Using all available data in the intent-to-treat sample (see the “Methods” section) and with the MADRS score as the primary outcome measure, the linear mixed model indicated a significant interaction between time and drug (F10,245=3.22, P<.001). Post hoc tests showed significantly fewer depressive symptoms when patients were receiving ketamine compared with placebo from 40 minutes to 3 days postinfusion (P<.001) (). Comparisons at baseline and at days 7, 10, and 14 postinfusion were not significant following correction for multiple comparisons (P=.46, P=.21, P=.13, and P=.09, respectively). The effect sizes were 0.52 (95% confidence interval [CI], 0.28-0.76) at 40 minutes, 0.67 (95% CI, 0.42-0.91) at day 1, and 0.22 (95% CI, −0.03 to 0.48) at day 14. The largest effect was seen 2 days after infusion (d=0.80; 95% CI, 0.55-1.04).
Figure 2 Change in depression scale scores during 2 weeks in patients with bipolar disorder given placebo and ketamine (n=18). Values are expressed as generalized least-square means and standard errors for the intent-to-treat analysis. BDI indicates Beck Depression (more ...)
Examining subjects who completed the study yielded similar results. The interaction between drug and time was significant (F10,191=2.55, P=.007). Post hoc tests indicated significant drug differences from 40 minutes through day 7. The effect sizes were similar in size to the intent-to-treat analysis (eg, d=0.72; 95% CI, 0.44-1.00 at day 1).
To examine potential carryover effects in the intent-to-treat sample, a single linear mixed model was used to compare the baseline MADRS scores for each drug and drug order. The model showed no significant effects (order: F1,16=1.48, P=.24; drug: F1,14=0.01, P=.94; order×drug: F1,14=1.69, P=.22). Patients receiving ketamine first had a nonsignificant decrease in MADRS scores from the first baseline rating (mean MADRS score, 31.2 [SD, 4.4]) to the second-phase baseline rating (mean, 29.4 [SD, 8.1]; F14=0.91, P=.36). Patients receiving placebo first also had a nonsignificant decrease in MADRS scores from the first- (mean, 33.9 [SD, 4.8]) to the second-phase baseline rating (mean, 32.9 [SD, 3.8]; F14=0.78, P=.39).
An additional analysis was conducted to understand the potential for carryover effects. The primary analysis was run using only the first-phase data, so the drug factor was a between-subjects measure. In this case, the drug × time interaction approached significance (F10,148=1.71, P=.08). The drug main effect was not significant (F1,16=1.92, P=.19), but the time effect was significant (F10,148=2.93, P=.002). Given the small sample size, effect sizes were calculated to determine whether they differed between the first phase and the full study. Results indicated that effect sizes were similar to the full study. For instance, the effect at 40 minutes was 0.63 (95% CI, −0.04 to 1.30) and the effect at day 1 was 0.66 (95% CI, −0.01 to 1.33); these values compare with 0.52 and 0.67, respectively, in the full analysis.
shows the proportion of responders () and remitters () at each point in the intent-to-treat sample. No patients responded or remitted while taking placebo through the first 3 days; 1 patient (6%) receiving placebo had response and remission at days 7 and 10. Nine of 16 (56%) patients receiving ketamine responded, and 2 of 16 (13%) remitted at 40 minutes; 7 of 16 (44%) responded and 5 of 16 (31%) patients receiving ketamine remitted after 1 day.
Figure 3 Proportion of responders and remitters after ketamine or placebo infusion by Montgomery-Asberg Depression Rating Scale (MADRS) score. A, Proportion of responders (50% improvement on MADRS) from 40 minutes to day 14 postinfusion (n=18). B, Proportion of (more ...)
When only completers were included in the analysis, the McNemar test showed a significantly higher response rate from 40 minutes through day 3 with ketamine, but only the result at 230 minutes remained significant after applying the Hochberg-adjusted Bonferroni procedure to adjust for multiple comparisons. None of the remission rates were significantly different. Twelve of 17 (71%) patients responded to ketamine and 1 of 16 (6%) responded to placebo at some point during the trial. The median time to initial response was 40 minutes. After responding, losing response was defined as reaching less than 25% improvement from baseline. Under those conditions, the response to ketamine lasted an average of 6.8 days (standard error, 1.4 days); 4 patients responded for 1 week, and 3 additional patients had a response lasting 2 weeks or more.
To confirm the change in depressive symptoms as assessed by the MADRS, similar statistical models were used for the secondary measures. For the Hamilton Scale for Depression, a significant interaction was observed between drug and time (F10,251=2.75, P=.003). When receiving ketamine, patients had fewer depressive symptoms from 40 minutes to 3 days and at 14 days postinfusion. Similar results were obtained for the Beck Depression Inventory (F10,205=3.76, P<.001), in which differences were present for the same times (). With the visual analog scale, depressive symptoms were lower with ketamine from 40 minutes to 3 days postinfusion (F10,187=3.92, P<.001).
