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The relationship of brain weight to body mass index (BMI) upon autopsy in young people with severe mental illness
Schizophrenia Research 123 (2010) 86–87
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Letter to the Editors The relationship of brain weight to body mass index (BMI) upon autopsy in young people with severe mental illness
Weight gain and metabolic complications associated with antipsychotics are areas of great concern among clinicians and researchers. In addition to medical consequences of obesity, weight gain may be related to changes in brain morphology. Evidence in the general population suggests a relationship between obesity and brain differences, including structure and/or volume, inverse correlations between body mass index (BMI) with brain volume, increased atrophy and hyperintensities (Gunstad et al., 2008; Gustafson et al., 2004; Jagust, 2007). Increasing BMI may be associated with functional consequences including cognitive performance (Gunstad et al., 2007), cognitive decline (Kalmijn et al., 2000) and dementias (Gustafson et al., 2003). Cognitive and neurophysiological abnormalities associated with functional deficits are well-documented characteristics of serious mental illness. Differences between brain volumes in schizophrenia and the general population have been documented, such as lower brain and mean cerebral volume and increased ventricular volumes (Wright et al., 2000). Changes have been reported throughout the course of illness in schizophrenia, and may also occur with antipsychotic treatment (Lieberman et al., 2005; Hulshoff Pol and Kahn, 2008). Therefore, the potential association of obesity with brain changes may be of additional concern in this population. To explore the potential association between obesity and brain weight, we analyzed autopsy reports of 60 young people with severe mental illness. This study was approved by the State of Maryland Department of Health and Mental Hygiene (DHMH) and the University of Maryland—Baltimore Institutional Review Boards. A database was used to identify inpatients started on clozapine or other antipsychotics in the State of Maryland mental health system between 1990 and 2002, and died before 2004. Death records were retrieved from the DHMH Division of Vital Statistics, and autopsy reports were collected from the Office of the Chief Medical Examiner. Between 1990 and 2004, 403 deaths occurred among 4434 (9%) severely mentally ill persons treated with clozapine or other antipsychotics. A majority of the non-clozapine treated group had been treated with risperidone, as well as other typical or atypical antipsychotics, but none had been treated with clozapine. 194 deaths occurred in the clozapine group and 209 deaths in people treated with other antipsychotics. Autopsy data were available for 60 patients (clozapine 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.04.009
N = 32, other N = 28). Three patients were underweight, 19 normal weight, 9 overweight, and 29 obese. Descriptive statistics (age, gender, race, diagnosis, antipsychotic, BMI, and brain weight) were collected. Because clozapine has a unique receptor affinity profile, and has been associated with larger weight gain risk, this antipsychotic was also examined separately. The relationship between BMI and brain weight was assessed using Pearson's correlation coefficient. A multivariate ANOVA model was employed to estimate the association between brain weight and BMI categories after adjusting for gender and age difference. The sample was 70% male (n = 42), 70% with psychotic disorder diagnosis (n = 37/53), and 67% white (n = 40), mean age at death of 38.2 (9.6) years, mean BMI of 29.6 (8.7) kg/m2, and mean brain weight of 1322.6 (162.6) g. The two antipsychotic groups were similar in demographics, except more clozapinetreated subjects had a psychotic disorder diagnosis (schizophrenia, schizoaffective disorder, and other psychotic disorder); clozapine had 83% (n = 24), and the other antipsychotic group 54% (n = 13), respectively (χ 2 = 5.0939, df = 1, p = 0.02). A trend towards greater mean BMI was noted in the clozapine group; clozapine 31.7 (8.8) kg/m2, other antipsychotics 27.3 (8.2) kg/m 2 (χ 2 = 3.7678, df = 1, p = 0.052). Although numeric differences in brain weight by BMI classification were seen, with decreasing brain weight