Aspirin in Young Psychotic Patients

Study Overview
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Brief Summary
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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
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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 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 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.

Official Title
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Aspirin as Adjuvant Therapy in Young Psychotic Patients

Conditions
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Psychosis, Acute Psychosis, Schizophrenia

Intervention / Treatment
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* Drug: Aspirin
* Drug: Placebo
* Drug: Pantoprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 28 years of life diagnostic categories from F 20 to F 29, according to ICD 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, 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 28 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aspirin & pantoprazole<br>Aspirin 1000 mg/pd per os in two doses Pantoprazole 40 mg/pd per os in two doses for gastric protection | Drug: Aspirin<br>* 1000 mg pd in two doses<br>* Other names: Acetylsalicylic acid;Drug: Pantoprazole<br>* Pantoprazole 40 mg/pd in two doses, for gastric protection<br>* Other names: Controloc;|
| Placebo Comparator: Placebo<br>Two pills in the morning and two in the evening All pills (aspirin, pantoprazole an placebo) will be the same looking- in the same capsules. | Drug: Placebo<br>* two pills twice a day (instead of aspirin and pantoprazole)<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of Soft Neurological Signs | NSS will be assessed by Heidelberg NSS Scale, 16 items scale (motor coordination, integrative functions, complex motor tasks, orientation, hard signs) | Change from baseline after six weeks of treatment | 
| Changes of psychopathology | PANSS total, positive, negative and general psychopathology scores | Change after six weeks of treatment from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Cognition | MoCA scale scores | Change after six weeks of treatment from baseline | 
| Change of marker of inflammation- CRP | Change of C-reactive protein (CRP) after 6 week of treatment | Change after six weeks of treatment from baseline | 
| Change of marker of inflammation- WBC | Change of White Blood Cells count after 6 week of treatment | Change after six weeks of treatment from baseline | 
| Change of Cytokine profile- Th1 | Change of Th1 immune response | Change after six weeks of treatment from baseline | 
| Change of Cytokine profile- Th2 | Change of Th2 immune response | Change after six weeks of treatment from baseline | 
| Change of Cytokine profile- type 17 | Change of Type-17 immune response | Change after six weeks of treatment from baseline |