Reading of the Week: PTSD & Treatment – What’s Evidence Based? JAMA Psychiatry’s New Network Meta-analysis

From the Editor

Just over a century ago, Dr. Charles Myers wrote “A Contribution To The Study Of Shell Shock” in The Lancet, the first paper on shell shock. Today, our understanding of PTSD has greatly evolved.

But what’s the most effective treatment for people with PTSD?

This week, we consider the new paper by the University of Basel’s Jasmin Merz and her co-authors. They use a network meta-analysis to determine whether patients do better with medications, psychotherapy, or both; in other words, they attempt to analyze different studies in this area, but not necessarily those that do direct comparisons (that’s my Twitter-length biostatistical summary). They find: “The available evidence is sparse and appears not to support the use of pharmacological therapy as first-line treatment for posttraumatic stress disorder…”

We also consider an editorial that runs with the study. Murray B. Stein and Sonya B. Norman, both of University of California San Diego, are critical, commenting that aspects of the study may be “hard to swallow.”

DG

“Comparative Efficacy and Acceptability of Pharmacological, Psychotherapeutic, and Combination Treatments in Adults With Posttraumatic Stress Disorder: A Network Meta-analysis”

Jasmin Merz, Guido Schwarzer, Heike Gerger

JAMA Psychiatry, 12 June 2019 Online First

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2735127

Co-author Heike Gerger

Posttraumatic stress disorder (PTSD) is a highly debilitating mental disorder, which is characterized by psychological and behavioral symptoms including re-experiencing of the trauma, avoidance of stimuli associated with the trauma, negative alterations in cognitions and mood, as well as hyperarousal. The estimated lifetime prevalence of PTSD among adults is approximately 8%. Among the 10% to 20% of trauma survivors who develop PTSD, the disorder becomes chronic in many cases, leads to considerable disease burden as well as social and occupational impairment, and is associated with a high risk of psychiatric and medical comorbidity, substantial economic and societal costs, and increased risk of suicide.

Several beneficial treatments for PTSD are available, including pharmacological treatments and a variety of different psychotherapeutic treatment approaches. A previous network meta-analysis reported that outcome differences between individual psychotherapeutic approaches (eg, cognitive behavioral therapy, prolonged exposure, seeking safety, and eye movement desensitization and reprocessing) are nonsignificant and mostly occur in underpowered studies. Accordingly, treatment guidelines typically recommend different types of trauma-focused psychotherapeutic treatments as first-line PTSD treatment. Concerning pharmacological therapies, however, recommendations are inconsistent.

So opens a new paper by Merz et al.

Here’s what they did:

• “We searched Embase, Medline, PsycINFO, Cochrane Controlled Trials Register, and PSYNDEX for studies published between January 1, 1980, and February 28, 2018.”
• RCTs were included, with medication and psychotherapeutic treatments.
• “Our primary outcome was PTSD symptom severity measured on a continuous validated scale. We assessed treatment outcomes immediately after treatment termination and long-term outcomes as indicated by the longest available follow-up assessment.”
• “A network was created including 3 jointly randomizable treatments: first, psychotherapeutic PTSD treatments; second, pharmacological PTSD treatments; and third, combinations of psychotherapeutic and pharmacological PTSD treatments.” They did a series of comparisons, and employed statistical analyses.

Here’s what they found:

• “The systematic database search identified 11 416 records. After the initial screening of titles and abstracts, 46 full-text articles were considered potentially relevant. Twelve published RCTs with a total of 922 participants were included in our analyses…”
• “Risk of bias was considered low in 3 studies, moderate in 8, and high in 1.”
• “At the end of treatment, the comparative benefit between pharmacological and psychotherapeutic treatments and their combinations showed no significant superiority of any treatment approach.”
• “At the longest available follow-up, psychotherapeutic treatments were significantly more beneficial than pharmacological treatments… and the combined treatments were slightly but not significantly superior to psychotherapeutic treatment alone… but the combined treatments were significantly more beneficial than pharmacological treatments alone…”
• “With respect to the comparative acceptability of the 3 treatment approaches, we found slightly lower dropout rates in psychotherapeutic treatments than in the pharmacological and combined treatments, but the differences were not statistically significant…”

A few thoughts:

1. The authors do a network meta-analysis to compare certain treatments. But they didn’t have much material to draw from. In total, across the studies, there were just 922 participants. Ouch. To put that number in perspective: the Cipriani depression network meta-analysis involved data from over 120,000 people.

