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第6届国际双相性精神障碍会议热点
Highlights of the 6th International Conference on Bipolar Disorder
2005年6月16－18日
美国宾夕法尼亚州匹兹堡
June 16-18, 2005; Pittsburgh, Pennsylvania
Katherine E. Burdick, PhD; Nisali A. Gunawardane,
MA
Dr. Robin Murray[1] presented results from the Maudsley Twin Studies[2] demonstrating a number of significant overlapping features in patients with schizophrenia and bipolar disorder. Data presented included very similar concordance rates in both monozygotic and dizygotic twins for mania and schizophrenia, with some twin pairs exhibiting differential illnesses (one cotwin with bipolar disorder and the other with schizophrenia). Of note, within their cohort they have identified 1 trio of monozygotic triplets in which each individual carries a different diagnosis (bipolar disorder, schizophrenia, and schizoaffective disorder). These data support the notion that patients with bipolar disorder and schizophrenia share a number of common genetic risk factors, indicating some overlapping susceptibility genes.
Certain premorbid features, including motor deficits and lower intellectual functioning, seem to differentiate subjects who are at risk for bipolar disorder from those who are at risk for schizophrenia.[3] Specifically, child offspring of a schizophrenic parent demonstrate subtle motor abnormalities during development and have a lower intelligence quotient (IQ) than healthy children without such genetic risk. In contrast, child offspring of bipolar parents do not exhibit these impairments; rather, children at risk for bipolar disorder actually demonstrate superior motor skill development than healthy control children. IQ is also higher in children at risk for bipolar disorder as compared with healthy control children, but the difference is not statistically significant.
Dr. Murray also presented neuroimaging data[4] that illustrated differences in gray matter changes in patients with schizophrenia vs patients with bipolar disorder. While reduced volume was noted in both patient groups, the regions of change do not overlap. In contrast, white matter changes in patients with schizophrenia and bipolar disorder are similar and may indicate a common underlying neuropathology.
According to Dr. Murray, these data suggest that children who are at risk for bipolar disorder and those who are at risk for schizophrenia share a common underlying genetic liability for both of these illnesses, but that children who go on to develop schizophrenia may undergo some type of developmental insult, which leads to some of the neurocognitive features that are seen premorbidly and are prominent in schizophrenia.
Dr. Carlos Zarate[5] presented neuroimaging data derived from a treatment trial of pramipexole in a group of treatment-resistant bipolar II depressed subjects.[6] The antidepressant properties of pramipexole have been demonstrated in a number of studies[7,8] to date, suggesting that the role of dopamine in depression should not be overlooked. The neural mechanisms that are responsible for the noted efficacy of dopaminergic agonists in treating depression are unknown.
Data were presented from a positron emission tomography scans of 15 bipolar II patients prior to treatment with pramipexole and again after a 6-week trial. Change in regional metabolism was reported and compared by group (placebo vs pramipexole). While there were no significant changes in metabolism in patients taking placebo, the pramipexole-treated subjects demonstrated decreased metabolism in the left ventrolateral and bilateral anteromedial prefrontal cortex. These changes were positively, though not statistically significantly, associated with a positive antidepressant response to pramipexole. These data suggest that drug-induced changes in metabolism may serve as a marker of treatment response associated with an advantageous effect of pramipexole on brain metabolism. Studies with larger samples will be important.
John Geddes, MD, Professor of Epidemiological Psychiatry at the University of Oxford, United Kingdom, discussed the discrepancy between evidence-based treatment guidelines and current clinical practice for the treatment of bipolar depression.[9]
Data were presented from randomized, controlled trials[10] on the efficacy of current drug treatments for bipolar depression. Four randomized, placebo-controlled trials of antidepressants demonstrated the superior efficacy of antidepressants vs placebo, suggesting that the successful use of antidepressant treatment in bipolar depression is comparable to treatment in unipolar depression. In randomized, placebo-controlled trials that assessed the risk of switching to mania, tricyclics appeared to be more likely to induce mania as compared with other classes of antidepressant medications. Finally, previous trials of lamotrigine vs placebo indicated that lamotrigine significantly reduced depressive symptoms when compared with placebo.
