Bipolar Depression Research Articles

Cariprazine Augmentation in Treatment-Resistant Bipolar Depression: Data from a Retrospective Observational Study.

Treatment-resistant bipolar depression is one of the leading problems in psychiatry with serious consequences on patients functioning, quality of life and resource utilization. Despite this, there is a lack of consensus on diagnostic criteria and treatment algorithms. The objective of the present study is to assess the acute effectiveness and tolerability of cariprazine in the management of treatment resistant bipolar depression. This is a four weeks retrospective multicentric observational study on patients with treatment resistant bipolar depression receiving cariprazine in augmentation to the current treatment. Cariprazine dosage changed during the follow-up period according to clinical judgment. Since data followed a non-normal distribution, non-parametric tests were used to pursue the analysis. The effectiveness of cariprazine was assessed through the mean change in Hamilton Depression rating scale (HAM-D) scores from baseline to endpoint. For missing values, a "Last Observation Carried Forward" approach was applied. Fifty-one patients were enrolled. Four patients (7.8%) discontinued cariprazine mainly due to adverse events. Mean cariprazine dose was 1.7 mg/day. The mean HAM-D score decreased significantly from baseline (T0) to week 4 (T4) at each evaluation point. Fourty-five one percent of the patients benefited of cariprazine add-on strategy: 23.5% achieved a clinical response and 21.6% were remitters. Among the completers, 70.6% experienced at least one adverse event. All side effects were mild to moderate. Cariprazine seems to be an effective and well tolerated option in the management of patients with treatment resistant bipolar depression.

SERUM URIC ACID LEVELS IN UNIPOLAR AND BIPOLAR DEPRESSION: A COMPARATIVE MINI-REVIEW

Depression is a common mental health disorder that can be classified as either unipolar or bipolar. There is growing evidence that suggests certain illnesses could be influenced by serum uric acid (SUA). The processes, diagnostic ramifications, and potential treatments for the association between SUA levels and unipolar and bipolar depression are examined in this mini-review, which summarizes recent research on the subject.

The Transition Between Depressive Episode and Manic Episode During the Treatment of Bipolar Disorder

Bipolar disorder (BD) is characterized by periodic alternations between depressive and manic episodes. It belongs to a complex group of severe and persistent conditions. This category includes bipolar I disorder (BDI) and bipolar II disorder (BDII). The definition of BDI hinges primarily on the manifestation of a syndromal manic episode. Conversely, BDII is characterized by the occurrence of both a syndromal hypomanic episode and a major depressive episode, which jointly constitute its defining features. BDI is the most common type in clinics. The duration of episodes and the time spent in the manic phases and depressive periods of bipolar disorder are not clearly defined for subtypes of the disorder. This paper analyzes the duration of manic episodes and depressive episodes in bipolar disorder, and explores the switch from major depression to bipolar depression. By analyzing and comparing the data and results in essays, it is still hard to tell the exact duration and the occurrence of the episodes. But the effects of drugs can be summarized during the treatment of bipolar disorders. At the same time, it discovers that during treatment of major depression, bipolar disorder occurs. In conclusion, the duration is different for different people, and it depends on many subjective influences. During treatment of major depression, the transition from major depression to bipolar depression will happen indeed, but the probability is very small. This research may provide a new concern that doctors and scientists should pay more attention to the treatment of such mental diseases and keep an eye on the switch.

