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International Journal of Psychiatry in Clinical Practice, 2011; Early Online, 1–5

ORIGINAL ARTICLE

Several prescription patterns of antipsychotic drugs influence cognitive functions in Japanese chronic schizophrenia patients

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HIKARU HORI, REIJI YOSHIMURA, ASUKA KATSUKI, KENJI HAYASHI, ATSUKO IKENOUCHI-SUGITA, WAKAKO UMENE-NAKANO & JUN NAKAMURA Department of Psychiatry, University of Occupational and Environmental Health Japan, School of Medicine, Kitakyushu, Japan

Abstract Objective. We hypothesized that an excessive dose of antipsychotic drug and/or a larger number of antipsychotic drug worsens cognitive functions in schizophrenia patients. To confirm the hypothesis, we compared several cognitive functions in the patients taking a second-generation antipsychotic drug (SGA) only (SGA monotherapy group) with those in patients taking more than two kinds of antipsychotic drugs (polypharmacy group). Methods. The cognitive functions of 136 chronic schizophrenia patients were evaluated using the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J). Results. A significantly negative correlation was found between the composite score in the BACS-J and the chlorpromazine equivalence of doses of antipsychotic drugs in whole patients (r ⫽ –0.43, P ⬍ 0.001). Schizophrenia patients in the polypharmacy group had lower composite scores than those in the SGA monotherapy group in the BACS-J. No difference was observed in the composite score and the primary score in each item in the BACS-J between patients with first- plus second-generation antipsychotic drug (FGA ⫹ SGA group) and those with two kinds of SGA (SGA ⫹ SGA group). Conclusion. These results suggest that an excessive dose of antipsychotic drugs regardless of FGA and SGA might cause the deterioration of cognitive functions in chronic Japanese schizophrenia patients. Key Words: Cognitive function, schizophrenia, polypharmacy, monopharmacy, Brief Assessment of Cognition in

Schizophrenia, Japanese-language version (BACS-J)

Introduction Schizophrenia is associated with wide-ranging deficits in neurocognitive function, including verbal memory, working memory, motor function, verbal fluency, attention and processing speed, and executive function [1–4], and these deficits are considered to be central to the pathophysiology of the illness. These components of cognitive dysfunction in schizophrenia also have an impact on functional outcome, as they are all correlated with poor functional abilities [2]. The enhancement of cognitive functioning is considered to be an important component of the treatment for schizophrenia [5,6]. Investigators have recently focused on the cognitive pathology of schizophrenia and have sought to assess the effects of treatment in this regard. A large number of studies have demonstrated that the therapeutic effects of first-generation antipsychotic drugs (FGAs) are limited to the positive symptoms of the

illness and have substantially deteriorate cognitive impairments [7,8], whereas second-generation antipsychotic drugs (SGAs) may ameliorate or at least less worsen cognitive deficits [9–15]. Our concern in the present study is to investigate the association between the dose of antipsychotic drugs and cognitive functions evaluated by Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) in chronic schizophrenia patients. We hypothesized that the SGA monotherapy group would have higher scores of BACS-J than the polypharmacy group regardless of FGAs or SGAs.

Methods The subjects were 136 chronic Japanese schizophrenia patients those included in/out patients who were treated in the University of Occupational and Environmental Health Hospital. Seventy-two were males and

Correspondence: Hikaru Hori, Department of Psychiatry, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 8078555, Japan. Tel: ⫹81 936 917253. Fax: ⫹81 936 924894. E-mail: [email protected] (Received 21 June 2011; accepted 26 September 2011) ISSN 1365-1501 print/ISSN 1471-1788 online © 2011 Informa Healthcare DOI: 10.3109/13651501.2011.631018

