Treatment-Resistant Schizophrenia

Treatment-resistant schizophrenia (TRS) is a condition that affects about a third of people with schizophrenia, who do not respond well to standard antipsychotic medications. TRS is a major challenge for the management and prognosis of schizophrenia, as it is associated with more severe symptoms, poorer quality of life, higher risk of suicide, and higher health care costs. In this essay, I will discuss the definition, signs and symptoms, causes, diagnosis, treatment, complications, and therapies of TRS.

What is Treatment-Resistant Schizophrenia?

TRS is usually defined as a failure to achieve adequate symptom relief after trying at least two antipsychotic drugs of sufficient dose and duration, as prescribed by a doctor. However, there is no consensus on the exact criteria or time frame for diagnosing TRS, and different studies may use different definitions. Some factors that may influence the diagnosis of TRS include the type, dose, and duration of antipsychotic drugs, the severity and duration of symptoms, the adherence to treatment, the presence of comorbidities, and the response criteria.

What are the Main Signs and Symptoms?

The signs and symptoms of TRS are similar to those of schizophrenia, but they are more persistent and disabling. They include positive symptoms, such as hallucinations, delusions, and disorganized speech and behavior; negative symptoms, such as apathy, anhedonia, and social withdrawal; and cognitive symptoms, such as impaired attention, memory, and executive functions. TRS may also cause affective symptoms, such as depression, anxiety, and mood swings; and somatic symptoms, such as weight gain, metabolic syndrome, and movement disorders.

How Does Treatment-Resistant Schizophrenia Develop?

The causes of TRS are not fully understood, but they may involve multiple biological, psychological, and environmental factors. Some possible causes of TRS include:

  • Neurotransmitter dysfunction: TRS may result from an imbalance or dysfunction of various neurotransmitters in the brain, such as dopamine, glutamate, serotonin, and gamma-aminobutyric acid (GABA). These neurotransmitters are involved in regulating mood, cognition, perception, and behavior, and they may be affected by genetic variations, epigenetic modifications, or environmental influences.
  • Neuroinflammation: TRS may be linked to chronic inflammation in the brain and nervous system, which may be triggered by infections, stress, trauma, or autoimmune disorders. Neuroinflammation may damage the brain cells and circuits, and alter the immune system and the blood-brain barrier, leading to neurodegeneration and neurotoxicity.
  • Schizophrenia subtype: TRS may represent a distinct subtype of schizophrenia, with a different disease course, prognosis, and response to treatment. Some researchers have proposed that TRS may be classified into two subtypes: primary TRS, which is present from the onset of schizophrenia and is more resistant to treatment; and secondary TRS, which develops over time and is more responsive to treatment.

Diagnosing Treatment-Resistant Schizophrenia

The diagnosis of TRS is based on the clinical judgment of a psychiatrist, who will evaluate the patient’s history, symptoms, response to treatment, and other relevant factors. The psychiatrist may use various tools and scales to assess the severity and impact of the symptoms, such as the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale (CGI), and the Global Assessment of Functioning (GAF). The psychiatrist may also order some tests to rule out other possible causes of the symptoms, such as medical conditions, substance abuse, or medication side effects.

Treatment-Resistant Schizophrenia NICE Guidelines

Treatment-resistant schizophrenia (TRS) is a condition in which people with schizophrenia do not respond adequately to at least two different antipsychotic drugs. The NICE (National Institute for Health Care Excellence, UK) guidelines for managing TRS are as follows:

  • Offer clozapine to adults with schizophrenia whose illness has not responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs. At least one of the drugs should be a non-clozapine second-generation antipsychotic.
  • Before starting clozapine, offer the person a full discussion of the benefits and potential side effects of the drug, including the risk of agranulocytosis and the need for regular blood monitoring.
  • Start clozapine at a low dose (12.5 mg daily or less) and increase gradually, following the schedule suggested by the summary of product characteristics. Adjust the dose to achieve the optimal clinical response, while minimizing side effects.
  • Monitor the physical health of people taking clozapine, including weight, blood pressure, blood glucose, and lipid levels, as well as signs of constipation, excessive sedation, and seizures.
  • If clozapine is ineffective or not tolerated, review the diagnosis and consider a trial of another antipsychotic drug, either on its own or in combination with clozapine.
  • If the person has persistent positive symptoms despite adequate trials of antipsychotic drugs, offer cognitive behavioral therapy (CBT) and family intervention, and review the person’s adherence to medication and any substance misuse.

