Can Quetiapine Prolong the Antidepressant Effect of Ketamine?: A 5-Year Follow-up Study

Major depressive disorder (MDD) remains a leading cause of disability and a substantial proportion of patients do not achieve remission with first- and second-line treatments. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist with additional dopaminergic and μ-opioid activity, has demonstrated rapid antidepressant effects in treatment-resistant patients, but these benefits are often short-lived, with many responders relapsing within days. Previous efforts to sustain ketamine's benefit using sequential treatments such as lamotrigine and riluzole have not shown efficacy, leaving relapse prevention after ketamine as an important clinical challenge. This study is a post hoc analysis aimed at examining whether concomitant use of quetiapine, an atypical antipsychotic with recognised antidepressant and mood-stabilising properties, is associated with prolonged antidepressant effects following ketamine treatment. Amiaz and colleagues report clinical outcomes up to 5 years after an initial course of intravenous ketamine infusions in a small cohort of electroconvulsive therapy (ECT) referrals, focusing on time to relapse and long-term mood and anxiety measures when quetiapine was part of baseline medication regimens.

Participants were treatment-resistant depressive patients referred for ECT at the Chaim Sheba Medical Center and were enrolled between September 2014 and August 2015, with a 5-year follow-up in 2019–2020. Inclusion criteria required a DSM-5 diagnosis of major depressive disorder or bipolar I/II disorder with a current depressive episode, failure to respond to at least two adequate antidepressant trials in the current episode, and an Inventory of Depressive Symptomatology–Clinician-Rated (IDS-C) score ≥32. Subjects had to be on a stable therapeutic antidepressant dose for at least 4 weeks. Exclusion criteria included current substance or alcohol abuse, active suicidality, psychotic symptoms, rapidly cycling bipolar disorder, neurological illness likely to affect mood, significant uncontrolled cardiovascular or endocrine conditions, and pregnancy or recent initiation of female hormonal treatment. Ethical approval and informed consent were obtained, and Good Clinical Practice guidelines were followed. The active intervention consisted of ketamine given as slow intravenous infusions at 0.5 mg/kg over 40 minutes. A multidisciplinary team monitored vital signs at frequent intervals during administration. The protocol delivered an initial infusion and responders—defined as a ≥4-point decrease on the Clinical Global Impression–Improvement (CGI-I) and/or ≥50% reduction in IDS-C—received additional infusions to complete a six-infusion course, with dosing frequency described as twice per week for the subsequent infusions. Clinical assessments included IDS-C, Hamilton Rating Scale for Depression (HAM-D), Montgomery–Åsberg Depression Rating Scale (MADRS), Hamilton Rating Scale for Anxiety (HAM-A), CGI-Severity (CGI-S) and CGI-I. Assessments occurred at baseline, after 3, 6 and 10 weeks, and at 1 and 5 years. Medication concomitants were recorded; at baseline 14 of 16 patients were on antipsychotics, five of whom were taking quetiapine. Statistical analyses reported in the extracted text included paired t-tests and Wilcoxon signed-rank tests to compare baseline with follow-up visits, and comparisons of time to relapse between medication groups.

Sixteen patients received at least one ketamine infusion. Ten completed the full six-infusion course, two completed five treatments, two completed two treatments, and two received only one treatment. Among the six who did not finish all planned treatments, two discontinued because they felt cured and four stopped because they felt worse. Clinical outcomes at the end of follow-up showed 6 patients in complete symptomatic remission, 3 partial responders, and 7 nonresponders. Paired t-tests and Wilcoxon signed-rank tests comparing baseline to assessments after six treatments, at 10 weeks, 1 year and 5 years indicated overall reductions in depressive and anxiety scores relative to baseline across the cohort. At baseline, all patients were on antidepressants and 14 (88%) were also prescribed antipsychotics: quetiapine (5), aripiprazole (3), olanzapine (3), ziprasidone (1), perphenazine (1), and clothiapine (1). Time from last ketamine treatment to relapse differed markedly by antipsychotic: patients taking quetiapine had a mean time to relapse of 965.83 ± 824.68 days versus 80.5 ± 114.3 days for those on other neuroleptics; this difference was statistically significant (Z = 7.0039, P = 0.0001). Depression and anxiety measures at 1 year and 5 years remained lower than baseline. During the trial no significant changes in vital signs were detected. Six patients were lost to follow-up (including three initial nonresponders and one early relapser); two patients died (one within the first year and one after four years); and two developed substance use disorders that resulted in an opiate overdose in one case and the need for rehabilitation in another.

Amiaz and colleagues interpret their open-label findings as providing preliminary evidence that a subset of treatment-resistant patients benefit from ketamine infusions, with 6 of 16 achieving complete remission and a further 3 showing partial improvement—outcomes the authors describe as broadly consistent with prior literature. The investigators highlight the striking difference in relapse timing between patients who were taking quetiapine at baseline and those on other antipsychotics, noting that quetiapine-treated patients had a substantially prolonged time to relapse after ketamine infusion. The authors acknowledge important limitations that temper the conclusions. The study is small, open-label and post hoc in nature, with a non-randomised allocation of concomitant antipsychotics. Loss to follow-up and patient attrition may have biased long-term results, since several nonresponders were among those lost and two participants died during the interval. The possibility that observed long-term benefits reflect the intrinsic effects of quetiapine rather than a synergistic effect with ketamine is explicitly recognised. Given these constraints, the investigators state that their findings are suggestive rather than definitive and call for a placebo-controlled, randomised trial to test whether quetiapine genuinely prevents relapse after ketamine treatment.

In this small, open study the combination of ketamine infusions with quetiapine co-prescription was associated with a markedly longer time to relapse compared with other neuroleptics, suggesting the combination might prevent early relapse after ketamine. The authors conclude that a randomised, placebo-controlled trial is required to test the hypothesis that quetiapine extends ketamine's antidepressant effect.