Raymond W. Lam

Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder

Bipolar I disorder (BD) has a poorer longer-term outcome than previously thought, with persistent cognitive impairment and functional decline. The neurobiological underpinnings that might underlie these changes remain unknown. Changes in brain-derived neurotrophic factor (BDNF) levels and cytokines are potential candidates. The aim of this study was to examine both cytokine and BDNF levels and their relationship in BD patients in the early and late stages of the disorder. We measured serum BDNF, TNF-alpha, IL-6 and IL-10 levels in a total of 60 patients with BD I and we compared those in early stages of illness with those in late stages of illness and also compared both groups with 60 matched healthy controls. BDNF was decreased only in those patients in the late stage of bipolar disorder. Moreover, BDNF levels were negatively correlated with length of illness. In contrast, all interleukins and TNF-alpha were increased in the early stages of BD, compared to controls. While TNF-alpha and IL-6 continued to be significantly higher than controls at late stages of BD, IL-10 did not. When levels were compared between patients at early and late stages of illness, there was a significant decrease in BDNF and IL-6 in the later stage of BD compared to the early stage. Inversely, TNF-alpha showed a significant increase at the later stage. Failure of inflammatory defences in the late stage of the disorder may account for reduction in BDNF and continued elevations in cytokines; thus these may have the potential to serve as markers of illness progression in BD.

A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression.

OBJECT Deep brain stimulation (DBS) has been recently investigated as a treatment for major depression. One of the proposed targets for this application is the subcallosal cingulate gyrus (SCG). To date, promising results after SCG DBS have been reported by a single center. In the present study the authors investigated whether these findings may be replicated at different institutions. They conducted a 3-center prospective open-label trial of SCG DBS for 12 months in patients with treatment-resistant depression. METHODS Twenty-one patients underwent implantation of bilateral SCG electrodes. The authors examined the reduction in Hamilton Rating Scale for Depression (HRSD-17) score from baseline (RESP50). RESULTS Patients treated with SCG DBS had an RESP50 of 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS, however, increased to 62% when defined as a reduction in the baseline HRSD-17 of 40% or more. Reductions in depressive symptomatology were associated with amelioration in disease severity in patients who responded to surgery. CONCLUSIONS Overall, findings from this study corroborate the results of previous reports showing that outcome of SCG DBS may be replicated across centers.

The interpersonal expression of perfection: Perfectionistic self-presentation and psychological distress.

A concept involving the interpersonal expression of perfection, perfectionistic self-presentation, is introduced. It is argued that perfectionistic self-presentation is a maladaptive self-presentational style composed of three facets: perfectionistic self-promotion (i.e., proclaiming and displaying ones perfection), nondisplay of imperfection (i.e., concealing and avoiding behavioral demonstrations of ones imperfection), and nondisclosure of imperfection (i.e., evading and avoiding verbal admissions of ones imperfection). Several studies involving diverse samples demonstrate that perfectionistic self-presentation is a valid and reliable construct and a consistent factor in personal and interpersonal psychological distress. It is argued that the need to promote ones perfection or the desire to conceal ones imperfection involves self-esteem regulation in the interpersonal context.

Chronotherapeutics (light and wake therapy) in affective disorders

The Committee on Chronotherapeutics, delegated by the International Society for Affective Disorders (ISAD), makes the following recommendations after reviewing the evidence as of November 2004. (1) Wake therapy is the most rapid antidepressant available today: approximately 60% of patients, independent of diagnostic subtype, respond with marked improvement within hours. Treatment can be a single or repeated sleep deprivation, total (all night) or partial (second half of the night). Relapse can be prevented by daily light therapy, concomitant administration of SSRIs, lithium (for bipolar patients), or a short phase advance of sleep over 3 days following a single night of wake therapy. Combinations of these interventions show great promise. (2) Light therapy is effective for major depression--not only for the seasonal subtype. As an adjuvant to conventional antidepressants in unipolar patients, or lithium in bipolar patients, morning light hastens and potentiates the antidepressant response. Light therapy shows benefit even for patients with chronic depression of 2 years or more, outperforming their weak response to drugs. This method provides a viable alternative for patients who refuse, resist or cannot tolerate medication, or for whom drugs may be contraindicated, as in antepartum depression. (3) Given the urgent need for new strategies to treat patients with residual depressive symptoms, clinical trials of wake therapy and/or adjuvant light therapy, coupled with follow-up studies of long-term recurrence, are a high priority.

Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Metaanalysis:

Objective: Systematic reviews show that repetitive transcranial magnetic stimulation (rTMS) is superior to sham control conditions in patients with major depressive disorder, but the clinical relevance is not clear. None have specifically examined outcomes in patients with treatment-resistant depression (TRD). Method: A systematic review was conducted by identifying published randomized controlled trials of active rTMS, compared with a sham control condition in patients with defined TRD (that is, at least one failed trial). The primary outcome was clinical response as determined from global ratings, or 50% or greater improvement on a rating scale. Other outcomes included remission and standardized mean differences in end point scores. Metaanalysis was conducted for absolute risk differences using random effects models. Sensitivity and subgroup analyses were also conducted to explore heterogeneity and robustness of results. Results: A total of 24 studies (n = 1092 patients) met criteria for quantitative synthesis. Active rTMS was significantly superior to sham conditions in producing clinical response, with a risk difference of 17% and a number-needed-to-treat of 6. The pooled response and remission rates were 25% and 17%, and 9% and 6% for active rTMS and sham conditions, respectively. Sensitivity and subgroup analyses did not significantly affect these results. Dropouts and withdrawals owing to adverse events were very low. Conclusions: For patients with TRD, rTMS appears to provide significant benefits in short-term treatment studies. However, the relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggest that further studies are needed before rTMS can be considered as a first-line monotherapy treatment for TRD.

Quality of life in bipolar disorder: A review of the literature

A sizable body of research has now examined the complex relationship between quality of life (QoL) and depressive disorder. Uptake of QoL research in relation to bipolar disorder (BD) has been comparatively slow, although increasing numbers of QoL studies are now being conducted in bipolar populations. We aimed to perform a review of studies addressing the assessment of generic and health-related QoL in patients with bipolar disorder.A literature search was conducted in a comprehensive selection of databases including MEDLINE up to November 2004. Key words included: bipolar disorder or manic-depression, mania, bipolar depression, bipolar spectrum and variants AND quality of life, health-related QoL, functional status, well-being and variants. Articles were included if they were published in English and reported on an assessment of generic or health-related QoL in patients with BD. Articles were not included if they had assessed fewer than 10 patients with BD, were only published in abstract form or only assessed single dimensions of functioning.The literature search initially yielded 790 articles or abstracts. Of these, 762 did not meet our inclusion criteria, leaving a final total of 28 articles. These were sub-divided into four categories (assessment of QoL in patients with BD at different stages of the disorder, comparisons of QoL in Patients with BD with that of other patient populations, QoL instrument evaluation in patients with BD and treatment studies using QoL instruments to assess outcome in Patients with BD) and described in detail.The review indicated that there is growing interest in QoL research in bipolar populations. Although the scientific quality of the research identified was variable, increasing numbers of studies of good design are being conducted. The majority of the studies we identified indicated that QoL is markedly impaired in patients with BD, even when they are considered to be clinically euthymic. We identified several important avenues for future research, including a need for more assessment of QoL in hypo/manic patients, more longitudinal research and the development of a disease-specific measure of QoL for patients with BD.

Bipolar disorder and quality of life: a patient-centered perspective.

