Clinical trial NCT02685748: Aspirin in Young Psychotic Patients
Official title: Aspirin as Adjuvant Therapy in Young Psychotic Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Psychosis
Acute Psychosis
Schizophrenia
Lead sponsor: Clinic for Psychiatric Disorders, Dr Laza Lazarevic
Sponsor class: OTHER
Collaborators: name: Stanley Medical Research Institute
First posted: 2016-02-19
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 28
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this double blind randomized clinical trial the investigators are going to exam influence of adjuvant Aspirin therapy on soft neurological signs (Heidelberg scale), positive and negative symptoms (PANSS), cytokine profile and inflammatory factors, as well as on cognition (MoCA) in young psychotic patients.

Detailed description: Schizophrenia as psychiatric paradigm is one of the most mysterious mental illness, for decades remains a challenge to many clinicians and researchers with its complex, fundamental mechanisms.

Soft neurological signs (SNS) are described as non-localized neurological abnormalities that cannot be associated with damage of a specific brain region. It is believed that they are not part of a well-defined neurological syndrome. They include neurological abnormalities with deficits in sensory integration, motor coordination and sequencing of complex motor acts. They have a higher prevalence in schizophrenic patients compared to healthy population. Moreover, SNS have been consistently demonstrated in neuroleptic naive patients in the first episode of illness. There is also an increased prevalence in non- schizophrenic relatives of patients with schizophrenia. It is considered that they are not potentiated by antipsychotics. For all these reasons it is believed that they are the inherent quality of schizophrenia - "trait" marker, or endophenotypes.

According to the so-called "Two hit" hypothesis in the development of schizophrenia, there are two periods of increased vulnerability. The first one is in a fetal age when it comes to the interaction of genetic and environmental factors such as infection and inflammatory processes who may also serve this function. The second period of vulnerability is a period of adolescence, or early adult age when the influence of environmental factors leads to clinical manifestations of the disease. It is thought that cytokines have key role in the first strike.

Cytokines are mediators of communication between the neural elements in all aspects of the development of the nervous system. Until now, numerous studies indicated modification of specific cytokines in psychotic disorders and their possible role in the proposed concept of "microglial hypothesis" of schizophrenia. Hypothesis of activation Th1 and Th2 immune response, with a predominance of Th2 immune response is proposed in schizophrenia. Type-17 cytokines are important in mediating tissue damage in autoimmune diseases. Regulatory cytokines suppress immune responses and maintain self-tolerance.

Consequently, the question is whether the combination of antipsychotic drugs with anti-inflammatory drugs is more useful than independent antipsychotic therapy? Laan and colleagues in 2010. carried out a randomized, double- blind, placebo - controlled study to determine if the adjuvant aspirin therapy could be useful for patients who are already taking antipsychotics. They concluded that the therapy antipsychotic + aspirin was significantly superior to placebo + antipsychotic therapy. PANSS score was significantly lower in the aspirin group.

The aim of the study would be to determine the effects of adjuvant aspirin therapy on Soft Neurological Signs, PANSS and the cytokine profile. The investigators expect the reduction of PANSS scores in both groups of patients (aspirin group and placebo group). If there is no significant changes of SNS between groups, the results would support SNS as trait characteristics of schizophrenia.

The research would be done on hospitalized patients at the Clinic for Psychiatric Disorders "Dr Laza Lazarevic" in Belgrade. Part of the study (immunology) will be done on Medical Faculty University of Kragujevac.

The study would be a randomized, double-blind, placebo controlled in two parallel groups of 50 to 60 patients who are neuroleptic naive or previously minimally medicated (in the past 6 months without any antipsychotic treatment) with the duration of the illness up to seven years. The study would involve the patients of both sexes, aged 18 to 28 years, according to ICD 10 (10th revision of the International Statistical Classification of Diseases and Related Health Problems) criteria to satisfy diagnosis F 20 to F 29. Each patient who enters the hospital and meets the inclusion criteria would be taken into consideration. If patient satisfies exclusion criteria and sign consent, then s/he would be randomized into two groups: Experimental group (antipsychotic + aspirin) and Control group (antipsychotic + placebo). Patients in experimental group (EG) would receive 1,000 mg of aspirin pro die and pantoprazole 40 mg pro die in two doses for gastric protection.

