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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 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;

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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 antagonists, and 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). , a 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 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, 1997; Mielke et al., 1998). Nevertheless, the European plus propentopylline 900 mg/day (300 mg three times per day) and agency for the evaluation of medicinal products did not approve 25 to risperidone 6 mg/day plus placebo for an eight week, double- propentofylline for treatment of dementia due to lack of strong data. blind, and placebo controlled study. Patients were randomized to Therefore, it is still considered as investigational drug and is not receive propentopylline or placebo in a 1:1 ratio using a computer- marketed. It enhances extracellular adenosine level via inhibition of generated code. Throughout the study, the person who admini- adenosine uptake, and prevents the enzymatic degradation of cyclic strated the medications, the rater and the patients were blind to and cyclic monophosphate assignments. Pharmaceutical form of propentopylline was film- through inhibition of cyclic phosphodiesrerases (Noble coated tablet and purchased from Aventis Pharma. Starting dosage and Wagstaff, 1997). Few details of pharmacokinetic properties of of risperidone was 2 mg/day and was increased to 6 mg/day with 728 S. Salimi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 726–732

2mgincrementsindailydosageforthefirsttwodays.Starting subjects factor (group) and the five measurements during treat- dosage of was propentofylline 300 mg three times per day. Patients ment as the within-subjects factor (time) were considered. This in the placebo group received three tablets similar to propentofyl- was done for positive, negative, general psychopathology line in terms of size and color. During the washout period, the subscales and PANSS total scores. A Greenhouse–Geisser patients received if necessary. Lorazepam was the correction was used for sphericity. To compare the two groups drug of choice. Patients also received biperiden if they had faced at baseline and the outcome of two groups at the end of the trial, extrapyramidal symptoms. The patients did not receive any psy- an unpaired Student's t-test with a two-sided p value was used. chotropic medications except the trial protocol during the study. To compare the demographic data and frequency of side effects Patients were assessed by a psychiatrist at baseline and after 2, 4, 6 between the protocols, Fisher's exact test was performed. and 8 weeks after the started. Side effects were Results are presented as mean±SD. Differences were con- systematically recorded throughout the study and were assessed sidered significant with pb0.05. To consider, α=0.05, and the using a checklist administered by a resident of psychiatry on day 7, final difference between the two groups at least score of 5 on the 14, 28, 42 and 56 (Table 3). PANSS rating scale, S=5 and power=0.8 (according to the pilot study of this research), the sample size was calculated at 2.4. Outcome least 15 in each group. Intention to treat (ITT) analysis with last observation carried forward (LOCF) procedure was performed. The principal measure of the outcome was the PANSS. The Effect size was calculated from partial eta (Cohen, 1988). rater used standardized instructions in the use of PANSS. The Statistical significance required two-tailed pb0.05. Data were mean total and subtotal PANSS scores were used as the main analyzed by using commercially available statistical packages outcome measure. The extrapyramidal symptoms were assessed (SPSS 13.00. Chicago, IL, USA). using the Extrapyramidal Symptoms Rating Scale (ESRS) (part one: parkinsonism, dystonia, dyskinesia; sum of 11 items) 3. Results (Chouinard et al., 1980). Eighty one patients were screened for the study and 50 were 2.5. Statistical analysis randomized to trial medication (25 patients in each group) (Fig. 1). No significant differences were identified between A two-way repeated measures analysis of variance (time- patients randomly assigned to the group 1 or 2 condition with treatment interaction) was used. The two groups as a between- regard to basic demographic data including age, age of first

Fig. 1. Trial profile. S. Salimi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 726–732 729

