Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

The psychological burden of the COVID-19 pandemic and associated lockdown measures: Experience from 4000 participants.

BACKGROUND: In February 2020 the first cases of COVID-19 were identified in Kuwait. Inevitably as many countries worldwide, the general public were negatively affected by the pandemic. Unemployment, uncertainty, distress, increasing deaths, lockdown measures all of which are potential burdens on mental health. AIM: To assess the impact of COVID19 outbreak on mental health in Kuwait, and to explore the potential influencing risk factors. METHODS: We conducted an online questionnaire-based study in Kuwait between 25th May 2020 to 30th May 2020. Questions were based on demographics, lifestyle during outbreak, depression and anxiety assessment. Total PHQ9 and GAD7 scores were calculated for each responder. RESULTS: We had 4132 responders. Most were females (69.31%), married (59.37%), between the age of 21-30 (23.84%) and non-smokers (81.46%). Only (7.96%) had a positive past psychiatric history, (32.04%) had a past history of a chronic medical disease. During the outbreak most of the responders lost their jobs (39.21%) and only (12.83%) were attending work regularly, only (6.82%) worked in the healthcare sector. 59.27% report increased social media use compared to before the lockdown. When asked about their daily time spent following COVID19-related news, most (37.8%) spend more than 2 hours and (7.74%) spend more than 4 hours. The overall prevalence of depressive symptoms was (30.13%) and the prevalence of anxiety symptoms was (25.28%). LIMITATIONS: In the cross-sectional nature of the study. CONCLUSION: The COVID-19 pandemic caused a burden on mental health. Psychological support and mental health awareness should be implemented and made accessible to all individuals during pandemics.

Arabic Translation, Validation and Cultural Adaptation of the 7-Item Hamilton Depression Rating Scale in Two Community Samples.

OBJECTIVES: Depression is a common mental disorder, the severity of which is frequently assessed via interview-based clinical scales such as the 7-item Hamilton Depression Rating Scale (HAMD-7). The current study aimed to translate and examine the validity of an Arabic version of the HAMD-7 scale. METHODS: This study took place between February and March 2016 in the Psychiatry Department of King Saud University, Riyadh, Saudi Arabia. The HAMD-7 scale was translated into Arabic using forward and backward translation methods. A total of 153 Arabic speakers were recruited to test the translated scale, including 57 medical students and 96 members of the general public. The Arabic version of the HAMD-7 scale was completed by trained investigators during face-to-face interviews with the participants. In order to assess convergent validity, participants also completed an Arabic version of the self-assessed Patient Health Questionnaire-9 (PHQ-9) scale. Subsequently, the test-retest reliability of the translated HAMD-7 scale was evaluated two weeks later during a second interview. RESULTS: Overall, HAMD-7 scores were positively correlated with PHQ-9 scores (r = 0.633-0.749). Moreover, the translated HAMD-7 scale proved to be reliable in terms of test-retest reliability (intra-class correlation coefficient: 0.807; P <0.001). With regards to internal consistency, the Cronbach's α values ranged between 0.607-0.756. CONCLUSION: The Arabic HAMD-7 scale was found to be reliable and valid among two samples of Arabic speakers in Saudi Arabia. However, further research among Arab-speaking patients diagnosed with depression is needed in order to establish its usefulness in assessing the severity of depressive symptoms.

A medication assessment tool to evaluate prescribers' adherence to evidence-based guidelines in bipolar disorder.

Background The goal of evidence-based clinical practice has led to an increased interest in the development of tools to measure adherence to national guidelines in different diseases. This aids in detecting and measuring inappropriate prescribing to specific patient groups by using quality standards extracted from evidence-based guidelines, and ultimately provide the basis of consistent standardized prescribing. Objective To design and validate a medication assessment tool to assess prescribers' adherence to international guideline recommendations in the management of bipolar disorder (MATBD). Setting Outpatient psychiatry clinic at a secondary healthcare setting in Kuwait. Method International guidelines concerned with the management of bipolar disorder were reviewed in order to develop MATBD. Face and content validity of the developed tool (MATBD) was performed with a research and expert group. A 4-point Likert scale was used to assess the expert group's level of agreement to individual criterion. Content validity ratio (CVR) was calculated for each criterion (n = 54) and the content validity index (CVI) was calculated for each section (n = 5) of the MATBD. Finally, feasibility testing was performed on 19 patient records to confirm the tool's fitness for purpose. Main Outcomes Measure Perceived relevance, utility, and clarity of individual criteria, and reliability of their application to clinical settings. Results Face validity and content validity were achieved with a research and expert group (n = 14). Content validity ratio (CVR) was demonstrated for 54 criteria; criteria with a negative CVR were removed. This resulted in a draft MATBD comprising of 52 criteria (CVI: 0.814). Feasibility testing on 19 patients' records resulted in a final MATBD comprising of 49 criteria divided into 3 sections: initial assessment, acute management and monitoring. Conclusion A medication assessment tool was developed and validated to be used as a means of profiling potential opportunities for medication therapy management optimization, and improving therapeutic interventions regarding the management of bipolar disorder.

