Atypical antipsychotics have become the gold standard and the first treatment option for mental illness in recent years because of their high tolerability, efficacy, and the lower tendency to cause extrapyramidal side effects 1,21,2. These drugs are used not only in the treatment of psychosis but also in the treatment of neuroses and affective disorders 3,43,4.
Atypical antipsychotics are also known as second-generation antipsychotics (SGAs). This group includes the following drugs: clozapine (CLZ), risperidone (RIS), olanzapine (OL), quetiapine (QUET), ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, sertindole, zotepine, amisulpride, bifeprunox, and melperone 5,65,6.
However, despite all the benefits provided by these drugs, the growing collection of case reports and clinical trials describing metabolic complications such as, particularly, body weight gain 7 increased food intake 8,98,9, increased amount of visceral fat 10, reduced motor activity 11,1211,12, and new-onset diabetes has drawn attention on the high association between the risk for obesity and antipsychotic medication 13–1613–1613–1613–16.
Some studies have identified younger, antipsychotic-naive patients with first-episode of psychosis as a population vulnerable to adverse metabolic effects from SGAs. These patients gained more weight and developed significant lipid and glucose abnormalities within 8–12 weeks after treatment initiation. The differences in the effects of various SGAs are well described, with CLZ and OL being associated with the highest metabolic risk 17.
Data coming from the majority of the studies suggest that the prevalence of diabetes in schizophrenic patients is almost 1.5–2 times greater than the prevalence reported in the general population 18.
Although there is an ongoing discussion on whether metabolic disease is a part of the natural etiology of schizophrenia, there is a large amount of evidence attributing it to the side effects of antipsychotic treatment 19,2019,20. The incidence of diabetes is nearly 10% greater in schizophrenic patients treated with atypical antipsychotics (AAPs) when compared with those treated with typical antipsychotic drugs 21.
A retrospective case record audit of 85 patients aged 16–27 years showed that 55% of male and 42% of female patients were overweight or obese at a median treatment duration of 8 months. The duration of antipsychotic therapy was associated with higher BMI (r=0.28, P<0.01). More than 40% of the total sample had high waist circumference. Of the 64 patients with complete metabolic data, eight (12.5%) met full International Diabetes Federation criteria for metabolic syndrome, and another 21 (32.8%) had either increased waist with one metabolic abnormality or normal waist and two metabolic abnormalities 22.
It should be noted that metabolic syndrome (MSx) is a serious public health concern that describes a cluster of disorders that occur together and increase the prevalence of coronary artery disease, stroke, and type 2 diabetes. Although there is no consensus on the definition of MSx, several variables including large waist circumference, high fasting blood sugar, abdominal obesity, low high-density lipoprotein cholesterol level, hypertriglyceridemi, and hypertension are major risk factors for MSx. The prevalence of MSx based on Adult Treatment Panel III (ATP III) criteria varies from 7 to 58% across studies 23
It seems that some of the mechanisms associated with weight gain and insulin resistance induced by AAPs are the following: the action of AAPs as antagonists of many receptors results in increased expression of neuropeptide Y (NPY) and melanin-concentrating hormone receptor 1 (MCHR1), decreased expression of leptin-induced AMPK (AMP-activated protein kinase), reduction of lipolysis in white adipose tissue, and reduction in orexin and consequent thermogenesis. Hyperglycemia is caused by α2 antagonism and inactive muscarinic receptors, which reduce the release of insulin induced by ACh. These changes contribute to hyperphagic behavior, reduced thermogenesis, fat accumulation, and consequent weight gain in this population 14.
On the basis of the US Food and Drug Administration guidelines, in most of the studies body mass gain is considered clinically significant when an increase in total body weight of at least 7% from the baseline occurs 24. Also, the severity of adverse events differ according to drug tolerance as well as the types of medications, showing a rank order of liability in weight gain, which can be described as follows: CLZ=OL>QUET≥RIS≥amisulpride≥aripiprazole≥ziprasidone 7.
The relationship between CLZ treatment and susceptibility to weight gain is, in most cases, described in a time-related manner, with both rapid and progressive effects 7.
For example, chronic CLZ treatment causes an increase between 5.3 and 6 kg of weight after 10 weeks and up to 9.2 kg after 68 weeks 25.
