Ethosuximide in MDD

Overview

Introduction

• A new rapid-acting antidepressant akin to ketamine on the rise?

Rationale (why care?)

Ethosuximide

• already widely used as anticonvulsant agent
• known and better side-effect profile vs ketamine and esketamine
• rapid antidepressant action in rodents
• potential for use in treatment-resistant MDD (both es/ketamine)

Lateral Habenula

Rationale (but…how?)

• Lateral Habenula (LHb) burst fire inhibition = rapid-acting antidepressant
• NMDA + T-VSCC = burst fire
• A AND B = C -> inhibit A OR inhibit B = inhibit C

Primary Goals

• Is ethosuximide any good for depression?

Methods

• Double-blind
• Randomized
• Placebo controlled
• Three mental health centres in China
• Three different doses
• 80 participants, 4 groups (3 ethosuximide, 1 placebo)

Results

:(

Author's Conclusion

:(

Authors

Funding and Support

• National Nature Science Foundation of China
• Wuxi Technology Bureau
• Wuxi Municipal Health and Family Planning commission

Conflict of interest

One researcher (Dr. K. Hashimoto) has a pending patent for "Application of R-ketamine and salt thereof as pharmaceuticals" by Chiba Univesity, and has received research support by Otsuka, Sumitomo-Dainippon, and Taisho pharmaceutical companies.

Introduction

Background and rationale

• Reference to prior preclinical studies.
• Information regarding the role and mechanism of action of ketamine and its relation to ethosuximide was provided
• Motivation: good parts of ketamine less the bad parts

Hypothesis and research question

• Hypothesis: ethosuximide is efficacious for treatment of MDD in treatment-naive patients
• Objective: to evaluate the antidepressant efficacy of ethosuximide in comparison with placebo in treatment-naive adult patients with MDD
• Primary outcome: HAM-D score change from baseline vs placebo over 5h and 2 weeks
• Secondary outcomes: MADRS/HAM-A/VAS score change from baseline vs placebo over 5h and 2 weeks

Methods

Design

• Multicenter, Double-blind, Placebo-controlled
• First RCT for ethosuximide: no sample size estimation

Recruitment

• Adults 18-65 with confirmed single or recurrent MDD based on MINI
• No information on method of recruitment was provided
• No information on compensation: none?

Screening

• No pre-screening information was provided

Screening

• inclusion criteria
  • score of 18 on 17-item HAM-D AND no antidepressant treatments in past 6 months

Screening

• Exclusion criteria
  • substance abuse/treatment in previous 3 months
  • active suicidal intent
  • pregnancy
  • bipolar
  • psychotic disorder or current psychotic symptoms
  • unstable medical illness
  • significant neurological illness
  • abnormal serologic findings

Participants

• 112 patients assessed, 17 declined to participate, 32 did not meet inclusion criteria
• 80 randomly assigned evenly to 4 groups known only to pharmacy administrators (double-blind)
  • Ethosuximide 500mg
  • Ethosuximide 1000mg
  • Ethosuximide 1500mg
  • Placebo
• even distribution

Administration

• Each group has x1 dose on first day of treatment
• 1500mg and placebo groups had repeat dose daily for 2 weeks
• Timing of doses in the day, preparation of oral medication (pill, tablet, liquid, gel, etc.) not discussed

Assessment

• HAM-D and MADRS were used for scoring
• Visual Analog Scale (VAS) was used to monitor dependent symptoms
• HAM-D, HAM-A, MADRS, and VAS were administered at 1h and 5h after single dose oral administration
• for repeat group, HAM-D, MADRS, HAM-A, and VAS were measured at
  • baseline
  • end of first week
  • end of second week

Measures

• HAM-D, HAM-A, MADRS, VAS
• General demographics data:
  • age
  • gender
  • years of education
  • height
  • weight
  • length of MDE

Statistical Analysis

• data collected as means +/- std deviation
• Baseline characteristics compared using Pearson x² test for categorical variables
• One-way analysis of variance (ANOVA) used for continuous variables
• primary outcome: HAM-D
• secondary outcome: MADRS, HAM-A, and VAS
• changes in baseline in above measures were assessed with repeated measures one-way ANOVAs followed by post-hoc Fisher's least significant difference test

Results

Scores

Statistical Significant

Primary outcome (HAM-D)

Statistical Significant

Secondary outcome

Statistical Significant

No significance

Clinical Significance

?

Reliability

• The good
  • Primary outcome based on objective measures (HAM-D, HAM-A, MADRS, VAS)
  • 100% rate of completion
  • Double blind
  • Similar groups at the start of the study, treated equally except treatment
  • All patients analyzed
  • Low (<40%) placebo response

Reliability

• The bad
  • Sample size assumed based on animal studies, no statistical analysis
• The ugly
  • …

Generally Reliable

Conclusion

Statistical Interpretation

Results indicate that ethosuximide does not have antidepressant actions in non-medicated patients with MDD

• There isn't much room for artistic interpretation
• Both primary and secondary outcomes: large P-value = No significance
• High placebo response
  • >40% response muddies the water
  • this study -> low placebo response

Limitations

• Only 80 patients -> "preliminary results"
  • Needs bigger samples
• Strict inclusion criteria
  • "unclear whether findings will generalize to all patients with treatment-resistant MDD."

Conclusion

• No severe adverse events
  • Did not mention what adverse events, if any, were reported by patients
• Did not alter VAS score after 2 weeks -> low potential for abuse

Conclusion (2)

• Demonstrated antidepressant effect of ethosuximide in rats with absence epilepsy and comorbid depression-like behaviour
• Also effective in rats subjected to chronic restraint stress

It seems that antidepressant-like effects of ethosuximide are limited to WAG/Rij rats, which suggests a link between absence seizures and depressive-like behaviours in this strain of rats.

Conclusion (3)

• Previous studies failed to produce antidepressant effect in a stress model of chronic social defeat
  • R-ketamine did show antidepressant effect
• This study supports the above

Conclusion (4)

We could not find any antidepressant effect of ethosuximide on the clinician-reported HAM-D and MADRS scores after single and repeated oral administration. Therefore, it is unlikely that ethosuximide elicits ketamine-like rapid-acting antidepressant actions in patients with MDD, but the negative findings need to be replicated by other research groups.

Discussion

Interpretation

Results appropriately interpreted

Explanation

• Adequately explained limitations except
  • Standardization process among 3 centers
  • Medication administration process
  • Randomization process (computer? dice? deck of cards?)

Consistent

Consistent conclusion

Generalizable

• Ethnicity was not discussed at all
• HAM-D scores had a relatively low std dev
• Use of ethosuximide in treatment-naive patients is unlikely at this point

Literature correspondence

• R-ketamine vs ethosuximide in rats
  • doi:10.1016/j.pnpbp.2019.109652
  • doi:10.1093/ijnp/pyy065
  • doi:10.1093/ijnp/pyy072

Clinical practice

No change at this point

Future

• Ethosuximide in treatment-resistant MDD (under way)
• Bigger sample size
• Different populations (wider range of ethnicities), multinational
• Humans with absence seizure and comorbid MDD
• Targeting other parts of the same pathway (different medications)

QA?