Schizophrenia Spectrum and Other Psychotic Disorders, Treatment-resistant Schizophrenia
Conditions
Keywords
Immunopsychiatry, Schizophrenia spectrum disorder, treatment-resistant
Brief summary
This study evaluates the addition of rituximab to 12 patients diagnosed with treatment resistant schizophrenia spectrum disorder in an open trial.
Detailed description
Immunological factors may be determinants for some psychiatric disorders, thus immunomodulation may be helpful. Rituximab (antibodies against CD20, cluster of differentiation), a standard treatment for multiple sclerosis, is an anti-inflammatory drug, hitherto not tested for psychiatric disorders. The aim of this study is to investigate whether the psychiatric symptoms of treatment-resistant adult psychiatric patients, diagnosed with schizophrenia spectrum disorder (SSD), are significantly improved after treatment with rituximab. Our purpose is to implement recent insights from Immunopsychiatry to find efficacious, but still tolerable treatment for these patients. This is a single-site, 20-week, open pilot, add-on treatment as usual, trial, where the patients will be followed for 1 year. Rituximab will be administered with one single dose of 1000 mg. Investigators will analyse inflammatory and metabolic biomarkers in relation to the primary outcome, treatment response (defined as clinically relevant reduction in the validated measure PANSS). Other outcomes are much or very much improved on Clinical Global Impression - Improvement scale (CGI-I) and change in Personal and Social Performance Scale measuring overall disability.
Interventions
DRUGRituximab
Infusion
Sponsors
Örebro University, Sweden
Region Örebro County
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
(Swedish citizens): 1. patient ages 18 to 40 years 2. a duration of illness exceeding 2 years 3. correspond to Markedly ill, Severely ill or Among the most extremely ill patients on the Clinical Global Impression - Severity scale (CGI-S) 4. Global Assessment of Functioning below 50 5. Schizophrenia spectrum disorder according to The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). 6. treatment resistance, i.e. failing to remit despite adequate treatments 7. if female and with any risk for pregnancy, willing to use contraceptives 8. if antipsychotic treatment is prescribed the plasma concentrations of the drug must be tested and shown to be within therapeutic interval. 9. subjects should be judged by the investigator to be lucid and oriented to person, place, time, and situation when giving the informed consent. 10. immunoglobulin levels within the normal range
Exclusion criteria
1. on-going immunomodulatory treatment 2. pregnancy or breast-feeding 3. weight below 40 kg 4. clinically relevant on-going infection 5. chronic infections 6. positive screening test for hepatitis B, C, HIV or tuberculosis 7. any change of psychotropic medication within the previous 4 weeks 8. much or very much improved already at baseline according to CGI-I i.e. scores of 1 or 2 by the clinician 9. severe heart failure (NYHA grade IV) or other severe heart disease or history of cardiac arrhythmia or myocardial infarction 10. unable to make an informed decision to consent to the trial 11. in compulsory treatment 12. treatment with clozapine within the last 2 months 13. previous treatments with immunosuppressive agents 14. malignancy currently or within 2 years prior to inclusion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Positive and Negative Syndrome Scale (PANSS) | week 20 | Change in symptoms measured as change in Positive and Negative Syndrome Scale (PANSS) score from baseline. PANSS measures symptom severity of patients with schizophrenia and is a clinically based interview. PANSS measures positive symptoms (7 items, range 7-49), which refer to e.g. hallucinations and delusions; negative symptoms (e.g. loss of normal functions) (7 items, range 1-7) and general disability (16 Items, range 16 -112) separately. Higher scores denote more symptoms and disability. PANSS total score range from 30-210. At least 40 % reduction in PANSS total score is regarded as response. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression-Severity (CGI-S) Scale | week 20 | CGI-S is a clinician rated measure of overall clinical severity that is rated on a scale between 1 and 7. A person with no clinical complaints or problems will get a score of 1. The score 7 indicates the highest level of severity is phrased as Among the most extremely ill patients. |
| Clinical Global Impression-Improvement (CGI-I) in Relation to Inflammatory Markers | week 20 | Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Change in inflammatory markers in blood (gene expression and proteins) towards normality, in relation to clinical response will be measured. |
