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ABSTRACTIntroductionRecently, the European Medicines Agency (EMA) received reports of suicidal thoughts and self-injury associated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) liraglutide and semaglutide.Research design and methodsHerein, we sought to evaluate suicidality associated with all GLP-1 RAs relative to other glucose-lowering agents currently approved by the United States Food and Drug Administration (FDA). Reports of suicidal ideation, “depression/suicidal”, suicidal behavior, suicidal attempts, and completed suicide associated with GLP-1 RA exposure reported to the FDA between 2005 and October 2023 were obtained from the FDA Adverse Event Reporting System (FAERS). We present data using the reporting odds ratio (ROR). The ROR was considered significant when the lower limit of the 95% confidence interval (CI) was greater than 1.0.ResultsDisproportionate reporting of suicidal ideation and “depression/suicidal” was observed with semaglutide and liraglutide. Disproportionate reporting of suicidal behavior, suicide attempts, and completed suicide was not observed for any of the FDA-approved GLP-1 RAs.ConclusionsUsing the Bradford Hill criteria, however, and taking into consideration confounders, no causal link between GLP-1 RAs and suicidality exists.

ABSTRACTIntroductionMajor depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common complications of childbirth that is underdiagnosed and undertreated, adversely impacting the mental health of women, children, and partners.Available antidepressant medications require weeks to months before showing effect. In this setting, zuranolone, an oral neuroactive steroid and a positive allosteric modulator of GABAAreceptors, is an attractive alternative as a rapid-acting antidepressant treatment.Areas coveredThis article reviews zuranolone (SAGE217), focusing on available clinical studies in individuals with PPD and MDD. This paper adds to the extant literature by presenting the efficacy data as Number Needed to Treat (NNT) to facilitate indirect comparisons with other antidepressants.Expert opinionZuranolone is a novel rapid-acting (i.e. two week course) oral antidepressant for the treatment of adults with PPD with ongoing clinical trials evaluating its efficacy in adults with MDD. Zuranolone is well tolerated with no significant safety concerns in any clinical trials completed to date. Zuranolone will be scheduled by the Drug Enforcement Agency (DEA).

AbstractNonalcoholic fatty liver disease (NAFLD) is a complex metabolic-inflammatory disease associated with poor outcomes and decreased quality of life. NAFLD is overrepresented in patients with psychiatric disorders like depression, bipolar disorder, and schizophrenia; however, a comprehensive review on NAFLD and psychiatric disorders remains to be delineated. This review endeavors to investigate the association of NAFLD with psychiatric disorders, including shared pathogenesis and future clinical derivatives. Extant literature suggests that patients with psychiatric disorders (in particular, mood disorders) are more susceptible to the development of NAFLD due to multiple reasons, including but not limited to hypothalamic–pituitary–adrenal axis dysregulation, metabolic syndrome, and chronic perceived stress. Moreover, the clinical manifestations of mood disorders (e.g., anhedonia, psychomotor retardation, lifestyle modification, etc.), and potentially long-term treatment with weight-gaining agents, differentially affect these patients, making them more prone to NAFLD. Considering the increased morbidity associated with both mood disorders and NAFLD, our review recommends regular screenings for NAFLD in select patients with mood disorders exhibiting signs of increased risk (i.e., obesity, metabolic syndrome, diabetes, or family history of NAFLD) for better diagnosis and holistic care of both potentially interrelated conditions.

Treatment‐resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision‐making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision‐making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo‐resistant (e.g., due to inadequacy of treatment trials or non‐adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non‐response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co‐administered with an antidepressant) are established as efficacious in the management of TRD. Some second‐generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine‐fluoxetine combination has been studied in FDA‐defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA‐approved for individuals with TRD, with accelerated theta‐burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non‐inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual‐based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

While new add-on treatments have been developed for augmentation in depression with benefits demonstrated compared to placebo, none have demonstrated superiority compared to previously available interventions until now. In a phase IIIb, randomized, active-controlled trial (ESCAPE-TRD), Reif et al.1demonstrate the superiority of esketamine compared to quetiapine augmentation (the current standard-of-care).

