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Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships with clinical phenotypes and cognitive deficits

  • D. C. Chen (a1), X. D. Du (a2), G. Z. Yin (a2), K. B. Yang (a1), Y. Nie (a1), N. Wang (a1), Y. L. Li (a1), M. H. Xiu (a1), S. C. He (a3), F. D. Yang (a1), R. Y. Cho (a4), T. R. Kosten (a5), J. C. Soares (a4), J. P. Zhao (a6) and X. Y. Zhang (a1) (a4)...

Schizophrenia patients have a higher prevalence of type 2 diabetes mellitus with impaired glucose tolerance (IGT) than normals. We examined the relationship between IGT and clinical phenotypes or cognitive deficits in first-episode, drug-naïve (FEDN) Han Chinese patients with schizophrenia.


A total of 175 in-patients were compared with 31 healthy controls on anthropometric measures and fasting plasma levels of glucose, insulin and lipids. They were also compared using a 75 g oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR). Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS).


Of the patients, 24.5% had IGT compared with none of the controls, and they also had significantly higher levels of fasting blood glucose and 2-h glucose after an oral glucose load, and were more insulin resistant. Compared with those patients with normal glucose tolerance, the IGT patients were older, had a later age of onset, higher waist or hip circumference and body mass index, higher levels of low-density lipoprotein and triglycerides and higher insulin resistance. Furthermore, IGT patients had higher PANSS total and negative symptom subscale scores, but no greater cognitive impairment except on the emotional intelligence index of the MCCB.


IGT occurs with greater frequency in FEDN schizophrenia, and shows association with demographic and anthropometric parameters, as well as with clinical symptoms but minimally with cognitive impairment during the early course of the disorder.

Corresponding author
*Address for correspondence: X. Y. Zhang, M.D., Ph.D., UT Center of Excellence on Mood Disorders (UTCEMD), Biomedical and Behavioral Sciences Building (BBSB), 1941 East Road, Houston, TX 77054, USA. (Email:
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Aas, M, Dazzan, P, Mondelli, V, Melle, I, Murray, RM, Pariante, CM (2014). A systematic review of cognitive function in first-episode psychosis, including a discussion on childhood trauma, stress, and inflammation. Frontiers in Psychiatry 4, 182.
Alkelai, A, Greenbaum, L, Lupoli, S, Kohn, Y, Sarner-Kanyas, K, Ben-Asher, E, Lancet, D, Macciardi, F, Lerer, B (2012). Association of the type 2 diabetes mellitus susceptibility gene, TCF7L2, with schizophrenia in an Arab-Israeli family sample. PLOS ONE 7, e29228.
Allen, KV, Frier, BM, Strachan, MW (2004). The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations. European Journal of Pharmacology 490, 169175.
Arranz, B, Rosel, P, Ramirez, N, Duenas, R, Fernandez, P, Sanchez, JM, Navarro, MA, San, L (2004). Insulin resistance and increased leptin concentrations in non-compliant schizophrenia patients but not in antipsychotic-naïve first-episode schizophrenia patients. Journal of Clinical Psychiatry 65, 13351342.
Barch, DM, Carter, CS, Arnsten, A, Buchanan, RW, Cohen, JD, Geyer, M, Green, MF, Krystal, JH, Nuechterlein, K, Robbins, T, Silverstein, S, Smith, EE, Strauss, M, Wykes, T, Heinssen, R (2009). Selecting paradigms from cognitive neuro-science for translation into use in clinical trials: proceedings of the third CNTRICS meeting. Schizophrenia Bulletin 35, 109114.
Biessels, GJ, Staekenborg, S, Brunner, E, Brayne, C, Scheltens, P (2006). Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurology 5, 6474.
Bou Khalil, R (2012). Atypical antipsychotic drugs, schizophrenia, and metabolic syndrome in non-Euro-American societies. Clinical Neuropharmacology 35, 141147.
Bruehl, H, Wolf, OT, Sweat, V, Tirsi, A, Richardson, S, Convit, A (2009). Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Research 1280, 186194.
Buckley, PE, Evans, D (2006). First-episode schizophrenia. A window of opportunity for optimizing care and outcomes. Postgraduate Medicine (Spec No.), 519.
