Hanna O. Woldeyohannes

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.

Bipolar disorder and metabolic syndrome: an international perspective.

INTRODUCTION The ubiquity and hazards posed by abnormal body composition and metabolic parameters in the bipolar population are a priority research and clinical issue. Herein, we summarize and synthesize international studies describing the rate of US National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III])- and International Diabetes Federation (IDF)-defined metabolic syndrome and its criterion components in individuals with bipolar disorder. METHODS We conducted a PubMed search of all English-language articles published between January 2005 and July 2009 with the following search terms: metabolic syndrome and bipolar disorder, mania and manic-depression. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. RESULTS The rate of metabolic syndrome in individuals with bipolar disorder is increased relative to the general population. Disparate estimates are reported ranging from comparability to approximately twofold greater than the general population. The increased hazard for metabolic syndrome amongst bipolar individuals is now documented in twelve countries from Europe, Australia, Asia, North and South America. The co-occurrence of metabolic syndrome in the bipolar population is associated with a more complex illness presentation, less favourable response to treatment, and adverse course and outcome. The association between metabolic syndrome and bipolar disorder is mediated/moderated by both iatrogenic and non-iatrogenic factors. DISCUSSION The increased hazard for metabolic syndrome in bipolar populations is due to the clustering of traditional (and emerging) risk factors as well as iatrogenic and health systems factors. Extant data support recommendations for prioritizing, surveillance, prevention, diagnosis and management of metabolic syndrome as routine care of the bipolar patient.

Medical comorbidity in bipolar disorder: reprioritizing unmet needs

Purpose of review The aim of this review is to synthesize results from extant investigations which report on the co-occurrence of bipolar disorder and medical comorbidity. Recent findings We conducted a MEDLINE search of all English-language articles published between January 2004 and November 2006. Most studies report on medical comorbidity in bipolar samples; relatively fewer studies report the reciprocal association. Individuals with bipolar disorder are differentially affected by several ‘stress-sensitive’ medical disorders notably circulatory disorders, obesity and diabetes mellitus. Neurological disorders (e.g. migraine), respiratory disorders and infectious diseases are also prevalent. Although relatively few studies have scrutinized the co-occurrence of bipolar disorder in medical settings, individuals with epilepsy, multiple sclerosis, migraine and circulatory disorders may have a higher prevalence of bipolar disorder. A clustering of traditional and emerging (e.g. immunoinflammatory activation) risk factors presage somatic health issues in the bipolar disorder population. Iatrogenic factors and insufficient access to primary, preventive and integrated healthcare systems are also contributory. Summary Somatic health issues in individuals with bipolar disorder are ubiquitous, under-recognized and suboptimally treated. Facile screening for risk factors and laboratory abnormalities along with behavioral modification for reducing medical comorbidity are warranted.

Mood Disorders and Obesity: Understanding Inflammation as a Pathophysiological Nexus

The aim of this review is to evaluate the evidentiary base supporting the hypothesis that the increased hazard for obesity in mood disorder populations (and vice versa) is a consequence of shared pathophysiological pathways. We conducted a PubMed search of all English-language articles with the following search terms: obesity, inflammation, hypothalamic-pituitary-adrenal axis, insulin, cognition, CNS, and neurotransmitters, cross-referenced with major depressive disorder and bipolar disorder. The frequent co-occurrence of mood disorders and obesity may be characterized by interconnected pathophysiology. Both conditions are marked by structural and functional abnormalities in multiple cortical and subcortical brain regions that subserve cognitive and/or affective processing. Abnormalities in several interacting biological networks (e.g. immuno-inflammatory, insulin signaling, and counterregulatory hormones) contribute to the co-occurence of mood disorders and obesity. Unequivocal evidence now indicates that obesity and mood disorders are chronic low-grade pro-inflammatory states that result in a gradual accumulation of allostatic load. Abnormalities in key effector proteins of the pro-inflammatory cascade include, but are not limited to, cytokines/adipokines such as adiponectin, leptin, and resistin as well as tumor necrosis factor alpha and interleukin-6. Taken together, the bidirectional relationship between obesity and mood disorders may represent an exophenotypic manifestation of aberrant neural and inflammatory networks. The clinical implications of these observations are that, practitioners should screen individuals with obesity for the presence of clinically significant depressive symptoms (and vice versa). This clinical recommendation is amplified in individuals presenting with biochemical indicators of insulin resistance and other concurrent conditions associated with abnormal inflammatory signaling (e.g. cardiovascular disease).

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.

The effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder

BACKGROUND Persistent impairment in cognitive function has been described in euthymic individuals with bipolar disorder. Collective work indicates that obesity is associated with reduced cognitive function in otherwise healthy individuals. This sub-group post-hoc analysis preliminarily explores and examines the association between overweight/obesity and cognitive function in euthymic individuals with bipolar disorder. METHODS Euthymic adults with DSM-IV-TR-defined bipolar I or II disorder were enrolled. Subjects included in this post-hoc analysis (n=67) were divided into two groups (normal weight, body mass index [BMI] of 18.5-24.9 kg/m2; overweight/obese, BMI ≥ 25.0 kg/m2). Demographic and clinical information were obtained at screening. At baseline, study participants completed a comprehensive cognitive battery to assess premorbid IQ, verbal learning and memory, attention and psychomotor processing speed, executive function, general intellectual abilities, recollection and habit memory, as well as self-perceptions of cognitive failures. RESULTS BMI was negatively correlated with attention and psychomotor processing speed as measured by the Digit Symbol Substitution Test (P<0.01). Overweight and obese bipolar individuals had a significantly lower score on the verbal fluency test when compared to normal weight subjects (P<0.05). For all other measures of cognitive function, non-significant trends suggesting a negative association with BMI were observed, with the exception of measures of executive function (i.e., trail making test B) and recollection memory (i.e., process-dissociation task). CONCLUSION Notwithstanding the post-hoc methodology and relatively small sample size, the results of this study suggest a possible negative effect of overweight/obesity on cognitive function in euthymic individuals with bipolar disorder. Taken together, these data provide the impetus for more rigorous evaluation of the mediational role of overweight/obesity (and other medical co-morbidity) on cognitive function in psychiatric populations.

