Treatment Choices for Resistant Bipolar Disorder

Summary and Comment |
November 19, 2012

Treatment Choices for Resistant Bipolar Disorder

  1. Jonathan Silver, MD

Several options exist, including clozapine.

  1. Jonathan Silver, MD

Three recent articles discuss various adjunctive strategies available for the many patients with bipolar disorder (BD) that responds incompletely to mood stabilizers.

Rapid-cycling bipolar disorder (RCBD) may be more refractory to treatment than other bipolar types. In the open-label phase of a two-phase study, 133 depressed RCBD patients started on lithium plus divalproex. Only 14% stabilized; 10% withdrew due to adverse effects; 17% were nonadherent. In the double-blind phase, 49 nonresponders were randomized to placebo or lamotrigine. These two groups showed no difference in response rates.

To examine the possible efficacy of clozapine for refractory disease, investigators used a Danish database of 21,473 patients diagnosed with BD. Only 326 received clozapine, and they were more ill than the other BD patients (living alone, 76.7% vs. 43.8%; institutionalized, 20.3% vs. 2.5%; psychiatric hospitalizations, 26.8 vs. 8.9; depressive episodes, 2.8 vs. 2.3; manic episodes, 3.5 vs. 2.1; mixed states, 2.0 vs. 0.9). There were no data on rapid cycling. Measures during the 2 years before clozapine administration were compared with measures during the following 2 years. Clozapine was associated with fewer hospitalizations, bed-days, co-administered psychotropic drugs, and medical hospitalizations for intentional self-harm/overdose.

An evidence-based review examined innovative options for treatment-resistant mania or depression and long-term maintenance. For example, combining lamotrigine with quetiapine may be effective for depression, whereas adjunctive aripiprazole is not. Other treatments reviewed included ketamine, pramipexole, thyroid supplementation, and repetitive transcranial magnetic stimulation. The authors caution that many studies have small and heterogeneous patient populations. The review did not report on study funding.


These articles help us to decide on appropriate therapeutic options for difficult-to-treat patients with bipolar disorder. Lamotrigine seems ineffective in refractory rapid-cycling bipolar disorder. Clozapine, although difficult to use because of adverse effects, is a viable option for some patients. Whether it also benefits RCBD is unknown. Some innovative treatments hold promise but need confirmation in larger trials, and we always need to remember that negative results may never be published.


Reader Comments (1)

Walter Doege

These articles are very helpful to clinical thinking regarding pharmachotherapy of severe Bipolar Disorder (BD) emphasizing creativity for the right treatment choice, I mean, the treatment that promotes disorder symptomatology control, social and family integration. The focus on pharmachotherapy choices is appropriate because severe BD presents severe and dramatic clinical picture. Some important topics: first: the basis for treatment approach is diagnosis. So, I mention refractory diagnosis, resistant diagnosis, difficult-to-treat diagnosis, incompleting response diagnosis as dimensional based response treatment diagnosis. Severe BD present some genomic and epigenetic patterns and the response to pharmachotherapeutic treatment for diagnosis ground is a matter of elaboration. Second: many drugs are available in contemporary psychiatry. Even though, I mention the importance of the use of a clinical thinking framework. In this way, traditional drugs have its place. I mention lithium when used as monotherapy and in these BD patients as a main drug used for more than two years (from late studies that I agree) together with old and newer drugs as clozapine. I mention also carbamazepine and gabaergic agonists and for cognitive symptoms of attention and alertness methilphenidate. One or two drugs are basis for adjunctive drugs and treatment options. In absence of contra indications, lithium is the main mood stabilizer choice.Third: the new treatment choices does exist and deep transcranial magnetic stimulation is a promise choice and an advance in relation to convulsive therapy. Recent reports present beneficial effect of ketamine for severe manic states. Psychiatric treatment is well done when diagnosis based. I observe in severe BD patients the challenge for correct diagnosis and extreme caution related to no diagnosis, misdiagnosis, co morbidity psychiatric and non psychchiatric diagnosis, age, sex, family and social dimensions. So, severe psychiatric patients are a challenge for diagnosis and treatment. Pharmachotherapy, psychotherapy, family and social support are the basis of any good psychiatric treatment following accepted guidelines and protocols. Finally, as in my experience, diagnosis is the basis for treatment as occurs in any good medical practice. Psychiatry itself is a clinical expertise medical specialty regarding the absence of patognomonic findings. Drug response is one topic in this complex clinical issue of severe psychiatric disorders.

Competing interests: None declared

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