A Possible Paradigm Shift

Abstract

This month, guest editors Laura N. Antar, MD, PhD, and Eric Hollander, MD, and colleagues examine hypotheses about the relationship between inflammation and psychiatric illness. Their articles focus on a possible mechanism of psychiatric disorders that could constitute a major paradigm shift. As a psychiatry resident in the 1960s, I was taught that depression was caused by “anger turned inward,” rather than the humoral theories based on early Greek and Chinese medicine. About the same time, the effectiveness of antipsychotics was becoming realized with the use of chlorpromazine. This, taken together with the antidepressant effects of imipramine and iproniazid, led to the psychopharmacologic revolution and a marked increase in neurobiologic research. Following my residency, I was a fellow at the National Institute of Mental Health (NIMH), also in the mid-1960s, where I was focused on the norepinephrine depletion theory of depression. Also at that time, the NIMH was investigating the role of serotonin. We discovered changes in MHPG (a metabolite of norepinephrine) in patients with depression and our excitement grew. Had we established a biochemical basis for depression? My excitement was immense. The development of fluoxetine in the midto late-1980s shifted the attention to selective serotonin reuptake inhibitors (SSRIs). It was a new twist on the neurotransmitter theme, ultimately becoming the dominant truth. For a while, norepinephrine was nearly forgotten, as was dopamine, despite the fact that it is key in hedonic functions (one of the primary dysfunctions in depression). Maybe the avoidance of developing more potent dopaminergic medications was due to the fear of developing addictive substances. As the therapeutic limitations of the new-generation antidepressants that were more specific in their effect became evident, the field started to realize that the “dirtier” the drug (meaning it affected more neurotransmitters), the more effective it might be for treatment-resistant patients. (Tricyclic antidepressants and monoamine oxidase inhibitors are in this category.)