- Email: [email protected]
Rosiglitazone and cognitive function in clozapine-treated patients with schizophrenia: A pilot study
Psychiatry Research 200 (2012) 79–82
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Rosiglitazone and cognitive function in clozapine-treated patients with schizophrenia: A pilot study Zhenghui Yi a, Xiaoduo Fan b,c,n, JiJun Wang a, Dengtang Liu a, Oliver Freudenreich b,c, Donald Goff b,c, David C. Henderson b,c a
Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China Schizophrenia Program, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA c Harvard Medical School, Boston, MA, USA b
a r t i c l e i n f o
abstract
Article history: Received 12 June 2011 Received in revised form 19 May 2012 Accepted 21 May 2012
Studies have shown that insulin resistance is associated with cognitive impairment. Peroxisome proliferator-activated receptor-g (PPAR-g) agonists improve insulin sensitivity. The purpose of this study was to evaluate the effect of rosiglitazone, a PPAR-g agonist, on cognition in clozapine-treated patients with schizophrenia. In an eight-week double-blind, placebo-controlled pilot trial, clozapinetreated patients with schizophrenia were randomized to receive rosiglitazone (4 mg/day) or placebo. A neuropsychological battery including the Digit Span subtest from the Wechsler Adult Intelligence ScaleIII (WAIS-III), the verbal fluency test, the Hopkins Verbal Learning Test (HVLT), the Trail-Making Test (TMT) and the Wisconsin Card Sorting Test (WCST) was administered at baseline and week eight. Nineteen patients completed the study. There were no significant differences on any demographic or general clinical variables between the rosiglitazone group (n ¼ 9) and the placebo group (n ¼ 10). When baseline scores were controlled, there were no significant differences in change scores of cognitive performance over eight weeks between the two groups. In this pilot study, rosiglitazone had no cognitive benefit in clozapine-treated patients with schizophrenia. Future studies with longer treatment duration and larger sample size are needed to further explore the potential role of rosiglitazone in improving cognitive function in patients with schizophrenia. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Rosiglitazone Schizophrenia Cognition Clozapine Insulin resistance
1. Introduction Convergent evidence has identified cognitive deficits in schizophrenia, especially in the domains of attention, verbal memory, and executive function (Mortimer, 1997; Wobrock et al., 2009; Kishi et al., 2010). Cognitive deficits have been shown to be relatively independent of acute expression of positive symptoms such as hallucinations and delusions, remain prominent in many schizophrenia patients who become stable after treatment with antipsychotic agents such as clozapine, and are related to real life functioning in this patient population (Bilder et al., 1992; Green, 1996; Meltzer and McGurk, 1999; Akdede et al., 2006). Cognitive deficits have become a focus of interest in schizophrenia research. Studies have suggested that cognitive deficits might be related to insulin resistance and inflammation (Areosa and Grimley, 2002; Awad et al., 2004; Dickinson and Harvey, 2009; McNay et al., 2010). A previous study has revealed that insulin can modulates memory
n Corresponding author at: Freedom Trail Clinic, 25 Staniford Street, Boston, MA 02114, USA. E-mail address: [email protected] (X. Fan).
0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.05.020
(Biessels et al., 2004). In rodents, insulin receptors and insulinsensitive glucose transporters are selectively co-localized in brain areas involved with memory; these structures provide a platform for physiological actions, such as increased insulin signaling, and selective increases in cerebral glucose utilization that could modulate memory (Watson and Craft, 2003; Craft and Watson, 2004). Streptozotocin, a compound that impairs secretion of insulin from beta cells in the pancreas, has been found to induce diabetes and result in severe deficits in learning and memory formation in rats performing a water maze task (Biessels et al., 1998). Patients with schizophrenia have an increased prevalence of obesity, type 2 diabetes, and dyslipidemia, which increase the risk for cardiovascular diseases and mortality (Monteleone et al., 2009). Part of the increased cardiometabolic risk in this patient population is attributable to the use of antipsychotic medications, especially the second-generation antipsychotics, such as clozapine. Studies have shown that clozapine is associated with insulin resistance and impaired glucose metabolism (Kamran et al., 1994; Henderson et al., 2000, 2005, 2007; Koller et al., 2001). Peroxisome proliferator-activated receptor-g (PPAR-g) agonists improve insulin sensitivity, decrease inflammation, inhibit beta-stimulated secretion of pro-inflammatory products, arrest
80
Z. Yi et al. / Psychiatry Research 200 (2012) 79–82
the evolution of activated macrophages, and inhibit expression of cyclooxygenase-2. PPAR-g agonists may protect neural tissue from the deleterious influence of inflammation and insulin resistance (Combs et al., 2000; Sastre et al., 2003). Our previous study found that the PPAR-g agonist rosiglitazone improved insulin sensitivity and glucose metabolism in clozapine-treated patients with schizophrenia (Henderson et al., 2009). Therefore, PPAR-g agonists may represent promising candidates to treat cognitive deficits seen in various patient populations. In a placebo-controlled, double-blind study in 30 patients with early Alzheimer’s disease, subjects receiving rosiglitazone exhibited better delayed recall than the placebo group (Watson et al., 2005). Another study showed that rosiglitazone reversed memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer’s disease mouse model (Escribano et al., 2009). The purpose of the present study was to examine the effect of rosiglitazone on cognitive function in schizophrenia. We conducted an eight-week double-blind, placebo-controlled pilot trial in clozapine-treated patients with schizophrenia.
