Can Tirzepatide (a dual GIP and GLP-1 receptor agonist) cause mood swings in patients with type 2 diabetes, particularly those with a history of depression or anxiety?

Tirzepatide and Mood Swings: Clinical Evidence and Management

Direct Answer

Tirzepatide can cause psychiatric adverse events including mood disturbances, though these occur in only 1.2% of reported cases, with depression (50.3%) and anxiety (38.7%) being the most common manifestations. 1

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Psychiatric Adverse Event Profile

Incidence and Severity

• Depression is the most frequently reported psychiatric adverse event (50.3% of psychiatric reports), followed by anxiety (38.7%) and suicidal ideation (19.6%) 1
• Psychiatric adverse events comprised only 1.18% (372 out of 31,444) of total adverse event reports for GLP-1 receptor agonists including tirzepatide in the EudraVigilance database 1
• Women accounted for 65% of psychiatric adverse event reports, suggesting potential sex-based differences in susceptibility 1
• Nine deaths and 11 life-threatening outcomes were reported, primarily from completed suicidal attempts and depression, occurring predominantly in men (8 out of 9 fatal outcomes) 1

Comparison to Other Adverse Events

• Gastrointestinal adverse events are far more common than psychiatric symptoms, occurring in 39-49% of patients depending on dose (5mg, 10mg, or 15mg respectively) 2
• Nausea and diarrhea are the most frequent adverse events at any dose of tirzepatide 2
• Drug discontinuation due to adverse events was highest with the 15mg dose (10%), though the specific contribution of psychiatric symptoms to discontinuation is not separately quantified 2

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Clinical Context and Risk Assessment

Patients with Pre-existing Mental Health Conditions

• Routine screening for depression is recommended at least annually in all patients with diabetes, especially those with self-reported history of depression 3
• Beginning at diagnosis of complications or when there are significant changes in medical status, consider assessment for depression 3
• History of depression, current depression, and antidepressant medication use are risk factors for the development of type 2 diabetes 3
• Elevated depressive symptoms and depressive disorders affect one in four people with type 1 or type 2 diabetes 3

Anxiety Considerations

• Consider screening for anxiety in people exhibiting anxiety or worries regarding diabetes complications, insulin injections, taking medications, and/or hypoglycemia that interfere with self-management behaviors 3
• Refer for treatment if anxiety is present 3

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Mechanism and Neurological Effects

Central Nervous System Distribution

• GLP-1 receptors are expressed in multiple brain regions including the hypothalamus, brainstem, hippocampus, neocortex, spinal cord, and cerebellum, which may explain neuropsychiatric effects 4
• GLP-1 receptor agonists induce meal termination in parabrachial neurons through hypothalamic suppression and regulate energy intake through brainstem signaling 4
• The distribution of GLP-1 receptors in the central nervous system may contribute to the occurrence of psychiatric adverse events 4

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Practical Management Recommendations

Pre-Treatment Screening

• Screen all patients for history of depression and anxiety before initiating tirzepatide, using age-appropriate validated depression screening measures 3
• Document any personal or family history of psychiatric disorders, including suicidal ideation or attempts 1
• Consider more intensive monitoring in women, who comprise 65% of psychiatric adverse event reports 1

Monitoring During Treatment

• Assess patients at least every 3 months after reaching maintenance dose for psychiatric symptoms, in addition to standard efficacy and safety monitoring 4
• Use validated screening measures for depression and anxiety at each visit 3
• Immediately refer to mental health professionals if patients report new or worsening depression, anxiety, or suicidal ideation 3

When to Discontinue or Avoid Tirzepatide

• Discontinue tirzepatide immediately if patient develops suicidal ideation or severe depression 1
• Consider alternative weight loss or diabetes management strategies in patients with active severe depression or recent suicidal ideation 1
• Integrate mental health providers into the diabetes treatment team when patients are receiving psychological therapy 3

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Critical Caveats

Severity vs. Frequency

• While psychiatric adverse events are rare (1.2%), their severity can be life-threatening, with 9 deaths and 11 life-threatening outcomes reported 1
• The fatal outcomes warrant heightened vigilance despite low overall incidence 1

Sex-Based Differences

• Women have significantly higher rates of depression than men in diabetes populations generally 3
• However, fatal psychiatric outcomes with tirzepatide occurred predominantly in men (8 out of 9 deaths) 1
• This paradox requires clinical awareness: monitor women more frequently for symptoms, but recognize that men may have more severe outcomes 1

Comparison to Other GLP-1 Receptor Agonists

• The psychiatric adverse event profile appears similar across GLP-1 receptor agonists (semaglutide, liraglutide, and tirzepatide) 1
• No specific evidence suggests tirzepatide has higher psychiatric risk than other agents in this class 1

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Integration with Diabetes Care

Collaborative Care Model

• When a person with diabetes is receiving psychological therapy, the mental/behavioral health professional should be incorporated into or collaborate with the diabetes treatment team 3
• Person-centered collaborative care approaches can improve both depression and medical outcomes 3
• Referrals for treatment of depression should be made to mental health providers with experience using cognitive behavioral therapy, interpersonal therapy, or other evidence-based treatment approaches 3

Ongoing Monitoring

• Adults with a history of depressive symptoms need ongoing monitoring of depression recurrence within the context of routine care 3
• Routine monitoring with age-appropriate validated measures can help identify if referral is warranted 3

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Alternative Considerations

When Psychiatric Symptoms Emerge

• Do not automatically attribute mood changes to tirzepatide alone—consider diabetes distress, hypoglycemia-related anxiety, and medication burden 3
• Evaluate for hypoglycemia unawareness, which can co-occur with fear of hypoglycemia and anxiety 3
• Blood glucose awareness training or other evidence-based interventions can help reestablish awareness and reduce fear 3

Medication Selection in High-Risk Patients

• For patients with significant psychiatric history requiring GLP-1 receptor agonist therapy, consider semaglutide 2.4mg for its proven cardiovascular benefit (20% reduction in cardiovascular death, nonfatal MI, or stroke) if cardiovascular disease is present 4
• Tirzepatide demonstrates superior weight loss (20.9% vs 14.9% with semaglutide) but lacks long-term cardiovascular outcome data 4
• Balance the superior metabolic efficacy of tirzepatide against the uncertain psychiatric risk profile in vulnerable patients 5, 1