Depression: McIntyre RS

Keck PE, McIntyre RS, Shelton RC. · Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · CNS Spectr. · Pubmed #18163039 links to  free full text

Abstract: Although certain aspects of bipolar disorder are well understood, there is a need for more information concerning management of acute bipolar depression, the effect of comorbid conditions, and long-term management of bipolar disorder. The outpatient presenting with bipolar disorder often presents with many of the key problems related to the long-term course of the disorder, including misdiagnosis and treatment non-adherence. Depressive symptoms are also prevalent during the course of bipolar disorder, with studies finding that depression can cause a low-grade "darkness" that longitudinally affects outpatients with bipolar disorder. These variable and persistent depressive symptoms may cause severe functional impairment and increased suicidality. Pharmacologic treatment of bipolar disorder typically includes anti-manic and mood-stabilizing medication. Although some studies find antidepressants have some positive effect, researchers have found that antidepressants, including selective serotonin reuptake inhibitors, when used as monotherapy or in conjunction with mood stabilizers, have little benefit for the treatment of bipolar disorder and may increase the likelihood of a switch into mania, hypomania, or mixed episodes. For long-term outpatient treatment, lamotrigine and lithium are proven to be highly effective. However, clinicians should also stress psychosocial treatment approaches, such as cognitive-behavioral therapy, as a principle of chronic disease management for long-term outpatients. Data on pharmacotherapy and psychosocial treatments are emerging, and clinicians should integrate these two treatment options into the standard of care. This expert roundtable supplement focuses on the treatment and management of the bipolar outpatient at risk for a depressive relapse as well as patients experiencing both acute and long-term symptoms of the disorder. Two case studies are presented to elucidate the best practices for the varying clinical states of bipolar disorder.

Yatham LN, Kennedy SH, O'Donovan C, Parikh SV, MacQueen G, McIntyre RS, Sharma V, Beaulieu S, Anonymous00162. · Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada. · Bipolar Disord. · Pubmed #17156158 No free full text.

Abstract: In 2005, the Canadian Network for Mood and Anxiety Treatments (CANMAT) published guidelines for the management of bipolar disorder. This update reviews new evidence since the previous publication and incorporates recommendations based on the most current evidence for treatment of various phases of bipolar disorder. It is designed to be used in conjunction with the 2005 CANMAT Guidelines. The recommendations for the management of acute mania remain mostly unchanged. Lithium, valproate and several atypical antipsychotics continue to be recommended as first-line treatments for acute mania. For the management of bipolar depression, new data support quetiapine monotherapy as a first-line option. Lithium and lamotrigine monotherapy, olanzapine plus selective serotonin reuptake inhibitors (SSRI), and lithium or divalproex plus SSRI/bupropion continue to remain the other first-line options. First-line options in the maintenance treatment of bipolar disorder continue to be lithium, lamotrigine, valproate and olanzapine. There is recent evidence to support the combination of olanzapine and fluoxetine as a second-line maintenance therapy for bipolar depression. New data also support quetiapine monotherapy as a second-line option for the management of acute bipolar II depression. The importance of comorbid psychiatric and medical conditions cannot be understated, and this update provides an expanded look at the prevalence, impact and management of comorbid conditions in patients with bipolar disorder.

Enns MW, Swenson JR, McIntyre RS, Swinson RP, Kennedy SH, Anonymous00077. · Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba. · Can J Psychiatry. · Pubmed #11441774 No free full text.

Abstract: BACKGROUND: The Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments partnered to produce clinical guidelines for psychiatrists for the treatment of depressive disorders. METHODS: A standard guidelines development process was followed. Relevant literature was identified using a computerized Medline search supplemented by review of bibliographies. Operational criteria were used to rate the quality of scientific evidence, and the line of treatment recommendations included consensus clinical opinion. This section, on Axis I, Axis II, and Axis III comorbidity, is 1 of 7 articles that were drafted and reviewed by clinicians. Revised drafts underwent national and international expert peer review. RESULTS: Comorbid depression on Axis I is particularly prevalent in patients with anxiety disorders, substance use disorders, and eating disorders, but it also occurs in patients with schizophrenia, attention-deficit hyperactivity disorder (ADHD), and dementia. Depressive comorbidity has implications for assessment, management, and outcome. The relation between depression and personality disorders is complex. Patient with this comorbidity often require longer, more intense, and multimodal therapies. Depression is also prevalent in medical illnesses, requires careful diagnosis, and responds to standard antidepressant treatments. CONCLUSIONS: Comorbidity can influence the course and outcome of both associated conditions. Depression-specific psychotherapy and/or pharmacotherapy should be considered when comorbid depression is diagnosed.

