Treatment Of Major Depressive Episodes Research Articles

Family environment and depressive episode are associated with relapse after first-episode psychosis.

WHAT IS KNOWN ON THE SUBJECT?: Relapse rates are high among patients who have experienced first-episode psychosis (FEP). Psychotic relapses are associated with worse quality of life and poorer functionality of the FEP patient. The use of psychoactive substances, non-adherence to drug treatment, and high expressed emotion (EE) are notable predictors of relapse after the FEP. Although some studies have suggested that psychotic relapse may be associated with a family environment with high levels of emotional over-involvement (EOI), this finding is still inconsistent across different cultures. EE specific components must be evaluated and interpreted according to the context of cultural norms. There is a scarcity of studies on the role of depression in the occurrence of relapses after the FEP, and the results remain uncertain. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: This study explored the predictors of psychotic relapses in Brazilian patients who experienced FEP. Our results indicate that 29.2% of the patients relapsed after the FEP. Patients diagnosed with depression and high-EOI in the family environment were predictors of psychotic relapses in this population. This study expands knowledge about the cultural specificity of EOI and the role of depression in psychotic relapse. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Nursing professionals must consider the implications of the family environment and depression in the course of psychosis. Family interventions and the appropriate treatment of depression are important for improving the prognosis of FEP patients. ABSTRACT: Introduction Psychotic relapse may be associated with relatives' high emotional over-involvement (EOI) and with a diagnosis of major depressive episode (MDE) among first-episode psychosis (FEP) patients, but the results are still inconsistent across different cultures. Aim Evaluate the predictors of relapse in FEP patients. Method Prospective cohort study with 6-month follow-up conducted with 65 dyads of patients and relatives from an early intervention unit in Brazil. At the baseline interview, relatives answered to a sociodemographic data form and to the Family Questionnaire. Patients provided sociodemographic and clinical data and answered the Measurement of Treatment Adherence; the Alcohol, Smoking and Substance Involvement Screening Test; the Severity of Dependence Scale to assess cannabis dependence, and the MDE module of the Mini-International Neuropsychiatric Interview. Psychotic relapses were evaluated using items from the Brief Psychiatric Rating Scale. The data were analysed using multiple logistic regression. Results 29.2% of the patients presented at least one psychotic relapse. High-EOI and MDE were predictors of psychotic relapses. Discussion Our findings expand the knowledge about the cultural specificity of EOI and the role of depression in psychotic relapse. Implications for practice Family nursing interventions and the appropriate treatment of MDE must be considered in the care of FEP patients.

Computerized Memory Specificity Training (c-MeST) for major depression: A randomised controlled trial

Given modest response and high relapse after treatment for Major Depressive Episodes (MDE), the development and refinement of treatments to target cognitive vulnerabilities is indicated. Memory Specificity Training (MeST) remediates deficits in recalling detailed memories of past experiences through repeated practice of autobiographical memory retrieval. This randomised controlled trial aimed to assess the efficacy of an online, computerized version of MeST (c-MeST) for MDE. Adults (N = 245, 88.4% female; M age = 46.4) with a current MDE were randomised to the c-MeST program or wait-list control group. Significantly fewer participants in the c-MeST group, relative to control, met criteria for an MDE at one-month follow-up (35.7% c-MeST vs. 60.6% control), but not at other time-points. The c-MeST group, relative to the control group, scored significantly higher on memory specificity at all time-points following baseline (d = 0.53–0.93), and lower on depressive symptoms at one (d = 0.57) and three-month follow-up (d = 0.67). Changes in memory specificity mediated the effect of c-MeST on depressive symptoms at follow-up. c-MeST can improve memory specificity and depressive symptoms in people with an MDE, and may speed the rate of recovery. Future studies can further examine the mechanisms through which this occurs.

Baseline predictors of cognitive change in the treatment of major depressive episode: systematic review.

