From Medscape Education Psychiatry & Mental Health

Treating Depression in Patients With Comorbid Diabetes CME

Leonard E. Egede, MDAlmost half of all adults with diabetes have unrecognized depression.[6]

Depression is associated with poor glycemic control,increased mortality, and decreased quality of life.Clinicians need to be aggressive in using available treatment options to achieve remission of depression. But treating depression may not by itself lead to optimization of glycemic control. Physicians and other healthcare providers may need to combine psychotherapy with pharmacotherapy while maintaining focus on diabetes education and treatment.

Epidemiology and Burden of Disease

Recent national estimates show that approximately 26 million people in the United States (11.3% of adults) had diabetes in 2007.[1] Diabetes is a leading cause of morbidity, mortality, increased health services utilization, and increased healthcare costs. Depression is also very common in the United States with lifetime estimates of major depressive disorder of 16.2%.[2] Depression is associated with increased morbidity, mortality, disability, workplace absenteeism, diminished or lost work productivity, and increased use of healthcare resources.[3,4] The overlap between diabetes and depression is high, with about 11% of adults with diabetes having comorbid major depression and 31% having clinically relevant depression.[5] A significant proportion of depression in adults with diabetes is unrecognized. In a recent study, 45% of all adults with diabetes were found to have unrecognized depression.[6] Multiple large epidemiologic studies have shown that depression is twice as likely in adults with diabetes compared to adults without diabetes.[7,8] Therefore it is important for physicians to pay attention to the likelihood of depression in adults with diabetes.

Underrecognition of Depression in Patients With Diabetes

Up to 50% of depressed patients with diabetes are unrecognized.[6,9,10] There are several reasons for the low recognition of depression in patients with diabetes. One reason is the difficulty providers have in separating the symptoms of depression from the symptoms of poor management of diabetes (eg, fatigue, weight gain or weight loss, appetite changes, and sleep disturbances).[11,12] Another reason is the stigma and negative perceptions associated with depression. Other reasons include financial constraints, side effects of antidepressants, and implication of a mental health diagnosis on employment and insurability. Poor provider knowledge of evidence-based guidelines, reimbursement issues associated with mental health diagnoses, insufficient referral networks in rural and suburban communities[13] and the fragmentation of health care (ie, the longstanding practice of packaging mental health services as a “carve-out” program)[10] further compound the problem. These factors impede recognition and treatment for depression, especially among individuals with diabetes.

Effect of Depression on Diabetes Outcomes: Glycemic Control, Complications, and Mortality

There is strong evidence that depression is associated with poor glycemic control.[14,15] There is also good evidence that depression is associated with increased risk of diabetes complications including diabetic retinopathy, nephropathy, neuropathy, microvascular and macrovascular complications, and sexual dysfunction.[16-19] Multiple studies have also established that depression increases the risk for death in adults with diabetes.[20-22]

Effect of Depression on Self-Care Behaviors

Certain behaviors are essential for good glycemic control including diet, physical activity, medication adherence, and self-monitoring of blood glucose. However, multiple studies have shown that depression negatively affects these essential self-care behaviors. Depression is significantly associated with missed medical appointments, poor self-care behaviors and poor medication adherence across multiple studies[23-27] and a likely mechanism is poor perceived control.[28]

Effect of Depression on Functional Status, Productivity, and Quality of Life

Recent studies have documented the adverse effects of depression on functional status, productivity, and quality of life in individuals with diabetes. In one study, adults with diabetes and depression had a 7-fold increased odds of functional disability compared with adults without diabetes and depression.[29] In a second study, odds of disability were 4-fold higher in individuals with both depression and diabetes compared with 1.7-fold in those with diabetes alone.[19] Depression has also been linked to decreased work productivity[30] and decreased quality of life[31,32] in adults with diabetes.

Symptoms of Depression and Screening Tools for Depression in Primary Care

The depressive disorders include major depression, minor depression, and dysthymia. According to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Revised, [33]the clinical diagnosis of major depression is based on the presence of any 5 of the following symptoms: depressed mood or anhedonia (ie, markedly diminished interest or pleasure in activities) during the same 2-week period and significant weight loss when not dieting or weight gain; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think or concentrate; and recurrent thoughts of death, suicidal ideation, or a suicide attempt. To meet criteria,[33] these symptoms should represent a change from previous functioning and should occur most of the day.

