Administration of ketamine for unipolar and bipolar depression

Treatment-resistant depression (TRD), commonly defined as failure to respond to more than two antidepressant trials, affects an estimated 10–30% of people with major depressive disorder and carries high risks of suicide, relapse and socioeconomic burden. Ketamine, an NMDA-receptor antagonist first introduced as an anaesthetic, attracted interest after animal and serendipitous clinical observations suggested rapid antidepressant effects; subsequent small clinical trials have reported robust, short-lived reductions in depressive symptoms. Despite ketamine's long history in anaesthesia and known pharmacology, uncertainties remain about optimal dosing and administration, duration of benefit, long-term safety, interaction with other medications and how to translate trial protocols into routine clinical practice. Kraus and colleagues set out to review clinical trials of ketamine in unipolar and bipolar depression to summarise efficacy, response and remission rates, and the safety profile, and to offer practical information for clinicians. The review sought studies using standardised depression outcome measures and aimed to focus on clinically relevant end points, primarily 24-h post-treatment effects; a patient consent form for clinical application was developed as supplementary material to aid implementation in practice.

The investigators conducted searches in Medline, Scopus and Web of Science using terms such as 'ketamine, ketanest, depression, bipolar depression, antidepressant, suicide, suicidality' and combinations, with coverage up to November 2015. Inclusion criteria were peer-reviewed clinical trials in patients meeting DSM-IV (or similar) criteria for unipolar or bipolar disorder, use of standardised and reliable depression rating scales as primary outcomes, and exclusion of studies in other primary psychiatric diagnoses or purely neuroimaging investigations. Reference lists of relevant trials and reviews were also checked. The search identified 12 trials in unipolar major depressive disorder and seven trials in bipolar depression. Primary outcome measures across trials were standard clinician-rated scales: HAM-D in four trials and MADRS in eight trials; self-report scales included BDI and QIDS in some studies. Secondary measures included BPRS for psychotic symptoms, CADSS for dissociation, SSI for suicidal ideation and CGI among others. All included trials had institutional ethics approval. Methodological approaches varied: six studies used repeated-measures ANOVA/ANCOVA, five used general linear mixed models, and one used a Wilcoxon signed-rank test. Heterogeneity in timing of assessments led the reviewers to prioritise effects at 24 h post-treatment; response was defined uniformly as a 50% reduction from baseline on the depression rating scales. Trial designs were heterogeneous: double-blind placebo-controlled crossover designs, open-label single- or longitudinal infusion studies, and studies with active controls (for example midazolam) were included. Most trials used intravenous racemic ketamine, typically 0.5 mg/kg infused over 40 min, but the review also included bolus regimens (0.2 mg/kg), other infusion rates (0.27 mg/kg), intranasal administration (50 mg total by mucosal atomisation) and trials of S-ketamine at 0.2 and 0.4 mg/kg. Some studies examined single infusions, while others tested repeated dosing schedules (for example three or six infusions over days) or compared repeated ketamine with electroconvulsive therapy (ECT). Several trials allowed ketamine as an add-on to stable antidepressant or mood-stabilising medication.

