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Investigation of clinical factors influencing cognitive function in Japanese schizophrenia
Neuroscience Research 66 (2010) 340–344
Contents lists available at ScienceDirect
Neuroscience Research journal homepage: www.elsevier.com/locate/neures
Investigation of clinical factors influencing cognitive function in Japanese schizophrenia Taro Kishi a,c,*, Masatsugu Moriwaki a,b, Kunihiro Kawashima a,c,d, Tomo Okochi a,c, Yasuhisa Fukuo a,c, Tsuyoshi Kitajima a,c, Osamu Furukawa b, Hiroshi Naitoh a, Kiyoshi Fujita b, Nakao Iwata a,c a
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan Okehazama Hospital, Toyoake, Aichi 470-1168, Japan Japan Science and Technology Agency, CREST, Kawaguchi, Saitama, Japan d Jindai Hospital, Toyota, Aichi 470-0361, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 October 2009 Received in revised form 1 December 2009 Accepted 8 December 2009 Available online 16 December 2009
Several investigators have reported cognitive dysfunction in chronic schizophrenia that was associated with insight and social skills. Such cognitive dysfunction seriously hinders an immediate return to normal life. Recently, Kaneda et al. reported that the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) was superior in the evaluation of the cognitive function. We investigated which clinical factors (age, sex, duration of illness, level of education, smoking status, the Positive and Negative Syndrome Scale (PANSS) score and medication dosage) affected cognitive dysfunction in 115 Japanese schizophrenic patients, with the use of multiple regression analysis. We detected an association between composite score, verbal memory, working memory and executive function and PANSS total score. Moreover, most cognitive tasks were associated with a negative PANSS score but not a positive PANSS score or general score. We also showed an association between age and verbal fluency and attention in schizophrenia. In addition, anxiolytics/hypnotics (diazepam-equivalent) were associated with composite score, working memory and motor speed. In conclusion, cognitive function was associated with PANSS score, especially negative PANSS score. Because anxiolytics/ hypnotics might have a detrimental influence on cognitive function, we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible. Crown Copyright ß 2009 Published by Elsevier Ireland Ltd on behalf of the Japan Neuroscience Society. All rights reserved.
Keywords: Cognitive function Brief Assessment of Cognition in Schizophrenia Japanese-language version (BACS-J) Schizophrenia Positive and Negative Syndrome Scale (PANSS) Anxiolytics/hypnotics
1. Introduction Several investigators have reported that cognitive dysfunction of schizophrenia in chronic status is a principal pathological condition disturbing the social function (Barch, 2005; Barch and Smith, 2008; Carter et al., 2008). Cognitive impairment in these patients is significantly associated with insight, social skills, and delay to return a normal life (Monteiro et al., 2008). Recently, Kaneda et al. (2007) reported that the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) is superior in the evaluation of cognitive function for schizophrenic patients in clinical use. Authors reported that the time required for testing with BACS is only approximately 30 min, with minimal extra time for scoring and training. BACS is simple
* Corresponding author at: Department of Psychiatry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 4701192, Japan. Tel.: +81 562 93 9250; fax: +81 562 93 1831. E-mail address: [email protected] (T. Kishi).
and easy, and, unlike the Wechsler Adult Intelligence Scale-Revised (WAIS-R), it has the advantage of being able to investigate several cognitive functions including verbal memory, working memory, motor speed, attention, executive functions and verbal fluency as primary measures (Kaneda et al., 2007). We replicated that study using larger samples (115 schizophrenic patients) than the original study (Kaneda et al., 2007). Also, there is less evidence for BACS compared with other psychological tests. In addition, cognitive functions are influenced by age, gender, duration of illness, smoking status, the Positive and Negative Syndrome Scale (PANSS) score and medication dosage (antipsychotics and benzodiazepine) in schizophrenic patients (Carter et al., 2008; Castle and Murray, 1991; Fagiolini and Goracci, 2009; Hofer et al., 2005; Ochoa and Lasalde-Dominicci, 2007; Reilly et al., 2008; Ritsner, 2007; Woodward et al., 2005). Several investigations reported that smoking behavior reinforces the cognitive functions (Carter et al., 2008; Ochoa and LasaldeDominicci, 2007). As the medication dosage of antipyshcotic increased, schizophrenics are given more sedation, and this may make their cognitive functions worse. Simons et al. (2007) reported
0168-0102/$ – see front matter . Crown Copyright ß 2009 Published by Elsevier Ireland Ltd on behalf of the Japan Neuroscience Society. All rights reserved. doi:10.1016/j.neures.2009.12.007
T. Kishi et al. / Neuroscience Research 66 (2010) 340–344
341
Table 1 Patient and control demographics and disposition. Schizophrenic patients n Current smoker/non-smoker, n (%) Sex (males/females) Age, years (mean SD)a Level of education, years (mean SD)a Duration of illness, day (mean SD)a
115 32/83, (27.8%) 75/40 52.0 15.4 13.2 2.84 9950 5871
Clinical diagnosis, n (%) Paranoid type Disorganized type Residual type PANSS total score
33 (28.7%) 11 (9.57%) 71 (61.7%) 80.0 21.1
Antipsychotics Monopharmacy/polypharmacy, n (%) Each kind of antipsychotic in monotherapy group (RIS/OLZ/ARP/QTP/PS/BNS/HPD/TP), nb
45/70, (39.1%) 14/11/11/4/1/1/2/1
Medication dosage Antipsychotics (mg/day)c, (mean SD)a Antiparkinsonian drugs, n (%) Mood stabilizers, n (%) Anxiolytics/hypnotics, n (%) (mg/day)d, (mean SD)a
694 52.5 0 (0%) 21 (21%) 75 (65.2%) (8.77 10.2)
a b c d
SD: standard deviation. RIS: risperidone, OLZ: olazapine, ARP: aripiprazole, QTP: quetiapine, PS: perospirone, BNS: blonar. Chlorpromazine-equivalent. Diazepam-equivalent.
