Ethosuximide in MDD

Armin Moradi




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

Rationale (why care?)


  • 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?


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



Author's Conclusion



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.


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



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


  • 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?


  • No pre-screening information was provided


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


  • 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


  • 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


  • 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


  • 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


  • 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



  Control 500mg 1000mg 1500mg
HAM-D 25.20 +- 5.75 26.15 +- 6.56 23.95 +- 4.37 26.85 +- 4.06
HAM-A 10.35 +- 2.18 11.30 +- 2.60 10.95 +- 2.63 10.65 +- 2.01
MADRS 26.90 +- 5.71 28.20 +- 6.84 26.00 +- 4.65 28.90 +- 4.19

Statistical Significant

Primary outcome (HAM-D)

Time P-value
5h 0.243
2w 0.263

Statistical Significant

Secondary outcome

Test Time P-value
MADRS 5h 0.214
  2w 0.260
HAM-A 5h 0.425
  2w 0.824
VAS 5h 0.472
  2w 0.623

Statistical Significant

No significance

Clinical Significance



  • 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


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

Generally Reliable


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


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


  • 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.



Results appropriately interpreted


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


Consistent conclusion


  • 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

Clinical practice

No change at this point


  • 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)