Ketamine for treatment-resistant depression: recent developments and clinical applications

Unipolar major depressive disorder (MDD) is highly prevalent and a leading cause of global disability. Existing antidepressants that target monoamine systems relieve symptoms in roughly half of patients and commonly take 6–12 weeks to produce a clinical response. Patients who fail two or more adequate antidepressant trials are classified as having treatment-resistant depression (TRD), a group in which response rates to standard treatments are substantially lower. Emerging evidence implicates glutamatergic dysfunction and impaired neuronal plasticity in depression, which has motivated investigation of non-monoaminergic agents. This review by Schwartz and colleagues examines recent developments in the clinical use of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist and established anaesthetic, as a rapidly acting antidepressant for TRD. The authors focus on clinically important questions such as effective dose, route of administration, duration of benefit and safety, and they consider evidence for ketamine in bipolar depression, PTSD and acute suicidal ideation. The review aims to inform primary and specialty clinicians about current evidence and gaps that bear on clinical application.

The paper is a literature review of clinical research on ketamine for mood and related disorders. The investigators searched PubMed and Google Scholar for articles published between 1980 and February 2016 without language restrictions. Search terms included 'depression', 'ketamine', 'treatment resistant', 'antidepressant' and 'primary care'. Schwartz and colleagues prioritised clinical trials, examining both open-label and randomised studies. Reference lists of retrieved reports were hand-searched to identify additional relevant publications. The review synthesises findings from single-dose and repeated-administration trials, intranasal versus intravenous routes, studies addressing suicidal ideation and cognition, safety data, and emerging predictors of response. The extracted text does not present a formal risk-of-bias assessment or a detailed meta-analytic protocol authored by the review team, although the authors refer to existing meta-analyses in the literature.

Clinical trials consistently show rapid antidepressant effects following subanaesthetic ketamine. Multiple studies using a 0.5 mg/kg intravenous (IV) infusion over 40 minutes report response rates of approximately 50–70% in patients with TRD. Symptom relief can begin within 2 hours and, after a single infusion, may persist for days to, in some reports, up to 2 weeks. Variability in reported duration reflects heterogeneity across study samples (age, sex, illness duration, comorbidity). A meta-analysis cited (Romeo et al.) pooled six double-blind, randomised, placebo-controlled cross-over trials (two in bipolar disorder) and found that ketamine reduced depression severity significantly from day 1 through day 7 in unipolar MDD, whereas in bipolar depression the benefit was present through days 1–4. Across trials, ketamine tended to show greater improvement in unipolar than bipolar samples. Meta-analytic examinations did not find that comorbid anxiety, prior antidepressant treatment history, or illness duration significantly moderated the ketamine–placebo difference, suggesting ketamine’s efficacy in populations that often respond poorly to standard antidepressants. Route of administration and adjunctive treatments have been investigated to a limited extent. IV ketamine is the most-studied route; intranasal (IN) administration has shown positive effects but comparisons are constrained because IN data derive largely from a single small study (N=20) and from ongoing sponsored trials. Several trials that allowed concomitant antidepressant or augmentation treatment reported efficacy without washout, indicating that ketamine can be effective as an adjunct in clinical practice. Evidence on repeated infusions is mixed but encouraging. In one study of six IV infusions over 2 weeks, 70.8% of 24 unmedicated patients with unipolar depression responded, with an average response duration of 18 days; early response at 4 hours after the first infusion strongly predicted later response. Another study of 28 participants receiving three or six infusions while on antidepressants reported a 29% overall response rate, with 11% responding within 6 hours and durations of response after the final infusion ranging from 25 to 168 days. Across studies, response to a treatment series could often be predicted by response to the first one or two infusions, suggesting limited rationale for continuing a course if early response is absent. Ketamine appears to reduce suicidal ideation (SI) rapidly. Reviews and individual studies report decreases in SI after single doses, with effects maintained up to 2 weeks after repeated infusions in some reports. A small emergency-room study (N=14) found that a lower, rapid IV dose (0.20 mg/kg over 1–2 minutes) reduced SI at 40 minutes postinfusion. A larger inpatient study (N=24) reported rapid improvement in SI within 24 hours compared with an active control (midazolam). Some evidence links ketamine’s antisuicidal effects to improvements in anhedonia and executive/cognitive functioning; for example, Lally and colleagues reported 87% of patients improved on anhedonia at 4 hours postinfusion, with anhedonia improvement correlating with overall depression improvement. Investigations of clinical predictors of response have identified several candidate variables. Slower baseline processing speed predicted greater improvement in depression at 24 hours, a pattern opposite to findings with standard antidepressants. Other reported predictors include higher body mass index (BMI), a family history of alcohol use disorder in a first-degree relative, and dimensional anxious depression. The extracted text does not present validated biomarker predictors; research on genetic and peripheral and central neurobiological predictors is ongoing but not yet ready for clinical use. Safety data in trials indicate that subanaesthetic ketamine (0.1–1 mg/kg) commonly produces transient neuropsychiatric and neurocognitive effects and modest increases in heart rate and blood pressure. Adverse events reported within the infusion period and up to about 4 hours afterwards include dizziness, blurred vision, headache, nausea or vomiting, dry mouth, restlessness, impaired coordination and concentration, and dissociation. Cardiovascular monitoring is advised for patients with pre-existing cardiac disease. Long-term safety remains uncertain; chronic recreational use has been associated with memory impairment and urinary tract problems, but trial participants receiving lower, less frequent therapeutic doses have sometimes shown cognitive improvement rather than decline. From a service perspective, ketamine is FDA-approved as an anaesthetic but not as an antidepressant; specialists are administering it off-label in the absence of a standardised clinical protocol. Most randomised trials have used 0.5 mg/kg IV, and a US NIMH-sponsored study is testing doses from 0.1 to 1.0 mg/kg. Intranasal S-ketamine trials sponsored by industry are ongoing or completed but publication is pending, and intranasal self-administration raises questions about accessibility and diversion risk.

