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Discover Clozaril Long-term Effects, Risks, Benefits, FAQs

Last Updated on February 18, 2026 by Diane Ridaeus

Alternative to Meds Editorial Team
Medically Reviewed by Dr Samuel Lee MD

The long-term effects of Clozaril (generic clozapine) include both benefits and risks. More is being learned about how antipsychotics work well for some, and for others, why they sometimes fail to achieve the results that were hoped for. Clozapine was synthesized in the 1950s, made available in the 70s in Europe, but was later withdrawn for safety concerns described in more detail below.

We hope you may find the additional information provided about safe tapering techniques, and alternatives, helpful to consider, and to discuss with your prescriber. Links are provided for more in-depth study on these topics.


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Important Prescribing Information about Clozaril Long-Term Effects

clozaril carries five black box warningsThe FDA mandated that the manufacturer of Clozaril significantly expand the “box warning” for this antipsychotic medication before allowing it back on the market in 1989. These warnings will be listed below, along with an expanded description of each. The revised warnings describe the potential risks that have come to the attention of the medical community and the FDA. While some of these occurred in short-term Clozaril trials, some are also known to be long-term effects of Clozaril. The latter were reported post-marketing; hence, were not included in the original drug packaging. And the package insert also clearly states that the warnings on the package are risks that continue over time.

In today’s medical landscape, Clozaril has come to be prescribed exclusively for patients who have experienced treatment-resistive schizophrenia or treatment-resistive mania in bipolar.

Some of the benefits that have been reported on the use of Clozaril include the absence of movement disorders such as tardive dyskinesia, and also minimal elevation of prolactin. Elevated prolactin is a side effect of many antipsychotics, that causes male breast enlargement, and can interrupt the menstrual cycle and cause other female sexual issues. Another benefit was found in clinical trials comparing Zyprexa to Clozaril: Clozaril was associated with a delay in recurrent suicidal behaviors compared to Zyprexa.1-4,6

The Box Warnings for Clozaril Explained

Agranulocytosis

Agranulocytosis is the death of white blood cells. White blood cells are the body’s first and vital line of defense against pathogens and infections. Clozaril poses a significant risk for this potentially life-threatening event. To begin taking Clozaril, the patient must have a healthy baseline of white blood cells, including neutrophils. While taking Clozaril, the prescriber must provide regular WBC testing to make sure this risk is avoided. Regularly testing the white blood count must continue even after Clozaril is discontinued, for at least 4 weeks.1,2

Seizures

Seizures are known to occur with the use of Clozaril/clozapine. Seizures have been demonstrated to be more likely at higher doses of the drug. For safety, while taking Clozaril, the person should not engage in any activities where sudden loss of consciousness would endanger him/herself or others, such as driving, flying, or operating machinery.1,2

Myocarditis

Myocarditis is the inflammation of heart muscle, leading to impaired blood flow, arrhythmias, and other serious health risks.  Myocarditis left untreated can often be fatal. It occurs most often in the first month of treatment with Clozaril, but is not limited to the initial stages of treatment. If myocarditis develops, the recommendation from the FDA is to promptly discontinue taking Clozaril. However, FDA guidance also cautions that one should never suddenly stop taking Clozaril or any antipsychotic medication. It’s not wise or safe to try stopping without guidance and oversight — always seek medical help and guidance for antipsychotic withdrawal.1,2,5

Orthostatic Hypotension

Hypotension, or low blood pressure, is a fairly common condition especially in the frail or elderly population. For some, there are no discernable symptoms. Others may experience sweating, nausea, and dizziness. However, orthostatic hypotension is a potentially life-threatening condition that is worsened due to neurological dysfunction. In an orthostatic hypotension event, what occurs is a sudden collapse of blood pressure, that can result in dizziness, lightheadedness, fainting, falls, respiratory failure, and cardiac arrest. If Clozaril is stopped suddenly, this has resulted in orthostatic hypotension. (Please review the information above on myocarditis, and always seek medical oversight before suddenly stopping Clozaril.) 1,2,13

Increased Risk of Death in the Elderly

Many drug trials have clearly shown that elderly persons with dementia taking antipsychotic medications died at nearly twice the rate compared to persons not taking antipsychotics. The causes of death in the 10-week trials included those mentioned in the previous box warnings, plus pneumonia or other infections. While 10 weeks is not short-term, longer-term trials would be helpful to reveal if this risk escalated over time or not. Ethically speaking, it would be hard to justify a longer-term trial where the potential risks were so great.1,2

Information About Treatment-Resistive Schizophrenia, and Treatment-Resistive Mania in Bipolar

As discussed in the video above, Clozaril is typically reserved for patients who experience what is termed treatment-resistive schizophrenia. The same guidelines apply to treatment-resistive mania in bipolar conditions. In such cases, multiple other antipsychotics must have failed to provide a desired outcome, meaning at least two or more failed trials before a Clozapine prescription is warranted.