Minor depression is similar to major depression in that patients experience depressed mood or anhedonia during the same 2-week period. However, the patient’s symptoms are fewer than the 5 items required to make a diagnosis of major depression.[33] Dysthymia is characterized by depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least 2 years.[33] In addition, at least 2 of the following symptoms should be present while the patient is depressed: poor appetite or overeating; low self-esteem; insomnia or hypersomnia; poor concentration or difficulty making decisions; low energy or fatigue; and feelings of hopelessness. Patients with dysthymia typically have fewer symptoms (less than 5) than is required to make a diagnosis of major depression.[33]

The diagnosis of depression is based on clinical findings. Several valid and reliable screening instruments are available.[34-39] The 9-itemPatient Health Questionnaire (PHQ-9)[39] is an easy to use depression screening instrument. The PHQ-9 is a brief questionnaire that scores each of the 9 DSM-IV criteria for depression as “0” (not at all) to “3” (nearly every day). PHQ-9 scores ≥10 have a sensitivity of 88% and a specificity of 88% for major depression. PHQ-9 scores of 5, 10, 15, and 20 represent mild, moderate, moderately severe, and severe depression, respectively.[39]Screening programs are most likely to be effective if there is staff support and coordinated referral to specialty mental health treatment.[40]

Importance of Assessing Risk for Suicide and Tools for Brief Suicide Risk Screening

It is critical to assess for the risk of suicide in all patients who present with symptoms of depression in primary care because approximately 45% of completed suicides occurred in patients who had contacted their primary care physician in the month preceding the act.[41] There are several protocols for assessing suicide risk. A simple and validated protocol[42] involves using a 2-stage process. The first stage involves screening for suicidal ideation with item 9 of the PHQ-9 — “Over the last 2 weeks, how often have you been bothered by thoughts that you would have been better off dead or of hurting yourself in some way?” If the patient denies these thoughts then they should be considered low risk for suicide and no further assessment is necessary. If the patient endorses these thoughts, then they should be asked “are you having thoughts of harming yourself in some way?” If the response is negative, then they should be considered low risk and no further assessment is necessary.

Patients endorsing active suicide ideation should undergo the second stage of assessment to investigate severity, nature and frequency of thoughts of self-harm; attempts at self-harm in the past month or previously; specificity of current plans and capacity to implement them; strength of death wishes; intensity of hopelessness; and impulse control and availability of preventive deterrents.[42] Patients endorsing active thoughts of self-harm without an articulated plan should receive same day evaluation by a mental health specialist.[43] Patients with a specific plan for self-harm require immediate assessment for safety and should be transported to an emergency room.[43]

Because patients may conceal intent, providers should obtain additional information from collateral sources when possible. These sources may include spouses/partners, family members, colleagues, and friends.[44] Suicide risk assessment should be an ongoing process and the risk of suicide should be monitored over the course of treatment. In addition to evaluating for the risk of suicide, it is also pertinent to assess for the patients risk to others (ie, violence toward others, homicidal ideation or intent).[44] History of substance abuse, psychosis, aggression or violence to others should raise a “red flag” and prompt further evaluation for the patients risk to others.[44] As in the case for suicide risk assessment, information from collateral sources should be obtained when possible.

Initiation of Treatment, Ongoing Management, and Duration of Treatment

Before initiating therapy, it is important to obtain additional history and perform a full physical examination and appropriate diagnostic tests.[44] The history should assess for prior episodes of depression, response to previous treatments, past symptoms of mania or hypomania, current life stressors, family history of mood disorders and suicide, review of over the counter medications and evaluation of past and current use of illicit substances.[44] A physical examination and appropriate initial diagnostic tests should be performed to rule out possible medical causes of depressive symptoms, especially thyroid disease and coexisting medical conditions such as hypertension and cardiac disease that may influence the choice of antidepressants.[44]

Once a clinical diagnosis of depression is established and the patient has been evaluated for suicide, the options for treatment are pharmacotherapy and psychotherapy. Because few primary care practices are set up to offer evidence-based psychotherapy for depression, the viable option for most primary care providers is pharmacotherapy. In general, the evidence suggests that pharmacotherapy and evidence-based psychotherapy are equally effective treatment options and that all classes of antidepressant medications are equally efficacious.[44,45] Newer pharmacotherapies such as the selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and bupropion are easier to dose, better tolerated by patients, and have fewer side effects and drug-drug interactions than the older agents such as the tricyclic antidepressants or monoamine oxidase inhibitors.[44,45] MAOIs require significant dietary restrictions, have major drug-drug interactions and should probably be avoided in individuals with diabetes.

