A pilot, open-label, 8-week study evaluating the efficacy, safety and tolerability of adjunctive minocycline for the treatment of bipolar I/II depression.

OBJECTIVES: The objectives of the study were to determine if adjunctive minocycline mitigates depressive symptom severity and improves cognitive function in individuals with bipolar I/II disorder (BD). The study also aimed to determine if changes in depressive and/or cognitive symptoms over the course of treatment were associated with changes in circulating inflammatory cytokine levels. METHODS: A total of 29 (intention-to-treat: n=27) adults meeting DSM-IV-TR criteria for a major depressive episode as part of bipolar I or II disorder (i.e. Hamilton Depression Rating Scale 17-item [HAMD-17] ≥20) were enrolled in an 8-week, open-label study with adjunctive minocycline (100 mg bid). The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale (MADRS). The HAMD-17, Clinical Global Impression-Severity (CGI-S), cognitive test composite scores and plasma cytokines were secondary outcome measures. Plasma cytokines were measured with the 30 V-Plex Immunoassay from Meso Scale Discovery. RESULTS: Adjunctive minocycline was associated with a reduction in depressive symptom severity from baseline to week 8 on the MADRS (P<.001, d=0.835), HAMD-17 (P<.001, d=0.949) and CGI-S (P<.001, d=1.09). Improvement in psychomotor speed, but not verbal memory or executive function, was observed only amongst individuals exhibiting a reduction in depression severity (P=.007, d=0.826). Levels of interleukin (IL)-12/23p40 (P=.002) were increased, while levels of IL-12p70 (P=.001) and C-C motif chemokine ligand 26 (CCL26) (P<.001) were reduced from baseline to week 8. A reduction in CCL26 levels was associated with a less favourable treatment response (P<.001). CONCLUSIONS: Results from the pilot study suggest that adjunctive minocycline may exert antidepressant effects in individuals with bipolar depression, possibly by targeting inflammatory cytokines.

Anhedonia and cognitive function in adults with MDD: results from the International Mood Disorders Collaborative Project.

BACKGROUND: Cognitive dysfunction is common in major depressive disorder (MDD) and a critical determinant of health outcome. Anhedonia is a criterion item toward the diagnosis of a major depressive episode (MDE) and a well-characterized domain in MDD. We sought to determine the extent to which variability in self-reported cognitive function correlates with anhedonia. METHOD: A post hoc analysis was conducted using data from (N=369) participants with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR)-defined diagnosis of MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. The IMDCP is a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Canada, and the Cleveland Clinic, Cleveland, Ohio. Measures of cognitive function, anhedonia, and depression severity were analyzed using linear regression equations. RESULTS: A total of 369 adults with DSM-IV-TR-defined MDD were included in this analysis. Self-rated cognitive impairment [ie, as measured by the Adult ADHD Self-Report Scale (ASRS)] was significantly correlated with a proxy measure of anhedonia (r=0.131, p=0.012). Moreover, total depression symptom severity, as measured by the total Montgomery-Åsberg Depression Rating Scale (MADRS) score, was also significantly correlated with self-rated measures of cognitive dysfunction (r=0.147, p=0.005). The association between anhedonia and self-rated cognitive dysfunction remained significant after adjusting for illness severity (r=0.162, p=0.007). CONCLUSIONS: These preliminary results provide empirical data for the testable hypothesis that anhedonia and self-reported cognitive function in MDD are correlated yet dissociable domains. The foregoing observation supports the hypothesis of overlapping yet discrete neurobiological substrates for these domains.

Advancing biomarker research: utilizing 'Big Data' approaches for the characterization and prevention of bipolar disorder.

