Abstract
Purpose of Review
Mental health disorders, such as schizophrenia, bipolar disorder, and anxiety and depression disorder, are associated with increased risk for type 2 diabetes. Studies report varying rates of type 2 diabetes among people with severe mental illness, ranging 1.5–5.0-fold elevated risk than in the general population, whereas the etiology is complex and multifactorial. Among other factors, this is partly attributed to adverse metabolic effects of antipsychotic and antidepressant medications. This review aims to summarize literature evidence on the diabetogenic effect of commonly used psychiatric medications.
Recent Findings
From the first generation antipsychotics, thioridazine and clorpromazine are associated with high, while fluphenazine, aloperidol, and perphenazide with low risk for type 2 diabetes. From the second generation antipsychotics, the highest risk for type 2 diabetes has been found with olanzapine and clozapine, while the risk is low to moderate with the other medications of this category. Anticonvulsants, mood stabilizers, tricyclic, and tetracyclic antidepressants increase mildly to moderately the risk. Selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, serotonin modulators and stimulators, serotonin antagonists and reuptake inhibitors, norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors have not been associated with increased risk for type 2 diabetes.
Summary
First and second generation antipsychotics have been associated with increased risk, while anticonvulsants, mood stabilizers, and antidepressants increase modestly the risk for type 2 diabetes. Healthcare professional should be aware of the potential diabetogenic effect of antipsychotic medications and prompt screening is required for the early diagnosis of type 2 diabetes in this population.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
The comorbidity between severe mental illnesses (SMI) and increased prevalence of type 2 diabetes mellitus (T2D) is well established in many different studies. Particularly, prevalence estimations of T2D among patients with schizophrenia in the European countries range from 11.3% in the UK [1] to 22% in a cross-sectional study in Finland [2]. Accordingly, T2D prevalence varies 1.7–3.2-fold higher [3,4,5,6,7] among patient populations with bipolar disorder in comparison with the general population, whereas factors such as female gender, age over 40, and obesity appear to have significant additional risk [7, 8]. Similarly, a retrospective analysis in the USA using the 2002–2014 Nationwide Inpatient Sample databases measured the rate of depression among patients with T2D to 15.4% in 2014, whereas prevalence reached 7.6% in 2002, respectively [9], reflecting also the increasing tendency.
Apart from common diabetogenic factors applying in the general population, such as smoking, hypertension, obesity, poor diet, limited physical activity, and hyperlipidemia, unique conditions attribute additionally on diabetes onset among individuals suffering from psychiatric problems. Specifically, the excessive sedentary lifestyle followed often by persons with SMI [10, 11], social determinants and the limited access to primary medical care [12] contribute to diabetes onset. Further, a shared genetic etiology is proposed for diabetes and mental illness co-occurrence, given the observed higher prevalence of diabetes in young patients, newly diagnosed with schizophrenia or bipolar disorder and treatment-naive [13,14,15, 16••]. Additionally, many psychiatric drug regiments are markedly considered responsible for increased the risk of diabetes and other metabolic disorders, though literature is not always consistent [17, 18].
Consideration of the increasing prescription of psychotropic medications, not only as required by official recommendations and therapeutic guidelines, but also as often applied off label, strengthens the need for deep knowledge of their potential diabetogenic side effects. Therefore, the purpose of this review is to clarify, according to literature search, not only the prospective relation of psychotropic substances use, and mainly first-generation antipsychotics (FGA), second-generation antipsychotics (SGA), antidepressants (AD), mood stabilizers (MD), with the development of diabetes, but also the extent to which their use has direct effects on diabetogenic metabolic pathways. A MEDLINE search was conducted via PubMed using in various combinations the following keywords: First Generation Antipsychotics, Second Generation Antipsychotics, Antidepressants, Mood stabilizers, anxiolytics, hypnotics, side effects, diabetes. Only English-language articles published from 1995 to 2017 were included and reviewed.
Antipsychotics
Second-generation antipsychotics (SGAs) represent the first line treatment for psychotic disorders. They present high affinity for dopamine D2 receptors in the mesolimbic pathway and serotonin receptors (particularly 5-hydroxy-tryptamine 2A receptor [5-HT2A], 5-hydroxy-tryptamine 2C receptor [5-HT2C], and 5-hydroxy-tryptamine 1A receptor [5-HT1A]), both regulating feeding behavior [19, 20], ranging from risperidone acting overwhelmingly on serotonin receptors, to amisulpride with no serotonergic activity. Therefore, they present with lower propensity to produce extrapyramidal side effects [20, 21]. However, the majority of SGAs are associated with significant weight gain and further T2D development [22,23,24] (Table 1). This is additionally due to their high affinity with Muscarinic M2 and M3 receptors, which are considered relevant for glucose homeostasis, controlling cholinergic-dependent insulin release [29,30,31,32,33]. FGAs are not particularly selective and block dopamine receptors in all of the pathways (mesolimbic, mesocortical, tuberoinfundibular, and nigrostriatal pathways) [34]. Finally, weak genetic evidence suggests association of antipsychotic induced weight gain with leptin, G-protein and promelanin-concentrating hormone signaling, as well with cannaboid receptor activity and a-adrenergic transmission [19, 35,36,37,38].
Comparison between SGAs with first FGAs revealed a 1.3-folds elevated risk for diabetes [39], an effect intermediated either by weight gain, or in 25% of cases [40] though direct impairment in glucose homeostasis, potentially via blockade of central and peripheral M3 receptors [41, 42]. Similarly, another study revealed increased T2D risk for both patient groups treated with SGA (adjusted hazard ratio [HR] 1.32, 95% confidence intervals [CI] 1.01–1.75) or those under FGA treatment (adjusted HR 1.82, 95% CI 1.30–2.55) against control patients without schizophrenia and psychotropic medication [43]. Furthermore, a meta-analysis reported 2.1% T2D prevalence among antipsychotic-naïve patients, whereas the prevalence was 12.8% for antipsychotic receivers [44]. Nevertheless, a systematic review of 22 prospective, randomized, control trials, though short-term followed, detected no difference in glycemic abnormalities between placebo and antipsychotic cohorts [27].
