Major Depressive DisorderPhase 2NCT05895747
5-HTP and Creatine for Depression R33 Phase
A Phase 2 study testing Low Dose 5-hydroxytryptophan, High Dose 5-hydroxytryptophan and Low Dose Creatine Monohydrate in people with Major Depressive Disorder, run by University of Utah at 1 site in United States.
Trial summary
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 100mg BID + creatine 5g daily, 5-HTP 200mg BID + creatine 10g daily, vs double placebo, for 8 weeks. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Low Dose 5-hydroxytryptophan, High Dose 5-hydroxytryptophan and Low Dose Creatine Monohydrate
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 106 participants
- Where
- 1 siteUnited States
- Study dates
- 28 Sep 2023to 30 Sep 2027
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults age 18-65 years inclusive
- Current diagnosis of MDD identified by the MINI (Mini Neuropsychiatric Interview)
- 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
Who cannot join
- Any non-MDD and non-anxiety psychiatric diagnosis, as identified by the MINI
- 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 (except well controlled asthma)
- Current smoking
- History of cardiac disease or QTc > 500ms
Show all 14Show fewer
- 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/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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Utah Department of Psychiatry
Salt Lake City, Utah, 84108
Brent Kious, 8015851418, brent.kious@hsc.utah.edu
About this study
Official title: 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 100mg BID + creatine 5g daily, 5-HTP 200mg BID + creatine 10g daily, vs double placebo, for 8 weeks. The ability of the interventions to affect biomarkers associated with depression will be assessed using brain phosphorus magnetic resonance spectroscopy, functional connectivity imaging, and plasma serotonin levels.
Read the detailed description
Major depressive disorder (MDD) has a lifetime prevalence of over 16% and is associated with reduced work productivity, disability, increased mortality, and increased rates of suicide attempts and completed suicides. Unfortunately, ~34% fail to respond to standard ADs (ADs). 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. Smoking also promotes hypoxia and is linked to increased risks of suicide and depression. Of special relevance to this study, living at high altitude produces relative hypoxia even after months, and is linked to increased risks of suicide and depression. 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), and alters mitochondrial dynamics in the hippocampus. 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. 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. Hypoxia could also promote MDD by altering serotonin (5-HT) production. Chronic hypoxia reduces 5-HT in the forebrain and brainstem in rodents. The conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase is oxygen-dependent and slowed by hypoxia. Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) are not as effective at altitude, 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, and resting state functional connectivity (fcMRI) studies suggest that depression involves reduced connectivity between frontal cortical regions and the amygdala, while AD response correlates with normalization of those connections. Alterations in connectivity associated with AD response are correlated with changes in brain metabolites, 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. Moreover, Cr produces improvements in mood correlated with normalization of PCr levels and structural connectivity. 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. 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 with dose variation and evaluate their correlation with clinical outcomes. The study will have the following aims:
Aim 1. Replicate the clinically meaningful changes in biological signatures (PCr:tP ratios as measured by 31P-MRS, sgACC connectivity as measured by fcMRI, and whole blood serotonin) demonstrated in the R61 phase, following the decision rule noted above.
Aim 2. Demonstrate that the changes in each of the above markers that is carried over from the R61 phase are correlated with changes in depression as measured by the 17-item Hamilton Depression Rating Scale, which would be studied in a subsequent efficacy trial.
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.