Only one researcher would know in which group patient belongs (would be responsible only for randomization, would not be rater or treating psychiatrist). The same researcher would give boxes with medications marked with the patient's name. In fact, all medications (aspirin, pantoprazole, and placebo) would be packaged in the same looking capsules.

The protocol would consist of three planned visits for patients in both groups. On the first visit blood samples would be taken for the implementation of immunological tests as well as for laboratory inflammatory factors; patients would be subjected to clinical psychiatric and physical examination, BMI measurement; PANSS scale will be done. After calming the signs of acute psychosis, on 3rd day, patients would be examined with Heidelberg and MoCA scale; patients would start to take Aspirin or Placebo. At the end of 6th week from the second visit (+/- 3 days), on the third visit, blood samples would be taken again for analyzing cytokine profile and inflammatory factors. PANSS, Heidelberg and MoCA scales would be performed again.

The investigators would consider the following factors: patient sex, age of the patients, clinical characteristics, the role of heredity, type of therapy/ prescribed typical or atypical antipsychotic; side effects of treatment and type of treatment response. Serum concentrations of cytokines will be examined with commercial ELISA tests.

Eligibility criteria: Inclusion Criteria:

* 18 to 28 years of life
* diagnostic categories from F 20 to F 29, according to ICD 10 (International Classification of Diseases Version 10) criteria
* duration of illness ≤ 7 years

Exclusion Criteria:

* Substance abuse
* Primary cognitive impairment
* Contraindications and special caution for acetylsalicylic acid and pantoprazole: hypersensitivity to aspirin and other NSAIDs or pantoprazole, ulcers, gastritis, pregnancy, haemophilia, bleeding disorders, gout, asthma, COPD (Chronic obstructive pulmonary disease), bronchospasm induced by NSAIDs, angioedema, urticaria, haemolytic anaemia, use of warfarin or methotrexate, diabetes, reduced function of liver and/or kidney, heart failure, surgical/dental intervention, interactions with certain psychotropic drugs

Primary outcomes:
measure: Neurological Soft Signs
timeFrame: Comparison of total scores on Heidelberg scale between groups (aspirin and placebo group) after 6 weeks of treatment.
measure: Psychopathology Symptoms Assessed by PANSS
timeFrame: Comparison of total scores on PANSS (aspirin and placebo group) after 6 weeks of treatment.
Secondary outcomes:
measure: Cognitive Assessment by MoCA Scale
timeFrame: Comparison of total scores on MoCA scale (aspirin and placebo group) after 6 weeks of treatment.
measure: Marker of Inflammation: C-reactive Protein (CRP)
timeFrame: Comparison of CRP levels between groups (aspirin and placebo group) after six weeks of treatment.
measure: Marker of Inflammation- White Blood Cells (WBC)
timeFrame: Comparison of WBC levels (aspirin and placebo group) after 6 weeks of treatment.
measure: Cytokine Profile- Th1- Interferon Gamma (IFN-γ)
timeFrame: Comparison of IFN Gamma levels (aspirin and placebo group) after 6 weeks of treatment
measure: Cytokine Profile- Th2-Interleukin 4 (IL4)
timeFrame: Comparison of IL 4 levels (aspirin and placebo group) after 6 weeks of treatment
measure: Cytokine Profile- Type 17- Interleukin 17 (IL17)
timeFrame: Comparison of IL 17 levels (aspirin and placebo group) after 6 weeks of treatment
Other outcomes:
Locations:
city: Belgrade
country: Serbia
facility: Clinic for psychiatric disorders Dr Laza Lazarevic
Study officials:
affiliation: Clinic for psychiatric disorder Dr Laza Lazarević
name: Dragana Pavićević, psychiatrist
role: PRINCIPAL_INVESTIGATOR
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