ICI-204,636 - AN INITIAL APPRAISAL OF ITS PHARMACOLOGICAL PROPERTIES AND CLINICAL POTENTIAL IN THE TREATMENT OF SCHIZOPHRENIA

ICI-204,636 is a dibenzothiazepine analogue which is at an advanced st age of clinical development for the treatment of schizophrenia. It has binding affinities for a variety of receptors including alpha(1)-adre nergic, serotonin 5-HT2-, alpha(2)-adrenergic, dopamine D-2-, 5-HT1A- and dopamine D-1-receptors. However, ICI-204,636 has virtually no bind ing affinity for muscarinic receptors. Studies using several animal be havioural models have generally shown ICI-204,636 to have significant antipsychotic activity combined with a low potential for extrapyramida l effects. Electrophysiological investigation in rats demonstrated a s elective effect of ICI-204,636 on mesolimbic versus nigrostriatal dopa minergic pathways, a phenomenon suggested to be predictive of antipsyc hotic activity and low potential for extrapyramidal effects. However, this mesolimbic selectivity was not confirmed in a behavioural study i n rats. Data from a few phase II noncomparative and comparative clinic al trials indicate that ICI-204,636 appears to be effective in the tre atment of acute exacerbation of subchronic or chronic schizophrenia, a lthough few study details are currently available. At dosages less tha n or equal to 750 mg/day, ICI-204,636 was superior to placebo in impro ving schizophrenia symptomatology, although, since the effect was only transient in one study, results were equivocal. Significant antipsych otic effect was seen within 7 to 14 days after initiation of therapy. In a comparison with chlorpromazine, ICI-204,636 produced similar redu ctions in symptom scale scores. The most commonly reported adverse eff ects of ICI-204,636 include somnolence, agitation, headache, insomnia and elevated liver function tests. ICI-204,636 elevates plasma prolact in levels in rats to a similar extent to that produced by haloperidol but the effect appears to be transient. Similarly, in patients with sc hizophrenia, ICI-204,636 does not produce sustained elevations in plas ma prolactin levels. Based on animal data and initial clinical results , ICI-204,636 may have a low propensity to induce extrapyramidal effec ts, although it remains to be proven whether the severity is lower tha n that seen with conventional antipsychotics. In summary, ICI-204,636 is a new agent with demonstrated antipsychotic activity and a possible low propensity to cause extrapyramidal effects. As expected for a dru g in late phase III development, there are many questions concerning I CI-204,636 which must be answered before its overall place in therapy can be defined.