Schizophrenia is a chronic mental illness which becomes manifest as an acute psychosis with positive schizophrenic symptoms such as paranoia, hallucinations and illusions after a prodromal phase with negative symptoms. Schizophrenia is treated by administering second-generation antipsychotic drugs which exert a D2 and 5-HT2A antagonistic effect. In schizophrenia, in the mesolimbic system and the hippocampus dopamine and serotonin hyperactivity and hypoactivity of presynaptic inhibitory neurotransmitters (GABA and glutamate) have been reported.
In the prefrontal cortex, D1 dopamine hyperactivity and M4 acetylcholine hypoactivity was found. An antagonistic interaction between D1 dopaminergic and M4 muscarinic cholinergic neurons has also been described. The alterations of some neuropeptides, such as neurotensin, cholecystokinin and tachykinins will be also mentioned. Dopamine hyperactivity, via D2 receptors, can be found in the mesolimbic system and the hippocampus and D1 dopamine hyperactivity in the prefrontal cortex.
In schizophrenia, serotonin hyperactivity via 5-HT2A receptors is partly encoded in polymophisms of the serotonin transporter gene. A GABA hypofunction, via GABAA receptors, has been reported in the mesolimbic system and the hippocampus and it has been correlated with cognitive dysfunction. Among the altered neuropetides in schizophrenia, cholecystokinin, neurotensin and tachykinins will be mentioned. Cholecystokinin (CCK) levels were found to be decreased in the striatum, the nucleus accumbens and in the frontal and temporal cortices. The CCKA gene is associated with persistent auditory hallucinations in schizophrenia. It should be examined whether CCKA receptor agonists could be used as an additional therapy to improve these symptoms. In schizophrenic patients, neurotensin levels were reduced in the mesolimbic system and the prefrontal cortex. Neurotensin agonists, which activate the NTS1 receptor and the neurotensin NT69L analogue, have been proved to show an antipsychotic effect. Neurokinin A and B are of importance in the pathophysiology of schizophrenia.
Neurokinin-3 receptor antagonists could have antipsychotic properties, because in the mesolimbic system they reduce the activity of D2 dopaminergic neurons. Risperidone is a D2 and 5-HT2A antagonist with a great affinity for the D2 receptor. Due to its mechanism of action, it induces extrapyramidal symptoms (EPS) more often than olanzapine, and hyperprolactinemia. It improves negative symptoms, for example social withdrawal, autism and depression, like other antipsychotic drugs such as ziprasidone. It causes metabolic side effects, but less often than olanzapine. Olanzapine is a SGA with a greater affinity for the 5-HT2A receptor than risperidone.
Olanzapine has a superior effect than other second-generation antipsychotic drugs to improve negative schizophrenic symptoms and causes less often EPS than risperidone. In comparison to other SGAs, it causes metabolic side effects (glucose and cholesterol increases, weight gain) to a great extent. Quetiapine is a SGA with a greater affinity for the 5-HT2A receptor than olanzapine; seldom causes EPS and it is a prolactin-sparing SGA. It has a therapeutic effect on positive and negative symptoms like risperidone.
Ziprasidone is a SGA with an additional antidepressant effect through a 5-HT1A agonistic effect. It improves positive and negative schizophrenic effects and has side effects, which are comparable to those induced by olanzapine. Clozapine has a D3, D4 and 5-HT2A antagonistic effect and exerts the strongest antipsychotic effect. It seldom causes EPS and is a prolactin-sparing antipsychotic drug. The occurrence of neutropenia, which may occur in 3% of the patients, must be controlled by a weakly blood cell count.
Aripiprazole has a different mechanism of action. It has a D2 partial agonism, a 5-HT2A antagonistic effect and a 5-HT1A agonistic effect. It has been shown to have a secure antipsychotic effect and seldom causes EPS and weight gain. Up to now, there has not been chosen a way to select the appropriate antipsychotic drug.
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