Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

Abstract

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

Atypical Antipsychotics and a Src Kinase Inhibitor (PP1) Prevent Cortical Injury Produced by the Psychomimetic, Noncompetitive NMDA Receptor Antagonist MK-801

“…The most potent atypical antipsychotic drugs were olanzapine, risperidone, and clozapine with ziprasidone and quetiapine being an order of magnitude less potent. This potency profile is similar to that observed in the treatment of humans with psychosis (Leo and Regno, 2000;Miyamoto et al, 2005;Sprague et al, 2004). This animal data must be considered with caution since only a few atypical antipsychotics were tested, a variety of drugs block injury produced by MK-801, and both oral and i.p.…”

“…Although doses vary, the average doses of the atypicals used to treat psychosis in humans are as follows: risperidone, 4-8 mg/day; olanzapine 5-20 mg/day; clozapine 6.25-400 mg/ day; ziprasidone 40-160 mg/day; and quetiapine 130-800 mg/day (Leo and Regno, 2000;Miyamoto et al, 2005;Sprague et al, 2004). This potency profile compares roughly to the potency in the present study of olanzapine4risper-idone4clozapine4ziprasidone4quetiapine.…”

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

“…Amphetamine, an indirect dopaminergic agonist, decreases PPI via dopamine D2 receptors (Ralph-Williams et al, 2002) that inhibit AC activity (Neves et al, 2002). Conversely, haloperidol, a typical antipsychotic that blocks D2 receptors (cf., Miyamoto et al, 2005) and increases cAMP signaling in forebrain structures (Berndt and Schwabe, 1973;Kaneko et al, 1992;Kaplan et al, 1999;Dwivedi et al, 2002; but see Kebabian et al, 1972;Carenzi et al, 1975), increases PPI (Ouagazzal et al, 2001). Thus, there appears to be a relationship between cAMP and PPI levels.…”

Distinct endocrine effects of chronic haloperidol or risperidone administration in male rats

“…Both drugs act on multiple neurotransmitter receptors, although each drug can be characterized by a unique receptor binding profile (Goldstein, 2000). Haloperidol acts primarily on dopamine D2 receptors with lower activity at D1, D3, D4, 5-HT2A and α1 adrenergic receptors (Goldstein, 2000 andMiyamoto et al, 2005). On the other hand, as with many atypical antipsychotics, risperidone possesses high serotonin (5-HT2A) receptor antagonism combined with relatively milder D2 receptor antagonism, compared to either its activity on 5-HT2A receptors or haloperidol's activity on D2 receptors (Goldstein, 2000, Megens et al, 1994and Miyamoto et al, 2005.…”

“…Haloperidol acts primarily on dopamine D2 receptors with lower activity at D1, D3, D4, 5-HT2A and α1 adrenergic receptors (Goldstein, 2000 andMiyamoto et al, 2005). On the other hand, as with many atypical antipsychotics, risperidone possesses high serotonin (5-HT2A) receptor antagonism combined with relatively milder D2 receptor antagonism, compared to either its activity on 5-HT2A receptors or haloperidol's activity on D2 receptors (Goldstein, 2000, Megens et al, 1994and Miyamoto et al, 2005. Current literature on the effects of haloperidol and risperidone on body weight gain and food intake vary, which is mostly likely due to the widely different drug treatment designs (dose and duration of drug treatment, mode of administration, diet composition, species and gender of experimental subjects).…”