Some studies have also underlined the potential gender-dependent effect of AAPs. This observation is consistent with the former suggestion of a major vulnerability of women to the AAP-induced weight gain. Nevertheless, the effect of CLZ treatment upon weight gain in women is still unclear and involves all the atypical drugs accountable for inducing weight gain 26.
Similar to CLZ treatment, OL affects weight gain during the first year of treatment and induces a moderate increase in weight over time (weight gain of 10 kg during 7 months of treatment and a range of increase of 6–12 kg after 6–12 months, according to some studies) 27.
Another matter of debate is the distinction between AAP effects on patients with chronic disease and effects on patients with the first episode of psychotic disorder. There was a higher magnitude of weight gain in psychotic patients by OL and, to a lesser degree, by RIS and HAL. Interestingly, some studies show that younger patients and patients with negative symptoms (e.g. socially withdrawn or with poor speech function) at baseline could be more susceptible to weight gain. Hence, the possibility that younger patients might be at a higher risk of being overweight or obese should be taken into consideration 28.
Impaired glucose homeostasis
OL and CLZ appear to have the highest tendency to disturb glucose metabolism compared with the other antipsychotic drugs available on the market 29–3129–3129–31. Also, the higher propensity of these drugs to induce diabetic ketoacidosis and new-onset type II diabetes mellitus had been generally related to increased adiposity. However, OL can cause glucose dysregulation through a mechanism other than weight gain 32.
The results of many studies on RIS treatment and glucose homeostasis have led to inconsistent conclusions. Schizophrenic patients who had pre-existing risk factors for diabetes developed insulin resistance in the context of weight gain during treatment with RIS 33.
Recent harmacoepidemiologic studies have confirmed significant prevalence of type II diabetes in patients receiving RIS 34,3534,35.
Also, another study suggests that AAP-induced diabetes does not always take a type 2 presentation in which weight gain and insulin resistance are implicated. Sometimes the disease presents as diabetic ketoacidosis 36. In contrast, several studies have reported either reduced or absent risk of associated diabetogenic effects 37,3837,38.
Similar to RIS treatment, the link between QUET therapy and diabetes has led to inconclusive results 39.
Ways to prevent the occurrence of metabolic syndrome are being studied.
Nonpharmacological measures include the following: following a balanced diet, regular physical activity and other lifestyle changes; monitoring of weight, symptoms of hyperglycemia, blood sugar, and lipid levels in chronically medicated patients; taking note of CVD risk factors in personal history and in family history; increasing awareness (through accessible information leaflets, health promotion, and use of side-effect checklists and improving access to healthcare); and by working collaboratively with general practitioners utilizing the forum of annual health checkups 40.
Apart from these preventive measures, one needs to carry out a careful and individual balance of the potential benefits of prolonged treatment against the risk of health hazards associated with the use of antipsychotics 41.
In 2004, the American Diabetic Association and three other associations, including the American Psychiatric Association, developed guidelines to screen for metabolic syndrome but, in practice, adherence to the guidelines is not very strict and varies across centers 40.
Pharmacological alternatives include the following: decreasing the doses of drugs; switching to another antipsychotic that produces fewer metabolic effects, such as aripiprazole, ziprasidone, etc.; and using other drugs or supplements to avoid metabolic disturbances. A pilot study has investigated the short-term effects of vitamin D3 supplementation on weight gain and glucose and lipid metabolism in antipsychotic-treated patients because previous studies have linked vitamin D deficiency to hypertension, dyslipidemia, diabetes mellitus, and cardiovascular disease. However, the results have not been conclusive and it is suggested that a randomized trial with a longer follow-up period would be helpful in further evaluation of the effects of vitamin D342.
Other studies suggest that folate supplementation may turn out to be an easy and effective clinical tool for prevention and/or treatment of metabolic syndrome associated with AAP treatment, but clearly more research needs to be done in this area 43.
A systematic review and meta-analysis suggest that metformin is useful for the short-term treatment of OL-induced weight gain. Other studies also suggest its use in other atypical antipsychotics-induced weight gain. Further long-term studies are needed to extend our observations and improve this strategy 44,4544,45.
Although this is an issue still under study, in this article we intend to review the problem of metabolic syndrome associated with different atypical antipsychotics presently in use.
The aim of the study was to review the range and prevalence of metabolic disturbances as adverse effects of the use of atypical antipsychotics and to mark the differences between the drugs of this particular group in the context of metabolic adverse effects.
We conducted a review of the articles on this topic using Pubmed and the following key words: atypical antipsychotics AND metabolic syndrome.