McIntyre RS. · No affiliation provided · Expert Opin Drug Saf. · Pubmed #18759703 No free full text.

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McIntyre RS, Konarski JZ, Gupta S. · No affiliation provided · Ann Clin Psychiatry. · Pubmed #18058278 No free full text.

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McIntyre RS, Rasgon NL, Kemp DE, Nguyen HT, Law CW, Taylor VH, Woldeyohannes HO, Alsuwaidan MT, Soczynska JK, Kim B, Lourenco MT, Kahn LS, Goldstein BI. · Mood Disorders Psychopharmacology Unit, University Health Network, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. · Curr Diab Rep. · Pubmed #19192425 No free full text.

Abstract: The metabolic syndrome and its components are associated with depressive symptomatology. This article discusses the rate of co-occurrence and the points of pathophysiologic commonality between the metabolic syndrome and major depressive disorder.

Kemp DE, Muzina DJ, McIntyre RS, Calabrese JR. · Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, Ohio, USA. · Dialogues Clin Neurosci. · Pubmed #18689288 No free full text.

Abstract: For the majority of patients with bipolar disorder, major depressive episodes represent the most debilitating and difficult-to-treat illness dimension. Patients spend significantly more time depressed than manic or hypomanic, and attempt suicide more frequently during this illness phase, yet the availability of treatments remains limited. The discovery of more effective therapeutics for managing depressive episodes is arguably the greatest unmet need in bipolar disorder. This article provides an evidence-based summary of pharmacological treatments for the acute and longitudinal management of bipolar depression. Clinical trial results are reviewed for a diverse array of compounds, inclusive of traditional mood stabilizers (eg, lithium and divalproex), atypical antipsychotics, unimodal antidepressants, and modafinil. Where applicable, differences in efficacy across compounds are examined through discussion of number needed to treat and effect size determinations. A pragmatic clinical approach is presented for management of the depressed phase of bipolar disorder.

Konarski JZ, McIntyre RS, Kennedy SH, Rafi-Tari S, Soczynska JK, Ketter TA. · Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. · Bipolar Disord. · Pubmed #18199239 No free full text.

Abstract: 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.

Muzina DJ, Kemp DE, McIntyre RS. · Cleveland Clinic Neurological Institute, Psychiatry & Psychology, Cleveland, OH 44195, USA. · Ann Clin Psychiatry. · Pubmed #18058287 No free full text.

Abstract: BACKGROUND: Bipolar disorder is a highly prevalent mood disorder, frequently misdiagnosed as unipolar major depressive disorder. METHODS: In order to summarize the historical and clinical features that may distinguish bipolar disorder and major depressive disorder, a MedLine search was conducted of all English-language articles published between 1996 and 2006 using the key search terms bipolar disorder and manic-depression cross-referenced with major depressive disorder. RESULTS: Better methods for arriving at the correct diagnosis of bipolar disorder include a clinical history that evaluates symptoms beyond narrow DSM-IV criteria and the use of self-reported screening tools. Twenty-six separate features were identified that are believed to aid in the differentiation of bipolar disorder from unipolar major depressive disorder. CONCLUSIONS: It is estimated that as many as 1 in 5 depressed outpatients may have undeclared bipolar disorder. Recognition of bipolar disorder can be improved by increasing the clinical acumen of diagnosticians and through the use of screening tools.

Konarski JZ, McIntyre RS, Soczynska JK, Kennedy SH. · Mood Disorders Psychopharmacology Unit, University Health Network, ON, Canada. · Ann Clin Psychiatry. · Pubmed #18058284 No free full text.

Abstract: 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.

McIntyre RS, Soczynska JK, Konarski JZ, Woldeyohannes HO, Law CW, Miranda A, Fulgosi D, Kennedy SH. · Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, ON, Canada. · Ann Clin Psychiatry. · Pubmed #18058283 No free full text.

Abstract: 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.

McIntyre RS, Soczynska JK, Woldeyohannes HO, Lewis GF, Leiter LA, MacQueen GM, Miranda A, Fulgosi D, Konarski JZ, Kennedy SH. · University of Toronto, Department of Psychiatry, Toronto, ON, Canada. · Expert Opin Pharmacother. · Pubmed #17685880 No free full text.

Abstract: 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.

McIntyre RS, Soczynska JK, Woldeyohannes HO, Alsuwaidan M, Konarski JZ. · University of Toronto, Department of Psychiatry, Toronto, ON, Canada. · Expert Opin Pharmacother. · Pubmed #17563257 No free full text.

Abstract: 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.