Schwartz and colleagues interpret the assembled literature as supporting ketamine’s rapid antidepressant efficacy in treatment-resistant unipolar depression, with additional evidence suggesting benefit in bipolar depression, PTSD and acute suicidal ideation. They highlight that ketamine’s mechanism is thought to involve rapid induction of synaptic plasticity, potentially via increased brain-derived neurotrophic factor (BDNF) translation and glycogen synthase kinase-3 (GSK-3) inhibition, which may explain its swift onset compared with traditional antidepressants. The authors position these findings relative to earlier research by noting that ketamine appears effective even in clinical subgroups who typically do poorly with monoaminergic treatments; meta-analytic results showing benefit regardless of comorbid anxiety or prior treatment failure are emphasised. They also note important differences in duration of benefit between unipolar and bipolar depression, which has practical implications for treatment frequency planning. Key limitations acknowledged in the review include heterogeneity across study samples and designs, small sample sizes in some trials (notably intranasal studies), limited inclusion of patients at highest suicide risk, and scarce data on long-term safety and optimal maintenance regimens. The authors stress that controlled conditions used in trials—dosing, monitoring and patient selection—should guide clinical application and that there is insufficient evidence to endorse routine self-administration or unmonitored community use. Ongoing trials are expected to clarify optimal dosing, routes of administration and predictors of response, but at present biological predictors remain experimental and are premature for clinical adoption. In terms of clinical implications, the paper advises that primary care physicians and specialists should be aware of ketamine as a rapidly acting option for severe, treatment-resistant cases and for urgent settings involving suicidal ideation, while balancing potential benefits against uncertain long-term risks and the need for monitoring. The authors present a cautiously optimistic view that ketamine could become an important tool in treating severe mood and anxiety disorders, provided further evidence clarifies safety, dosing and durability.

A substantial and growing body of clinical studies supports ketamine’s short-term efficacy as a rapidly acting treatment for patients with treatment-resistant unipolar depression, with additional evidence for bipolar depression, PTSD and reductions in suicidal ideation. Clinicians and patients should be mindful that optimal dosing, routes of administration, long-term safety and maintenance strategies remain incompletely defined. The authors conclude that, while cautious optimism is warranted, further controlled research is needed before widespread adoption outside specialised, monitored settings.