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Objectives The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) guidelines provided clinicians with pragmatic treatment recommendations for bipolar disorder (BD). While these guidelines included commentary on how mixed features may direct treatment selection, specific recommendations were not provided- a critical gap which the current update aims to address. Method Overview of research regarding mixed presentations in BD, with treatment recommendations developed using a modified CANMAT/ISBD rating methodology. Limitations are discussed, including the dearth of high-quality data and reliance on expert opinion. Results No agents met threshold for first line treatment of DSM-5 manic or depressive episodes with mixed features. For mania + mixed features second line treatment options include asenapine, cariprazine, divalproex, and aripiprazole. In depression + mixed features, cariprazine and lurasidone are recommended as second line options. For DSM-IV defined mixed episodes, with a longer history of research, asenapine and aripiprazole are first line, and olanzapine (monotherapy or combination), carbamazepine, and divalproex are second line. Research on maintenance treatments following a DSM-5 mixed presentation is extremely limited, with third-line recommendations based on expert opinion. For maintenance treatment following a DSM-IV mixed episode, quetiapine (monotherapy or combination) is first line, and lithium and olanzapine identified as second line options. Conclusion The CANMAT and ISBD groups hope these guidelines provide valuable support for clinicians providing care to patients experiencing mixed presentations, as well as further influence investment in research to improve diagnosis and treatment of this common and complex clinical state. more...

The field of study addressing the relationship between FSD and male sexual dysfunction (MSD) represents a pivotal worldwide health issue as interrelationship between FSD and MSD studies are still inconclusive.To review the interrelationship between FSD and MSD and to conclude whether there is a definitive risk of men developing sexual dysfunction when his partner is suffering from FSD.The investigation was conducted following the standard practice for conducting and reporting the findings of systematic reviews and meta-analyses comprising of 4 electronic databases, that is, Embase, PsycInfo, Cochrane Library and Ovid (Medline) from inception to December 2019. Search strategies were developed based on relevant keywords with appropriate truncation and Boolean operators' approach. The quality of studies was employed using the McMaster Critical Review Form for Quantitative Studies and were assessed by independent reviewers. The levels of evidence of the included studies were also determined.MSD who had been exposed to FSD.From more than 8,000 studies searched, 26 studies were finally included, and most included studies have reasonable quality. Meta-analysis found a significant sexual dysfunction in men who are partnered with women with FSD. It found a consistent correlation between FDS and sexual dysfunction in men with a significant 3-fold increase in MSD who are partnered with women with FSD (odds ratio = 3.011, 95% confidence interval: 1.856-4.885, P =.001, I² = 42.26%). Among subtypes of MSD, likelihood increased 4-fold for erectile dysfunction and that of premature ejaculation doubled. The data for several other domains on their components were mixed.These findings support the notion that clinicians should evaluate sexual function pertaining to both partners and encompassing several dimensions and needing an interdisciplinary approach.This review exhaustively examines data search from vast electronic databases and as the comparison of studies is extracted from English journal publications, not all regions worldwide are represented.This meta-analysis and systematic review found an association between sexual dysfunction in men partnered with women with FSD, especially in the domains of erectile and ejaculatory function. Chew PY, Choy CL, Sidi Hb,et al. The Association Between Female Sexual Dysfunction and Sexual Dysfunction intheMale Partner: A Systematic Review and Meta-analysis. J Sex Med 2021;18:99-112. more...

Objective:Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice.Methods:A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question–answer format.Results:Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response.Conclusions:Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers. more...

BackgroundAvailable evidence on the comparative efficacy and acceptability of psychotherapies for post-traumatic stress disorder (PTSD) in children and adolescents remains uncertain.ObjectiveWe aimed to compare and rank the different types and formats of psychotherapies for PTSD in children and adolescents.MethodsWe searched eight databases and other international registers up to 31 December 2020. The pairwise meta-analyses and frequentist network meta-analyses estimated pooled standardised mean differences (SMDs) and ORs with random-effects model. Efficacy at post-treatment and follow-up, acceptability, depressive and anxiety symptoms were measured.FindingsWe included 56 randomised controlled trials with 5327 patients comparing 14 different types of psychotherapies and 3 control conditions. For efficacy, cognitive processing therapy (CPT), behavioural therapy (BT), individual trauma-focused cognitive–behavioural therapy (TF-CBT), eye movement desensitisation and reprocessing, and group TF-CBT were significantly superior to all control conditions at post-treatment and follow-up (SMDs between −2.42 and −0.25). Moreover, CPT, BT and individual TF-CBT were more effective than supportive therapy (SMDs between −1.92 and −0.49). Results for depressive and anxiety symptoms were similar to the findings for the primary outcome. Most of the results were rated as ‘moderate’ to ‘very low’ in terms of confidence of evidence.ConclusionsCPT, BT and individual TF-CBT appear to be the best choices of psychotherapy for PTSD in young patients. Other types and different ways of delivering psychological treatment can be alternative options. Clinicians should consider the importance of each outcome and the patients’ preferences in real clinical practice. more...

The link between depression and anxiety status and cancer outcomes has been well-documented but remains unclear. We comprehensively quantified the association between depression and anxiety defined by symptom scales or clinical diagnosis and the risk of cancer incidence, cancer-specific mortality, and all-cause mortality in cancer patients. Pooled estimates of the relative risks (RRs) for cancer incidence and mortality were performed in a meta-analysis by random effects or fixed effects models as appropriate. Associations were tested in subgroups stratified by different study and participant characteristics. Fifty-one eligible cohort studies involving 2,611,907 participants with a mean follow-up period of 10.3 years were identified. Overall, depression and anxiety were associated with a significantly increased risk of cancer incidence (adjusted RR: 1.13, 95% CI: 1.06–1.19), cancer-specific mortality (1.21, 1.16–1.26), and all-cause mortality in cancer patients (1.24, 1.13–1.35). The estimated absolute risk increases (ARIs) associated with depression and anxiety were 34.3 events/100,000 person years (15.8–50.2) for cancer incidence and 28.2 events/100,000 person years (21.5–34.9) for cancer-specific mortality. Subgroup analyses demonstrated that clinically diagnosed depression and anxiety were related to higher cancer incidence, poorer cancer survival, and higher cancer-specific mortality. Psychological distress (symptoms of depression and anxiety) was related to higher cancer-specific mortality and poorer cancer survival but not to increased cancer incidence. Site-specific analyses indicated that overall, depression and anxiety were associated with an increased incidence risks for cancers of the lung, oral cavity, prostate and skin, a higher cancer-specific mortality risk for cancers of the lung, bladder, breast, colorectum, hematopoietic system, kidney and prostate, and an increased all-cause mortality risk in lung cancer patients. These analyses suggest that depression and anxiety may have an etiologic role and prognostic impact on cancer, although there is potential reverse causality; Furthermore, there was substantial heterogeneity among the included studies, and the results should be interpreted with caution. Early detection and effective intervention of depression and anxiety in cancer patients and the general population have public health and clinical importance. more...