ABSTRACTIntroductionCognitive impairment is a core feature of bipolar disorder (BD) that impedes recovery by preventing the return to optimal socio-occupational functioning and reducing quality of life. Presently, there are no efficacious treatments for cognitive impairment in BD, but many pharmacological interventions are being considered as they have the potential to target the underlying pathophysiology of the disorder.Areas coveredThis review summarizes the available evidence for pharmacological interventions for cognitive impairment in bipolar disorder. We searched PubMed, MedLine, and PsycInfo from inception to December 1st,2022. Traditional treatments, such as lithium, anticonvulsants (lamotrigine), antipsychotics (aripiprazole, asenapine, cariprazine, lurasidone, and olanzapine), antidepressants (vortioxetine, fluoxetine, and tianeptine) and psychostimulants (modafinil), and emerging interventions, such as acetylcholinesterase inhibitors (galantamine and donepezil), dopamine agonists (pramipexole), erythropoietin, glucocorticoid receptor antagonists (mifepristone), immune modulators (infliximab, minocycline and doxycycline), ketamine, metabolic agents (insulin, metformin, and liraglutide), probiotic supplements, and Withania somniferaare discussed.Expert opinionThe investigation of interventions for cognitive impairment in BD is a relatively under-researched area. In the past, methodological pitfalls in BD cognition trials have also been a critical limiting factor. Expanding on the existing literature and identifying novel pharmacological and non-pharmacological treatments for cognitive impairment in BD should be a priority.

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

AbstractObjectiveMore than 50% patients with major depressive disorder (MDD) have severe functional impairment. The restoration of patient functioning is a critical therapeutic goal among patients with MDD. We conducted a systematic review and network meta-analysis to evaluate the efficacy of pharmacological treatments on self-rated functional outcomes using the Sheehan Disability Scale in adults with MDD in randomized clinical trials.MethodsPubMed, EMBASE, PsycINFO, Cochrane Library, and ClinicalTrials.gov were searched from inception to December 10, 2019. Summary statistics are reported as weighted mean differences with 95% confidence intervals. Interventions were ranked using the surface under the cumulative ranking probabilities.ResultsWe included 42 randomized controlled trials (RCTs) (n = 18 998) evaluating the efficacy of 13 different pharmacological treatments on functional outcomes, as measured by the Sheehan Disability Scale (SDS). Duloxetine was the most effective pharmacological agent on functional outcomes, followed by (ranked by efficacy): paroxetine, levomilnacipran, venlafaxine, quetiapine, desvenlafaxine, agomelatine, escitalopram, amitriptyline, bupropion, sertraline, vortioxetine, and fluoxetine. Serotonin and norepinephrine reuptake inhibitors were more effective than other drug classes. Additionally, the comparison-adjusted funnel plot suggested the publication bias between small and large studies was relatively low.ConclusionsOur results indicate that there may be differences across antidepressant agents and classes with respect to self-reported functional outcomes. Validation and replication of these findings in large-scale RCTs are warranted. Our research results will be clinically useful for guiding psychiatrists in treating patients with MDD and functional impairment. PROSPERO registration number CRD42018116663.

AbstractCognitive impairment is common in bipolar disorder and is emerging as a therapeutic target to enhance quality of life and function. A systematic search was conducted on PubMed, PsycInfo, Cochrane, clinicaltrials.gov, and Embase databases for blinded or open-label randomized controlled trials evaluating the pro-cognitive effects of pharmacological, neurostimulation, or psychological interventions for bipolar disorder. Twenty-two trials were identified, evaluating a total of 16 different pro-cognitive interventions. The methodological quality of the identified trials were assessed using the Cochrane Risk of Bias tool. Currently, no intervention (i.e., pharmacologic, neurostimulation, cognitive remediation) has demonstrated robust and independent pro-cognitive effects in adults with bipolar disorder. Findings are preliminary and methodological limitations limit the interpretation of results. Methodological considerations including, but not limited to, the enrichment with populations with pre-treatment cognitive impairment, as well as the inclusion of individuals who are in remission are encouraged. Future trials may also consider targeting interventions to specific cognitive subgroups and the use of biomarkers of cognitive function.

