Treatment Advances in Bipolar Disorder—Making Up
for Lost Time
Much ground has been gained in recent years in improving treatments for people with bipolar disorder. These exciting developments are long overdue. As recently as 1993, only one medication, lithium, was approved for the treatment of this severe, recurrent illness. Psychotherapeutic strategies had been either neglected or abandoned. Several factors seem to have contributed to this protracted period of therapeutic quiescence. First, lithium was presumed to be an effective medication for most phases of bipolar disorder for most patients. Clinical lore had long held that most patients recovered fully from affective episodes and went on to experience long periods of euthymia and good functioning. Psychotherapeutic approaches were either thought to be irrelevant in this biological illness or appropriated willy-nilly from applications in other ill-nesses. Subsequent studies have shown that these beliefs were seriously wrong. Only a minority of patients with bipolar disorder experience the salutary effects of lithium monotherapy (Maj 2000). Many patients have great diffi-culty returning to their previous level of functioning after experiencing an affective episode, and recurrent episodes can lead to permanent disability (Keck et al 1998). Bipolar disorder was the sixth leading cause of disability world-wide in 1990 and, without further treatment advances, was projected to remain so into this century (Murray and Lopez 1996). The cost of this illness in human suffering is profound and immeasurable (Coryell et al 1993). The articles in this issue of Biological Psychiatry document recent research efforts to gain ground in the struggle to improve the lives of people with bipolar disorder.
The treatment of bipolar disorder is usually conceptu-alized as consisting of the acute treatment of affective episodes (manic, mixed, and depressive) and prophylactic treatment to prevent future episodes and eradicate interepi-sode or subsyndromal symptoms. That the role of medi-cations in the treatment of all aspects of this illness is crucial is beyond dispute. The role of specific forms of psychotherapy, tailored to the unique needs of patients with bipolar disorder, in the maintenance phase of treat-ment offers the promise of filling large gaps left by straightforward pharmacotherapy.
The most significant advances in the pharmacologic treatment of bipolar disorder have occurred in the treatment of acute mania. This should not be surprising, since mood-stabilizing medications have traditionally been antimanic agents. In the last 6 years two
medica-tions, divalproex and olanzapine, have received ap-proval in the United States for the treatment of acute bipolar mania. Both medications also appear to fill a treatment void in being equally effective in manic and mixed episodes. Chlorpromazine, haloperidol, carbam-azepine, risperidone, and ziprasidone have been effica-cious in the treatment of acute bipolar mania in ran-domized, double-blind, controlled trials. Two major groups of medications, the atypical antipsychotics (quetiapine, aripiprazole, and iloperidone, in addition to risperidone, olanzapine, and ziprasidone) and the new antiepileptics (gabapentin, pregabalin, lamotrigine, topiramate, tiagabine, oxcarbazepine, and zonisamide), are being actively investigated as potential treatments for bipolar disorder. The need for medications that act quickly, are well tolerated, have efficacy in all compo-nents of the manic syndrome (mood, behavior, cogni-tion, and psychosis), ameliorate mixed as well as manic presentations, and can be parlayed into effective main-tenance therapy remains substantial. Two recent studies have shown that treatment with the combination of risperidone (Sachs and Risperidone Study Group 1999) or olanzapine (Tohen et al. 2000) and lithium or divalproex is more effective than monotherapy with lithium or divalproex in acute mania (with or without psychosis). Although treatment of acute mania with an antipsychotic and lithium or divalproex has been com-monplace for years, these were the first studies to actually demonstrate that such a strategy is more effective than treatment with one agent alone.
The pharmacologic treatment of bipolar depression remains vastly understudied. Two important placebo-controlled trials were concluded in the last several years (Calabrese et al 1999; Nemeroff et al, in press); however, many critical questions regarding the treat-ment of bipolar depression are unanswered. Although a variety of antidepressants with novel mechanisms of action and improved side effect profiles are available (e.g., selective serotonin reuptake inhibitors, bupropion, venlafaxine, nefazodone, mirtazapine) or in develop-ment (e.g., reboxetine, neurokinin 1 and corticotropin-releasing hormone antagonists), the vast majority of these medications have not been systematically studied in patients with bipolar depression. With the exception of lamotrigine, the new antiepileptics and atypical antipsychotics have not been studied in bipolar
depres-© 2000 Society of Biological Psychiatry 0006-3223/00/$20.00
sion. This is a crucial area of study for these new medications in order to determine whether they are bona fide mood stabilizers. The optimal duration of antide-pressant treatment (in conjunction with a mood stabi-lizer) balanced against the largely unknown probability of switch induction in patients with bipolar I disorder is also unclear from the available research. The pharma-cologic treatment of bipolar II disorder has been the most neglected. Remarkably, it is still not clear whether treatment with a mood stabilizer (as opposed to antide-pressant treatment alone) is necessary for many of these patients.
