Wednesday, June 6, 2012

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.


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.


“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.

Next: Fuller Torrey attacks ...


Stanley Holmes said...

You rise the level of the scientific debate. I was a bit sad that Whitaker's reply to Torrey contained accusations of dishonesty. Mental illness treatment has so much complexity that it requires a open dialogue between all sides (disagreements or evidence of mistakes should not be sufficient for accusations of dishonesty).

On the dopamine issue, Whitaker never denied that dopamine might be involved, and never denied that drugs can provide short-term relief, but he strongly doubted that high-sensitivity is specific to schizophrenia or mental illness (specificity is important regarding the design of treatment). He is focused on the long-term impact of drugs (as well as any abusive usage), it is a legitimate focus. It is also fair to put the burden of proof on his opponents. Whitaker should not need to prove anti-psychotics are dangerous, simply showing that some of the pharma or doctors claims about schizophrenia treatment are not supported by evidence is scandalous enough by itself.

In a ideal medical world, Whitaker discourse might be considered partly ideological. In the current imperfect world, I believe his discourse is overall as honest and sound than his opponents. And that way, he is helping keep psychiatry honest. It was good to hear Dr. Torrey acknowledge that drugs are often abused, and lifelong treatment is not for everybody.

In any case, your blog and website is definitely a priceless resource of objective knowledge.

Anonymous said...

I know of a woman who has taken both Haldol and Seroquel for well over 3 years. She takes BOTH together, each day. In addition to Lithium, Wellbutrin, and Klonopin. She still has bouts of manic symptoms.. though she takes enough of all meds to put down 2 raging elephants.

When I did pharmacy precerts for a large health insurer.. a psych nurse called in one morning to have authorized Seroquel 600mg three times a day. That is, 1800mg of Seroquel A DAY for a patient. Far over what was "allowed" to be authorized. When I asked the reason for such a large request? "What can I say, she has Bipolar and she is crazy that's why."

She had been, per history, on 1200mg per day and they were uping her dosage to 1800mg. She had been on it for well over 2 years.

Seroquel, Risperdal, Abilify, etc.. is often prescribed for sleep regulation and anger management (explosive intermittent anger). APs are used for so many things now so far from what they initially are and were intended for and the longer you are on them.. the longer you must stay on them. Sometimes, life long.... T

John McManamy said...

Many thanks, Stanley. The abusive usage is a very big deal, which I have covered in earlier posts and on mcmanweb and which I will certainly revisit in relation to this conversation.

John McManamy said...

Hi, Anonymous. I agree a hundred percent. Incompetent docs who overmedicate patients is the biggest obstacle in most people's recovery. Sadly, what you describe is all too typical. I look forward to reviewing this issue in a future post.

Willa Goodfellow said...

I think I'm starting to figure this thing out. Are D2 receptors concentrated in the frontal cortex, btw?

I think of dopamine as the motivator neurotransmitter, which is why antipsychotics relieve positive symptoms, but leave people with a mother load of negative symptoms.

But I also think of schizophrenia primarily as a thought disorder. And what does thinking have to do with motivation?

I think I have moved from week one to week two in Schizophrenia 101.

John McManamy said...

Hey, Willa. My understanding: We have D2 receptors in the frontal cortex. So when antipsychotics shut down psychosis in the lower brain regions they are also shutting down thinking and concentration in the cortical regions, plus messing with mid-brain-cortical circuits that involve motivation.

SZ is primarily a thought disorder. my understanding re motivation is that our cortical areas cannot make a decision without input from the midbrain Such as the VTA), through dopamine pathways.

It's the midbrain that "wants" and makes demands, and communicates to the cortical areas via dopamine. The brain then makes a decision to get work done, make dinner, have sex, etc. If these circuits are interfered with (ie D2 receptors in the cortex are blocked and other stuff) we are not motivated to work, make dinner, have sex, etc.

Turn it the other way around. Too much dopamine or too much sensitivity to dopamine and our frontal cortex and ACC lack the ability to modulate the rest of the brain. This is classic lack of impulse control. We say the first thing that comes into our heads, we are reckless in our work, we gorge ourselves on food, we behave inappropriately.

Like you, my focus is on mood disorders, and like you I realized that to understand mood disorders I needed to branch out. The mood disorders experts tend to be way too specialized, not too many think globally.

This led me to checking out SZ. Since SZ involves a near-total collapse of the brain, involving many brain systems, these experts have to think globally.

So, in studying SZ I learn a lot about the brain (and in particular dopamine systems). In learning a lot about the brain, I gain insights into mood disorders that I never would have had be simply listening to the mood disorders specialists.

Anyway, here's an article on mcmanweb on dopamine. I'm going to have to go back and add something on the fine points of dopamine receptors. Ah, the learning goes on:

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Anonymous said...

I am still slogging through the end of Whitaker's book, very glad to have found these posts of yours to read along with it. I am increasingly disturbed by Whitaker's willingness to write misleadingly about the data, to the point where I now question whether the book was even written in good faith. Case in point, this passage from chapter 16:

"...from 1894 to 1896 ... [people admitted to the North Wales Asylum] regularly got better over the course of three months to a year and went home. ... [Psychotic patients] averaged only 1.23 hospitalizations in a ten-year period. ... patients admitted for a first episode of psychosis in the 1990's averaged 3.96 hospitalizations over the course of ten years - more than three times the number a century earlier. Patients today are clearly more chronically ill than they were a century ago."

Actually, this is far from the "clear" conclusion, if we don't know the average length of a modern hospitalization for psychosis. I don't, but I know my adult son was never hospitalized more than 10 days, and was always released with the expectation that most of his recovery would occur at home.

So, if 4 modern hospitalizations equal about 40 days, this is far less time in hospital than the "three months to a year," of the 1800's. If our current treatment modalities are resulting in more readmissions over ten years, you could easily conclude that it is the early release from the expensive, in-patient treatment setting that is causing the tendency for readmission, not the use of psychotropics.

John McManamy said...

Great point, Anonymous. And what you noted is not an isolated incidence. His book is so full of misrepresentations like this that it calls into question everything he has written. This is unfortunate, as Whitaker turns out to be his own worst enemy. He makes a lot of valid (if unproven) points we all need to be talking about, but it is pretty clear that a propagandist suppressing relevant facts is making the presentation, not a journalist.

Case in point: In the Chouinard supersensitivity psychosis studies, Whitaker reported the risk of a type of rebound psychosis induced by staying on antipsychotics. He didn't mention that Chouinard also stated that there is a remedy for this.

Imagine: Whitaker is scaring the crap out of everyone taking antipsychotics, strongly implying you should never start these drugs or wean your way off of them (okay, fair enough). Then he leaves out Chouinard's vital piece of advice of how you can stay on an antipsychotic and reduce your risk of supersensitivity psychosis or clear up the symptoms.

In lieue of a high dose antipsychotic (which would might overcome the symptoms but at a possible high cost of doing business) it may be possible to stay on a lower dose with a mood stabilizer.

So - if Whitaker were interested in the welfare of those he purports to care about rather than in serving his own ends, he would have reported this.

Whitaker is making a lot of money off of our population. Which would be fine if he were motivated by helping us out. I really see no evidence of this motivation.

I could write a lot more. This will do for now. Again, thanks for writing.