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Understanding Treatment-Resistant Schizophrenia : Causes, Symptoms, How to Live with it, Outlook

Schizophrenia is a complex mental health condition that is difficult to treat and manage. It is a serious and chronic illness that has an impact on how a person thinks, behaves, and feels. The condition usually involves a combination of environmental, genetic, and brain chemistry factors as the underlying cause. People with this disease experience a variety of symptoms, with the most common ones being delusions and hallucinations. They also have difficulty in expressing their emotions. While antipsychotic drugs have been found to greatly improve the symptoms of many people with schizophrenia, unfortunately, there are many patients who have a condition known as treatment-resistant schizophrenia, or TRS. Treatment-resistant schizophrenia is not an easy condition to manage and people having this condition often face many problems in managing their illness. Read on to find out more about how to live with treatment-resistant schizophrenia.

What is Treatment-resistant Schizophrenia?

Schizophrenia is a complex mental health disorder that can be difficult to treat. As the name suggests, treatment-resistant schizophrenia is a type of schizophrenia that fails to respond to the conventional first-line schizophrenia medications most of the time. Most symptoms of treatment-resistant schizophrenia tend to persist even while the patient is on medication, and in many cases, they may even worsen. In order to qualify for a diagnosis of treatment-resistant schizophrenia, a patient needs to have undergone at least 12 weeks of schizophrenia treatment, and it should have involved the patient taking at least two medications for a period of at least six weeks without experiencing any improvement.(1,2)  Patients have to take the right medication and that too at the right dosage and as per the doctor’s recommendations. Nevertheless, a person who does not take their prescribed medication or only takes it sometimes does not qualify for a diagnosis of treatment-resistant schizophrenia. This is, of course, because they are not taking the treatment as the doctor has prescribed, and thus the treatment is not working.

Delusions, hallucinations, and disorganized thinking patterns are some of the common symptoms that come along with schizophrenia and can be tough to manage. These signs are typically known as the symptoms of psychosis, and these experiences are a sign of a lapse in the person’s ability to understand and distinguish reality. It is surprising to learn that around a third of all patients with schizophrenia show very little improvement with treatment, while seven percent of patients do not show any improvement with the treatment.(2,3)

A study was done in 2020 that estimated that almost 34 percent of patients with schizophrenia suffer from treatment-resistant schizophrenia.(4) A patient who has treatment-resistant schizophrenia is likely to need different medications and other combinations of treatments, including psychotherapy and support from a social worker.(5,6,7)

However, an earlier research had estimated that this percentage could be as high as 50 percent.(8) It is important to understand, though, that schizophrenia itself is considered to be a rare mental health condition and it is believed to estimate around 0.32 percent of the population in the world.(9)

Causes of Treatment-Resistant Schizophrenia and How to Recognize the Symptoms?

Treatment-resistant schizophrenia (TRS) is usually never diagnosed as what it is since it is not possible to tell it apart from treatment-responsive schizophrenia. This is because Treatment-resistant schizophrenia presents with the exact same set of symptoms, which are then segregated into two different categories that are outlined in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, text revision (DSM-5-TR).(10) The two categories for separating the symptoms of schizophrenia are negative and positive symptoms.

Positive symptoms of schizophrenia are the ones that are related to a person’s present-day ability and functioning and may include:(11,12)

  • Hallucinations
  • Delusions
  • Disorganized behavior
  • Disorganized thoughts

On the other hand, negative symptoms of schizophrenia are those that affect a person’s baseline abilities and take them away, including:(13,14)

  • Alogia or reduction in speech quantity
  • Blunted affect or reduced emotional expression
  • Asociality or withdrawal
  • Avolition or the lack of any motivation and goal-directed activity
  • Anhedonia or reduced pleasure expression
  • Depression

While it is possible that the continuous presence of negative or positive symptoms in a patient may show the presence of treatment-resistant schizophrenia, it is actually the persistent presence of positive symptoms that is known to be one of the most defining features of Treatment-resistant schizophrenia.(15)

The interesting fact is that experts don’t really know what causes treatment-resistant schizophrenia or even how to predict who will respond to treatment and who won’t. It is believed that there are numerous neurotransmitters that play a role in the development of schizophrenia.(2) The neurotransmitter dopamine is known to play an important part. Dopamine is responsible for supporting the reward and motivation part of the brain. Some evidence has shown that dopamine is especially overactive in people who have schizophrenia.(16,17)

Some of the differences that have been noted between treatment-resistant schizophrenia and treatment-responsive schizophrenia include:

  • In Treatment-resistant schizophrenia, there is a higher decrease in the gray matter of the brain, especially in the frontal parts of the brain.
  • There is a reduced thickness in the brain’s dorsolateral prefrontal cortex region in Treatment-resistant schizophrenia.
  • In TRS, there is an increase in the volume of basal ganglia white matter
  • There is reduced global functioning connectivity in the thalamic subregions of the brain along with the thalamocortical circuits in the brain in Treatment-resistant schizophrenia.