- Conditions
- Major Depressive Disorder
- Being tested
- Low Dose 5-hydroxytryptophan, High Dose 5-hydroxytryptophan, Low Dose Creatine Monohydrate, High Dose Creatine Monohydrate, Placebo
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low Dose 5-hydroxytryptophanDrug
Also called 5-HTP
5-hydroxytryptophan 100mg PO BID
High Dose 5-hydroxytryptophanDrug
Also called 5-HTP
5-hydroxytryptophan 200mg PO BID
Low Dose Creatine MonohydrateDrug
Also called creatine
Creatine monohydrate 5g PO qday
High Dose Creatine MonohydrateDrug
Also called creatine
Creatine monohydrate 10g PO qday
PlaceboDrug
Also called dextrose
Creatine-matched placebo and 5-HTP-matched placebo; Placebo will be dextrose either encapsulated (5-HTP matched) or as loose powder (creatine matched)
| Study group | Role | What they receive |
|---|---|---|
| Low Dose 5-hydroxytryptophan and Creatine Monohydrate | Experimental | 5-HTP 100mg PO BID plus creatine 5g PO Qday Receives: Drug: Low Dose 5-hydroxytryptophan; Drug: Low Dose Creatine Monohydrate; Drug: Placebo |
| High Dose 5-hydroxytryptophan and Creatine Monohydrate | Experimental | 5-HTP 200mg PO BID plus creatine 10mg PO Qday Receives: Drug: High Dose 5-hydroxytryptophan; Drug: High Dose Creatine Monohydrate |
| Double Placebo | Placebo comparator | Creatine-matched placebo and 5-HTP-matched placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
17-Item Hamilton Depression Rating Scale
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.
Measured: 8 weeks
Secondary outcomes (1)
Montgomery Asberg Depression Rating Scale
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
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jun 2023
- Study start28 Sep 2023
- Primary completion1 Jul 2027 (estimated)
- Study completion30 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 106 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Utah
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Brent Michael Kious, MD, PhD, University of Utah
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05895747
- Sponsor's protocol ID
- IRB_00132830_R33
- Status last verified
- Aug 2026
- First submitted
- 25 May 2023
- Last updated
- 27 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT05895747
- Acronym / sponsor ID
- IRB_00132830_R33
- Conditions
- Major Depressive Disorder
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 106 participants (estimated)
- Lead sponsor
- University of UtahUniversity, hospital or other
- Study start
- 28 Sep 2023 (actual)
- Primary completion
- 1 Jul 2027 (estimated)
- Study completion
- 30 Sep 2027 (estimated)
- First posted
- 9 Jun 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 100mg BID + creatine 5g daily, 5-HTP 200mg BID + creatine 10g daily, vs double placebo, for 8 weeks. The ability of the interventions to affect biomarkers associated with depression will be assessed using brain phosphorus magnetic resonance spectroscopy, functional connectivity imaging, and plasma serotonin levels.
Detailed description
Major depressive disorder (MDD) has a lifetime prevalence of over 16% and is associated with reduced work productivity, disability, increased mortality, and increased rates of suicide attempts and completed suicides. Unfortunately, ~34% fail to respond to standard ADs (ADs). 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. Smoking also promotes hypoxia and is linked to increased risks of suicide and depression. Of special relevance to this study, living at high altitude produces relative hypoxia even after months, and is linked to increased risks of suicide and depression. 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), and alters mitochondrial dynamics in the hippocampus. 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. 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. Hypoxia could also promote MDD by altering serotonin (5-HT) production. Chronic hypoxia reduces 5-HT in the forebrain and brainstem in rodents. The conversion of tryptophan to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase is oxygen-dependent and slowed by hypoxia. Animal studies have shown that selective serotonin reuptake inhibitors (SSRIs) are not as effective at altitude, 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, and resting state functional connectivity (fcMRI) studies suggest that depression involves reduced connectivity between frontal cortical regions and the amygdala, while AD response correlates with normalization of those connections. Alterations in connectivity associated with AD response are correlated with changes in brain metabolites, 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. Moreover, Cr produces improvements in mood correlated with normalization of PCr levels and structural connectivity. 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. 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 with dose variation and evaluate their correlation with clinical outcomes. The study will have the following aims:
Aim 1. Replicate the clinically meaningful changes in biological signatures (PCr:tP ratios as measured by 31P-MRS, sgACC connectivity as measured by fcMRI, and whole blood serotonin) demonstrated in the R61 phase, following the decision rule noted above.