AbstractBackgroundHigher body mass index (BMI) has been found to predict greater antidepressant response to intravenous (IV) ketamine treatment. We evaluated the association between BMI and response to repeat-dose IV ketamine in patients with treatment-resistant depression (TRD).MethodsAdults (N = 230) with TRD received four infusions of IV ketamine at a community-based clinic. Changes in symptoms of depression (ie, Quick Inventory for Depressive Symptomatology-Self-Report 16; QIDS-SR16), suicidal ideation (SI; ie, QIDS-SR16SI item), anxiety (ie, Generalized Anxiety Disorder-7 Scale), anhedonic severity (ie, Snaith–Hamilton Pleasure Scale), and functioning (ie, Sheehan Disability Scale) following infusions were evaluated. Participants were stratified by BMI as normal (18.0-24.9 kg/m2; n = 72), overweight (25-29.9 kg/m2; n = 76), obese I (30-34.9 kg/m2; n = 47), or obese II (≥35.0 kg/m2; n = 35).ResultsSimilar antidepressant effects with repeat-dose ketamine were reported between BMI groups (P= .261). In addition, categorical partial response (P= .149), response (P= .526), and remission (P= .232) rates were similar between the four BMI groups.ConclusionsThe findings are limited by the observational, open-label design of this retrospective analysis. Pretreatment BMI did not predict response to IV ketamine, which was effective regardless of BMI.

AbstractBackgroundBenzodiazepine (BZD) prescription rates have increased over the past decade in the United States. Available literature indicates that sociodemographic factors may influence diagnostic patterns and/or prescription behaviour. Herein, the aim of this study is to determine whether the gender of the prescriber and/or patient influences BZD prescription.MethodsCross-sectional study using data from the Florida Medicaid Managed Medical Assistance Program from January 1, 2018 to December 31, 2018. Eligible recipients ages 18 to 64, inclusive, enrolled in the Florida Medicaid plan for at least 1 day, and were dually eligible. Recipients either had a serious mental illness (SMI), or non-SMI and anxiety.ResultsTotal 125 463 cases were identified (i.e., received BZD or non-BZD prescription). Main effect of patient and prescriber gender was significant F(1, 125 459) = 0.105, P= 0 .745, partial η2< 0.001. Relative risk (RR) of male prescribers prescribing a BZD compared to female prescribers was 1.540, 95% confidence intervals (CI) [1.513, 1.567], whereas the RR of male patients being prescribed a BZD compared to female patients was 1.16, 95% CI [1.14, 1.18]. Main effects of patient and prescriber gender were statistically significant F(1, 125 459) = 188.232, P< 0.001, partial η2= 0.001 and F(1, 125 459) = 349.704, P< 0.001, partial η2= 0.013, respectively.ConclusionsMale prescribers are more likely to prescribe BZDs, and male patients are more likely to receive BZDs. Further studies are required to characterize factors that influence this gender-by-gender interaction.

AbstractBackgroundPatients unsuccessfully treated by neurostimulation may represent a highly intractable subgroup of depression. While the efficacy of intravenous (IV) ketamine has been established in patients with treatment-resistant depression (TRD), there is an interest to evaluate its effectiveness in a subpopulation with a history of neurostimulation.MethodsThis retrospective, posthoc analysis compared the effects of four infusions of IV ketamine in 135 (x̄ = 44 ± 15.4 years of age) neurostimulation-naïve patients to 103 (x̄ = 47 ± 13.9 years of age) patients with a history of neurostimulation. The primary outcome evaluated changes in depression severity, measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16). Secondary outcomes evaluated suicidal ideation (SI), anxiety severity, measured by the Generalized Anxiety Disorder 7-Item (GAD-7), and consummatory anhedonia, measured by the Snaith–Hamilton Pleasure Scale (SHAPS).ResultsFollowing four infusions, both cohorts reported a significant reduction in QIDS-SR16Total Score (F(4, 648) = 73.4, P< .001), SI (F(4, 642) = 28.6, P< .001), GAD-7 (F(2, 265) = 53.8, P< .001), and SHAPS (F(2, 302) = 45.9, P< .001). No between-group differences emerged. Overall, the neurostimulation-naïve group had a mean reduction in QIDS-SR16Total Score of 6.4 (standard deviation [SD] = 5.3), whereas the history of neurostimulation patients reported a 4.3 (SD = 5.3) point reduction.ConclusionIV ketamine was effective in reducing symptoms of depression, SI, anxiety, and anhedonia in both cohorts in this large, well-characterized community-based sample of adults with TRD.

