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Is Clinical Depression Caused by a Serotonin Imbalance?

Posted Jan 14 2009 8:13pm

Is Clinical Depression Caused by a Serotonin Imbalance? A Response to Peter Kramer


Jonathan Leo, Ph.D.
Jeffrey Lacasse, Ph.D.


The claim that depression is caused by an imbalance of serotonin is often made in the mainstream media. In a recent paper in Society we report on our efforts to examine the supporting evidence used by journalists who make such claims. We corresponded with a pharmaceutical company, several psychiatrists, and the National Institute of Mental Health. For the most part we received few citations of scientific papers, and those that were cited did not provide evidence for a causal connection between serotonin and depression. In our experience, there are few scientists familiar with the data that will publicly defend the serotonin theory of depression.

We also believe that debate between researchers holding conflicting viewpoints is an essential part of scientific progress. We were therefore pleased to see that Peter Kramer, author of Listening to Prozac, recently posted a defense of the theory on his blog. Dr. Kramer had previously made public comments responding to critiques of the serotonin theory in 2006, stating, “ While it’s true that one could say that these drug companies are using a very oversimplified metaphor - and a metaphor for something that may not even exist at all - it’s also wrong to suggest that it has no relationship to contemporary theories of mood regulation.

Since we agreed with this statement, we were intrigued by Dr. Kramer’s recent defense of the serotonin theory. In his blog posting, Dr. Kramer cites evidence to support the serotonin theory, much of it from a recent review article in the New England Journal of Medicine. All of the studies Kramer discusses are interesting research projects, but for us, the important question is: Do these studies provide enough scientific evidence to support the ubiquitous statements in the media about depression?  As just a few examples:  “Mental illness are simply chemical imbalances,” or “Depression is thought to be caused by a chemical imbalance in the brain.” Below, we analyze the evidence presented.


Alteration in 5-HT1B Receptor Function by p11 in Depression-Like States (2006) Science,311: p77. In reference to this paper, Kramer states: “Other studies have found that serotonin receptors function less efficiently in depressed patients. A protein named p11 is implicated: depressed patients have less of it in the brain.”  The paper in question is a four page paper that examines the interaction of the serotonin 1B receptor with p11 in rodents. Out of the four pages, the authors devote one sentence to p11 in humans. In what can only be called a preliminary report, as very few details are supplied, the authors report that p11 mRNA is decreased in the anterior cingulate cortex in patients who suffered from depression (p.79). The study used fifteen patients and fifteen controls. Seven of the patients committed suicide. Patients who commit suicide are very likely not a fair representation of the average patient diagnosed with depression, but this problem aside, the authors do not mention whether the patients had a history of medication exposure - an obvious question.

An e-mail inquiry and subsequent reply from E. Fuller Torrey, the head of the Stanley Foundation, which supplied the brains for the study, confirmed that the majority of the patients had been prescribed medication - whether they filled these prescriptions and/or took the medications is unknown. Dr. Torrey did mention that one possibility is that the patients who committed suicide stopped taking their medication, implying that the lack of medication was a contributing factor to their suicide. Thus the lower level of p11 in the depressed patients could be due to long-term antidepressant use, to the withdrawal effect, or to a combination of both. Therefore, a major piece of evidence that Kramer uses to defend the serotonin theory is a comparison of 15 patients with a history of medication use, which was only one minor component of a larger study.  We do not think that our concern with prior medication use is excessive. In the words of Ross Baldessarini, professor of psychiatry,  “Almost any psychotropic drug that’s given for more than a few weeks leads to changes in brain function such that when you stop, the brain has to reset its thermostat.”

Major Depressive Disorder, New England Journal of Medicine (NEJM), 358:55. In this review article, the authors discuss numerous avenues of research into depression. While the authors discuss serotonin they do not supply any direct evidence for the idea that low serotonin is the cause of depression. For instance, they discuss tryptophan depletion studies. Tryptophan is a rate limiting enzyme involved in serotonin production in the brain. It was originally hypothesized that tryptophan depletion would lead to low serotonin, which in turn would lead to a lowering of mood. Yet, as the authors point out, in healthy subjects this has not been the case.

The authors also discuss an oft-cited study by Caspi et al. which investigated common polymorphisms of the promoter for the serotonin transporter gene.  Yet, the NEJM’s piece also includes the oft-made characterization about the study, which leaves out some important details. According to the NEJM, “Caspi et al. found that 5-HTTTLPR predicted depression only in association with defined life stresses” (p. 56).  However, this needs to be qualified by pointing out two important points: 1) Just the presence of the short form of the gene did not predict depression - after all following major life stressors only 35% of the short form carriers developed depression (If 65% of the carriers do not develop depression, it seems hard to characterize it as predictive). One needs to qualify the statement in the NEJM by saying that carriers of the short form were more likely than carriers of the long form to develop depression after major life stressors (It is the comparison that is important). Yet, besides pointing out that it is the difference between long and short form that is important, even more qualifications are warranted. 2) In addition, “defined life stressors” must be qualified; the carriers of the short form were at a disadvantage only if they were exposed to three or more major life stressors.  For those people who only suffered one or two life stressors, the findings were reversed and the patients with the short form actually were less likely to be depressed - in this case the short form was protective (See Figure 3, p. 389 of the Caspi study). A subsequent study by Shelley Taylor and her colleagues at UCLA found that people with two copies of the gene’s short form were actually less likely to have depression symptoms if they had positive childhood experiences.