Caro, JJ, Ward, A, Levinton, C, Robinson, K (2002). The risk of diabetes during olanzapine use compared with risperidone use: a retrospective database analysis. Journal of Clinical Psychiatry 63, 11351139.
Chen, S, Broqueres-You, D, Yang, G, Wang, Z, Li, Y, Wang, N, Zhang, X, Yang, F, Tan, Y (2013). Relationship between insulin resistance, dyslipidaemia and positive symptom in Chinese antipsychotic-naive first-episode patients with schizophrenia. Psychiatry Research 210, 825829.
Citrome, LL, Holt, RI, Zachry, WM, Clewell, JD, Orth, PA, Karagianis, JL, Hoffmann, VP (2007). Hoffmann VP. Risk of treatment-emergent diabetes mellitus in patients receiving antipsychotics. Annals of Pharmacotherapy 41, 15931603.
Dasgupta, A, Singh, OP, Rout, JK, Saha, T, Mandal, S (2010). Insulin resistance and metabolic profile in antipsychotic naïve schizophrenia patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry 34, 12021207.
Davis, KL, Kahn, RS, Ko, G, Davidson, M (1991). Dopamine in schizophrenia: a review and reconceptualization. American Journal of Psychiatry 148, 14741486.
De Hert, M, van Winkel, R, Van Eyck, D, Hanssens, L, Wampers, M, Scheen, A, Peuskens, J (2006). Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study. Clinical Practice and Epidemiology in Mental Health 2, 14.
Dickinson, D, Gold, JM, Dickerson, FB, Medoff, D, Dixon, LB (2008). Evidence of exacerbated cognitive deficits in schizophrenia patients with comorbid diabetes. Psychosomatics 49, 123131.
Ferentinos, P, Dikeos, D (2012). Genetic correlates of medical comorbidity associated with schizophrenia and treatment antipsychotics. Current Opinion in Psychiatry 25, 381390.
Fernandez-Egea, E, Bernardo, M, Donner, T, Conget, I, Parellada, E, Justicia, A, Esmatjes, E, Garcia-Rizo, C, Kirkpatrick, B (2009). Metabolic profile of antipsychotic-naive individuals with non-affective psychosis. British Journal of Psychiatry 194, 434438.
Fernandez-Egea, E, Bernardo, M, Parellada, E, Justica, A, Garcia-Rizo, C, Esmatjes, E, Conget, I, Kirkpatrick, B (2008 a). Glucose abnormalities in the siblings of people with schizophrenia. Schizophrenia Research 103, 110113.
Fernandez-Egea, E, Miller, B, Bernardo, M, Donner, T, Kirkpatrick, B (2008 b). Parental history of type 2 diabetes in patients with nonaffective psychosis. Schizophrenia Research 98, 302306.
Franks, PW, Pare, G (2016). Putting the genome in context: gene–environment interaction in type 2 diabetes. Current Diabetes Reports 16, 57.
García-Tornadu, I, Ornstein, AM, Chamson-Reig, A, Wheeler, MB, Hill, DJ, Arany, E, Rubinstein, M, Becu-Villalobos, D (2010). Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance. Endocrinology 151, 14411450.
Geijselaers, SL, Sep, SJ, Stehouwer, CD, Biessels, GJ (2015). Glucose regulation, cognition, and brain MRI in type 2 diabetes: a systematic review. Lancet. Diabetes and Endocrinology 3, 7589.
Gillett, M, Royle, P, Snaith, A, Scotland, G, Poobalan, A, Imamura, M, Black, C, Boroujerdi, M, Jick, S, Wyness, L, McNamee, P, Brennan, A, Waugh, N (2012). Non-pharmacological interventions to reduce the risk of diabetes in people with impaired glucose regulation: a systematic review and economic evaluation. Health Technology Assessment 16, 1236.
Goff, DC, Hill, M, Barch, D (2011). The treatment of cognitive impairment in schizophrenia. Pharmacology Biochemistry and Behavior 99, 445453.
Gold, SM, Dziobek, I, Sweat, V, Tirsi, A, Rogers, K, Bruehl, H, Tsui, W, Richardson, S, Javier, E, Convit, A (2007). Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia 50, 711719.
Green, MF, Horan, WP, Lee, J (2015). Social cognition in schizophrenia. Nature Reviews Neuroscience 16, 620631.
