Rethinking Antipsychotics - Part I

In May, I came back from the American Psychiatric Association Annual Meeting rather surprised to find that psychiatry was finally openly acknowledging that: 1) treating patients with antipsychotics poses serious health risks, and 2) that antipsychotics are far from the magic bullets that the drug companies have been making them out to be.

Mind you, there is a place for smart antipsychotics meds strategies, but it appears that many of us have been the victims of spectacularly dumb ones.

Some background:

Antipsychotics were discovered by accident in the 1940s. The drugs bind to the neurons' dopamine D2 receptors, blocking dopamine transmission, thus dampening the over-stimulation of the brain that dopamine is implicated in. Thorazine is the oldest of what are now called first-generation antipsychotics. Haldol, another first-generation med, is still in common use.

Antipsychotics first came on the market to treat psychosis in schizophrenia, but were quickly pressed into service for mania (as well as psychosis) in bipolar disorder.

Clozaril represents the first of what are now called new-generation antipsychotics, or atypical antipsychotics. The drug was first marketed in Europe in the 1970s, and entered the US market in the 1980s. Because of the potentially lethal risk of agranulocytosis and myocarditis, the drug is recommended only as a last option for treatment-resistant patients.

Three new atypicals entered the market in the 1990s - Risperdal, Zyprexa, and Seroquel. Geodon and Abilify followed in the early 2000s. Invega (a derivative of Risperdal) just came on the scene. All of the atypicals (except Clozaril and Invega) have FDA indications for both schizophrenia and bipolar mania. In addition, Seroquel and a combination Zyprexa-Prozac pill, Symbyax, are approved for bipolar depression.

Because these new generation agents bind more loosely to the dopamine D2 receptor (thereby allowing some pleasurable dopamine in), the drug companies have been able to tout these meds as kinder and gentler, without a lot of the onerous side effects. The psychiatric profession and various patient-family advocacy groups quickly bought into the hype. In 2006, the industry earned $18 billion in antipsychotic sales worldwide.

Starting in 2000, a number of studies began challenging the claim that atypicals are more efficacious and have a better side effects profile than the older generation meds. The main point of contention is that the old generation meds may have been getting a bad rap because patients back in the days of Haldol and Thorazine used to receive extremely high meds doses. Indeed, back then, it was standard practice when starting treatment to raise the dose until the patient exhibited muscular twitching and involuntary spasms. Then the psychiatrist would reduce the dose slightly.

These spasms are collectively known as EPS (extrapyramidal symptoms). Generally, they are transient. But they may manifest chronically and permanently (usually after about six months) as "tardive dyskinesia." A 2004 meta-analysis of 11 long-term studies found that those on Haldol had a greater risk of incurring tardive dyskinesia than those on atypicals (5.4 percent risk vs 0 to 1.5 percent risk), though the study's authors noted that the doses in the Haldol studies were relatively higher.