| Personal and Social Performance Scale (PSP) | week 20 | Personal and Social Performance Scale (PSP) gives a score for disability. The PSP is a 100-point single-item rating scale (range 1-100), subdivided into 10 equal intervals. Lower scores denote lower functioning. The ratings are based mainly on the assessment of patient's functioning in four main areas: 1) socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disturbing and aggressive behaviours. Change in score between enrolment and week 20 will be measured. |
| Clinical Global Impression-Improvement (CGI-I). | week 20 | Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Three different informants base their CGI-I evaluations on independent assessments: a) The treating clinician, b) The patient's self-assessment and c) A next of kin. Range 3-21. A lower score depicts larger improvement. |
| Adverse Event: Any Adverse Reactions (AAR). Safety and Tolerability of Rituximab | week 20 | Any Adverse reactions (AAR) is a rating scale developed for this study and is not a validated questionnaire. It consists of a list of 26 symptoms. AAR maps adverse events related to rituximab treatment. These items are assessed for severity on a Likert scale (4 levels: none; mild; moderate; severe) and frequency (3 levels: occasionally; daily; several times daily). AAR is assessed by the clinician. An adverse event scale was required as an outcome measure by the Swedish Medical Products Agency. |
| Clinical Global Impression-Improvement (CGI-I). Proportion of Responders. | week 20 | Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Three different informants base their CGI-I evaluations on independent assessments: a) The treating clinician, b) The patient's self-assessment and c) A next of kin. If the mean value of these three is below 2.5 then the patient will be regarded as a responder (representing much or very much improved since baseline). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Life Quality Measured With Brunnsviken Brief Quality of Life Scale (BBQ) | week 40 | BBQ is a 12-item self-rated measurement of life satisfaction. BBQ is a Likert scale, range 0-48. Higher scores denote higher life satisfaction. |
| Positive and Negative Syndrome Scale (PANSS) | week 40 | Change in symptoms measured as change in Positive and Negative Syndrome Scale (PANSS) score from baseline. PANSS measures symptom severity of patients with schizophrenia and is a clinically based interview. PANSS measures positive symptoms (7 items, range 7-49), which refer to e.g. hallucinations and delusions; negative symptoms (e.g. loss of normal functions) (7 items, range 1-7) and general disability (16 Items, range 16 -112) separately. Higher scores denote more symptoms and disability. PANSS total score range from 30-210. At least 40 % reduction in PANSS total score is regarded as response. |
| Clinical Global Impression-Improvement (CGI-I). Proportion of Responders. | week 40 | Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Three different informants base their CGI-I evaluations on independent assessments: a) The treating clinician, b) The patient's self-assessment and c) A next of kin. If the mean value of these three is below 2.5 then the patient will be regarded as a responder (representing much or very much improved since baseline). |
| Personal and Social Performance Scale (PSP) | week 40 | Personal and Social Performance Scale (PSP) gives a score for disability. The PSP is a 100-point single-item rating scale (range 1-100), subdivided into 10 equal intervals. Lower scores denote lower functioning. The ratings are based mainly on the assessment of patient's functioning in four main areas: 1) socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disturbing and aggressive behaviours. Change in score between enrolment and week 40 will be measured. |
| Clinical Global Impression-Severity (CGI-S) Scale | week 40 | Clinical Global Impression-Severity (CGI-S) scale is a clinician rated measure of overall clinical severity that is rated on a scale between 1 and 7. A person with no clinical complaints or problems will get a score of 1. The score 7 indicates the highest level of severity is phrased as Among the most extremely ill patients. |
| Clinical Global Impression-Improvement (CGI-I) in Relation to Inflammatory Markers | week 40 | Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Change in inflammatory markers in blood (gene expression and proteins) towards normality, in relationship to clinical response Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Change in inflammatory markers in blood (gene expression and proteins) towards normality, in relation to clinical response (assessed by the clinician) will be measured. |