that cognitive dysfunction was associated with negative symptoms . Also, cognitive function turns worse with age. However, there are few evidences in this field with Japanese schizophrenia. Here, we investigated which clinical factors affected cognitive functions in Japanese schizophrenic patients by using the multiple regression analysis. 2. Materials and methods 2.1. Subjects One hundred fifteen schizophrenic patients (75 males and 40 females: mean age standard deviation (SD) 52.0 15.4 years) were recruited. All subjects were unrelated to each other, ethnically Japanese, and lived in the central area of Japan. The patients were diagnosed according to DSM-IV criteria 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) and a review of medical records. All the patients met the following inclusion criteria: (1) age 25–70 years, (2) no systemic or neurologic disease, (3) no electroconvulsive therapy, (4) no history of head trauma, (5) no lifetime history of substance dependence or history of substance abuse within 3 months and (6) maintenance of main antipsychotic drug therapy for 2 months. The clinical backgrounds of participating patients are shown in Table 1. The study was described to subjects and written informed consent
was obtained from each. This study was approved by the Ethics Committees at Fujita Health University School of Medicine and Okehazama Hospital. 2.2. Evaluation of symptoms Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) and the Japaneselanguage version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) (Kaneda et al., 2007) as assessment tools. The BACS-J includes brief assessments of verbal memory, working memory, motor speed, verbal fluency, attention, and executive function. The primary measure from each test of the BACS-J was standardized by creating z-scores whereby the subjects mean of healthy control was set to zero and the standard deviation set to one. All data of healthy control was available from Kaneda et al.’s (2007) study. And, a composite score was calculated by averaging all z-scores of the six primary measures from the original BACS, using the means and the standard deviations of first test patients (Keefe et al., 2004). Detailed information about BACS can be seen in their papers (Kaneda et al., 2007; Keefe et al., 2004). 2.3. Statistical analysis First, we performed a replication using a larger sample (115 schizophrenic patients) than in Kaneda et al.’s (2007) study. The
Table 2 Correlations among BACS-J measures for patients with schizophrenia. Mean of raw scorea Verbal memory Working memory Motor speed Verbal fluency Attention Executive function Composite score * a b c
23.8 11.1 13.2 4.93 50.5 19.7 13.8 5.01 34.4 15.7 10.3 6.65
Mean of z-scorea,b 3.15 1.36 3.l0 1.94 3.45 7.61 2.34 l.67 3.90 l.85 3.72 2.69 4.94 2.56
Verbal memoryc
Working memoryc
Motor speedc
Verbal fluencyc
0.628* 0.414* 0.670* 0.589* 0.507* 0.660*
0.531* 0.713* 0.706* 0.585* 0.780*
0.496* 0.695* 0.455* 0.876*
0.689* 0.542* 0.748*
Attentionc
0.654* 0.861*
Executive functionc
0.715*
P < 0.0001. Mean score standard deviation (SD). A composite score was calculated by averaging all z-scores of the six primary measures from the B ACS-J, using the first test patient means and the standard deviations. Pearson correlations between each primary measures of BACS-J.