However, not all cases of TRS always present with different neurobiology when compared to the treatment-responsive cases. Due to this, many experts are often hesitant to indicate neurobiology as one of the major underlying causes of Treatment-resistant schizophrenia.

An older study done in 2007 suggested that treatment-resistant schizophrenia could also be related to the exact extent of neuronal damage that is often present in many schizophrenia cases.(18) At the same time, a 2019 research done on over 1000 people found that treatment-resistant schizophrenia was more common in people who had an early age onset of psychosis along with poor levels of functioning before the symptoms began developing.(19)

Nevertheless, the exact cause of Treatment-resistant schizophrenia remains unknown. What is important, though, is to understand ways in which treatment-resistant schizophrenia can be managed.

How to Live with Treatment-Resistant Schizophrenia?

It is important to know that not much is actually understood about what would be the best treatment approach for treating treatment-resistant schizophrenia. Many experts believe that this type of schizophrenia could be a true subtype of schizophrenia, one that presents with different pathological markers that can be treated with non-conventional treatment approaches.(20)

At present, both the British Association of Psychopharmacology (BAP and the American Psychiatric Association (APA) consider the use of atypical antipsychotic medication known as clozapine to be the first choice of treatment for treatment-resistant schizophrenia.(21) Clozapine is currently the only medication that has been shown to treat treatment-resistant schizophrenia effectively.(22)

At the same time, though, when it comes to treating treatment-resistant schizophrenia, medication is not the only component of treatment. People having TRS need to also take certain steps to improve their overall well-being and immunity, including regular exercise, meeting and interacting with other socially, as well as having a healthy sleeping routine.

For people who are using clozapine for the treatment of Treatment-resistant schizophrenia, again, it is not always that simple. Nearly 40 to 70 percent of people with schizophrenia who are treated with clozapine do not respond to this medication. In cases where clozapine is not effective, doctors refer to such scenarios as ultra-treatment-resistant schizophrenia, even though this is not covered in the DSM diagnosis.(23,24)

Doctors often try out an augmented approach to managing cases of ultra-treatment-resistant schizophrenia. This involves still using clozapine but in combination with some other pharmacological agents like aripiprazole or brexpiprazole. Other supportive psychotherapy options are also used to manage ultra-treatment-resistant schizophrenia, including:

  • Cognitive behavioral therapy (CBT)
  • Repetitive transcranial magnetic stimulation (rTMS)
  • Electroconvulsive therapy (ECT)
  • Deep brain stimulation(25,26)

A small study carried out in 2019 looked at ten treatment-resistant schizophrenia cases as well as schizoaffective disorder cases and found that an antipsychotic medication called pimavanserin, which is usually used in Parkinson’s disease, can be successful when clozapine is ineffective.(27)

What is the Outlook for Treatment-Resistant Schizophrenia?

It is no doubt very challenging to manage treatment-resistant schizophrenia, and a person may continue to experience issues with their treatment. A study carried out in 2022 on 63 participants with treatment-resistant schizophrenia discovered that 25 percent of the patients responded well to clozapine as the first-line treatment.(28)

There are some factors that are associated with a higher chance of getting a good response to treatment. These include:

  • Not waiting for over seven years to try clozapine for treatment-resistant schizophrenia
  • Having better social functioning in childhood and adolescence years before being diagnosed with schizophrenia
  • Being diagnosed with the paranoid subtype of schizophrenia
  • Trying out at least one atypical antipsychotic schizophrenia medication

All said and done, though, it is never really possible to predict how a patient will respond to treatment.


Treatment-resistant schizophrenia comes with many challenges, especially when it comes to living with TRS. Treatment-resistant schizophrenia can cause immense anxiety to a patient and also disrupt their life and social relationships. However, being diagnosed with treatment-resistant schizophrenia does not automatically mean that this type of schizophrenia cannot be treated. When you find the right doctor and the right treatment and drug dosage, you are likely to experience relief from your symptoms.

There are many other types of therapies and interventions that can help in cases of treatment-resistant schizophrenia. Psychotherapy, for example, can help a person be able to manage their schizophrenia symptoms better, while also learning how to advocate for themselves. Behavioral therapies help patients learn how to live with their treatment-resistant schizophrenia. On the other hand, brain stimulation therapies like electroconvulsive therapy can help provide relief over the long term as it helps ‘reset’ the brain, thus alleviating the symptoms.

