Safety Aspects of Antipsychotics

CATIE trial results have raised the question whether new „atypical“ neuroleptics (olanzapine, risperidone, amisulpride, quetiapine and ziprasidone) are superior to „typical“ ones like perphenazine, haloperidol, fluphenazine [1]. Outcomes of clinical studies are not applicable for evaluation of efficacy and tolerance of „atypical“ neuroleptics due to selection criteria and limitations for co-therapeutics. Moreover, severe side effects of neuroleptics have to be observed over a longer period of time in a broad patient population. The pharmacovigilance system AGATE (Arbeitsgemeinschaft Arzneimitteltherapie bei psychiatrischen Erkrankungen), a network of 39 hospitals, collects reports of side effects. These are clinically-pharmacologically verified. Results are reported to the Arzneimittelkommission der deutschen Aerzteschaft and the BfArM (Bundesinstitut fuer Arzneimittel und Medizinprodukte). The definition of a „severe side effect“ meets international criteria. Evaluation of unexpected side effects of clozapine, olanzapine, amisulpride, quetiapine, aripiprazole, risperidone and haloperidol is based on a six-category-system. Documentation between 1993 and 2005 included 2002 patients and 7399 prescriptions. Cases rated with „1“ (side effect possibly related to the drug, uncommon side effect, uncommon time course, possibility of other causes >50%), 2 (side effect likely related to the drug, known side effect, possibility of other causes <50%) and 3 (side effect related to the drug and reoccurrence of side effect after re-exposition of the drug) and interactions of two or more drugs meeting criteria 1–3. The highest frequency of side effects related to EPMS has been observed with haloperidol treatment in 52 out of 196 patients, followed by grand mal seizures in 19 patients. 34 out of 198 patients, who received clozapine, suffered from grand mal seizures followed by 23 patients with delirious symptoms. Olanzapine has been associated with 166 severe side effects, above all from the EPMS spectrum disorders in 30 patients. Weight gain was reported in 23 out of 166 patients. Risperidone was accused in 169 side effect cases, headed by 48 EPMS spectrum disorders, 19 cases of liver dysfunction and 10 with galactorrhoea. Amisulpride was involved in 46, quetiapine in 48 reports of side effects whereas aripiprazole was only mentioned 7 times. The overall incidence of the relative frequency of side effect reports decreased from clozapine > haloperidol > olanzapine > risperidone > amisulpride > quetiapine. Newer substances are subject to the same side effects as older ones with respect to extrapyramidal side effects. Clozapine alone merits the term „atypical neuroleptic“. Ad hoc signals can be considered as first important information for a single undesired event, regardless drawing conclusions on the overall frequency of side effects of a drug. This is the principle task of a spontaneous evaluation system. Literature: [1] Lieberman J A, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353(12): 1209–23.