STRENGTHS AND LIMITATIONS OF THIS STUDY

This is the first randomised, double-blind clinical trial on dextromethorphan in major depressive disorder.

Group sequential adaptive design will allow two interim analyses and will save resources.

Being a single-centre study, generalisability may be limited.

The study is not going to compare the time to response between the study groups.

Evaluation of multiple doses of dextromethorphan and a longer follow-up period with multiple time points would have strengthened the study data.

Background

Major depressive disorder (MDD) is a common psychiatric disorder with a substantial socioeconomic burden with a global prevalence rate of 16%.1 The underlying pathophysiology of depression is still not understood completely.2 Among the different proposed hypotheses, the most accepted is the monoamine hypothesis, which is the basis of conventional antidepressant medications like tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors. Although many medications are available, a significant proportion of patients become either partial responders (less than 25% improvement on a depression rating scale), non-responders (improvement between 25% and 50% on a rating scale) or treatment-resistant depression (TRD) patients (when at least two trials with antidepressants from different pharmacological classes in adequate dose, duration and compliance fail to produce a significant clinical improvement).3–5 Another major concern is the therapeutic lag period with all these monoaminergic antidepressants. Additionally, most of the available antidepressant medications have many adverse effects, which increase with increments in dose. The discovery of the rapid and sustained antidepressant effect of a subanaesthetic dose of ketamine, especially in the treatment of non-responders and treatment-resistant cases,1 6 has led to extensive clinical and preclinical research in the recent past. The US Food and Drug Administration (FDA) has also approved esketamine nasal spray for the treatment of TRD in adults.7 As repeated doses of ketamine are related to abusive potential and many other adverse effects,8 the search for a similar antidepressant agent is going on that acts via a similar mechanism with a better safety profile.

Dextromethorphan, a US FDA-approved over-the-counter antitussive medication, has a similar property of non-competitively blocking N-methyl-D-aspartate (NMDA) receptors of glutamate, like ketamine.9 Additionally, dextromethorphan has serotonin reuptake transporter (SERT) inhibitory and norepinephrine transporter (NET) inhibitory properties,10 so it can also increase the availability of serotonin in synapses, hence may achieve a synergistic effect with SSRIs.11 12 In 2010, US-FDA approved dextromethorphan plus quinidine (Nuedexta) for use in pseudobulbar affect,9 10 13 and currently, it is under investigation as a potential antidepressant agent in MDD (NCT01882829, NCT02153502).10 13 A phase IIa clinical trial by Murrough et al has reported acceptable tolerability and efficacy of dextromethorphan/quinidine combination in TRD.14 In 2022, the US FDA approved dextromethorphan hydrobromide and bupropion hydrochloride fixed-dose combination (Auvelity) for the treatment of MDD in adult patients.15 Akbar et al, in their systematic review, evaluated the efficacy and safety of the dextromethorphan-bupropion combination for depression and highlighted the importance of evaluating the potential impact of combining dextromethorphan with other CYP2D6 inhibitors, such as antidepressants known to interact with CYP2D6, specifically in patients diagnosed with MDD.16 Previous preclinical and clinical studies14 17–25 on dextromethorphan in depression have been presented in online supplemental table S1.

In the present background, we hypothesise that the major concerns of antidepressant therapy, like therapeutic latency, lack of efficacy and adverse drug reactions, may be overcome by adding dextromethorphan to SSRI in MDD. As SSRIs inhibit CYP2D6, the addition of quinidine with dextromethorphan may not be reasonable and, hence, not considered in the present study. Our literature search found that, to date, there is no randomised controlled trial on dextromethorphan as an add-on therapy to first-line antidepressants like SSRIs. So, the present randomised controlled trial has been planned with an objective to evaluate the efficacy and safety of add-on dextromethorphan to SSRIs in MDD.

Objectives of the studyPrimary objective

To evaluate the change in symptoms of Depression using the Montgomery-Asberg Depression Rating Scale (MADRS) score from baseline after 8 weeks treatment with add-on dextromethorphan in patients with MDD.

Secondary objectives

To evaluate the treatment response rate (defined as a reduction of ≥50% of the MADRS score from baseline) at 8 weeks.

To evaluate the remission rate (defined as a score of <7 MADRS post-treatment) after 8 weeks.

To evaluate clinical status assessed by Clinical Global Impression (CGI) (severity and improvement) from baseline after 8 weeks.

To evaluate the neurotrophic effect of add-on dextromethorphan in terms of change in serum level of brain-derived neurotrophic factor (BDNF) from baseline after 8 weeks.

To evaluate the serum level of dextromethorphan after 8 weeks.

To evaluate the adverse drug effect profile of oral dextromethorphan.

