Antibiotic May Augment CBT for Anxiety, OCD, PTSD

Fran Lowry

January 26, 2017

D-Cycloserine (DCS), an antibiotic used to treat tuberculosis, may augment exposure-based cognitive-behavioral therapy (CBT) in patients with anxiety-related disorders, at least in the short term, new research suggests.

"Exposure-based CBT is a very powerful treatment for anxiety, OCD [obsessive-compulsive disorder], and posttraumatic stress disorder [PTSD]. While DCS significantly augmented this treatment, the effects were very small, with an effect size equal to 0.25, or less than 4 points difference between DCS and placebo on a scale ranging between 0 to 100," David Mataix-Cols, PhD, from the Karolinska Institute, Stockholm, Sweden, who led the study on behalf of the DCS Anxiety Consortium, told Medscape Medical News.

"However, more research is needed. It may be that for certain patients and under certain conditions, DCS may show more powerful effects than those shown in this study," he added.

Dr David Mataix-Cols

Results of the meta-analysis were published online January 25 in JAMA Psychiatry.

Antidepressants: No Moderating Effect

Exposure-based CBT is the treatment of choice for patients with anxiety, OCD, and PTSD. However, some patients do not have a sufficient response.

This has led researchers to explore ways of augmenting CBT with pharmacologic agents, including DCS.

The meta-analysis included 22 trials with a total of 1073 patients. In 21 of the trials, individual participant data were obtained for 1047 patients.

When controlling for antidepressant use, participants who were administered DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% confidence interval [CI], -0.81 to -6.43; P = .01; d = -0.25) than those who received placebo.

However, there was no improvement in patients who received DCS vs placebo from pretreatment to midtreatment assessments (mean difference, -1.66, 95% CI, -1.60 to 4.92; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98; 95% CI, -0.03 to 5.99; P = .05; d = 0.19).

Post hoc analyses showed that symptom severity was lower for patients who received DCS than for those who received placebo at both posttreatment assessment (difference, -3;19; 95% CI, -0.95 to -5.43; P = .006; d = -0.21) and follow-up (difference, -2.54; 95% CI, -0.04 to -5.04; P = .05; d = -0.16).

Results also showed that antidepressant use did not moderate any of the effects of DCS on outcome. However, participants taking antidepressants improved more from pretreatment assessment to follow-up than those not taking antidepressants (difference, -4.32; 95% CI, -0.64 to -8.01; P = .02, d = -0.28).

Still Under Investigation

Dr Mataix-Cols noted that the study had sufficient power to detect small effects, but it had less power to detect study-level moderating factors and predictors and for subgroup analyses.

"Similarly, only four of the included studies involved children and adolescents, which limits the generalizability of our results to younger populations. Another limitation is that different studies employed different outcome measures, and for this reason, these had to be transformed into ranked scores to ensure a single metric across studies," he said.

"Because CBT is such a powerful treatment for most patients, we suspected that the [augmenting] effects of DCS would probably be small," said Dr Mataix-Cols.

"Accordingly, very large samples of patients are needed to show statistically significant differences between groups. Previous studies and meta-analyses were underpowered to detect such small effects. Combining the raw data from all available studies to date gave us the power we needed to address the question of whether DCS is an efficacious augmenting strategy, over and above CBT," he added.

The DCS Anxiety Consortium had a second research question.

"Previous research from our group had suggested that there may be undesirable interactions between DCS and antidepressants, whereby patients taking both types of drugs would have significantly worse outcomes, but we were unable to replicate this finding," Dr Mataix-Cols said.

Some studies have shown less than stellar results with DCS in this setting.

Dr Mataix-Cols noted that although the effect size of 0.25 is small, the results suggest future research avenues.

"While we have shown that the effects of DCS appeared to be very small for regular patients, it is unknown if the effects may be stronger for patients who have failed to respond to CBT. Future studies should also explore if DCS may be more helpful if only administered after successful exposure sessions," Dr Mataix-Cols said.

"For clinicians, the results suggest that they should be cautious and not start prescribing DCS regularly until more evidence is available. This remains a treatment under investigation," he said.

A Matter of Timing?

Study coauthor Eric Storch, PhD, All Children's Hospital Guild Endowed Chair and professor, University of South Florida, Tampa, added that the article is conclusive in suggesting that there is a slight benefit with DCS, but things still remain unknown.

"There has been some very exciting work that looked at the success of the exposure session and found that such success was a critical factor for DCS to work as an augmenting agent. But we couldn't examine this in the meta-analysis," Dr Storch told Medscape Medical News.

He would also like to see more research in children and adolescents.

"The second question is the extent to which these data extrapolate to kids, since there have only been four, maybe five at this point," he said.

In July 2016, Dr Storch and colleagues published results of a randomized, placebo-controlled trial that concluded that augmenting CBT with DCS provided no added benefit in children and adolescents with OCD.

The trial showed there was no separation between placebo and DCS, but the key may lie in the timing of the drug's administration.

"It's the question of when to give it, and that was something that we didn't examine in that study, when it would work. It goes back to the element of how we think D-cycloserine would work," Dr Storch said.

"The idea is that we are enhancing the learning of fear memories, and in a good exposure session, you are teaching patients that the feared outcome is not going to happen. You are revising that fear memory.

"That means that every exposure session does not necessarily have the same outcome. Some are good, and you may be augmenting a good session; some are okay, and some are bad for whatever reason. And then you are augmenting that. So that's one of the key things that this current paper could not determine simply because the data were not there," he said.

One avenue to explore might be to administer DCS after a positive session, said Dr Storch. "That's one thought, but it hasn't been conclusively studied. We don't know if that approach might be more effective," he said.

Dr Mataix-Cols and Dr Storch report no relevant financial relationships.

JAMA Psychiatry. Published online January 25, 2017. Full text


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