BackgroundObsessive-compulsive disorder (OCD) is an anxiety disorder with significant morbidity whose pathophysiology is not fully understood. Neuroimaging studies have characterized OCD in terms of elevated striatal and prefrontal reactivity to emotion provocation. This neural model may be informed by investigation of functional connectivity in OCD, identifying alterations in how sensory information is integrated into frontostriatal regions.MethodsThe current study employed functional magnetic resonance imaging (fMRI) to compare neural activity and connectivity in 31 OCD patients (12 washing and 19 checking subtypes) and 17 healthy volunteers in an emotion provocation paradigm using visual stimuli.ResultsOCD status was associated with hyper-activation of the posterior cingulate (PCg) in response to emotion provocation. Additionally, OCD patients demonstrated elevated PCg functional connectivity with the visual cortices and frontostriatal regions. Exploratory analyses suggested that stimulus-provoked activity and connectivity was elevated for checking subtypes in motor cortices, and elevated in washing subtypes in the anterior insula and orbitofrontal cortex.ConclusionsThe PCg's role in moderating connectivity between the visual cortex and frontolimbic regions is muted in OCD, consistent with the PCg's suggested role in regulating attention towards emotional stimuli. Exploratory analyses suggest distinct PCg connectivity profiles in OCD subtypes, with checking linked to motor activation, but washing linked to a network supporting emotional salience. The study was not powered to fully investigate the effects of medication, patients often endorsed secondary symptom subtypes that muddied washing/checking distinctions, and the emotion provocation paradigm was of limited intensity compared to life stressors. more...

Background Chronic Major Depressive Disorder (CMDD) is a common, disabling illness that is often complicated by high reactivity to social stress. To further elucidate the nature of this reactivity, the current study evaluated whether the personality dimensions of neuroticism and extraversion influenced cortisol responses to a social challenge in CMDD patients vs. controls. Methods Fifty participants with CMDD and 58 healthy controls completed the Trier Social Stress Test (TSST) using a standard protocol. Neuroticism and extraversion were measured using the Revised NEO Personality Inventory. Hierarchical linear regressions assessed associations between independent variables neuroticism and extraversion and dependent variable cortisol area-under-the-curve increase (AUCi) in response to the TSST in the two study groups. Results The extraversion-by-group interaction was a significant predictor of cortisol AUCi, while no significant findings related to neuroticism were found. Simple slopes analysis revealed a significant negative association between extraversion and AUCi in the CMDD group, but not in healthy controls. Post-hoc analysis of the raw cortisol data over time found that CMDD participants with higher extraversion scores had significantly higher pre-challenge cortisol levels than did other study participants, however this did not explain or confound the AUCi results. Conclusions In participants with CMDD but not in controls, higher levels of extraversion were associated with higher pre-challenge cortisol levels and decreased cortisol reactivity during the TSST, however these two findings were statistically independent. These findings underline the importance of considering personality factors when studying stress biology in CMDD patients. Extraversion may prove to be an important intermediate target for both research and clinical work in this complex, heterogenous and often treatment-resistant population. more...

PURPOSE Cancer is a growing public health issue in low- and lower-middle–income countries (LLMICs), but the mental health consequences in this setting have not been well-characterized. We aimed to systematically evaluate the available literature on the prevalence, associates, and treatment of mental disorders in patients with cancer in LLMICs. METHODS We systematically searched Medline, PsycINFO, EMBASE, and CINAHL. We performed a random effects meta-analysis to determine the pooled prevalence of major depression or anxiety disorders in this population, defined by Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases criteria. We qualitatively reviewed studies that examined the prevalence of depressive or anxiety disorders defined by self-report tools, the prevalence of other mental disorders, associated factors of depressive and anxiety symptoms, and the treatment of mental disorders in this population. RESULTS Forty studies spanning a 15-year period were included in the review. The pooled prevalence defined by Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases criteria was 21% for major depression (95% CI, 15 to 28) and 18% for anxiety disorders (95% CI, 8 to 30). Depressive and anxiety symptoms were most frequently associated with advanced disease and low levels of education. Among the four studies evaluating treatment, three evaluated the effectiveness of psychotherapy and one evaluated a yoga program. CONCLUSION The prevalence of depression and anxiety in patients with cancer generally appears higher in LLMICs than in upper-income countries. Our findings demonstrate the existence of a significant and underappreciated disease burden. We suggest that clinicians remain vigilant to psychiatric symptoms. Improved screening and treatment are likely to improve quality of life and reduce both morbidity and mortality. more...

Background Major Depressive Disorder (MDD) is characterized by objective and subjective cognitive deficits. Discrepancies between objective and subjective cognitive performance can reflect under- to over-estimations of cognitive abilities, and these discrepancies are referred to as cognitive self-appraisals. Despite evidence that low self-appraisals are associated with depression, the modifiability of self-appraisals and their association with treatment outcome remains unclear. The current study examined whether self-appraisals change following antidepressant treatment. Furthermore, we investigated the association of self-appraisals with treatment outcome. Methods As part of the CAN-BIND-1 clinical trial, 154 patients with MDD completed measures of objective and subjective cognitive abilities, depressive symptoms, and functional outcomes (work productivity, psychosocial functioning, and quality of life) at baseline and post-escitalopram treatment. Self-appraisals were calculated based on discrepancies between objective and subjective cognitive abilities, with higher scores indicating overestimation of cognitive abilities. Results Baseline self-appraisals were not predictive of treatment outcomes. However, self-appraisals increased from pre- to post-treatment. Moreover, pre-post treatment increases in self-appraisals were associated with positive treatment response and remission, decreases in depressive symptoms, and improvements in work productivity, psychosocial functioning, and quality of life. Limitations The pre-post intervention design precluded examining the temporal precedence of change in self-appraisals versus depressive symptoms and functional outcomes. Conclusions Findings are the first to demonstrate that self-appraisals are treatment-sensitive and are associated with treatment outcomes and recovery from MDD. Cognitive self-appraisals may represent a key marker of treatment response and a valuable target for assessment and intervention, as well as a potential mechanism underlying risk and recovery. more...

Objectives: Cannabis use is proposed as a risk factor for psychosis and is associated with depressive disorders. However, the relationship between recreational cannabis use and its longitudinal implications on anxiety conditions is less studied. The aim of this investigation is to systematically evaluate published literature and perform a meta-analysis of the data. Methods: A systematic search was performed of MEDLINE, Embase, and PsychINFO from inception to May 31, 2020, in addition to a hand search. Longitudinal studies that evaluated the relationship of cannabis use and development of anxiety were included. Where applicable, adjusted odds ratios ( ORs) were extracted, pooled, and evaluated using random-effects meta-analysis. Results: After screening of unique abstracts ( n = 6835), the final evaluation included 24 studies, of which 10 reported ORs that were analyzed quantitatively. Cannabis use was significantly associated with increased odds of developing any anxiety conditions ( OR = 1.25; 95% CI, 1.01 to 1.54). Cannabis use was not significantly associated with developing generalized anxiety disorder, panic disorder, or social anxiety disorder. Review of studies not reporting OR revealed mixed results but are suggestive of a link between cannabis use and increased rates/severity of anxiety. Conclusions: Published evidence suggests that cannabis use is likely associated with increased risk of anxiety in the long term but variability of study designs precludes declaration of a causal relationship. Awareness of this association is of relevance for both clinical practice and mental health policy implementation. more...

