Reconsidering Dietary Polyunsaturated Fatty Acids in Bipolar Disorder: A Translational Picture.

Inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the proposed role of PUFA metabolism in neuroinflammation, modulation of brain PUFA metabolism by antimanic medications in rodent models, and anti-inflammatory pharmacotherapy in bipolar disorder and in major depressive disorder (MDD). Although the convergence of findings between preclinical and postmortem clinical data is compelling, we investigate why human trials of PUFA as treatment are mixed. We view the biomarker and treatment study findings in light of the evidence for the hypothesis that arachidonic acid hypermetabolism contributes to bipolar disorder pathophysiology and propose that a combined high n-3 plus low n-6 diet should be tested as an adjunct to current medication in future trials.

Omega-3 and Omega-6 Polyunsaturated Fatty Acids in Bipolar Disorder: A Review of Biomarker and Treatment Studies.

OBJECTIVE: There is growing evidence that inflammation is an important mediator of pathophysiology in bipolar disorder. The omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) metabolic pathways participate in several inflammatory processes and have been linked through epidemiologic and clinical studies to bipolar disorder and its response to treatment. We review the data on PUFAs as biomarkers in bipolar disorder and n-3 PUFA used as treatment for bipolar disorder. DATA SOURCES: PubMed and CINAHL were searched for articles on PUFA and bipolar disorder published in the English language through November 6, 2013, with an updated search conducted on August 20, 2015. Keywords searched included omega 3 fatty acids and bipolar disorder, omega 3 fatty acids and bipolar mania, omega 3 fatty acids and bipolar depression, omega 3 fatty acids and mania, omega 3 fatty acids and cyclothymia, omega 3 fatty acids and hypomania, fatty acids and bipolar disorder, essential fatty acids and bipolar disorder, polyunsaturated fatty acids and bipolar disorder, DHA and bipolar disorder, and EPA and bipolar disorder. STUDY SELECTION: Studies selected measured PUFAs as biomarkers or introduced n-3 PUFA as treatment. RESULTS: We identified 17 relevant human clinical articles that either compared PUFA levels between a bipolar disorder group and a control group or used a PUFA intervention to treat depression or mania in bipolar disorder. Human studies suggest low n-3 red blood cell PUFA concentrations and correlations with clinical severity in studies of plasma concentrations in symptomatic bipolar disorder. Results of published n-3 PUFA dietary supplementation trials for bipolar disorder indicate efficacy in treatment for mania or depression in 5 of 5 open-label trials, efficacy in treatment of depression in 1 of 7 randomized controlled trials, and a signal for treatment of depression in 1 meta-analysis. CONCLUSIONS: Biomarker studies of PUFA and treatment studies of n-3 PUFA in bipolar disorder show promise for indicating a way forward in the study of PUFA in bipolar disorder. Investigation of the intake and metabolism of the n-3 and n-6 PUFA when supplementation is provided in treatment trials might offer clues for identification of when and how PUFA may be important for treatment in bipolar disorder.

Direct comparison of the psychometric properties of multiple interview and patient-rated assessments of suicidal ideation and behavior in an adult psychiatric inpatient sample.

