Limbic selectivity of clozapine
Authors: James Longhurst
Journal: The Lancet (1997)

Lyn Pilowsky and colleagues (Aug 16, p 490)1Pilowsky LS Mulligan RS Acton PD et al.Limbic selectivity of clozapine.Lancet. 1997; 350: 490-491Summary Full Text Full Text PDF PubMed Scopus (148) Google Scholar make an important contribution to neuropsychiatric research with their demonstration of a selective reduction in striatal dopamine D2 receptor occupancy in patients on clozapine. They break new ground by reporting the first in-vivo evidence for the neuroanatomical selectivity, which is thought to underlie clozapine's unique clinical profile. However, their conclusion that “drug discovery for new antipsychotics should concentrate on highly selective D2 blockers” requires some clarification. There are three main dopaminergic tracts thought to be involved in the mechanism of action of clozapine: those from the ventral tegmental area to the limbic system and prefrontal cortex, and that from the substantia nigra to the striatum. - Presynaptic serotonin (5-HT2) receptors on dopaminergic neurons inhibit dopamine release in the prefrontal cortex and striatum, but not in the limbic system.2Young CR Longhurst JG Bowers MB et al.The expanding indications for clozapine.J Clin Exp Psychopharmacol. 1997; 5: 216-234Crossref PubMed Scopus (46) Google Scholar 5-HT2 receptor antagonists release dopaminergic neurons from this inhibition, which results in increased dopamine concentrations in the striatum and prefrontal cortex.3Kapur S Remington G Serotonin-dopamine interaction and its relevance to schizophrenia.Am J Psychiatry. 1996; 153: 466-476PubMed Google Scholar Although clozapine has the same in-vitro affinity for striatal D2 receptors as it does for such receptors elsewhere in the brain, it is also a potent 5-HT2 antagonist.4Nordstrom AL Farde L Nyberg S et al.D1, D2, and 5HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophernic patients.Am J Psychiatry. 1995; 152: 1444-1449PubMed Google Scholar In vivo, this action would be expected to selectively decrease serotonin-mediated inhibition of nigrostriatal dopaminergic neurons, leading to increased dopamine in the striatum, and thus reduced drug occupancy of D2 receptors, as Pilowsky and colleagues describe. Such localised increases in dopaminergic activity should keep to a minimum extrapyramidal adverse effects (via the striatum) and ameliorate negative symptoms (via the prefrontal cortex),2Young CR Longhurst JG Bowers MB et al.The expanding indications for clozapine.J Clin Exp Psychopharmacol. 1997; 5: 216-234Crossref PubMed Scopus (46) Google Scholar, 3Kapur S Remington G Serotonin-dopamine interaction and its relevance to schizophrenia.Am J Psychiatry. 1996; 153: 466-476PubMed Google Scholar both of which are consistent with the known clinical profile of clozapine. This hypothesis is further supported by the finding that a good therapeutic response to clozapine is associated with a low ratio of the dopamine metabolite homovanillic acid to the serotonin metabolite 5-hydroxyindoleacetic acid in the cerebrospinal fluid during treatment with clozapine.5Pickar D Owen RR Litman RE et al.Clinical and biological response to clozapine in patients with schizophrenia: crossover comparison with fluphenazine.Arch Gen Psychiatry. 1992; 49: 345-353Crossref PubMed Scopus (344) Google Scholar Clozapine's potent 5-HT2 receptor antagonism seems to have a major role in its unique clinical profile. In the search for new antipsychotics with clozapine-like clinical characteristics, attention should be directed towards combined D2/5-HT2 antagonists, which are most likely to show similar limbic selectivity.