Olanzapine (Olz) is one of the most effective
antipsychotic drugs commonly used for treating
schizophrenia. Unfortunately, Olz administration is associated with severe
weight gain and metabolic disturbances. Both patients and clinicians are highly interested in the development of new
antipsychotics which are as effective as atypical
antipsychotics but which have a lower propensity to induce metabolic side effects. In the present study, we examined two new derivatives of Olz; OlzEt (2-ethyl-4-(4'-methylpiperazin-1'-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine), and OlzHomo (2-ethyl-4-(4'-methyl-1',4'-diazepan-1'-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine), for their tendency to induce
weight gain in rats.
Weight gain and metabolic changes were measured in female Sprague Dawley rats. Animals were treated orally with Olz, OlzEt, OlzHomo (3 or 6 mg/kg/day), or vehicle (nā=ā8), three times daily at eight-hour intervals for 5 weeks. Furthermore, a
phencyclidine (PCP)-treated rat model was used to examine the prevention of PCP-induced hyperlocomotor activity relevant for
schizophrenia therapy. Male Sprague Dawley rats were pre-treated with a single dose (3 mg/kg/day) of Olz, OlzEt, OlzHomo, or vehicle (nā=ā12), for 2 weeks. Locomotor activity was recorded following a
subcutaneous injection with either saline or PCP (10 mg/kg). Olz was found to induce
weight gain,
hyperphagia, visceral fat accumulation, and metabolic changes associated with reduced histamatergic
H1 receptor density in the hypothalamus of treated rats. In contrast, OlzEt and OlzHomo presented promising
antipsychotic effects, which did not induce
weight gain or fat deposition in the treated animals. Behavioural analysis showed OlzEt to attenuate PCP-induced hyperactivity to a level similar to that of Olz; however, OlzHomo showed a lower propensity to inhibit these stereotyped behaviours. Our data suggest that the therapeutic effectiveness of OlzHomo may be delivered at a higher dose than that of Olz and OlzEt. Overall, OlzEt and OlzHomo may offer a better pharmacological profile than Olz for treating patients with
schizophrenia. Clinical trials are needed to test this hypothesis.