Adjunctive 5-Hydroxytryptophan Slow-Release for Treatment-Resistant Depression: Clinical and Preclinical Rationale.
Serotonin transporter (SERT) inhibitors treat depression by elevating brain extracellular 5-hydroxytryptamine (5-HTExt). However, only one-third of patients respond adequately. Treatment-resistant depression (TRD) is a major unmet need. Interestingly, elevating 5-HTExtbeyond what is achieved by a SERT inhibitor appears to treat TRD. Adjunctive administration of 5-hydroxytryptophan (5-HTP) safely elevates 5-HTExtbeyond the SERT inhibitor effect in humans; however, 5-HTP cannot be a clinically viable drug because of its poor pharmacokinetics. A slow-release (SR) delivery mode would be predicted to overcome the pharmacokinetic limitations of 5-HTP, substantially enhancing the pharmacological action and transforming 5-HTP into a clinically viable drug. Animal studies bear out this prediction. Thus, adjunct 5-HTP SR could be an important new treatment for TRD. Here, we review the clinical and preclinical evidence for this treatment.
Department of Cell Biology, Duke University, Durham, NC 27710, USA.
Jacob P R
JPR
Jacobsen
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27710, USA.
Andrew D
AD
Krystal
Rush Medical College, Chicago, IL 60612, USA.
K Ranga R
KRR
Krishnan
Department of Cell Biology, Duke University, Durham, NC 27710, USA; Department of Medicine, Duke University, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: marc.caron@dm.duke.edu.
Marc G
MG
Caron
D006916:5-Hydroxytryptophan / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D006916:5-Hydroxytryptophan; D018687:Antidepressive Agents, Second-Generation; D003692:Delayed-Action Preparations; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
5-hydroxytryptophan; Antidepressant; depression; treatment-resistant depression
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