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.

The prevalence and clinical characteristics associated with Diagnostic and Statistical Manual Version-5-defined anxious distress specifier in adults with major depressive disorder: results from the International Mood Disorders Collaborative Project.

OBJECTIVES: The aim of the study was to evaluate the prevalence of and illness characteristics in adults with major depressive disorder (MDD) with anxious distress specifier (ADS) enrolled in the International Mood Disorders Collaborative Project, which is a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto, Canada and the Cleveland Clinic, Cleveland, Ohio, USA. METHODS: Data from participants who met criteria for a current major depressive episode as part of MDD (n = 830) were included in this post hoc analysis. Diagnostic and Statistical Manual Version-5-defined ADS was operationalized as the presence of at least two out of three proxy items instead of two out of five specifiers. RESULTS: A total of 464 individuals (i.e. 56%) met criteria for ADS. There were no between-group differences in sociodemographic variables (e.g. gender, employment, marital status). Greater severity of illness was observed in adults with ADS as evidenced by a higher number of hospitalizations, higher rates of suicidal ideation, greater depressive symptom severity, greater workplace impairment, decreased quality of life, and greater self-reported cognitive impairment. CONCLUSIONS: Our findings underscore the importance of evaluating ADS in adults with MDD as its presence identifies a subpopulation with greater illness-associated burden and hazards.

Binge eating in adults with mood disorders: Results from the International Mood Disorders Collaborative Project.

A post hoc analysis was conducted using data from participants (N=631) with a DSM-IV-TR defined diagnosis of major depressive disorder (MDD) or bipolar disorder (BD) who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. It was determined that 20.6% of adults with mood disorders as part of the IMDCP fulfilled criteria for binge eating behaviour (BE). A higher percentage of individuals with BD met criteria for BE when compared to MDD (25.4% vs. 16%; p=0.004) Univariate analyses indicated that individuals with a mood disorder (i.e., MDD or BD) and BE had greater scores on measures of anxiety severity (p=0.013) and higher rates of lifetime and current substance dependence, lifetime alcohol abuse (p=0.007, p=0.006, and p=0.015, respectively), Attention Deficit Hyperactivity Disorder (ADHD) (p=0.018) and measures of neuroticism (p=0.019). Individuals with a mood disorder and concurrent BE had lower scores on measures of conscientiousness (p=0.019). Individuals meeting criteria for BE were also significantly more likely to be obese (i.e., BMI≥30kg/m2) (50% vs. 25.5%; p<0.001). Binge eating is common amongst adults utilising tertiary care services principally for a mood disorder. The presence of BE identifies a subset of adults with mood disorders who have greater illness complexity as evidenced by course of illness variables and comorbidity. Screening for BE amongst individuals with mood disorders is warranted; parsing neurobiological substrates subserving non-homeostatic eating behaviour amongst individuals with mood disorders is a future research vista.

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.

The impact of cognitive impairment on perceived workforce performance: results from the International Mood Disorders Collaborative Project.