OBJECTIVE: Compare the accuracy, agreement, internal consistency, and interrater reliability of 3 interviews to assess suicidal ideation and behavior in accordance with US Food and Drug Administration guidance about reporting categories. METHOD: Adults admitted to a psychiatric inpatient unit (N = 199) completed 3 assessments of past month and lifetime suicidal ideation and behavior-the Columbia Suicide Severity Rating Scale (C-SSRS), the Suicide Tracking Scale (STS), and the Sheehan Suicidality Tracking Scale (S-STS)-in randomized, counterbalanced order. "Missing gold standard" latent class analyses defined categories for ideation and behavior. Analyses also evaluated the S-STS mapping to C-SSRS categories. Three trained judges re-rated 89 randomly selected interview videotapes. Cohen κ, the primary outcome measure, quantified agreement above chance. Data were collected between November 2011 and June 2013. RESULTS: All 3 assessments showed excellent accuracy for suicidal ideation (κ = 0.72 to 1.00) and attempts (κ = 0.82 to 0.95) calibrated against latent classes. Interrater agreement ranged from κ = 0.52 to 1.00. Interrater agreement about more granular C-SSRS categories varied more widely (κ = 0.48 to 1.00), and the C-SSRS and S-STS assigned significantly different numbers of cases to many categories. Cronbach α was < 0.55 for the C-SSRS ideation and between 0.78 and 0.92 for the other scales. CONCLUSIONS: All 3 assessments showed good accuracy for broad categories of suicidal ideation and behavior. More granular, specific categories usually were rated reliably, but the C-SSRS and S-STS differed significantly in regard to which patients were assigned to these subcategories. Using any of these interviews would improve reliability over unstructured assessment in evaluating suicidal ideation and behavior. Clinical predictive validity of these interviews, and particularly the more granular categories, remains to be shown.

Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment.

OBJECTIVES: Omega (n)-3 and n-6 polyunsaturated fatty acids (PUFAs) are molecular modulators of neurotransmission and inflammation. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and those of n-6 PUFAs higher in subjects with bipolar disorder (BD) compared to healthy controls (HCs), and would correlate with symptom severity in subjects with BD, and that effective treatment would correlate with increased n-3 but lower n-6 PUFA levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids. METHODS: This observational, parallel group study compared biomarkers between HCs (n = 31) and symptomatic subjects with BD (n = 27) when ill and after symptomatic recovery (follow-up). Plasma concentrations of five PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)], two saturated fatty acids (palmitic acid and stearic acid) and two monounsaturated fatty acids (palmitoleic acid and oleic acid) were measured in esterified (E) and unesterified (UE) forms. Calculated ratios included UE:E for the five PUFAs, ratios of n-3 PUFAs (DHA:ALA, EPA:ALA and EPA:DHA), and the ratio of n-6:n-3 AA:EPA. Comparisons of plasma fatty acid levels and ratios between BD and HC groups were made with Student t-tests, and between the BD group at baseline and follow-up using paired t-tests. Comparison of categorical variables was performed using chi-square tests. Pearson's r was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis. RESULTS: UE EPA was lower in subjects with BD than in HCs, with a large effect size (Cohen's d = 0.86, p < 0.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA concentration between the BD and HC groups after Bonferroni correction for 40 comparisons, at p < 0.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA concentration. Exploratory comparison showed lower UE:E EPA in the BD than the HC group (p < 0.0001). At follow-up in the BD group, UE, E DHA:ALA, and UE EPA:ALA were decreased (p < 0.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. No plasma fatty acid level or ratio correlated with self-reported n-3 PUFA intake or use of medication by class. CONCLUSIONS: A large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state may be important factors in vulnerability to a mood state. Altered n-3 PUFA ratios could indicate changes in PUFA metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n-3 and decrease n-6 dietary PUFA intake.

Effects of mental health benefits legislation: a community guide systematic review.

CONTEXT: Health insurance benefits for mental health services typically have paid less than benefits for physical health services, resulting in potential underutilization or financial burden for people with mental health conditions. Mental health benefits legislation was introduced to improve financial protection (i.e., decrease financial burden) and to increase access to, and use of, mental health services. This systematic review was conducted to determine the effectiveness of mental health benefits legislation, including executive orders, in improving mental health. EVIDENCE ACQUISITION: Methods developed for the Guide to Community Preventive Services were used to identify, evaluate, and analyze available evidence. The evidence included studies published or reported from 1965 to March 2011 with at least one of the following outcomes: access to care, financial protection, appropriate utilization, quality of care, diagnosis of mental illness, morbidity and mortality, and quality of life. Analyses were conducted in 2012. EVIDENCE SYNTHESIS: Thirty eligible studies were identified in 37 papers. Implementation of mental health benefits legislation was associated with financial protection (decreased out-of-pocket costs) and appropriate utilization of services. Among studies examining the impact of legislation strength, most found larger positive effects for comprehensive parity legislation or policies than for less-comprehensive ones. Few studies assessed other mental health outcomes. CONCLUSIONS: Evidence indicates that mental health benefits legislation, particularly comprehensive parity legislation, is effective in improving financial protection and increasing appropriate utilization of mental health services for people with mental health conditions. Evidence was limited for other mental health outcomes.

