Special thanks to Don Klein, MD and Bruce Thyer, PhD for helpful discussions, but all opinions expressed are the author’s alone.
Is there any benefit to adding psychotherapy to well-managed treatment with antidepressants? This clinically important question was addressed in a large-scale, exceptionally well-resourced study.
Despite appearing in the respected JAMA Psychiatry, the article will not get the attention it deserves. Its results are complex and nuanced. I had to read it carefully a number of times, along with its accompanying editorial to grasp its full significance. However, the study’s disappointing, downright disconcerting findings will keep it from getting widely disseminated.
There was no press release for the study and very little press coverage so far. One of the few mentions in the media is balanced –once you get passed the hyped title — and includes quotes from the lead author:
“We know they both work so you assume when you put them together it’s going to work better,” says lead author Steven D. Hollon of the psychology department of Vanderbilt University in Nashville, Tennessee.
He would have liked to see that additive effect for the whole group of depressed patients, but for about two thirds of patients, adding cognitive therapy didn’t matter, Hollon said.
Imagine a study evaluating the benefit of adding antidepressant medication to well-delivered cognitive therapy and that the results were similarly disappointing. The study would be well-publicized (“Depressed persons don’t need meds if they are getting adequate therapy”) in part because of the cognitive therapy lobby, but also because the message resonates with the anti-medication side in the antidepressant wars. Unlike results of the present study, these hypothetical results would be trumpeted because they are consistent with entrenched opinions.
The silence greeting the article has much in common with supporters of a soccer team not wanting to discuss a disappointing loss. Opinions about antidepressants and psychotherapy are as partisan as loyalties to soccer teams. There is nothing sinister going on here. But it makes for a bad progression from the availability of evidence to changing practice.
In this post, I will examine some of the specifics of the study and their broader implications. There are some sobering things to be learned. Among them:
- State-of-the-art treatment combining antidepressants and cognitive therapy continued over a long period of time leaves many patients still depressed.
- Adding psychotherapy does not improve outcomes for many patients if they are already receiving well-managed, personalized treatment with antidepressants.
- Whatever cognitive therapy contributes might be achieved cheaply and more simply with supportive therapy or enhanced clinical management of the antidepressants.
- Therapists need guidance as to what to do when manualized psychotherapy is not having its intended effect, including how to inform and discuss with patients.
But to begin such discussions we need to dive into the details of the methods and the particular interventions being evaluated. And bring in what we already know about treatment of depression, particularly the gross inadequacies in routine care.
The abstract to the paper is available here. As with other papers behind pay walls, you will have to access this one through a University library or email the corresponding author, firstname.lastname@example.org. The excellent editorial by Michael Thase is also behind a pay wall, but you can email him at email@example.com.
Finally, the registration of the trial is available here.
The objective of the study was
To determine the effects of combining cognitive therapy (CT) with ADM [antidepressant medication] vs ADM alone on remission and recovery in major depressive disorder (MDD).
The trial design was exceptionally complex and involved providing acute treatment of up to 18 months, removal of patients who did not meet criteria for remission with 18 months, and transitioning of the remaining patients into continuation treatment.
Acute treatment lasted until the patient met the criteria for remission, defined as 4 consecutive weeks of minimal symptoms; continuation treatment lasted to the point of recovery, defined as another 26 consecutive weeks without relapse. Patients did not need to maintain the symptom levels required for remission to meet the criteria for recovery. Participants who experienced relapse during continuation were required to meet remission criteria again before they were eligible to meet the criteria for recovery. Patients who did not meet the symptomatic criteria for remission within 18 months of treatment were removed from the study and referred for other treatment, as were patients who did not meet criteria for recovery within 36 months. Patients who met only the symptomatic criterion for remission at month 18 (or recovery at month 36) continued treatment until it was determined whether they also met the temporal criteria. Thus, up to 19 months were allowed for remission and up to 42 months for recovery.
