Esketamine Adjuvant Therapy for Patients With Chronic Visceral Pain Comorbid Major Depressive Disorder

A Randomized Controlled, Single-blind, Esketamine Adjuvant Therapy for the Efficacy and Safety of Patients With Chronic Visceral Pain Comorbid Major Depressive Disorder

Ketamine is a dissociative anesthetic and powerful analgesic. At low doses, ketamine can desensitize the central pain pathway and modulate opioid receptors. Studies have generally found that preoperative use of ketamine can reduce opioid consumption by approximately 50% and sub-anaesthetic doses of it have a rapid antidepressant effect, especially refractory depression. Studies have confirmed that esketamine, the S(+) enantiomer of ketamine, has a stronger affinity for NMDA receptors, which can achieve the same effect at smaller doses. While the incidence of neuropsychiatric side effects is significantly lower. On March 4, 2019, the U.S. Food and Drug Administration (FDA) first approved esketamine nasal spray with a new mechanism of action for the treatment of adult patients with refractory depression. Based on the analgesic and antidepressant effects of ketamine, the investigators speculate that esketamine may be effective for patients with chronic visceral pain comorbid depression. At present, the research evidence in this area is relatively lacking. Therefore, this study aims to explore the difference in the efficacy and safety of esketamine as an adjuvant therapy and positive control drug-pregabalin in patients with chronic visceral pain comorbid depression.

Detailed Description: According to the inclusion criteria and exclusion criteria, select patients with chronic visceral pain comorbid depression.

Filtering and grouping period: During this phase, the patient will sign an informed consent form, and then conduct a structured clinical evaluation to determine whether it meets the "depressive disorder" in the DSM-IV-TR diagnostic criteria. According to the ICD-11, determine whether the patients have chronic visceral pain.

Acute treatment period: Randomize patients into the following treatment groups: intravenous administration of esketamine (3 groups, 0.125, 0.25, 0.50 mg/kg)， and duloxetine is co- administered orally. Pregabalin capsules were administered combined with duloxetine orally.

observation period: After 2 weeks, esketamine treatment was discontinued, and observation was continued for 2 weeks. Maintain duloxetine and pregabalin treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Major Depressive Disorder; Chronic Visceral Pain
• Intervention / Treatment: Drug: Pregabalin 75mg tid + Duloxetine; Drug: Intravenous administration of esketamine 0.125 mg/kg+Duloxetine; Drug: Intravenous administration of esketamine 0.25 mg/kg +Duloxetine; Drug: Intravenous administration of esketamine 0.50 mg/kg+Duloxetine

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tianmei SI, PhD., MD; Phone Number: 86-1062723748; Email: si.tian-mei@163.com
• Study Contact Backup: Name: Yunai Su, PhD; Phone Number: 86-10-62723767; Email: suyunai@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. aged 18 to 55
2. Those who can understand and obey the research plan
3. Sign the informed consent form voluntarily
4. Those who meet the DSM-IV-TR depression diagnostic criteria and have first or second episodes of depression
5. Hamilton Depression Scale score ≥ 14 points
6. Those who meet the ICD-11 pain diagnostic criteria, and visual analogue scale score ≥ 7 points. Those who have chronic visceral pain instead of cancer pain.

7. No systemic use of antidepressants and analgesics within 2 weeks after enrollment.

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Exclusion Criteria:

1. Female patients who are pregnant, breastfeeding, or preparing to conceive
2. Allergic to duloxetine or pregabalin in the past.
3. A history of serious or unstable physical diseases, such as cardiovascular/liver/kidney/respiratory/ endocrine/nervous/ blood system disease.
4. A history of epileptic seizures or brain injury, or any neurological disease (including multiple sclerosis, degenerative diseases such as acute lateral sclerosis, Parkinson's disease and movement disorders, etc.);
5. In the last 12 months, the patient has the following medical history or its main diagnosis (DSM-IV-TR) is organic mental disorder, schizophrenia, schizoaffective mental disorder, delusional mental disorder, indeterminate mental disorder, Bipolar disorder, psychotic characteristics that are coordinated or uncoordinated with the mood, and history of substance abuse (including alcohol, psychoactive substances, etc.).
6. Patients with a history of adverse reactions to multiple drugs.
7. The patient is taking psychotropic drugs, including benzodiazepines, sleeping pills, anticonvulsants, etc.
8. During the depressive episode, treatment with at least 2 antidepressants in a sufficient course of treatment or at least one SSRI antidepressant treatment is ineffective. A sufficient dose of treatment means treatment with fluoxetine ≥40 mg/day (or sertraline ≥100 mg/day, paroxetine> 40 mg/day, fluvoxamine> 100 mg/day, citalopram> 40 mg /Day, escitalopram> 20 mg/day, venlafaxine> 150 mg/day, duloxetine> 80 mg/day)
9. Received electroconvulsive therapy within 6 months before enrollment.

