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Background: Psilocybin-assisted psychotherapy (PAP) is a promising treatment option for depression, with randomized controlled trials (RCTs) providing preliminary support for its safety and efficacy. However, there is a lack of consistency across existing treatment protocols and psychotherapeutic approaches. The objective of this review is to summarize and compare current psychotherapy methods of PAP in treating depression and distress in life-threatening illnesses. We sought to comprehensively summarize published psychotherapy protocols from clinical trials to provide insights for future practices., Methods: A systematic search of four databases (Embase, MEDLINE, PsycINFO, CINAHL) for data relating to psychotherapy protocols was conducted by two independent reviewers., Results: In total, our search identified 1869 articles; after removing duplicates, we screened 1107 articles. We included 70 articles in the full-text review and determined that 28 were eligible for the final review. All protocols include sessions before (preparatory) and after (integration) the psychedelic dosing session with supportive monitoring. However, there was substantial variability and inconsistencies in all other aspects of therapy protocols (e.g., duration and number of sessions, model of therapy). Additionally, significant limitations were identified in the frequent need for more clarity in the description of therapeutic approaches., Conclusion: In published clinical trials, PAP has consisted of preparation, supportive dosing, and integration sessions. Beyond this basic framework, significant heterogeneity and lack of clarity were identified in reported psychotherapy protocols, meaning a validated and universally agreed upon protocol for PAP currently does not exist. Future studies should more clearly define and report psychotherapeutic components to identify the safest and most efficacious approaches to PAP., Competing Interests: Declaration of competing interest Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition DiscoveryFoundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He was formerly the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health). Dr. Roger McIntyre has received research grant support from Global Alliance for Chronic Diseases/Canadian Institutes of Health Research (CIHR)/National Natural Science Foundation of China's Mental Health Team Grant; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Zoe Doyle is a Clinical Project Lead at Braxia Scientific and a Project Lead at Braxia Health (Canadian Rapid Treatment Centre of Excellence). None of the remaining authors have any potential competing interests to disclose., (Copyright © 2024. Published by Elsevier Ltd.)

Neurological manifestations have been widely reported in adults with COVID-19, yet the extent of involvement among the pediatric population is currently poorly characterized. The objective of our systematic review is to evaluate the association of SARS-CoV-2 infection with neurological symptoms and neuroimaging manifestations in the pediatric population. A literature search of Cochrane Library; EBSCO CINAHL; Global Index Medicus; OVID AMED, Embase, Medline, PsychINFO; and Scopus was conducted in accordance with the Peer Review of Electronic Search Strategies form (October 1, 2019 to March 15, 2022). Studies were included if they reported (1) COVID-19-associated neurological symptoms and neuroimaging manifestations in individuals aged <18 years with a confirmed, first SARS-CoV-2 infection and were (2) peer-reviewed. Full-text reviews of 222 retrieved articles were performed, along with subsequent reference searches. A total of 843 no-duplicate records were retrieved. Of the 19 identified studies, there were ten retrospective observational studies, seven case series, one case report, and one prospective cohort study. A total of 6985 individuals were included, where 12.8% (n = 892) of hospitalized patients experienced neurocognitive impairments which includes: 1) neurological symptoms (n = 294 of 892, 33.0%), 2) neurological syndromes and neuroimaging abnormalities (n = 223 of 892, 25.0%), and 3) other phenomena (n = 233 of 892, 26.1%). Based on pediatric-specific cohorts, children experienced more drowsiness (7.3% vs. 1.3%) and muscle weakness (7.3% vs. 6.3%) as opposed to adolescents. Agitation or irritability was observed more in children (7.3%) than infants (1.3%). Our findings revealed a high prevalence of immune-mediated patterns of disease among COVID-19 positive pediatric patients with neurocognitive abnormalities., Competing Interests: Declaration of competing interest Dr. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Dr. Roger Ho has received research funding from NUS iHeathtech Other Operating Expenses (R-722-000-004-731). Dr. Rodrigo B. Mansur has received research grant support from the Canadian Institutes of Health Research (CIHR), the Physicians' Services Incorporated (PSI) Foundation and the Baszucki Brain Research Fund; and support from an Academic Scholars Award from the Department of Psychiatry, University of Toronto. Dr. Joshua D. Rosenblat is the medical director of the Braxia Health (formally known as the Canadian Rapid Treatment Center of Excellence and is a fully owned subsidiary of Braxia Scientific Corp) which provides ketamine and esketamine treatment for depression; he has received research grant support from the American Psychiatric Association, the American Society of Psychopharmacology, the Canadian Cancer Society, the Canadian Psychiatric Association, the Joseph M. West Family Memorial Fund, the Timeposters Fellowship, the University Health Network Centre for Mental Health, and the University of Toronto and speaking, consultation, or research fees from Allergan, COMPASS, Janssen, Lundbeck, and Sunovion. Dr. Taeho G. Rhee was supported in part by the National Institute on Aging (NIA) through Yale School of Medicine (#T32AG019134) in the past 3 years. Dr. Rhee has also been funded by the NIA and National Institute of Mental Health (#R21MH117438 and R21AG070666) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. Kayla M. Teopiz has received personal fees from Braxia Scientific Corp., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: A low protein diet (LPD) for chronic kidney disease (CKD) is a core dietary therapy to slow CKD progression. A study showed depressive symptoms are more common in populations with an LPD. In this cross-sectional study, we evaluated depressive symptoms and health-related quality of life (HRQOL) in patients with CKD., Methods: A total of 571 CKD patients were enrolled in this study. The LPD was defined with dietary protein intake ≤0.8 g/kg/day. We divided the CKD into mild CKD and advanced CKD according to severity, as well as diabetic kidney disease (DKD) and non-DKD according to DM. The logistic regression analysis was performed to evaluate the association between an LPD and depressive symptoms as well as HRQOL in CKD patients and each subgroup., Results: An LPD had significantly higher unadjusted Odds Ratio (OR) (1.81, [95% for Confidence Interval (CI), 1.18-2.76]) and multivariate-adjusted OR (1.80, [1.15-2.81]) for depressive symptoms. Moreover, an LPD showed significantly higher unadjusted OR (2.08, 1.44-3.01]) and multivariate OR (2.04, [1.38-3.02]) for poor HRQOL. In DKD subgroups, an LPD had a significant increase in unadjusted OR (2.00, [1.12-3.57]) and multivariate OR (1.99, [1.01-3.44]) for depressive symptoms. The advanced CKD group also showed that an LPD had significantly higher unadjusted OR (1.97, [1.13-3.42]) and multivariate OR (2.03, [1.12-3.73]) for depressive symptoms., Conclusions: An LPD for CKD patients was significantly associated with depressive symptoms and poor HRQOL. Subgroup analysis indicated that DKD and advanced CKD are more predisposed to depressive symptoms and poor HRQOL., Competing Interests: Declaration of competing interest RSM has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC); speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, Atai Life Sciences. RSM is a CEO of Braxia Scientific Corp., (Copyright © 2023. Published by Elsevier Ltd.)

