Barriers to progress--the impact of tolerability problems

Side-effects of antipsychotic treatment are important factors in patients' compliance with treatment regimens. Of particular relevance to compliance are extrapyramidal symptoms (EPS), sedation, weight gain and sexual dysfunction. The new, atypical antipsychotics offer several tolerability benefits over conventional neuroleptics, particularly with respect to EPS. However, differences in their receptor binding characteristics result in different side-effect profiles. All novel antipsychotics have a high 5-HT2 to D2 receptor binding ratio, which is postulated to be important for a low liability for EPS. Ziprasidone, a new antipsychotic in the late stages of clinical development, has a low affinity for some receptor types, activation of which has been linked with adverse events such as sedation, postural hypotension, weight gain and cognitive impairment; for example, ziprasidone has minimal activity at muscarinic (M1), histaminergic (H1) and alpha1-adrenergic receptors. In short- and long-term clinical trials, ziprasidone had a low liability for side-effects typically associated with poor compliance, such as EPS, weight gain and sexual dysfunction. The tolerability profiles of the new antipsychotics represent a major improvement over the older neuroleptics. The more favourable the benefit/risk ratios of these new drugs throughout all phases of treatment, the greater the likelihood that patients will have better outcomes.