International Society for Bipolar Disorders Task Force on Suicide: meta-analyses and meta-regression of correlates of suicide attempts and suicide deaths in bipolar disorder.

OBJECTIVES: Bipolar disorder is associated with a high risk of suicide attempts and suicide death. The main objective of the present study was to identify and quantify the demographic and clinical correlates of attempted and completed suicide in people with bipolar disorder. METHODS: Within the framework of the International Society for Bipolar Disorders Task Force on Suicide, a systematic review of articles published since 1980, characterized by the key terms bipolar disorder and 'suicide attempts' or 'suicide', was conducted, and data extracted for analysis from all eligible articles. Demographic and clinical variables for which ≥ 3 studies with usable data were available were meta-analyzed using fixed or random-effects models for association with suicide attempts and suicide deaths. There was considerable heterogeneity in the methods employed by the included studies. RESULTS: Variables significantly associated with suicide attempts were: female gender, younger age at illness onset, depressive polarity of first illness episode, depressive polarity of current or most recent episode, comorbid anxiety disorder, any comorbid substance use disorder, alcohol use disorder, any illicit substance use, comorbid cluster B/borderline personality disorder, and first-degree family history of suicide. Suicide deaths were significantly associated with male gender and first-degree family history of suicide. CONCLUSIONS: This paper reports on the presence and magnitude of the correlates of suicide attempts and suicide deaths in bipolar disorder. These findings do not address causation, and the heterogeneity of data sources should limit the direct clinical ranking of correlates. Our results nonetheless support the notion of incorporating diagnosis-specific data in the development of models of understanding suicide in bipolar disorder.

A review of factors associated with greater likelihood of suicide attempts and suicide deaths in bipolar disorder: Part II of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder.

OBJECTIVES: Many factors influence the likelihood of suicide attempts or deaths in persons with bipolar disorder. One key aim of the International Society for Bipolar Disorders Task Force on Suicide was to summarize the available literature on the presence and magnitude of effect of these factors. METHODS: A systematic review of studies published from 1 January 1980 to 30 May 2014 identified using keywords 'bipolar disorder' and 'suicide attempts or suicide'. This specific paper examined all reports on factors putatively associated with suicide attempts or suicide deaths in bipolar disorder samples. Factors were subcategorized into: (1) sociodemographics, (2) clinical characteristics of bipolar disorder, (3) comorbidities, and (4) other clinical variables. RESULTS: We identified 141 studies that examined how 20 specific factors influenced the likelihood of suicide attempts or deaths. While the level of evidence and degree of confluence varied across factors, there was at least one study that found an effect for each of the following factors: sex, age, race, marital status, religious affiliation, age of illness onset, duration of illness, bipolar disorder subtype, polarity of first episode, polarity of current/recent episode, predominant polarity, mood episode characteristics, psychosis, psychiatric comorbidity, personality characteristics, sexual dysfunction, first-degree family history of suicide or mood disorders, past suicide attempts, early life trauma, and psychosocial precipitants. CONCLUSION: There is a wealth of data on factors that influence the likelihood of suicide attempts and suicide deaths in people with bipolar disorder. Given the heterogeneity of study samples and designs, further research is needed to replicate and determine the magnitude of effect of most of these factors. This approach can ultimately lead to enhanced risk stratification for patients with bipolar disorder.

Epidemiology, neurobiology and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: Part I of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder.

OBJECTIVES: Bipolar disorder is associated with elevated risk of suicide attempts and deaths. Key aims of the International Society for Bipolar Disorders Task Force on Suicide included examining the extant literature on epidemiology, neurobiology and pharmacotherapy related to suicide attempts and deaths in bipolar disorder. METHODS: Systematic review of studies from 1 January 1980 to 30 May 2014 examining suicide attempts or deaths in bipolar disorder, with a specific focus on the incidence and characterization of suicide attempts and deaths, genetic and non-genetic biological studies and pharmacotherapy studies specific to bipolar disorder. We conducted pooled, weighted analyses of suicide rates. RESULTS: The pooled suicide rate in bipolar disorder is 164 per 100,000 person-years (95% confidence interval = [5, 324]). Sex-specific data on suicide rates identified a 1.7:1 ratio in men compared to women. People with bipolar disorder account for 3.4-14% of all suicide deaths, with self-poisoning and hanging being the most common methods. Epidemiological studies report that 23-26% of people with bipolar disorder attempt suicide, with higher rates in clinical samples. There are numerous genetic associations with suicide attempts and deaths in bipolar disorder, but few replication studies. Data on treatment with lithium or anticonvulsants are strongly suggestive for prevention of suicide attempts and deaths, but additional data are required before relative anti-suicide effects can be confirmed. There were limited data on potential anti-suicide effects of treatment with antipsychotics or antidepressants. CONCLUSION: This analysis identified a lower estimated suicide rate in bipolar disorder than what was previously published. Understanding the overall risk of suicide deaths and attempts, and the most common methods, are important building blocks to greater awareness and improved interventions for suicide prevention in bipolar disorder. Replication of genetic findings and stronger prospective data on treatment options are required before more decisive conclusions can be made regarding the neurobiology and specific treatment of suicide risk in bipolar disorder.

