Principal Investigator: Brent Kious
Keywords: Depression , Treatment-resistant depression , Nutritional supplements Department: Psychiatry
IRB Number: 00132830 Co Investigator: Younghoon Sung
Specialty: Psychiatry, Psychiatry
Sub Specialties: Mood Disorders
Recruitment Status: Recruiting

Contact Information

Hailey Nielson

Simple Summary

The purpose of this study is to determine whether two nutritional supplements--creatine and 5-hydroxytryptophan--can improve symptoms of depression in persons who have not responded well enough to conventional antidepressants. It also uses brain imaging and laboratory work to measure the effects of the supplements on brain energy storage and serotonin production.

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 We propose 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, we 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, we will attempt to replicate the above findings and evaluate their correlation with clinical outcomes. Our 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. We hypothesize 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. We hypothesize 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. We hypothesize 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. We hypothesize that HAM-D scores will improve over 8 weeks in all treatment groups, with the greatest changes in the 5-HTP+Cr group.Our 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.

Inclusion Criteria

In the R61 phase, ~60 men and women with SSRI/SNRI-resistant depression (up to 75 subjects allowing for ~20% attrition) will be randomly assigned in a 1:1:1:1 ratio to either 5-HTP+creatine, creatine+placebo, 5-HTP+placebo, or placebo + placebo for eight weeks.

Using purposive sampling, men and women with depression who have not responded to an adequate trial of an SSRI or SNRI will be recruited for this trial. Individuals will be considered for participation if they are between the ages of 25-40 years, meet DSM-5 criteria for a current major depressive episode based on the Structured Clinical Interview for DSM-5 (SCID-5), and exhibit a Hamilton Depression Rating Score (HAM-D) of 16 or greater. An age range of 25-40 was chosen based on considerations of participant ability to consent, declining overall physical health with advanced age, and to minimize heterogeneity in brain structure and connectivity associated with both early adult remodeling and age-related degeneration. In addition to the above criteria, subjects will be regarded as having treatment-resistant depression if they have been taking a therapeutic dose of any FDA-approved selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for at least 8 weeks with a stable dose for at least 4 weeks but have continued clinically-significant depressive symptoms.

Participants will be eligible for inclusion if they have been adequately adherent to any FDA-approved SSRI or SNRI at standard doses for at least 8 weeks. Eligible SSRIs and dose ranges include citalopram 20mg-40mg per day, escitalopram 10mg-30mg per day,148 fluoxetine 20mg-80mg per day,149 fluvoxamine 100mg-300mg per day,150 sertraline 50mg-200mg per day,151 or paroxetine 20mg-50mg per day.152 Eligible SNRIs and dose ranges include venlafaxine 75mg-300mg per day,153 duloxetine 30-120mg per day,154 desvenlafaxine 50mg-100mg per day,155 and levomilnacipran 40-120mg per day.156 Adequate adherence will be assessed according to participant report and is defined as completion of at least 75% of scheduled doses. To be eligible, participants should have been receiving the baseline SSRI dose for at least 4 weeks but may have had dose adjustments prior to that period.  Subjects will be required to reside at 4000ft or above for at least 12 weeks to assure that they are chronically hypoxic. To thoroughly assess subjects’ antidepressant treatment histories, an Antidepressant Treatment Response Questionnaire (ATRQ) will be administered at the screening visit.

Exclusion Criteria

Individuals who meet criteria for any psychiatric condition apart from MDD on the SCID-5 will not be invited to participate, with the exception of subjects who meet criteria for anxiety disorders (social anxiety disorder, generalized anxiety disorder, specific phobias, panic disorder, agoraphobia, post-traumatic stress disorder). Individuals with current smoking or vaping will be excluded because of the anticipated effects of smoking or vaping on relative hypoxia. Individuals with substance use disorders will not be included because substance use disorders typically confound the diagnosis of depression and can contribute to treatment resistance.

Individuals will not be considered for study participation if they have renal disease because to date it cannot definitively be stated if short and long-term creatine usage is or is not harmful to the kidneys. In our pilot study we had excluded subjects if they were diabetic because of concern that creatine might influence insulin production, but a recent study has suggested that creatine is safe in diabetes and may even improve glycemic control.157 Accordingly, subjects with diabetes will not be excluded. Since gastrointestinal discomfort has been anecdotally reported in some individuals taking creatine and 5-HTP, individuals with gastrointestinal diseases, such as colitis (e.g. infectious colitis, ulcerative colitis, Crohn’s disease, and ischemic colitis) or diverticulitis, will be excluded. Individuals with a diagnosed seizure disorder will also be excluded, because in one report, the authors suggest that creatine might be implicated in seizure activity, although the reported seizure activity was associated with hypoglycemia, secondary to cardiac arrest.158 Moreover, the seizure events were reported through the Food and Drug Administration’s MedWatch System, but did not undergo a formal review.

