Arun V. Ravindran

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2009

The Canadian Network for Mood and Anxiety Treatments published guidelines for the management of bipolar disorder in 2005, with updates in 2007 and 2009. This third update, in conjunction with the International Society for Bipolar Disorders, reviews new evidence and is designed to be used in conjunction with the previous publications.The recommendations for the management of acute mania remain largely unchanged. Lithium, valproate, and several atypical antipsychotic agents continue to be first-line treatments for acute mania. Monotherapy with asenapine, paliperidone extended release (ER), and divalproex ER, as well as adjunctive asenapine, have been added as first-line options.For the management of bipolar depression, lithium, lamotrigine, and quetiapine monotherapy, as well as olanzapine plus selective serotonin reuptake inhibitor (SSRI), and lithium or divalproex plus SSRI/bupropion remain first-line options. Lurasidone monotherapy and the combination of lurasidone or lamotrigine plus lithium or divalproex have been added as a second-line options. Ziprasidone alone or as adjunctive therapy, and adjunctive levetiracetam have been added as not-recommended options for the treatment of bipolar depression. Lithium, lamotrigine, valproate, olanzapine, quetiapine, aripiprazole, risperidone long-acting injection, and adjunctive ziprasidone continue to be first-line options for maintenance treatment of bipolar disorder. Asenapine alone or as adjunctive therapy have been added as third-line options.

Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. II. Psychotherapy alone or in combination with antidepressant medication

BACKGROUND In 2001, the Canadian Psychiatric Association and the Canadian Network for Mood and Anxiety Treatments (CANMAT) partnered to produce evidence-based clinical guidelines for the treatment of depressive disorders. A revision of these guidelines was undertaken by CANMAT in 2008-2009 to reflect advances in the field. This article, one of five in the series, reviews new studies of psychotherapy in the acute and maintenance phase of MDD, including computer-based and telephone-delivered psychotherapy. METHODS The CANMAT guidelines are based on a question-answer format to enhance accessibility to clinicians. Evidence-based responses are based on updated systematic reviews of the literature and recommendations are graded according to the Level of Evidence, using pre-defined criteria. Lines of Treatment are identified based on criteria that included evidence and expert clinical support. RESULTS Cognitive-Behavioural Therapy (CBT) and Interpersonal Therapy (IPT) continue to have the most evidence for efficacy, both in acute and maintenance phases of MDD, and have been studied in combination with antidepressants. CBT is well studied in conjunction with computer-delivered methods and bibliotherapy. Behavioural Activation and Cognitive-Behavioural Analysis System of Psychotherapy have significant evidence, but need replication. Newer psychotherapies including Acceptance and Commitment Therapy, Motivational Interviewing, and Mindfulness-Based Cognitive Therapy do not yet have significant evidence as acute treatments; nor does psychodynamic therapy. LIMITATIONS Although many forms of psychotherapy have been studied, relatively few types have been evaluated for MDD in randomized controlled trials. Evidence about the combination of different types of psychotherapy and antidepressant medication is also limited despite widespread use of these therapies concomitantly. CONCLUSIONS CBT and IPT are the only first-line treatment recommendations for acute MDD and remain highly recommended for maintenance. Both computer-based and telephone-delivered psychotherapy--primarily studied with CBT and IPT--are useful second-line recommendations. Where feasible, combined antidepressant and CBT or IPT are recommended as first-line treatments for acute MDD.

Stress, coping, uplifts, and quality of life in subtypes of depression: a conceptual frame and emerging data

BACKGROUND Depressive illness is associated with several functional disturbances, including increased stress perception and reliance on emotion focused coping styles, reduced perception of uplifting events, and impairment of several aspects of quality of life. Inasmuch as different subtypes of depression may be accompanied by differing neuroendocrine profiles, it was of interest to establish whether they could also be distinguished from one another on the basis of functional behavioral indices. METHODS Major stressors, day-to-day stressors and uplift perception, coping styles, and quality of life were assessed in control participants, as well as in acute or chronically (dysthymia) depressed patients exhibiting either typical or atypical features, and in treatment resistant major depressive patients. RESULTS Relative to controls, the depressive groups had higher perceptions of day-to-day stressors (hassles), reduced perception of uplifting events, excessive reliance on emotion-focused coping strategies, and diminished quality of life. Among depressed patients the hassles, coping styles and some elements of quality of life were related to symptom severity, as well as treatment-resistance. LIMITATIONS Data concerning stress, coping and quality of life were collected retrospectively, and the number of subjects in each condition was small. Hence, the relationship of the outcome measures to depression need to be considered cautiously. CONCLUSIONS Quality of life represents a functional index of the behavioral and cognitive impact of depression. This outcome measure is sensitive to differences as a function of depressive characteristics, and may prove to be a useful assessment tool in evaluating treatment efficacy.

