Neurological Disorders

Therapeutic effect of novel antidepressant drugs interfering with receptors of neurotransmitters and neuropeptides

Abstract

Felix-Martin Werner

Major depression is a frequent psychiatric disease, which is mainly treated by different antidepressant drugs. However, one third of the depressive patients remain treatment-resistant. In major depression, in the brainstem, hippocampus and prefrontal cortex, alterations of neurotransmitters and neuropeptides and the belonging neural networks are updated. Starting from these findings, novel antidepressant drugs and combination of different antidepressant drugs are suggested. In the prefrontal cortex, glutamatergic neurons, which receive a postsynaptic excitatory potential from D2 dopaminergic neurons, exert a presynaptic inhibition upon M1 muscarinic cholinergic neurons via NMDA receptors. Medium spiny GABAergic/somatostatin neurons, which receive projections from M1 muscarinic cholinergic neurons, presynaptically inhibit D2 dopaminergic neurons via GABAA/somatostatin1 receptors. The combination of an NMDA receptor antagonist, for example ketamine with an M1 muscarinic cholinergic receptor antagonist, for example scopolamine, exert a rapid, long-lasting antidepressant effect. In preclinical studies, the antidepressant effect of orvepitant, an NK1 receptor antagonist, has been demonstrated: this antagonist reaches a complete antagonism of NK1 receptors. In clinical studies, the combination of an NMDA receptor antagonist with an M1 muscarinic cholinergic receptor antagonist should be investigated indepth as well as the therapeutic effect of orvepitant. In clinical studies, the antidepressant effect of a triple reuptake inhibitor should be examined and compared to current antidepressant drugs. The superior therapeutic effect of antidepressant drugs like venlafaxine, a selective noradrenaline and serotonin reuptake inhibitor and bupropion, a selective dopamine and nordrenaline reuptake inhibitor and their adverse effects will be pointed out. Non-pharmacological measures to enhance the antidepressant effect will also be discussed.