Semaglutide for the treatment of cognitive dysfunction in major depressive disorder: A randomized clinical trial.

Badulescu S, Gill H, Shah H, Brudner R, Phan L, Di Vincenzo JD, Tabassum A, Armanyous M, Llach CD, Rosenblat JD, McIntyre RS, Mansur RB

Med (New York, N.Y.)10 Nov 2025Cited by 7 (Europe PMC)

PMID41218611DOI10.1016/j.medj.2025.100916PepBankPUB-41218611

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Summary

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Text rights: Publisher copyright. Results still quote short attributed sentences.

Results from this study7

7 results from studies that gave the peptide. 7 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with major depressive disorder and cognitive impairment, oral semaglutide did not improve the executive function composite versus placebo.
In plain wordsIn adults with depression and cognitive problems, oral semaglutide did not improve executive function more than placebo.
Peptide
Semaglutide
Outcome
No significant changeExecutive function composite score
Study
n = 72
Comparator
Placebo
Analysis
Primary
Outcome group
Cognition and memory · Nervous system and cognition
Studied dose
14 mg · oral · 16 weeksAs given in this study (human).
Measurements
Adjusted Z score difference
0.32 Z score
semaglutide minus placebo
Source sentences
Summary
Semaglutide did not improve executive function (adjusted Z score difference [semaglutide - placebo]: 0.32, 95% confidence interval [CI]: -0.92 to 1.58, p = 0.60).
3 context sentences(design, population, supporting numbers)
Summary · context
This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345).
Summary · context
Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese.
Summary · context
Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide.
Report a problemFND-4121861101
02HumanRandomized controlled trialEfficacy outcome
In adults with major depressive disorder and cognitive impairment, oral semaglutide improved the global cognition composite versus placebo in a preplanned secondary analysis.
In plain wordsIn adults with depression and cognitive problems, oral semaglutide improved a global thinking score more than placebo in a secondary analysis.
Peptide
Semaglutide
Outcome
IncreaseGlobal cognition composite score
Study
n = 72
Comparator
Placebo
Analysis
Secondary
Outcome group
Cognition and memory · Nervous system and cognition
Studied dose
14 mg · oral · 16 weeksAs given in this study (human).
Measurements
Global cognition difference
2.39 points
semaglutide minus placebo
Source sentences
Summary
Preplanned secondary analysis showed treatment effects for global cognition (2.39, 95% CI: 0.19 to 4.60, p = 0.03)
3 context sentences(design, population, supporting numbers)
Summary · context
This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345).
Summary · context
Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese.
Summary · context
Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide.
Report a problemFND-4121861102
03HumanRandomized controlled trialEfficacy outcome
In adults with major depressive disorder and obesity, oral semaglutide reduced body weight versus placebo.
In plain wordsIn adults with depression and overweight, oral semaglutide lowered body weight more than placebo.
Peptide
Semaglutide
Outcome
DecreaseBody weight
Study
n = 72
Comparator
Placebo
Analysis
Secondary
Outcome group
Body weight · Metabolic and weight
Studied dose
14 mg · oral · 16 weeksAs given in this study (human).
Measurements
Adjusted mean difference in body weight
−6.03 kg
semaglutide minus placebo
Source sentences
Summary
body weight (kg) (adjusted mean difference -6.03, 95% CI: -8.76 to -3.29, p < 0.001).
3 context sentences(design, population, supporting numbers)
Summary · context
This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345).
Summary · context
Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese.
Summary · context
Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide.
Report a problemFND-4121861103
04HumanRandomized controlled trialEfficacy outcome
In adults with major depressive disorder, oral semaglutide did not change depressive symptom severity versus placebo.
In plain wordsIn adults with depression, oral semaglutide did not change depression symptom severity compared with placebo.
Peptide
Semaglutide
Outcome
No significant changeDepressive symptom severity
Study
n = 72
Comparator
Placebo
Analysis
Secondary
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
14 mg · oral · 16 weeksAs given in this study (human).
Source sentences
Summary
Treatment did not affect depressive symptom severity or the frequency of suicidal ideation.
3 context sentences(design, population, supporting numbers)
Summary · context
This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345).
Summary · context
Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese.
Summary · context
Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide.
Report a problemFND-4121861104
05HumanRandomized controlled trialSafety outcome
In adults with major depressive disorder, oral semaglutide did not change the frequency of suicidal ideation versus placebo.
In plain wordsIn adults with depression, oral semaglutide did not change how often suicidal thoughts occurred compared with placebo.
Peptide
Semaglutide
Outcome
No significant changeFrequency of suicidal ideation
Study
n = 72
Comparator
Placebo
Analysis
Secondary
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
14 mg · oral · 16 weeksAs given in this study (human).
Source sentences
Summary
Treatment did not affect depressive symptom severity or the frequency of suicidal ideation.
3 context sentences(design, population, supporting numbers)
Summary · context
This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345).
Summary · context
Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese.
Summary · context
Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide.
Report a problemFND-4121861105
06HumanRandomized controlled trialSafety outcome
In adults with major depressive disorder, gastrointestinal side effects were common in the oral semaglutide group.
In plain wordsIn adults with depression, stomach and bowel side effects were common among people taking oral semaglutide.
Peptide
Semaglutide
Outcome
Not applicableGastrointestinal side effects
Study
n = 35
Outcome group
Gastrointestinal adverse events · Gastrointestinal
Studied dose
14 mg · oral · 16 weeksAs given in this study (human).
Source sentences
Summary
Gastrointestinal side effects were common in the semaglutide group
3 context sentences(design, population, supporting numbers)
Summary · context
This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345).
Summary · context
Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese.
Summary · context
Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide.
Report a problemFND-4121861106
07HumanRandomized controlled trialSafety outcome
In adults with major depressive disorder, no serious adverse events occurred in the oral semaglutide group.
In plain wordsIn adults with depression, no serious adverse events were reported in people taking oral semaglutide.
Peptide
Semaglutide
Outcome
Not applicableSerious adverse events
Study
n = 35
Outcome group
Adverse events · Whole body
Studied dose
14 mg · oral · 16 weeksAs given in this study (human).
Source sentences
Summary
with no serious adverse events.
3 context sentences(design, population, supporting numbers)
Summary · context
This was a 16-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT04466345).
Summary · context
Eligible adults met DSM-5-defined criteria for MDD, exhibited pre-treatment evidence of cognitive impairment, and were overweight/obese.
Summary · context
Patients were randomized (1:1) to receive an adjunctive placebo or 14 mg oral semaglutide.
Report a problemFND-4121861107

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 2NCT04466345