Efficacy of Spironolactone as an Adjunctive Therapy to Risperidone to Improve Symptoms of Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled, Clinical Trial
Abstract
Objective: Spironolactone (C24H32O4S), a potent mineralocorticoid receptor (MR) inhibitor, is a potassium-sparing diuretic that is traditionally used to treat fluid build-up in the body or for its anti-androgenic properties. This study is a double-blind, placebo-controlled, randomized clinical trial assessing the beneficial effects of spironolactone in addition to risperidone in improving negative symptoms of schizophrenia.
Method: 40 patients with chronic schizophrenia, aged 18–60 years, were assigned to two groups: risperidone + spironolactone or risperidone + placebo. Risperidone was administered to both the spironolactone and placebo groups with a dose up to 6 mg/day throughout the trial. Spironolactone (C24H32O4S) was ordered 100 mg/day for the full 8-week course of the study. Patients were rated on the Positive and Negative Syndrome Scale (PANSS) at four time points: baseline, weeks two, four, and eight. The PANSS negative subscale score was the main objective.
Results: PANSS negative, positive, and total scores showed significantly greater improvements in the spironolactone relative to the placebo group from baseline to the trial endpoint (P (Cohen’s d): 0.004 (0.96), 0.007 (0.90), and 0.042 (0.66), respectively). Similarly, ANOVA also presented significant time × treatment interaction effect for spironolactone on PANSS negative (F = 9.04; ηp2 = 0.19; df = 1.38; P = 0.002), positive (F = 3.43; ηp2 = 0.08; df = 2.72; P = 0.023), and total (F = 3.94; ηp2 = 0.09; df = 2.05; P = 0.022) scores. However, spironolactone did not cause significant decrease in the general psychiatric pathology score of PANSS.
Conclusion: Our findings suggest the efficacy and safety of spironolactone as an adjunctive therapy to risperidone in improving the symptoms of schizophrenia.
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13. Carlson RV, Boyd KM, Webb DJ. The revision of the Declaration of Helsinki: past, present and future. Br J Clin Pharmacol. 2004;57(6):695-713.
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17. Ghamari-Givi H, Molavi P, Heshmati R. Exploration of the Factor Structure of Positive and Negative Syndrome Scale in Schizophrenia Spectrum Disorders (In Persian). J Clin Psychol. 2010;2(2):1-10.
18. Khalaj M, Saghazadeh A, Shirazi E, Shalbafan MR, Alavi K, Shooshtari MH, et al. Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial. J Psychiatr Res. 2018;103:104-11.
19. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res. 2005;76(2-3):247-65.
20. Becker BJ. Synthesizing standardized mean-change measures. Math Statistic Psycho.1988;41(2):257-78.
21. Jasbi M, Sadeghi Bahmani D, Karami G, Omidbeygi M, Peyravi M, Panahi A, et al. Influence of adjuvant mindfulness-based cognitive therapy (MBCT) on symptoms of post-traumatic stress disorder (PTSD) in veterans - results from a randomized control study. Cogn Behav Ther. 2018;47(5):431-46.
22. Rattehalli RD, Zhao S, Li BG, Jayaram MB, Xia J, Sampson S. Risperidone versus placebo for schizophrenia. Cochrane Database Syst Rev. 2016;12(12):Cd006918.
23. Harrison PJ, Law AJ. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006;60(2):132-40.
24. Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease. Proc Natl Acad Sci U S A. 2006;103(17):6747-52.
25. Weickert CS, Tiwari Y, Schofield PR, Mowry BJ, Fullerton JM. Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity. Transl Psychiatry. 2012;2(4):e104.
26. Agarwal A, Zhang M, Trembak-Duff I, Unterbarnscheidt T, Radyushkin K, Dibaj P, et al. Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity. Cell Rep. 2014;8(4):1130-45.
27. Deakin IH, Law AJ, Oliver PL, Schwab MH, Nave KA, Harrison PJ, et al. Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. Neuroreport. 2009;20(17):1523-8.
28. Deakin IH, Nissen W, Law AJ, Lane T, Kanso R, Schwab MH, et al. Transgenic overexpression of the type I isoform of neuregulin 1 affects working memory and hippocampal oscillations but not long-term potentiation. Cereb Cortex. 2012;22(7):1520-9.
29. Kato T, Kasai A, Mizuno M, Fengyi L, Shintani N, Maeda S, et al. Phenotypic characterization of transgenic mice overexpressing neuregulin-1. PLoS One. 2010;5(12):e14185.
