What alternative obesity medications can be considered for a patient with type 2 diabetes and a history of depression or anxiety who is concerned about the psychiatric side effects of tirzepatide (glucagon-like peptide-1 (GLP-1) receptor agonist)?

Alternative Obesity Medications for Patients with Type 2 Diabetes and Depression/Anxiety Concerns

For a patient with type 2 diabetes and a history of depression or anxiety who is concerned about psychiatric side effects of tirzepatide, semaglutide 2.4mg weekly represents the optimal alternative, offering superior weight loss (14.9% at 68 weeks), proven cardiovascular benefit, and a psychiatric adverse event rate of only 1.2%. 1

Evidence on Psychiatric Safety of GLP-1 Receptor Agonists

Actual Psychiatric Risk Profile

• Psychiatric adverse events comprised only 1.2% of total reports for semaglutide, liraglutide, and tirzepatide in the EudraVigilance database analysis from 2021-2023 1
• Depression was the most commonly reported psychiatric event (50.3% of psychiatric reports), followed by anxiety (38.7%) and suicidal ideation (19.6%), though these represented a tiny fraction of overall users 1
• A qualitative study found that participants with obesity and/or type 2 diabetes described an overall positive impact of GLP-1 receptor agonists on their mental health, especially improved control of eating behaviors 2

Clinical Context

The psychiatric concerns with tirzepatide appear overblown based on available evidence. However, if your patient remains concerned, alternative medications exist with comparable or better safety data.

Primary Alternative: Semaglutide 2.4mg Weekly

This is your best alternative for maximum efficacy with established psychiatric safety.

Efficacy Profile

• Achieves 14.9% total body weight loss at 68 weeks, with 64.9% of patients achieving ≥10% weight loss 3
• Reduces HbA1c by approximately 1.48% from baseline 3
• Provides dual benefits of glycemic control and substantial weight loss in patients with type 2 diabetes 3

Cardiovascular Advantage

• Reduces composite cardiovascular death, nonfatal MI, or nonfatal stroke by 20% (HR 0.80,95% CI 0.72-0.90) in patients with established cardiovascular disease 3
• This cardiovascular benefit is proven, unlike tirzepatide which only has favorable safety trends 3

Psychiatric Safety

• Same 1.2% psychiatric adverse event rate as tirzepatide in pharmacovigilance data 1
• Qualitative studies show positive mental health impact, particularly improved eating behavior control 2

Dosing Schedule

• Start at 0.25mg weekly for 4 weeks 3
• Increase to 0.5mg weekly for 4 weeks 3
• Advance to 1.0mg weekly for 4 weeks 3
• Escalate to 1.7mg weekly for 4 weeks 3
• Reach maintenance dose of 2.4mg weekly after 16 weeks 3

Contraindications

• Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 4, 3
• History of pancreatitis requires caution 4

Secondary Alternative: Liraglutide 3.0mg Daily

Consider this if weekly injections are not tolerated or if the patient prefers daily dosing.

Efficacy Profile

• Achieves 5.6% weight loss at 1 year and 4.3% at 3 years 4
• Significantly less potent than semaglutide 2.4mg but still FDA-approved for obesity management 4
• Approved for adolescents ≥12 years, indicating robust safety profile 4

Dosing Schedule

• Titrate weekly by 0.6mg as tolerated 4
• Start at 0.6mg daily, advance to 1.2mg, then 1.8mg, then 2.4mg, reaching 3.0mg daily 4

Side Effect Profile

• Nausea, vomiting, diarrhea, constipation, headache, fatigue 4
• Same contraindications as semaglutide regarding thyroid cancer and MEN2 4
• Requires monitoring for pancreatitis, acute gallbladder disease, and suicidal ideation 4

Third Alternative: Naltrexone ER/Bupropion ER

This option is particularly relevant given your patient's depression/anxiety history, as bupropion is the only antidepressant that consistently promotes weight loss.

Unique Advantage for Depression

• Bupropion is the only antidepressant shown to consistently promote weight loss 4
• May provide dual benefit of treating depression while promoting weight loss 4
• However, bupropion is activating and can exacerbate anxiety or be inappropriate for bipolar disorder 4

Efficacy Profile

• Achieves 4.2-5.2% weight loss at 1 year 4
• Significantly less effective than GLP-1 receptor agonists 4

Dosing Schedule

• Week 1: 1 tablet (8/90mg) once daily in morning 4
• Week 2: 1 tablet (8/90mg) twice daily 4
• Week 3: 2 tablets (16/180mg) in morning and 1 tablet (8/90mg) at bedtime 4
• Week 4 onward: 2 tablets (16/180mg) twice daily 4

Critical Contraindications

• Severe depression 4
• Seizure disorder 4
• Anorexia nervosa or bulimia nervosa 4
• Drug or alcohol withdrawal 4
• Concomitant MAOI use (within 14 days) 4

Side Effects

• Nausea, headache, vomiting, constipation, diarrhea, anxiety, xerostomia 4
• Worsening depression or suicidal ideation 4
• Seizures (bupropion lowers seizure threshold) 4

Discontinuation Criteria

• If patient has not lost at least 5% of baseline body weight at 12 weeks on maintenance dose, discontinue 4

Fourth Alternative: Phentermine/Topiramate ER

Consider this if the patient has comorbid migraines, as topiramate is FDA-approved for migraine prevention.

