By Robert Whitaker
August 13, 2022
Source: Mad in America
Photo / Image Source: Unsplash,
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The Other Half of the Chemical Imbalance Story
While researchers did not discover that people diagnosed with depression had abnormal serotonin systems before they took an antidepressant, they did discover that the compounds induced the very abnormality hypothesized to cause the disorder in the first place.
The basic mechanism of an SSRI is well known. When a presynaptic neuron releases serotonin into the tiny gap between neurons (known as the synapse), the serotonin molecules bind with receptors on the post-synaptic neuron, and then, in a flash, the serotonin is removed from the synapse. An enzyme metabolizes a small amount of the serotonin; the rest is quickly pumped back into the presynaptic neuron, entering via a channel known as SERT. In a 1975 paper, Eli Lilly scientists reported that fluoxetine, the compound that would be marketed as Prozac, blocked this reuptake process, causing a “pile-up of serotonin at the synapse.”
However, the presynaptic neuron has “autoreceptors” on its terminal membrane that monitor serotonin levels in the synapse, and with serotonin levels piling up, these autoreceptors begin to scream, as one scientist quipped, “turn off the serotonin machine.”
The presynaptic neurons begin to fire at a lower rate, while the postsynaptic neurons decrease the density of their receptors for serotonin.
In other words, the drug puts down the accelerator on serotonergic transmission, and the brain responds by putting on the brake.
Over time, other changes may kick in. There are feedback loops that connect different neurotransmitter systems to each other, and so this initial response to the drug is likely a prelude to a host of downstream changes that have yet to be identified. However, the initial response to fluoxetine was fleshed out early, and it told of how fluoxetine, rather than normalize serotonergic pathways, induced profound abnormalities in this system.
In 1996, NIMH director Steven Hyman published a paper titled “Initiation and Adaptation: A Paradigm for Understanding Psychotropic Drug Action” that told of how all psychiatric drugs could be understood to create abnormalities in brain function.
Psychiatric drugs, he wrote, create “create perturbations in neurotransmitter function.” In response to this perturbation, the brain goes through a series of compensatory adaptations, and in each instance, the immediate adaption is for the brain to oppose the effects of the drug. An antipsychotic blocks dopamine transmission, and in response the brain’s dopaminergic pathways spring into high gear, at least for a time. An antidepressant ups serotonergic levels in the synapse, and in response, the brain puts a brake on its serotonergic pathways. These compensatory adaptations, Hyman wrote, “are rooted in homeostatic mechanisms that exist, presumably, to permit cells to maintain their equilibrium in the face of alterations in the environment or changes in the internal mileu.”
Hyman was describing adaptive changes known as “oppositional tolerance” to a drug. After a period of time, he continued, the “chronic administration” of the drug causes “substantial and long-lasting alterations in neural function.” As part of this process, there are changes in intracellular signaling pathways and gene expression. After a few weeks, he concluded, the person’s brain is functioning in a manner that is “qualitatively as well as quantitatively different from the normal state.”
“Qualitatively as well as quantitatively different” than normal. Indeed, two Eli Lilly scientists, Ray Fuller and David Wong, early on observed that fluoxetine, since it disrupted serotonergic pathways, could be used to study “the role of serotonin neurons in various brain functions—behavior, sleep, regulation of pituitary hormone releases, pain responsiveness and so on.” To conduct such experiments, researchers could administer fluoxetine to animals to observe which functions became compromised. They would look for pathologies to appear.
Such was the state of scientific knowledge about antidepressants as a treatment for depression by the end of the 1990s. There was no evidence that depressed patients suffered
from low serotonin before they took an antidepressant, but research had shown that once they did, their brain would begin functioning in a manner that was “qualitatively as well as quantitatively different from the normal state.”
Antidepressants were promoted to the public as “normalizing agents,” when in fact researchers knew they were “abnormalizing” agents.
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