ABSTRACTIntroductionKetamine is an established intervention for treatment-resistant depression (TRD). However, long-term adverse effects with repeated doses remain insufficiently characterized. Although several animal models have shown N-methyl-D-aspartate glutamate receptor antagonists to produce various neuropathological reactions, attention surrounding the risk of brain lesions has been minimal.Areas coveredThe current review focuses on potential neuropathological changes associated with ketamine. Search terms included variations of ketamine, Olney lesions, tau hyperphosphorylation, and parvalbumin interneurons.Expert opinionDaily high-dose ketamine use in substance use disorder (SUD) populations was associated with clear neurotoxic effects, while no studies specifically evaluated effects of ketamine protocols used for TRD. It is difficult to discern effects directly attributable to ketamine due to methodological factors, such as comorbidities and dramatic differences in dose in SUD populations versus infrequent sub-anesthetic doses typically prescribed for TRD. Taken together, animal models and human ketamine SUD populations suggest potential neuropathology with chronic high-dose ketamine exposure exceeding those recommended for adults with TRD. It is unknown whether repeat sub-anesthetic dosing of ketamine in adults with TRD is associated with Olney lesions or other neuropathologies. In the interim, practitioners should be vigilant for this possibility recognizing that the condition itself is associated with neurodegenerative processes.

ABSTRACTIntroductionHallucinogen persisting perception disorder (HPPD) affects a subset of persons who use hallucinogens and is defined as the repeated experience of hallucinations and other perceptual disturbances as a result of prior intoxications. As select hallucinogens are under development for the treatment of selectmental disorders, there is a need to better characterize this disorder.Areas coveredA scoping review of the literature on HPPD was completed from inception to July 2021. Topics covered in the review herein include treatments for HPPD, prevalence or incidence data on HPPD among different classes of hallucinogens, risk factors for HPPD, and data pertaining to the pathophysiology of HPPD.Expert opinionHallucinogen persisting perception disorder appears to be an uncommon yet serious event associated with prior hallucinogen exposure. The renewed interest in psychedelics as potential treatment options for select mental disorders, especially agents with hallucinogenic potential, provides the impetus to characterize HPPD in its frequency, risk and protective factors, key characteristics, as well as other clinical and treatment-related factors.

ABSTRACTIntroductionIntranasal (IN) esketamine represents an innovative treatment for individuals with treatment resistant depression and depression with suicidal ideation and behavior. Herein, we synthesize extant long-term studies (≥ 4 weeks) regarding this treatment.Research design and methodsThe interventional studies of IN esketamine in patients with depression having a study period of at least four weeks were included for our synthesis. A meta-analysis was undertaken for the efficacy and safety parameters of adjunctive IN esketamine vs IN placebo with an oral antidepressant. The data excluded from meta-analysis were synthesized narratively.ResultsAfter pooling data from seven randomized controlled trials, treatment with adjunctive IN esketamine vs IN placebo was safe overall, and more effective at decreasing depressive symptoms (d = −0.239; 95%CI = −0.335,-0.142;p < 0.0001), with higher response (RR = 1.221; 95% CI = 1.055,1.428; p = 0.017) and remission (RR = 1.366; 95% CI = 1.182,1.578; p < 0.0001) rates. The year-long trials showed that treatment with adjunctive IN esketamine led to lower relapse rates with no considerable long-term side effects.ConclusionIntranasal esketamine was demonstrated to be safe, well tolerated, and rapidly effective in individuals with treatment resistant depression, suicidal ideation, and suicidal behavior.

Psilocybin-assisted psychotherapy (PAP) has been associated with antidepressant effects. Trials to date have typically excluded participants with complex presentations. Our aim was to determine the feasibility of PAP in a complex population, including high levels of treatment resistance in major depressive and bipolar disorder and patients with baseline suicidality and significant comorbidity. We also evaluated flexible repeated doses over a 6-month period.

Background The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults.Methods CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process.Results The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted.Conclusions The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.

ABSTRACTIntroductionThe large percentage of adults with major depressive disorder (MDD) insufficiently responding and/or tolerating conventional monoamine-based antidepressants invites the need for mechanistically novel treatments. Convergent evidence implicates glutamatergic signaling as a potential therapeutic target in MDD.Areas coveredThe synthesis herein of preclinical and clinical studies indicates that dextromethorphan (DXM) is well tolerated and exhibits clinically significant antidepressant effects; DXM combined with bupropion has demonstrated replicated and relatively rapid onset efficacy in adults with MDD. DXM efficacy has been preliminarily reported in adults with bipolar depression. The combination of DXM and bupropion represents a pharmacokinetic and pharmacodynamic synergy which may account for the rapidity of action in MDD.Expert opinionThe combination of DXM and bupropion is a safe, well tolerated and efficacious treatment option in adults with MDD. Priority questions are whether DXM/bupropion is uniquely effective across discrete domains of psychopathology (e.g. anhedonia, reward processing, general cognitive systems) and/or whether it is able to significantly improve patient-reported outcomes (e.g. quality of life, psychosocial functioning). The availability of ketamine/esketamine and DXM/bupropion instantiates the relevance of glutamate as a treatment target in MDD. Studies in bipolar depression with DXM/bupropion are warranted as well as in MDD with suicidality.