OBJECTIVE: To provide a strategic framework for the prevention of bipolar disorder (BD) that incorporates a 'Big Data' approach to risk assessment for BD. METHODS: Computerized databases (e.g., Pubmed, PsychInfo, and MedlinePlus) were used to access English-language articles published between 1966 and 2012 with the search terms bipolar disorder, prodrome, 'Big Data', and biomarkers cross-referenced with genomics/genetics, transcriptomics, proteomics, metabolomics, inflammation, oxidative stress, neurotrophic factors, cytokines, cognition, neurocognition, and neuroimaging. Papers were selected from the initial search if the primary outcome(s) of interest was (were) categorized in any of the following domains: (i) 'omics' (e.g., genomics), (ii) molecular, (iii) neuroimaging, and (iv) neurocognitive. RESULTS: The current strategic approach to identifying individuals at risk for BD, with an emphasis on phenotypic information and family history, has insufficient predictive validity and is clinically inadequate. The heterogeneous clinical presentation of BD, as well as its pathoetiological complexity, suggests that it is unlikely that a single biomarker (or an exclusive biomarker approach) will sufficiently augment currently inadequate phenotypic-centric prediction models. We propose a 'Big Data'- bioinformatics approach that integrates vast and complex phenotypic, anamnestic, behavioral, family, and personal 'omics' profiling. Bioinformatic processing approaches, utilizing cloud- and grid-enabled computing, are now capable of analyzing data on the order of tera-, peta-, and exabytes, providing hitherto unheard of opportunities to fundamentally revolutionize how psychiatric disorders are predicted, prevented, and treated. High-throughput networks dedicated to research on, and the treatment of, BD, integrating both adult and younger populations, will be essential to sufficiently enroll adequate samples of individuals across the neurodevelopmental trajectory in studies to enable the characterization and prevention of this heterogeneous disorder. CONCLUSIONS: Advances in bioinformatics using a 'Big Data' approach provide an opportunity for novel insights regarding the pathoetiology of BD. The coordinated integration of research centers, inclusive of mixed-age populations, is a promising strategic direction for advancing this line of neuropsychiatric research.

Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions.

BACKGROUND: Few reports have aimed to describe the mediational effect of cognitive deficits on functional outcomes in major depressive disorder (MDD), and relatively few interventions are demonstrated to mitigate cognitive deficits in MDD. METHODS: Studies enrolling subjects between the ages of 18-65 were selected for review. Bibliographies from identified articles were reviewed to identify additional original reports aligned with our objectives. RESULTS: Cognitive deficits in MDD are consistent, replicable, nonspecific, and clinically significant. The aggregated estimated effect size of cognitive deficits in MDD is small to medium. Pronounced deficits in executive function (≥1 SD below the normative mean) are evident in ∼20-30% of individuals with MDD). Other replicated abnormalities are in the domains of working memory, attention, and psychomotor processing speed. Mediational studies indicate that cognitive deficits may account for the largest percentage of variance with respect to the link between psychosocial dysfunction (notably workforce performance) and MDD. No conventional antidepressant has been sufficiently studied and/or demonstrated robust procognitive effects in MDD. CONCLUSIONS: Cognitive deficits in MDD are a principal mediator of psychosocial impairment, notably workforce performance. The hazards posed by cognitive deficits in MDD underscore the need to identify a consensus-based neurocognitive battery for research and clinical purposes. Interventions (pharmacological, behavioral, neuromodulatory) that engage multiple physiological systems implicated in cognitive deficits hold promise to reduce, reverse, and prevent cognitive deficits.

The effect of lisdexamfetamine dimesylate on body weight, metabolic parameters, and attention deficit hyperactivity disorder symptomatology in adults with bipolar I/II disorder.

OBJECTIVES: We primarily sought to determine the effect of adjunctive lisdexamfetamine dimesylate (LDX) on anthropometric and metabolic parameters. Our secondary aim was to evaluate the effect of LDX on attention deficit hyperactivity disorder (ADHD) symptom severity in adults with bipolar I/II disorder. METHODS: Forty-five stable adults (i.e., non-rapid cycling, absence of clinically significant hypo/manic symptoms) with bipolar I/II disorder and comorbid ADHD were enrolled in a phase IV, 4-week, flexible dose, open-label study of adjunctive LDX. All subjects were initiated at 30 mg/day of adjunctive LDX for the first week with flexible dosing (i.e., 30-70 mg/day) between weeks 2 and 4. RESULTS: Of the 45 subjects enrolled, 40 received adjunctive LDX (mean dose = 60 ± 10 mg/day). A statistically significant decrease from baseline to endpoint was evident in weight (p < 0.001), body mass index (p < 0.001), fasting total cholesterol (p = 0.011), low density lipoprotein cholesterol (p = 0.044), high density lipoprotein cholesterol (p = 0.015) but not triglycerides, or blood glucose. Significant reductions were also observed in leptin (p = 0.047), but not in ghrelin, adiponectin, or resistin levels. Diastolic blood pressure and pulse increased significantly over time but on average remained within the normal range (p < 0.001). There was a significant reduction from baseline to endpoint in the total score of the ADHD Self-Report Scale. Significant improvement from baseline to endpoint was also observed in the Montgomery-Åsberg Depression Rating Scale total score as well as the Clinical Global Impression Severity and Improvement score. CONCLUSIONS: Short-term adjunctive LDX treatment was well tolerated by this sample of adults with stable bipolar I/II disorder. Lisdexamfetamine dimesylate offered beneficial effects on body weight, body mass index and several metabolic parameters. In addition to demonstrating short-term (i.e., 4 weeks) safety and tolerability, beneficial effects of LDX were also observed in mitigating depressive and ADHD symptom severity.