Over the past two decades, ketamine has emerged as a novel effective and rapid-acting antidepressant. While the vast majority of studies on ketamine have focused on its ability to reduce the severity of depression broadly, its effectiveness in specific domains such as cognition, anhedonia, suicidality, and workplace/social/scholastic functionality has been neglected. Similarly, current treatments (e.g., SSRIs and SNRIs) aim to improve overall depression severity, which often results in the persistence of one or more residual symptom domains and prevents full recovery to premorbid functionality. In this review, we narratively synthesize the literature pertaining to the effectiveness of ketamine in treating key domains of depressive symptomatology (i.e., cognition, anhedonia, suicidality, and psychosocial functionality). Our findings suggest that ketamine is effective across domains varyingly, with the strongest evidence being for its ability to reduce suicidality. The rapid acting nature of ketamine further supports its use in treating suicidality and potentially preventing the completion of suicide. Evidence for the effectiveness of ketamine in other domains is weak, primarily due to a lack of robust studies specifically designed to assess these domains as primary outcomes. Future studies should scrutinize the effects of ketamine on specific domains of depression to optimize its implementation., Competing Interests: Declaration of competing interest Dr Roger Ho received funding from National University of Singapore iHeathtech Other Operating Expenses (A-0001415-09-00). Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He is the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health). Dr. Roger S McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes,Neumora Therapeutics, Boehringer Ingelheim,Sage,Biogen,Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals,Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Kayla M. Teopiz has received personal fees from Braxia Scientific Corp., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Previous studies have evaluated the relationship between anhedonia and suicidality; however, to our knowledge, there has been no quantitative synthesis evaluating the foregoing association to date. Herein, this meta-analysis aims to provide a quantitative synthesis of the extant literature reporting on the association between levels of anhedonia across all dimensions (e.g., anticipatory, consummatory) amongst individuals endorsing suicidality. Online databases (i.e., PubMed, PsycINFO, Google Scholar) were searched from inception to 13 June 2022. Studies which assessed an aspect of suicidality (i.e., ideation, attempts) and a validated anhedonia scale were included. The risk of bias was assessed using the ROBINS-1 tool, and the quality of the sources was evaluated using GRADE criteria. The results of the studies were quantitatively synthesized using Pearson's r effect sizes via a random-effects meta-analysis. A total of 20 studies and 11,212 individuals were included in the final quantitative synthesis. Overall, results indicate that anhedonia has a significant and moderate correlation with suicidality in general and psychiatric populations (r = 0.31, p < 0.001 and r = 0.32, p < 0.001 respectively). Sub-analysis suggests a larger effect of anticipatory and consummatory interpersonal anhedonia (r = 0.40, p < 0.001). The identification of increased levels of anhedonia in individuals with suicidality indicates that anhedonia may be a core risk factor for suicidal ideation and behaviours. Future studies should endeavour to develop a comprehensive risk assessment encompassing all domains of anhedonia which can be utilized in a primary care setting as a potential prevention strategy for suicidal behaviours and outcomes., Competing Interests: Declaration of competing interest Dr. Roger McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage,Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He is the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health).Dr. Rodrigo B. Mansur has received research grant support from the Canadian Institute of Health Research (CIHR); Physician Services Inc (PSI) Foundation; the Baszucki Brain Research Fund; and an Academic Scholars Award, University of Toronto. Dr. Roger Ho has received research grant support from National Medical Research Council (Singapore), and NUS iHeathtech Other Operating Expenses (R-722-000-004-731); Dr. Rhee was supported in part by the National Institute on Aging (NIA) through Yale School of Medicine (#T32AG019134) in the past 3 years. Dr. Rhee has also been funded by the NIA (#R21AG070666), National Institute of Mental Health (#R21MH117438) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. Dr. Rhee serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. Dr. Rhee has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. Dr. Rhee is currently a co-editor-in-chief of Mental Health Science and is pending to receive honorarium payments annually from the publisher, John Wiley & Sons, Inc., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

While ketamine has been used clinically over the past decades, it has only been recently shown to be a promising therapy for treatment-resistant depression (TRD). However, ketamine and related dissociative agents may also be misused recreationally, creating significant concerns for abuse liability when prescribed for depression. Although the abuse potential of ketamine is widely recognized, there is limited evidence on the differential abuse liability of ketamine enantiomers, (S)-ketamine and (R)-ketamine. The current scoping review aims to summarize the extant literature on the abuse liability of (R,S)-ketamine and the enantiomers. A systematic search was conducted on the Embase, Medline, and APA PsycInfo databases from 1947 to July 29, 2021. Clinical and preclinical studies that assessed the abuse potential of (R,S)-ketamine, (S)-ketamine, and (R)-ketamine were screened and assessed for eligibility by two independent reviewers. A total of 65 eligible studies were identified; 55 were preclinical studies and 10 were clinical studies. Only 4 preclinical studies evaluated the abuse liability of ketamine enantiomers. Available preclinical evidence suggests that (R,S)-ketamine and (S)-ketamine have greater risk for abuse compared to (R)-ketamine. (R)-ketamine, at the antidepressant-relevant doses in rodents, appears to be safe with minimal liability for abuse. Although the abuse potential of (R,S)-ketamine is well-established in animals, limited clinical studies indicate that single or repeated ketamine administrations in professionally controlled settings did not result in misuse, dependence, diversion and/or gateway activity in patients with TRD. However, most clinical studies were retrospective and did not systematically evaluate the abuse liability of ketamine via validated psychological scales/questionnaires. Future randomized controlled trials are warranted to ascertain the abuse liability of racemic, (S)- and (R)-ketamine in TRD population, especially among patients with comorbid substance use disorders., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ketamine is a promising therapeutic option in treatment-resistant