Peripheral biomarkers to differentiate bipolar depression from major depressive disorder: a real-world retrospective study

BackgroundBipolar depression (BPD) is often misdiagnosed as a major depressive disorder (MDD) in clinical practice, which may be attributed to a lack of robust biomarkers indicative of differentiated diagnosis. This study analysed the differences in various hormones and inflammatory markers to explore peripheral biomarkers that differentiate BPD from MDD patients.MethodsA total of 2,048 BPD and MDD patients were included. A panel of blood tests was performed to determine the levels of sex hormones, stress hormones, and immune-related indicators. Propensity score matching (PSM) was used to control for the effect of potential confounders between two groups and further a receiver operating characteristic (ROC) curve was used to analyse the potential biomarkers for differentiating BPD from MDD.ResultsCompared to patients with MDD, patients with BPD expressed a longer duration of illness, more hospitalisations within five years, and an earlier age of onset, along with fewer comorbid psychotic symptoms. In terms of biochemical parameters, MDD patients presented higher IgA and IgM levels, while BPD patients featured more elevated neutrophil and monocyte counts. ROC analysis suggested that combined biological indicators and clinical features could moderately distinguish between BPD and MDD. In addition, different biological features exist in BPD and MDD patients of different ages and sexes.ConclusionsDifferential peripheral biological parameters were observed between BPD and MDD, which may be age-sex specific, and a combined diagnostic model that integrates clinical characteristics and biochemical indicators has a moderate accuracy in distinguishing BPD from MDD.

Can retinal nerve fiber layer (RNFL) thickness be a marker for distinguishing bipolar depression from unipolar depression?

Objective We aimed to compare retinal nerve fiber layer (RNFL) thickness and ganglion cell complex (GCC) thickness in bipolar disorder (BD) and major depressive disorder (MDD). Method The study included thirty MDD, thirty-two BD participants in depressive episode, and thirty-seven controls matched according to age, gender, body mass index (BMI), and smoking status. Optic coherence tomography (OCT) measurements were performed for both participants and controls. The RNFL and GCC thickness were measured and recorded automatically by a spectral OCT device. Participants were also subjected to Hamilton Depression Rating Scale (HAM-D). Results RNFL superior thickness was significantly lower in BD participants, compared to the MDD participants and controls (p = 0.001). GCC inferior (p = 0.022) and inferonasal (p = 0.005) thickness were detected lower in BD group, compared to the control groups. In the BD group, HAM-D scores were negatively correlated with RNFL-temporal (p = 0.049, r= −0.357), GCC inferotemporal (p = 0.02, r= −0.416) and superotemporal thickness (p = 0.002, r= −0.546). Conclusions RNFL thickness were lower in BD participants compared to the MDD and controls and, GCC thickness were lower in BD participants compared to the controls. Our findings support the hypothesis that neurodegeneration is part of the pathogenesis of BD. Future research are needed to confirm the lack of RNFL thickness in MDD, which could have immediate therapeutic consequences as well as implications for distinguishing BD from MDD.

Differentiating Stages of Bipolar and Unipolar Depression-The Possible Role of sICAM-1 and sVCAM-1.

Increased immune-inflammatory activation has been repeatedly linked to etiopathogenesis and the progression of both major depressive disorder (MDD) and bipolar depression (BD). We explore the role of soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in diagnostic differentiation and disorder progression in patients with MDD and BD. Serum levels of sICAM-1 and sVCAM-1 were measured in 137 patients (MDD = 93 and BD = 44) and compared with 73 healthy controls. The severity of psychopathology was assessed using the Hamilton Depression Rating Scale and Clinical Global Impression Scale. After adjustment for multiple confounders, we noticed significant downregulation of sVCAM-1 and upregulation of sICAM-1 levels in both patient groups. Decreased sVCAM-1 levels were detected in patients with acute episodes of BD when compared to MDD. Immune mediators were related to indicators of progression in both mood disorders. They also followed different post-treatment normalization patterns in MDD and BD and in relation to the stage of each disorder. Adhesion molecules could potentially be useful in discriminating between patients with MDD and BD and determining the possible progression of the disorders. Future nosological methods should include time-dependent pathoplasticity and biological correlates, at least for affective disorders.

Safety of Electroconvulsive Therapy in a Patient With Bipolar Mania Receiving Oral Anticoagulants: A Case Report.

Safety of Electroconvulsive Therapy in a Patient With Bipolar Mania Receiving Oral Anticoagulants: A Case Report.