A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder.

BACKGROUND: Neurocognitive deficits are prevalent, persistent, and implicated as mediators of functional impairment in adults with bipolar disorder. Notwithstanding progress in the development of pharmacological treatments for various phases of bipolar disorder, no available treatment has been proven to be reliably efficacious in treating neurocognitive deficits. Emerging evidence indicates that insulin dysregulation may be pertinent to neurocognitive function. In keeping with this view, we tested the hypothesis that intranasal insulin administration would improve measures of neurocognitive performance in euthymic adults with bipolar disorder. METHODS: Sixty-two adults with bipolar I/II disorder (based on the Mini International Neuropsychiatric Interview 5.0) were randomized to adjunctive intranasal insulin 40 IU q.i.d. (n = 34) or placebo (n = 28) for eight weeks. All subjects were prospectively verified to be euthymic on the basis of a total score of ≤ 3 on the seven-item Hamilton Depression Rating Scale (HAMD-7) and ≤ 7 on the 11-item Young Mania Rating Scale (YMRS) for a minimum of 28 consecutive days. Neurocognitive function and outcome was assessed with a neurocognitive battery. RESULTS: There were no significant between-group differences in mean age of the subjects {i.e., mean age 40 [standard deviation (SD) = 10.15] years in the insulin and 39 [SD = 10.41] in the placebo groups, respectively}. In the insulin group, n = 27 (79.4%) had bipolar I disorder, while n = 7 (21.6%) had bipolar II disorder. In the placebo group, n = 25 (89.3%) had bipolar I disorder, while n = 3 (10.7%) had bipolar II disorder. All subjects received concomitant medications; medications remained stable during study enrollment. A significant improvement versus placebo was noted with intranasal insulin therapy on executive function (i.e., Trail Making Test-Part B). Time effects were significant for most California Verbal Learning Test indices and the Process Dissociation Task-Habit Estimate, suggesting an improved performance from baseline to endpoint with no between-group differences. Intranasal insulin was well tolerated; no subject exhibited hypoglycemia or other safety concerns. CONCLUSIONS: Adjunctive intranasal insulin administration significantly improved a single measure of executive function in bipolar disorder. We were unable to detect between-group differences on other neurocognitive measures, with improvement noted in both groups. Subject phenotyping on the basis of pre-existing neurocognitive deficits and/or genotype [e.g., apolipoprotein E (ApoE)] may possibly identify a more responsive subgroup.

Inflammatory biomarkers in depression: an opportunity for novel therapeutic interventions.

Currently available antidepressants are effective in less than two thirds of depressed patients, with even lower remission rates in the context of co-morbid medical illness. A rapidly expanding evidence base suggests that maladaptive inflammatory immune responses may be a common pathophysiology underlying depression, particularly in the presence of a general medical condition. The inflammatory hypothesis of depression marks a significant shift away from monoamine-based approaches and is a major step towards developing novel treatments that directly target causal factors of depression. Many antidepressants exert anti-inflammatory effects and there is an emerging literature documenting the efficacy of anti-inflammatory agents as adjunctive treatments for depression. Identification of inflammatory biomarkers in depression will require a re-conceptualization of both the diagnostic phenomenology and the experimental approaches to studying multi-determined psychiatric disorders. In addition to their application in diagnosis, predicting prognosis, and monitoring severity and response to treatment, inflammatory biomarkers may serve as novel therapeutic targets in the treatment of depression.

Frequency and correlates of gambling problems in outpatients with major depressive disorder and bipolar disorder.