associated with higher BMI classification, this relationship was not significant. The overall group demonstrated no association between BMI category and brain weight (F = 1.48 df = 2, p = 0.24) or in BMI and brain weight (r = −0.09, p = 0.48, z = −0.09, CI95% [−0.34,0.16]). A significant correlation between BMI and brain weight, however, was observed in nonclozapine-treated patients (n = 28, r = − 0.43, p = 0.02, z = 0.46, CI95% [−0.69, −0.07]) suggesting heavier patients had smaller brain weights. This was not found in the clozapinetreated group (n = 32, r = 0.09, p = 0.62, z = 0.09, CI95% [−0.27, 0.43]). Male subjects showed a trend towards correlation (n = 42, r = −0.29, p = 0.065, z = −0.30, CI95% [−0.54, 0.02]), but not the female sample (n = 18, r = 0.17, p = 0.54, z = 0.16, CI95% [− 0.34, 0.58]). Correlations between brain weight and body weight did not differ between races, diagnoses, or gender. In the analysis of 60 antipsychotic-treated patients, a significant inverse correlation between BMI and brain weight was found in the sample of people (n = 28) with severe mental illness who received non-clozapine antipsychotics. However, we found no significant effect in our overall sample, possibly due to the small sample size. A limitation of this
Letter to the Editors
study was that the significant finding in the non-clozapine treated group was one of a number of subgroup comparisons conducted in this small sample, and the p-value was not adjusted for multiple comparisons. Furthermore, data regarding length of illness, length of treatment, concomitant medications, premorbid or comorbid conditions or underlying causes of death were not available. In addition, no longitudinal information of brain structure was available, and though brain weight is measured at autopsy, more specific measuremements of brain structures and volume were not performed. However, the limitations of these findings should not discourage further study. Determining the potential for brain changes associated with obesity is of great importance in schizophrenia. The relationship between the effects of schizophrenia, antipsychotics, and obesity appears complicated. However, given the metabolic complications of antipsychotics, it warrants further exploration. In conclusion, general population studies demonstrate associations between brain weight and BMI. This association is likely complex, and causality cannot be determined in cross sectional studies. Longitudinal studies in the severely mentally ill should be prospectively designed, include imaging to accurately measure white and gray matter volume and specific brain regions, and consider how antipsychotics may impact these findings. Acknowledgements This project was funded by the National Institute of Mental Health (NIMH R03 MH069871-01; Kelly, PI) and the Advanced Centers for Intervention and Services Research (NIMH P50 MH 40279; Carpenter, PI).
References Gunstad, J., Paul, R.H., Cohen, R.A., Tate, D.F., Spitznagel, M.B., Gordon, E., 2007. Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. Compr. Psychiatry 48 (1), 57–61. Gunstad, J., Paul, R.H., Cohen, R.A., Tate, D.F., Spitznagel, M.B., Grieve, S., Gordon, E., 2008. Relationship between body mass index and brain volume in healthy adults. Int. J. Neurosci. 118 (11), 1582–1593. Gustafson, D., Rothenburg, E., Blennow, K., Steen, B., et al., 2003. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch. Intern. Med. 163, 1524–1528. Gustafson, D., Steen, B., Skoog, I., 2004. Body mass index and white matter lesions in elderly women. An 18-year longitudinal study. Int. Psychogeriatr. 16, 327–336. Hulshoff Pol, H.E., Kahn, R.S., 2008. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr. Bull. 34 (7), 354–366. Jagust, W., 2007. What can imaging reveal about obesity and the brain? Curr. Alzheimer Res. 4, 135–139. Kalmijn, S., Foley, D., White, L., Burchfiel, C.M., Curb, J.D., et al., 2000. Metabolic cardiovascular syndrome and risk of dementia in Japanese–
87
American elderly men. The Honolulu–Asia aging study. Arterioscler. Thromb. Vasc. Biol. 2255–2260. Lieberman, J.A., Tollefson, G.D., Charles, C., Zipursky, R., 2005. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch. Gen. Psychiatry 62 (4), 361–370. Wright, I.C., Rabe-Hesketh, S., Woodruff, P.W., David, A.S., Murray, R.M., Bullmore, E.T., 2000. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 157 (1), 16–25.
