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Primary Care Update

Safe and effective care for your patients with diabetes

Diabetes mellitus is often associated with psychiatric problems and psychiatric treatment can complicate diabetes management. This case-based review will increase your awareness of drug-drug and drug-disease interactions.

Vol. 1, No. 1 / January 2002

Type 2 diabetes mellitus is one of the most common and costly chronic diseases, afflicting 16 million people nationwide. According to American Diabetes Association statistics, the disease each year costs the United States more than $100 billion in health-care expenses and lost productivity.

Diabetes is associated with many psychiatric conditions, yet psychiatrists may not be aware that patients under treatment for mental disorders are suffering from diabetes or have problems related to their psychopharmacologic therapy. With changing criteria for the diagnosis of diabetes, new evidence about the prevention and treatment of this disease, and a growing link between diabetes and psychiatric issues, the practicing psychiatrist should be knowledgeable about such possible interactions.

The following three cases illustrate these challenges and offer pearls for patient management.


Type 1 diabetes is caused by an autoimmune phenomenon leading to beta-cell failure and absolute deficiency in insulin. Type 2 diabetes is characterized by tissue receptor resistance to insulin (aggravated by genetic factors, obesity, aging, and other problems), beta cell dysfunction (with defects in the timing and amount of insulin secretion), and changes in hepatic glucose output and glucose transport. Patients with type 2 diabetes will initially lose phase one (early) insulin secretion in response to a glucose load.

Unregulated production of hepatic glucose ultimately leads to abnormal fasting blood sugars. The beta cells will initially compensate, but will eventually fail. Thus, postprandial blood sugars will increase, reflecting the loss of early insulin secretion, but return relatively rapidly to normal. Gradually, fasting blood sugars will also rise as insulin resistance becomes more pronounced and the imbalance in hepatic glucogenesis occurs. Eventually, with absolute beta cell failure, patients with type 2 diabetes will require insulin to offset their insulinopenic state.

Case 1: Diabetes and depression

L.S., age 54, has a five-year history of type 2 diabetes. On referral, he presents with increasing lethargy, difficulty concentrating, and irritability. His mental status examination discloses anhedonia, moderate irritability, depressed mood, loss of appetite, and overall lethargy. He emphatically denies suicidal thoughts, but feels “overwhelmed with life.” His referring physician notes that he also suffers from hyperlipidemia and hypertension, and continues to smoke one pack per day. His current medications include atorvastatin, enalapril, glucophage, and one baby aspirin per day. His weight is 247 pounds. Other than mild background retinopathy and mild peripheral neuropathy, his last physical examination was normal. His last HbA1c was 8.8%, and his creatinine was 1.7.

How do you manage this patient?

The challenge Type 2 diabetes mellitus affects more than one in 17 persons in the U.S., and physicians diagnose approximately 800,000 cases yearly. Yet one third of individuals with diabetes are undiagnosed, and multiple studies suggest we are falling short of accepted guidelines for care. Diabetes remains the leading cause of blindness, renal failure, and non-traumatic amputation in adults. While care for patients with diabetes will largely fall to primary care physicians (it is the third most common problem seen by family physicians) and endocrinologists, psychiatrists will often also see these patients.

Case 1 concluded While this patient’s history clearly suggests major depressive disorder, the possibility of other medical complications (e.g., worsening renal function or lactic acidosis from metformin therapy) should be entertained. A serum lactate level was normal and a metabolic panel, including renal function, was stable. The patient responded well to the addition of a selective serotonin reuptake inhibitor (SSRI) for his major depressive disorder.

Comment Many patients with diabetes will present with symptoms and signs suggestive of depression and anxiety. Patients with diabetes are more likely to develop depression, a disorder that worsens the outcomes for such individuals. These patients are likely to take multiple medications and have many medical comorbidities. Therapy of psychiatric disorders in patients with diabetes may be complicated by drug-drug and drug-disease interactions. When patients with diabetes present with symptoms of a mental disorder, a careful assessment is essential.


The diagnosis of diabetes depends on the demonstration of either fasting glucose intolerance (plasma glucose 126) or abnormal response to glucose challenge (plasma glucose 200 following a 75 gm glucose challenge). Testing is repeated and not done at a time of stress, such as during an acute illness. The HbA1c is not recommended for the diagnosis of diabetes.

