Atypical Antipsychotics: New Directions and New Challenges in the Treatment of Schizophrenia

Abstract

"Atypical" antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT2 or D4 receptors, or a more rapid dissociation from the dopamine D2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a "pharmacological shotgun" strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.

Time Course of the Antipsychotic Effect and the Underlying Behavioral Mechanisms

“…Second, because our experiments designed to identify the behavioral mechanisms of antipsychotics were carried out primarily by using haloperidol, whether the same mechanisms are also responsible for the effects of atypical antipsychotics such as clozapine or quietapine has not been tested and is still an open question. Because of the unique receptor binding profile associated with each antipsychotic drug (Kapur and Remington, 2001), it is possible that some antipsychotics may work differently via different neurochemical mechanisms (eg 5-HT 2A , a 2 adrenoceptors). Finally, the subjects used in this study were normal rats, whereas antipsychotics are usually used to treat patients with schizophrenia.…”

Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia

“…Typical and atypical neuroleptics are known to bind with different affinities to dopamine and serotonin receptors (29), but the downstream effects of these drugs are not well known. When patients were subdivided according to medication received, we noticed that the expression of all OR genes tended to differ among the three subgroups (atypical neuroleptic, typical neuroleptic, and not treated with neuroleptics before death).…”

Dopamine D4Receptors Modulate GABAergic Signaling in Pyramidal Neurons of Prefrontal Cortex

“…Given its high affinity for atypical antipsychotic drugs that constitute a major improvement in the treatment of schizophrenia (Van Tol et al, 1991;Kapur and Remington, 2001), D 4 receptor has been suggested to play an important role in PFC cognitive functions and therefore to be involved in the pathophysiology of neuropsychiatric disorders (for review, see Oak et al, 2000). In agreement with this, D 4 receptor antagonists have been found to alleviate stress-induced working memory deficits in monkeys (Murphy et al, 1996) and to ameliorate the cognitive deficits exhibited by monkeys after long-term treatment with the psychotomimetic drug phencyclidine (Jentsch et al, 1997(Jentsch et al, , 1999.…”