Thursday, December 22, 2011

Antidepressants = Psychotherapy = Placebo ?

Jacques Barber et al. have recently published the results of a randomized, controlled study conducted between 2001 and 2007, comparing antidepressant therapy, short-term dynamic psychotherapy, and placebo in a 16-week course of treatment for 156 depressed adults.  Here is a link to the abstract:

The bottom line in the study was that there was no significant difference between antidepressants, psychotherapy, or placebo. Response rates were 31% for medication,   28% for psychotherapy, and  24% for placebo -- which has a low probability of being statistically different.  Remission rates were 26% for medication, 22% for psychotherapy, and 20% for placebo. 

Critics trying to explain these findings might attempt to argue that the psychotherapy or the medication regime was not sufficient, etc. -- but I do not see this to be true.  The medications (venlafaxine or sertraline) were given at quite sufficient doses for good lengths of time.  The psychotherapy was not CBT (which has a larger research evidence base) but there is little reason, in my opinion, to believe that the therapy style was inferior.

The authors attempt to do some secondary analyses looking for explanations, but their conclusions seem quite weak to me (e.g. regarding race or gender).   The fact that they spin these conclusions into a prominently framed set of "clinical points" seems quite inappropriate to me -- this is a negative study, there are no "clinical points" to be found here, unless they recommend placebos and cessation of other therapies!

There are a number of issues from this study that I do find very important to discuss:

1) despite a massive amount of data showing that various therapies (e.g. antidepressants or psychotherapy) are effective for various problems, there are examples of carefully-conducted negative studies, such as this one.  These results cannot simply be explained away as statistical aberration:  there must be a reason why one group of people responds to a treatment, while another does not.  Many of these reasons are poorly understood.  It may be that the diagnostic category of "major depressive disorder" is inadequate, in that it correlates poorly on its own with treatment responsiveness.

2) the subjects in this study had a high degree of comorbidity (e.g. substance abuse problems, anxiety disorders, and axis II problems).  While the severity and chronicity of depression was not found to actually correlate with treatment responsiveness, I suspect that the comorbidities would substantially affect response to a relatively short-term course of therapy. 

3) the subjects in this study were socioeconomically disadvantaged; while the effect of SES was also not found to "influence the initial findings,"  I believe that low SES is not necessarily a direct negative influence upon mental health; rather it is an indirect factor which for many people increases the likelihood of some profound mental health negatives (e.g. unemployment, lack of meaningful or satisfying employment, lack of healthy or safe community, lack of availability to do healthy or meaningful leisure activities, not enough money to eat healthily, etc.).  I believe that the environmental adversities need to be looked at very closely in a study of this type.

This leads to what I believe is an obvious explanation for the findings here:  there is no therapy for depression that is likely to help unless ALL contributing factors (including obvious environmental contributing factors) are addressed.   By way of analogy, I believe it is pointless to treat insomnia using a powerful sedative if a person is sleeping in a room which is continuously noisy, cold, and prone to break-ins by violent intruders.  The environmental issues need to be addressed first!  Another analogy I have often used is of trying to repair a water supply system for a city:  it is a waste of effort to pipe in more water from rivers, or to dig a deeper reservoir, if the walls of the reservoir and the pipes are leaking or bursting because of structural defects.   In order for a therapeutic strategy to work, the "leaks" have to be repaired first.  For a person with anemia, it is not an appropriate strategy to simply give a blood transfusion:  while a transfusion may be necessary, it will not be sufficient--and could even make matters worse-- if the underlying cause of blood loss is not addressed and treated.

In the case of medications or psychotherapy, I believe these can be very helpful, but only if environmental adversity is also remedied.  In some instances, of course,  relief of a psychiatric symptom could help a person to improve the environmental circumstances.  But in most other cases, I think the issue is broader, and could be considered a political or social policy matter.