T. Kishi et al. / Neuroscience Research 66 (2010) 340–344
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Table 3 Multiple regression analysis of BACS-J measures with clinical variables. SRCc Composite score
Verbal memory
Working memory
Motor speed
Verbal fluency
Attention
Executive function
a b c d
P valued
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnoticsb
0.317 0.122 0.12 0.0931 0.114 0.245
0.0686 0.241 0.234 0.591 0.287 0.0194
0.116 0.246
0.292 0.0206
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnoticsb
0.176 0.0746 0.0440 0.157 0.172 0.315
0.331 0.491 0.677 0.386 0.127 0.00450
0.0729 0.103
0.525 0.345
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnotics
0.148 0.0831 0.121 0.0802 0.0233 0.220
0.417 0.449 0.259 0.661 0.837 0.0466
0.0233 0.251
0.841 0.0252
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnotics
0.254 0.194 0.129 0.0271 0.0827 0.184
0.149 0.0674 0.207 0.877 0.446 0.0813
0.120 0.258
0.282 0.0168
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnoticsb
0.422 0.0758 0.0622 0.329 0.106 0.155
0.0240 0.493 0.564 0.0771 0.354 0.163
0.128 0.189
0.278 0.0936
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnoticsb
0.448 0.0903 0.162 0.188 0.0778 0.161
0.0122 0.392 0.117 0.287 0.475 0.127
0.116 0.204
0.300 0.0579
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnotics
0.229 0.0797 0.0308 0.0378 0.152 0.270
0.191 0.445 0.762 0.828 0.161 0.0108
0.0743 0.118
0.502 0.263
Chlorpromazine-equivalent. Diazepam-equivalent. SRC: standardized regression coefficient. Bold represents significant P value.
Total P valued
0.00200
0.0383
0.0745
0.00510
0.124
0.00620
0.00350
T. Kishi et al. / Neuroscience Research 66 (2010) 340–344
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Table 4 Multiple regression analysis of BACS-J measures with PANSS subcategories. Positive PANSS score P value Composite score Verbal memory Working memory Motor speed Verbal fluency Attention Executive function a b
a
0.727 0.467 0.550 0.955 0.367 0.265 0.731
Negative PANSS score b
SRC
0.00469 0.0972 0.0808 0.00785 0.120 0.150 0.0455
P value
a
0.0282 0.0260 0.0243 0.359 0.00190 0.00970 0.00630
SRC
Total P valuea
General PANSS score b
0.287 0.289 0.296 0.122 0.406 0.340 0.354
P value 0.631 0.963 0.788 0.384 0.591 0.931 0.838
a
SRC
b
0.0771 0.00747 0.0436 0.144 0.0857 0.0140 0.0324
0.0172 0.0113 0.0332 0.147 0.00860 0.0192 0.00490
Bold represents significant P value. SRC: standardized regression coefficient.
relationship among the BACS-J measures was determined by calculating Pearson correlations among the scores. For all BACS-J primary measures and composite score, test–retest reliability was measured with Pearson correlations. Second, because several investigators have reported significant differences in cognitive functions with age, gender, duration of illness, level of education, smoking status, PANSS total score and medication dosage (antipsychotics and benzodiazepine) in schizophrenic patients (Carter et al., 2008; Castle and Murray, 1991; Fagiolini and Goracci, 2009; Hofer et al., 2005; Ochoa and Lasalde-Dominicci, 2007; Reilly et al., 2008; Ritsner, 2007; Woodward et al., 2005), we performed a multiple regression analysis of the possible correlations between BACS-J primary measures (verbal memory, working memory, motor speed, attention, executive functions and verbal fluency, respectively) or composite score and clinical variables. In these analyses, composite score or BACS-J primary measure was set as the dependent variable, and age, gender, duration of illness, level of education, smoking status (smoker or non-smoker), PANSS score and medication dosage (antipsychotics and benzodiazepine) were set as the independent variables. We detected an association between most of the BACS-J primary measures and PANSS score. Therefore, third, we investigated which PANSS score (positive, negative or general score) affected cognitive functions on schizophrenic patients with the use of multiple regression analysis. In these analyses, composite score or BACS-J primary measure was set as the dependent variable, and PANSS score (positive, negative or general score) was set as the independent variables. The significance level for all statistical tests was 0.05. All statistical analyses were performed using JMP (JMP 5.0. 1J, SAS Japan Inc., Tokyo, Japan). 3. Results 3.1. Evaluation of cognitive function on schizophrenic patients using BACS-J There was a strong correlation between composite scores and each BACS-J primary measure (Table 2). 3.2. Cognitive function in schizophrenia reflects clinical variables We detected a correlation between total PANSS score and composite score, verbal memory, working memory and executive function (Table 3). We also showed a correlation between age and verbal fluency and attention in schizophrenia (Table 3). In addition, anxiolytics/hypnotics (diazepam-equivalent) were correlated with composite score, working memory and motor speed (Table 3). However, gender, duration of illness, level of education, dosage of antipsychotics and smoking state were not correlated with composite score or BACS-J primary measures in multiple regression analysis (Table 3).