Green, MF, Nuechterlein, KH, Gold, JM, Barch, DM, Cohen, J, Essock, S, Fenton, WS, Frese, F, Goldberg, TE, Heaton, RK, Keefe, RS, Kern, RS (2004). Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biological Psychiatry 56, 301307.
Han, M, Huang, XF, Chen da, C, Xiu, M, Kosten, TR, Zhang, XY (2013). Diabetes and cognitive deficits in chronic schizophrenia: a case–control study. PLOS ONE 8, e66299.
Hartling, L, Abou-Setta, AM, Dursun, S, Mousavi, SS, Pasichnyk, D, Newton, AS (2012). Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis. Annals of Internal Medicine 157, 498511.
Harvey, PD (2009). Pharmacological cognitive enhancement in schizophrenia. Neuropsychology Review 19, 324335.
Harvey, PD (2014). What is the evidence for changes in cognition and functioning over the lifespan in patients with schizophrenia? Journal of Clinical Psychiatry 75 (Suppl. 2), 3438.
Hassing, LB, Hofer, SM, Nilsson, SE, Berg, S, Pedersen, NL, McClearn, G, Johansson, B (2004). Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study. Age and Ageing 33, 355361.
Henderson, DC, Nguyen, DD, Copeland, PM, Hayden, DL, Borba, CP, Louie, PM, Freudenreich, O, Evins, AE, Cather, C, Goff, DC (2005). Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. Journal of Clinical Psychiatry 66, 11161121.
Henderson, DC, Vincenzi, B, Andrea, NV, Ulloa, M, Copeland, PM (2015). Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses. Lancet Psychiatry 2, 452464.
Holt, RI (2004). Diagnosis, epidemiology and pathogenesis of diabetes mellitus: an update for psychiatrists. British Journal of Psychiatry. Supplement 47, S55S63.
Holt, RI (2015). The prevention of diabetes and cardiovascular disease in people with schizophrenia. Acta Psychiatrica Scandinavica 132, 8696.
Hu, H, Sawhney, M, Shi, L, Duan, S, Yu, Y, Wu, Z, Qiu, G, Dong, H (2015). A systematic review of the direct economic burden of type 2 diabetes in China. Diabetes Therapy 6, 716.
Keefe, RS (2007). Cognitive deficits in patients with schizophrenia: effects and treatment. Journal of Clinical Psychiatry 68 (Suppl. 14), 813.
Kirkpatrick, B, Fernandez-Egea, E, Garcia-Rizo, C, Bernardo, M (2009). Differences in glucose tolerance between deficit and nondeficit schizophrenia. Schizophrenia Research 107, 122127.
Kumar, R, Looi, JC, Raphael, B (2009). Type 2 diabetes mellitus, cognition and brain in aging: a brief review. Indian Journal of Psychiatry 51 (Suppl. 1), S35S38.
Kusumi, I, Ito, K, Uemura, K, Honda, M, Hayashishita, T, Miyamoto, K, Sawayama, H, Kako, Y, Tsuchida, S, Hashimoto, N, Koyama, T (2011). Screening for diabetes using monitoring guidance in schizophrenia patients treated with second-generation antipsychotics: a 1-year follow-up study. Progress in Neuropsychopharmacology and Biological Psychiatry 35, 19221926.
Lin, PI, Shuldiner, AR (2010). Rethinking the genetic basis for comorbidity of schizophrenia and type 2 diabetes. Schizophrenia Research 123, 234243.
Ma, E, Wang, H, Guo, J, Tian, R, Wei, L (2015). The association between the rs11196218A/G polymorphism of the TCF7L2 gene and type 2 diabetes in the Chinese Han population: a meta-analysis. Clinics 70, 593599.
Manschot, SM, Biessels, GJ, de Valk, H, Algra, A, Rutten, GE, van der Grond, J, Kappelle, LJ, Utrecht Diabetic Encephalopathy Study Group (2007). Metabolic and vascular determinants of impaired cognitive performance and abnormalities on brain magnetic resonance imaging in patients with type 2 diabetes. Diabetologia 50, 23882397.
Manschot, SM, Brands, AM, van der Grond, J, Kessels, RP, Algra, A, Kappelle, LJ, Biessels, GJ (2006). Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 55, 11061113.
