Psychopharmacology: a dogma crumbles

Roughly a decade before I was born, Albert Hofmann, a Swiss chemist working with ergot alkaloids, a class of compounds that seemed promising in Ob-Gyn medicine, first synthesized LSD. An accidental exposure to this compound suggested to him that the drug had remarkable psychoactive properties. A few days later he intentionally took what would be considered a heroic dose leading to a legendary moment in the history of psychedelics. Just a few years later, Hofmann would go on to isolate and synthesize Psilocybin from mushrooms long used in Mexican indigenous traditions.

By the 1950s and early 1960s, the scientific community, appreciating that such compounds could exert powerful effects on the human psyche; lent interest and momentum toward the advancement of biological approaches in psychiatry.

Just as Albert Hofmann participated in a kind of medical serendipity—discovering that his compound LSD, intended intended to be useful in women's health—physicians treating tuberculosis stumbled into a similar surprise. Patients receiving treatment with drugs such as Iproniazid were observed to show unexpected improvements in mood.

It was soon recognized that these drugs inhibited monoamine oxidase, an enzyme responsible for the breakdown of neurotransmitters such as serotonin, dopamine, and norepinephrine. From this observation emerged a new class of medications—the monoamine oxidase inhibitors—among the first of modern antidepressants; the era of psychopharmacology was in full swing.

Thirty years later, by the time my career in psychiatry was beginning, biological psychiatry was well entrenched and the psychological side of the profession was waning. A core feature of biological psychiatry over the decades has been the monoamine hypothesis—the idea that a group of chemically related neurotransmitters in the brain, including dopamine, serotonin, and norepinephrine, play a central role in the treatment of a wide range of conditions, from attention disorders to schizophrenia. The hypothesis has been supported by the observation that most psychiatric medications, in one way or another, affect these neurotransmitter.

Biological psychiatry has achieved important successes, including a reduction in the need for hospitalization for many severe conditions. It very much has encouraged a 'medical model,' wherein a tight relationship between diagnosis and pharmacological treatment is thought to exist.

Around the early 2000s, however, the dogma associated with the monoamine hypothesis began to loosen with the rise of increasingly sophisticated neuroimaging techniques, particularly functional MRI. For the first time researchers could observe brain activity while patients are awake and conscious revealing that distributed neural networks—rather than isolated neurotransmitter systems, form the substrate of human experience. Of particular interest has the identification of functional connectivity between a small, deep brain region, the subgenual anterior cingulate cortex (Brodmann area 25), and the broader cortex, the region associated with the highest levels of human cognition. Area 25 had been identified as a key node in the biology of severe depression after striking neurosurgical results were reported when this region was appropriately stimulated in treatment-resistant patients. The monoamine hypothesis has been further challenged by the introduction of new drugs, ketamine being a prime example, that are beneficial without directly impacting on the classic monoamine receptors: dopamine, serotonin, and norepinephrine.

This modern trend of beginning to focus on neural circuits rather than isolated neurotransmitters is exciting because it is inviting us to imagine an integration of mental health treatment approaches: psychotherapy, transcranial magnetic stimulation (TMS,) psychedelics, and even meditation. All have a role to play in modulating these circuits. Many of the networks are so commonly observed that they are being named. Beyond the 'default mode network,' a number of large-scale neural systems have been identified, including networks involved in salience detection, executive control, emotional processing, and attention. These networks are associated with disparate conditions including disorder of attention, psychosis, and of course, mood.

From the vantage point of my own life and long career, psychiatry now appears to be coming full circle. When the Swiss scientist Albert Hofmann elucidated the structure of psilocybin in the mid-20th century, the profound effects of chemicals on the mind energized the emerging field of psychopharmacology. In its zeal, psychiatry lost its focus in talking to patients. The decades of medicalization of psychiatry created a shift that brought real advances but also, at times, too narrow perspective on the human experience.

Now, in our current era, we find ourselves upon a new horizon, one that emphasizes neural circuits, the heart of lived experience. We, in psychiatry are challenged to embrace a broad spectrum of interventions, biological and psychological alike. Hopefully this will encourage an increased respect and collaboration between the disciplines.