depression (TRD). The acute efficacy of ketamine in TRD has been demonstrated in replicated randomised-controlled trials (RCTs), but the generalizability of RCT data to real-world practice is limited. To this end, we conducted a systematic review (Search date: 25/12/2021; 1482 records identified) and meta-analysis of studies evaluating the real-world clinical effectiveness of ketamine in TRD patients. Four overlapping syntheses (Total n = 2665 patients; k = 79 studies) and 32 meta-regressions (Total n = 2050; k = 37) were conducted. All results suggest that the mean antidepressant effect is substantial (mean ± 95% CI, % responded = 45 ± 10%; p< 0.0001, % remitted = 30 ± 5.9%; p< 0.0001, Hedges g of symptomatological improvement = 1.44 ± 0.609; p < 0.0001), but the effect varies considerably among patients. The more treatment-resistant cases were found to remit less often (p < 0.01), but no such effect on response was evident (p > 0.05). Meta-regressions also confirmed that the therapeutic effect does not significantly decline with repeated treatments (p > 0.05). These results demonstrate that even the most treatment-resistant patients may benefit from ketamine, and that mid-to-long term treatment is effective in many patients., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Following recovery from COVID-19, an increasing proportion of individuals have reported the persistence and/or new onset of symptoms which collectively have been identified as post-COVID-19 syndrome by the National Institute for Health and Care Excellence. Although depressive symptoms in the acute phase of COVID-19 have been well characterized, the frequency of depression following recovery of the acute phase remains unknown. Herein, we sought to determine the frequency of depressive symptoms and clinically-significant depression more than 12 weeks following SARS-CoV-2 infection. A systematic search of PubMed, Ovid Medline and Google Scholar for studies published between January 1, 2020 and June 5, 2021 was conducted. Frequency and factors associated with depression in post-COVID-19 syndrome were recorded and qualitatively assessed through narrative synthesis. Methodological quality and risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale (NOS) for prospective cohort studies. Of 316 articles identified through our systematic search, eight studies were included. The frequency of depressive symptoms +12 weeks following SARS-CoV-2 infection ranged from 11 to 28%. The frequency of clinically-significant depression and/or severe depressive symptoms ranged from 3 to 12%. The severity of acute COVID-19 was not associated with the frequency of depressive symptoms. However, the component studies were highly heterogeneous with respect to mode of ascertainment, time of assessment, and location and age of patients. The majority of studies did not include an unexposed control group. Future research should endeavour to produce a standardized classification of post-COVID-19 syndrome, and as well as include unexposed control groups., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There is a need for innovation with respect to therapeutics in psychiatry. Available evidence indicates that the trace amine-associated receptor 1 (TAAR1) agonist SEP-363856 is promising, as it improves measures of cognitive and reward function in schizophrenia. Hedonic and cognitive impairments are transdiagnostic and constitute major burdens in mood disorders. Herein, we systematically review the behavioural and genetic literature documenting the role of TAAR1 in reward and cognitive function, and propose a mechanistic model of TAAR1's functions in the brain. Notably, TAAR1 activity confers antidepressant-like effects, enhances attention and response inhibition, and reduces compulsive reward seeking without impairing normal function. Further characterization of the responsible mechanisms suggests ion-homeostatic, metabolic, neurotrophic, and anti-inflammatory enhancements in the limbic system. Multiple lines of evidence establish the viability of TAAR1 as a biological target for the treatment of mood disorders. Furthermore, the evidence suggests a role for TAAR1 in reward and cognitive function, which is attributed to a cascade of events that are relevant to the cellular integrity and function of the central nervous system., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Predictors of antidepressant response and adverse effects to ketamine remain poorly understood due to contradictory results. The objective of the systematic review herein is to identify and evaluate the extant literature assessing pharmacogenomic predictors of ketamine clinical benefits and adverse effects. Electronic databases were searched from inception to July 2021 to identify relevant articles. Twelve articles involving 1,219 participants with TRD, 75 who underwent elective surgeries and received ketamine as an anesthetic, 49 with pain, and 68 healthy participants met the inclusion criteria and enrolled to this review. While identified articles reported mixed results, three predictors emerged: 1) Val66Met (rs6265) brain derived neurotrophic factor (BDNF; Met allele) was associated with reduced antidepressant and anti-suicidal effects, 2) CYP2B6*6 (e.g., CYB2B6 metabolizer) was associated with more severe dissociative effects and 3) NET allelic (rs28386840) variant were associated with greater cardiovascular complications (e.g., moderate to severe treatment emergent hypertension). Several important limitations were identified, most notably the small sample sizes and heterogeneity of study design and results. Taken together, preliminary evidence suggests the potential for pharmacogenomic testing to inform clinical practices; however, further research is needed to better determine genetic variants of greatest importance and the clinical validity of pharmacogenomics to help guide ketamine treatment planning., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A proportion of individuals with major depressive disorder (MDD) do not receive adequate therapeutic benefit from conventional monoaminergic antidepressant drugs, leading to treatment-resistant depression (TRD). Ketamine has been shown to provide rapid and significant efficacy in treating patients with TRD. The majority of published studies have investigated the adjunctive efficacy of ketamine with one or more monoaminergic antidepressants. There remains a clinical need to ascertain the relative effectiveness of ketamine monotherapy versus adjunctive ketamine treatment in adults with TRD. In this retrospective study, we investigate multidimensional, self-reported outcomes (i.e., antidepressant, anti-suicidality, antianxiety, and anti-functional impairment) of 220 patients to compare monotherapy (n = 39) and adjunctive (n = 181) ketamine treatment for TRD at a community-based clinic. Both groups had clinically and statistically significant antidepressant effects (p < 0.05). Individuals receiving ketamine monotherapy exhibited a significantly greater reduction on the suicidal ideation (SI) item of the Quick Inventory for Depressive Symptomatology-Self Report 16-Item (QIDS-SR 16 ) than the adjunctive group, with a small effect size [F (1, 265) = 4.73; p = 0.03*; partial η 2  = 0.02], and a