Research regarding the prophylactic treatment of bipolar disorder has been dormant for many years. In addition, the efficacy of new psychotropic medications as long-term mood stabilizers has been very difficult to study in recent times; however, this is perhaps the most important aspect of the pharmacologic treatment of this recurrent illness (i.e., the development of well-tolerated medications with staying power over the long haul). Maintenance studies of lithium, divalproex, and car-bamazepine indicate that these agents possess efficacy in this phase of illness management, but that only a minority of patients do well with treatment with any one of these agents alone. Although combinations of mood stabilizers and of antipsychotics and mood stabilizers are commonly used in maintenance treatment, such strategies have not yet been shown to be efficacious in rigorous studies. Similarly, when a combination of an antipsychotic and a mood stabilizer is used to treat acute mania, there are no data to indicate when to taper and discontinue the antipsychotic following resolution of the acute episode. Although olanzapine received an indication for the treatment of acute mania, its efficacy as a maintenance treatment has not been established. Some evidence suggests that, unlike typical antipsy-chotics, some of the atypical agents possess antidepres-sant properties, perhaps by virtue of their serotonin2
antagonist effects. If these antidepressant effects are borne out in clinical trials, they may thus have bidirec-tional (antimanic and antidepressant) thymoleptic ef-fects, in short, mood-stabilizing properties.
As Frank et al (2000) note in their article, “sustained euthymia in bipolar disorder may remain an elusive goal in the absence of sophisticated treatments that address both the biological and psychological aspects of this disorder.” In developing interpersonal and social rhythm therapy (IPSRT), they have devised one of the few psychotherapeutic strategies based on theoretical and empirical findings regarding factors that influence the course of bipolar disorder. This effort marks the first time that a manual-based form of individual psycho-therapy intended to address multiple aspects of bipolar
disorder (prevention of manic, mixed, and depressive episodes; enhancement of treatment compliance) has been studied prospectively in a large, long-term ran-domized trial. Although the data presented are only preliminary findings, they are intriguing. First, only 23% of patients who entered the preventative phase of treatment entered on lithium alone, although lithium monotherapy was the pharmacologic treatment goal. Second, IPSRT helped patients achieve more stable social rhythms. Third, an association between social rhythm disruption and onset of manic episodes was apparent. Finally, changes in treatment in general in-creased the risk of relapse, and the loss of IPSRT, in particular, increased the risk of depressive relapse. Data from the completion of this study should provide important answers regarding the impact of this form of psychotherapy on the course of bipolar disorder.
Miklowitz et al (2000) attempted to improve the outcome of patients with bipolar I disorder using a different approach that also combined the effects of psychotherapy and pharmacotherapy. This randomized, 9-month, controlled trial compared manual-based fam-ily-focused psychoeducational treatment (FFT) with treatment as usual in patients recovering from an acute affective episode. This strategy is particularly targeted at the immediate postillness aftercare period, a time of heightened vulnerability to relapse and keen importance in facilitating rehabilitation. The results of this study suggest that FFT provided greater preventative benefit than treatment as usual for depressive episodes. The results also raised a number of interesting questions for further study, including whether the prophylactic ef-fects of FFT endure beyond the period of participation, and whether these effects are as significant when compared with a control form of psychotherapy matched for amount and intensity of contact.
Overall, a number of unanswered fundamental ques-tions regarding the treatment of patients with bipolar disorder remain. Primarily the pharmaceutical industry and private foundations have driven recent pharmacologic treatment advances. Two major initiatives undertaken in the late 1990s, the Stanley Foundation Bipolar Network (Leverich et al, in press) and the NIMH Bipolar STEP Network (Sachs et al 2000) should help make up for lost time in improving treatments for people with bipolar disorder.
Paul E. Keck, Jr
Biological Psychiatry Program Department of Psychiatry
University of Cincinnati College of Medicine 231 Bethesda Avenue
P.O. Box 670559
Cincinnati OH 45267-0559
Editorial BIOL PSYCHIATRY 431
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