Available online at www.sciencedirect.com Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 726–732 www.elsevier.com/locate/pnpbp A placebo controlled study of the propentofylline added to risperidone in chronic schizophrenia Samarand Salimi a, Akbar Fotouhi b, Abolfazl Ghoreishi c, Mohammad-Kamran Derakhshan d, Mohammad-Reza Khodaie-Ardakani d, Mohammad-Reza Mohammadi a, Ahmad-Ali Noorbala a, Seyed-Ali Ahmadi-Abhari a, Mohammad Hajiazim e, ⁎ Seyed-Hesameddin Abbasi f, Shahin Akhondzadeh a, a Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, Tehran, Iran b Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran c Departement of Psychiatry, Zanjan University of Medical Sciences, Zanjan, Iran d Razi Psychiatric Hospital, Welfare Sciences University, Iran e Semnan University of Medical Sciences, Garmsar, Iran f National Iranian Oil Company, Central Hospital, Tehran, Iran Received 10 August 2007; received in revised form 9 November 2007; accepted 17 November 2007 Available online 23 November 2007 Abstract Impaired activity of the purinergic system is a plausible common factor that could be responsible for many aspects of schizophrenia. Based on purinegic hypothesis of schizophrenia, pharmacological treatments enhancing adenosine activity could be effective treatment in schizophrenia. Propentofylline is a novel xantine derivative which is being developed for treatment of degenerative and vascular dementia. It enhances extracellular adenosine level via inhibition of adenosine uptake. The purpose of the present investigation was to assess the efficacy of propentofylline as an adjuvant agent in the treatment of chronic schizophrenia in an 8-week double blind and placebo controlled trial. Eligible participants in this study were 50 patients with chronic schizophrenia. 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, 25 to risperidone 6 mg/day plus propentofylline 900 mg/ day (300 mg TDS) and 25 to risperidone 6 mg/day plus placebo. The principal measure of the outcome was Positive and Negative Syndrome Scale (PANSS). Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and propentofylline showed a significant superiority over risperidone alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. The means Extrapyramidal Symptoms Rating Scale for the placebo group were higher than in the propentofylline group over the trial. However, the differences were not significant. The present study indicates propentofylline as a potential adjunctive treatment strategy for chronic schizophrenia. Nevertheless, results of larger controlled trials are needed, before recommendation for a broad clinical application can be made. © 2007 Elsevier Inc. All rights reserved. Keywords: Adenosine; Propentofylline; Schizophrenia 1. Introduction Abbreviation: DSM, Diagnosis and Statistical Manual of Mental Disorders; ESRS, Extrapyramidal Symptoms Rating Scale; LOCF, Last Observation Schizophrenia is a devastating neurobiologic disorder that typi- Carried Forward; PANSS, Positive and Negative Syndrome Scale. cally strikes the brain function of adolescents and young adults, ⁎ Corresponding author. Psychiatric Research Center, Roozbeh Psychiatric Hospital, Tehran University of Medical Sciences, South Kargar Street, Tehran occurring in about 1 of every 100 people worldwide (Jablensky 13337, Iran. Tel.: +98 21 88281866; fax: +98 21 55419113. et al., 1991; Mohammadi and Akhondzadeh, 2001). The patho- E-mail address: [email protected] (S. Akhondzadeh). physiology of schizophrenia remains puzzling (Anderson, 2000; 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.11.021 S. Salimi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 726–732 727 Akhondzadeh, 2006). Inadequate response to both typical and propentofylline are available. Administration of propentofylline atypical antipsychotics occurs in 30–40% of patients. Of these 100 mg 3 times daily for at least four weeks produced a mean patients, 40–60% may then respond to the atypical antipsychotic plasma concentration of 43.3 µg/L in 5 elderly patients with organic clozapine (Akhondzadeh, 2006). Atypical antipsychotic medica- bran disorders (Noble and Wagstaff, 1997). The purpose of the tions are often distinguished from conventional antipsychotics present investigation was to assess the efficacy of propentofylline as based on clinical advantages such as a low potential for causing an adjuvant agent in the treatment of chronic schizophrenia in an 8- extrapyramidal symptoms, efficacy for the negative symptoms of week double blind and placebo controlled