Antianhedonic effects of serial intravenous subanaesthetic ketamine in anxious versus nonanxious depression

Anxious depression, defined as unipolar or bipolar depression with high levels of anxiety symptoms, is common and typically associated with more severe illness, poorer treatment outcomes and lower quality of life than nonanxious depression. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has attracted attention because it can produce rapid antidepressant, antisuicidal and antianhedonic effects that differ from conventional antidepressants. Previous studies comparing ketamine’s effects in anxious versus nonanxious depression have been inconsistent, and no drug specifically approved to target anhedonia exists despite its high prevalence in major depressive disorder (MDD) and bipolar disorder (BD). Zheng and colleagues conducted a post hoc analysis to determine whether baseline anxiety status modifies the antianhedonic response to repeated subanaesthetic intravenous ketamine. The study specifically tested the hypothesis that people with anxious depression would show a poorer reduction in anhedonic symptoms after six 0.5 mg/kg infusions (over 40 minutes) than those with nonanxious depression, using standard clinical scales to measure anxiety and anhedonia.

This work is a post hoc analysis of a larger, ongoing clinical trial of adjunctive ketamine for mood disorders (registration number ChicCTR-OOC-17012239). The protocol and broader project design have been described elsewhere; the extracted text reports that all participants gave written informed consent and the study had institutional ethics approval. Eligible participants were aged 18–65 with a DSM-5 diagnosis of unipolar or bipolar depression without psychotic features, a HAMD-17 score ≥17 at screening, and evidence of treatment-resistant depression (TRD) and/or current suicidal ideation. TRD was defined as failure to respond to at least two classes of antidepressants at adequate dosages, and suicidal ideation for inclusion required a score ≥2 on the Beck Scale for Suicide Ideation (SSI) part I. Exclusions included other serious mental disorders (for example, substance dependence, schizophrenia), serious unstable medical illness, and pregnancy or breastfeeding. Intervention comprised six intravenous infusions of ketamine at 0.5 mg/kg administered over 40 minutes, given three times weekly (Monday, Wednesday, Friday) across 12 days. Infusions were performed after overnight fasting, vital signs were monitored every 10 minutes during each infusion, and participants were permitted to continue concomitant psychotropic medications. Anxious depression was classified using the Hamilton Depression Rating Scale Anxiety-Somatization factor (HAMD-AS), with a cutoff ≥7; this factor includes items addressing psychic and somatic anxiety, general and gastrointestinal somatic symptoms, hypochondriasis and insight. Anhedonia was assessed using a predefined MADRS anhedonia subscale composed of MADRS items 1, 2, 6, 7 and 8; assessments occurred before each infusion, at 4 hours and 1 day after each infusion, and at two weeks after the sixth infusion. Antianhedonic response and remission at day 13 (24 hours after the last infusion) were defined as ≥50% and ≥75% reductions in anhedonia scores relative to baseline, respectively. Interrater reliability for MADRS ratings showed intraclass correlation coefficients >0.90. Statistical comparisons between anxious and nonanxious groups used t-tests or Mann–Whitney U tests for continuous variables and χ2 or Fisher’s exact tests for categorical variables. Longitudinal changes were analysed with linear mixed models, controlling for baseline anhedonia, and Bonferroni correction was applied for multiple comparisons. A two‑sided p < 0.05 was considered statistically significant.

A total of 135 participants were analysed, of whom 92 (68.1%) met criteria for anxious depression and 43 for nonanxious depression. At baseline, the anxious group had higher HAMD-AS scores (9.1 ± 1.9 versus 5.2 ± 1.1, p < 0.001) and higher HAMD-17 scores (25.1 ± 5.2 versus 20.9 ± 3.6, p < 0.001); baseline MADRS total scores were numerically higher in the anxious group (33.8 ± 8.5 versus 30.7 ± 6.0) but this difference reached only borderline significance (p = 0.06). The anxious subgroup also had a higher prevalence of a family history of psychiatric disorders (p = 0.01). After the sixth infusion (day 13), antianhedonic response (≥50% reduction) and remission (≥75% reduction) rates in the anxious group were 47.8% (95% CI 37.4%–58.2%) and 17.4% (95% CI 9.5%–25.3%), respectively. Corresponding rates in the nonanxious group were 51.2% (95% CI 35.6%–66.7%) for response and 27.9% (95% CI 13.9%–41.9%) for remission. These between‑group differences in response and remission rates were not statistically significant (all p > 0.05). Both groups showed a significant reduction in MADRS-derived anhedonia scores relative to baseline from the first infusion through the last infusion and at the two‑week follow-up (all p < 0.05). In linear mixed models that controlled for baseline anhedonia, there was a strong main effect of time (F = 63.2, p < 0.001), a marginal time-by-group interaction (F = 1.7, p = 0.05), and no significant main effect of group (anxious versus nonanxious; F = 0.5, p = 0.46). The extracted text does not report additional subgroup, safety or adverse event data in detail.

Zheng and colleagues report that repeated subanaesthetic ketamine infusions produced rapid reductions in anhedonic symptoms in patients with anxious depression, and that overall efficacy in reducing anhedonia appeared similar between anxious and nonanxious depressed participants. The investigators highlight three principal findings: a high prevalence of anxious depression in their sample (68.1%), rapid amelioration of anhedonia with ketamine in the anxious subgroup, and generally comparable antianhedonic effects across anxious and nonanxious patients. The authors contextualise their results within prior literature showing mixed findings for ketamine’s antidepressant effects in anxious versus nonanxious depression; some single‑infusion studies have reported greater benefit in anxious patients, whereas others have reported lesser benefit. They note that their finding—rapid antianhedonic effects with repeated infusions regardless of baseline anxiety—adds to evidence that ketamine can target anhedonia across depressive subtypes. The discussion also emphasises that anxious depression is a clinically important and often treatment‑resistant subtype, which reinforces the need to study novel interventions. Several limitations acknowledged by the investigators temper interpretation. First, participants were allowed to continue psychotropic medications, so concomitant treatments may have contributed to symptom change; the authors recommend drug‑free designs to isolate ketamine’s effects. Second, the absence of a placebo or active control arm limits causal inference. Third, pooling participants with MDD and BD introduced clinical heterogeneity. Finally, while the MADRS‑based anhedonia subscale is commonly used, the authors suggest that dedicated anhedonia instruments such as the Snaith–Hamilton Pleasure Scale (SHPS) would be preferable in future work. On the basis of these findings, the study team calls for further research using randomized, placebo‑controlled designs, including studies comparing single versus multiple infusions, employing specific anhedonia scales and, where feasible, enrolling medication‑free participants to clarify ketamine’s independent antianhedonic effects.

The authors conclude that repeated intravenous infusions of ketamine rapidly reduce anhedonic symptoms in people with anxious depression, although individuals with anxious depression displayed a somewhat weaker antianhedonic response than nonanxious depressed patients in this preliminary analysis.