significantly higher proportion of partial responders at post-infusion 4 (p = 0.034*). No other between-group differences were significant. Limitations include the small sample, single-centred, open-label, non-randomized, uncontrolled, retrospective nature of this study and indication bias. Our real-world evidence suggests that ketamine may be effective as monotherapy or adjunct to monoamine-based treatments. A priority research and clinical vista is to identify subsets of individuals with TRD who are most likely to have a desired therapeutic outcome with monotherapy versus adjunctive ketamine treatment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Psychedelics are a hallucinogenic class of psychoactive drugs with the primary effect of activating non-ordinary states of consciousness. Due to the positive preliminary findings of these drugs in the treatment of psychiatric disorders, the number of registered clinical studies has risen significantly. In this paper, clinical studies registered on clinicaltrials.gov that evaluate the treatment of any psychiatric disorder with psychedelics (excluding ketamine) are summarized and analyzed. 70 registered studies were identified from a clinicaltrials.gov search on December 3, 2020. The majority of studies aim to investigate methylenedioxymethamphetamine (MDMA) (45.7%) and psilocybin (41.4%). Studies evaluating ayahuasca, lysergic acid diethylamide (LSD), ibogaine hydrochloride, salvia divinorum, 5-MeO-DMT and DMT fumarate were less common at 1.4%, 4.2%, 2.8%, 1.4%, 1.4% and 1.4% of total registered studies, respectively. Most of the studies on MDMA, psilocybin, ayahuasca and salvia divinorum investigated their therapeutic effect on post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). LSD was investigated for MDD, anxiety, and severe somatic disorders and ibogaine hydrochloride was investigated for substance and alcohol use disorders. 5-MeO-DMT and DMT fumarate were both investigated for MDD. Only 21/70 registered studies had published results with the majority not yet completed. In view of the large number of ongoing studies investigating psychedelics, it is imperative that these studies are considered by researchers and stakeholders in deciding the most relevant research priorities for future proposed studies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Fibromyalgia (FM) is a condition associated with chronic pain in muscles and soft tissues. Extant literature has demonstrated an association between FM, mood symptoms and suicidal behaviour. This systematic review aims to synthesize available literature assessing the prevalence of suicidality in FM populations and qualitatively review the included articles., Methods: PsycINFO, Google Scholar and PubMed databases were systematically searched for studies published from database inception to 15 February 2020. Studies were included that assessed FM as a primary or co-primary disease condition, as well as an assessment of suicidal behaviour (suicidal ideations (SI), suicide attempts (SA) and death by suicide (SC)). The quality of the studies was assessed using the Newcastle-Ottawa Scale., Results: 699 unique articles were reviewed for eligibility. Data were derived from nine studies (cross-sectional: k = 5; retrospective cohort: k = 4) that assessed suicidal behaviour in FM participants (SI: k = 5, SC: k = 3, SA: k = 3). Four studies assessing SI found elevated rates of SI among FM participants. Three studies found elevated risk for SC and three studies found increased SA in FM participants relative to the general population. In two studies, this association was no longer significant after adjusting for depression and other psychiatric comorbidities., Conclusion: Preliminary findings suggest that FM is associated with significantly higher risks for SI, SA and SC compared to the general population. There may be unique risk factors underlying suicidal behaviour in FM patients and the interaction between FM and other known risk factors (i.e., mental illness) require further investigation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Suicide accounts for approximately 800,000 deaths per year globally. Previous research has shown that intranasal esketamine and intravenous ketamine can rapidly decrease the severity of depressive symptoms and suicidal ideation. However, the majority of clinical trials excluded individuals with moderate to high baseline suicidality scores (e.g., suicidal ideation with plan/intent at the time of recruitment). The current review aims to evaluate the effect of esketamine and ketamine in patients with suicidal ideation at baseline. A systematic search was conducted on EMBASE, PsychInfo and PubMed from inception to July 2020 following the PRISMA guidelines. 15 studies met inclusion criteria. Results from esketamine trials did not demonstrate antisuicidal effects, as between-group differences were not found. Intravenous ketamine appeared to rapidly decrease the severity of suicidal ideation and depressive symptoms in individuals with baseline suicidal ideation, though retrospective studies suggest that these effects may be short-lasting. During the double-blind treatment phases, 2.4% of patients from the treatment groups and 1.5% of patients from control groups attempted suicide, with zero deaths by suicide in both the treatment and control groups during this phase. Based on the overall pooled samples, studies were assessed to be relatively safe, and the continual inclusion of this study population in future clinical trials is encouraged. Future research should aim to assess the longitudinal efficacy of ketamine in patients with baseline suicidality., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The majority of antidepressant medication trials have focused on adult populations (ages 18-65), with much less research in older and younger populations. Moreover, key differences in the efficacy and safety of antidepressants have been identified between these age groups. Ketamine has emerged as a promising new treatment for treatment resistant depression (TRD). The objective of this review is to summarize and synthesize the extant literature on the effectiveness, safety and tolerability of ketamine for depression in special age populations (age ≤18 and ≥ 60). Following PRISMA guidelines, a systematic review was performed, searching EMBASE, PsycInfo, and PubMed from inception through July 2020. Studies reporting the use of any ketamine formulation with variable routes of administration to treat clinically diagnosed depression in adolescents or older adults were included. Thirteen studies were included in the analysis and ten observed rapid (≤2 week latency) antidepressant effects following ketamine treatments, with better outcomes following larger, repeated doses, and in open-label rather than blinded settings. Two case reports in adolescents assessed measures of suicidal ideation and both found ketamine to effectuate rapid anti-suicidal effects. Ketamine appears to be safe and well-tolerated in adolescents and older adults. The small quantity, high heterogeneity, and generally low quality of available studies precludes statistical syntheses and significantly limits the strength of our conclusions. Preliminary proof-of-concept studies are