Mathers, CD, Loncar, D (2006). Projections of global mortality and burden of disease from 2002 to 2030. PloS Medicine 3, e442.
Matthews, DR, Hosker, JP, Rudenski, AS, Naylor, BA, Treacher, DF, Turner, RC (1985). Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412419.
Mayeda, ER, Whitmer, RA, Yaffe, K (2015). Diabetes and cognition. Clinics in Geriatric Medicine 31, 101115.
McCleery, A, Ventura, J, Kern, RS, Subotnik, KL, Gretchen-Doorly, D, Green, MF, Hellemann, GS, Nuechterlein, KH (2014). Cognitive functioning in first-episode schizophrenia: MATRICS Consensus Cognitive Battery (MCCB) profile of impairment. Schizophrenia Research 157, 3339.
Meyer, JM, Stahl, SM (2009). The metabolic syndrome and schizophrenia. Acta Psychiatrica Scandinavica 119, 414.
Mitchell, AJ, Vancampfort, D, Sweers, K, van Winkel, R, Yu, W, De Hert, M (2013). Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders – a systematic review and meta-analysis. Schizophrenia Bulletin 39, 306318.
Miyamoto, S, Miyake, N, Jarskog, LF, Fleischhacker, WW, Lieberman, JA (2012). Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Molecular Psychiatry 17, 12061227.
Moheet, A, Mangia, S, Seaquist, ER (2015). Impact of diabetes on cognitive function and brain structure. Annals of the New York Academy of Sciences 1353, 6071.
Ono, S, Suzuki, Y, Fukui, N, Sugai, T, Watanabe, J, Tsuneyama, N, Saito, M, Someya, T (2013). The prevalence of glucose intolerance in Japanese schizophrenic patients with a normal fasting glucose level. Journal of Clinical Psychopharmacology 33, 525527.
Palmer, BW, Dawes, SE, Heaton, RK (2009). What do we know about neuropsychological aspects of schizophrenia? Neuropsychology Review 19, 365384.
Paquin, K, Wilson, AL, Cellard, C, Lecomte, T, Potvin, S (2014). A systematic review on improving cognition in schizophrenia: which is the more commonly used type of training, practice or strategy learning? BMC Psychiatry 14, 139.
Petrikis, P, Tigas, S, Tzallas, AT, Papadopoulos, I, Skapinakis, P, Mavreas, V (2015). Parameters of glucose and lipid metabolism at the fasted state in drug-naïve first-episode patients with psychosis: evidence for insulin resistance. Psychiatry Research 229, 901904.
Rajji, TK, Miranda, D, Mulsant, BH (2014). Cognition, function, and disability in patients with schizophrenia: a review of longitudinal studies. Canadian Journal of Psychiatry 59, 1317.
Rajji, TK, Mulsant, BH (2008). Nature and course of cognitive function in late-life schizophrenia: a systematic review. Schizophrenia Research 102, 122140.
Ryan, MCM, Collins, P, Thakore, JH (2003). Impaired fasting glucose and elevation of cortisol in drug naïve first-episode schizophrenia. American Journal of Psychiatry 160, 284289.
Sanz, CM, Ruidavets, JB, Bongard, V, Marquie, JC, Hanaire, H, Ferrieres, J, Andrieu, S (2013). Relationship between markers of insulin resistance, markers of adiposity, HbA1c, and cognitive functions in a middle-aged population-based sample: the MONA LISA study. Diabetes Care 36, 15121521.
Sarwar, N, Gao, P, Seshasai, SR, Gobin, R, Kaptoge, S, Di Angelantonio, E, Ingelsson, E, Lawlor, DA, Selvin, E, Stampfer, M, Stehouwer, CD, Lewington, S, Pennells, L, Thompson, A, Sattar, N, White, IR, Ray, KK, Danesh, J (2010). Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375, 221522122.
Schreiber, R, Newman-Tancredi, A (2014). Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT(1A) receptor activation. Neurobiology of Learning and Memory 110, 7280.
Sengupta, S, Parrilla-Escobar, MA, Klink, R, Fathalli, F, Ying Kin, Ng, Stip, E, Baptista, T, Malla, A, Joober, R (2008). Are metabolic indices different between drug-naive first-episode psychosis patients and healthy controls? Schizophrenia Research 102, 329336.
