Atypical Antipsychotic-induced Mitochondrial Dysfunction in Patients With Schizophrenia

Schizophrenia Clinical Trial

Official title:

A Randomized Controlled Trial to Evaluate Atypical Antipsychotic-induced Mitochondrial Dysfunction in Patients With Schizophrenia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06236451
• Other study ID #: PGThesis/2023-24/100
• Status: Recruiting
• Phase: Phase 4
• Start date: April 5, 2024
• Est. completion date: September 30, 2025

Study information

• Verified date: April 2024
• Source: All India Institute of Medical Sciences, Bhubaneswar
• Contact: Rituparna Maiti, MD
• Phone: 9438884191
• Email: pharm_rituparna[@]aiimsbhubaneswar.edu.in
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Schizophrenia is a serious mental disorder with a global prevalence of 1%. The main cause of this condition is dysfunction in the signaling of neurotransmitters dopamine, serotonin, glutamate and Gamma-aminobutyric acid .According to recent research, a disturbed cellular energy state caused by mitochondrial dysfunction is thought to be a factor in the development of schizophrenia. The aim of the treatment of schizophrenia is to reduce symptoms and is mainly based on the monoamine hypothesis. Atypical antipsychotics are the first-line of treatment. Certain typical and atypical antipsychotic medications have been shown in prior preclinical research to decrease mitochondrial respiratory chain complex I activity. In contrast to individuals who were drug-naive, Casademont et al. found a significant decrease in complex I activity with haloperidol and risperidone in one cross-sectional observational study. Also, there is evidence suggesting that mitochondrial dysfunction is linked to the extrapyramidal side effects seen with antipsychotics. To date, there are no randomized controlled trials that assess the effect of these drugs on mitochondrial functions. Hence, the present randomized controlled trial has been planned to evaluate and compare the clinical and biochemical markers of mitochondrial dysfunction in schizophrenia patients treated with the atypical antipsychotics risperidone and aripiprazole.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: September 30, 2025
• Est. primary completion date: August 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Patients meeting the DSM-5 criteria for diagnosis of schizophrenia.
• Treatment naiv¨ e patients or patients who had not taken any antipsychotic drugs for at least 4 weeks before recruitment.
• Patients of either sex between the ages of 18 and 60 years.
• Legally authorized representative (LAR) of patients consenting to participate in the study by signing the informed consent form.

Exclusion Criteria:

• Patients diagnosed with other psychiatric disorders including schizoaffective disorder or schizophrenia with somatoform disorders.
• Highly agitated patients who need immediate indoor-based treatment.
• Patients with known mitochondrial disorders (MELAS, LHON, Leigh syndrome, KearnsSayre syndrome, MERRF etc.)
• Patients with history of comorbidities like cardiovascular, renal, hepatic, neurological, respiratory or endocrinal diseases or malignancies.
• Patients with history of substance abuse.
• Pregnant or lactating mothers.

Related Conditions & MeSH terms

• Mitochondrial Diseases
• Schizophrenia

Intervention

Drug:
• Aripiprazole
Aripiprazole will be started at dose of 10 mg/day and increased to a stable dose of 20 mg/day over 2-3 weeks and will be continued till 12 weeks.
• Risperidone
Risperidone will be started at dose of 2 mg/day and increased to a stable dose of 6 mg/day over 2-3 weeks and continued till 12 weeks.

Locations

Country	Name	City	State
India	All India Institute of Medical Sciences (AIIMS)	Bhubaneswar	Odisha

Sponsors (1)

Lead Sponsor	Collaborator
All India Institute of Medical Sciences, Bhubaneswar

Country where clinical trial is conducted

India, 

References & Publications (10)

Casademont J, Garrabou G, Miro O, Lopez S, Pons A, Bernardo M, Cardellach F. Neuroleptic treatment effect on mitochondrial electron transport chain: peripheral blood mononuclear cells analysis in psychotic patients. J Clin Psychopharmacol. 2007 Jun;27(3): — View Citation

Fizikova I, Dragasek J, Racay P. Mitochondrial Dysfunction, Altered Mitochondrial Oxygen, and Energy Metabolism Associated with the Pathogenesis of Schizophrenia. Int J Mol Sci. 2023 Apr 28;24(9):7991. doi: 10.3390/ijms24097991. — View Citation

