A neurobiological hypothesis of treatment-resistant depression - mechanisms for selective serotonin reuptake inhibitor non-efficacy

Abstract

First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are <50%. The authors examine the putative biological substrates underlying "treatment resistant depression (TRD)" with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin system becomes impervious to the desired enhancement of serotonin neurotransmission by SSRIs. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple serotonin deficit state but rather an excess of midbrain peri-raphe serotonin and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in serotonin-mediated neuroplasticity. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part by "flooding" 5-HT1A autoreceptors by serotonin itself. Certain factors putatively exacerbate this scenario - presence of the short arm of the serotonin transporter gene, early-life adversity and comorbid bipolar disorder - each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing serotonin neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for "stacked" interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic, and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on serotonin neurons. Future studies are recommended to test this biologically based approach for treatment of TRD.

Keywords: dorsal raphe; glutamate; hippocampus; lamotrigine; selective serotonin reuptake inhibitors; somatodendritic 5-HT1A autoreceptors; treatment-resistant depression; α2-heteroreceptors.

Figure 1

Normal functioning serotonergic neuron. The schema depicts a normally functioning serotonin neuron located in the dorsal raphe. A number of features are highlighted. Glutamatergic afferents arise from layer V pyramidal neurons of the medial prefrontal cortex (mPFC), which project, directly via a single axon directly to the dorsal raphe. Activation of 5-HT_2A receptors in the mPFC activates these cortical neurons whereas activation of 5-HT_1A receptors diminish glutamatergic outflow from the mPFC. The absence of rapid response to SSRIs was attributed to the shutdown of dorsal raphe neuron firing following acute enhancement of a negative feedback loop via somatodendritic 5-HT_1A receptors located on the cell bodies of serotonin neurons in the dorsal raphe. Increasing norepinephrine neurotransmission from locus ceruleus firing through α₂-heteroreceptors produces inhibition of dorsal raphe serotonin neuron firing. Histamine exerts an inhibitory effect on serotonin neuronal firing through histamine H₁ receptors. Serotonin neurotransmission enhances neuroplastic effects and intracellular transduction cascades following post-synaptic agonism of 5-HT_1A receptors located in the hippocampus, ultimately resulting in an increase in neurogenesis. Normative neurotransmission at each synaptic junction is represented by the depiction of five “neurotransmitter molecules” located within the synaptic junction and five in the presynapse.

Figure 2

Serotonergic neurotransmission under stress and/or hyperglutamatergic states. Glutamatergic excitatory input activates a small population of serotonin neurons in the posterior part of the dorsal raphe, which leads to accumulation of extracellular serotonin, spreading to the anterior regions of the dorsal raphe thereby suppressing serotonin outflow through activation of somatodendritic 5-HT_1A autoreceptors. Stress induces glutamatergic neurotransmission directed into the dorsal raphe and stress therefore “floods” the dorsal raphe with serotonin, thus “choking” serotonin outflow. Activation of 5-HT_2A receptors in the mPFC activates Layer V cortical neurons enhancing glutamatergic input into the dorsal raphe. High peri-raphe 5-HT has been putatively demonstrated by high cisternal CSF taps in adversely reared non-human primates where elevations of CSF 5-HIA have been noted in adversely reared subjects in comparison to normally reared controls. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part, by “flooding” 5-HT_1A autoreceptors by serotonin itself. Factors, which may exacerbate this scenario, such as presence of the short arm of the serotonin transporter gene, early life adversity and comorbid bipolar disorder, are generally associated with SSRI-treatment resistance. An excess of midbrain peri-raphe serotonin is associated with a subsequent deficit at important fronto-limbic projection sites, with a compromise in serotonin-mediated neuroplasticity.

Figure 3

Effect of addition of an SSRI in a TRD patient. SSRI addition would induce a flood of serotonin in the region of the dorsal raphe and would tend to shut down serotonin neuronal firing through agonism of 5-HT_1A autoreceptors and would tend to exacerbate rather than improve a deficit state of serotonin at the distal projection site. Raising the dose of the SSRI, which is common practice in an upward titration strategy, may in fact, exacerbate the situation of flooding the extracellular fluid with serotonin and further preventing the possibility of serotonin neurotransmission enhancement. The serotonin system may impervious to the physiological process of an increment of SSRI producing a commensurate enhancement of serotonin neurotransmission. Rather, an increment in SSRI reduces the likelihood of serotonergic neurotransmission enhancement as the dosage increase exacerbates the build-up of serotonin in the peri-raphe area, thus enhancing shutdown of serotonin firing through 5-HT_1A-autoreceptor agonism. Of note, the magnitude of peri-raphe serotonin build-up overwhelms the capacity of 5-HT_1A autoreceptor to down-regulate.

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.