Treatment Options for Treatment-resistant Schizophrenia

The main treatment for TRS is clozapine, a second-generation antipsychotic drug that has proven efficacy and superiority over other antipsychotics for TRS. Clozapine works by modulating the activity of dopamine, serotonin, and other neurotransmitters in the brain, and by reducing neuroinflammation and oxidative stress. Clozapine can improve the positive, negative, cognitive, and affective symptoms of TRS, and reduce the risk of suicide and hospitalization. However, clozapine also has some serious side effects, such as agranulocytosis, which is a potentially fatal condition that lowers the white blood cell count and increases the risk of infections. Therefore, clozapine requires regular blood monitoring and strict adherence to treatment.


TRS can cause various complications that affect the physical, mental, and social well-being of the patients and their caregivers. Some of the complications of TRS include:

  • Physical health problems: TRS can increase the risk of developing various physical health problems, such as cardiovascular disease, diabetes, obesity, metabolic syndrome, and movement disorders. These problems may be caused by the symptoms of TRS, the side effects of the medications, or lifestyle factors, such as poor diet, physical inactivity, smoking, and substance abuse.
  • Mental health problems: TRS can worsen the mental health of the patients, causing more depression, anxiety, mood swings, suicidal ideation, and self-harm. These problems may be caused by the distress and stigma of having TRS, the lack of social support, or the comorbidity of other psychiatric disorders, such as bipolar disorder, personality disorder, or post-traumatic stress disorder.
  • Social and occupational problems: TRS can impair the social and occupational functioning of the patients, leading to more isolation, loneliness, discrimination, unemployment, poverty, homelessness, and criminality. These problems may be caused by the cognitive and negative symptoms of TRS, low self-esteem and self-efficacy, or the lack of access to education, training, and rehabilitation services.

Therapeutic Approaches for Treatment-Resistant Schizophrenia

In addition to pharmacological treatment, TRS may benefit from various psychological and psychosocial therapies that aim to enhance the coping skills, functioning, and quality of life of the patients and their caregivers. Some of the therapies that may help TRS include:

  • Cognitive-behavioral therapy (CBT): CBT is a form of psychotherapy that helps patients identify and challenge their distorted thoughts and beliefs, and replace them with more realistic and positive ones. CBT can also help patients manage their emotions, cope with stress, and improve their self-esteem and self-care.
  • Family therapy: Family therapy is a form of psychotherapy that involves the family members of the patients, and helps them understand, communicate, and support each other better. Family therapy can also help the family members cope with the burden and stress of caring for a person with TRS, and reduce the conflict and tension in the family.
  • Social skills training: Social skills training is a form of psychoeducation that teaches the patients how to interact and communicate with others effectively, and how to develop and maintain social relationships. Social skills training can also help the patients improve their social cognition, such as their ability to recognize and interpret social cues, emotions, and intentions.
  • Cognitive remediation: Cognitive remediation is a form of cognitive training that aims to improve the cognitive functions of the patients, such as attention, memory, executive functions, and problem-solving. Cognitive remediation can also help the patients enhance their learning and academic performance, and increase their chances of finding and keeping a job.


TRS is a complex and challenging condition that affects a significant proportion of people with schizophrenia and requires a comprehensive and individualized approach to treatment and care. TRS can be defined as a failure to respond to standard antipsychotic medications and can cause more severe and persistent symptoms, and more physical, mental, and social complications.

The main treatment for TRS is clozapine, a second-generation antipsychotic drug that has proven efficacy and superiority over other antipsychotics, but also has some serious side effects that require regular monitoring. TRS may also benefit from various psychological and psychosocial therapies that can enhance the coping skills, functioning, and quality of life of the patients and their caregivers. TRS is a condition that deserves more attention and research, as it has a significant impact on the lives of patients, their families, and society.


(1) Treatment-resistant schizophrenia: Causes, symptoms, and more.
(2) What Is Treatment-Resistant Schizophrenia? – WebMD.
(3) Clinical indicators of treatment-resistant psychosis.
(4) Schizophrenia Treatment: Medication, Therapy, and Self-Care – Psych Central.