3.3. Cognitive function and PANSS subcategories Most of the BACS-J primary measures were correlated with negative PANSS score but not positive PANSS score or general score. Motor speed was not correlated with any PANSS subcategory (Table 4). 4. Discussion We investigated several cognitive functions in schizophrenic patients and controls using a larger sample than the previous report (Kaneda et al., 2007), and evaluated cognitive functions in schizophrenic patients using BACS-J. There was a strong correlation between all BACS-J primary measures and composite score. Kaneda et al. (2007) reported no correlation between verbal memory and motor speed, between verbal memory and verbal fluency, between attention and working memory, between executive function and verbal fluency, or between executive function and motor speed. We considered that the difference in some of the results in our study and the previous study might be due to the following reasons: (1) the influence on cognitive function of differences in the kind of antipsychotics, shown in several studies (Carter et al., 2008; Woodward et al., 2005); (2) a difference in the number of patients in each study; (3) differences in clinical background in each study. Therefore, we investigated which clinical factors affected cognitive functions in schizophrenic patients with the use of multiple regression analysis. Most BACS-J primary measures or composite scores were correlated with PANSS score, especially negative PANSS score. Kaneda et al. (2007) reported that a positive PANSS score was significantly correlated with working memory, but we did not detect such a correlation in this study. Simons et al. (2007) cognitive dysfunction is associated with negative symptoms. Also, verbal fluency and attention were associated with age but not PANSS score. In addition, dosage of anxiolytics/hypnotics (diazepam-equivalent) was correlated with working memory and motor speed. However, gender, duration of illness, level of education, dosage of antipsychotics and smoking state were not correlated with BACS-J primary measure or composite score in multiple regression analysis. Generally, patients with insomnia and severe anxiety were prescribed benzodiazepine drugs. In Japan, benzodiazepine is more widely used than in other countries (Yamawaki, 1999). Because anxiolytics/hypnotics might have a negative influence on cognitive function (Lagnaoui et al., 2004; Verdoux et al., 2005), we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible. A few points of caution should be noted in interpreting our results. First, several studies have shown that differences in the kind of antipsychotics influenced cognitive function. In this study, these differences were not analyzed. We also did not investigate more detailed information as to medication therapy (which antipsychotic drugs with these patients were taking at the time
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of assessment, and for how long) in this study. Second, 21 patients needed to take mood stabilizers such as valproic acid and carbamazepine. Since mood stabilizers influenced cognitive function in schizophrenic patients (Hosak and Libiger, 2002), our results for these 21 schizophrenic patients may have been influenced by the mood stabilizers. In conclusion, cognitive function was associated with PANSS score, especially negative PANSS score. Also, because anxiolytics/ hypnotics might have a negative influence on cognitive function, we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible. Acknowledgements We thank Mr. S. Maeda, Ms. E. Nakamura, Ms. M. Tojo, Ms. Y. Matsumoto, Ms. M. Tani, Ms. S. Isogai, Ms. M. Niwa and Ms. Y. Kato for their technical support. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Japan Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation). References Barch, D.M., 2005. The cognitive neuroscience of schizophrenia. Annu. Rev. Clin. Psychol. 1, 321–353. Barch, D.M., Smith, E., 2008. The cognitive neuroscience of working memory: relevance to CNTRICS and schizophrenia. Biol. Psychiatry 64 (1), 11–17. Carter, C.S., Barch, D.M., Buchanan, R.W., Bullmore, E., Krystal, J.H., Cohen, J., Geyer, M., Green, M., Nuechterlein, K.H., Robbins, T., Silverstein, S., Smith, E.E., Strauss, M., Wykes, T., Heinssen, R., 2008. Identifying cognitive mechanisms targeted for treatment development in schizophrenia: an overview of the first meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative. Biol. Psychiatry 64 (1), 4–10.
Castle, D.J., Murray, R.M., 1991. The neurodevelopmental basis of sex differences in schizophrenia. Psychol. Med. 21 (3), 565–575. Fagiolini, A., Goracci, A., 2009. The effects of undertreated chronic medical illnesses in patients with severe mental disorders. J. Clin. Psychiatry 70 (3), 22–29. Hofer, A., Baumgartner, S., Bodner, T., Edlinger, M., Hummer, M., Kemmler, G., Rettenbacher, M.A., Fleischhacker, W.W., 2005. Patient outcomes in schizophrenia II: the impact of cognition. Eur. Psychiatry 20 (5–6), 395–402. Hosak, L., Libiger, J., 2002. Antiepileptic drugs in schizophrenia: a review. Eur. Psychiatry 17 (7), 371–378. Kaneda, Y., Sumiyoshi, T., Keefe, R., Ishimoto, Y., Numata, S., Ohmori, T., 2007. Brief assessment of cognition in schizophrenia: validation of the Japanese version. Psychiatry Clin. Neurosci. 