<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04504253</url>
  </required_header>
  <id_info>
    <org_study_id>IRB_00129040</org_study_id>
    <nct_id>NCT04504253</nct_id>
  </id_info>
  <brief_title>A Pilot Study of Creatine Monohydrate as an Augmenting Agent for ECT in Persons With Major Depressive Disorder</brief_title>
  <official_title>A Pilot Study of Creatine Monohydrate as an Augmenting Agent for ECT in Persons With Major Depressive Disorder</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Utah</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      We propose to determine if augmentation of electroconvulsive therapy (ECT) utilized for the&#xD;
      treatment of major depressive disorder (MDD) with daily oral creatine will lead to an&#xD;
      accelerated response to treatment, an overall increase in response rate, and will protect&#xD;
      against cognitive adverse effects associated with ECT. We propose to conduct a two-arm,&#xD;
      parallel, randomized, double-blinded, placebo-controlled trial, with a treatment group&#xD;
      receiving 20 g oral loading dose of creatine for 1 week starting the day before initiating&#xD;
      ECT, followed by 5 g oral creatine daily for roughly five weeks, including the approximately&#xD;
      three-week ECT treatment course and a two-week follow-up period. Response to treatment will&#xD;
      be assessed using the Quick Inventory of Depressive Symptomatology (QIDS) at each treatment&#xD;
      and the 17-item Hamilton Depression Rating Scale (HAM-D17) at the end of each week.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A. Prevalence and Impact of Depression&#xD;
&#xD;
      MDD has a lifetime prevalence of over 16% and is associated with significant personal and&#xD;
      social costs, including lost work productivity, disability, diminished quality of life,&#xD;
      increased mortality, increased rates of suicide attempts and completed suicides. The&#xD;
      financial impact of depression in the United States is significant, with an estimated&#xD;
      economic burden of individuals with MDD of approximately $210.5 billion dollars annually,&#xD;
      including direct costs, suicide-related costs, and workplace costs. Although MDD is often&#xD;
      regarded as a single disorder, it may encompass a variety of different etiologies with&#xD;
      overlapping symptoms and signs. An additional complication of MDD is the high risk of disease&#xD;
      recurrence; the presence of two or more chronic medical conditions, female gender, never&#xD;
      having been married, activity limitation, and less contact with family are all significant&#xD;
      predictors of MDD persistence.&#xD;
&#xD;
      MDD can be challenging to treat clinically, especially due to its propensity to be&#xD;
      treatment-resistant. Treatment-resistant Depression (TRD) is currently defined as failure to&#xD;
      achieve remission after two or more adequate pharmacologic trials. Current literature&#xD;
      suggests that the majority of individuals with MDD do not reach and subsequently maintain a&#xD;
      fully remitted state. Furthermore, results from the STAR-D trial indicate that the overall&#xD;
      likelihood of failure to achieve remission is increased with increasing number of failed&#xD;
      medication trials. At this time, the adjunctive use of atypical antipsychotics has been&#xD;
      well-investigated, but less is known about alternative adjunctive agents.&#xD;
&#xD;
      Current clinical guidelines for the treatment of depression establish basic principles for&#xD;
      establishing a treatment plan, preparing for potential need for long-term treatment, and&#xD;
      assessment of remission. For moderate major depression, first line treatment includes&#xD;
      antidepressant monotherapy and psychotherapy. For severe major depression, antidepressant&#xD;
      therapy can be augmented with an antipsychotic or ECT. Due to the overall disease burden of&#xD;
      unmanaged MDD, the prevalence of treatment resistant depression, high rates of primary&#xD;
      treatment failure, the additional study of alterative adjunctive therapy is both appropriate&#xD;
      and potentially impactful.&#xD;
&#xD;
      B. Efficacy of ECT in Treatment of MDD&#xD;
&#xD;
      ECT is considered to be a first line treatment for depression with psychotic features, but it&#xD;
      is also often used to treat patients with treatment-resistant depression (TRD). According to&#xD;
      a 2015 metanalysis, approximately one third of patients with MDD do not respond to ECT, with&#xD;
      failed medication trials and longer depressive episodes being the strongest predictors of&#xD;
      poor response. For treatment-resistant depression, the overall response rate is approximately&#xD;
      58%, compared to a 70% response rate in patients without TRD. When assessing the overall&#xD;
      efficacy of ECT, both remission and response are used, although remission is more frequently&#xD;
      used in clinical practice. In general, response has been defined as a 50% decrease in&#xD;
      baseline depression screening scores, while remission is defined as a score &lt;7 on the&#xD;
      HAM-D17, or &lt;10 with the 24-item HAM-D.&#xD;
&#xD;
      Assessments of remission in MDD after ECT treatment suggest that chronic depression,&#xD;
      medication resistance, longer episode duration, and younger age are all statistically&#xD;
      significant predictors of non-remission. Remission rates in ECT tend to be robust; data from&#xD;
      the CORE trial suggested an overall remission rate of 87%, which further delineates into 95%&#xD;
      remission rate with the presence of psychotic features and 83% without. Again, however, rates&#xD;
      of response and remission with ECT are lower for patients with treatment-resistant&#xD;
      depression, who may make up the majority of patients receiving ECT in clinical samples.&#xD;
&#xD;
      Although ECT is an effective treatment for MDD, up to one third of patients experience&#xD;
      significant memory loss and other adverse cognitive effects after receiving ECT. Strategies&#xD;
      to limit ECT's effects on memory, such as altering electrode placement (e.g., from bitemporal&#xD;
      to bifrontal), ensuring days off between treatments, and modulating pulse width, amplitude,&#xD;
      and frequency, may all have some benefit. Still, cognitive complaints remain one of the most&#xD;
      significant side-effects of ECT, and concerns about these effects represent a major reason&#xD;
      that patients who could benefit from ECT choose not to pursue it. Nootropic agents, thyroid&#xD;
      hormone, and donepezil have all been studied to mitigate the cognitive side effects, but no&#xD;
      consistent benefit has been shown and no current adjunctive medication is recommended.&#xD;
&#xD;
      C. ECT Augmentation&#xD;
&#xD;
      In order to maximize the efficacy of ECT in the treatment of MDD, several studies have&#xD;
      analyzed the benefit of augmentation with a variety of antidepressants, anesthetic agents,&#xD;
      and nutritional supplements. The most thoroughly studied has been adjunctive ketamine&#xD;
      administration with ECT, although findings have been inconsistent. A metanalysis of RCTs&#xD;
      investigating adjunctive ketamine and ECT in 2019 did not find that ketamine improves the&#xD;
      efficacy of ECT when compared to other anesthetic agents, although it was suggested that&#xD;
      ketamine could lead to improvement of depressive symptoms in the acute phases of ECT when&#xD;
      used in combination. There was no improvement in depressive symptoms with ketamine&#xD;
      augmentation by the end of the ECT series. The effect of ketamine on the neurocognitive side&#xD;
      effects associated with ECT remains unclear, but no clear benefit has been shown. In&#xD;
      addition, the long-term efficacy and safety of ketamine use in ECT is unknown, particularly&#xD;
      in the setting of maintenance treatment.&#xD;
&#xD;
      Many secondary agents have been studied in conjunction with ECT therapy, including caffeine&#xD;
      sodium benzoate (CSB), hyperventilation, and methylxanthines. However, these agents have&#xD;
      primarily been studied for their potential to lower seizure threshold or increase overall&#xD;
      seizure duration during ECT, without clear effects on overall ECT efficacy or symptom&#xD;
      improvement apart from effects on seizure characteristics. Less is understood about the&#xD;
      effects of nutritional supplementation, such as folate, thyroid hormone, tryptophan, or&#xD;
      S-adenosylmethionine (SAM-e). A case study from 2015 demonstrated improvement in response to&#xD;
      ECT after folate supplementation.&#xD;
&#xD;
      There is some research that has demonstrated associations between response/remission in ECT&#xD;
      and serum levels of various vitamins and essential nutrients. A 1994 study examining the&#xD;
      association between serum 5-methyltetrahydrofolate (5-MeTHF) levels and ECT response did not&#xD;
      demonstrate any significant association between ECT response and serum 5-MeTHF levels,&#xD;
      although low serum 5-MeTHF levels were positively correlated with depression symptom&#xD;
      severity. A pilot study has further analyzed serum levels of vitamin B12, folate, S100B,&#xD;
      homocysteine, and procalcitonin in patients undergoing ECT, and found that decreased vitamin&#xD;
      B12 and folate levels in conjunction with elevated homocysteine and S100B levels lead to&#xD;
      increased sensitivity to ECT, as evidenced by increased remission rates. Thyroid hormone has&#xD;
      been studied in the setting of ECT therapy, both as an adjunctive treatment for depressive&#xD;
      symptoms and as an agent to reduce neurocognitive deficits associated with ECT and has been&#xD;
      demonstrated to reduce ECT associated amnesia and promote a decrease in depressive symptoms.&#xD;
      Still, thyroid hormone has not been widely used in clinical practice, possibly because of&#xD;
      concerns about adverse effects.&#xD;
&#xD;
      D. Creatine and Depression&#xD;
&#xD;
      There is a growing body of literature surrounding the use of standardized,&#xD;
      pharmaceutical-grade nutrients (nutraceuticals) as augmentation therapy in the setting of&#xD;
      treatment resistant depression. A 2016 metanalysis concluded that adjunctive use of SAM-e,&#xD;
      l-methylfolate, omega-3, and vitamin D with antidepressant therapy leads to a reduction in&#xD;
      depressive symptoms, while isolated studies showed a similar effect with the use of creatine,&#xD;
      folinic acid, and an amino acid combination.&#xD;
&#xD;
      Creatine is a naturally-occurring organic acid that is known to play a role in brain energy&#xD;
      homeostasis and is hypothesized to be involved in the pathophysiology of depression via&#xD;
      altered energy metabolism. Oral creatine supplementation has been shown to increase cerebral&#xD;
      phosphocreatine levels, which is hypothesized to shift cerebral creatine kinase activity,&#xD;
      leading to increased ATP production. Early literature suggests that creatine may have an&#xD;
      antidepressant effect when used as adjunctive therapy in MDD, due to its role in altering&#xD;
      brain bioenergetics. Creatine has been shown to lead to an earlier treatment response in&#xD;
      patients treated with escitalopram, with positive response to therapy as early as 2 weeks&#xD;
      after beginning treatment. To date, no studies have investigated the use of creatine as an&#xD;
      adjunctive therapy to ECT.&#xD;
&#xD;
      Inadequate tissue bioenergetic functioning is thought to be related to disease pathology that&#xD;
      affects predominately organs that are comparatively highly metabolically active, like the&#xD;
      brain, liver, heart, and skeletal muscle. Because creatine supplementation has the potential&#xD;
      to increase bioenergetic stores, it may produce an antidepressant response by enabling&#xD;
      synaptogenesis, increasing connectivity between frontal cortical regions and the amygdala, or&#xD;
      enhancing frontal cortical functioning. ECT is thought to produce an antidepressant effect&#xD;
      largely by promoting synaptogenesis in frontal cortical regions via alterations in the&#xD;
      activity of NMDA and AMPA receptors, leading to upregulations in BDNF. Accordingly, creatine&#xD;
      has the potential to augment the efficacy of ECT by increasing bioenergetic stores available&#xD;
      for synaptogenesis. There is also some evidence to suggest that creatine has activity at NMDA&#xD;
      receptors, functioning as a neuromodulator that is released in response to electrical&#xD;
      stimulation. Its activity at NMDA receptors is potentially another explanation for its&#xD;
      antidepressant effect.&#xD;
&#xD;
      In a mouse model study of hyperhomocystinemia, a condition that leads to impaired creatine&#xD;
      kinase activity, creatine supplementation was shown to have neuroprotective effects, with&#xD;