Heidi J. Wehring Fang Liu Robert P. McMahon Elena A. Spieker Kimberly R. Warren Douglas L. Boggs Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States Raymond C. Love University of Maryland School of Pharmacy, Baltimore, MD, United States Dwight Dickinson Department of Psychiatry, University of Maryland School of Medicine, VISN 5 Mental Illness Research, Education and Clinical Center, Baltimore, MD, United States Joo Cheol Shim Inje University, Paik Hospital, Republic of Korea David Fowler Office of the Chief Medical Examiner, Baltimore, MD, United States Deanna L. Kelly Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States Corresponding author. University of Maryland School of Medicine, PO Box 21247 Baltimore, MD 21228, United States. Tel.: +1 410 402 6860; fax: +1 410 402 6880. E-mail address: [email protected] (D. L. Kelly). 20 January 2010
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Letter to the Editors The relationship of brain weight to body mass index (BMI) upon autopsy in young people with severe mental illness
Weight gain and metabolic complications associated with antipsychotics are areas of great concern among clinicians and researchers. In addition to medical consequences of obesity, weight gain may be related to changes in brain morphology. Evidence in the general population suggests a relationship between obesity and brain differences, including structure and/or volume, inverse correlations between body mass index (BMI) with brain volume, increased atrophy and hyperintensities (Gunstad et al., 2008; Gustafson et al., 2004; Jagust, 2007). Increasing BMI may be associated with functional consequences including cognitive performance (Gunstad et al., 2007), cognitive decline (Kalmijn et al., 2000) and dementias (Gustafson et al., 2003). Cognitive and neurophysiological abnormalities associated with functional deficits are well-documented characteristics of serious mental illness. Differences between brain volumes in schizophrenia and the general population have been documented, such as lower brain and mean cerebral volume and increased ventricular volumes (Wright et al., 2000). Changes have been reported throughout the course of illness in schizophrenia, and may also occur with antipsychotic treatment (Lieberman et al., 2005; Hulshoff Pol and Kahn, 2008). Therefore, the potential association of obesity with brain changes may be of additional concern in this population. To explore the potential association between obesity and brain weight, we analyzed autopsy reports of 60 young people with severe mental illness. This study was approved by the State of Maryland Department of Health and Mental Hygiene (DHMH) and the University of Maryland—Baltimore Institutional Review Boards. A database was used to identify inpatients started on clozapine or other antipsychotics in the State of Maryland mental health system between 1990 and 2002, and died before 2004. Death records were retrieved from the DHMH Division of Vital Statistics, and autopsy reports were collected from the Office of the Chief Medical Examiner. Between 1990 and 2004, 403 deaths occurred among 4434 (9%) severely mentally ill persons treated with clozapine or other antipsychotics. A majority of the non-clozapine treated group had been treated with risperidone, as well as other typical or atypical antipsychotics, but none had been treated with clozapine. 194 deaths occurred in the clozapine group and 209 deaths in people treated with other antipsychotics. Autopsy data were available for 60 patients (clozapine 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.04.009
N = 32, other N = 28). Three patients were underweight, 19 normal weight, 9 overweight, and 29 obese. Descriptive statistics (age, gender, race, diagnosis, antipsychotic, BMI, and brain weight) were collected. Because clozapine has a unique receptor affinity profile, and has been associated with larger weight gain risk, this antipsychotic was also examined separately. The relationship between BMI and brain weight was assessed using Pearson's correlation coefficient. A multivariate ANOVA model was employed to estimate the association between brain weight and BMI categories after adjusting for gender and age difference. The sample was 70% male (n = 42), 70% with psychotic disorder diagnosis (n = 37/53), and 67% white (n = 40), mean age at death of 38.2 (9.6) years, mean BMI of 29.6 (8.7) kg/m2, and mean brain weight of 1322.6 (162.6) g. The two antipsychotic groups were similar in demographics, except more clozapinetreated subjects had a psychotic disorder diagnosis (schizophrenia, schizoaffective disorder, and other psychotic disorder); clozapine had 83% (n = 24), and the other antipsychotic group 54% (n = 13), respectively (χ 2 = 5.0939, df = 1, p = 0.02). A trend towards greater mean BMI was noted in the clozapine group; clozapine 31.7 (8.8) kg/m2, other antipsychotics 27.3 (8.2) kg/m 2 (χ 2 = 3.7678, df = 1, p = 0.052). Although numeric differences in brain weight by BMI classification were seen, with decreasing brain weight associated with higher BMI classification, this relationship was not significant. The overall group demonstrated