Hardy RE, Chung I, Yu Y, Loh SHY, Morone N, Soleilhavoup C, Travaglio M, Serreli R, Panman L, Cain K, Hirst J, Martins LM, MacFarlane M, Pryde KR. The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain c — View Citation

Leucht S, Davis JM, Engel RR, Kane JM, Wagenpfeil S. Defining 'response' in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacology. 2007 Sep;32(9):1903-10. doi: 10.1038/sj.npp.1301325. Epub 2007 Feb 7. — View Citation

Luptak M, Fisar Z, Hroudova J. Effect of Novel Antipsychotics on Energy Metabolism - In Vitro Study in Pig Brain Mitochondria. Mol Neurobiol. 2021 Nov;58(11):5548-5563. doi: 10.1007/s12035-021-02498-4. Epub 2021 Aug 8. — View Citation

Modica-Napolitano JS, Lagace CJ, Brennan WA, Aprille JR. Differential effects of typical and atypical neuroleptics on mitochondrial function in vitro. Arch Pharm Res. 2003 Nov;26(11):951-9. doi: 10.1007/BF02980205. — View Citation

Rajasekaran A, Venkatasubramanian G, Berk M, Debnath M. Mitochondrial dysfunction in schizophrenia: pathways, mechanisms and implications. Neurosci Biobehav Rev. 2015 Jan;48:10-21. doi: 10.1016/j.neubiorev.2014.11.005. Epub 2014 Nov 15. — View Citation

Scaini G, Rochi N, Morais MO, Maggi DD, De-Nes BT, Quevedo J, Streck EL. In vitro effect of antipsychotics on brain energy metabolism parameters in the brain of rats. Acta Neuropsychiatr. 2013 Feb;25(1):18-26. doi: 10.1111/j.1601-5215.2012.00650.x. — View Citation

Schaefer AM, Phoenix C, Elson JL, McFarland R, Chinnery PF, Turnbull DM. Mitochondrial disease in adults: a scale to monitor progression and treatment. Neurology. 2006 Jun 27;66(12):1932-4. doi: 10.1212/01.wnl.0000219759.72195.41. — View Citation

Venegas V, Halberg MC. Measurement of mitochondrial DNA copy number. Methods Mol Biol. 2012;837:327-35. doi: 10.1007/978-1-61779-504-6_22. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Mitochondrial respiratory chain complex I activity	Mitochondrial respiratory chain complex I activity will be measured in platelets using a commercially available ELISA (enzyme-linked immunosorbent assay) kit at baseline and at 12 weeks of follow-up.	12 weeks
Secondary	Change in Serum lactate	Serum lactate will be measured using spectrophotometry at baseline and at 12 weeks follow up	12 weeks
Secondary	Change in Serum creatine kinase	Serum creatine kinase will be measured using autoanalyzer at baseline and at 12 weeks	12 weeks
Secondary	Change in Newcastle Mitochondrial Disease Adult Scale (NMDAS) scores	Newcastle Mitochondrial Disease Adult Scale (NMDAS) scoring of all patients will be assessed at baseline and at 12 weeks of follow-up. The NMDAS offers a range of 0 to 5 points for each question. The results from each of the first three sections' questions are added together to determine each section's score. The more severe the ailment, the higher the score.	12 weeks
Secondary	Change in Positive and Negative Syndrome Scale (PANSS) scores	Positive and Negative Syndrome Scale (PANSS) scoring will be done at baseline and at 12 weeks follow-up. Out of the 30 items included in the PANSS, 7 constitute a Positive Scale, 7 a Negative Scale, and the remaining 16 a General Psychopathology Scale. The scores for these scales are arrived at by summation of ratings across component items. Therefore, the potential ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale. The more severe the ailment, the higher the score.	12 weeks
Secondary	Responder rate	A patient with a reduction of Positive and Negative Syndrome Scale (PANSS) scores by =50% from baseline will be considered a 'responder'..	12 weeks
Secondary	Change in Serum pyruvate	Serum pyruvate will be measured using spectrophotometry at baseline and at 12 weeks follow up.	12 weeks