Objectives: Several quantitative studies have now examined the relationship between quality of life (QoL) and bipolar disorder (BD) and have generally indicated that QoL is markedly impaired in patients with BD. However, little qualitative research has been conducted to better describe patients’ own experiences of how BD impacts upon life quality. We report here on a series of in-depth qualitative interviews we conducted as part of the item generation phase for a disease-specific scale to assess QoL in BD. Methods: We conducted 52 interviews with people with BD (n=35), their caregivers (n=5) and healthcare professionals (n=12) identified by both convenience and purposive sampling. Clinical characteristics of the affected sample ranged widely between individuals who had been clinically stable for several years through to inpatients who were recovering from a severe episode of depression or mania. Interviews were tape recorded, transcribed verbatim and analyzed thematically. Results: Although several interwoven themes emerged from the data, we chose to focus on 6 for the purposes of this paper: routine, independence, stigma and disclosure, identity, social support and spirituality. When asked to prioritize the areas they thought were most important in determining QoL, the majority of participants ranked social support as most important, followed by mental health. Conclusions: Findings indicate that there is a complex, multifaceted relationship between BD and QoL. Most of the affected individuals we interviewed reported that BD had a profoundly negative effect upon their life quality, particularly in the areas of education, vocation, financial functioning, and social and intimate relationships. However, some people also reported that having BD opened up new doors of opportunity.

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.

A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes

BACKGROUND There is growing interest in glutamatergic agents in depression, particularly ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist. We aimed to assess the efficacy of ketamine in major depressive episodes. METHOD We searched EMBASE, PsycINFO, CENTRAL, and Medline from 1962 to January 2014 to identify double-blind, randomized controlled trials with allocation concealment evaluating ketamine in major depressive episodes. Clinical remission, response and depressive symptoms were extracted by two independent raters. The primary outcome measure was clinical remission at 24 h, 3 days and 7 days post-treatment. Analyses employed a random-effects model. RESULTS Data were synthesized from seven RCTs employing an intravenous infusion and one RCT employing intranasal ketamine, representing 73 subjects in parallel arms and 110 subjects in cross-over designs [n = 34 with bipolar disorder (BD), n = 149 with major depressive disorder (MDD)]. Ketamine was associated with higher rates of clinical remission relative to comparator (saline or midazolam) at 24 h [OR 7.06, number needed to treat (NNT) = 5], 3 days (OR 3.86, NNT = 6), and 7 days (OR 4.00, NNT = 6), as well as higher rates of clinical response at 24 h (OR 9.10, NNT = 3), 3 days (OR 6.77, NNT = 3), and 7 days (OR 4.87, NNT = 4). A standardized mean difference of 0.90 in favor of ketamine was observed at 24 h based on depression rating scale scores, with group comparisons revealing greater efficacy in unipolar depression compared to bipolar depression (1.07 v. 0.68). Ketamine was associated with transient psychotomimetic effects, but no persistent psychosis or affective switches. CONCLUSION Our meta-analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression. Additional research is required to determine optimal dosing schedules, route, treatment schedules, and the potential efficacy of other glutamatergic agents.

Which antidepressants have demonstrated superior efficacy? A review of the evidence

A review of published evidence of superior efficacy of a particular antidepressant in major depressive disorder may assist clinicians in making considered treatment choices. To identify such candidates, an international group of experts met to assess published evidence (identified through searches in Medline and Embase databases and discussions with experts in the field) from randomized, controlled trials and meta-analyses comparing two antidepressants under conditions of fair comparison. Criteria were defined to judge the strength of evidence. Two pivotal studies in moderate-to-severe major depressive disorder that demonstrate superiority on the primary efficacy measure, or alternatively one pivotal study supported by consistent results from meta-analyses, was considered to constitute evidence for definite superiority. Three antidepressants met these criteria: clomipramine, venlafaxine, and escitalopram. Three antidepressants were found to have probable superiority: milnacipran, duloxetine, and mirtazapine. Only escitalopram was found to have definite superiority in the treatment of severe depression; probable superiority was identified for venlafaxine and possible superiority for milnacipran and clomipramine. This review of published data found evidence that only a very few antidepressants are shown to be more effective than others.