Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12.

The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41.

MRI correlates of suicide attempt history in unipolar depression.

BACKGROUND: Suicide represents a major health problem in the United States, and prediction of suicide attempts is difficult. No structural neuroimaging studies have been done to specifically examine findings in patients who have attempted suicide. The objective of this study was to compare MRI findings in unipolar patients with and without a history of a suicide attempt. METHODS: In this post hoc analysis, 20 unipolar subjects with a history of a suicide attempt were matched by age and gender to unipolar subjects without a history of an attempt. Subjects were also matched on parameters such as cardiovascular history, electroconvulsive treatment history, and history of psychosis. Subjects with a history of any neurologic condition were excluded. There were no significant differences in age of onset of depression, number of episodes of depression, and Hamilton Depression scores between the two groups. T2-weighted magnetic resonance imaging (MRI) scans were rated using the Coffey and Boyko rating scales. RESULTS: Unipolar patients with a history of a suicide attempt demonstrated significantly more subcortical gray matter hyperintensities compared with patients without such a history. CONCLUSIONS: Patients with abnormal MRI findings may be at higher risk for mood disorders and suicide attempts because of disruption of critical neuroanatomic pathways. Gray matter hyperintensities in the basal ganglia may be especially associated with risk for suicide attempts.

Suicide prevention: increasing education and awareness.

Suicide is a serious and complex public health problem. Health care providers, including both psychiatrists and primary care physicians, are just beginning to understand the intricacies involved in suicide and its prevention. Suicide rates continue to rise, making the education of the public and physicians regarding awareness and prevention, recognition of a wide range of risk factors, and research into suicide prevention strategies very important.

Suicide and bipolar disorder.

Suicide, which is both a stereotypic yet highly individualized act, is a common endpoint for many patients with severe psychiatric illness. The mood disorders (depression and bipolar manic-depression) are by far the most common psychiatric conditions associated with suicide. At least 25% to 50% of patients with bipolar disorder also attempt suicide at least once. With the exception of lithium--which is the most demonstrably effective treatment against suicide-remarkably little is known about specific contributions of mood-altering treatments to minimizing mortality rates in persons with major mood disorders in general and bipolar depression in particular. Suicide is usually a manifestation of severe psychiatric distress that is often associated with a diagnosable and treatable form of depression or other mental illness. In a clinical setting, an assessment of suicidal risk must precede any attempt to treat psychiatric illness.

Effects of medical interventions on suicidal behavior. Introduction.

BACKGROUND: Knowledge of effective means of preventing suicide, based on research evidence, is strikingly limited, but there are indications that specific treatments may reduce suicidal risk in patients with major affective disorders. METHOD: An international symposium was held in Miami, Fla., February 26-28, 1998, to discuss current knowledge of the Effects of Medical Interventions on Suicidal Behavior. Participant experts prepared summary reports of their contributions. RESULTS: Participants considered what is known about the effects of medical treatments on suicidal risk, as well as proposed approaches to future research. This supplement summarizes the proceedings of the symposium. CONCLUSION: The symposium strongly supported the proposition that suicide is amenable to ethical scientific investigation, suggested that evidence supporting suicide risk-reduction can be developed, and strongly encouraged studies to test the effects of specific interventions on suicidal risk. It also encouraged greater efforts at public and professional education to understand suicide as a result of mood and other psychiatric disorders, and to improve their early recognition and enhance timely access to effective treatment by the psychiatric and general medical community.

The risk of suicide in patients with bipolar disorders.

Patients with bipolar disorder have a high risk of committing suicide, but determining the exact risk is complicated. For many years, the lifetime suicide risk in bipolar disorder was accepted as 15%, but recent researchers have suggested that the lifetime suicide risk may be lower. The group of bipolar patients at highest risk of suicide are young men who are in an early phase of the illness, especially those who have made a previous suicide attempt, those abusing alcohol, and those recently discharged from the hospital. The risk is also increased in patients who are in the depressed phase of bipolar illness, who have mixed states, or who have psychotic mania. Lithium prophylaxis appears to decrease suicide attempts.

