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Depression in Women With Diabetes

Linda S. Griffith, MSW, LCSW, and Patrick J. Lustman, PhD

Major depression occurs twice as frequently in women as in men in industrialized countries.¹ It is three times more prevalent in adults with diabetes as it is in the general population in the United States.² Consequently, women with diabetes are at an increased risk for depression occurrence as a result of both gender and disease.

Major depression is a mental disturbance with well-recognized adverse effects on physical and psychological functioning. The emotional disorder has importance for women with diabetes that far exceeds these known influences. Scientific investigation has established an association between the presence of major depression and poor glycemic control,³ poor adherence to the diabetes regimen,^4,5 and an increased risk for diabetes complications.^6,7 Major depression adversely affects health behaviors necessary for good diabetes management (e.g., diet, exercise, smoking cessation programs, and abstinence from substance use).⁸

Sad mood is a common part of the human experience. Therefore, it is necessary to distinguish depression that is a normal response to intermittent stress from depression that is pathological sadness. The former is a mild, transient mood state during which sad feelings are experienced for a few hours or possibly a day or two. The latter is a state of enduring despondency characterized by multiple affective (loss of interest and pleasure, guilt) and somatic (difficulties with sleep and appetite, fatigue) symptoms. The condition is considered a diagnosable medical disorder and is known as major depression. The term depression is used as a synonym for major depression in the following discussion.

Prevalence of Depression
Depression affects ~5-8% of the general population at some point during their lifetime and occurs twice as frequently in women as in men.⁹ Lifetime rates for depression from the Epidemiologic Catchment Area (ECA) Study conducted during the late 1970s were 10.5% for women versus 5.2% for men, with the typical age of onset between 27 and 35 years.^10,11

While investigation into gender differences in depression is barely 20 years old,¹² and higher rates of depression for both sexes have been found in more recent population-based studies,¹³ three gender-specific findings are worth noting. First, the 2:1 female-male ratio in developed countries continues to be a robust finding in both national and international epidemiological studies.¹ Second, higher rates of depression for females as compared with males are evident as early as adolescence and persist throughout the lifespan.^13,14 Third, women attempt suicide twice as often as men yet represent 25% of the group who succeed.^15,16

The prevalence and significance of depression in diabetes has been the focus of intense investigation during the past 10 years.^3,17 Gavard evaluated 20 studies from an epidemiological perspective and concluded that ~15-20% of adults with type 1 or type 2 diabetes experience major depression during their lifetime.² This prevalence rate is 3-4 times greater in diabetes than that observed in the general population. The two controlled studies^17,18 that examined differences by gender and disease found that women with diabetes were at greater risk for depression than were both men with diabetes and nondiabetic women. Four uncontrolled studies^3,19-21 reported an increased prevalence of depression in females compared with males, although differences were significant in only one study.³

The limited data available suggest that depression in diabetes appears to follow the same female preponderant pattern as that seen in the general population. Whether the prevalence of depression is any different in women with diabetes than in women with other chronic medical illnesses is not known.² In studies of primary care patients, depression prevalence continues to be female predominant, but methodologically disparate investigations have made rigorous comparisons between medical illnesses difficult.^2,22

Early epidemiological research relied on institutional records and treatment populations and thus may have been biased because women seek health care more frequently than do men.^1,23 However, studies using community samples and not subject to this bias indicate that the 2:1 gender ratio for depression remains a strong and consistent finding in the general population.^13,24 Since care-seeking behavior cannot account for the increased prevalence of depression in women, other explanations have been proposed, including biological vulnerability via genetic, endocrine, and immune processes^25-28 and psychosocial causes such as poverty, abuse, and stressful life events.^29,30 To date, no one explanation accounts for the increased prevalence of depression in women,³¹ and it is likely that each of these explanations has some merit.

Similarly, the explanations for higher prevalence rates of depression in diabetes are varied. We have suggested that the origins of depression in diabetes are unknown but probably multifaceted.³² Like depression in the medically well, the illness is a complex interaction of biological and psychological factors associated with the individual and with diabetes. Whether the reasons for depression in women with diabetes are different from those in men with diabetes or from those in women without diabetes is not known. Prevalence findings provide supportive evidence for understanding etiological associations but do not alone establish causal relationships. More importantly for women with diabetes, prevalence data highlight the frequent co-occurence of these two disorders and the significant potential for harmful interactions.

Significance of Depression
Depression compromises many aspects of a woman's health. In addition to increased medical morbidity and impaired quality of life, depression contributes to increased health-care utilization, functional disability, and greater work absenteeism.^33-35 For women with diabetes, depression has the potential for more severe consequences³⁶ (Figure 1). Depression has been directly associated with glucose dysregulation^36,37 and with other factors (e.g., obesity, physical inactivity, and regimen noncompliance) that indirectly contribute to impaired glycemic control.^38-40 Depression has been associated with an increased risk for disease complications, particularly retinopathy⁷ and macrovascular disease,^6,41 and this risk is independent of its association with poor glycemic control.⁷

Obesity increases the risk for macrovascular disease in diabetes, particularly when it is coupled with physical inactivity.⁴² Hence diet, weight management, and exercise are vital components of the medical regimen.

