Ketamine as Add-On Treatment in Psychotic Treatment-Resistant Depression

Major depressive disorder (MDD) with psychotic features carries a worse prognosis than non-psychotic MDD, with heavier symptom burden, greater relapse risk, and frequent misdiagnosis. Standard treatments endorsed in clinical guidelines prioritise combined antidepressant and antipsychotic therapy or electroconvulsive therapy (ECT), yet a subset of patients remain treatment-resistant. Ketamine and its enantiomers have emerged as rapid-acting antidepressant agents, and esketamine nasal spray has regulatory approval as an add-on in treatment-resistant depression (TRD) and certain acute indications. Nevertheless, most clinical trials exclude patients with psychotic features because of concerns that ketamine could exacerbate psychosis; consequently, evidence on safety and efficacy in psychotic MDD is limited. Siwek and colleagues set out to contribute data on the safety and tolerability of intravenous ketamine as an add-on to standard of care in psychotic TRD. The paper reports four hospitalised patients with MDD and psychotic features drawn from a naturalistic observational registry at a tertiary mood disorders unit (NCT04226963), describing clinical course during a standardised course of ketamine infusions and short- to longer-term follow-up. The authors frame the report as addressing a gap in the literature on whether ketamine precipitates psychotic worsening and on its antidepressant and antisuicidal effects in this subgroup.

This is a case series drawn from a naturalistic registry of patients treated at a tertiary referral unit. Inclusion criteria for the registry included a DSM-5 diagnosis of major depressive disorder or bipolar disorder and treatment-resistant depression, with TRD defined in this paper as failure to remit after an 8-week therapeutic antidepressant (or combination) trial and/or ECT following at least two trials of first-line evidence-based treatments. Exclusion criteria listed were pregnancy or breastfeeding, ketamine hypersensitivity, uncontrolled hypertension, and other somatic conditions judged by investigators to compromise safety. Psychometric assessment used the Montgomery–Åsberg Depression Rating Scale (MADRS) in a structured interview, with response defined as a 50% reduction from baseline MADRS and remission reported as "MADRS 12 at day 21" in the extracted text (the comparator symbol is not clearly reported in the extraction). Other measures included the Columbia Suicide Severity Rating Scale (C-SSRS), Young Mania Rating Scale (YMRS), Clinician-Administered Dissociative States Scale (CADSS), and Brief Psychiatric Rating Scale (BPRS). Outcome ratings were collected before infusions and on days 1, 8, 14, 21 and at day 35 (one week post-treatment). All four subjects had MDD of duration between one and ten years, were hospitalised for the index psychotic major depressive episode (hospitalisations lasted 2–6 months), and had failed multiple antidepressant treatments; one patient had previously received four ECT sessions that were discontinued because of post-ECT delirium. The ketamine regimen followed the commonly used protocol of 0.5 mg/kg intravenous infusion over 40 minutes, administered twice weekly for four weeks for a total of eight infusions per patient. Dosage reductions for intolerability were noted as an option but were not described as applied in these cases. Concomitant care included ongoing psychotropic medications as clinically indicated and elements of cognitive-behavioural intervention (psychoeducation and behavioural activation) delivered twice weekly during hospitalisation. The extracted text does not clearly report a formal statistical analysis plan or inferential methods, consistent with a descriptive case-series design.

All four patients experienced rapid clinical improvement after initiation of ketamine and achieved remission of psychotic symptoms during the infusion series. No case showed psychotic exacerbation in the short- or longer-term observation reported. Adverse events were mild, transient, and self-limiting: patient 1 reported nausea during the first infusion that resolved within 20 minutes and no further adverse events; patient 2 had mild dizziness during the first three infusions resolving within about 10 minutes; patient 3 reported no adverse effects; and patient 4 experienced mild dizziness after the first and second infusions resolving within 20 minutes. The authors note no relevant cardiovascular or haemodynamic changes across cases as reported in the extracted text. Individual course details are summarised in the extraction. Patient 1 showed rapid mood improvement and full remission of psychotic symptoms after the first infusion; at discharge she was prescribed venlafaxine ER 225 mg, mirtazapine 45 mg and olanzapine 5 mg and sustained full remission at a 1-year follow-up. Patient 2 regained psychomotor function after the fourth infusion, was asymptomatic for psychosis at discharge, and remained so at a 2-year follow-up; discharge medications included sertraline 200 mg and quetiapine 200 mg. Patient 3's nihilistic delusions resolved after the third infusion and the major depressive episode was asymptomatic after the sixth infusion; discharge medications included venlafaxine ER 300 mg, mirtazapine 45 mg and pregabalin 150 mg. Patient 4 improved rapidly after the second infusion with resolution of psychotic symptoms and suicidal thoughts; discharge medications included venlafaxine ER 375 mg, mirtazapine 45 mg and lurasidone 74 mg. The extraction does not present numerical MADRS, CADSS, BPRS or C-SSRS scores for each time point, so effect-size estimates and formal response/remission rates beyond the case descriptions cannot be reported from the provided text.

Siwek and colleagues interpret these four cases as supportive of a favourable safety and tolerability profile for intravenous ketamine used as an add-on in psychotic TRD, including in a patient presenting with suicidality. The clinical observations are presented as consistent with limited prior reports and small studies that have not found ketamine to precipitate or worsen psychosis; in several cited small series and pooled analyses short-term adverse effects tended to be mild, self-limiting dissociative phenomena that resolved within an hour or so post-infusion. The authors note instances from the literature in which ketamine or esketamine was associated with rapid improvement of both depressive and psychotic symptoms in individual cases and small cohorts, and they reference a small meta-analysis and post-hoc analyses suggesting antidepressant effects in patients with a history of psychosis without induction of psychotic symptoms. Beyond clinical outcomes, the discussion broadens to conceptual issues raised by the authors: psychotic features modify the course and treatment response of mood disorders, neurophysiological methods (for example EEG and event-related potentials) may be useful for mechanistic research, and biomarker studies of ketamine's effects remain preliminary. The paper reports that available biomarker, neuroimaging and neurophysiological studies are consistent with ketamine-induced synaptic plasticity and changes in functional connectivity, but notes that no biomarker has been validated for routine clinical use. The authors explicitly acknowledge important limitations. This report comprises only four heterogeneous cases drawn from a naturalistic registry, so selection bias is possible and causality cannot be inferred; generalisation is not supported. Potential confounders such as diet, nicotine use and physical activity can influence pharmacokinetics and pharmacodynamics, although the extracted text states these four patients were nonsmokers without substance-use disorders and had low activity levels. Follow-up duration varied from two months to two years, limiting longitudinal inference. Given these constraints, the authors frame the report as hypothesis-generating and recommend that a history of psychosis should not be an automatic exclusion from therapeutic ketamine exposure, while noting that such patients may experience greater short-term dissociative symptoms. They call for controlled studies to prospectively evaluate ketamine in depressed patients with current psychotic features.

The authors conclude that these four cases add to literature supporting ketamine's rapid antidepressant and antisuicidal effects in treatment-resistant depression and demonstrate a favourable safety and tolerability profile when administered intravenously as an adjunct to standard of care in psychotic TRD. In the cases described there were no clinically relevant cardiovascular or haemodynamic changes and no psychotomimetic exacerbations during acute treatment or in follow-up, although the authors emphasise the limited and hypothesis-generating nature of the evidence.