      suggestion of memory improvement. Other mouse model studies have shown that creatine can&#xD;
      generate improvement of spatial memory, when compared to a traditional diet, as well as&#xD;
      improve learning and mitochondrial function. Several human studies have also demonstrated&#xD;
      that creatine supplementation is associated with multiple cognitive improvements, including&#xD;
      effects on attention, mood, working and long-term memory, and mental fatigue. These data&#xD;
      suggest that creatine is a potential approach for addressing the cognitive side effects&#xD;
      associated with ECT therapy.&#xD;
&#xD;
      E. Creatine Safety and Toxicity&#xD;
&#xD;
      Retrospective and prospective studies in humans have found no evidence for long-term or&#xD;
      short-term significant side effects from creatine supplementation taken at recommended doses.&#xD;
      Most controlled studies of creatine report an absence of side effects or report no&#xD;
      differences in the incidence of side effects between creatine and placebo. Mihic and&#xD;
      colleagues have demonstrated that creatine loading increases fat-free mass, but does not&#xD;
      affect blood pressure or plasma creatinine in adult men and women.&#xD;
&#xD;
      Reports in the popular media of links between creatine use and muscle strains, muscle cramps,&#xD;
      heat intolerance, and other side effects are not supported by the medical literature. Studies&#xD;
      conducted in athletes and military personnel indicate a substantial safety level of both&#xD;
      short- and long-term creatine supplementation in healthy adults. Concerns about high-dose&#xD;
      creatine's association with renal toxicity are based exclusively on two published case&#xD;
      reports; in one of the cases the patient had a documented pre-existing kidney condition.&#xD;
      Literature reviews and expert consensus panels have concluded there is no evidence supporting&#xD;
      an association between creatine and renal disease.&#xD;
&#xD;
      Concern has been raised regarding creatine's potential for adverse effects on the kidneys and&#xD;
      renal system, in part because creatine supplementation can increase urinary creatine and&#xD;
      creatinine excretion. In response to the concerns regarding creatine and renal toxicity,&#xD;
      Poortman's conducted studies of the effect of creatine supplementation on renal function,&#xD;
      showing that short-term supplementation does not alter glomerular filtration rate, and that&#xD;
      chronic supplementation of up to five years' duration did not impair renal function in&#xD;
      healthy athletes. Other researchers conducted a retrospective study of participants who had&#xD;
      been taking oral creatine from 0.8 to 4 years, at an average dose of 9.7 grams per day. Data&#xD;
      was collected on 65 health-related variables. These included a complete blood count, 27 serum&#xD;
      chemistries, and anthropometric data including vital signs and % body fat. On all 65&#xD;
      variables, group means fell within the normal clinical range. The authors concluded that that&#xD;
      long-term creatine supplementation does not result in adverse health effects.&#xD;
&#xD;
      Evidence to date suggests that even aged, debilitated, medically fragile patients are able to&#xD;
      tolerate creatine supplementation. Bender and colleagues studied elderly patients with&#xD;
      Parkinson's Disease who had received either placebo or four grams/day of creatine for two&#xD;
      years. They found no differences between the creatine and placebo groups in laboratory&#xD;
      markers of renal dysfunction. Interestingly, the participants who received creatine performed&#xD;
      better on the depression subscale of the Unified Parkinson Disease Rating Scale.&#xD;
&#xD;
      No strong evidence exists linking creatine supplementation and gastrointestinal discomfort.&#xD;
      These reports remain anecdotal, as there are no documented reports of creatine over placebo&#xD;
      resulting in stomach concerns.&#xD;
&#xD;
      1. Overview&#xD;
&#xD;
      Study Timeline&#xD;
&#xD;
      Week Procedures&#xD;
&#xD;
      Visit 1 Eligibility screening: MINI, HAM-D17, MOCA, QIDS, Labs, CGI, BSS, ATRQ&#xD;
&#xD;
      Visit 2 QIDS&#xD;
&#xD;
      31P-MRS Scan 1&#xD;
&#xD;
      Start creatine 20g per day or placebo&#xD;
&#xD;
      Start ECT (treatments 1 up to 3) as per routine&#xD;
&#xD;
      Week 2 (Subjects may begin to complete ECT, moving to follow-up phase) Creatine 5g per day or&#xD;
      placebo&#xD;
&#xD;
      Continuing ECT (treatments 3 or 4 through 6 or 7) as per routine&#xD;
&#xD;
      QIDS before each ECT&#xD;
&#xD;
      HAM-D17 , CGI, BSS, MOCA at end of week&#xD;
&#xD;
      Week 3 (Most subjects will complete ECT, moving to follow-up phase) Creatine 5g per day or&#xD;
      placebo&#xD;
&#xD;
      Continuing ECT (treatments 3 or 4 through 6 or 7) as per routine&#xD;
&#xD;
      QIDS before each ECT&#xD;
&#xD;
      HAM-D17 , CGI, BSS, MOCA at end of week&#xD;
&#xD;
      31P-MRS Scan 2 (if ECT complete)&#xD;
&#xD;
      Week 4 (Almost all subjects will complete ECT, moving to follow-up phase) Creatine 5g per day&#xD;
      or placebo&#xD;
&#xD;
      Continuing ECT (treatments 3 or 4 through 6 or 7) as per routine&#xD;
&#xD;
      QIDS before each ECT&#xD;
&#xD;
      HAM-D17 , CGI, BSS, MOCA at end of week&#xD;
&#xD;
      31P-MRS Scan 2 (if ECT completed this week)&#xD;
&#xD;
      Follow-up phase: 2 weeks (to start after completion of ECT or after week 4, whichever comes&#xD;
      first) Creatine 5g per day or placebo (for two weeks)&#xD;
&#xD;
      HAM-D17, CGI, BSS, MOCA two weeks after completion of ECT series&#xD;
&#xD;
      31P-MRS Scan 2 (if not yet completed)&#xD;
&#xD;
      All procedures performed by study personnel are research-related, but will be performed in&#xD;
      addition to routine care (see Table 1). None of the study activities will be considered&#xD;
      standard of care. There will be no cost to study subjects for their participation.&#xD;
      Participants will be compensated for their time and travel. Study visits will be supervised&#xD;
      by a board-certified/board-eligible psychiatrist or psychiatry resident and will be conducted&#xD;
      either by a board-certified/board-eligible psychiatrist, psychiatry resident, or an at least&#xD;
      baccalaureate degree level research assistant with training in the specific measures used.&#xD;
      Laboratory and other study interpretation will be conducted by a&#xD;
      board-certified/board-eligible psychiatrist.&#xD;
&#xD;
      To determine if an individual is eligible for study participation, a screening visit will be&#xD;
      conducted. Initially, a HAM-D17 will be administered to determine if the patient exhibits&#xD;
      depressive symptoms that are sufficiently severe for inclusion in the study. Next, the Mini&#xD;
      International Neuropsychiatric Interview (MINI) will be administered to confirm a diagnosis&#xD;
      of a current major depressive episode. Study subjects will receive a baseline basic metabolic&#xD;
      panel (BMP) to assess for renal insufficiency, and vitals (these may have been obtained in&#xD;
      the course of ongoing clinical care). The QIDS, Antidepressant Treatment Response&#xD;
      Questionnaire (ATRQ), Clinical Global Impression (CGI), Beck Suicide Scale (BSS), and a MoCA&#xD;
      will be administered. Each participant will be assessed for history of ECT therapy, current&#xD;
      medications, and any other medical history.&#xD;
&#xD;
      Once entered into the study, depressed subjects will be randomized to receive either creatine&#xD;
      or placebo using a random-digit method that is based on computer-generated numbers. Block&#xD;
      randomization created by Investigational Drug Services (IDS) will be used to ensure equal&#xD;
      treatment allocation within each block. 50% of the trial's clinical subjects will be&#xD;
      randomized to placebo and the other 50% to active treatment. The study will be conducted as a&#xD;
      double-blind trial, with neither participants nor research staff aware of participant&#xD;
      assignment. Except in cases of medical emergency, the double-blind will not be &quot;broken&quot; until&#xD;
      recruitment is closed and the final participant has completed 6 weeks of treatment and 4&#xD;
      weeks of follow-up. The blind will be broken following the culmination of the study or at the&#xD;
      request of a medical professional dealing with a medical emergency in a case in which it&#xD;
      would help a study participant.&#xD;
&#xD;
      2. Electroconvulsive Therapy&#xD;
&#xD;
      Participants will be recruited from a population of patients who have already been referred&#xD;
      for ECT and who have had initial clinical assessments to determine whether ECT is indicated.&#xD;
      As this study is an add-on to standard clinical care only, routine ECT procedures will be&#xD;
      followed, though the ECT service (attending psychiatrist, anesthesiologist) will be notified&#xD;
      of subject participation. In general, subjects will, after being medically cleared for ECT&#xD;
      (psychiatric exam, physical exam, EKG, laboratory studies if indicated), received bifrontal&#xD;
      ECT every other day for between 6 and up to roughly 14 treatments, with a total duration of&#xD;
      treatment lasting between two and four weeks. Anesthesia for ECT is provided by a&#xD;
      board-certified anesthesiologist and comprises the use of methohexital, midazolam, etomidate,&#xD;
      or ketamine, as indicated, and at the discretion of the anesthesiologist. Participants may&#xD;
      receive interventions designed to augment the likelihood of a seizure being achieved, such as&#xD;
      a caffeine infusion, hyperventilation, or other techniques, at the discretion of the treating&#xD;
      ECT psychiatrist and anesthesiologist. After ECT, participants are monitored for recurrent&#xD;
      seizure/status epilepticus and for vital sign abnormalities for roughly thirty minutes, then&#xD;
      released to home (if outpatient) with 24 hour per day supervision by adult family members, or&#xD;
      else escorted back to the inpatient unit, where they again receive 24 hour per day&#xD;
      supervision by unit staff. Prior to each treatment, subjects complete a Quick Inventory of&#xD;
      Depressive Symptoms (QIDS) to assess their overall burden of depressive symptoms. The exact&#xD;
      duration of treatment/number of treatments is determined by the treating ECT psychiatrist,&#xD;
      based on clinical response. The study will record all pertinent variables related to ECT as&#xD;
      noted in the clinical record, including number of treatments, QIDS score, number of seizures&#xD;
      per treatment session, seizure duration, adverse effects, augmentation strategies, anesthesia&#xD;
      type, and vitals.&#xD;
&#xD;
      2. Drug Dosing&#xD;
&#xD;
      Participants who have been assigned to the creatine arm of the trial will receive a 20g&#xD;
      loading dose daily for 1 week starting as soon as possible before ECT begins and after&#xD;
      completion of the 31P-MRS; this will be administered in 4 divided doses of 5g each.&#xD;
      Participants will then receive 5 g creatine daily throughout the course of ECT therapy (~3&#xD;
      weeks), with continuation for an additional 2 weeks after the completion of the acute series&#xD;
      of ECT, again at 5g daily (thus, up to 5 weeks total supplementation with creating 5g per&#xD;
      day, depending on the length of ECT) Placebo recipients will receive an inert, relatively&#xD;
      tasteless powder matched to creatine (e.g., glucose). Creatine doses are based on doses that&#xD;
      have previously been shown to be safe and efficacious.&#xD;
&#xD;
      3. Measures&#xD;
&#xD;
      We plan to use the following for determining participant baseline and data collection:&#xD;
&#xD;
        -  Hamilton Depression Rating Scale (HAM-D17) (at baseline, the end of week 1, the end of&#xD;
           week 2, the end of week 3, and two weeks after completion of the ECT series)&#xD;
&#xD;
        -  Quick Inventory of Depressive Symptomatology (QIDS) (at baseline and prior to each ECT&#xD;
           session)&#xD;
&#xD;
        -  Antidepressant Treatment Response Questionnaire (ATRQ) (at baseline)&#xD;
&#xD;
        -  Mini International Neuropsychiatric Interview (MINI) (at baseline)&#xD;
&#xD;
        -  Clinical Global Impressions Scale (CGI) illness improvement subscale (CGI-I) (at&#xD;
           baseline, week 1, week 2, week 3, and two weeks after completion of the ECT series)&#xD;
&#xD;
        -  Beck Suicide Scale (BSS) at baseline, week 1, week 2, week 3, and two weeks after&#xD;
           completion of the ECT series)&#xD;
&#xD;
        -  Montreal Cognitive Assessment (MoCA) at baseline, week 1, week 2, week 3, and two weeks&#xD;
           after completion of the ECT series)&#xD;
&#xD;
           4. Imaging&#xD;
&#xD;