Sharma, T, Antonova, L (2003). Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment. Psychiatric Clinics of North America 26, 2540.
Simpson, N, Maffei, A, Freeby, M, Burroughs, S, Freyberg, Z, Javitch, J, Leibel, RL, Harris, PE (2012). Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro . Molecular Endocrinology 26, 17571772.
Smith, M, Hopkins, D, Peveler, RC, Holt, RI, Woodward, M, Ismail, K (2008). First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. British Journal of Psychiatry 192, 406411.
Spelman, LM, Walsh, PI, Sharifi, N, Collins, P, Thakore, JH (2007). Impaired glucose tolerance in first episode drug-naive patients with schizophrenia. Diabetic Medicine 24, 481485.
Stubbs, B, Vancampfort, D, De Hert, M, Mitchell, AJ (2015). The prevalence and predictors of type two diabetes mellitus in people with schizophrenia: a systematic review and comparative meta-analysis. Acta Psychiatrica Scandinavica 132, 144157.
Tai, ES, Lim, SC, Tan, BY, Chew, SK, Heng, D, Tan, CE (2000). Screening for diabetes mellitus – a two step approach in individuals with impaired fasting glucose improves detection of those at risk of complications. Diabetic Medicine 17, 771775.
van Winkel, R, De Hert, M, Van Eyck, D, Hanssens, L, Wampers, M, Scheen, A, Peuskens, J (2006). Screening for diabetes and other metabolic abnormalities in patients with schizophrenia and schizoaffective disorder: evaluation of incidence and screening methods. Journal of Clinical Psychiatry 67, 14931500.
Venkatasubramanian, G, Chittiprol, S, Neelakantachar, N, Naveen, MN, Thirthall, J, Gangadhar, BN, Shetty, KT (2007). Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia. American Journal of Psychiatry 164, 15571560.
Wang, S, Song, K, Srivastava, R, Fathzadeh, M, Li, N, Mani, A (2015). The protective effect of transcription factor 7-like 2 risk allele rs7903146 against elevated fasting plasma triglyceride in type 2 diabetes: a meta-analysis. Journal of Diabetes Research 2015, 468627.
Whiting, DR, Guariguata, L, Weil, C, Shaw, J (2011). IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice 94, 311321.
Wu, JQ, Chen da, C, Tan, YL, Xiu, MH, Yang, FD, Soares, JC, Zhang, XY (2016). Cognitive impairments in first-episode drug-naive and chronic medicated schizophrenia: MATRICS Consensus Cognitive Battery in a Chinese Han population. Psychiatry Research 238, 196202.
Wu, X, Huang, Z, Wu, R, Zhong, Z, Wei, Q, Wang, H, Diao, F, Wang, J, Zheng, L, Zhao, J, Zhang, J (2013). The comparison of glycometabolism parameters and lipid profiles between drug-naive, first-episode schizophrenia patients and healthy controls. Schizophrenia Research 150, 157162.
Yogaratnam, J, Biswas, N, Vadivel, R, Jacob, R (2013). Metabolic complications of schizophrenia and antipsychotic medications – an updated review. East Asian Archives of Psychiatry 23, 2128.
Zhang, BH, Han, M, Zhang, XY, Hui, L, Jiang, SR,Yang, FD, Tan, YL, Wang, ZR, Li, J, Huang, XF (2015). Gender differences in cognitive deficits in schizophrenia with and without diabetes. Comprehensive Psychiatry 63, 19.
Zhang, X, Hui, L, Liu, Y, Wang, ZQ, You, Y, Miao, LN, Sun, SL, Guan, SL, Xiang, Y, Kosten, TR, Zhang, XY (2013). The type 2 diabetes mellitus susceptibility gene IGF2BP2 is associated with schizophrenia in a Han Chinese population. Journal of Clinical Psychiatry 74, e287e292.
Zhen, YF, Zhang, J, Liu, XY, Fang, H, Tian, LB, Zhou, DH, Kosten, TR, Zhang, XY (2013). Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology 227, 93100.
Zhou, Y, Cui, J, Wang, J, Chen, N, Tan, S, Zhang, D, Xue, Z, Song, S, Wang, Y, Li, Y, Gao, W, Duan, J (2009). Clinical reliability and validity of the Chinese version of Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. Chinese Journal of Psychiatry 42, 2933.
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