Anxiety symptoms, as assessed by both the Hamilton Anxiety Rating Scale and the visual analog scale, decreased significantly. A linear mixed model using the Hamilton Anxiety Rating Scale showed significantly less anxiety for subjects receiving ketamine compared with placebo (F7,147=2.10, P=.047) at the first postinfusion observation and at 230 minutes through day 3. Drug differences were significant at day 10 but not at days 7 or 14 (eFigure). Similar findings were obtained with the visual analog scale, which showed significantly fewer symptoms in subjects receiving ketamine (F10,254=3.02, P=.001) from 40 minutes through day 2.
The linear mixed model with manic symptoms, as assessed by the Young Mania Rating Scale, showed a significant interaction between time and drug (F10,220=2.50, P=.007) (). Patients receiving ketamine had significantly higher scores at 40 minutes, but significantly lower scores at days 2 and 14. The difference at 40 minutes came from a nonsignificant decrease in Young Mania Rating Scale scores on placebo and a slight, nonsignificant increase when receiving ketamine. Compared with baseline, there was no significant change in manic symptoms in patients receiving placebo, but Young Mania Rating Scale scores significantly declined with ketamine from 80 minutes through day 2 postinfusion. One patient who was concomitantly receiving lithium reached a Young Mania Rating Scale score of 15 at 40 minutes while taking ketamine, but the symptoms were no longer higher than baseline by 80 minutes. Of the patients receiving placebo and valproate, one patient reached a score of 13 on day 7 and a score of 21 on day 10.
Change in psychiatric scale scores in patients with bipolar disorder given placebo and ketamine (n=18). Values are expressed as generalized least-square means and standard errors for the intent-to-treat analysis.
The statistical model for Brief Psychiatric Rating Scale positive symptoms showed a significant drug×time interaction (F10,248=4.45, P<.001) (). Ketamine and placebo differed only at 40 minutes postinfusion, and this difference was due to a small, nonsignificant decrease with placebo and an even smaller increase with ketamine. On the Clinician Administered Dissociative Scale, the significant interaction (F10,263=16.52, P<.001) pointed to a ketamine/placebo difference at 40 minutes only where patients had a large increase on ketamine ().
Spearman correlations were used to examine the relationship between change in depressive symptoms and in positive and dissociative symptoms. The unusual distribution of changes in positive and dissociative symptoms drove the use of the nonparametric correlation. We found no significant correlations between change in MADRS scores at various points and change in Brief Psychiatric Rating Scale positive or Clinician Administered Dissociative Scale symptoms, either with ketamine or placebo. Forty minutes after ketamine infusion, the correlation between MADRS scores and Brief Psychiatric Rating Scale positive symptoms was r = 0.08 (P = .76); the correlation between MADRS scores and Clinician Administered Dissociative Scale symptoms was r=0.23 (P=.40). At day 1 postinfusion, the correlations were r = 0.09 (P = .75) for Brief Psychiatric Rating Scale positive symptoms and r=−0.08 (P=.76) for Clinician Administered Dissociative Scale symptoms.
Pearson correlations showed that plasma ketamine and norketamine levels after 40 minutes were not significantly related to change in MADRS score at 40 minutes (ketamine: r = −0.18, P = .51; norketamine: r=0.34, P=.20). Correlations did not change after 40 minutes.
An analysis of individual MADRS items showed that 8 of 10 symptoms changed significantly, even after correction for multiple comparisons. Reduced sleep and suicidal thoughts were not significant, and reduced appetite scores were significantly increased. All other symptoms decreased significantly.
The influence of mood stabilizer on response rates was not significant with ketamine (Fisher exact test, P
=.59; lithium: 8 of 10 responded [80%], valproate: 4 of 7 responded [57%]) or placebo (Fisher exact test, P
=.38; lithium: 0 of 10 responded [0%], valproate: 1 of 6 responded [17%]). Time to first response to ketamine, as assessed by Kaplan-Maier survival analysis, was also not significant (log-rank test,
=.30; mean: lithium, 4083 minutes [standard error, 2542 minutes]; and valproate, 8679 minutes [standard error, 3758 minutes]). All responders to ketamine had an initial response within the first hours after infusion. An additional linear mixed model was performed after adding the type of mood stabilizer (lithium or valproate) as a factor in the model, but no significant effects were observed (mood stabilizer, F1,15
=.65; mood stabilizer×time, F10,207
=.97; mood stabilizer×drug, F1,140
=.42; mood stabilizer×time×drug, F10,232
No serious adverse events occurred during the study. Adverse events occurring during the infusion in 10% or more of subjects receiving ketamine or placebo included feeling woozy or loopy, feeling lethargic or drowsy, cognitive impairment, fear or anxiety, nausea, dizziness, odd sensations, blurred vision, and headache. Adverse events associated only with ketamine (≥10% of subjects) included dissociation; feeling strange, weird, or bizarre; dry mouth; tachycardia; and increased blood pressure. The 2 subjects who experienced increased blood pressure and tachycardia returned to normal within minutes after the infusion. No adverse event was significantly different from placebo at 80 minutes or thereafter (eTable). No significant changes occurred in electrocardiography, respiratory, or laboratory values during the study.