Imaging techniques such as CAT have shown that enlargement of the lateral ventricles is a frequent feature of schizophrenia. Such structural changes do not appear to be associated with the nature or duration of neuroleptic therapy and are found in affective disorders. The changes found in the schizophrenic brain may be triggered by environmental factors such as birth complications. In addition, selective reduction in the size of the temporal lobe commonly occurs in schizophrenics and such changes appear to be lateralized in the left hemisphere. Regional blood flow studies, and the measurement of regional glucose metabolism, has provided evidence of reduced frontal lobe function (hypofunctionality).
Table 11.7. Activity profile of typical and atypical antipsychotic drugs
Influence of DA system
Ideal Typical Atypical
A10 Prefrontal cortex A10 Limbic system A9 Striatum
Negative symptoms ;
Positive symptoms ;
Extrapyramidal effects -
Atypical neuroleptics such as clozapine and risperidone have been developed because it was found that up to 20% of schizophrenic patients did not respond to ''classical'' neuroleptics of the phenothiazine or butyrophenone type, while those patients who do initially respond to such medication frequently relapse during the first 2 years of treatment. Another reason for developing novel neuroleptics has been motivated by the finding that the ''classical'' neuroleptics have little beneficial effect either on the chronic course of the illness or on the negative symptoms. The negative symptoms of schizophrenia are frequently problematic to the patient and tend to be persistent, disabling and difficult to treat. In addition, the side effects of the ''classical'' neuroleptics which are associated with the sedative, anticholinergic and extrapyramidal effects of these drugs often result in poor compliance.
The potential advantage of the atypical antipsychotics arises from their ability to act on both positive and negative symptoms, to have a reduced tendency to cause extrapyramidal side effects, to be less sedative and to have little antimuscarinic activity. In terms of their actions on central neurotransmitters, the atypical neuroleptics can be divided into broad classes, namely those drugs such as remoxipride and amisulpride which are highly selective as D2 receptor antagonists and those that have a relatively weak D2 antagonistic action but which are potent inhibitors of 5-HT2A receptors. This latter group includes clozapine, risperidone, zotepine, sertindole, olanzapine and amperozide.
It has been postulated that the 5-HT2 antagonistic action of the atypical neuroleptics plays an important role in their efficacy in reducing the negative symptoms. There is evidence from PET studies in man that atypical neuroleptics such as clozapine occupy 80-90% of 5-HT2 receptors whereas the ''classical'' neuroleptics, such as haloperidol, occupy hardly any 5-HT2 receptors even at high therapeutic doses. The precise mechanism whereby such a high affinity of the atypical neuroleptics leads to a reduction in the negative symptoms of schizophrenia is uncertain. It is hypothesized that hypofrontality is associated with the negative symptoms and that the blockade of 5-HT2 receptors in the corticolimbic region of the brain reduces such symptoms. Experimental studies in rats have shown that serotonin modifies the pattern of dopamine release. When treated with the psychotomimetic drug phencyclidine, which can induce both positive and negative symptoms of schizophrenia in man under experimental conditions, the activity of the dopaminergic terminals in the frontal cortex is reduced. This hypofunctioning dopaminergic system can be normalized by treatment with 5-HT2 antagonists. It therefore appears that 5-HT2 antagonists cause an indirect activation of midbrain dopami-nergic cell activity, together with an increase in dopamine release in the frontal cortex.
The consequence of the combination of D2 and 5-HT2 receptor antagonism is therefore the selective enhancement of dopaminergic activity in the prefrontal cortex and, as a consequence, a correction of the regional imbalance between the cortical and midbrain dopaminergic systems.
Regarding the extrapyramidal side effects commonly found after treatment with the ''classical'' neuroleptics, PET studies of schizophrenia patients have shown that such drugs occupy 70-80% of D2 receptors in the basal ganglia at therapeutic doses. It has been calculated that a D2 receptor occupancy in the basal ganglia of approximately 80% carries a high risk that the patient will develop extrapyramidal side effects. Furthermore, Canadian studies have shown that the occurrence of extrapyramidal side effects was a major predictor for the subsequent development of tardive dyskinesia.
Thus the atypical neuroleptics with their lower affinity for D2 receptors in the basal ganglia, and their high affinity for 5-HT2 receptors in the frontal cortex, appear to combine therapeutic efficacy with a reduced tendency to cause neurological side effects.
Was this article helpful?
Being addicted to drugs is a complicated matter condition that's been specified as a disorder that evidences in the obsessional thinking about and utilization of drugs. It's a matter that might continue to get worse and become disastrous and deadly if left untreated.