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Multiple studies show that diabetes approximately doubles the risk of comorbid depression. Furthermore, major depressive disorder is a risk factor for the subsequent development of type 2 diabetes mellitus. Treatments for depression in the setting of diabetes must be evaluated for their effects on blood glucose levels, propensity for weight gain, possible concomitant use for diabetic neuropathy and potential drug interactions.
April Bonus Edition 2005
Discussion of the relationship between glucose metabolism and psychiatric illness has occurred for at least three centuries. The eminent English physician Thomas Willis, M.D., first documented an interaction between psychiatric illness and diabetes mellitus (DM) in the late-17th century. Willis, who coined the term diabetes mellitus, made the following statement: "Sadness, or long sorrow, as likewise convulsions, and other depressions and disorders of the animal spirits, are used to generate or foment this morbid disposition."
Diabetes mellitus is a common, chronic condition affecting approximately 6.3% of the population (Centers for Disease Control and Prevention, 2003). Rather than a single disease entity, DM is a group of metabolic illnesses with hyperglycemia as the central feature. It is important to distinguish between type 1 and type 2 DM. Type 1 DM, formerly called insulin-dependent DM, is a juvenile-onset disease involving autoimmune destruction of insulin-secreting pancreatic b cells. Type 2 DM, formerly called non-insulin-dependent DM, is an adult-onset disorder that begins with resistance to the effects of insulin. Age, obesity and lack of physical activity are major risk factors for type 2 DM, and there is a strong genetic predisposition to the illness. Approximately 90% to 95% of individuals with diabetes have type 2 DM (American Diabetes Association [ADA], 2004).
Epidemiology and Pathophysiology
Multiple investigators have studied the relationship between depression and DM. Although published reports vary by method of diagnosing depression and reported prevalence of depression in DM, Anderson et al. (2001) completed a comprehensive meta-analysis of 42 studies demonstrating that the presence of diabetes consistently doubles the odds of comorbid depression. Furthermore, when depression and diabetes coexist, the severity of diabetes increases. A meta-analysis demonstrated the association of depression with hyperglycemia (Lustman et al., 2000a), as well as diabetic complications including retinopathy, nephropathy, neuropathy, sexual dysfunction and macrovascular disease (de Groot et al., 2001). Black et al. (2003) found additionally that comorbid depression predicts greater mortality in patients with type 2 DM.
This relationship may not be unique to unipolar depression. Most studies of depression and DM do not distinguish between unipolar and bipolar depression. Several reports show that hospitalized patients with bipolar disorder also have increased rates of diabetes compared to general populations (Cassidy et al., 1999; Lilliker, 1980; Regenold et al., 2002). These studies have been criticized, however, for the potential ascertainment bias inherent in studying a sample of hospitalized patients whose frequent contact with health care professionals may increase their chance for diabetes diagnosis.
Classically, development of depression in individuals with diabetes has been viewed as a reaction to the stress of a chronic medical illness, rather than as the product of a pathophysiologic interrelationship (Jacobson, 1993). Although this may be the case for some individuals, recent reports suggest a more complex relationship. In a follow-up study from the original Epidemiological Catchment Area Study, Eaton et al. (1996) found that patients with a lifetime diagnosis of major depressive disorder (MDD) in 1981 had approximately twice the relative risk of developing type 2 DM in the ensuing 13 years--even after controlling for diabetes risk factors such as age, race and body mass index. Therefore, depression can precede and be a risk factor for diabetes.
Despite considerable investigation, the nature of the relationship between depression and diabetes and the mechanisms involved are not completely understood. It is likely there are multiple mechanisms that differ across individuals. Interestingly, the two disorders have some overlap in their pathophysiology. Both depression and type 2 DM share metabolic abnormalities including insulin resistance and non-suppression in the Dexamethasone Suppression Test (DST) (Cameron et al., 1984; Hudson et al., 1984; Talbot and Nouwen, 2000). Furthermore, MDD, insulin resistance and diabetes have all been found to be independent risk factors for magnetic resonance imaging evidence of brain white matter disease (Kamide et al., 1997; Lenze et al., 1999; Schmidt et al., 1992). The possibility that brain white matter disease could predispose individuals with DM to depression has been suggested (Geringer et al., 1988). Geringer et al. and Viinamaki et al. (1995) have both reported that diabetic neuropathy is a risk factor for depression in diabetes. It has been postulated that a parallel neuropathic process might occur in the brain (Geringer et al., 1988). Lastly, although controlled for in some studies, the contribution of psychotropic medications to weight gain may also predispose some individuals with depression to type 2 DM.