Overall sample and study designs: In the 12 trials of unipolar depression included in the review, 226 patients with major depressive disorder (119 female) received ketamine. Study designs comprised double-blind, placebo-controlled crossovers, open-label single- or multiple-infusion protocols and active-control trials. Intravenous racemic ketamine was the dominant formulation and dosing regime, most commonly 0.5 mg/kg over 40 min; other regimens included 0.2 mg/kg boluses, 0.27 mg/kg infusions, intranasal 50 mg, and S-ketamine at lower doses. Several studies delivered single infusions, while others evaluated repeated administrations or compared repeated ketamine with ECT. Antidepressant efficacy: All reviewed trials reported a rapid and substantial antidepressant effect. At the 24-h primary outcome, average response rates were reported at 59% (range 37–88%). Mean reductions across scales at 24 h were approximately 10.9 points on the HAM-D, 15.7 points on the BDI and 20.8 points on the MADRS. Ketamine was consistently superior to placebo and, in trials using active control, superior to a single infusion of midazolam. Studies that compared three consecutive ketamine infusions with three sessions of ECT reported greater improvement after ketamine at 48 h, 72 h and one week. One trial suggested that response to the first infusion predicted subsequent response status with further administrations. Relapse and durability: Benefit was typically transient. Early trials reported that 92% of ketamine recipients relapsed within two weeks. Repeated-infusion series showed relapse in most patients despite multiple doses; for example, one study reported eight of nine patients relapsed at a mean of 30 (±13) days after the first infusion or 19 (±13) days after the sixth. Other trials reported relapse rates near 60% within about 30 days. Attempts to prolong response with adjunctive agents such as riluzole did not prevent relapse in the cited study. Safety and tolerability in unipolar trials: Acute psychotomimetic or positive symptoms measured with BPRS were transient and generally resolved within hours; one report showed a mean BPRS peak at about 40 min post-infusion with return to baseline by two hours. Common acute adverse events across studies included dizziness, blurred vision, restlessness, nausea/vomiting, headache, perceptual disturbances, confusion, transient elevations in blood pressure and euphoria. One study reported 47 patients (17%) experienced dissociative symptoms such as depersonalisation or altered time perception; these were reversible and not severely distressing. Serious adverse events were rare: the review notes a hypotension/bradycardia event linked to a vasovagal response, a suicide attempt in one study and one unrelated fall injury. Intranasal administration produced generally fewer side effects and a mean systolic blood pressure increase of 7.6 mmHg at 40 min in the cited trial. Concomitant medications showed interactions of interest: benzodiazepines may prolong ketamine half-life and reduce some metabolites and have been associated with diminished antidepressant response in some observations; lamotrigine did not attenuate transient side effects nor enhance antidepressant effects in the reported data. Ketamine in bipolar depression: Seven trials addressed bipolar depression, typically administering i.v. ketamine as an adjunct to mood stabilisers (lithium or valproate). Early trials reported clinical improvement maintained for 14 days in 71% and 79% of patients respectively. A series from Poznan examined biochemical and clinical correlates: in 25 bipolar patients, 13 (52%) were responders and BDNF declined after seven days in non-responders; NGF, NT3, NT4 and GDNF did not change significantly. Another study found higher baseline vitamin B12 levels in responders versus non-responders, while homocysteine and folic acid did not differ. Neurocognitive testing in 18 bipolar patients showed improved performance on the third day after a single infusion, an effect that correlated with baseline neuropsychological impairment and appeared independent of mood change. In a larger, as-yet unpublished cohort of 53 bipolar patients, HAM-D scores decreased by a mean 15.6 ± 7.4 points at 24 h (other time-point data in the extraction are partially incomplete), and by two weeks mean scores were reported as 11.8 ± 8.1 points; on day 7, 27 subjects met response criteria. That cohort showed a higher response frequency in males (77%) than females (43%), though extracted text contains some missing fragments and the sample characteristics and some time-point values were not entirely clear from the extraction.

Kraus and colleagues interpret the accumulated trial evidence as indicating that intravenous and intranasal ketamine produce rapid, robust antidepressant and anti-suicidal effects in both unipolar and bipolar depression, with response rates reported up to 88% in some trials and the largest effects observed at 24 h and lasting for several days to about two weeks. The authors highlight practical advantages of ketamine: established use and availability in hospital settings, known anaesthetic pharmacology and the possibility of outpatient administration in medically stable patients under monitoring. Compared with more invasive TRD interventions such as ECT or DBS, ketamine’s side effects are typically short-lived and manageable. At the same time, the reviewers stress important limitations and uncertainties. Most evidence derives from small, rigorously controlled research settings that may not generalise to routine clinical practice. Blinding is difficult because ketamine produces obvious acute effects, raising the possibility of expectancy bias; the authors therefore recommend future use of active controls or low-dose comparators. Durability of effect is a major unresolved problem: relapse rates are high and no established strategies reliably prolong antidepressant benefit. Predictors of response reported across studies include higher body mass index, family history of alcohol abuse and absence of prior suicide attempts in some analyses, and initial response appears predictive of later response to repeated dosing. Safety concerns noted include transient haemodynamic and psychotomimetic effects, possible interactions with benzodiazepines, and a current absence of systematic long-term data on risks such as cystitis, neurotoxicity or dependency. The authors caution against unregulated provision in 'ketamine clinics' and advise treatment by experienced clinicians with monitoring and long-term follow-up. On mechanisms, the discussion summarises converging evidence beyond simple NMDA antagonism: animal and early human studies implicate downstream AMPA-receptor activation, increased BDNF synthesis, mTOR signalling and changes in limbic and prefrontal metabolic and connectivity patterns (for example pgACC activity and ACC–amygdala connectivity). The authors note that other glutamatergic agents have generally not replicated ketamine’s clinical effects, underscoring a complex pharmacology that remains incompletely understood and motivating continued research into NMDA-modulating and related agents.

The reviewers conclude that low-dose ketamine provides a rapid and effective antidepressant and antisuicidal option for severely ill patients with unipolar or bipolar depression, and that it can be administered without necessarily discontinuing stable antidepressant or mood-stabilising drugs. The principal unresolved issue is the transient nature of benefit and lack of established methods to prolong response; repeat dosing and alternative administration routes (intranasal, sublingual, oral) are under investigation but raise concerns about tolerance and dependency. Consequently, the authors recommend careful patient selection, administration by experienced clinicians with cardiovascular and clinical monitoring, and systematic long-term follow-up while further research explores optimised regimens and novel glutamatergic therapeutics.