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Elevated serum levels of tumor necrosis factor-α in clozapine-associated obesity in chronic schizophrenia
Schizophrenia Research 106 (2008) 367–368
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 Editor Elevated serum levels of tumor necrosis factor-α in clozapine-associated obesity in chronic schizophrenia
The pathophysiology of the weight gain may involve tumor necrosis factor-α (TNF-α), because this pleiotropic cytokine, which is mainly synthesized in adipocities and macrophages, is involved in the regulation of metabolic process, weight, and feeding behavior (Bulló-Bonet et al., 1999; Baptista and Beaulieu, 2002). Some animal experiments suggest that TNF-alpha may promote body weight gain (Uysal et al., 1997; Ventre et al., 1997). Clozapine increases serum concentrations of TNF-α (Pollmächer et al., 1996), and increased levels of TNF-α produce sedation, hyperinsulinemia, insulin resistance and hypertriglyceridemia (Argilés et al., 1997). Therefore, elevated TNF-α may occur in clozapine-associated obesity among schizophrenics. In a cross-sectional naturalistic study, 102 Han Chinese inpatients as meeting DSM-IV criteria for schizophrenia were rated. All patients were ill for at least 5 years and on a stable dose of clozapine monotherapy for at least 1 year. The average dose was 223.8 ± 86.7 mg/day (range 100–400 mg/day). The mean duration of clozapine treatment was 4.7 ± 3.7 years (range from 1–19 years). We calculated BMI as weight over squared height (kg/m2), and classified 26 patients as obese (BMI ≥ 28) and 76 as normal weight (18.5 ≤ BMI b 24) using the Working Group on Obesity in China (WGOC) criteria. Serum TNF-alpha levels were measured in duplicate with sandwich ELISA using a commercially available kit by the same investigator who was blind to the clinical status of the subjects. Both the BMI and TNF-alpha levels were determined between 7 and 9 am after fasting overnight. The patient's psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) on the same day when the TNF-alpha levels were measured. Table 1 shows a significant difference in sex and age between the obese and normal weigh groups (both p b 0.05). The mean serum TNF-alpha level was significantly higher in the obese than normal weight group (F =6.06, df =1,100, p =0.02) (Table 1). When sex and age were added as covariates, there was still a significant difference in TNF-alpha (F2= 6.36, df =1,98, p = 0.013). TNF-alpha levels showed significant inverse relationships with the PANSS negative subscale (r=−0.27, n=102, p=0.015), the PANSS general psychopathology (r=−0.37, n=102, p=0.0001), and the PANSS total score (r=−0.34, n=102, p=0.0001). In addition, there was a significant positive correlation between TNF-alpha and BMI (r=0.24, n=102, p=0.018). In addition, the 0920-9964/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2008.08.030
daily dose of clozapine did not correlate with TNF-alpha levels (pN 0.05). This study found that serum levels of TNF-alpha were elevated in schizophrenics with clozapine-associated obesity and that the TNF-alpha levels were associated with the severity of schizophrenic symptoms. However, these results should be considered preliminary, since a correction for multiple testing was not applied. Furthermore, the cross-sectional character of the current study does not allow any conclusion regarding the cause of increased TNF levels in obese patients. An increase of TNF-alpha serum levels were found in obese normal subjects and correlated positively with the BMI and insulin and leptin levels (Tsukui et al., 2000). Several studies have suggested a relation between atypical antipsychotic induced weight gain and cytokines such as TNF-alpha (Basile et al., 2001; Baptista and Beaulieu, 2002). Furthermore, schizophrenic patients with abnormally elevated TNF-alpha levels due to a genetic polymorphism (A/A genotype for the G308A polymorphism of the TNF-alpha gene) had greater weight gain than patients with the other genotype (and lower TNF-alpha levels) during clozapine administration (Basile et al., 2001). That study suggests that TNF-alpha may promote obesity in patients treated with atypical antipsychotics. However, most experimental evidence suggests that TNFalpha decreases appetite and body weight (Plata-Salamán, 2000). Moreover, no published study has reported obesity directly induced by TNF-alpha. Thus, the increased TNF-alpha appears to play a complex role in the physiological