McIntyre RS, Soczynska JK, Woldeyohannes HO, Miranda A, Konarski JZ. · Department of Psychiatry, University of Toronto, Toronto, ON, Canada. · Expert Opin Pharmacother. · Pubmed #17472545 No free full text.

Abstract: Aripiprazole is a psychotropic agent with a novel pharmacologic profile. The purpose of this article is to review the pharmacology, efficacy and safety of aripiprazole in bipolar disorder. The authors conducted a PubMed search of all English-language articles published between January 1995 and February 2007. The key search term was 'aripiprazole' combined with: 'randomized controlled trial', 'pharmacology', 'pharmacokinetics', 'pharmacodynamics', 'depression', 'mania', 'maintenance' and 'bipolar disorder'. Abstracts and proceedings from national and international psychiatric meetings were also reviewed. The search was augmented with a manual review of relevant article reference lists. This review is limited to pivotal registration, as well as acute and maintenance, randomized controlled trials in bipolar disorder. Aripiprazole is established as efficacious in acute mania and in the maintenance treatment of bipolar disorder. Aripiprazole has a favorable safety and tolerability profile, with minimal propensity for clinically significant weight gain and metabolic disruption. Extrapyramidal side effects, such as akathisia, are reported and may be treatment limiting in some cases. The hazard risk for tardive dyskinesia in the bipolar population is unknown. Aripiprazole constitutes an alternative mood-stabilizing pharmacologic avenue in bipolar disorder; its comparative efficacy in long-term recurrence prevention and bipolar depression is a future research vista.

McIntyre RS, Fallu A, Konarski JZ. · Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Clin Ther. · Pubmed #17213009 No free full text.

Abstract: BACKGROUND: Mental disorders are highly prevalent, heterogeneous, and of multifactorial etiology. Collectively, they are associated with significant morbidity, mortality, and economic cost. Wellness is the optimal outcome in the management of chronic medical and psychiatric disorders. OBJECTIVES: This review provides a synopsis of definitions and operational criteria for remission in major depressive disorder, bipolar disorder, schizophrenia, anxiety disorders, and attention-deficit/hyperactivity disorder (ADHD). The overall goals were to propose a treatment framework that gives primacy to therapeutic outcomes and to provide a rationale for psychiatry to quantify and measure patient outcome. METHODS: Articles proposing definitions for remission were identified using a MEDLINE search (1966-April 2005) of the English-language literature (key terms: remission, anxiety disorders, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder, and schizophrenia). RESULTS: Operationalizing and quantifying critical end points in psychiatric disorders may help sharpen the focus of therapeutic activity and benefit patient outcome. In the absence of a validated biomarker of psychiatric illness activity, symptomatic remission and functional restoration are the only available markers of wellness in psychiatry. There is an emerging consensus regarding a definition for remission in major depressive disorder; several working definitions for bipolar disorder, schizophrenia, and anxiety disorders have been proposed. Developments in adult mood disorders-albeit incomplete-have been informative; managing psychiatric disorders that first appear in childhood (eg, ADHD) may also benefit by objectifying patient outcome. CONCLUSIONS: Research is needed to determine the impact of applying a remission-focused model of illness management--emphasizing quantifiable, objective, and measurable end points--on overall patient outcomes.

McIntyre RS, Soczynska JK, Konarski JZ, Kennedy SH. · University of Toronto, Department of Psychiatry, University Health Network, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada. · Expert Opin Drug Saf. · Pubmed #16370964 No free full text.

Abstract: 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.

McIntyre RS, Konarski JZ, Misener VL, Kennedy SH. · Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada. · Ann Clin Psychiatry. · Pubmed #16075661 No free full text.

Abstract: 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.

Konarski JZ, McIntyre RS, Grupp LA, Kennedy SH. · Institute of Medical Science, University of Toronto, Canada. · J Psychiatry Neurosci. · Pubmed #15944742 links to  free full text

Abstract: Contemporary mechanistic models of several psychiatric disorders propose abnormalities in the structure and function of distinct neural networks. The cerebellum has both anatomic and functional connections to the prefrontal cortex, the subcortical limbic structures and monoamine-producing brainstem nuclei. Conspicuously, however, the cerebellum has been underemphasized in neuropsychiatric research. A growing confluence of scientific data indicate that the cerebellum may not be irrelevant, which suggests that an integrated model of neuropsychiatric disorders should include a role for the cerebellum and its relevant neural connections. This review summarizes the published data describing and characterizing the putative role of the cerebellum in normal and abnormal mood regulation, with specific attention to states of psychosis, depression and mania. The available evidence suggests that a functional role for the cerebellum should be considered in future neuropsychiatric studies.

