Neural response to emotional stimuli associated with successful antidepressant treatment and behavioral activation.

BACKGROUND: Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently available treatments have limited efficacy and combination strategies are frequently used. Several lines of research have demonstrated that MDD patients experience impairments in various components of affective processing, including regulation of affective states. AIM: To identify baseline and 1-week neuroimaging predictors of response to a 6-week trial of fluoxetine/olanzapine combination treatment during an affective processing task. METHODS: Twenty-one MDD patients and 18 healthy controls were enrolled in the study. MDD patients were treated for 6 weeks with fluoxetine (40-60 mg/day) and olanzapine (5-12.5mg/day). All participants viewed images from the International Affective Picture Rating System during a functional magnetic resonance (fMRI) scan at baseline and 1 week. RESULTS: There was a 57% response rate (defined as a 50% decrease in Hamilton Rating Scale for Depression-17 item) at 6 weeks. At baseline, responders had increased premotor activity while viewing negative images compared to non-responders and healthy controls. Higher baseline premotor activity was also predictive of greater percent change on the HAMD-17 and improvement in negative disposition and behavioral drive. Non-responders exhibited increased insular activity at baseline compared to responders. Higher activity in the posterior cingulate cortex was also predictive of greater percent change on the HAMD-17. Change from baseline to 1 week did not produce any significant predictive findings. CONCLUSIONS: Treatment with fluoxetine/olanzapine demonstrated similar biomarkers of response to monotherapeutic strategies. In particular, posterior cingulate cortex, anterior insula, and premotor cortex may show predictive differences in their response to affective images prior to treatment. Further research needs to be conducted to determine the utility of early changes in emotion circuitry in predicting antidepressant response.

Predictors of nonresponse to cognitive behavioural therapy or venlafaxine using glucose metabolism in major depressive disorder.

BACKGROUND: Longitudinal neuroimaging investigations of antidepressant treatment offer the opportunity to identify potential baseline biomarkers associated with poor outcome. METHODS: To explore the neural correlates of nonresponse to cognitive behavioural therapy (CBT) or venlafaxine (VEN), we compared pretreatment (18)F-fluoro-2-deoxy-d-glucose positron emission tomography scans of participants with major depressive disorder responding to either 16 weeks of CBT (n = 7) or VEN treatment (n = 9) with treatment nonresponders (n = 8). RESULTS: Nonresponders to CBT or VEN, in contrast to responders, exhibited pretreatment hypermetabolism at the interface of the pregenual and subgenual cingulate cortices. LIMITATIONS: Limitations of our study include the small sample sizes and the absence of both arterial sampling to determine absolute glucose metabolism and high-resolution structural magnetic resonance imaging coregistration for region-of-interest analyses. CONCLUSION: Our current findings are consistent with those reported in previous studies of relative hyperactivity in the ventral anterior cingulate cortex in treatment-resistant populations.

Medical and substance-related comorbidity in bipolar disorder: translational research and treatment opportunities.

It is well established that individuals with bipolar disorder are differentially affected by substance-related as well as medical disorders (ie, cardiometabolic disorders, respiratory disorders, neurological disorders, and infectious diseases). Emerging evidence indicates that some comorbid conditions (eg, diabetes mellitus) in bipolar individuals may be subserved by overlapping neurobiological networks. Disturbances in glucocorticoid/insulin signaling and immunoinflammatory effector systems are points of pathophysiological commonality between bipolar disorder and "stress-sensitive" medical disorders. Subphenotyping bipolar disorder as a function of comorbidity and temporality of onset may provide an opportunity for refining disease pathophysiological models and developing innovative disease-modifying therapies.

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 (chi2 = 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.

Insulin, insulin-like growth factors and incretins: neural homeostatic regulators and treatment opportunities.

Mood disorders may be conceptualized as progressive neurodegenerative disorders associated with cognitive decline. Novel treatments capable of preserving and/or enhancing cognitive function represent an area of priority for research in the future. Insulin, insulin-like growth factor (IGF)-1 and incretins may play a critical role in both physiological and pathophysiological processes of the CNS. An emerging paradigm regarding the pathophysiology of mood disorders posits that alterations in biological networks that mediate stress compromise optimal neuronal and glial function. A growing body of evidence indicates that central administration of insulin may enhance cognitive function in both healthy and cognitively impaired individuals. The neuroactive peptides, insulin, IGF-1 and incretins, or agents that facilitate their central effects (e.g. insulin-sensitizing agents), may constitute novel and possibly disease-modifying neurocognitive treatments.