Diagnosis and Treatment Considerations
Clinical management of depression in patients with comorbid diabetes rests on four basic principles:
1. Recognize the diabetes diagnosis.
2. Consider the diabetes when making decisions about depression management.
3. Educate the patient.
4. Collaborate with primary care physicians and diabetes specialists.
Before diabetes can be managed, it must be diagnosed. Estimates show that about 30% of diabetes cases in the United States are undiagnosed (CDC, 2003). Given that psychiatrists are often the main physician contact for patients with severe mental illness, they play a vital role in recognizing the signs and symptoms of new-onset diabetes as well as the potentially life-threatening symptoms of hyper- and hypoglycemia (Table 1). A study by Dixon et al. (2004) suggested that the regular mental health care received by patients with both diabetes and severe mental illness may be a factor contributing to their better glycemic control compared to diabetics without severe mental illness. A consensus conference statement made by the ADA, American Psychiatric Association and others (ADA et al., 2004) now recommends periodic monitoring of fasting blood glucose, as well as lipids, blood pressure, weight and personal/family history in patients receiving atypical antipsychotics. This is important, given the association of these medications with the new onset of type 2 DM. Prudent patient care may dictate extending this surveillance to patients treated for depression. Diabetes diagnosis should influence depression treatment decisions. Four major areas merit consideration, as shown in Table 2.
Monoamine oxidase inhibitors present several challenges when used in patients with DM. Reports link MAOIs with sudden hypoglycemia requiring emergency intervention (Goodnick, 1997). This effect could be particularly troubling with concomitant use of diabetes medications such as insulin and the sulfonylureas that can cause hypoglycemia. Additionally, both MAOIs and diabetes require dietary restrictions. In terms of weight, phenelzine (Nardil) appears to induce weight gain, although reports on other MAOIs are mixed (Zimmermann et al., 2003).
The tricyclic antidepressants are established treatments for peripheral diabetic neuropathy. Tricyclic antidepressants increase weight, although specific agents differ substantially in amount of weight gain (Zimmermann et al., 2003). They may indirectly improve diabetes by improving depression but also have a direct hyperglycemic effect. Lustman et al. (1997) conducted a double-blind, placebo-controlled study of nortriptyline (Pamelor, Aventyl) in patients with poorly controlled diabetes, some of whom also had active MDD. The study found nortriptyline effectively treated major depression in diabetes. However, path analysis showed the direct effect of nortriptyline was to worsen glycemic control (independent of weight gain), whereas depression improvement had an independent beneficial effect on glycosylated hemoglobin.
The selective serotonin reuptake inhibitors present important benefits and risks in the treatment of comorbid depression and diabetes. Fluoxetine (Prozac) is the most-studied SSRI. A randomized, placebo-controlled study demonstrated fluoxetine effectively reduced depressive symptoms in an eight-week trial, with a trend toward improved glycemic control in patients with diabetes (both types 1 and 2) and MDD (Lustman et al., 2000b). Further evidence for potential benefits in glycemic control came from a study by Ghaeli et al. (2004), in which fasting blood glucose significantly decreased in nondiabetic participants with MDD who were treated with fluoxetine. The same study found significantly increased fasting blood glucose in patients without diabetes treated with the TCA imipramine (Tofranil). Accordingly, hypoglycemia can occur when adding an SSRI to a diabetes regimen, particularly if it includes insulin or sulfonylurea oral hypoglycemic medications (tolbutamide [Orinase], glipizide [Glucotrol], glyburide [Diabeta], glimepiride [Amaryl]). Additional care is required when adding SSRIs that inhibit the 2C9 isoenzyme of the cytochrome P450 liver enzyme system (fluoxetine, fluvoxamine [Luvox], paroxetine [Paxil], sertraline [Zoloft]) to the sulfonylureas, because the sulfonylureas are primarily metabolized by the 2C9 isoenzyme. Inhibiting the 2C9 isoenzyme will increase sulfonylurea levels, potentially leading to dangerous hypoglycemia (Cozza et al., 2003).
