Treatment resistant schizophrenia (TRS) explained


Schizophrenia is a chronic and severe mental disorder affecting 20 million people worldwide. Schizophrenia is characterized by distortions in thinking, perception, emotions, language, sense of self and behaviour. Common experiences include hallucinations (hearing voices or seeing things that are not there) and delusions (fixed, false beliefs). Schizophrenia can impair the patient’s ability to function normally, resulting in difficulties with relationships with others, and in work and study.

Schizophrenia typically begins when the patient is a teenager or a young adult. There are effective treatments for schizophrenia, and people affected can often lead a productive life and be integrated in society.

Treatment resistant schizophrenia

TRS is the name for schizophrenia that has not responded to at least two medicines used to treat the condition. Around one-third of schizophrenia patients have the treatment resistant form of the disease.

Symptoms of TRS

Schizophrenia is a psychosis, a type of mental illness characterized by distortions in thinking, perception, emotions, language, sense of self and behaviour. Common experiences include:
• Hallucination: hearing, seeing or feeling things that are not there;
• Delusion: fixed false beliefs or suspicions not shared by others in the person’s culture and that are firmly held even when there is evidence to the contrary;
• Abnormal behaviour: disorganised behaviour such as wandering aimlessly, mumbling or laughing to self, strange appearance, self-neglect or appearing unkempt;
• Disorganised speech: incoherent or irrelevant speech; and/or
• Disturbances of emotions: marked apathy or disconnect between reported emotion and what is observed such as facial expression or body language.

Treatment resistant schizophrenia must be managed by the doctor to help patients enjoy a better quality of life

Patients with TRS may have schizophrenia symptoms that are not well controlled. These symptoms can impact many areas of daily life such as the ability to do things independently, self-care, cooking, work and study. Simple things like taking a bus to attend an appointment may become difficult. Symptoms can also affect the patient’s social life, leading to isolation. These difficulties may cause patients to feel depressed and stressed and even frightened in some situations. They may also feel frustrated that despite taking medicines as their doctor had instructed, they have not worked well.

When schizophrenia is not managed well by the initial treatment, the doctor may need to change the medication to ensure the best treatment. The doctor will discuss treatment options with the patient.

What is clozapine?

Clozapine is one of a number of antipsychotic medicines called second-generation (or atypical) antipsychotic medicines. Atypical antipsychotics were developed to provide effective treatments for schizophrenia. You may have been prescribed Clozaril®, which is the same medicine as clozapine. Medicines normally have two names, one is the generic name (in this case, clozapine) and the other is the brand name chosen by the pharmaceutical company that markets the medicine (in this case Clozaril®).

People with schizophrenia have too much chemical activity in their brain. Clozapine interacts with receptors in the brain to decrease the chemical activity.

Clozapine is the only medicine licensed for TRS

The National Institute for Heath and Care Excellence (NICE) in the United Kingdom and the American Psychiatric Association recommend clozapine for the treatment of TRS after two other medicines have failed to treat the condition successfully.

To help reduce the risk of side-effects, the doctor will start the patient on a low dose of clozapine. This will be increased slowly so that the doctor can check how the patient reacts. The aim is to find the lowest effective dose for the patient: the dose that has the best effect with the fewest side-effects.

Clozaril® (clozapine) is taken in tablet form. The medicine is taken once or twice a day as directed by the doctor. As doses are increased, the dose can be divided unevenly, with the larger portion taken at bedtime. The patient should follow their doctor’s advice about dividing the dose.

Managing schizophrenia

It is important that patients take their clozapine medicine as directed by their doctor to achieve the best outcomes for patients with TRS being treated with clozapine, it is important that:

  • Patients take their medicine as directed by the doctor and/or nurse

  • Patients who do not take clozapine as instructed by their doctor are more likely to find the treatment less effective. The patient’s doctor or nurse will be able to provide more information about how to take clozapine if needed.

  • Side-effects are managed by your doctor and/or nurse

  • All medicines can have side-effects. The doctor can explain the possible side-effects and will monitor the patient so they can be spotted early. The doctor will know how to manage any side-effects should they occur.

This will include monitoring of: the effectiveness of Clozaril® (clozapine), the results of regular blood tests for blood-related side effects, and any other side-effects.

Side-effects with medicines for schizophrenia

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side-effects not listed in the package leaflet.