promising, however, rigorously designed randomized controlled trials (RCTs) are still required to ascertain effectiveness, safety and tolerability in these groups., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Women are disproportionately represented amongst samples of adults with treatment-resistant depression (TRD). Ketamine has demonstrated rapid and robust efficacy in adults with TRD. Herein, we sought to determine whether the effectiveness of intravenous (IV) ketamine was influenced by menopausal status in women with TRD. We defined premenopausal women as those under the age of 45 (n = 52), while postmenopausal women (n = 54) were those over the age of 51. Participants received four IV ketamine infusions over one-to-two weeks at a community-based center for adults with TRD. The primary outcome of interest was the change in depressive symptom severity as measured by the Quick Inventory of Depressive Symptomatology Self-Report 16 (QIDS-SR 16 ) following four infusions, compared to pretreatment. The secondary outcomes were improvements in suicidal ideation (SI; i.e., QIDS-SR 16 SI item), anxiety (i.e., Generalized Anxiety Disorder-7 scale), anhedonic severity (i.e., Snaith-Hamilton Pleasure Scale), and workplace and psychosocial function (i.e., Sheehan Disability Scale). Menopausal status did not influence overall treatment response, F (4, 280) = 1.83, p = .123, η p 2  = 0.025. Both premenopausal and postmenopausal participants demonstrated similar response rates (30% and 26%, respectively) and remission rates (both 13%) to IV ketamine treatment following four infusions. Premenopausal women experienced improvements in social function more rapidly than postmenopausal women, F (2, 174) = 1.65, p = .047, η p 2  = 0.019. Postmenopausal women experienced reduction in SI more rapidly than premenopausal women, F (4, 280) = 2.72, p = .030, η p 2  = 0.037. These preliminary post-hoc findings provide the impetus for future studies to investigate the moderational role of menopausal status, as defined by hormone levels, on response to IV ketamine for TRD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Early symptomatic improvement with monoamine-based antidepressants is predictive of treatment response. The objective of this study was to determine if early symptomatic improvements with intravenous (IV) ketamine predicted treatment response to an acute course of four infusions., Method: 134 adults with treatment resistant depression (TRD) received four ketamine infusions over one to two weeks. Depressive symptoms were measured using the Quick Inventory for Depressive Symptomatology Self-Report 16 (QIDS-SR 16 ) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR 16 scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR 16 scores after controlling for baseline characteristics., Results: Early improvement post-infusion 1 (β = -3.52, 95% BCa CI [-5.40, -1.78]) and 2 (β = -3.16, 95% BCa CI [-5.75, -1.59]) both significantly predicted QIDS-SR 16 scores post-infusion 4. Early improvers had significantly lower QIDS-SR 16 scores at post-infusion 4 (post-infusion 1 improvers: M = 9.8, SD = 4.5; post-infusion 2 improvers: M = 10.6, SD = 5.7) compared to non-early improvers (post-infusion 1 non-improvers: M = 13.7, SD = 5.8; post-infusion 2 non-improvers: M = 14.1, SD = 5.3) when controlling for baseline characteristics. The majority (58%) of individuals who did not improve post-infusions 1 or 2 still experienced an antidepressant response or partial response (≥20% reduction in QIDS-SR 16 ) post-infusion 4., Limitations: This is a post-hoc analysis of an open-label study., Conclusion: Early improvement was associated with greater antidepressant effects following a course of four ketamine infusions. However, individuals who did not show early improvements still had a high likelihood of experiencing clinically significant symptom reduction after the fourth infusion, suggesting that completing four infusions, regardless of early symptom changes, is appropriate and merited., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ecological momentary assessment (EMA) for mental disorders, using application-based (app) technology capable of passive and ambient data collection, has been insufficiently evaluated and validated with rigorous, adequately-powered, high-quality studies. Herein, we sought to validate the mind.me application for the assessment of depressive symptoms in adults. Adults (ages 18-65) who self-identified as having clinically significant depressive symptoms [i.e. Patient Health Questionnaire 9 (PHQ-9) ≥ 5] utilized the mind.me app-a mobile phone technology that collects data passively and continuously, and is capable of integrating broad multimodal data [e.g., location variance (e.g. GPS), behavioural (e.g. social network activity), and communication data (e.g. SMS texting, phone calls)]. The primary outcome was predictive accuracy (i.e. convergent validity with depressive symptom measurement, as captured by the PHQ-9). 200 subjects were enrolled in the study (mean age 46 ± 12.71). The average PHQ-9 score was 12.8 ± 6.9. The predictive accuracy of the mind.me app was 0.91 ± 0.06. The sensitivity was 0.98 and the specificity was 0.93. The mind.me app was rated by 200 users as highly usable and informative to their illness. The mind.me app exhibits robust predictive accuracy in detecting depressive symptoms in adults with clinically relevant depressive symptoms. The mind.me app more specifically demonstrates convergence with the PHQ-9., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The efficacy of ketamine in reducing suicidal ideation (SI) has been previously reported. We aimed to evaluate acute anti-SI effects of single-dose ketamine in different formulations/routes of administration by pooling results from randomized controlled trials (RCTs). A systematic search was conducted on Cochrane, Embase, Medline, and PubMed from inception to July 1st, 2020. Studies were selected based on pre-determined eligibility criteria. Effect sizes of different formulations/routes at various time points were computed using random-effects models. With data from nine eligible RCTs (n = 197), the pooled effect size for anti-SI effects at the 24-h time point was 1.035 (N = 6, CI: 0.793 to 1.277, p < 0.001) for intravenous (IV) racemic ketamine and 1.309 (N = 1, CI: 0.857 to 1.761, p < 0.001) for intranasal (IN) esketamine. An additional five RCTs were available for qualitative analysis. RCTs were identified for oral/sublingual ketamine for depression, however, none of these trials reported anti-SI effects preventing quantitative analysis for these routes of delivery. No RCTs for intramuscular (IM) ketamine were identified. The findings suggest that single-dose IV ketamine/IN esketamine is associated with robust reductions in suicidal thoughts at 2-h, 4-h, and 24-h post-intervention. In addition, future studies on IM/oral/sublingual ketamine and comparative studies are warranted to evaluate the anti-SI efficacy of distinct formulations and routes of administration., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Numerous pharmacological treatments for mood disorders are currently available; however, rates of treatment resistance, relapse and recurrence remain high. Therefore, novel