Antipsychotics—Clinical Effectiveness
Essential Concepts
A large clinical trial, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), compared risperidone, olanzapine, quetiapine, and ziprasidone with perphenazine. Only 26% of subjects who entered this 18-month trial completed their assigned treatment, suggesting less-than-optimal effectiveness (efficacy and tolerability) of currently available antipsychotics.
Antipsychotics are selected based on individualized risk-benefit assessments (balancing psychiatric stability with day-to-day tolerability and long-term medical morbidity, particularly cardiovascular risk). To find the best medication for a patient usually requires sequential trials in a collaborative manner.
Include long-acting antipsychotics in the list of choices to routinely offer your patients, not only to those who refuse medications.
Switching antipsychotics to reduce long-term cardiovascular risk can be an appropriate clinical decision, albeit at the risk of psychiatric instability.
“Plus ça change, plus c’est la même chose.”
(“The more things change, the more they stay the same.”)
—Alphonse Karr, French critic, journalist, writer, editor of Les Guêpes where the epigram was published in 1849
The arrival of second-generation antipsychotics (SGAs) in the 1990s led to great excitement among both patients and psychiatrists. Although this optimism might seem naïve and unbridled today, it is important to remember that psychiatric drug development had made little (some would say no) progress beyond chlorpromazine, even though the limits of dopamine antagonists, both in terms of efficacy and side
effects (i.e., tardive dyskinesia), had become painfully clear. This changed with the publication of one of the truly seminal trials in psychiatry, the Kane trial (Kane et al., 1988), which showed that clozapine can be effective in patients who are refractory to first-generation antipsychotics (FGAs). In the following decade, SGAs other than clozapine became available for clinical use and became the treatment of choice for many patients in the United States.
effects (i.e., tardive dyskinesia), had become painfully clear. This changed with the publication of one of the truly seminal trials in psychiatry, the Kane trial (Kane et al., 1988), which showed that clozapine can be effective in patients who are refractory to first-generation antipsychotics (FGAs). In the following decade, SGAs other than clozapine became available for clinical use and became the treatment of choice for many patients in the United States.
However, almost all data supporting the superiority of SGAs had came from industry-sponsored drug trials, and some became convinced that the claims of superiority of SGAs were the result of comparing SGAs to what are today considered excessive haloperidol doses (Geddes et al., 2000). Others found somewhat better efficacy for some (clozapine, olanzapine, and risperidone), but not all, compared to FGAs, consistent with the heterogeneity of SGAs (Davis et al., 2003). Clinicians also started to notice that SGAs (while having a lower risk for tardive dyskinesia) had shifted the side-effect burden to metabolic problems.
CLINICAL ANTIPSYCHOTIC TRIALS OF INTERVENTION EFFECTIVENESS
To remedy this lack of independent and generalizable data, the National Institute of Mental Health (NIMH) decided to sponsor a large, randomized trial, CATIE, comparing the SGAs available at the time (olanzapine, quetiapine, risperidone; ziprasidone was added after the trial was at about the midway point; aripiprazole was not available) with each other and with a fairly low dose of the midpotency antipsychotic perphenazine (Phase I). In all, 1,493 patients were recruited from more than 50 representative sites in the United States and followed, double blind after randomization, for 18 months. The main outcome variable was all-cause discontinuation, a summary measure combining efficacy and tolerability. The focus of CATIE on effectiveness (to understand how a drug performs in real-world settings) is rather different than the typical pharmacologic efficacy trial (in which drug effects are studied under ideal conditions in homogeneous populations). CATIE patients who failed their initially assigned treatment because of lack of efficacy could go on to a second phase that included treatment with clozapine. The main results of Phase I were disappointing: Only 26% of subjects completed the trial on their initially assigned antipsychotic, pointing
toward major problems with available antipsychotics (Lieberman et al., 2005). Phase II confirmed the superiority of clozapine over available SGAs (McEvoy et al., 2006). Some clinical lessons from CATIE are summarized in Table 14.1. Another randomized trial conducted in Europe, CUtLASS 1 (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) similarly found older FGAs (in particular, one not available in the United States, sulpiride) as effective and as well tolerated as SGAs (Jones et al., 2006). In the end, the SGAs might not have been the major advance for all patients they were once hoped to be, and I think we will revisit the use of FGAs, particularly some midpotency FGAs.
toward major problems with available antipsychotics (Lieberman et al., 2005). Phase II confirmed the superiority of clozapine over available SGAs (McEvoy et al., 2006). Some clinical lessons from CATIE are summarized in Table 14.1. Another randomized trial conducted in Europe, CUtLASS 1 (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) similarly found older FGAs (in particular, one not available in the United States, sulpiride) as effective and as well tolerated as SGAs (Jones et al., 2006). In the end, the SGAs might not have been the major advance for all patients they were once hoped to be, and I think we will revisit the use of FGAs, particularly some midpotency FGAs.
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