61 (6), 602–609. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13 (2), 261–276. Keefe, R.S., Goldberg, T.E., Harvey, P.D., Gold, J.M., Poe, M.P., Coughenour, L., 2004. The brief assessment of cognition in schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr. Res. 68 (2–3), 283–297. Lagnaoui, R., Depont, F., Fourrier, A., Abouelfath, A., Begaud, B., Verdoux, H., Moore, N., 2004. Patterns and correlates of benzodiazepine use in the French general population. Eur. J. Clin. Pharmacol. 60 (7), 523–529. Monteiro, L.C., Silva, V.A., Louza, M.R., 2008. Insight, cognitive dysfunction and symptomatology in schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 258 (7), 402–405. Ochoa, E.L., Lasalde-Dominicci, J., 2007. Cognitive deficits in schizophrenia: focus on neuronal nicotinic acetylcholine receptors and smoking. Cell. Mol. Neurobiol. 27 (5), 609–639. Reilly, J.L., Lencer, R., Bishop, J.R., Keedy, S., Sweeney, J.A., 2008. Pharmacological treatment effects on eye movement control. Brain Cogn. 68 (3), 415–435. Ritsner, M.S., 2007. Predicting quality of life impairment in chronic schizophrenia from cognitive variables. Qual. Life Res. 16 (6), 929–937. Simons, C.J., Jacobs, N., Jolles, J., van Os, J., Krabbendam, L., 2007. Subclinical psychotic experiences and cognitive functioning as a bivariate phenotype for genetic studies in the general population. Schizophr. Res. 92 (1–3), 24–31. Verdoux, H., Lagnaoui, R., Begaud, B., 2005. Is benzodiazepine use a risk factor for cognitive decline and dementia? A literature review of epidemiological studies. Psychol. Med. 35 (3), 307–315. Woodward, N.D., Purdon, S.E., Meltzer, H.Y., Zald, D.H., 2005. A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int. J. Neuropsychopharmacol. 8 (3), 457–472. Yamawaki, S., 1999. The use and development of anxiolytics in Japan. Eur. Neuropsychopharmacol. 9 (6), S413–S419.
Contents lists available at ScienceDirect
Neuroscience Research journal homepage: www.elsevier.com/locate/neures
Investigation of clinical factors influencing cognitive function in Japanese schizophrenia Taro Kishi a,c,*, Masatsugu Moriwaki a,b, Kunihiro Kawashima a,c,d, Tomo Okochi a,c, Yasuhisa Fukuo a,c, Tsuyoshi Kitajima a,c, Osamu Furukawa b, Hiroshi Naitoh a, Kiyoshi Fujita b, Nakao Iwata a,c a
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan Okehazama Hospital, Toyoake, Aichi 470-1168, Japan Japan Science and Technology Agency, CREST, Kawaguchi, Saitama, Japan d Jindai Hospital, Toyota, Aichi 470-0361, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 15 October 2009 Received in revised form 1 December 2009 Accepted 8 December 2009 Available online 16 December 2009
Several investigators have reported cognitive dysfunction in chronic schizophrenia that was associated with insight and social skills. Such cognitive dysfunction seriously hinders an immediate return to normal life. Recently, Kaneda et al. reported that the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) was superior in the evaluation of the cognitive function. We investigated which clinical factors (age, sex, duration of illness, level of education, smoking status, the Positive and Negative Syndrome Scale (PANSS) score and medication dosage) affected cognitive dysfunction in 115 Japanese schizophrenic patients, with the use of multiple regression analysis. We detected an association between composite score, verbal memory, working memory and executive function and PANSS total score. Moreover, most cognitive tasks were associated with a negative PANSS score but not a positive PANSS score or general score. We also showed an association between age and verbal fluency and attention in schizophrenia. In addition, anxiolytics/hypnotics (diazepam-equivalent) were associated with composite score, working memory and motor speed. In conclusion, cognitive function was associated with PANSS score, especially negative PANSS score. Because anxiolytics/ hypnotics might have a detrimental influence on cognitive function, we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible. Crown Copyright ß 2009 Published by Elsevier Ireland Ltd on behalf of the Japan Neuroscience Society. All rights reserved.
Keywords: Cognitive function Brief Assessment of Cognition in Schizophrenia Japanese-language version (BACS-J) Schizophrenia Positive and Negative Syndrome Scale (PANSS) Anxiolytics/hypnotics
1. Introduction Several investigators have reported that cognitive dysfunction of schizophrenia in chronic status is a principal pathological condition disturbing the social function (Barch, 2005; Barch and Smith, 2008; Carter et al., 2008). Cognitive impairment in these patients is significantly associated with insight, social skills, and delay to return a normal life (Monteiro et al., 2008). Recently, Kaneda et al. (2007) reported that the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) is superior in the evaluation of cognitive function for schizophrenic patients in clinical use. Authors reported that the time required for testing with BACS is only approximately 30 min, with minimal extra time for scoring and training. BACS is simple
* Corresponding author at: Department of Psychiatry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 4701192, Japan. Tel.: +81 562 93 9250; fax: +81 562 93 1831. E-mail address: [email protected] (T. Kishi).
