Depression clinical trials worldwide: a systematic analysis of the ICTRP and comparison with ClinicalTrials.gov

Abstract

Major depressive disorder (MDD), commonly known as depression, affects over 300 million people worldwide as of 2018 and presents a wide range of clinical symptoms. The international clinical trials registry platform (ICTRP) introduced by WHO includes aggregated data from ClinicalTrials.gov and 17 other national registers, making it the largest clinical trial platform. Here we analysed data in ICTRP with the aim of providing comprehensive insights into clinical trials on depression. Applying a novel hidden duplicate identification method, 10,606 depression trials were identified in ICTRP, with ANZCTR being the largest non- ClinicalTrials.gov database at 1031 trials, followed by IRCT with 576 trials, ISRCTN with 501 trials, CHiCTR with 489 trials, and EUCTR with 351 trials. The top four most studied drugs, ketamine, sertraline, duloxetine, and fluoxetine, were consistent in both groups, but ClinicalTrials.gov had more trials for each drug compared to the non-ClinicalTrials.gov group. Out of 9229 interventional trials, 663 unique agents were identified, including approved drugs (74.5%), investigational drugs (23.2%), withdrawn drugs (1.8%), nutraceuticals (0.3%), and illicit substances (0.2%). Both ClinicalTrials.gov and non-ClinicalTrials.gov databases revealed that the largest categories were antidepressive agents (1172 in ClinicalTrials.gov and 659 in non-ClinicalTrials.gov) and nutrients, amino acids, and chemical elements (250 in ClinicalTrials.gov and 659 in non-ClinicalTrials.gov), indicating a focus on alternative treatments involving dietary supplements and nutrients. Additionally, 26 investigational antidepressive agents targeting 16 different drug targets were identified, with buprenorphine (opioid agonist), saredutant (NK2 antagonist), and seltorexant (OX2 antagonist) being the most frequently studied. This analysis addresses 40 approved drugs for depression treatment including new drug classes like GABA modulators and NMDA antagonists that are offering new prospects for treating MDD, including drug-resistant depression and postpartum depression subtypes.

Fig. 1. Annual numbers of registered trials between registries.

a When considering this comparison, ClinicalTrials.gov consistently outpaced non-ClinicalTrials.gov databases in most years. However, an interesting anomaly occurred in 2018 when non-ClinicalTrials.gov databases reached their peak with 501 registered trials, while ClinicalTrials.gov reported 484 registrations. Notably, ClinicalTrials.gov experienced a remarkable peak in 2005. b Taking a closer look at individual non-ClinicalTrials.gov registries, we found that ANZCTR led the pack with the highest number of clinical trials, totaling 1 031. ANZCTR exhibited two peaks, one in 2013 and another in 2019. Other prominent databases included IRCT with 576 trials and ISRCTN with 501 trials. Despite CHiCTR’s total of 489 trials, it displayed an exceptional growth pattern, registering the highest number of trials in a single year, reaching 160 trials. CT ClinicalTrials.gov; N-CT non-ClinicalTrials.gov, ACTRN Australian New Zealand Clinical Trials Registry, CHiCTR Chinese Clinical Trial Registry, CTRI Clinical Trials Registry - India, DRKS German Clinical Trials Register, EUCTR, EU Clinical Trials Register, IRCTN Iranian Registry of Clinical Trials, ISRCTN International Standard Randomized Controlled Trial Number Registry, JPRN Japan Primary Registries Network, NTR The Netherlands National Trial Register, PACTR Pan African Clinical Trial Registry.

Fig. 2. Drugs in ClinicalTrials.gov and non-ClinicalTrials.gov.

Among the drugs studied in clinical trials, ketamine stands out as the most extensively researched, with 100 trials listed in ClinicalTrials.gov and 37 in non-ClinicalTrials.gov sources. Additionally, three other drugs that garnered significant attention were sertraline, duloxetine, and fluoxetine. ClinicalTrials.gov generally hosted more studies for each drug. Venlafaxine was another notable drug, making it to the top 10 drugs in both ClinicalTrials.gov and non- ClinicalTrials.gov listings. However, in the non-ClinicalTrials.gov category, venlafaxine was surpassed by agomelatine (with 15 trials) and paroxetine (with 16 trials). Notably, some less common substances like Lactobacillus Helveticus, minocycline, modafinil, celecoxib, erythropoietin, and hesperidin made appearances in the non-ClinicalTrials.gov group, but each of these drugs had fewer than 5 trials associated with them. In contrast, in the ClinicalTrials.gov group, we found such intriguing drugs as minocycline, mifepristone, and psilocybin, each with fewer than 20 trials. It’s worth highlighting that a novel NMDA receptor modulator called rapastinel was exclusively found among the top drugs listed on ClinicalTrials.gov.

