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.

Next: Fuller Torrey attacks ...

Whitaker vs Torrey: Crunching Numbers

This is the fourth in our series of pieces dealing with Fuller Torrey’s response to Robert Whitaker’s 2010 “Anatomy of an Epidemic.” In his review, Dr Torrey asserts that on matters of schizophrenia and antipsychotic drugs, “Whitaker got it mostly wrong.” The same day that Torrey published his review, Whitaker in a blog post issued an angry rebuttal and his own counter-attack.

In our most recent installment, we discussed Whitaker’s heavy reliance on a 2007 publication of a Harrow-Jobe 15-year longitudinal study which found that about 40 percent of schizophrenia patients did well when taken off their antipsychotic medication. What the authors of the study found of greater significance, however, was the fact that the patients who did well were those with a “good prognosis” to begin with.

In his book, Whitaker made the barest passing reference to Harrow’s real findings, neither reporting on the primary results of the study nor how this information can be used to help patients with schizophrenia achieve better outcomes. Rather, Whitaker interpreted the study to mean that “that the drugs worsened long-term outcomes” (p 118).

Had this been a long-term trial of antipsychotics as Whitaker would have us believe, the authors would have conducted an entirely different study. There would have been at least two evenly-matched groups of patients, one on antipsychotic meds and one not on antipsychotic meds, if not at the very beginning of the study then at a key stage further along.

The catch is long-term studies of this type are impossible to conduct. The costs are prohibitive and no review board would dare permit such an enterprise. But the real world affords untold opportunities to observe the natural course of schizophrenia without meds. As Torrey scathingly notes:

[Whitaker] fails to focus any attention on the fact that on any given day in the United States half of all individuals with schizophrenia, or about one million people, are not being treated. This is a huge natural experiment to test his thesis. Many of these individuals are found in public shelters, sleeping under bridges, in jails, and in prisons. If Whitaker had spent more time in these settings observing the outcome of this natural experiment, instead of delivering lectures on his vision of the impending antipsychotic apocalypse, he would have written a very different book.

In this regard, Whitaker’s highly selective use and non-use of information becomes a major issue, akin to writing “Gone with the Wind” without noting that there is a Civil War going on.

So, is there any legitimacy to Whitaker interpreting the Harrow study his own way? Yes. It’s called “secondary analysis,” a fairly common practice amongst researchers and journalists. Basically, one mines other people’s data in search of new - and often startling - insights. And Whitaker certainly had more than enough data to work with.

The 2007 Harrow-Jobe article tells us that 12 of 64 patients with schizophrenia (19 percent) experienced a period of recovery over 15 years. Of these: Eight of 12 (40 percent) were no longer on any meds and two of five were on meds but no longer on antipsychotics.

In contrast, only two of 39 patients (5 percent) on antipsychotics experienced a period of recovery. Moreover, 19 of 23 patients (83 percent) with uniformly poor outcomes after 15 years were on antipsychotics. Tellingly, 64 percent of these patients had psychotic activity at the 15-year point vs only 28 percent not on antipsychotics.

Harrow’s numbers back up Whitaker, right? Wrong. Recall, the Harrow study involved an apples-to-oranges comparison - good prognosis patients vs bad prognosis patients. The good prognosis patients, identified at the beginning of the study, were the ones most likely to get better in the first place and therefore were in a position to go off their meds.

For Whitaker’s secondary analysis to work, he would have had to show that the “good prognosis” patients who stayed on antipsychotics did worse than the good prognosis patients who went off antipsychotics. (It would have been useful to compare results in the bad prognosis group, as well, but this finding wouldn’t have had the same significance, as we don’t have high expectations for this group.)

So - we’re looking for an apples-to-apples comparison. Easy to show, right? We just pull up the relevant number and ...

No number. Whitaker doesn’t cite one. No problem. We’ll find the number in the 2007 Harrow-Jobe study that Whitaker refers to. Wait, this is weird. The number isn’t in the study, either. The authors slice and dice the data in a multiplicity of ways, but the closest they come to what we’re looking for is a finding that 17 percent of the good prognosis patients were on antipsychotics after 4.5 years and 13 percent after 15 years.

No mention of how these particular patients actually fared. Why? The answer is simple (okay, complicated for me). Let’s assume one-third of the patients in the study were good prognosis patients. Let’s make the number 20. If only 13 percent of these patients were on antipsychotics at the 15-year mark, we are looking at a study sample of two, at most three, patients.

A three-patient sample? Okay, let’s be generous and double it. A six-patient sample?

In his blog, Whitaker insists that “in every subgroup of patients (by prognostic type), those off medication had better long-term outcomes (in the aggregate).” In making his claim, Whitaker relies upon this paragraph from Harrow-Jobe:

In addition, global outcome for the group of patients with schizophrenia who were on antipsychotics was compared with that for the off-medication schizophrenia patients with similar prognostic status. Starting with the 4.5-year follow-ups and extending to the 15-year follow-ups the off medication subgroup tended to show better global outcomes at each follow-up.

Had Whitaker actually asked, “how much? how many?” he would have realized the absurdity of his assertion.

Conclusion: Whitaker’s secondary analysis fails. Totally, absolutely, completely. Case closed, right? Not so fast:

When the dust settles, we still have two key pieces of data that simply will not go away: Eight in 12 patients not on meds (plus two of five on meds but no antipsychotics) experiencing periods of recovery vs only two of 39 on antipsychotics.

Still a very small sample size. Still apples-to-oranges. Still other factors in play such as the type of life experience and personal make-up that separates good prognosis from bad prognosis patients.

But when all is said and done, Whitaker is perfectly justified in saying: “Hey, hold on a minute, have a look at these figures.” And we need to be listening.

Likewise, Torrey is perfectly correct in insisting that Whitaker got it wrong. Again, we need to be listening.

More to come ...

Previous Whitaker vs Torrey pieces:

At Last, a Conversation

Collision Course

Digging Deeper

Whitaker vs Torrey: Digging Deeper

This is the third in our series of pieces dealing with Fuller Torrey’s response to Robert Whitaker’s 2010 “Anatomy of an Epidemic.” In his review, Dr Torrey asserts that on matters of schizophrenia and antipsychotic drugs, “Whitaker got it mostly wrong.” The same day that Torrey published his review, Whitaker in a blog post issued an angry rebuttal and his own counter-attack.

Previously, we examined Whitaker’s use of two studies he cited in support of his thesis that mental illness is on the rise because of psychiatric medications rather than despite them.

In the first instance, Torrey busted Whitaker for blatantly misrepresenting one study’s findings. The study involved a mere passing reference, but was illustrative of the highly selective cherry-picking that Whitaker employs throughout his book. Whitaker counter-attacked, accusing Torrey of “dishonesty,” but failed to answer the charge.

In the second instance, Torrey dismissed two WHO studies that Whitaker heavily relied upon, characterizing them as “discredited.” Essentially, Torrey (citing various researchers) interprets these studies as an apples-to-oranges comparison. The studies (which found better outcomes among the third-world patients surveyed) - serve as a textbook example of why no finding can be taken at face value. Basically, both Torrey and Whitaker were justified in interpreting these studies the way they did. It would have been helpful, however, had Whitaker addressed Torrey’s apples-to-oranges issue. Instead, he issued another gratuitous “dishonesty” charge.

Let’s move on ...