BACKGROUND: Cognitive dysfunction and depression severity are key mediators of workplace adjustment in adults with major depressive disorder (MDD). Herein, we sought to determine the extent to which measures of depression severity and cognitive dysfunction were associated with perceived global disability, workplace performance and quality of life. METHOD: A post hoc analysis was conducted using data from 260 participants with a diagnosis of DSM-IV-TR-defined MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. Measures of workplace function, global disability, depression severity, cognitive function, and quality of life were employed. These data were analyzed using a multiple variable linear regression equations. RESULTS: Perceived global disability was significantly predicted by clinical ratings of depression severity (ß=0.54), and perceived inattention (ß=0.24), accounting for 37% of the variance. In addition, perceived inattention (ß=0.58) and clinical ratings of depression severity (ß=0.18), were also significant predictors of perceived workplace productivity/performance, accounting for 38% of the variance. Finally, both clinical ratings of depression severity (ß=-0.54), and perceived inattention (ß=-0.18) were significant inverse predictors of perceived quality of life, accounting for 34% of the variance. CONCLUSION: The overarching finding in the analysis herein is that workplace performance variability is explained by subjective measures of cognitive dysfunction to a greater extent than total depression symptom severity. Conversely, total depression symptom severity accounts for a greater degree of variability in global measures of disability relative to cognitive measures. Treatment strategies for adults with major depressive disorder should address issues of cognitive dysfunction to improve workforce participation and performance.

The prevalence and illness characteristics of DSM-5-defined "mixed feature specifier" in adults with major depressive disorder and bipolar disorder: Results from the International Mood Disorders Collaborative Project.

BACKGROUND: A substantial proportion of individuals with mood disorders present with sub-syndromal hypo/manic features. The objective of this analysis was to evaluate the prevalence and illness characteristics of the Diagnostic and Statistical Manual Version-5 (DSM-5) - defined mixed features specifier (MFS) in adults with major depressive disorder (MDD) and bipolar disorder (BD). METHOD: Data from participants who met criteria for a current mood episode as part of MDD (n=506) or BD (BD-I: n=216, BD-II: n=130) were included in this post-hoc analysis. All participants were enrolled in the International Mood Disorders Collaborative Project (IMDCP): a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto and the Cleveland Clinic, Cleveland, Ohio. Mixed features specifier was operationalized as a score ≥ 1 on 3 or more select items on the Young Mania Rating Scale (YMRS) or ≥ 1 on 3 select items of the Montgomery Åsberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale (HAMD-17) during an index major depressive episode (MDE) or hypo/manic episode, respectively. RESULTS: A total of 26.0% (n=149), 34.0% (n=65), and 33.8% (n=49) of individuals met criteria for MFS during an index MDE as part of MDD, BD-I and BD-II, respectively. Mixed features specifier during a hypo/manic episode was identified in 20.4% (n=52) and 5.1% (n=8) in BD-I and BD-II participants, respectively. Individuals with MDE-MFS as part of BD or MDD exhibited a more severe depressive phenotype (p=0.0002 and p<0.0002, respectively) and reported a higher rate of alcohol/substance use disorder in the context of BD but not MDD (p=0.002). Individuals with MFS were more likely to have co-existing heart disease suggestive of a distinct pattern of comorbidity and neurobiology. LIMITATIONS: Data were post-hoc and obtained from individuals utilizing a university-based mood disorder centre which may affect generalizability. CONCLUSIONS: Diagnostic and Statistical Manual Version-5-defined MFS is common during an MDE as part of MDD and BD. The presence of MFS identifies a subgroup of individuals with greater illness complexity and possibly a higher rate of cardiovascular comorbidity. The results herein underscore the common occurrence of MFS in adults with either BD or MDD. Moreover, the results of our analysis indicate that adults with mood disorders and MFS have distinct clinical characteristics and comorbidity patterns.

The putative impact of metabolic health on default mode network activity and functional connectivity in neuropsychiatric disorders.

The default mode network (DMN) describes a distributed network of brain regions that are predominantly activated and engaged during periods of spontaneous, stimulus independent thought (i.e., at rest) and remain quiescent during attention-demanding, goal-directed tasks. Replicated evidence in functional neuroimaging studies suggests that midline cortical and subcortical brain regions responsible for memory, self-relevant emotional and mental processes, as well as information integration comprise the DMN. The DMN is posited to represent self-referential mental activity via a dynamic interplay of cognitive and emotional processes by integrating information from the external environment with introspective thoughts to generate an autobiographical concept of the self. It has been amply documented that irregularities in the DMN and its functional connectivity are associated with various neuropsychiatric disorders. Moreover, accumulating evidence also suggests that individuals with select medical disorders (i.e., metabolic disorders) demonstrate alterations in DMN activity and functional connectivity. However, there is a paucity of data evaluating whether individuals with metabolically-based medical conditions, exhibiting altered DMN activity and functional connectivity, are at increased risk for developing neuropsychiatric disorders. Likewise, potential mechanisms (e.g., altered brain metabolism, insulin resistance) mediating these changes and their implications for novel treatment approaches have yet to be elucidated. Taken together, the overarching aim of this review is to provide a synthetic overview that suggests that this neural circuit may represent a common (or convergent) substrate affected in individuals with select neuropsychiatric and metabolic disorders.