McIntyre RS, Konarski JZ. · Department of Psychiatry, University of Toronto, Toronto, ON, Canada. · Expert Opin Pharmacother. · Pubmed #15934897 No free full text.

Abstract: Major depressive disorder (MDD) is a prevalent, chronic, medical disorder that encompasses a broad constellation of symptoms. The salience of painful physical symptoms in depressive presentations is increasingly appreciated. Duloxetine is a novel, potent, balanced, dual monoamine reuptake-inhibitor antidepressant indicated for the symptomatic relief of MDD. Duloxetine is marketed as an antidepressant that has inherent analgesic properties for depressed patients who present with prominent painful physical symptoms. Taken together, available evidence indicates that duloxetine provides a higher probability of, and shorter time to, remission than some antidepressants (e.g., fluoxetine). Duloxetine also offers symptom relief for painful physical symptoms in depressed patients. Pharmacoeconomic and cost-impact modelling analyses should be reformulated to consider duloxetine's symptom-alleviating effect on the somatic dimension of depressive illness.

McIntyre RS, Konarski JZ. · Mood Disorders Psychopharmacology Unit, University Health Network, University of Toronto, Toronto, Ontario M5T 1R8, Canada. · J Clin Psychiatry. · Pubmed #15762832 No free full text.

Abstract: Atypical antipsychotics have unequivocally advanced the pharmacotherapy of bipolar disorder. These broad-spectrum medications offer efficacy against core symptoms of mania, and evidence supports the use of several agents as treatment options in depressed and maintenance phases of the disorder. Atypical antipsychotics also have a reduced propensity for provoking acute or tardive neurologic adverse events compared with their therapeutic predecessors, the conventional antipsychotics. These agents are not, however, a panacea and are associated with several problematic tolerability and safety concerns. Although classified together, atypical antipsychotics are heterogeneous in their tolerability and safety profiles, an issue that is relevant to individualizing treatment selection. This article reviews relevant adverse events attributable to the use of atypical antipsychotic agents, with particular consideration of the bipolar disorder population.

Khullar A, McIntyre RS. · Department of Psychiatry, University of Alberta, Edmonton. · Can Fam Physician. · Pubmed #15526874 links to  free full text

Abstract: OBJECTIVE: To provide family physicians with a contemporary approach to formulating a treatment model for major depressive disorder that integrates definitions of new therapeutic end points, familiarizes them with tools for assessing these end points, and describes newer methods for enhancing outcome. SOURCES OF INFORMATION: Canadian Psychiatric Association Guidelines for the Treatment of Depressive Disorders, relevant articles from a MEDLINE search using the MeSH headings"full remission" and "depression," and the authors' clinical experience. MAIN MESSAGE: Major depressive disorder is an episodic, relapsing, and sometimes chronic illness. Depressive symptoms in primary care settings are often vague reports of anhedonia, anxiety, and nonspecific somatic complaints. Therapeutic objectives in depression are full remission of depressive symptoms, prevention of recurrence, and restoration of function. Depression rating scales can be useful for monitoring and treating depression. CONCLUSION: The proposed therapeutic model anticipates the chronic course of illness, defines treatment end points, encourages longer duration of treatment, and includes both pharmacologic and lifestyle therapies. The 7-item Hamilton Depression Rating Scale can assist clinicians in determining when full remission has occurred.

McIntyre RS, Mancini DA, Lin P, Jordan J. · Department of Psychiatry, University of Toronto, Ont. · Can Fam Physician. · Pubmed #15318676 links to  free full text

Abstract: OBJECTIVE: To provide an evidence-based summary of medications commonly used for bipolar disorders and a practical approach to managing bipolar disorders in the office. QUALITY OF EVIDENCE: Articles from 1990 to 2003 were selected from MEDLINE using the key words "bipolar disorder," "antiepileptics," "antipsychotics," "antidepressants," and "mood stabilizers." Good-quality evidence for many of these treatments comes from randomized trials. Lithium, divalproex, carbamazepine, lamotrigine, oxcarbazepine, and some novel antipsychotics all have level I evidence for treating various aspects of the disorder. MAIN MESSAGE: Treatment of bipolar disorder involves three therapeutic domains: acute mania, acute depression, and maintenance. Lithium has been a mainstay of treatment for some time, but antiepileptic drugs like divalproex, carbamazepine, and lamotrigine, along with novel antipsychotic drugs like olanzapine, risperidone, and quetiapine, alone or in combination, are increasingly being used successfully to treat acute mania and to maintain mood stability. CONCLUSION: Bipolar disorder is more common in family practice than previously believed. Drug treatments for this complex disorder have evolved rapidly over the past decade, radically changing its management. Treatment now tends to be very successful.