OBJECTIVE: To investigate the frequency of gambling in people who have been diagnosed with major depressive disorder (MDD) or bipolar disorder (BD). Secondary objectives were to examine: sex differences in the rates of gambling behaviour, the temporal relation between onset of mood disorders and problem gambling, psychiatric comorbidities associated with problem gambling, and the influences of problem gambling on quality of life. METHOD: People (aged 18 years and older) who met criteria for lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined MDD or BD I or II, and were confirmed by the Mini International Neuropsychiatric Interview, were enrolled. Participants were recruited from 5 sites in Canada and 1 in the United States. Prevalence of past-year problem gambling was assessed with the Canadian Problem Gambling Index. Associated comorbidities with problem gambling are presented. RESULTS: A total of 579 participants were enrolled (female: n = 379, male: n = 200). Prevalence of problem gambling did not differ significantly between the MDD (12.5%) and the BD (12.3%) groups. There was a significant difference in the prevalence of problem gambling between males (19.5%) and females (7.8%) in the BD group (chi-square = 8.695, df = 1, P = 0.003). Among people meeting criteria for problem gambling, the mood disorder was the primary onset condition in 71% of cases. People with a mood disorder with comorbid current panic disorder (OR = 1.96; 95% CI 1.02 to 3.75), obsessive-compulsive disorder (OR = 1.86; 95% CI 1.01 to 3.45), specific phobia (OR = 2.36; 95% CI 1.17 to 4.76), alcohol dependence (OR = 5.73; 95% CI 3.08 to 10.65), or lifetime substance dependence (OR = 2.05; 95% CI 1.17 to 3.58), had significantly increased odds of problem gambling. Problem gambling across MDD and BD populations was also associated with lower quality of life ratings. CONCLUSION: These results reaffirm a higher prevalence of gambling both in BD and in MDD populations, compared with previously published community samples. Our study also identifies risk factors for gambling behaviours within these populations.

Metabolic syndrome and major depressive disorder: co-occurrence and pathophysiologic overlap.

The metabolic syndrome and its components are associated with depressive symptomatology. This article discusses the rate of co-occurrence and the points of pathophysiologic commonality between the metabolic syndrome and major depressive disorder.

Relation between cigarette smoking and cognitive function in euthymic individuals with bipolar disorder.

BACKGROUND: Individuals with bipolar disorder have higher rates of cigarette smoking and cognitive deficits when compared to the general population. Emerging evidence indicates that both smoking and cognitive deficits are associated with more severe illness presentation and course. METHODS: The data were derived from a study evaluating a novel treatment for cognitive function in bipolar disorder. Smoking status was determined by self-report; cognitive function was evaluated with a comprehensive cognitive battery, which included measures of psychomotor speed, attention, memory, learning and executive function. The relations between smoking status and cognitive measures were evaluated with two independent-samples t-test and multiple regression. RESULTS: The sample comprised forty-three subjects with bipolar disorder (Type I/II). There were no consistent differences in neuropsychological performance between current smokers (N=16) and non-smokers (N=27) on most tasks. The occurrence of subjective cognitive failures, as measured with the Cognitive Functioning Questionnaire, was non-significantly lower for smokers compared to non-smokers. Lifetime "smoking load" was negatively associated with premorbid intelligence as estimated by the National Adult Reading Test. CONCLUSION: This pilot study provides preliminary evidence that cigarette smoking may exert a salutary effect on subjective, but not objective, measures of cognitive function in euthymic bipolar patients. A larger sample size evaluating this hypothesis would be less vulnerable to type II error.

Efficacy of Adjunctive Infliximab vs Placebo in the Treatment of Adults With Bipolar I/II Depression: A Randomized Clinical Trial.

