Review article
Neuropsychopharmacology and the genetics of schizophrenia
A history of the diagnosis of schizophrenia
Thomas A. Ban
Department of Psychiatry, Vanderbilt University, Nashville, TN, USA
Accepted 10 May 2004 - Available online 25 July 2004
6. Neuropharmacology
Neuropsychopharmacology is dedicated to the study of action, and the identification of the structures responsible for the psychotropic effects of centrally acting drugs (Ban, 1996). Its roots are in Bernard’s (1869) recognition that drugs provide a physiological scalpel for the study of the physiology of the brain.
The essential prerequisites of neuropharmacological research were fulfilled by the late 1950s with the introduction of a host of psychotropic drugs (Ban,1969), and the advancement of the spectrophotofluorimeter, an instrument having the resolution power to measure changes in the concentration of cerebral monoamines, and their metabolites, involved in neuronal transmission at the synaptic cleft (Carlsson, 1998).
Developments in the neuropharmacology of schizophrenia were triggered in the early 1960s by the finding of an increase in the nialamide-induced accumulation of 3-0-methylated metabolites of dopamine and norepinephrine in chlorpromazine or haloperidol treated mouse (Carlsson and Lindqvist, 1963). The increase in the accumulation of 3 methoxytyramine and normetanephrine was attributed to a compensatory increase of tyrosine hydroxylase activity to the drug-induced blockade of catecholamine receptors (Engel, 1976). Postulation of a relationship between dopamine receptor blockade and antipsychotic (antischizophrenic) effects led to the introduction of a series of tests based on antagonism to dopamine agonists, e.g., antagonism to amphetamine-induced stereotype, or antagonism to apomorphine-induced vomiting, in the pharmacological screening for antipsychotic drugs (Janssen, 1998). It also provided that antipsychotics block dopamine receptors (Creese et al., 1975) and to the postulation of the dopamine hypothesis of schizophrenia (Snyder, 1976).
Development of receptor binding assays during the 1970s, and identification of receptor subtypes during the 1980s, led to the delineation of the receptor profile of each antipsychotic drug (Richelson, 1999). Employment of positron emission tomography in the late 1990s established that a 60% to 80% dopamine-D2 receptor blockade-that can be attained by the daily administration of 2-3 mg of haloperidol-suffices for optimal therapeutic effects (Kapur, 1998), and that doses in which most of the old antipsychotics are used, which produce a higher than 80% dopamine-D2 receptor occupancy induce severe extrapyramidal signs. (Farde et al., 1992) and other manifestations of drug-induced decrease of dopaminergic transmission e.g., brandykinesia, tardive dyskinesia (Knable et al., 1997).
Employment of the new technology made clear that the effectiveness of drugs in schizophrenia cannot be reduced to their dopamine-D2 receptor blocking effect. Clozapine, a substance with relatively low affinity to dopamine-D2 receptors, but relatively high affinity to serotonin-5HT2 receptors, was found to be effective, i.e., superior to an inactive placebo in the treatment of schizophrenia (Ackenheil and Hippius, 1977; Gross and Langer, 1966). Other drugs with a higher affinity to the serotonin-5HT2 receptors, than to the dopamine-D2 receptors, such as risperidone, olanzapine, quetiapine. Were found to be also consistently superior to placebo in the treatment of schizophrenia (Woods et al., 2001).
By referring to clozapine as an atypical antipsychotic, it is implied that antipsychotic drugs belong to two distinct categories, i.e., typical dopamine-D2 receptor blockers, and atypical, serotonin-5HT2A receptor blockers. However, this does not seem to be the case. Determination of receptor affinities revealed that typicality is a dimension rather than a category (Stip, 2000). Arnt and Skarsfeld (1998) reported that some antipsychotic drugs, e.g., risperidone, qualify as an atypical antipsychotic only at daily doses up to 4mg and atypical antipsychotic at daily doses greater than 8mg. In selected group of 10 antipsychotics, there is one, thioridazine, which has low affinity to both-the dopamine-D2 and the serotonin-HT2A receptors- and there are two, sertindole and risperidone, which have high affinity to both receptors. There are two drugs, fluphenazine and haloperidol, which have high affinity to the dopamine-D2 and low affinity to the serotonin-5HT2A receptors, and there are two drugs, clozapine and ziprasidone, which have high affinity to the serotonin-5HT2A and low affinity to the dopamine-D2 receptors. There are also three drugs, i.e., loxapine, chlorpromazine, and olanzapine, which have relatively higher affinity to the serotoin-5HT2A than the dopamine-D2 receptors.
Separation of receptor subtypes was further refined by the introduction genetic technology. By the late 1990s, with the employment of receptor cloning, five subtypes of the dopamine receptor, 14 subtypes of the serotonin receptor, and five subtypes of the muscarinic-cholinergic receptor, etc. Had been identified (Bonner et al., 1987; Sokoloff and Schwartz, 1995). The new genetic technology opened the path for tailoring antipsychotic drugs to receptor affinities (Bischoff et al., 1992). By using cell lines transfected with cloned receptors for finding chemicals which fit specific receptors, the new computational structural biology (Paul, 1996) allows for designing drugs with receptor profiles that would fit disease as keys fit their locks.