and easy, and, unlike the Wechsler Adult Intelligence Scale-Revised (WAIS-R), it has the advantage of being able to investigate several cognitive functions including verbal memory, working memory, motor speed, attention, executive functions and verbal fluency as primary measures (Kaneda et al., 2007). We replicated that study using larger samples (115 schizophrenic patients) than the original study (Kaneda et al., 2007). Also, there is less evidence for BACS compared with other psychological tests. In addition, cognitive functions are influenced by age, gender, duration of illness, smoking status, the Positive and Negative Syndrome Scale (PANSS) score and medication dosage (antipsychotics and benzodiazepine) in schizophrenic patients (Carter et al., 2008; Castle and Murray, 1991; Fagiolini and Goracci, 2009; Hofer et al., 2005; Ochoa and Lasalde-Dominicci, 2007; Reilly et al., 2008; Ritsner, 2007; Woodward et al., 2005). Several investigations reported that smoking behavior reinforces the cognitive functions (Carter et al., 2008; Ochoa and LasaldeDominicci, 2007). As the medication dosage of antipyshcotic increased, schizophrenics are given more sedation, and this may make their cognitive functions worse. Simons et al. (2007) reported
0168-0102/$ – see front matter . Crown Copyright ß 2009 Published by Elsevier Ireland Ltd on behalf of the Japan Neuroscience Society. All rights reserved. doi:10.1016/j.neures.2009.12.007
T. Kishi et al. / Neuroscience Research 66 (2010) 340–344
341
Table 1 Patient and control demographics and disposition. Schizophrenic patients n Current smoker/non-smoker, n (%) Sex (males/females) Age, years (mean SD)a Level of education, years (mean SD)a Duration of illness, day (mean SD)a
115 32/83, (27.8%) 75/40 52.0 15.4 13.2 2.84 9950 5871
Clinical diagnosis, n (%) Paranoid type Disorganized type Residual type PANSS total score
33 (28.7%) 11 (9.57%) 71 (61.7%) 80.0 21.1
Antipsychotics Monopharmacy/polypharmacy, n (%) Each kind of antipsychotic in monotherapy group (RIS/OLZ/ARP/QTP/PS/BNS/HPD/TP), nb
45/70, (39.1%) 14/11/11/4/1/1/2/1
Medication dosage Antipsychotics (mg/day)c, (mean SD)a Antiparkinsonian drugs, n (%) Mood stabilizers, n (%) Anxiolytics/hypnotics, n (%) (mg/day)d, (mean SD)a
694 52.5 0 (0%) 21 (21%) 75 (65.2%) (8.77 10.2)
a b c d
SD: standard deviation. RIS: risperidone, OLZ: olazapine, ARP: aripiprazole, QTP: quetiapine, PS: perospirone, BNS: blonar. Chlorpromazine-equivalent. Diazepam-equivalent.
that cognitive dysfunction was associated with negative symptoms . Also, cognitive function turns worse with age. However, there are few evidences in this field with Japanese schizophrenia. Here, we investigated which clinical factors affected cognitive functions in Japanese schizophrenic patients by using the multiple regression analysis. 2. Materials and methods 2.1. Subjects One hundred fifteen schizophrenic patients (75 males and 40 females: mean age standard deviation (SD) 52.0 15.4 years) were recruited. All subjects were unrelated to each other, ethnically Japanese, and lived in the central area of Japan. The patients were diagnosed according to DSM-IV criteria 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) and a review of medical records. All the patients met the following inclusion criteria: (1) age 25–70 years, (2) no systemic or neurologic disease, (3) no electroconvulsive therapy, (4) no history of head trauma, (5) no lifetime history of substance dependence or history of substance abuse within 3 months and (6) maintenance of main antipsychotic drug therapy for 2 months. The clinical backgrounds of participating patients are shown in Table 1. The study was described to subjects and written informed consent
was obtained from each. This study was approved by the Ethics Committees at Fujita Health University School of Medicine and Okehazama Hospital. 2.2. Evaluation of symptoms Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) and the Japaneselanguage version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) (Kaneda et al., 2007) as assessment tools. The BACS-J includes brief assessments of verbal memory, working memory, motor speed, verbal fluency, attention, and executive function. The primary measure from each test of the BACS-J was standardized by creating z-scores whereby the subjects mean of healthy control was set to zero and the standard deviation set to one. All data of healthy control was available from Kaneda et al.’s (2007) study. And, a composite score was calculated by averaging all z-scores of the six primary measures from the original BACS, using the means and the standard deviations of first test patients (Keefe et al., 2004). Detailed information about BACS can be seen in their papers (Kaneda et al., 2007; Keefe et al., 2004). 2.3. Statistical analysis First, we performed a replication using a larger sample (115 schizophrenic patients) than in Kaneda et al.’s (2007) study. The
Table 2 Correlations among BACS-J measures for patients with schizophrenia. Mean of raw scorea Verbal memory Working memory Motor speed Verbal fluency Attention Executive function Composite score * a b c
23.8 11.1 13.2 4.93 50.5 19.7 13.8 5.01 34.4 15.7 10.3 6.65
Mean of z-scorea,b 3.15 1.36 3.l0 1.94 3.45 7.61 2.34 l.67 3.90 l.85 3.72 2.69 4.94 2.56
Verbal memoryc
Working memoryc
Motor speedc
Verbal fluencyc
0.628* 0.414* 0.670* 0.589* 0.507* 0.660*
0.531* 0.713* 0.706* 0.585* 0.780*
0.496* 0.695* 0.455* 0.876*
0.689* 0.542* 0.748*
Attentionc
0.654* 0.861*
Executive functionc
0.715*
P < 0.0001. Mean score standard deviation (SD). A composite score was calculated by averaging all z-scores of the six primary measures from the B ACS-J, using the first test patient means and the standard deviations. Pearson correlations between each primary measures of BACS-J.
