Back when I was growing up in the early 1960s, there was a popular song out by Bobby Vee, called “Devil or Angel”. I believe it contained lyrics along the lines of, “Dear, whichever you are, I need you.” The title of the song might also be a good summation of the way psychotropic drugs are portrayed in the popular press and other media. And, sad to say, even some of my colleagues in the mental health profession fall into one of two armed camps, when it comes to the role of medications for mood and behavior. This dichotomy parallels the schism described in Tanya Luhrmann’s influential study of psychiatry, aptly entitled, Of Two Minds. Very roughly, Luhrmann argued that the field of psychiatry is still divided between those who see mental illness as a psychological problem amenable to psychosocial therapies; and those who see it as a problem of abnormal brain chemistry, best treated by pharmacotherapy. Despite many attempts to bridge this conceptual chasm — Dr. George Engel’s “biopsychosocial model” is one example — the schism persists to this day.

And this is truly a shame. The “Angel or Devil” dichotomy does nobody any favors, and certainly does not help patients with serious emotional disturbances. In truth, the human brain is the crucible in which all the elements of our experience and sensation are transformed into thought, feeling, and action. We can affect the function and structure of the brain directly, by altering its chemical constituents; or we can affect its function and structure indirectly, by pouring helpful words into the ear of the patient. Speech, music, poetry, art, and a myriad of other “inputs” are all transduced into neuronal connections and electrochemical processes in the brain.

This does not mean that we ought to greet our patients by asking, “How are your serotonin molecules this morning, Mrs. Jones?” Part of our shared behavior as human beings is the use of language that speaks to our felt experience, not our neurons. But this does not mean that our experience is ultimately something over and above the workings of our brains. Moreover, far from being “cosmetic” in nature, many psychotropic medications work at the most fundamental level of the gene, actually increasing the production of nerve growth factors.

These are all reasons why we should not dismiss psychotropic medications out of hand. They are neither agents of the devil, as some extremist factions argue; nor are they angels of redemption, as one might conclude from the “rainbow and butterfly” ads put out by some pharmaceutical companies. Psychotropic medications, as I tell my patients, are neither a crutch nor a magic wand; they are a bridge between feeling bad and feeling better. The patient must still walk — sometimes painfully — across that bridge. This means doing the hard work of changing thoughts, feelings, and behaviors. Medications can often aid that process, and are sometimes needed to get the patient’s work in therapy moving. For example, some patients with very severe depression are so lethargic and cognitively impaired that they can’t fully engage in psychotherapy. After three or four weeks of antidepressant treatment, many of them are able to benefit from “talk therapy”, which then may provide long-term protection against depressive relapse. Some evidence suggests that initial antidepressant treatment can help “set up” the patient for subsequent long-term psychotherapy. As a recent review by Dr. Timothy J. Petersen [1] concluded,

“…sequential use of psychotherapy after induction of remission with acute antidepressant drug therapy may confer a better long-term prognosis in terms of preventing relapse or recurrence and, for some patients, may be a viable alternative to maintenance medication therapy.”

Other evidence indicates that talk therapy and medication work synergistically — one reinforcing the other. Medications may help more with “somatic” aspects of depression, such as impaired sleep and appetite; psychotherapy, more with cognitive aspects, such as guilt or hopelessness. Evidence from brain imaging studies suggest that each intervention may work through overlapping but somewhat different mechanisms: antidepressant medication seems to work “from the bottom up”, arousing lower brain centers associated with emotion. Psychotherapy appears to work from “the top down” by changing neural patterns in higher brain centers, such as the prefrontal cortex.

Given the huge literature on psychotropic medications, I am focusing on antidepressants in this essay — a diverse group of agents that has been the focus of tremendous controversy. In recent years, for example, questions have been raised regarding both the efficacy and safety of antidepressants. There is a voluminous literature on these topics, but here is my best professional synopsis. Antidepressants seem to “show their stuff” more robustly in cases of severe depression, but this may be partly an artifact of how most studies are designed and analyzed. For example, the most recent review from Kirsch and colleagues [2] suggests that in mild-to-moderate depression, antidepressants do not work better than a sugar pill (placebo). In very severe depression, Kirsch et al found, the newer antidepressants outperform placebo, though their benefits are not as robust as in earlier studies (1960s-70s) of the “old” tricyclic antidepressants.

However, we need to put these recent findings in perspective. Numerous posts on the internet have declared, based on the Kirsch et al study, that “Antidepressants Don’t Work!” But this is not what the study showed. Rather, it lumped together results from 47 antidepressant trials and found that the active drug showed a clinically significant “separation” from placebo only in the most severe cases of depression. This is actually much better than finding that antidepressants work only for very mild depression! That said, the Kirsch study attributed the apparent benefit of antidepressants in the most severely ill patients to reduced responsiveness to placebo rather than to increased effectiveness of the drug.

There are a number of problems with the Kirsch study, many of which are nicely discussed in Dr. Grohol’s recent blog (2/26/08) on this website. For one thing, the entire Kirsch study turns on whether a 2-point improvement in a single depression rating scale (the Hamilton Rating Scale for Depression, or HAM-D) amounts to a “clinically significant” (not just statistically significant) change. That is, of course, a matter of judgment. Second, the Kirsch study looked only at antidepressant trials in the FDA data base done prior to 1999; an analysis of more recent trials might have produced different results. Third, the kind of “number crunching” that goes on in any meta-analysis (basically, a study of studies) can obscure not only individual differences, but also subgroup differences. That is, a given patient with certain depressive symptoms—or a subgroup with certain features—may do quite well on an antidepressant, but the results are “submerged” in the overall mediocre success rate in the study as a whole.

There are many other reasons why studies of antidepressants may be yielding less than spectacular results in more recent decades, and the interested reader can find details in an editorial by Kobak and colleagues, in the February 2007 Journal of Clinical Psychopharmacology. These authors point out, among other things, that if the interviews producing HAM-D depression scores are not performed skillfully, the results of the study may be distorted. Kobak and colleagues pointed to several instances in which poor interviewing technique led to outcomes showing little difference between the antidepressant and placebo; conversely, good interviewing technique led to a more robust improvement rate (“effect size”) for the antidepressant. It is not clear how many such “junk interview” studies were included in the Kirsch et al meta-analysis.