Mirtazapine orally disintegrating tablet versus sertraline: a prospective onset of action study.

This multinational, randomized, double-blind study was specifically designed to prospectively compare the onset of antidepressant efficacy of mirtazapine orally disintegrating tablets and sertraline at dosages commonly used in clinical practice. A total of 345 patients with major depressive episode (DSM-IV) received mirtazapine (30–45 mg/d) or sertraline (50–150 mg/d) for 8 weeks. Mirtazapine was administered in the newly developed fast dissolving, orally disintegrating tablet formulation. Assessments were performed at baseline and on days 4, 7, 10, 14, 28, 42, and 56. The primary efficacy variable (mean absolute change from baseline in the Hamilton Depression Rating Scale [HAMD] total score [17 items]) showed that mirtazapine was significantly (P < 0.05) more effective than sertraline at all assessments during the first 2 weeks of the study. After this time, HAMD total scores were similar in both groups. These findings were supported by analysis of the HAMD response rate (ie, ≥50% reduction in HAMD total score from baseline), HAMD remission rate (HAMD total score of ≤7), and the Montgomery-Åsberg Depression Rating Scale (MADRS). Both treatments were well tolerated. In addition, mirtazapine had a greater effect than sertraline on sexual functioning. In conclusion, this first prospective onset of action study using the orally disintegrating tablet indicates that mirtazapine has a faster onset of therapeutic effect than sertraline. The orally disintegrating tablet formulation of mirtazapine used in this study is known to enhance the convenience and compliance by the patient.

Lymphocyte subsets associated with major depression and dysthymia: modification by antidepressant treatment.

Major depression and dysthymia (chronic, low grade depression) were associated with an increase in the number of CD16/56 (natural killer; NK) cells in blood, whereas other lymphocyte subsets (CD3, CD4, CD8, CD19, and the CD4/CD8 ratio) did not differ from control subjects.After treatment with a specific serotonin reuptake inhibitor, the symptoms of depression were alleviated in both the major depressive and dysthymic patients. Likewise, NK cell numbers declined to control values in these treated groups. Among the major depressive patients, the NK cell number reached control values within 4 weeks, whereas 6 months of treatment was required for such an effect to be achieved in the dysthymic patients. Although plasma levels of epinephrine, norepinephrine, cortisol, and ACTH were not different between groups, among the major depressive patients ACTH was inversely correlated with total lymphocytes, CD3, and CD19, and epinephrine was directly related to the CD4 and CD4/CD8 ratio. Among dysthymics, ACTH was unrelated to any of the lymphocyte subsets, but norepinephrine was directly related to total lymphocytes, CD3, CD4, and NK cells. The data are interpreted in terms of stress perception among major depressive and dysthymic patients and the potential impact of stressor experiences on immune processes.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder Section 3. Pharmacological Treatments

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Pharmacological Treatments” is the third of six sections of the 2016 guidelines. With little new information on older medications, treatment recommendations focus on second-generation antidepressants. Results: Evidence-informed responses are given for 21 questions under 4 broad categories: 1) principles of pharmacological management, including individualized assessment of patient and medication factors for antidepressant selection, regular and frequent monitoring, and assessing clinical and functional outcomes with measurement-based care; 2) comparative aspects of antidepressant medications based on efficacy, tolerability, and safety, including summaries of newly approved drugs since 2009; 3) practical approaches to pharmacological management, including drug-drug interactions and maintenance recommendations; and 4) managing inadequate response and treatment resistance, with a focus on switching antidepressants, applying adjunctive treatments, and new and emerging agents. Conclusions: Evidence-based pharmacological treatments are available for first-line treatment of MDD and for management of inadequate response. However, given the limitations of the evidence base, pharmacological management of MDD still depends on tailoring treatments to the patient.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 2. Psychological Treatments.

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) has revised its 2009 guidelines for the management of major depressive disorder (MDD) in adults by updating the evidence and recommendations. The target audiences for these 2016 guidelines are psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Psychological Treatments” is the second of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 25 questions under 5 broad categories: 1) patient characteristics relevant to using psychological interventions; 2) therapist and health system characteristics associated with optimizing outcomes; 3) descriptions of major psychotherapies and their efficacy; 4) additional psychological interventions, such as peer interventions and computer- and technology-delivered interventions; and 5) combining and/or sequencing psychological and pharmacological interventions. Conclusions: First-line psychological treatment recommendations for acute MDD include cognitive-behavioural therapy (CBT), interpersonal therapy (IPT), and behavioural activation (BA). Second-line recommendations include computer-based and telephone-delivered psychotherapy. Where feasible, combining psychological treatment (CBT or IPT) with antidepressant treatment is recommended because combined treatment is superior to either treatment alone. First-line psychological treatments for maintenance include CBT and mindfulness-based cognitive therapy (MBCT). Patient preference, in combination with evidence-based treatments and clinician/system capacity, will yield the optimal treatment strategies for improving individual outcomes in MDD.

