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

Key points to remember:

  • If you or someone you know has been diagnosed with psychotic depression, treatment may involve both antidepressant and antipsychotic medications.
  • Continuing treatment with Zoloft (sertraline) and Zyprexa (olanzapine) even after a patient is considered stable can be effective in preventing relapses
  • Doctors can use pharmacogenetic tests like Pillcheck to guide treatment with both types of medications.

Major depressive disorder with psychotic features (psychotic depression) can be a severely disabling disorder. Psychotic depression is characterized by abnormal perceptions that may include delusions, hallucinations, and is linked to a high risk of suicide. For psychotic depression that is resistant to treatment, your doctor may recommend electroconvulsive therapy, along with a combination of an antidepressant and antipsychotic medication.

Zoloft (sertraline) is one of the most commonly prescribed antidepressants used for the treatment of anxiety, depression, PTSD and other mental health conditions. As with all antidepressants, it can cause multiple side effects, including reduced sexual drive, gastrointestinal upset (diarrhea, heartburn, nausea, vomiting), weight gain or loss, excessive sleepiness, and dizziness when standing up. Sertraline is used in combination with antipsychotics when patients also have psychotic symptoms.

Zyprexa (olanzapine) is an antipsychotic medication that is prescribed together with Zoloft to reduce the risk of psychosis. Continuing treatment with antidepressants and antipsychotics plays a vital role in controlling psychotic depression symptoms even when people feel well and are considered to be stable. A recent clinical study found that patients with psychotic depression in remission had a lower risk of disease relapse if they continued treatment with both Zyprexa and Zoloft, compared with those treated with only Zoloft. Continuation of olanzapine was linked with excessive weight gain. However, the clinical benefit for most patients outweighs the potential adverse effects of olanzapine.

Patients with psychotic depression should adhere to a healthy diet and take part in regular exercise to counteract the olanzapine-induced weight gain and should be monitored for signs of Type 2 Diabetes. If patients have elevated HbA1c levels, which is an indicator of an elevated risk of diabetes, they may be started on metformin or other antidiabetic medications. Reduced clearance of Zoloft or of Zyprexa may affect long-term tolerability of these drugs and the risk of weight gain and other side effects.

For medical professionals: An explanation of the pharmacogenetic factors affecting drug response

A person’s Zyprexa dosage might be adjusted based on one’s inherited metabolic profile and lifestyle. Smokers may need a higher Zyprexa dose if they have a CYP1A2 Inducible phenotype, while people with reduced CYP2D6 function may need a dose reduction to lower the risk of side effects. Pharmacogenetic testing can help physicians to guide dose adjustment, and it can save time to reach a steady-state drug concentration that’s key for effective treatment.

Patients with inherently reduced CYP2C19 function are more likely to experience Zoloft side effects. Clinical Pharmacogenetic Guidelines for CYP2D6, CYP2C19 and Selective Serotonin Reuptake Inhibitors recommend switching sertraline (Zoloft) to another antidepressant for people with absent CYP2C19 function, while dose reduction may help to resolve issues for people with reduced CYP2C19 activity. Contrastingly, ultrarapid CYP2C19 metabolizers have a reduced response to sertraline, as well as citalopram.

For patients with a reduced Zoloft response, alternative combined treatment with quetiapine and venlafaxine may help to control symptoms. Similar to STOP-PD II Randomized Clinical Trial findings for patients with psychotic depression, a combination of quetiapine and venlafaxine was more efficacious than venlafaxine alone.

Quetiapine is metabolized by the CYP3A5 enzyme, while clearance of venlafaxine is dependent on CYP2D6 metabolism. Patients with altered CYP2D6 status can use Pristiq (desvenlafaxine), which is a newer formulation that is not affected by this liver enzyme.


Pharmacogenetic testing can assist physicians in making treatment decisions and help to improve treatment tolerability for people with psychotic depression.

Selected references:

Flint AB, 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. doi:10.1001/jama.2019.10517

Yatham LN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20:97-170.

Hicks JK et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015 Aug; 98(2): 127–134.

Oquendo MA et al.  A computer algorithm for calculating the adequacy of antidepressant treatment in unipolar and bipolar depression.  J Clin Psychiatry. 2003;64(7):825-833.

Wijkstra J 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.

Leucht S, et al.  Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.  Lancet. 2013;382(9896):951-962.

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