CHAPTER 2: The Pathophysiology of Schizophrenia

Schizophrenia is a clinically and neurobiologically heterogeneous disorder that affects approximately 1% of the population worldwide. In the last century it has undergone and continues to undergo substantial changes in its conceptualization, the earlier concepts being driven mainly by clinical symptom classification, while in more recent years neurobiological findings are increasingly implemented. Many individuals experience a variety of symptoms, often in the symptom domains of positive, negative or affective symptoms as well as cognitive impairment. Affected individuals typically experience initial symptoms in the later teens or early adulthood, leading in a majority of cases to a chronic course of the disorder. Functional impairment is generally substantial, resulting in substantial burden of disease and reduced quality of life for the individual. The discovery of antipsychotic drugs in the mid 1950s fundamentally changed the prognosis for the patients, as mainly positive symptoms for the first time became amenable to treatment. However, though antipsychotic drugs have been developed further, overall efficacy has not been improved substantially, but the available antipsychotics vary mainly in their safety and tolerability profile, as well as individual response rates, which still cannot be predicted reliably.

An increasing amount of neurobiological data has been accumulated in the last decades, providing evidence for the involvement of dopamine and glutamate as well as other neurotransmitters in the etiopathology of various symptoms in schizophrenia. Evidence of structural abnormalities (e.g. volumetric reductions) has been found in neuropathological and neuroimaging studies. Cognitive impairment and its association with prefrontal cortical function have been well documented. The contribution of genetic factors is well established in addition to environmental and developmental factors, though the contribution of various candidate genes still remains to be elucidated in detail. The totality of neurobiological data has prompted integrative neurobiological theories, which are likely to have implications for drug discovery and drug development efforts in the future.