Case Report: Oral semaglutide-associated depression in a patient with type 2 diabetes mellitus: a dose-dependent recurrence confirmed on rechallenge and managed with vortioxetine-bupropion combination therapy.

Alanazi AS, Alanazi BA

Frontiers in psychiatry24 Jul 2026

PMID42569002PMCIDPMC13448544DOI10.3389/fpsyt.2026.1893173PepBankPUB-42569002

Summary

BackgroundOral semaglutide carries a neuropsychiatric safety profile that continues to evolve. Large clinical trials have not, at the group level, demonstrated excess psychiatric adverse events-but pharmacovigilance databases and case reports have documented a signal for depression and suicidal ideation in individual patients. A dose-dependent onset with rechallenge has not, to our knowledge, been previously described for the oral formulation, though such an association cannot be established from a single observation.Case presentationWe describe a 54-year-old man with type 2 diabetes and no psychiatric history who developed moderately severe major depression (Patient Health Questionnaire-9 [PHQ-9]: 18; Hamilton Depression Rating Scale 17 items [HDRS-17]: 22) within 2 weeks of escalating oral semaglutide from 3 to 7 mg daily. Vortioxetine 10 mg combined with bupropion XL 150 mg produced remission within 4 weeks (PHQ-9: 6). On structured rechallenge, depression returned when the dose was re-escalated to 7 mg (PHQ-9: 17; HDRS-17: 20). Permanent discontinuation was followed by sustained remission.ConclusionAs far as we are aware, this is the first reported case of a dose-related, rechallenge-associated depressive episode tied in time to oral semaglutide and treated with a vortioxetine-bupropion combination. A Naranjo score of 7 puts the relationship in the probable range, though that reading is held back by the usual limits of a single case and by an incomplete washout before rechallenge. The step from 3 to 7 mg may be a point of raised psychiatric risk in vulnerable patients, and watching mood during titration looks like a sensible precaution.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study3

3 results from studies that gave the peptide. 3 results from people.

01HumanCase report or seriesSafety outcome
In a 54-year-old man with type 2 diabetes, moderately severe major depression developed within 2 weeks of escalating oral semaglutide from 3 to 7 mg daily.
In plain wordsIn one man with type 2 diabetes, depression began within 2 weeks of raising oral semaglutide from 3 to 7 mg daily.
Peptide
Semaglutide
Outcome
IncreaseMajor depression after dose escalation
Study
n = 1
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
3 to 7 mg daily · oralAs given in this study (human).
Measurements
PHQ-9
18
case patient
HDRS-17
22
case patient
Source sentences
Summary
We describe a 54-year-old man with type 2 diabetes and no psychiatric history who developed moderately severe major depression (Patient Health Questionnaire-9 [PHQ-9]: 18; Hamilton Depression Rating Scale 17 items [HDRS-17]: 22) within 2 weeks of escalating oral semaglutide from 3 to 7 mg daily.
Show in the study text Report a problemFND-4256900201
02HumanCase report or seriesSafety outcome
In a 54-year-old man with type 2 diabetes, depression returned when oral semaglutide was re-escalated to 7 mg.
In plain wordsIn one man with type 2 diabetes, depression came back when oral semaglutide was raised to 7 mg again.
Peptide
Semaglutide
Outcome
IncreaseDepression recurrence on rechallenge at 7 mg
Study
n = 1
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
7 mg daily · oralAs given in this study (human).
Measurements
PHQ-9
17
case patient
HDRS-17
20
case patient
Source sentences
Summary
On structured rechallenge, depression returned when the dose was re-escalated to 7 mg (PHQ-9: 17; HDRS-17: 20).
1 context sentence(design, population, supporting numbers)
Summary · context
We describe a 54-year-old man with type 2 diabetes and no psychiatric history who developed moderately severe major depression (Patient Health Questionnaire-9 [PHQ-9]: 18; Hamilton Depression Rating Scale 17 items [HDRS-17]: 22) within 2 weeks of escalating oral semaglutide from 3 to 7 mg daily.
Show in the study text Report a problemFND-4256900202
03HumanCase report or seriesSafety outcome
In a 54-year-old man with type 2 diabetes, permanent discontinuation of oral semaglutide was followed by sustained remission of depression.
In plain wordsIn one man with type 2 diabetes, depression stayed in remission after oral semaglutide was stopped for good.
Peptide
Semaglutide
Outcome
DecreaseDepression after permanent discontinuation
Study
n = 1
Outcome group
Anxiety and mood · Mental health and mood
Studied dose
Dose not stated · oralAs given in this study (human).
Source sentences
Summary
Permanent discontinuation was followed by sustained remission.
1 context sentence(design, population, supporting numbers)
Summary · context
We describe a 54-year-old man with type 2 diabetes and no psychiatric history who developed moderately severe major depression (Patient Health Questionnaire-9 [PHQ-9]: 18; Hamilton Depression Rating Scale 17 items [HDRS-17]: 22) within 2 weeks of escalating oral semaglutide from 3 to 7 mg daily.
Show in the study text Report a problemFND-4256900203

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Version 2Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

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