Objective Differential predictors of response to alternative treatment options are needed to improve the outcomes in major depressive disorder. The symptom dimension comprising loss of interest and reduced activity has been reported as a predictor of poor outcome of treatment with antidepressants. We hypothesized that augmentation with partial dopamine agonist aripiprazole will be effective for individuals with pronounced interest-activity symptoms. Methods We tested the hypothesis in the 2-phase Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1). All participants had a primary diagnosis of major depressive disorder confirmed with the Mini-International Neuropsychiatric Interview. In phase 1, 188 individuals received escitalopram monotherapy 10-20 mg daily for 8 weeks. In phase 2, nonresponders received augmentation with aripiprazole 2-10 mg daily while responders continued escitalopram monotherapy for another 8 weeks. Outcomes were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) every 2 weeks. Effects of baseline interest-activity symptoms on outcomes were tested in repeated-measures mixed-effects models. Results Higher baseline interest-activity score (indicative of more severe loss of interest and reduction in activity) predicted worse outcome of escitalopram monotherapy in phase 1 (b = 1.75; 95% CI, 0.45 to 3.05; P = .009), but the association disappeared with the augmentation option in phase 2 (b = -0.19; 95% CI, -1.30 to 0.92; P = .739). A significant interaction between the baseline interest-activity score and aripiprazole reflected the opposite direction of the relationship between baseline interest-activity score and degree of improvement with escitalopram monotherapy versus aripiprazole augmentation (b = -1.60; 95% CI, -2.35 to -0.84; P Conclusions Individuals with prominent loss of interest and reduction in activity benefit less from escitalopram monotherapy and more from aripiprazole augmentation. Future trials may test the benefits of early prodopaminergic augmentation guided by interest-activity symptoms. Trial registration ClinicalTrials.gov identifier: NCT01655706. more...

Major depressive disorder (MDD) in children and adolescents is a recurrent and disabling condition globally but its pathophysiology remains poorly elucidated and there are limited effective treatments available. We performed metabolic profiling of plasma samples based on ultra-high-performance liquid chromatography equipped with quadrupole time-offlight mass spectrometry to explore the potential biomarkers of depression in children and adolescents with MDD. We identified several perturbed pathways, including fatty acid metabolism—particularly the polyunsaturated fatty acids metabolism, and purine metabolism—that were associated with MDD in these young patients. In addition, inosine was shown as a potential independent diagnostic biomarker for MDD, achieving an area under the ROC curve of 0.999 in discriminating drug-naive MDD patients and 0.866 in discriminating drug-treated MDD from healthy controls. Moreover, we found evidence for differences in the pathophysiology of MDD in children and adolescents to that of adult MDD, specifically with tryptophan metabolism. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and the pathophysiology and diagnostic biomarker of child and adolescent MDD. more...

The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe. more...

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. “Complementary and Alternative Medicine Treatments” is the fifth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 12 questions for 2 broad categories of complementary and alternative medicine (CAM) interventions: 1) physical and meditative treatments (light therapy, sleep deprivation, exercise, yoga, and acupuncture) and 2) natural health products (St. John’s wort, omega-3 fatty acids; S-adenosyl-L-methionine [SAM-e], dehydroepiandrosterone, folate, Crocus sativus, and others). Recommendations were based on available data on efficacy, tolerability, and safety. Conclusions: For MDD of mild to moderate severity, exercise, light therapy, St. John’s wort, omega-3 fatty acids, SAM-e, and yoga are recommended as first- or second-line treatments. Adjunctive exercise and adjunctive St. John’s wort are second-line recommendations for moderate to severe MDD. Other physical treatments and natural health products have less evidence but may be considered as third-line treatments. CAM treatments are generally well tolerated. Caveats include methodological limitations of studies and paucity of data on long-term outcomes and drug interactions. more...

Background Coronavirus disease 2019 (COVID-19) has evolved into a worldwide pandemic, and has been found to be closely associated with mental and neurological disorders. We aimed to comprehensively quantify the association between mental and neurological disorders, both pre-existing and subsequent, and the risk of susceptibility, severity and mortality of COVID-19. Methods In this systematic review and meta-analysis, we searched PubMed, Web of Science, Embase, PsycINFO, and Cochrane library databases for studies published from the inception up to January 16, 2021 and updated at July 7, 2021. Observational studies including cohort and case-control, cross-sectional studies and case series that reported risk estimates of the association between mental or neurological disorders and COVID-19 susceptibility, illness severity and mortality were included. Two researchers independently extracted data and conducted the quality assessment. Based on I2 heterogeneity, we used a random effects model to calculate pooled odds ratios (OR) and 95% confidence intervals (95% CI). Subgroup analyses and meta-regression analysis were also performed. This study was registered on PROSPERO (registration number: CRD 42021230832). Finding A total of 149 studies (227,351,954 participants, 89,235,737 COVID-19 patients) were included in this analysis, in which 27 reported morbidity (132,727,798), 56 reported illness severity (83,097,968) and 115 reported mortality (88,878,662). Overall, mental and neurological disorders were associated with a significant high risk of infection (pre-existing mental: OR 1·67, 95% CI 1·12-2·49; and pre-existing neurological: 2·05, 1·58-2·67), illness severity (mental: pre-existing, 1·40, 1·25-1·57; sequelae, 4·85, 2·53-9·32; neurological: pre-existing, 1·43, 1·09-1·88; sequelae, 2·17, 1·45-3·24), and mortality (mental: pre-existing, 1·47, 1·26-1·72; neurological: pre-existing, 2·08, 1·61-2·69; sequelae, 2·03, 1·66-2·49) from COVID-19. Subgroup analysis revealed that association with illness severity was stronger among younger COVID-19 patients, and those with subsequent mental disorders, living in low- and middle-income regions. Younger patients with mental and neurological disorders were associated with higher mortality than elders. For type-specific mental disorders, susceptibility to contracting COVID-19 was associated with pre-existing mood disorders, anxiety, and attention-deficit hyperactivity disorder (ADHD); illness severity was associated with both pre-existing and subsequent mood disorders as well as sleep disturbance; and mortality was associated with pre-existing schizophrenia. For neurological disorders, susceptibility was associated with pre-existing dementia; both severity and mortality were associated with subsequent delirium and altered mental status; besides, mortality was associated with pre-existing and subsequent dementia and multiple specific neurological diseases. Heterogeneities were substantial across studies in most analysis. Interpretation The findings show an important role of mental and neurological disorders in the context of COVID-19 and provide clues and directions for identifying and protecting vulnerable populations in the pandemic. Early detection and intervention for neurological and mental disorders are urgently needed to control morbidity and mortality induced by the COVID-19 pandemic. However, there was substantial heterogeneity among the included studies, and the results should be interpreted with caution. More studies are needed to explore long-term mental and neurological sequela, as well as the underlying brain mechanisms for the sake of elucidating the causal pathways for these associations. Funding This study is supported by grants from the National Key Research and Development Program of China, the National Natural Science Foundation of China, Special Research Fund of PKUHSC for Prevention and Control of COVID-19, and the Fundamental Research Funds for the Central Universities. more...

