Perspective Current and Novel Approaches to the Drug Treatment of Schizophrenia Michael Rowley,* ,† Linda J. Bristow, ‡ and Peter H. Hutson* Merck Sharp and Dohme, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K. Received June 7, 2000 1. Incidence and Clinical Characteristics Schizophrenia is a devastating psychiatric illness that affects approximately 1% of the world population ir- respective of ethnic, economical, or cultural bound- aries: features that suggest the disorder has no simple, single causative factor. With current drug therapy, approximately 25% of patients recover to some extent within 5 years of starting treatment and about 65% of patients have recurring problems over many years. The remaining 10-15% of patients develop long-term inca- pacity and around 15% commit suicide. There are substantial costs, both direct and indirect, incurred by this disorder including those of drug treatment, resi- dential accommodation, physician and other healthcare services, and loss of productivity in the workplace. Clinical symptoms are apparent relatively early in life, generally occurring between the ages of 15 and 45. They are characterized by the presence of positive symptoms, for example auditory hallucinations, disorganized thoughts, delusions, and irrational fears, and negative symptoms, including social withdrawal, diminished affect, poverty of speech, lack of energy, and the inability to experience pleasure. In addition, schizophrenic pa- tients may suffer cognitive deficits including impaired attention, verbal fluency, memory recall, and executive function. 2. Aetiology The aetiology of the disorder is unknown: subtle structural changes are present in some brain regions although the consistency of these findings between studies is not particularly good (for an extensive, critical review of the neuropathology of schizophrenia see ref 1). Probably the most reliable findings are the small (6%) reduction of brain weight and somewhat variable increase of ventricular volume, although the latter also occurs in other neuropsychiatric disorders and therefore is not considered diagnostic. More recent studies using magnetic resonance imaging (MRI) techniques have confirmed the ventricular enlargement and additionally shown a decrease in the volume of specific brain regions. These include the thalamus 2 and temporal lobe struc- tures including the hippocampal formation, 3 amygdala, and parahippocampal gyrus. 4 Similarly, positron emis- sion tomography (PET) and functional MRI studies have demonstrated that not only are these regions physically affected, they are also implicated in some of the symp- toms of the disorder. Thus, specific neuronal circuits or pathways involving the thalamus, caudate-putamen, anterior cingulate, limbic and primary auditory cortex, hippocampus, and parahippocampal gyrus are activated in schizophrenics during auditory hallucinations. 5,6 Cy- toarchitectural changes including an alteration in the number, size, or orientation of neurones in several brain regions including the hippocampal formation, thalamus, and entorhinal cortex have been reported, but such findings are inconsistent. 1 At present it is not known how or why these structural changes occur. However, as there is little evidence of glial cell proliferation or associated glial cell proteins, and as the structural changes appear not to be progressive, degenerative mechanisms are not thought to be involved. Familial studies have shown that the risk of develop- ing schizophrenia is greater in family members than in * To whom correspondence should be addressed. M.R. e-mail: Michael_Rowley@Merck.com. P.H. e-mail: Peter_Hutson@Merck.com. † Current address: IRBM, Via Pontina Km 30,600, 00040 Pomezia- Rome, Italy. ‡ Current address: Merck Research Laboratories, 505 Coast Bou- levard South, La Jolla, CA 92037. © Copyright 2001 by the American Chemical Society Volume 44, Number 4 February 15, 2001 10.1021/jm0002432 CCC: $20.00 © 2001 American Chemical Society Published on Web 02/08/2001