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Table 3 Multiple regression analysis of BACS-J measures with clinical variables. SRCc Composite score
Verbal memory
Working memory
Motor speed
Verbal fluency
Attention
Executive function
a b c d
P valued
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnoticsb
0.317 0.122 0.12 0.0931 0.114 0.245
0.0686 0.241 0.234 0.591 0.287 0.0194
0.116 0.246
0.292 0.0206
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnoticsb
0.176 0.0746 0.0440 0.157 0.172 0.315
0.331 0.491 0.677 0.386 0.127 0.00450
0.0729 0.103
0.525 0.345
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnotics
0.148 0.0831 0.121 0.0802 0.0233 0.220
0.417 0.449 0.259 0.661 0.837 0.0466
0.0233 0.251
0.841 0.0252
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnotics
0.254 0.194 0.129 0.0271 0.0827 0.184
0.149 0.0674 0.207 0.877 0.446 0.0813
0.120 0.258
0.282 0.0168
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnoticsb
0.422 0.0758 0.0622 0.329 0.106 0.155
0.0240 0.493 0.564 0.0771 0.354 0.163
0.128 0.189
0.278 0.0936
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnoticsb
0.448 0.0903 0.162 0.188 0.0778 0.161
0.0122 0.392 0.117 0.287 0.475 0.127
0.116 0.204
0.300 0.0579
Age Sex Level of education, years (mean SD) Duration of illness, day (mean SD) Current smoker/non-smoker PANSS Medication dosage (mg/day) Antipsychoticsa Anxiolytics/hypnotics
0.229 0.0797 0.0308 0.0378 0.152 0.270
0.191 0.445 0.762 0.828 0.161 0.0108
0.0743 0.118
0.502 0.263
Chlorpromazine-equivalent. Diazepam-equivalent. SRC: standardized regression coefficient. Bold represents significant P value.
Total P valued
0.00200
0.0383
0.0745
0.00510
0.124
0.00620
0.00350
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Table 4 Multiple regression analysis of BACS-J measures with PANSS subcategories. Positive PANSS score P value Composite score Verbal memory Working memory Motor speed Verbal fluency Attention Executive function a b
a
0.727 0.467 0.550 0.955 0.367 0.265 0.731
Negative PANSS score b
SRC
0.00469 0.0972 0.0808 0.00785 0.120 0.150 0.0455
P value
a
0.0282 0.0260 0.0243 0.359 0.00190 0.00970 0.00630
SRC
Total P valuea
General PANSS score b
0.287 0.289 0.296 0.122 0.406 0.340 0.354
P value 0.631 0.963 0.788 0.384 0.591 0.931 0.838
a
SRC
b
0.0771 0.00747 0.0436 0.144 0.0857 0.0140 0.0324
0.0172 0.0113 0.0332 0.147 0.00860 0.0192 0.00490
Bold represents significant P value. SRC: standardized regression coefficient.
relationship among the BACS-J measures was determined by calculating Pearson correlations among the scores. For all BACS-J primary measures and composite score, test–retest reliability was measured with Pearson correlations. Second, because several investigators have reported significant differences in cognitive functions with age, gender, duration of illness, level of education, smoking status, PANSS total score and medication dosage (antipsychotics and benzodiazepine) in schizophrenic patients (Carter et al., 2008; Castle and Murray, 1991; Fagiolini and Goracci, 2009; Hofer et al., 2005; Ochoa and Lasalde-Dominicci, 2007; Reilly et al., 2008; Ritsner, 2007; Woodward et al., 2005), we performed a multiple regression analysis of the possible correlations between BACS-J primary measures (verbal memory, working memory, motor speed, attention, executive functions and verbal fluency, respectively) or composite score and clinical variables. In these analyses, composite score or BACS-J primary measure was set as the dependent variable, and age, gender, duration of illness, level of education, smoking status (smoker or non-smoker), PANSS score and medication dosage (antipsychotics and benzodiazepine) were set as the independent variables. We detected an association between most of the BACS-J primary measures and PANSS score. Therefore, third, we investigated which PANSS score (positive, negative or general score) affected cognitive functions on schizophrenic patients with the use of multiple regression analysis. In these analyses, composite score or BACS-J primary measure was set as the dependent variable, and PANSS score (positive, negative or general score) was set as the independent variables. The significance level for all statistical tests was 0.05. All statistical analyses were performed using JMP (JMP 5.0. 1J, SAS Japan Inc., Tokyo, Japan). 3. Results 3.1. Evaluation of cognitive function on schizophrenic patients using BACS-J There was a strong correlation between composite scores and each BACS-J primary measure (Table 2). 3.2. Cognitive function in schizophrenia reflects clinical variables We detected a correlation between total PANSS score and composite score, verbal memory, working memory and executive function (Table 3). We also showed a correlation between age and verbal fluency and attention in schizophrenia (Table 3). In addition, anxiolytics/hypnotics (diazepam-equivalent) were correlated with composite score, working memory and motor speed (Table 3). However, gender, duration of illness, level of education, dosage of antipsychotics and smoking state were not correlated with composite score or BACS-J primary measures in multiple regression analysis (Table 3).