Summary Background Depressive disorders are common in children and adolescents. Antidepressants, psychotherapies, and their combination are often used in routine clinical practice; however, available evidence on the comparative efficacy and safety of these interventions is inconclusive. Therefore, we sought to compare and rank all available treatment interventions for the acute treatment of depressive disorders in children and adolescents. Methods We did a systematic review and network meta-analysis. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, ProQuest, CINAHL, LiLACS, international trial registries, and the websites of regulatory agencies for published and unpublished randomised controlled trials from database inception until Jan 1, 2019. We included placebo-controlled and head-to-head trials of 16 antidepressants, seven psychotherapies, and five combinations of antidepressant and psychotherapy that are used for the acute treatment of children and adolescents (≤18 years old and of both sexes) with depressive disorder diagnosed according to standard operationalised criteria. Trials recruiting participants with treatment-resistant depression, bipolar disorder, psychotic depression, treatment duration of less than 4 weeks, or an overall sample size of fewer than ten patients were excluded. We extracted data following a predefined hierarchy of outcome measures, and assessed risk of bias and certainty of evidence using validated methods. Primary outcomes were efficacy (change in depressive symptoms) and acceptability (treatment discontinuation due to any cause). We estimated summary standardised mean differences (SMDs) or odds ratios (ORs) with credible intervals (CrIs) using network meta-analysis with random effects. This study was registered with PROSPERO, number CRD42015020841. Findings From 20 366 publications, we included 71 trials (9510 participants). Depressive disorders in most studies were moderate to severe. In terms of efficacy, fluoxetine plus cognitive behavioural therapy (CBT) was more effective than CBT alone (–0·78, 95% CrI −1·55 to −0·01) and psychodynamic therapy (–1·14, −2·20 to −0·08), but not more effective than fluoxetine alone (–0·22, −0·86 to 0·42). No pharmacotherapy alone was more effective than psychotherapy alone. Only fluoxetine plus CBT and fluoxetine were significantly more effective than pill placebo or psychological controls (SMDs ranged from −1·73 to −0·51); and only interpersonal therapy was more effective than all psychological controls (–1·37 to −0·66). Nortriptyline (SMDs ranged from 1·04 to 2·22) and waiting list (SMDs ranged from 0·67 to 2·08) were less effective than most active interventions. In terms of acceptability, nefazodone and fluoxetine were associated with fewer dropouts than sertraline, imipramine, and desipramine (ORs ranged from 0·17 to 0·50); imipramine was associated with more dropouts than pill placebo, desvenlafaxine, fluoxetine plus CBT, and vilazodone (2·51 to 5·06). Most of the results were rated as “low” to “very low” in terms of confidence of evidence according to Confidence In Network Meta-Analysis. Interpretation Despite the scarcity of high-quality evidence, fluoxetine (alone or in combination with CBT) seems to be the best choice for the acute treatment of moderate-to-severe depressive disorder in children and adolescents. However, the effects of these interventions might vary between individuals, so patients, carers, and clinicians should carefully balance the risk-benefit profile of efficacy, acceptability, and suicide risk of all active interventions in young patients with depression on a case-by-case basis. Funding National Key Research and Development Program of China. more...

Medical research is moving toward prevention strategies during prodromal states. Postpartum blues (PPB) is often a prodromal state for postpartum depression (PPD), with severe PPB strongly associated with an elevated risk for PPD. The most common complication of childbearing, PPD has a prevalence of 13%, but there are no widespread prevention strategies, and no nutraceutical interventions have been developed. To counter the effects of the 40% increase in monoamine oxidase A (MAO-A) levels that occurs during PPB, a dietary supplement kit consisting of monoamine precursor amino acids and dietary antioxidants was created. Key ingredients (tryptophan and tyrosine) were shown not to affect their total concentration in breast milk. The aim of this open-label study was to assess whether this dietary supplement reduces vulnerability to depressed mood at postpartum day 5, the typical peak of PPB. Forty-one healthy women completed all study procedures. One group (n = 21) received the dietary supplement, composed of 2 g of tryptophan, 10 g of tyrosine, and blueberry juice with blueberry extract. The control group (n = 20) did not receive any supplement. PPB severity was quantitated by the elevation in depressed mood on a visual analog scale following the sad mood induction procedure (MIP). Following the MIP, there was a robust induction of depressed mood in the control group, but no effect in the supplement group [43.85 ± 18.98 mm vs. 0.05 ± 9.57 mm shift; effect size: 2.9; F(1,39) = 88.33, P < 0.001]. This dietary supplement designed to counter functions of elevated MAO-A activity eliminates vulnerability to depressed mood during the peak of PPB. more...

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. This section is the first of six guidelines articles. Results: In Canada, the annual and lifetime prevalence of MDD was 4.7% and 11.3%, respectively. MDD represents the second leading cause of global disability, with high occupational and economic impact mainly attributable to indirect costs. DSM-5 criteria for depressive disorders remain relatively unchanged, but other clinical dimensions (sleep, cognition, physical symptoms) may have implications for depression management. e-Mental health is increasingly used to support clinical and self-management of MDD. In the 2-phase (acute and maintenance) treatment model, specific goals address symptom remission, functional recovery, improved quality of life, and prevention of recurrence. Conclusions: The burden attributed to MDD remains high, whether from individual distress, functional and relationship impairment, reduced quality of life, or societal economic cost. Applying core principles of care, including comprehensive assessment, therapeutic alliance, support of self-management, evidence-informed treatment, and measurement-based care, will optimize clinical, quality of life, and functional outcomes in MDD. more...

Background Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people. Methods We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023. Findings We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference −0·51, 95% credible interval [CrI] −0·99 to −0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I2 values were 33·21% for efficacy and 0% for tolerability. Interpretation When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated. more...

Cross-sectional, questionnaire-based study.To test the hypothesis that self-perceived functional impairment and religiosity/spirituality (S/R) predict depression among traumatic spinal cord injury (SCI) patients in Sri Lanka.Ragama Rheumatology and Rehabilitation Hospital, Ragama, Sri Lanka.The Spinal Cord Independence Measure, Benefit Through Spirituality/Religiosity Scale, Sheehan Disability Inventory and Beck Depression Inventory-II (BDI-II) were administered to 61 consenting in-patients with traumatic SCI between June and July 2014. A linear regression model on BDI-II score was developed to examine the impact of self-perceived functional impairment and S/R activities on psychiatric outcomes in context of various sociodemographic variables.Psychiatric consequences of SCI were reflected in a 41% prevalence of depression. Thirty-six percent (RPerceived functional impairment in work, social and family domains predicted depressive symptomatology among SCI inpatients in Sri Lanka, while perceived benefit through S/R protected against depression. The findings emphasize the need for rehabilitative programming to support patients' S/R activities and mental wellbeing, promoting reintegration into their community roles. more...

OBJECTIVE To report the symptomatic and functional outcomes in patients with major depressive disorder (MDD) during a 2-phase treatment trial and to estimate the value of early improvement after 2 weeks in predicting clinical response to escitalopram and subsequently to adjunctive treatment with aripiprazole. METHODS Participants with MDD (N = 211) identified with the Montgomery-Asberg Depression Rating Scale (MADRS) and confirmed with the Mini-International Neuropsychiatric Interview were recruited from 6 outpatient centers across Canada (August 2013 through December 2016) and treated with open-label escitalopram (10-20 mg) for 8 weeks (Phase 1). Clinical and functional outcomes were evaluated using the MADRS, Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Sheehan Disability Scale (SDS), and Lam Employment Absence and Productivity Scale (LEAPS). Participants were evaluated at 8 and 16 weeks for clinical and functional response and remission. Phase 1 responders continued escitalopram while nonresponders received adjunctive aripiprazole (2-10 mg) for a further 8 weeks (Phase 2). RESULTS After Phase 1, MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10) were, respectively, 47% and 31%, and SDS response (score ≤ 12) and remission (score ≤ 6) were, respectively, 53% and 24%. Response to escitalopram was maintained in 91% of participants at week 16, while 61% of the adjunctive aripiprazole group achieved MADRS response during Phase 2. Response and remission rates with the QIDS-SR were lower than with the MADRS. The LEAPS demonstrated significant occupational improvement (P < .05). Early symptomatic improvement predicted outcomes with modest accuracy. CONCLUSIONS This study demonstrates comparable symptomatic and functional outcomes to those of other large practical-design studies. There was a high response rate with the adjunctive use of aripiprazole in escitalopram nonresponders. Given the limited value of early clinical improvement to predict outcome, integration of clinical and biological markers deserves further exploration. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01655706. more...

