SchizophRenia Schizophrenia : disease & treatment

Abstract

Schizophrenia: disease & treatment Schizophrenia affects approximately 1% of the global population and is characterized by positive, negative and cognitive symptoms, all of which significantly impact quality of life for the patient (FiguRe 1). Positive symptoms include delusions, hallucinations and disorganized speech and can be thought of as symptoms that are ‘added’ to the normal behavioral repertoire. Negative symptoms include decreased pleasure seeking, poverty of speech and a lack of motivation; these symptoms can be thought of as behaviors that are generally ‘subtracted’ from the normal repertoire. Cognitive deficits are some of the most profound in schizophrenic patients and can include problems with memory, attention and sensory gating; various combinations of these symptoms, along with varying levels of severity, contribute to dysfunction in work, self-care and interpersonal relationships [1]. Current treatments exemplified by the typical and atypical antipsychotics (especially clozapine) alleviate the positive symptoms associated with schizophrenia in most patients; however, up to 30% of patients are treatment resistant. In addition, many of the typical antipsychotics which possess high affinity for the dopamine D2 receptor (haloperidol, chlorpromazine) exhibit extrapyramidal motor side effects, a major liability of this class of drugs. The atypical antipsychotics, including clozapine, aripiprazole and lurasidone, generally have a more favorable side-effect profile for motor effects but still have liability for weight gain and the associated metabolic disorders. Moreover, in the case of clozapine, agranulocytosis, can be life threatening and must be monitored throughout treatment. The major limitation of all anti psychotics developed to date is that, while they can control positive symptoms in some cases, none of the current treatments address the negative or cognitive symptoms associated with schizophrenia, representing one of the greatest unmet medical needs in psychiatric drug development [2]. The following sections highlight recent findings regarding genetic evidence for HDAC dysfunction in patients with schizophrenia, protein acetylation status, the potential for HDAC inhibitors to be used in conjunction with previously approved antipsychotics, and the potential of HDAC inhibitors to be utilized as standalone treatments for the negative and cognitive symptoms associated with schizophrenia.