We limited the search to the last 5 years and to the human species. We decided to review different types of articles: clinical trials, meta-analysis, and reviews. Comparative tables on the metabolic effects caused by different antipsychotics of this group have been attached.
The results of different studies in relation to the metabolic adverse effects caused by atypical antipsychotics are presented in Table 1. It also compares the occurrence of these with the use of different drugs of AAPs.
The effects on weight are presented in Tables 2 and 3.
The available data suggest that the atypical antipsychotics that are significantly associated with weight gain are CLZ=OL>QUET≥RIS.
In contrast, the drugs that are less associated with weight gain are ziprasidone<aripiprazole<amisulpride.
On the basis of the results of several studies it can be reported that the greatest weight gain appears after the first psychotic episode and in the early years; thereafter, the weight gain tends to be lower 1,531,53. The tendency of women being more likely to gain weight has also been noticed 26.
OL and CLZ appear to have the highest tendency to disturb glucose metabolism compared with the other antipsychotic drugs available on the market 29–3129–3129–31. It is also worthy to note that diabetes occurring during treatment with antipsychotic drugs does not necessarily have to be of type II. It can also manifest as diabetic ketoacidosis 36
It should be kept in mind that MSx is a serious public health concern that describes a cluster of disorders which occur together and increase the chance of having coronary artery disease, stroke, and type 2 diabetes.
Therefore, certain preventive measures need to be taken. Of these, pharmacological measures include: decreasing the doses of drugs, switching to another antipsychotic known to result in fewer metabolic side effects, and using other drugs or supplements to avoid metabolic disturbances. Nonpharmacological measures include: following a balanced diet, regular physical activity and other lifestyle changes, monitoring of weight, symptoms of hyperglycemia, blood sugar, and lipid levels in chronically medicated patients, taking into account personal history of CVD risk factors and family history of CVD risk factors, increasing awareness of the importance of collaboration with general practitioners in annual health checkups, and carrying out a careful and individual risk–benefit balance.
With respect to AAP-naive patients it might be beneficial to start their treatment with the medication that is known to result in fewer metabolic side effects. Increasing young patients’ awareness of the side effects and emphasizing the importance of lifestyle changes as a form of prevention may be of great help. This group of patients tends to have low cardiovascular risk at the beginning of therapy; therefore, introducing the necessary lifestyle changes (physical exercise, low-fat diet, encouraging them to undergo regular checkups at their general practitioner) appears the best way to keep them in the low-risk category.
The limitation found in the studies was that the large proportion of early dropouts and the incomplete reports of the outcomes made it difficult to draw firm conclusions in some studies.
Well-designed trials are necessary to establish the relative effects of different SGA drugs.
Some results are based on only 10 short-term to medium-term studies, studies that have small sample numbers and/or are not randomized and controlled. Therefore, we must not draw firm conclusions.
To conclude, OL and CLZ are the atypical antipsychotics most associated with metabolic syndrome. Data on other drugs of this group are inconclusive, but it seems that QUET and RIS are also related to metabolic risk, whereas asenapine, RIS, and ziprasidone are the lowest risk-linked drugs.
Conflicts of interest
There are no conflicts of interest
1. Briles JJ, Rosenberg DR, Brooks BA, Roberts MW, Diwadkar VA. Review of the safety of second-generation antipsychotics: are they really “atypically” safe for youth and adults? Prim Care Companion CNS Disord 2012; 14:3.
2. Komossa K, Rummel-Kluge C, Schwarz S, Schmid F, Hunger H, Kissling W, Leucht S. Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2011; 1:CD006626.
3. Faidley TD, Luhman CM, Galloway ST, Foley MK, Beitz DC. Effect of dietary fat source on lipoprotein composition and plasma lipid concentrations in pigs. J Nutr 1990; 120:1126–1133.
4. Maher AR, Theodore G. Summary of the comparative effectiveness review on off-label use of atypical antipsychotics. J Manag Care Pharm 2012; 18 (Suppl B):S1–20.
5. Stahl SM. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications
, 4th ed. 2013; Cambridge: Cambridge University Press.
6. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31–41.
7. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19 (Suppl 1):1–93.
8. Eder U, Mangweth B, Ebenbichler C, Weiss E, Hofer A, Hummer M, et al.. Association of olanzapine-induced weight gain
with an increase in body fat. Am J Psychiatry 2001; 158:1719–1722.