As a Phase 4 trial, the investigators assumed that the efficacy of both the ADM and CT have already been established so that the focus could be on whether these two efficacious treatments could be usefully combined. All patients received antidepressant treatment and half were randomized to receiving cognitive therapy as well. There was no pill placebo or other comparison group. The decision not to have a condition controlling for attention and support makes sense, but it introduces ambiguity in the interpretability of the ultimate results, as we will see.
The trial registration
The registration is entitled “Preventing the Recurrence of Depression With Drugs and Psychotherapy” and occurred after the first patients were accruing, not before. The title of the registration is discrepant with the actual published study, which does not mention prevention and downplays recurrence as an outcome.
The patient population had to have recurrent or chronic major depressive disorder, with the exclusion criteria were a current diagnosis of a psychotic disorder, a history of nonaffective psychotic disorder, substance abuse during the last three months requiring detoxification, and having either a schizotypal, antisocial, or borderline personality disorder.
There were three primary outcomes declared:
- Time to remission
- Time to recovery
- Time to recurrence
All patients received acute treatment until they met criteria for remission. Continuation treatment was provided until the point of recovery…Dosages were raised as rapidly as possible and kept at maximum tolerated levels for at least 4 weeks. Treatment in patients who exhibited only a partial response was augmented with additional medications, and treatment in those who showed minimal response (or little additional response following augmentation) was switched to another ADM. Most patients were given multiple trials with easier-to-manage selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors before treatment was switched to more difficult-to-manage tricyclic antidepressants or monoamine oxidase inhibitors.
So, unlike many ADM trials, this one involved providers being able to switch between antidepressants or add additional medications, not just adjust dosage. This is impressive, state-of-the-art, algorithm-based treatment, involving regularly assessing patient outcomes and making decisions about intensifying or changing treatments, based on set rules. You can find more about algorithm-based treatment here.
The therapists met weekly for 90 minutes at each site to review cases, with onsite supervision provided by 3 of the authors (R.J.D., P.R.Y., and S.D.H.). The therapists followed the procedures outlined in the original treatment manual for CT of depression, augmented when indicated for patients with comorbid Axis II disorders. The protocol called for 50-minute sessions to be held twice weekly for at least the first 2weeks, at least weekly thereafter during acute treatment, and then at least monthly during continuation. Therapists were free to vary the session frequency to meet the needs of the patient.
This too is state-of-the-art treatment. The three supervisors, including the first author and principal investigator Steve Hollon, have been very involved in the promotion of cognitive therapy for depression and could be expected to provide expert implementation and supervision.
Patients treated with antidepressants alone had a recovery rate of 62.5%, which was raised to 73.5% among those who received CT as well.
- There were no differences in remission rate between patients assigned to ADM alone (60.3% by month 12) and those assigned to combined treatment (63.6%).
- Fewer patients assigned to combined treatment dropped out and this group also had fewer adverse events, which the authors attribute to their less time in an episode of depression.
- Recall that the trial registration indicated the study was supposedly aimed at preventing relapse. You have to search to find that there were no differences between the two groups in relapse, 80 relapses in 54 patients retained in the ADM alone group versus 71 in 48 patients vs in the combined group. Note the modest size of the samples of the two groups for which risk of relapse could even be calculated.
These are not impressive results for CT. The authors performed post hoc subgroup analyses
in which they found no effect for rate of recovery for the two thirds of patients with less severe or less chronic depression, but a sizable effect for the remaining patients who met these criteria. Basically, the number needed to treat (NNT) was 3 in this subgroup of patients with severe, nonchronic depression [Update: 10/19/2014 Corrected from earlier "chronic"]. That is impressive, but needs to be replicated, because analyses were post-hoc and underpowered. Such effects tend to be weaker or disappear all together when replication is attempted in a larger sample.
- There were still no differences for remission in these subgroup analyses.
- Recall patients with schizotypal, antisocial, or borderline were excluded. But those with other personality disorders took longer to recover than did patients without a personality disorder.
My interpretation of the results
Three things to keep in mind as we begin discussion of some unsettling results:
- The study design does not address whether antidepressants add anything to what is achieved with cognitive therapy. To do so would require a study in which all patients receive cognitive therapy and only some were randomized to antidepressants.