             1. Magnetic Resonance Imaging (Siemens 3T MRI system)&#xD;
&#xD;
                MRI scans will be conducted twice: after the baseline visit and prior to initiating&#xD;
                ECT, and following completion of the ECT series (i.e., after ~3 weeks, and during&#xD;
                the 2 week post-ECT follow-up period). The 3.0 Tesla Siemens Prisma whole-body&#xD;
                clinical scanner (Siemens Medical Solutions, Erlangen, Germany) located within the&#xD;
                University Neuropsychiatric Institute (UNI) will be used to acquire this data.&#xD;
                Participants will first undergo a routine anatomic MRI protocol, which includes MRI&#xD;
                images acquired in the axial and coronal planes. Specifically, the anatomic scan&#xD;
                protocol consists of a T1 weighted structural scan (MP2RAGE), and double-echo T2&#xD;
                weighted scan, and a Fluid Attenuated Inversion Recovery scan (FLAIR). The purposes&#xD;
                of the MR anatomic screening session include screening subjects for gross&#xD;
                structural abnormalities and acquiring images for use in brain cortical thickness&#xD;
                measurements. Anatomic MRI examinations will be performed with Siemens 64 channel&#xD;
                head coil. After localization, anatomical imaging will be obtained using a&#xD;
                T1-weighted, sagittal oriented 3D-Magnetization Prepared Rapid Gradient Echo&#xD;
                (MPRAGE) sequence (TR/TE/TI 5000/2.93/700 ms, matrix 256x256, FOV 256x256 mm, flip&#xD;
                angle 4 degree, slice thickness 1.0 mm, slab 176 mm, bandwidth 240 Hz/pixel). Axial&#xD;
                proton-density and T2 weighted images will be acquired to screen for brain&#xD;
                structural abnormalities using 2D Double echo T2 weighted turbo spin echo (TSE)&#xD;
                sequence (TR 7110 ms, TE 28/84 ms, FOV 240x210, slice thickness 3 mm, flip 150°,&#xD;
                bandwidth 179 Hz/pixel). FLAIR sequence (TR/TE/TI 8000/90/2500 ms, slice thickness&#xD;
                5 mm, FOV 240x168, voxel size 0.8x0.6x5.0 mm, bandwidth 200 Hz/pixel, turbo factor&#xD;
                13) will be used to detect juxtacortical-cortical lesions. All anatomic MRI images&#xD;
                will be read by a board-certified, CAQ neuroradiologist to screen for structural&#xD;
                abnormalities.&#xD;
&#xD;
             2. Measurement of In-Vivo Brain Chemistry Using Phosphorus-31 Magnetic Resonance&#xD;
                Spectroscopy (31P-MRS)&#xD;
&#xD;
                Phosphorus spectroscopy data will be acquired on the same Siemens 3T system. We aim&#xD;
                to keep the duration of each MRSI examination at or under 25 minutes. A 3D-MRSI&#xD;
                sequence with elliptically weighted phase-encoding will be used to collect 31P-MRSI&#xD;
                data to minimize T2 signal decay. Acquisition parameters will be: data matrix size&#xD;
                16x16x8; TR 2000 ms; tip-angle 90 degree for hard RF pulse; Rx bandwidth ±1 kHz;&#xD;
                complex-points 1024; readout duration 256 ms; pre-acquisition delay 0.3ms; FOV&#xD;
                240x240 mm2 ; 16 NEX.&#xD;
&#xD;
             3. Spectral Analysis of 31P-MRS Data&#xD;
&#xD;
      Spectroscopy will be analyzed using Liner Combination of Model Spectra (LCModel), which&#xD;
      analyzes an in vivo spectrum as a linear combination of model in vitro spectra from&#xD;
      individual metabolite solutions. This model is fully automatic and user independent. A nearly&#xD;
      model-free constrained regularization method is used for convolution and baseline. For&#xD;
      quantification, absolute metabolite concentrations (institutional units) will be estimated&#xD;
      using the unsuppressed water signal as an internal concentration reference. Also, total&#xD;
      creatine levels will be used as a denominator for calculating the relative concentration for&#xD;
      the comparison with previous reports. The standard Siemens libraries of model metabolite&#xD;
      spectra provided with LCModel will be used in the basis set. The metabolites from the basis&#xD;
      set will include alanine, aspartate, creatine, gamma-amino butyric acid, glucose, glutamine,&#xD;
      glutamate, glycerophosphocholine, glutathione, myo-inositol, scyllo-inositol, lactate,&#xD;
      N-acetylaspartate, N-acetylaspartylglutamate, phosphocholine, phosphocreatine,&#xD;
      phosphoethanolamine, and taurine. For the reliability of detection, the Cramer-Rao lower&#xD;
      bounds (CRLB) will be determined: the acceptable upper limit of estimated standard deviations&#xD;
      will be set at 20%.&#xD;
&#xD;
      Post processing of 31P-MRS data will be conducted using jMRUI software (jMRUI v. 4.0,&#xD;
      European Community) with the AMARES algorithm (Advanced Method for Accurate, Robust and&#xD;
      Efficient Spectral fitting of MRS data with use of prior knowledge). Before fitting the FID&#xD;
      (Free-induction-decay) data, a Hamming filter will be applied to reduce signal contamination&#xD;
      from neighboring voxels, with apodization of 10 Hz line broadening. Fourier transformation,&#xD;
      frequency shifts correction, and zero-order/first order phase correction as well as baseline&#xD;
      correction will be applied. The structural image-processing tool FSL (FMRIB Software Library,&#xD;
      Release 4.1, University of Oxford) will be used to account for gray matter, white matter, and&#xD;
      cerebrospinal fluid (CSF), in order to correct the partial volume effects on metabolite&#xD;
      concentrations. The MRS grid will be positioned over the images in an identical fashion&#xD;
      between baseline and treatment scans for each participant. The peak area for each 31P-MRS&#xD;
      metabolite will be calculated as a percentage of the total phosphorus signal.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 3, 2020</start_date>
  <completion_date type="Anticipated">August 2, 2023</completion_date>
  <primary_completion_date type="Anticipated">August 2, 2023</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Randomized, double-blind, placebo-controlled. Block randomization protocol.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>HAMD-17</measure>
    <time_frame>3-6 weeks</time_frame>
    <description>17-item Hamilton Depression Rating Scale; Maximum Score 54. Minimum Score 0. Higher scores are correlated with more severe depression</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>QIDS</measure>
    <time_frame>3-6 weeks</time_frame>
    <description>Quick Inventory of Depressive Symptoms; Scores range from 0 to 27. Higher scores are correlated with more severe depression.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">16</enrollment>
  <condition>Major Depressive Disorder</condition>
  <arm_group>
    <arm_group_label>Creatine monohydrate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Week 1: Creatine monohydrate 5g PO QID&#xD;
Week 2 up to Week 6: Creatine monohydrate 5g PO qday</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Week 1: Placebo 5g PO QID&#xD;
Week 2 up to Week 6: Placebo 5g PO qday</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Creatine monohydrate</intervention_name>
    <description>Creatine monohydrate loose powder</description>
    <arm_group_label>Creatine monohydrate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo control (dextrose 5mg) matched to creatine monohydrate loose powder</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Participants with a diagnosis of Major Depressive Disorder with moderate to severe symptoms&#xD;
        will be randomly assigned in a 1:1 ratio to either ECT with creatine augmentation or ECT&#xD;
        with placebo augmentation or 6 weeks. Individuals must meet criteria for major depressive&#xD;
        episode for a duration of at least 2 months in order to participate. Participants must be&#xD;
        greater than 18 years of age and considered to be a good candidate for ECT based on&#xD;
        clinical assessment. Individuals who are pregnant or breast-feeding or who possess any&#xD;
        other contraindication to ECT will not be invited to participate. Participants can receive&#xD;
        ECT treatments in either inpatient or outpatient setting at the University Neuropsychiatric&#xD;
        Institute.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Individuals who meet diagnostic criteria for other psychiatric conditions apart from major&#xD;
        depressive disorder (including Bipolar I, Bipolar II, or personality disorders) will not be&#xD;
        invited to participate. Individuals with substance use disorders will be excluded because&#xD;
        substance use disorders typically confound the diagnosis of depression and can contribute&#xD;
        to treatment resistance. Individuals will not be considered for study participation if they&#xD;
        have renal disease because to date it cannot definitively be stated if short and long-term&#xD;
        creatine usage is or is not harmful to the kidneys. Appropriate renal function will be&#xD;
        determined based on normal creatinine clearance, determined by routine laboratory work&#xD;
        (basic metabolic panel).&#xD;
&#xD;
        Participants who are already undergoing electroconvulsive therapy (ECT) or transcranial&#xD;
        magnetic stimulation (TMS) for the treatment of depression, or who have completed a course&#xD;
        of ECT within a month of the baseline visit, will not be invited to participate given the&#xD;
        possibility of confounding treatment effects as well as increased seizure risk. Individuals&#xD;
        currently undergoing psychotherapy remain eligible to participate.&#xD;
&#xD;
        Participants who have implanted ferromagnetic hardware, implanted electronic devices, or&#xD;
        retained ferromagnetic materials from surgery or injuries will not be invited to&#xD;
        participate as these represent contraindications to MRI. Likewise, individuals who are&#xD;
        unable to tolerate confinement in the MRI scanner will not be invited to participate.&#xD;
&#xD;
        Individuals who lack capacity to consent to treatment or to participate in the study will&#xD;
        be excluded. Patients who are hospitalized involuntarily will also be excluded. Individuals&#xD;
        demonstrating active psychosis or any other clinical characteristic making them&#xD;
        inappropriate candidates for treatment will be excluded. Patients with pre-existing&#xD;
        neurologic condition, any major neurocognitive disorder, or known traumatic brain injury&#xD;
        will not be invited to participate.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Brent Kious, MD</last_name>
    <phone>8015851418</phone>
    <email>brent.kious@hsc.utah.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Rebecca Jacobs</last_name>
    <phone>(801) 829-7382</phone>
    <email>rebecca.jacobs@utah.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Utah Department of Psychiatry</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84108</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Brent Kious</last_name>
      <phone>801-585-1418</phone>
      <email>brent.kious@hsc.utah.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>August 4, 2020</study_first_submitted>
  <study_first_submitted_qc>August 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2020</study_first_posted>
  <last_update_submitted>May 16, 2022</last_update_submitted>
  <last_update_submitted_qc>May 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Utah</investigator_affiliation>
    <investigator_full_name>Brent Michael Kious, MD, PhD</investigator_full_name>
    <investigator_title>Assistant Professor, Psychiatry</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Depressive Disorder</mesh_term>
    <mesh_term>Depression</mesh_term>
    <mesh_term>Depressive Disorder, Major</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04504253
org study id: IRB_00129040
nct id: NCT04504253
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
We propose to determine if augmentation of electroconvulsive therapy (ECT) utilized for the
      treatment of major depressive disorder (MDD) with daily oral creatine will lead to an
      accelerated response to treatment, an overall increase in response rate, and will protect
      against cognitive adverse effects associated with ECT. We propose to conduct a two-arm,
      parallel, randomized, double-blinded, placebo-controlled trial, with a treatment group
      receiving 20 g oral loading dose of creatine for 1 week starting the day before initiating
      ECT, followed by 5 g oral creatine daily for roughly five weeks, including the approximately
      three-week ECT treatment course and a two-week follow-up period. Response to treatment will
      be assessed using the Quick Inventory of Depressive Symptomatology (QIDS) at each treatment
      and the 17-item Hamilton Depression Rating Scale (HAM-D17) at the end of each week.
A. Prevalence and Impact of Depression