Acetyl-L-carnitine and alpha-lipoic acid: possible neurotherapeutic agents for mood disorders?

BACKGROUND: Mood disorders are associated with decrements in cognitive function, which are insufficiently treated with contemporary pharmacotherapies. OBJECTIVES: To evaluate the putative neurotherapeutic effects of the mitochondrial cofactors, L-carnitine, acetyl-L-carnitine, and alpha-lipoic acid; and to provide a rationale for investigating their efficacy in the treatment of neurocognitive deficits associated with mood disorders. METHODS: A PubMed search of English-language articles published between January 1966 and March 2007 was conducted using the search terms carnitine and lipoic acid. RESULTS: L-carnitine and alpha-lipoic acid may offer neurotherapeutic effects (e.g., neurocognitive enhancement) via disparate mechanisms including antioxidant, anti-inflammatory, and metabolic regulation. Preliminary controlled trials in depressed geriatric populations also suggest an antidepressant effect with acetyl-L-carnitine. CONCLUSIONS: L-carnitine and alpha-lipoic acid are pleiotropic agents capable of offering neuroprotective and possibly cognitive-enhancing effects for neuropsychiatric disorders in which cognitive deficits are an integral feature.

The hepatic safety profile of duloxetine: a review.

BACKGROUND: Hepatotoxicity related to the use of duloxetine resulted in rewording of the US product insert. OBJECTIVE: To characterize the hepatic safety profile of duloxetine. METHODS: We conducted a PubMed search of all English-language articles published between January 1990 and December 2007 and contacted the manufacturer (Eli Lilly, Inc.). RESULTS: Elevations of alanine aminotransferase to three times the upper limit of normal occurs in 0.9-1.7% of duloxetine-treated patients versus 0.0-0.3% of placebo-treated patients. Hepatocellular, cholestatic and mixed hepatocellular-cholestatic forms of hepatic injury have been described. CONCLUSION: Duloxetine does not appear to pose a greater hazard for hepatic toxicity when compared to other conventional antidepressants. Systematic monitoring of liver aminotransferases does not appear to be warranted with routine duloxetine use.

Bipolar disorder and suicide: research synthesis and clinical translation.

Attempted suicide and suicide are prevalent in individuals with bipolar disorder (BD). Extant evidence indicates that history of suicide attempts, percentage of time spent in a depressed state, and hostility are factors associated with suicide attempts and completed suicide. Childhood adversity (eg, sexual and physical abuse) is emerging as a risk factor for suicide attempts in adults with BD. The pertinacity of medical comorbidity (eg, obesity, metabolic syndrome) in the bipolar population is further underscored by its preliminary association with suicidality. Biomarkers such as cerebrospinal fluid monoamine metabolite levels may be predictive of suicide attempts and lethality in BD. Compelling evidence supports an antisuicide effect of long-term lithium prophylaxis; lithium's salutary effect is mediated primarily by reduced lethality of suicidal acts. Conventional unimodal antidepressants may engender or exacerbate suicidality in susceptible individuals with BD. A nascent database suggests that adjunctive psychosocial interventions may further reduce suicide risk in bipolar individuals.

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.

Neuroimaging approaches in mood disorders: technique and clinical implications.

BACKGROUND: Clinical research in mood disorders increasingly involves advanced neuroimaging techniques. The encompassing aim of this review is to provide the mental health care practitioner with a pragmatic understanding of neuroimaging approaches and their possible clinical application. METHODS: We conducted a literature search of English-language articles using the search terms, major depressive disorder and bipolar disorder, cross-referenced with available neuroimaging technologies and analytical approaches, The search was supplemented with a manual review of relevant references. We organize the review by reviewing frequently asked questions on the topic of neuroimaging by mental health-care providers. RESULTS: Magnetic resonance (MR) approaches provide information on white and gray matter pathology (segmentation), cellular metabolism (MRS), oxygen consumption (BOLD), and neurocircuitry (DTI). Radionuclide-based neuroimaging methodologies provide quantitative estimates of brain glucose metabolism, regional blood flow, and ligand-receptor/transporter binding. Clinical implications of neuroimaging methodologies are reviewed. CONCLUSIONS: Advances in neuroimaging technology have refined models of disease pathophysiology in mood disorders and the mechanistic basis of antidepressant action. Multivariate analysis of functional and structural neuroimaging data, longitudinal analysis in the depressed and remitted states, and inclusion of representative patients with medical and psychiatric comorbidities will enhance the clinical translation of future research findings.