2. Is the small number a big problem? In a word: yes. Remember what a network meta-analysis is. In the accompanying editorial, Dr. Stein and Norman explain concisely: “Meta-analyses compile, digest, and compare data from head-to-head trials (ie, ones comparing treatment A vs treatment B) to provide an integrated assessment of their relative efficacy. Network meta-analyses go a step further to compare the reported effectiveness of interventions that may or may not have been evaluated directly against each other. In other words, trials of treatment A vs treatment B and trials of treatment B vs treatment C may enable inferences about the effectiveness of treatment A vs treatment C.” (We will discuss the editorial more in a moment.)

3. But without a direct comparison, we need to be extremely careful about the studies that go into a network meta-analysis – for example, the studies need to be relatively similar in what they are measuring and when. Otherwise, it’s garbage in, garbage out.

4. So – does this study expand our understanding of PTSD treatment? The paper runs with an editorial that is harsh in its criticism.

“When Does Meta-analysis of a Network Not Work? Fishing for Answers”

Murray B. Stein, Sonya B. Norman

JAMA Psychiatry, 12 June 2019 Online First

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2735125

Murray B. Stein

Just as bluefin tuna are high on the aquatic food chain, systematic reviews and meta-analyses are at the top of the evidence hierarchy. Tuna swallow up smaller fish that have eaten minnows, which have eaten plankton and so on, accumulating the nutrients – and the toxins (eg, mercury) – of their prey. Meta-analyses, too, acquire and filter data and the misinformation (eg, biases) from the studies they aggregate. Indiscriminate consumption of tuna or meta-analyses can be hazardous to brain health.

So begins a colourful editorial by Dr. Murray B. Stein and Sonya B. Norman, both of the University of California San Diego.

The authors make a few points about network meta-analyses and this study:

• “Merz et al included all available studies in their network meta-analysis. In so doing, they amalgamated data from studies that had vastly differing objectives (eg, proof of principle, confirmation of efficacy, comparative effectiveness)…”
• “Yet their decision, for example, to include a trial with 14 patients (9 in one arm and 5 in the other) highlights the subjectivity and user variability involved in conducting meta-analyses, even when following recommended procedures (eg, ones for assessing risk of bias in a study).”
• With regard to psychotherapies: “A downside is that this approach is likely to catch many different kinds of fish in its net, resulting in confusion about which of these ichthyological specimens are palatable and can be reasonably consumed and compared. For example, numerous studies have found specific trauma-focused psychotherapies (eg, prolonged exposure, cognitive processing therapy) to be effective, and these treatments have the highest recommendation across all clinical practice guidelines for PTSD. Yet this network meta-analysis made no distinction between trauma-focused or other psychotherapies…”
• With regard to medications: “By the same token, this network meta-analysis did not distinguish between established, US Food and Drug Administration–approved pharmacological treatments administered at therapeutic dosage and duration (eg, sertraline at 100-200 mg for 8-12 weeks) from augmentation trials for patients who did not respond to treatment (eg, addition of atypical antipsychotics to selective serotonin reuptake inhibitors) from one-time administration of experimental agents (eg, 3,4-methylenedioxymethamphetamine [MDMA]).”

They don’t mince their words:

Treating all psychotherapies as one modality and all pharmacotherapies as another and then comparing them, directly and indirectly, risks serving up (to continue with the marine life metaphor) a hard-to-swallow homogenized fish patty of inferences instead of the sushi-grade information we crave.

The authors go on to note the lack of study of PTSD:

For a disorder widely acknowledged as an important public health problem, the lack of PTSD trials, particularly ones evaluating pharmacotherapies, is troubling.

Rather than simply advocated more RCTs: “[the field needs] larger trials that will enable the intelligent parsing of patient heterogeneity to develop guidelines for personalized treatment. To succeed in that effort, researchers also need to look beyond PTSD diagnosis to examine individual and disease characteristics that may contribute to PTSD symptom severity and persistence.”

A few thoughts:

1. This is a harsh editorial. Strip away the talk about fish, and they have little positive to say about this study.

2. The authors raise good points, particularly with regard to the lack of solid studies in the field.

3. They make a good point about pushing past RCTs.

4. Network meta-analyses are more and more commonly published. They offer a new way of considering basic questions. But caution: some network meta-analyses are more equal than others.
5. For more on Dr. Myers and the original paper on shell shock, see this past Reading: http://davidgratzer.com/reading-of-the-week/reading-of-the-week-on-d-day-three-papers-on-shell-shock-one-by-dr-charles-myers/.

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.