5-HTP and Creatine for Depression

November 30, 2023 updated by: Brent Michael Kious, MD, PhD, University of Utah

31P-MRS and Resting State Functional Connectivity Analysis of the Effects of 5-hydroxytryptophan and Creatine for Antidepressant Augmentation in Patients With SSRI/SNRI-resistant Major Depressive Disorder

This is a three-armed clinical trial examining the effect of 5-hydroxytryptophan and creatine monohydrate as augmenting agents for the treatment of depression. Subjects will be randomized between 5-HTP + placebo, creatine + placebo, and 5-HTP + creatine, for 8 weeks. The ability of the interventions to affect biomarkers associated with depression will be assessed using brain phosophorus magnetic resonance spectroscopy, functional connectivity imaging, and plasma serotonin levels.

Study Overview

Detailed Description

Major depressive disorder (MDD) has a lifetime prevalence of over 16%1 and is associated with reduced work productivity,2 disability,3 increased mortality,4 and increased rates of suicide attempts5 and completed suicides.6 Unfortunately, ~34% fail to respond to standard ADs (ADs).7 Environmental and patient-level factors that increase the risk of MDD could pinpoint novel mechanisms underlying the disorder. One such factor may be relative hypoxia. Persons with hypoxic medical conditions, such as asthma and chronic obstructive pulmonary disease, are at higher risk of depression and suicide compared to those with other chronic medical conditions.8-12 Smoking also promotes hypoxia13 and is linked to increased risks of suicide and depression.14-16 Of special relevance to this study, living at high altitude produces relative hypoxia even after months,17 and is linked to increased risks of suicide18-22 and depression.23,24 Hypoxia could contribute to MDD in at least two ways. First, brain bioenergetics are altered in both hypoxia and MDD. Hypoxia reduces several neurochemical markers of brain activity, including phosphocreatine (PCr) and n-acetylaspartate (NAA),25 and alters mitochondrial dynamics in the hippocampus.26,27 Proton magnetic resonance spectroscopy (1H-MRS) shows that high-altitude residents have altered whole brain pH and reduced inorganic phosphate to total phosphate (tP) ratios compared to persons dwelling at sea-level.28 In depressed patients, phosphorus MRS (31P-MRS) shows reduced nucleotide triphosphate (NTP) concentrations and decreased PCr concentrations; AD response is associated with increases in PCr and NTP.29 Hypoxia could also promote MDD by altering serotonin (5-HT) production. Chronic hypoxia reduces 5-HT in the forebrain and brainstem in rodents.30 The conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase is oxygen-dependent and slowed by hypoxia.31,32 Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) are not as effective at altitude,33 possibly because of inadequate 5-HT production. Reductions in 5-HT synthesis and inefficiencies in bioenergetics could both contribute to altered brain functional connectivity. MDD may disrupt cortical emotion regulation,34 and resting state functional connectivity (fcMRI) studies suggest that depression involves reduced connectivity between frontal cortical regions and the amygdala,35 while AD response correlates with normalization of those connections.36 Alterations in connectivity associated with AD response are correlated with changes in brain metabolites,37 suggesting a link to brain bioenergetics.

This suggests two natural supplements as interventions for depression. Oral creatine monohydrate (Cr) could improve bioenergetics in MDD, as Cr alters brain tCr, PCr, and NTP levels.38 Moreover, Cr produces improvements in mood39 correlated with normalization of PCr levels40 and structural connectivity.41 Alterations in 5-HT synthesis due to hypoxia could be rectified by 5-HTP, as its conversion to 5-HT is not oxygen-dependent. 5-HTP elevates brain 5-HT levels and has AD efficacy in clinical trials.42 The proposed study is a two-phase, three-armed trial to evaluate whether SSRI/SNRI augmentation with the supplements Cr, 5-HTP, or their combination (5-HTP+Cr) can enhance AD response in treatment-resistant MDD. In the R61 phase, the study will assess the ability of the interventions to alter biological signatures associated with depression, as measured by 31P-MRS, fcMRI, and changes in whole blood 5-HT. In the R33 phase, the study will attempt to replicate the above findings and evaluate their correlation with clinical outcomes. The study will have the following aims:

  • Aim 1 (R61+R33): To identify 31P-MRS correlates of AD response in subjects with MDD receiving Cr, 5-HTP, or 5-HTP+Cr. It is hypothesized that subjects' frontal cortical metabolism will normalize compared to controls over 8 weeks in those receiving Cr or 5-HTP+Cr but not those receiving only 5-HTP.
  • Aim 2 (R61+R33): To identify resting state fcMRI correlates of AD response in subjects with MDD receiving Cr, 5-HTP, or 5-HTP+Cr. It is hypothesized that resting functional connectivity in prefrontal regions will normalize (with improvement in hypoconnectivity between subgenual cingulate cortex and the remaining brain) over 8 weeks in all treatment groups compared to controls, with the greatest changes in the 5-HTP+Cr group.
  • Aim 3 (R61+R33: To characterize changes in whole blood 5-HT levels in study participants. It is hypothesized that whole blood 5-HT will increase over 8 weeks in subjects receiving 5-HTP or 5-HTP+Cr, but not those receiving only Cr.
  • Aim 4 (R33): To describe changes in HAM-D scores in study participants randomized between SSRI/SNRI augmentation with 5-HTP, Cr, or 5-HTP+Cr. It is hypothesized that HAM-D scores will improve over 8 weeks in all treatment groups, with the greatest changes in the 5-HTP+Cr group.

Study results will help elucidate the potential efficacy of a novel combination of nutritional supplements in persons with MDD, given strong epidemiologic and physiologic evidence suggesting that relative hypoxia can contribute to depression through alterations in brain bioenergetics and 5-HT synthesis. Target engagement will be indicated by improvements in functional connectivity and frontal cortical energy metabolism.

Study Type

Interventional

Enrollment (Actual)

38

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

    • Utah
      • Salt Lake City, Utah, United States, 84108
        • University of Utah Department of Psychiatry

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

25 years to 40 years (Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Adults age 25-40 years inclusive
  • Current diagnosis of MDD identified by the SCID-5
  • Current HAM-D17 score of > 16
  • Adequate adherence to any FDA approved SSRI or SNRI for at least 8 weeks
  • Right-handed
  • Residing at > 4000 ft for at least 12 weeks

Exclusion Criteria:

  • Any non-MDD and non-anxiety psychiatric diagnosis, as identified by the SCID-5
  • History of or current diagnosis of renal disease, such as chronic renal failure, acute renal failure or end stage renal disease
  • Current colitis or diverticulitis
  • History of or current pulmonary disease
  • Current smoking
  • History of cardiac disease or QTc > 500ms
  • History of fibromyalgia or any rheumatological condition
  • History of or current seizure disorder
  • Current serious suicide risk identified by the Columbia Severity Suicide Rating Scale
  • Current treatment with an antipsychotic, mood stabilizer, or non-SSRI or SNRI antidepressant except for bupropion at FDA-approved doses or trazodone up to 200mg, or use of any supplements apart from standard multivitamins
  • Positive pregnancy test, pregnancy, failure to use adequate birth control method
  • Previous diagnosis of serotonin syndrome or evidence of serotonin syndrome
  • Pre-existing eosinophilia (absolute eosinophil count > 500/uL)
  • Contraindications to MRI: ferromagnetic implants, implanted devices, claustrophobia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 5-HTP + Placebo
5-hydroxytryptophan 100mg PO BID plus placebo matched to creatine monohydrate
5-HTP 100mg PO BID
Other Names:
  • creatine monohydrate
placebo matched to 5-HTP
Active Comparator: Creatine + Placebo
Creatine 5g PO qday plus placebo matched to 5-HTP
placebo matched to 5-HTP
Creatine monohydrate 5g PO qday
Active Comparator: Creatine + 5-HTP
Creatine 5g PO qday plus 5-hydroxytryptophan 100mg PO BID
5-HTP 100mg PO BID
Other Names:
  • creatine monohydrate
Creatine monohydrate 5g PO qday
Placebo Comparator: Double Placebo
Creatine-matched placebo and 5-HTP-matched placebo
Dextrose either as loose powder (matched to creatine) or encapsulated (matched to 5-HTP)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
17-Item Hamilton Depression Rating Scale
Time Frame: 8 weeks
Hamilton Depression Rating Scale response: >=50% reduction in baseline score; maximum possible score is 52, minimum possible score is 0. Higher scores suggest more severe depression.
8 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Montgomery Asberg Depression Rating Scale
Time Frame: 8 weeks
Montgomery Asberg Depression Rating Scale; Response is a >=50% reduction in baseline score; minimum score 0; maximum score 60; higher scores suggest more severe depression
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2021

Primary Completion (Actual)

August 1, 2023

Study Completion (Estimated)

March 1, 2024

Study Registration Dates

First Submitted

May 15, 2020

First Submitted That Met QC Criteria

May 19, 2020

First Posted (Actual)

May 20, 2020

Study Record Updates

Last Update Posted (Estimated)

December 4, 2023

Last Update Submitted That Met QC Criteria

November 30, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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