Combined catecholamine and indoleamine depletion following response to ECT.

The mechanism of action of electroconvulsive therapy (ECT) in treating major depression is unknown. We studied two candidate mechanisms through inhibiting simultaneously the synthesis of noradrenaline and serotonin in patients immediately after successful treatment with ECT using a randomised, placebo-controlled, double-blind crossover design. There were no significant changes in depression scores under any experimental conditions, or between the amine-depleted and placebo groups despite reductions of 61% in serum homovanillic acid, 47% in 3-methoxy-4-hydroxyenylethyleneglycol, and 89% in serum tryptophan. Catecholamine and serotonin availability may not be necessary for maintaining the initial antidepressant response to ECT.

Anxiety as a symptom of mixed mania: implications for DSM-5.

The recently released preliminary proposal for the DSM-5 diagnostic system includes modification of the mixed mania diagnosis symptom set. That definition includes the long-overdue exclusion of nonspecific signs and symptoms, as well as the inclusion of psychomotor retardation. Anxiety is specifically excluded from the definition. The current report reviews studies to establish that psychomotor retardation would have limited utility in the definition, in contrast to anxiety, which is a core symptom of the mixed manic subtype.

The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments.

OBJECTIVES: Safety monitoring is an important aspect of bipolar disorder treatment, as mood-stabilising medications have potentially serious side effects, some of which may also aggravate existing medical comorbidities. This paper sets out the International Society for Bipolar Disorders (ISBD) guidelines for the safety monitoring of widely used agents in the treatment of bipolar disorder. These guidelines aim to provide recommendations that take into consideration the balance between safety and cost-effectiveness, to highlight iatrogenic and preventive clinical issues, and to facilitate the broad implementation of therapeutic safety monitoring as a standard component of treatment for bipolar disorder. METHODS: These guidelines were developed by an ISBD workgroup, headed by the senior author (MB), through an iterative process of serial consensus-based revisions. After this, feedback from a multidisciplinary group of health professionals on the applicability of these guidelines was sought to develop the final recommendations. RESULTS: General safety monitoring recommendations for all bipolar disorder patients receiving treatment and specific monitoring recommendations for individual agents are outlined. CONCLUSIONS: These guidelines are derived from evolving and often indirect data, with minimal empirical cost-effectiveness data available to provide guidance. These guidelines will therefore need to be modified to adapt to different clinical settings and health resources. Clinical acumen and vigilance remain critical ingredients for safe treatment practice.

Gray and white matter brain volumes in older adults with bipolar disorder.

OBJECTIVES: Structural magnetic resonance imaging (MRI) studies have been inconsistent in demonstrating volumetric differences in subjects with bipolar disorder. Most studies have not found difference in total gray or white matter in bipolar patients compared with controls, but there have been several studies suggesting that regional abnormalities are present. These have predominately been located in the frontal and temporal lobes. Since age has been inversely correlated with total gray matter in patients, analyses of gray matter changes in older adults or in studies that have included older subjects have been difficult. This study assessed the presence of gray matter volume, and the potential for regional volumetric differences in older adults with bipolar disorder. METHODS: Fifty-six older adults with DSM-IV bipolar disorder (mean age 60.5) and 43 non-psychiatrically ill controls (mean age 58.1) had structured interviews and MRI scanning on a 1.5T GE Scanner. Image parcellation divided the cerebrum into 16 units. Volumetric differences were examined using the multivariate linear regression models with alpha = 0.05. RESULTS: Relative to controls, the older adults with bipolar disorder had significantly smaller gray matter volumes bilaterally in the inferior frontal areas. White matter volume was also reduced in these same areas but did not reach statistical significance when controlled for gender and age. No significant difference was noted in total gray or white matter volumes. CONCLUSIONS: Older adults with bipolar disorder showed gray matter volumetric deficits in inferior frontal lobe regions which include structures identified as contributing to the anterior limbic network.

Stressful life events in older bipolar patients.

