Prednisolone Addition for Patients With Recent-onset Psychotic Disorder

Prednisolone Addition for Patients With Recent-onset Psychotic Disorder: the Role of Immune-modulating Strategies in the Treatment of Psychosis

Treatment with prednisolone can be used as a proof of concept to investigate the possibility of immune modulation as a treatment for schizophrenia. It is expected that daily treatment with prednisolone in addition to antipsychotic treatment reduces psychotic symptoms and improves cognition, as compared to placebo. The investigators propose to investigate the effects of administering the corticosteroid prednisolone versus placebo in addition to standard antipsychotic medication in patients with early stage schizophrenia or related disorders, hypothesizing that a decrease in the overall low-grade cerebral inflammation due to prednisolon treatment will be expressed as a decrease in overall symptom severity., Secondly, addition of prednisolone is hypothesised to slow down cognitive deterioration in recent-onset psychosis patients. Finally, the investigators aim to determine whether indirect immunological parameters of the hypothesised low grade inflammation status in schizophrenia are shifted due to the addition of prednisolone.

Study Overview

• Status: Terminated
• Conditions: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder; Psychotic Disorder NOS
• Intervention / Treatment: Drug: Prednisolone; Drug: Placebo Oral Tablet

Detailed Description

In the current study, the investigators aim to investigate the effect of additional treatment with prednisolone on symptomatic improvement, global functioning, cognition and on immunological parameters in patients with early-stage psychotic disorder, applying a randomized double-blind placebo-controlled add-on design. A placebo-controlled design was chosen in order to differentiate between clinical effects of prednisolone and effects associated with experimental treatment, such as induced expectations of participants. Prednisolone or placebo is provided next to existent antipsychotic medication as the investigators do not intend to replace existing treatment, this study being a Proof of Concept trial. It would carry considerable risks for patients to taper down existent antipsychotic medication and randomize patients to either placebo or a type of therapy for which the efficacy still has to be proven, even for a short period of time.

90 patients with schizophrenia, schizoaffective or schizophreniform disorder, or psychotic disorder NOS (not otherwise specified) will be included, with an age of 18-70 years and a time interval between the onset of psychosis and study entry not exceeding seven years. All 90 in- and outpatients will be randomized 1:1 to either prednisolone or placebo daily for 6 weeks. Prednisolone will be initiated at 40mg/day for 3 days and the 4 remaining days of the first week 30mg/dag will be used. During the treatment period, patients will be seen at weekly intervals to assess symptom severity, depressive mood and suicidal ideation, global functioning and side effects.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, 2060
    • ZNA
• Denmark
  • Risskov, Denmark, 8240
    • University Aarhus
• Netherlands
  • Sliedrecht, Netherlands, 3361XV
    • Yulius
  • Utrecht, Netherlands, 3508 GA
    • UMC Utrecht

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. A DSM-IV-R diagnosis of: 295.x (schizophrenia, schizophreniform disorder, or schizoaffective disorder) or 298.9 (psychosis NOS)
2. Onset of psychosis no longer than 7 years ago
3. Minimum total PANSS score of 60
4. Age 18 -70 years
5. Patients are treated with antipsychotic medication
6. Written informed consent is obtained
7. Female patients of childbearing potential need to utilize a proper method of contraception (the pill, vaginal ring, hormonal patch, intrauterine device, cervical cap, condom, contraceptive injection, diaphragm) in case of sexual intercourse during the study.

Exclusion Criteria:

1. Presence of any of the contra-indications of prednisolone as reported in the SPC.
2. Presence of diabetes mellitus or random (non-fasting) glucose levels exceeding 11 mmol/L at screening, severe heart failure, severe osteoporosis or systemic fungal infections.
3. Body Mass Index (BMI) of >30.0
4. Current or chronic use of systemic glucocorticosteroids (temporary use is permitted, if stopped 1 month before start of treatment trial)
5. Chronic use of non-steroidal anti-inflammatory drugs, defined as daily use during more than 2 months. Intermittent use is permitted, if stopped at least 1 month before start of treatment trial.
6. Pregnancy or breast-feeding. A urine pregnancy test will be performed at screening.
7. Concurrent use of certain types of medication:

1. liver enzyme inducing medication such as carbamazepine, riphampicine, primidone, barbiturates and phenytoine

2. HAART medication (both HIV protease inhibitors and (non)-nucleoside reverse transcriptase inhibitors), especially efavirenz, ritonavir and lopinavir.

3. telaprevir and boceprevir in treatment of Hepatitis C

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prednisolone; Prednisolone will be initiated at 40 mg for three days, after which it will be phased out within 6 weeks after start, following treatment guidelines for Inflammatory Bowel Diseases (2008).	Drug: Prednisolone; prednisolone will be will be initiated during the first week at 40mg/day for 3 days and 30mg/day for 4 days, followed by a decrease of 5mg/day per week during the remaining 5 weeks; in the second week, patients will use 25 mg/day, in the third week 20 mg/day is used etc. In the last week the patients will only take prednisolone on day 1-3 and day 5 and 7; a tapering scheme in line with the treatment guidelines for Inflammatory Bowel Diseases (2008).
Placebo Comparator: Placebo Oral Tablet; Placebo will be initiated at 40 mg for three days, after which it will be phased out within 6 weeks after start, following the treatment schedule of the experimental arm	Drug: Placebo Oral Tablet; Dosing following the tapering scheme of the treatment of the treatment arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in symptom severity	Change in symptom severity is expressed as a change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of the 6-week treatment.	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in cognitive functioning	Cognitive functioning is measured through the Brief Assessment of Cognition in Schizophrenia (BACS).	6 months
Change in GAF scores	Global Assessment of Functioning	1 year
Measurement of various immunological biomarkers	Cytokine panels will be analysed	6 months
Improvement of PANSS scores in follow-up	PANSS follow-up; 4 months, 6 months and 12 months	1 year
Score on the Calgary Depression Scale for Schizophrenia (CDSS)	CDSS scores will be analysed	6 weeks
Incidences of key SAEs and SUSARs	Safety analyses	1 year

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Investigators: Principal Investigator: Iris Sommer, Prof. Dr., UMC Utrecht

Publications and helpful links

General Publications

• Nasib LG, Gangadin SS, Rossum IW, Boudewijns ZSRM, de Witte LD, Wilting I, Luykx J, Somers M, Veen N, van Baal C, Kahn RS, Sommer IE. The effect of prednisolone on symptom severity in schizophrenia: A placebo-controlled, randomized controlled trial. Schizophr Res. 2021 Apr;230:79-86. doi: 10.1016/j.schres.2021.01.024. Epub 2021 Mar 10.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): May 1, 2019
• Study Completion (Actual): May 1, 2019

Study Registration Dates

• First Submitted: October 27, 2016
• First Submitted That Met QC Criteria: October 27, 2016
• First Posted (Estimate): October 31, 2016

Study Record Updates

• Last Update Posted (Actual): June 24, 2019
• Last Update Submitted That Met QC Criteria: June 21, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Disease; Psychotic Disorders; Mental Disorders; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Prednisolone
• Other Study ID Numbers: NL46653

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No