Risk factors for type 2 diabetes mellitus include:

  • Obesity
  • Family history of diabetes
  • Race/ethnicity (African-American, Hispanic, Asian-American, Pacific Islander)
  • Age ≥ 45
  • Sedentary lifestyle
  • Previous history of impaired glucose tolerance
  • History of gestational diabetes or birth weight of child of 4 kg or more
  • Hypertension
  • HDL 35 ≤ mg per dL or triglyceride 250 ≥ mg per dL

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


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


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


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


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


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



Hypoglycemia; may displace metglitinides and other protein-bound agents from serum proteins and cause hypoglycemia


Hypoglycemic unawareness


May exacerbate autonomic neuropathy, orthostatic hypotension


Highly protein bound and metabolized by CYP-3A4 (may effect metglitinide metabolism)


Liver metabolism


CYP-3A4 metabolized; may induce metglitinide metabolism


Highly protein bound


May decrease hypoglycemic effect of sulfonylureas


Some (e.g., triazolam, alprazolam) metabolized by CYP/liver


Protein bound; CYP-3A4 metabolism


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.

Comment Medications commonly used by psychiatrists (e.g., atypical antipsychotics) may be associated with weight gain that exacerbates or precipitates type 2 diabetes.

The psychiatrist also must be aware of other potential medical comorbidities of treatment. Drug-drug interactions may occur with agents that are hepatic metabolized, including commonly used therapies for bipolar disorder (Table 2).

Metglitinides are metabolized by the CYP-3A4 system and drugs such as barbiturates and carbamazepine may induce this enzyme and reduce effectiveness. MAO inhibitors are associated with hypoglycemia with a number of agents, including sulfonylureas, and highly protein-bound agents such as the MAO inhibitors may displace repaglinide and increase its hypoglycemic activity. Fluoxetine and other SSRIs may cause hypoglycemic unawareness. Oral hypoglycemia agents themselves can be associated with hypoglycemia, and the onset may be confused with anxiety or panic attacks. The older sulfonylureas may cause inappropriate ADH (SIADH). Biguanides are occasionally associated with potentially catastrophic lactic acidosis.

Case 3: Disordered eating in an adolescent with type 1 diabetes

B.C., a 17-year-old with type 1 diabetes mellitus, is referred to a psychiatrist for a possible eating disorder. She was diagnosed with diabetes when she was 4. Over the past year her diabetes self-care has become increasingly erratic. B.C.’s mother notes that the patient often skips her insulin altogether, is preoccupied with her weight, and consumes large amounts of junk food. B.C. also admits to purging when she has been particularly lax with her diet.

Interaction between psychiatric and endocrine disorders Disordered eating appears to be frequent in adolescent girls and women with diabetes. Conscious underdosing of insulin and irregular eating habits may occur when patients are concerned about their body image, feel a stigma about using insulin, or fear they won’t fit in with friends.


Diabetes treatment requires a comprehensive approach embracing education, regular history and physical examinations, routine laboratory evaluations, and establishment of counseling goals. The foundation of care lies on appropriate diet and exercise.

Increasingly, a “stepped care approach” to medication is being advocated based on the patient’s stage of disease. For individuals with early type 2 diabetes, risk factor modification, diet, and exercise may be sufficient. Later, as further insulin resistance occurs, oral hypoglycemic agents must be added. A number of therapeutic options are available (Table 1). Finally, late in the course of type 2 diabetes, as absolute insulin deficiency occurs, combination therapy and insulin are used. Insulin is also often required for initial therapy to “rescue” the overstressed beta cells and overcome “glucose toxicity.”

Little evidence exists to guide the choice of treatment of type 2 diabetes, and nuances of therapy are beyond the scope of this article. However, several points are worth reinforcing:

  • Ideal treatment is geared to normalizing the blood sugar at all times and achieving a near normal A1c (6.5% to 7%).
  • Lifestyle modifications are important, and even relatively small changes in weight can substantially increase insulin sensitivity.
  • Risk factor modification (e.g., smoking, lipids, hypertension) is extremely important.
  • Therapy for type 2 diabetes is not static. As the disease progresses, more aggressive therapy is often required.
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