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