| Changes in Cognitive Functioning | week 20 | The clinical assessment includes four sections of the Wechsler intelligence scales for adults (WAIS-IV); block design (range 1-19), letter number sequencing (range 1-19), digit symbol coding (range 1-19), and digit span (range 1-19). A full scale IQ of each participant will be estimated using the mean of the four scaled scores available and multiplying them by 11. A higher score denotes a cognitive improvement. |
| Clinical Global Impression-Improvement (CGI-I). | week 40 | Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Three different informants base their CGI-I evaluations on independent assessments: a) The treating clinician, b) The patient's self-assessment and c) A next of kin. If the mean value of these three is below 2.5 then the patient will be regarded as a responder (representing much or very much improved since baseline). Range 3-21. A lower score depicts larger improvement. |
| B-cell Subpopulations in Relation to Clinical Response | week 20 | B-cell depletion at week 5, and B-cell subpopulations at week 20 in relation to clinical response (CGI-I) (assessed by the clinician) and baseline levels of B-cells. |
Countries
Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab 1000 mg rituximab infusion once | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Rituximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 27.3 years STANDARD_DEVIATION 7 |
| Positive and Negative Syndrome Scale (PANSS) | 99 units on a scale STANDARD_DEVIATION 32 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment Sweden | 9 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 4 Participants |
| The Personal and Social Performance Scale (PSP) | 32.0 units on a scale STANDARD_DEVIATION 10.2 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 9 |
| other Total, other adverse events | 1 / 9 |
| serious Total, serious adverse events | 1 / 9 |
Outcome results
Primary
Positive and Negative Syndrome Scale (PANSS)
Change in symptoms measured as change in Positive and Negative Syndrome Scale (PANSS) score from baseline. PANSS measures symptom severity of patients with schizophrenia and is a clinically based interview. PANSS measures positive symptoms (7 items, range 7-49), which refer to e.g. hallucinations and delusions; negative symptoms (e.g. loss of normal functions) (7 items, range 1-7) and general disability (16 Items, range 16 -112) separately. Higher scores denote more symptoms and disability. PANSS total score range from 30-210. At least 40 % reduction in PANSS total score is regarded as response.
Time frame: week 20
Population: Eight patients reached week 20.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Positive and Negative Syndrome Scale (PANSS) | 72.9 score on a scale | Standard Deviation 36.2 |
Secondary
Adverse Event: Any Adverse Reactions (AAR). Safety and Tolerability of Rituximab
Any Adverse reactions (AAR) is a rating scale developed for this study and is not a validated questionnaire. It consists of a list of 26 symptoms. AAR maps adverse events related to rituximab treatment. These items are assessed for severity on a Likert scale (4 levels: none; mild; moderate; severe) and frequency (3 levels: occasionally; daily; several times daily). AAR is assessed by the clinician. An adverse event scale was required as an outcome measure by the Swedish Medical Products Agency.
Time frame: week 20
Secondary
Clinical Global Impression-Improvement (CGI-I).
Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Three different informants base their CGI-I evaluations on independent assessments: a) The treating clinician, b) The patient's self-assessment and c) A next of kin. Range 3-21. A lower score depicts larger improvement.
Time frame: week 20
Secondary
Clinical Global Impression-Improvement (CGI-I) in Relation to Inflammatory Markers
Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Change in inflammatory markers in blood (gene expression and proteins) towards normality, in relation to clinical response will be measured.
Time frame: week 20
Secondary
Clinical Global Impression-Improvement (CGI-I). Proportion of Responders.
Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Three different informants base their CGI-I evaluations on independent assessments: a) The treating clinician, b) The patient's self-assessment and c) A next of kin. If the mean value of these three is below 2.5 then the patient will be regarded as a responder (representing much or very much improved since baseline).
Time frame: week 20
Secondary
Clinical Global Impression-Severity (CGI-S) Scale
CGI-S is a clinician rated measure of overall clinical severity that is rated on a scale between 1 and 7. A person with no clinical complaints or problems will get a score of 1. The score 7 indicates the highest level of severity is phrased as Among the most extremely ill patients.