It is important that people with this subtype of schizophrenia should have full knowledge about the condition and work with a professional healthcare team that has experience in dealing with treatment-resistant schizophrenia.


  1. Potkin, S.G., Kane, J.M., Correll, C.U., Lindenmayer, J.P., Agid, O., Marder, S.R., Olfson, M. and Howes, O.D., 2020. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ schizophrenia, 6(1), p.1.
  2. Schizophrenia – StatPearls – NCBI Bookshelf (no date). Available at: https://www.ncbi.nlm.nih.gov/books/NBK539864/ (Accessed: April 6, 2023).
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  4. Potkin, S.G., Kane, J.M., Correll, C.U., Lindenmayer, J.P., Agid, O., Marder, S.R., Olfson, M. and Howes, O.D., 2020. The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research. NPJ schizophrenia, 6(1), p.1.
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  7. Dickerson, F.B. and Lehman, A.F., 2006. Evidence-based psychotherapy for schizophrenia. The Journal of nervous and mental disease, 194(1), pp.3-9.
  8. Nucifora Jr, F.C., Woznica, E., Lee, B.J., Cascella, N. and Sawa, A., 2019. Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiology of disease, 131, p.104257.
  9. Schizophrenia (no date) World Health Organization. World Health Organization. Available at: https://www.who.int/news-room/fact-sheets/detail/schizophrenia (Accessed: April 6, 2023).
  10. Rowe, S. (2022) What’s the DSM-5?, Psych Central. Psych Central. Available at: https://psychcentral.com/lib/dsm-5 (Accessed: April 6, 2023).
  11. Fletcher, P.C. and Frith, C.D., 2009. Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia. Nature Reviews Neuroscience, 10(1), pp.48-58.
  12. Lewine, R.R., Fogg, L. and Meltzer, H.Y., 1983. Assessment of negative and positive symptoms in schizophrenia. Schizophrenia bulletin, 9(3), pp.368-376.
  13. Andreasen, N.C., 1982. Negative symptoms in schizophrenia: definition and reliability. Archives of general psychiatry, 39(7), pp.784-788.
  14. Blanchard, J.J. and Cohen, A.S., 2006. The structure of negative symptoms within schizophrenia: implications for assessment. Schizophrenia bulletin, 32(2), pp.238-245.
  15. Buchanan, R.W., 2007. Persistent negative symptoms in schizophrenia: an overview. Schizophrenia bulletin, 33(4), pp.1013-1022.
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  17. Davis, K.L., Kahn, R.S., Ko, G. and Davidson, M., 1991. Dopamine in schizophrenia: a review and reconceptualization. The American journal of psychiatry.
  18. Medina-Hernández, V., Ramos-Loyo, J., Luquin, S., Sánchez, L.C., García-Estrada, J. and Navarro-Ruiz, A., 2007. Increased lipid peroxidation and neuron specific enolase in treatment refractory schizophrenics. Journal of psychiatric research, 41(8), pp.652-658.
  19. Legge, S.E., Dennison, C.A., Pardiñas, A.F., Rees, E., Lynham, A.J., Hopkins, L., Bates, L., Kirov, G., Owen, M.J., O’Donovan, M.C. and Walters, J.T., 2020. Clinical indicators of treatment-resistant psychosis. The British Journal of Psychiatry, 216(5), pp.259-266.
  20. Gillespie, A.L., Samanaite, R., Mill, J., Egerton, A. and MacCabe, J.H., 2017. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? A systematic review. BMC psychiatry, 17(1), pp.1-14.
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  23. Orsolini, L., Bellagamba, S., Salvi, V. and Volpe, U., 2022. A case report of clozapine-treatment-resistant schizophrenia successfully managed with brexpiprazole combination therapy. Asian Journal of Psychiatry, 72, p.103121.
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  26. Corripio, I., Roldán, A., McKenna, P., Sarró, S., Alonso-Solis, A., Salgado, L., Alvarez, E., Molet, J., Pomarol-Clotet, E. and Portella, M., 2022. Target selection for deep brain stimulation in treatment resistant schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 112, p.110436.
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  28. Aissa, A., Jouini, R., Ouali, U., Zgueb, Y., Nacef, F. and El Hechmi, Z., 2022. Clinical predictors of response to clozapine in Tunisian patients with treatment resistant schizophrenia. Comprehensive Psychiatry, 112, p.152280.
Team PainAssist
Team PainAssist
Written, Edited or Reviewed By: Team PainAssist, Pain Assist Inc. This article does not provide medical advice. See disclaimer
Last Modified On:April 30, 2023

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