MethodsStudy design

The proposed study is a randomised, double-blind, add-on placebo-controlled, parallel-arm, group sequential design clinical trial. The study protocol has been prepared following the guidelines of Standard Protocol Item Recommendations for Interventional Trials and registered with ClinicalTrials.gov. The present study is a single-centred study and will be conducted in the departments of Pharmacology and Psychiatry of our institute. The approval from the Institutional Ethics Committee, All India Institute of Medical Sciences, Bhubaneswar, India, was obtained on 14 December 2021.

The present trial will follow a group sequential design with two interim analyses. The first interim analysis will be done after completion of follow-up of 34 participants (17 in each group), and the second interim analysis will be done after completion of 60 participants (30 in each group) (figure 1). If the z value breaches the O'Brien-Fleming boundary of futility or efficacy during any interim analysis, the trial will be stopped (figure 2).

Figure 1

Study flow chart. SSRI, selective serotonin reuptake inhibitor.

Figure 2

O'Brien Fleming boundary targets along with sample size provided the allocation ratio is maintained as 1:1 throughout the study. (Z-score 2.868, 2.060 and 1.708 corresponds to a p value of 0. 0.0021, 0.0197 and 0.0438, respectively).

Study population and eligibility

Patients attending the outpatient psychiatry department of our institute with MDD will be screened, and enrolment will be done as per predefined inclusion and exclusion criteria. After direct communication with the principal investigator, detailed information regarding interventions, assessment methods, benefits and potential adverse reactions will be explained, and a patient information sheet will be provided to the participants. Written informed consent will be obtained from all participants before they participate in the study (participant informed consent form has been provided under online supplemental material).

Diagnostic criteria

The diagnosis of depression will be solely clinical and Diagnostic, and the Statistical Manual of Mental Disorders-5 (DSM5) criteria26 for diagnosing MDD will be followed:

‘A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest or pleasure.

Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad, empty, hopeless) or observation made by others (eg, appears tearful).

Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation.

Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month) or decrease or increase in appetite nearly every day.

Insomnia or hypersomnia nearly every day.

Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).

Fatigue or loss of energy nearly every day.

Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).

Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).

Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

B. The symptoms cause clinically significant distress or impairment in social, occupational or other important areas of functioning.

C. The episode is not attributable to the physiological effects of a substance or another medical condition.’

Inclusion criteria

Patients diagnosed with MDD (DSM5) of either gender within the age group of 18–65 years.

Patients with MADRS scores ≥7 and ≤34 (patients having mild to moderate MDD).

Patients who are on a stable dose of sertraline 50 mg or any other SSRI therapy in an equivalent dose (fluoxetine 20 mg/day, paroxetine 20 mg/day, escitalopram 10 mg/day, fluvoxamine 75 mg/day).27

Patients who have given written informed consent.

Exclusion criteria

Patients who have been treated with electroconvulsive therapy recently.

History of epilepsy, or other major neurological or medical disorders, head trauma.

Patients with a history of bipolar depression.

Patients with schizophrenia or other psychotic disorders.

Patients with cognitive impairment.

Initiating or stopping formal psychotherapy within 6 weeks before enrolment.

Patients with comorbidities like any malignancies, hepatic, renal, cardiovascular, neurological or endocrinal, or respiratory dysfunction.

Substance abuse history of psychoactive agents.

Pregnant and lactating mothers.

Sample size calculation

The sample size has been calculated based on the expected change in the primary outcome measure (MADRS score), and for the calculation, data have been taken from a previous randomised, controlled trial done by Kamijima et al where the mean (SD) difference in MADRS score was 7.2 (SD 7) between the groups.28 Our calculation found that a sample size of 42/group (N=84) can achieve a power of 90% to detect an intergroup difference of 5 in the MADRS score, considering an SD of 7, alpha as 0.05 and allocation ratio 1:1.

We have planned a group sequential design with three analyses (two interim and the final analysis) during the course of the study. To control the increase in the chance of occurrence of type I error during the interim analyses, the O'Brien-Fleming boundary (with z scores and p value) has been defined as provided in figure 2. The study will be terminated if the Z value of the effect size crosses the boundary on either side during an interim analysis. Sample size calculation was done using the software R (rpact).29

Randomisation, allocation concealment and blinding

All the recruited patients will be randomised into two treatment groups by block randomisation using computer-generated codes. The fixed block size of 6 has been decided to be used for random code generation. The allocation ratio will be 1:1 throughout the study. For blinding purposes, the random allocation code of the participants will be generated by the investigator, who will not be involved in patient recruitment. The sequentially numbered and identical-looking medication dispensers will be used for allocation concealment. The randomisation sequence will be blinded to both participants and the investigators. For interim analysis, the randomisation code will be opened, and the analysis will be done by an investigator who will be blinded to the group allocation.