Complementary and alternative medicine (CAM) therapies are a group of diverse medical and health systems, practices, and products not currently considered to be part of conventional medicine. These therapies are growing in popularity, with approximately 50% of patients with depressive disorders reported to use some form of alternative treatment. Often perceived as natural and safer alternatives without many of the adverse effects commonly associated with pharmacotherapy, CAM therapies have great potential in the management of treatment-resistant depression (TRD). Many CAM therapies work via mechanisms other than those of antidepressant medications and, as such, may be viable options for patients who have failed to achieve remission with pharmacotherapy and for those who cannot adhere to medications due to intolerable adverse effects. Moreover, augmentation of pharmacotherapy with CAMs can be a practical option for partial responders for whom antidepressant medication doses cannot be increased due to issues of safety and tolerability. However, the evidence on efficacy and safety of different CAM interventions in TRD is limited. The aim of this chapter is to present the available evidence on CAM therapies for TRD, to serve as a guide for the clinician to tailor an alternate therapeutic approach for patients with treatment resistance. Based on the available data on efficacy, safety, and practicality, the most robust evidence is for exercise, mindfulness-based cognitive therapy, and omega-3 fatty acids as adjunctive treatments. There is less evidence on efficacy of yoga, light therapy, and S-adenosyl-L-methionine. Despite current limitations in the availability of studies in TRD, there is a growing body of evidence in support of specific CAMs in TRD, indicating therapeutic potential. As such, CAM therapies as add-on to evidence-based first-line interventions may be considered as part of an integrative approach to the management of treatment resistance. more...

Objective Both Mindfulness Based Cognitive Therapy (MBCT) and Cognitive Therapy (CT) enhance self-management of prodromal symptoms associated with depressive relapse, albeit through divergent therapeutic procedures. We evaluated rates of relapse in remitted depressed patients receiving MBCT and CT. Decentering and dysfunctional attitudes were assessed as treatment-specific process markers. Method Participants in remission from Major Depressive Disorder (MDD; N = 166) were randomized to 8 weeks of either MBCT (N = 82) or CT (N = 84) and were followed for 24 months, with process markers measured every 3 months. Attendance in both treatments was high (6.3/8 session) and treatment fidelity and competence were evaluated. Relapse was defined as a return of symptoms meeting the criteria for major depression on Module A of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (SCID). Results Intention-to-treat analyses indicated no differences between MBCT and CT in either rates of relapse to MDD or time to relapse across 24 months of follow up. Both groups experienced significant increases in decentering and participants in CT reported greater reductions in dysfunctional attitudes. Within both treatments, participants who relapsed evidenced lower decentering scores than those who stayed well over the follow up. Conclusions This is the first study to directly compare relapse prophylaxis following MBCT and CT directly. The lack of group differences in time to relapse supports the view that both interventions are equally effective and that increases in decentering achieved via either treatment are associated with greater protection. These findings lend credence to Teasdale et al.'s (2002) contention that, even though they may be taught through dissimilar methods, CT and MBCT help participants develop similar metacognitive skills for the regulation of distressing thoughts and emotions. (PsycINFO Database Record more...

Lithium is a commonly prescribed treatment for bipolar disorder. Many early studies on which its use has been historically based no longer meet current research standards. A large number of studies with more modern designs have been recently published warranting a review. New research adds to the evidence for lithium's efficacy in mania and maintenance. There is also additional evidence, albeit less robust, to support its benefit in bipolar depression and mixed episodes. Meta-analyses of mainly observational data have found reduced suicidal behavior in bipolar patients taking lithium. Careful monitoring and prescribing can reduce the risk of adverse effects. more...

Postpartum depression (PPD) is the most common complication of childbearing with a 13 % prevalence rate, and there is no widespread approach for prevention. There is an appealing theoretical rationale for oral tyrosine to help prevent PPD. However, the effect of oral tyrosine on its total and free concentrations in breast milk and plasma of breastfeeding mothers is not known. Twenty-four healthy breastfeeding women were randomly assigned to 0, 2, 5, or 10 g of oral tyrosine. Free and total tyrosine in breast milk and free tyrosine in plasma were measured. Free tyrosine was also measured in 12 different infant formulas. Total tyrosine in breast milk did not rise, but there was a slight tendency towards a reduction (up to −12 %; repeated measures ANOVA (RMANOVA): p = 0.074). Maternal plasma tyrosine rose (RMANOVA: p more...

Background Postpartum depression (PPD) is the most common complication of childbearing with a 13% prevalence. Vulnerability to depressed mood has an important role in the onset of major depressive episodes (MDE), but has not been investigated in postpartum. The aim is to assess whether day-5 postpartum blues and severity of dysfunctional attitudes predicts vulnerability to depressed mood. Methods About 45 healthy women were recruited: group 1 (n=12) was day-5 postpartum during the typical peak of postpartum blues. Group 2 (n=11) was within 18 months postpartum and reported a vulnerability to cry (and had elevated dysfunctional attitudes but no MDE). Group 3 (n=11) was within 18 months postpartum and no vulnerability to cry. Group 4 (n=11) was not recently postpartum. Vulnerability to depressed mood was measured by the change in the visual analog scale from the sad mood induction procedure (MIP). Results Univariate analysis of covariance demonstrated that day-5 postpartum blues and level of dysfunctional attitudes were highly predictive of change in sad mood (postpartum blues: F(1,41)=12.9, p Limitations Although the effects were robust, sample sizes were 11–12 within each group. Conclusion Two factors (day-5 postpartum and severity of dysfunctional attitudes) predicted vulnerability to sad mood. Since the severity of postpartum blues predicts PPD, MIP on day-5 postpartum represents a quantitative measure that can be applied to screen novel, early interventions for preventing PPD. Interventions to prevent PPD through increasing resilience against mood induction should target postpartum women with greater severity of dysfunctional attitudes. more...

Background With the largest proportion of world's total population, the mental health pandemic in China and related challenges of treating mental disorders could influence the accomplishment of UN Sustainable Development Goals, which include mental health. Therefore, understanding China's current mental health status after rapid economic and social transformations, including urbanisation, industrialisation, globalisation and informatisation, could strengthen awareness of mental health, and aid the proposal of solutions to prevent and control mental disorders. Methods We did a systematic search of the literature using PubMed, Embase, PsycINFO, CNKI, and Wanfang databases to find relevant studies published between Jan 1, 1990, and Dec 31, 2018. Articles in English and Chinese were included. The search terms included “urbanisation”, “industrialisation”, “globalisation”, “informatisation”, “mental disorders[MeSH Term]” and “China”. Findings During the past three decades, both the disease and economic burden of mental disorders have increased in China. Rapid urbanisation and industrialisation have resulted in increasing internal migration and left-behind families, who have poorer mental health status than their peers. The ageing population will lead to higher prevalence of mental and neurological disorders, such as depression and dementia. Adoption of unhealthy diets can directly affect mental health, as well as indirectly by facilitating intermediate risk factors such as obesity. Increased alcohol intake and smoking can induce increased alcohol and nicotine dependence, and even illicit drug abuse. Additionally, internet and social media use can not only increase internet or gaming addiction, but also facilitate exposure and delivery channels via the internet. The growth of urbanisation and manufactories has also increased air, light, and noise pollution that can further induce mental problems. Interpretation Social and economic transformations have triggered increasing disease and economic burden of mental disorders. We propose three priorities to deal with these challenges: identify social and economic effects on mental health on the basis of high-quality qualitative and quantitative analysis, improve mental health awareness and literacy, and enhance the mental health-care system and promote implementation research. Lessons from China can be a great reference for low-and-middle-income countries (LMICs) and upper-middle-income countries in prevention and control mental disorders. Funding National Natural Science Foundation of China. more...

