Aspirin in Young Psychotic Patients
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 2/Phase 3 |
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 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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Aspirin & pantoprazole Aspirin 1000 mg/pd per os in two doses Pantoprazole 40 mg/pd per os in two doses for gastric protection |
Drug: Aspirin
1000 mg pd in two doses
Other Names:
Drug: Pantoprazole
Pantoprazole 40 mg/pd in two doses, for gastric protection
Other Names:
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Placebo Comparator: Placebo 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
two pills twice a day (instead of aspirin and pantoprazole)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Changes of Soft Neurological Signs [Change from baseline after six weeks of treatment]
NSS will be assessed by Heidelberg NSS Scale, 16 items scale (motor coordination, integrative functions, complex motor tasks, orientation, hard signs)
- Changes of psychopathology [Change after six weeks of treatment from baseline]
PANSS total, positive, negative and general psychopathology scores
Secondary Outcome Measures
- Change of Cognition [Change after six weeks of treatment from baseline]
MoCA scale scores
- Change of marker of inflammation- CRP [Change after six weeks of treatment from baseline]
Change of C-reactive protein (CRP) after 6 week of treatment
- Change of marker of inflammation- WBC [Change after six weeks of treatment from baseline]
Change of White Blood Cells count after 6 week of treatment
- Change of Cytokine profile- Th1 [Change after six weeks of treatment from baseline]
Change of Th1 immune response
- Change of Cytokine profile- Th2 [Change after six weeks of treatment from baseline]
Change of Th2 immune response
- Change of Cytokine profile- type 17 [Change after six weeks of treatment from baseline]
Change of Type-17 immune response
Eligibility Criteria
Criteria
Inclusion Criteria:
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18 to 28 years of life
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diagnostic categories from F 20 to F 29, according to ICD 10 criteria
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duration of illness ≤ 7 years
Exclusion Criteria:
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Substance abuse
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Primary cognitive impairment
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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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Clinic for psychiatric disorders Dr Laza Lazarevic | Belgrade | Serbia | 11000 |
Sponsors and Collaborators
- Clinic for Psychiatric Disorders, Dr Laza Lazarevic
- Stanley Medical Research Institute
Investigators
- Principal Investigator: Dragana Pavićević, psychiatrist, Clinic for psychiatric disorder Dr Laza Lazarević
Study Documents (Full-Text)
More Information
Additional Information:
- Stoyanova M, Hranov L. Soft neurological signs in patients with bipolar disorder. European Psychiatry, 2014: 29 (1) 1
- Schröder J, Heuser M. Neurological Soft Signs in First -Episode Schizophrenia. Directions in Psychiatry 2008, Vol. 28 (19): 243-57.
- Howard, J. (2013) The cytokine hypothesis: A neurodevelopmental explanation for the emergence of schizophrenia later in life. Advances in Bioscience and Biotechnology, 4, 81-88
Publications
- Avgustin B, Wraber B, Tavcar R. Increased Th1 and Th2 immune reactivity with relative Th2 dominance in patients with acute exacerbation of schizophrenia. Croat Med J. 2005 Apr;46(2):268-74.
- Bachmann S, Bottmer C, Schröder J. Neurological soft signs in first-episode schizophrenia: a follow-up study. Am J Psychiatry. 2005 Dec;162(12):2337-43.
- Bombin I, Arango C, Buchanan RW. Significance and meaning of neurological signs in schizophrenia: two decades later. Schizophr Bull. 2005 Oct;31(4):962-77. Epub 2005 Jun 15. Review.
- Borovcanin M, Jovanovic I, Radosavljevic G, Djukic Dejanovic S, Bankovic D, Arsenijevic N, Lukic ML. Elevated serum level of type-2 cytokine and low IL-17 in first episode psychosis and schizophrenia in relapse. J Psychiatr Res. 2012 Nov;46(11):1421-6. doi: 10.1016/j.jpsychires.2012.08.016. Epub 2012 Sep 10.
- Borovcanin M, Jovanovic I, Radosavljevic G, Djukic Dejanovic S, Stefanovic V, Arsenijevic N, Lukic ML. Antipsychotics can modulate the cytokine profile in schizophrenia: attenuation of the type-2 inflammatory response. Schizophr Res. 2013 Jun;147(1):103-109. doi: 10.1016/j.schres.2013.03.027. Epub 2013 Apr 16.
- Feigenson KA, Kusnecov AW, Silverstein SM. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci Biobehav Rev. 2014 Jan;38:72-93. doi: 10.1016/j.neubiorev.2013.11.006. Epub 2013 Nov 15. Review.
- Heinrichs DW, Buchanan RW. Significance and meaning of neurological signs in schizophrenia. Am J Psychiatry. 1988 Jan;145(1):11-8. Review.
- Hirjak D, Wolf RC, Koch SC, Mehl L, Kelbel JK, Kubera KM, Traeger T, Fuchs T, Thomann PA. Neurological abnormalities in recent-onset schizophrenia and asperger-syndrome. Front Psychiatry. 2014 Aug 6;5:91. doi: 10.3389/fpsyt.2014.00091. eCollection 2014.
- Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010 May;71(5):520-7. doi: 10.4088/JCP.09m05117yel.
- Maynard TM, Sikich L, Lieberman JA, LaMantia AS. Neural development, cell-cell signaling, and the "two-hit" hypothesis of schizophrenia. Schizophr Bull. 2001;27(3):457-76. Review.
- Mayoral M, Bombín I, Castro-Fornieles J, González-Pinto A, Otero S, Parellada M, Moreno D, Baeza I, Graell M, Rapado M, Arango C. Longitudinal study of neurological soft signs in first-episode early-onset psychosis. J Child Psychol Psychiatry. 2012 Mar;53(3):323-31. doi: 10.1111/j.1469-7610.2011.02475.x. Epub 2011 Oct 25.
- Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009 Jun;63(3):257-65. Review.
- Mousa A, Bakhiet M. Role of cytokine signaling during nervous system development. Int J Mol Sci. 2013 Jul 4;14(7):13931-57. doi: 10.3390/ijms140713931. Review.
- Schröder J, Niethammer R, Geider FJ, Reitz C, Binkert M, Jauss M, Sauer H. Neurological soft signs in schizophrenia. Schizophr Res. 1991 Dec;6(1):25-30.
- Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014 Jan;40(1):181-91. doi: 10.1093/schbul/sbt139. Epub 2013 Oct 8.
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