Also of note with the Caspi study is that the marker in question is not a rare mutation found in only a small percentage of the population. Approximately 70% of the population carries this “susceptibility” gene. One possible conclusion is that they have not discovered something unique about the subset of people diagnosed with depression, but have discovered something about human nature in general. Of course there are mechanisms in the makeup of the human brain that respond to environmental stressors. But finding these mechanisms does not mean that we have found a marker for a disease. If 70% of us have a gene that plays a role in our response to stress should this be considered “normal” or “pathological?” Complicating interpretation of this data, while some studies have found similar results to Caspi, other groups have not (Gillespie, 2005).

Kramer also touches on the efficacy of the SSRIs when he says, “The NEJM notes that a third of depressed patients do not respond to antidepressants. In those who do respond, what the authors call ‘the monoamine-deficiency hypothesis extended’ remains the most powerful explanation of the drugs’ mechanism of action.” Leaving efficacy aside, it is important to point out that showing how a drug acts at the molecular level does not necessarily equate to understanding the etiology of a condition - in this case determining that a drug acts on the serotonin receptor or serotonin system does not prove that depression is caused by low serotonin. If we followed the simple logic that “mechanism equals disease” then we could assume that every drug with a behavioral effect on the nervous system does so because of a chemical imbalance - something which is certainly not true. In many cases a drug will relieve a symptom but not treat the root cause of the problem. Take a long distance runner with a pulled muscle. Pain medication will relieve the pain - a symptom - but we do not attribute the cause of the pulled muscle to a chemical imbalance. Many drugs - both legal and illegal - act on the monoamine system: SSRIs, amphetamines, methylphenidate [Ritalin], mushrooms, coffee, cocaine, etc.

The authors of the NEJM piece state: “A strong point of the monoamine theory is its predictive power. Almost every compound that has been synthesized or discovered for the purpose of inhibiting norepinephrine or serotonin reuptake has been proved to be a clinically effective antidepressant.” We would go one step further and point out that based on the predictive power of the monoamine theory, even though the legal and illegal drugs have similar pharmacological properties, the chemical imbalance theory will only be applied to the use of drugs sold by a pharmaceutical company. Take the performance enhancing effects of amphetamines. If they are sold by a pharmaceutical company to improve classroom performance in a child this is considered acceptable, but selling amphetamines to a baseball player seeking to increase his batting average, can get you five to ten - and the player can wind up unemployed. The justification for the difference between the two scenarios? One case involves treatment for a supposed chemical imbalance, and one case involves a cheater. The demarcation between the two scenarios is not based on the pharmacological profile of amphetamines but on marketing and societal mores.

Elevated Monoamine Oxidase A Levels in the Brain: An Explanation for the Monoamine Imbalance of Major Depression, Archives of General Psychiatry, 63, 1209-1216. This is one of the more interesting papers on this topic. MAO-A is an enzyme that breaks down the neurotransmitters serotonin, norepinephrine, and dopamine. The authors’ hypothesis is that MAO-A levels are higher in the brain during untreated depression, which they believe could explain the monoamine theory of major depression. They used positron emission tomography (PET) scanning on 17 patients diagnosed with depression and 17 healthy patients, and measured their levels of MAO-DVs, an indicator of MAO-A. The group of depressed patients had higher mean (average) levels of MAO-A. Thus, one interpretation is that these higher levels of MAO-A enzymes cause major depression. After critically appraising this paper, we have several questions:

Does this paper establish that increased MAO-A is the cause of major depression? Or, alternatively, does it simply document an association? We wonder if higher mean MAO-A among a group of depressives might be a sign of depression, rather than the cause. Consider that many people get nervous before public speaking, and, frequently, their heart rate quickens and their blood pressure goes up. But most people would not say that high blood pressure is the biochemical explanation for public speaking anxiety. Similarly, how do we know that lower MAO-A in depressed individuals is not simply a sign of depression, rather than the cause? Certainly, further experiments are required before causal claims can be made regarding MAO-A in depression.

Have the results been replicated? The answer is no. This is a study of 17 depressives and 17 healthy patients in Canada. Time will tell if independent research teams are able to replicate this finding with other patients. Certainly, important findings should be replicated, repeatedly, by as many different research teams as possible. The history of science, and in particular psychiatric science, is full of exciting preliminary findings followed by failed replication attempt s.

Are the results specific to depression? Keep in mind that MAO does not just break down serotonin, but also norepinephrine and dopamine. These three neurotransmitters are implicated in almost every DSM-IV-defined mental disorder. In future experiments, rather than healthy volunteers, it would be interesting to see patients diagnosed with major depression compared to patients diagnosed with other non-affective mental disorders (e.g., ADHD). Until such experiments are performed, we think many will question whether these findings are specific to depression.