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

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10–20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders.

ABSTRACTObjectivesRigorous clinical trials suggest ketamine is safe and well-tolerated in patients with treatment-resistant depression (TRD). There is a paucity of data on the safety and tolerability of ketamine in community-based clinics treating patients with TRD.MethodsRetrospective data was analyzed from 203 patients with TRD who received repeat-dose IV ketamine. Safety was operationalized as hemodynamic changes. Tolerability was evaluated through the reporting of adverse events and dissociation symptom severity, as measured by the Clinician-Administered Dissociative States Scale.ResultsKetamine was well-tolerated, with less than 5% of patients withdrawing due to tolerability concerns. Blood pressure significantly increased during infusion, with 44.3% meeting criteria for treatment-emergent hypertension (i.e., blood pressure ≥ 165/100 mmHg). 12% of patients exhibiting hypertension required pharmacological intervention. The most frequently reported adverse events included drowsiness (56.4%), dizziness (45.2%), dissociation (35.6%), and nausea (13.3%). Dissociation severity significantly attenuated after the first infusion, but plateaued for subsequent infusions.ConclusionIntravenous ketamine was safe and well-tolerated. Hypertension was commonly observed and was often transient. Dissociation was most frequently reported after the first infusion but remained a consistent but not treatment-limiting adverse event thereafter. No patients exhibited psychosis, mania, or new onset suicidality with IV ketamine.

During the past two decades, it has been amply documented that neuropsychiatric disorders (NPDs) disproportionately account for burden of illness attributable to chronic non-communicable medical disorders globally. It is also likely that human capital costs attributable to NPDs will disproportionately increase as a consequence of population aging and beneficial risk factor modification of other common and chronic medical disorders (e.g., cardiovascular disease). Notwithstanding the availability of multiple modalities of antidepressant treatment, relatively few studies in psychiatry have primarily sought to determine whether improving cognitive function in MDD improves patient reported outcomes (PROs) and/or is cost effective. The mediational relevance of cognition in MDD potentially extrapolates to all NPDs, indicating that screening for, measuring, preventing, and treating cognitive deficits in psychiatry is not only a primary therapeutic target, but also should be conceptualized as a transdiagnostic domain to be considered regardless of patient age and/or differential diagnosis.

Convergent evidence demonstrates that immune dysfunction (e.g. chronic low-grade inflammatory activation) plays an important role in the development and progression of mood disorders. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is a pleiotropic cellular cascade that transduces numerous signals, including signals from the release of cytokines and growth factors. The JAK/STAT signaling pathway is involved in mediating several functions of the central nervous system, including neurogenesis, synaptic plasticity, gliogenesis, and microglial activation, all of which have been implicated in the pathophysiology of mood disorders. In addition, the antidepressant actions of current treatments have been shown to be mediated by JAK/STAT-dependent mechanisms. To date, two JAK inhibitors (JAKinibs) have been approved by the U.S. Food and Drug Administration and are primarily indicated for the treatment of inflammatory conditions such as rheumatoid arthritis. Indirect evidence from studies in populations with inflammatory conditions indicates that JAKinibs significantly improve measures of mood and quality of life. There is also direct evidence from studies in populations with depressive disorders, suggesting that JAK/STAT pathways may be involved in the pathophysiology of depression and that the inhibition of specific JAK/STAT pathways (i.e. via JAKinibs) may be a promising novel treatment for depressive disorders.