Table 1 Baseline data Propentofylline group Placebo group p Gender Male: 16, female: 9 Male: 15, female: 10 ns Age (mean±SD) 33.12±7.17 (year) 34.24±7.59 (year) ns Marital status Single: 14, married: 8, divorced: 3 Single: 16, married: 7, divorced: 2 ns Level of education Under diploma: 16, diploma: 6, higher diploma: 3 Under diploma: 15, diploma: 8, higher diploma: 2 ns Time since diagnosis 93.12±66.01 (month) 90.00±48.86 (month) ns Type of schizophrenia Paranoid: 15 Paranoid: 13 ns Disorganized: 5 Disorganized: 6 Undifferentiated: 5 Undifferentiated: 6 Number of life-time 4.20±0.40 4.16±0.34 ns hospitalization (Mean±SD) Medications history Typical antipsychotic(haloperidol) and atypical Typical antipsychotic(haloperidol) and atypical ns antipsychotics (risperidone or olanzapine): 19 antipsychotics (risperidone or olanzapine): 17 Only atypical antipsychotics: (risperidone or Only atypical antipsychotics: (risperidone or olanzapine): 6 olanzapine): 8 onset of illness, gender, marital status, level of education, mean of both treatments on the positive subscale scores of PANSS duration of illness and number of life-time hospitalization rating scale (pb0.0001; partial eta=0.04, f=0.20). In the pro- (Table 1). Although the number of dropout in the placebo group pentofylline and placebo group, post hoc comparisons showed was higher than the propentofylline group (1 in the propentofyl- a significant change from week 2 and 4 respectively. The differ- line group and 2 in the placebo group), no significant difference ence between the two treatments was significant at the endpoint was observed in the two groups in terms of dropout. (week 8) (t=2.03,df=48, p=0.04).

3.1. Positive symptoms 3.2. Negative symptoms

The mean±SD scores of two groups of patients are shown in The mean±SD scores of two groups of patients are shown in Fig. 2. There were no significant differences between the two Fig. 3. There were no significant differences between the two groups at week 0 (baseline) on the PANSS (t=0.16,df=48, p= groups at week 0 (baseline) on the PANSS (t=0.32, df=48, 0.87). The difference between the two treatments was significant p=0.74). The difference between the two treatments was not as indicated by the effect of group, the between-subjects factor significant as indicated by the effect of group, the between- (Greenhouse–Geisser corrected: p=0.03; partial eta: 0.087 and subjects factor (Greenhouse–Geisser corrected: p=0.62; partial f=0.31). The behavior of the two treatment groups was similar eta=0.005 and f=0.20). The behavior of the two treatment across time (groups-by-time interaction, Greenhouse–Geisser groups was similar across time (groups-by-time interaction, corrected: F=2.43, df= 1.79, p=0.09). In addition, a one-way Greenhouse–Geisser corrected: F=0.86, df=1.81, p=0.41). In repeated measures analysis of variance showed a significant effect addition, a one-way repeated measures analysis of variance

Fig. 2. Mean±SD of the two protocols on the positive subtotal scores of the Fig. 3. Mean±SD of the two protocols on the negative subtotal scores of the PANSS. ns=non-significant and ⁎b0.05. PANSS. ns=non-significant. 730 S. Salimi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 726–732 showed a significant effect of both treatments on the negative subscale scores of PANSS rating scale (pb0.0001; partial eta=0.01 and f=0.1). In both groups post hoc comparisons showed a significant change from week 4. The difference between the two treatments was not significant at the endpoint (week 8) (t=0.63, df=48, p=0.52).