Treatment-emergent symptoms during short-term ketamine administration in treatment-resistant bipolar depression: A retrospective cross-sectional descriptive study

Symptoms that emerge during pharmacological treatment of bipolar depression are frequently observed, underscoring the necessity for comprehensive treatment monitoring. This observational study sought to observe the correlation of eight intravenous ketamine infusions with treatment-emergent depressive symptoms in treatment-resistant bipolar depression patients who maintained their baseline psychotropic and chronic somatic treatments. Depressive symptoms were evaluated using the Inventory of Depressive Symptomatology Self-Report 30 (IDS-SR30). Treatment-emergent symptoms TES were defined as symptoms absent at baseline but present at the conclusion of the study. The most common TES included decreased appetite, increased weight, hypersomnia, and diurnal mood variation. Conversely, feelings of sadness, altered perceptions of the future, decreased interest in sex, and physical discomfort were absent in all patients. Notably, 13.6 % of patients reported thoughts of death or suicide. Larger-scale studies, integrating clinician-rated and patient-reported outcome measures, are essential to deepen our understanding of treatment-emergent symptoms. Establishing regulatory or professional definitions for treatment-emergent symptoms is warranted to improve the robustness of future research endeavors.

Personality traits, bipolar depression symptoms, and coping mechanisms among Chinese junior college students

Personality traits, bipolar depression symptoms, and coping mechanisms among Chinese junior college students

Relationship between anhedonia, biological rhythms, functioning and depression severity in patients with bipolar disorder.

The purpose of this study was to examine relationship between anhedonia, disruption of biological rhythms, functioning and depression severity in patients with bipolar disorder (BD). The sample included 58 patients with bipolar depression aged 18-65 years. The participants were assessed using the following scales: Dimensional Anhedonia Rating Scale (DARS), Snaith-Hamilton Pleasure Scale (SHAPS), Quick Inventory of Depressive Symptomatology- self-report (QIDS-SR), Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), Functioning Assessment Short Test (FAST). Correlations between the variables were calculated. We built linear regression models with FAST or QIDS-SR as a dependent variable. Mediation analysis was performed. Statistically significant correlations were observed between the included variables. Biological rhythms dysregulation and anhedonia were independent predictors of the level of functioning or depression severity. Mediation analysis demonstrated statistically significant mediation of the relationship between anhedonia and depression severity/functioning by the BRIAN score. We demonstrated for the first time the interactions between anhedonia, dysregulation of biological rhythms and functioning/depression severity in patients with BD. Reward deficits by causing disruption of rhythm of daily activities and social contacts may result in more difficulties in functioning and higher intensity of depressive symptoms.

The influence of age on ECT efficacy in depression, mania, psychotic depression and schizophrenia: A transdiagnostic analysis

AimECT use is variable across age groups. We aim to investigate the effect of age on ECT response among patients with depression, psychotic depression, mania and schizophrenia. MethodsOur retrospective observational study included patients from the Institute of Mental Health (Singapore) who were initiated on ECT (March 2017–February 2023). MADRS and BPRS scores were assessed 1–2 days before the first ECT and after the 6th session. The association between age group and ECT response was analyzed by ANOVA and generalized linear regression. A one-way sensitivity analysis was performed with age as a continuous variable. Results166 (15.7%) patients were “young-age (≤26 years)”, 634 (60%) patients were in the “middle-age (27–59 years)” group and 256 (24.3%) were “old-age (≥60 years)”. The association between older age and post-ECT improvement in patients with depression was significant in the categorical age analysis but it did not persist in the sensitivity analysis. No significant association between age and ECT response was noted in patients with bipolar disorder and schizophrenia as evidenced by both categorical and continuous age analyses. In a small subgroup with psychotic depression, younger patients improved significantly more than older patients post-ECT. ConclusionPatients with unipolar or bipolar depression, mania, or schizophrenia, regardless of age, respond favourably to ECT. Other associated factors such as psychomotor and psychotic symptoms, disease severity and number of failed pharmacotherapies should be considered in predicting ECT response. Younger patients with psychotic depression may respond better to ECT.

