Additional antidepessant pharmacological options in compliance with the classical neurotransmitters and neuropeptides involved

Introduction: In major depression exist a hypoactivity of the monoamines serotonin, noradrenaline and dopamine, a hyperactivity of the presynaptically inhibitory neurotransmitter GABA and glutamate and alterations of some neuropeptides. A neural network is developed in the midbrain, the hypothalamus and the hippocampus in order to derive additional antidepressant pharmacotherapies.

Material/Methods: In the „mood center“ of the midbrain, glutaminergic strongly inhibit via the subtype 5 of the metabotropic glutamate receptors (m5GluR) serotonergic neurons which, partly due to polymorphisms of the serotonin transporter gene have a low activity via 5-HT1A receptors. GABAergic neurons strongly inhibit via GABAB receptors nordrenergic neurons with a low activity via alpha1 receptors. In the hypothalamus CRH containing neurons strongly activate via CRH1 receptors glutaminergic neurons which strongly inhibit serotonergic neurons in the midbrain via m5GluR receptors. Galanin neurons in the hypothalamus weakly activite serotonergic neurons in the hippocampus via GAL2 receptors. In the hippocampus GABAergic strongly inhibit D2 dopaminergic neurons via GABAA receptors and glutaminergic neurons strongly inhibit 5-HT2A serotonergic neurons via NMDA receptors. Other serotonergic neurons activate serotonergic neurons in the hippocampus via 5-HT7 receptors. Substance P containing neurons transmit an activating impulse via NK1 receptors GABAergic neurons, and in the dentate gyrus neuropeptide Y neurons activate GABAergic neurons via NPY1 receptors.

Results: In compliance with the neural network described, the following drugs can be administered in the treatment of major depression:

• GABAB antagonists which increase noradrenaline levels through a descreased presynaptic inhibition,

• M5GluR and NMDA antagonists which increased serotonin levels,

• CRH1 receptor antagonists which increase serotonin levels through a reduced presynaptic inhibition via m5GluR receptors,

• GAL2 agonists which enhance serotonin neurotransmission,

• 5-HT7 antagonists,

• NK1 receptors antagonists which enhance GABAergic neurotransmission and

• NPY1 receptor antagonists.

Conclusion: It is essential to examine neural networks in the brain regions involved in major depression in order to optimize a multimodal antidepressant pharmacotherapy.

Fig. 1: Brain centers involved in major depression