Background Depressed and anxious patients often combine complementary and alternative medicine (CAM) therapies with conventional pharmacotherapy to self-treat symptoms. The benefits and risks of such combination strategies have not been fully evaluated. This paper evaluates the risk-benefit profile of CAM augmentation to antidepressants in affective conditions. Methods PubMed was searched for all available clinical reports published in English up to December 2012. Data were evaluated based on graded levels of evidence for efficacy and safety. Results Generally, the evidence base is significantly larger for depression than for anxiety disorder. In unipolar depression, there is Level 2 evidence for adjunctive sleep deprivation (SD) and Free and Easy Wanderer Plus (FEWP), and Level 3 for exercise, yoga, light therapy (LT), omega-3 fatty acids, S-adenosylmethionine and tryptophan. In bipolar depression, there is Level 1 evidence for adjunctive omega-3s, Level 2 for SD, and Level 3 for LT and FEWP. In anxiety conditions, exercise augmentation has Level 3 support in generalized anxiety disorder and panic disorder. Though mostly well-tolerated, these therapies can only be recommended as third-line interventions due to the quality of available evidence. Limitations Overall, the literature is limited. Studies often had methodological weaknesses, with little information on long-term use and on potential drug–CAM interactions. Many CAM studies were not published in English. Conclusions While several CAM therapies show some evidence of benefit as augmentation in depressive disorders, such evidence is largely lacking in anxiety disorders. The general dearth of adequate safety and tolerability data encourages caution in clinical use. more...

Several studies have examined whether ethnicity as an independent factor can influence the individual's dosage of antipsychotics. However, there has been inconsistency in the results of these studies, particularly between white and non-white populations. This retrospective study tests the hypothesis of different dosing of antipsychotics in white Europeans vs. non-white Europeans considering both the self-reported ethnicity and the geographical ancestry calculated using 196 DNA markers.We collected self-reported ethnicity and DNA samples from 209 schizophrenia patients. We tested the association between self-reported and genetically-determined ethnicity with the chlorpromazine equivalent dose of each antipsychotic prescribed at the time of the assessment.We did not find any significant difference between self-reported white European -ethnicity and chlorpromazine equivalent doses (p=0.972). Furthermore, when we considered the geographical ancestry determined by the 196 SNPs, we could not find any correlation between the European ancestry and chlorpromazine equivalent dose.Our preliminary analysis shows that there is no evidence that different ethnic groups receive different dose of antipsychotics. more...

Anhedonia has traditionally been considered a characteristic feature of schizophrenia, but the true nature of this deficit remains elusive. This study sought to investigate consummatory and anticipatory pleasure as it relates to motivation deficits. Eighty-four outpatients with schizophrenia and 81 healthy controls were administered the Temporal Experience of Pleasure Scale (TEPS), as well as a battery of clinical and cognitive assessments. Multivariate analyses of variance were used to examine the experience of pleasure as a function of diagnosis, and across levels of motivation deficits (i.e. low vs. moderate. vs. high) in schizophrenia. Hierarchical regression analyses were also conducted to evaluate the predictive value of amotivation in relation to the TEPS. There were no significant differences between schizophrenia and healthy control groups for either consummatory or anticipatory pleasure. Within the schizophrenia patients, only those with high levels of amotivation were significantly impaired in consummatory and anticipatory pleasure compared to low and moderate groups, and compared to healthy controls. Further, our results revealed that amotivation significantly predicts both consummatory and anticipatory pleasure, with no independent contribution of group. Utilizing study samples with a wide range of motivation deficits and incorporating objective paradigms may provide a more comprehensive understanding of hedonic deficits. more...

Throughout the world, antidepressants (AD) and phosphodiesterase-5 inhibitors (PDE-5i) are the commonly prescribed psychopharmacological agents for treating patients with co-morbid mental health problem and sexual dysfunction (SD). The serotonergic and noradrenergic ADs, although effective, are not without any SD adverse-effects, especially erectile dysfunction (ED). ED is a failure to obtain a satisfactory erection for rewarding sexual coitus during the phases of male’s sexual arousal. It is recognized as an important reason why non-adherence to treatment was observed in patients who were on AD. AD intervention caused remission to some of the pre- treatment psychopathology of ED. However, in many patients, AD potentially magnified the unwanted sexual sideeffects. This made the situation challenging for the mental health professional. These challenges are based on the complexity of ED, its etiology and the associated risk factors, which further add to its AD side-effect. The neuro-psychopharmacological basis for AD treatment selection was deliberated. Bio-psycho-social interventions are recommended at two pivotal stages. Firstly, a step should be taken for proper assessment (e.g. detailed history, psychosocial and laboratory investigations); and identify few modifiable risk factors for ED and associated mental health issues. Secondly, with guidance of an algorithm pathway, a practical intervention should include strategies such as dose reduction, augmentation or changing to an AD with lesser or no sexual adverse-effects. It is recommended that bupropion and mirtazepine to be prescribed when patients develop adverse sexual effects with serotonin selective reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI) and tricyclic antidepressant (TCA). Few suggestions which may be borne in mind are revising sexual scripts and improving sexual techniques, life-style modifications, psychotherapy and other nonpharmacological approaches which may be beneficial to both patients and their partners. more...

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. more...

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. This section on “Special Populations” is the sixth of six guidelines articles. Results: Recent studies inform the treatment of MDD in children and adolescents, pregnant and breastfeeding women, women in perimenopause or menopause, and the elderly. Evidence for efficacy of treatments in these populations is more limited than for the general adult population, however, and risks of treatment in these groups are often poorly studied and reported. Conclusions: Despite the limited evidence base, extant data and clinical experience suggest that each of these special populations can benefit from the systematic application of treatment guidelines for treatment of MDD. more...

Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers (“biomarkers”) of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10–20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2–10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research. ClinicalTrials.gov identifier NCT01655706 . Registered July 27, 2012. more...

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. There is renewed interest in refined approaches to brain stimulation, particularly for treatment resistant major depressive disorder (MDD). Methods The CANMAT guidelines are based on a question–answer format to enhance accessibility to clinicians. An evidence-based format was used with updated systematic reviews of the literature and recommendations were graded according to Level of Evidence using pre-defined criteria. Lines of Treatment were identified based on criteria that included evidence and expert clinical support. This section on “Neurostimulation Therapies” is one of 5 guidelines articles. Results Among the four forms of neurostimulation reviewed in this section, electroconvulsive therapy (ECT) has the most extensive evidence, spanning seven decades. Repetitive transcranial magnetic (rTMS) and vagus nerve stimulation (VNS) have been approved to treat depressed adults in both Canada and the United States with a much smaller evidence base. There is also emerging evidence that deep brain stimulation (DBS) is effective for otherwise treatment resistant depression, but this is an investigational approach in 2009. Limitations Compared to other modalities for the treatment of MDD, the data based is limited by the relatively small numbers of randomized controlled trials (RCTs) and small sample sizes. Conclusions There is most evidence to support ECT as a first-line treatment under specific circumstances and rTMS as a second-line treatment. Evidence to support VNS is less robust and DBS remains an investigational treatment. more...