McIntyre RS, O'Donovan C. · Department of Psychiatry, University of Toronto, Ontario. · Can J Psychiatry. · Pubmed #15147032 No free full text.

Abstract: Depression is among the most disabling and costly illnesses in the world. Despite good short-term efficacy outcomes in the treatment of depression, long-term outcomes remain disappointing. Depression continues to be missed or underdiagnosed and undertreated, and comorbidities are frequently not identified. Of particular concern is the low rate of depression treated to full remission. Treating only to response leaves patients with residual depressive symptoms and an increased risk of a recurrent or chronic course. Anything less than full remission should be considered a treatment failure. This article examines the substantial psychiatric, medical, functional, and economic costs associated with not achieving remission. Available pharmacoeconomic data and randomized, controlled clinical trials published in the last 5 years identified through Medline searches with terms including burden, cost, economics, serotonin reuptake inhibitors (also, specific agents), venlafaxine, nefazadone, mirtazapine, psychotherapy, remission, and depression were reviewed. One of the limiting factors to this review is that few trials have compared the effects of various antidepressant strategies on clinically relevant outcomes such as depression-free days and patient productivity, making the full benefit of remission more difficult to measure. Patients who fail to achieve a full remission have a more recurrent and chronic course, increased medical and psychiatric comorbidities, greater functional burden, and increased social and economic costs. Cost-effective treatment for depression includes antidepressant therapies with higher remission rates. Antidepressants with a dual mechanism of action and combination therapies are associated with higher remission rates, more depression-free days, reduced pain-symptom morbidity, reduced health service utilization, and improved productivity.

McIntyre RS, Müller A, Mancini DA, Silver ES. · Department of Psychiatry, University of Toronto, Ont. · Can Fam Physician. · Pubmed #12729241 links to  free full text

Abstract: OBJECTIVE: To provide family physicians with practical ways of managing depressed patients responding insufficiently to initial antidepressant treatment. QUALITY OF EVIDENCE: A search of MEDLINE and relevant bibliographies showed most studies could be categorized as level III evidence. Few well controlled studies (eg, level I evidence) specify treatment of next choice in rigorously defined treatment-refractory depression (TRD). MAIN MESSAGE: Failure to achieve and sustain full symptom remission affects relatively few treated depressed patients. Most chronically depressed people are not absolutely resistant but are relatively resistant to treatment; they fail to achieve the goals of treatment because of improper diagnosis or insufficient treatment application. The literature on TRD has largely focused on medication strategies; fewer studies investigated psychosocial approaches. The best established augmentation strategies are lithium salts and triidothyronine (T3). Combination antidepressants have become clinical psychiatrists' preferred treatment, despite limited evidence. Electroconvulsive therapy (ECT) remains a feasible option for TRD, but response rates are poor among people with TRD. High relapse rates after ECT remain a serious and common clinical dilemma. CONCLUSION: Family physicians should familiarize themselves with some new strategies to modify inadequate response to initial antidepressant treatment.

Yatham LN, Kennedy SH, Schaffer A, Parikh SV, Beaulieu S, O'Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Young AH, Alda M, Milev R, Vieta E, Calabrese JR, Berk M, Ha K, Kapczinski F. · Department of Psychiatry, University of British Columbia,2255 Wesbrook Mall, Vancouver, BC V6T 2A1, , Canada. · Bipolar Disord. · Pubmed #19419382 No free full text.

Abstract: The Canadian Network for Mood and Anxiety Treatments (CANMAT) published guidelines for the management of bipolar disorder in 2005, with a 2007 update. This second update, in conjunction with the International Society for Bipolar Disorders (ISBD), reviews new evidence and is designed to be used in conjunction with the previous publications. The recommendations for the management of acute mania remain mostly unchanged. Lithium, valproate, and several atypical antipsychotics continue to be first-line treatments for acute mania. Tamoxifen is now suggested as a third-line augmentation option. The combination of olanzapine and carbamazepine is not recommended. For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. New data support the use of adjunctive modafinil as a second-line option, but also indicate that aripiprazole should not be used as monotherapy for bipolar depression. Lithium, lamotrigine, valproate, and olanzapine continue to be first-line options for maintenance treatment of bipolar disorder. New data support the use of quetiapine monotherapy and adjunctive therapy for the prevention of manic and depressive events, aripiprazole monotherapy for the prevention of manic events, and risperidone long-acting injection monotherapy and adjunctive therapy, and adjunctive ziprasidone for the prevention of mood events. Bipolar II disorder is frequently overlooked in treatment guidelines, but has an important clinical impact on patients' lives. This update provides an expanded look at bipolar II disorder.