Table 1 Comparison of obese and non-obese patients with schizophrenia
Sex, M/F Age (years) Education (years) Age at onset (years) Duration of illness (years) Hospitalization times Dose of clozapine PANSS total score P subscore N subscore G subscore BMI (kg/m2) TNF-alpha level (ng/ml)
X2 or t
df
p
68/8 48.3 ± 4.5 9.3 ± 2.2 23.9 ± 6.0 24.3 ± 7.1
0.11 −2.3 0.6 −0.8 −0.9
2 1,100 1,100 1, 100 1,100
0.95 0.022 0.56 0.43 0.37
3.6 ± 1.8 243.4 ± 300.9 77.0 ± 18.1 16.1 ± 6.4 25.2 ± 6.2 35.7 ± 9.8 21.4 ± 2.2 9.8 ± 1.8
0.6 −0.4 −0.1 1.3 −1.3 −0.2 18.3 6.1
1.100 1,100 1,100 1,100 1,100 1,100 1, 100 1,100
0.53 0.72 0.90 0.20 0.18 0.86 0.000 0.016
Obese patients
Non-obese patients
(n = 26)
(n = 76)
20/6 46.0 ± 3.6 9.6 ± 1.4 22.9 ± 4.8 23.0 ± 4.7 3.8 ± 2.2 219.2 ± 118.2 76.5 ± 19.4 17.8 ± 5.2 23.3 ± 6.6 35.3 ± 11.2 29.9 ± 1.5 11.8 ± 2.6
368
Letter to the Editor
mechanisms regulating bodyweight gain in schizophrenic patients treated with clozapine (Baptista and Beaulieu, 2002). Acknowledgments This study was funded by the Stanley Medical Institute Foundation (03T-459, 05T-726) (XYZ), and the Department of Veterans Affairs, VISN 1, Mental Illness Research, Education and Clinical Center (MIRECC) and National Institute on Drug Abuse K05-DA0454 and P50-DA18827 (TRK). References Argilés, J.M., López-Soriano, J., Busquets, S., López-Soriano, F.J., 1997. Journey from cachexia to obesity by TNF. FASEB J. 11, 743–751. Baptista, T., Beaulieu, S., 2002. Are leptin and cytokines involved in body weight gain during treatment with antipsychotic drugs? Can. J. Psychiatry 47, 742–749. Basile, V.S., Masellis, M., McIntyre, R.S., Meltzer, H.Y., Lieberman, J.A., Kennedy, J.L., 2001. Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J. Clin. Psychiatry 62 (Suppl 23), 45–66. Bulló-Bonet, M., García-Lorda, P., López-Soriano, F.J., Argilés, J.M., Salas-Salvadó, J., 1999. Tumour necrosis factor, a key role in obesity? FEBS Lett. 451, 215–219. Plata-Salamán, C.R., 2000. Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition 16, 1009–1012. Pollmächer, T., Hinze-Selch, D., Mullington, J., 1996. Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J. Clin. Psychopharmacol. 16, 403–409. Tsukui, S., Kanda, T., Nara, M., Nishino, M., Kondo, T., Kobayashi, I., 2000. Moderate-intensity regular exercise decreases serum tumor necrosis factor-alpha and HbA1c levels in healthy women. Int. J. Obes. Relat. Metab. Disord. 24, 1207–1211. Uysal, K.T., Wiesbrock, S.M., Marino, M.W., Hotamisligil, G.S., 1997. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610–614. Ventre, J., Doebber, T., Wu, M., MacNaul, K., Stevens, K., Pasparakis, M., Kollias, G., Moller, D.E., 1997. Targeted disruption of the tumor necrosis factor-alpha
gene: metabolic consequences in obese and nonobese mice. Diabetes 46, 1526–1531.
Da Chun Chen1 Ling Yan Qi1 Mei Hong Xiu1 Lian Yuan Cao Fan Wang Song Chen Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing,100096, PR China 1 These authors contributed equally to this work. Gui Ying Wu Therese A. Kosten Thomas R. Kosten⁎ Xiang Yang Zhang⁎ Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, 77030, USA ⁎Corresponding authors. Kosten is to be contacted at Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, VA Medical Center, Research Building 110, Room 229, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel.: +1 713 794 7032; fax: +1 713 794 7938. Zhang, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, VA Medical Center, Research Building 109, Room 130, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel.: +1 7137911414x5824; fax: +1 713 794 7938.
