In this concise and persuasive book, Kirsch debunks what he calls the myth of antidepressants and the brain chemistry imbalance theory of depression. Kirsch is a clinical psychologist, lecturer in medicine at Harvard Medical School and professor of psychology at Plymouth University in the UK, and an expert on placebo effects. The latter fact is the most relevant as placebo, Kirsch argues, is what antidepressants essentially are.

With a thesis sure to cause suicidal ideation among the $19 billion dollar antidepressant industry, the most important thing of course is what the data tells us. Performing a meta-analysis of published research findings on SSRIs and SNRIs, Kirsch and colleagues found that antidepressants worked only very slightly better for treating depression than placebos did. Using a Freedom of Information Act request to obtain a variety of unpublished studies performed by pharmaceutical companies, Kirsch followed up with analysis of an even larger set of studies. The same results held, antidepressants worked only very slightly better than placebos, and this difference was not clinically significant. In other words, once side effects are taken into account, you’d probably be better off taking sugar pills than Prozac.

Kirsch takes us carefully through this analysis, discussing the results of a host of studies as well as research design and limitations. The data is clear. The placebo effect is the major explanation for any improvement experienced by patients taking antidepressants. This can be demonstrated by a variety of studies showing only minimal improvement from taking active antidepressants over placebos. In addition, taking any other drugs with notable side effects—benzodiazepines, opiates, stimulants, etc.—also provided more improvement to the patients than placebos. In other words, almost any substance that the user knows is active because of the presence of side effects is more or less equivalent to antidepressants. This finding itself illustrates what is called the active placebo effect: if patients believe that a drug is going to help them and can tell by the side effects that what they are taking is not an inactive placebo, it often will help them, regardless of what it actually is.

Kirsch introduces the topic in a short preface and takes us through the data and results in chapters 1 and 2. In chapter 3 he responds to various critiques of his work. In chapter 4 he delves into a topic that might be of great interest to Erowid readers: the chemical imbalance theory of depression. This theory posits that depression is caused by a lack of serotonin, norepinephrine, dopamine or some combination of these in brain synapses. The evidence for this theory, as Kirsch discusses, is shoddy beyond belief, relying on weak and contradictory findings from a number of early studies of psychopharmacological agents. Drugs that were supposed to induce depression by lowering levels of serotonin paradoxically decreased depressions, but the studies demonstrating this were ignored. Additionally, meta-analysis of studies that experimentally lowered monoamine neurotransmitter levels showed no discernable effects on mood. (Drugs that inhibit serotonin reuptake, and other drugs that inhibit the monoamine oxidase enzymes that break down monoamine neurotransmitters such as serotonin and dopamine are two classes of pharmaceuticals that have been prescribed to treat depression.)

This leads to an intriguing question for illegal drug users. If the chemical imbalance theory of depression is an illusion, what does that say about the temporary depression sometimes experienced by users after stimulant or MDMA use: the “Tuesday blues” (aka “suicide Tuesday”) syndrome? The assumption has been that serotonin depletion following MDMA use leads to these episodes of depression; but have users just heard about this assumption, and is their perceived depression merely a self-fulfilling prophecy or nocebo (negative placebo) effect?¹

Kirsch continues with a detailed explanation of placebo effects in chapters 5 and 6, tracing the history of the concept and its use. There is a lot of astounding material in these chapters, such as the fact that “placebo surgeries” for some conditions work as well as real surgeries. The gist is that placebo works mainly on expectations—if you expect that something you are doing, like taking a pill, is going to make you better, you get better.

Kirsch finishes by discussing alternatives to antidepressants in chapter 7, concluding that psychotherapy (particularly cognitive-behavioral therapy) and/or exercise work better for depression than any pharmaceutical or herbal products, they are cheaper, and obviously they have fewer negative side effects. One can imagine the makers of Paxil or Effexor being depressed after seeing the evidence for this; however, they should go jogging instead of sampling their own wares.

Overall this is a fascinating and challenging book. It boldly asserts the placebo principle as being far more important than most people would ever suspect, and it proves that most antidepressants are basically worthless for treating depression beyond the benefits one would get from consuming placebo. This is a book that should be read by anyone considering using antidepressants or prescribing them to others.

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1) Psychological explanations for the Tuesday blues have also been proposed, with one idea being that MDMA might make a user feel so good that, by comparison, the “life they come back to” when they aren’t on drugs seems pale in comparison. Additionally, MDMA users often keep different hours and may not get enough sleep during their weekend use, which could contribute to depressive effects early the next week.