New Insights into the Biology of Schizophrenia through the Mechanism of Action of Clozapine

Abstract

Many studies have detected in the brain of schizophrenic patients various morphological and structural abnormalities in various regions and in particular in the cortical and limbic areas. These abnormalities might in part result from neurodevelopmental disturbances suggesting that schizophrenia might have organic causes. These abnormalities may be the primary event in schizophrenia and be responsible for altered dopaminergic, but not only dopaminergic, neurotransmission in these regions. If schizophrenia is in some way strictly related to brain morphological abnormalities it becomes hard to believe that a curative treatment will ever be possible. Considering this scenario, treatment of schizophrenia will be restricted to symptomatic and preventive therapy and therefore, more effective and better tolerated antipsychotics are necessary. The widely used classical antipsychotic drugs present some disadvantages. They do not improve all symptoms of schizophrenia, are not effective in all patients, produce a number of unpleasant and serious, and partly irreversible, motor side effects. The atypical antipsychotic clozapine constitutes a major advance in particular for patients not responding to conventional neuroleptics. To explain the unique therapeutic effect of clozapine many hypothesis have been proposed. Most of the explanations given so far assume that the D2 blockade is the basis for the antipsychotic activity of clozapine and that the difference in respect to other antipsychotics is due to the contribution of other receptor interactions. Considering the dopaminergic receptor, in particular the recently discovered D4 receptor subtype, it has been observed that even if several classical neuroleptics exhibit high affinity to the D4 receptor, clozapine is more selective for this subtype compared to D2 receptors. Moreover clozapine, differently from all other conventional neuroleptics, is a mixed but weak D1/D2 antagonist. This observation has prompted speculation that the synergism between D1 and D2 receptors might allow antipsychotic effects to be achieved below the threshold for unwanted motor side effects. Probably the D1 antagonistic activity exerted by clozapine at low doses enhances preferentially the extracellular concentration of dopamine in specific areas of the brain, such as the prefrontal cortex, where a dopaminergic hypoactivity has been suggested to be in part responsible for negative symptoms of schizophrenia. The clozapine enhancement of dopaminergic activity in this brain area might explain its efficacy against schizophrenia negative symptoms. However, it cannot be excluded that the affinities displayed by clozapine for other nondopaminergic receptors also contribute to its unique therapeutic profile. The various hypotheses mentioned in this review need to be further validated or disproved. The only way to do that is developing new drugs where the postulated mechanistic profile is specifically realized and to clinically test these compounds.

Phospholipase C-β1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

“…Clozapine binds with high affinity to D4, 5-HT 1A, 2A , a1 adrenergic, histamine H1 and muscarinic receptors, and with lower affinity for D1, D2, D3 and D5 receptors. [58][59][60][61][62] While the significant effect of haloperidol upon PPI, independent of genotype, is consistent with previous studies, 63 clozapine mediated a complete rescue of PPI deficits in the KO mice. Thus, at the level of PPI behavior, environmental enrichment is acting in a parallel manner to clozapine, an atypical antipsychotic drug with clinical efficiency.…”

The Latent Inhibition Model Dissociates between Clozapine, Haloperidol, and Ritanserin

“…It is commonly asserted that both typical and atypical APD's are effective against positive symptoms whereas atypical APD's have higher efficacy for negative symptoms/ treatment-resistant schizophrenia, and that therefore, an animal model which is sensitive to both classes of APD's, may have predictive validity for the former condition whereas a model which is sensitive to atypical but not typical APD's may have predictive validity for the latter condition/s (Arnt and Skarsfeldt 1998;Brunello et al 1995;Kinon and Lieberman 1996). Viewed in this light, LI potentiation may have predictive validity for the treatment of positive symptoms and LI disruption may have predictive validity for the treatment of negative symptoms/treatment resistant schizophrenia.…”

“…There are several criteria for this distinction, extensively reviewed elsewhere (Arnt 1995;Arnt and Skarsfeldt 1998;Brunello et al 1995;Kinon and Lieberman 1996). The most accepted criteria of atypicality are reduced capacity to cause extrapyramidal side effects, superior therapeutic efficacy for negative symptoms/ treatment-resistant schizophrenia, and reduced capacity to induce catalepsy in rodents.…”

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

“…During the last decade, large efforts have been made to understand the mode of antipsychotic action of clozapine, but despite a large number of studies, our knowledge remains fragmentary. It is established that clozapine not only interacts with all DA receptors (the D 4 subtype showing the highest affinity (19 nM; Van Tol et al, 1991)), but also with other metabotropic receptors, for example, those for serotonin (5HT 1 and 5HT 2 ; Canton et al, 1990), acetylcholine (Snyder et al, 1974), noradrenaline (see Coward, 1992), and histamine (see Brunello et al, 1995;see Coward, 1992). Previous studies also point to an interaction with some ionotropic receptors, for example, the N-methyl-D-aspartate (NMDA) receptor (Arvanov et al, 1997;Ossowska et al, 1999) and the GABA A receptor (Squires and Saederup, 1998).…”