2. Methods 2.1. Subjects Subjects were recruited from the Freedom Trial Clinic at the Erich Lindemann Mental Health Center and were studied at the Mallinckrodt General Clinical Research Center (GCRC) at Massachusetts General Hospital (MGH), Boston. The study was approved by the institutional review boards of MGH, and the Massachusetts Department of Mental Health. Outpatients between the ages of 18 and 65 years from diverse social, economic and racial backgrounds with the diagnosis of schizophrenia or schizoaffective disorder were screened for the study. Eligibility was determined by interview and a medical record review for history and recent laboratory values. After providing written informed consent, subjects underwent a diagnostic evaluation by a research psychiatrist using the Structured Clinical Interview for DSM-IV (SCID) (Spitzer et al., 1992). Patients treated with clozapine for at least one year were included in the study. The exclusion criteria were as follows: current substance abuse; type 1 or 2 diabetes; thyroid disease; pregnancy; significant medical conditions including severe cardiovascular, hepatic or renal diseases; and unstable psychiatric condition.
2.4. Statistical analysis Descriptive statistics were used to describe demographic and clinical characteristics of the study sample. The chi-squared test was used to access differences in frequency. Group comparisons were performed using independent t-tests for continuous variables and chi-squared tests for categorical variables. An analysis of covariance (ANCOVA) was used to examine change scores from baseline to week eight between groups after controlling for baseline scores. For all analyses, a value of Po 0.05 (two-tailed) was used for statistical significance.
3. Results Thirty-two subjects consented to participate in the study. Seven subjects withdrew consent before baseline assessment; three subjects were ineligible based on abnormal baseline laboratory values (two for abnormal liver function tests, one for elevated fasting glucose). Two subjects were hospitalized after consenting (one for psychotic decompensation and one for new onset diabetes); one subject withdrew from the study after significant weight gain. Nineteen subjects completed the study. Table 1 presents demographic and clinical characteristics for the subjects who completed the study. There were no differences between the placebo and rosiglitazone groups on age, age of illness onset, education, gender, race, smoking status, clozapine daily dose, clozapine treatment duration, and PANSS scores. Table 2 presents means and standard deviations of neuropsychological test scores for the Digit Span (forward and backward), the verbal fluency test (total score), the HVLT (immediate recall and delayed recall), the TMT (forms A and B) and the WCST (perseverative errors and categories completed) at baseline and week eight. When baseline scores were controlled for, there were no significant differences in change scores on cognitive performance over eight weeks between the rosiglitazone group and the placebo group (P’s 40.05). There were no significant differences in change scores over eight weeks on the PANSS total or subscale scores between the two groups (data not shown).
2.2. Study procedure
4. Discussion
The study was a double-blind placebo-controlled study evaluating the effect of rosiglitazone (4 mg/day) on cognitive function in patients with schizophrenia. Following baseline assessment (demographics and clinical characteristics including the Positive and Negative Syndrome Scale (PANSS) scores), 19 subjects (male: female 14:5) were eligible for randomization to rosiglitazone (n¼ 9) or placebo (n¼ 10). Patients were maintained on their prior antipsychotic treatment regimen during the study period.
We believe that the present study was the first clinical trial to examine the potential cognitive benefit of rosiglitazone in patients with schizophrenia. In this study, rosiglitazone treatment (4 mg/day) for eight weeks had no significant beneficial effect on cognition (verbal fluency, verbal memory, working memory and executive function) in patients with schizophrenia, even though we previously reported that rosiglitazone improved insulin sensitivity and glucose metabolism (Henderson et al., 2009). Our results differ from the findings in patients with Alzheimer’s disease, where rosiglitazone treatment for six months was associated with significant cognitive improvement (Watson et al., 2005). The discrepancy in findings may be explained by differences in study populations, rosiglitazone dosing, and treatment duration. The limitations of the present study include a relatively small sample size and the relatively short intervention time period (eight weeks). In conclusion, the present pilot study failed to demonstrate cognitive benefits of rosiglitazone in clozapine-treated schizophrenia patients. Some reports suggest that rosiglitazone is associated with an increased risk of heart attack. Future studies with a larger sample size and a longer intervention time period are needed to further explore the potential role of rosiglitazone in improving cognitive function as well as the drug’s safety in patients with schizophrenia.