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. Methods The CANMAT guidelines are based on a question–answer format to enhance accessibility to clinicians. An evidence-based format was used with updated systematic reviews of the literature and recommendations were graded according to Level of Evidence using pre-defined criteria. Lines of Treatment were identified based on criteria that included Levels of Evidence and expert clinical support. This section on “Pharmacotherapy” is one of 5 guideline articles. Results Despite emerging data on efficacy and tolerability differences amongst newer antidepressants, variability in patient response precludes identification of specific first choice medications for all patients. All second-generation antidepressants have Level 1 evidence to support efficacy and tolerability and most are considered first-line treatments for MDD. First-generation tricyclic and monoamine oxidase inhibitor antidepressants are not the focus of these guidelines but generally are considered second- or third-line treatments. For inadequate or incomplete response, there is Level 1 evidence for switching strategies and for add-on strategies including lithium and atypical antipsychotics. Limitations Most of the evidence is based on trials for registration and may not reflect real-world effectiveness. Conclusions Second-generation antidepressants are safe, effective and well tolerated treatments for MDD in adults. Evidence-based switching and add-on strategies can be used to optimize response in MDD that is inadequately responsive to monotherapy. more...

Background Major depressive disorder (MDD) is one of the most burdensome illnesses in Canada. The purpose of this introductory section of the 2009 revised CANMAT guidelines is to provide definitions of the depressive disorders (with an emphasis on MDD), summarize Canadian data concerning their epidemiology and describe overarching principles of managing these conditions. This section on “Classification, Burden and Principles of Management” is one of 5 guideline articles in the 2009 CANMAT guidelines. Methods The CANMAT guidelines are based on a question–answer format to enhance accessibility to clinicians. An evidence-based format was used with updated systematic reviews of the literature and recommendations were graded according to the Level of Evidence using pre-defined criteria. Lines of Treatment were identified based on criteria that included evidence and expert clinical support. Results Epidemiologic data indicate that MDD afflicts 11% of Canadians at some time in their lives, and approximately 4% during any given year. MDD has a detrimental impact on overall health, role functioning and quality of life. Detection of MDD, accurate diagnosis and provision of evidence-based treatment are challenging tasks for both clinicians and for the health systems in which they work. Limitations Epidemiologic and clinical data cannot be seamlessly linked due to heterogeneity of syndromes within the population. Conclusions In the eight years since the last CANMAT Guidelines for Treatment of Depressive Disorders were published, progress has been made in understanding the epidemiology and treatment of these disorders. Evidence supporting specific therapeutic interventions is summarized and evaluated in subsequent sections. more...

Summary Background Acute depression has been associated with increased hypothalamic–pituitary–adrenal (HPA) reactivity. While chronicity of depressive illness influences symptoms, course and outcome, its effect on the HPA axis has not been extensively evaluated. The current study evaluated cortisol stress responses to a social challenge in chronic major depressive disorder (CMDD). Methods Cortisol stress responses to the Trier Social Stress Test (TSST) were compared in 26 participants with CMDD and 28 healthy controls using repeated measures analysis of variance (RANOVA). In addition, group differences in area under the curve (AUC) and peak percentage change in cortisol were examined. Results The RANOVA indicated a significant sex by condition interaction in cortisol responses to the social challenge. Post-hoc testing of pair-wise group differences revealed that in females, CMDD subjects had greater cortisol levels in response to the TSST than did controls. Similarly, AUC was greater in females with CMDD than in female controls. Neither of these differences was significant in males. However, male CMDD subjects exhibited a significantly decreased peak percentage change in cortisol in response to the TSST than did male controls. Conclusions Males and females with CMDD exhibited unique differences in cortisol responses to the social challenge relative to controls. In females, CMDD subjects had greater overall secretion of cortisol whereas in males, CMDD subjects had a blunted peak response to the social stressor. Sex differences are an important consideration in future work in this population. more...

OBJECTIVE To evaluate the efficacy, safety, and tolerability of adjunctive osmotic-release oral system (OROS) methylphenidate in outpatients with major depressive disorder (MDD) receiving a stable oral antidepressant regimen. METHOD This multicenter, double-blind, randomized, placebo-controlled, parallel-group, 5-week trial enrolled 145 subjects who met DSM-IV-TR criteria for MDD and who had failed 1 to 3 previous antidepressant monotherapies (including current antidepressant) of adequate dose and duration. Augmentation therapy was initiated with 18 mg of OROS methylphenidate and increased to a maximum dose of 54 mg of OROS methylphenidate until an optimal dose was achieved. Efficacy scales included the Montgomery-Asberg Depression Rating Scale (MADRS), 7 atypical items from the 31-item Hamilton Rating Scale for Depression, the Clinical Global Impressions-Severity of Illness (CGI-S) scale, the CGI-Improvement scale (CGI-I), the Sex Effects scale, the Multidimensional Assessment of Fatigue (MAF) scale, and the Apathy Evaluation Scale (AES). Subjects were recruited at 17 community and academic centers across Canada. The study was conducted from June 8, 2005, to April 18, 2006. RESULTS There was no statistically significant difference between the groups at endpoint on the MADRS. OROS methylphenidate was superior to placebo in improving apathy and fatigue as measured by the AES and the MAF. Statistically significant differences using mixed-model analysis were observed on the AES at all visits and at endpoint (p = .01) and on the MAF (p < .01). No differences were observed on other secondary measures, including the CGI-I and CGI-S. There were no clinically significant findings on electrocardiogram. CONCLUSIONS OROS methylphenidate did not demonstrate statistical significance on the MADRS at endpoint. Apathy and fatigue were significantly improved with OROS methylphenidate treatment, which was well tolerated with minimal side effects. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov identifier NCT00246233. more...

Background Many studies have used the admixture analysis to separate age-at-onset (AAO) subgroups in bipolar disorder, but none of them examined first episode patients. Objective The purpose of this study was to investigate the influence of clinical variables on AAO in first episode bipolar patients. Methods The admixture analysis was applied to identify the model best fitting the observed AAO distribution of a sample of 194 patients with DSM-IV diagnosis of bipolar disorder and the finite mixture model was applied to assess the effect of clinical covariates on AAO. Results Using the BIC method, the model that was best fitting the observed distribution of AAO was a mixture of three normal distributions. We identified three AAO groups: early age-at-onset (EAO) ( µ =18.0, σ =2.88), intermediate-age-at-onset (IAO) ( µ =28.7, σ =3.5), and late-age-at-onset (LAO) ( µ =47.3, σ =7.8), comprising 69%, 22%, and 9% of the sample respectively. Our first episode sample distribution model was significantly different from most of the other studies that applied the mixture analysis. Limitations The main limitation is that our sample may have inadequate statistical power to detect the clinical associations with the AAO subgroups. Conclusions This study confirms that bipolar disorder can be classified into three groups based on AAO distribution. The data reported in our paper provide more insight into the diagnostic heterogeneity of bipolar disorder across the three AAO subgroups. more...