Mediators of sexual functioning and marital quality in chronically depressed adults with and without a history of childhood sexual abuse.

INTRODUCTION: Sexual dysfunction is common among depressed adults. Childhood sexual abuse (CSA) and depressive symptomology are among the risk factors for sexual dysfunction, and these factors may interact to predict adult relationship functioning. Several models have been developed postulating interactions between these variables. AIM: We tested models of the effects of CSA and elucidate the associations between CSA, sexual dysfunction, depression severity, anxiety, and relationship quality in chronically depressed adults. METHODS: Baseline data from 808 chronically depressed outpatients enrolled in the Research Evaluating the Value of Augmenting Medication with Psychotherapy study were evaluated using structural equation modeling. MAIN OUTCOME MEASURES: The Inventory of Depressive Symptomology, self-report version (IDS-SR) assessed depression severity, and the Mood and Anxiety Symptom Questionnaire Anxious Arousal subscale assessed anxiety. Sexual function was assessed with the Arizona Sexual Experiences Scale (ASEX), and the Quality of Marriage Index (QMI) assessed relationship quality for patients in stable relationships. RESULTS: CSA scores predicted depression severity on the IDS-SR, as well as lower relationship quality and sexual satisfaction. ASEX scores were significantly associated with depression severity but were not correlated with the QMI. Two models were evaluated to elucidate these associations, revealing that (i) depression severity and anxious arousal mediated the relationship between CSA and adult sexual function, (ii) anxious arousal and sexual functioning mediated the association between CSA and depression symptoms, and (iii) when these models were combined, anxious arousal emerged as the most important mediator of CSA on depression which, in turn, mediated associations with adult sexual satisfaction and relationship quality. CONCLUSIONS: Although CSA predicts lower relationship and sexual satisfaction among depressed adults, the long-term effects of CSA appear to be mediated by depressive and anxious symptoms. It is important to address depression and anxiety symptoms when treating patients with CSA who present with sexual dysfunction or marital concerns.

Gender differences, clinical correlates, and longitudinal outcome of bipolar disorder with comorbid migraine.

OBJECTIVE: Migraine is a common comorbidity of bipolar disorder and is more prevalent in women than men. We hypothesized comorbid migraine would be associated with features of illness and psychosocial risk factors that would differ by gender and impact outcome. METHOD: A retrospective analysis was conducted to assess association between self-reported, physician-diagnosed migraine, clinical variables of interest, and mood outcome in subjects with DSM-IV bipolar disorder (N = 412) and healthy controls (N = 157) from the Prechter Longitudinal Study of Bipolar Disorder, 2005-2010. Informed consent was obtained from all participants. RESULTS: Migraine was more common in subjects with bipolar disorder (31%) than in healthy controls (6%) and had elevated risk in bipolar disorder women compared to men (OR = 3.5; 95% CI, 2.1-5.8). In men, migraine was associated with bipolar II disorder (OR = 9.9; 95% CI, 2.3-41.9) and mixed symptoms (OR = 3.5; 95% CI, 1.0-11.9). In comparison to absence of migraine, presence of migraine was associated with an earlier age at onset of bipolar disorder by 2 years, more severe depression (ß = .13, P = .03), and more frequent depression longitudinally (ß = .13, P = .03). Migraine was correlated with childhood emotional abuse (P = .01), sexual abuse (P = 4 × 10⁻³), emotional neglect (P = .01), and high neuroticism (P = 2 × 10⁻³). Protective factors included high extraversion (P = .02) and high family adaptability at the trend level (P = .08). CONCLUSIONS: Migraine is a common comorbidity with bipolar disorder and may impact long-term outcome of bipolar disorder, particularly depression. Clinicians should be alert for migraine comorbidity in women and in men with bipolar II disorder. Effective treatment of migraine may impact mood outcome in bipolar disorder as well as headache outcome. Joint pathophysiologic mechanisms between migraine and bipolar disorder may be important pathways for future study of treatments for both disorders.