Proposed explanations to those inconsistent findings are beyond methodological problems such as sample size, medication pre-exposure of tested groups, duration and dose of daily medication received, control for therapy adherence, severity, duration and type of psychiatric disorder, homogeneity of case group (schizophrenia, schizoaffective disorders, psychosis), way of diabetes diagnosis estimation (self-report, anti-diabetes drugs, American Diabetes Association (ADA) criteria) or the differences in metabolic traits measured such as homeostasis model insulin resistance (HOMA-IR), glycated hemoglobin A1c (HbA1c), fasting glucose, the follow-up period, but also other unobserved confounding factors, such as the unbalanced diet, the physical activity, the sleep duration, psychiatric disease severity. Notably, the heterogeneity inside each group of SGAs and FGAs potentially reflects differences in terms of diabetogenic effect.
Accordingly, other studies attempted to evaluate the diabetogenic role of each antipsychotic regiment separately. A large, population-based study conducted in Denmark with 345,937 cases treated with antipsychotics and 1,426,488 controls found 1.45% for clozapine, 1.29% for olanzapine, and 1.23% for risperidone, 1.94% for sertindole, 1.57% for perphenazine, 1.94% for ziprasidone, and even 1.17 for haloperidol increased diabetes risk [25], whereas no increase in diabetes risk was detected for aripiprazole, amisulpride or quetiapine. On the other hand, a study on newly-onset schizophrenia patients revealed diabetes incidence patients with olanzapine initiation therapy (hazard ratio, HR = 1.41) and with mid-potency conventional antipsychotics (HR = 1.60) [45]. Moreover, a Food and Drug Administration (FDA) database analysis on T2D onset, reported the following adjusted ratios hierarchy for diabetes-mellitus-related adverse outcomes: olanzapine 9.6 (95% CI 9.2–10.0), risperidone 3.8 (95% CI 3.5–4.1), quetiapine 3.5 (95% CI 3.2–3.9), clozapine 3.1 (95% CI 2.9–3.3), ziprasidone 2.4 (95% CI 2.0–2.9) aripiprazole 2.4 (95% CI 1.9–2.9) and haloperidol 2.0 (95% CI 1.7–2.3) [28]. Clozapine and olanzapine are consistently associated with greater weight gain risk. [46]. Among SGAs, clozapine and olanzapine are detected to have the higher risk for causing weight gain and glucose dysregulation, iloperidone, paliperidone, quetiapine, and risperidone a medium risk and aripiprazole, asenapine, lurasidone, and ziprasidone present with a low risk reported in another study [47]. One additional study [26•] conducted in Medicaid-enrolled youths, detected higher risk for diabetes incident for SGA initiators concomitantly to antidepressant use (odds ratio [OR] 1.54, 95% CI 1.17–2.03, p = 0.002), when compared to only SGA initiators. Furthermore, first-episode and antipsychotic-naïve patients with schizophrenia as compared to chronic patients are more vulnerable to severe weight gain, rapidly during the first few weeks, due to antipsychotics [47].
Antidepressants
The prevalence of depression in T2D is estimated 10–30% [48] and the comorbidity is associated with poor glycemic control, apart from increased T2D complications [49]. Literature results suggest that antidepressants could potentially influence T2D regulation, beneficial or deleteriously. Therefore, a review and meta-analysis of 14 randomized control trials [50] suggests sertraline (Selective Serotonin Reuptake Inhibitors, SSRIs) for better glycemic control, as no effect was detected by nortriptyline (Tricyclic Antidepressant, TCAs), paroxetine (SSRIs), and fluoxetine (SSRIs).
On the other hand, there is a considerable literature on the potential diabetogenic adverse effects of antidepressants, partially through inducing weight gain [51], mainly after exposure to high Histamine1-receptor (H1) affinity ADs [52]. Similarly, hyperglycemia was linked to the use of high affinity H1 and 5-hydroxy-tryptamine 2c [5HT2c] receptors in a study conducted with the Adverse Drug Reaction Database [53]. Sedative effect, the increase in appetite, and weight gain induced by ADs represent the most popular factors linking ADs with T2D [54,55,56]. A review of 17 case reports [57, 58] detected hyperglycemia between 3 weeks and 5 months after antidepressant treatment initiation of paroxetine, clomipramine and mirtazapine, a reversible effect within a week after drug abstinence. Cross-sectional studies, such as the Finish Prevalence, Prediction and Prevention of Diabetes (FFD) program [59, 60] and the Hordaland Health Survey, Norway, comparing 461 patients taking SSRIs with 25,315 not taking [61] detected no association between antidepressant use and T2D.
On the other hand, the population-based cross-sectional National Health and Nutrition Examination Studies [62] exploring the association between pre-diabetes and T2D with depression and antidepressant use identified significant linkage, when antidepressants were applied (OR 1.75 [95% CI 1.20–2.54]). Further, case-control studies provide evidence of diabetogenic effect of antidepressants. Specifically, the U.K. General Practice Research Database [63], including a cohort of 165,958 patients with depression, detected increased risk of T2D (OR 1.84 CI [1.35–2.52]) by moderate to highly daily dose of antidepressants use for over 24 months, for both SSRIs and TCAs. Similarly, a Finnish occupational study comparing 851 people who developed T2D with 4234 T2D free people [64], evaluated increased risk of T2D in individuals consuming ADs with severe depression (OR 2.65 [CI 1.31–5.39]) or even without (OR 1.93 [CI 1.48–2.51]).