2.3. Neuropsychological tests Five neuropsychological tests were administrated to each subject at baseline and week eight. The Digit Span subtest (forward and backward) from the Wechsler Adult Intelligence Scale-III (WAIS-III) (Wechsler, 1997) is used to evaluate attention. The verbal fluency test (FAS) requires the generation of as many words as possible starting with the letter F, A or S (1 min each). The verbal fluency test reflects executive function (Benton and Hamsher, 1989). The Hopkins Verbal Learning Test (HVLT) has been widely used to assess verbal memory (Shapiro et al., 1999). A list of 12 words from three taxonomic categories is presented to the subject with words read aloud at the rate of approximately one word every 2 s. The test includes three learning trials and a delayed recall trial. In the Trail-Making Test (TMT), subjects are asked to connect a series of numbers (Form-A), or connect alternating letters and numbers (Form-B, e.g. 1-A-2-B-3) (Reitan, 1992). The TMT reflects attention and executive function. The Wisconsin Card Sorting Test (WCST) is used to assess executive function and problem solving. In this computerized test, subjects match cards on a monitor to one of four key cards. They are not told how to match the cards, but instead are told whether their matches are correct or not. If the subject matches correctly 10 consecutive times, the matching rule changes, but the subject is not told of the rule change. The test was modified in the present study. The number of cards was reduced from 128 to 64 (Heaton, 1981).
Z. Yi et al. / Psychiatry Research 200 (2012) 79–82
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Table 1 Demographic and clinical characteristics of the study sample. Placebo (n¼ 10)
Age (years) Age of illness onset (years) Education (years) Clozapine dose (mg/d) Clozapine treatment duration (years) PANSS-positive PANSS-negative PANSS-general PANSS-total
Rosiglitazone (n¼9)
t
d.f.
P
Mean
S.D.
Mean
S.D.
39.7 28.4 12.8 363 8 13.9 17.5 30.4 61.8
7.5 9.6 2.4 133 3 6.9 7.8 8.2 17.9
41.4 25.9 12.3 361 9 14.4 15.6 27.9 57.9
10.3 10.0 2.1 167 4 4.9 4.2 6.6 12.6
0.35 0.28 0.57 0.20 0.55 0.19 0.66 0.73 0.54
17 17 17 17 17 17 17 17 17
0.63 0.78 0.67 0.98 0.59 0.85 0.52 0.48 0.59
n
%
n
%
v2
d.f.
P
Gender Male Female
7 3
70 30
7 2
77 23
0.15
1
0.70
Race Caucasian Hispanic
8 2
80 20
9 0
100 0
2.00
1
0.16
Smoking status Yes No
5 5
50 50
4 5
44 56
0.06
1
0.81
Family history of diabetes Yes No
3 7
30 70
6 3
67 33
2.55
1
0.11
Table 2 Comparison of cognitive performance between the rosiglitazone group and the placebo group. Placebo (n¼ 10) Baseline Mean
Rosiglitazone (n¼ 9) Week eight
S.D.
Mean
Baseline S.D.
Mean
ANCOVA Week eight
S.D.
Mean
S.D.
F
d.f.
P
Digit span Forward Backward
10.00 5.89
2.06 2.57
10.00 6.44
2.29 2.60
9.44 6.00
2.70 2.18
10.00 6.44
2.35 2.30
0.95 0.03
1, 15 1, 15
0.43 0.87
Verbal fluency total
31.40
9.12
29.70
13.39
26.67
8.03
27.67
10.17
0.84
1, 16
0.37
HVLT Immediate recall Delayed recall
15.22 3.63
5.74 2.56
15.33 3.50
5.05 2.98
15.33 5.29
6.18 1.98
16.22 4.71
6.24 2.21
0.12 0.01
1, 15 1, 12
0.74 0.94
62.89 116.13
22.62 36.09
60.56 100.50
26.61 34.45
49.20 112.67
17.87 33.51
52.89 98.67
35.32 33.45
0.45 0.00
1, 15 1, 14
0.51 0.98
14.00 1.25
6.09 1.39
14.25 0.75
7.76 1.39
15.75 1.25
11.65 1.16
17.00 1.00
12.00 1.20
0.19 0.47
1, 13 1, 13
0.67 0.51
TMT Form A Form B WCST Perseverative errors Categories completed
Note: group comparisons of change scores were performed using analysis of covariance (ANCOVA) controlling for baseline cognitive scores; WCST ¼ Wisconsin Card Sorting Test; HVLT¼Hopkins Verbal Learning Test; TMT¼ Trail-Making Test.
