Figure 4.

Points of intervention in TRD. A treatment approach on a plausible neurobiological model is proposed, which aims to prevent mPFC-induced serotonin shutting down the dorsal raphe. Utilizing an incremental approach, lamotrigine is recommended as a first step to curb glutamatergic inflow to the dorsal raphe. Aripiprazole will further reduce raphe glutamatergic input by blocking 5-HT_2A receptors in the medial prefrontal cortex and protecting 5-HT_1A autoreceptors from serotonin auto-inhibition through partial 5-HT_1A agonism. Quetiapine’s metabolite, N-desalkyl quetiapine, acts as an antagonist at α₂-heteroreceptors, thus protecting the raphe neurons from shutdown by norepinephrine overdrive. Finally, drugs like quetiapine also possess potent antihistaminergic effects for histamine H₁ receptors. Histamine through H₁ may reduce serotonin firing. Based on the view that each neurotransmitter system mentioned – glutamate, serotonin, noradrenaline, and histamine – are activated by stress and exert a partial inhibitory effect on serotonin outflow, monotherapy may well be inadequate. Rather, a “stacking” approach to pharmacotherapy is proposed and creating a formal database using this method is worthy of pursuing.