10. Those who are currently at serious risk of suicide, and a score of 3 or higher in item 3 of the 17-HAMD .

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pregabalin group; Pregabalin capsules were administered orally (75 mg, tid), combined administration of duloxetine.	Drug: Pregabalin 75mg tid + Duloxetine; Pregabalin capsules were administered orally (75 mg, 3 times a day), combined administration of duloxetine (60-120 mg/day）.
Experimental: 0.125 mg/kg esketamine group; Intravenous administration of esketamine 0.125 mg/kg，and duloxetine is co- administered orally.	Drug: Intravenous administration of esketamine 0.125 mg/kg+Duloxetine; Intravenous administration of esketamine 0.125 mg/kg （2 times per week)， combined oral administration of duloxetine (60-120 mg/day）
Experimental: 0.25 mg/kg esketamine group; Intravenous administration of esketamine 0.25mg/kg，and duloxetine is co- administered orally.	Drug: Intravenous administration of esketamine 0.25 mg/kg +Duloxetine; Intravenous administration of esketamine 0.25 mg/kg （2 times per week)， combined oral administration of duloxetine (60-120 mg/day）
Experimental: 0.50 mg/kg esketamine group; Intravenous administration of esketamine 0.50 mg/kg，and duloxetine is co- administered orally.	Drug: Intravenous administration of esketamine 0.50 mg/kg+Duloxetine; Intravenous administration of esketamine 0.50 mg/kg （2 times per week)， combined oral administration of duloxetine (60-120 mg/day）

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analogue Scale (VAS)	The pain VAS is a unidimensional measure of pain intensity, which has been widely used in diverse adult populations, including those with chronic visceral pain. The minimus value is 0 and the maximum value is 10. Higher scores mean a worse outcome.	Day 0 to Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hamilton Depression Rating Scale (HAMD)	The questionnaire is designed for adults and is used to rate the severity of their depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. The minimum value is 0 and the maximum value is 52. Higher scores mean a worse outcome.	Day 0 to Day 28
Short Form 12 Health Survey (SF-12)	SF-12 is a 12-item, patient-reported survey of patient health, and is widely used since it produces similar results for physical and mental health scores with far less respondent burden for producing scores of overall mental and physical well-being. The SF-12 yields an eight-scale profile of scores as well as physical and mental health summary measures. Answers to questions of these subscales are combined (weighted) with Physical Component Summary (PCS-12) and Mental Component Summary (MCS-12) scale scores. SF-12 scales and summary measures are scored so that a higher score indicates a better health state. After recoding raw scores for some items (BP, GH, VT, and one item from MH), the raw scores could be transformed to provide scores for eight scales, each ranging from 0 (the worst) to 100 (the best).	Day 0 to Day 28
Hamilton Anxiety Scale (HAMA)	The HAMA is a psychological questionnaire used by clinicians to rate the severity of a patient's anxiety. The scale consists of 14 items designed to assess the severity of a patient's anxiety. Each of the 14 items contains a number of symptoms, and each group of symptoms is rated on a scale of zero to four, with four being the most severe. The minimum value is 0 and the maximum value is 56. Higher scores mean a worse outcome.	Day 0 to Day 28
Changes in serum inflammatory factors	Explore the action mechanism of esketamine on patients with chronic visceral pain comorbid depression from the level of blood inflammatory factors, including cytokines IL-1beta, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha, etc.	Day 0 to Day 28
Electroencephalogram (EEG)	Calculate the time-frequency characteristics of EEG data in each frequency band (delta wave, <4 Hz; theta wave, 4-8 Hz; alpha wave, 8-12 Hz and beta wave, 12-30 Hz) during the study period.	Day 0 to Day 28
Functional magnetic resonance imaging (fMRI)	The regional brain activity, including fractional amplitude of low frequency fluctuation (fALFF) and regional homogeneity (ReHo) values, will be computed and assessed. In addtion, the large-scale brain networks and edge-wise connections in patients will be explored based on the theory of brain networks during the study period.	Day 0 to Day 28

Collaborators and Investigators

• Sponsor: Peking University

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2021
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): March 1, 2023

Study Registration Dates

• First Submitted: March 14, 2021
• First Submitted That Met QC Criteria: April 14, 2021
• First Posted (Actual): April 19, 2021

Study Record Updates

• Last Update Posted (Actual): April 19, 2021
• Last Update Submitted That Met QC Criteria: April 14, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Efficacy and Safety; Pregabalin; Esketamine; Major depressive disorder; Chronic Visceral Pain
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Pain; Neurologic Manifestations; Nociceptive Pain; Depression; Depressive Disorder; Disease; Depressive Disorder, Major; Visceral Pain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Anti-Anxiety Agents; Anticonvulsants; Serotonin and Noradrenaline Reuptake Inhibitors; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Duloxetine Hydrochloride; Pregabalin; Esketamine
• Other Study ID Numbers: Esketamine20210221

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No