Time frame: week 20
Secondary
Personal and Social Performance Scale (PSP)
Personal and Social Performance Scale (PSP) gives a score for disability. The PSP is a 100-point single-item rating scale (range 1-100), subdivided into 10 equal intervals. Lower scores denote lower functioning. The ratings are based mainly on the assessment of patient's functioning in four main areas: 1) socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disturbing and aggressive behaviours. Change in score between enrolment and week 20 will be measured.
Time frame: week 20
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental | Personal and Social Performance Scale (PSP) | 53.1 score on a scale | Standard Deviation 22.2 |
Other Pre-specified
B-cell Subpopulations in Relation to Clinical Response
B-cell depletion at week 5, and B-cell subpopulations at week 20 in relation to clinical response (CGI-I) (assessed by the clinician) and baseline levels of B-cells.
Time frame: week 20
Other Pre-specified
Changes in Cognitive Functioning
The clinical assessment includes four sections of the Wechsler intelligence scales for adults (WAIS-IV); block design (range 1-19), letter number sequencing (range 1-19), digit symbol coding (range 1-19), and digit span (range 1-19). A full scale IQ of each participant will be estimated using the mean of the four scaled scores available and multiplying them by 11. A higher score denotes a cognitive improvement.
Time frame: week 20
Other Pre-specified
Clinical Global Impression-Improvement (CGI-I).
Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Three different informants base their CGI-I evaluations on independent assessments: a) The treating clinician, b) The patient's self-assessment and c) A next of kin. If the mean value of these three is below 2.5 then the patient will be regarded as a responder (representing much or very much improved since baseline). Range 3-21. A lower score depicts larger improvement.
Time frame: week 40
Other Pre-specified
Clinical Global Impression-Improvement (CGI-I) in Relation to Inflammatory Markers
Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Change in inflammatory markers in blood (gene expression and proteins) towards normality, in relationship to clinical response Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Change in inflammatory markers in blood (gene expression and proteins) towards normality, in relation to clinical response (assessed by the clinician) will be measured.
Time frame: week 40
Other Pre-specified
Clinical Global Impression-Improvement (CGI-I). Proportion of Responders.
Clinical Global Impression-Improvement scale (CGI-I) measures change of symptoms on a 7 point Likert scale. A CGI-I score of 1 or 2 corresponds to be much or very much improved. Three different informants base their CGI-I evaluations on independent assessments: a) The treating clinician, b) The patient's self-assessment and c) A next of kin. If the mean value of these three is below 2.5 then the patient will be regarded as a responder (representing much or very much improved since baseline).
Time frame: week 40
Other Pre-specified
Clinical Global Impression-Severity (CGI-S) Scale
Clinical Global Impression-Severity (CGI-S) scale is a clinician rated measure of overall clinical severity that is rated on a scale between 1 and 7. A person with no clinical complaints or problems will get a score of 1. The score 7 indicates the highest level of severity is phrased as Among the most extremely ill patients.
Time frame: week 40
Other Pre-specified
Life Quality Measured With Brunnsviken Brief Quality of Life Scale (BBQ)
BBQ is a 12-item self-rated measurement of life satisfaction. BBQ is a Likert scale, range 0-48. Higher scores denote higher life satisfaction.
Time frame: week 40
Other Pre-specified
Personal and Social Performance Scale (PSP)
Personal and Social Performance Scale (PSP) gives a score for disability. The PSP is a 100-point single-item rating scale (range 1-100), subdivided into 10 equal intervals. Lower scores denote lower functioning. The ratings are based mainly on the assessment of patient's functioning in four main areas: 1) socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disturbing and aggressive behaviours. Change in score between enrolment and week 40 will be measured.
Time frame: week 40
Other Pre-specified
Positive and Negative Syndrome Scale (PANSS)
Change in symptoms measured as change in Positive and Negative Syndrome Scale (PANSS) score from baseline. PANSS measures symptom severity of patients with schizophrenia and is a clinically based interview. PANSS measures positive symptoms (7 items, range 7-49), which refer to e.g. hallucinations and delusions; negative symptoms (e.g. loss of normal functions) (7 items, range 1-7) and general disability (16 Items, range 16 -112) separately. Higher scores denote more symptoms and disability. PANSS total score range from 30-210. At least 40 % reduction in PANSS total score is regarded as response.
Time frame: week 40