9. Gothelf D, Falk B, Singer P, Kairi M, Phillip M, Zigel L, et al.. Weight gain
associated with increased food intake and low habitual activity levels in male adolescent schizophrenic inpatients treated with olanzapine. Am J Psychiatry 2002; 159:1055–1057.
10. Ryan MC, Flanagan S, Kinsella U, Keeling F, Thakore JH. The effects of atypical antipsychotics on visceral fat distribution in first episode, drug-naive patients with schizophrenia. Life Sci 2004; 74:1999–2008.
11. Allison DB, Newcomer JW, Dunn AL, Blumenthal JA, Fabricatore AN, Daumit GL, et al.. Obesity among those with mental disorders: a National Institute of Mental Health meeting report. Am J Prev Med 2009; 36:341–350.
12. Archie S, Wilson JH, Osborne S, Hobbs H, McNiven J. Pilot study: access to fitness facility and exercise levels in olanzapine-treated patients. Can J Psychiatry 2003; 48:628–632.
13. Bolger A, Verdolini N, Agius M. Can metabolic side effects of antipsychotics be reversed by lifestyle changes? Psychiatr Danub 2014; 26 Suppl 1 (Suppl 1):330–335.
14. Volpato AM, Zugno AI, Quevedo J. Recent evidence and potential mechanisms underlying weight gain
and insulin resistance due to atypical antipsychotics. Rev Bras Psiquiatr 2013; 35:295–304.
15. Teff KL, Rickels MR, Grudziak J, Fuller C, Nguyen HL, Rickels K. Antipsychotic-induced insulin resistance and postprandial hormonal dysregulation independent of weight gain
or psychiatric disease. Diabetes 2013; 62:3232–3240.
16. Riordan HJ, Antonini P, Murphy MF. Atypical antipsychotics and metabolic syndrome in patients with schizophrenia: risk factors, monitoring, and healthcare implications. Am Health Drug Benefits 2011; 4:292–302.
17. Pramyothin P, Khaodhiar L. Metabolic syndrome with the atypical antipsychotics. Curr Opin Endocrinol Diabetes Obes 2010; 17:460–466.
18. Mathews M, Muzina DJ. Atypical antipsychotics: new drugs, new challenges. Cleve Clin J Med 2007; 74:597–606.
19. Vestri HS, Maianu L, Moellering DR, Garvey WT. Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology 2007; 32:765–772.
20. Yang LH, Chen TM, Yu ST, Chen YH. Olanzapine induces SREBP-1-related adipogenesis in 3T3-L1 cells. Pharmacol Res 2007; 56:202–208.
21. Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R. Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002; 159:561–566.
22. Curtis J, Henry C, Watkins A, Newall H, Samaras K, Ward PB. Metabolic abnormalities in an early psychosis service: a retrospective, naturalistic cross-sectional study. Early Interv Psychiatry 2011; 5:108–114.
23. Grahovac T, Ružić K, Dadić-Hero E, Sepić-Grahovac D, Sabljić V. Weight gain
– as possible predictor of metabolic syndrome. Psychiatr Danub 2011; 23:105–107.
24. Sachs GS, Guille C. Weight gain
associated with use of psychotropic medications. J Clin Psychiatry 1999; 60 (Suppl 21):16–19.
25. Taylor DM, McAskill R. Atypical antipsychotics and weight gain
– a systematic review. Acta Psychiatr Scand 2000; 101:416–432.
26. Bai YM, Lin CC, Chen JY, Lin CY. Weight gain
among patients on clozapine. Psychiatr Serv 1999; 50:704–705.
27. Strassnig M, Miewald J, Keshavan M, Ganguli R. Weight gain
in newly diagnosed first-episode psychosis patients and healthy comparisons: one-year analysis. Schizophr Res 2007; 93:90–98.
28. Alvarez-Jiménez M, González-Blanch C, Crespo-Facorro B, Hetrick S, Rodríguez-Sánchez JM, Pérez-Iglesias R, Vázquez-Barquero JL. Antipsychotic-induced weight gain
in chronic and first-episode psychotic disorders: a systematic critical reappraisal. CNS Drugs 2008; 22:547–562.
29. Muench J, Hamer AM. Adverse effects of antipsychotic medications. Am Fam Physician 2010; 81:617–622.
30. Nielsen J, Skadhede S, Correll CU. Antipsychotics associated with the development of type 2 diabetes in antipsychotic-naive schizophrenia patients. Neuropsychopharmacology 2010; 35:1997–2004.
