Schizophrenia is a serious mental illness that affects 1% of the world population. This destructive illness is characterized by dysfunctions of the thinking process, including hallucinations and delusions, which are clinically referred to as the “positive” symptoms due to their outward appearance. In addition, patients develop a pattern of withdrawal from the outside world and lack of pleasure seeking activities; these are referred to as the “negative” symptoms of the disease. What may be most devastating for families is watching the decline in cognitive and higher-order thinking processes of their loved ones which can occur quite early in life. This aspect of the disease, which represents the third symptom cluster, is often not widely recognized and may result in patients no longer being able to function in activities such as work, school, and day-to-day decision making. Currently, the positive symptoms are responsive to antipsychotics as described below. However, the negative symptoms and cognitive dysfunction usually remain untreated due to lack of available drugs that target these areas. This results in a critical need for development of improved options for individuals suffering from this disease so that a more complete response of their symptoms can occur resulting in a more manageable life for them and those around them.
WHAT TREATMENTS ARE AVAILABLE?
The first drugs available to treat schizophrenia were identified by accident in the 1950s beginning with chlorpromazine- the first of the so called ‘typical’ class of antipsychotics. At the time these drugs were championed as the greatest advance in psychiatric care resulting deinstitutionalization movement in hospitals worldwide and the first drug therapies with a true antipsychotic mechanism of action. In years that followed a number of unwanted side-effects were discovered with typical antipsychotics- notably Parkinson’s-like movement disorders such as involuntary tremors and body rigidity. These movement disorders or so-called extrapyramidal side effects (EPS) can become permanent if treatment is left unchanged or even after medication is stopped. Additional typical antipsychotics, including haloperidol, emerged in the 1950s and 1960s with very similar biological mechanisms of action and thus differed only slightly in their side-effect profile. In the 1970s second generation drugs for schizophrenia, known as ‘atypical’ antipsychotics, were introduced beginning with clozapine in 1971. These drugs, which now include more than twenty currently on the market, continue to retain the same fundamental mode of action on the dopamine system as that found with typical antipsychotics even though their full pharmacological profile is ; however, they appeared to be better tolerated with fewer EPS and hence their classification as atypical. Today however, we now know there are a number of serious side-effects found with atypical antipsychotics- including metabolic syndrome (weight gain), sexual dysfunction and agranulocytosis (white blood cell reduction). Moreover, clinical studies have recently shown that improvements in EPS may in fact be marginal for atypical drugs, patient compliance is still poor and cardiovascular risk (sudden cardiac death) appears to be similar for both classes of drugs after long term chronic treatment. Because these drugs focus primarily on dopamine receptor antagonism as the primary mechanism of action they are mostly effective at treating the positive symptoms of the disease and thus fail to provide significant relief in treating both the negative and the cognitive symptoms.
HOW IS THE VANDERBILT CENTER FOR NEUROSCIENCE DRUG DISCOVERY INVOLVED?
With the additional understanding of schizophrenia at the molecular and brain circuit level that has taken place over the past decade promising and exciting new strategies are now being validated in order to maximally treat all three symptom clusters. Just in the last few years genetic studies are shedding light on possible risk factors for the disease and these studies are leading to the identification of new molecular pathways that are providing novel targets for intervention.