trial. schizophrenia, and a greater potential for efficacy in cases of treatment-resistant schizophrenia (Akhondzadeh, 2006). However, 2. Methods these agents are not a magic bullet and are associated with their own attendant treatment complications, such as weight gain, diabetes 2.1. Setting and hyperprolactinemia. Although the dopamine hypothesis of schizophrenia remains the leading neurochemical hypothesis, other This investigation was a prospective, 8-week, double blind neurotransmitter receptors may also be involved in the pathogenesis study of parallel groups of patients with chronic schizophrenia of schizophrenia (Akhondzadeh, 2006). Over the past 25 years a and was undertaken in three Psychiatric Hospitals in Iran, from general consensus has been reached on the crucial role of adenosine October 2005 to May 2007. in the CNS as a modulator of neurotransmission and a neuro- protective agent against ischemic- and seizure-induced neuronal 2.2. Participants injury (Erfurth and Schmauss, 1995; Guieu et al., 1996; Brundege and Dunwiddie, 1997; Stone, 2005). Adenosine has also been Eligible participations in the study were 50 patients with proposed to be a potent regulator of cerebral blood flow. Besides its chronic schizophrenia (19 women and 31 men) age ranging from more general involvement in cellular metabolism, specific actions 19 to 47 years. All participants were inpatients, who were recently of adenosine in the CNS as neuroprotective are believed to be admitted in an acute exacerbation, and met DSM-IV-TR criteria mediated through specific receptors, which have been cloned and for schizophrenia (American Psychiatric Association, 2000). The classified as A1,A2A,A2B and A3 receptors (Erfurth and Schmauss, minimum score of 60 on Positive and Negative Syndrome Scale 1995; Guieu et al., 1996; Brundege and Dunwiddie, 1997). There is (PANSS) was required for entry into the study (Kay et al., 1987). a large amount of data showing that adenosine plays a role opposite The PANSS includes 30 items on three subscales (scoring range 1 to dopamine in the brain (Darlsson et al., 1999). Adenosine agonists to 7), 7 items covering positive symptoms, 7 items covering and antagonists produce behavioral effects similar to dopamine negative symptoms and 16 covering general psychopathology. In antagonists and dopamine agonists, respectively. Preclinically, addition, a total score presents all three parts. The patients did not adenosine and its analogs exert antipsychotic, anxiolytic, sedative, receive neuroleptics from a week prior to entering the trial or anticonvulsant and anti aggressive effects (Erfurth and Schmauss, depot neuroleptic at least two months before the study. Patients 1995; Guieu et al., 1996). Similarly to amphetamine and NMDA were excluded from the study if they had a clinically significant receptor antagonists, caffeine and theophylline produce hyperlo- organic and neurological disorder, concurrent Axis 1 DSM-IV-TR comotor responses in rodents, which can be reversed by diagnosis, current abuse or dependence on drugs within 6 months, antipsychotics. In healthy subjects, high doses of adenosine anta- serious psychotic disorders other than schizophrenia, use of any gonists can produce psychosis (Lara et al., 2006). Allopurinol, a medications identified as contradicted with propentofylline and well-known hypouricemic drug that inhibits xantine oxidase, has history of allergic reaction to propentofylline. Pregnant or lac- been used as add-on drug in the treatment of poorly responsive tating women and those of reproductive age without adequate schizophrenic patients. Indeed, the neuropsychiatric effects of contraception were also excluded. The trial was performed in allopurinol in schizophrenia have been suggested to be secondary accordance with the Declaration of Helsinki and subsequent to its inhibitory effect of purine degradation, enhancing adenosi- revisions (World Medical Association, 2000) and approved by nergic activity (Lara et al., 2001; Akhondzadeh et al., 2005; each institutional review board. Written informed consents were Brunstein et al., 2005, 2007). Unfortunately, direct or indirect obtained before entering into the study. adenosine agonists with clear effects on the brain are not yet available for human use. Propentofylline is a xantine derivative 2.3. Intervention which was developed for treatment of degenerative and vascular dementia (Kittner et al., 1997; Marcusson et al., 1997; Noble and Patients were randomly allocated, 25 to risperidone 6 mg/day Wagstaff,