      MDD has a lifetime prevalence of over 16% and is associated with significant personal and
      social costs, including lost work productivity, disability, diminished quality of life,
      increased mortality, increased rates of suicide attempts and completed suicides. The
      financial impact of depression in the United States is significant, with an estimated
      economic burden of individuals with MDD of approximately $210.5 billion dollars annually,
      including direct costs, suicide-related costs, and workplace costs. Although MDD is often
      regarded as a single disorder, it may encompass a variety of different etiologies with
      overlapping symptoms and signs. An additional complication of MDD is the high risk of disease
      recurrence; the presence of two or more chronic medical conditions, female gender, never
      having been married, activity limitation, and less contact with family are all significant
      predictors of MDD persistence.

      MDD can be challenging to treat clinically, especially due to its propensity to be
      treatment-resistant. Treatment-resistant Depression (TRD) is currently defined as failure to
      achieve remission after two or more adequate pharmacologic trials. Current literature
      suggests that the majority of individuals with MDD do not reach and subsequently maintain a
      fully remitted state. Furthermore, results from the STAR-D trial indicate that the overall
      likelihood of failure to achieve remission is increased with increasing number of failed
      medication trials. At this time, the adjunctive use of atypical antipsychotics has been
      well-investigated, but less is known about alternative adjunctive agents.