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64 females, and their ages ranged from 20 to 61 years (mean ⫾ SD ⫽ 34.9 ⫾ 11.3 years). Of the 136 patients, 72 were treated with second-generation antipsychotic monopharmacy and 64 were treated with antipsychotic polypharmacy. The patients were diagnosed according to DSM-IV criteria [16] with the consensus of at least two experienced psychiatrists on the basis of a structured interview using the Structured Clinical Interview for DSM-IV disorders (SCID-1) [17] and a review of medical records. Schizophrenic symptoms were rated using the Positive and Negative Syndrome Scale [18]. All patients were prescribed a stable dose of antipsychotic medication for at least 3 months or more prior to the BACS-J evaluation. Seventy-two of the 136 patients (SGA monotherapy group) were being treated with a single second-generation antipsychotic medication (risperidone, n ⫽ 28; olanzapine, n ⫽ 25; aripiprazole, n ⫽ 16; quetiapine, n ⫽ 2; and perospirone, n ⫽ 1) and 64 with a combination of antipsychotic drugs regardless of FGAs and SGAs. This study was approved by the ethics committees at the University of Occupational and Environmental Health. Patients were evaluated using the BACS-J [19] as an assessment tool. The BACS-J includes brief assessments of verbal memory, working memory, motor speed, verbal fluency, attention and processing speed, and executive function. The primary measure from each test of the BACS-J was standardized by creating z-scores in which the mean of healthy controls was set to zero and the standard deviation set to one. All data on the healthy controls were taken from the study of Kaneda [19]. A composite score was calculated by averaging all z-scores for the six primary measures from the original BACS using the means and standard deviations of the first test patients [20]. Detailed information about the BACS-J can be found in these previous reports [19, 20]. Daily doses of antipsychotics were converted to approximate chlorpromazine equivalents (CPZeq)

using published guidelines [21,22]. The patients were divided into two subgroups by medication patterns. In other words, patients taking only a secondgeneration antipsychotic drug were defined as the SGA monopharmacy group, whereas those taking two kinds of antipsychotic drugs were defined as the polypharmacy group. Furthermore, the polypharmacy group was divided into three groups. Patients taking a FGA and a SGA were defined as the FGA ⫹ SGA group. Those taking two secondgeneration antipsychotic drugs were defined as the SGA ⫹ SGA group. The rest of the patients were taking three or more antipsychotic drugs, were discarded in the present investigation. The characteristics of each group are shown in Table I. Averages are reported in terms of means and standard deviations (SD). Demographic characteristics and test results were compared between groups. We used the t-test and chi-square test to compare various factors between the SGA monopharmacy group and the polypharmacy group. One-way analysis of variance (ANOVA) was used to make comparisons among the SGA monopharmacy group, the SGA ⫹ SGA group, and the FGA ⫹ SGA group. Bonferroni’s correction was used as a post-hoc test. Pearson’s correlation was used to evaluate the relation between two variables. Statistical significance was set at P ⬍ 0.05. Results A negative correlation was found between the composite score of BACS-J and the CPZeq dose of antipsychotic drugs (Figure 1). In addition, a significantly negative correlation was also observed between the primary scores of each component in BACS-J and the CPZeq dose of antipsychotic drugs (Table II). Patients in the FGA ⫹ SGA group and the SGA ⫹ SGA group had lower BACS-J scores than those in the SGA monopharmacy group. No significant differences between the SGA ⫹ SGA group and

Table I. Demographics and clinical characteristics of schizophrenia patients. SGA P value (polypharmacy SGA Polypharmacy monopharmacy group vs. SGA monopharmacy group group monopharmacy group) group SGA ⫹ SGA Sex (male/female) 35/29 Age (years) 37.3 ⫾ 12.8 Education (years) 12.2 ⫾ 2.3 Handedness (right/left) 60/4 Smoking (yes/no) 24/40 Age at onset (years) 24.7 ⫾ 6.7 CPZeq of total 888.3 ⫾ 468.1 antipsychotic drugs (mg/day)a PANSS total score 72.6 ⫾ 10.0 aCPZeq

, chlorpromazine-equivalent.