Furthermore, a Canadian case-control study [65], aiming to evaluate the magnitude of the diabetogenic effect of different antidepressant categories, detected no difference between TCAs and SSRIs (OR 1.05[CI 0.86–1.28], whereas the diabetogenic effect was significantly elevated when SSRIs and TCAs were applied concurrently, as compared with TCAs alone (OR 1.89 [CI 1.35–2.65]). Another retrospective cohort study [66], comparing 31,552 adults under antidepressant treatment and 9136 under benzodiazepine prescription from Texas Medicaid database, evaluated double elevated T2D risk with antidepressants, while the association was estimated also separately for the TCAs (HR 1.759 [95% CI 1.517–2.040]), for serotonin-norepinephrine reuptake inhibitors (SNRIs) (HR 1.566 [95% CI 1.351–1.816]), SSRIs (HR 1.481 [95% CI 1.318–1.665]) and other antidepressants (HR 1.376 [95% CI 1.198–1.581]). On the contrary, the Dutch pharmacy database study [67] following 60,516 individuals from initiation of antidepressants, benzodiazepine, and diabetes treatment, estimated almost no risk for T2D onset under antidepressants (HR 1.05 [95% CI 0.88–1.26]), higher for benzodiazepine use (HR 1.37 [95% CI 1.12–1.68]), and even higher (HR 1.37 [95% CI 1.12–1.68]) for the concomitant use of both ADs and benzodiazepines.
A study evaluated elevated risk of T2D in patients with moderate to severe depression by 93–165% compared with the general population, when applied conventional antidepressants [64, 68, 69], though not in a causal way. Further, treatment short-termly with SSRIs, the most frequently prescribed antidepressants, improves glucose regulation in the general population [70], whereas no glycaemic dysregulation was detected after 1 year use of SSRIs in patients with established T2D [71], potentially due to its known anorexigenic properties [72]. A placebo-controlled trial of an antidepressant [73], as well as an observational study [74] comparing glycaemic traits before and after antidepressant therapy in people with depression failed to detect effects on insulin sensitivity, despite the improvement in depression management. Further, two other studies present improved insulin resistance in patients with depression under AD therapy [75, 76]. On the contrary, long-term application of at least moderate doses of antidepressants (TCAs and SSRIs) has been linked with elevated T2D risk [64, 77, 78]. A meta-analysis, though involving only observational studies, detected elevation in diabetes onset likelihood (OR 51.50 [95% CI 1.08–2.10], HR 51.19, [95% CI: 1.08–1.32]) [79]. Finally, most studies [47, 80] provide evidence for increased diabetes risk with the concurrent use of TCAs and SSRIs (OR = 1.89) [65], the long-term use of both tricyclic TCAs (incidence rate ratio, IRR = 1.77) and SSRIs (IRR = 2.06) when applied in at least moderate daily doses [77], as well as when use of antidepressant medication refers to highly-risk patients [81]. Further, amitriptyline, imipramide, and mirtazapine are associated substantially with weight gain, nortriptyline and paroxetine seem to have intermediate effect, whereas bupropion and fluoxetine are related to weight loss [22] (Table 2).
Outcomes of all these studies should be interpreted with caution, due to heterogeneity of methodological structure making often comparisons between studies impossible or on ground of differences in the population examined, whether they refer to the general population or specifically to samples with depression, who more often undertake diabetes screening [63, 86, 87]. Furthermore, conflicting results could be ascribed to disparities in each antidepressant drug molecule or group effect, or consequence of different glycemic traits measured between different studies, such as insulin secretion, insulin resistance [75, 88, 89]. Finally, high rates of off-label psychotropic medication application strengthen the request for clinical trials to better estimate the efficacy and safety of these treatments [77].
Other Psychotropic Medications
Little research has been held to evaluate the potential diabetogenic effect of other psychiatric regiments applied to manage SMI, or in terms of their synergistic action, when they are applied concomitantly with antipsychotics or ADs. Mood stabilizers, especially valproate [82] and lithium [83] (Table 2), have been associated with insulin resistance and diabetes risk,[84, 90] related possibly to weight gain [91], and/or fatty liver infiltration [92]. Other studies also relate valproate with increased levels of triglycerides and glucose, and insulin abnormalities [85].
Conversely, in youth with concomitant ADs and stimulant use, the duration of stimulant use or the cumulative stimulant doses were not associated with T2D onset [26•, 93•]. Further, the concomitant with ADs application of anxiolytics, alpha 2 adrenergic agonists and hypnotics in the youths revealed no additional T2D risk [26•]. Another study detected no effect of anxiolytics, and/or hypnotics use on HbA1c levels [94].
Prevention and Therapy
Clinical practice guidelines and individualized medicine are keys to improve health of patients with SMI. Overall, literature suggests SSRIs as safer choice in terms of T2D prevention. Concerning tricyclic antidepressants studies present a tendency towards increasing T2D risk, although causality is not established, therefore closer glucose monitoring is recommended when applied. Furthermore, among second generation agents, olanzapine and clozapine seem to have the strongest diabetogenic potential, however almost all antipsychotics (FGA, SGA) are associated with diabetogenic effects, noticeably at younger age, due to low background risk for T2D [95]. Additionally, mood stabilizers seem to elevate T2D risk.