no association between BMI category and brain weight (F = 1.48 df = 2, p = 0.24) or in BMI and brain weight (r = −0.09, p = 0.48, z = −0.09, CI95% [−0.34,0.16]). A significant correlation between BMI and brain weight, however, was observed in nonclozapine-treated patients (n = 28, r = − 0.43, p = 0.02, z = 0.46, CI95% [−0.69, −0.07]) suggesting heavier patients had smaller brain weights. This was not found in the clozapinetreated group (n = 32, r = 0.09, p = 0.62, z = 0.09, CI95% [−0.27, 0.43]). Male subjects showed a trend towards correlation (n = 42, r = −0.29, p = 0.065, z = −0.30, CI95% [−0.54, 0.02]), but not the female sample (n = 18, r = 0.17, p = 0.54, z = 0.16, CI95% [− 0.34, 0.58]). Correlations between brain weight and body weight did not differ between races, diagnoses, or gender. In the analysis of 60 antipsychotic-treated patients, a significant inverse correlation between BMI and brain weight was found in the sample of people (n = 28) with severe mental illness who received non-clozapine antipsychotics. However, we found no significant effect in our overall sample, possibly due to the small sample size. A limitation of this
Letter to the Editors
study was that the significant finding in the non-clozapine treated group was one of a number of subgroup comparisons conducted in this small sample, and the p-value was not adjusted for multiple comparisons. Furthermore, data regarding length of illness, length of treatment, concomitant medications, premorbid or comorbid conditions or underlying causes of death were not available. In addition, no longitudinal information of brain structure was available, and though brain weight is measured at autopsy, more specific measuremements of brain structures and volume were not performed. However, the limitations of these findings should not discourage further study. Determining the potential for brain changes associated with obesity is of great importance in schizophrenia. The relationship between the effects of schizophrenia, antipsychotics, and obesity appears complicated. However, given the metabolic complications of antipsychotics, it warrants further exploration. In conclusion, general population studies demonstrate associations between brain weight and BMI. This association is likely complex, and causality cannot be determined in cross sectional studies. Longitudinal studies in the severely mentally ill should be prospectively designed, include imaging to accurately measure white and gray matter volume and specific brain regions, and consider how antipsychotics may impact these findings. Acknowledgements This project was funded by the National Institute of Mental Health (NIMH R03 MH069871-01; Kelly, PI) and the Advanced Centers for Intervention and Services Research (NIMH P50 MH 40279; Carpenter, PI).
References Gunstad, J., Paul, R.H., Cohen, R.A., Tate, D.F., Spitznagel, M.B., Gordon, E., 2007. Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. Compr. Psychiatry 48 (1), 57–61. Gunstad, J., Paul, R.H., Cohen, R.A., Tate, D.F., Spitznagel, M.B., Grieve, S., Gordon, E., 2008. Relationship between body mass index and brain volume in healthy adults. Int. J. Neurosci. 118 (11), 1582–1593. Gustafson, D., Rothenburg, E., Blennow, K., Steen, B., et al., 2003. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch. Intern. Med. 163, 1524–1528. Gustafson, D., Steen, B., Skoog, I., 2004. Body mass index and white matter lesions in elderly women. An 18-year longitudinal study. Int. Psychogeriatr. 16, 327–336. Hulshoff Pol, H.E., Kahn, R.S., 2008. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr. Bull. 34 (7), 354–366. Jagust, W., 2007. What can imaging reveal about obesity and the brain? Curr. Alzheimer Res. 4, 135–139. Kalmijn, S., Foley, D., White, L., Burchfiel, C.M., Curb, J.D., et al., 2000. Metabolic cardiovascular syndrome and risk of dementia in Japanese–
87
American elderly men. The Honolulu–Asia aging study. Arterioscler. Thromb. Vasc. Biol. 2255–2260. Lieberman, J.A., Tollefson, G.D., Charles, C., Zipursky, R., 2005. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch. Gen. Psychiatry 62 (4), 361–370. Wright, I.C., Rabe-Hesketh, S., Woodruff, P.W., David, A.S., Murray, R.M., Bullmore, E.T., 2000. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 157 (1), 16–25.
Heidi J. Wehring Fang Liu Robert P. McMahon Elena A. Spieker Kimberly R. Warren Douglas L. Boggs Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States Raymond C. Love University of Maryland School of Pharmacy, Baltimore, MD, United States Dwight Dickinson Department of Psychiatry, University of Maryland School of Medicine, VISN 5 Mental Illness Research, Education and Clinical Center, Baltimore, MD, United States Joo Cheol Shim Inje University, Paik Hospital, Republic of Korea David Fowler Office of the Chief Medical Examiner, Baltimore, MD, United States Deanna L. Kelly Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States Corresponding author. University of Maryland School of Medicine, PO Box 21247 Baltimore, MD 21228, United States. Tel.: +1 410 402 6860; fax: +1 410 402 6880. E-mail address: [email protected] (D. L. Kelly). 20 January 2010