36/36 32.9 ⫾ 9.5 13.0 ⫾ 2.5 68/4 20/52 25.4 ⫾ 6.8 445.1 ⫾ 208.1

0.58 0.02 0.06 0.86 0.22 0.53 ⬍ 0.01

67.8 ⫾ 10.8

⬍ 0.01

FGA ⫹ SGA P value

36/36 6/6 14/12 0.94 0.41 32.9 ⫾ 9.5 32.3 ⫾ 8.8 35.8 ⫾ 12.4 0.26 13.0 ⫾ 2.5 12.3 ⫾ 2.8 12.1 ⫾ 2.1 68/4 12/0 26/0 0.33 20/52 2/10 7/19 0.71 0.82 25.4 ⫾ 6.8 24.8 ⫾ 8.5 24.4 ⫾ 6.0 445.1 ⫾ 208.1 991.7 ⫾ 564.4 842.3 ⫾ 475.9 ⬍ 0.01 67.8 ⫾ 10.8

73.9 ⫾ 5.8

70.3 ⫾ 10.8

0.14

Combination therapy and cognition in schizophrenia 1 0.5 0 0

500

1000

1500

2000

CPZeq (mg) 2500

Working memory

Motor speed

Attention and Verval processing Executive Composite fluency speed function score

0 –0.5

–1 –1.5

–1

–2

Z-score

Z-score

–0.5

Verval memory

3

–2.5 –3

–1.5 –2

–3.5 –2.5

–4

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Figure 1. Correlation between antipsychotic dosage and BACS composite score (r ⫽ –0.43, P ⬍ 0.001).

FGA ⫹ SGA group in the primary scores in the BACS-J was observed regarding working memory, motor speed, verbal fluency or executive function. The SGA monopharmacy group had higher composite scores than the FGA ⫹ SGA group with respect to verbal memory, motor speed, verbal fluency and attention and processing speed. On the other hand, no significant differences were found among the three groups regarding working memory and executive function (Figure 2).

Discussion The most important finding in the present study was that a negative correlation was observed between the CPZeq dose of antipsychotic drugs and the composite BACS-J score in all whole subjects. A significant correlation has been previously found between the dose of antipsychotic drugs and cognitive impairments in schizophrenia patients [23,24]. A high dose of antipsychotics was also associated with multiple cognitive deficits [25] and increased cognitionrelated complaints [26]. Furthermore, dose reduction led to a significant cognitive improvement [27]. On the other hand, another study showed no correlation between antipsychotic dosages and cognitive impairments [28]. The result in the present study was basically in accordance with results of Elie et al. [23] and Wang et al. [24]. In short, the results Table II. Correlation between antipsychotic dosage and BACS primary and composite scores.

Verbal memory Working memory Motor speed Verbal fluency Attention and processing speed Executive function Composite score

r

P value

--0.34 --0.17 --0.31 --0.33 --0.32 --0.21 --0.43

⬍ 0.0001 0.04 0.0002 0.0001 0.0002 0.01 ⬍ 0.0001

–3

Figure 2. A post-hoc analysis of BACS-J scores in each group. , SGA monopharmacy group; , SGA ⫹ SGA group; , FGA ⫹ SGA group. *P ⬍ 0.05.

in the present study reconfirmed that a high dose of antipsychotic drugs brings a definitive cognitive deterioration in schizophrenia patients. The polypharmacy groups had more severe cognitive impairments in verbal memory, working memory, motor function, verbal fluency, attention and processing speed, and executive function in comparison with the SGA monopharmacy group. The age and the PANSS scores, and CPZeq dose of antipsychotic drugs were different between the two groups. Thus, it is possible that those factors may have influenced the cognitive impairments in the present study. We demonstrated that the SGA monopharmacy group had superior cognitive functions to the SGA ⫹ SGA group. Thus, it is plausible that treatment with two kinds of SGAs worsens cognitive functions because of the total dose in spite of their advantages in cognitive functions. Recent research in East Asian countries showed that the polypharmacy of SGAs was increasing [29,30]. Antipsychotic polypharmacy regimens are used for various reasons [26,31], with the one cited most often being the wish to bolster medication effectiveness when treating patients with refractory psychotic symptoms [32]. A recent case–control study of psychiatric inpatients however demonstrated that treatment with antipsychotic polypharmacy was associated with major increases in drug exposure and longer duration of hospitalization without apparent clinical benefit [19]. Indeed, the CPZeq of the antipsychotic dose was definitely higher in the SGA ⫹ SGA group than in the SGA monopharmacy group. Interestingly, no differences in the BACS-J scores between the FGA ⫹ SGA group and the SGA ⫹ SGA group about each item of BACS-J regardless of the CPZeq of their doses. These results suggest that the polypharmacy regardless of