Should Depressive Syndromes Be Reclassified as "Metabolic Syndrome Type II"?

BACKGROUND: A nascent explanatory theory regarding the pathophysiology of major depressive disorder posits that alterations in metabolic networks (e.g., insulin and glucocorticoid signaling) mediate allostasis. METHOD: We conducted a PubMed search of all English-language articles published between January 1966 and September 2006. The search terms were: neurobiology, cognition, neuroprotection, inflammation, oxidative stress, glucocorticoids, metabolic syndrome, diabetes mellitus, insulin, and antidiabetic agents, cross-referenced with the individual names of DSM-III-R/IV/-TR-defined mood disorders. The search was augmented with a manual review of article reference lists; articles selected for review were determined by author consensus. RESULTS: Disturbances in metabolic networks: e.g., insulin-glucose homeostasis, immuno-inflammatory processes, adipokine synthesis and secretion, intra-cellular signaling cascades, and mitochondrial respiration are implicated in the pathophysiology, brain volumetric changes, symptomatic expression (e.g., neurocognitive decline), and medical comorbidity in depressive disorders. The central nervous system, like the pancreas, is a critical modulator of the metabolic milieu and is endangered by chronic abnormalities in metabolic processes. We propose the notion of "metabolic syndrome type II" as a neuropsychiatric syndrome in which alterations in metabolic networks are a defining pathophysiological component. CONCLUSION: A comprehensive management approach for depressive disorders should routinely include opportunistic screening and primary prevention strategies targeting metabolically mediated comorbidity (e.g., cardiovascular disease). Innovative treatments for mood disorders, which primarily target aberrant metabolic networks, may constitute potentially novel, and disease-modifying, treatment avenues.

Comparing features of bipolar disorder to major depressive disorder in a tertiary mood disorders clinic.

BACKGROUND: We sought to describe features that distinguish individuals with bipolar disorder from major depressive disorder. METHODS: A retrospective chart review of adult outpatients (N = 1000) seeking evaluation and treatment was conducted at the Mood Disorders Psychopharmacology Unit (MDPU), University Health Network, University of Toronto between October 2002 and November 2005 was conducted. Sociodemographic parameters, illness-characteristics and therapeutic interventions were evaluated and compared. RESULTS: The MDPU referring diagnosis were major depressive disorder (52%), bipolar disorder (29%), and unspecified (19%). Of all individuals with a non-bipolar entry diagnosis (n = 699), 23% (n = 159) were subsequently diagnosed with bipolar disorder (p < 0.001); the majority of whom (n = 117, 74%) received a non-bipolar I disorder diagnosis [e.g. bipolar II disorder (n = 71); bipolar NOS disorder (n = 46) (p < 0.001)]. Higher rates of unemployment/disability, previous depressive episodes, psychiatric hospitalization, comorbid hypertension, and lifetime substance use disorders, as well as an earlier age of illness-onset were more frequently endorsed by individuals with a diagnosis of bipolar disorder. Fifteen percent of individuals who were newly-diagnosed with bipolar disorder reported a history of antidepressant-associated mania. CONCLUSIONS: The majority of individuals with a newly-diagnosed bipolar disorder at this tertiary center have a non-bipolar I disorder (i.e., bipolar spectrum). Several indices of illness severity differentiate individuals with bipolar disorder from major depressive disorder.

Substance use disorders and overweight/obesity in bipolar I disorder: preliminary evidence for competing addictions.

OBJECTIVE: This investigation was undertaken to explore the relationship between alcohol/illicit drug dependence and overweight/obesity in individuals with bipolar I disorder. METHOD: The data for this analysis were procured from the Canadian Community Health Survey-Mental Health and Well-Being (CCHS) conducted by Statistics Canada in 2002. Bipolar I disorder was defined as persons screening positive for a lifetime manic episode using the World Mental Health 2000 version of the Composite International Diagnostic Interview (WMH-CIDI). Substance abuse and illicit drug dependence were determined using criteria commensurate with the DSM-IV-TR. Overweight and obesity were defined as a body mass index of 25.0 to 29.9 and greater than or equal to 30.0 kg/m(2), respectively. RESULTS: The total sample comprised 36,984 individuals (>or= 15 years old) screening positive for a lifetime manic episode. Subgroup analysis indicated that overweight/obese bipolar individuals had a significantly lower rate of substance dependence than the normal weight sample (13% vs. 21%, p < .01). Conversely, bipolar individuals who screened positive for substance dependence had a lower rate of overweight/obesity when compared with non-substance-dependent bipolar respondents (39% vs. 54%, p< .01). The inverse association between the presence of these 2 co-morbid conditions in bipolar I disorder continued to be statistically significant in multivariate analysis (OR = 0.57, 95% CI = 0.34 to 0.95, p < .05). CONCLUSION: An inverse relationship between the presence of comorbid overweight/obesity and substance use disorders was observed in bipolar I disorder. These results suggest that comorbid addictive disorders (i.e., substance use and compulsive overeating) may compete for the same brain reward systems.