OBJECTIVE: Theories about the impact of stressful life events (SLE) in bipolar disorder have focused on their role early in the disease. Few studies have examined SLE in older bipolar patients. We wanted to assess the impact of SLE in late life bipolar disorder METHODS: We evaluated negative SLE experienced by older bipolar subjects compared with younger bipolar subjects and older controls for number, type, and their association with phase of illness, age of onset, and previous episodes. RESULTS: Both younger and older bipolar subjects have more SLE than similarly aged controls. There was no significant difference in the number of stressors that younger and older bipolar subjects experienced, based on mood state, previous episodes, or age-of-onset. Both older and younger depressed bipolar subjects reported more SLE in the previous 12 months compared with those in a manic state. CONCLUSIONS: Negative SLE are much more prevalent in bipolar patients compared with age-matched controls, and continue to be frequent in later life.

Ketamine: stimulating antidepressant treatment?

SUMMARY: The appeal of ketamine - in promptly ameliorating depressive symptoms even in those with non-response - has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine's potential as an option for treating depression and provide a synthesis of perspectives - derived from evidence and clinical experience - and to consider strategies for future investigations. DECLARATION OF INTERESTS: G.S.M. Grant/research support: National Health Medical Research Council, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for Abbott, AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; consultant: AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. M.A.F. Grant support: AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer. Consultant (Mayo): Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals. CME/travel support: American Physician Institute, CME Outfitters. Financial interest/Mayo Clinic 2016: AssureRx. S.H.K. Grant/research support: Brain Canada, Bristol Meyer Squibb, CIHR, Janssen, Johnson & Johnson, Lundbeck, Ontario Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion. T.A.K. Grant/research support (through Stanford University): Sunovion Pharmaceuticals and Merck & Co., Inc.; consultant/advisory board bember: Allergan, Inc., Janssen Pharmaceuticals, Myriad Genetic Laboratories, Inc., and Sunovion Pharmaceuticals; lecture honoraria (not Speaker's Bureau payments): GlaxoSmithKline, and Sunovion Pharmaceuticals; royalties from American Psychiatric Publishing, Inc. Also, AstraZeneca Pharmaceuticals LP provided publication support to Parexel for preparation of a manuscript. Spouse employee and stockholder of Janssen Pharmaceuticals. R.W.L. Honoraria for speaking/advising/consulting, and/or received research funds: AstraZeneca, Brain Canada, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Coast Capital Savings, Johnson and Johnson, Lundbeck, Lundbeck Institute, Pfizer, Servier, St. Jude Medical, Takeda University, Health Network Foundation, and Vancouver Coastal Health Research Institute. R.M. Investigator Janssen trials of esketamine; 'paid-for' ketamine clinic operated by Oxford Health NHS Foundation Trust - fees used to support the Trust. M.J.O. Consultant: Sunovion and Acadia Pharmaceuticals. Full-time employee of U.S. Department of Veterans Affairs. M.E.T. Advisory/Consultant: Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex Inc., Neuronetics Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle), Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals Inc., Trius Therapeutical Inc. and Takeda. Grant support: Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health, and Otsuka Pharmaceuticals. Speakers Bureau: None since June, 2010. Equity Holdings: MedAvante, Inc. Royalties: American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Spouse's employment: Peloton Advantage, which does business with Pfizer. M.T. Full-time employee at Lilly 1997 to 2008. Honoraria/consulted: Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Allergan, Otsuka, Merck, Sunovion, Forest, Geodon Richter Plc, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Minerva, Wyeth and Wiley Publishing. Spouse was full time-employee at Lilly 1998-2013. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Cortical white matter microstructural abnormalities in bipolar disorder.

This article reports on preliminary findings describing microstructural abnormalities in the white matter of cortical areas thought to be associated with bipolar disorder. In all, 14 patients with bipolar disorder and 21 nonpsychiatrically ill control subjects underwent MR imaging including a diffusion tensor imaging (DTI) pulse sequence (six directions, b=1000 mm(2)/s). DTI data were analyzed on a workstation using a program that allowed calculation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) within the following three white matter fiber tracts bilaterally: the orbital frontal cortex, and the superior and middle frontal gyri. These values were compared across patient groups. The left and right orbital frontal white matter exhibited significantly higher ADC values in bipolar subjects than control subjects on both the left (p=0.028) and right (p=0.011). Microstructural changes in the white matter of the orbital frontal areas as reflected by increased ADC values appear to be associated with bipolar disorder. Further research is needed to better understand the interaction of microstructural changes and bipolar symptoms and whether these changes are specific to bipolar disorder.

An open label trial of C-1073 (mifepristone) for psychotic major depression.