The Harrow-Jobe Study

Whitaker’s Position

This 15 (later 20)-year longitudinal study, published in 2007, served as Exhibit A in Whitaker’s case against antipsychotic medications. In his book, Whitaker interprets the study results to advance his claim that patients with schizophrenia fare worse on meds over the long-term than those not on meds. According to Whitaker (p 115):

...The off-med group began to improve significantly, and by the end of 4.5 years, 39 percent were “in recovery” and more than 60 percent were working. In contrast, outcomes for the medication group worsened during this thirty-month period. ...

Whitaker in his book did note that Harrow in an interview attributed better outcomes to “stronger sense of self” and “better personhood,” but Whitaker did not elaborate why these factors were significant. Instead, he kept his focus exclusively on meds vs non-meds.

Later in his book (p 311), Whitaker accuses both the NIMH and NAMI of failing to promote (and by implication suppressing) the study’s optimistic finding:

... I also searched the NMIH and NAMI websites for some mention of the studies listed above and I found zilch. ... Forty percent of those off medications recovered over the long term! But that finding directly contradicted the message that NAMI has promoted to the public for decades ...

Torrey’s Response

In his review, Dr Torrey points out that the Harrow-Jobe study is not exactly the hot news that Whitaker makes it out to be. Since at least as far back as 1938, Torrey reports, numerous schizophrenia outcome studies have found that “on average one-quarter of the patients recovered completely, one-quarter had a continuous illness, and the other half had intermediate outcomes between these two extremes.”

Of critical importance, citing one researcher: “There are relatively benign and malignant forms of illnesses generally diagnosed as schizophrenia.” This leads to what the study was really all about, with Torrey noting that “Harrow et al. even explicitly state that their study provides no evidence on whether very long-term use of antipsychotic medication produces undesirable effects for some SZ [individuals with schizophrenia].”

Once again, we have an apples-to-oranges issue. As I observed in a number of previous blog posts, rather than comparing a meds group to a non-meds group as we are used to seeing in clinical trials, the study actually compared a “good prognosis” group to a “bad prognosis” group. These patients were identified at the beginning of the study, then followed over 15, then 20 years.

Predictably, the good prognosis group had better results, with more of them in a position to go off their antipsychotics and to function well. But, according to Torrey, Whitaker twisted these findings to serve his own purposes:

Using tortured logic, he asserts that the Harrow et al. study proves that long-term antipsychotic use causes brain damage and is responsible for many of the symptoms of schizophrenia, when in fact the study does nothing of the kind.

Whitaker’s Comeback

In his blog post, Whitaker breaks down those parts of the Harrow-Jobe study that showed how all the subgroups of non-medicated patients fared better without antipsychotic medications. This includes both “good prognosis” patients and “bad prognosis” patients. Says Whitaker:

Although [Harrow] didn’t provide the global data for these two subtypes, he did report this finding: “In addition, global outcome for the group of patients with schizophrenia who were on antipsychotics were compared with the off-medication schizophrenia patients with similar prognostic status. Starting with the 4.5-year followup and extending to the 15-year follow-up, the off-medication subgroup tended to show better global outcomes at each follow-up.”


In other words, in every subgroup of patients (by prognostic type), those off medication had better long-term outcomes (in the aggregate).

Whitaker (predictably) assigns another “dishonesty moment” to Torrey. This is based on the fact that Whitaker did not cite the Harrow-Jobe study for the proposition “that long-term antipsychotic use causes brain damage and is responsible for many of the symptoms of schizophrenia,” as Torrey claimed. Rather, Whitaker kept his interpretation to outcomes.

Nevertheless, Whitaker in his book (p 118-119,) linked the Harrow-Jobe study to a study that did suggest that “drugs made patients more vulnerable to psychosis over the long-term,” and (p 120) he noted that “we can also see how this drug-induced chronicity has  contributed to the rise in the number of disabled mentally ill."

What Harrow et al Actually Say

From a 2005 article (free on PubMed):

More recent data of ours suggest that some of the schizophrenia patients who go off antipsychotics are a different type of patient. They have better premorbid developmental achievements, have more favorable prognostic characteristics, and are more resilient and less vulnerable to psychopathology (or “healthier”), leading to their better functioning.

And from the 2007 article Whitaker refers to (you have to pay $50 for this, the abstract is free):

The results suggest that the subgroup of schizophrenia patients not on medications was different in terms of being a self-selected group having better earlier prognostic and developmental potential.

And the key finding from the wider dataset (including patients with other diagnoses), in a 2009 article (available free on PubMed):

A more external locus of control is related to fewer periods of recovery, to both depressed mood and psychosis, and to various aspects of personality.

Locus of control (LOC) “refers to the extent to which an individual perceives events in his or her life as being a consequence of his or her actions, and thus under his or her perceived control.” Internal LOC is good. External LOC is bad.

Of the schizophrenia patients in recovery over 15 years, according to the 2009 article, 67 percent had internal LOC. In the overall sample, 75 percent had internal LOC.

Basically, Harrow et al are telling us that an individual’s personal make-up is a key predictor to recovery, perhaps THE key. In their study, these were the patients more likely to go off their meds and do well off their meds. In the authors’ own words (2007):

Patients who are internally orientated and have better self-esteem are the types of patients who are more likely, if their functioning improves, to urge that they try functioning without medications ...

This is worth restating: According to Harrow et al, based on their study findings, doctors should be encouraged to consider taking a good prognosis patient who is doing well off his or her meds. This is an entirely different proposition than what Whitaker would have us believe - namely, get EVERYONE off their meds as soon as possible.

Whitaker doesn’t say this in so many words, but the thrust of his interpretation of the study  - namely “that the drugs worsened long-term outcomes” (p 118) - leaves himself open to Torrey’s charge of using “tortured logic.”

What Whitaker is doing is making a “secondary analysis,” a common and legitimate practice that can often yield far more interesting insights than the primary analysis. The catch is that you have to read Whitaker’s book microscopically to know he is making this of kind analysis. He certainly does not trumpet Harrow et al’s real findings, much less explain them, and this is disturbing, to say the least.

This brings us to the crucial question, does Whitaker’s secondary analysis hold up?

To be continued ... 

Collision Course: Whitaker vs Torrey

This is the second in a series of pieces dealing with Fuller Torrey’s response to Robert Whitaker’s 2010 “Anatomy of an Epidemic.” In his review, Dr Torrey asserts that on matters of schizophrenia and antipsychotic drugs, “Whitaker got it mostly wrong.”

My first piece laid out the background to the controversy, namely my view (spread across numerous pieces throughout 2010 and 2011) that Whitaker had not made his case that psychiatric meds have caused a mental illness epidemic. Nevertheless, he made a very strong “case to answer,” one that demands a considered point-by-point response, preferably from a leading psychiatrist. More then two years went by since the publication of “Anatomy,” with no signs of intelligent life from psychiatry. Last week, Torrey broke the silence. Better late than never.

The same day that Torrey published his review, Whitaker in a blog post issued an angry rebuttal that cited Torrey for at least four instances of “dishonesty,” as well as using the occasion to attack Torrey and the Treatment Advocacy Center for its aggressive stance on assisted outpatient treatment (which a good many of us - myself included - also have serious issues with).

Lost in the noise was that on key points Whitaker has failed to respond to Torrey’s criticisms. Let’s get started:

The 1994 Outcome Study

Whitaker’s Position:

In the foreword to his book, Whitaker says that he “encountered two research findings that didn’t make sense.” One of these was a 1994 study conducted by researchers at Harvard, which found that “outcomes for schizophrenia patients in the United States had worsened during the past two decades ...”

He says no more about the study and makes no further mention of it in the rest of his book.

