Sex differences in rates of obesity in bipolar disorder: postulated mechanisms.

OBJECTIVE: The increased standardized mortality ratio (SMR) from cardiovascular disease (CVD) in women with bipolar disorder (BD), relative to men with BD and individuals of both sexes in the general population, provides the impetus to identify factors that contribute to the differential association of obesity with BD in women. METHODS: We conducted a selective PubMed search of English-language articles published from September 1990 to June 2012. The key search terms were bipolar disorder and metabolic syndrome cross-referenced with gender, sex, obesity, diabetes mellitus, hypertension, and dyslipidemia. The search was supplemented with a manual review of relevant article reference lists. Articles selected for review were based on author consensus, the use of a standardized experimental procedure, validated assessment measures, and overall manuscript quality. RESULTS: It is amply documented that adults with BD are affected by the metabolic syndrome at a rate higher than the general population. Women with BD, when compared to men with BD and individuals of both sexes in the general population, have higher rates of abdominal obesity. The course and clinical presentation of BD manifest differently in men and women, wherein women exhibit a higher frequency of depression predominant illness, a later onset of BD, more seasonal variations in mood disturbance, and increased susceptibility to relapse. Phenomenological factors can be expanded to include differences in patterns of comorbidity between the sexes among patients with BD. Other factors that contribute to the increased risk for abdominal obesity in female individuals with BD include reproductive life events, anamnestic (e.g., sexual and/or physical abuse), lifestyle, and iatrogenic. CONCLUSIONS: A confluence of factors broadly categorized as broad- and sex-based subserve the increased rate of obesity in women with BD. It remains a testable hypothesis that the increased abdominal obesity in women with BD mediates the increased SMR from CVD. A clinical recommendation that emerges from this review is amplified attention to the appearance, or history, of factors that conspire to increase obesity in female patients with BD.

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.

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.

The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders.

Incretins are a group of gastrointestinal hormones detected both peripherally and in the central nervous system (CNS). Recent studies have documented multiple effects of incretins on brain structure and function. Research into the neurological effects of incretins has primarily focused on animal models of neurodegenerative disorders (e.g., Alzheimer's Disease, Huntington's and Parkinson's diseases). Mood disorders (e.g. bipolar disorder (BD), major depressive disorder (MDD)) are associated with similar alterations in brain structure and function, as well as a range of cognitive deficits (e.g. memory, learning, executive function). Brain abnormalities and cognitive deficits are also found in populations with metabolic disorders (e.g., diabetes mellitus Type 2). In addition, individuals with mood disorders often have co-morbid metabolic conditions, thus treatment strategies which can effectively treat both cognitive deficits and metabolic abnormalities represent a possible integrated treatment avenue. In particular, glucagon-like peptide-1 (GLP-1) and its more stable, longer-lasting analogues have been demonstrated to exert neuroprotective and anti-apoptotic effects, reduce beta-amyloid (Aß) plaque accumulation, modulate long-term potentiation and synaptic plasticity, and promote differentiation of neuronal progenitor cells. In animal models of behaviour, treatment with GLP-1 receptor agonists has been demonstrated to improve measures of cognitive function including learning and memory, as well as reduce depressive behaviour. Available GLP-1 treatments also have a favourable metabolic profile which includes weight loss and reduced risk for hypoglycemia. Systematic evaluation of the effects of GLP-1 treatment in psychiatric populations who evince cognitive deficits represents a promising treatment avenue.

A theoretical framework informing research about the role of stress in the pathophysiology of bipolar disorder.

BACKGROUND: The staggering illness burden associated with Bipolar Disorder (BD) invites the need for primary prevention strategies. Before preventative strategies can be considered in individuals during a pre-symptomatic period (i.e., at risk), unraveling the mechanistic steps wherein external stress is transduced and interacts with genetic vulnerability in the early stages of BD will be a critical conceptual necessity. METHODS: Herein we comprehensively review extant studies reporting on stress and bipolar disorder. The overarching aim is to propose a conceptual framework to inform research about the role of stress in the pathophysiology of BD. Computerized databases i.e. PubMed, PsychInfo, Cochrane Library and Scielo were searched using the following terms: "bipolar disorder" cross-referenced with "stress", "general reaction to stress", "resilience", "resistance", "recovery" "stress-diathesis", "allostasis", and "hormesis". RESULTS: Data from literature indicate the existence of some theoretical models to understand the influence of stress in the pathophysiology of BD, including classical stress-diathesis model and new models such as allostasis and hormesis. In addition, molecular mechanisms involved in stress adaptation (resistance, resilience and recovery) can also be translated in research strategies to investigate the impact of stress in the pathophysiology of BD. LIMITATIONS: Most studies are retrospective and/or cross sectional, do not consider the period of development, assess brain function with only one or few methodologies, and use animal models which are not always similar to human phenotypes. CONCLUSION: The interaction between stress and brain development is dynamic and complex. In this article we proposed a theoretical model for investigation about the role of stress in the pathophysiology of BD, based on the different kinds of stress adaptation response and their putative neurobiological underpinnings.

A review of published evidence reporting on the efficacy and pharmacology of lurasidone.

INTRODUCTION: Lurasidone is a benzisothiazol derivative, approved by the US Food and Drug Administration for the acute treatment of adults with schizophrenia. Lurasidone's binding affinities are highest for the 5-HT(2A), 5-HT(7), and D(2) receptors; with lower and similar binding affinities for the norepinephrine α(2C) and 5-HT(2C) receptor subtypes. It has demonstrated efficacy in fixed-dose studies across a variable dose range (i.e., 40 - 160 mg), with a recommended starting dose of 40 mg and a maximum recommended dose of 80 mg. Lurasidone's preclinical profile is predictive not only of efficacy against psychotic and negative symptoms but also of affective symptomatology and cognitive deficits. Controlled trials are currently underway to evaluate lurasidone's efficacy in bipolar depression as well as its procognitive effects in individuals with schizophrenia. Lurasidone is administered once a day with ≥ 350 calories of food, regardless of fat content. Lurasidone is not known to adversely affect body composition, anthropometrics, metabolic and/or electrocardiographic parameters. Although prolactin elevation might be observed, prolactin-related adverse events are rarely reported. AREAS COVERED: This paper presents the pharmacodynamics and pharmacokinetics of lurasidone, and discusses its efficacy, safety and tolerability data. EXPERT OPINION: Lurasidone's simplicity of use and favorable metabolic profile are distinct advantages relative to several other agents (e.g., olanzapine). Outcomes in cognitive data analyses are awaited to determine if there is a key differentiator between lurasidone and other atypical agents with respect to efficacy. Moreover, lurasidone's efficacy in bipolar depression is awaited to determine whether this agent can be considered as a treatment alternative for depressive symptoms in adults with bipolar disorder.

Novel therapeutic targets in depression: minocycline as a candidate treatment.

Mood disorders are marked by high rates of non-recovery, recurrence, and chronicity, which are insufficiently addressed by current therapies. Several patho-etiological models have been proposed that are not mutually exclusive and include but are not limited to the monoamine, inflammatory, neurotrophic, gliotrophic, excitatory, and oxidative stress systems. A derivative of these observations is that treatment(s) which target one or more of these mechanistic steps may be capable of mitigating, or preventing, disparate psychopathological features. Minocycline is an agent with pleiotropic properties that targets multiple proteins and cellular processes implicated in the patho-etiology of mood disorders. Moreover, preclinical and preliminary clinical evidence suggests that minocycline possesses antidepressant properties. Herein, we provide the rationale for conducting a randomized, controlled trial to test the antidepressant properties of minocycline.