Considering stopping Zoloft or Zyprexa due to side effects? PGx testing can help you continue treatment and reduce the risk of relapse

Psychotic depression is a severe form of depression in which a person also has delusions or hallucinations. It is usually treated with a combination of an antidepressant, such as Zoloft (sertraline), and an antipsychotic, such as Zyprexa (olanzapine). Side effects, especially weight gain, lead many people to want to stop once they feel better. Yet stopping too early greatly increases the risk of relapse. Managing side effects, and choosing the right dose for your body, can help you stay on treatment safely. Your genes and habits such as smoking affect how your body handles these medications.

What is psychotic depression and how is it treated?

In psychotic depression, also called major depression with psychotic features, severe depression is accompanied by false beliefs (delusions) or hearing or seeing things that are not there (hallucinations). It carries a high risk of suicide and needs prompt treatment. The Canadian CANMAT guidelines recommend treating it with an antidepressant combined with an antipsychotic, or with electroconvulsive therapy (ECT). An antidepressant alone is usually not enough: in a randomized trial, venlafaxine combined with quetiapine worked better than venlafaxine alone.

Why is it risky to stop Zoloft or Zyprexa too early?

In the STOP-PD II trial, led from the University of Toronto, 126 people whose psychotic depression was in remission after treatment with sertraline plus olanzapine either continued both drugs or switched olanzapine to a placebo. Over 36 weeks, 20% of those who stayed on olanzapine relapsed, compared with 55% of those who stopped it. The trade-off was more weight gain and a rise in cholesterol with olanzapine.

Stopping an antidepressant suddenly can also cause discontinuation symptoms such as dizziness and irritability. Never stop either medication without talking to your prescriber. Read more in Antidepressant withdrawal: when and how to taper antidepressants.

How can side effects be managed instead of stopping treatment?

• Weight gain and metabolic changes with olanzapine: regular monitoring of weight, waist size, blood sugar (including HbA1c) and cholesterol, together with a healthy diet and regular exercise. If blood sugar rises, your doctor may add metformin. GLP-1 drugs such as semaglutide (Ozempic), used for diabetes and weight loss, may also bring mental health benefits: in a US study of more than 70,000 adults with schizophrenia and type 2 diabetes, starting a GLP-1 drug was linked to 24% fewer psychiatric hospital stays and 29% fewer psychiatric emergency visits.
• Common sertraline side effects such as nausea, diarrhea, sleep changes and sexual side effects often improve with time or a dose adjustment.
• Adjusting the dose or switching to another medication, guided by your prescriber and, where useful, by your genetic results.

How do genes and smoking affect these medications?

• Sertraline (Zoloft) is broken down mainly by CYP2C19, with help from CYP2B6. According to the 2023 CPIC antidepressant guideline, poor metabolizers of either enzyme have higher sertraline levels and may do best with a lower starting dose and slower dose increases, or a different antidepressant. Rapid and ultrarapid CYP2C19 metabolizers can start at a standard dose; if sertraline does not work, another antidepressant may be considered.
• Olanzapine (Zyprexa) is broken down mainly by CYP1A2. Smoking speeds up CYP1A2, so smokers often need a higher olanzapine dose. If you quit smoking, olanzapine levels can rise and the dose may need to be lowered, so tell your prescriber.
• Venlafaxine depends on CYP2D6. The CPIC guideline suggests considering another antidepressant for CYP2D6 poor metabolizers. Desvenlafaxine (Pristiq) is not significantly affected by CYP2D6.
• Quetiapine is broken down mainly by CYP3A4, so drugs that block or speed up CYP3A4 can change its levels.

Can a pharmacogenetic test help?

Pillcheck reports CYP2C19, CYP2B6, CYP2D6, CYP1A2, CYP3A4 and other genes that affect antidepressants and antipsychotics, with 355 medications in total. A Pillcheck pharmacist reviews your results, your other medications and factors such as smoking, and recommends options and doses to discuss with your prescriber. This can help you stay on effective treatment with fewer side effects.

Summary

• Psychotic depression is usually treated with an antidepressant plus an antipsychotic, or with ECT.
• In the STOP-PD II trial, continuing olanzapine with sertraline cut the relapse rate from 55% to 20%.
• Weight gain and other side effects can be monitored and managed instead of stopping treatment.
• CYP2C19 and CYP2B6 affect sertraline, CYP1A2 and smoking affect olanzapine, and CYP2D6 affects venlafaxine.
• Talk to your prescriber before stopping or changing any medication.

Frequently asked questions

Can I stop Zyprexa once my psychotic depression is in remission?

Talk to your prescriber first. In the STOP-PD II trial, people who stopped olanzapine were much more likely to relapse than those who continued it.

How can I limit weight gain on olanzapine?

Regular monitoring of weight, blood sugar and cholesterol, a healthy diet and exercise help. Your doctor may also add metformin or a GLP-1 drug if blood sugar rises.

Does smoking affect olanzapine?

Yes. Smoking speeds up the breakdown of olanzapine, so smokers may need a higher dose. If you quit, tell your prescriber, because levels can rise.

Do genes affect how I respond to sertraline?

Yes. CYP2C19 and CYP2B6 affect sertraline levels, and the 2023 CPIC guideline gives dosing recommendations based on these genes.

Can a genetic test help me stay on treatment?

A pharmacogenetic test can help your prescriber choose medications and doses that suit your body, which may reduce side effects that lead people to stop treatment.

References

Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of Continuing Olanzapine vs Placebo on Relapse Among Patients With Psychotic Depression in Remission: The STOP-PD II Randomized Clinical Trial. JAMA. 2019;322(7):622-631.

Wijkstra J, Burger H, van den Broek WW, et al. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand. 2010;121(3):190-200.

Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults. Can J Psychiatry. 2024;69(9):641-687.

Davoodian N, Williams LJ, Berk M, et al. GLP-1 receptor agonist initiation and risk of psychiatric hospitalisation and emergency department presentation in adults with schizophrenia and type 2 diabetes in the USA: an observational cohort study using electronic health records data. Lancet Psychiatry. 2026;13(11):931-942.

Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68.