Torrey’s Response:

In his review, Dr Torrey notes that what the study actually said was “quite different,” namely that when a broad definition of schizophrenia was in vogue, outcomes were a lot better. Moreover, “the data showed a clear improvement in outcomes during the 1960s and 1970s following the introduction of antipsychotic drugs.” Outcomes worsened during the 1980s and 1990s, “which the authors attributed to the introduction of a narrow definition of schizophrenia.”

The broad and narrow definitions are no mere diagnostic quibbling. The narrow (DSM) version (introduced in 1980) mandates six months of symptoms.

Torrey also noted that Whitaker “later added that the worsened outcomes were due to the use of antipsychotic drugs.”

Whitaker’s Comeback:

In his blog post, Whitaker claims that he only mentioned the study in passing in the foreword to his book, as something that “piqued my curiosity,” thus implying that his use of the study was not worthy of Torrey’s attention. Surprisingly, in his defense, Whitaker acknowledges that the study authors said exactly what Torrey said they said, namely:

... the researchers reasoned that improved outcomes in the middle part of the century were due to both a change in diagnostic criteria that broadened the definition to include patients who were less ill at disease onset and then to the introduction of neuroleptics.

Then Whitaker served up his own theory of why maybe - sort of - the study supports his thesis anyway. (We won’t get into that here.)

Torrey’s big mistake? Whitaker made no specific reference to this study when he talked about worsened outcomes on antipsychotic medications, as Torrey stated in his review. This brought down Whitaker’s wrath in the form of “dishonesty moment number one" for Torrey.

Actually, though, on page 118 of his book, Whitaker says, “We have followed the trail of documents to a surprising end ...” Why wouldn’t we assume the Harvard study was part of that paper trail?

Verdict:

Dishonesty moment to Whitaker, big time. This is an egregious example of a journalist misciting a study to serve his own ends, then conveniently forgetting about it when the actual facts failed to support his thesis. This is hardly the only example of Whitaker’s highly selective cherry-picking in his book. Torrey was perfectly correct to call out Whitaker.

As for Torrey’s “dishonesty moment,” using a flimsy pretext to brand a critic as dishonest violates all the basic principles of playing well with others.

Finally, Whitaker totally failed to address Torrey’s extremely relevant point concerning broad and narrow diagnostic criteria. More about that, coming right up ...

The WHO Outcome Study

Whitaker’s Position:

Whitaker devotes considerable attention in his book to two World Health Organization studies that found that those with schizophrenia in developing countries had much better outcomes than those in developed nations. As Whitaker reported in his book (p 111):

... the bottom line is clear: In countries where patients hadn’t been regularly maintained on antipsychotics earlier in their illness, the majority had recovered and were doing well fifteen years later.

Whitaker then goes on (p 119) to link this study to other studies to conclude that “evidence for long-term recovery rates are higher for nonmedicated patients appears in studies and investigations of many different types.”

Torrey’s Response:

Dr Torrey in his review evinces far less enthusiasm, noting that the WHO study claim “has continued to be criticized over the years and has now been largely discredited.” At issue, once again, is broad and narrow diagnostic criteria. Citing various sources, Torrey notes that many of those enrolled in the third world centers probably did not have true schizophrenia (some of the patients were referred by religious and traditional healers). More likely, the researchers were dealing with a good number of those suffering from “acute reactive psychosis,” which have much better outcomes than schizophrenia.

Torrey also cites a five-year 2011 study on a cohort of Ethiopian patients with findings that contradict the WHO studies. Finally:

Faced with such criticisms, the authors of the WHO studies have recently modified their claims, stating that “we do not argue that the prognosis of schizophrenia in developing countries is groupwise uniformly milder” and acknowledging that “the proportions of continuous unremitting illness…did not differ significantly across the two types [developed and developing] of setting.”

Whitaker’s Comeback:

Predictably, Whitaker assigns Torrey another “dishonesty moment.” This is based on the fact that far from “modifying their claims,” the authors of the WHO studies in the same paper Torrey cited actually vigorously defended their findings. Says Whitaker:

Dr. Torrey, in his review, was intent on discrediting the findings from this WHO study, which reported superior outcomes in poor countries where only a small percentage of patients were regularly maintained on antipsychotics. To do so, he implied that the WHO investigators now agreed with the critics of the study, when that is not true.

Verdict:

We have a big wet loogie on the table, which Whitaker fails to address, namely: The authors of the WHO studies have explicitly acknowledged that the patients in the third-world countries had a milder prognosis than those in the developed countries. Why is this important? If we are comparing apples to oranges, then the findings of the WHO study are totally meaningless.

More likely, the “apples to oranges” controversy merely raises questions about the study rather than discredits it, as Torrey maintains. If anything, the WHO study is a textbook example of why no finding can be taken at face value. Certainly, we all know this when it comes to clinical trials sponsored by drug companies.

What is particularly disturbing is that Whitaker would have been aware of the “apples to oranges” controversy when he wrote "Anatomy of an Epidemic." Yet he makes only a fleeting reference to it in his book, and only in the context of vindicating the first WHO study (as if there were no reason to question the second study). A straightforward and thorough stating of the controversy would hardly have undermined both studies' findings or Whitaker’s thesis. If anything, preemptively dealing with this concern would have greatly strengthened Whitaker’s argument, along with his credibility.

Instead, we are left with the feeling that Whitaker is hiding something.

Keep in Mind ...

In past blog posts, I have been supportive of Whitaker, but I have also not hesitated to point out numerous examples of where he played fast and loose with the facts, or where - quite frankly - he failed to turn in his homework. I continue to be supportive of Whitaker, but I also support any critic of Whitaker acting in good faith. In my 13 years researching and writing on mental illness, one vital lesson stands out loud and clear: Never - never-ever-ever - take anyone (and I include myself here) at face value. Always maintain a healthy skepticism, even if the party involved claims to be speaking for you - especially if the party involved claims to be speaking for you.

To act otherwise is to place your life on the line. Our illness takes no prisoners.

Much more to come ...  

Torrey Responds to Whitaker: At Last, a Conversation

I have devoted considerable space on this blog to Robert Whitaker’s 2010 “Anatomy of a of an Epidemic,” which posits that mental illness is on the rise because of psychiatric medications, rather than in spite of them. In reviewing Whitaker, I read the same studies he cited in his book and came to the conclusion that Whitaker had not made his case.

Nevertheless, I pointed out that Whitaker had made a very strong “case to answer.” In other words, until someone (presumably a psychiatrist with weighty credentials) made a convincing counter-argument (preferably in a point-by-by rebuttal), Whitaker’s thesis - whatever one’s misgivings - stood as the authority.

I also stated that Whitaker had initiated a conversation that we badly need to have. Whitaker was also very clear that he wanted to have this kind of discussion.  

To my dismay - and to the shame of psychiatry - that conversation never eventuated. Daniel Carlat of Tufts University in two blogs issued what was essentially a collegial light dusting, taking issue with Whitaker’s presentation of the evidence in a friendly sort of way, but hardly knocking any holes in his main arguments.

Andrew Nierenberg of Harvard purported to “rebut” and “refute” Anatomy of an Epidemic in response to a grand rounds Whitaker delivered at Mass General. The so-called rebuttal amounted to an irrational and high-volume hissy fit (one punctuated by totally unprofessional ad hominem attacks) that I could only characterize as “sick, very sick.”

A few commentators quibbled about Whitaker’s interpretation of the term, “Epidemic,” tossing in an ad hominem attack or two for good measure, but otherwise avoiding engagement.