      Current clinical guidelines for the treatment of depression establish basic principles for
      establishing a treatment plan, preparing for potential need for long-term treatment, and
      assessment of remission. For moderate major depression, first line treatment includes
      antidepressant monotherapy and psychotherapy. For severe major depression, antidepressant
      therapy can be augmented with an antipsychotic or ECT. Due to the overall disease burden of
      unmanaged MDD, the prevalence of treatment resistant depression, high rates of primary
      treatment failure, the additional study of alterative adjunctive therapy is both appropriate
      and potentially impactful.

      B. Efficacy of ECT in Treatment of MDD

      ECT is considered to be a first line treatment for depression with psychotic features, but it
      is also often used to treat patients with treatment-resistant depression (TRD). According to
      a 2015 metanalysis, approximately one third of patients with MDD do not respond to ECT, with
      failed medication trials and longer depressive episodes being the strongest predictors of
      poor response. For treatment-resistant depression, the overall response rate is approximately
      58%, compared to a 70% response rate in patients without TRD. When assessing the overall
      efficacy of ECT, both remission and response are used, although remission is more frequently
      used in clinical practice. In general, response has been defined as a 50% decrease in
      baseline depression screening scores, while remission is defined as a score <7 on the
      HAM-D17, or <10 with the 24-item HAM-D.