Interventions

Patients in the test group will get a dextromethorphan 30 mg capsule once daily orally as an add-on to ongoing SSRI treatment, whereas patients in the control group will get an identical-looking capsule containing a placebo (starch) once daily in addition to SSRI. Both placebo and test medication have to be consumed for 8 weeks.

Study procedure and data collection

Patients aged 18–65 years, of either gender, attending the psychiatry outpatient department of our institute, and having a diagnosis of MDD will be screened. Enrolment will be done after considering the predefined inclusion and exclusion criteria and obtaining written informed consent. A detailed history and basic clinical details will be recorded. At baseline, MADRS and CGI-S scores will be recorded. A 5 mL venous blood will be collected to estimate serum BDNF level at baseline. By using computer-generated algorithms, recruited patients will be randomised into test and control groups. Patients in the test group will get dextromethorphan 30 mg once daily orally as an add-on to ongoing SSRI treatment, whereas patients in the control group will get an identical-looking capsule containing a placebo (starch) once daily in addition to SSRI. Both placebo and test medication have to be consumed for 8 weeks. All patients are going to be followed up after 8 weeks, and post-treatment re-evaluation of all the above parameters, that is, MADRS scores, CGI scores, and serum BDNF levels, will be done. The detailed visit schedule is presented in online supplemental table S2. There can be unscheduled visits due to deterioration of depressive symptoms or adverse drug reactions. Treatment-emergent adverse events will be reported and managed according to severity. Causality assessment will be done for adverse drug reactions by using the WHO-Uppsala Monitoring Centre (WHO-UMC) system.

Outcome measuresPrimary outcome measure

MADRS scores at baseline and 8 weeks follow-up. MADRS is a 10-item diagnostic questionnaire to measure the severity of depressive episodes in patients with mood disorders. Each item yields a score of 0–6; the overall score thus ranges from 0 to 60. The higher MADRS score indicates more severe depression.30

Secondary outcome measures

The response rate of the patients, that is, percentage of patients showing 50% decrease in MADRS scores from baseline, at 8-week follow-up.

The remission rate, that is, percentage of patients achieving MADRS scores <7 at 8-week follow-up.

CGI scores: CGI-S (severity) at both baseline and follow-up and CGI-I (improvement) at 8 weeks. The CGI provides an overall clinician-determined summary measure that considers all available information, including a knowledge of the patient’s history, psychosocial circumstances, symptoms, behaviour and the impact of the symptoms on the patient’s ability to function. The CGI has two components: the CGI-Severity, which rates illness severity, and the CGI-Improvement, which rates change from the initiation (baseline) of treatment on a 7-point scale.31

Serum BDNF level at baseline and at 8-week follow-up. Serum BDNF levels will be measured using a commercially available human ELISA kit.

Serum dextromethorphan level after completion of 8-week therapy using high-performance liquid chromatography (HPLC). For quantitative analysis of dextromethorphan, the HPLC method with fluorometric detection will be done as described by Lin et al.32

Safety evaluation: During the follow-up visit, the occurrence of treatment-emergent adverse events will be assessed by non-directive questioning of the patient. Patients can directly access the investigators to report any adverse effects they have experienced. Whether previously known or not, all adverse events will be recorded with their description, intensity, duration, action taken, outcome and causal relationship to SSRIs and dextromethorphan. Treatment-emergent adverse events will be reported and managed according to severity. Causality assessment will be done for adverse drug reactions by using the WHO-UMC system.

Evaluation of medication adherence

The patient will be asked to return the remaining medication at the end of the 8-week period. The medication adherence (SSRI and dextromethorphan) will be calculated by pill count method. The patient will be considered compliant if there is >80% adherence to the pills used. Additionally, the serum dextromethorphan level will give an idea of compliance.

Discontinuation

In case of the following emergencies, participants will be allowed to discontinue and withdraw from the current study: (a) any allergic reactions or adverse events that should be withdrawn according to the physician’s judgement and (b) poor compliance (<80% medication adherence).

Data management

All demographic and clinical data will be captured in a case report form (CRF), and the data entry will be done with the sequence code of each recruited patient. One investigator will monitor the clinical data once a week. Signed consent forms will be attached to the individual CRF and will be accessible only to authorised investigators. A specific investigator will access and analyse the final datasheet.