That all changed last week with an article posted on the website of the Treatment Advocacy Center. Anatomy of a Non-Epidemic - A Review by DrTorrey, read the heading. “How Whitaker Got it Wrong,” read the subheading.

E Fuller Torrey (pictured above) has a way of getting a rise out of certain mental health advocates. Dr Torrey is the founder of the Treatment Advocacy Center (TAC), which pushes for aggressive outpatient treatment laws for those with severe mental illness. The issue is a hot-button one, and TAC and Torrey have come under considerable criticism for their position and their tactics (including from this writer).

But Torrey has paid Whitaker the ultimate compliment of intelligently and thoughtfully responding to Whitaker. Too often, in our focus on personalities, we lose sight of the issues. Advocates who should know better have elevated Whitaker to the status of cult hero who can do no wrong. This is a grave disservice to both Whitaker and the people we purport to serve.

Torrey, too, enjoys a certain cult following, particularly among first-generation NAMI parents, as well as villain status from a host of mental health advocates. We will discuss these matters in a future blog. But, for right now, let’s focus on the issues. Essentially, Torrey has shifted the whole discussion. He has convincingly answered Whitaker’s “case to answer.” This hardly means that Torrey is right and Whitaker is wrong. Indeed, a constructive synthesis would move the discussion to a new level, one that Whitaker and Torrey could easily agree upon - the need for some serious research.

In other words, if the scientific evidence is insufficient to either support Whitaker’s case or to rebut it, then let’s put some serious money into unearthing the evidence.

In future blog posts, we will explore point-by-point Dr Torrey’s responses to Whitaker. In the meantime, this disclosure: Dr Torrey wrote a very glowing back-cover blurb for my 2006 book, “Living Well with Depression and Bipolar Disorder.”  The blurb states: “Very helpful for those affected by bipolar disorder and their families ... I recommend this book enthusiastically.”

I have had no other involvement with Dr Torrey and none with the Treatment Advocacy Center.

Stay tuned ... 

Shedding Light on Brain Research: A Scientist Responds to Whitaker

Last week, I wrote a piece highly critical of a post Robert Whitaker published on his blog, Mad in America. His post attacked a very recent Scripps Institute study, which became the basis of his own editorializing on the research agenda of the NIMH, namely that “decades of such brain research has not produced any notable therapeutic payoff.”

My post noted that Whitaker had a point concerning one issue (namely, the need to control for the effects of psychiatric meds in genes-brain research), but that he had left out some critical information about the study and that his editorializing was way off-base.

You can check out Whitaker's post: Rethinking Brain Research in Psychiatry.

And my post: Robert Whitaker: Dangerous in America

Several days ago, I emailed Elizabeth Thomas PhD (pictured here), lead author of the study in question. I did not ask her to take sides. I simply directed her to both blogs (if she were morbidly curious about our food fight) and asked for points of clarification. Following is her response in full, published here with her permission ...

Hi, John

Thanks for your email. Yes, I was morbidly curious about your blogging battle with Mr. Whitaker and I did want to respond. Sorry this is long-winded…..

First to defend our work a bit. Like most researchers working with post-mortem brain tissue, we are aware that a confounding factor in post-mortem research on schizophrenia is the unknown effect of antipsychotic drugs, which are known to alter gene expression. (I have actually published two reviews on the topic of antipsychotic drugs and regulation of gene expression [1, 2]). It is an issue that cannot be avoided, as most if not all collected brains deemed “psychiatric” are due to information from a psychiatrist’s report and, hence that patient would be receiving some type of medication.

Just FYI, to address this in our research, we do typically do two things: 1) treat rodents with the drug in question, to look for effect on gene expression in the brain; and 2) perform correlation analysis between expression values in each human subject and the recorded drug dose of each subject. In our recent paper, we did provide drug information in Suppl. Table 1 for a portion of the subjects we studied; unfortunately, drug information was not available for the Harvard subjects.

Nonetheless, Mr. Whitaker is correct in that we should have discussed the potential effects of antipsychotic drug exposure in that paper, as we have in previous studies using post-mortem brains from some of these same subjects ([4, 5]). As it turns out, previous studies have looked at the effects of antipsychotic drugs on histone acetylation in rodent brain [5, 6], as Mr. Whitaker suggested should be done.

It was found that haloperidol, one of the most commonly used drugs, did not alter global histone acetylation in the brain, but could elevate a phospho-acetyl mark on histone H3 at a particular residue [5]. Another study found that clozapine and sulpiride could elicit small increases in acetylation of histone H3 [6]. Hence, the findings in our paper showing lower histone acetylation in patients, who in fact were treated with haloperidol or other D2 receptor antagonists, are unlikely due to drug treatment (if you want to use the rodent argument). I regret that we did not mention these studies in the current paper.

The finding that histone acetylation is lower at certain gene promoters is consistent with a lowered gene expression profiles for these given genes that have been observed in subjects with schizophrenia. On a whole, dozens of papers have shown that brains from patients with schizophrenia show substantial deficits in gene expression; this was the impetus for our studies investigating whether epigenetic mechanisms of gene regulation could be responsible and or contributing to this phenomenon. 

Certainly, we cannot rule out that antipsychotic drugs could have an effect on gene expression in these subjects, but drug exposure is unlikely to explain the wide range of gene expression deficits detected. In any case, I do think Mr. Whitaker is correct about the importance of studies that would address the question of how psychotropic drugs may be affecting the developing brain, as many of these drugs are now given to younger patients.

Despite Mr. Whitaker’s claim that my response to our work was “the usual concluding pronouncement from such studies”, the reality is, in my opinion, that our findings provide a starting point to consider the only real new drug development for psychiatric disorders the field has seen in 50 years. Because we have shown that histone acetylation is lower in young subjects with schizophrenia, and that the acetylaton marks we studied are known to govern gene regulation, the use of compounds that could elevate histone acetylation (i.e. histone deacetylase [HDAC] inhibitors) could be useful to of restoring abnormal histone acetylation patterns and accompanying gene expression deficits in schizophrenia, leading to improved clinical outcome.

The possibility that these compounds could improve symptoms is supported by a recent study by Engmann et al., 2011 [7], who showed that the HDAC inhibitor, MS-275 could rescue cognitive deficits in a mouse model of schizophrenia. And further, that the mechanism for beneficial effects were via restoration of histone H3K18 acetylation deficits in the mouse brain. Other ongoing studies are testing other HDAC inhibitors in different rodent models of psychiatric disorders as well. (If my recent NIH application is funded, we will be testing novel HDAC inhibitors in a prenatal immune activation model of psychiatric disease).

As for your question about testing whether psychotropic drugs alter epigenetic pathways: There are two studies, as I mentioned above, that have been published, although the drawbacks of these studies were that only short-term treatments were used and epigenetic changes at specific genomic loci were not tested (only global levels measured by Western blotting).

A more important issue, in my opinion, is whether epigenetic drugs, such as HDAC inhibitors will truly represent a novel therapeutic avenue for psychiatric disorders. I would argue YES. New and improved HDAC inhibitors are currently being developed for various CNS disorders and my prediction is that they will also prove to be beneficial in treating patients with psychiatric disorders.

While it is expected that such compounds will have some “to be determined” side effects, they are unlikely to cause the same detrimental side effects of Parkinsonian symptoms and metabolic syndrome associated with the currently used antipsychotic medications. There is one recent clinical trial that has been completed showing improvement with valproate (an HDAC inhibitor) in schizophrenia, and several other trials are underway. (For more information see the clinical trial gov website). (Although it must be noted that the currently FDA approved HDAC inhibitors, such as valproate, are broadly acting compounds, unlike the ones in development, which would be more specific, hence less likely to cause unwanted side effects).