3.3. General psychopathological symptoms

The mean±SD scores of two groups of patients are shown in Fig. 4. There were no significant differences between the two groups at week 0 (baseline) on the PANSS (t=0.60, df=48, p=0.54). The difference between the two treatments was significant as indicated by the effect of group, the between subjects factor (Greenhouse–Geisser corrected: p=0.05; partial eta=0.07 and f=0.27). The behavior of the two treatment groups was not similar across time (groups-by-time interaction, Greenhouse–Geisser corrected: F=5.22, df=1.65, p=0.01). In Fig. 5. Mean±SD of the two protocols on the total scores of the PANSS. addition, a one-way repeated measures analysis of variance ns=non-significant and ⁎⁎b0.01. showed a significant effect of both treatments on the general psychopathological symptoms subscale scores of PANSS rating scale (pb0.0001; partial eta=0.09 and f=0.32). In both groups one-way repeated measures analysis of variance showed a post hoc comparisons showed a significant change from week 2. significant effect of both treatments on the total scores of The difference between the two treatments was significant at the PANSS rating scale (pb0.0001; partial eta=0.02 and f=0.14). endpoint (week 8) (t=2.71, df=48, p=0.009). In both groups post-hoc comparisons showed a significant change from week two. The difference between the two 3.4. PANSS total scores treatments was significant at the endpoint (week 8) (t=2.46, df=48, p=0.01). The mean±SD scores of two groups are shown in Fig. 5. There were no significant differences between the two groups at 3.5. Extrapyramidal symptoms rating scale week 0 (baseline) on the PANSS (t=0.35, df=48, p=0.72). The difference between the two treatments was significant as Although the means ESRS for the placebo group were higher indicated by the effect of group, the between-subjects factor than propentofylline group over the eight weeks of trial, the (Greenhouse–Geisser corrected: p=0.01; partial eta=0.11 and differences were not statistically significant (Table 2). No f=0.35). The behavior of the two treatment groups was not significant difference was observed between the overall mean similar across time (groups-by time interaction, Greenhouse– biperiden dosages (mg) in two groups (109.04±113.12 and Geisser corrected: F=4.25, df=1.57; p=0.02). In addition, a 139.04±80.19 for propentofylline and placebo group respec- tively; mean±SD) (p=0.28; t=1.08; df=48). The cumulative dose of biperidine in the propentofylline and placebo group was 2726 mg and 3300 mg respectively. Moreover, the difference between the two treatments in terms of the number of days of biperiden treatment was not significant (18.47 ±18.95 and 23.55±13.37 for propentofylline and placebo group respec- tively; mean±SD)(p=0.27; t=1.09; df=48).

Table 2 Extrapyramidal symptoms based on extrapyramidal symptoms rating scale Mean±SD Mean±SD p propentofylline group placebo group Week 0 1.16±2.79 1.13±3.16 0.96 Week 1 4.58±5.50 5.50±6.44 0.59 Week 2 7.00±9.94 8.72±11.05 0.56 Week 4 4.80±3.40 6.28±6.79 0.27 Week 6 3.40±3.46 5.16±5.00 0.15 Fig. 4. Mean±SD of the two protocols on the general psychopathology subtotal Week 8 2.36±2.34 3.72±3.80 0.13 scores of the PANSS. ns=non-significant and ⁎⁎⁎b0.001. S. Salimi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 726–732 731