Declaration of interest Dr. Fan has received research support or honoraria from Eli Lilly, AstraZeneca, Bristol-Myer-Squibb, Janssen, and Pfizer. Dr. Freudenreich has received research support or honoraria from AstraZeneca, Bristol-Myer-Squibb, Janssen, Eli Lilly, Cephalon and Pfizer. Dr. Goff has received research support or honoraria from Bristol-Myers Squibb, Indevus Pharmaceuticals, H. Lundbeck, Schering-Plough, Eli Lilly, Takeda, Biovail, Sovay, Hoffman-La Roche, Cypress, Dainippon Sumitomo, Abbott Laboratories, Genentech, Pfizer, Janssen, Novartis, PamLab, and GlaxoSmithKline and Endo Pharmaceuticals. He served on a DSMB for Otsuka. Dr.
Henderson has received research support or honoraria from Takeda, Janssen, Solvay, Novartis, Covance, Alkermis, and Pfizer. Drs. Yi, Wang and Liu report no disclosures. Dr. Yi and Dr. Fan were responsible for the analysis and interpretation of the data for this article. All authors were responsible for the writing of the article.
Acknowledgments This project was funded by the Stanley Foundation and a NARSAD Yong Investigator Award (DCH). The project described
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Z. Yi et al. / Psychiatry Research 200 (2012) 79–82
was supported by Grant numbers M01-RR-01066 and 1 UL1 RR025758-03, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. This project was also funded by Shanghai Municipal Health Bureau Research Projects of China (2009097) (ZY) References ¨ ukl ¨ u, ¨ M., Yazici, Akdede, B.B., Anil Ya˘gcio˘glu, A.E., Alptekin, K., Turgut, T.I., Tum ¨ gus ¨ -, A., Meltzer, H.Y., 2006. A double-blind M.K., Jayathilake, K., Tunca, Z., Go˘ study of combination of clozapine with risperidone in patients with schizophrenia: effects on cognition. Journal of Clinical Psychiatry 67, 1912–1919. Areosa, S.A., Grimley, E.J., 2002. Effect of the treatment of type II diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database of Systematic Reviews 4, CD003408. Awad, N., Gagnon, M., Messier, C., 2004. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. Journal of Clinical and Experimental Neuropsychology 26, 1044–1080. Benton, A.L., Hamsher, K., 1989. Multilingual aphasia examination, second ed. AJA Associates, Iowa City, IA. Biessels, G.J., Kamal, A., Urban, I.J., Spruijt, B.M., Erkelens, D.W., Gispen, W.H., 1998. Water maze learning and hippocampal synaptic plasticity in streptozotocindiabetic rats: effects of insulin treatment. Brain Research 27, 125–135. Biessels, G.J., Bravenboer, B., Gispen, W.H., 2004. Glucose, insulin and the brain: modulation of cognition and synaptic plasticity in health and disease: a preface. European Journal of Pharmacology 490, 1–4. Bilder, R.M., Turkel, E., Lipschutz-Broch, L., Lieberman, J.A., 1992. Antipsychotic medication effects on neuropsychological functions. Psychopharmacology Bulletin 28, 353–366. Combs, C.K., Johnson, D.E., Karlo, J.C., Cannady, S.B., Landreth, G.E., 2000. Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. Journal of Neuroscience 20, 558–567. Craft, S., Watson, G.S., 2004. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurology 3, 169–178. Dickinson, D., Harvey, P.D., 2009. Systemic hypotheses for generalized cognitive deficits in schizophrenia: a new take on an old problem. Schizophrenia Bulletin 35, 403–414. Escribano, L., Simo´n, A.M., Pe´rez-Mediavilla, A., Salazar-Colocho, P., Del Rı´o, J., Frechilla, D., 2009. Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer’s disease mouse model. Biochemical and Biophysical Research Communications 379, 406–410. Green, M.F., 1996. What are the functional consequences of neurocognitive deficits in schizophrenia? American Journal of Psychiatry 153, 321–330. Heaton, R.K., 1981. Wisconsin Card Sort Manual. Psychological Assessment Resources, Odessa, FL. Henderson, D.C., Cagliero, E., Gray, C., Nasrallah, R.A., Hayden, D.L., Schoenfeld, D.A., Goff, D.C.., 2000. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five year naturalistic study. American Journal of Psychiatry 157, 975–981. Henderson, D.C., Cagliero, E., Copeland, P.M., Borba, C.P., Evins, E., Hayden, D., Weber, M.T., Anderson, E.J., Allison, D.B., Daley, T.B., Schoenfeld, D., Goff, D.C., 2005. Glucose metabolism in patients with schizophrenia treated with
atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis. Archives of General Psychiatry 62, 19–28. Henderson, D.C., Cagliero, E., Copeland, P.M., Louie, P.M., Borba, C.P., Fan, X., Freudenreich, O., Goff, D.C., 2007. Elevated hemoglobin A1c as a possible indicator of diabetes mellitus and diabetic ketoacidosis in schizophrenia patients receiving atypical antipsychotics. Journal of Clinical Psychiatry 68, 533–541. Henderson, D.C., Fan, X., Sharma, B., Copeland, P.M., Borba, C.P., Boxill, R., Freudenreich, O., Cather, C., Eden Evins, A., Goff, D.C., 2009. A double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with schizophrenia. Acta Psychiatrica Scandinavica 119, 457–465. Kamran, A., Doraiswamy, P.M., Jane, J.L., Hammett, E.B., Dunn, L., 1994. Severe hyperglycemia associated with high doses of clozapine. American Journal of Psychiatry 151, 1395. Kishi, T., Moriwaki, M., Kawashima, K., Okochi, T., Fukuo, Y., Kitajima, T., Furukawa, O., Naitoh, H., Fujita, K., Iwata, N., 2010. Investigation of clinical factors influencing cognitive function in Japanese schizophrenia. Neuroscience Research 66, 340–344. Koller, E., Schneider, B., Bennett, K., Dubitsky, G., 2001. Clozapine-associated diabetes. American Journal of Medicine 111, 716–723. McNay, E.C., Ong, C.T., McCrimmon, R.J., Cresswell, J., Bogan, J.S., Sherwin, R.S., 2010. Hippocampal memory processes are modulated by insulin and high-fatinduced insulin resistance. Neurobiology of Learning and Memory 93, 546–553. Meltzer, H.Y., McGurk, S.R., 1999. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophrenia Bulletin 25, 233–255. Monteleone, P., Martiadis, V., Maj, M., 2009. Management of schizophrenia with obesity, metabolic, and endocrinological disorders. Psychiatric Clinics of North America 32, 775–794. Mortimer, A., 1997. Cognitive function in schizophrenia—do neuroleptics make a difference? Pharmacology, Biochemistry, and Behavior 56, 789–795. Reitan, R.M., 1992. Trail making test: manual for administration and scoring. Reitan Neuropsychology Laboratory, Tucson, AZ. Sastre, M., Dewachter, I., Landreth, G.E., Willson, T.M., Klockgether, T., van Leuven, F., Heneka, MT., 2003. Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. Journal of Neuroscience 23, 9796–9804. Shapiro, A.M., Benedict, R.H., Schretlen, D., Brandt, J., 1999. Construct and concurrent validity of the Hopkins Verbal Learning Test-Revised. Clinical Neuropsychologist 13, 348–358. Spitzer, R.L., Williams, J.B., Gibbon, M., First, M.B., 1992. The Structured Clinical Interview for DSM-III-R (SCID). I. History, rationale, and description. Archives of General Psychiatry 49, 624–629. Watson, G.S., Craft, S., 2003. The role of insulin-resistance in the pathogenesis of Alzheimer’s disease: implication for treatment. CNS Drugs 17, 27–45. Watson, G.S., Cholerton, B.A., Reger, M.A., Baker, L.D., Plymate, S.R., Asthana, S., Fishel, M.A., Kulstad, J.J., Green, P.S., Cook, D.G., Kahn, S.E., Keeling, M.L., Craft, S., 2005. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. American Journal of Geriatric Psychiatry 13, 950–958. Wechsler, D., 1997. Weschler adult intelligence scales, third ed. Harcourt Brace and Co., San Antonio, TX. Wobrock, T., Ecker, U.K., Scherk, H., Schneider-Axmann, T., Falkai, P., Gruber, O., 2009. Cognitive impairment of executive function as a core symptom of schizophrenia. World Journal of Biological Psychiatry 10, 442–451.