treatments acting outside of the conventionally targeted monoamine system are urgently needed to improve patient outcomes. Emerging and converging evidence suggests that immune dysfunction, oxidative stress, impaired cerebral blood flow (CBF) and decreased neurotrophic factors all contribute to mood disorder pathophysiology and are therefore treatment targets of interest. Pentoxifylline (PTX) is a phosphodiesterase inhibitor with potent anti-inflammatory and antioxidant effects, with additional pleiotropic effects that lead to improved CBF and increases in brain derived neurotrophic factor (BDNF) levels. The direct effect of non-specific phosphodiesterase inhibition may also improve alertness and cognitive function through enhancing second messenger systems. Replicated preclinical studies have demonstrated antidepressant-like effects in animal models. Small preliminary clinical trials have demonstrated promising results for antidepressant and procognitive effects, however, have yet to be replicated in larger mood disorder samples. Only one randomized clinical trial (RCT) specifically assessed the effects of adjunctive PTX in major depressive disorder (MDD), showing clinically and statistically significant antidepressant effects compared to placebo. No studies have assessed PTX in bipolar disorder (BD), where inflammation and altered CBF have also been strongly implicated. Taken together, PTX presents as a promising pleiotropic agent with several potential novel mechanisms of action meriting further evaluation in clinical trials to evaluate target engagement, antidepressant, procognitive and mood stabilizing effects., Competing Interests: Declaration of Competing Interest RSM discloses that he has been on advisory boards and/or received honoraria for educational activities and/or research grants from Neurocrine, COMPASS, Sunovion, Janssen, Allergan, Lundbeck, Pfizer, Shire, Purdue, and Otsuka. JDR discloses that he has been on advisory boards and/or received honoraria for educational activities and/or research grants from Allergan, Lundbeck and COMPASS. All other authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3β, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A potential role for leptin in the pathophysiology of bipolar disorder (BD) has been proposed. We recently investigated the effects of the tumor necrosis factor-alpha (TNF-α) antagonist infliximab in individuals with bipolar depression. Leptin is known to interact with the TNF-α system. Herein, we aimed to explore infliximab's effects on leptin and its relationship with brain structure and function. Sixty adults with bipolar depression were enrolled in this randomized, double-blind, 12-week clinical trial of adjunctive infliximab (n = 29) and saline control (n = 31), which were administered intravenously at weeks 0, 2, and 6. Plasma concentrations of leptin, TNF-α and soluble TNF receptors (sTNFR) 1 and 2 were assessed at weeks 0, 2, 6, and 12. We observed a significant decrease in leptin levels in infliximab-treated patients, relative to placebo. Infliximab treatment also significantly reduced TNF-α and sTNFR2, but not sTNFR1 levels. Changes in sTNR2 levels at week 6 significantly determined changes in leptin at week 12 in infliximab-, but not placebo-treated participants. Improvements in verbal memory and increases in global cortical volume were associated with reduction in leptin levels in the treatment group. Mediation analysis indicated that cognitive improvement in infliximab-treated patients was mediated by reductions in leptin levels, which in its turn were determined by decreases in sTNR2 levels. In conclusion, infliximab treatment reduced plasma leptin levels in individuals with BD, through modulation of sTNFR2. Decreases in leptin signaling were associated with an increase in global cortical volume and better performance in a verbal memory task., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

As interest has grown in the potential psychiatric applications of ketamine, the number of registered clinical trials has grown substantially. Herein, we summarize and analyze clinical trials registered with ClinicalTrials.gov that assess the treatment of any psychiatric disorder with ketamine or ketamine enantiomers (e.g., S-ketamine, R-ketamine), with a focus on ongoing clinical trials. A ClinicalTrials.gov search on February 21, 2020 returned 140 registered trials. Frequency data was analyzed to determine the distribution of study designs. The majority of trials (70%) investigated the therapeutic effect of ketamine in mood disorders (unipolar: 60%, bipolar: 0.7%, both: 5.7%). Suicidal ideation (13.1%), post-traumatic stress disorder (5.4%), and obsessive-compulsive disorder (3.6%) were also investigated. Intravenous (IV) administration was the most common route with 87% of the studies using IV ketamine. Single-dose studies represented 50% of IV ketamine studies. Few studies were assessing maintenance treatment. Most studies were phase I or II with few definitive phase III trials registered. Given the large number of ongoing studies assessing psychiatric application of ketamine, researchers and relevant stakeholders should consider not only completed, published studies, but also ongoing registered studies in adjudicating the most relevant research questions. More definitive phase III trials and maintenance studies of IV ketamine for mood disorders are required, as numerous completed and ongoing studies have already assessed and demonstrated the proof-of-concept of acute antidepressant effects in phase I and II trials., Competing Interests: Declaration of competing interest RSM declares that he has been on advisory boards and/or received honoraria for educational activities and/or research grants from AstraZeneca, Bristol-Myers Squibb, Janssen-Ortho, Eli Lily, Forest, Lundbeck, Pfizer, Shire, Merck, Sepracor, and Otsuka. JDR is a sub-investigator for the COMPASS Psilocybin for Treatment Resistant Depression Study. RSM is the director of and JDR is a staff psychiatrist at a clinic that administers intravenous ketamine. All other authors in this manuscript have reported no relevant conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Aberrations in neurodevelopmental trajectories have been implicated in the neurobiology of several mental disorders and evidence indicates a pathophysiological and genetic overlap of schizophrenia and bipolar disorder (BD). In this narrative review, we summarize findings related to developmental and perinatal factors as well as epidemiological, clinical, neuropsychological, brain imaging, postmortem brain and genomic studies that provide evidence for a putative neurodevelopmental pathogenesis and etiology of BD. Overall, aberrations in neurodevelopmental pathways have been more consistently implicated in the pathophysiology of schizophrenia compared to BD. Nevertheless, an accumulating body of evidence indicates that dysfunctional neurodevelopmental pathways may be implicated in the underlying pathophysiology of at least a subset of individuals with BD particularly those with an early age of illness onset and those exhibiting psychotic symptoms. A heuristic neurodevelopmental model for the pathophysiology of BD based on the findings of this review is proposed. Furthermore, we critically discuss clinical and research implications of this model. Finally, further research directions for this emerging field are provided., Competing Interests: Declaration of Competing Interest Dr. Husain has received grant/research support from the Stanley Medical Research Institute (SMRI), the Physician’s Services Incorporated (PSI) Foundation, the Pakistan Institute of Living and Learning and the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King’s College London. Dr. Berk has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, MRFF, Beyond Blue, Rotary Health, A2 milk company, Meat and Livestock Board, Woolworths, Avant and the Harry Windsor Foundation, has been a speaker for Astra Zeneca, Lundbeck, Merck, Pfizer, and served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Lundbeck Merck, Pfizer and Servier. Dr. Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Generalitat de Catalunya (PERIS), the Spanish Ministry of Science, Innovation and Universities (CIBERSAM), EU Horizon 2020, and the Stanley Medical Research Institute. Dr. Soares has received grant/research support from Bristol-Meyers Squibb, Forest Laboratories, Merck and Elan Pharmaceuticals, and is a consultant for Pfizer, Abbot, and Astellas Pharma, Inc. Dr. Zanotti-Fregonara has received fees as a speaker for Eli Lilly. The remaining authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Environmental stressors, such as childhood maltreatment, have been recognized to contribute to the development of depression. Growing evidence suggests that epigenetic changes are a key mechanism by which stressors interact with the genome leading to stable changes in DNA structure, gene expression, and behaviour. The current review aimed to evaluate the relationship between stress-associated epigenetic changes and depression. Human studies were identified via systematic searching of PubMed/Medline from inception to February 2018. Seventeen articles were identified. Stress-associated epigenetic changes in the following genes were correlated with depression: NRC31, SLCA4, BDNF, FKBP5, SKA2, OXTR, LINGO3, POU3F1 and ITGB1. Epigenetic changes in glucocorticoid signaling (e.g., NR3C1, FKBP5), serotonergic signaling (e.g. SLC6A4), and neurotrophin (e.g., BDNF) genes appear to be the most promising therapeutic targets for future research. However, continued research is warranted due to inconsistent findings regarding the directionality of epigenetic modification. Future studies should also aim to control for the use of psychotropic agents due to their widespread use in depressed populations and established effects on DNA methylation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Anhedonia is defined as a diminished ability to experience interest or pleasure, and is a critical psychopathological dimension of major depressive disorder (MDD). The purpose of the current systematic review is to evaluate the therapeutic efficacy of pharmacological treatments on measures of anhedonia in adults with MDD. Electronic databases Cochrane Library (CENTRAL), Ovid MEDLINE, PubMed, PsycINFO, and Google Scholar were searched from inception to June 1, 2018 for longitudinal studies utilizing pharmacotherapy for the treatment of anhedonia in patients with MDD. A total of 17 eligible studies were identified (i.e., evaluated the effects of pharmacotherapy on a measure of anhedonia). Among the identified studies, the efficacy of 14 different pharmacotherapies on measures of anhedonia were evaluated, including melatonergic agents (i.e. agomelatine), monoaminergic agents (i.e. moclobemide, clomipramine, bupropion, venlafaxine, fluoxetine, amitifadine and levomilnacipran, escitalopram, and sertraline), glutamatergic agents (i.e., ketamine and riluzole), stimulants (i.e., methylphenidate), and psychedelics (i.e., psilocybin). Based on the available evidence, most antidepressants demonstrated beneficial effects on measures of anhedonia as well as the other depressive symptoms. Only escitalopram/riluzole combination treatment was ineffective in treating symptoms of anhedonia in MDD. Continued research is warranted to further support the efficacy of mechanistically-distinct antidepressants in treating symptoms of anhedonia in MDD. Future research should also aim to parse out the heterogeneous effects of different pharmacotherapies on anhedonic symptoms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cognitive dysfunction is a principal determinant of functional impairment in major depressive disorder (MDD) and often persists during periods of euthymia. Abnormalities in the glutamate system, particularly in N-methyl-d-aspartate receptors (NMDARs) activity, have been shown to contribute to both mood and cognitive symptoms in MDD. The current narrative review aims to evaluate the potential pro-cognitive effects of targeting the glycine site of NMDARs in the treatment of psychiatric disorders, with a special focus on how these results may apply to MDD. Literature databases were searched from inception to May 2018 for relevant pre-clinical and clinical studies evaluating antidepressant and pro-cognitive effects of NMDAR glycine site modulators in both MDD and non-MDD samples. Six glycine site modulators with pro-cognitive and antidepressant properties were identified: d-serine (co-agonist), d-cycloserine (partial agonist), d-alanine (co-agonist), glycine (agonist), sarcosine (co-agonist) and rapastinel (partial agonist). Preclinical animal studies demonstrated improved neuroplasticity and pro-cognitive effects with these agents. Numerous proof-of-concept clinical trials demonstrated pro-cognitive and antidepressant effects trans-diagnostically (e.g., in healthy participants, MDD, schizophrenia, anxiety disorders, major neurocognitive disorders). The generalizability of these clinical studies was limited by the small sample sizes and the paucity of studies directly evaluating cognitive effects in MDD samples, as most clinical trials were in non-MDD samples. Taken together, preliminary results suggest that the glycine site of NMDARs is a promising target to ameliorate symptoms of depression and cognitive dysfunction. Additional rigorously designed clinical studies are required to determine the cognitive effects of these agents in MDD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Orexins are neuropeptides that are postulated to play a central role in the regulation of the sleep-wake cycle, appetite, affect, and reward circuitry. The objectives of the current review are to comprehensively evaluate (1) the potential role of orexins in the pathophysiology of major depressive disorders (MDD) and (2) the orexin system as a novel target in the treatment of MDD. Dysfunction of the sleep-wake cycle is observed as a central feature of MDD pathophysiology. Orexin system disturbances produce sleep-wake dysfunction, as observed in MDD. Orexin antagonists have been shown to treat insomnia effectively without disrupting normal sleep architecture in both preclinical (e.g., animal models) and clinical studies. Orexin antagonists are generally safe, well-tolerated, and associated with an acceptable long-term adverse effect profile with relatively low propensity for tolerance or dependence. Orexin antagonists have