Depression often causes increased food intake and decreased activity over several weeks or months, and these factors in turn can cause weight gain and thwart efforts aimed at good glycemic control. Robinson³⁸ found that currently depressed adults with diabetes had significantly higher body mass indexes compared with nondepressed adults with diabetes. Investigating the relationship between cardiovascular risks, central abdominal adiposity, and waist-to-hip ratio (WHR), Lloyd found that depressive symptomatology was an independent predictor of WHR in women with diabetes.⁴³ It has been found that depressed adults with diabetes respond poorly to programs aimed at changing negative health behaviors (i.e., weight management, smoking cessation),^19,44 and thus collateral treatment of depression may be important to the success of these lifestyle interventions. Taken together, these data reveal the significant negative effects that depression can have on appetite, activity level, weight, and glycemic control.

Depression Across the Life Cycle
The significance of depression for women should also be considered from a developmental perspective as women acquire characteristics at various life stages (e.g., adolescence, pregnancy, menopause) that may precipitate an episode of depression and negatively affect diabetes.

Adolescence. Epidemiological studies report no significant gender differences in the risk of depression for prepubertal boys and girls in the general population, but between the ages of 10 and 15 years, the risk increases dramatically for girls. Adolescent girls are at twice the risk of developing depression as adolescent boys.^24,45

Findings on gender differences in depression for adolescents with diabetes have been inconsistent,^46,47 but a recent study by Kovacs and associates found that while gender was not a risk factor for the first depressive episode in early adolescents with diabetes,⁴⁸ its effect was evident by late adolescence. Girls with diabetes with a mean age of 17.4 years had a significantly greater depression prevalence than did boys with diabetes,⁴⁸ a finding consistent with studies of the general population.^45,49 Kovacs and associates advise that adolescent girls with type 1 diabetes be monitored closely for signs and symptoms of depression.

This gender-related risk for depression in women with diabetes is intriguing, considering that women with diabetes are also at greatest risk for eating disorders⁵⁰ during adolescence. The prevalence rate of anorexia nervosa in the United States is 1%, and up to 4% for bulimia nervosa, with the frequency of eating disorders for men about one-tenth that for women. Depression and eating disorders have a long association, but the exact nature of the association remains controversial, and the sequence in which these disorders develop varies.^51,52

Although research has failed to clearly establish a greater prevalence of clinical eating disorders in young women with diabetes, these problems are not uncommon, nor is their association with depression.⁵⁰ Furthermore, whether or not clinical eating disorders are more prevalent in diabetes, it appears that subclinical problems related to weight and eating are commonplace. Rapaport reported that approximately one-third of women taking insulin struggle with symptoms of anorexia and bulimia nervosa (e.g., preoccupation with food, body image, restrictive and/or binge eating, excessive exercise, induced vomiting, insulin misuse), and depression was a frequent comorbid finding.⁵⁰ In her study of regimen adherence in 193 adolescent boys and girls, Littlefield found noncompliance with the diabetes regimen through binge eating was significantly related to depressive symptoms and lower levels of self-efficacy and self-esteem.⁵ The associations were strongest in the girls. The potential threat that comorbid depression and eating disorders pose for glycemic control makes their recognition and treatment crucial for optimal diabetes management.

Pregnancy. Depression is common during pregnancy.^53,54 Its presence has been associated with adverse outcomes such as impaired maternal self-care,⁵⁵ increased risk for postpartum depression,^54,56,57 and negative effects on children.⁵⁸ The mechanisms associated with depression that contribute to poor pregnancy outcomes are not known but most probably involve both behavioral and hormonal pathways.⁵⁹

The lack of available information about depression in diabetic pregnancies is surprising given that normoglycemia is the goal of management during pregnancy, and depression may oppose efforts to maintain good control. Depression has been the most frequently reported major psychiatric disorder in high-risk pregnancy studies to date.^60-62 These studies did not uniformly report the percentage of patients with diabetes, although it is likely that a substantial number had either pregestational or gestational diabetes. Rothaar and associates⁶³ measured depression and anxiety in 11 women with diabetes and 11 women without diabetes and found that the women with diabetes scored significantly higher for state depression than those without diabetes.

Whether the presence of depression during pregnancy undermines the important goal of maintaining normoglycemia has not been empirically established. An association between psychological stress and diminished glycemic control has been reported in pregnant women with gestational diabetes.⁶⁴ With maternal and fetal well-being dependent upon good glycemic control, further study is needed to clarify the risk factors and significance of depression in diabetic pregnancies.