3.3. Cognitive function and PANSS subcategories Most of the BACS-J primary measures were correlated with negative PANSS score but not positive PANSS score or general score. Motor speed was not correlated with any PANSS subcategory (Table 4). 4. Discussion We investigated several cognitive functions in schizophrenic patients and controls using a larger sample than the previous report (Kaneda et al., 2007), and evaluated cognitive functions in schizophrenic patients using BACS-J. There was a strong correlation between all BACS-J primary measures and composite score. Kaneda et al. (2007) reported no correlation between verbal memory and motor speed, between verbal memory and verbal fluency, between attention and working memory, between executive function and verbal fluency, or between executive function and motor speed. We considered that the difference in some of the results in our study and the previous study might be due to the following reasons: (1) the influence on cognitive function of differences in the kind of antipsychotics, shown in several studies (Carter et al., 2008; Woodward et al., 2005); (2) a difference in the number of patients in each study; (3) differences in clinical background in each study. Therefore, we investigated which clinical factors affected cognitive functions in schizophrenic patients with the use of multiple regression analysis. Most BACS-J primary measures or composite scores were correlated with PANSS score, especially negative PANSS score. Kaneda et al. (2007) reported that a positive PANSS score was significantly correlated with working memory, but we did not detect such a correlation in this study. Simons et al. (2007) cognitive dysfunction is associated with negative symptoms. Also, verbal fluency and attention were associated with age but not PANSS score. In addition, dosage of anxiolytics/hypnotics (diazepam-equivalent) was correlated with working memory and motor speed. However, gender, duration of illness, level of education, dosage of antipsychotics and smoking state were not correlated with BACS-J primary measure or composite score in multiple regression analysis. Generally, patients with insomnia and severe anxiety were prescribed benzodiazepine drugs. In Japan, benzodiazepine is more widely used than in other countries (Yamawaki, 1999). Because anxiolytics/hypnotics might have a negative influence on cognitive function (Lagnaoui et al., 2004; Verdoux et al., 2005), we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible. A few points of caution should be noted in interpreting our results. First, several studies have shown that differences in the kind of antipsychotics influenced cognitive function. In this study, these differences were not analyzed. We also did not investigate more detailed information as to medication therapy (which antipsychotic drugs with these patients were taking at the time
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of assessment, and for how long) in this study. Second, 21 patients needed to take mood stabilizers such as valproic acid and carbamazepine. Since mood stabilizers influenced cognitive function in schizophrenic patients (Hosak and Libiger, 2002), our results for these 21 schizophrenic patients may have been influenced by the mood stabilizers. In conclusion, cognitive function was associated with PANSS score, especially negative PANSS score. Also, because anxiolytics/ hypnotics might have a negative influence on cognitive function, we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible. Acknowledgements We thank Mr. S. Maeda, Ms. E. Nakamura, Ms. M. Tojo, Ms. Y. Matsumoto, Ms. M. Tani, Ms. S. Isogai, Ms. M. Niwa and Ms. Y. Kato for their technical support. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Japan Health Sciences Foundation (Research on Health Sciences focusing on Drug Innovation). References Barch, D.M., 2005. The cognitive neuroscience of schizophrenia. Annu. Rev. Clin. Psychol. 1, 321–353. Barch, D.M., Smith, E., 2008. The cognitive neuroscience of working memory: relevance to CNTRICS and schizophrenia. Biol. Psychiatry 64 (1), 11–17. Carter, C.S., Barch, D.M., Buchanan, R.W., Bullmore, E., Krystal, J.H., Cohen, J., Geyer, M., Green, M., Nuechterlein, K.H., Robbins, T., Silverstein, S., Smith, E.E., Strauss, M., Wykes, T., Heinssen, R., 2008. Identifying cognitive mechanisms targeted for treatment development in schizophrenia: an overview of the first meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative. Biol. Psychiatry 64 (1), 4–10.
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