Case 2: A patient on risperidone who develops diabetes
G.L., 47, has a longstanding history of schizophrenia. She has been on risperidone for one year and has done well, but has gained 14 pounds and now weighs 212 pounds. G.L. complains of difficulty seeing and returns for assessment. What next?
Psychiatric drug use and diabetes The incidence of mental health problems is increased in individuals with diabetes and psychiatric disorders may increase diabetic morbidity. Certain medications commonly used by psychiatrists may trigger diabetic complications and some hypoglycemic agents may be associated with potential drug-drug interactions or other difficulties (Tables 1 and 2).
Approximately 40% of patients with type 2 diabetes remain undiagnosed. It is estimated that diagnosis is delayed by 4 to 7 years after the development of their disease, and patients frequently present with established retinopathy, renal disease, or macrovascular disease. As the diagnostic criteria have changed and more patients are obese and lead sedentary lifestyles, the prevalence of recognized diabetes is increasing.
Table 1
Therapeutic options for type 2 diabetes treatment
| Class | Representative agents | Mechanism of action | Side effects, cautions, and notes | Common uses |
|---|---|---|---|---|
| First-generation sulfonylureas | Tolbutamide (Orinase), chlorpropamide (Diabinese), tolazamide (Tolinase) | Stimulate insulin secretion | Weight gain, hypoglycemia, fever, disulfiram type reaction. Caution: if significant hepaticor renal impairment; MAOIs may exacerbate hypoglycemia | Generic versions are least expensive oral hypoglycemics |
| Newer-generation sulfonylureas | Glipizide (Glucotrol, Glucotrol XL), glyburide (DiaBeta, Glynase), glimepiride (Amaryl) | Stimulate insulin secretion | Weight gain, hypoglycemia. Caution: with significant hepatic impairment; glyburide has active metabolite that may accumulate with renal dysfunction; MAOIs may exacerbate hypoglycemia | More potent; glipizide may lack some of the side effects of first-generation agents; common initial monotherapy |
| Metglitinides | Repaglinide (Prandin), nateglinide (Starlix) | Stimulate insulin secretion | Very short half life—must be given right before meals; metabolized by CYP-450 3A4 (may be induced by medications such as carbamazepine); highly protein bound; contraindicated in pregnancy | May help patients who have transient loss of diet control, postprandial hyperglycemia |
| Biguanides | Metformin (Glucophage, Glucophage XR) | Reduce hepatic glucose output and enhance insulin sensitivity | Gastrointestinal problems common initially; must be withheld before imaging with contrast media; lactic acidosis; contraindicated if renal or hepatic dysfunction, CHF, dehydration, hypoxemia; metallic taste | Overweight patients; favorable effects on lipids; fasting hyperglycemia |
| Thiazolidinediones | Pioglitazone (Actos), rosiglitazone (Avandia) | Enhance insulin sensitivity (cellular uptake of insulin) and inhibit hepatic glucose production | Hepatic toxicity; delayed onset of action; weight gain and fluid retention; contraindicated with CHF, liver disease | Useful as monotherapy or in combination; does not cause hypoglycemia and might ameliorate hyperlipidemia |
| Alpha-glucosidase inhibitors | Acarbose (Precose), miglitol (Glyset) | Inhibit breakdown and absorption of carbohydrates | Flatulence; need for high carbohydrate diet; cannot correct hypoglycemia with sucrose, maltose, or starch (but do not cause hypoglycemia on their own); contraindicated in patients with substantive renal and hepatic disease | Early in treatment for postprandial hyperglycemia; less potent than other agents |
| Combination agents | Glyburide/metformin (Glucovance) | As above | As above | Failure to meet goals on one agent alone; may reduce side effects of higher doses of either agent alone |
| Insulin | Short acting (Lispro and regular—aspart pending release); intermediate (NPH and Lente); long-acting (Ultralente and glargine) | Replace insulin, reduce hepatic glucose production, increase glucose uptake | Hypoglycemia; weight gain; must currently be injected | Failure to meet goals with oral agents or unable to take oral agents or to overcome glucose toxicity |
Table 2
Selected psychiatric drugs that interact with diabetes agents and patients with diabetes
| Drug Class | Effect |
|---|---|
| MAOIs | Hypoglycemia; may displace metglitinides and other protein-bound agents from serum proteins and cause hypoglycemia |
| SSRIs | Hypoglycemic unawareness |
| Tricyclics | May exacerbate autonomic neuropathy, orthostatic hypotension |
| Nefazodone | Highly protein bound and metabolized by CYP-3A4 (may effect metglitinide metabolism) |
| Bupropion | Liver metabolism |
| Carbamazepine | CYP-3A4 metabolized; may induce metglitinide metabolism |
| Valproate | Highly protein bound |
| Phenytoin | May decrease hypoglycemic effect of sulfonylureas |
| Benzodiazepines | Some (e.g., triazolam, alprazolam) metabolized by CYP/liver |
| Buspirone | Protein bound; CYP-3A4 metabolism |
| Antipsychotics | Weight gain may exacerbate or precipitate diabetes; liver metabolized |
| Note: Except for case reports, most of these agents are only theoretically implicated in the above drug-drug interactions (DDIs) or drug-disease interactions. Remember to assess all medications used in persons with diabetes, many of which do have substantial potential for DDIs. | |
The growing association of impaired glucose tolerance with progression to diabetes, the availability of effective interventions, and the high burden of morbidity for unrecognized diabetes suggest that more aggressive screening may be warranted.
Case 2 concluded Weight gain associated with atypical antipsychotic agents is all too common, and will often tip a patient “over the edge” from impaired glucose tolerance to type 2 diabetes. G.L. was referred to her primary care physician for assessment. Her fasting blood glucose Commonly used psychiatric medications may cause weight gain that exacerbates or precipitates type 2 diabetes was 312. Repeat FBG was 299. An ophthalmologic evaluation disclosed background changes consistent with diabetic retinopathy. Type 2 diabetes was diagnosed.
This patient deserves aggressive attention to modifiable risk factors, and warrants therapy for diabetes. Appropriate modification of diet, exercise, smoking and other risk factors—and medical comanagement—are critical. This includes attention to the psychotropic drugs she is taking.