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In our residency program’s journal club, I’ve been advocating the juicy figure approach for actually getting through monthly journals. If after an article title has led you to read the abstract and you’re still interested, skim down to the figure that presents the main findings. You’re going straight to the reason the paper was published, is the idea.
Hi! Jim Phelps here for the Psychopharmacology Institute. Let’s do that with this article entitled “Adjunctive Ketamine with Relapse Prevention-Based Psychological Therapy in the Treatment of Alcohol Use Disorder.” The juicy figure here is Figure 3. Here, we see the percentage of days abstinent over 6 months for 4 treatment arms. Placebo plus psychoeducation must be the control therapy because the next curve up in higher abstinent days is placebo plus psychological therapy. The next higher curve is ketamine plus psychoeducation, and the topmost with the highest percentage of abstinent days is ketamine plus psychological therapy. So, already, we can conclude that the authors found what they were hoping to find: A combination of ketamine and psychotherapy leads to the best outcomes.
Now, let’s begin the necessary inquiries. First, these results are probably statistically significant. We’ll check that. But are they clinically significant? Ah, here we go. In the caption of the juicy figure, confidence intervals are not overlapping for the 2 most extreme groups at 12 and 24 weeks. In other words, the combination of ketamine and active psychotherapy beat placebo plus psychoeducation, but none of the other differences were significant. The authors described this as a pilot study, although they had about 100 participants, with 20 to 25 participants per arm. That size could limit statistical significance even if clinical significance was substantial. So, let’s look at that.
At 24 weeks, the ketamine plus therapy group had 86 days of abstinence vs the placebo plus psychoeducation group, which had 70 days. That’s 16 more days in a 6-month period for the ketamine plus therapy group than the placebo plus psychoeducation group. In other words, a 10% increase in abstinent days for the ketamine therapy group compared with placebo with psychoeducation. Is that worth it clinically? To judge that, we need to know what the treatments actually looked like. If ketamine was repeatedly administered or if the therapy was really intensive, maybe a 10% gain is not big enough.
So, skimming back to the method section, we find that there were 3 weekly ketamine infusions, and psychotherapy was a 7-session program delivered by psychologists described as “mindfulness-based relapse prevention to support development of an enjoyable and meaningful life without alcohol.” Seven sessions with psychologists—that’s moderately intensive. The control condition was the same duration with the same therapist providing alcohol education about the forces driving addiction, biological effects, and ways to improve healthy living and nutrition but no mindfulness training and no personalizing of relapse prevention strategies. Otherwise, though, it was the same amount of contact with the same well-trained therapists. No wonder the placebo groups didn’t differ too much. Here, the abstinent rates over 6 months were 70 days for the placebo plus psychoeducation group vs 79 days for the placebo plus the more deliberate psychotherapy. Nine more days over 6 months. All that points at ketamine as the more powerful driver of response in this study.
In this rapid journal reading approach, I now want to see the authors’ opinion about the significance of their findings. So, we jump to the first paragraphs of the discussion. Their main point was that the duration of benefit was impressive. A ketamine effect on drinking abstinence was still visible at 6 months compared with the effect in major depression, where the benefit is generally gone in 2 weeks. Moreover, with the sustained reduction in drinking, liver function improved over the course of the trial for all 4 groups.
Let’s then check generalizability. Are the participants in this study like your patients? Might they have been unusually likely to respond? Ah, it looks like not. They had an average of 8 prior quit attempts. One-quarter of them had already tried ketamine. Some of them had already tried it up to 10 times. On top of that, half had tried psilocybin or LSD. Tough crowd. You can see why their sustained abstinence impressed the authors—86 days instead of 70 at 6 months. Unfortunately, their experience with ketamine and other drugs nearly destroyed the study blinding. One hundred percent of those who got ketamine knew that’s what they had received, whereas only one-quarter of the placebo group thought they got ketamine. I’d have thought this actually might have widened the gap between groups more than it seems to have. Overall, there were no serious adverse events, and the adverse effects seen were mild. Therefore, the authors suggest that a patient who is using alcohol can still be considered for ketamine treatment.
And in conclusion, the authors say, “Three subanesthetic infusions of ketamine supported abstinence from alcohol and that abstinence may be further enhanced when ketamine is combined with psychotherapy.”
For more on this, the study also reports Hamilton Depression Scale results, including subscores. So, you’ll have to dig into the paper, which is linked here at the Psychopharmacology Institute.
Abstract
Objective:
Early evidence suggests that ketamine may be an effective treatment to sustain abstinence from alcohol. The authors investigated the safety and efficacy of ketamine compared with placebo in increasing abstinence in patients with alcohol use disorder. An additional aim was to pilot ketamine combined with mindfulness-based relapse prevention therapy compared with ketamine and alcohol education as a therapy control.
Methods:
In a double-blind placebo-controlled phase 2 clinical trial, 96 patients with severe alcohol use disorder were randomly assigned to one of four conditions: 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education. The primary outcomes were self-reported percentage of days abstinent and confirmed alcohol relapse at 6-month follow-up.
Results:
Ninety-six participants (35 women; mean age, 44.07 years [SD=10.59]) were included in the intention-to-treat analysis. The treatment was well tolerated, and no serious adverse events were associated with the study drug. Although confidence intervals were wide, consistent with a proof-of-concept study, there were a significantly greater number of days abstinent from alcohol in the ketamine group compared with the placebo group at 6-month follow-up (mean difference=10.1%, 95% CI=1.1, 19.0), with the greatest reduction in the ketamine plus therapy group compared with the saline plus education group (15.9%, 95% CI=3.8, 28.1). There was no significant difference in relapse rate between the ketamine and placebo groups.
Conclusions:
This study demonstrated that treatment with three infusions of ketamine was well tolerated in patients with alcohol use disorder and was associated with more days of abstinence from alcohol at 6-month follow-up. The findings suggest a possible beneficial effect of adding psychological therapy alongside ketamine treatment.
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Reference
Grabski, M., McAndrew, A., Lawn, W., Marsh, B., Raymen, L., Stevens, T., Hardy, L., Warren, F., Bloomfield, M., Borissova, A., Maschauer, E., Broomby, R., Price, R., Coathup, R., Gilhooly, D., Palmer, E., Gordon-Williams, R., Hill, R., Harris, J., … Morgan, C. J. (2022). Adjunctive ketamine with relapse prevention–based psychological therapy in the treatment of alcohol use disorder. American Journal of Psychiatry, 179(2), 152-162.
