Effect of Exenatide Use on Cognitive and Affective Functioning in Obese Patients With Type 2 Diabetes Mellitus: Exenatide Use Mediates Depressive Scores Through Increased Perceived Stress Levels

J Clin Psychopharmacol. 2021 Jul-Aug;41(4):428-435. doi: 10.1097/JCP.0000000000001409.

Abstract

Purpose/background: Glucagon-like peptide-1 (GLP-1) is a molecule used to treat type 2 diabetes mellitus (T2DM). Given their widespread expression in the nervous system, GLP-1 receptors also play a role in regulating mood and cognitive function. Here, we aimed to compare obese patients with T2DM, with or without exenatide (a GLP-1R agonist) use on cognitive and affective functioning.

Methods/procedures: A total of 43 patients with T2DM (23 on exenatide and 20 without exenatide) were evaluated with the Snaith-Hamilton Pleasure Scale, Cognitive Failures Questionnaire, Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7, Childhood Trauma Questionnaire, Perceived Stress Scale (PSS), and Chronic Stress Scale, in addition to laboratory-based measures of reward learning (the probabilistic reward task) and working memory (Letter-N-Back task).

Findings/results: Patients on exenatide had higher body mass index (BMI) (37.88 ± 5.44 vs 35.29 ± 6.30; P = 0.015), PHQ-9 (9.70 ± 4.92 vs 6.70 ± 4.66; P = 0.026), and PSS (29.39 ± 6.70 vs 23.35 ± 7.69; P = 0.015) scores. Other stress scales (Childhood Trauma Questionnaire and Chronic Stress Scale), Generalized Anxiety Disorder-7 scores, response bias, or discriminability as assessed by probabilistic reward task and self-report (Cognitive Failures Questionnaire) and laboratory-based (Letter-N-Back) cognitive measures were not significantly different between groups (both Ps > 0.05). Multivariate linear regression analyses adding BMI and PSS as covariates revealed that although BMI had no effect (P = 0.5), PSS significantly predicted PHQ-9 scores (P = 0.004). Mediation analysis showed that exenatide users reported higher PSS, with greater PSS associated with higher PHQ-9 levels (b = 0.236). There was no evidence on exenatide directly influencing PHQ-9 independent of PSS (c' = 1.573; P = 0.305; 95% bootstrap confidence interval, -1.487 to 4.634).

Implications/conclusions: Based on previous research and our findings, exenatide use might be mediating depression scores through disrupting stress responses.

MeSH terms

  • Affective Symptoms* / diagnosis
  • Affective Symptoms* / drug therapy
  • Affective Symptoms* / physiopathology
  • Anti-Obesity Agents / administration & dosage
  • Anti-Obesity Agents / adverse effects
  • Cognition* / drug effects
  • Cognition* / physiology
  • Depression* / diagnosis
  • Depression* / drug therapy
  • Depression* / physiopathology
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / psychology
  • Exenatide* / administration & dosage
  • Exenatide* / adverse effects
  • Female
  • Glucagon-Like Peptide-1 Receptor* / agonists
  • Glucagon-Like Peptide-1 Receptor* / metabolism
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Male
  • Middle Aged
  • Obesity* / drug therapy
  • Obesity* / psychology
  • Psychological Techniques
  • Self Concept
  • Stress, Psychological / diagnosis
  • Stress, Psychological / physiopathology
  • Treatment Outcome

Substances

  • Anti-Obesity Agents
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Exenatide