When I joined in on National Public Radio last week, a caller asked about “chemical imbalance.” Was there a test of his neurotransmitters that could determine whether he had depression and might benefit from medication? I assume that the inquiry was innocent and sincere, but the “chemical imbalance” issue has also been used as a stick with which to beat medical psychiatry. Isn’t the “imbalance” image misleading? How can the field have ventured down so obviously mistaken a path? Is depression a disease after all, if no one can demonstrate consistent neurotransmitter differences in patients’ brains?

In a prior posting, I reviewed recent findings that support the biogenic amine theory of depression. Here, I want to ask, what would it mean if that line of inquiry reached a dead end. Because something like that may just have happened — in neurology.

Last fall, the journal Neurology featured an opinion piece by J. Eric Ahlskog titled “Beating a Dead Horse: Dopamine and Parkinson Disease.” The essay came to my attention via an editorial advancing similar views, by my neurologist colleague Joseph H. Friedman in last month’s issue of Medicine & Health/Rhode Island.

Readers familiar with Oliver Sacks's Awakenings will know that Parkinson Disease, or PD, is a movement disorder traditionally associated with a deficit of the neurotransmitter dopamine in a part of the brain called the substantia nigra. Ahlskog argues against the last part of this formulation. It’s time, he says, to give up on dopamine and the substantia nigra.

He lays out a series of arguments. Recent research has shown that early in the course of Parkinsonism, dopamine transmission can be normal, and although damage to brain cells is evident, the substantia nigra is spared. Sorts of harm once thought exclusive to PD have now been found in a variety of diseases. Many PD symptoms — like depression, PD can entail low mood, disturbed sleep, apathy, and anxiety — seem to involve other neurotransmitters, and even some of the movement disorders have nothing to do with dopamine transmission. Medications that ought to worsen PD through their effects on dopaminergic cells do not. Medications like Sinemet that ought to help PD through their effects on dopamine tend eventually to lose their efficacy. And so on. Ahlskog’s argument is that it is time for researchers to turn in other directions. Friedman adds that Lewy bodies, balls of condensed protein gumming up the brain, were once a requirement for diagnosing PD on autopsy; now it is clear that some forms of PD do not involve Lewy bodies.

Of course, there is no scandal here. No one is shocked to discover Sinemet “poop out.” No one suggests that, absent evidence of uniform, characteristic pathology in the brain, PD is not a disease. There is no scandal involving the failure or incompleteness of the neurotransmitter theory of PD. To the contrary, moving past dopamine is recognized as a step forward.

PD and depression are very different conditions. The efficacy of dopamine-enhancing medication remains greater in the middle stages of PD than that of serotonin- or norepinephrine-enhancing medications in mood disorder. Still the response, or lack of one, to the “dead horse” problem in neurology is instructive.

In psychiatry, the neurotransmitter story has gotten stronger, as it becomes apparent that genes and brain enzymes that regulate serotonin are abnormal in some forms of mood disorder. At the same time, it is clear the field needs to go “on beyond serotonin” if it is to solve the mystery of depression. That is the way of science. Theories obtain for a while, and then they need to be modified; often it is apparent even while the theories prevail that they are incomplete. That tentativeness — which is also to say that promise, that opening to further progress — should say nothing about the standing of psychiatry or of depression, just as the current crisis in neurology research raises no doubts at all about the sincerity of researchers and clinicians or the legitimacy of PD as a disease of mind, brain, body, and behavior.

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