Statistical analysis

Categorical variables such as gender, remission rate and response rate will be represented as percentage/proportion and continuous data like age, MADRS score, CGI score, serum BDNF as mean±SD or median and IQR if the data is non-parametric. For performing statistical analyses, R software will be used.33 For the calculation of statistical significance, a p<0.05 will be considered. Analyses will be conducted with the intention-to-treat principle. Missing values will be analysed using multiple imputations, and the pooled data will be used for analysis. Fisher’s exact test will compare categorical variables between the groups. For comparing means/medians, the unpaired t-test/ Mann-Whitney U test (between the groups) and the two-sided paired t-test/Wilcoxon signed-rank test (within the group) will be used. The correlation between serum BDNF and disease severity treatment response will be checked using Pearson’s correlation coefficient calculation. Logistic regression will be performed to assess the factors affecting the response rates in MDD patients.

Ethics and dissemination

This study was approved by the Institutional Ethics Committee of All India Institute of Medical Sciences, Bhubaneswar, India, and the study conformed to the provisions of the Declaration of Helsinki and ICMR’s ethical guidelines for biomedical research on human subjects (2017). After explaining the benefits and harm of the study, written informed consent will be taken from all participants. The confidentiality of the study subjects will be maintained throughout the study duration by restricting access to specific investigators. They can exit from the study at their discretion. Being an academic clinical trial with limited funding, there will be no provision of post-trial access to the trial medication. In case of any treatment-emergent adverse events, the participant will be treated free of cost in the institute. The results of this research will be presented at academic conferences and published in peer-reviewed journals. The International Committee of Medical Journal Editors guidelines on authorship criteria will be followed, and the manuscript will be drafted and edited by the authors, not by any professional writers. The protocol is available on ClinicalTrials.gov, and the participant-level data set will be available from the corresponding author on reasonable request.

Study status

The recruitment started on 10 February 2022, and the follow-up of the 60th patients was completed on 30 September 2023. The second interim analysis was done for the primary outcome measure in October 2023. The result of the second interim analysis showed a statistically significant difference between the study groups in terms of reduction of MADRS score from baseline to the 8-week follow-up, and the O'Brien Fleming boundary was breached. Hence, the trial was terminated, and all secondary outcome measures were assessed.

Patient and public involvement

Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Discussion

Therapeutic latency, lack of efficacy and adverse drug reactions are the major limitations of current antidepressant therapies. To overcome these treatment hurdles, add-on therapy to conventional antidepressant medications may lead to better therapeutic outcomes. As dextromethorphan has the property of non-competitively blocking NMDA receptors (like ketamine) with additional SERT and NET inhibitory action, we hypothesise that adding dextromethorphan to the SSRI regimen can improve clinical outcomes in MDD. So, the present randomised controlled trial has been planned to evaluate the efficacy and safety of add-on dextromethorphan to SSRIs in MDD.

In the present randomised controlled trial, the potential of add-on therapy of dextromethorphan will be evaluated in comparison to add-on placebo therapy. The efficacy parameters are the change in MADRS scoring, responder rate, remission rate and change in serum BDNF from baseline. MADRS is an established and validated scoring system to assess the severity of depression and is used widely by psychiatrists for research and clinical practice. The definition of response and remission rate has been validated by Riedel et al, and the present study will follow the same.34 On the other hand, the neurotrophic hypothesis of depression is based on BDNF, a neurotrophin that plays a significant role in the survival and development of neurons.35 36 The connection between the BDNF signalling pathway and MDD is well established; hence, serum BDNF has been used as a biomarker in this study.37 38 The estimation of serum dextromethorphan will help to assess compliance and ensure the therapeutic level required for the drug effect. Though SSRIs and dextromethorphan are well-tolerated medications, all treatment-emergent adverse events will be monitored.

The proposed clinical trial is the first registered trial on dextromethorphan as an add-on therapy to first-line antidepressants like SSRIs in MDD. The major strength of the study lies in its robust methodology and statistical analysis. The proposed study has certain limitations. First, as the study is a single-centre study, the generalisability of the data may be limited. Second, the outcome parameter, like time to response, could have been included to compare therapeutic latency between the groups. Third, instead of a single dose level of 30 mg, multiple doses could have been evaluated. Investigators opted for a safe dose for the present exploratory study. However, depending on the study results, a higher dose of 45 mg and 60 mg may be evaluated in future. Fourthly, a longer follow-up period with multiple time points would have strengthened the study data. However, the previous clinical trials on dextromethorphan in MDD by Iosifescu et al and Tabuteau et al were for a duration of 6 weeks.39 40 So, we expect to generate clinically meaningful data with a follow-up period of 8 weeks. If the study results prove favourable, prescribing add-on dextromethorphan to first-line antidepressants, the dose requirement of antidepressant medications may decrease, there may be less chance of adverse drug reactions, and it may lead to better compliance and better clinical outcomes. Hence, the present study is expected to generate evidence on the use of adjuvant dextromethorphan with first-line antidepressant medications in MDD and contribute to practising guidelines.

Ethics statementsPatient consent for publication

Consent obtained directly from patient(s).