Efficacy and tolerability of monoamine oxidase inhibitors for the treatment of depressive episodes in mood disorders: A systematic review and network meta-analysis.

Monoamine oxidase inhibitors (MAOIs) are considered third-line treatments for treatment resistant depression; however, they are underused in clinical practice. This study aimed to assess the efficacy, tolerability, and acceptability of MAOIs for the treatment of depression in comparison with other antidepressant treatments. A systematic review and network meta-analysis of randomised clinical trials was performed to compare the efficacy, tolerability and acceptability between MAOIs and other antidepressant treatments for the treatment of depressive episodes. A total of 83 double-blinded, randomised controlled trials were included in the analysis, with 7765 participants assigned to an active treatment and 1844 assigned to placebo. Several MAOIs, including isocarboxazid, phenelzine, tranylcypromine and moclobemide, showed significantly higher efficacy compared with placebo. The tolerability and acceptability of MAOIs was comparable to other antidepressants. A disproportionate number of studies investigating the most commonly used MAOIs, such as moclobemide and phenelzine, and a lack of specific studies focusing on treatment-resistant and atypical depression. MAOIs are similar in efficacy to other antidepressants for the treatment of depression. However, more studies are needed comparing MAOI treatment in people with treatment-resistant, atypical and bipolar depression.

Heart Rate Variability Biofeedback Efficacy on Fatigue and Energy Levels in Fibromyalgia: A Secondary Analysis of RCT NCT0412183.

Background: Fibromyalgia syndrome (FMs) is a chronic condition characterized by widespread musculoskeletal pain and a range of complex symptoms, with chronic fatigue being a central feature significantly impacting daily life. The aim of this study was to analyze the secondary outcomes, specifically those related to perceived energy and fatigue symptoms in a randomized controlled trial (RCT) assessing the efficacy of heart rate variability biofeedback (HRV-BF) as an adjunctive treatment for FMs. Methods: Sixty-four FMs patients were randomly assigned to either receive 10 HRV-BF training sessions alongside standard pharmacological therapy (experimental group) or standard therapy alone for 10 weeks (control group). For this secondary analysis, potential improvements in specific items were evaluated regarding perceived energy (Item 10 of the Short-Form Health Survey), the ability to walk and climb stairs (Item 7 and Item 11 of the Fibromyalgia Impact Questionnaire, respectively), and the impact of pain on movement ability (Item 17 of the Bodily and Emotional Perception of Pain). Results: The experimental group demonstrated an improvement in the perception of energy, the ability to walk, and the impact of pain on movement ability. However, the same improvement was not observed in the ability to climb stairs. Conclusions: Fatigue assessment has emerged as a crucial factor for evaluating treatment efficacy in FMs and related conditions linked to altered energy levels, such as bipolar depression, and can offer valuable insights for precisely guiding HRV-BF treatments. ClinicalTrials.gov with code: NCT04121832.

Reliable Change Indices and Minimum Detectable Change for the Montreal Cognitive Assessment in Electroconvulsive Therapy for Depression.

The Montreal Cognitive Assessment (MoCA) is a commonly used brief cognitive screening tool for monitoring adverse cognitive effects of electroconvulsive therapy (ECT). The aim of this study was to examine three statistical methods for detecting reliable change in the MoCA following ECT. In a prospective cohort study, 47 patients (mean age 55.2 [SD = 12.8], 59.6% female) with unipolar or bipolar depression treated with an acute course of brief-pulse ECT (72.3% right unilateral) and 47 depressed controls without ECT exposure were tested on the MoCA at baseline and retested at comparable time intervals. ECT patients' performance was also compared to published normative data from a community-based sample of older adults. We calculated proportions of ECT patients remaining stable, declining, and improving following ECT using practice-corrected reliable change index, standardized regression-based formulas, and minimum detectable change cutoff of ±4 MoCA points. Using the three methods, 72.3%-78.7% of ECT patients remained stable, 17.0%-23.4% declined, and 4.3% improved in MoCA performance following ECT compared to the two control groups. All three methods yield consistent estimates of reliable change in MoCA scores from pre- to post-brief-pulse ECT. The minimum detectable change approach may be the most efficient and accessible method of detecting change due to simplicity of calculation.