Yoga in the treatment of mood and anxiety disorders: A review

BACKGROUND Patient use of complementary and alternative treatments, including yoga, to manage mood and anxiety disorders, has been well documented. Despite research interest, there are few recent reviews of the evidence of the benefit of yoga in these conditions. METHOD The PubMed, Medline and PsycInfo databases were searched for literature published up to July 2008, relating to yoga and depressive and anxiety disorders. RESULTS The paucity of reported studies and several methodological constraints limit data interpretation. In depressive disorders, yoga may be comparable to medication and the combination superior to medication alone. There is reasonable evidence for its use as second-line monotherapy or augmentation to medication in mild to moderate major depression and dysthymia, with early evidence of benefit in more severe depression. In anxiety disorders, yoga may be superior to medication for a subgroup of patients, but its benefits in specific conditions are still largely unknown. Second-line monotherapy is indicated in performance or test anxiety, but only preliminary evidence exists for obsessive-compulsive disorder and post-traumatic stress disorder. Yoga appears to be superior to no treatment and progressive relaxation for both depression and anxiety, and may benefit mood and anxiety symptoms associated with medical illness. It shows good safety and tolerability in short-term treatment. CONCLUSION Reasonable evidence supports the benefit of yoga in specific depressive disorders. The evidence is still preliminary in anxiety disorders. Given its patient appeal and the promising findings thus far, further research on yoga in these conditions is encouraged.

A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major depressive disorder

BACKGROUND Recent studies have suggested clinical differences among selective serotonin reuptake inhibitors. In a 12-week randomized, multicenter, double-blind trial, the antidepressant and anxiolytic efficacy of the selective serotonin reuptake inhibitors paroxetine and fluoxetine was compared in patients with moderate to severe depression. METHODS A total of 203 patients were randomized to fixed doses (20 mg/day) of paroxetine or fluoxetine for the first six weeks of therapy. From week 7-12, dosing could be adjusted biweekly, as required (paroxetine 20-50 mg/day, and fluoxetine 20-80 mg/day). The mean prescribed doses were paroxetine 25.5 mg/day (range 20.0-40.2 mg/day), and fluoxetine 27.5 mg/day (range 20.0-59.5 mg/day). Emergence of motor nervousness or restlessness was assessed using the ESRS scale for akathisia. RESULTS Both active treatments demonstrated comparable antidepressant efficacy (HAM-D, CGI). Anxiolytic activity of the two drugs (COVI, STAI, HAM-D) was also comparable. However, paroxetine was found to be superior to fluoxetine on two subscore measures at week 1 of therapy (HAM-D Agitation item, p < 0.05; Psychic Anxiety item, p < 0.05), with no differences detected after week 2. The overall incidence of adverse effects was comparable in the two treatment groups. Constipation, dyspepsia, tremor, sweating and abnormal ejaculation were more common in paroxetine-treated subjects, whereas nausea and nervousness were more frequent in fluoxetine-treated patients. Weight loss was more common in the fluoxetine versus paroxetine group (11.88% versus 2.94%, respectively). ESRS scores for akathisia were low throughout the study and showed little change. LIMITATIONS Differences observed between the two drugs in antianxiety effects were limited to two measures of anxiety among several others. DISCUSSION The data indicate that paroxetine and fluoxetine have comparable antidepressant and anxiolytic efficacy. Paroxetine appears to produce an earlier improvement in agitation and psychic anxiety symptoms compared with fluoxetine.

MAO-A gene polymorphisms are associated with major depression and sleep disturbance in males

We investigated whether the genetic variants of the MAO-A gene were associated with major depression and/or the clusters of depressive symptoms. The EcoRV and the uVNTR polymorphisms were studied in a population of 191 patients with major depression and 233 control subjects. The EcoRV polymorphism was found to be associated with depression in males but not in females. Haplotype analysis revealed that one of the haplotypes (EcoRV2-uVNTR1) was significantly more frequent among male patients than male controls. Among the HAMD symptom clusters, insomnia scores were significantly higher in male patients carrying allele 2 of the EcoRV polymorphism. These data suggest that the EcoRV and uVNTR polymorphisms may be involved in the pathogenesis of major depression and associated with insomnia in depressed patients.