Serotonin and Depression

In 1965, Joseph Schildkraut put forth the hypothesis that depression was associated with low levels of norepinephrine [6], and later researchers theorized that serotonin was the neurotransmitter of interest [7]. In subsequent years, there were numerous attempts to identify reproducible neurochemical alterations in the nervous systems of patients diagnosed with depression. For instance, researchers compared levels of serotonin metabolites in the cerebrospinal fluid of clinically depressed suicidal patients to controls, but the primary literature is mixed and plagued with methodological difficulties such as very small sample sizes and uncontrolled confounding variables. In a recent review of these studies, the chairman of the German Medical Board and colleagues stated, “Reported associations of subgroups of suicidal behavior (e.g. violent suicide attempts) with low CSF–5HIAA [serotonin] concentrations are likely to represent somewhat premature translations of findings from studies that have flaws in methodology” [8]. Attempts were also made to induce depression by depleting serotonin levels, but these experiments reaped no consistent results [9]. Likewise, researchers found that huge increases in brain serotonin, arrived at by administering high-dose L-tryptophan, were ineffective at relieving depression [10].
Contemporary neuroscience research has failed to confirm any serotonergic lesion in any mental disorder, and has in fact provided significant counterevidence to the explanation of a simple neurotransmitter deficiency. Modern neuroscience has instead shown that the brain is vastly complex and poorly understood [11]. While neuroscience is a rapidly advancing field, to propose that researchers can objectively identify a “chemical imbalance” at the molecular level is not compatible with the extant science. In fact, there is no scientifically established ideal “chemical balance” of serotonin, let alone an identifiable pathological imbalance. To equate the impressive recent achievements of neuroscience with support for the serotonin hypothesis is a mistake.

With direct proof of serotonin deficiency in any mental disorder lacking, the claimed efficacy of SSRIs is often cited as indirect support for the serotonin hypothesis. Yet, this ex juvantibus line of reasoning (i.e., reasoning “backwards” to make assumptions about disease causation based on the response of the disease to a treatment) is logically problematic—the fact that aspirin cures headaches does not prove that headaches are due to low levels of aspirin in the brain. Serotonin researchers from the US National Institute of Mental Health Laboratory of Clinical Science clearly state, “[T]he demonstrated efficacy of selective serotonin reuptake inhibitors…cannot be used as primary evidence for serotonergic dysfunction in the pathophysiology of these disorders” [12].
Reasoning backwards, from SSRI efficacy to presumed serotonin deficiency, is thus highly contested. The validity of this reasoning becomes even more unlikely when one considers recent studies that even call into question the very efficacy of the SSRIs. Irving Kirsch and colleagues, using the Freedom of Information Act, gained access to all clinical trials of antidepressants submitted to the Food and Drug Administration (FDA) by the pharmaceutical companies for medication approval. When the published and unpublished trials were pooled, the placebo duplicated about 80% of the antidepressant response [13]; 57% of these pharmaceutical company–funded trials failed to show a statistically significant difference between antidepressant and inert placebo [14]. A recent Cochrane review suggests that these results are inflated as compared to trials that use an active placebo [15]. This modest efficacy and extremely high rate of placebo response are not seen in the treatment of well-studied imbalances such as insulin deficiency, and casts doubt on the serotonin hypothesis.

Also problematic for the serotonin hypothesis is the growing body of research comparing SSRIs to interventions that do not target serotonin specifically. For instance, a Cochrane systematic review found no major difference in efficacy between SSRIs and tricyclic antidepressants [16]. In addition, in randomized controlled trials, buproprion [17] and reboxetine [18] were just as effective as the SSRIs in the treatment of depression, yet neither affects serotonin to any significant degree. St. John's Wort [19] and placebo [20] have outperformed SSRIs in recent randomized controlled trials. Exercise was found to be as effective as the SSRI sertraline in a randomized controlled trial [21]. The research and development activities of pharmaceutical companies also illustrate a diminishing role for serotonergic intervention—Eli Lilly, the company that produced fluoxetine (Prozac), recently released duloxetine, an antidepressant designed to impact norepinephrine as well as serotonin. The evidence presented above thus seems incompatible with a specific serotonergic lesion in depression.

Although SSRIs are considered “antidepressants,” they are FDA-approved treatments for eight separate psychiatric diagnoses, ranging from social anxiety disorder to obsessive-compulsive disorder to premenstrual dysphoric disorder. Some consumer advertisements (such as the Zoloft and Paxil Web sites) promote the serotonin hypothesis, not just for depression, but also for some of these other diagnostic categories [22,23]. Thus, for the serotonin hypothesis to be correct as currently presented, serotonin regulation would need to be the cause (and remedy) of each of these disorders [24]. This is improbable, and no one has yet proposed a cogent theory explaining how a singular putative neurochemical abnormality could result in so many wildly differing behavioral manifestations.

In short, there exists no rigorous corroboration of the serotonin theory, and a significant body of contradictory evidence. Far from being a radical line of thought, doubts about the serotonin hypothesis are well acknowledged by many researchers, including frank statements from prominent psychiatrists, some of whom are even enthusiastic proponents of SSRI medications (see Table 1).

However, in addition to what these authors say about serotonin, it is also important to look at what is not said in the scientific literature. To our knowledge, there is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder, while there are many articles that present counterevidence. Furthermore, the Diagnostic and Statistical Manual of Mental Disorders (DSM), which is published by the American Psychiatric Association and contains the definitions of all psychiatric diagnoses, does not list serotonin as a cause of any mental disorder. The American Psychiatric Press Textbook of Clinical Psychiatry addresses serotonin deficiency as an unconfirmed hypothesis, stating, “Additional experience has not confirmed the monoamine depletion hypothesis” [25].