Contents lists available at SciVerse ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Rosiglitazone and cognitive function in clozapine-treated patients with schizophrenia: A pilot study Zhenghui Yi a, Xiaoduo Fan b,c,n, JiJun Wang a, Dengtang Liu a, Oliver Freudenreich b,c, Donald Goff b,c, David C. Henderson b,c a
Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China Schizophrenia Program, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA c Harvard Medical School, Boston, MA, USA b
a r t i c l e i n f o
abstract
Article history: Received 12 June 2011 Received in revised form 19 May 2012 Accepted 21 May 2012
Studies have shown that insulin resistance is associated with cognitive impairment. Peroxisome proliferator-activated receptor-g (PPAR-g) agonists improve insulin sensitivity. The purpose of this study was to evaluate the effect of rosiglitazone, a PPAR-g agonist, on cognition in clozapine-treated patients with schizophrenia. In an eight-week double-blind, placebo-controlled pilot trial, clozapinetreated patients with schizophrenia were randomized to receive rosiglitazone (4 mg/day) or placebo. A neuropsychological battery including the Digit Span subtest from the Wechsler Adult Intelligence ScaleIII (WAIS-III), the verbal fluency test, the Hopkins Verbal Learning Test (HVLT), the Trail-Making Test (TMT) and the Wisconsin Card Sorting Test (WCST) was administered at baseline and week eight. Nineteen patients completed the study. There were no significant differences on any demographic or general clinical variables between the rosiglitazone group (n ¼ 9) and the placebo group (n ¼ 10). When baseline scores were controlled, there were no significant differences in change scores of cognitive performance over eight weeks between the two groups. In this pilot study, rosiglitazone had no cognitive benefit in clozapine-treated patients with schizophrenia. Future studies with longer treatment duration and larger sample size are needed to further explore the potential role of rosiglitazone in improving cognitive function in patients with schizophrenia. & 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Rosiglitazone Schizophrenia Cognition Clozapine Insulin resistance
1. Introduction Convergent evidence has identified cognitive deficits in schizophrenia, especially in the domains of attention, verbal memory, and executive function (Mortimer, 1997; Wobrock et al., 2009; Kishi et al., 2010). Cognitive deficits have been shown to be relatively independent of acute expression of positive symptoms such as hallucinations and delusions, remain prominent in many schizophrenia patients who become stable after treatment with antipsychotic agents such as clozapine, and are related to real life functioning in this patient population (Bilder et al., 1992; Green, 1996; Meltzer and McGurk, 1999; Akdede et al., 2006). Cognitive deficits have become a focus of interest in schizophrenia research. Studies have suggested that cognitive deficits might be related to insulin resistance and inflammation (Areosa and Grimley, 2002; Awad et al., 2004; Dickinson and Harvey, 2009; McNay et al., 2010). A previous study has revealed that insulin can modulates memory
n Corresponding author at: Freedom Trail Clinic, 25 Staniford Street, Boston, MA 02114, USA. E-mail address: [email protected] (X. Fan).
0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.05.020
(Biessels et al., 2004). In rodents, insulin receptors and insulinsensitive glucose transporters are selectively co-localized in brain areas involved with memory; these structures provide a platform for physiological actions, such as increased insulin signaling, and selective increases in cerebral glucose utilization that could modulate memory (Watson and Craft, 2003; Craft and Watson, 2004). Streptozotocin, a compound that impairs secretion of insulin from beta cells in the pancreas, has been found to induce diabetes and result in severe deficits in learning and memory formation in rats performing a water maze task (Biessels et al., 1998). Patients with schizophrenia have an increased prevalence of obesity, type 2 diabetes, and dyslipidemia, which increase the risk for cardiovascular diseases and mortality (Monteleone et al., 2009). Part of the increased cardiometabolic risk in this patient population is attributable to the use of antipsychotic medications, especially the second-generation antipsychotics, such as clozapine. Studies have shown that clozapine is associated with insulin resistance and impaired glucose metabolism (Kamran et al., 1994; Henderson et al., 2000, 2005, 2007; Koller et al., 2001). Peroxisome proliferator-activated receptor-g (PPAR-g) agonists improve insulin sensitivity, decrease inflammation, inhibit beta-stimulated secretion of pro-inflammatory products, arrest
80
Z. Yi et al. / Psychiatry Research 200 (2012) 79–82
the evolution of activated macrophages, and inhibit expression of cyclooxygenase-2. PPAR-g agonists may protect neural tissue from the deleterious influence of inflammation and insulin resistance (Combs et al., 2000; Sastre et al., 2003). Our previous study found that the PPAR-g agonist rosiglitazone improved insulin sensitivity and glucose metabolism in clozapine-treated patients with schizophrenia (Henderson et al., 2009). Therefore, PPAR-g agonists may represent promising candidates to treat cognitive deficits seen in various patient populations. In a placebo-controlled, double-blind study in 30 patients with early Alzheimer’s disease, subjects receiving rosiglitazone exhibited better delayed recall than the placebo group (Watson et al., 2005). Another study showed that rosiglitazone reversed memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer’s disease mouse model (Escribano et al., 2009). The purpose of the present study was to examine the effect of rosiglitazone on cognitive function in schizophrenia. We conducted an eight-week double-blind, placebo-controlled pilot trial in clozapine-treated patients with schizophrenia.
2. Methods 2.1. Subjects Subjects were recruited from the Freedom Trial Clinic at the Erich Lindemann Mental Health Center and were studied at the Mallinckrodt General Clinical Research Center (GCRC) at Massachusetts General Hospital (MGH), Boston. The study was approved by the institutional review boards of MGH, and the Massachusetts Department of Mental Health. Outpatients between the ages of 18 and 65 years from diverse social, economic and racial backgrounds with the diagnosis of schizophrenia or schizoaffective disorder were screened for the study. Eligibility was determined by interview and a medical record review for history and recent laboratory values. After providing written informed consent, subjects underwent a diagnostic evaluation by a research psychiatrist using the Structured Clinical Interview for DSM-IV (SCID) (Spitzer et al., 1992). Patients treated with clozapine for at least one year were included in the study. The exclusion criteria were as follows: current substance abuse; type 1 or 2 diabetes; thyroid disease; pregnancy; significant medical conditions including severe cardiovascular, hepatic or renal diseases; and unstable psychiatric condition.