Importance: To our knowledge, no study has previously evaluated whether individuals with bipolar depression enriched a priori on the basis of biochemical and/or phenotypic immuno-inflammatory activation would differentially respond to an anti-inflammatory agent for the treatment of depressive symptoms. Objective: To assess the antidepressant efficacy of adjunctive infliximab, a monoclonal antibody targeting tumor necrosis factor, in adults with bipolar I and bipolar II depression and inflammatory conditions. Design, Setting, and Participants: This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at 2 outpatient tertiary care sites in Canada and the United States. Eligible adults (aged 18-65 years) met DSM-5-defined criteria for bipolar I or bipolar II depression and exhibited pretreatment biochemical and/or phenotypic evidence of inflammatory activation. Participants were enrolled between October 1, 2015, and April 30, 2018. Data analysis was performed from May 1 through July 31, 2018, using modified intent-to-treat analysis. Interventions: Patients were randomized to receive 3 intravenous infusions of infliximab therapy or placebo at baseline and at weeks 2 and 6 of the 12-week study. Main Outcomes and Measures: The primary efficacy outcome was baseline-to-end point (ie, week-12) change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. History of childhood maltreatment, as assessed by the Childhood Trauma Questionnaire, was used for exploratory analyses as 1 of several secondary outcomes. Results: A total of 60 participants were randomized to infliximab (n = 29 [48%]; mean [SD] age, 45.0 [11.7] years; 20 of 28 female [71%]) or to placebo (n = 31 [52%]; mean [SD] age, 46.8 [10.2] years; 26 of 30 female [87%]) across study sites. Overall baseline-to-end point change in MADRS total score was observed across treatment × time interaction (χ2 = 10.33; P = .04); reduction in symptom severity was not significant at week 12 (relative risk, 1.09; 95% CI, 0.80-1.50; df = 1; P = .60). As part of a secondary analysis, a significant treatment × time × childhood maltreatment interaction was observed in which infliximab-treated individuals with childhood history of physical abuse exhibited greater reductions in MADRS total score (χ2 = 12.20; P = .02) and higher response rates (≥50% reduction in MADRS total score) (χ2 = 4.05; P = .04). Conclusions and Relevance: Infliximab did not significantly reduce depressive symptoms compared with placebo in adults with bipolar depression. Results from secondary analyses identified a subpopulation (ie, those reporting physical and/or sexual abuse) that exhibited a significant reduction in depressive symptoms with infliximab treatment compared with placebo. Trial Registration: ClinicalTrials.gov identifier: NCT02363738.

Insulin, insulin-like growth factors and incretins: neural homeostatic regulators and treatment opportunities.

Mood disorders may be conceptualized as progressive neurodegenerative disorders associated with cognitive decline. Novel treatments capable of preserving and/or enhancing cognitive function represent an area of priority for research in the future. Insulin, insulin-like growth factor (IGF)-1 and incretins may play a critical role in both physiological and pathophysiological processes of the CNS. An emerging paradigm regarding the pathophysiology of mood disorders posits that alterations in biological networks that mediate stress compromise optimal neuronal and glial function. A growing body of evidence indicates that central administration of insulin may enhance cognitive function in both healthy and cognitively impaired individuals. The neuroactive peptides, insulin, IGF-1 and incretins, or agents that facilitate their central effects (e.g. insulin-sensitizing agents), may constitute novel and possibly disease-modifying neurocognitive treatments.

Bipolar disorder and suicide: research synthesis and clinical translation.

Attempted suicide and suicide are prevalent in individuals with bipolar disorder (BD). Extant evidence indicates that history of suicide attempts, percentage of time spent in a depressed state, and hostility are factors associated with suicide attempts and completed suicide. Childhood adversity (eg, sexual and physical abuse) is emerging as a risk factor for suicide attempts in adults with BD. The pertinacity of medical comorbidity (eg, obesity, metabolic syndrome) in the bipolar population is further underscored by its preliminary association with suicidality. Biomarkers such as cerebrospinal fluid monoamine metabolite levels may be predictive of suicide attempts and lethality in BD. Compelling evidence supports an antisuicide effect of long-term lithium prophylaxis; lithium's salutary effect is mediated primarily by reduced lethality of suicidal acts. Conventional unimodal antidepressants may engender or exacerbate suicidality in susceptible individuals with BD. A nascent database suggests that adjunctive psychosocial interventions may further reduce suicide risk in bipolar individuals.

The hepatic safety profile of duloxetine: a review.

BACKGROUND: Hepatotoxicity related to the use of duloxetine resulted in rewording of the US product insert. OBJECTIVE: To characterize the hepatic safety profile of duloxetine. METHODS: We conducted a PubMed search of all English-language articles published between January 1990 and December 2007 and contacted the manufacturer (Eli Lilly, Inc.). RESULTS: Elevations of alanine aminotransferase to three times the upper limit of normal occurs in 0.9-1.7% of duloxetine-treated patients versus 0.0-0.3% of placebo-treated patients. Hepatocellular, cholestatic and mixed hepatocellular-cholestatic forms of hepatic injury have been described. CONCLUSION: Duloxetine does not appear to pose a greater hazard for hepatic toxicity when compared to other conventional antidepressants. Systematic monitoring of liver aminotransferases does not appear to be warranted with routine duloxetine use.

