Jakub Z. Konarski

Differences in Brain Glucose Metabolism Between Responders to CBT and Venlafaxine in a 16-Week Randomized Controlled Trial

OBJECTIVE Neuroimaging investigations reveal changes in glucose metabolism (fluorine-18-fluorodeoxyglucose positron emission tomography [PET]) associated with response to disparate antidepressant treatment modalities, including cognitive behavior therapy (CBT), antidepressant pharmacotherapies, and deep brain stimulation. Using a nonrandomized design, the authors previously compared changes following CBT or paroxetine in depressed patients. In this study, the authors report changes in fluorine-18-fluorodeoxyglucose PET in responders to CBT or venlafaxine during a randomized controlled trial. METHODS Subjects meeting DSM-IV-TR criteria for a major depressive episode and a diagnosis of a major depressive disorder received a fluorine-18-fluorodeoxyglucose PET scan before randomization and after 16 weeks of antidepressant treatment with either CBT (N=12) or venlafaxine (N=12). Modality-specific and modality-independent regional brain metabolic changes associated with response status were analyzed. RESULTS Response rates were comparable between the CBT (7/12) and venlafaxine (9/12) groups. Response to either treatment modality was associated with decreased glucose metabolism bilaterally in the orbitofrontal cortex and left medial prefrontal cortex, along with increased metabolism in the right occipital-temporal cortex. Changes in metabolism in the anterior and posterior parts of the subgenual cingulate cortex and the caudate differentiated CBT and venlafaxine responders. CONCLUSIONS Responders to either treatment modality demonstrated reduced metabolism in several prefrontal regions. Consistent with earlier reports, response to CBT was associated with a reciprocal modulation of cortical-limbic connectivity, while venlafaxine engaged additional cortical and striatal regions previously unreported in neuroimaging investigations.

Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder

BACKGROUND As patients with mood disorders manifest heterogeneity in phenomenology, pathophysiology, etiology, and treatment response, a biological classification of mental disease is urgently needed to advance research. Patient and methodological variability complicates the comparison of neuroimaging study results and limits heuristic model development and a biologically-based diagnostic schema. OBJECTIVE We have critically reviewed and compared the magnetic resonance neuroimaging literature to determine the degree and directionality of volumetric changes in brain regions putatively implicated in the pathophysiology of major depressive disorder (MDD) versus bipolar disorder (BD). METHODS A total of 140 published magnetic resonance imaging investigations evaluating subjects with BD or MDD were selected to provide a summary and interpretation of volumetric neuroimaging results in MDD and BD. Further commentary on the pathophysiological implications, and putative cellular and pharmacological mechanisms, is also provided. RESULTS While whole brain volumes of patients with mood disorders do not differ from those of healthy controls, regional deficits in the frontal lobe, particularly in the anterior cingulate and the orbitofrontal cortex, appear to consistently differentiate subjects with mood disorders from the general population. Preliminary findings also suggest that subcortical structures, particularly the striatum, amygdala, and hippocampus, may be differentially affected in MDD and BD. CONCLUSIONS Structural neuroimaging studies have consistently identified regional abnormalities in subjects with mood disorders. Future studies should strive to definitively establish the influence of age and medication.

Bipolar disorder and diabetes mellitus: epidemiology, etiology, and treatment implications

INTRODUCTION Bipolar disorder (BD) is a highly prevalent and disabling condition with significant mortality risk from suicide and other unnatural causes. This ignominious description is alongside recent observations that the majority of excess deaths in BD are secondary to medical comorbidity. The medical burden in BD is associated with a clustering of risk factors (e.g., obesity, smoking, unhealthy dietary habits) and inadequate utilization of preventative and primary healthcare. Diabetes mellitus (DM) is also a prevalent multifactorial disease which imparts substantial illness burden. Preliminary investigations indicate that patients who suffer from BD with comorbid DM have a more severe course and outcome, lower quality of life, higher prevalence of medical comorbidity and higher cost of illness. METHODS We conducted a MedLine search of all English-language articles 1966-2004 using the key words: bipolar disorder, major depressive disorder, diabetes mellitus, glucose metabolism, mortality, overweight, obesity, body mass index. The search was supplemented with manual review of relevant references. Priority was given to randomized controlled data, when unavailable; studies of sufficient sample size are presented. RESULTS Subpopulations of BD patients should be considered at high risk for DM. The prevalence of DM in BD may be three times greater than in the general population. CONCLUSIONS Bipolar disorder populations may be an at-risk group for glucose metabolic abnormalities. Opportunistic screening and vigilance for clinical presentations suggestive of DM is encouraged.

