What is the best approach for a patient with a history of substance use disorder, currently on Seroquel (quetiapine) and transitioning to Thorazine (chlorpromazine), who is experiencing significant weight gain and is already on metformin, with potential access to GLP1 (glucagon-like peptide-1) receptor agonists for weight loss?

Managing Weight Gain in a Patient Transitioning from Seroquel to Thorazine with History of Substance Use Disorder

Yes, initiate a GLP-1 receptor agonist for weight loss in this patient, as it addresses both the antipsychotic-induced weight gain and may provide additional benefit for substance use disorder management. 1, 2

Immediate Antipsychotic Management Strategy

Switch from Seroquel (quetiapine) to a weight-neutral antipsychotic rather than Thorazine (chlorpromazine). Both quetiapine and chlorpromazine are among the highest weight-gain-inducing antipsychotics available. 3, 4

• Lurasidone or ziprasidone are the most weight-neutral antipsychotic options and should be prioritized over chlorpromazine for this patient experiencing significant weight gain. 3
• Aripiprazole demonstrates lower risk for weight gain compared to quetiapine or chlorpromazine and represents another viable alternative. 3
• Gradual cross-titration is essential when switching antipsychotics, informed by the half-life and receptor profile of each medication to minimize risk of symptom relapse. 3

Why Thorazine is Problematic

• Chlorpromazine (Thorazine) is a first-generation antipsychotic with significant weight gain potential, comparable to olanzapine and clozapine among the worst offenders. 3, 4
• The distinction between first-generation and second-generation antipsychotics should not guide treatment choice; pharmacodynamic profiles and side-effect burden are what matter. 3
• Switching from one high-weight-gain agent (quetiapine) to another (chlorpromazine) will not solve the weight problem. 3, 5

GLP-1 Receptor Agonist Selection and Initiation

Start tirzepatide 5 mg subcutaneously once weekly as the preferred GLP-1 receptor agonist, given its superior weight loss efficacy of 20.9% at 72 weeks. 1

Dosing Algorithm

• Week 1-4: Tirzepatide 5 mg weekly 1
• Week 5-8: Increase to 10 mg weekly if tolerated 1
• Week 9-12: Increase to 15 mg weekly based on tolerance and response 1
• Assess response at 12 weeks: If less than 5% weight loss achieved, discontinue and switch to alternative agent (semaglutide 2.4 mg weekly). 1, 6

Alternative GLP-1 Options

• Semaglutide 2.4 mg weekly produces 14.9% weight loss at 68 weeks and has proven cardiovascular benefits, reducing cardiovascular death, nonfatal MI, or nonfatal stroke by 20%. 1
• Liraglutide 3.0 mg daily is another FDA-approved option but requires daily injections. 6

Critical Safety Screening Before GLP-1 Initiation

Screen for absolute contraindications before prescribing any GLP-1 receptor agonist: 1, 6

• Personal or family history of medullary thyroid carcinoma
• Multiple endocrine neoplasia syndrome type 2
• History of acute pancreatitis

Monitoring Requirements

• Monitor for suicidal thoughts and self-injurious behavior, particularly relevant given this patient's psychiatric history and substance use disorder. 7
• Check for pancreatitis symptoms (severe abdominal pain) 1
• Monitor blood pressure as weight loss may necessitate adjustment of any antihypertensive medications 1
• Assess for gallbladder disease symptoms 1

Unique Advantage for Substance Use Disorder

GLP-1 receptor agonists show emerging evidence for reducing substance use behaviors, making them particularly appropriate for this patient with substance use disorder history. 2

• Preclinical evidence suggests GLP-1R agonists reduce alcohol and substance use through mechanisms related to reward processing, stress response, and cognitive function. 2
• Clinical trials are underway testing GLP-1R agonists specifically in people with substance use disorders, with early safety and efficacy signals. 2
• This represents a potential dual benefit: addressing weight gain while potentially supporting substance use disorder recovery. 2

Metformin Continuation

Continue metformin throughout GLP-1 therapy as it provides complementary weight loss benefit (approximately 3% weight loss) and does not interfere with GLP-1 receptor agonist efficacy. 8, 9

• Metformin is explicitly recommended to attenuate weight gain when used with high-weight-gain antipsychotics like clozapine. 3
• The combination of metformin plus GLP-1 receptor agonist is safe and may provide additive metabolic benefits. 8, 9

Mandatory Lifestyle Intervention Components

GLP-1 therapy must be combined with structured lifestyle modification to maximize efficacy and maintain long-term weight loss. 1

Dietary Requirements

• Achieve 500-750 kcal/day energy deficit through reduced fat intake and increased dietary fiber 1
• Target approximately 1,500-1,800 kcal/day for men or 1,200-1,500 kcal/day for women 1

Exercise Requirements

• Include resistance training to preserve lean body mass during weight loss 1
• Deliver at least 16 behavioral counseling sessions over 6 months with trained interventionists 1

Critical Pitfalls to Avoid

Do not continue Thorazine (chlorpromazine) as the target antipsychotic - this perpetuates the weight gain problem rather than solving it. 3, 4

Do not use phentermine or other sympathomimetic agents in this patient with substance use disorder history, as these are contraindicated due to abuse potential. 6

Do not delay GLP-1 initiation - weight gain from antipsychotics is rapid in the initial period and continues long-term; early intervention is critical. 5

Monitor closely for psychiatric decompensation during antipsychotic switching, as this is a vulnerable period requiring careful cross-titration. 3

Titrate GLP-1 doses gradually over 16-20 weeks to minimize gastrointestinal adverse effects (nausea, vomiting) which could compromise adherence. 1

Treatment Continuation Strategy

Plan for long-term GLP-1 therapy, as weight regain occurs after cessation and this patient will likely require ongoing antipsychotic treatment. 1

• Reassess at 12 weeks: if less than 5% weight loss, switch to alternative GLP-1 agent 1, 6
• Continue indefinitely if effective, as discontinuation leads to weight regain 1
• Monitor every 3 months after initial titration period for efficacy and safety 6