Effects of medical interventions on suicidal behavior. Summary and conclusions.

BACKGROUND: An international symposium evaluated current knowledge of the epidemiology, psychobiology, and effects of medical treatment on suicidal behavior. METHOD: Moderators summarized the main findings and conclusions of the participants on the basis of presentations and consensus statements at the meeting. RESULTS: Despite striking advances in the medical treatment of mood disorders in the past half-century, rates of suicidal acts have changed little in the general population. Evidence of reduction of long-term rates of suicidal acts in specific at-risk populations remains very limited, particularly persons with major affective illnesses and other common, primary or comorbid psychiatric and substance use disorders. It is plausible that reduction of psychiatric morbidity should limit suicidal risk, but very little is known about specific effects of most psychiatric treatments or other interventions aimed at suicide prevention. An exception is substantial evidence of lower suicidal risk during long-term lithium treatment that was not equaled with carbamazepine. However, diagnosis and timely therapeutic interventions reach only a minority of psychiatrically ill persons at risk for suicide. CONCLUSION: Renewed efforts are strongly urged to: (1) improve public and professional awareness of risk factors for suicide, (2) enhance earlier access to appropriate clinical assessment and increasingly safe and effective treatments for affective and psychotic disorders, and (3) encourage and support research to clarify specific benefits and risks of medical treatments and social interventions aimed at preventing suicide.

Pilot study on patients' and spouses' attitudes toward potential genetic testing for bipolar disorder.

OBJECTIVE: The purpose of this pilot study was to gain information about attitudes of individuals with bipolar disorder and their spouses toward some of the ethical and social issues arising from rapidly advancing genetic research on bipolar disorder. METHOD: Patients with bipolar disorder and their unaffected spouses were asked to answer questionnaires assessing their knowledge and attitudes about treatment response rates for bipolar disorder, probability of inheritance, genetic testing, disclosure of genetic information, abortion, marriage, and child-bearing. RESULTS: The overwhelming majority of the patients and spouses said that they would take advantage of genetic tests for bipolar disorder if such tests were to become available. Most patients and spouses agreed that the benefits of knowing whether one carries a gene for bipolar disorder would outweigh the risks. The decisive majority of respondents also felt that they would not abort a fetus that carried a gene for bipolar disorder. Furthermore, most patients and spouses agreed that the knowledge that one of them carried a gene for bipolar disorder would not have deterred them from marriage or childbearing. CONCLUSIONS: The results of this study suggest that most individuals believe that they would benefit from the use of genetic testing for bipolar disorder if it were to become available. Follow-up studies using a broader patient sample and nonclinical control groups would be useful in further evaluating the issues addressed in this pilot study.

Genetics of manic depressive illness.

Manic depressive illness is a common and frequently debilitating familial psychiatric disorder. Efforts to understand the mechanisms of inheritance have been hindered by the complexity of the phenotype, which may range from benign mood swings to chronic psychosis, and by apparently nonmendelian modes of transmission. Early reports of linkage to chromosomal loci have fallen into doubt; however they have helped encourage the development of more sophisticated methods for analyzing complex phenotypes. Using such methods, linkage of manic depressive illness to loci on chromosome 18 has been reported and apparently replicated, and work is proceeding to identify genes associated with what is probably a genetically heterogeneous set of disorders. As molecular mechanisms of inheritance are elucidated, it will be important to consider the ethical implications of genetic testing in a clinically and genetically complex disorder such as manic depressive illness.

Effect of lithium maintenance on suicidal behavior in major mood disorders.

We reviewed evidence of a possible antisuicide action of lithium maintenance treatment in mood disorders. Of 28 published studies involving over 17,000 patients with major affective illnesses, most yielded supportive evidence: risk of suicides and attempts averaged 3.2 versus 0.37 per 100 patient-years without versus with lithium (8.6-fold difference). In a new study of 284 bipolar I- and II-disordered patients, corresponding rates (2.2 vs. 0.39/100 patient-years) differed by 5.6-fold (p < 0.001); moreover, after discontinuing lithium, rates of suicidal acts rose by 7-fold (16-fold within the first year), and fatalities increased by nearly 9-fold. Lithium maintenance treatment in recurring major mood disorders has strong evidence of antisuicide effects not demonstrated with any other mood stabilizer. Close association of suicide and depression in bipolar disorder emphasizes the need for improved identification and treatment of bipolar depression.