The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms

Objective: To synthesise results from investigations reporting on the effect of antidepressants on glucose–insulin homeostasis. Method: The authors conducted a MedLine search of all English language articles from 1966 to October 2005 using the keywords: bipolar disorder, major depressive disorder, diabetes mellitus, glucose homeostasis, and the name of each antidepressant that has been indicated for major depression in Canada and the US up to October 2005. The search was supplemented with a manual review of relevant references. Both preclinical and clinical investigations were reviewed. Results: Some serotonergic antidepressants (e.g., fluoxetine) reduce hyperglycaemia, normalise glucose homeostasis and increase insulin sensitivity, whereas some noradrenergic antidepressants (e.g., desipramine) exert opposite effects. Dual-mechanism antidepressants (e.g., duloxetine and venlafaxine) do not appear to disrupt glucose homeostatic dynamics, whereas nonselective hydrazine monoamine oxidase inhibitors (e.g., phenelzine) are associated with hypoglycaemia and an increased glucose disposal rate. Conclusion: Some antidepressants exert a clinically significant effect on metabolism relevant to both therapeutic outcome and adverse events.

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.

The prevalence and impact of migraine headache in bipolar disorder: results from the Canadian Community Health Survey.

Objective.—To report on the prevalence of comorbid migraine in bipolar disorder and the implications for bipolar age of onset, psychiatric comorbidity, illness course, functional outcome, and medical service utilization.

Calculated bioavailable testosterone levels and depression in middle-aged men

BACKGROUND The association between circulating total testosterone (TT) levels and depressive symptoms remains unclear. We sought to determine the relationship between physiologically active bioavailable testosterone (BT) and depressive symptoms in middle-aged men with and without major depressive disorder (MDD). METHODS We assessed and compared calculated BT levels in two groups of middle-aged men (40-65 years): untreated subjects meeting DSM-IV-TR-defined criteria for a major depressive episode as part of major depressive disorder (N=44) and a matched non-depressed control group (N=50). RESULTS Depressed men had lower mean BT levels (3.51+/-1.69 vs. 4.69+/-2.04 nmol/L; p=0.008) and TT levels (11.94+/-4.63 vs. 17.64+/-1.02 nmol/L; p<0.001) when compared to the control group. Biochemical hypogonadism (i.e., BT level< or =2.4 nmol/L or TT level< or =12.14 nmol/L) was also more prevalent in depressed men vs. non-depressed controls (34% vs. 6%, p<0.001; 61% vs. 14%, p<0.001, respectively). CONCLUSIONS Changes in physiologically active BT concentration may be a vulnerability factor for depressive symptoms in middle-aged depressed men.

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 (χ2 = 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.

The effect of antidepressants on lipid homeostasis: a cardiac safety concern?

Objective: The authors sought to summarise and synthesise results from investigations which report on the effect of antidepressants on serum lipid homeostasis. Method: The authors conducted a MedLine search of all English-language articles from 1966 to March 2006 using the search terms: major depressive disorder, bipolar disorder, lipids, triglycerides, cholesterol, low-density lipoprotein, high-density lipoprotein, and the non-proprietary names of conventional antidepressants indicated for the treatment of major depressive disorder in North America as of March 2006. The search was supplemented with a manual review of retrieved articles for any further citations reporting the effects of antidepressants on lipid homeostasis. Results: Despite the paucity of well-characterised investigations, the unfavourable effect of weight gain promoting antidepressants (e.g., tricyclics, mirtazapine) on serum lipid parameters (i.e., triglycerides and low-density lipoprotein cholesterol) is a consistent finding. Weight-neutral antidepressants (e.g., bupropion, venlafaxine, duloxetine), however, are less likely to disrupt the lipid milieu. A weight-independent effect on lipid homeostasis is less consistently reported. Conclusion: Some antidepressants unfavourably influence the lipid milieu; mediating factors other than weight gain are not well-established. Pivotal studies evaluating the therapeutic index of antidepressants need to systematically collect and report data on the lipid effects of antidepressants.

Hormone replacement therapy and antidepressant prescription patterns: a reciprocal relationship

Major depressive disorder is a prevalent and disabling condition.[1][1] The causes of mood disorders are heterogeneous, involving a complicated interplay of both psychosocial and biological variables.[2][2],[3][3] In an analysis of adult women, the psychosocial variables that predicted major