Diabetes in Schizophrenia

Diabetes and weight gain are common in psychiatric patients.  Many psychiatric medications cause weight gain, e.g. the anti-depressants doxepin (Sinequan), amitriptyline (Elavil), and mirtazapine (Remeron), the mood-stabilizers lithium, and divalproex (Depakote), and the anti-psychotics thioridazine (Mellaril), chlorpromazine (Thorazine), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal).  While risperidone, lithium, and perhaps mirtazapine weight gain are more modest, the others are often associated with an average 20 pound weight gain over time.  While some patients do not gain any weight, others gain much more than 20 pounds. 

It may be that depression, bipolar disorder, and schizophrenia cause weight gain themselves, but certain medications are definitely worse than others.  In any case, psychiatrists have often ignored this issue until recently.  There is a growing realization that weight gain is associated with diabetes and early death.  Of course, to many patients a large weight gain can be quite depressing.  The careful choice of medications can all but avoid weight gain in psychiatric care.  This can be done by choosing to first try out medications which minimize weight gain, switching away from medications if weight gain develops, and sometimes using a supplement to minimize the weight gain which occurs.

Since magnesium, folate, and vitamin D all help reduce the risk of diabetes and high blood pressure, everyone, especially those with schizophrenia, should take supplements.  A rat study found that olanzapine (Zyprexa) decreases melatonin levels and that adding melatonin as a supplement offsets most of the impact.  Whether this is true of some other psychiatric medications which cause weight gain is unknown. 

Much of my information of weight gain due to neuroleptics can be found under each medication's webpage.

Schizophrenia Has High Rate of Diabetes, Hypertension, and Smoking: In a study of 689 adults in the Clinical Trials of Antipsychotic Treatment Effectiveness (CATIE) Schizophrenia Trial, the ten-year coronary heart disease risk was elevated in male (9.4% vs. 7.0%) and female (6.3% vs. 4.2%) schizophrenia patients compared to controls (p=0.0001). Schizophrenia patients had higher rates of smoking (68% vs. 35%), diabetes (13% vs. 3%), and hypertension (27% vs. 17%) and lower HDL cholesterol levels (43.7 vs. 49.3 mg/dl)(p<0.001). A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls. Goff DC, et al. MGH-Harvard. Schizophr Res. 2005 Sep 27

Conventional and Geodon Safer than Risperdal, Seroquel, or Zyprexa: Using integrated seven-state Medicaid managed care claims database for a case-control study of 283 bipolar patients with diabetes and 1134 controls, of the 283 cases, 49% received atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, and clozapine) and 47% were prescribed conventional antipsychotics. Compared with patients receiving conventional antipsychotics, the risk of diabetes was greatest among patients taking risperidone had a 280% high risk, olanzapine 270%), and quetiapine 150%. The risk for developing diabetes was also associated with weight gain (150%), hypertension (60%), and substance abuse (50%). Risk of diabetes mellitus associated with atypical antipsychotic use among medicaid patients with bipolar disorder: a nested case-control study. Guo JJ, et al. University of Cincinnati, Ohio. Pharmacother 2007 Jan;27(1):27-35.

VA Study Finds 600% Increased Risk of Diabetes Onset in Veterans with Schizophrenia: In a 2004 two-year follow-up study of over 50,000 veterans being treated at VA clinics for schizophrenia, the average annual rate of new cases of diabetes was 4.40% compared to 0.63% for the general population of the same age.  Compared to veterans being treated with traditional anti-psychotics like haloperidol, those on four atypical anti-psychotics which cause weight gain had higher rates of onset: clozapine (6.43%), quetiapine (5.2%), olanzapine (5.03%), and risperidone (4.45%).  It took one year of treatment for diabetes to start showing up. (presented at MHM conference, Harrisburg PA, 2/23/05). Ed: Most of the increased risk is probably due to the illness and not medication.