2.4. Statistical analysis Descriptive statistics were used to describe demographic and clinical characteristics of the study sample. The chi-squared test was used to access differences in frequency. Group comparisons were performed using independent t-tests for continuous variables and chi-squared tests for categorical variables. An analysis of covariance (ANCOVA) was used to examine change scores from baseline to week eight between groups after controlling for baseline scores. For all analyses, a value of Po 0.05 (two-tailed) was used for statistical significance.
3. Results Thirty-two subjects consented to participate in the study. Seven subjects withdrew consent before baseline assessment; three subjects were ineligible based on abnormal baseline laboratory values (two for abnormal liver function tests, one for elevated fasting glucose). Two subjects were hospitalized after consenting (one for psychotic decompensation and one for new onset diabetes); one subject withdrew from the study after significant weight gain. Nineteen subjects completed the study. Table 1 presents demographic and clinical characteristics for the subjects who completed the study. There were no differences between the placebo and rosiglitazone groups on age, age of illness onset, education, gender, race, smoking status, clozapine daily dose, clozapine treatment duration, and PANSS scores. Table 2 presents means and standard deviations of neuropsychological test scores for the Digit Span (forward and backward), the verbal fluency test (total score), the HVLT (immediate recall and delayed recall), the TMT (forms A and B) and the WCST (perseverative errors and categories completed) at baseline and week eight. When baseline scores were controlled for, there were no significant differences in change scores on cognitive performance over eight weeks between the rosiglitazone group and the placebo group (P’s 40.05). There were no significant differences in change scores over eight weeks on the PANSS total or subscale scores between the two groups (data not shown).
2.2. Study procedure
4. Discussion
The study was a double-blind placebo-controlled study evaluating the effect of rosiglitazone (4 mg/day) on cognitive function in patients with schizophrenia. Following baseline assessment (demographics and clinical characteristics including the Positive and Negative Syndrome Scale (PANSS) scores), 19 subjects (male: female 14:5) were eligible for randomization to rosiglitazone (n¼ 9) or placebo (n¼ 10). Patients were maintained on their prior antipsychotic treatment regimen during the study period.
We believe that the present study was the first clinical trial to examine the potential cognitive benefit of rosiglitazone in patients with schizophrenia. In this study, rosiglitazone treatment (4 mg/day) for eight weeks had no significant beneficial effect on cognition (verbal fluency, verbal memory, working memory and executive function) in patients with schizophrenia, even though we previously reported that rosiglitazone improved insulin sensitivity and glucose metabolism (Henderson et al., 2009). Our results differ from the findings in patients with Alzheimer’s disease, where rosiglitazone treatment for six months was associated with significant cognitive improvement (Watson et al., 2005). The discrepancy in findings may be explained by differences in study populations, rosiglitazone dosing, and treatment duration. The limitations of the present study include a relatively small sample size and the relatively short intervention time period (eight weeks). In conclusion, the present pilot study failed to demonstrate cognitive benefits of rosiglitazone in clozapine-treated schizophrenia patients. Some reports suggest that rosiglitazone is associated with an increased risk of heart attack. Future studies with a larger sample size and a longer intervention time period are needed to further explore the potential role of rosiglitazone in improving cognitive function as well as the drug’s safety in patients with schizophrenia.
2.3. Neuropsychological tests Five neuropsychological tests were administrated to each subject at baseline and week eight. The Digit Span subtest (forward and backward) from the Wechsler Adult Intelligence Scale-III (WAIS-III) (Wechsler, 1997) is used to evaluate attention. The verbal fluency test (FAS) requires the generation of as many words as possible starting with the letter F, A or S (1 min each). The verbal fluency test reflects executive function (Benton and Hamsher, 1989). The Hopkins Verbal Learning Test (HVLT) has been widely used to assess verbal memory (Shapiro et al., 1999). A list of 12 words from three taxonomic categories is presented to the subject with words read aloud at the rate of approximately one word every 2 s. The test includes three learning trials and a delayed recall trial. In the Trail-Making Test (TMT), subjects are asked to connect a series of numbers (Form-A), or connect alternating letters and numbers (Form-B, e.g. 1-A-2-B-3) (Reitan, 1992). The TMT reflects attention and executive function. The Wisconsin Card Sorting Test (WCST) is used to assess executive function and problem solving. In this computerized test, subjects match cards on a monitor to one of four key cards. They are not told how to match the cards, but instead are told whether their matches are correct or not. If the subject matches correctly 10 consecutive times, the matching rule changes, but the subject is not told of the rule change. The test was modified in the present study. The number of cards was reduced from 128 to 64 (Heaton, 1981).