The American Diabetes Association (ADA) highlights the importance of patients’ annual screening for people with SMI for pre-diabetes or diabetes. To test for T2D diabetes, fasting plasma glucose, 2-h plasma glucose after 75-g oral glucose tolerance test, and HbA1c are equally appropriate. Changes in weight, glycemic control, blood pressure, and cholesterol levels should be carefully monitored and the treatment regimen should be reassessed [96]. Foremost, motivation in the direction of healthy lifestyle choices, such as tobacco cessation, weight management, healthy eating, sleep quality, physical activity, and effective strategies for coping with stress represent priorities for health providers. Notwithstanding these, collaborative, multidisciplinary teams are best suited to provide care for people with chronic conditions such as SMI and to facilitate patients’ self-management. Prioritizing timely and appropriate intensification of lifestyle and/or pharmacological therapy for patients who have not achieved the recommended metabolic targets, redefining the roles of the health care delivery team and empowering patient self-management are fundamental to achieve diabetes prevention and bring optimal therapeutic results [96]. HbA1c control every three 3 months, fasting lipid profile, including total, LDL (low density cholesterol), and HDL cholesterol (high-density cholesterol) and triglycerides, liver function tests, spot urinary albumin–to–creatinine ratio, serum creatinine and estimated glomerular filtration rate belong to the regular monitoring plan of T2D patients. Vaccination against pneumonia for all people with T2D through 64 years of age, additionally to vaccination against influenza for all T2D patients is highly recommended. Particular attention should be paid in the follow up of SMI people, under regular treatment with combinations of antipsychotic, antidepressants and MS, given the limited data on the diabetogenic adverse effects of combination regimes.
Conclusion
This review implies the association between specific antidepressants, such as tricyclics and antipsychotics, applied separately or concomitantly with the incidence of T2D. On the contrary, other ADs, such as SSRIs, are considered to be neutral, or even beneficial over the short-term use, leading to a better control of depressive symptoms and encouraging actions in the direction of a more advantageous T2D self-management. Given the high prevalence of AD and antipsychotic use and the heterogeneity inside each medication category, a finer classification according to their pharmacological profile, could serve in better elucidating the nature and magnitude of this association. Comprehensive evaluation of the risk of T2D associated to psychiatric medication is becoming of utmost importance for the clinicians to help patients follow efficient and safe treatments. Future large sample, longitudinal, highly phenotyped studies could help drawing definite recommendations on medications safety.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Schoepf D, Potluri R, Uppal H, Natalwala A, Narendran P, Heun R. Type-2 diabetes mellitus in schizophrenia: increased prevalence and major risk factor of excess mortality in a naturalistic 7-year follow-up. Eur Psychiatry. 2012;27(1):33–42. https://doi.org/10.1016/j.eurpsy.2011.02.009.
Suvisaari J, Perala J, Saarni SI, Harkanen T, Pirkola S, Joukamaa M, et al. Type 2 diabetes among persons with schizophrenia and other psychotic disorders in a general population survey. Eur Arch Psychiatry Clin Neurosci. 2008;258(3):129–36. https://doi.org/10.1007/s00406-007-0762-y.
Wandell P, Ljunggren G, Wahlstrom L, Carlsson AC. Diabetes and psychiatric illness in the total population of Stockholm. J Psychosom Res. 2014;77(3):169–73. https://doi.org/10.1016/j.jpsychores.2014.06.012.
Crump C, Sundquist K, Winkleby MA, Sundquist J. Comorbidities and mortality in bipolar disorder: a Swedish national cohort study. JAMA Psychiatry. 2013;70(9):931–9. https://doi.org/10.1001/jamapsychiatry.2013.1394.
Bai YM, Su TP, Chen MH, Chen TJ, Chang WH. Risk of developing diabetes mellitus and hyperlipidemia among patients with bipolar disorder, major depressive disorder, and schizophrenia: a 10-year nationwide population-based prospective cohort study. J Affect Disord. 2013;150(1):57–62. https://doi.org/10.1016/j.jad.2013.02.019.
Svendal G, Fasmer OB, Engeland A, Berk M, Lund A. Co-prescription of medication for bipolar disorder and diabetes mellitus: a nationwide population-based study with focus on gender differences. BMC Med. 2012;10(1):148. https://doi.org/10.1186/1741-7015-10-148.
Wysokinski A, Strzelecki D, Kloszewska I. Levels of triglycerides, cholesterol, LDL, HDL and glucose in patients with schizophrenia, unipolar depression and bipolar disorder. Diabetes Metab Syndr. 2015;9(3):168–76. https://doi.org/10.1016/j.dsx.2015.04.004.
Goldstein BI, Liu SM, Zivkovic N, Schaffer A, Chien LC, Blanco C. The burden of obesity among adults with bipolar disorder in the United States. Bipolar Disord. 2011;13(4):387–95. https://doi.org/10.1111/j.1399-5618.2011.00932.x.
Chima CC, Salemi JL, Wang M, Mejia de Grubb MC, Gonzalez SJ, Zoorob RJ. Multimorbidity is associated with increased rates of depression in patients hospitalized with diabetes mellitus in the United States. J Diabetes Complicat. 2017;31(11):1571–9. https://doi.org/10.1016/j.jdiacomp.2017.08.001.
Janney CA, Fagiolini A, Swartz HA, Jakicic JM, Holleman RG, Richardson CR. Are adults with bipolar disorder active? Objectively measured physical activity and sedentary behavior using accelerometry. J Affect Disord. 2014;152-154:498–504. https://doi.org/10.1016/j.jad.2013.09.009.
Jerrell JM, McIntyre RS, Tripathi A. Incidence and costs of cardiometabolic conditions in patients with schizophrenia treated with antipsychotic medications. Clin Schizophr Relat Psychoses. 2010;4(3):161–8. https://doi.org/10.3371/CSRP.4.3.2.
Brown S, Birtwistle J, Roe L, Thompson C. The unhealthy lifestyle of people with schizophrenia. Psychol Med. 1999;29(3):697–701. https://doi.org/10.1017/S0033291798008186.
Garcia-Rizo C, Kirkpatrick B, Fernandez-Egea E, Oliveira C, Meseguer A, Grande I, et al. “Is bipolar disorder an endocrine condition?” glucose abnormalities in bipolar disorder. Acta Psychiatr Scand. 2014;129(1):73–4. https://doi.org/10.1111/acps.12194.