With regard to body weight, a meta-analysis shows fluoxetine can achieve moderate but statistically significant weight loss in adults with type 2 DM (Norris et al., 2004). Evidence for weight loss or gain with other SSRIs is mixed (Zimmermann et al., 2003). Despite evidence for improved depression, improved glycemic control and weight loss with SSRIs, one area in which they lack effectiveness is neuropathy. Although extensively studied, SSRIs are not appropriate monotherapy for diabetic neuropathy (Duby et al., 2004).
The serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine (Effexor) and duloxetine (Cymbalta) present potential advantages in the treatment of comorbid diabetes and depression. Neither drug has been specifically studied for treatment of depression and comorbid diabetes. However, SNRIs are treatments for neuropathy. Several randomized, double-blind, placebo-controlled studies suggest high-dose venlafaxine may be as effective as TCAs in treatment of neuropathy (Rowbotham et al., 2004; Sindrup et al., 2003). Last September, duloxetine became the first medication to receive a U.S. Food and Drug Administration indication for pain caused by diabetic peripheral neuropathy. Venlafaxine is not thought to affect body weight (Zimmermann et al., 2003). An open-label, 52-week trial of duloxetine for MDD showed a mean weight gain of approximately 5 lb (Raskin et al., 2003).
To our knowledge, there are no studies of mirtazapine (Remeron) for depression with comorbid diabetes or for diabetic neuropathy. However, it can cause significant weight gain (Zimmermann et al., 2003). A single case report described new-onset type 2 DM in conjunction with mirtazapine-induced weight gain (Fisfalen and Hsiung, 2003).
There are also no studies of bupropion (Wellbutrin) specifically for the treatment of depression comorbid with diabetes. A placebo-controlled trial of bupropion in men with diabetes and erectile dysfunction who weren't depressed showed no worsening of sexual function and no change in measures of diabetic control during treatment (Rowland et al., 1997). Bupropion appears to be at least weight-neutral, if not weight-decreasing (Appolinario et al., 2004).
Psychotherapy is also an effective treatment for depression in diabetes. Lustman et al. (1998) conducted a randomized, controlled trial of cognitive-behavioral therapy (CBT) versus no specific antidepressant treatment in 51 patients with type 2 DM and MDD. Eighty-five percent of patients in the CBT group achieved remission versus 27% of controls. After 10 weeks, posttreatment glycosylated hemoglobin levels were not different in the two groups; however, at six-month follow-up, the CBT group showed significantly lower glycosylated hemoglobin. The authors hypothesized that, given the biology of glycosylated hemoglobin as a measure of glycemic control over 120 days, improvement in glycemic control would not be captured without a lag time.
Given that psychotropics can affect glucose control, patients require education. Warn patients of possible disturbances in blood glucose with medication adjustments, and ask them to maintain daily blood glucose records to track these potential changes. Furthermore, as both hyper- and hypoglycemia can cause delirium and a host of psychiatric symptoms including anxiety, paranoia and hallucination, patients with depression or other psychiatric illness and diabetes should be advised that their symptoms can be misinterpreted as symptoms of an underlying psychiatric illness. Patients should therefore be encouraged to obtain medical identification bracelets or necklaces to alert others to check a blood glucose level when they observe mental status changes.
Collaboration with other treating clinicians is essential in providing optimal care to patients with depression and diabetes. Coordinating care with providers who are treating other diabetic complications and comorbidities is essential to prevent untoward drug interactions and to have an informed view of a patient's overall health.
Depression and diabetes often occur together. The reasons for the co-occurrence are complex and remain a topic of considerable research. Regardless, treatment of depression with diabetes requires special considerations. Recognizing the symptoms of hyper- and, especially, hypoglycemia can be life saving. Careful prescription of psychiatric medication and collaboration among health care professionals are essential to the management of patients with diabetes and depression.
Dr. Regenold is assistant professor and director of the division of geriatric psychiatry in the department of psychiatry at the University of Maryland School of Medicine and the University of Maryland Medical Center.
Dr. Marano is a geriatric psychiatrist and research fellow at the University of Maryland Medical Center.
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