"Integrating Kuwait's mental health system to end stigma: a call to action".

Despite the global prevalence of mental illness and its negative effects on the economy in terms of healthcare spending, many affected individuals do not receive timely or adequate treatment due to stigmatization of such disorders in their communities. Being labeled as mentally ill can have detrimental consequences in several cultures. In Kuwait, the stigma associated with visiting the country's main provider of mental health services, the Psychological Medicine Hospital, is an obstacle for many seeking professional help for mental health. Cultural acceptance of visiting the local primary care clinic, however, allows frequent contact with primary care physicians who often find themselves frustrated at their inability to provide psychiatric services because it is not part of their training. The refusal of the patient to be referred to a stigmatized institution further increases the challenges of treating such patients for these physicians. The integration of mental health care into general health services is a concept encouraged by the World Health Organization's 2001 World Health Report and should be considered in order to overcome this dilemma. Such integrated care would serve as a cost-effective solution to facilitating the treatment of these individuals and reducing the stigma associated with mental disorders through education.

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 mental health needs of immigrant workers in Gulf countries.

The oil-rich member states of the Gulf Cooperation Council (GCC) attract large numbers of migrant workers. The reported rates of psychiatric morbidity among these migrant workers are higher than among nationals, while the mental health services in the GCC countries remain inadequate in terms of both staff and service delivery. The multi-ethnic origin of migrants poses considerable challenges in this respect. The development of mental illness in migrants, especially when many of them remain untreated or inadequately treated, results in their premature repatriation, and the mentally ill migrant ends up facing the same economic hardships which led to migration in the first place. The availability of trained interpreters and transcultural psychiatrists, psychologists and social workers should make psychiatric diagnoses more accurate. Suitable rehabilitation services are also needed.

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 effect of personality dimensions on functional outcomes in mood disorders.

INTRODUCTION: Functional impairment associated with mood disorders may be related to a characteristic "profile" of normative personality dimensions. METHODS: Individuals (age ≥ 18 years) with MDD (n = 400) or BD (n = 317), as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR), were enrolled in the IMDCP. Personality was evaluated with the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI), and functionality with the Sheehan Disability Scale and Endicott Work Productivity Scale. Path analysis using linear multiple regressions was performed to identify direct and indirect effects of personality on functional impairment. RESULTS: Lower conscientiousness exerted a significant direct effect on global (p = 0.017) and family life dysfunction in individuals with MDD (p = 0.002), as well as lower work productivity in both MDD (p = 0.020) and BD (p = 0.018). Lower extraversion exerted a significant direct effect on social impairment in individuals with BD (p = 0.017). Higher neuroticism and agreeableness as well as lower extraversion exerted indirect effects on global and social dysfunction in individuals with MDD via their effects on depression severity. In BD, higher neuroticism and openness indirectly affected global dysfunction. Family dysfunction was indirectly affected by higher neuroticism and openness as well as lower extraversion in MDD and BD. CONCLUSION: The results suggest that discrete personality dimensions may exert direct and indirect effects on functional outcomes in individuals with mood disorders. Personalizing disease management approaches in mood disorders with emphasis on vocational rehabilitation may benefit from measurement and intervention targeting personality.

Obesity and mental illness: implications for cognitive functioning.

A priority research and clinical agenda is to identify determinants of cognitive impairment in individuals with neuropsychiatric disorders (NPD). The bidirectional association between NPD and cognitive performance has been reported to be mediated and/or moderated by obesity in a subset of individuals. Obesity can be conceptualized as a neurotoxic phenotype among individuals with NPD as evidenced by alterations in the structure and function of neural circuits and disseminated networks, diminished cognitive performance, and adverse effects on illness trajectory. The neurotoxic effect of obesity provides a rationale for screening, treating, and preventing obesity in neuropsychiatric populations. Research endeavors that aim to refine mediators and moderators of this association as well as novel strategies to reverse the injurious process of obesity on cognition are warranted.

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.