Cognitive impairment is a core feature of depression and has a negative effect on a person's functioning, in psychosocial and interpersonal areas, and on workforce performance. Cognitive impairment often persists, even with the remittance of mood symptoms. One potential way of improving treatment of cognitive impairment would be to identify variables that predict cognitive change in patients with depression. To systematically examine findings from studies that investigate baseline variables and how they predict, or correlate with, cognitive change in mood disorders, and to examine methodological issues from these studies. Studies that directly measured associations between at least one baseline variable and change in cognitive outcome in patients with current major depressive episode were identified using PubMed and Web of Science databases. Narrative review technique was used because of the heterogeneity of patient samples, outcome measures and study procedures. The review was registered on PROSPERO with registration number CRD42020150975. Twenty-four studies met the inclusion criteria. Evidence from the present review for prediction of cognitive change from baseline variables was limited for demographic factors, with some preliminary evidence for depression, cognitive and biological factors. Identification of patterns across studies was difficult because of methodological variability across studies. Findings from the present review suggest there may be some baseline variables that are useful in predicting cognitive change in mood disorders. This is an area warranting further research focus.

Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator

Zuranolone (SAGE-217) is a novel, synthetic, clinical stage neuroactive steroid GABAA receptor positive allosteric modulator designed with the pharmacokinetic properties to support oral daily dosing. In vitro, zuranolone enhanced GABAA receptor current at nine unique human recombinant receptor subtypes, including representative receptors for both synaptic (γ subunit-containing) and extrasynaptic (δ subunit-containing) configurations. At a representative synaptic subunit configuration, α1β2γ2, zuranolone potentiated GABA currents synergistically with the benzodiazepine diazepam, consistent with the non-competitive activity and distinct binding sites of the two classes of compounds at synaptic receptors. In a brain slice preparation, zuranolone produced a sustained increase in GABA currents consistent with metabotropic trafficking of GABAA receptors to the cell surface. In vivo, zuranolone exhibited potent activity, indicating its ability to modulate GABAA receptors in the central nervous system after oral dosing by protecting against chemo-convulsant seizures in a mouse model and enhancing electroencephalogram β-frequency power in rats. Together, these data establish zuranolone as a potent and efficacious neuroactive steroid GABAA receptor positive allosteric modulator with drug-like properties and CNS exposure in preclinical models. Recent clinical data support the therapeutic promise of neuroactive steroid GABAA receptor positive modulators for treating mood disorders; brexanolone is the first therapeutic approved specifically for the treatment of postpartum depression. Zuranolone is currently under clinical investigation for the treatment of major depressive episodes in major depressive disorder, postpartum depression, and bipolar depression.

A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol

BackgroundRecent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes.MethodsAcross four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality.DiscussionThis multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery.Trial registrationClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.

P277 Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

P277 Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

Adherence to treatment guidelines in clinical practice for using electroconvulsive therapy in major depressive episode

BackgroundECT is the most effective treatment of major depressive episode (MDE) but remains a neglected treatment. The French Society for Biological Psychiatry and Neuropsychopharmacology aimed to determine whether prescribing practice of ECT followed guidelines recommendations. MethodsThis multicenter, retrospective study included adult patients with major depressive disorder (MDD) or bipolar disorder (BD), who have been treated with ECT for MDE. Duration of MDE and number of lines of treatment received before ECT were collected. The reasons for using ECT, specifically first-line indications (suicidality, urgency, presence of catatonic and psychotic features, previous ECT response, patient preference) were recorded. Statistical comparisons between groups used standard statistical tests. ResultsSeven hundred and forty-five individuals were included. The mean duration of MDE before ECT was 10.1 months and the mean number of lines of treatment before ECT was 3.4. It was significantly longer for MDD single episode than recurrent MDD and BD. The presence of first-line indications for using ECT was significantly associated to shorter duration of MDE (9.1 vs 13.1 months, p<0.001) and lower number of lines of treatment before ECT (3.3 vs 4.1, p<0.001). LimitationsThis is a retrospective study and not all facilities practicing ECT participated that could limit the extrapolation of the results. Conclusion: Compared to guidelines, ECT was not used as first-line strategy in clinical practice. The presence of first-line indications seemed to reduce the delay before ECT initiation. The improvements of knowledge and access of ECT are needed to decrease the gap between guidelines and clinical practice.