References:
1. Thomas, E.A. Molecular Profiling of Antipsychotic Drug Function: Convergent Mechanisms in the Pathology and Treatment of Psychiatric Disorders. Molecular Neurobiology 34:109-28 (2006).
2. Thomas, E.A. Transcriptomics of antipsychotic drug function: What have we learned from rodent studies? Current Psychopharmacology, In Press.
3. Narayan, S., Tang, B., Steven Head, S.R., Gilmartin, T.J., Sutcliffe, J.G., Dean, B. and Thomas, E.A. Molecular Profiles of Schizophrenia in the CNS at Different Stages of Illness. Brain Research 1239:235-248 (2008).
4. Narayan, S., Head, S.R., Gilmartin, T.J., Dean, B. and Thomas, E.A. Evidence for Disruption of Sphingolipid Metabolism in Schizophrenia. Journal of Neuroscience Research 87:278-288 (2009).
5. Li J, Guo Y, Schroeder FA, Youngs RM, Schmidt TW, Ferris C, Konradi C, Akbarian S. Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling. J Neurochem. 2004 Sep;90(5):1117-31.
6. Dong E, Nelson M, Grayson DR, Costa E, and Guidotti A. Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci U S A 2008; 105: 13614-9.
7. Engmann O, Hortobágyi T, Pidsley R, Troakes C, Bernstein HG, Kreutz MR, Mill J, Nikolic M, Giese KP. Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition. Brain. 2011 Aug;134(Pt 8):2408-21

Finally, thank you for supporting NIH funding for basic and medical research in your blog – we are definitely in dire need and without continued funding, we will not be able to address these critical questions that could help patients with psychiatric disorders.

Best wishes,

Elizabeth A. Thomas, Ph.D.
Associate Professor

Department of Molecular Biology

The Scripps Research Institute

3030 Science Park Rd, SP2030

La Jolla, CA  92037

Robert Whitaker: Dangerous in America - Part II

Yesterday, I reported on Robert Whitaker’s dangerous tendency to play fast and loose with the facts in support of his own agenda. This worked in his 2010 book, “Anatomy of an Epidemic,” which I was largely supportive of despite my strong reservations over the way he misrepresented the studies he relied upon to make his point, not to mention his unpardonable cheap shots fueled by his profound ignorance in areas he proved too lazy to research.

Nevertheless, the strands of his argument held together, and his concerns matched our concerns. Essentially, Whitaker had made a strong “case to answer” that our meds may bring on the very conditions they are supposed to prevent. Nearly two years following the publication of his book, in the absence of psychiatry failing to answer his case, I concluded two months ago that “Whitaker stands as the most authoritative voice on psychiatric treatment.”

I strongly urge everyone to read Whitaker’s book, discuss it with your friends, do your own research, and reach your own conclusions. The life you save may be your own.

In his last two posts on his blog Mad in America, however, Whitaker appears to have lost touch with both the facts and the people he purports to serve. As I reported yesterday, in a piece posted on Jan 12 Whitaker egregiously misreported the facts of an NIMH-funded study in support of his own idiosyncratic white whale hunt.

But who has time to fact-check Whitaker? Especially those willing to take him at his word.

Nevertheless, one of his own readers smelled a rat. In a comment to his post, Don B noted “his approach to the whole problem of mental illness comes off as the outsider who knows it all about what he has never personally experienced.”

Don’s post is long and involved, but the gist of it involves his resentment over Whitaker thinking that “he knows what is best for me. If he is politically correct, he wouldn’t dare tell a woman that he knows how it feels to get raped or to have a miscarriage. But like many others, he does not shrink from telling those of us with mental illness what choices to make.”

As if to prove Don’s point, in his next blog post Whitaker makes the bizarre and totally irresponsible claim that the NIMH is advancing some kind of eugenics agenda. I'm not making this up. It's actually in the title of his post, that reads in full: "The Taint of Eugenics in NIMH-Funded Research Today." Apparently, NIMH research is warped from the outset, and Whitaker's proof for this is a repetition of his nonsense from his previous post about no miracle cures in the last 30 years.

In Whitaker’s own words:

[NIMH head] Insel’s list tells of a research enterprise devoted to identifying what is genetically wrong with the “mentally ill.” As the history of eugenics reminds us, that is a pursuit, unless it is handled with great care, that can engender bad social policy and a great deal of harm.

Right, Whitaker, and President Obama is a Muslim born in Kenya ramming European socialism down our throats.

Okay, Whitaker, reality check: There is something wrong with us. Profoundly so. Otherwise, I would be employable. Otherwise, a dear friend of mine would not have thrown himself in front of a train. Otherwise a friend from my past would not have shot himself with a gun. Otherwise, someone I know would not be sitting in a prison cell as I write this. Otherwise, otherwise, otherwise ...

Do you think mental illness is a fucking picnic, Whitaker? I know you have done a lot of talking, but have you actually done any listening? Do you actually know what it’s like when you can’t get out of bed in the morning? When the mysterious force inside your head that is keeping you there is every bit as strong as all the gravity Newton could ever contemplate?

Shut up, Whitaker. I’m not finished: Do you know what it’s like when your brain goes on strike? To be clinically dead but breathing? Or to experience a psychic pain so intense that, yes, the one way out - the unthinkable - is the totally logical choice?

Or maybe it’s the other way around. Your brain runs away from you. Suddenly, you’re thinking and feeling and doing all kinds of crazy shit. Try living inside of my head for one second of that, Whitaker. I dare you to write your stupid shit after that.

Wait, there’s more. The finger-pointing, the ostracism, the social isolation. That’s right, Whitaker, when something goes wrong - yes wrong - the people around us do not exactly respond with the same forbearance as Father Damien in a colony of lepers. And there we are, our lives in ruins, left to pick up the pieces.

And - oh, yeh - our families, our loved ones, our friends and colleagues. For one second, Whitaker, can you even begin to imagine what mental illness does to these innocent bystanders?

One day, Whitaker, we should sit down and have a beer together. Then I can tell you all this to your face.

Robert Whitaker: Dangerous in America

On his Mad in America blog, in a Jan 12 post Rethinking Brain Research in Psychiatry, Robert Whitaker, author of "Anatomy of an Epidemic," made the very legitimate point that brain studies on those with mental illness fail to account for the effects of exposure to psychiatric drugs.

Agreed. So, if you slice and dice the brains of deceased individuals with schizophrenia and bipolar and compare them to “healthy” brains, as scientists at the Scripps Institute very recently did, and find that DNA “stays too tightly wound” in the brain cells of schizophrenia subjects, is the effect attributable to the illness, as the researchers suggested, or to the meds the patients have been on all these years, as Whitaker argues needs to be controlled for?

Furthermore: If we can’t say for sure, is the study actually worth the paper it’s printed on? No to everything, says Whitaker most emphatically. “First, let’s look at this particular study,” says Whitaker, who then does not look at this particular study. What Whitaker fails to mention is the study’s real finding and its implications: that a certain gene regulation process observed in neurological disorders also has a correlation to schizophrenia.

The study, published in Translational Psychiatry, sheds very important light on the developing field of epigenetics, which is rewriting the entire book on genetics. If you haven’t heard of epigenetics, don’t worry - you will. I first reported on the topic back in 2004, when a PubMed search listed but one author researching bipolar from an epigenetic perspective. Now epigenetics is emerging as the main event. Last year, I heard Jonathan Sebat of UCSD talk about “copy number variants” in schizophrenia and autism.