Cohen D, De Hert M. Endogenic and iatrogenic diabetes mellitus in drug-naive schizophrenia: the role of olanzapine and its place in the psychopharmacological treatment algorithm. Neuropsychopharmacology. 2011;36(11):2368–9. https://doi.org/10.1038/npp.2011.94.
Foley DL, Mackinnon A, Morgan VA, Watts GF, Castle DJ, Waterreus A, et al. Effect of age, family history of diabetes, and antipsychotic drug treatment on risk of diabetes in people with psychosis: a population-based cross-sectional study. Lancet Psychiatry. 2015;2(12):1092–8. https://doi.org/10.1016/S2215-0366(15)00276-X.
•• Correll CU, Detraux J, De Lepeleire J, De Hert M. Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World Psychiatry. 2015;14(2):119–36. https://doi.org/10.1002/wps.20204. A very important review on the side-effects of antipsychotics, antidepressants, and mood stabilizers on several physical diseases.
Sugai T, Suzuki Y, Yamazaki M, Shimoda K, Mori T, Ozeki Y, et al. High prevalence of obesity, hypertension, hyperlipidemia, and diabetes mellitus in Japanese outpatients with schizophrenia: a nationwide survey. PLoS One. 2016;11(11):e0166429. https://doi.org/10.1371/journal.pone.0166429.
Citrome L, Jaffe A, Levine J, Martello D. Incidence, prevalence, and surveillance for diabetes in New York state psychiatric hospitals, 1997-2004. Psychiatr Serv. 2006;57(8):1132–9. https://doi.org/10.1176/ps.2006.57.8.1132.
Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med. 2011;17(2):97–107. https://doi.org/10.1016/j.molmed.2010.10.010.
Correll CU. From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics. Eur Psychiatry. 2010;25(Suppl 2):S12–21. https://doi.org/10.1016/S0924-9338(10)71701-6.
Correll CU. Balancing efficacy and safety in treatment with antipsychotics. CNS Spectr. 2007;12(10 Suppl 17):12–20, 35.
De Hert M, Cohen D, Bobes J, Cetkovich-Bakmas M, Leucht S, Ndetei DM, et al. Physical illness in patients with severe mental disorders. II. Barriers to care, monitoring and treatment guidelines, plus recommendations at the system and individual level. World Psychiatry. 2011;10(2):138–51. https://doi.org/10.1002/j.2051-5545.2011.tb00036.x.
De Hert M, Mauri M, Shaw K, Wetterling T, Doble A, Giudicelli A, et al. The METEOR study of diabetes and other metabolic disorders in patients with schizophrenia treated with antipsychotic drugs. I. Methodology. Int J Methods Psychiatr Res. 2010;19(4):195–210. https://doi.org/10.1002/mpr.322.
Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19(Suppl 1):1–93.
Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry. 2010;197(4):266–71. https://doi.org/10.1192/bjp.bp.109.076935.
• Rubin DM, Kreider AR, Matone M, Huang YS, Feudtner C, Ross ME, et al. Risk for incident diabetes mellitus following initiation of second-generation antipsychotics among Medicaid-enrolled youths. JAMA Pediatr. 2015;169(4):e150285. https://doi.org/10.1001/jamapediatrics.2015.0285. An important retrospective national cohort study examining besides others the risk associated with multiple-drug regimens, including stimulants and antidepressants, as well as individual second Generation Antipsychotics.
Bushe C, Leonard B. Association between atypical antipsychotic agents and type 2 diabetes: review of prospective clinical data. Br J Psychiatry Suppl. 2004;47:S87–93.
Baker RA, Pikalov A, Tran QV, Kremenets T, Arani RB, Doraiswamy PM. Atypical antipsychotic drugs and diabetes mellitus in the US Food and Drug Administration Adverse Event database: a systematic Bayesian signal detection analysis. Psychopharmacol Bull. 2009;42(1):11–31.
Reynolds GP, Kirk SL. Metabolic side effects of antipsychotic drug treatment—pharmacological mechanisms. Pharmacol Ther. 2010;125(1):169–79. https://doi.org/10.1016/j.pharmthera.2009.10.010.
Coccurello R, Moles A. Potential mechanisms of atypical antipsychotic-induced metabolic derangement: clues for understanding obesity and novel drug design. Pharmacol Ther. 2010;127(3):210–51. https://doi.org/10.1016/j.pharmthera.2010.04.008.
Johnson DE, Nedza FM, Spracklin DK, Ward KM, Schmidt AW, Iredale PA, et al. The role of muscarinic receptor antagonism in antipsychotic-induced hippocampal acetylcholine release. Eur J Pharmacol. 2005;506(3):209–19. https://doi.org/10.1016/j.ejphar.2004.11.015.
Silvestre JS, Prous J. Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes. Methods Find Exp Clin Pharmacol. 2005;27(5):289–304. https://doi.org/10.1358/mf.2005.27.5.908643.
Bishara D, Taylor D. Asenapine monotherapy in the acute treatment of both schizophrenia and bipolar I disorder. Neuropsychiatr Dis Treat. 2009;5:483–90.
Olfson M, Marcus SC. National trends in outpatient psychotherapy. Am J Psychiatry. 2010;167(12):1456–63. https://doi.org/10.1176/appi.ajp.2010.10040570.
Morrato EH, Nicol GE, Maahs D, Druss BG, Hartung DM, Valuck RJ, et al. Metabolic screening in children receiving antipsychotic drug treatment. Arch Pediatr Adolesc Med. 2010;164(4):344–51. https://doi.org/10.1001/archpediatrics.2010.48.
