Monday, April 16, 2012


Part I: On the Efficacy of Psychotherapy & Psychopharmaceuticals for Depression

In Manufacturing Depression: The Secret History of a Modern Disease (Simon & Schuster, 2010) author Gary Greenberg cites studies from 1975 and 1980 and a 1995 Consumer Reports reader survey in support of the 1936 finding that "all forms of [psycho]therapy, competently practiced, were equally effective" (pp. 299-300). Greenberg summarizes:
The conclusion is inescapable: to the extent that therapy succeeds, it's not due to the particular help that's offered, but rather to the fact that something is offered in the first place, and by a person whom the patient expects, and believes, will help. Therapy, no less than drugs, works by the placebo effect.

This shouldn't be a surprise. To the extent that it is understood, the placebo effect seems to be the result of a patient's entering into a caring relationship with a healer, which is a much more explicit feature of psychotherapy than of general medicine. Nor should this be bad news. It just means that when therapists listen with empathy, when we offer support and understanding, when we help people to pick up their pieces and fashion a story out of them, to make as much sense of their lives as they can and to withstand the uncertainty of whatever is left over, when we provide a space in which they are free to be just as confused and demoralized and ambivalent as they really are—that when we do all that, and when we do it well, it really does help. It would no doubt be better to have a world in which we therapists weren't necessary, where narrative coherence wasn't so hard to come by and people weren't driven into private rooms to plumb the depths of their fears and their hopelessness, but that's not this world, so having those rooms, and the professionals who occupy them, is the next best thing. [pp. 300-301]
Regarding cognitive behavioral therapy in particular, Greenberg writes:
Other studies ... strengthen the finding that to the extent that cognitive therapy works for depression, it is not because its specific ingredients act on specific pathologies. Instead, according to the meta-analysts, cognitive therapy's success depends largely on the therapeutic alliance, therapist empathy, the allegiance of the therapist to his technique, and the expectations of the patient ... How therapy is conducted is more important ," as one researcher put it, "than what therapy is conducted." [p. 309]
Elsewhere Greenberg quotes a telling admission from the American Psychiatric Association's document, A Research Agenda for the DSM-V:
The major problem for mental disorders as currently defined is that their causes and pathophysiological mechanisms remain largely unknown. It is expected that, at some point in the future (perhaps decades from now), the pathophysiological states predisposing or contributing to major mental disorders will be identified ... once it is possible to define a mental disorder based on the identification of its underlying pathology, then it would surely make sense to follow the course of other medical conditions and have the presence of disorder be based solely on pathology and not on the effect this pathology exerts on the individual's functioning.
One take-home lesson from this is that by 2002 the psychiatric profession knew that the chemical imbalance theory of depression is speculative, not established fact.

Regarding the efficacy of psychopharmaceuticals, here's a quote from "Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy" by Turner et al., a study Greenberg cites in his discussion of antidepressants:
Among 74 FDA-registered studies, 31%, accounting for 3449 study participants, were not published. Whether and how the studies were published were associated with the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive.
In the paper's discussion section the authors write:
We found a bias toward the publication of positive results. Not only were positive results more likely to be published, but studies that were not positive, in our opinion, were often published in a way that conveyed a positive outcome. We analyzed these data in terms of the proportion of positive studies and in terms of the effect size associated with drug treatment. Using both approaches, we found that the efficacy of this drug class is less than would be gleaned from an examination of the published literature alone. According to the published literature, the results of nearly all of the trials of antidepressants were positive. In contrast, FDA analysis of the trial data showed that roughly half of the trials had positive results.
To distill this: Drug companies suppress the results of clinical trials which show the drug they're trying to get approved for consumers is ineffective. So, if they don't dump the drug, they keep trying until they get a positive result they want to publish.

Greenberg also cites a 2002 article by Kirsch et al, "The Emperor's New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration". The authors studied clinical trials data for six popular antidepressants: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), venlafaxine (Effexor), nefazodone (Serzone), and citalopram (Celexa). Here are the final two paragraphs of their article:
To summarize, the data submitted to the FDA reveal a small but significant difference between antidepressant drug and inert placebo. This difference may be a true pharmacological effect, or it may be an artifact associated with the breaking of blind by clinical trial patients and the psychiatrists who are rating the severity of their conditions. Further research is needed to determine which of these is the case.

In any case, the difference is relatively small (about 2 points on the HAM-D), and its clinical significance is dubious. Research is therefore needed to assess the additivity of antidepressant drug and placebo effects. If there is a powerful antidepressant effect, then it is being masked by a nonadditive placebo effect, in which case current clinical trial methodology may be inappropriate for evaluating these medications, and alternate methodology need to be developed. Conversely, if the drug effect is as small as it appears when drug/placebo differences are estimated, then there may be little justification for the clinical use of these medications. The problem, then, would be to find an alternative, as the clinical response to both drug and placebo is substantial. Placebo treatment has the advantage of eliciting fewer side effects. However, the deception that is inherent in clinical administration of placebos inhibits their use. Thus, the development of nondeceptive methods of eliciting the placebo effect would be of great importance.
In layperson's terms: We can't really tell from the clinical data if the billions of dollars worth of antidepressants prescribed to Americans every year are really helping them or not. The lead author, Irving Kirsch, published a book on the subject in 2010, along with a summary of sorts in The Huffington Post.

Kirsch was the lead author in a 2008 article, "Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration," also cited by Greenberg. The authors found:
Using complete datasets (including unpublished data) and a substantially larger dataset of this type than has been previously reported, we find that the overall effect of new-generation antidepressant medications is below recommended criteria for clinical significance. We also find that efficacy reaches clinical significance only in trials involving the most extremely depressed patients, and that this pattern is due to a decrease in the response to placebo rather than an increase in the response to medication.

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