Background: Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD). Methods: Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review. Results: All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250–350mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250–350mg daily). Conclusions: All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects. more...

Since the previous publication of Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines in 1997, there has been a substantial increase in evidence-based treatment options for bipolar disorder. The present guidelines review the new evidence and use criteria to rate strength of evidence and incorporate effectiveness, safety, and tolerability data to determine global clinical recommendations for treatment of various phases of bipolar disorder. The guidelines suggest that although pharmacotherapy forms the cornerstone of management, utilization of adjunctive psychosocial treatments and incorporation of chronic disease management model involving a healthcare team are required in providing optimal management for patients with bipolar disorder. Lithium, valproate and several atypical antipsychotics are first-line treatments for acute mania. Bipolar depression and mixed states are frequently associated with suicidal acts; therefore assessment for suicide should always be an integral part of managing any bipolar patient. Lithium, lamotrigine or various combinations of antidepressant and mood-stabilizing agents are first-line treatments for bipolar depression. First-line options in the maintenance treatment of bipolar disorder are lithium, lamotrigine, valproate and olanzapine. Historical and symptom profiles help with treatment selection. With the growing recognition of bipolar II disorders, it is anticipated that a larger body of evidence will become available to guide treatment of this common and disabling condition. These guidelines also discuss issues related to bipolar disorder in women and those with comorbidity and include a section on safety and monitoring. more...

Diagnostic criteria for generalized anxiety disorder(GAD) have shifted in the past 20 years, fromDSM-III/III-R to DSM-IV, resulting in anincreased emphasis on psychic symptoms (anxietyand worry), and decreased emphasis on somaticand autonomic symptoms. The DSM-IV diagnos-tic criteria of GAD contained three somatic anxietysymptoms of a total of six (50%), while in DSM-III-R there were 12 such symptoms (67%) of 18.Studies have confirmed that this reduction insomatic symptoms is associated with increaseddiagnostic reliability (1–3).That a cluster of symptoms lacks nosological ordiscriminative value does not mean that the symp-toms do not contribute to the clinical presentationand distress associated with the disorder. Thisdictum is illustrated by sampling of randomizedclinical trials (RCTs) in GAD over the past twodecades: for patients enrolled in RCTs using DSM-III criteria, the Hamilton anxiety rating scale(HAM-A) somatic factor contributed 37–42% oftotal HAM-A severity (4–6). Among eight RCTsreported in the past 5 years using DSM-IV criteria,the HAM-A-somatic factor contributed a similar42–46% of total HAM-A severity (Rickels K,Pollack MH, Lydiard RB et al. Efficacy and safetyof pregabalin and alprazolam in GAD. Posterpresentation, APA annual meeting San Francisco,May 2002; Kasper S, Blagden M, Sehers S et al. Aplacebo-controlled study of pregabalin and venla-faxine treatment of GAD. Poster presentation,APA Annual meeting San Francisco, May 2002)(7–12). This quite constant proportion suggeststhat despite the considerable shift in diagnosticDahl AA, Ravindran A, Allgulander C, Kutcher SP, Austin C, Burt T.Sertraline in generalized anxiety disorder: efficacy in treating the psychicand somatic anxiety factors.Acta Psychiatr Scand 2005: 111: 429–435. Blackwell Munksgaard2005.Objective: The objective was to study the efficacy of sertraline onsymptoms of psychic and somatic anxiety in patients suffering frommoderate-to-severe generalized anxiety disorder (GAD).Method: Out-patients with DSM-IV GAD were randomized to12 weeks of double-blind treatment with placebo. The psychic andsomatic anxiety factors of the Hamilton Anxiety Rating Scale (HAM-A) and the Quality of Life, Enjoyment, and Satisfaction Questionnairewere analyzed.Results: Treatment with sertraline resulted in significantly greater lastobservation carried forward (LOCF)-endpoint improvement thanplacebo on both the HAM-A psychic and somatic anxiety factors. AtLOCF-endpoint, all items on the HAM-A psychic factor were moreimproved on sertraline than placebo, as were three of seven items onthe somatic factor. Reduction of secondary depressive symptoms wasmore correlated with endpoint improvement in quality of life thaneither psychic- or somatic anxiety.Conclusion: Sertraline treatment demonstrated efficacy for both thepsychic and somatic anxiety symptoms of GAD. more...

Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O’Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI. The evolution of CANMAT Bipolar Disorder Guidelines: past, present, and future. Bipolar Disord 2013: 15: 58–60. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd. more...

Background: With more effective treatments and improved outcomes in thalassemia, there is increasing focus on its psychological sequelae. Most published data on this topic are from high-income countries and much less so from low- and middle-income countries, where thalassemia is more prevalent. Aim: The aim of this study was to systematically evaluate the psychiatric morbidity and quality of life in relation to demographic- and illness-related variables among Sri Lankan patients with thalassemia. Methods: This cross-sectional investigation was conducted at the University of Kelaniya Teaching Hospital in Sri Lanka. Patients with all forms of thalassemia, over 12 years of age, and in stable medical condition (n = 120) were recruited. Assessment tools included a general demographic questionnaire, the Beck Depression Inventory-II, and the World Health Organization Quality of Life Measure–Brief. Statistical analysis was conducted using linear regressions, Chi-squares, and analyses of variance. Results: Lack of family support, longer duration of inpatient admission, and female gender were associated with higher depression scores and reduced quality of life. Environmental and social quality of life were positively correlated with levels of peer support in males, while increased support from religion correlated with lower depression scores and higher satisfaction with environmental and psychological quality of life in women. There was no association between the type of thalassemia and either depression or quality of life measures. Conclusion: Several factors may influence the psychological state and well-being of patients with thalassemia in Sri Lanka. Specific service innovations (some gender-specific) may help to address these factors to improve treatment outcome and well-being. more...

Objective Delineating clinically meaningful subgroups within heterogeneous depressed populations is a major challenge. As outlined in the Research Domain Criteria Strategy, biomarkers may help to empirically classify such patients. Following this basic strategy, the current pilot study examined whether the cortisol awakening response (CAR) following admission to hospital predicts treatment response in heterogeneous depressed patients completing a 4-week alternate milieu inpatient program. Methods The Alternate Inpatient Milieu program at the Centre for Addiction and Mental Health is composed of both individual-based and group-based programming designed to promote a recovery-oriented, collaborative treatment environment. The current sample consisted of 25 consecutive patients with various forms of complex/chronic depression who completed the full program. Saliva samples were collected at 0, 30 and 60 min after awakening on 2 consecutive days following admission. Linear regressions controlling for baseline depression scores were used to assess whether the CAR AUCg ( a rea u nder the c urve g round) and/or AUCi ( a rea u nder the c urve i ncrease) at admission predicted the change in depression scores from admission to discharge based on the Quick Inventory of Depressive Symptoms scale. Results The CAR AUCi, but not the CAR AUCg, at admission significantly predicted treatment response over the 4-week hospital stay. In these naturalistic patients with major depressive disorder, high CAR reactivity as assessed using the AUCi was associated with a better treatment response ( t =2.20; df =2,24; P =.039). The CAR was easy to implement and well accepted by patients and staff. Conclusion This pilot study suggests that CAR reactivity at admission may help to identify a subgroup of depressed patients most likely to respond clinically to a 4-week alternate milieu inpatient program. more...