Aim 2. Demonstrate that the changes in each of the above markers that is carried over from the R61 phase are correlated with changes in depression as measured by the 17-item Hamilton Depression Rating Scale, which would be studied in a subsequent efficacy trial.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Low Dose 5-hydroxytryptophan and Creatine Monohydrate | Experimental | Drug: Low Dose 5-hydroxytryptophan, Drug: Low Dose Creatine Monohydrate, Drug: Placebo5-HTP 100mg PO BID plus creatine 5g PO Qday |
| High Dose 5-hydroxytryptophan and Creatine Monohydrate | Experimental | Drug: High Dose 5-hydroxytryptophan, Drug: High Dose Creatine Monohydrate5-HTP 200mg PO BID plus creatine 10mg PO Qday |
| Double Placebo | Placebo comparator | Drug: PlaceboCreatine-matched placebo and 5-HTP-matched placebo |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Adults age 18-65 years inclusive
- Current diagnosis of MDD identified by the MINI (Mini Neuropsychiatric Interview)
- Current HAM-D17 score of >= 16
- Adequate adherence to any FDA approved SSRI or SNRI for at least 8 weeks
- Right-handed
Key exclusion criteria (14 listed)
- Any non-MDD and non-anxiety psychiatric diagnosis, as identified by the MINI
- 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 (except well controlled asthma)
- Current smoking
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Low Dose 5-hydroxytryptophanAlso: 5-HTP5-hydroxytryptophan 100mg PO BID | Drug | Low Dose 5-hydroxytryptophan and Creatine Monohydrate |
| High Dose 5-hydroxytryptophanAlso: 5-HTP5-hydroxytryptophan 200mg PO BID | Drug | High Dose 5-hydroxytryptophan and Creatine Monohydrate |
| Low Dose Creatine MonohydrateAlso: creatineCreatine monohydrate 5g PO qday | Drug | Low Dose 5-hydroxytryptophan and Creatine Monohydrate |
| High Dose Creatine MonohydrateAlso: creatineCreatine monohydrate 10g PO qday | Drug | High Dose 5-hydroxytryptophan and Creatine Monohydrate |
| PlaceboAlso: dextroseCreatine-matched placebo and 5-HTP-matched placebo; Placebo will be dextrose either encapsulated (5-HTP matched) or as loose powder (creatine matched) | Drug | Double Placebo, Low Dose 5-hydroxytryptophan and Creatine Monohydrate |
Primary outcome
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.
1 secondary outcome
Montgomery Asberg Depression Rating Scale
Time frame: 8 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Aug 2026.
- Individual participant dataSharing planned: No
Related trials for Major Depressive Disorder
RecruitingPhase 1
Open-Label Psilocybin Study in Transdiagnostic Population
Transdiagnostic, Depression - Major Depressive Disorder
Not yet recruitingPhase 2
Assessing of Behavioral Risk and Response to Electromagnetic and Psychedelic Therapies
PTSD, PTSD - Post Traumatic Stress Disorder
RecruitingPhase 2
A Study to Evaluate TNX-102 SL Monotherapy Versus Placebo in Participants With Major Depressive Disorder (MDD)
Major Depressive Episode (MDE), Major Depressive Disorder (MDD)
RecruitingPhase 1
Mechanism of Action Underlying Ketamine's Antidepressant Effects: The AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression
Depression, Major Depressive Disorder
Not yet recruiting
Acceptance and Committment Therapy Combined With Ketamine in Difficult-to-Treat Depression.
Major Depressive Disorder (MDD)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Low Dose 5-hydroxytryptophan, High Dose 5-hydroxytryptophan and Low Dose Creatine Monohydrate in people with Major Depressive Disorder, run by University of Utah at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Brent Kious, MD (8015851418, brent.kious@hsc.utah.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
17-Item Hamilton Depression Rating Scale (time frame: 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Aug 2026.