Below, we have created a figure with content similar to figure 2, p.1212, in their article. (We cannot reproduce the original figure due to copyright). This figure is most similar to the results presented for the midbrain, hippocampus, and putamen. The pattern holds true less so for the results from the posterior cingulated cortex and thalamus.

What do we make of the fact that there is overlap between healthy and depressed patients? Several healthy patients have higher levels of MAO-A than depressed patients, and some depressed patients have lower levels of MAO-A than healthy patients. For instance, in the figure above, if we consider that the healthy patients have “normal” levels of MAO-A, then eight out of the seventeen depressed patients would fall in the normal range, or conversely 7 of the healthy patients would fall in the same range as the depressed patients. In other words, while there might be differences in group means, this does not mean that individual patients can be identified on the basis of their MAO-A levels. This is quite different than the diagnosis of diabetes, a medical condition to which clinical depression is often compared, in which lab tests are used to accurately diagnose patients.

Are the author’s conclusions congruent with the existing clinical trial data? Recent research has challenged the efficacy of SSRIs. For instance, a recent systematic review concluded, “ Among adults with moderate to severe major depression in the clinical trials we reviewed, paroxetine was not superior to placebo in terms of overall treatment effectiveness and acceptability ” (Barbui, Toshiaki, & Cirpiani, 2008, p. 296). We are confused as to how such findings line up with the proposal that serotonin imbalance causes depression. Michael Thase, an academic psychiatrist and pharmaceutical company-funded clinical trialist, has proposed that one or two out of ten patients prescribed an SSRI have a clinically significant response. Would proponents of the chemical imbalance theory interpret this to mean that 80-90% of patients prescribed SSRIs do not have a serotonin imbalance?

To top it all off, there are many debatable issues regarding statistical reporting, generalizability, and the other issues that face all such small neuroimaging studies.

Thus, while the Meyer study is an interesting piece of research, and is an important contribution to the field (and we certainly look forward to seeing future reports of MAO) we do question using it, as Kramer does, as primary evidence in support of the idea that depression is caused by low serotonin. In other words, the problem lies not with the ongoing laboratory research, but with prematurely drawing conclusions from these data.


We are pleased that Kramer has put in writing what he thinks is the best evidence for the serotonin theory, however, we are concerned that readers of his blog may mistakenly conclude that there is indeed powerful new evidence for the serotonin theory. As we have shown, an in-depth look at these studies finds the results to be tentative, at best. Hypotheses regarding serotonin and depression have been generated that need to be rigorously tested, as has been the case for forty years.

Overall, this discussion illustrates the difficulties of the scientific process and the perils of justificationary thinking. If a psychiatrist begins with the belief that serotonin deficiency causes depression and proceeds from there, there will always be studies to be cited. Unfortunately, much of this evidence collapses under critical scrutiny.

We would prefer a more rigorous scientific model. Important components would include replication, acceptance and integration of counter-evidence, active attempts to falsify the theory being tested, and a solid grasp of the methodological limitations involved with the research. Fortunately, we find that most scientists are quite aware of these limitations. In fact, when scientists discuss the biological basis of mood with other scientists, it is almost as if there are a set of ground rules that everyone agrees with, such as: (a) There are extremely subtle nuances to many of these studies; (b) it is important to refrain from drawing too many conclusions from the latest findings; (c) finding a biological difference between people diagnosed with depression and “normals” does not automatically warrant the jump to causation; and (d) environmental triggers play an extremely important role in why someone’s mood might be lowered. Yet, in the popular press all these qualifications disappear and instead the public is inundated with declarations that “mental disorders are caused by chemical imbalances.”

In a sense there are two entirely different discussions going on about the theory: In the media and the advertisements serotonin deficiency is presented as simple and straightforward, but in scientific circles it is treated as tenuous at best.  In scientific circles the debate seems to be not so much about the strength of the theory but about the appropriateness of using it with patients given the lack of clear data - one prominent academic psychiatrist states that the serotonin theory is a metaphor which he will not use with his own patients; another practicing psychiatrist states that that the evidence presented by Dr. Kramer “doesn’t mean much” in clinical practice but admits to telling patients they have a chemical imbalance all the same.

We continue to wonder if the scientific evidence justifies such behavior, let alone massive marketing campaigns which inform the general public that depression is the result of a serotonin imbalance. In the matter of informed consent, we question whether patients who are told they have a chemical imbalance really understand how little direct evidence there is for the theory.

We encourage reporters to dig deeper and to question whether the evidence in support of the theory justifies simplistic claims about the cause of depression, and to carefully consider the claims made by  psychiatrists and other experts about the serotonin theory. In his blog posting, Kramer argues that the miserably depressed Zoloft Ovoid creature is smarter than the critics have made him or her out to be. We agree with Kramer that the Ovoid is intelligent, however, given its ability to convince the media that there is substantial evidence in support of the serotonin theory, it appears that the Ovoid’s talents seem to lie in the marketing, and not the scientific, realm.

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