UK: Please continue to report suspected side effects to the MHRA through the Yellow Card Scheme. Please report all suspected side effects that are serious or result in harm. Serious reactions are though that are fatal, life-threatening, disabling or incapacitating, those that cause congenital abnormality or result in hospitalisation, and those that are considered medically significant for any reason. It is easiest and quickest to report side effects online via the Yellow Card website: or via the YellowCard app available from the Apple App Store or GooglePlay Store. Ireland: Please continue to report suspected side effects to: HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website:; Email: Adverse events can also be reported directly to Viatris via:

Agranulocytosis (a white blood cell abnormality) is uncommon in patients taking clozapine

One of the side-effects of clozapine, agranulocytosis is when not enough white blood cells are produced in the body. Although this condition can be serious if left untreated, the doctor will monitor the number of white blood cells in the patient’s blood and will adjust the treatment if necessary. Agranulocytosis is uncommon in patients taking clozapine7 and should not stop the doctor from considering it as a therapy for TRS (any patient with a history of agranulocytosis should not be prescribed clozapine).

Weight gain with clozapine

Patients taking clozapine may experience weight gain. Weight gain is a common side-effect seen in most drugs that treat schizophrenia. Please talk to your doctor, pharmacist or nurse if weight gain begins to be an issue.

In addition to discussing any weight gain while on clozapine with your healthcare professional, the National Health Service has devised a weight loss plan that will help you lose weight in a safe manner - and keep it off.8

The NHS Choices weight loss keys to success are:

  • Make realistic changes to your diet and physical activity that can become a part of your regular routine

  • The best way to lose weight is to make long-term changes to diet and physical activity that result in a steady rate of weight loss

  • Aim to lose weight at around 0.5kg to 1kg a week (1lb to 2lb), until you achieve a healthy body mass index (BMI)

Tips for losing weight include:8

  • Don’t skip breakfast

  • Eat regular meals

  • Eat plenty of fruit and veg

  • Get more active

  • Drink plenty of water

  • Eat high-fibre foods

  • Use a smaller plate

  • Cut down on alcohol

For more help and advice, go to the NHS Choices website

Clozapine and constipation

Constipation may occur in patients taking drugs for schizophrenia, including clozapine.

Everyone has their own normal bowel habit, and this will differ from person to person. Symptoms of constipation include9:

  • Passing fewer stools than is normal for you

  • Dry, hard and lumpy, or unusually large stools that are difficult to pass

  • Bloating, stomach pain, and cramps

Generally, a few simple changes to your lifestyle and diet will relieve your constipation. However, you should talk to your doctor, pharmacist, or nurse if constipation becomes an issue.

Tips to help with your constipation include10:

  • Drink plenty of fluids

  • Try to cut down on caffeine and fizzy drinks

  • Add more fibre to your diet:

    • Wholemeal bread

    • Potatoes with their skins on

    • Fruit and vegetables

    • Nuts, seeds, and oats

  • Become more active:

    • Have a daily walk

    • Go swimming

    • Take up cycling

    • Join a fitness or dance class

Try not to ignore a need to go to the toilet, as doing so can increase the likelihood of your becoming constipated. Try to establish a regular toilet routine so that you become used to going to the toilet at a specific time, e.g. first thing in the morning.

For more help and advice on constipation and how to manage it, visit the NHS Choices: Live Well - Digestive health page.

It is important that the patient’s blood is monitored for abnormalities while receiving clozapine therapy?

Blood monitoring will help the doctor detect and quickly treat any blood related side-effects if they occur.

Viatris is the name of the drug company that markets Clozaril® (clozapine). Viatris supports patients and their healthcare professionals through Clozaril® Connect, a programme to help diagnose, treat, and manage patients with TRS who benefit from clozapine.

The role of the Clozaril® Patient Monitoring Service (CPMS) is key for keeping patients safe from side effects such as blood cell abnormalities whilst taking clozapine.


  1. Kane J, Marder S, Schooler N, Wirshing W, Umbricht D, Baker R, et al. Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized double-blind comparison. Arch Gen Psychiatry 2001; 58: 965-72.
  2. Azorin JM, Spiegel R, Remington G, Vanelle JM, Péré JJ, Giguere M, et al. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 2001; 158(8): 1305-13.
  3. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry 2001; 158(4): 518-26.
  4. Wahlbeck K, Cheine M, Essali A, Adams C. Evidence of clozapine’s effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials. Am J Psychiatry 1999; 156(7): 990-9.
  5. Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009 Jan 21; (1): CD000059.
  6. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT. Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry 1998; 155(6): 751-60.
  7. Clozaril® Summary of Product Characteristics (SmPC). Available at: (accessed March 2018).
  8. NHS Choices:Live well-Healthy weight. Available at: (Last accessed March 2021)
  9. NHS: conditions-constipation. Available at: accessed March 2021)
  10. NHS Choices: Live Well - Digestive health page (Last accessed March 2021)