Moons T, Claes S, Martens GJ, Peuskens J, Van Loo KM, Van Schijndel JE, et al. Clock genes and body composition in patients with schizophrenia under treatment with antipsychotic drugs. Schizophr Res. 2011;125(2–3):187–93. https://doi.org/10.1016/j.schres.2010.10.008.
van Winkel R, Moons T, Peerbooms O, Rutten B, Peuskens J, Claes S, et al. MTHFR genotype and differential evolution of metabolic parameters after initiation of a second generation antipsychotic: an observational study. Int Clin Psychopharmacol. 2010;25(5):270–6. https://doi.org/10.1097/YIC.0b013e32833bc60d.
van Winkel R, Rutten B, Peerbooms O, Peuskens J, van Os J, De Hert M. MTHFR and risk of metabolic syndrome in patients with schizophrenia. Schizophr Res. 2010;121(1–3):193–8. https://doi.org/10.1016/j.schres.2010.05.030.
Smith M, Hopkins D, Peveler RC, Holt RI, Woodward M, Ismail K. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2008;192(6):406–11. https://doi.org/10.1192/bjp.bp.107.037184.
Scheen AJ, De Hert MA. Abnormal glucose metabolism in patients treated with antipsychotics. Diabetes Metab. 2007;33(3):169–75. https://doi.org/10.1016/j.diabet.2007.01.003.
Deng C. Effects of antipsychotic medications on appetite, weight, and insulin resistance. Endocrinol Metab Clin N Am. 2013;42(3):545–63. https://doi.org/10.1016/j.ecl.2013.05.006.
Weston-Green K, Huang XF, Deng C. Second generation antipsychotic-induced type 2 diabetes: a role for the muscarinic M3 receptor. CNS Drugs. 2013;27(12):1069–80. https://doi.org/10.1007/s40263-013-0115-5.
Liao CH, Chang CS, Wei WC, Chang SN, Liao CC, Lane HY, et al. Schizophrenia patients at higher risk of diabetes, hypertension and hyperlipidemia: a population-based study. Schizophr Res. 2011;126(1–3):110–6. https://doi.org/10.1016/j.schres.2010.12.007.
Mitchell AJ, Vancampfort D, De Herdt A, Yu W, De Hert M. Is the prevalence of metabolic syndrome and metabolic abnormalities increased in early schizophrenia? A comparative meta-analysis of first episode, untreated and treated patients. Schizophr Bull. 2013;39(2):295–305. https://doi.org/10.1093/schbul/sbs082.
Nielsen J, Skadhede S, Correll CU. Antipsychotics associated with the development of type 2 diabetes in antipsychotic-naive schizophrenia patients. Neuropsychopharmacology. 2010;35(9):1997–2004. https://doi.org/10.1038/npp.2010.78.
Megna JL, Schwartz TL, Siddiqui UA, Herrera Rojas M. Obesity in adults with serious and persistent mental illness: a review of postulated mechanisms and current interventions. Ann Clin Psychiatry. 2011;23(2):131–40.
Hasnain M, Vieweg WV, Hollett B. Weight gain and glucose dysregulation with second-generation antipsychotics and antidepressants: a review for primary care physicians. Postgrad Med. 2012;124(4):154–67. https://doi.org/10.3810/pgm.2012.07.2577.
Ali S, Stone MA, Peters JL, Davies MJ, Khunti K. The prevalence of co-morbid depression in adults with type 2 diabetes: a systematic review and meta-analysis. Diabetic Med. 2006;23(11):1165–73. https://doi.org/10.1111/j.1464-5491.2006.01943.x.
Petrak F, Herpertz S. Treatment of depression in diabetes: an update. Curr Opin Psychiatry. 2009;22(2):211–7. https://doi.org/10.1097/YCO.0b013e3283207b45.
van der Feltz-Cornelis CM, Nuyen J, Stoop C, Chan J, Jacobson AM, Katon W, et al. Effect of interventions for major depressive disorder and significant depressive symptoms in patients with diabetes mellitus: a systematic review and meta-analysis. Gen Hosp Psychiatry. 2010;32(4):380–95. https://doi.org/10.1016/j.genhosppsych.2010.03.011.
Serretti A, Mandelli L. Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry. 2010;71(10):1259–72. https://doi.org/10.4088/JCP.09r05346blu.
Salvi V, Barone-Adesi F, D'Ambrosio V, Albert U, Maina G. High H1-affinity antidepressants and risk of metabolic syndrome in bipolar disorder. Psychopharmacology. 2016;233(1):49–56. https://doi.org/10.1007/s00213-015-4085-9.
Derijks HJ, Meyboom RH, Heerdink ER, De Koning FH, Janknegt R, Lindquist M, et al. The association between antidepressant use and disturbances in glucose homeostasis: evidence from spontaneous reports. Eur J Clin Pharmacol. 2008;64(5):531–8. https://doi.org/10.1007/s00228-007-0441-y.
Sussman N, Ginsberg DL, Bikoff J. Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials. J Clin Psychiatry. 2001;62(4):256–60. https://doi.org/10.4088/JCP.v62n0407.
Sachs GS, Guille C. Weight gain associated with use of psychotropic medications. J Clin Psychiatry. 1999;60(Suppl 21):16–9.
Frank E, Kupfer DJ, Buhari A, McEachran AB, Grochocinski VJ. Imipramine and weight gain during the long-term treatment of recurrent depression. J Affect Disord. 1992;26(1):65–72. https://doi.org/10.1016/0165-0327(92)90036-6.
Barnard K, Peveler RC, Holt RI. Antidepressant medication as a risk factor for type 2 diabetes and impaired glucose regulation: systematic review. Diabetes Care. 2013;36(10):3337–45. https://doi.org/10.2337/dc13-0560.
Khoza S, Barner JC. Glucose dysregulation associated with antidepressant agents: an analysis of 17 published case reports. Int J Clin Pharm. 2011;33(3):484–92. https://doi.org/10.1007/s11096-011-9507-0.
Pyykkonen AJ, Raikkonen K, Tuomi T, Eriksson JG, Groop L, Isomaa B. Depressive symptoms, antidepressant medication use, and insulin resistance: the PPP-Botnia study. Diabetes Care. 2011;34(12):2545–7. https://doi.org/10.2337/dc11-0107.