Sexual functioning in patients with recurrent major depressive disorder enrolled in the PREVENT study.

The incidence of treatment-emergent sexual dysfunction in the acute and continuation phases of the prevention of recurrent episodes of depression with venlafaxine ER for two years (PREVENT) study was assessed. Adult outpatients with recurrent major depressive disorder were randomly assigned to receive venlafaxine extended release (ER; 75-300 mg/day) or fluoxetine (20-60 mg/day). Sexual dysfunction was assessed using items from the 17-item Hamilton Rating Scale for Depression (HAM-D(17)) and the Inventory of Depressive Symptomatology-Self-Report (IDS-SR). The baseline rates of sexual dysfunction based on the HAM-D(17) and IDS-SR items were 57.9% and 48.8%, respectively. The rates of new-onset sexual dysfunction for the venlafaxine ER-treated (44.8%, HAM-D(17); 38.4%, IDS-SR) and fluoxetine-treated patients (52.9%, HAM-D(17); 50.0%, IDS-SR) were similar; approximately 80% of the cases resolved during treatment. Treatment response was associated with lower rates of new-onset sexual dysfunction compared with nonresponse. The patients who remitted were the least likely to experience sexual dysfunction during antidepressant treatment.

Sleep quality during euthymia in bipolar disorder: the role of clinical features, personality traits, and stressful life events.

BACKGROUND: Poor sleep quality is known to precede the onset of mood episodes and to be associated with poor treatment outcomes in bipolar disorder (BD). We sought to identify modifiable factors that correlate with poor sleep quality in BD independent of residual mood symptoms. METHODS: A retrospective analysis was conducted to assess the association between the Pittsburgh Sleep Quality Index and clinical variables of interest in euthymic patients with DSM-IV BD (n = 119) and healthy controls (HC; n = 136) participating in the Prechter Longitudinal Study of Bipolar Disorder. Multivariable linear regression models were constructed to investigate the relationship between sleep quality and demographic and clinical variables in BD and HC participants. A unified model determined independent predictors of sleep quality. RESULTS AND DISCUSSION: Euthymic participants with BD and HC differed in all domains. The best fitting unified multivariable model of poor sleep quality in euthymic participants with BD included rapid cycling (ß = .20, p = .03), neuroticism (ß = .28, p = 2 × 10(-3)), and stressful life events (ß = .20, p = .02). Poor sleep quality often persists during euthymia and can be a target for treatment. Clinicians should remain vigilant for treating subjective sleep complaints independent of residual mood symptoms in those sensitive to poor sleep quality, including individuals with high neuroticism, rapid cycling, and recent stressful life events. Modifiable factors associated with sleep quality should be targeted directly with psychosocial or somatic treatment. Sleep quality may be a useful outcome measure in BD treatment studies.

Collaborative care to improve the management of depressive disorders: a community guide systematic review and meta-analysis.