also been shown to possess antidepressant-like properties in some animal models of MDD. Extant evidence indicates that orexin-modulating treatments exert pleiotropic effects on multiple neural systems implicated in the phenomenology of mood disorders and suggests orexins as a promising target for investigation and intervention in mood disorders. To date, no human clinical trials evaluating the antidepressant effects of orexin antagonists in MDD have been completed. Given the promising results from preclinical studies, clinical trials are merited to evaluate the antidepressant effects of orexin antagonists in MDD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Despite significant advances in pharmacological and non-pharmacological treatments, mood disorders remain a significant source of mental capital loss, with high rates of treatment resistance, requiring a coordinated effort in investigation and development of efficient, tolerable and accessible novel interventions. Ketogenic diet (KD) is a low-carb diet that substantially changes the energetic matrix of the body including the brain. It has been established as an effective anticonvulsant treatment, and more recently, the role of KD for mental disorders has been explored. Ketogenic diet has profound effects in multiple targets implicated in the pathophysiology of mood disorders, including but not limited to, glutamate/GABA transmission, monoamine levels, mitochondrial function and biogenesis, neurotrophism, oxidative stress, insulin dysfunction and inflammation. Preclinical studies, case reports and case series have demonstrated antidepressant and mood stabilizing effects of KD, however, to date, no clinical trials for depression or bipolar disorder have been conducted. Because of its potential pleiotropic benefits, KD should be considered as a promising intervention in research in mood disorder therapeutics, especially in treatment resistant presentations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Sirtuins are NAD + -dependent histone deacetylases that play essential roles in cell survival, energy metabolism, inflammation, and aging; therefore, sirtuins are potential therapeutic targets in the treatment of type 2 diabetes, cancer, inflammatory and metabolic disorders, and neurodegenerative diseases. Available evidence provides the basis for hypothesizing that sirtuins 1, 2, and 3 (SIRT1, SIRT2, and SIRT3) may have a mechanistic role subserving mood disorders (i.e. downregulation) and associated co-morbidity (e.g. metabolic disorders). Specifically, the domains of general cognitive processes, as well as cognitive emotional processing may be particularly relevant to sirtuin physiology. Given the role of sirtuins in the perpetuation of circadian rhythmicity, and evidence of dysfunctional circadian cycling in mood disorders, sirtuins may be an underlying etiological factor that links circadian rhythm functionality with mood disorders. Caloric restriction, and caloric restriction mimetics (e.g. resveratrol) are all capable of upregulating sirtuin isoforms implicated in stress response syndromes. Repurposing existing treatments and/or discovery of novel agents capable of modulating sirtuin physiology may represent genuinely novel approaches for trans-diagnostic domains affected in mood disorders and other brain-based illnesses., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Heterogeneity in response to conventional antidepressants is a well-recognized limitation of evidence-based pharmacological treatments of major depressive disorder (MDD). Abnormal activation of inflammatory pathways is postulated as one likely mechanism contributing to treatment resistance in MDD. In a subset of depressed patients, the balance between pro- and anti-inflammatory cytokines is thought to be altered, causing mood symptoms due to inflammation, as seen in co-morbid depression associated with inflammatory conditions (e.g. psoriasis, hepatitis C, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis). The objectives of the current narrative review are to critically evaluate the literature about the effects of cytokine blockers on clinical outcomes in MDD and in the reduction of depressive symptom severity in individuals using these medications primarily to treat inflammatory conditions. A small number of clinical trials assessing the effects of cytokine blockers for depression and depressive symptoms have been completed. These trials suggest that in individuals with immune dysfunction (e.g. elevated pro-inflammatory cytokine levels), cytokine blockers may allow for improved clinical outcomes in MDD that would not be achievable with current conventional antidepressants alone. Additional well-designed clinical trials to assess the clinical utility of anti-inflammatory medications for the treatment of depression and depressive symptoms are merited. Further, the use of anti-inflammatories show promise for disease modifying effects that may alter illness trajectory, rather than solely ameliorating current mood symptoms., (Copyright © 2018. Published by Elsevier Inc.)

Evidence supports inflammatory involvement in mood and cognitive symptoms across psychiatric, neurological and medical disorders; however, inflammation is not a sensitive or specific characteristic of these diagnoses. The National Institute of Mental Health Research Domain Criteria (RDoC) ask for a shift away from symptom-based diagnoses toward a transdiagnostic neurobiological focus in the study of brain illnesses. The RDoC matrix may provide a useful framework for integrating the effects of inflammation on brain function. Based on preclinical and clinical findings, relevant relationships span negative and positive valence systems, cognitive systems, systems for social processes and arousal/regulatory systems. As an exemplar, we consider the psychopathological domain of anhedonia, conceptualizing the relevance of inflammation (e.g., cellular immunity) and downstream processes (e.g., indoleamine 2,3-dioxygenase activation and oxidative inactivation of tetrahydrobiopterin) across RDoC units of analysis (e.g., catecholamine neurotransmitter molecules, nucleus accumbens medium spiny neuronal cells, dopaminergic mesolimbic and mesocortical reward circuits, animal paradigms, etc.). We discuss implications across illnesses affecting the brain, including infection, major depressive disorder, stroke, Alzheimer's disease and type 2 diabetes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy. During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders. Therefore, the purpose of this synthetic review is threefold: 1) to review the evidence for an association between inflammation and mood disorders, 2) to discuss potential pathophysiologic mechanisms that may explain this association and 3) to present novel therapeutic options currently being investigated that target the inflammatory-mood pathway. Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces 'sickness behavior' resembling depressive symptomatology. Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes. Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy; however, further research is needed to establish the therapeutic benefit and appropriate dosage., (Copyright © 2014 Elsevier Inc. All rights reserved.)