Importance of intervention timing in the effectiveness of antipsychotics.
The use of early pharmacological intervention in treating young patients with schizophrenia is a debating issue for psychiatrists. However, on the basis of developmental theory, early antipsychotic intervention can be beneficial in terms of protecting neurons from further deterioration. This study investigated whether the initiation of second-generation antipsychotic (SGA) treatment at a younger age can effectively reverse schizophrenia-relevant behavioral and neurochemical features, namely acoustic prepulse inhibition (PPI) and accumbal dopamine (DA) efflux, respectively. Risperidone (RIS, 1mg/kg/day) or olanzapine (OLA, 2.5mg/kg/day) was administered for 6weeks in rats subjected to isolation rearing (IR) in adolescence or young adulthood. Behavioral testing was performed at 3 and 5 (for locomotor activity) and 2 and 4 (for PPI) weeks after the initiation of the pharmacological regimen. An additional PPI test was performed 6weeks after the initiation of the pharmacological regimen to assess the acute add-on effect of RIS or OLA. Dopamine (DA) efflux of the nucleus accumbens was evaluated through in vivo microdialysis at the end of the study, for measuring both the baseline levels after the chronic regimen and the responsiveness to acute add-on RIS or OLA treatment. Our results demonstrated that the effects of SGAs on PPI and accumbal DA efflux were dissociated. Specifically, RIS intervention was more beneficial for adolescent than young adult IR rats in restoring their PPI deficit, whereas OLA was age-independently effective in stimulating the accumbal DA efflux. Both PPI and accumbal DA could be employed to reflect IR-induced abnormalities, in which accumbal DA appeared to be more suitable in depicting the long-term effect of IR, whereas PPI might be a more accurate biological index for revealing the advantages of early RIS intervention.
Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC; Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan, ROC. Electronic address: yiaping@ndmctsgh.edu.tw.
Yia-Ping
YP
Liu
Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan, ROC.
Yu-Yin
YY
Yang
Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan, ROC.
Fang-Jung
FJ
Wan
Division of Medical Research and Education, Cheng Hsin General Hospital, Taipei, Taiwan, ROC.
Che-Se
CS
Tung
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001569:Benzodiazepines / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D000077152:Olanzapine; D065808:Prepulse Inhibition / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000008:administration & dosage*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology; D012741:Sexual Maturation; D012934:Social Isolation; D013997:Time Factors
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine; D004298:Dopamine
Dopamine efflux; Early antipsychotic intervention; Isolation rearing; Prepulse inhibition; Schizophrenia