Therefore Clozaril is generally not prescribed as a first-line treatment for the symptoms of schizophrenia or bipolar-related mania, but is considered a “third-line” choice. This includes the situation where several other antipsychotic drugs may have demonstrated efficacy at first, but waned over time.

According to several sources of clinical statistics, treatment-resistive cases of schizophrenia and bipolar mania represent approximately 30% of this patient population.9,10

Understanding Clozaril Long-Term Effects and Mechanism of Action

Research is ongoing concerning why some antipsychotics have little to no effect on troubling schizophrenic or bipolar symptoms, and why Clozaril has had some success in a segment of this population.

clozaril's mechanism of actionThe drug’s label clearly states the mechanism of action for Clozaril is unknown, as is the mechanism of action for all other antipsychotic medications. It has been hypothesized since the 1970s that antipsychotics block dopamine. That has largely been the consensus of how antipsychotics work.

However, it has been suggested that Clozaril’s mechanism of action is likely more complex. For example, Clozaril is not associated with movement disorders, like many dopamine-blocking drugs are. And, Clozaril is particularly known to induce hyper-salivation, where in contrast, many other antipsychotics cause dry mouth. It is thought that acetylcholine (another type of neurotransmitter) being stimulated at certain receptors possibly explains this hypersalivation side effect of Clozaril in 90% of the people who take the drug. It may be that instead of targeting the suppression of dopamine, Clozaril stimulates other receptors such as the cholinergic muscarinic receptors, and possibly others. Research has been ongoing to try and determine the exact mechanisms of action of Clozaril and of other antipsychotics as well.12

Hopefully, this type of research will help understand and resolve the barrier long-term effects of Clozaril can present. And could help introduce treatments that work better without these liabilities and risks.

Notes on the Development of Antipsychotics for Treatment-Resistive Schizophrenia

The development of antipsychotics to treat schizophrenia is a fascinating journey worth exploring. According to recently published research in the Sage Journal,12 we learn that the introduction of LSD into the world of 1943 sparked an attempt to locate a drug that would block LSD’s psychedelic effects. LSD is a drug that is known to mimic psychosis, hallucinations, disordered thinking, and other symptoms that are very similar to those found in schizophrenia. And, if a drug could block or reverse those effects, the question was then would it work for schizophrenia patients?

This arm of the research world produced many drugs that hoped to find a way to reverse such symptoms. First generation antipsychotics were followed by second generation or atypical antipsychotics, which for some were helpful, but not all. And for some, the risks definitely outweighed any benefits.7-11

Recently, a drug being developed called “JRT” has been proposed as an improved antipsychotic medication which is identical to LSD but with 2 altered molecules. Time and future research will tell if JRT or other pharmaceuticals can provide a better answer for treatment-resistive schizophrenia, without the liability of long-term effects associated with Clozaril and similar drugs.12

About Alternate Treatments, Safe Tapering Guidelines

While some people experience relief and no significant long-term effects of Clozaril, the story is not the same for everyone. ATMC has helped many people who really were on the edge of hopelessness, using holistic alternatives and supports to regain a more satisfactory quality of life, along with the safe and gradual reduction of medication, resulting in the elimination of troubling symptoms.

You are invited to learn more about the science-based techniques and treatments offered at the center by visiting these pages:

• Antipsychotic Tapering
• Antipsychotic Alternatives
• Treatment for Emotional and Physical Symptoms
• Medication Withdrawal and Neurochemistry E-book
1 (800) 301-3753 for Help with Clozaril Side Effects & Risks

FAQs

Is it true that Clozaril works by balancing serotonin and dopamine in the brain?
According to the FDA, the exact mechanisms and complexities of how Clozaril works are unknown.
What percentage of schizophrenia diagnoses are termed treatment-resistive?
Approximately 30% of schizophrenia diagnoses are termed “treatment-resistive,” meaning that multiple courses of antipsychotic medications have not produced adequate remission or relief of symptoms.
I have tried multiple antipsychotic drugs, all without success. Are there other alternatives I could consider besides starting on Clozaril?
ATMC has helped many persons suffering from symptoms that medications did not help. There are holistic treatments including orthomolecular and environmental medicine applications that could be effective at reducing and eliminating unwanted symptoms without relying solely on medication to do so.
Is Clozaril prescribed for first-episode psychosis or other schizophrenia type symptoms?
No. Clozaril has many potential safety issues and is considered a drug of last resort because of these risks.
What are some of the drug-drug interactions to avoid while taking Clozaril?
Unfortunately, drug interactions with Clozaril have not been systematically evaluated at this time. However, the FDA advises out of caution to avoid any taking any other agents that affect the CNS such as benzodiazepines, antidepressants, agents that suppress bone marrow, lower blood pressure, or any psychotropics that have similar side effects of Clozaril. Additionally, the use of caffeine is not recommended as it may elevate plasma levels of Clozaril and produce adverse effects.
Can I breast-feed while taking Clozaril?
No.  Studies indicate that Clozaril is released into the breast milk and the FDA advises against breast-feeding while taking Clozaril.
Can I drive while taking Clozaril?
No. Due to the risks of seizure, one should not drive or operate machinery while taking Clozaril.