CONTEXT: To improve the quality of depression management, collaborative care models have been developed from the Chronic Care Model over the past 20 years. Collaborative care is a multicomponent, healthcare system-level intervention that uses case managers to link primary care providers, patients, and mental health specialists. In addition to case management support, primary care providers receive consultation and decision support from mental health specialists (i.e., psychiatrists and psychologists). This collaboration is designed to (1) improve routine screening and diagnosis of depressive disorders; (2) increase provider use of evidence-based protocols for the proactive management of diagnosed depressive disorders; and (3) improve clinical and community support for active client/patient engagement in treatment goal-setting and self-management. EVIDENCE ACQUISITION: A team of subject matter experts in mental health, representing various agencies and institutions, conceptualized and conducted a systematic review and meta-analysis on collaborative care for improving the management of depressive disorders. This team worked under the guidance of the Community Preventive Services Task Force, a nonfederal, independent, volunteer body of public health and prevention experts. Community Guide systematic review methods were used to identify, evaluate, and analyze available evidence. EVIDENCE SYNTHESIS: An earlier systematic review with 37 RCTs of collaborative care studies published through 2004 found evidence of effectiveness of these models in improving depression outcomes. An additional 32 studies of collaborative care models conducted between 2004 and 2009 were found for this current review and analyzed. The results from the meta-analyses suggest robust evidence of effectiveness of collaborative care in improving depression symptoms (standardized mean difference [SMD]=0.34); adherence to treatment (OR=2.22); response to treatment (OR=1.78); remission of symptoms (OR=1.74); recovery from symptoms (OR=1.75); quality of life/functional status (SMD=0.12); and satisfaction with care (SMD=0.39) for patients diagnosed with depression (all effect estimates were significant). CONCLUSIONS: Collaborative care models are effective in achieving clinically meaningful improvements in depression outcomes and public health benefits in a wide range of populations, settings, and organizations. Collaborative care interventions provide a supportive network of professionals and peers for patients with depression, especially at the primary care level.

Boosting serotonin in the brain: is it time to revamp the treatment of depression?

Abnormalities in serotonin systems are presumably linked to various psychiatric disorders including schizophrenia and depression. Medications intended for these disorders aim to either block the reuptake or the degradation of this neurotransmitter. In an alternative approach, efforts have been made to enhance serotonin levels through dietary manipulation of precursor levels with modest clinical success. In the last 30 years, there has been little improvement in the pharmaceutical management of depression, and now is the time to revisit therapeutic strategies for the treatment of this disease. Tryptophan hydroxylase (TPH) catalyzes the first and rate-limiting step in the biosynthesis of serotonin. A recently discovered isoform, TPH2, is responsible for serotonin biosynthesis in the brain. Learning how to activate this enzyme (and its polymorphic versions) may lead to a new, more selective generation of antidepressants, able to regulate the levels of serotonin in the brain with fewer side effects.

Optimizing depression treatment to increase the likelihood of remission.

Depression is one of the highest ranking causes of disease burden worldwide but remains underrecognized and undertreated in clinical settings. Measurement-based care is the standard of care strived for by leading psychiatric researchers and is considered treatment as usual in other areas of medicine. However, routine measurement has yet to be implemented in all clinical practices for the detection and treatment of mental disorders such as depression. Physicians may help to improve illness outcomes and reduce illness burdens of patients with depression by using measurement-based care, including standardized measurement instruments and treatment algorithms in all phases of the treatment process.

Performance improvement CME: improving outcomes in depression.

Performance Improvement CME (PI CME) is an educational activity in which clinicians retrospectively assess their current clinical practice, choose areas for improvement and implement interventions based on treatment guidelines and health care standards, and then re-evaluate their clinical practice to assess the improvements made. This PI CME focuses on improving the detection and initial treatment of depression, enhancing patients' treatment response, and preventing relapse and recurrence.

A review of the current guidelines for depression treatment.

A variety of American and European guidelines are available for clinicians treating major depressive disorder and depressive subtypes. Major Western guidelines published since 2000 make similar recommendations for all stages of treatment for depression, including a reliance on measurement-based care. First-line treatment is usually a serotonin reuptake inhibitor, psychotherapy, or a combination of pharmacotherapy and psychotherapy. Next-step treatment recommendations are switching or augmentation, depending on patient response to the initial treatment. Maintenance therapy continues the approach that led to remission. The American Psychiatric Association will release a new treatment guideline to offer information on developments made since the last guidelines were published in 2000. Despite progress made during the last decade, no major breakthroughs in the treatment of depression have occurred, and genetic testing developments allowing for personalized care remain the goal of research.