Treatment of bipolar depression: clinical practice vs. adherence to guidelines-data from a Bavarian drug surveillance project.

Pharmacotherapy of bipolar depression (BPD) is confronted with major clinical challenges, like limited evidence-based treatment options, regular cases of treatment resistance, and risk of treatment-emergent affective switches. Medical guidelines can support practitioners to make decisions based on current scientific evidence. The objective of this study is to evaluate to what extent recommendations of the 2019 German S3 guidelines "Diagnosis and Treatment of Bipolar Disorders" are reflected in clinical practice in inpatient treatment. We conducted a descriptive analysis of prescription numbers in 2,627 patients with BPD in a naturalistic inpatient setting analyzing data from the ongoing Bavarian multicenter drug safety project Pharmaco-Epidemiology and Vigilance (Pharmako-EpiVig) from the years 2014-2022. Of the patients, 38% were not administered any drug explicitly recommended for treatment of BPD, that is, quetiapine, lamotrigine, carbamazepine, or olanzapine. Only 6% of the patients received monotherapy with one of those drugs. Of the patients, 34% were administered ≥4 psychotropic drugs simultaneously. Patients received 912 different therapy regimens of mono or combination therapy with mood stabilizers (MS), atypical antipsychotics (AAP), and antidepressants. Of the patients, 72% received an antidepressant and 6% without concomitant prescription of an AAP or MS. Prescription rates of venlafaxine (21% to 14%) and tricyclic antidepressants (9% to 6%) decreased significantly from the first (2014-2016) to the last (2020-2022) observed time period. Of the patients, 60% received an MS. Prescription rate of valproate (22% to 14%) decreased significantly, while lithium prescription increased significantly (29% to 35%). Of the patients, 71% were administered an AAP. Quetiapine was the most prescribed drug overall (43%). Only two patients were administered a combination of olanzapine and fluoxetine. Our results demonstrate a substantial gap between guideline recommendations and current clinical practice. The remarkable heterogeneity in treatment regimens, with no discernible dominant treatment approach, is in part a reflection of the complexity of bipolar disorder but also substantiates the need of comprehensive recommendations regarding combination therapies. Increase in lithium prescription is an encouraging development due to its unique efficacy in maintenance treatment. To improve the quality of clinical practice guideline implementation, more randomized controlled trials shouldbeconducted in the future to prospectively investigate different implementation strategies.

A Nationwide Target Trial Emulation Assessing the Risk of Antidepressant-Induced Mania Among Patients With Bipolar Depression.

Antidepressants are commonly used to treat bipolar depression but may increase the risk of mania. The evidence from randomized controlled trials, however, is limited by short treatment durations, providing little evidence for the long-term risk of antidepressant-induced mania. The authors performed a target trial emulation to compare the risk of mania among individuals with bipolar depression treated or not treated with antidepressants over a 1-year period. The authors emulated a target trial using observational data from nationwide Danish health registers. The study included 979 individuals with bipolar depression recently discharged from a psychiatric ward. Of these, 358 individuals received antidepressant treatment, and 621 did not. The occurrence of mania and bipolar depression over the following year was ascertained, and the intention-to-treat effect of antidepressants was analyzed by using Cox proportional hazards regression with adjustment for baseline covariates to emulate randomized open-label treatment allocation. The fully adjusted analyses revealed no statistically significant associations between treatment with an antidepressant and the risk of mania in the full sample (hazard rate ratio=1.08, 95% CI=0.72-1.61), in the subsample concomitantly treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.63-2.13), and in the subsample not treated with a mood-stabilizing agent (hazard rate ratio=1.16, 95% CI=0.65-2.07). Secondary analyses revealed no statistically significant association between treatment with an antidepressant and bipolar depression recurrence. These findings suggest that the risk of antidepressant-induced mania is negligible and call for further studies to optimize treatment strategies for individuals with bipolar depression.

