Aspirin in Young Psychotic Patients

Schizophrenia Clinical Trial

Official title:

Aspirin as Adjuvant Therapy in Young Psychotic Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02685748
• Other study ID #: #15T-006
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: July 20, 2017
• Est. completion date: December 31, 2019

Study information

• Verified date: January 2020
• Source: Clinic for Psychiatric Disorders, Dr Laza Lazarevic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: December 31, 2019
• Est. primary completion date: December 31, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 28 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Psychosis
• Mental Disorders
• Psychosis
• Psychotic Disorders
• Schizophrenia

Intervention

Drug:
• Aspirin
1000 mg pd in two doses
• Placebo
two pills twice a day (instead of aspirin and pantoprazole)
• Pantoprazole
Pantoprazole 40 mg/pd in two doses, for gastric protection

Locations

Country	Name	City	State
Serbia	Clinic for psychiatric disorders Dr Laza Lazarevic	Belgrade

Sponsors (2)

Lead Sponsor	Collaborator
Clinic for Psychiatric Disorders, Dr Laza Lazarevic	Stanley Medical Research Institute

Country where clinical trial is conducted

Serbia, 

References & Publications (15)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Heinrichs DW, Buchanan RW. Significance and meaning of neurological signs in schizophrenia. Am J Psychiatry. 1988 Jan;145(1):11-8. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009 Jun;63(3):257-65. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Changes of psychopathology	PANSS total, positive, negative and general psychopathology scores	Change after six weeks of treatment from baseline
Secondary	Change of Cognition	MoCA scale scores	Change after six weeks of treatment from baseline
Secondary	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
Secondary	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
Secondary	Change of Cytokine profile- Th1	Change of Th1 immune response	Change after six weeks of treatment from baseline
Secondary	Change of Cytokine profile- Th2	Change of Th2 immune response	Change after six weeks of treatment from baseline
Secondary	Change of Cytokine profile- type 17	Change of Type-17 immune response	Change after six weeks of treatment from baseline

External Links

•   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
•   Schröder J, Heuser M. Neurological Soft Signs in First -Episode Schizophrenia. Directions in Psychiatry 2008, Vol. 28 (19): 243-57.
•   Stoyanova M, Hranov L. Soft neurological signs in patients with bipolar disorder. European Psychiatry, 2014: 29 (1) 1