Back to the study: The devastating effects of the acetylation of histones (which appears to drive the “tightly wound” DNA dynamic) is the narrow story. The insights the study sheds into the dynamics of epigenetics is the wider story. Both together add up to the real story. Here is the scientific gobbledygook from the research article:

The major findings from this study are: (1) histone ac-H3K9K14 levels are correlated with gene expression levels for several schizophrenia-related genes, including GAD1; (2) age is strongly negatively associated with promoter-associated histone acetylation levels in normal subjects and those with bipolar disorder, but not schizophrenia and (3) histone H3K9K14 levels are hypoacetylated at the promoter regions of important genes in young subjects with schizophrenia.

Maybe another group of scientists will discover that psychiatric meds are involved in the histone acetylation process, but a further study would require funding, and here Whitaker has his own agenda.

Whitaker says the researchers at Scripps could have “administered neuroleptics to healthy rats.” Huh? This was an epigenetics study, not a drug company pre-clinical trial. Does Whitaker even know the difference? Has Whitaker even heard of epigenetics?

“This is why I think it is time for the NIMH to reallocate its research dollars,” says Whitaker. “Decades of such brain research has not produced any notable therapeutic payoff.”

And it is an absolute certainty that there will be no payoff if propagandists such as Whitaker have their way. For there to be any kind of therapeutic pay-off, first we need to find out what is really going on in the brain. NIMH research has led the way in busting old myths (ironically, Whitaker relies on this research in Anatomy of an Epidemic) and has totally changed how we think about brain function and mental illness.

But it also reveals how little we truly know. Alas, there are no easy answers. All the low-hanging therapeutic fruit has already been plucked. Research is badly underfunded, especially with no short-term pay-offs in sight. Today's research efforts are for the benefit of future generations. That's what civilization is all about. We work, we sacrifice, for those who come after us. But there are no guarantees in the frustrating and noble quest for knowledge.

Rebutting Whitaker: Not Such a Good Idea - Part II

On Saturday, I published a piece that said it is not such a good idea to claim to rebut (or for that matter refute or repudiate) Robert Whitaker and his 2010 book, “Anatomy of an Epidemic.” Not unless Whitaker happens to be a flat-earther making up his own facts.

The danger with framing a counter-argument in the form of a rebuttal is that you have to declare in advance that you are about to score a first-round knock-out. So, even if you win on points in 15 rounds you have lost. Earlier this year, Andrew Nierenberg of Harvard went for the knock-out, and disgraced himself and psychiatry in the process.  (See Part I and Part II to "Whitaker vs Quack Psychiatry.")

Rebuttals are hardly an impossibility, but you need to bring both your A-game and a measure of respect for the other side and all interested parties. For a stellar example, go to YouTube and view Robert Lustig’s masterful demolition of conventional and scientific wisdom concerning weight gain and obesity.

The most recent rebuttal claim on Whitaker came in the form of a confused two-part commentary by William Glazer MD on Behavioral Healthcare. In my previous piece, I showed how Dr Glazer most unambiguously failed in his claims that Whitaker’s thesis was “sensational” and “scientifically unsound.”

Would Dr Glazer have been more successful had he merely set out to knock holes in Whitaker’s arguments? Let’s examine the hole-knocking:

Whitaker advanced the novel proposition that psychiatric meds have caused an increase (rather than an expected decrease) in mental illness. Exhibit A in Glazer’s counter-argument were two authoritative population studies done ten years apart. The early 2000s data was virtually the same as the early 1990s data.

But Whitaker went a lot further back in his comparisons, digging into research from the sixties and earlier. Glazer’s comparing modern data to modern data was the equivalent of a cheap accounting stunt. This is where Glazer really sets his foot in it. In citing the mental illness prevalence data at 29 percent and 30 percent from both studies, Dr Glazer makes this extraordinary statement:

These figures hardly support the notion of an “epidemic” of mental illness, the assertion on which Whitaker rests his case, as well as the provocative title of his book.

No mental illness epidemic, Dr Glazer? Really? Let’s examine the threshold levels for what constitutes an epidemic. In 2003, the US Surgeon General declared: “We have an epidemic of childhood obesity.” How many kids were obese? Fifteen percent (triple the rate of forty years earlier).

Glazer is on far more solid ground when he takes issue with other population and disability figures Whitaker cites in his book, but this was already covered by Daniel Carlat in his two blog pieces earlier this year. (See my reviews: A Discussion at Last, and When Is Speculation Justified?) I, too, have expressed my concerns with Whitaker over this, but these hardly rate as rebuttals. Quibble all we want, we are still looking at an alarming 30 percent prevalence rate of mental illness, an epidemic.

Now we get to the meat of Whitaker’s arguments, namely: 1) Prolonged antipsychotic use may result in a form of “rebound psychosis”; 2) In many cases, schizophrenia patients may do better not on meds; 3) Prolonged antidepressant use may set up “oppositional tolerance” that worsens the course of depression.

In numerous blog pieces, I cited Whitaker with moving violations for playing fast and loose with the evidence. In short, the studies Whitaker cites do not actually prove his claims. But they do support his claims. The scientific conversation is full of this type of discourse. Thus, support that is short of proof carries a certain level of scientific validity. So - can Glazer knock out the supports? Or will he choose instead to recycle Nierenberg personal insults? You guessed it:

“Mr. Whitaker needs a basic course on principles of epidemiologic research, specifically on the concept of ‘susceptibility bias.’”

This is the same Dr Nierenberg who in debating Whitaker miscited a longitudinal study as “restrospective.” Um - who needs the basic course?

Speaking of longitudinal studies, Glazer also repeats Nierenberg’s mischaracterization of an NIMH study as a 20-year study supporting the long-term effects of antidepressants. If there were such a study, then we might have some strong counter-evidence to the “oppositional tolerance" hypothesis that Whitaker advances. Yes, there was an NIMH study, but it merely investigated long-term illness outcomes, not long-term antidepressant use. The study does not say that patients were on antidepressants for 20 years, nor does it purport to make a finding based on long-term use.

Zen koan: If psychiatrists quote howling mistatements from fellow psychiatrists enough times, do the howling misstatements eventually become scientific fact?

Yes, apparently. In the words of Dr Glazer:

The knowledge base for psychiatric medications is evolving, but it has not come anywhere near the point where conclusions can be reached about whether they cause disability. Such a conclusion should rest in the hands of scientists, not reporters.

I could go on and on, rebutting Dr Glazer's rebuttals, but I have better things to do. Instead, I will leave the last word to someone who actually knows what she is talking about. Corinna West is actively involved in the recovery movement. In a blog piece entitled, It Feels So Great To Be Off Meds, she writes: 

I’m not anti-medication, but I am anti-bullshit. I know that medications truly help some people, and some people do well on them. Those people should feel free to continue using them. However, I think all people should be given honest information about psychiatric meds before being put on them. We should be told how hard they can be to get off, and that there is not a ton of research showing long term effectiveness for medications. We should be given the truth that the chemical imbalance theory has not proven to be true. We should be given help and support for getting back off the medications as soon as possible. This would be the best way to help the 40% of people that do not respond to any given medication and might actually be harmed by it. In our current system, people unhelped by medications are only given more medications as well as the message that they are doing something wrong if they’re not recovering.

