New Drugs

Atypical Antipsychotics

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), ziprasidone (Geodon), and aripiprazole (Abilify).  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 pre-treatment dietary counseling.  Notwithstanding, the idiom, "The proof of the pudding is 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."


Scott Zentner