In this article, we present rationales for using complex combination therapy in treatment-refractory bipolar patients and discuss the agents available for use in this therapeutic approach. We review a case example of successful remission that was achievable only with complex combination therapy, and examine its theoretical implications. Practical approaches to devising the optimal complex combination treatment for individual patients are explained, and we look to the development of new methodologies and a more systematic database for decision making in the future.

The recurrent and frequently chronic course of affective disorders requires careful delineation of the number, frequency, and pattern of prior and current episodes and their response to pharmacotherapies to help develop optimal assessment and treatment approaches for these Potentially lethal medical illnesses. To better track and monitor the longitudinal course of unipolar and bipolar illness and to promote more effective management, we developed the retrospective and prospective National Institute of Mental Health Life Chart Methodology (NIMH-LCM). The principles of retrospective and prospective life charting are the focus of this article. Following introductory background information on affective disorders, the influence of Kraepelin's work and his use of life charts are reviewed as the basis and framework for the NIMH-LCM. The use of life charting both retrospectively and prospectively is discussed, with examples of its utility and benefits.

Antiepileptic drugs (AEDs) have diverse psychotropic profiles. Some AEDs have proven to be efficacious in the treatment of mood disorders, especially bipolar disorder. Others are ineffective as primary treatments but may be useful adjuncts for mood disorders or comorbid conditions. Valproate (acute mania and mixed episodes), carbamazepine (acute mania and mixed episodes), and lamotrigine (maintenance to delay recurrence) have United States Food and Drug Administration indications for the treatment of bipolar disorder. This article provides an overview of data on the use of AEDs in bipolar disorder, including acute mania and depression, prophylaxis, and rapid cycling.

While severity of manic episodes can be successfully reduced, repeated recurrences are common with ~40% of patients meeting criteria for rapid cycling after aggressive treatment. Manic episodes present much earlier in children of bipolars and due to unique presentation physicians often mistakenly diagnose such children with attention-deficit/hyperactivity disorder. Differential symptoms include suicidal thoughts, grandiosity, hallucinations, and depressive withdrawal. Such children may require the usual combination treatment with a mood stabilizer and an antipsychotic, with the addition of a stimulant as well. Treatment of adults and children often includes second-generation antipsychotics, which have increasingly shown efficacy both as monotherapy and adjunctive treatments of acute mania. Most recently, some anticonvulsants have demonstrated acute antimanic properties as well and more studies of their role in bipolar disorder are underway.

Recent advances in functional neuroimaging (including positron emission tomography, single-photon emission tomography, and fast magnetic resonance imaging) have allowed better understanding of the brain regions involved in regulating normal and pathological moods. Repetitive transcranial magnetic stimulation (rTMS) has the ability to stimulate or temporarily impair brain regions, which makes it a powerful tool for directly testing theories of the neurologic basis of mood regulation.

Depressed subjects have deficits in facialemotion recognition that resemble the deficits found in persons with focal right hemisphere brain damage. To locate the brain regions responsible for this problem, the authors imaged regional cerebral blood flow (rCBF) with H2O15 positron emission tomography in 10 mood-disordered patients, as well as in 10 age- and sex-matched healthy comparison subjects, while the subjects matched photographs for facial emotion or, as a control, facial identity. While matching faces for emotion, mood-disordered subjects had decreased rCBF activation bilaterally in their temporal lobes, as well as in the right insula, compared with healthy comparison subjects. Abnormal function of limbic and paraiimbic regions may partially explain the facial emotion-recognition deficits previously noted in depressed subjects.

Approximately 40% of bipolar patients experience rapid cycling, and half of these suffer from ultra-rapid or ultradian cycling. These patterns are also common in children. Rapid-cycling bipolar disorder is difficult to bring to remission and often requires treatment with four or more classes of psychotropic medications. Lithium, even in combination with anticonvulsants or antidepressants, is often associated with residual episodic depressions. Concerns with adjunctive antidepressant treatment include their low response and remission rates and their tendency to cause switch into mania. Atypical antipsychotics and selected agents within the anticonvulsant class are becoming increasingly important in the treatment of rapid cycling. In the absence of clear treatment guidelines, the use and sequencing of drugs in complex combination treatment remains exploratory, but should be individualized based on careful prospective mood charting by the patient. Use of several drugs below their side-effect thresholds may prevent certain side effects. In children, long-term safety considerations are particularly important in the absence of a strong controlled clinical trials database.

Recent data indicate that bipolar illness is underdiagnosed and therefore undertreated in the community (Slide 1). A recent survey of >85,000 households in the United States found a 3.7% positive screen for prominent bipolar symptomatology. Using the Mood Disorder Questionnaire, which has good specificity and sensitivity in outpatient clinics, the study also found that the prevalence was higher, 9.3%, among patients 18–24 years of age. However, most disappointing was that only 20% of the positive screens were diagnosed as bipolar, and among those, most were not treated with mood stabilizers. In addition, 31% of patients had been diagnosed with unipolar depression. Several studies have shown that approximately 20% to 40% of presumptively unipolar patients actually have bipolar II or bipolar disorder not otherwise specified. Combined, the data show that bipolar disorder, bipolar depression in particular, is highly prevalent and often misdiagnosed or unrecognized.

Two recent studies found virtually the same data showing that depression is the predominant problem in naturalistically treated bipolar outpatients. Judd and colleagues found that depression was three times more prevalent than mania in bipolar patients. This is exactly what was found in the Stanley Foundation bipolar outpatient follow-up study, which rated the study's first 258 patients every day for 1 year (Slide 2). The study found that patients were ill almost 50% of the time; they were depressed 33% of the days in the year, and hypomanic or manic 10.8% of the days. This occurred despite aggressive treatment with a variety of agents, such as mood stabilizers, antidepressants, and benzodiazepines in 50% of the patients, and typical or atypical neuroleptics in almost 50% of the patients. Thus, even bipolar patients who are intensively treated in academic settings have a very substantial degree of morbidity, particularly depression.

Unlike the other articles in this series on rTMS, this paper will not include clinical research or magnetic stimulation experiments. Instead, we will focus on an animal model of epilepsy called kindling and a procedure that we have recently developed to inhibit kindled seizures called quenching. Both procedures involve direct intracerebral electrical stimulation of the brain. We demonstrate that low-frequency stimulation, which does not disrupt ongoing behavior, can have profound and long-lasting effects on both seizure development and fully kindled seizures.

At this point, we do not know how well these models relate, either mechanistically or phenomenologically, to the effects of repeated transcranial magnetic stimulation (rTMS); however, we believe that at the very least, some of the principles emerging from studying these phenomena may be relevant to our thinking about rTMS and its potential treatment utility. Specifically, we discuss the possible relationship between quenching and rTMS with regards to parameters of induction, possible common mechanisms, and potential treatment implications.