BACKGROUND: The rationale for treating patients with psychotic major depression (PMD) with glucocorticosteroid receptor (GR) antagonists is explained. METHODS: Thirty patients with PMD, with Hamilton Rating Scale for Depression (HAMD-21) scores of 18 or greater, were assigned in an open label trial to receive 50 mg, 600 mg, or 1200 mg of mifepristone for 7 days. RESULTS: All the subjects completed the protocol; there were no dropouts. Side effects were mild and sporadic. Of 19 subjects in the combined 600- and 1200-mg group, 13 had a 30% or greater decline in their Brief Psychiatric Rating Scale (BPRS) scores, compared with 4 of 11 in the 50-mg group. In the 600- and 1200-mg group, 12 of 19 subjects showed a 50% decline in the BPRS positive symptom subscale, a more sensitive index for the symptoms seen in PMD, compared with 3 of 11 in the 50-mg group; 8 of 19 subjects in the 600- and 1200-mg group had a 50% decline in the HAMD-21, compared with 2 of 11 in the 50-mg group. CONCLUSIONS: These results suggest that short term use of GR antagonists may be effective in the treatment of psychotic major depression and that further blinded studies are warranted.

Investigation of Notch3 as a candidate gene for bipolar disorder using brain hyperintensities as an endophenotype.

The purpose of the study was to consider MRI hyperintensities as a potential endophenotype for bipolar disorder (BPD) and to investigate Notch3 (CADASIL) as a candidate gene for BPD. MRI scans were performed on 21 members of a family with a high incidence of BPD. Two-point and multipoint linkage analyses were performed and two exons of Notch3 were investigated with SSCP. Fifteen of 21 family members had MRI hyperintensities, including all bipolar patients and six family members with no affective illness. Two-point linkage analysis yielded negative results for all models. Multipoint linkage analysis yielded negative results except for Model 1a, in which a maximal LOD score was -1.24. A mutation screen of Exons 3 and 4 was negative. Notch3 does not appear to be a candidate gene for BPD in this family.

Seasonal variation of mixed and pure episodes of bipolar disorder.

BACKGROUND: Although seasonal patterns of manic episodes have been reported, the seasonal variation of mixed states of bipolar disorder has received little attention. In the current report we address that concern as well as the overall seasonality of manic episodes. METHODS: The seasonal pattern of 304 psychiatric hospital admissions for treatment of mixed or manic bipolar episodes over a 3-year period were analyzed employing two definitions of mixed manic states: DSM-III-R and an ROC derived definition. RESULTS: The frequency of all manic episodes combined peaked in early spring, with a nadir in late fall. Pure manic admissions showed a similar pattern. Mixed manic admissions had a significantly different pattern, with a peak in late summer and a nadir in November. The differences between pure and mixed manic admissions were demonstrated with the use of the ROC definition for mixed states. LIMITATIONS: Effects of medications and medication non-compliance may dampen natural seasonal patterns of episodes. CONCLUSIONS: The different seasonal pattern of mixed and pure manic episodes support the separation of mixed episodes as a distinct clinical subtype.

The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders.

OBJECTIVE: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. METHOD: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. RESULTS: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. CONCLUSIONS: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Risk factors of attempted suicide in bipolar disorder.

Suicide rates of bipolar patients are among the highest of any psychiatric disorder, and improved identification of risk factors for attempted and completed suicide translates into improved clinical outcome. Factors that may be predictive of suicidality in an exclusively bipolar population are examined. White race, family suicide history, and history of cocaine abuse were predictive of suicidal histories. Gender, nicotine use, medical comorbidity, and history of alcohol and other drug abuse were not, although a trend was noted for a history of benzodiazepine abuse. Attempts, although less common among African Americans, were equally as violent. Likewise, attempts were as violent among females as males, in distinction to general population studies.

Insight in bipolar disorder: relationship to episode subtypes and symptom dimensions.

BACKGROUND: The study of insight in bipolar disorder has received limited attention, despite its potential impact on treatment compliance and prognosis. In the current study we compare insight levels during different phases of bipolar disorder, and consider its relationship to symptoms dimensions and epidemiologic variables. METHODS: Insight ratings obtained from 156 bipolar subjects in any phase of bipolar disorder were compared. A regression analysis was also conducted to identify symptom dimensions predictive of insight levels. RESULTS: Greater impairments in insight were observed during pure manic episodes than during mixed or depressed episodes, or during euthymia. Depressive symptoms were associated with better insight. Improvements in insight with treatment were neither complete nor universal. Lack of insight was unrelated to age, years of illness, age of first psychiatric illness, or lifetime number of hospitalizations. CONCLUSIONS: Although psychosis may be associated with impaired insight, other variables also impact on degree of impaired insight. Specifically, depressed mood appears to be associated with preservation of insight. That relationship may transcend strict syndromal diagnosis.