May antidepressant drugs worsen the conditions they are supposed to treat? The clinical foundations of the oppositional model of tolerance.

In recent years there has been a considerable debate on antidepressant drugs. Continued drug treatment with antidepressant medications may stimulate processes that run counter to the initial acute effects of a drug. The oppositional model of tolerance may explain loss of treatment efficacy during maintenance treatment and the fact that some side effects tend to occur only after a certain time. These processes may also direct the illness into a treatment-unresponsive course, including manifestations of bipolar disorder or paradoxical reactions. When drug treatment ends, oppositional processes no longer encounter resistance, resulting in potential onset of new withdrawal symptoms, persistent post-withdrawal disorders, hypomania, and resistance to treatment if it is reinstituted. In all these cases, antidepressant medications may constitute a form of iatrogenic comorbidity, which increases chronicity and vulnerability to depressive episodes. Antidepressant medications are essential drugs for the treatment of major depressive episodes. They are less likely, however, to provide protection for relapse prevention. Current prescription practices need to be reformulated in light of consideration of vulnerabilities and adverse effects of treatment. The oppositional model of tolerance provides a conceptual framework for weighing all these elements in the individual case. The model does not appear to apply to all patients who undergo treatment with AD, but only to a part of them. Studying the variables that are associated with such occurrence in certain patients and not in others would be one of the most important tasks of current therapeutic research. Current diagnostic systems in psychiatry do not consider the iatrogenic components of psychopathology, and can be applied to only patients who are drug free. They are suited for a patient who no longer exists: most of the cases that are seen in psychiatric clinical practice receive psychotropic drugs and such treatment is likely to affect prognosis and treatment choices.

Pregabalina i duloksetyna w praktyce psychiatry. Najczęściej pojawiające się pytania i wątpliwości

Pregabalin was firstly used as an anti-epileptic drug, but later it there was found a new indication, especially generalized anxiety and neuropathic pain. Duloxetine was firstly used in the treatment of diabetic neuropathy, but in later years it was registered in the treatment of major depressive episodes and generalized anxiety. Both are very effective, but their use is limited by reimbursement recommendations. The paper presents situations in which the use of these drugs can give significant benefits.

Pramipexole in the treatment of unipolar and bipolar depression. A systematic review and meta-analysis.

Several depressed patients do not respond to traditional antidepressants. Our aim was to systematically review the effectiveness and safety of pramipexole in unipolar and bipolar depression. We conducted a systematic review of randomized clinical trials (RCTs) and observational studies on pramipexole for patients with major depressive episodes, following PRISMA guidelines. Our primary outcome measure was treatment response at endpoint. The study protocol was registered on PROSPERO: CRD42018108699. We found five RCTs, three open-label trials and five observational studies, with 504 participants (57% women; mean age, 45.3years; mean sample size, 39; median duration of treatment, 8weeks; mean follow-up duration, 45weeks; mean maximum dose, 1.62mg). We found an overall short-term response rate of 52.2% and remission rate of 36.1%, and an overall long-term response rate of 62.1% and remission rate of 39.6%. In RCTs, patients treated with pramipexole had a superior response rate compared with placebo (RR: 1.77; 95% CI: 1.11-2.82) and similar to SSRIs (RR: 0.93; 95% CI: 0.44-1.95). Acceptability and tolerability were good, with nausea being the most frequent side-effect. Our study found some evidence for an effect of pramipexole for the treatment of major depressive episodes.

