Depression symptomatology is uniquely human and difficult to model in animal behavioral models. All clinically effective antidepressants were developed based on initial clinical pilot trials and observations. The EVX-101 rationale is similar, based on convergent multi-pronged clinical data.
1. Elevating extracellular serotonin beyond the SSRI/SNRI effect enhances antidepressant efficacy. Multiple clinical reports find that adding a second serotonergic compound to antidepressant therapy, to enhance extracellular serotonin (aka 5-HText) additionally, treats additional patients. Such second serotonergic compounds include tryptophan, monoamine oxidase inhibitors, 5-HTP, and methylfolate. Based on available clinical evidence, all such compounds appear effective in augmenting antidepressant efficacy. However, all have drawbacks related to safety, pharmacokinetics, and/or mechanism, which precludes their general clinical use.
2. Evidence that serotonin deficiency is causal in SSRI/SNRI non-response. CNS metabolomics biomarkers of serotonin deficiency segregate with poor antidepressant response to SSRI/SNRIs. Conversely, suicidality and co-morbid borderline personality disorder, two conditions associated with CNS serotonin deficiency, predict poor antidepressant response to SSRI/SNRIs.
3. PET imaging: SSRI/SNRIs elevate extracellular serotonin inconsistently in humans. The serotonin transporter, the main target of SSRI/SNRIs, is just one of many regulators of extracellular serotonin. In fact, recent human brain imaging data show that chronic SSRI treatment only elevates brain extracellular serotonin modestly, on average, and not at all in some humans. Further, brain imaging finds that SSRIs short-term may even decrease extracellular serotonin in the human frontal cortex, likely due to auto-inhibitory feedback. These latter findings could help explain early adverse events and the delayed onset of therapeutic efficacy.
4. 5-HTP and SSRI synergizes in elevating extracellular serotonin in humans. Neuroendocrine (cortisol, prolactin) biomarker studies consistently finds that 5-HTP alone is modestly effective in elevating brain extracellular serotonin. In contrast, adjunctive 5-HTP strongly augments the extracellular serotonin elevation produced by SSRIs.
5. Reports of adjunctive 5-HTP + carbidopa antidepressant effects in humans. Several pilot reports, totaling ~200 subjects, report that adjunctive 5-HTP/carbidopa augments the antidepressant effect of SSRI-like or other serotonergic antidepressants.
6. 5-HTP has a good human safety record. Experimental clinical studies with 5-HTP has been pursued since the 1950s. Thousands of subjects have been dosed with 5-HTP, in doses often exceeding 1g/day, with or without carbidopa, and with or without another serotonergic drug. Yet, there are no reports of serotonin syndrome, other serious events, or death associated with 5-HTP (NIH, FDA).
7. 5-HTP's human half-life and time to peak plasma levels are too short for a drug. As a rule of thumb, drugs must be dosed at least every two half-lives to maintain steady exposure and efficacy. With a half-life of 2h, 5-HTP would have to be dosed 6 times per day, which is unattaintable in a real-life clinical setting. Further, 5-HTP's rapid absorption (Tmax = 1.5h) and resultant serotonin spikes is associated with gastrointestinal and other side effects.
8. Extracellular serotonin elevation must be sustained for antidepressant efficacy in humans. In previously depressed patients treated to remission with an SSRI, SNRI, or another serotonergic antidepressant, acutely reversing the extracellular serotonin elevation causes acute relapse. The relapse occurs within hours. This demonstrates that the antidepressant effect is directly sustained in real time by the elevation in extracellular serotonin.
9. Advanced slow-release delivery technologies can transform the drug-properties of fast pharmacokinetics compounds. Over the last decades, slow-release drug delivery technologies have been implemented that can markedly improve the therapeutic potential of short-acting compounds. Examples of such compounds include nifedipine, L-DOPA/carbidopa, venlafaxine, dimethyl fumarate, minocycline, methylphenidate, and niacin.