30. Yin DM, Chen YJ, Lu YS, Bean JC, Sathyamurthy A, Shen C, et al. Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1. Neuron. 2013;78(4):644-57.
31. Marín O, Rico B. A new beginning for a broken mind: balancing neuregulin 1 reverses synaptic dysfunction. Neuron. 2013;78(4):577-9.
32. Walker EF, Trotman HD, Pearce BD, Addington J, Cadenhead KS, Cornblatt BA, et al. Cortisol levels and risk for psychosis: initial findings from the North American prodrome longitudinal study. Biol Psychiatry. 2013;74(6):410-7.
33. Walker E, Mittal V, Tessner K. Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annu Rev Clin Psychol. 2008;4:189-216.
34. Guest PC, Schwarz E, Krishnamurthy D, Harris LW, Leweke FM, Rothermundt M, et al. Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia. Psychoneuroendocrinology. 2011;36(7):1092-6.
35. Mondelli V, Dazzan P, Hepgul N, Di Forti M, Aas M, D'Albenzio A, et al. Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: the role of stress and of antipsychotic treatment. Schizophr Res. 2010;116(2-3):234-42.
36. Steen NE, Tesli M, Kähler AK, Methlie P, Hope S, Barrett EA, et al. SRD5A2 is associated with increased cortisol metabolism in schizophrenia spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(8):1500-6.
37. Belvederi Murri M, Pariante CM, Dazzan P, Hepgul N, Papadopoulos AS, Zunszain P, et al. Hypothalamic-pituitary-adrenal axis and clinical symptoms in first-episode psychosis. Psychoneuroendocrinology. 2012;37(5):629-44.
2. Bowie CR, Harvey PD. Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr Dis Treat. 2006;2(4):531-6.
3. Correll CU, Schooler NR. Negative Symptoms in Schizophrenia: A Review and Clinical Guide for Recognition, Assessment, and Treatment. Neuropsychiatr Dis Treat. 2020;16:519-34.
4. Bowie CR, Harvey PD. Cognition in schizophrenia: impairments, determinants, and functional importance. Psychiatr Clin North Am. 2005;28(3):613-33, 26.
5. Chue P, Lalonde JK. Addressing the unmet needs of patients with persistent negative symptoms of schizophrenia: emerging pharmacological treatment options. Neuropsychiatr Dis Treat. 2014;10:777-89.
6. Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry. 2006;63(10):1079-87.
7. Jann MW. Implications for atypical antipsychotics in the treatment of schizophrenia: neurocognition effects and a neuroprotective hypothesis. Pharmacotherapy. 2004;24(12):1759-83.
8. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2(3):258-70.
9. Chan HY, Chang CJ, Chiang SC, Chen JJ, Chen CH, Sun HJ, et al. A randomised controlled study of risperidone and olanzapine for schizophrenic patients with neuroleptic-induced acute dystonia or parkinsonism. J Psychopharmacol. 2010;24(1):91-8.
10. Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol Psychiatry. 2013;74(6):400-9.
11. Bradley AJ, Dinan TG. A systematic review of hypothalamic-pituitary-adrenal axis function in schizophrenia: implications for mortality. J Psychopharmacol. 2010;24(4 Suppl):91-118.
12. Wehr MC, Hinrichs W, Brzózka MM, Unterbarnscheidt T, Herholt A, Wintgens JP, et al. Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice. EMBO Mol Med. 2017;9(10):1448-62.
13. Carlson RV, Boyd KM, Webb DJ. The revision of the Declaration of Helsinki: past, present and future. Br J Clin Pharmacol. 2004;57(6):695-713.
14. Association AP. Diagnostic and Statistical Manual of Mental Disorders 5th edition: DSM 5. Arlington VA: American Psychiatric Association2013.
15. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76.
16. ABOLGHASEMI A. THE RELATIONSHIP OF META-COGNITIVE BELIEFS WITH POSITIVE AND NEGATIVE SYMPTOMS IN THE SCHIZOPHRENIA PATIENTS (In Persian).J Clin Psychol Pers. 2007;5(2),1-10.
17. Ghamari-Givi H, Molavi P, Heshmati R. Exploration of the Factor Structure of Positive and Negative Syndrome Scale in Schizophrenia Spectrum Disorders (In Persian). J Clin Psychol. 2010;2(2):1-10.
18. Khalaj M, Saghazadeh A, Shirazi E, Shalbafan MR, Alavi K, Shooshtari MH, et al. Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial. J Psychiatr Res. 2018;103:104-11.
19. Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res. 2005;76(2-3):247-65.
20. Becker BJ. Synthesizing standardized mean-change measures. Math Statistic Psycho.1988;41(2):257-78.
21. Jasbi M, Sadeghi Bahmani D, Karami G, Omidbeygi M, Peyravi M, Panahi A, et al. Influence of adjuvant mindfulness-based cognitive therapy (MBCT) on symptoms of post-traumatic stress disorder (PTSD) in veterans - results from a randomized control study. Cogn Behav Ther. 2018;47(5):431-46.
22. Rattehalli RD, Zhao S, Li BG, Jayaram MB, Xia J, Sampson S. Risperidone versus placebo for schizophrenia. Cochrane Database Syst Rev. 2016;12(12):Cd006918.
23. Harrison PJ, Law AJ. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006;60(2):132-40.
24. Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, et al. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease. Proc Natl Acad Sci U S A. 2006;103(17):6747-52.
25. Weickert CS, Tiwari Y, Schofield PR, Mowry BJ, Fullerton JM. Schizophrenia-associated HapICE haplotype is associated with increased NRG1 type III expression and high nucleotide diversity. Transl Psychiatry. 2012;2(4):e104.
26. Agarwal A, Zhang M, Trembak-Duff I, Unterbarnscheidt T, Radyushkin K, Dibaj P, et al. Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity. Cell Rep. 2014;8(4):1130-45.
27. Deakin IH, Law AJ, Oliver PL, Schwab MH, Nave KA, Harrison PJ, et al. Behavioural characterization of neuregulin 1 type I overexpressing transgenic mice. Neuroreport. 2009;20(17):1523-8.
28. Deakin IH, Nissen W, Law AJ, Lane T, Kanso R, Schwab MH, et al. Transgenic overexpression of the type I isoform of neuregulin 1 affects working memory and hippocampal oscillations but not long-term potentiation. Cereb Cortex. 2012;22(7):1520-9.
29. Kato T, Kasai A, Mizuno M, Fengyi L, Shintani N, Maeda S, et al. Phenotypic characterization of transgenic mice overexpressing neuregulin-1. PLoS One. 2010;5(12):e14185.
30. Yin DM, Chen YJ, Lu YS, Bean JC, Sathyamurthy A, Shen C, et al. Reversal of behavioral deficits and synaptic dysfunction in mice overexpressing neuregulin 1. Neuron. 2013;78(4):644-57.
31. Marín O, Rico B. A new beginning for a broken mind: balancing neuregulin 1 reverses synaptic dysfunction. Neuron. 2013;78(4):577-9.
32. Walker EF, Trotman HD, Pearce BD, Addington J, Cadenhead KS, Cornblatt BA, et al. Cortisol levels and risk for psychosis: initial findings from the North American prodrome longitudinal study. Biol Psychiatry. 2013;74(6):410-7.
33. Walker E, Mittal V, Tessner K. Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annu Rev Clin Psychol. 2008;4:189-216.
34. Guest PC, Schwarz E, Krishnamurthy D, Harris LW, Leweke FM, Rothermundt M, et al. Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia. Psychoneuroendocrinology. 2011;36(7):1092-6.
35. Mondelli V, Dazzan P, Hepgul N, Di Forti M, Aas M, D'Albenzio A, et al. Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: the role of stress and of antipsychotic treatment. Schizophr Res. 2010;116(2-3):234-42.
36. Steen NE, Tesli M, Kähler AK, Methlie P, Hope S, Barrett EA, et al. SRD5A2 is associated with increased cortisol metabolism in schizophrenia spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(8):1500-6.
37. Belvederi Murri M, Pariante CM, Dazzan P, Hepgul N, Papadopoulos AS, Zunszain P, et al. Hypothalamic-pituitary-adrenal axis and clinical symptoms in first-episode psychosis. Psychoneuroendocrinology. 2012;37(5):629-44.
| Files | ||
| Issue | Vol 17 No 1 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijps.v17i1.8045 | |
| Keywords | ||
| Controlled Clinical Trial Hypothalamo-Hypophyseal System Schizophrenia Spironolactone | ||
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How to Cite
1.
Zandifar A, Badrfam R, Sanjari Moghaddam H, Akhondzadeh S. Efficacy of Spironolactone as an Adjunctive Therapy to Risperidone to Improve Symptoms of Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled, Clinical Trial. Iran J Psychiatry. 2022;17(1):14-23.
