The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder.

OBJECTIVE: Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. METHODS: A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. RESULTS: Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. CONCLUSIONS: There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.

Depression, Anxiety, and Other Mental Disorders in Patients With Cancer in Low- and Lower-Middle-Income Countries: A Systematic Review and Meta-Analysis.

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.

Peripheral inflammatory biomarkers define biotypes of bipolar depression.

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/ß) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r2 = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK.

Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies.

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.

Psychiatric disorders among people with cancer in low- and lower-middle-income countries: study protocol for a systematic review and meta-analysis.

INTRODUCTION: Cancer is a rapidly growing public health problem in low- and lower-middle-income countries (LLMICs). There is evidence from upper-income countries that comorbid mental illness is common and can adversely impact cancer outcomes. Little is known about this burden in LLMICs. This systematic review has two aims. The first is to review the prevalence and patterns of psychiatric comorbidity in adults with cancer in LLMICs. The second is to review psychiatric treatment outcomes in this population. METHODS AND ANALYSIS: The review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. A systematic search of electronic databases (MEDLINE, PsycInfo, Embase and CINAHL) will be conducted. Studies will be included if they report the prevalence of psychiatric comorbidity, or if they evaluate psychiatric treatment outcomes, in adults with cancer living in LLMICs. The search will be limited to studies published in peer-reviewed journals between March 2002 and March 2017. The reference lists of included studies will be hand searched. Critical appraisal will be performed using Quality Assessment Tools from the National Institute of Health. Pooled prevalence meta-analysis is planned. ETHICS AND DISSEMINATION: Ethics approval is not required as no primary data will be collected. The results will be presented at conferences and published in a peer-reviewed journal. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017057103.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments.

BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "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.

Contribution of sex hormones to gender differences in schizophrenia: A review.

Female patients with schizophrenia tend to have a more benign course and better outcomes than males. One proposed explanation is the differential influence of male and female sex hormones, including estrogen, progesterone, testosterone, and dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). Such benefit may be mediated by their effects on neurotransmitters and neuroprotection. Besides altered estrogen and DHEA/DHEAS levels in female patients, data is equivocal on hormonal differences between patients and controls. However, several reports note a mostly negative correlation between estrogen levels and symptom severity in both genders, and a positive correlation between estrogen levels and neurocognition but mainly in females. Adjunctive estrogen appears to improve symptoms in both genders. Progesterone levels have inconsistent links to symptom severity in both genders, and correlate positively with neurocognition but only in males. Estrogen-progesterone combination shows preliminary benefits as augmentation for both symptoms and neurocognition in females. Testosterone levels correlate inversely with negative symptoms in males and have inconsistent associations with neurocognition in both genders. Testosterone augmentation reduced negative symptoms in male patients in a pilot investigation, but has not been evaluated for neurocognition in either gender. DHEA/DHEAS have mixed results for their association with, and clinical utility for, symptoms and neurocognition in both genders. Overall, data on the impact of sex hormones on clinical course or as treatment for schizophrenia is limited, but estrogen has most evidence for positive influence and clinical benefit. The possibly greater tolerability and broader impact of these hormones versus existing medications support further exploration of their use.

Complementary and alternative therapies as add-on to pharmacotherapy for mood and anxiety disorders: a systematic review.

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.

Canadian Network for Mood and Anxiety Treatments (CANMAT) Clinical guidelines for the management of major depressive disorder in adults. V. Complementary and alternative medicine treatments.

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 widespread interest in complementary and alternative medicine (CAM) therapies in the treatment of 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 "Complementary and Alternative Medicine Treatments" is one of 5 guideline articles. RESULTS: There is Level 1 evidence to support light therapy in seasonal MDD and St. John's wort in mild to moderate MDD. There is also some evidence for the use of exercise, yoga and sleep deprivation, as well as for omega-3 fatty acids and SAM-e . Support for other natural health products and therapies is still limited. LIMITATIONS: The evidence base remains limited and studies often have methodological problems, including small samples, variability in dose, short duration of treatment, unknown quality of the agent and limited long-term data. Safety data are also sparse with little information about drug interactions. CONCLUSIONS: Some CAM treatments have evidence of benefit in MDD. However, problems with standardization and safety concerns may limit their applicability in clinical practice.

Effect of valproate on plasma levels of interleukin-6 in healthy male humans.

Valproate exerts many biochemical and physiological effects and may have a modulating effect on the immune system. The present study aimed to determine whether there is a treatment effect of valproate on plasma levels of the pro-inflammatory cytokine, interleukin (IL)-6, in healthy male humans. Plasma levels of IL-6 were measured in 10 healthy male humans before and after 7 days of treatment with 1000 mg per day of valproate (i.e. 500 mg in the morning and 500 mg in the evening). All the healthy subjects had no past or current psychiatric disorder. They reported to the outpatient clinic at 09.00 h for baseline sampling. Subsequently, they were commenced on valproate 1000 mg per day for 7 days. They took the last dose of valproate at 22.00 h on the day 7, and post-treatment blood sampling for plasma levels of IL-6 was carried out on day 8. An additional blood sample was also taken from each subject at the same time to measure plasma levels of valproic acid for drug compliance. We found a significant increase in plasma levels of IL-6 after the 7 days of valproate treatment in healthy male subjects. Furthermore, there was a significant positive correlation between the changes in plasma IL-6 and blood levels of valproic acid. The findings of this study are consistent with previous studies on subjects with epilepsy, suggesting a modulating effect of valproate on the pro-inflammatory cytokine IL-6 in humans. However, studies with a larger number of participants and employing a double-blind, placebo-control group are required to confirm the findings, and also the levels of other cytokines should be measured to generalize the effect to the immune system.