Z. Yi et al. / Psychiatry Research 200 (2012) 79–82
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Table 1 Demographic and clinical characteristics of the study sample. Placebo (n¼ 10)
Age (years) Age of illness onset (years) Education (years) Clozapine dose (mg/d) Clozapine treatment duration (years) PANSS-positive PANSS-negative PANSS-general PANSS-total
Rosiglitazone (n¼9)
t
d.f.
P
Mean
S.D.
Mean
S.D.
39.7 28.4 12.8 363 8 13.9 17.5 30.4 61.8
7.5 9.6 2.4 133 3 6.9 7.8 8.2 17.9
41.4 25.9 12.3 361 9 14.4 15.6 27.9 57.9
10.3 10.0 2.1 167 4 4.9 4.2 6.6 12.6
0.35 0.28 0.57 0.20 0.55 0.19 0.66 0.73 0.54
17 17 17 17 17 17 17 17 17
0.63 0.78 0.67 0.98 0.59 0.85 0.52 0.48 0.59
n
%
n
%
v2
d.f.
P
Gender Male Female
7 3
70 30
7 2
77 23
0.15
1
0.70
Race Caucasian Hispanic
8 2
80 20
9 0
100 0
2.00
1
0.16
Smoking status Yes No
5 5
50 50
4 5
44 56
0.06
1
0.81
Family history of diabetes Yes No
3 7
30 70
6 3
67 33
2.55
1
0.11
Table 2 Comparison of cognitive performance between the rosiglitazone group and the placebo group. Placebo (n¼ 10) Baseline Mean
Rosiglitazone (n¼ 9) Week eight
S.D.
Mean
Baseline S.D.
Mean
ANCOVA Week eight
S.D.
Mean
S.D.
F
d.f.
P
Digit span Forward Backward
10.00 5.89
2.06 2.57
10.00 6.44
2.29 2.60
9.44 6.00
2.70 2.18
10.00 6.44
2.35 2.30
0.95 0.03
1, 15 1, 15
0.43 0.87
Verbal fluency total
31.40
9.12
29.70
13.39
26.67
8.03
27.67
10.17
0.84
1, 16
0.37
HVLT Immediate recall Delayed recall
15.22 3.63
5.74 2.56
15.33 3.50
5.05 2.98
15.33 5.29
6.18 1.98
16.22 4.71
6.24 2.21
0.12 0.01
1, 15 1, 12
0.74 0.94
62.89 116.13
22.62 36.09
60.56 100.50
26.61 34.45
49.20 112.67
17.87 33.51
52.89 98.67
35.32 33.45
0.45 0.00
1, 15 1, 14
0.51 0.98
14.00 1.25
6.09 1.39
14.25 0.75
7.76 1.39
15.75 1.25
11.65 1.16
17.00 1.00
12.00 1.20
0.19 0.47
1, 13 1, 13
0.67 0.51
TMT Form A Form B WCST Perseverative errors Categories completed
Note: group comparisons of change scores were performed using analysis of covariance (ANCOVA) controlling for baseline cognitive scores; WCST ¼ Wisconsin Card Sorting Test; HVLT¼Hopkins Verbal Learning Test; TMT¼ Trail-Making Test.
Declaration of interest Dr. Fan has received research support or honoraria from Eli Lilly, AstraZeneca, Bristol-Myer-Squibb, Janssen, and Pfizer. Dr. Freudenreich has received research support or honoraria from AstraZeneca, Bristol-Myer-Squibb, Janssen, Eli Lilly, Cephalon and Pfizer. Dr. Goff has received research support or honoraria from Bristol-Myers Squibb, Indevus Pharmaceuticals, H. Lundbeck, Schering-Plough, Eli Lilly, Takeda, Biovail, Sovay, Hoffman-La Roche, Cypress, Dainippon Sumitomo, Abbott Laboratories, Genentech, Pfizer, Janssen, Novartis, PamLab, and GlaxoSmithKline and Endo Pharmaceuticals. He served on a DSMB for Otsuka. Dr.
Henderson has received research support or honoraria from Takeda, Janssen, Solvay, Novartis, Covance, Alkermis, and Pfizer. Drs. Yi, Wang and Liu report no disclosures. Dr. Yi and Dr. Fan were responsible for the analysis and interpretation of the data for this article. All authors were responsible for the writing of the article.
Acknowledgments This project was funded by the Stanley Foundation and a NARSAD Yong Investigator Award (DCH). The project described
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