Fig. 3. Drugs in the non-ClinicalTrials.gov group.

Upon closer examination of the non-ClinicalTrials.gov group, we identified five databases with the largest number of clinical trials: ANZCTR (978 trials), IRCT (576 trials), ISRCT (501 trials), CHiCTR (489 trials), and EUCTR (351 trials). While the top drugs differed among these databases, it’s noteworthy that ketamine, sertraline, duloxetine, fluoxetine, and venlafaxine consistently ranked in the top 10 drugs in all five databases. The presence of unique drugs in each database highlights the importance of analyzing each database to gain a comprehensive understanding. For example, the ANZCTR database featured unexpected entries such as nicotine, amino acids, codeine, and even sunflower oil in clinical trials. The IRCT database exclusively highlighted Lactobacillus Helveticus as one of the top studied drugs. ISRCTN notably focused on agomelatine, with nearly 10 trials dedicated to this drug, which differed significantly from the CHiCTR database where agomelatine appeared in only 1 trial. CHiCTR, in turn, emphasized drugs like fluoxetine, paroxetine, and ketamine. Despite these variations, it’s important to note that in all databases, the overall number of clinical trials for each drug did not exceed 15 trials, indicating that the research landscape is characterized by a wide array of drugs being studied in relatively small numbers. The EUCTR database stood out for its relatively higher concentration of trials centered around specific drugs, including 14 trials on duloxetine, 10 trials on psilocybin, and 8 trials on ketamine. Additionally, two experimental drugs, TAK-653 (present in the EUCTR, 1 trial) and JNJ-54175446 (in ISRCTN, 1 trial), were identified.

Fig. 4. Drug categories in the ClinicalTrials.gov and non-ClinicalTrials.gov groups.

The figure illustrates the proportion of drug categories per registry, focusing on depression trials with an interventional study design that involved drug treatment. In total, there were 3058 such trials analyzed. Antidepressive agents emerged as the most prevalent drug category, with a total of 1172 agents in ClinicalTrials.gov and 659 agents in the non-ClinicalTrials.gov group. Interestingly, less than 5% of antidepressive agents were investigational, with the majority already approved for use. Notably, most investigational drugs were found in the nutrients, amino acids, and chemical elements category, which was more abundant in the non-ClinicalTrials.gov databases (over 600 agents compared to 250 agents in the ClinicalTrials.gov group). The third most common category was analgesics, comprising entirely approved drugs. In the ClinicalTrials.gov database, antipsychotic agents occupied the fourth position, whereas in the non-ClinicalTrials.gov databases, the fourth spot was taken by anti-infective agents. In general, approved agents significantly outnumbered investigational ones in all categories. However, it’s worth noting that there were specific categories with a very small number of agents that were almost exclusively investigational. For instance, in the ClinicalTrials.gov database, categories like solvents, hallucinogens, and GABA agents fell into this group, whereas in the non-ClinicalTrials.gov group, the neurotransmitters category was entirely composed of investigational agents. These findings suggest a predominant focus on approved agents in depression trials.

Fig. 5. Investigational drugs in depression treatment.

During the analysis of investigational antidepressive agents, several drugs emerged as the most common candidates for study. The indicated phases represent the highest phases that these drugs have reached in clinical trials. The frequency of each drug corresponds to the number of times the drug was mentioned in clinical trials. Among these investigational drugs, several reached the highest phase of 4. These drugs include buprenorphine, reboxetine, tianeptine, mianserin, hypericin, and melitracen. Two drugs, lanicemine and rolipram, were in phase 1 of clinical trials, indicating early-stage research. There were also two drugs for which phase division was not applicable (NA): lofepramine and amitriptylinoxide. Notably, buprenorphine was the only drug with more than 15 trials dedicated to its study. Interestingly, among the top investigational agents for depression treatment, no antibiotics or NSAIDs (non-steroidal anti-inflammatory drugs) were found, highlighting the focus on other types of compounds and therapies in trials.