By Andrew A. Nierenberg, MD
Guest Columnist
Boston, MA, USA

Andrew A. Nierenberg, MD

In the past year, scandalous stories appeared in the press questioning the validity of research. Researchers could not reproduce key findings in psychology and basic science. What, then, to believe? How, then, can science move forward? These stories and their questions shake the very foundations of how we get to know what we know and how to go about discovering new things. But the most profound implication of these stories is in the public sphere: should we, as a country, continue to fund research if it's so questionable? In fact, Congress has decreased funding for research in the past decade, despite evidence that the return on these investments is substantial. If the public and their representatives don't value science, funding of science will continue to decrease and we are at risk of losing a generation of scientists along with the infrastructure that supports their work.

A parallel set of stories has emerged in books written for the public that claim antidepressants don't work, that the pharmaceutical-academic psychiatry complex is just a dishonest and corrupt enterprise that pushes dangerous drugs just to make a profit, and that, if anything, psychiatric drugs including antidepressants cause people to develop psychiatric disorders. These books accuse psychiatric clinical researchers of lying to people by using unproven theories of brain chemical imbalances that require medications to correct. A review of two of these books in the New York Review of Books by a former editor of the New England Journal of Medicine essentially accused psychiatry of just making up diagnoses (disease mongering) and that that psychiatric medications simply do not work. The review was an uncritical repeat of the reviewed books' main arguments.

Several of these books converge on the notion that depression is relatively trivial and all people need is exercise, natural treatments, or psychotherapy. And yet, even psychotherapy is not sacrosanct: a study reported in the press showed that the effect of psychotherapy for depression has been exaggerated. But the authors of these books ignore the real problem: people with depression suffer and kill themselves. Suicide is the second cause of death in young people. Over 40,000 people in US die by killing themselves and 60% of gun deaths are suicides. Depression is among the most prevalent and disabling disorders worldwide. In the context of these tragic outcomes of depression, why do the authors of these books have such antipathy against and outrage about antidepressants and psychiatry? I will not claim to know, but I will speculate that the heart of the war on antidepressants is that science is messy.

Lisa Feldman-Barrett published a stunning rebuttal to a story in the New York Times about the non-reproducibility of psychology findings. She wrote that this is the way it should be. Sometimes small deviations in protocols can affect the outcomes in unexpected ways. The scientist's job is to embrace the non-reproducibility and find the sources of inconsistencies. By examining the inconsistencies, we can learn. Science is a mess, not linear, and rarely predictable.

Back in 1939, Abraham Flexner, the great reformer of medical education, wrote a remarkable article in Harper's Magazine entitled, "The Usefulness of Useless Knowledge." He stated that most major advances in science were unpredictable and that society should support talented scientists asking good questions by following their curiosity. You never know what you will find and you never know exactly where it will lead.

Which leads me to think about a peculiar accusation against psychiatry in general, and antidepressants in particular. In the 1960's, a group of researchers postulated that brain chemistry was a possible cause of depression and that a so-called imbalance of brain chemistry needed to be corrected. Part of this theory arose from the mostly serendipitous clinical findings about the first antidepressants, monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. The MAOIs inhibit key enzymes that break down neurotransmitters, the chemicals that are released by one neuron and then travel across small spaces between the neurons (synapses) to stimulate receptors on other neurons. By preventing the breakdown of those neurotransmitters, the MAOIs increase the concentration of neurotransmitters in the synapse and in complex ways, that we still do not fully understand, treat depression. But exploring these mechanisms is not how the MAOIs were found. Instead, a tuberculosis drug just happened to have MAOI properties. When they were given to depressed tuberculosis patients, the patients started to dance on the wards after they got their medications. Thus, clinicians carefully observing patients led to the discovery of the antidepressant effects of MAOIs.

Similarly, the original tricyclic antidepressant, imipramine, was discovered clinically by Roland Kuhn in the 1950's when he was testing it as an antipsychotic – it did not work but he observed that it did seem to help people with schizophrenia who were depressed. He then tried imipramine in a group of depressed patients and reported: "The patients appear, in general, more animated; their voices, previously weak and depressed, now sound louder; they are more communicative, the lamentations and sobbing have disappeared. The depression, which had manifested itself through sadness, irritation and a sensation of dissatisfaction, now gave way to friendly, joyous and accessible feelings." Since then, the antidepressants have become among the most widely prescribed medications in medicine.

Based on the clinical findings with MAOIs and imipramine, researchers such as Schildkraut postulated a theory that these medications were correcting some sort of neurotransmitter imbalance, but were unable to find an unequivocal biochemical difference between depressed patients compared to healthy controls. But the theory did serve a purpose to provoke the field to seek the root biological causes or correlates of depression. Subsequent research found that people with depression have multiple dysregulations in the complex networks of interlocking neurotransmitters, receptors, gene expression, and neuronal connectivity. The initial theory of a chemical imbalance evolved into a more nuanced theory of stress, neurobiology, and information processing.

Rather than examine the complex growing evidence about the neurobiology of depression, and fueled by great passion and anger, some of the critics have accused psychiatrists of lying to patients by telling them that they have a chemical imbalance. And others have analyzed data to claim that antidepressants work no better than placebo and cause great harm by increasing suicide. If I were prone to find conspiracies, I would begin to think that these lay books look like a coordinated war on antidepressants. But perhaps the authors have simply mistaken the difficult and messy nature of science and clinical research as a larger pattern of conspiracy to do harm.

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Andrew A. Nierenberg, MD