Medical and substance-related comorbidity in bipolar disorder: translational research and treatment opportunities.

It is well established that individuals with bipolar disorder are differentially affected by substance-related as well as medical disorders (ie, cardiometabolic disorders, respiratory disorders, neurological disorders, and infectious diseases). Emerging evidence indicates that some comorbid conditions (eg, diabetes mellitus) in bipolar individuals may be subserved by overlapping neurobiological networks. Disturbances in glucocorticoid/insulin signaling and immunoinflammatory effector systems are points of pathophysiological commonality between bipolar disorder and "stress-sensitive" medical disorders. Subphenotyping bipolar disorder as a function of comorbidity and temporality of onset may provide an opportunity for refining disease pathophysiological models and developing innovative disease-modifying therapies.

The relationship between childhood abuse and suicidality in adult bipolar disorder.

This study evaluates the effect of childhood sexual and physical abuse on suicidality in adults with bipolar disorder. We conducted a retrospective chart review of adult outpatients (N= 381) with DSM-IV-TR-defined bipolar disorder seeking evaluation and treatment at an academic specialty research program (i.e., Mood Disorders Pharmacology Unit, University Health Network, University of Toronto) between October 2002 and November 2005. Eighteen percent (n = 68) of adult patients with bipolar disorder had a recorded history of childhood abuse (p = 0.009). Sixty-three percent (n = 43) of bipolar patients with a history of childhood abuse reported lifetime suicidality (chi2 = 6.885, df= 1, p = 0.009). Logistic regression analysis indicated that Childhood abuse was a significant predictor of lifetime suicidality in adult bipolar patients (OR = 2.05, CI = 1.19-3.510). Childhood abuse is associated with suicidal ideation and suicide attempts in adults with bipolar disorder. Anamnestic inquiry regarding childhood maltreatment is salient to risk assessment, illness management planning, preventative strategies, and treatment interventions in bipolar disorder.

Problem gambling in bipolar disorder: results from the Canadian Community Health Survey.

OBJECTIVE: This investigation was undertaken to explore the prevalence and associated features of problem gambling amongst individuals with bipolar I disorder. METHODS: The data for this analysis were procured from the Canadian Community Health Survey: Mental Health and Well-being (CCHS 1.2) conducted by Statistics Canada. Individuals screening positive for a lifetime (World Mental Health- Composite International Diagnostic Interview) WMH-CIDI-defined manic episode (i.e. bipolar I disorder) or depressive episode (i.e. major depressive disorder) and current (i.e. past 12-month) problem gambling were compared to the general population without these disorders. Past year problem gambling was operationalized with the Canadian Problem Gambling Index (CPGI). RESULTS: The sample consisted of 36,984 individuals (> or = 15 years old); the weighted prevalence of problem gambling was significantly higher (6.3%) amongst the population with bipolar disorder as compared to the general population (2.0%, p<0.001) and those with major depressive disorder (2.5%, p<0.01). Compared to those without bipolar disorder, the odds of problem gambling for bipolar individuals were over twice as high (OR=2.3; 95% CI 1.4-3.7), even when controlling for potential confounders. Males also had higher odds of problem gambling (OR=1.8; 95% CI 1.4-2.3), as did individuals without post-secondary education (OR=1.4; 95% CI 1.1-1.8). Persons who were married/cohabiting had lowered odds of problem gambling, compared with those who were unmarried (OR=0.6; 95% CI 0.5-0.8). Comorbid alcohol dependence (OR=3.4; 95% CI 2.3-5.0) and illicit drug dependence (OR=2.6; 95% CI 1.1-6.2) each conferred an increased risk for problem gambling. Physical activity level (moderate to active) was associated with a decreased risk for problem gambling (OR=0.8; 95% CI 0.6-0.9). CONCLUSIONS: Individuals with bipolar I disorder are differentially affected by problem gambling. Opportunistic screening for problem gambling is warranted, particularly in persons with comorbid alcohol or substance dependence.

Neuroimaging approaches in mood disorders: technique and clinical implications.

