Bipolar Disorder Treatment Emerges from the Doldrums

After 50 years of dependence on the traditional lithium, physicians have a number of targeted options

Bipolar Disorder Treatment Emerges from the Doldrums After 50 years of dependence on the traditional lithium, physicians have a number of targeted options.

Bipolar disorder—the disease previously known as manic depression—does not capture the lay or medical headlines to the same extent as schizophrenia. Yet it is just as devastating for sufferers, and the economic burden can be some 70 percent of that arising from schizophrenia. And, until recently, there has been something of a relative drought, as the mainstay of treatment was first used more than 125 years ago.

However, there are now emerging roles for some anticonvulsants and atypical antipsychotics that are beginning to augment the effectiveness of traditional management. Moreover, mechanistic studies are beginning to offer targets for novel medications. Also, the first head-to-head studies are beginning to emerge. It seems that the therapeutic drought could soon be over.

Certainly, there appears to be a considerable market for new treatments for bipolar disorder, as exemplified by valproate. In New York, around half the patients diagnosed with bipolar or schizoaffective disorders receive valproate, as does almost one in three people suffering from schizophrenia. In 1998, Abbott Laboratories’ sales of valproate attributable to prescriptions for bipolar disease alone increased by $130m (₤106m)—equivalent to 25 percent. Indeed, Abbott said that valproate is the most prescribed agent for manic episodes and sales for this indication are now greater than those for epilepsy (Curr. Opinion in CPNS Investigational Drugs 1999; 1:466–9). However, the unmet needs in bipolar disease suggest that there is considerable room for further improvement.

Co-morbidities may offer particular opportunities for targeted interventions. To take one example: divalproex sodium is effective in people who abuse substances (J. Clin. Psych. 2000; 61:916–21). Lithium’s inefficacy in this group of patients is one of its main limitations.

Lithium may also produce less than optimal outcomes in some of the disease variants. Bipolar disorder is expressed as a number of subtypes, including antidepressant-associated hypomania, patients with full-blown major depression who experience a few manic symptoms (such as racing thoughts and sexual arousal) and rapid cycling. In the latter, patients experience at least four cycles of depression and mania a year. Rapid cycling is common—one-fifth of bipolar patients develop transient rapid cycles some time in the course of their disease (J. Affect. Disord. 2000; 59 Suppl. 1:S5–30). These subtypes differ in their response to treatment. For example, the calcium-channel blocker nimodipine may be effective against treatment-resistant subtypes, such as ultra-rapid-cycling bipolar disorders and brief recurrent depressions (Bipolar Disord. 2000; 2:165–73). Carbamazepine may be particularly effective in rapidly cycling bipolar disorder.

Given this diagnostic variation, it is perhaps not surprising that academics are currently debating the nature of bipolar disease. The traditional model suggests that bipolar disorder is a different disease from unipolar depression. However, a more recent model suggests that mania and depression are two distinct illnesses. The depressive phase is the same disease entity as unipolar depression (Bipolar Disord. 1999; 1:25–30). Such debates are of more than academic interest. They could influence, for example, whether it is possible to develop a single treatment or whether patients need therapy targeted to each phase.

Currently, lithium is the mainstay of management. But there is a considerable proportion of patients for whom lithium is inappropriate or ineffective. For example, mixed or dysphoric mania, rapid cycling mania, and associated substance abuse tend to respond poorly to lithium (J. Clin. Psychopharmacol. 2000; 20:607–14). Moreover, mood stabilizers appear less effective against depression than mania. Unfortunately, current antidepressants may increase the risk of mania and rapid cycling (J. Clin. Psychiatry 1999; 60:79–88). As a result, psychiatrists increasingly treat such patients with adjuvant, either anticonvulsants or atypical antipsychotics (CNS Drug 2000; 14:81–94).

Anticonvulsants are now well established as alternatives to lithium. Divalproex (sodium valproate and valproic acid) is, for example, approved in the US for the management of acute mania in bipolar disorder (Curr. Opinion in CPNS Investigational Drugs 1999; 1:466–9). Moreover, lamotrigine appears to be emerging as an effective adjuvant. For example, in a double-blind, placebo-controlled study (J. Clin. Psychiatry 1999; 60:79–88) of lamotrigine (50 mg or 200 mg daily) in 195 outpatients with bipolar I (“classic”) depression, lamotrigine showed significant antidepressant efficacy compared with placebo, and improvement emerged by the third week of treatment. By the end of the seven-week study, 51 percent and 41 percent of patients taking lamotrigine 200 mg and 50 mg, respectively, showed improved Clinical Global Impression scores, compared with 26 percent on placebo.

The more recently developed anticonvulsant topiramate also appears to be an add-on treatment for patients with bipolar mania. A study of 18 patients suggested that the drug is effective in both the manic and mixed phases, with some hints of a benefit on depression. Moreover, topiramate appears to induce weight loss (Bipolar Disord. 1999; 1:42–53).

However, not all anticonvulsants are as effective as these examples. For example, doses of gabapentin between 900 mg and 3600 mg daily were ineffective in a placebo-controlled trial. However, based on gabapentin plasma levels, some patients did not comply (Bipolar Disord. 2000; 2:249–55). Moreover, in a comparison of lamotrigine and gabapentin given as monotherapy, 52 percent and 26 percent showed much or very much improvement on the Clinical Global Impression scale, compared with 23 percent on placebo.

