Does Clozapine interact with Sertraline?(3+ effects)

In this article, we will discuss the interactions between Clozapine and Sertraline. We will also discuss what side effects one may experience by combining these two medications and how to manage the side effects associated with this interaction.

Does Clozapine interact with Sertraline?

Yes, Clozapine does interact with Sertraline. Clozapine and Sertraline are both medications used to treat different mental health conditions.

Clozapine, an atypical antipsychotic medication, is typically prescribed for treatment-resistant Schizophrenia, while Sertraline (brand name Zoloft) is widely prescribed for the management of depressive disorders (1,2).

In clinical practice, Clozapine and Sertraline are often used in combination to enhance their therapeutic benefits in treating treatment-resistant Schizophrenia and major depressive disorders (3,4). This dual approach, employing both Clozapine and Sertraline, proves more effective in addressing negative and depressive symptoms compared to single-drug therapy.

However, since both Clozapine and Sertraline affect serotonergic pathways, their concurrent use can increase the risk of side effects, such as serotonin syndrome and cardiac arrhythmia (2,3,4). Additionally, Sertraline’s effect on Clozapine metabolism may exacerbate side effects associated with this interaction (3).

If your treatment plan involves both of these medications, it is important to maintain open communication with your healthcare provider. You should closely monitor your response to this medication combination and report any concerning symptoms to ensure your treatment remains safe and effective.

What does research suggest?

Several research studies have attributed the interaction between Clozapine and Sertraline to their metabolism by the Cytochrome P450 enzymes (CYP450) and their effects on the neurotransmitters in the brain. This interaction is caused by their inhibitory and additive effects when used together.

Sertraline is known to increase the levels of Clozapine in the CNS through a mechanism involving the inhibition of Cytochrome P450 enzymes. Clozapine is primarily metabolized by Cytochrome P450 isoenzyme 1A2 (CYP1A2).

Sertraline inhibits this enzyme, increasing levels of Clozapine in the CNS, potentially causing several side effects (3).

Furthermore, Clozapine is also metabolized by CYP2D6. Sertraline also inhibits this enzyme causing an augmentation of Clozapine levels within the CNS (3).

Some studies have attributed the interaction between Clozapine and Sertraline to their effects on the neurotransmitters in the brain. Sertraline and Clozapine both inhibit the reuptake of Serotonin in the CNS causing an increase in Serotonin levels in the CNS. This interaction potentially results in Serotonin Syndrome, and Seizures.

What are the potential effects of Clozapine-Sertraline interaction?

Clozapine-sertraline interaction can have both therapeutic and potentially adverse effects. These effects vary among individuals and are dependent on factors such as the dosage of the medications and genetic differences in individuals.

Therapeutic effects:

Dual therapy with Sertraline and Clozapine is a common treatment approach used in the management of mental health disorders such as treatment-resistant schizophrenia and major depressive disorders.

Sertraline is primarily used in the management of depressive symptoms while Clozapine is used in the management of Psychotic symptoms (1,2,3). These medications work synergistically to provide symptom relief for patients with complex conditions such as treatment-resistant schizophrenia with comorbid depressive symptoms.

Additionally, this combination promotes long-term stability by addressing a wider range of symptoms.

Adverse effects:

A combination of these medications may cause unwanted side effects (2,3,4), including:

  • Increased risk of Serotonin Syndrome: Both Clozapine and Sertraline influence Serotonin levels in the brain. When taken together, Serotonin levels may increase to toxic levels due to inhibition of Serotonin reuptake. Serotonin syndrome is characterized by symptoms such as agitation, rapid heart rate, high blood pressure, and confusion.
  • Cardiovascular and QT Prolongation: Both Sertraline and Clozapine can lower blood pressure. When used together, there is an increased risk of orthostatic hypotension, particularly in geriatric patients.

Additionally, dual therapy with these medications may lead to QT prolongation, resulting in irregular heart rhythms and potentially fatal cardiac arrest.

  • Central Nervous system effects: While Sertraline is known to cause tremors, combining Clozapine and Sertraline may exacerbate neurologic effects such as tremors and movement disorders.

How to minimise the adverse effects of taking Clozapine with Sertraline?

  • Regular monitoring and assessment of symptoms: While using this drug combination, it is essential to have frequent consultations with your primary healthcare provider. They need to closely monitor you for potential side effects and negative interactions.
  • Dose adjustments and scheduling: Your doctor may modify the dosages of one or both medications to balance therapeutic effects and minimize side effects. Additionally, your healthcare provider will determine the optimal drug schedule for dual therapy with these medications.
  • Consideration of alternative medications: In the event of a severe interaction, such as serotonin syndrome, your doctor may adjust your treatment plan by discontinuing one or both medications or transitioning you to alternative medications with fewer side effects.


Individuals on dual therapy with Clozapine and Sertraline should schedule regular check-ins and maintain open communication with their healthcare provider. This practice promotes careful management of the medication combination, aiming to achieve the best possible outcomes while minimizing potential risks.

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Haidary HA, Padhy RK. Clozapine [Internet]. StatPearls Publishing; 2018 [cited 2023 Sep 25]. Available from:



Singh HK, Saadabadi A. Sertraline [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2020 [cited 2023 Sep 25]. Available from:



Edinoff AN, Fort JM, Woo JJ, Causey CD, Burroughs CR, Cornett EM, et al. Selective Serotonin Reuptake Inhibitors and Clozapine: Clinically Relevant Interactions and Considerations. Neurology International [Internet]. 2021 Sep 1 [cited 2023 Sep 25];13(3):445–63. Available from:



Rodriguez Campos A, Rodriguez Andrés L, Medina Ojeda G, Santos Carrasco I, Gonçalves Cerejeira J, Gonzaga A. Monitoring sertraline and clozapine levels. European Psychiatry [Internet]. 2022 Jun [cited 2023 Sep 25];65(S1):S718–8. Available from:


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