U.S.: Metabolic Syndrome Very High in Schizophrenia, Especially Females: The metabolic syndrome (MS) combined being overweight, fasting glucose over 100, hypertensive, and high cholesterol.  Of 1460 patients in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, 689 met analysis criteria for MS. MS prevalence was 42.7% using AHA derived criteria. In females it was 54.2% vs. 36.6% (p=.0003) for males. 73.4% of all females met the waist circumference criterion compared to 36.6% of males. CATIE males were 138% more likely to have MS than the NHANES matched sample, and CATIE females 251% more likely than their NHANES counterparts. Even when controlling for differences in body mass index, CATIE males were still 85% more likely to have MS than the NHANES male sample, and CATIE females 137% more likely to have MS than females in NHANES. Prevalence of the metabolic syndrome in patients with schizophrenia: Baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. McEvoy JP, et al. Duke University. Schizophr Res. 2005 Aug 29

Finland Study Finds Metabolic Syndrome 270% Higher in Schizophrenia: In a study of 5613 members of the Northern Finland 1966 Birth Cohort, the prevalence of metabolic syndrome was higher in subjects with schizophrenia compared with the comparison group (19% vs. 6%, p = .010). The prevalence of metabolic syndrome in subjects with other psychoses was 5%. After controlling for sex, the results of logistic regression analysis showed that the risk of metabolic syndrome in schizophrenia was 3.7. A 4-Fold Risk of Metabolic Syndrome in Patients With Schizophrenia: The Northern Finland 1966 Birth Cohort Study. Saari KM, Lindeman SM, et al. University of Oulu, Oulu, Finland. J Clin Psychiatry. 2005 May;66(5):559-563.

Olanzapine (Zyprexa) and Clozapine Increase Diabetes Risk: In a study of 3663 Medicaid patients who developed type 2 diabetes after starting treatment for schizophrenia and 14,523 who had not developed diabetes, with a 52-week exposure window, the risks were 41% higher with olanzapine and clozapine or 58% if on both, but no significant increase with risperidone or quetiapine. Antipsychotic exposure and type 2 diabetes among patients with schizophrenia: a matched case-control study of California Medicaid claims. Lambert BL, Chou CH, et al. University of Illinois, Chicago. Pharmacoepidemiol Drug Saf. 2005 Mar 22

Diabetes Starting on Atypical Antipsychotics No Higher Than on Antidepressants or Traditional: In a retrospective study of outpatients on atypical antipsychotics (10,265), traditional antipsychotics (4,607), antidepressants (60,856) or antibiotics (59,878) in the database of a large pharmaceutical benefit manager) in a 12-month period, the annual rate of new cases of diabetes as measured using new prescriptions for antidiabetic drugs after a 6-month lead-in period were 7.5/1000/year for atypical antipsychotics, 11.3 for traditional antipsychotics, 7.8 for antidepressants and 5.1 for antibiotics. In multivariable analyses, age, male sex and Chronic Disease Score were associated with greater odds of diabetes onset. There were no statistically significant differences in outcome between the atypical antipsychotic, traditional antipsychotic and antidepressant groups. Multivariable comparisons among specific agents showed increased odds of diabetes for clozapine, olanzapine, ziprasidone and thioridazine (relative to risperidone), but these comparisons did not reach statistical significance. Atypical antipsychotic drugs and diabetes mellitus in a large outpatient population: a retrospective cohort study. Ostbye T, Curtis LH, et al. Duke University. Pharmacoepidemiol Drug Saf. 2004 Sep 16. Ed: While this study is better liked by drug companies, the VA study is likely to be more sensitive for schizophrenic patients since it is a very large prospective study of a more similar population.  This second study does suggest that some anti-depressants should also be of concern.  Both studies find very high rates for new diabetes suggesting that taking magnesium and vitamin D to reduce the risk of diabetes is a very wise idea. I recommend these supplements to everyone.  See my Recommendations for Healthy Living.

Olanzapine Increased Diabetes Risk; Ziprasidone Decreased It: In 191 randomly selected patients who were being treated with ziprasidone or olanzapine, significant differences on QTc interval were not observed. Weight gain was observed with olanzapine (P<0.001) but not with ziprasidone (P>0.05). Adverse metabolic changes associated with olanzapine on total cholesterol (P=0.01), triglycerides (P=0.05) and haemoglobin A1C (HbA1C) (P<0.05) were seen, whereas favourable metabolic effects were observed in ziprasidone for total cholesterol (P<0.05), low-density lipoprotein (LDL) (P<0.01), high-density lipoprotein (HDL) (P<0.05) and HbA1c (P<0.05). Comparison of the metabolic effects observed in patients treated with ziprasidone versus olanzapine. Brown RR, Estoup MW. Veterans Affairs, Portland, Oregon. Int Clin Psychopharmacol. 2005 Mar;20(2):105-12.