Atypical antipsychotics might also offer another useful adjuvant treatment. For example, a review of atypical antipsychotics in bipolar and schizoaffective disorder (J. Clin. Psychopharm. 1999; 19:354–61) concluded that clozapine is effective as monotherapy, while risperidone is inactive when given alone.

However, olanzapine probably has the best-established record of the atypical antipsychotics in mania. Indeed, olanzapine is now approved in the US for this indication (J. Clin. Psychiatry 2000; 61: Suppl. 14:33–42). In one key study, 48.6 percent of patients treated with olanzapine (5–20 mg daily) responded, compared with 24.2 percent on placebo. While somnolence, dizziness, dry mouth, and weight gain were more common with olanzapine than placebo, Parkinsonism, akathisia, and dyskinesias did not emerge. No patient discontinued treatment (Am. J. Psychiatry 1999; 156:702–9). In another study of 10 patients with either bipolar disorder or unipolar major depression, olanzapine was moderately effective in six cases. Eight developed side effects, most commonly weight gain (Bipolar Disord. 2000; 2:196–9).

Against this background, side effects could offer a key point of differentiation in the mania market. This was underscored by a recent review (J. Clin. Psychiatry 2000; 61 Suppl. 14:33–42) that suggests that differences between the atypicals’ propensity to cause weight gain may be especially relevant in bipolar disorder. As mentioned above, standard mood stabilizers often lead to weight gain.

Relatively few head-to-head studies have been performed comparing antipsychotics and anticonvulsants. During a 12-week study, fewer patients reported side effects with Depakote® (divalproex sodium delayed-release tablets) compared to olanzapine. For example, 29 percent of the Depakote group developed somnolence compared to 47 percent of the olanzapine-treated patients. For weight gain, the proportions were 10 percent and 25 percent, respectively. The mean weight gain over the 12 weeks was 5.5 lb. And 8.8 lb., respectively. “Patients are often concerned about cosmetic side effects and other health issues of their medications,” said Alan Swann, junior professor at the research, psychiatry, and behavior sciences department of the University of Texas Medical School, Houston, US. “In this study there was a statistically significant difference in weight gain between the divalproex-treated and olanzapine0treated groups.”

The study showed that in bipolar patients with acute mania, Depakote did not differ in efficacy from olanzapine, according to the results that were released at the American College of Neuropsychopharmacology late last year. However, total outpatient costs for Depakote-treated patients were about half those of the olanzapine-treated group, largely reflecting the lower acquisition price of Depakote. Over the 12 weeks, treating patients with Depakote cost an average of $550 (₤387) compared to $1,100 for olanzapine.

“In this study, the outpatient costs associated with use of olanzapine were about double the costs of the Depakote treatment group,” added Swann. “With similar efficacy, the difference in cost, coupled with the potential incidence of side effects, could be important factors to consider when evaluating treatment options for bipolar patients experiencing mania.”

Finally, basic research is beginning to yield some novel therapeutic targets. For example, several lines of evidence implicate a dysfunction of mitochondria in bipolar disorder. One strand suggests that certain mutations in mitochondrial DNA (as distinct from nucleic DNA) appear to be associated with an increased risk of developing bipolar disorder. Scientists researching the role of mitochondrial dysfunction in bipolar disorder believe the mutations may alter intracellular calcium-signaling systems (Bipolar Disord. 2000; 2:180–90), which ties in with the emerging therapeutic actions of calcium-channel antagonists.

Moreover, studies of lithium’s mode of action offer a number of possible targets. Lithium seems to act by inhibiting several enzymes, including inositol monophosphatase, a family of phophomonoesterases, and some protein kinases. Ongoing studies are beginning to determine which of these is responsible for lithium’s therapeutic actions (Ann. Rev. Pharmacol. Toxicol. 2001; 41:789–813).

For example, some researchers believe that lithium depletes intracellular inositol levels, which are essential for the normal function of the phosphoinositide-signaling pathway. The exact mechanism is uncertain, although the traditional view is that lithium inhibits inositol monophosphatase. However, a recent study suggests that lithium, carbamazepine (also used as an adjuvant), and valproate inhibit sodium/myo-inositol co-transport, which modulates uptake of myo-inositol. This dampens phosphoinositide signaling (Bipolar Disord. 2000; 2:102–7). Discriminating between these pathways might lead to new therapeutic targets.

Similarly, the added efficacy offered by anticonvulsants might yield new therapeutic approached. For example, there is a growing recognition that valproate and lithium need to be taken for some time before the maximum effect emerges. This suggests that altered gene expression might be therapeutically important and differential effects on transcription factors could explain the variations in therapeutic efficacy between the drugs. Against this background, some analogs of valproate, some of the agent’s metabolites and pro-drugs offer possible therapeutic leads (Curr. Opinion in CPNS Investigational Drugs 1999; 1:466–9).

In conclusion, bipolar disorder is relatively prevalent and, in common with schizophrenia, imposes an economic toll that is out of proportion to its epidemiology. Despite being a potentially large market, the mainstay of treatment has been known for 125 years and widely used for more than 50 years. It is hard to escape the conclusion that, until recently, bipolar disorder did not really receive the attention it deserved from the pharmaceutical sector. That is beginning to change. Indeed, recent advances in the treatment of bipolar disorder suggest that the therapeutic drought could be over.

This article was contributed by science writer Mark Greener. It was originally published in Pharmaceutical Business News. PBN is an imprint of Informa Publishing Group, Ltd., and a sister publication of D&MD Newsletter. For more information on PBN or Informa Publishing, please visit informapharma.com

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