Intravenous Administration Of Adenosine Triphosphate And Phosphocreatine Combined With Fluoxetine In Major Depressive Disorder:A Randomized,Double-Blind,Placebo-Controlled Study

Background:Major depressive disorder is a common psychiatric disorder.With systematic antidepressant treatment,50-75%of patients exert treatment response but require 4-6 weeks to have symptoms alleviated.Therefore,researchers anticipate the development of novel fast-acting antidepressants.Previous studies have revealed the decrease of bio-energetic metabolism may contribute to the occurrence of depression,while our basic study team has found adenosine triphosphate(ATP)and phosphocreatine(PCr)as fast-acting antidepressants in the depressed animal model.ATP and PCr have already been widely prescribed clinically as energy supplements for cells.This will be the first clinical attempt of intravenous administration of ATP and PCr combined with oral fluoxetine in major depressive disorder.Objective:Our pilot study aims to evaluate the feasibility and safety to conduct a full-scale trial of intravenous administration of ATP or PCr combined with oral fluoxetine to the patient with moderate to severe major depressive disorder.The preliminary exploring of the antidepressant effect of the augmentation therapy than fluoxetine alone might allow us to get clinical insights beyond the results from preclinical animal studies.Method:This trial is designed as a single-center,randomized,double-blind,placebo-controlled clinical pilot study,conducted at Zhujiang Hospital,Southern Medical University,Guangzhou,China.Patients will be assessed and hospitalized in the Neurology Department of the hospital.All the enrolled patients should meet the diagnosis criteria of moderate to severe MDD(HAMD-18>20),and meet none of the exclusion criteria.Patients willing to participate in our program have signed the informed paper before initiating our treatment.The patients will received a total of 6 weeks of intermittent antidepressant treatment,including:intravenous administration for the first 2 weeks(phosphocreatine/adenosine triphosphate/0.9%sodium chloride)and oral antidepressant(fluoxetine,20 mg),once in the morning).After hospitalization,there will be followed by an oral fluoxetine 4 weeks treatment.Feasibility indicators include eligibility rate,drug compliance,and dropout rate etc.Safety indicators include general changes in vital signs before and after treatment,physical examination(before treatment,7d ± 2,14d±2,28d±2),laboratory tests(before treatment,14d±2),and electrocardiogram and electroencephalogram examinations(before treatment,14d ± 2)and antidepressant adverse reaction scale(before treatment,7d ± 2,14d ± 2,28d ± 2,42d ± 2),and any clinical adverse event throughout the medication will be well-recorded.The efficacy measures included the Hamilton Depression Scale-24 and the Patient Health Questionnaire Self-Rating Depression Scale-9(before treatment,7d±2,14d±2,28d±2,42d±2).Results:In our pilot study,from May 2017 to January 2018,a total of 57 subjects were screened,37 of them met the study inclusion/exclusion criteria,20 subjects were finally enrolled in our study,and a total of 18 of enrolled patients completed 14 days of hospitalization.A total of 17 enrolled patients completed the complete clinical research process,of which 3 were withdrawn from the clinical trial.The 17 subjects who completed our study satisfaction survey were basically satisfied about their treatment results,hospital environment,and their feeling of safeness while taking part in our study.There were no significant statistically differences in the vital signs and laboratory tests of 18 subjects who participated in and completed the combination treatment regimen.No clinical adverse events occurred in any of our enrolled patient.The side effects of the 18 subjects under the combination regimen were:drowsiness,reduced salivation,lassitude,headache,nausea,constipation,dizziness,diarrhea,postural hypotension,palpitation.Their reported severity types were all in mild degree,and occasional occurred.No medical intervention was initiated.Three of these patients who experienced mild palpitations during intravenous infusion,and the symptoms alleviated after adjusting for its drip rate.Conclusions:Intravenous administration of adenosine triphosphate and phosphocreatine combined with fluoxetine in moderate to severe major depressive disorder is a feasible clinical study.It is safe to initiate such treatment scheme to patients with moderate to severe major depressive disorder.