Obesity: Worse with Zyprexa, Risperdal, and Seroquel than Traditionals or Geodon and Abilify: Using a national electronic medical records database, a naturalistic impact of second generation anti-psychotics on BMI was evaluated. Of 9394 adults, there were 1514 cases of increased BMI after initial prescription. Risperidone (OR 1.39), quetiapine (OR 1.36), and olanzapine (OR 1.76) were significantly more likely to cause BMI increase compared with first-generation antipsychotics (FGAs). Aripiprazole (OR 0.72), and ziprasidone (OR 0.68) were less likely to induce weight gain compared with FGAs. Clozapine (OR 1.01) was no different from FGAs. Naturalistic impact of second-generation antipsychotics on weight gain. Brixner DI, et al. University of Utah. . Ann Pharmacother 2006 Apr;40(4):626-32.

Obesity: Melatonin Reduces Weight Gain in Rats with Diet-induced Obesity. Melatonin had no effect on plasma insulin level, but it decreased plasma glucose (13%), leptin (28%), and triglyceride (28%) levels. In pinealectomized high-fat diet rats, body weight gain and feed efficiency were increased 4 wk after surgery. Adipose tissue weight, insulinemia, and glycemia had a tendency to increase. Treatment with melatonin prevented in part these changes. Melatonin may act as a regulator of body weight in a model of obesity and may prevent some of the side effects on glucose homeostasis such as decreased insulin sensitivity. Prunet-Marcassus B, et al. Universitaire Paul Sabatier, Toulouse, France. Endocrinology. 2003 Dec;144(12):5347-52. 

Obesity: Melatonin Reduces Olanzapine and Age Induced Fat Stores: The atypical antipsychotic drug olanzapine increases body weight and visceral adiposity in schizophrenia. In rats, aging-associated increased body weight and visceral adiposity are reversed by administration of the pineal hormone melatonin. Four groups (n=11/group) of female rats (240-250 g) were treated for 8 weeks with olanzapine, melatonin, olanzapine+melatonin, or vehicle alone. At week 8, olanzapine treatment reduced nocturnal plasma melatonin by 55% (p<0.001), which was restored to control levels by olanzapine+melatonin. Body weight increased 18% in rats treated with olanzapine alone, 10% with olanzapine+melatonin, 5% with melatonin alone, and 7% with vehicle control. Melatonin may be useful for the management of olanzapine-induced weight gain in humans. Olanzapine-Induced Weight Gain and Increased Visceral Adiposity is Blocked by Melatonin Replacement Therapy in Rats. Raskind MA, et al. University of Washington, Seattle. Neuropsychopharmacology 10 May 2006.

Obesity: Melatonin Signals Fat Storage Release in Animals during Winter’s Long Nights: Many animals show seasonal changes in adiposity that are triggered by changes in the photoperiod. In short "winterlike" days, the nocturnal duration of pineal melatonin (MEL) secretion increases resulting in body fat decreases. These decreases in body fat are mediated through increases in the sympathetic drive on white adipose tissue (WAT). The central nervous system (CNS) origins of the sympathetic outflow from brain to WATinclude the suprachiasmatic nucleus (SCN), an area necessary for the reception of season-encoded MELsignals in certain animals. The increased duration of MEL secretion in short days may increase MEL(1a)-receptor stimulation that, in turn, increases the sympathetic drive on WAT, thereby increasing lipolysis and decreasing adiposity. CNSsympathetic outflow neurons to white fat that express MEL receptors may mediate seasonal adiposity. Song CK, Bartness TJ. Georgia State University, Atlanta, GA.Am J Physiol Regul Integr Comp Physiol. 2001 Aug;281(2):R666-72

Thomas E. Radecki, M.D., J.D.

modern-psychiatry.com