Uses of Electroconvulsive Therapy in Conditions Other than Major Depressive Episode

The effectiveness of electroconvulsive therapy (ECT) in the treatment of unipolar and bipolar major depressive episodes (MDE) is well known, and the US Food and Drug Administration has recently reclassified ECT devices to a less restrictive category for treatment of MDE and catatonia. In this review, we look at the existing evidence supporting the use of ECT in conditions other than MDE, such as bipolar mania and mixed states, schizophrenia, catatonia, Parkinson's disease, agitation in dementia, and status epilepticus. [ Psychiatr Ann . 2019;49(4):157–163.]

Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis

ObjectiveTo estimate the comparative clinical efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults.DesignSystematic review with pairwise and network meta-analysis.Data sourcesElectronic search...

Monoamine Oxidase B Total Distribution Volume in the Prefrontal Cortex of Major Depressive Disorder

Monoamine oxidase B (MAO-B) is an important, high-density enzyme in the brain that generates oxidative stress by hydrogen peroxide production, alters mitochondrial function, and metabolizes nonserotonergic monoamines. Recent advances in positron emission tomography radioligand development for MAO-B in humans enable highly quantitative measurement of MAO-B distribution volume (MAO-B VT), an index of MAO-B density. To date, this is the first investigation of MAO-B in the brain of major depressive disorder that evaluates regions beyond the raphe and amygdala. To investigate whether MAO-B VT is elevated in the prefrontal cortex in major depressive episodes (MDEs) of major depressive disorder. This case-control study was performed at a tertiary care psychiatric hospital from April 1, 2014, to August 30, 2018. Twenty patients with MDEs without current psychiatric comorbidities and 20 age-matched controls underwent carbon 11-labeled [11C]SL25.1188 positron emission tomography scanning to measure MAO-B VT. All participants were drug and medication free, nonsmoking, and otherwise healthy. The MAO-B VT in the prefrontal cortex (PFC). The second main outcome was to evaluate the association between MAO-B VT in the PFC and duration of major depressive disorder illness. Twenty patients with MDEs (mean [SD] age, 34.2 [13.2] years; 11 women) and 20 healthy controls (mean [SD] age, 33.7 [13.1] years; 10 women) were recruited. Patients with MDEs had significantly greater MAO-B VT in the PFC (mean, 26%; analysis of variance, F1,38 = 19.6, P < .001). In individuals with MDEs, duration of illness covaried positively with MAO-B VT in the PFC (analysis of covariance, F1,18 = 15.2, P = .001), as well as most other cortex regions and the thalamus. Fifty percent (10 of 20) of patients with MDEs had MAO-B VT values in the PFC exceeding those of healthy controls. Greater MAO-B VT is an index of MAO-B overexpression, which may contribute to pathologies of mitochondrial dysfunction, elevated synthesis of neurotoxic products, and increased metabolism of nonserotonergic monoamines. Hence, this study identifies a common pathological marker associated with downstream consequences poorly targeted by the common selective serotonin reuptake inhibitor treatments. It is also recommended that the highly selective MAO-B inhibitor medications that are compatible for use with other antidepressants and have low risk for hypertensive crisis should be developed or repurposed as adjunctive treatment for MDEs.

Pharmacological Treatment of Major Depressive Episodes with Mixed Features: A Systematic Review.

We reviewed clinical studies investigating the pharmacological treatment of major depressive episodes (MDEs) with mixed features diagnosed according to the dimensional criteria (more than two or three [hypo]manic symptoms+principle depressive symptoms). We systematically reviewed published randomized controlled trials on the pharmacological treatment of MDEs with mixed features associated with mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). We searched the PubMed, Cochrane Library, and ClinicalTrials.gov databases through December 2017 with the following key word combinations linked with the word OR: (a) mixed or mixed state, mixed features, DMX, mixed depression; (b) depressive, major depressive, MDE, MDD, bipolar, bipolar depression; and (c) antidepressant, antipsychotic, mood stabilizer, anticonvulsant, treatment, medication, algorithm, guideline, pharmacological. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We found few randomized trials on pharmacological treatments for MDEs with mixed features. Of the 36 articles assessed for eligibility, 11 investigated MDEs with mixed features in mood disorders: six assessed the efficacy of antipsychotic drugs (lurasidone and ziprasidone) in the acute phase of MDD with mixed features, although four of these were post hoc analyses based on large randomized controlled trials. Four studies compared antipsychotic drugs (olanzapine, lurasidone, and ziprasidone) with placebo, and one study assessed the efficacy of combination therapy (olanzapine+fluoxetine) in the acute phase of BD with mixed features. Pharmacological treatments for MDEs with mixed features have focused on antipsychotics, although evidence of their efficacy is lacking. Additional well-designed clinical trials are needed.

