Bipolar disorder is an episodic chronic mental illness affecting about 5.7 million US adults. It involves varying degrees of mania (e.g., a decreased need for sleep, hyperactivity, and excessive involvement in risky activities) and depression, and the condition is classified into several types depending on the severity of symptoms.

The cause of bipolar disorder is unknown, though it is partly genetic, and some associated genes have been identified. A number of neurotransmitters have been implicated, as well as cell signaling pathways within neurons.

Because the condition is not well understood, no drugs have been developed specifically for bipolar disorder. Pharmacological treatment involves generically available lithium, anticonvulsants (epilepsy drugs, especially Depakote [ABT], generically available carbamazepine, and Lamictal [GSK]), and the antipsychotics (particularly the second-generation agents, or SGAs, which are used to treat schizophrenia; please see our Schizophrenia Indication Report for additional information on these drugs). Treatment is complicated by the fact that the drugs differ in their relative efficacy for manic and depressive symptoms.

Lithium, the first drug approved for bipolar treatment, is used for all phases of the disease, but can cause serious toxicity at levels just above its therapeutic range. As a result, it has lost share to Depakote, Lamictal, and the SGAs. Depakote, which may have advantages in certain types of patients, grew in usage substantially after it was approved in the US for bipolar disorder in 1995, but has been challenged by the rise of Lamictal (which has more evidence for preventing depressive symptoms) and the SGAs.

SGAs are used in a significant, though not majority, portion of the bipolar market. While not generally superior to lithium and the anticonvulsants, they can have benefits in certain patients and are also used in combination with these drugs. All of the SGAs have shown efficacy in mania, but there is varying data for support in depressive episodes and maintenance, though all are currently used for the latter. Further studies may help certain candidates to better differentiate themselves. They are also differentiated from lithium and the anticonvulsants, as well as from each other, by their side effect profiles, which have an impact on usage as in schizophrenia, though typical dosages for SGAs in bipolar disorder are lower.

Among the SGAs, Seroquel (AZN) is the market leader for bipolar disorder. Its demonstrated efficacy for depressive episodes and the perception that it helps with anxiety and insomnia (as does Depakote) have bolstered a strong promotional share in physician detailing. It is also thought to lead to less weight gain than Zyprexa (LLY) and avoids motor side effects associated with certain other SGAs. An sNDA for maintenance in conjunction with lithium or Depakote was submitted in 2007, though we do not think this will greatly increase its use, and the weight gain seen with the combinations is of some concern. Seroquel is trailed by Zyprexa, Risperdal (JNJ, SGP; generics should be available in 2008), and Abilify (BMY). Abilify was a later entrant with less weight gain but a poor showing against bipolar depressive symptoms, though approval in unipolar depression in late 2007 is likely helping the drug. Geodon (PFE) also has a benefit of lower weight gain, but is a late entrant and has some side effect issues. Geodon is being studied for depressive episodes and maintenance, and while we have some concerns about the maintenance trial, success--particularly for treating and preventing bipolar depression--could help boost its share of bipolar patients.

The introduction of generic Risperdal this year, followed by Depakote and Lamictal patient expirations, will likely reduce usage of other branded SGAs as well, though because of differences in the response of individual patients and side effects, we think there will still be a significant market for the other approved drugs, as well as for new drugs with improved product profiles. The branded market will be curtailed further, however, when Zyprexa and Seroquel patents expire in 2011.

There are currently three drugs in development with NDAs submitted. Asenapine (SGP) is an SGA that has shown success in two Phase III bipolar mania trials, however, we think the FDA could well require the maintenance data, which would delay approval, and it is still unclear whether asenapine will have any significant advantages over current options. Seroquel XR (AZN), a long-acting formulation of Seroquel, was submitted for bipolar mania and depression, but detailed results of its pivotal trials have not yet been released. Since the Seroquel IR patent only expires in 2011 and the two are priced similarly, insurers have not placed restrictions (or higher copays) on the drug in schizophrenia, and we expect the situation will be similar in bipolar disorder, though once Seroquel IR becomes generic, they will likely place restrictions, particularly for new patients. Risperdal Consta (JNJ, SGP, ALKS) is an injectable formulation of Risperdal given every two weeks, and has shown efficacy in frequent relapsers, with other data still pending. However, since bipolar patients are more independent than schizophrenic ones, they may not be under as much pressure from caregivers to come in frequently for treatment. In addition, Risperdal Consta is likely to face off-label competition from paliperidone palmitate (JNJ), which is given monthly.

Invega (JNJ) is a metabolite of Risperdal in Phase III development for bipolar mania and maintenance. While we expect it to be efficacious, competition from generic Risperdal in 2008 along with consequent insurance restrictions (like in schizophrenia, for which it is approved) are likely to hamper its growth.

Of the other drugs in development, we expect positive results from AZ-004 (ALXA), an inhalable antipsychotic, which began a phase III trial in acute agitation earlier this year in schizophrenia and with one in bipolar disorder set to begin later in the year. We believe the inhalable route may be popular in bipolar disorder, though it would only be used in the acute setting. We also expect a positive outcome for Nuvigil (CEPH), which is an isomer of the stimulant Provigil, as Provigil has had a successful trial in the indication. Nuvigil is currently in a Phase II study for bipolar depression.

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