9 Results of recent clinical studies further raise concern over the modest advances that have been achieved over the last five decades in developing more effective drugs for treating schizophrenia. While meta-analyses comparing the first-generation antipsychotics to the secondgeneration antipsychotics

do suggest some modest Alisertib in vivo superiority of the second-generation Inhibitors,research,lifescience,medical antipsychotics, these effects are limited to positive symptoms known to be sensitive to D2 receptor antagonism.10 In the large-scale CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial, Lieberman et al11 compared several second-generation antipsychotics with a first-generation antipsychotic, perphenazine. The majority of patients in each group discontinued their antipsychotics owing to inefficacy or intolerable side effects. When clozapine was compared with other second-generation antipsychotics, Inhibitors,research,lifescience,medical it did exhibit modest but significant superiority over these other drugs. A separate study carried out in England, Cost Utility of the Latest Antipsychotic Drugs and Schizophrenia Study (CUtLASS 1), also found few differences in effectiveness between first-generation antipsychotics and second-generation antipsychotics in non-refractory patients.12 As pointed out by Lieberman,13 both the CATIE and the CUtLASS studies are “effectiveness” studies, which examine the

therapeutic response in real-world clinical situations. This design is Inhibitors,research,lifescience,medical markedly different from the randomized clinical trial of

Inhibitors,research,lifescience,medical “efficacy,” in which a new drug is compared with placebo in a very select group of patients subject to a myriad of exclusionary criteria. Thus, basing a drug discovery effort for schizophrenia on the assumption that it is primarily a disorder of dopaminergic dysfunction has led to the introduction of antipsychotics that are marginally more efficacious than their “progenitors,” chlorpromazine and haloperidol. Starting about 20 years ago, psychopharmacologists began to focus on other components of schizophrenia rather than just the antipsychotic responsive positive symptoms (ie, hallucinations, delusion, and thought disorder). Negative Inhibitors,research,lifescience,medical symptoms including apathy, poverty of thought, anhedonia, lack of drive, disorganization, and social isolation were observed to covary independently of positive symptoms, be much more enduring, and correlate inversely with outcome.14,15 With advances in neuropsychology, much more rigorous testing delineated the specific Thymidine kinase impairments in memory, problem-solving, and executive functions, which were noted a century ago with the designation of “dementia praecox.”16,17 At the same time, progress in both structural and functional brain imaging revealed substantial cortical involvement in schizophrenia. On average, cortical volume is reduced and lateral ventricular volume is increased in individuals with a first episode of schizophrenia, and these differences increase over the next 5 to 10 years.