Background: The therapeutic potential of subanesthetic doses of ketamine appears promising in unipolar depression; however, its effectiveness in treating bipolar depression (BD) remains uncertain.Objective: This systematic review aimed to summarize findings on the use of ketamine for the treatment of BD by assessing its efficacy, safety, and tolerability.Design: Systematic review.Methods: We conducted a systematic review of studies that investigated the use of ketamine for adults with BD. We searched PubMed and Embase for relevant randomized-controlled trials, open-label trials, and retrospective chart analyses published from inception to 13 March 2023.Results: Eight studies were identified [pooled n= 235; mean (SD) age: 45.55 (5.54)]. All participants who received intravenous (IV) ketamine were administered a dose of 0.5–0.75 mg/kg as an adjunctive treatment to a mood-stabilizing agent, whereas participants who received esketamine were administered a dosage ranging from 28 to 84 mg. Flexible dosing was used in real-world analyses. A total of 48% of participants receiving ketamine achieved a response (defined as ⩾50% reduction in baseline depression severity), whereas only 5% achieved a response with a placebo. Real-world studies demonstrated lower rates of response (30%) compared to the average across clinical trials (63%). Reductions in suicidal ideation were noted in some studies, although not all findings were statistically significant. Ketamine and esketamine were well tolerated in most participants; however, six participants (2% of the overall sample pool, 5 receiving ketamine) developed hypomanic/manic symptoms after infusions. Significant dissociative symptoms were observed at the 40-min mark in some trials.Conclusion: Preliminary evidence suggests IV ketamine as being safe and effective for the treatment of BD. Future studies should focus on investigating the effects of repeated acute and maintenance infusions using a randomized study design.

ABSTRACTIntroduction: Treatment resistant depression (TRD) represents approximately 20% of all individuals receiving care for major depressive disorder. The opioidergic system is identified as a novel target which hitherto has not been sufficiently investigated in adults with TRD. The combination product buprenorphine + samidorphan is an opioid modulatory agent which has demonstrated replicated evidence of efficacy in TRD without abuse liability.Areas covered: Databases Pubmed, Google Scholar and clinicaltrials.gov were searched from inception through December 2017 for clinical trial information, pharmacokinetics, and pharmacodynamics of buprenorphine + samidorphan. Herein we provide a summary of the available information. Eight clinical trials were identified for inclusion, of the eight trials, five trials had available results and are included in detail in our review.Expert opinion: Buprenorphine + samidorphan has demonstrated efficacy in TRD. Extant evidence surrounding the safety and tolerability profile of buprenorphine + samidorphan does not identify any significant safety concerns. Additional studies are needed in order to assess the long-term safety and efficacy of this product.

ABSTRACTIntroduction: To determine, via narrative, non-systematic review of pre-clinical and clinical studies, whether the effect of cannabis on hepatic biotransformation pathways would be predicted to result in clinically significant drug-drug interactions (DDIs) with commonly prescribed psychotropic agents.Areas covered: A non-systematic literature search was conducted using the following databases: PubMed, PsycInfo, and Scopus from inception to January 2017. The search term cannabiswas cross-referenced with the terms drug interactions, cytochrome, cannabinoids, cannabidiol, and medical marijuana. Pharmacological, molecular, and physiologic studies evaluating the pharmacokinetics of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), both in vitroand in vivo, were included. Bibliographies were also manually searched for additional citations that were relevant to the overarching aim of this paper.Expert opinion: Δ9-Tetrahydrocannabinol and CBD are substrates and inhibitors of cytochrome P450 enzymatic pathways relevant to the biotransformation of commonly prescribed psychotropic agents. The high frequency and increasing use of cannabis invites the need for healthcare providers to familiarize themselves with potential DDIs in persons receiving select psychotropic agents, and additionally consuming medical marijuana and/or recreational marijuana.

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A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM–5 codified a new nosological entity, the “mixed features specifier,” referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM–IV definition of “mixed states” wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mixed features specifier provides a less restrictive definition of mixed mood states, compared to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), including mood episodes that manifest with subthreshold symptoms of the opposite mood state. A limited number of studies have assessed the efficacy of treatments specifically for DSM-5–defined mixed features in mood disorders. As such, there is currently an inadequate amount of data to appropriately inform evidence-based treatment guidelines of DSM-5 defined mixed features. However, given the high prevalence and morbidity of mixed features, treatment recommendations based on the currently available evidence along with expert opinion may be of benefit. This article serves to provide these interim treatment recommendations while humbly acknowledging the limited amount of evidence currently available. Second-generation antipsychotics (SGAs) appear to have the greatest promise in the treatment of bipolar disorder (BD) with mixed features. Conventional mood stabilizing agents (ie, lithium and divalproex) may also be of benefit; however, they have been inadequately studied. In the treatment of major depressive disorder (MDD) with mixed features, the comparable efficacy of antidepressants versus other treatments, such as SGAs, remains unknown. As such, antidepressants remain first-line treatment of MDD with or without mixed features; however, there are significant safety concerns associated with antidepressant monotherapy when mixed features are present, which merits increased monitoring. Lurasidone is the only SGA monotherapy that has been shown to be efficacious specifically in the treatment of MDD with mixed features. Further research is needed to accurately determine the efficacy, safety, and tolerability of treatments specifically for mood episodes with mixed features to adequately inform future treatment guidelines.