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FGA ⫹ SGA or SGA ⫹ SGA is a key for cognitive deteriorations. We should carefully interpret the results in the present study. It is possible that schizophrenic patients with serious psychotic symptoms might develop the deterioration of cognitive functions and had an excessive dose of antipsychotic drugs. Anyway, our methodology using a cross-sectional study in the present study was not appropriate. Thus, we are planning a longitudinal follow-up study on cognitive changes in schizophrenia patients. Another important issue is that the drug–drug interactions (additive and/or synergistic) or pharmacodynamic effects of two antipsychotic drugs might influence cognitive impairment. The present study was a cross-sectional survey employing only one evaluation of the cognitive functions using BACS-J. Since all patients had chronic schizophrenia, the findings in the present study could not be generalized to the early stages of schizophrenia patients. Moreover, the sample size was small, which may have resulted in type II errors. In conclusion, chronic schizophrenia patients in the polypharmacy group had significantly lower cognitive functions than those in the SGA monotherapy group evaluated by the BACS-J. Furthermore, no difference was found in the cognitive functions between the FGA ⫹ SGA group and the SGA ⫹ SGA group.

Key points • Excessive dose of antipsychotic drugs might cause the deterioration of cognitive functions in schizophrenia patients • Schizophrenia patients in the polypharmacy group had significantly lower cognitive functions than those in the SGA monotherapy group • No difference was found in the cognitive functions between the FGA ⫹ SGA group and SGA ⫹ SGA group

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13] [14]

Acknowledgement None.

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Statement of Interest

[16]

All authors declare that they have no conflicts of interest.

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References [1] Friedberg DJ, Brenner A, Lysaker PH. Verbal memory intrusions in schizophrenia: associations with self-reflectivity,

[18]

symptomatology and neurocognition. Psychiatry Res 2010;179(1):6–11. Green MF, Kern RS, Braff DL, Mintz J. Neurocognitive deficits and functional outcome in schizophrenia: Are we measuring the ‘right stuff’? Schizophr Bull 2000;26(1): 119–36. Sharma T, Antonova L: Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment. Psychiatr Clin North Am 1999;26(1):25–40. White T, Schmidt M, Karatekin C. Verbal and visuospatial working memory development and deficits in children and adolescents with schizophrenia. Early Interv Psychiatry 2010;4(4):305–13. Green MF, Barnes TR, Danion JM, Gallhofer B, Meltzer HY, Pantelis C. The FOCIS international survey on psychiatrists’ opinions on cognition in schizophrenia. Schizophr Res 2005;74(2–3):253–61. Hofer A, Baumgartner S, Bodner T, Edlinger M, Hummer M, Kemmler G, et al. Patient outcomes in schizophrenia: The impact of cognition. Eur Psychiatr 2005;20(5–6):395–402. Medalia A, Gold J, Merriam A. The effects of neuroleptics on neuropsychological test results of schizophrenia. Arch Clin Neuropsychol 1998;3(3):249–71. Spohn H E, Strauss ME. Relation of neuroleptic and anticholinergic medication to cognitive functions in schizophrenia. Schizophr Res 1989;98(4):367–80. Bender S, Dittmann-Balcar A, Schall U, Wolstein J, Klimke A, Riedel M, et al. Influence of atypical neuroleptics on executive functioning in patients with schizophrenia: a randomized, double-blind comparison of olanzapine vs. clozapine. Int J Neuropsychopharmacol 2006;9(2):135–45. Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or shizoaffective disorder. Am J Psychiatry 2002;159(6):1018–28. Harvey PD, Bowie CR, Loebel A. Neuropsychological normalization with long–term atypical antipsychotic treatment: results of a six-month randomized, double-blind comparison of ziprasidone vs olanzapine. J Neuropsychiatry Clin Neurosci 2006;18(1):54–63. Keefe RS, Young CA, Rock SL, Purdon SE, Gold JM, Breier A; HGGN study Group. One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia. Schizophr Res 2006;81(1): 1–15. Miller AL, Craig CS. Combination antipsychotics: pros, cons, and questions. Schizophr Bull 2003;28(1):105–9. Sumiyoshi C, Sumiyoshi T, Roy A, Jayathilake K, Meltzer HY. Atypical antipsychotic drugs and organization of longterm semantic memory: multidimensional scaling and cluster analyses of category fluency performance in schizophrenia. Int J Neuropsychopharmacol 2006;9(6):677–83. Thornton AE, Van Snellenberg JX, Sepehry AA, Honer W. The impact of atypical antipsychotic medications on long-term memory dysfunction in schizophrenia spectrum disorder: a quantitative review. J Psychopharmacol 2006;20(3):335–46. American Psychiatric Association. DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association; 1994. First MB, Spitzer RL, Gibbon M, Williams BW. Structured Clinical Interview for DSM-IV Axis I disorders, Patient edition (SCID-P), version 2. New York: New York State Psychiatric Institute, Biometrics Research; 2005. Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale (PANSS) manual. Schizophr Bull 1987;13: 261–76.