The Association between Conventional Antidepressants and the Metabolic Syndrome A Review of the Evidence and Clinical Implications

Major depressive disorder is a prevalent recurrent medical syndrome associated with inter-episodic dysfunction. The metabolic syndrome is comprised of several established risk factors for cardiovascular disease (i.e. abdominal obesity, dyslipidaemia, dysglycaemia and hypertension). The criterion items of the metabolic syndrome collectively represent a multi-dimensional risk factor for cardiovascular disease and type 2 diabetes mellitus. Extant evidence indicates that both major depressive disorder and the metabolic syndrome, albeit distinct, often co-occur and are possibly subserved by overlapping pathophysiology and causative mechanisms. Conventional antidepressants exert variable effects on constituent elements of the metabolic syndrome, inviting the need for careful consideration prior to treatment selection and sequencing. Initiating and maintaining antidepressant therapy should include routine surveillance for clinical and/or biochemical evidence suggestive of the metabolic syndrome.

A preclinical and clinical rationale for quetiapine in mood syndromes

The main objective of this review is to discuss results from preclinical studies that aim to elucidate the putative mechanistic basis of the antidepressant action of quetiapine. Results from pivotal, randomized clinical trials in bipolar depression are also briefly reviewed. The authors conducted a PubMed search of all English-language articles published between January 1990 and December 2006. The key search term was quetiapine paired with: serotonin, dopamine, noradrenaline, glutamate, γ-aminobutyric acid, signal transduction, neurogenesis, oxidative stress, glucocorticoid, antidepressant, major depressive disorder, bipolar disorder and randomized controlled trial. The search was augmented with a manual review of relevant article reference lists. Articles selected for review were based on author consensus, adequacy of sample size, the use of standardized experimental procedures, validated assessment measures and overall manuscript quality. Quetiapine enhances central serotonergic neurotransmission via its high affinity for serotonergic receptors (e.g., 5-HT2A receptor antagonism and partial agonistic activity at the 5-HT1A receptor). Activation of the 5HT1A receptor results in an increase in prefrontal cortex dopaminergic neurotransmission. Affinity for the α2-adrenoceptor mediates a relative increase in extracellular noradrenergic release in the prefrontal cortex. Emerging evidence indicates that quetiapines principal, active, human plasma metabolite, N-desalkyl quetiapine, has high affinity for, and is a potent inhibitor of, the noradrenergic transporter. This latter finding is a point of commonality with other conventional antidepressant agents and may differentiate quetiapine from other atypical antipsychotics. Activity at other intracellular targets (e.g., signal transduction pathways and nerve growth transcription factors), neurotransmitters, inflammatory and oxidative stress networks, and endocrine systems may also mediate the antidepressant effects of quetiapine. The in vitro pharmacodynamic profile of quetiapine is predictive of antidepressant activity in mood syndromes. Available clinical evidence has established quetiapine as an effective monotherapy in bipolar depression.

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., Alzheimers Disease, Huntingtons and Parkinsons 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 (Aβ) 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.

Attention-Deficit/Hyperactivity Disorder in Adults With Bipolar Disorder or Major Depressive Disorder: Results From the International Mood Disorders Collaborative Project

OBJECTIVE Relatively few studies have evaluated the clinical implications of lifetime attention-deficit/hyperactivity disorder (ADHD) in adults with bipolar disorder or major depressive disorder (MDD). Herein, we sought to determine the prevalence as well as the demographic and clinical correlates of lifetime ADHD in persons with a mood disorder. METHOD The first 399 patients enrolled in the International Mood Disorders Collaborative Project (IMDCP) were evaluated for lifetime ADHD using the Mini-International Neuropsychiatric Interview-Plus (MINI-Plus) as the primary instrument to derive current and lifetime DSM-IV diagnoses. All analyses of variables of interest were conducted utilizing the MINI-Plus, the Adult ADHD Self-Report Scale-v1.1, and the Wender Utah Rating Scale-Short Form. The effect of ADHD on clinical presentation, course of illness variables, comorbidity, anamnesis, treatment, and outcome are reported. The IMDCP is a joint initiative of the Mood Disorders Psychopharmacology Unit at the University Health Network, University of Toronto, Toronto, Ontario, Canada, and the Cleveland Clinic Center for Mood Disorders Treatment and Research at Lutheran Hospital, Cleveland, Ohio. All data for this study were procured between January 2008 and January 2009. RESULTS The percentages of subjects with MDD or bipolar disorder meeting the DSM-IV criteria for lifetime adult ADHD were 5.4% and 17.6% (P < .001), respectively. Lifetime comorbid ADHD in both mood disorder populations was associated with earlier age at illness onset (MDD, P = .049; bipolar disorder, P = .005), a higher number of psychiatric comorbidities (eg, MDD and current panic disorder with agoraphobia [P = .002]; bipolar disorder and social phobia [P = .012]), and decreased quality of life (MDD, P = .018). CONCLUSIONS The overarching findings herein are that the adult ADHD phenotype is commonly reported by individuals with MDD or bipolar disorder and is associated with a greater illness burden and complexity.