Pharmacological Treatment of Major Depressive Episodes with Mixed Features: A Systematic Review

Pharmacological Treatment of Major Depressive Episodes with Mixed Features: A Systematic Review

Antidepressants and Mood Stabilizers: Novel Research Avenues and Clinical Insights for Bipolar Depression.

The concept of the bipolar-spectrum and of mixed features being a bridge between major depressive disorders and bipolar disorders (BDs) has become increasingly important in mood-disorder diagnoses. Under these circumstances, antidepressants (ADs) and mood stabilizers (MSs) should be used with caution in the treatment of major depressive episodes (MDEs) and to obtain long-term stability in BDs. Before treating MDEs, screening tools, specific symptom evaluation and medical history should be used to distinguish between bipolarity and mixed features in patients for whom AD monotherapy may present a risk. In these patients, a combination of ADs plus MSs or atypical antipsychotics is recommended, rather than AD monotherapy. Studies evaluating MSs for bipolar depression suggest that lamotrigine is the most reliable treatment and lithium has modest effects; there is a lack of clear evidence regarding the efficacy of valproate and carbamazepine. Recently, significant progress has been made with respect to the pathophysiology of mood disorders and the application of potential biomarkers. There is an opportunity to study novel drug mechanisms through the rediscovery of fast-acting drugs such as ketamine. It is anticipated that future research developments will involve the discovery of potential targets for new drugs and their application to personalized treatments.

Number of pulses or number of sessions? An open-label study of trajectories of improvement for once-vs. twice-daily dorsomedial prefrontal rTMS in major depression

BackgroundRepetitive transcranial magnetic stimulation (rTMS) shows efficacy in the treatment of major depressive episodes (MDEs), but can require ≥4–6 weeks for maximal effect. Recent studies suggest that multiple daily sessions of rTMS can accelerate response without reducing therapeutic efficacy. However, it is unresolved whether therapeutic effects track cumulative number of pulses, or cumulative number of sessions. ObjectiveThis open-label study reviewed clinical outcomes over a 20–30 session course of high-frequency bilateral dorsomedial prefrontal cortex (DMPFC)-rTMS among patients receiving 6000 pulses/day delivered either in twice-daily sessions 80 min apart (at 20 Hz) or single, longer, once-daily sessions (at 10 Hz). MethodsA retrospective chart review identified 130 MDD patients who underwent 20–30 daily sessions of bilateral DMPFC-rTMS (Once-daily, n = 65; Twice-daily, n = 65) at a single Canadian clinic. ResultsMixed-effects modeling revealed significantly faster improvement (group-by-time interaction) for twice-daily versus once-daily DMPFC-rTMS. Across both groups, the pace of improvement showed a consistent relationship with number of cumulative sessions, but not with cumulative number of pulses. Although the twice-daily group completed treatment in half as many days, final clinical outcomes did not differ significantly between groups on dichotomous measures (response/remission rates: once-daily, 35.4%/33.8%; twice-daily, 41.5%/35.4%), or continuous measures, or on overall response distribution. ConclusionsTwice-daily rTMS appears feasible, tolerable, and capable of achieving comparable results to once-daily rTMS, while also reducing course length approximately twofold. Therapeutic gains tracked the cumulative number of sessions, not pulses. Future randomized studies comparing once-daily to multiple-daily rTMS sessions, while controlling for number of pulses, may be warranted.