Int J Psych Clin Pract Downloaded from informahealthcare.com by Sangyo Ika Daigaku on 12/06/11 For personal use only.

Combination therapy and cognition in schizophrenia [19] Kaneda Y, Sumiyoshi T, Keefe RS, Ishimoto Y, Numata S, Ohmori, T. Brief assessment of cognition in schizophrenia: validation of the Japanese version. Psychiatry Clin Neurosci 2007;61(6):602–9. [20] Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res 2004;68(2–3):283–97. [21] American Psychiatric Association. Practice Guidelines for the Treatment of Patients with Schizophrenia. Washington, DC: American Psychiatric Press; 1997. [22] Inagaki A, Inada T, Fujii Y. Equivalent dose of psychotropics. Seiwa Shoten: Tokyo; 1999 (in Japanese). [23] Elie D, Poirier M, Chianetta J, Durand M, Gregoire C, Grignon S. Cognitive effects of antipsychotic dosage and polypharmacy: a study with the BACS in patients with schizophrenia and schizoaffective disorder. J Psychopharmacol 2010;24(7):1037–44. [24] Wang Y, Cui J, Chan RC, Deng Y, Shi H, Hong X, et al. Meta-analysis of prospective memory in schizophrenia: nature, extent, and correlates. Schizophr Res 2009;114 (1–3):64–70. [25] Hori H, Noguchi H, Hashimoto R, Nakabayashi T, Omori M, Takahashi S, et al. Antipsychotic medication and cognitive function in schizophrenia. Shizophrenia Res 2006;86:138–46. [26] Moritz S, Woodward TS, Krausz M, Naber D; PERSIST Study Group: Relationship between neuroleptic dosage and

[27]

[28]

[29]

[30]

[31]

[32]

5

subjective cognitive dysfunction in schizophrenic patients treated with either conventional or atypical neuroleptic medication. Int Clin Psychopharmacol 2002;17:41–4. Kawai N, Yamakawa Y, Baba A, Nemoto K, Tachikawa H, Hori T, et al. High-dose of multiple antipsychotics and cognitive function in schizophrenia: the effect of dose-reduction. Prog Neuropsychopharmacol Biol Psychiatry 2006;30: 1009–14. Midorikawa A, Hashimoto R, Noguchi H, Saitoh O, Kunugi H, Nakamura K. Impairment of motor dexterity in schizophrenia assessed by a novel finger movement test. Psychiatry Res 2008;159:281–89. Nakano W, Yang S-Y, Fujii S. The characteristics of pharmacotherapy for inpatients with schizophrenia in Japan-Results from the international survey of psychotic drug prescription pattern in East Asia. Jpn J Clin Psychopharmacol 2010;13:103–13. Sim K, Su A, Fujii S, Yang SY, Chong MY, Unqvari GS, et al. Antipsychotic polypharmacy in patients with schizophrenia: a multicentre comparative study in East Asia. Br J Clin Pharmacol 2004;58:178–83. Schumacher JE, Makela EH, Griffin HR, Multiple antipsychotic medication prescribing patterns. Ann Pharmacotherapy 2003;37:951–5. Tapp A, Wood AE, Secrest L, Erdmann J, Cubberley L, Kizieh N. Combination antipsychotic therapy in clinical practice. Psychiatr Serv 2003;54:55–9.