Efficacy Profile

• Achieves 8.6-9.3% weight loss at 1 year on high dose (15mg/92mg) 4
• Achieves 8.7% weight loss at 2 years on high dose 4
• More effective than naltrexone/bupropion but less than GLP-1 receptor agonists 4

Dosing Schedule

• Week 1: 3.75mg/23mg once daily 4
• Week 2: 3.75mg/23mg twice daily 4
• Week 3-12: 7.5mg/46mg once daily (recommended dose) 4
• If inadequate response: escalate to 15mg/92mg once daily 4

Discontinuation Criteria

• If patient has not lost at least 3% body weight after 12 weeks on recommended dose (7.5mg/46mg), discontinue or escalate 4
• If patient has not lost at least 5% after 12 additional weeks on maximum dose (15mg/92mg), discontinue 4

Side Effects

• Paresthesias, dizziness, dysgeusia, insomnia, constipation, anxiety, depression 4
• Cognitive impairment (concentration and memory) 4
• Acute angle-closure glaucoma 4
• Anxiety and panic attacks 4

Critical Contraindications

• Pregnancy (FDA requires Risk Evaluation and Mitigation Strategy due to orofacial cleft risk) 4
• Seizure disorder 4
• Cardiovascular disease (due to phentermine component) 4

Special Consideration for Depression/Anxiety

• Patients with histories of depression on SSRIs or SNRIs were included in clinical trials (EQUIP, CONQUER, SEQUEL) 4
• However, anxiety and panic attacks are listed side effects 4

Algorithm for Medication Selection

Step 1: Assess Cardiovascular Disease Status

• If established CVD present: Choose semaglutide 2.4mg weekly for proven 20% cardiovascular risk reduction 3
• If no CVD: Proceed to Step 2

Step 2: Assess Depression/Anxiety Severity and Type

• If severe depression: Avoid naltrexone/bupropion (contraindicated) 4
• If generalized anxiety disorder or panic disorder: Avoid phentermine/topiramate (can exacerbate) 4
• If depression without severe anxiety: Consider naltrexone/bupropion for dual benefit 4
• If bipolar disorder: Avoid naltrexone/bupropion (bupropion inappropriate) 4

Step 3: Prioritize by Weight Loss Goal

• If maximum weight loss needed (>10%): Semaglutide 2.4mg weekly (14.9% loss) 3
• If moderate weight loss acceptable (5-10%): Phentermine/topiramate ER (8.6-9.3% loss) or liraglutide 3.0mg daily (5.6% loss) 4
• If modest weight loss acceptable (<5%): Naltrexone/bupropion (4.2-5.2% loss) 4

Step 4: Consider Practical Factors

• If patient refuses injections: Naltrexone/bupropion or phentermine/topiramate ER (both oral) 4
• If patient has comorbid migraines: Phentermine/topiramate ER (topiramate FDA-approved for migraines) 4
• If patient prefers daily dosing: Liraglutide 3.0mg daily 4

Monitoring Requirements

For Semaglutide or Liraglutide

• Monitor every 4 weeks during titration for gastrointestinal tolerance, weight loss progress, and blood pressure 3
• After reaching maintenance dose, assess every 3 months for weight, blood pressure, cardiovascular risk factors, and medication adherence 3
• Monitor for signs of pancreatitis (persistent severe abdominal pain) and gallbladder disease 4, 3
• Monitor for suicidal ideation and behavior 4

For Naltrexone/Bupropion

• Monitor blood pressure and heart rate (can increase) 4
• Monitor closely for worsening depression or suicidal ideation 4
• Check electrolytes and creatinine before and during treatment 4
• Evaluate at 12 weeks: discontinue if <5% weight loss 4

For Phentermine/Topiramate

• Monitor electrolytes and creatinine before and during treatment 4
• Monitor for cognitive impairment 4
• Check for acute angle-closure glaucoma symptoms 4
• Evaluate at 12 weeks: discontinue if <3% weight loss on recommended dose 4

Common Pitfalls to Avoid

• Do not dismiss psychiatric concerns as unfounded - while the 1.2% rate is low, the severity of some outcomes warrants acknowledgment 1
• Do not assume bupropion is safe for all depression - it can exacerbate anxiety and is inappropriate for bipolar disorder 4
• Do not forget pregnancy risk with phentermine/topiramate - requires Risk Evaluation and Mitigation Strategy 4
• Do not combine GLP-1 receptor agonists - semaglutide and liraglutide should never be used together 3
• Do not ignore the need for lifestyle modification - all medications must be combined with reduced-calorie diet and minimum 150 minutes/week physical activity 3