31. Reynolds GP, Kirk SL. Metabolic side effects of antipsychotic drug treatment – pharmacological mechanisms. Pharmacol Ther 2010; 125:169–179.
32. Ramankutty G. Olanzapine-induced destabilization of diabetes in the absence of weight gain
. Acta Psychiatr Scand 2002; 105:235–236. discussion 236-237.
33. Wirshing DA, Pierre JM, Eyeler J, Weinbach J, Wirshing WC. Risperidone-associated new-onset diabetes. Biol Psychiatry 2001; 50:148–149.
34. Buse JB, Cavazzoni P, Hornbuckle K, Hutchins D, Breier A, Jovanovic L. A retrospective cohort study of diabetes mellitus and antipsychotic treatment in the United States. J Clin Epidemiol 2003; 56:164–170.
35. Lambert BL, Cunningham FE, Miller DR, Dalack GW, Hur K. Diabetes risk associated with use of olanzapine, quetiapine, and risperidone in veterans health administration patients with schizophrenia. Am J Epidemiol 2006; 164:672–681.
36. Dibben CR, Kalavalapalli SS, Linnington HE, Hynes FA, Dinneen SF, Adler AI, McKenna PJ. Diabetes associated with atypical antipsychotic treatment may be severe but reversible: case report. Int J Psychiatry Med 2005; 35:307–311.
37. Fuller MA, Shermock KM, Secic M, Grogg AL. Comparative study of the development of diabetes mellitus in patients taking risperidone and olanzapine. Pharmacotherapy 2003; 23:1037–1043.
38. Gianfrancesco FD, Grogg AL, Mahmoud RA, Wang RH, Nasrallah HA. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry 2002; 63:920–930.
39. Van Winkel R, De Hert M, Wampers M, Van Eyck D, Hanssens L, Scheen A, Peuskens J. Major changes in glucose metabolism, including new-onset diabetes, within 3 months after initiation of or switch to atypical antipsychotic medication in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2008; 69:472–479.
40. Parrinello MC. Prevention of metabolic syndrome from atypical antipsychotic medications: applying Rogers' diffusion of innovations model in clinical practice. J Psychosoc Nurs Ment Health Serv 2012; 50:36–44.
41. Teeluckdharry S, Sharma S, O'Rourke E, Tharian P, Gondalekar A, Nainar F, Roy M. Monitoring metabolic side effects of atypical antipsychotics in people with an intellectual disability. J Intellect Disabil 2013; 17:223–235.
42. Thakurathi N, et al.. Open-label pilot study on vitamin D(3) supplementation for antipsychotic-associated metabolic anomalies. Int Clin Psychopharmacol 2013; 28:275–282.
43. Burghardt KJ, Ellingrod VL. Detection of metabolic syndrome in schizophrenia and implications for antipsychotic therapy: is there a role for folate? Mol Diagn Ther 2013; 17:21–30.
44. Praharaj SK, Jana AK, Goyal N, Sinha VK. Metformin for olanzapine-induced weight gain
: a systematic review and meta-analysis. Br J Clin Pharmacol 2011; 71:377–382.
45. Hasnain M, Vieweg WV, Fredrickson SK. Metformin for atypical antipsychotic-induced weight gain
and glucose metabolism dysregulation: review of the literature and clinical suggestions. CNS Drugs 2010; 24:193–206.
46. Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Leucht S. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010. CD006633.
47. Minassian A, Young JW. Evaluation of the clinical efficacy of asenapine in schizophrenia. Expert Opin Pharmacother 2010; 11:2107–2115.
48. Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L, et al.. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010. CD006654.
49. Komossa K, Rummel-Kluge C, Schmid F, Hunger H, Schwarz S, Srisurapanont M, et al.. Quetiapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010. CD006625.
50. Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Silveira da Mota Neto JI, et al.. Amisulpride versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010. CD006624.
51. Piparva KG, Buch JG, Chandrani KV. Analysis of adverse drug reactions of atypical antipsychotic drugs in psychiatry OPD. Indian J Psychol Med 2011; 33:153–157.
52. Bou Khalil R. Atypical antipsychotic drugs, schizophrenia, and metabolic syndrome in non-Euro-American societies. Clin Neuropharmacol 2012; 35:141–147.
53. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA 2009; 302:1765–1773.