Sociotropy/autonomy and vulnerability to specific life events in patients with unipolar depression and bipolar disorders.

Followed samples of unipolar and bipolar patients for a 6-month period, with independent assessment of symptoms and life events. Patients were initially categorized into subtypes using Beck's Sociotropy/Autonomy Scale, with the prediction that onset or exacerbation of symptoms, as well as more total symptoms, would occur for sociotropic individuals experiencing more negative interpersonal events than achievement events, and for autonomous-achievement patients experiencing more achievement events than interpersonal events. Results were confirmed for unipolars, indicating that the course of disorder was associated with the occurrence of personally meaningful life events, but not for bipolars. Further research is recommended to examine whether the effect is equally robust for both subtypes of unipolars, whether longer study duration may be required for bipolars, and whether a cognitive self-schema mechanism may account for the specific vulnerability to a subset of stressful events.

Mood disorders and patterns of creativity in British writers and artists.

Extremes in mood, thought and behavior--including psychosis--have been linked with artistic creativity for as long as man has observed and written about those who write, paint, sculpt or compose. The history of this long and fascinating association, as well as speculations about its reasons for being, have been discussed by several modern authors and investigators, including Koestler (1975), Storr (1976), Andreasen (1978), Becker (1978), Rothenberg (1979), Richards (1981), Jamison (in press) and Prentky (in press). The association between extreme states of emotion and mind and creativity not only is fascinating but also has significant theoretical, clinical, literary and societal-ethical implications. These issues, more thoroughly reviewed elsewhere (Jamison et al. 1980; Richards 1981; Jamison, in press), include the understanding of cognitive, perceptual, mood and behavioral changes common to manic, depressive and creative states; the potential ability to lessen the stigma of mental illness; effects of psychiatric treatment (for example, lithium) on creativity; and concerns raised about genetic research on mood disorders. The current study was designed to ascertain rates of treatment for affective illness in a sample of eminent British writers and artists; to study differences in subgroups (poets, novelists, playwrights, biographers, artists); to examine seasonal patterns of moods and productivity; and to inquire into the perceived role of very intense moods in the writers' and artists' work. One of the major purposes of this investigation was to look at possible similarities and dissimilarities between periods of intense creative activity and hypomania. Hypothesized similarities were based on the overlapping nature of mood, cognitive and behavioral changes associated with both; the episodic nature of both; and possible links between the durational, frequency and seasonal patterns of both experiences.

Maintenance lithium treatment: side effects and compliance.

Fifty-one bipolar patients receiving maintenance lithium treatment were evaluated for the presence of side effects, their degree of distress, and the association of these side effects with compliance. Cognitive side effects and weight gain were the most disturbing to patients, whereas thirst and polyuria were the most common. Self-reported noncompliance correlated most highly with coordination (r = .38, p less than .01) and cognition (r = .30, p less than .05) side effects. Current depressed mood also showed a strong correlation with side effect scores, especially those for cognitive disturbances. However, the correlations between noncompliance and coordination and cognitive side effects were just as strong when the effects of depressed mood were partialled out. These findings indicate the link between noncompliance and lithium-induced central nervous side effects and suggest that related treatment issues must be addressed to ensure maximum clinical response.

Suicide prevention in depressed women.

This paper focuses on risk factors and clinical states associated with suicide in depressed women and the necessity for thorough clinical evaluation of family and personal histories of suicidal, impulsive, and violent behaviors. Treatment issues addressed include the importance and content of detailed communication to patients and their families, medication noncompliance, the risks associated with the recovery and other high-risk periods, and problems associated with the adjunctive use of alcohol and other drugs.