Skip to main content

Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial

Abstract

Rational

It has been suggested that phosphodiesterase 5 inhibitors such as sildenafil may be effective in the treatment of negative symptoms of schizophrenia.

Objective

This study was designed to investigate the effect of sildenafil added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double-blind and randomized clinical trial.

Methods

Eligible participants in the study were 40 patients with chronic schizophrenia with ages ranging from 18 to 45 years. All patients were inpatients and were in the active phase of the illness and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion: 20 to risperidone (6 mg/day) plus sildenafil (75 mg/day) and 20 to risperidone (6 mg/day) plus placebo. The principal measure of outcome was Positive and Negative Syndrome Scale (PANSS).

Results

Although both protocols significantly decreased the score of the positive, negative, and general psychopathological symptoms over the trial period, the combination of risperidone and sildenafil showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores over the 8-week trial (between-subjects factor; F = 4.77, df = 1; P = 0.03; F = 5.91, df = 1, P = 0.02 respectively).

Conclusion

Therapy with 75 mg/day of sildenafil was well tolerated, and no clinically important side effects were observed. The present study indicates sildenafil as a potential adjunctive treatment strategy for treatment of negative symptoms of schizophrenia. This trial is registered with the Iranian Clinical Trials Registry (IRCT1138901151556N11).

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Abbasi SH, Behpournia H, Ghoreshi A, Salehi B, Raznahan M, Rezazadeh SA, Rezaei F, Akhondzadeh S (2010) The effect of mirtazapine add on therapy to risperidone in the treatment of schizophrenia: a double-blind randomized placebo-controlled trial. Schizophr Res 116:101–106

    Article  PubMed  Google Scholar 

  2. Akhondzadeh S (1998) The glutamate hypothesis of schizophrenia. J Clin Pharm Ther 23:243–246

    CAS  Article  PubMed  Google Scholar 

  3. Akhondzadeh S (2001) The 5-HT hypothesis of schizophrenia. IDrugs 4:295–300

    CAS  PubMed  Google Scholar 

  4. Akhondzadeh S (2006) Pharmacotherapy of schizophrenia: the past, present and future. Curr Drug Ther 1:1–7

    Article  Google Scholar 

  5. Akhondzadeh S, Mohammadi MR, Amini-Nooshabadi H, Davari Ashtiani R (1999) Cyproheptadine in treatment of chronic schizophrenia: a double-blind, placebo-controlled study. J Clin Pharm Ther 24:49–42

    CAS  Article  PubMed  Google Scholar 

  6. Akhondzadeh S, Rezaei F, Larijani B, Nejatisafa AA, Kashani L, Abbasi SH (2006) Correlation between testosterone, gonadotropins and prolactin and severity of negative symptoms in male patients with chronic schizophrenia. Schizophr Res 84:405–410

    Article  PubMed  Google Scholar 

  7. Akhondzadeh S, Tabatabaee M, Amini H, Ahmadi Abhari SA, Abbasi SH, Behnam B (2007) Celecoxib as adjunctive therapy in schizophrenia: a double-blind, randomized and placebo-controlled trial. Schizophr Res 90:179–185

    Article  PubMed  Google Scholar 

  8. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders. Fourth edition, text revision. American Psychiatric Association, Washington

    Book  Google Scholar 

  9. Buchanan RW (2007) Persistent negative symptoms in schizophrenia: an overview. Schizophr Bull 33:1013–1022

    Article  PubMed  Google Scholar 

  10. Buckley PF, Stahl SM (2007) Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac? Acta Psychiatr Scand 115:93–100

    CAS  Article  PubMed  Google Scholar 

  11. Carlsson ML, Carlsson A, Nilsson M (2004) Schizophrenia: from dopamine to glutamate and back. Curr Med Chem 11:267–277

    CAS  Article  PubMed  Google Scholar 

  12. Chouinard G, Ross-Chouinard A, Annables L, Jones BD (1980) Extrapyramidal symptoms rating scale (abstract). Can J Neurol Sci 7:233

    Google Scholar 

  13. Coyle JT (2006) Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26:365–384

    CAS  Article  PubMed  Google Scholar 

  14. Erhart SM, Marder SR, Carpenter WT (2006) Treatment of schizophrenia negative symptoms: future prospects. Schizophr Bull 32:234–237

    Article  PubMed  Google Scholar 

  15. Goff DC, Cather C, Freudenreich O, Henderson DC, Evins AE, Culhane MA, Walsh JP (2009) A placebo-controlled study of sildenafil effects on cognition in schizophrenia. Psychopharmacol 202:411–417