A comprehensive model of predictors of persistence and recurrence in adults with major depression: Results from a national 3-year prospective study

Identifying predictors of persistence and recurrence of depression in individuals with a major depressive episode (MDE) poses a critical challenge for clinicians and researchers. We develop using a nationally representative sample, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N = 34,653), a comprehensive model of the 3-year risk of persistence and recurrence in individuals with MDE at baseline. We used structural equation modeling to examine simultaneously the effects of four broad groups of clinical factors on the risk of MDE persistence and recurrence: 1) severity of depressive illness, 2) severity of mental and physical comorbidity, 3) sociodemographic characteristics and 4) treatment-seeking behavior. Approximately 16% and 21% of the 2587 participants with an MDE at baseline had a persistent MDE and a new MDE during the 3-year follow-up period, respectively. Most independent predictors were common for both persistence and recurrence and included markers for the severity of the depressive illness at baseline (as measured by higher levels on the general depressive symptom dimension, lower mental component summary scores, prior suicide attempts, younger age at onset of depression and greater number of MDEs), the severity of comorbidities (as measured by higher levels on dimensions of psychopathology and lower physical component summary scores) and a failure to seek treatment for MDE at baseline. This population-based model highlights strategies that may improve the course of MDE, including the need to develop interventions that target multiple psychiatric disorders and promotion of treatment seeking to increase access to timely mental health care.

Safety and acceptability of transcranial direct current stimulation for the acute treatment of major depressive episodes: Analysis of individual patient data

BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive brain stimulation modality that has been increasingly used for major depressive disorder (MDD) treatment. Although studies in healthy volunteers showed that the technique is well-tolerated, tDCS safety and acceptability have not been sufficiently explored in patients with MDD. MethodsWe collected individual patient data from 6 randomized clinical trials that had been previously identified in a systematic review and meta-analysis. Primary outcomes were safety (rate of adverse events) and acceptability (rate of dropouts). Secondary outcomes were clinical, demographic and treatment predictors of the primary outcomes. ResultsDropout rates between active (8.8%) and sham (12%) groups were not significantly different (OR= 0.7, p=0.38). Adverse event rates between active (73.5%) and sham (68.3%) groups were not significantly different (OR= 1.4, p= 0.23). Higher current densities were associated with lower adverse event rates. LimitationsDropout reasons were not systematically reported and adverse events were not collected using questionnaires standardized across studies. ConclusionsActive tDCS is as acceptable and safe as sham tDCS, as found in randomized clinical trials of MDD.

Ketamine for Depression, 2: Diagnostic and Contextual Indications.

There is a substantial body of literature comprising anecdotal material and descriptions of uncontrolled and randomized controlled trials addressing the use of subanesthetic doses of ketamine for the off-label treatment of major depressive episodes. This article examines diagnostic indications for the off-label use of ketamine as an antidepressant and possible contexts in which ketamine may be trialled. Ketamine is indicated in patients who are in a major depressive episode. Most of the research data have been collected from patients with major depressive disorder, but patients with bipolar depression have also been studied. Ketamine is effective in both diagnostic groups, but its benefits are impermanent, perhaps more so in bipolar depression. There are several contexts within this diagnostic framework when a ketamine trial may be considered. These include severe depression and depression that is refractory to conventional antidepressant medication; this is because there is little purpose in trialling an experimental treatment in patients who are less severely ill and those who are antidepressant responsive. More importantly, ketamine has demonstrated efficacy in the rapid reduction of suicidal symptoms and can therefore be trialled when rapid reduction in suicidality is necessary. Likewise, because of its swift and dramatic antidepressant action, it can be trialled in patients in whom improvement is urgently desired in order to allow the patient to attend to pressing life circumstances. Some data suggest that the use of ketamine early during the course of an antidepressant trial, or as anesthesia during electroconvulsive therapy, can improve early antidepressant outcomes. It is not clear whether the presence of psychotic symptoms is a contraindication for ketamine use. Issues related to these indications and contexts are briefly discussed.