There are 4 stages of treatment: response (4-8 weeks), remission (4-8 weeks), continuation (4-9 months), and maintenance (variable duration).[44] The goal of treatment in the acute phase is induction of full remission and return to full baseline functioning. An initial episode of depression should be treated for 6-9 months[44] The choice of initial pharmacologic agent should be guided by coexisting medical conditions (eg, hypertension, cardiac disease), patient preference, previous response or failure to antidepressants and tolerability. Patient education is critical to adherence and treatment success. Approximately 50%-70% of patients will respond to an initial agent and 50% of non-responders will respond to an alternative agent. Case management by nurses and greater collaboration between primary care providers and mental health specialists generally result in better patient outcomes.[46] The Figure shows an evidence-based algorithm for treating depression in primary care while Tables 1 and 2 show the classification, dosage, and side effects of commonly prescribed antidepressant medications in primary care.

Figure. Treatment algorithm for depression in primary care.

Table 1. Classification and Dosage of Commonly Prescribed Antidepressant Medications1

Drug Classa Generic Name Daily Dose Rangeb
Selective serotonin reuptake Escitalopram 10-20 mg
inhibitors (SSRI) Citalopram 20-60 mg
Fluoxetine 20-60 mg
Paroxetine 20-60 mg
Paroxetine, extended release 12.5-75 mg
Sertraline 50-200 mg
Serotonin norepinephrine Venlafaxine, immediate release 37.5-375 mg
reuptake inhibitors (SNRI) Venlafaxine, extended release 37.5-375 mg
Desvenlafaxine 50 mg
Duloxetine 60-120 mg
Dopamine norepinephrine Bupropion, immediate release 150-450 mg
reuptake inhibitor (DNRI) Bupropion, sustained release 150-450 mg
Bupropion, extended release 150-450 mg
Serotonin modulators Trazodone 150-600 mg
Nefazodonec 50-300 mg
Mirtazapine 15-45 mg
Tricyclic and teracyclic Amitriptyline 25-300 mg
antidepressants Imipramine 25-300 mg
Doxepin 25-300 mg
Desipramine 25-300 mg
Nortriptyline 25-200 mg
Trimiptaminec 25-300 mg
Protriptylinec 10-60 mg
Marprotilinec 75-225 mg

aMonoamine oxidase inhibitors are excluded because they are not used commonly in primary care
bLower dose reflects typical starting dose

cNot used commonly in primary care

Table 2. Side Effects of Commonly Prescribed Antidepressant Medications

Generic Name GI Disturbancea Anticholinergic Effects Weight Gain Weight Loss Sedation Insomnia Hypotension Sexual Dysfunction
Escitalopram 2+ 2+ 0 0 0 0 0 2+
Citalopram 2+ 1+ 0 0 2+ 2+ 2+ 2+
Fluoxetine 2+ 1+ 0 0 1+ 2+ 1+ 2+
Paroxetine 2+ 2+ 0 0 1+ 2+ 1+ 2+
Sertralineb 2+ 1+ 0 1+ 0 1+ 1+ 2+
Venlafaxine 3+ 2+ 0 1+ 0 2+ 0 2+
Duloxetine 3+ 2+ 0 0 2+ 2+ 0 2+
Bupropione 2+ 1+ 2+ 3+ 4+ 0 0 2+
Serotonin modulators
Trazodone 2+ 2+ 1+ 1+ 4+ 0 2+ 0
Nefazodone 2+ 2+ 0 0 2+ 2+ 0 0
Mirtazapinef 2+ 3+ 2+ 0 4+ 0 0 1+
Amitriptyline 1+ 4+ 2+ 0 4+ 0 4+ 1+
Doxepin 1+ 4+ 1+ 0 4+ 0 4+ 1+
Imipramine 1+ 4+ 1+ 0 4+ 0 4+ 1+
Desipramine 1+ 3+ 1+ 0 3+ 0 4+ 1+
Nortriptyline 1+ 3+ 1+ 0 3+ 0 4+ 1+

a0 = none or absent, 1+ = <5%, 2+ = 5%-20%, 3+ = 21%-40%, 4+ = >40%

bSertraline may cause hypoglycemia
cVenlafaxine and duloxetine may increase blood pressure in some patients
dUse with caution in patients with hypertension or heart disease
eBupropion stimulates insulin secretion in individuals with low, threshold, and high glucose levels
fMirtazapine is associated with hyperglycemia, hypercholesterolemia, and hypertriglyceridemia