Rebutting Whitaker: Not Such a Good Idea

In Oct last year, I began a series of pieces based on Robert Whitaker’s shot heard ‘round the world, his 2010 book “Anatomy of an Epidemic.” Whitaker’s astonishing thesis is that psychiatric meds have been a contributing factor to the apparent global rise in mental illness.

Yes, we know our meds may make us worse rather than better, but this comes up in the context of side effects or trade-offs (such as weight gain and cognitive impairments). Whitaker goes a step farther in claiming that many of our meds actually worsen the very conditions they were meant to alleviate, namely:

• Long-term antipsychotic use may bring on psychosis.
• Long-term antidepressant use may bring on depression and affective instability.
• Any kind of antidepressant use may turn those who never experienced mania in their lives into life-long bipolars.

In my initial series of blog pieces and numerous follow-ups, I took serious issue with Mr Whitaker’s fast and loose interpretation of the scientific evidence he cites in his book, not to mention his mindlessly unqualified endorsements of the antipsychiatry movement and his ill-informed cheap shots against advocacy groups that actually get off their asses and help people, such as NAMI (disclosure: I serve on the board of NAMI San Diego).

But I also concluded that Mr Whitaker had made the equivalent of a “case to answer,” a strong prosecutorial argument that demands an equally strong counter-argument from the other side. In other words, until psychiatry can present a convincing case of its own - on point, with strong scientific evidence - any fair-minded jury would have to decide in favor of Whitaker.

So, for right now, in the absence to date of any credible marshaling of the facts from psychiatry, Whitaker stands as the most authoritative voice on psychiatric treatment. A very sad state of affairs.

Yes, Daniel Carlat in two blog pieces (see my reviews: A Discussion at Last, and When Is Speculation Justified?) raised some thoughtful concerns, but he came across more like a woman (and in rare cases a man) on a first date wondering how to dress for the occasion. Andrew Nierenberg, one of psychiatry’s leading authorities on mood disorders, in a grand rounds debate, purported to “refute” and “repudiate” Whitaker, only to embarrass himself and his profession in a DSM-worthy display of disordered thinking and outrageous conduct. (See Part I and Part II to "Whitaker vs Quack Psychiatry.")

The latest criticism of Whitaker is in the form of a two-part piece (Part I and Part II) on "Behavioral Healthcare" by William Glazer MD. Dr Glazer runs his own consultancy, and has been affiliated with Yale and Harvard. Dr Glazer is a welcome voice to the conversation, but from the very beginning he sets up his counter-argument to fail.

“Rebuttal: Questioning the validity of ‘Anatomy of an Epidemic'”, reads the title to his first piece. “Whitaker's claims are ‘sensational’ but scientifically unsound,” reads the subheading.

So, to meet his own criteria in making his case, Dr Glazer would have to prove the falsity of Whitaker’s argument. Not only that, he would have to demonstrate that there is no scientific basis to Whitaker. The catch is that Whitaker is no mere flat-earther engaging in pseudo-science. His conclusions - as far-fetched as they may appear to someone considering the issue for the first time - are strongly grounded in findings published in mainstream journals, not to mention the observations of some of the leading experts in the field.

In addition, to shoot down Whitaker, Dr Glazer would have to marshal his own scientific evidence. This would involve citing studies that convincingly demonstrate the long-term efficacy and safety of numerous classes of psychiatric meds. You would think this would be a very easy mission to accomplish, but these studies simply do not exist. Here, for instance, is a key disclosure from the Depakote product labeling:

The effectiveness of valproate for long-term use in mania, i.e. for more than 3 weeks, has not been demonstrated in controlled clinical trials.

An older version of the labeling read:

The effectiveness of Depakote ER for long-term use in mania, i.e. for more than 3 weeks, has not been systematically evaluated in controlled clinical trials.

So here is the situation: We know it is common psychiatric practice to prescribe Depakote for long-term use in stable patients to prevent relapse or recurrence into mania. Yet the drug has only been successfully tested on a floridly manic group of patients for three weeks.

This is hardly an isolated example. Time and time again, in picking through the long-term data, (with the possible exception of lithium) all we come up with are the equivalent of 18-minute gaps in the tape.

Are we to conclude, then, that psychiatry is “scientifically unsound?” Yes, indeed, if we are to apply Dr Glazer’s extremely reckless terminology. I trust you get the point: The truth is certainly out there, but the facts are extremely hard to come by. The best we can do is make intelligent guesses based on the very limited information available to us.

In a sense, psychiatric treatment equates to meteorological forecasting - impressive in the short-term but highly problematic over the long-haul.  

So forget about rebutting Whitaker. Psychiatry is in no position to do that. The best it can do is interpret the same data in a way that helps all of us make informed decisions. I’m still waiting.

More to come ...

Antipsychotics - Wonder Years to Cynicism

I've spent the last three days updating and rearranging three of my mcmanweb articles on bipolar meds. Following is an edited extract from a much longer new article on antipsychotics ...

The Wonder Years

Antipsychotics were discovered by accident in the 1940s. The introduction of Thorazine as a "neuroleptic" or major tranquilizer in the early 1950s promised to do to psychiatry what antibiotics and other "wonder drugs" did to internal medicine. Indeed, deliverance from psychosis could be regarded as a medical miracle, and over the next ten years 50 million patients were administered the drug. Haldol, which came a bit later, is the best-known old-generation antipsychotic still in service.

The drugs bind to the neuron's dopamine D2 receptors, blocking dopamine transmission in the brain's mesolimbic pathway, thus serving as a damper against the type of overstimulation that results in psychosis. Unfortunately, antipsychotics also act on other dopamine pathways, resulting in a very high cost of doing business.

The introduction of Risperdal and Zyprexa in the early and mid 1990s raised false hopes of a "new and improved" class of antipsychotic. These new generation antipsychotics (referred to as atypical antipsychotics) bind more loosely to the dopamine D2 receptors, which reduces the risk of side effects such as EPS and tardive dyskinesia. In addition, there is a downstream serotonin affect. But their actions on other brain (and physical) systems creates a whole panoply of additional, and equally troubling, side effects.

Similarly, the introduction of Abilify in the next decade generated a buzz over a new breed of "Goldilocks" atypical antipsychotic that was purported to be "just right." But by then the reality was setting in that the new antipsychotics were simply newer versions of the old antipsychotics, albeit with better side effect profiles in certain respects, worse in others. Certainly, the proliferation in brands of the new antipsychotics is justified in giving patients a choice, but the principal choice appears to be in terms of side effects rather than efficacy. Annual world sales of antipsychotics total about $20 billion.

Cynicism Sets In

The 2005 publication of Phase 1 of the NIMH-underwritten schizophrenia trials (CATIE) served notice that the new generation meds were no more effective than the older ones. Moreover, only 26 percent of the patients completed the 18-month trial, a figure that corresponds with other clinical trial drop-out rates. The later publication of successive phases of CATIE revealed an extremely depressing picture of medicated patients struggling with both their illness and side effects, with low quality of life, and in terrible physical shape.

All of this information had long been available to the psychiatric profession - in studies published previously, on product labeling, and in daily litanies of complaints from patients - but only in light of CATIE are doctors actually beginning to pay attention.

Basically, the pharmaceutical industry oversold psychiatry on the new generation meds. Psychiatrists, in turn, paid more attention to smooth-talking drug reps than to their own patients. We know these meds work well in certain specific contexts (such as quickly knocking out mania and psychosis), but we need to accept their limitations and exercise sound judgment in using them.

Supersensitivity Psychosis?

