Serotonin Synthesis Amplification to Augment the Therapeutic Efficacy of Serotonin Reuptake Inhibitor Antidepressants

BACKGROUND: Elevating brain extracellular (active) serotonin has broad-spectrum therapeutic efficacy across multiple psychiatric indications, with relatively good safety, tolerability, and scalability. The main drugs used are the serotonin reuptake inhibitors (SRIs), originally tricyclic antidepressants (TCAs), and later mainly selective-serotonin reuptake inhibitors (SSRIs). METHODS: This article reviews key clinical and ancillary animal evidence supporting that serotonin synthesis amplification adjunctive therapy can safety augments SRI clinical efficacy when SRI monotherapy is insufficient. RESULTS: SRIs work by blocking the serotonin transporter. This causes a net shift of serotonin to the extracellular space and increased serotonin neurotransmission, which mediates the therapeutic efficacy. However, SRI efficacy is modest, inconsistent, and with a delayed onset. Conversely, SRIs seem to elevate forebrain extracellular serotonin only modestly, inconsistently, and with a delay. Clinical trials spanning 6 decades report that SRI efficacy can be augmented by adjunctive therapy with a compound that amplifies brain serotonin synthesis, presumably acting by elevating brain extracellular serotonin beyond the SRI effect. SRI adjunctive therapy with the serotonin precursors 5-hydroxytryptophan (5-HTP) and tryptophan has been used in practice and in trials, but both compounds have poor drug properties. Adjunctive therapy with methylfolate and lithium likewise seems to augment SRI clinical efficacy at least partly through serotonin synthesis amplification. CONCLUSIONS: Despite this encouraging evidence, no SRI adjunctive FDA-approved drug product uses a serotonin synthesis amplification pharmacology. Such a drug could exhibit general SRI-augmentation therapeutic potential and be scalable across clinical scenarios.