      Assessments of remission in MDD after ECT treatment suggest that chronic depression,
      medication resistance, longer episode duration, and younger age are all statistically
      significant predictors of non-remission. Remission rates in ECT tend to be robust; data from
      the CORE trial suggested an overall remission rate of 87%, which further delineates into 95%
      remission rate with the presence of psychotic features and 83% without. Again, however, rates
      of response and remission with ECT are lower for patients with treatment-resistant
      depression, who may make up the majority of patients receiving ECT in clinical samples.

      Although ECT is an effective treatment for MDD, up to one third of patients experience
      significant memory loss and other adverse cognitive effects after receiving ECT. Strategies
      to limit ECT's effects on memory, such as altering electrode placement (e.g., from bitemporal
      to bifrontal), ensuring days off between treatments, and modulating pulse width, amplitude,
      and frequency, may all have some benefit. Still, cognitive complaints remain one of the most
      significant side-effects of ECT, and concerns about these effects represent a major reason
      that patients who could benefit from ECT choose not to pursue it. Nootropic agents, thyroid
      hormone, and donepezil have all been studied to mitigate the cognitive side effects, but no
      consistent benefit has been shown and no current adjunctive medication is recommended.

      C. ECT Augmentation

      In order to maximize the efficacy of ECT in the treatment of MDD, several studies have
      analyzed the benefit of augmentation with a variety of antidepressants, anesthetic agents,
      and nutritional supplements. The most thoroughly studied has been adjunctive ketamine
      administration with ECT, although findings have been inconsistent. A metanalysis of RCTs
      investigating adjunctive ketamine and ECT in 2019 did not find that ketamine improves the
      efficacy of ECT when compared to other anesthetic agents, although it was suggested that
      ketamine could lead to improvement of depressive symptoms in the acute phases of ECT when
      used in combination. There was no improvement in depressive symptoms with ketamine
      augmentation by the end of the ECT series. The effect of ketamine on the neurocognitive side
      effects associated with ECT remains unclear, but no clear benefit has been shown. In
      addition, the long-term efficacy and safety of ketamine use in ECT is unknown, particularly
      in the setting of maintenance treatment.

      Many secondary agents have been studied in conjunction with ECT therapy, including caffeine
      sodium benzoate (CSB), hyperventilation, and methylxanthines. However, these agents have
      primarily been studied for their potential to lower seizure threshold or increase overall
      seizure duration during ECT, without clear effects on overall ECT efficacy or symptom
      improvement apart from effects on seizure characteristics. Less is understood about the
      effects of nutritional supplementation, such as folate, thyroid hormone, tryptophan, or
      S-adenosylmethionine (SAM-e). A case study from 2015 demonstrated improvement in response to
      ECT after folate supplementation.

      There is some research that has demonstrated associations between response/remission in ECT
      and serum levels of various vitamins and essential nutrients. A 1994 study examining the
      association between serum 5-methyltetrahydrofolate (5-MeTHF) levels and ECT response did not
      demonstrate any significant association between ECT response and serum 5-MeTHF levels,
      although low serum 5-MeTHF levels were positively correlated with depression symptom
      severity. A pilot study has further analyzed serum levels of vitamin B12, folate, S100B,
      homocysteine, and procalcitonin in patients undergoing ECT, and found that decreased vitamin
      B12 and folate levels in conjunction with elevated homocysteine and S100B levels lead to
      increased sensitivity to ECT, as evidenced by increased remission rates. Thyroid hormone has
      been studied in the setting of ECT therapy, both as an adjunctive treatment for depressive
      symptoms and as an agent to reduce neurocognitive deficits associated with ECT and has been
      demonstrated to reduce ECT associated amnesia and promote a decrease in depressive symptoms.
      Still, thyroid hormone has not been widely used in clinical practice, possibly because of
      concerns about adverse effects.

      D. Creatine and Depression

      There is a growing body of literature surrounding the use of standardized,
      pharmaceutical-grade nutrients (nutraceuticals) as augmentation therapy in the setting of
      treatment resistant depression. A 2016 metanalysis concluded that adjunctive use of SAM-e,
      l-methylfolate, omega-3, and vitamin D with antidepressant therapy leads to a reduction in
      depressive symptoms, while isolated studies showed a similar effect with the use of creatine,
      folinic acid, and an amino acid combination.

      Creatine is a naturally-occurring organic acid that is known to play a role in brain energy
      homeostasis and is hypothesized to be involved in the pathophysiology of depression via
      altered energy metabolism. Oral creatine supplementation has been shown to increase cerebral
      phosphocreatine levels, which is hypothesized to shift cerebral creatine kinase activity,
      leading to increased ATP production. Early literature suggests that creatine may have an
      antidepressant effect when used as adjunctive therapy in MDD, due to its role in altering
      brain bioenergetics. Creatine has been shown to lead to an earlier treatment response in
      patients treated with escitalopram, with positive response to therapy as early as 2 weeks
      after beginning treatment. To date, no studies have investigated the use of creatine as an
      adjunctive therapy to ECT.

      Inadequate tissue bioenergetic functioning is thought to be related to disease pathology that
      affects predominately organs that are comparatively highly metabolically active, like the
      brain, liver, heart, and skeletal muscle. Because creatine supplementation has the potential
      to increase bioenergetic stores, it may produce an antidepressant response by enabling
      synaptogenesis, increasing connectivity between frontal cortical regions and the amygdala, or
      enhancing frontal cortical functioning. ECT is thought to produce an antidepressant effect
      largely by promoting synaptogenesis in frontal cortical regions via alterations in the
      activity of NMDA and AMPA receptors, leading to upregulations in BDNF. Accordingly, creatine
      has the potential to augment the efficacy of ECT by increasing bioenergetic stores available
      for synaptogenesis. There is also some evidence to suggest that creatine has activity at NMDA
      receptors, functioning as a neuromodulator that is released in response to electrical
      stimulation. Its activity at NMDA receptors is potentially another explanation for its
      antidepressant effect.

      In a mouse model study of hyperhomocystinemia, a condition that leads to impaired creatine
      kinase activity, creatine supplementation was shown to have neuroprotective effects, with
      suggestion of memory improvement. Other mouse model studies have shown that creatine can
      generate improvement of spatial memory, when compared to a traditional diet, as well as
      improve learning and mitochondrial function. Several human studies have also demonstrated
      that creatine supplementation is associated with multiple cognitive improvements, including
      effects on attention, mood, working and long-term memory, and mental fatigue. These data
      suggest that creatine is a potential approach for addressing the cognitive side effects
      associated with ECT therapy.

      E. Creatine Safety and Toxicity

      Retrospective and prospective studies in humans have found no evidence for long-term or
      short-term significant side effects from creatine supplementation taken at recommended doses.
      Most controlled studies of creatine report an absence of side effects or report no
      differences in the incidence of side effects between creatine and placebo. Mihic and
      colleagues have demonstrated that creatine loading increases fat-free mass, but does not
      affect blood pressure or plasma creatinine in adult men and women.

      Reports in the popular media of links between creatine use and muscle strains, muscle cramps,
      heat intolerance, and other side effects are not supported by the medical literature. Studies
      conducted in athletes and military personnel indicate a substantial safety level of both
      short- and long-term creatine supplementation in healthy adults. Concerns about high-dose
      creatine's association with renal toxicity are based exclusively on two published case
      reports; in one of the cases the patient had a documented pre-existing kidney condition.
      Literature reviews and expert consensus panels have concluded there is no evidence supporting
      an association between creatine and renal disease.