Dr. Geddes is currently conducting a large-scale randomized trial comparing lamotrigine (indicated in American Psychiatric Association guidelines as a first line of treatment for acute bipolar depression and recommended for long-term treatment) and selective serotonin reuptake inhibitors (SSRIs). Changes in depressive symptoms will be measured every 3 months for 1 year. This study will investigate short-term remission using SSRIs vs lamotrigine as well as the potential advantage of lamotrigine in reducing manic-switching and other adverse events at 12 months. Dr. Geddes discussed the need to investigate short-term efficacy and long-term relapse prevention using different lines of treatment for bipolar depression and emphasized the importance of finding a balance between these treatment goals in future clinical trials.
Functionality was a major theme at the conference, entering into several of the presentations. Dr. Insel, Director of the National Institute of Mental Health (NIMH), opened his address[11] with the most recent results from the WHO Global Burden of Disease data.[12] According to these data, mental and substance abuse disorders are responsible for 37.6% of all years lived with disabilities for any medical condition worldwide. Within the United States, bipolar disorders ranked fourth most disabling among all diseases. In a subsequent report on the Stanley Bipolar Network,[13] Dr. Lori Altschuler addressed the observation that poor vocational and psychosocial functioning is experienced by many sufferers of bipolar disorders even when they are not in episode. Subsyndromal depression that persists between episodes appears to be the main culprit, explaining a significant portion of the risk for continued functional disability. Dr. Ronald Kessler, an author on 4 papers in the current issue of Archives of General Psychiatry concerning the National Comorbidity Survey Replication study,[14-17] reported that bipolar I patients themselves estimated having an average of 44.1 days within the past 12 months when they were functioning out of their principal vocational role (these values were 59.2 and 43.3 days, respectively, for bipolar II and subthreshold affective disorders).[18] Finally, the last day of the conference saw a session devoted to "Functioning: Definitions and Measurements."[19] This literature review by Dr. Gordon Johnson, supplementing a clinical presentation by Dr. Roy Chengappa, underscored the considerable evidence for occupational and social disability resulting from bipolar disorder. Presentations by Drs. Gin Malhi[20] and Judith Jaeger[21] offered new research concerning the possible role of neurocognitive deficits in explaining functional disability. Dr. Malhi presented data demonstrating neurocognitive deficits in unmedicated euthymic patients that persisted as they moved through different disease phases. Dr. Jaeger showed that neurocognitive deficits, detected while patients are first emerging from an acute episode, can predict functional recovery 1 year later. Hence, functional disability is becoming increasingly recognized by bipolar disorder researchers as an important disease consequence, requiring careful attention from care providers.
Dr. Insel's report[11] on the focus of the NIMH with regard to research on affective disorders strongly emphasized the goal of reducing mortality and disability among patients with bipolar disorder. He provided evidence that research in bipolar disorder, among other mental illnesses, has been taking the reverse translational route, as compared with diseases such as Parkinson's disease. Research in many of the dementing disorders begins with the identification of susceptibility genes, followed by the characterization of the impact of such genes on molecules and cell systems. This bottom-up approach allows for the construction of models for these illnesses and treatments discovered through research rather than serendipity, which has often been the case in psychiatry. He described an approach that reverses these steps in many of the psychiatric illnesses, including bipolar disorder. Effective treatments are stumbled upon, after which the next step has been to identify its mechanism of action, and then its effects on the cellular level, in hopes of learning more about the underlying biology of the disorder. Dr. Insel highlighted the need for psychiatry researchers to focus on improved diagnosis and detection, treatment and prevention, and finally the implementation of methods for studying those real-world patients who are generally not eligible for clinical trials (eg, substance abusers, homeless individuals, incarcerated subjects).
According to Dr. Insel, 2 types of translational research are important -- "bench-to-bedside" translational work and "bedside-to-practice" translation. The latter of the 2 should be used to hone in on the needs of society and the understudied but statistically common real-world bipolar patients. He went on to set a timeline for future directions aimed at the strategic prevention of bipolar disorder and other major mental illnesses, asking why psychiatry has come to accept that there is no cure for the diseases we study. He concluded by emphasizing the importance of maintaining that goal of prevention and cure.