Mood episodes with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)–defined mixed features are highly prevalent in bipolar disorder (BD), affecting ~40% of patients during the course of illness. Mixed states are associated with poorer clinical outcomes, greater treatment resistance, higher rates of comorbidity, more frequent mood episodes, and increased rates of suicide. The objectives of the current review are to identify, summarize, and synthesize studies assessing the efficacy of treatments specifically for BD I and II mood episodes (ie, including manic, hypomanic, and major depressive episodes) with DSM-5–defined mixed features. Two randomized controlled trials (RCTs) and 6 post-hoc analyses were identified, all of which assessed the efficacy of second-generation antipsychotics (SGAs) for the acute treatment of BD mood episodes with mixed features. Results from these studies provide preliminary support for SGAs as efficacious treatments for both mania with mixed features and bipolar depression with mixed features. However, there are inadequate data to definitively support or refute the clinical use of specific agents. Conventional mood stabilizing agents (eg, lithium and divalproex) have yet to have been adequately studied in DSM-5–defined mixed features. Further study is required to assess the efficacy, safety, and tolerability of treatments specifically for BD mood episodes with mixed features.

The pathophysiology of bipolar disorder (BD) remains poorly understood. Current psychopharmacologic treatments are often poorly tolerated and carry high rates of treatment resistance. Mounting evidence has suggested that innate immune system dysfunction may play a role in the pathophysiology of BD. Elevated proinflammatory cytokine levels have been identified. The innate immune system is a novel therapeutic target in BD. Lithium has been shown to have antiinflammatory properties. Further research is needed to establish the role of antiinflammatory agents in the treatment of BD; however, evidence from several clinical trials indicates that antiinflammatory agents may be incorporated into clinical practice soon.

Available evidence indicates that a single, low-dose administration of ketamine is a robust, rapid-onset intervention capable of mitigating depressive symptoms in adults with treatment-resistant mood disorders. Additional evidence also suggests that ketamine may offer antisuicide effects. Herein, we propose that the antidepressant effects reported with ketamine administration are mediated, in part, by targeting neural circuits that subserve cognitive processing relevant to executive function and cognitive emotional processing. Empirical support for the conceptual framework of the cognitive domain as a critical target of ketamine's action is the additional observation that pretreatment cognitive function predicts treatment outcomes with ketamine administration. The proposal that beneficial effects on cognitive function may be, in some individuals, the proximate mechanism mitigating symptom relief in mood disorders exists alongside the well-established deleterious effect of ketamine on cognitive function. During the past 5 years, there have been several reviews and meta-analyses concluding that ketamine has possible clinical benefits in refractory mood disorders. We introduce the conceptual framework that ketamine's salutary effects, notably in suicidality, may in part be via procognitive mechanisms.

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•53 older adults (≥60 years of age) with treatment-resistant depression received repeat-doses of intravenous ketamine (i.e., four infusions)•27% of older adults responded to IV ketamine after four infusions (i.e., 50% decrease in symptoms compared to pre-treatment)•36 participants experienced transient treatment-emergent hypertension•3 participants dropped out of treatment due to increased anxiety and/or inability to tolerate dissociative symptoms

We report a 74-year-old white woman with type 1 diabetes and major depressive disorder refractory to multiple medications who received 15 electroconvulsive therapy treatments with minimal improvement. After an accidental hypoglycemic seizure, the patient’s symptoms completely resolved. In conclusion, the present case reveals an instance where electroconvulsive therapy–induced seizures appeared to be minimally effective, whereas a single accidental hypoglycemia-induced seizure was incredibly effective for the resolutions of depressive symptoms. Although this case presents a single efficacious use of accidental insulin coma therapy, the applicability is limited because of the known risks of insulin coma therapy.