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

This randomized, double-blind, placebo-controlled, crossover, within-subjects study (n=36) investigated the effects of ketamine (35mg/70kg) treatment for anxious and non-anxious bipolar patients. Ketamine rapidly reduced symptoms of depression in patients with anxious bipolar depression to the same extent as those without anxiety.

Abstract

“Objective: Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non‐anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine’s ability to decrease symptoms of depression.

Methods: Thirty‐six patients with anxious (n = 21) and non‐anxious (n = 15) treatment‐resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg) over 40 min. Post‐hoc analyses compared changes in the Montgomery–Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in anxious versus non‐anxious depressed patients with bipolar disorder through 14 days post‐infusion. Anxious bipolar depression was defined as DSM‐IV bipolar depression plus a HDRS Anxiety/Somatization Factor score of ≥ 7.

Results: A linear mixed model revealed a significant effect of anxiety group on the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p < 0.001) suggested that both anxious and non‐anxious groups had an antidepressant response to ketamine. The drug‐by‐anxiety interactions were not significant (all p > 0.28).

Conclusions: Both anxious and non‐anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non‐anxious group. Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest a need for further investigations into ketamine’s novel role in the treatment of anxious bipolar depression.”

Authors: Dawn F. Ionescu, David A. Luckenbaugh, Mark J. Niciu, Erica M. Richards & Carlos A. Zarate Jr

Summary

Patients with comorbid anxiety disorders/anxiety symptoms and bipolar disorder have worse clinical outcomes compared to non-anxious bipolar disorder. Regarding patients with primary bipolar illness accompanied by symptoms of anxiety, high anxiety symptoms were significantly associated with alcohol abuse, cyclothymia, and more suicide attempts. High anxiety symptoms were also associated with a trend toward nonresponsiveness to lithium.

A review of 11 RCTs found that quetiapine and olanzapine were associated with significant improvements in anxiety symptoms in patients with bipolar depression, however, weight gain and increased cholesterol levels were also significant.

Ketamine is a novel antidepressant that differs from many currently available antidepressants and is clinically challenging to treat, especially during a depressive episode. It has been shown to improve suicidal ideation in patients with bipolar disorder.

Ketamine has been shown to effectively treat depression in patients with treatment-resistant bipolar disorder, but it remains unknown whether patients with baseline anxiety status have a poorer response to ketamine.

Patients and methods

A post-hoc analysis was performed on data from two separate, but identical, randomized crossover trials investigating ketamine for the treatment of bipolar depression.

Anxious depression definition

Patients with anxious bipolar depression had a baseline Hamilton Depression Rating Scale (HDRS) Anxiety/Somatization (A/S) Factor Score of 7 plus a current DSM-IV diagnosis of bipolar disorder (type I/II; currently depressed).

Main outcome measures

Patients were rated at baseline, 40, 80, 110, and 230 min post-infusion, and at Days 1, 2, 3, 7, 10, and 14 post-infusion for depression and anxiety.

Statistical analysis

Demographic variables were compared between anxious and non-anxious groups using v2 tests and t-tests, and factororial linear mixed models were used to examine the groups over time.

Results

The linear mixed models controlling for baseline revealed that the anxious group had less depression, but that ketamine worked just as well for anxious as nonanxious patients.

Discussion

In the present study, we found that ketamine reduced depressive symptoms in anxious patients with severe, treatment-resistant bipolar depression to the same extent as in patients without anxiety. Additionally, anxious patients did not differ significantly from non-anxious patients with regard to reported dissociative side effects due to ketamine.

We found that anxious depression predicts a better response to ketamine than non-anxious depressed patients, and that anxious bipolar depression predicts the same rapid antidepressant response to ketamine as non-anxious bipolar depression patients.

Several notable strengths of the present study should be considered, including the randomized, double-blind, placebo-controlled, crossover study design, the use of the HDRS A/S Factor Score to define anxious bipolar disorder, and the post-hoc nature of the study, which made it susceptible to type I error.

Ketamine can significantly reduce symptoms of depression in patients with treatment-resistant anxious bipolar depression, and further research into this mechanism is needed to develop more-targeted treatments.