Pyykkonen AJ, Raikkonen K, Tuomi T, Eriksson JG, Groop L, Isomaa B. Association between depressive symptoms and metabolic syndrome is not explained by antidepressant medication: results from the PPP-Botnia Study. Ann Med. 2012;44(3):279–88. https://doi.org/10.3109/07853890.2010.543921.
Raeder MB, Bjelland I, Emil Vollset S, Steen VM. Obesity, dyslipidemia, and diabetes with selective serotonin reuptake inhibitors: the Hordaland Health Study. J Clin Psychiatry. 2006;67(12):1974–82. https://doi.org/10.4088/JCP.v67n1219.
Mezuk B, Johnson-Lawrence V, Lee H, Rafferty JA, Abdou CM, Uzogara EE, et al. Is ignorance bliss? Depression, antidepressants, and the diagnosis of prediabetes and type 2 diabetes. Health Psychol. 2013;32(3):254–63. https://doi.org/10.1037/a0029014.
Kivimaki M, Batty GD. Antidepressant drug use and future diabetes risk. Diabetologia. 2012;55(1):10–2. https://doi.org/10.1007/s00125-011-2360-9.
Kivimaki M, Hamer M, Batty GD, Geddes JR, Tabak AG, Pentti J, et al. Antidepressant medication use, weight gain, and risk of type 2 diabetes: a population-based study. Diabetes Care. 2010;33(12):2611–6. https://doi.org/10.2337/dc10-1187.
Brown LC, Majumdar SR, Johnson JA. Type of antidepressant therapy and risk of type 2 diabetes in people with depression. Diabetes Res Clin Pract. 2008;79(1):61–7. https://doi.org/10.1016/j.diabres.2007.07.009.
Khoza S, Barner JC, Bohman TM, Rascati K, Lawson K, Wilson JP. Use of antidepressants and the risk of type 2 diabetes mellitus: a nested case-control study. Int J Clin Pharm. 2012;34(3):432–8. https://doi.org/10.1007/s11096-012-9608-4.
Knol MJ, Geerlings MI, Egberts AC, Gorter KJ, Grobbee DE, Heerdink ER. No increased incidence of diabetes in antidepressant users. Int Clin Psychopharmacol. 2007;22(6):382–6. https://doi.org/10.1097/YIC.0b013e3282202c0e.
Heald A, Pendlebury J, Anderson S, Narayan V, Guy M, Gibson M, et al. Lifestyle factors and the metabolic syndrome in schizophrenia: a cross-sectional study. Ann General Psychiatry. 2017;16(1):12. https://doi.org/10.1186/s12991-017-0134-6.
Hamer M, Batty GD, Seldenrijk A, Kivimaki M. Antidepressant medication use and future risk of cardiovascular disease: the Scottish Health Survey. Eur Heart J. 2011;32(4):437–42. https://doi.org/10.1093/eurheartj/ehq438.
Deuschle M. Effects of antidepressants on glucose metabolism and diabetes mellitus type 2 in adults. Curr Opin Psychiatry. 2013;26(1):60–5. https://doi.org/10.1097/YCO.0b013e32835a4206.
Lustman PJ, Clouse RE, Nix BD, Freedland KE, Rubin EH, McGill JB, et al. Sertraline for prevention of depression recurrence in diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2006;63(5):521–9. https://doi.org/10.1001/archpsyc.63.5.521.
Sweileh WM, Odeh JB, Shraim NY, Zyoud SH, Sawalha AF, Al-Jabi SW. Evaluation of defined daily dose, percentage of British National Formulary maximum and chlorpromazine equivalents in antipsychotic drug utilization. Saudi Pharm J. 2014;22(2):127–32. https://doi.org/10.1016/j.jsps.2013.03.003.
Paile-Hyvarinen M, Wahlbeck K, Eriksson JG. Quality of life and metabolic status in mildly depressed women with type 2 diabetes treated with paroxetine: a single-blind randomised placebo controlled trial. BMC Fam Pract. 2003;4:7. https://doi.org/10.1186/1471-2296-4-7.
Kopf D, Westphal S, Luley CW, Ritter S, Gilles M, Weber-Hamann B, et al. Lipid metabolism and insulin resistance in depressed patients: significance of weight, hypercortisolism, and antidepressant treatment. J Clin Psychopharmacol. 2004;24(5):527–31. https://doi.org/10.1097/01.jcp.0000138762.23482.63.
Okamura F, Tashiro A, Utumi A, Imai T, Suchi T, Tamura D, et al. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Metab Clin Exp. 2000;49(10):1255–60. https://doi.org/10.1053/meta.2000.9515.
Weber-Hamann B, Gilles M, Lederbogen F, Heuser I, Deuschle M. Improved insulin sensitivity in 80 nondiabetic patients with MDD after clinical remission in a double-blind, randomized trial of amitriptyline and paroxetine. J Clin Psychiatry. 2006;67(12):1856–61. https://doi.org/10.4088/JCP.v67n1204.
Andersohn F, Schade R, Suissa S, Garbe E. Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry. 2009;166(5):591–8. https://doi.org/10.1176/appi.ajp.2008.08071065.
Pan A, Sun Q, Okereke OI, Rexrode KM, Rubin RR, Lucas M, et al. Use of antidepressant medication and risk of type 2 diabetes: results from three cohorts of US adults. Diabetologia. 2012;55(1):63–72. https://doi.org/10.1007/s00125-011-2268-4.
Bhattacharjee S, Bhattacharya R, Kelley GA, Sambamoorthi U. Antidepressant use and new-onset diabetes: a systematic review and meta-analysis. Diabetes Metab Res Rev. 2013;29(4):273–84. https://doi.org/10.1002/dmrr.2393.