Another related issue is that I do not believe "depression" can be treated on its own without addressing all psychiatric and medical comorbidities at the same time.  Ongoing substance abuse, in my opinion, is often a powerful enough factor--psychologically as well as neurophysiologically--to completely dominate and dissolve the positive influences of psychotherapy or effective medication.  In this study, 30-40% of the cohort reported substance use problems. 

As a final thought, I think the "5 axis" model of diagnosis in the DSM system deserves some affirmation; many times, however, we only pay attention to Axis I (diagnoses such as depression or schizophrenia, etc.) or Axis II (personality disorder).  I think that studies such as this one highlight the necessity to look closely at Axes III (medical illnesses) and IV (social, community, financial, and relational problems).  It is likely that issues on these latter two axes can prevent any resolution of problems on the first two.


outlierpsychmd said...

psychopharmacologist Victoria,BC: another useless study cf.psychotherapy to inadequate dosages of Sertraline below 300-400mg daily and Venlafaxine below 450 mg daily. Also completely irrelevant in that adequate Rx of biological/genetic depressive spectrum disorders often requires robust sequential trials of antidepressants inclu MAOI's and TCA's if necessary, and of course one always needs to consider the possibility of undiagnosed Bipolar spectrum illnesses.Cheers

GK said...

Just because a study does not agree with one's viewpoint, it does not make it "irrelevant" or "useless."

This is a negative study, different from many positive studies using similar doses and treatment regimens.

It is interesting, though, to look at very-high dose regimens of antidepressants, even off-label dose regimes. I will be interested to review people's experiences with that strategy. I've posted elsewhere on this blog about some authors describing very high-dose moclobemide being much more helpful than ordinary doses (perhaps many of us neglect drugs such as moclobemide because we believe they don't work, but maybe the dose just wasn't adequate).

Similarly, I believe it is interesting to look at "very high-dose" psychotherapies, since I think many people fruitlessly dabble in psychological therapies, in the same manner that one would take a language course at a community centre once per week, without putting in the hundreds of hours of intensive practice required to actually learn the language fluently.

outlierpsychmd said...

My apologies for using such negative and disrespectful adjectives in challenging the validity of this study.

After 30 years in psychiatric practice and having had the privilege of seeing >8000 mainly mood disordered patients and their families, I do not consider Sertraline 300-400mg daily nor Venlafaxine 450mg daily high dosages, but rather essential to symptom remission and maintenance for many patients.

In my experience, Moclobemide is indeed a weak antidepressant, whereas the sadly underprescribed Tranylcypromine (Parnate)20-80mg daily is a terrific drug for depressed patients, particularly those with a significant anxiety component or symptoms of eating disorder (bulimia and obesity).

I also would be intrigued to hear from other psychiatrists about their experiences with antidepressant dosages.

Anonymous said...

Dear Dr. Kroeker, I'e been trying to contact you for a while now. Reason being I wanted to try Moclobemide at higher dosages (1200 mg or more) but that is just not being done in my country (Belgium in Europe).

I know my psychiatrist won't let me try this unless someone with authority says it's ok and it's been done before. Could you give me a short reply (aimed at my psychiatrist) convincing her to at least give it a try? I have nothing to lose and everything to win.

Thank you very much in advance!

GK said...

The best I could suggest is to obtain a full copy of the article by Magder et al. that I have referred to in my moclobemide posting (here' a quote from my posting:)
There was one case series study published in 2000 by Magder, Aleksic, and SH Kennedy, describing the successful use of very high-dose moclobemide in combination with lithium and/or trazodone for treatment-resistant depressed patients. The doses used were up to 1500-1650 mg/day, which is much higher than the usual maximum of 600 mg. They advocated using an MAOI diet at these doses. Moclobemide was well-tolerated, and the patients appeared to benefit over 1-2 years of follow-up. It's worth looking at this brief article in its entirety, here's a link to the abstract:

This is probably the most authoritative account of using high-dose moclobemide. Hope that helps...