Methods A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments.
Results Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects.
Conclusions The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.” (New England Journal of Medicine via Paul)
One weblog commentator summarizes it thus:
Treating psychotic illnesses, especially schizophrenia, has been an important part of my career, so I have alot of thoughts about this. I hasten to add that I haven’t yet read the article, just the abstract, so some of my questions might otherwise have been answered. It is not clear how the pts. were recruited, what inclusion criteria (including what definition of schizophrenia) and exclusion criteria were used. It is also not clear how dosages of the antipsychotics were determined within the ranges defined for each drug in the study; it would make a difference whether pts were at the top end which, for many of those drugs is arguably an excessive and poorly tolerated dose. Random assignment of medications to subjects will lead to higher discontinuation rates because of intolerance than careful match between patient and medication.
It is not clear what the balance was in the study of discontinuation because of ineffectiveness as opposed to discontinuation becuase of intolerability. My first take on the fact that patients continued with olanzapine, aripiprazole and perphenazine longer than they did with quetiapine and risperidone relates to the fact that risperidone is more poorly tolerated at therapeutic doses and quetiapine is, simply, a less effective medication at controlling schizophrenic symptoms. Let us drill down further into this concept of “ineffectiveness.” This can mean one of several things because there are several different symptom domains in schizophrenia. Different theoreticians and researchers parse them differently, but concepts of the disease include some or all of the following realms — ‘positive’ symptoms, cognitive symptoms, ‘negative’ or ‘deficit’ symptoms, associated depression and other mood symptoms, and aggression/hostility. Only some of these symptom realms are considered to be responsive to antipsychotics. If medication fails to control the torture of active psychotic symptoms, patients will not remain engaged with treaters, will not organize their behavior and follow through with plans, etc. But most pts with this disease, even with effective medication control of florid psychotic symptoms, do not necessarily develop much insight — acceptance of their illness and need for treatment — or improvement in the cognitive domain. Associated depression may not respond to antipsychotics although we are beginning to think that it may be a core domain of the suffering in the disease, in contrast to the older outmoded notion thatt there are thought disorders and mood disorders and never the twain shall meet. So discontinuation of an antipsychotic may not have related to the drugs sucking as much as the illness sucking.
What treatment context and psychosocial supports were used during the lengthy trial? Follow me here — if the study design includes drug discontinuation (for how long — a missed dose? a day? a week?) as a data endpoint, the findings are not surprising at all. In realworld biopsychosocial treatment of patients with schizophrenia, there are lapses, fits and starts in treatment continuity almost as a matter of course. But in realworld treatment, they are not endpoints. Supportive interventions often result in the restoration of interrupted treatment, or seamless change to a different medication if the prior one was ineffective, without the pt spiralling down into a fullblown decompensation requiring psychiatric hospitalization.
I firmly believe that the newer, so-called atypical antipsychotic medications are a treatment advance over the older first-generation antipsychotics (Thorazine and Haldol and their derivatives). They are far more tolerable, but I do not in the least believe the contention that they cause less side effects. Rather, they cause different ones. Unless a patient experiences morbid weight gain, the side effects of the newer agents, in contrast to the older ones, are not irreversibly damaging or disfiguring. And the newer drugs may have more effects in the mood and cognitive spheres, and even that of impoverishment and ‘negative’ symptoms, than the older agents. But they are not curative. Schizophrenia is such a devastating illness that, if someone is normalized with treatment, it is likely they did not have schizophrenia. Yes, it sucks. But medication treatment does not deserve to be slandered by an out-of-context interpretation of a non-naturalistic study with little bearing on how we treat individuals with the illness in the real world, in a multidisciplinary model with psychosocial support.