30 June 2008
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 Editor Elevated serum levels of tumor necrosis factor-α in clozapine-associated obesity in chronic schizophrenia
The pathophysiology of the weight gain may involve tumor necrosis factor-α (TNF-α), because this pleiotropic cytokine, which is mainly synthesized in adipocities and macrophages, is involved in the regulation of metabolic process, weight, and feeding behavior (Bulló-Bonet et al., 1999; Baptista and Beaulieu, 2002). Some animal experiments suggest that TNF-alpha may promote body weight gain (Uysal et al., 1997; Ventre et al., 1997). Clozapine increases serum concentrations of TNF-α (Pollmächer et al., 1996), and increased levels of TNF-α produce sedation, hyperinsulinemia, insulin resistance and hypertriglyceridemia (Argilés et al., 1997). Therefore, elevated TNF-α may occur in clozapine-associated obesity among schizophrenics. In a cross-sectional naturalistic study, 102 Han Chinese inpatients as meeting DSM-IV criteria for schizophrenia were rated. All patients were ill for at least 5 years and on a stable dose of clozapine monotherapy for at least 1 year. The average dose was 223.8 ± 86.7 mg/day (range 100–400 mg/day). The mean duration of clozapine treatment was 4.7 ± 3.7 years (range from 1–19 years). We calculated BMI as weight over squared height (kg/m2), and classified 26 patients as obese (BMI ≥ 28) and 76 as normal weight (18.5 ≤ BMI b 24) using the Working Group on Obesity in China (WGOC) criteria. Serum TNF-alpha levels were measured in duplicate with sandwich ELISA using a commercially available kit by the same investigator who was blind to the clinical status of the subjects. Both the BMI and TNF-alpha levels were determined between 7 and 9 am after fasting overnight. The patient's psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) on the same day when the TNF-alpha levels were measured. Table 1 shows a significant difference in sex and age between the obese and normal weigh groups (both p b 0.05). The mean serum TNF-alpha level was significantly higher in the obese than normal weight group (F =6.06, df =1,100, p =0.02) (Table 1). When sex and age were added as covariates, there was still a significant difference in TNF-alpha (F2= 6.36, df =1,98, p = 0.013). TNF-alpha levels showed significant inverse relationships with the PANSS negative subscale (r=−0.27, n=102, p=0.015), the PANSS general psychopathology (r=−0.37, n=102, p=0.0001), and the PANSS total score (r=−0.34, n=102, p=0.0001). In addition, there was a significant positive correlation between TNF-alpha and BMI (r=0.24, n=102, p=0.018). In addition, the 0920-9964/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2008.08.030
daily dose of clozapine did not correlate with TNF-alpha levels (pN 0.05). This study found that serum levels of TNF-alpha were elevated in schizophrenics with clozapine-associated obesity and that the TNF-alpha levels were associated with the severity of schizophrenic symptoms. However, these results should be considered preliminary, since a correction for multiple testing was not applied. Furthermore, the cross-sectional character of the current study does not allow any conclusion regarding the cause of increased TNF levels in obese patients. An increase of TNF-alpha serum levels were found in obese normal subjects and correlated positively with the BMI and insulin and leptin levels (Tsukui et al., 2000). Several studies have suggested a relation between atypical antipsychotic induced weight gain and cytokines such as TNF-alpha (Basile et al., 2001; Baptista and Beaulieu, 2002). Furthermore, schizophrenic patients with abnormally elevated TNF-alpha levels due to a genetic polymorphism (A/A genotype for the G308A polymorphism of the TNF-alpha gene) had greater weight gain than patients with the other genotype (and lower TNF-alpha levels) during clozapine administration (Basile et al., 2001). That study suggests that TNF-alpha may promote obesity in patients treated with atypical antipsychotics. However, most experimental evidence suggests that TNFalpha decreases appetite and body weight (Plata-Salamán, 2000). Moreover, no published study has reported obesity directly induced by TNF-alpha. Thus, the increased TNF-alpha appears to play a complex role in the physiological
