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The so-called "new generation" or "atypical" antipsychotic medications
have actually become the typical medications prescribed by psychiatrists today in the treatment of schizophrenia and other
psychotic disorders. Since the introduction of the first atypical, clozapine (Clozaril), in the U.S. market in 1990,
several others have followed including risperidone (Risperdal), olanzapine(Zyprexa), quetiapine (Seroquel), and most recently
ziprasidone (Geodon). The main advantage of these newer drugs over the traditional antipsychotic medications or neuroleptics
(e.g. Thorazine, Mellaril, Haldol, Prolixin, Navane, etc), theoretically lies in their neuronal receptor binding properties.
Specifically, these medications block the number 2, 5-hydroxytryptophan (aka 5HT2) receptor, though to a variable degree within
their class. This action presumably translates into a desirable, clinical effect of improved neuromuscular tolerance
and a decreased tendency for tardive dyskinesia, a treatment resistant movement disorder which can be a complication of long
term treatment with neuroleptics. Moreover, the atypicals, also as a result of this receptor function, may reduce the
severity of "negative" symptoms of schizophrenia, such as apathy in personal care and interests, social withdrawal, and flattening
of emotions. While providing this additional benefit to the patient, these medications are purported to be at least
equally effective in managing the "positive" symptoms of the illness; i.e. the more noticeable signs of schizophrenia such
as delusions, hallucinations, bizarre behavior, and agitation.
Despite conventional wisdom that the atypicals are overall
superior drugs compared to their ancestors, I'm far from being sold on this assertion. There is no question that the
old antipsychotic drugs have their shortcomings, particularly regarding the tolerance issue; and we psychiatrists all eagerly
await a better mouse trap; but I simply don't believe we're there yet. Clearly, I have consistently observed a reduction
in involuntary movement disorders as well as some impressive "awakenings" with the newer drugs, notably Zyprexa and Seroquel,
but often at the expense of adequate control of the core symptoms. For every patient I've treated, who has a net benefit
from a crossover to either of these agents, I see another who experiences a clinical decline, despite using therapeutic
dosages. This is typically manifested as a breakthrough of psychotic symptoms, often necessitating augmentation with
the original neuroleptic agent, which seemingly defeats the purpose of using the atypical to begin with. Some might
argue that this approach can be justified as "rational polypharmacy", by combining the best qualities of the old and new for
optimum effect. However, there is a paucity of research demonstrating the safety and efficacy of such a strategy.
In the case of Risperdal, I'm often able to use it effectively as a solo treatment, but observe a greater incidence of movement
disorders and prolactinemia in comparison to the others. The latter syndrome may lead to breast enlargement in both
sexes and decreased or absent menstruation in premenopausal females. To date, I've prescribed very little Geodon because
of a cumbersome requirement by my employer to order baseline ECG and electrolytes, due to a remote risk of cardiac arrhythmias.
Also, for Clozaril, there is an FDA mandate for indefinite monitoring of white blood cell counts because of a 1-2% chance
of agranulocytosis (a potentially fatal blood dyscrasia), which limits its practical usage as well.
Another problem with the atypicals is their propensity for causing
significant weight gain, probably also mediated through their 5HT2 antagonistic properties as an anti-satiety effect.
This phenomenon appears to be especially commonplace with Zyprexa and Clozaril. Anecdotally, I've seen
patients gain as much as 100 pounds, but the typical range is 20-40 pounds in our clinic, usually occurring over several months
of treatment. Obviously, if obesity develops, implications for impending cardiac morbidity and diabetes heighten concern
about the safety of these drugs. Lately, I've had some modest success in preventing weight increases with pretreatment
dietary counseling. Notwithstanding, the metaphor, "The proof of the pudding's in the eating", comes to mind.
When
these new drugs first burst on the scene, the pharmaceutical manufacturers spared no expense to entertain us front-line psychiatrists
with lavish dinners which were backdrops for lecture presentations by "hired-gun" academicians, extolling the atypicals as
silver bullets while decrying their predecessors. Some even used intimidation tactics by accusing audience members of
malpractice if they were still prescribing older antipsychotic medications. We were also told that despite a hundred
fold or more increase in pharmaceutical costs with the newer drugs, a cost savings would be appreciated long term in decreased
hospitalization rates. Unfortunately, outcome data from managed care organizations with atypicals on their formularies
have confirmed the dramatic rise in drug costs, but no significant reduction on the hospital end. Not a surprising finding,
considering that the available supply of inpatient psychiatric beds in this country has been far exceeded by demand for them
since the days of deinstitutionalization.
More recently, the "anti-oldies" sales pitch has softened considerably, as
the new drugs now have a solid foothold in the market. Today, sales representatives seem to be spending the bulk of
their energies in sales calls attacking their present day competition on safety, efficacy, and cost issues. And after
more than a decade of experience with the new generation antipsychotics, great expectations have not been realized.
Sometimes, in comparing my relationship with these drug companies, I feel like Charlie Brown having the football yanked away
by Lucy right before I kick it. And yet, my vulnerability to having the wool pulled over my eyes is likely to continue
as long as the cure remains elusive. Oh well, some sage advice by a seasoned colleague seems to apply here..."Be sure
to use a new medicine when it first comes out, before it quits working."
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