- This study did not have an inert control group such as wait list or no treatment and so any naturalistically occurring recovery in the absence of treatment gets attributed to the treatments. To some unknown degree, apparent effects of treatment are actually naturally occurring recovery that would have occurred in the absence of treatment.
- The study also does not have a psychotherapeutic control group like supportive therapy. We cannnot know whether any benefits achieved by adding cognitive therapy could have been obtained with a less intensive treatment, like supportive counseling or therapy or even simple encouragement and support for adherence.
- The study involved an extraordinary amount of patient-provider a contact time. It is unfortunate that exactly how much is not documented, but this is relevant to evaluating the cost effectiveness of prolonged treatment of depression in the absence of improvement.
The glass-is-half-empty interpretation of the study is that even when given state-of-the-art treatment that is more intensive and long-term than is typical, a quarter of depressed patients do not achieve remission or recovery. The quality and intensity of both pharmacological management and psychotherapy far exceeds what is routinely available in the community and probably what is even reimbursable by insurance.
Routine treatment for depression in the community is quite poor. The mean number of visits in a year for persons with a diagnosis of depression is only eight. Most depression treatment is with antidpressant medication, and most medication is given in non-mental health medical care settings, like primary care. Most primary care patients discontinue ADM treatment shortly after starting. Only 20-30% of depressed persons being treated exclusively in primary care settings receive adequate care and follow up. Said differently, 40% of depressed patients are administered treatment with little or no benefit over what would be obtained by remaining on a wait list, representing about 20% of the total cost of treating depression.
Some of the problems of routine care lie in poor reimbursement and provider indifference to practice guidelines. The guidelines for meds minimally require a follow-up visit in 5 to 7 weeks to determine whether progress is being made, adherence and patient education are adequate, and whether any adjustment or change in medication is needed. That does not typically happen.
But another part of the problem lies in patients’ perception that such an investment in time and effort is not worth the benefits they received. That may also reflect the inadequacies of the care they get, but it is a cost/benefit analysis that could lead patients to refuse more intensive treatment.
The bottom line, is doing the best we can, treatment for depression will leave many patients dissatisfied and continuing to be depressed. We need to be careful about misleading depressed patients about what they can expect.
More details are needed about how much treatment was provided to whom in this study. It is such an ambitious and costly study, and unlikely to be done again anytime soon, but it leaves a lot of questions on answered. We could at least begin to formulate some hypotheses knowing more what went on.
For instance, what did the cognitive therapists do, what specific interventions did they provide in seeing patients so regularly for so long in the absence of apparent benefit? Were the therapists even aware of the lack of a benefit? The therapists surely had to improvise in going well beyond what is indicated in the manual, which is most adapted to shorter term therapy. Did they simply resort to being supportive?
We cannot rule out that any benefits of cognitive therapy in the study are simply due to nonspecific support, reinforcement of positive expectations, and encouragement to adhere to medication. The cognitive therapy had impressively credentialed and carefully supervised therapists. But was this required for the effects that were obtained?
Finally, providers managing medication in the present study relied on algorithms to make decisions about whether and when to make changes in medication, including switching, augmenting, or simply changing dosage. Many of the specific algorithms do not have strong empirical validation, but the notion does have empirical support that at some point clinicians have a responsibility to change what they are doing does. For instance, there are practice guidelines recommending that after around five weeks, and positive clinical change is not evident, the current treatment should be re-examined.
Manualized psychotherapy has guidelines for to do within the therapeutic model when change is not occurring. But there are typically no guidelines as to when medication should be suggested, a different therapeutic approach or referral to another therapist offered, or therapy should be terminated as futile.
Certainly we can conceive of situations where such judgments are warranted, but there is almost no discussion in the psychotherapy literature. In the case of cognitive therapy for depression, observational data derived from clinical trials could be used to suggest when change should be occurring, and if it is not, the likelihood that it will occur later. Out of respect for patient autonomy and informed consent, I think it is incumbent on psychotherapists to evaluate the evidence they have and come up with provisional recommendations for switching or stopping treatment that can be empirically tested.