Table 1 Comparison of obese and non-obese patients with schizophrenia
Sex, M/F Age (years) Education (years) Age at onset (years) Duration of illness (years) Hospitalization times Dose of clozapine PANSS total score P subscore N subscore G subscore BMI (kg/m2) TNF-alpha level (ng/ml)
X2 or t
df
p
68/8 48.3 ± 4.5 9.3 ± 2.2 23.9 ± 6.0 24.3 ± 7.1
0.11 −2.3 0.6 −0.8 −0.9
2 1,100 1,100 1, 100 1,100
0.95 0.022 0.56 0.43 0.37
3.6 ± 1.8 243.4 ± 300.9 77.0 ± 18.1 16.1 ± 6.4 25.2 ± 6.2 35.7 ± 9.8 21.4 ± 2.2 9.8 ± 1.8
0.6 −0.4 −0.1 1.3 −1.3 −0.2 18.3 6.1
1.100 1,100 1,100 1,100 1,100 1,100 1, 100 1,100
0.53 0.72 0.90 0.20 0.18 0.86 0.000 0.016
Obese patients
Non-obese patients
(n = 26)
(n = 76)
20/6 46.0 ± 3.6 9.6 ± 1.4 22.9 ± 4.8 23.0 ± 4.7 3.8 ± 2.2 219.2 ± 118.2 76.5 ± 19.4 17.8 ± 5.2 23.3 ± 6.6 35.3 ± 11.2 29.9 ± 1.5 11.8 ± 2.6
368
Letter to the Editor
mechanisms regulating bodyweight gain in schizophrenic patients treated with clozapine (Baptista and Beaulieu, 2002). Acknowledgments This study was funded by the Stanley Medical Institute Foundation (03T-459, 05T-726) (XYZ), and the Department of Veterans Affairs, VISN 1, Mental Illness Research, Education and Clinical Center (MIRECC) and National Institute on Drug Abuse K05-DA0454 and P50-DA18827 (TRK). References Argilés, J.M., López-Soriano, J., Busquets, S., López-Soriano, F.J., 1997. Journey from cachexia to obesity by TNF. FASEB J. 11, 743–751. Baptista, T., Beaulieu, S., 2002. Are leptin and cytokines involved in body weight gain during treatment with antipsychotic drugs? Can. J. Psychiatry 47, 742–749. Basile, V.S., Masellis, M., McIntyre, R.S., Meltzer, H.Y., Lieberman, J.A., Kennedy, J.L., 2001. Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. J. Clin. Psychiatry 62 (Suppl 23), 45–66. Bulló-Bonet, M., García-Lorda, P., López-Soriano, F.J., Argilés, J.M., Salas-Salvadó, J., 1999. Tumour necrosis factor, a key role in obesity? FEBS Lett. 451, 215–219. Plata-Salamán, C.R., 2000. Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition 16, 1009–1012. Pollmächer, T., Hinze-Selch, D., Mullington, J., 1996. Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J. Clin. Psychopharmacol. 16, 403–409. Tsukui, S., Kanda, T., Nara, M., Nishino, M., Kondo, T., Kobayashi, I., 2000. Moderate-intensity regular exercise decreases serum tumor necrosis factor-alpha and HbA1c levels in healthy women. Int. J. Obes. Relat. Metab. Disord. 24, 1207–1211. Uysal, K.T., Wiesbrock, S.M., Marino, M.W., Hotamisligil, G.S., 1997. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610–614. Ventre, J., Doebber, T., Wu, M., MacNaul, K., Stevens, K., Pasparakis, M., Kollias, G., Moller, D.E., 1997. Targeted disruption of the tumor necrosis factor-alpha
gene: metabolic consequences in obese and nonobese mice. Diabetes 46, 1526–1531.
Da Chun Chen1 Ling Yan Qi1 Mei Hong Xiu1 Lian Yuan Cao Fan Wang Song Chen Center for Biological Psychiatry, Beijing HuiLongGuan Hospital, Beijing,100096, PR China 1 These authors contributed equally to this work. Gui Ying Wu Therese A. Kosten Thomas R. Kosten⁎ Xiang Yang Zhang⁎ Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, 77030, USA ⁎Corresponding authors. Kosten is to be contacted at Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, VA Medical Center, Research Building 110, Room 229, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel.: +1 713 794 7032; fax: +1 713 794 7938. Zhang, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, VA Medical Center, Research Building 109, Room 130, 2002 Holcombe Boulevard, Houston, Texas, 77030, USA. Tel.: +1 7137911414x5824; fax: +1 713 794 7938.
30 June 2008