    CAS  Article  Google Scholar 

  16. Gopalakrishnan R, Jacob KS, Kuruvilla A, Vasantharaj B, John JK (2006) Sildenafil in the treatment of antipsychotic-induced erectile dysfunction: a randomized, double-blind, placebo-controlled, flexible-dose, two-way crossover trial. Am J Psychiatry 163:494–499

    Article  PubMed  Google Scholar 

  17. Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale for schizophrenia. Schizophr Bull 13:261–276

    CAS  PubMed  Google Scholar 

  18. Laruelle M, Kegeles LS, Abi-Dargham A (2003) Glutamate, dopamine, and schizophrenia: from pathophysiology to treatment. Ann NY Acad Sci 1003:138–158

    CAS  Article  PubMed  Google Scholar 

  19. Mohammadi MR, Akhondzadeh S (2001) Schizophrenia: etiology and pharmacotherapy. IDrugs 4:1167–1172

    CAS  PubMed  Google Scholar 

  20. Möller HJ (2004) Non-neuroleptic approaches to treating negative symptoms in schizophrenia. Eur Arch Psychiatry Clin Neurosci 254:108–116

    Article  PubMed  Google Scholar 

  21. Murphy BP, Chung YC, Park TW, McGorry PD (2006) Pharmacological treatment of primary negative symptoms in schizophrenia: a systematic review. Schizophr Res 88:5–25

    Article  PubMed  Google Scholar 

  22. Noorbala AA, Akhondzadeh S, Davari-Ashtiani R, Amini-Nooshabadi H (1999) Piracetam in the treatment of schizophrenia: implications for the glutamate hypothesis of schizophrenia. J Clin Pharm Ther 24:369–374

    CAS  Article  PubMed  Google Scholar 

  23. Reneerkens OA, Rutten K, Steinbusch HW, Blokland A, Prickaerts J (2009) Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. Psychopharmacol 202:419–443

    CAS  Article  Google Scholar 

  24. Seeman P (2009) Glutamate and dopamine components in schizophrenia. J Psychiatry Neurosci 34:143–149

    PubMed  Google Scholar 

  25. Siuciak JA (2008) The role of phosphodiesterases in schizophrenia: therapeutic implications. CNS Drugs 22:983–993

    CAS  Article  PubMed  Google Scholar 

  26. Stahl SM (2007) Novel therapeutics for schizophrenia: targeting glycine modulation of NMDA glutamate receptors. CNS Spectr 12:423–427

    PubMed  Google Scholar 

  27. Ueoka Y, Tomotake M, Tanaka T, Kaneda Y, Taniguchi K, Nakataki M, Numata S, Tayoshi S, Yamauchi K, Sumitani S, Ohmori T, Ueno SI, Ohmori T (2010) Quality of life and cognitive dysfunction in people with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry (in press)

  28. Zhang HT (2010) Phosphodiesterase targets for cognitive dysfunction and schizophrenia—a New York Academy of Sciences meeting. IDrugs 13:166–168

    PubMed  Google Scholar 

Download references

Acknowledgment

This study was Dr. Raofeh Ghayyoumi’s postgraduate thesis toward the Iranian Board of Psychiatry.

Conflict of interest statement

We declare no conflict of interest.

Role of funding source

This study was supported by a grant from Tehran University of Medical Sciences to Prof. Shahin Akhondzadeh (grant no. 6551).

Competing interest

None.

Ethics approval

The protocol was approved by the Institutional Review Board (IRB) of Tehran University of Medical Sciences (grant no. 6651).

The trial group

Shahin Akhondzadeh was the principal investigator and provided statistical support. He was also the clinical neuropsychopharmacologist from December 2008 to May 2010. Raofeh Ghayyoumi was the resident psychiatrist and trialist from December 2008 to May 2010. Farzin Rezaei, Bahman Salehi, Azad Maroufi, and Mehrangiz Naderi were the clinical coordinators and psychiatrists from December 2008 to May 2010. Gholam-Reza Esfandiari and Fariba Ghebleh were the psychologists from December 2008 to May 2010. Amir-Hossein Modabbernia and Mina Tabrizi were the methodologists from December 2008 to May 2010.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Shahin Akhondzadeh.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Akhondzadeh, S., Ghayyoumi, R., Rezaei, F. et al. Sildenafil adjunctive therapy to risperidone in the treatment of the negative symptoms of schizophrenia: a double-blind randomized placebo-controlled trial. Psychopharmacology 213, 809–815 (2011). https://doi.org/10.1007/s00213-010-2044-z

Download citation

Keywords

  • Adjunctive therapy
  • Sildenafil
  • Negative symptoms
  • Schizophrenia