Strategies for pharmacotherapy of schizophrenia

Schizophrenia is a debilitating syndrome consisting of several symptom dimensions (positive and negative symptoms; cognitive and mood disturbances) with a large unmet treatment need. Until now, the primary focus has been on the development of single drugs for treating all symptoms. It is now realized that the pathophysiologies of the symptom dimensions are very different, requiring drugs acting through different mechanisms. Furthermore, even within each symptom dimension the pathophysiology may vary considerably. However, it may still be possible to develop a single drug with efficacy for broad symptomatology. Some examples of novel strategies are given, e.g., dopamine D 2 antagonists with additional actions on specific serotonin (5-HT) receptor subtypes (5-HT6 receptors for example), 5-HT2C agonists, phosphodiesterase (PDE10) inhibitors, NK3 antagonists and mGlu(2/3) agonists. However, it has recently become more common to attempt to develop adjunct treatments to dopamine D-2-antagonist antipsychotics, particularly for improvement in cognitive deficits, which are considered the main determinant of functional outcome. This review describes various strategies to improve cortical function, which is believed to be suboptimal in patients with cognitive deficits and negative symptoms. These include drug actions on dopamine, 5-HT, norepinephrine, nicotinic and muscarinic receptor subtypes, as well as various glutamatergic drug targets.