Sources:

1. FDA drug label Clozaril (clozapine) tablets for oral use approval 1989 [cited 2026 Feb 17]

2. Novartis Prescribing Information Clozaril (clozapine) (N.D.) published online (N.D.)[cited 2026 Feb 17]

3. Gurrera RJ, Gearin PF, Love J, Li KJ, Xu A, Donaghey FH, Gerace MR. Recognition and management of clozapine adverse effects: A systematic review and qualitative synthesis. Acta Psychiatr Scand. 2022 May;145(5):423-441. doi: 10.1111/acps.13406. Epub 2022 Mar 16. PMID: 35178700. [cited 2026 Feb 17]

4. Fitzsimons J, Berk M, Lambert T, Bourin M, Dodd S. A review of clozapine safety. Expert Opin Drug Saf. 2005 Jul;4(4):731-44. doi: 10.1517/14740338.4.4.731. PMID: 16011451. [cited 2026 Feb 17]

5. Masopust J, Urban A, Valis M, Malý R, Tůma I, Hosák L. Repeated occurrence of clozapine-induced myocarditis in a patient with schizoaffective disorder and comorbid Parkinson’s disease. Neuro Endocrinol Lett. 2009 Mar;30(1):19-21. PMID: 19300384. [cited 2026 Feb 17]

6. Wagner E., et al., Efficacy and safety of clozapine in psychotic disorders – a systematic quantitative meta-review revised and published in Springer Nature, 22 Sept 2021 [cited 2026 Feb 17]

7. Correll CU, Agid O, Crespo-Facorro B, de Bartolomeis A, Fagiolini A, Seppälä N, Howes OD. A Guideline and Checklist for Initiating and Managing Clozapine Treatment in Patients with Treatment-Resistant Schizophrenia. CNS Drugs. 2022 Jul;36(7):659-679. doi: 10.1007/s40263-022-00932-2. Epub 2022 Jun 27. Erratum in: CNS Drugs. 2022 Sep;36(9):1015. doi: 10.1007/s40263-022-00946-w. PMID: 35759211; PMCID: PMC9243911. [cited 2026 Feb 17]

8. Petch J, Martinez-Gonzalez B, Shergill S. Treatment-resistant schizophrenia: pathophysiology and the role of neuroimaging and therapeutics. BJPsych Advances. Published online 2026:1-9. doi:10.1192/bja.2025.10195 [cited 2026 Feb 17]

9. Correll CU, Howes OD. Treatment-Resistant Schizophrenia: Definition, Predictors, and Therapy Options. J Clin Psychiatry. 2021 Sep 7;82(5):MY20096AH1C. doi: 10.4088/JCP.MY20096AH1C. PMID: 34496461.[cited 2026 Feb 17]

10. Pandey A, Kalita K,  Treatment-resistive Schizophrenia: How far have we Traveled? Frontiers in Psych. 29 Aug 2022  [cited 2026 Feb 17]

11. Steven Parkes, Bethany Mantell, Ebenezer Oloyede, Graham Blackman, Patients’ Experiences of Clozapine for Treatment-Resistant Schizophrenia: A Systematic Review, Schizophrenia Bulletin Open, Volume 3, Issue 1, January 2022, sgac042 [cited 2026 Feb 17]

12. Morrison P D, Jahuar S, Young A H, The mechanism of action of clozapine, Sage Journal of Psychopharmacology 2025, Vol. 39(4) 297 –300 [cited 2026 Feb 17]

13. Magkas N, Tsioufis C, Thomopoulos C, Dilaveris P, Georgiopoulos G, Sanidas E, Papademetriou V, Tousoulis D. Orthostatic hypotension: From pathophysiology to clinical applications and therapeutic considerations. J Clin Hypertens (Greenwich). 2019 May;21(5):546-554. doi: 10.1111/jch.13521. Epub 2019 Mar 22. PMID: 30900378; PMCID: PMC8030387. [cited 2026 Feb 17]

Originally Published February __, 2026 by Diane Ridaeus


This content has been reviewed and approved by a licensed physician.

Dr. Samuel Lee

Dr. Samuel Lee is a board-certified psychiatrist, specializing in a spiritually-based mental health discipline and integrative approaches. He graduated with an MD at Loma Linda University School of Medicine and did a residency in psychiatry at Cedars-Sinai Medical Center and University of Washington School of Medicine in Seattle. He has also been an inpatient adult psychiatrist at Kaweah Delta Mental Health Hospital and the primary attending geriatric psychiatrist at the Auerbach Inpatient Psychiatric Jewish Home Hospital. In addition, he served as the general adult outpatient psychiatrist at Kaiser Permanente.  He is board-certified in psychiatry and neurology and has a B.A. Magna Cum Laude in Religion from Pacific Union College. His specialty is in natural healing techniques that promote the body’s innate ability to heal itself.

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