Robert Whitaker's 2010 "Anatomy of an Epidemic" raised the talking point that antipsychotics may create the ironic effect of worsening the course of psychosis, perhaps to the point of no-return. Whitaker presents his argument as unassailable fact, but the evidence is far more tenuous.

Whitaker bases his case on the investigations of Guy Chouinard and Barry Jones of McGill University back in the late 1970s.

Supersensitivity psychosis is analogous to rebound symptoms that occur in other illnesses when a medication is abruptly withdrawn or too rapidly lowered. In this case, we are talking about the brain, over the course of long-term antipsychotic administration, habituating to the med. In response to dopamine blockade from an antipsychotic, post-synaptic neurons compensate by increasing their receptor binding sites, setting up - the hypothesis goes - the ironic side effect of psychosis.

Chouinard and Jones clearly regard the effect as temporary, which may be countered by meds adjustments, which you won't find mentioned in Whitaker's book. Whitaker does bolster his case with a 15-year longitudinal study by Harrow and Jobe that found that patients with schizophrenia who weaned off their antipsychotics fared significantly better over the long term than those who stayed on their meds. What Whitaker failed to mention was the patients who went off their meds had been identified at the beginning of the study as "good prognosis" patients.

Lest we dismiss Whitaker as a mere propagandist, a prominent Harvard psychiatrist, Andrew Neirenberg, in a 2011 response to a Massachusetts General Hospital grand rounds delivered by Whitaker, purported to "repudiate" and "refute" Whitaker but wound up instead comparing Whitaker to Sarah Palin and other such nonsense without firing back with even circumstantial evidence of his own. (A full account is provided in my blog piece, Whitaker vs Quack Psychiatry, Part II.)

In short, Whitaker's interpretation, if not authoritative, is at least credible. At the very least, his thesis supports the easily observable phenomenon of a good many patients who only seem to get worse on their antipsychotic meds rather than better.

Nevertheless, Whitaker Is a Wimp

It turns out that the harshest critics of antipsychotics are those engaging in cutting edge schizophrenia research. John Krystal of Yale, for instance, told a packed room at the 2007 American Psychiatric Association that antipsychotics "aren't that great," especially when dopamine hyperactivity "can't account for the sustaining features of schizophrenia." Dr Krystal is researching a new class of meds targeting the GABA-glutamate pathways.

Ironically, should a completely new class of drugs find their way to market (which has not happened since the 1960s), the strongest critics will turn out to be the very drug companies that marketed their antipsychotics as the best thing since sliced bread. Then we will be exposed to drug industry marketing along the lines of how their newest best thing since sliced bread leaves their old best thing since sliced bread for dead.

Alas, both the hype and the criticism obscure one important fact - that for a good many people antipsychotics have been a godsend, or, at the very least, have offered an invaluable leg-up to individuals in distress. Don't expect miracles, use wisely.

Further Reading from McManweb 

Antipsychotics * Lithium and Mood Stabilizers * The Problem with Bipolar Meds * Treating Mania * Treating Hypomania * Treating Bipolar Depression

Hats Off to Whitaker

Just a quick note that last week Robert Whitaker received the prestigious Investigative Reporters and Editors Award for his book, "Anatomy of an Epidemic." As regular readers of this blog are well aware, I have published at least 10 commentaries here based on his book, plus several more that used his book as a starting point for other topics. Some of my commentary was highly critical of Whitaker, but always in the context of acknowledging him as a welcome and vital voice and a breath of fresh air.

In singling out Whitaker, the IRE notes:

This eye-opening investigation of the pharmaceutical industry and its relationship with the medical system lays out troubling evidence that the very medications prescribed for mental illness may, in increasing measure, be part of the problem. Whitaker marshals evidence to suggest medications “increase the risk that a person will become disabled” permanently by disorders such as depression, bipolar illness and schizophrenia. This book provides an in-depth exploration of medical studies and science and intersperses compelling anecdotal examples. In the end, Whitaker punches holes in the conventional wisdom of treatment of mental illness with drugs.

Took the words right out of my mouth. Please-please-please, read his book. Warm congrats, Robert, from a sometimes critic but a very ardent supporter.  

The Whitaker Aftermath - Assessing the Quality of Information

Over the last several days, I have been commenting on the commenters to Robert Whitaker’s commentary,  “Anatomy of an Epidemic.” Much of the discussion - actually all of it - focuses  on the quality of the studies Whitaker relied on to support his controversial thesis that psychiatric disabilities are on the rise because of the widespread use of psychiatric meds, not despite them.

As a general rule, the more startling an assertion, the higher the level of proof we demand. Thus, if I say, “I have my driver’s license,” you are not likely to ask me to pull it out of my wallet and show it to you. (Ironically, three years ago I did not have a driver’s license, so the joke would have been on you.) You get the picture.

Accordingly, any spirited debate you run across concerning the studies Whitaker relies on are not mere academic quibbles. If his sources are faulty, or if he is making conclusions unsupported by the data, then we can easily dismiss Whitaker.

I’ve been reporting on mental health studies since 1999. My approach to looking at information as a journalist is quite a bit different from that of an academic researcher or a clinician looking at the same information. In many ways, my criteria for reporting is far more strict. And in other key ways, far more loose.

Basically, my standard is that we work from the best set of facts we have for the purpose of improving our understanding right now, and I suspect this is where Whitaker is coming from. We don’t sit around waiting for the ultimate gold standard study that is never likely to materialize. An example:

In 2009, I ran a series of reader polls on Knowledge is Necessity that found: 1) Four in five rated their meds as either the single most important tool in managing their wellness or as just as important as their other wellness tools; 2) Only 14 percent reported their meds worked “very well”; 3) Only 14 percent reported they were back to where they wanted to be.

Something clearly is very wrong with this picture. My series of polls indicate we dangerously over-rely on our meds and one result is we don’t get well. (You can read all about it on mcmanweb.)

But this is a reader poll, not a scientific study. A scientific study of this sort would probably cost in the neighborhood of several hundred thousand to get done. Maybe more. I would probably have to spend two years hustling for the same grant money six zillion other researchers are competing for, a year or more working with a team of experts designing and implementing the study and processing the data, and another year or two actually getting the thing published, assuming I was lucky enough to find an editor interested in reading it.

In all likelihood, my submission would be reviewed by an academic “referee” in the pocket of the drug industry who would find a million reasons to reject it.

But assuming my submission were accepted, there would be six to 12 months of revisions before my research saw the light of day. Nine-tenths of the study article would involve me explaining my methodology. The other one-tenth would be divided between the facts we need to know and my interpretation of what the facts mean. A journal editor would have me on a very short leash. My really interesting observations would likely be edited out, to the point that the study yielded little of value to anyone.

So - five or six or more years, several hundred thousand dollars, a team of experts, and endless aggravation for a by-now nearly meaningless study that maybe 30 people would read. If I were lucky, Robert Whitaker would find out about my study, mention it in his next book, make me famous, and draw all the conclusions that I was not allowed to make.

Then enraged academics like Andrew Nierenberg would attack him for relying on a low-quality study that really said nothing of the sort and moreover came from a nobody like me.

See what we’re up against?

***

This is the first in a series of pieces that examines the quality of mental health information, from different types of academic studies to clinical trials to media reports and blogs to informal surveys to personal experience. We will look at the tricks of the trade employed by the drug industry, academic researchers, journalists, and bloggers. We will look at why a so-called gold-standard scientific study may not be worth the paper it is printed on and why an unscientific reader poll may yield quality information.

Stay tuned ...