      Concern has been raised regarding creatine's potential for adverse effects on the kidneys and
      renal system, in part because creatine supplementation can increase urinary creatine and
      creatinine excretion. In response to the concerns regarding creatine and renal toxicity,
      Poortman's conducted studies of the effect of creatine supplementation on renal function,
      showing that short-term supplementation does not alter glomerular filtration rate, and that
      chronic supplementation of up to five years' duration did not impair renal function in
      healthy athletes. Other researchers conducted a retrospective study of participants who had
      been taking oral creatine from 0.8 to 4 years, at an average dose of 9.7 grams per day. Data
      was collected on 65 health-related variables. These included a complete blood count, 27 serum
      chemistries, and anthropometric data including vital signs and % body fat. On all 65
      variables, group means fell within the normal clinical range. The authors concluded that that
      long-term creatine supplementation does not result in adverse health effects.

      Evidence to date suggests that even aged, debilitated, medically fragile patients are able to
      tolerate creatine supplementation. Bender and colleagues studied elderly patients with
      Parkinson's Disease who had received either placebo or four grams/day of creatine for two
      years. They found no differences between the creatine and placebo groups in laboratory
      markers of renal dysfunction. Interestingly, the participants who received creatine performed
      better on the depression subscale of the Unified Parkinson Disease Rating Scale.

      No strong evidence exists linking creatine supplementation and gastrointestinal discomfort.
      These reports remain anecdotal, as there are no documented reports of creatine over placebo
      resulting in stomach concerns.

      1. Overview

      Study Timeline

      Week Procedures

      Visit 1 Eligibility screening: MINI, HAM-D17, MOCA, QIDS, Labs, CGI, BSS, ATRQ

      Visit 2 QIDS

      31P-MRS Scan 1

      Start creatine 20g per day or placebo

      Start ECT (treatments 1 up to 3) as per routine

      Week 2 (Subjects may begin to complete ECT, moving to follow-up phase) Creatine 5g per day or
      placebo

      Continuing ECT (treatments 3 or 4 through 6 or 7) as per routine

      QIDS before each ECT

      HAM-D17 , CGI, BSS, MOCA at end of week

      Week 3 (Most subjects will complete ECT, moving to follow-up phase) Creatine 5g per day or
      placebo

      Continuing ECT (treatments 3 or 4 through 6 or 7) as per routine

      QIDS before each ECT

      HAM-D17 , CGI, BSS, MOCA at end of week

      31P-MRS Scan 2 (if ECT complete)

      Week 4 (Almost all subjects will complete ECT, moving to follow-up phase) Creatine 5g per day
      or placebo

      Continuing ECT (treatments 3 or 4 through 6 or 7) as per routine

      QIDS before each ECT

      HAM-D17 , CGI, BSS, MOCA at end of week

      31P-MRS Scan 2 (if ECT completed this week)

      Follow-up phase: 2 weeks (to start after completion of ECT or after week 4, whichever comes
      first) Creatine 5g per day or placebo (for two weeks)

      HAM-D17, CGI, BSS, MOCA two weeks after completion of ECT series

      31P-MRS Scan 2 (if not yet completed)

      All procedures performed by study personnel are research-related, but will be performed in
      addition to routine care (see Table 1). None of the study activities will be considered
      standard of care. There will be no cost to study subjects for their participation.
      Participants will be compensated for their time and travel. Study visits will be supervised
      by a board-certified/board-eligible psychiatrist or psychiatry resident and will be conducted
      either by a board-certified/board-eligible psychiatrist, psychiatry resident, or an at least
      baccalaureate degree level research assistant with training in the specific measures used.
      Laboratory and other study interpretation will be conducted by a
      board-certified/board-eligible psychiatrist.

      To determine if an individual is eligible for study participation, a screening visit will be
      conducted. Initially, a HAM-D17 will be administered to determine if the patient exhibits
      depressive symptoms that are sufficiently severe for inclusion in the study. Next, the Mini
      International Neuropsychiatric Interview (MINI) will be administered to confirm a diagnosis
      of a current major depressive episode. Study subjects will receive a baseline basic metabolic
      panel (BMP) to assess for renal insufficiency, and vitals (these may have been obtained in
      the course of ongoing clinical care). The QIDS, Antidepressant Treatment Response
      Questionnaire (ATRQ), Clinical Global Impression (CGI), Beck Suicide Scale (BSS), and a MoCA
      will be administered. Each participant will be assessed for history of ECT therapy, current
      medications, and any other medical history.

      Once entered into the study, depressed subjects will be randomized to receive either creatine
      or placebo using a random-digit method that is based on computer-generated numbers. Block
      randomization created by Investigational Drug Services (IDS) will be used to ensure equal
      treatment allocation within each block. 50% of the trial's clinical subjects will be
      randomized to placebo and the other 50% to active treatment. The study will be conducted as a
      double-blind trial, with neither participants nor research staff aware of participant
      assignment. Except in cases of medical emergency, the double-blind will not be "broken" until
      recruitment is closed and the final participant has completed 6 weeks of treatment and 4
      weeks of follow-up. The blind will be broken following the culmination of the study or at the
      request of a medical professional dealing with a medical emergency in a case in which it
      would help a study participant.

      2. Electroconvulsive Therapy

      Participants will be recruited from a population of patients who have already been referred
      for ECT and who have had initial clinical assessments to determine whether ECT is indicated.
      As this study is an add-on to standard clinical care only, routine ECT procedures will be
      followed, though the ECT service (attending psychiatrist, anesthesiologist) will be notified
      of subject participation. In general, subjects will, after being medically cleared for ECT
      (psychiatric exam, physical exam, EKG, laboratory studies if indicated), received bifrontal
      ECT every other day for between 6 and up to roughly 14 treatments, with a total duration of
      treatment lasting between two and four weeks. Anesthesia for ECT is provided by a
      board-certified anesthesiologist and comprises the use of methohexital, midazolam, etomidate,
      or ketamine, as indicated, and at the discretion of the anesthesiologist. Participants may
      receive interventions designed to augment the likelihood of a seizure being achieved, such as
      a caffeine infusion, hyperventilation, or other techniques, at the discretion of the treating
      ECT psychiatrist and anesthesiologist. After ECT, participants are monitored for recurrent
      seizure/status epilepticus and for vital sign abnormalities for roughly thirty minutes, then
      released to home (if outpatient) with 24 hour per day supervision by adult family members, or
      else escorted back to the inpatient unit, where they again receive 24 hour per day
      supervision by unit staff. Prior to each treatment, subjects complete a Quick Inventory of
      Depressive Symptoms (QIDS) to assess their overall burden of depressive symptoms. The exact
      duration of treatment/number of treatments is determined by the treating ECT psychiatrist,
      based on clinical response. The study will record all pertinent variables related to ECT as
      noted in the clinical record, including number of treatments, QIDS score, number of seizures
      per treatment session, seizure duration, adverse effects, augmentation strategies, anesthesia
      type, and vitals.

      2. Drug Dosing

      Participants who have been assigned to the creatine arm of the trial will receive a 20g
      loading dose daily for 1 week starting as soon as possible before ECT begins and after
      completion of the 31P-MRS; this will be administered in 4 divided doses of 5g each.
      Participants will then receive 5 g creatine daily throughout the course of ECT therapy (~3
      weeks), with continuation for an additional 2 weeks after the completion of the acute series
      of ECT, again at 5g daily (thus, up to 5 weeks total supplementation with creating 5g per
      day, depending on the length of ECT) Placebo recipients will receive an inert, relatively
      tasteless powder matched to creatine (e.g., glucose). Creatine doses are based on doses that
      have previously been shown to be safe and efficacious.