BACKGROUND: Clinical research in mood disorders increasingly involves advanced neuroimaging techniques. The encompassing aim of this review is to provide the mental health care practitioner with a pragmatic understanding of neuroimaging approaches and their possible clinical application. METHODS: We conducted a literature search of English-language articles using the search terms, major depressive disorder and bipolar disorder, cross-referenced with available neuroimaging technologies and analytical approaches, The search was supplemented with a manual review of relevant references. We organize the review by reviewing frequently asked questions on the topic of neuroimaging by mental health-care providers. RESULTS: Magnetic resonance (MR) approaches provide information on white and gray matter pathology (segmentation), cellular metabolism (MRS), oxygen consumption (BOLD), and neurocircuitry (DTI). Radionuclide-based neuroimaging methodologies provide quantitative estimates of brain glucose metabolism, regional blood flow, and ligand-receptor/transporter binding. Clinical implications of neuroimaging methodologies are reviewed. CONCLUSIONS: Advances in neuroimaging technology have refined models of disease pathophysiology in mood disorders and the mechanistic basis of antidepressant action. Multivariate analysis of functional and structural neuroimaging data, longitudinal analysis in the depressed and remitted states, and inclusion of representative patients with medical and psychiatric comorbidities will enhance the clinical translation of future research findings.

Comparing features of bipolar disorder to major depressive disorder in a tertiary mood disorders clinic.

BACKGROUND: We sought to describe features that distinguish individuals with bipolar disorder from major depressive disorder. METHODS: A retrospective chart review of adult outpatients (N = 1000) seeking evaluation and treatment was conducted at the Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto between October 2002 and November 2005 was conducted. Sociodemographic parameters, illness-characteristics and therapeutic interventions were evaluated and compared. RESULTS: The MDPU referring diagnosis were major depressive disorder (52%), bipolar disorder (29%), and unspecified (19%). Of all individuals with a non-bipolar entry diagnosis (n = 699), 23% (n = 159) were subsequently diagnosed with bipolar disorder (p < 0.001); the majority of whom (n = 117, 74%) received a non-bipolar I disorder diagnosis [e.g. bipolar II disorder (n = 71); bipolar NOS disorder (n = 46) (p < 0.001)]. Higher rates of unemployment/disability, previous depressive episodes, psychiatric hospitalization, comorbid hypertension, and lifetime substance use disorders, as well as an earlier age of illness-onset were more frequently endorsed by individuals with a diagnosis of bipolar disorder. Fifteen percent of individuals who were newly-diagnosed with bipolar disorder reported a history of antidepressant-associated mania. CONCLUSIONS: The majority of individuals with a newly-diagnosed bipolar disorder at this tertiary center have a non-bipolar I disorder (i.e., bipolar spectrum). Several indices of illness severity differentiate individuals with bipolar disorder from major depressive disorder.

Should Depressive Syndromes Be Reclassified as "Metabolic Syndrome Type II"?

BACKGROUND: A nascent explanatory theory regarding the pathophysiology of major depressive disorder posits that alterations in metabolic networks (e.g., insulin and glucocorticoid signaling) mediate allostasis. METHOD: We conducted a PubMed search of all English-language articles published between January 1966 and September 2006. The search terms were: neurobiology, cognition, neuroprotection, inflammation, oxidative stress, glucocorticoids, metabolic syndrome, diabetes mellitus, insulin, and antidiabetic agents, cross-referenced with the individual names of DSM-III-R/IV/-TR-defined mood disorders. The search was augmented with a manual review of article reference lists; articles selected for review were determined by author consensus. RESULTS: Disturbances in metabolic networks: e.g., insulin-glucose homeostasis, immuno-inflammatory processes, adipokine synthesis and secretion, intra-cellular signaling cascades, and mitochondrial respiration are implicated in the pathophysiology, brain volumetric changes, symptomatic expression (e.g., neurocognitive decline), and medical comorbidity in depressive disorders. The central nervous system, like the pancreas, is a critical modulator of the metabolic milieu and is endangered by chronic abnormalities in metabolic processes. We propose the notion of "metabolic syndrome type II" as a neuropsychiatric syndrome in which alterations in metabolic networks are a defining pathophysiological component. CONCLUSION: A comprehensive management approach for depressive disorders should routinely include opportunistic screening and primary prevention strategies targeting metabolically mediated comorbidity (e.g., cardiovascular disease). Innovative treatments for mood disorders, which primarily target aberrant metabolic networks, may constitute potentially novel, and disease-modifying, treatment avenues.