Table 3 Therapeutic benefit of adjunctive propentofylline in schizo- Number of patients with side effects phrenia is probably due to adenosine-glutamate interactions Side effects Risperidone+ Risperidone+ p (Lara et al., 2006). Adenosine has been shown to inhibit propentofylline placebo synaptic activity and the release of several neurotransmitters, 900 mg/day such as glutamate, acetylcholine and serotonin, by acting on Nausea 6 (24%) 2 (8%) ns presynaptic A1 receptors. Moreover, both A1 and A2a adeno- Gastrointestinal pain 5 (20%) 2 (8%) ns sine agonists prevent behavioral and neurophysiological effects Dyspepsia 5 (20%) 2 (8%) ns Dizziness 6 (24%) 2 (8%) ns of NMDA antagonists (Lara et al., 2006). Extrapyramidal side Headache 5 (20%) 2 (8%) effects measured by the ESRS did not show any differences Tremor 3 (12%) 5 (20%) ns between the two groups over the trial. The use of biperiden was Increased appetite 6 (24%) 6 (24%) ns greater in the group receiving risperidone+placebo but the Skin rash 1 (4%) 2 (8%) ns difference was not statistically significant. It is suggested that a Urinary retention 2 (8%) 3 (12%) ns free radical scavenger activity of propentofylline may be involved in this effect (Noble and Wagstaff, 1997). In addition, therapy with 900 mg/day of propentofylline was well tolerated, 3.6. Clinical complications and side effects and no clinically important side effects were observed. Gas- trointestinal disturbances, dizziness and headache were most Nine side effects were observed over the trial. The difference common events during the trial with propentofylline. The between the propentofylline and placebo in the frequency of therapeutic benefit of the combined therapy has to be attributed side effects was not significant (Table 3). to effects of propentofylline. To best of our knowledge, this study is the first clinical study that suggests the potential use of 4. Discussion propentofylline as adjunctive treatment and therefore it is not possible to draw any comparisons with other trials. Never- There is no doubt that atypical antipsychotics are effective theless, it is in line with recent studies that showed the beneficial against the acute psychotic symptoms of schizophrenia and in effects of (an adenosine uptake inhibitor) and preventing relapse. Nevertheless, atypical antipsychotics are allopurinol (an inhibitor of xantine oxidase), as adjunctive less than perfect and there is still a lot of room for improvement therapy for schizophrenia (Akhondzadeh et al., 2000; Lara et in the treatment of schizophrenia (Akhondzadeh, 2006). al., 2001; Akhondzadeh et al., 2005; Brunstein et al., 2005). The Impaired activity of the purinergic system is a plausible limitations of the present study, including the short period of common factor that could be responsible for many aspects of study and using only a fixed dose of propentofylline, should be schizophrenia (Lara and Souza, 2000). Based on purinegic taken into account and this indicates the need for further hypothesis of schizophrenia, pharmacological treatments research. In addition, from a scientific viewpoint, the therapeu- enhancing adenosine activity could be effective treatment in tic effects of propentofylline without an additional neuroleptic schizophrenia (Lara and Souza, 2000; Brunstein et al., 2007). drug would be more interesting. However, since neuroleptics Drugs that indirectly increase adenosine levels, such as are effective in antipsychotic treatment, ethic committees would propentofylline could stimulate A1 and A2A receptors simulta- not approve a study with propentofylline as the only drug for neously (Noble and Wagstaff, 1997). Indeed, propentofylline acutely ill schizophrenic patients. The present study indicates inhibits reuptake of the neuromudulator adenosine, resulting in propentofylline as a potential adjunctive treatment strategy for extracellular accumulation of this molecule and potentiation of chronic schizophrenia. Nevertheless, results of larger controlled the neuroprotective effects which it exerts via adenosine A1 and trials are needed, before recommendation for a broad clinical A2 receptors (Noble and Wagstaff, 1997). application can be made. As expected, both groups of patients showed significant improvement on the Positive and Negative Syndrome Scale and 4.1. The trial group on all subscales during the 8 weeks of treatment with risperidone. In agreement with our hypothesis, the propentofyl- Shahin Akhondzadeh: principal investigator and statistical line group had significantly greater improvement in the positive support, clinical neuropsychopharmacologist from Oct. 2005 to symptoms, general psychopathological symptoms and PANSS May. 2007. Samarand Salimi: resident of psychiatry, trialist total scores over 8 weeks trial. No significant differences were from Oct. 2005 to May 2007. Mohammad Reza Mohammadi: observed between the means of the two groups on the negative clinical coordinator, psychiatrist from Oct. 2005 to May 2007. scores. Clinical characteristics of the schizophrenic patients, Ahmad Ali Noorbala: clinical coordinator, psychiatrist from such as sex, age and duration of illness, did not differ between Oct. 2005 to May 2007. Seyed Ali Ahmadi Abhari: clinical groups and can not explain differences in the therapeutic out- coordinator, psychiatrist from Oct. 2005 to May 2007. come. In addition, to our knowledge, pharmacokinetic interac- Mohammad Hajiazim: clinical coordinator, psychiatrist from tion with propentofylline leading to higher plasma level of Oct. 2005 to May 2007. Mohammad- Reza Khodaie-Ardakani: risperdone, has not been reported. Moreover, a relatively high clinical coordinator, psychiatrist from Oct. 2005 to May 2007. dose of risperidone in this study suggests that the extra effect Mohammad-Kamran Derakhshan: resident of psychiatry, trialist of propentofylline is independent of risperidone's mechanism. from Oct. 2005 to May 2007. Akbar Fotouhi: epidemiologist, 732 S. Salimi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 726–732 methodological support 2007. Seyed–Hesameddin Abbasi: GP: Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. 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