An important component of treatment that is often overlooked is assessing for adequacy of treatment response. Adequacy of response should be based on objective measures such as a rating scale (eg, PHQ-9) and should be assessed within the first month. Patients with no symptomatic response after 1 month of treatment should not continue the treatment unmodified and 4-8 weeks of treatment is generally required to evaluate partial or adequate response.[44] Patients with no response should be switched to a different medication in the same class or from a different class (eg, within SSRIs or to an SNRI) after reevaluating the accuracy of the diagnosis, assessing for treatment adherence and tolerability, and excluding co-occurring diagnoses that may interfere with response.[44] After another 4-8 weeks, partial responders may require augmentation with a non-MAOI antidepressant, a non-antidepressant such as lithium, thyroid hormone, or second-generation antipsychotic or addition of psychotherapy.[44] However, primary care providers should be cautious about augmenting with non-antidepressants such as lithium, thyroid hormone or second-generation antipsychotics because of the increased risks associated with these treatments. Augmentation with non-monamine oxidase inhibitor antidepressant is probably more appropriate unless the primary care provider is comfortable and willing to monitor patients closely when using the non-antidepressant augmentation medications.

Once the patient goes into remission, patients should be continued on the same medications used to achieve remission for an additional 4-9 months to prevent relapse.[44] During the continuation phase, patients should be assessed in an ongoing fashion for symptoms, side effects, medication adherence and functioning using objective measures such as rating scales[44] In some patients, it may be necessary to maintain treatment after the continuation phase to reduce the risk of recurrent episodes. Patients who should receive maintenance treatment include those with 3 or more prior episodes of major depression, chronic major depression, multiple risk factors for recurrence (eg, residual symptoms, ongoing life stressors), severe initial episode with psychotic features, high suicide risk, or co-occurring psychiatric disorders.[44] These patients should continue at the effective dose used during acute and continuation phase and evaluated at regular intervals. Some patients may require treatment indefinitely; however, these patients may be better managed by psychiatrists.

Discontinuation of treatment should be considered after 6-9 months of a therapeutic dose of antidepressants in patients who go into remission and do not require maintenance treatment.[44] Discontinuation should be gradual with a slow taper or switch to a longer acting antidepressant at a lower dose to avoid or minimize discontinuation symptoms.[44] There should be a discussion about the risk of relapse and a process in place to monitor for relapse in patients who are discontinued from treatment.[44]

Unique Issues in Diabetes: The Need to Treat Both Depression and Diabetes

A common assumption in treating depressed patients with diabetes is that once the depression goes into remission, the patient’s diabetes control would improve. However, multiple clinical trials including pharmacotherapy and psychotherapy studies for depression suggest that this is not usually the case. Three major pharmacological trials found that treatment with antidepressant medications was associated with significant improvement in mood without concomitant improvement in glycemic control.[47-49] At least 3 other studies have examined whether psychotherapy alone or in combination with pharmacotherapy improve depression and diabetes outcomes[50-52] In those studies only cognitive behavioral therapy with or without diabetes education was associated with significant improvements in both mood and glycemic control.[50,52] These studies suggest that treating depression alone may not lead to optimization of glycemic control, although evidence-based psychotherapy seems to show some promise. The key message is that the provider should not focus on treating depression to the extent that they ignore good glycemic control. The goal should always be to achieve remission of depression while maintaining optimal glycemic control. This may require combining pharmacotherapy or psychotherapy treatment for depression with aggressive diabetes self-care and treatment.


Diabetes affected approximately 26 million people in the United States in 2007[1] and the lifetime estimate of major depressive disorder is 16.2%.[2] About 11% of adults with diabetes have comorbid major depression and 31% have clinically relevant depression.[5] There is strong evidence that depression is associated with poor glycemic control,[14,15] increased risk of diabetes complications,[16-19] poor self-care behaviors and poor medication adherence,[23-28] increased mortality,[20-22] and decreased quality of life.[29-32] However, almost half of all adults with diabetes have unrecognized depression.[6] Therefore it is important for providers to pay attention to the likelihood of depression in adults with diabetes. Evidence suggests that pharmacotherapy and evidence-based psychotherapy are equally effective treatment options and that all classes of antidepressant medications are equally efficacious[44,45] so providers should be aggressive in using available treatment options to achieve remission of depression. Nevertheless, providers should not focus on treating depression to the extent that they ignore good glycemic control. The goal should always be to achieve remission of depression while maintaining optimal glycemic control. This may require combining pharmacotherapy or psychotherapy treatment for depression with aggressive diabetes self-care and treatment.

Supported by an independent educational grant from Bristol-Meyers Squibb.


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