            Current suicide risk identified by administration of the Columbia Suicide Severity Rating Scale (C-SSRS)159 will exclude an individual’s participation. Individuals with a previous diagnosis of serotonin syndrome will not be included for participation.

Although there is no observational evidence to our knowledge that a history of serotonin syndrome increases future risk for that disorder, in theory, subjects’ physiologies (including central and peripheral serotonin metabolism, underlying cardiovascular conditions, and/or drug metabolism) may predispose them to that condition, suggesting that previous development of the syndrome increases risk. Accordingly, subjects with a

history of diagnosed serotonin syndrome or current evidence of serotonin syndrome will be excluded. Individuals with a history of serious pulmonary disease will also be excluded from the study, given that such conditions would introduce greater variability into assessments of hypoxia, because they would make screening for early signs of EMS more difficult, and because of the possible association between SSRI use and idiopathic pulmonary hypertension.160 Given the association between antidepressant use and the development of QT prolongation and torsade des pointes,161 individuals with evidence of QT prolongation (QTc > 500ms) on EKG or a history of cardiac disease will be excluded. Likewise, individuals with a history of major autoimmune or rheumatologic illness (rheumatoid arthritis, psoriatic arthritis, lupus, mixed connective tissue disease, ankylosing spondylitis, fibromyalgia, dermatomyositis, polymyositis, and related conditions) will be excluded from the study. This is because of the historical association between the use of L-tryptophan and the development of eosinophilia-myalgia syndrome (EMS; an inflammatory condition marked by high eosinophil concentrations and muscle aches).162 Exclusion of participants with preexisting rheumatological conditions will minimize confounds and facilitate the detection of any new cases of EMS. Individuals with a history of EMS will be excluded. Finally, to minimize confounds, individuals with pre-existing eosinophilia (absolute eosinophil count > 500/uL) will be excluded.

Individuals being treated with any non-SSRI/SNRI antidepressant (TCA, MAO-I, alpha receptor antagonist), any antipsychotic, any mood stabilizing medication, NMDA-receptor antagonist, or other antidepressant augmenting agent (including 5-HTP, creatine, l-methylfolate, tianeptine, s-adenosyl methionine) will also be excluded. We will allow individuals to enroll if they are taking adjunctive bupropion or trazodone up to 200mg PO QHS. Individuals taking any additional serotonergic medications (i.e., medications known to have been implicated in the development of serotonin syndrome) will not be included. These medications are listed in Table 1 below.163 Note that this table includes medications (e.g., mood stabilizers like lithium) that are also excluded from the study for other reasons. Although many of these medications are commonly prescribed and the exclusion of participants taking them may significantly impact recruitment, it is necessary to increase the margin of safety in the study by reducing the likelihood of new-onset serotonin syndrome.

Participants who are currently undergoing electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) for the treatment of depression, or who have completed a course of ECT within a month of the baseline visit will not be invited to participate given the possibility of confounding treatment effects as well as increased seizure risk. Individuals currently undergoing psychotherapy remain eligible to participate.

            Participants who have implanted ferromagnetic hardware, implanted electronic devices, or retained ferromagnetic materials from surgery or injuries will not be invited to participate as these represent contraindications to MRI. Likewise, individuals who are unable to tolerate confinement in the MRI scanner will not be invited to participate.


Table1: Excluded Medications and Drugs

Amphetamines (including dextroamphetamine, methamphetamine)


MDMA (Ecstasy)

Amphetamine derivatives (including fenfluramine, dexfenfluramine, phentermine)

Levodopa, Carbidopa-levodopa




Serotonin modulators (including nefazodone, vilazodone, trazodone > 200mg per day)

Tricyclic antidepressants (TCAs) (including amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine)

St. John’s wort (Hypericum perforatum)

5-HT3 receptor antagonists (including dolasetron, granisetron, ondansetron, palonosetron)









Ergot derivatives (ergotamine, methylergonovine)

Monoamine oxidase inhibitors (including phenelzine, tranylcypromine, isocarboxazid, moclobemide, selegiline, rasagiline, linezolid, isoniazid, tedizolid, methylene blue, procarbazine, Syrian rue


Participant Reimbursement

Participant reimbursement varies from visit to visit from $15 to $65 depending on visit length; total compensation is up to $235.