Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Specific in vitro and in vivo binding of 3H-raclopride a potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain

Background: Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2( D 2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile. Methods: Twelve patients with schizophrenia were randomly assigned to doses of 150 to 600 mg/d (n=3, at 150, 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of treatment, D2 and 5-HT2a occupancy were measured using positron emission tomography (PET) imaging, 12 to 14 hours after the last dose. Clinical efficacy and adverse effect ratings were obtained at baseline, at the time of PET scanning, and at 12 weeks. Two additional patients were included to examine the effects of the drug 2 to 3 hours after last dose. Results: Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and prolactin level elevation noted at baseline. It achieved these results with minimal (0%-27%) D2 occupancy 12 hours after the last dose. Study of the additional subjects revealed that quetiapine does give rise to transiently high (58%-64%) D2 occupancy 2 to 3 hours after a single dose that then decreases to minimal levels in 12 hours. Conclusions: Quetiapine shows a transiently high D2 occupancy, which decreases to very low levels by the end of the dosing interval. Quetiapine’s low D2 occupancy can explain its freedom from extrapyramidal symptoms and prolactin level elevation. The data suggest that transient D2 occupancy may be sufficient for its antipsychotic effect. Future studies controlling for nonpharmacological effects as well as activities on other receptors will be necessary to confirm this suggestion.

A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy.

It is no longer tenable to attribute all the antipsychotic action of antipsychotic drugs to dopamine (DA) D2 receptor blockade and subsequent development of depolarization inactivation of the mesolimbic or mesocortical DA neurons. The chief evidence for this position is that clozapine (CLOZ) does not differ from typical antipsychotic drugs in these regards but is more effective than typical neuroleptic drugs. The mechanism of action of atypical antipsychotic drugs related to CLOZ may involve reduction of dopaminergic activity in the mesolimbic system by a variety of mechanisms, including D1 and D2 receptor blockade. Relatively higher affinity for the serotonin (5HT)2 receptor than for the D2 receptor may also be important to the action of CLOZ-like compounds. Enhanced DA release in the mesocortical system may be relevant to the effectiveness of these agents in treating negative symptoms. Several other classes of new agents alter the dopaminergic system by means of alternative mechanisms. Partial DA agonists may modulate DA neurotransmission more adequately than pure antagonists by producing a mix of direct agonist and antagonistic effects. DA autoreceptor agonists and 5HT3 antagonists appear to act by diminishing the release of DA from some, but not all, DA neurons. Substituted benzamides are "pure" D2 antagonists with some in vivo selectivity for limbic D2 over striatal D2 receptors. Highly selective D1 antagonists have been proposed to produce equivalent antipsychotic activity and fewer extrapyramidal symptoms than D2 antagonists. Antagonists of the recently identified D3 receptors are being sought. Excessive stimulation of the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, leading to neurotoxicity or diminished activation of this receptor, is the target of novel approaches to treating schizophrenia. Phencyclidine (PCP) antagonists that would activate the NMDA receptor and sigma receptor antagonists are of interest as antipsychotic agents. Therapeutic strategies for treating schizophrenia, schizophrenia-related disorders, and other psychoses will likely be genuinely diverse in the next decade.

The Mechanism of Action of Novel Antipsychotic Drugs

It has always been something of a mystery as to why different diseases of the basal ganglia may produce completely opposite effects on movement. Thus, defective dopaminergic inhibitory input into the striatum in Parkinson’s disease causes an akinetic-rigid syndrome, while destruction of the striatum in Huntington’s disease usually causes chorea. This theoretic paradox may be resolved by more detailed examination of the exact sites of striatal damage in the two opposing conditions (1). C. D. Marsden

/pdf/striatal-inhomogeneities-and-basal-ganglia-function-3a8itjvcsm.pdf

Striatal inhomogeneities and basal ganglia function

Remoxipride, a new potential antipsychotic compound with selective anti-dopaminergic actions in the rat brain

The ergolene derivative MPME induces in the rat a behavioural syndrome associated with activation of dopamine D-1 receptors belonging to the dotted type of forebrain dopamine nerve terminals

K. Ängeby

Papers

Remoxipride, a new potential antipsychotic compound with selective anti-dopaminergic actions in the rat brain

The ergolene derivative MPME induces in the rat a behavioural syndrome associated with activation of dopamine D-1 receptors belonging to the dotted type of forebrain dopamine nerve terminals