sleep disorders (including restless leg syndrome), and obsessive-compulsive disorder. Also, combining gabapentin with other psychotropics with other mechanisms of action may have a more robust therapeutic effect than monotherapy.
Our preliminary observations with the selective GABA-reuptake inhibitor tiagabine were not promising. In an open study, only 3 of the first 17 SFBN patients with treatment-resistant affective disorders showed a partial response (moderate improvement on the Clinical Global Impressions Scale for Bipolar Illness [CGI-BP]) to adjunctive tiagabine treatment when the dosage was gradually increased. Serious side effects, including two patients with possible seizures, were noted.26 Similar results were seen when tiagabine doses were rapidly increased in eight patients with acute mania; none responded, and one had a major motor seizure.27
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.
1. Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990.
2. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000;57:481-9.
3. Denicoff KD, Smith-Jackson EE, Disney ER, et al. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry 1997a;58:470-8.
4. Greil W, Kleindienst N. The comparative prophylactic efficacy of lithium and carbamazepine in patients with bipolar I disorder. Int Clin Psychopharmacol 1999;14:277-81.
5. Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for one year with daily prospective ratings on the NIMH-LCM (submitted for publication, 2002).
6. Calabrese JR, Rapport DJ. Mood stabilizers and the evolution of maintenance study designs in bipolar I disorder. J Clin Psychiatry 1999;60(suppl 5):5-13.
7. McElroy SL, Frye M, Denicoff K, et al. Olanzapine in treatment-resistant bipolar disorder. J Affect Disord 1998;49:119-22.
8. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158:131-4.
9. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002;59:62-9.
10. Keck PE, Jr. New antiepileptics in the treatment of bipolar disorder. Syllabus and Proceedings Summary of the 2001 American Psychiatric Association Meeting, New Orleans, May 5-10, 2001. Abstract 34E, 93.
11. Post RM, Altshuler LL, Frye MA, et al. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disord 2001;3:259-65.
12. Post RM, Leverich GS, Nolen WA, et al. A reevaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Bipolar Treatment Network. Bipolar Disord 2002 (in press).
13. Altshuler L, Kiriakos L, Calcagno J, et al. The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry 2001;62:612-6.
14. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute remission from bipolar depression on rates of depressive relapse at one-year follow-up (submitted for publication 2002).
15. Suppes T, Brown ES, McElroy SL, et al. Lamotrigine for the treatment of bipolar disorder: a clinical case series. J Affective Disord 1999;53:95-8.
16. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999;60:79-88.
17. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000;20:607-14.
18. Obrocea GV, Dunn RM, Frye MA, et al. Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Biolog Psychiatry 2002;51:253-60.
19. McElroy SL, Suppes T, Keck PE, et al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biolog Psychiatry 2000;47:1025-33.
20. McIntyre RS, Mancini DA, McCann SM, et al. Topiramiate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord 2002;4:207-13.
21. Reife R, Pledger G, Wu SC. Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults. Epilepsia 2000;41(suppl 1):S66-S71.
22. Altshuler LL, Keck PE, Jr, McElroy SL, et al. Gabapentin in the acute treatment of refractory bipolar disorder. Bipolar Disord 1999;1:61-5.
23. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord 2000;2:249-55.
24. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol 2000;20:467-71.
25. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol 1999;19:341-8.
26. Suppes T, Chisholm K, Dhvule D, et al. Tiagabine in bipolar disorder: adverse events in an open case series (submitted for publication, 2002).
27. Grunze H, Erfurth A, Marcuse A, et al. Tiagabine appears not to be efficacious in the treatment of acute mania. J Clin Psychiatry 1999;60:759-62.
28. Stoll AL, Severus WE, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-12.
29. Horrobin DF, Peet M. A dose-ranging study of ethyl-eicosapentaenoate in treatment-unresponsive depression. Biolog Psychiatry 2001;49:37S.-
30. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477-9.
31. Bauer MS, Williford WO, Dawson EE, et al. Principles of effectiveness trials and their implementation in VA Cooperative Study #430: Reducing the efficacy-effectiveness gap in bipolar disorder. J Affect Disord 2001;67:61-78.
1. Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990.
2. Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000;57:481-9.
3. Denicoff KD, Smith-Jackson EE, Disney ER, et al. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry 1997a;58:470-8.
4. Greil W, Kleindienst N. The comparative prophylactic efficacy of lithium and carbamazepine in patients with bipolar I disorder. Int Clin Psychopharmacol 1999;14:277-81.
5. Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for one year with daily prospective ratings on the NIMH-LCM (submitted for publication, 2002).
6. Calabrese JR, Rapport DJ. Mood stabilizers and the evolution of maintenance study designs in bipolar I disorder. J Clin Psychiatry 1999;60(suppl 5):5-13.
7. McElroy SL, Frye M, Denicoff K, et al. Olanzapine in treatment-resistant bipolar disorder. J Affect Disord 1998;49:119-22.
8. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry 2001;158:131-4.
9. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002;59:62-9.
10. Keck PE, Jr. New antiepileptics in the treatment of bipolar disorder. Syllabus and Proceedings Summary of the 2001 American Psychiatric Association Meeting, New Orleans, May 5-10, 2001. Abstract 34E, 93.
11. Post RM, Altshuler LL, Frye MA, et al. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disord 2001;3:259-65.
12. Post RM, Leverich GS, Nolen WA, et al. A reevaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Bipolar Treatment Network. Bipolar Disord 2002 (in press).
13. Altshuler L, Kiriakos L, Calcagno J, et al. The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry 2001;62:612-6.
14. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute remission from bipolar depression on rates of depressive relapse at one-year follow-up (submitted for publication 2002).
15. Suppes T, Brown ES, McElroy SL, et al. Lamotrigine for the treatment of bipolar disorder: a clinical case series. J Affective Disord 1999;53:95-8.
16. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999;60:79-88.
17. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000;20:607-14.
18. Obrocea GV, Dunn RM, Frye MA, et al. Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders. Biolog Psychiatry 2002;51:253-60.
19. McElroy SL, Suppes T, Keck PE, et al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biolog Psychiatry 2000;47:1025-33.
20. McIntyre RS, Mancini DA, McCann SM, et al. Topiramiate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study. Bipolar Disord 2002;4:207-13.
21. Reife R, Pledger G, Wu SC. Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults. Epilepsia 2000;41(suppl 1):S66-S71.
22. Altshuler LL, Keck PE, Jr, McElroy SL, et al. Gabapentin in the acute treatment of refractory bipolar disorder. Bipolar Disord 1999;1:61-5.
23. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group. Bipolar Disord 2000;2:249-55.
24. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol 2000;20:467-71.
25. Pande AC, Davidson JR, Jefferson JW, et al. Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol 1999;19:341-8.
26. Suppes T, Chisholm K, Dhvule D, et al. Tiagabine in bipolar disorder: adverse events in an open case series (submitted for publication, 2002).
27. Grunze H, Erfurth A, Marcuse A, et al. Tiagabine appears not to be efficacious in the treatment of acute mania. J Clin Psychiatry 1999;60:759-62.
28. Stoll AL, Severus WE, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-12.
29. Horrobin DF, Peet M. A dose-ranging study of ethyl-eicosapentaenoate in treatment-unresponsive depression. Biolog Psychiatry 2001;49:37S.-
30. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477-9.
31. Bauer MS, Williford WO, Dawson EE, et al. Principles of effectiveness trials and their implementation in VA Cooperative Study #430: Reducing the efficacy-effectiveness gap in bipolar disorder. J Affect Disord 2001;67:61-78.