Cariprazine in the acute treatment of unipolar and bipolar depression: A systematic review and meta-analysis

BackgroundCariprazine has emerged as a promising augmenting treatment agent for unipolar depression and as a monotherapy option for bipolar depression. We evaluated cariprazine's efficacy in treating acute major depressive episodes in individuals with major depressive disorder (MDD) or bipolar disorder. MethodsA systematic review was conducted on MEDLINE, Embase, PsycINFO, Scopus and Web of Science, ClinicalTrials.gov and ScanMedicine. Study quality was assessed using the RoB 2 tool. Pairwise and dose-response meta-analyses were conducted with RStudio. Evidence quality was assessed with GRADE. ResultsNine RCTs meeting inclusion criteria encompassed 4889 participants. Cariprazine, compared to placebo, significantly reduced the MADRS score (MD = −1.49, 95 % CI: −2.22 to −0.76) and demonstrated significantly higher response (RR = 1.21, 95 % CI: 1.12 to 1.30) and remission (RR = 1.19, 95 % CI: 1.06 to 1.34) rates. Subgroup analysis unveiled statistically significant reductions in MADRS score in MDD (MD = −1.15, 95 % CI: −2.04 to −0.26) and bipolar I disorder (BDI) (MD = −2.53, 95 % CI: −3.61 to −1.45), higher response rates for both MDD (RR = 1.19, 95 % CI: 1.08 to 1.31) and BDI (RR = 1.27, 95 % CI: 1.10 to 1.46), and higher remission rates only for BDI (RR = 1.41, 95 % CI: 1.24 to 1.60). A higher rate of treatment discontinuation due to adverse events was observed. LimitationsReliance solely on RCTs limits generalisability; strict criteria might not reflect real-world diversity. ConclusionsCariprazine demonstrates efficacy in treating major depressive episodes, although variations exist between MDD and BDI and tolerability may be an issue.

Continuous theta burst stimulation for bipolar depression: A multicenter, double-blind randomized controlled study exploring treatment efficacy and predictive potential of kynurenine metabolites

BackgroundWhile theta burst stimulation (TBS) shows promise in Major Depressive Disorder (MDD), its effectiveness in bipolar depression (BD-D) remains uncertain. Optimizing treatment parameters is crucial in the pursuit of rapid symptom relief. Moreover, aligning with personalized treatment strategies and increased interest in immunopsychiatry, biomarker-based stratification of patients most likely to benefit from TBS might improve remission rates. We investigated treatment effectiveness of continuous TBS (cTBS) compared to sham in BD-D, and assessed the capacity of plasma kynurenine pathway metabolites to predict treatment outcome. MethodsThirty-seven patients with BD-D underwent accelerated active or sham cTBS treatment in a multicenter, double-blind, randomized controlled trial. Depressive symptoms were measured with the 17-item Hamilton Depression Rating Scale (HDRS-17) before treatment (T0), 3–4 days posttreatment (T1) and 10–11 days posttreatment (T2). Plasma tryptophan, kynurenine, kynurenic acid and quinolinic acid concentrations were quantified with ELISA. Linear mixed models were used for statistical analyses. ResultsAlthough the total sample showed depressive symptom improvement, active cTBS did not demonstrate greater symptom alleviation compared to sham. However, higher baseline quinolinic acid significantly predicted symptom improvement in the active treatment group, not in sham-stimulated patients. LimitationsThe modest sample size limited the power to detect significant differences with regard to treatment effect. Also, the follow-up period was 10–11 days, whereas similar studies usually follow up for at least one month. ConclusionMore research is required to optimize cTBS for BD-D and explore the involvement of quinolinic acid in treatment outcome.

Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review.

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders.

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.