Whitaker, Torrey, and Dopamine Supersensitivity: The Conversation Continues

This is the fifth in our series of pieces dealing with Fuller Torrey’s response to Robert Whitaker’s 2010 “Anatomy of an Epidemic.” I’m sure by now you have all had enough, but bear with me. We are learning - all of us - and there is no better way to shake issues loose than by closely observing and then analyzing the back and forth exchange between two of the most prominent voices in psychiatric treatment.

In my coverage of this debate, I am less concerned by who is right and who is wrong than in what we all stand to learn. Nowhere does this come in more loud and clear than on the topic of dopamine supersensitivity.

Whitaker makes reference to the phenomenon in Chapter Five of “Anatomy of an Epidemic,” where he (thankfully) demolishes the myth of “chemical imbalance of the brain.” Contrary to the impression your doctor may lead you to believe, the brain is not some sort of chemical soup that gets thrown out of whack by too much or too little serotonin or dopamine. Likewise, the brain is hardly restored to balance by tinkering with these chemical levels.

In essence, when it comes to an illness such as schizophrenia or addictions such as to cocaine, we find ourselves less concerned with “how much” dopamine is in the brain than in “how sensitive” the brain is to dopamine. The same applies to depression and serotonin.

The presynaptic neuron (the one you always see to the left or at the top on any given diagram) tends to get all the attention, as this is the neuron that releases neurotransmitters into the synapse - the gap - separating the other (postsynaptic) neuron on the left or the bottom. Below is a screenshot from an old Zoloft TV commercial. Here, you see a depressed brain with a “chemical imbalance,” with hardly any neurotransmitters in the synapse:

Now, thanks to Zoloft, we see neurotransmitters bursting out of “Nerve A” like nauseated passengers frantically disembarking from a Kenny G cruise. The swarm is headed straight toward a presumably receptive “Nerve B.” where we are left to assume a happy ending.

But wait. How truly receptive is Nerve B? Ah, that is the real question.

In chemical imbalance terms, if depression is about “too little” serotonin, schizophrenia is about “too much” dopamine. But how much is too much? We turn our attention to “Nerve B.” Whitaker in “Anatomy” (p 76) picks up on the action:

Having discovered that dopamine levels in never-medicated schizophrenics were normal, researchers turned their attention to a second possibility. Perhaps people with schizophrenia had an over-abundance of dopamine receptors. If so, the postsynapic neurons would be “hypersensitive” to dopamine, and this would cause the dopaminergic pathways to be overstimulated.

Whitaker goes on to say that in 1978, University of Toronto researcher Philip Seeman (pictured above) announced that this was indeed the case. Autopsies revealed that the brains of those with schizophrenia had 70 percent more D2 receptors than normal. Nevertheless, Whitaker notes that Seeman cautioned that the “long-term administration” of first-generation antipsychotics may have been the cause, not the schizophrenia.

Here, Whitaker frustratingly breaks off the natural flow of the narrative. Whitaker is pursuing his own agenda, but Dr Seeman, who has devoted his life to the study of dopamine receptors, has an entirely different story to tell, one we need to hear, in his own words, on his own terms. A 2007 article he wrote in Scholarpedia, “Dopamine and Schizophrenia,” best explains:

The discovery in the 1950s that the sedative drug chlorprozamine had both an antipsychotic effect and Parkinsonian side effects (such as tremors) led in the 1960s to a dopamine hypothesis for schizophrenia. By 1967, researchers were discussing “overstimulation of dopamine receptors” as a possible cause for schizophrenia, but it took until 1975 to identify the dopamine D2 receptor as the binding site of dopamine and antipsychotics.

According to Dr Seeman, citing a number of studies, in first episode patients who have never been treated with antipsychotics the density of D2 in the frontal cortex and striatum is elevated by 10 to 30 percent. These same patients experience decreases in D2 in other areas of the brain, as well as decreases in D1 receptors throughout the brain.

D1 and D2 do not operate in isolation. The decreases in D1 may switch a high-affinity D2 receptor into a low-affinity one (ie one not conducive to binding).

Here is the money quote from Seeman’s piece:

Because antipsychotics, including aripiprazole and bifeprunox, alleviate psychosis by inhibiting D2, it indicates that psychosis is associated with a hyper-dopamine state.

Dr Seeman goes on to explain the need for focussing on “how sensitive” rather than “how much.” In experiments involving the administration of low doses of stimulants, three-quarters of those with schizophrenia experienced psychosis or worsening psychosis, even when on an antipsychotic, as opposed to zero to a quarter of the control subjects. In Seeman’s words:

The data indicate that dopamine supersensitivity is prevalent in patients with schizophrenia.

Seeman describes a number of animal studies that suggest a variety of causes for schizophrenia and psychosis, including different gene variations, brain lesions, birth hypoxia during Caesarian section, stimulants, and steroids. All these result in dopamine supersensitivity. Rats given high doses of corticosterone, for instance, showed a 210 percent increase in D2 high-affinity receptors.

Dr Seeman also notes, citing studies by Chouinard, that “antipsychotic drugs themselves can occasionally induce an increase in the high-affinity state of dopamine D2 receptors and the associated state of behavioral dopamine supersensitivity.” Withdrawal of the antipsychotic, he explains, can unmask this dopamine supersensitivity and precipitate an episode of “supersensitivity psychosis.”

Chouinard’s findings of supersensitivity psychosis is where Whitaker comes back into the picture, to make his case for the harmful effects of the long-term administration of antipsychotics. But to make that case, Whitaker first needs to acknowledge the general principle of dopamine supersensitivity.

In other words, the best working theory we have for schizophrenia and psychosis at the moment has to do with study findings showing increases in dopamine D2 high-affinity receptors in key parts of the brain in rats and in humans. As Dr Seeman notes, there may be multiple causes and multiple gene variations for schizophrenia and psychosis along multiple neural pathways, but just about all of these have a way of “converging onto a similar set of brain D2High targets.”

Whitaker’s response? Three way out of context quotes (p 77). First:

“The dopaminergic theory of schizophrenia retains little credibility for psychiatrists.” This came out of the blue in a 1990 article by French researcher Pierre Deniker. The article actually acknowledges the “anti-dopaminergic action” of antipsychotics, but cautions against a one-size-fits-all approach to treatment.

Second:

There was “no good evidence for any perturbation of the dopamine function in schizophrenia.” The 1994 article that houses this quote, from John Kane of the Long Island Jewish Medical Center, actually talks up the newer generation atypical antipsychotics, with their putative (and still not proved) action on the serotonin system.

Finally:

“There is no compelling evidence that a lesion in the dopamine system is the primary cause of schizophrenia.” Whitaker’s use of this 2002 quote (Steven Hyman, former NIMH head) is supposed to lend weight to the proposition that chemical imbalance is a myth. But all Hyman is saying is what everyone agrees on: That schizophrenia, like all other mental illnesses, is heterogenous and multifactorial - many shapes and sizes, many different causes.

Hopefully, you see the point: One cannot talk up supersensitivity psychosis while trying (pathetically, at that) to discredit dopamine supersensitivity. To do so invites fierce attack by Fuller Torrey.

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