A single infusion of ketamine improves depression scores in patients with anxious bipolar depression

Anxious bipolar disorder — bipolar illness accompanied by prominent anxiety symptoms or a comorbid anxiety disorder — is increasingly recognised as a clinically important subtype because it is common (reported prevalence in some studies of approximately 25-50%) and is associated with worse outcomes than non-anxious bipolar disorder. Previous research has linked high anxiety within bipolar disorder to greater substance misuse, cyclothymia, more suicide attempts, non-remission on standard treatments and a need for more medication trials. Several conventional pharmacological agents have shown mixed or limited benefit for anxiety in bipolar depression, although some positive findings exist for quetiapine, olanzapine (and olanzapine–fluoxetine combination), and lurasidone; overall, however, anxious bipolar depression remains difficult to treat and understudied. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects in treatment-resistant mood disorders, including a single intravenous infusion (0.5 mg/kg over 40 minutes) producing fast symptom reduction that can last several days and rapidly reduce suicidal ideation. Ionescu and colleagues set out to determine whether baseline anxious status moderates ketamine’s antidepressant effect in bipolar depression. Specifically, the study examined ketamine’s impact on depression scores over 14 days post-infusion in patients classified as anxious versus non-anxious bipolar depression, asking whether anxious status attenuates ketamine’s benefit.

This report is a post-hoc analysis pooling data from two identical randomised, double-blind, placebo-controlled crossover trials of ketamine for treatment-resistant bipolar depression; pooled data were available for 36 inpatients. Patients were adults aged 18–65 years with DSM-IV bipolar disorder (type I or II) currently depressed, diagnosed by clinician interview and confirmed with the SCID. Anxiety disorders were permitted provided bipolar depression remained the primary diagnosis. Eligible participants had to have a Montgomery–Åsberg Depression Rating Scale (MADRS) score ≥ 20 at screening and at baseline (60 minutes before infusion) despite maintenance on a therapeutic mood stabiliser (lithium serum 0.6–1.2 mEq/L or valproate 50–125 μg/mL) for at least four weeks; other psychotropic medications and structured psychotherapy were withheld for at least two weeks before and throughout the study. All patients received a single open-label intravenous infusion of ketamine hydrochloride 0.5 mg/kg over 40 minutes as part of the larger crossover protocol. For the present analysis, participants were classified as anxious (n = 21) or non-anxious (n = 15) bipolar depression. Anxious depression was defined by a baseline Hamilton Depression Rating Scale (HDRS) Anxiety/Somatization (A/S) factor score ≥ 7 together with the DSM-IV bipolar diagnosis; the HDRS A/S factor comprises six items: psychic and somatic anxiety, general and gastrointestinal somatic symptoms, hypochondriasis, and insight. Primary outcome measures were MADRS and HDRS scores assessed at baseline (60 minutes pre-infusion), at 40, 80, 110 and 230 minutes post-infusion, and at Days 1, 2, 3, 7, 10 and 14. Secondary measures included the Clinician-Administered Dissociative States Scale (CADSS) for dissociative side effects and the Hamilton Anxiety Rating Scale (HAM-A) for anxiety symptoms. Demographic comparisons used chi-square tests for categorical variables and t-tests for continuous variables. Group-by-time effects on outcomes were analysed with factorial linear mixed models using a compound symmetry covariance structure and restricted maximum likelihood estimation, with baseline scores entered as covariates. Bonferroni-corrected simple effects tests were used post hoc, and significance was set at p < 0.05, two-tailed.

Anxious bipolar depression comprised 58% of the pooled sample (n = 21 anxious, n = 15 non-anxious). As expected by the classification criterion, anxious patients had significantly higher baseline HDRS A/S scores than non-anxious patients. Linear mixed-model analyses controlling for baseline revealed a significant main effect of anxiety group on overall depression severity measured by both MADRS and HDRS (p = 0.04 for each), indicating that the non-anxious group had lower depression scores in general. However, there was no significant interaction between anxiety group and drug condition for either MADRS (p = 0.51) or HDRS (p = 0.29), and no significant drug-by-time interactions involving group (MADRS drug×time p = 0.83; HDRS drug×time p = 0.62). Significant drug main effects (all p < 0.001) were observed, indicating that ketamine produced robust reductions in depressive symptoms in both anxious and non-anxious patients. Analyses of anxiety and dissociative side effects showed no significant differences attributable to anxious status. Specifically, there were no significant group effects or interactions for HAM-A (group p = 0.097; group×drug p = 0.30; group×drug×time p = 0.23) or CADSS (group p = 0.35; group×drug p = 0.47; group×drug×time p = 0.99). The extracted text refers to tables and figures for demographic and time-course data, but these items are not fully presented in the provided extract.

Ionescu and colleagues interpret their findings as showing that a single sub-anaesthetic intravenous infusion of ketamine rapidly reduces depressive symptoms in patients with anxious bipolar depression to the same extent as in patients without anxiety. This sample consisted of treatment-resistant individuals who had not responded to conventional therapies, yet anxious status did not predict a poorer response to ketamine nor increased dissociative side effects. The authors contrast this result with prior literature in which anxiety generally predicted worse outcomes for standard bipolar treatments, noting that ketamine may therefore overcome a treatment resistance typically associated with anxious presentations. The investigators highlight several implications: understanding the mechanisms by which ketamine yields rapid antidepressant effects in anxious, treatment-resistant bipolar patients could identify new therapeutic targets; and the equivalence of response across anxious and non-anxious subtypes is clinically notable given the historical challenge of treating anxious bipolar depression. They also reference prior work in unipolar depression in which anxious subtype predicted a better ketamine response and longer time to relapse, but stress that anxious bipolar depression did not predict a superior response in the present analysis—rather, ketamine produced similar rapid benefit across subtypes. The authors acknowledge strengths and limitations. Strengths include analysis within the context of randomised, double-blind, placebo-controlled crossover parent trials and a well-characterised sample maintained on stable lithium or valproate. Limitations noted are: the HDRS A/S factor score has not been previously validated as a definition of anxious bipolar disorder (though it has been used in unipolar research); potential confounding effects of concomitant mood stabilisers cannot be excluded; the post-hoc nature of the analysis increases susceptibility to type I error and underlines the need for a priori studies; and broader concerns regarding ketamine’s dissociative effects, abuse potential and unknown long-term safety limit immediate clinical translation. Finally, the authors call for further studies including repeat-dosing, active comparators, and exploration of DSM-5 anxious-bipolar specifiers and underlying mechanisms to better define ketamine’s utility for this difficult-to-treat subtype.