Laura Ashley Gallaugher

COGNITIVE DEFICITS AND FUNCTIONAL OUTCOMES IN MAJOR DEPRESSIVE DISORDER: DETERMINANTS, SUBSTRATES, AND TREATMENT INTERVENTIONS

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.

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.

Depression and Employment Status in Primary and Tertiary Care Settings

Objective: Major depressive disorder (MDD) is a leading cause of disability. Impairment in work function considerably adds to symptom burden and increases the economic impact of this disorder. Our study aimed to investigate the factors associated with work status in MDD within primary and tertiary care. Method: We used data from 2 large databases for our analysis—Study 1: the InSight database, a chart review of MDD patients treated by primary care physicians across Canada (n = 986); and Study 2: the International Mood Disorders Collaborative Project, a cross-sectional study of mood disorder patients (Canadian data only: n = 274). Results: Both studies demonstrated high rates of unemployment and disability (30.3% to 42.1%). Quebec showed the highest rate of unemployment (21%) and British Columbia had the greatest percentage of patients on disability (15%). Employed and unemployed groups were similar based on clinical characteristics; however, unemployed people may have higher age, prevalence of medical comorbidity, and greater likelihood of receiving a benzodiazepine. Increased disability rates were associated with history of childhood abuse, duration of current major depressive episode, comorbidity, benzodiazepine use, as well as greater depression and anxiety severity. The unemployed–disability groups had greater somatic symptoms and anhedonia. In keeping with this, anhedonia was the strongest predictor of disability. Absenteeism was also high across both studies. Conclusions: Unemployment and disability rates in MDD are high. The presence of anhedonia and medical comorbidity significantly influenced work status, emphasizing the need for treatment strategies to alleviate the additional symptom burden in this subpopulation.

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

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.

A randomized, double-blind, placebo-controlled, crossover trial evaluating the effect of intranasal insulin on cognition and mood in individuals with treatment-resistant major depressive disorder.

BACKGROUND Cognitive dysfunction in major depressive disorder (MDD) is identified as a primary therapeutic target; no current treatment is approved for the treatment of cognitive dysfunction in MDD. We examined whether intranasal insulin offered a beneficial effect across measures of cognitive function in adults with MDD. METHODS Thirty-five adults (18-65 years of age: 47.09±9.89) meeting criteria for a major depressive episode as per the Diagnostic and Statistical Manual (DSM)-IV-Treatment Revised were included in this randomized, double blind, placebo-controlled, crossover design study. Subjects were not stratified based on baseline cognitive deficit. Subjects were randomized to 4 weeks of either intranasal insulin 40 International Units (IU) taken four times a day (i.e., morning, afternoon, evening, and before bed) (QID) (n=19) or placebo (n=16). RESULTS No between group differences were observed in change from baseline on total Montgomery Åsberg Depression Rating Scale (MADRS) score (25.98±2.81), in either of the Positive or Negative subscales of the Positive and Negative Affect Schedule (PANAS), or on a global index of neurocognition. The possibility of practice and/or carry over effect could not be excluded. Methodological refinement (e.g., stratification of subjects based on baseline cognitive deficit) may have augmented assay sensitivity. CONCLUSION Intranasal insulin did not demonstrate statistically significant improvements on overall mood, aspects of emotional processing, neurocognitive function, or self-reported quality of life patient reported outcomes.

Admixture analysis of age at onset in major depressive disorder

OBJECTIVES This study aimed to determine the distributions of the age at onset (AAO) in patients with major depressive disorder (MDD) using admixture analysis and to determine the clinical differences between subgroups with different AAO. METHODS Participants were administered the Mini-International Neuropsychiatric Interview to obtain clinical data. Admixture analysis was performed using the STATA module DENORMIX to identify subgroups characterized by differences in AAO. RESULTS The best fit model was the three-component model with the following means, standard deviations and proportions: 14.60 (3.75) years (49.1%), 29.15 (6.75) years (34.1%) and 46.96 (6.06) years (16.8%) (χ(2)=3.64, 2 df, P=.162). The three subgroups were divided by AAO of 22 and 40. After controlling for duration of illness, there were no significant differences between the three AAO subgroups in terms of gender and psychiatric family history. However, the early-onset subgroup was significantly more likely to report being single compared to the intermediate- and late-onset groups. The proportion of individuals meeting criteria for lifetime comorbid panic disorders and obsessive-compulsive disorder did not differ significantly between the AAO groups. However, the early-onset group reported a higher incidence of attention-deficit/hyperactivity disorder (5.1% vs. 1.7% and 1.2%, P=.086), although this was not statistically significant. CONCLUSIONS Our study identified three characteristically different AAO subgroups in individuals suffering from MDD. The subgroups may reflect different underlying neurobiological mechanisms involved.

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.

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.

Correlates of benzodiazepine use in major depressive disorder: The effect of anhedonia

BACKGROUND Current treatment guidelines emphasize the limited role of benzodiazepines in Major Depressive Disorder (MDD), mainly due to the absence of long-term data, risk of abuse and potential adverse effects. However, benzodiazepines continue to be prescribed for long-term use in a significant number of patients. This study sought to evaluate benzodiazepine use in a large sample of MDD patients seen at a tertiary care clinic, and determine whether use is related to illness severity or complexity, as well as to identify the clinical predictors of benzodiazepine use. METHODS This was a naturalistic cross-sectional study conducted in MDD patients seen at the Mood Disorders Pyschopharmacology Unit at the University Health Network (N=326). Detailed information on current medication regimens was collected. A structured diagnostic interview, in addition to measures of symptom severity, quality of life, and personality were administered. Participants were grouped according to the presence or absence of prescribed benzodiazepines for daily use. RESULTS The prevalence of regular benzodiazepine use was 25%. Benzodiazepine users were more likely to be female, unemployed, have a history of child abuse, and have comorbid panic disorder. Depression and anxiety scores were not significantly different between groups, although anhedonia was greater in the benzodiazepine group. A logistic regression revealed anhedonia was the strongest predictor of regular benzodiazepine use. CONCLUSION The groups were similar in clinical profile suggesting benzodiazepine use is not necessarily linked to greater illness complexity or severity. Benzodiazepine use appears to be associated with specific diagnostic and symptom characteristics, possibly providing insight into the potential pharmacodynamic and neurobiological effects of frequent use.

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.