Thiazolidinediones: novel treatments for cognitive deficits in mood disorders?

The aim of this review is to provide a rationale for evaluating thiazolidinediones (TZDs) as putative treatments for cognitive deficits in individuals with mood disorders. A MedLine search of all English-language articles published between January 1966 and August 2006 was conducted. The search terms were: the non-proprietary names of TZDs (e.g., rosiglitazone and pioglitazone), peroxisome proliferator-activated receptor, cognition, neuroprotection, inflammation, oxidative stress, cellular metabolism and excitotoxicity cross-referenced with the individual names of mood (e.g., major depressive disorder and bipolar disorder) and dementing disorders (e.g., Alzheimer's disease) as defined in the Diagnostic and Statistical Manual of Mental Disorders third edition, revised/fourth edition, text revision (DSM-III-R/IV-TR). The search was augmented with a manual review of article reference lists. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures and overall manuscript quality. Contemporary pathophysiologic models of mood disorders emphasize alterations in neuronal plasticity, metabolism and cytoarchitecture with associated regional abnormalities in neuronal (and glial) density and morphology. These abnormalities are hypothesized to subserve cognitive deficits and other clinical features of mood disorders. TZDs may attenuate, abrogate and/or reverse the neurotoxic effects of depressive illness by means of disparate mechanisms, notably insulin signaling, anti-inflammation, glucocorticoid activity and cellular metabolism. Extant data provide the basis for formulating a hypothesis that TZDs may be salutary for cognitive deficits and several aspects of somatic health (e.g., cardiovascular disease) associated with mood disorders.

Maintenance treatment in bipolar disorder: a focus on aripiprazole.

Bipolar disorders (BD) are chronic medical syndromes heterogeneous in phenomenology, pathophysiology and treatment. The longitudinal course of bipolar disorders is often characterized by nonrecovery, subsyndromal symptoms, enduring cognitive deficits and impairment in psychosocial function. The risk for premature mortality from unnatural (e.g., suicide) as well as natural causes (e.g., cardiovascular disease) is significantly higher than the general population. The therapeutic objectives of maintenance therapy are to prevent relapse/recurrence, reduce the risk for premature mortality, promote functional restoration and enhance quality of life. A chronic disease management model, which includes pharmacologic and manual-based psychosocial interventions as paradigmatic components, provides a framework for best practice and optimal patient outcome. This article provides a succinct review of treatments approved by the US FDA for maintenance in bipolar disorders, with a focus on the most recently approved atypical antipsychotic, aripiprazole.

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, gamma-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 alpha2-adrenoceptor mediates a relative increase in extracellular noradrenergic release in the prefrontal cortex. Emerging evidence indicates that quetiapine's 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.

Medical comorbidity in bipolar disorder: re-prioritizing 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. immuno-inflammatory 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.

Relationship between regional brain metabolism, illness severity and age in depressed subjects.

We sought to examine the effects of age, depression chronicity, and treatment responsiveness on glucose metabolism in a large well-characterized sample of depressed men and a psychiatrically unaffected control group. The subjects were unmedicated, symptomatic, right-handed males (n=66) who met DSM-IV criteria for a major depressive episode in the context of a major depressive disorder (MDD, n=66) and never depressed, right-handed, healthy control subjects (HC, n=24). Subjects in the MDD group were subsequently classified as responders, or non-responders to a six-week trial of paroxetine monotherapy (20-60 mg). Statistical parametric mapping (SPM) was used to analyze the relationship between age and cerebral glucose metabolism (18-fluorodeoxyglucose positron emission tomography) and the modulation by treatment responsivity and a history of prior depressive episodes. Metabolic activity in the rostral and dorsal anterior cingulate cortex showed a significant negative correlation with age in MDD, but not in HC. Non-response to treatment and previous depressive episodes were associated with a higher degree of age-dependent hypometabolism in the rostral and anterior cingulate cortex. The age-dependent changes documented herein may influence the distinct clinical presentation and treatment response described in older-age depression.

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.