      3. Measures

      We plan to use the following for determining participant baseline and data collection:

        -  Hamilton Depression Rating Scale (HAM-D17) (at baseline, the end of week 1, the end of
           week 2, the end of week 3, and two weeks after completion of the ECT series)

        -  Quick Inventory of Depressive Symptomatology (QIDS) (at baseline and prior to each ECT
           session)

        -  Antidepressant Treatment Response Questionnaire (ATRQ) (at baseline)

        -  Mini International Neuropsychiatric Interview (MINI) (at baseline)

        -  Clinical Global Impressions Scale (CGI) illness improvement subscale (CGI-I) (at
           baseline, week 1, week 2, week 3, and two weeks after completion of the ECT series)

        -  Beck Suicide Scale (BSS) at baseline, week 1, week 2, week 3, and two weeks after
           completion of the ECT series)

        -  Montreal Cognitive Assessment (MoCA) at baseline, week 1, week 2, week 3, and two weeks
           after completion of the ECT series)

           4. Imaging

             1. Magnetic Resonance Imaging (Siemens 3T MRI system)

                MRI scans will be conducted twice: after the baseline visit and prior to initiating
                ECT, and following completion of the ECT series (i.e., after ~3 weeks, and during
                the 2 week post-ECT follow-up period). The 3.0 Tesla Siemens Prisma whole-body
                clinical scanner (Siemens Medical Solutions, Erlangen, Germany) located within the
                University Neuropsychiatric Institute (UNI) will be used to acquire this data.
                Participants will first undergo a routine anatomic MRI protocol, which includes MRI
                images acquired in the axial and coronal planes. Specifically, the anatomic scan
                protocol consists of a T1 weighted structural scan (MP2RAGE), and double-echo T2
                weighted scan, and a Fluid Attenuated Inversion Recovery scan (FLAIR). The purposes
                of the MR anatomic screening session include screening subjects for gross
                structural abnormalities and acquiring images for use in brain cortical thickness
                measurements. Anatomic MRI examinations will be performed with Siemens 64 channel
                head coil. After localization, anatomical imaging will be obtained using a
                T1-weighted, sagittal oriented 3D-Magnetization Prepared Rapid Gradient Echo
                (MPRAGE) sequence (TR/TE/TI 5000/2.93/700 ms, matrix 256x256, FOV 256x256 mm, flip
                angle 4 degree, slice thickness 1.0 mm, slab 176 mm, bandwidth 240 Hz/pixel). Axial
                proton-density and T2 weighted images will be acquired to screen for brain
                structural abnormalities using 2D Double echo T2 weighted turbo spin echo (TSE)
                sequence (TR 7110 ms, TE 28/84 ms, FOV 240x210, slice thickness 3 mm, flip 150°,
                bandwidth 179 Hz/pixel). FLAIR sequence (TR/TE/TI 8000/90/2500 ms, slice thickness
                5 mm, FOV 240x168, voxel size 0.8x0.6x5.0 mm, bandwidth 200 Hz/pixel, turbo factor
                13) will be used to detect juxtacortical-cortical lesions. All anatomic MRI images
                will be read by a board-certified, CAQ neuroradiologist to screen for structural
                abnormalities.

             2. Measurement of In-Vivo Brain Chemistry Using Phosphorus-31 Magnetic Resonance
                Spectroscopy (31P-MRS)

                Phosphorus spectroscopy data will be acquired on the same Siemens 3T system. We aim
                to keep the duration of each MRSI examination at or under 25 minutes. A 3D-MRSI
                sequence with elliptically weighted phase-encoding will be used to collect 31P-MRSI
                data to minimize T2 signal decay. Acquisition parameters will be: data matrix size
                16x16x8; TR 2000 ms; tip-angle 90 degree for hard RF pulse; Rx bandwidth ±1 kHz;
                complex-points 1024; readout duration 256 ms; pre-acquisition delay 0.3ms; FOV
                240x240 mm2 ; 16 NEX.

             3. Spectral Analysis of 31P-MRS Data

      Spectroscopy will be analyzed using Liner Combination of Model Spectra (LCModel), which
      analyzes an in vivo spectrum as a linear combination of model in vitro spectra from
      individual metabolite solutions. This model is fully automatic and user independent. A nearly
      model-free constrained regularization method is used for convolution and baseline. For
      quantification, absolute metabolite concentrations (institutional units) will be estimated
      using the unsuppressed water signal as an internal concentration reference. Also, total
      creatine levels will be used as a denominator for calculating the relative concentration for
      the comparison with previous reports. The standard Siemens libraries of model metabolite
      spectra provided with LCModel will be used in the basis set. The metabolites from the basis
      set will include alanine, aspartate, creatine, gamma-amino butyric acid, glucose, glutamine,
      glutamate, glycerophosphocholine, glutathione, myo-inositol, scyllo-inositol, lactate,
      N-acetylaspartate, N-acetylaspartylglutamate, phosphocholine, phosphocreatine,
      phosphoethanolamine, and taurine. For the reliability of detection, the Cramer-Rao lower
      bounds (CRLB) will be determined: the acceptable upper limit of estimated standard deviations
      will be set at 20%.

      Post processing of 31P-MRS data will be conducted using jMRUI software (jMRUI v. 4.0,
      European Community) with the AMARES algorithm (Advanced Method for Accurate, Robust and
      Efficient Spectral fitting of MRS data with use of prior knowledge). Before fitting the FID
      (Free-induction-decay) data, a Hamming filter will be applied to reduce signal contamination
      from neighboring voxels, with apodization of 10 Hz line broadening. Fourier transformation,
      frequency shifts correction, and zero-order/first order phase correction as well as baseline
      correction will be applied. The structural image-processing tool FSL (FMRIB Software Library,
      Release 4.1, University of Oxford) will be used to account for gray matter, white matter, and
      cerebrospinal fluid (CSF), in order to correct the partial volume effects on metabolite
      concentrations. The MRS grid will be positioned over the images in an identical fashion
      between baseline and treatment scans for each participant. The peak area for each 31P-MRS
      metabolite will be calculated as a percentage of the total phosphorus signal.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Randomized, double-blind, placebo-controlled. Block randomization protocol.
measure: HAMD-17
time frame: 3-6 weeks
description: 17-item Hamilton Depression Rating Scale; Maximum Score 54. Minimum Score 0. Higher scores are correlated with more severe depression
measure: QIDS
time frame: 3-6 weeks
description: Quick Inventory of Depressive Symptoms; Scores range from 0 to 27. Higher scores are correlated with more severe depression.
arm group label: Creatine monohydrate
arm group type: Experimental
description: Week 1: Creatine monohydrate 5g PO QID
Week 2 up to Week 6: Creatine monohydrate 5g PO qday
arm group label: Placebo
arm group type: Placebo Comparator
description: Week 1: Placebo 5g PO QID
Week 2 up to Week 6: Placebo 5g PO qday
intervention type: Dietary Supplement
intervention name: Creatine monohydrate
description: Creatine monohydrate loose powder
arm group label: Creatine monohydrate
intervention type: Drug
intervention name: Placebo
description: Placebo control (dextrose 5mg) matched to creatine monohydrate loose powder
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: Brent Kious, MD
phone: 8015851418
email: brent.kious@hsc.utah.edu
last name: Rebecca Jacobs
phone: (801) 829-7382
email: rebecca.jacobs@utah.edu
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Utah
investigator full name: Brent Michael Kious, MD, PhD
investigator title: Assistant Professor, Psychiatry
mesh term: Depressive Disorder
mesh term: Depression
mesh term: Depressive Disorder, Major
sharing ipd: No