New Ways of Antipsychotic Dosing Considering the few new medications being developed for schizophrenia, it is recognized that novel avenues of research are needed for drug treatment of schizophrenia. While current antipsychotic drugs primarily block dopamine D2 receptors or interfere with dopamine neurotransmission (1, 2), many drugs for non-D2 pathways and receptors have been tested as possible antipsychotics, but not with much success. These include antagonists or agonists at receptors for D1 (SCH 23390), D3 (BP897; ABT925), D4 (fananserin/sonepiprazole), cannabinoids (rimonabant), neurokinins (SR142801; osanetant), neurotensin (SR48692), glycine transport inhibitors, ampakines (CX516), and serotonin (MDL100907; SR 46349B). The hypoglutamate hypothesis of schizophrenia suggests that low stimulation of glutamate receptors may be a basis for the illness. In fact, Patil et al. (3) reported that activation of the metabotropic glutamate-2/3 receptors (mGluR2/3) by LY404039 (or its precursor, LY2140023) was clinically equi-effective as olanzapine in alleviating psychotic signs and symptoms of patients with schizophrenia. Recently, however, Kinon et al. (4) reported that the clinical efficacy of LY404039 was “inconclusive.” At present, therefore, it appears that at least a D2-blocking component is needed for the treatment of schizophrenia. In addition, while there is preclinical information in animals that stimulation of mGluR2/3 receptors might be therapeutic, the clinical efficacy of this approach has not yet been clearly established (4). While interference with dopamine transmission at D2 is the minimum drug requirement for treating schizophrenia, there are new ways and new drugs that optimize the dosing of patients to minimize side effects and rehospitalization. These new ways are based on the fact that some antipsychotics, such as clozapine, quetiapine, amisulpride, remoxipride and amoxapine, attach to the D2 receptor in vitro for brief periods of time (half-times of 15 to 66 seconds) before dissociating from the D2 receptors (5-7). In fact, the transient attachment (a few hours in vivo) of quetiapine to D2 has been confirmed in patients (8).