Blumenthal SR, Castro VM, Clements CC, Rosenfield HR, Murphy SN, Fava M, et al. An electronic health records study of long-term weight gain following antidepressant use. JAMA Psychiatry. 2014;71(8):889–96. https://doi.org/10.1001/jamapsychiatry.2014.414.
Rubin RR, Ma Y, Marrero DG, Peyrot M, Barrett-Connor EL, Kahn SE, et al. Elevated depression symptoms, antidepressant medicine use, and risk of developing diabetes during the diabetes prevention program. Diabetes Care. 2008;31(3):420–6. https://doi.org/10.2337/dc07-1827.
Pylvanen V, Knip M, Pakarinen A, Kotila M, Turkka J, Isojarvi JI. Serum insulin and leptin levels in valproate-associated obesity. Epilepsia. 2002;43(5):514–7. https://doi.org/10.1046/j.1528-1157.2002.31501.x.
McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet. 2012;379(9817):721–8. https://doi.org/10.1016/S0140-6736(11)61516-X.
Verrotti A, la Torre R, Trotta D, Mohn A, Chiarelli F. Valproate-induced insulin resistance and obesity in children. Horm Res. 2009;71(3):125–31. https://doi.org/10.1159/000197868.
Chang HH, Yang YK, Gean PW, Huang HC, Chen PS, Lu RB. The role of valproate in metabolic disturbances in bipolar disorder patients. J Affect Disord. 2010;124(3):319–23. https://doi.org/10.1016/j.jad.2009.12.011.
Kivimaki M, Batty GD, Jokela M, Ebmeier KP, Vahtera J, Virtanen M, et al. Antidepressant medication use and risk of hyperglycemia and diabetes mellitus: a noncausal association? Biol Psychiatry. 2011;70(10):978–84. https://doi.org/10.1016/j.biopsych.2011.07.008.
Knol MJ, Geerlings MI, Grobbee DE, Egberts AC, Heerdink ER. Antidepressant use before and after initiation of diabetes mellitus treatment. Diabetologia. 2009;52(3):425–32. https://doi.org/10.1007/s00125-008-1249-8.
Chang HH, Chi MH, Lee IH, Tsai HC, Gean PW, Yang YK, et al. The change of insulin levels after six weeks antidepressant use in drug-naive major depressive patients. J Affect Disord. 2013;150(2):295–9. https://doi.org/10.1016/j.jad.2013.04.008.
Chen YC, Shen YC, Hung YJ, Chou CH, Yeh CB, Perng CH. Comparisons of glucose-insulin homeostasis following maprotiline and fluoxetine treatment in depressed males. J Affect Disord. 2007;103(1–3):257–61. https://doi.org/10.1016/j.jad.2007.01.023.
McCreadie RG, Scottish Schizophrenia Lifestyle G. Diet, smoking and cardiovascular risk in people with schizophrenia: descriptive study. Br J Psychiatry. 2003;183:534–9.
Masuccio F, Verrotti A, Chiavaroli V, de Giorgis T, Giannini C, Chiarelli F, et al. Weight gain and insulin resistance in children treated with valproate: the influence of time. J Child Neurol. 2010;25(8):941–7. https://doi.org/10.1177/0883073809349461.
Luef GJ, Waldmann M, Sturm W, Naser A, Trinka E, Unterberger I, et al. Valproate therapy and nonalcoholic fatty liver disease. Ann Neurol. 2004;55(5):729–32. https://doi.org/10.1002/ana.20074.
• Burcu M, Zito JM, Safer DJ, Magder LS, dosReis S, Shaya FT, et al. Concomitant use of atypical antipsychotics with other psychotropic medication classes and the risk of type 2 diabetes mellitus. J Am Acad Child Adolesc Psychiatry. 2017;56(8):642–51. https://doi.org/10.1016/j.jaac.2017.04.004. An important retrospective cohort study assessing the association between antidepressant or stimulant use concomitant with second-generation antipsychotics and the risk of incident type 2 diabetes mellitus.
Mast R, Rauh SP, Groeneveld L, Koopman AD, Beulens JW, Jansen AP, et al. The use of antidepressants, anxiolytics, and hypnotics in people with type 2 diabetes and patterns associated with use: the Hoorn Diabetes Care System Cohort. Biomed Res Int. 2017;2017:5134602. https://doi.org/10.1155/2017/5134602.
Hammerman A, Dreiher J, Klang SH, Munitz H, Cohen AD, Goldfracht M. Antipsychotics and diabetes: an age-related association. Ann Pharmacother. 2008;42(9):1316–22. https://doi.org/10.1345/aph.1L015.
Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care 2017:40(Suppl 1):S4-S5. https://doi.org/10.2337/dc17-S003.
De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114–26. https://doi.org/10.1038/nrendo.2011.156.
Suvisaari J, Keinanen J, Eskelinen S, Mantere O. Diabetes and Schizophrenia. Curr Diab Rep. 2016;16(2):16. https://doi.org/10.1007/s11892-015-0704-4.
Salvi V, Grua I, Cerveri G, Mencacci C, Barone-Adesi F. The risk of new-onset diabetes in antidepressant users - A systematic review and meta-analysis. PloS one. 2017;12(7):e0182088. https://doi.org/10.1371/journal.pone.0182088.
Roopan S, Larsen ER. Use of antidepressants in patients with depression and comorbid diabetes mellitus: a systematic review. Acta neuropsychiatrica. 2017;29(3):127-39. https://doi.org/10.1017/neu.2016.54.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors of this manuscript declare no conflict of interest
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
This article is part of the Topical Collection on Cardiovascular Pharmacology
Rights and permissions
About this article
Cite this article
Mamakou, V., Eleftheriadou, I., Tentolouris, A. et al. Diabetogenic Effects Associated with Psychiatric Treatment. Curr Pharmacol Rep 4, 103–111 (2018). https://doi.org/10.1007/s40495-018-0126-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40495-018-0126-5