Outlook on improving pharmacotherapy in schizophrenia

Schizophrenia is undoubtedly an inheritable disorder. Hypoactivity of gamma-aminobutyric acid (GABA) is encoded in the GAD 67 gene and of glutamate in the neuregulin-1 and dysbindin-1 genes. The COMT gene, which catalyzes deactivation of dopamine, is associated with dopamine hyperactivity. In the pathophysiology of schizophrenia, hyperactivity of dopamine and serotonin and hypoactivity of glutamate and GABA have been described in the mesolimbic system, but in addition, alterations in the level of neuropeptides in schizophrenic patients have been reported.

In the mesolimbic system of schizophrenic patients, the following neuronal circuits can be suggested: serotonergic neurons transmit a postsynaptic excitatory impulse via 5-HT2A receptors to GABAergic neurons, which through GABAA receptors weakly inhibit dopaminergic neurons presynaptically. Dopaminergic neurons transmit an activating impulse to glutaminergic neurons via D2 receptors, which weakly inhibit serotonergic neurons presynaptically via NMDA (N-methyl-D-aspartate) receptors. In the A10 cell group, 5-HT2A receptors are located in the dopaminergic neurons, so that 5-HT2A antagonists reduce dopaminergic neurotransmission. Atypical neuroleptics (5-HT2A and D2 antagonists) have a huge antipsychotic effect and reduce side effects (e.g., dyskinesias), because the 5-HT2A antagonist effect is more potent than the D2 antagonist effect. The arising question is to know whether an additional therapy using GABAA and NMDA agonists could have a higher antipsychotic effect, since GABAA antagonists reduce dopaminergic neurotransmission and NMDA agonists reduce the activity of the serotonergic neurons.

Neuropeptide analogues and neuropeptides agonists or antagonists could be used as an additional therapy in schizophrenia. Neurotensin analogues could be of therapeutic value, and it is also important to know whether CCKA receptor agonists could be useful in patients with chronic auditory hallucinations, because the gene of the CCKA receptor is associated with these symptoms.

In sum, we discuss whether atypical neuroleptics combined with GABAA or NMDA agonists might have a higher antipsychotic effect and whether neurotensin analogues and CCKA receptor agonists administered as an additional therapy could be effective in chronic schizophrenia. An improved pharmacotherapy in schizophrenia is intended to improve patients' life quality and to reduce severity of acute psychosis.