Adult sexual functioning. Depression is associated with sexual dysfunction in women with diabetes,^65,66 but questions concerning the differential contribution of depression and neuropathy in this association remain unanswered. Leedom and associates⁶⁷ studied depression, neuropathy, and sexual difficulties in diabetes and found total sexual dysfunction scores correlated significantly with Beck Depression Inventory (BDI) scores in women with diabetes but not in men with diabetes. However, they also report a significant positive correlation between sexual dysfunction and higher BDI scores in diabetic women with neuropathy compared with diabetic women without neuropathy.

It would appear that both neuropathy and depression may contribute importantly to adult female sexual dysfunction. Nofzinger has speculated that a central neuropathy that affects the anterior paralimbic system may lead to disturbances in both primary motivations and drives, as well as in the limbic-cortico-visceral-neural pathways that connect primary affective states (i.e., sexual drive) with peripheral autonomic regulation of sexual function.⁶⁸

Menopause. The association of depression with menopause remains a somewhat controversial topic. Early research suggested that menopause produced an increased risk for depression, and this mood disorder was accorded its own psychiatric diagnosis-involutional melancholia.⁶⁹ Later, methodologically superior studies^70-71 failed to confirm the increased risk for depression during menopause, and involutional melancholia was consequently subsumed under major depression in the nomenclature.⁷²

The study of depression in older women is complicated by decreasing levels of estrogen during the perimenopausal and menopausal years. Such decreases are known to initiate mood fluctuations, diminished sexual drive, and signs and symptoms suggestive of peripheral neuropathy⁷³ in some women. Current evidence further suggests that estrogen has antidepressant qualities^27,74 and that menopausal women experience increased well-being with its usage.⁷⁵ Thus, estrogen replacement therapy is useful in treating the minor depressive symptoms of menopause in nonclinically depressed women. Antidepressant therapy is initiated if the mood symptoms become more severe and enduring and proceed to full-blown depression. Whether women with diabetes have different or additional experiences with depression independent of estrogen withdrawal during menopause is not known.

Identifying Depression in Women
Despite the increased prevalence of depression in diabetes and its potential for negatively influencing the medical illness and the individual's quality of life, it is recognized and treated in fewer than one-third of cases.⁷⁶ Impediments to recognition are varied and include failure of primary care physicians to inquire about affective symptoms, failure of patients to report psychological concerns for fear of appearing weak or somatic, and a resignation on the part of both care providers and receivers that depression is a secondary and natural consequence of diabetes. When depression is recognized, physicians and patients accordingly believe that improving the medical disease will result in improved depression symptoms and mood. Thus, management of diabetes frequently remains the sole focus of clinical care.

Historically, diagnosing depression in diabetes has been viewed as difficult and confusing because the two diseases share many of the same symptoms (e.g., fatigue, appetite, and sleep disturbances). The past decade of research has determined that, despite its complexity, accurate diagnosing of depression in diabetes is possible. With the use of self-report measures such as the BDI⁷⁷ and structured psychiatric interviews such as the National Institutes of Mental Health Diagnostic Interview Schedule (DIS),⁷⁸ confounding symptoms can be accurately evaluated and attributed to the correct disorder.⁷⁹

The BDI is a 21-item self-report measure that takes less than 10 minutes to complete. It has been shown to be reliable and valid in medical populations during various life stages.^59,80,81 The BDI is scored quickly by summing the ratings for each of the items. It is recommended that patients with depression symptoms lasting 2 weeks or longer and a BDI score > 16 undergo formal psychiatric assessment for depression.

Gender differences in the clinical expression of depressive symptoms on such measures as the BDI have been well scrutinized in the general population.⁸² Little research has considered such differences in the medically ill. The available data suggest that the reporting of depression symptoms (per the BDI) in women with diabetes appears similar to symptom reporting in men with diabetes and in women without diabetes.⁸³

The DIS uses criteria for diagnosing major depression according to the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV),⁸⁴ as outlined in Table 1. Sad mood or loss of interest or pleasure must be present for a period of 2 weeks and be accompanied by no less than four other criterion symptoms. These symptoms must also be associated with a significant decline or impairment in the individual's social or occupational functioning. Any symptom that is attributed to medication side effects or substance abuse cannot count toward a depression diagnosis. Finally, the DSM-IV depression criteria require that any symptom determined to be a result of a medical condition cannot be included in the diagnostic tally. This is particularly useful in diagnosing depression in diabetes, where symptoms of poorly controlled disease (e.g., fatigue, weight gain) might be misattributed to an emotional problem. The fact that the key diagnostic symptoms (i.e., sadness or loss of interest ) are not produced directly by diabetes and that symptoms attributed to medical causes are excluded in making the diagnosis increases the likelihood of accurate diagnosing of depression in diabetes.

Treating Depression
Successful treatment planning for women with diabetes and depression includes consideration of medical and psychological factors and gender-significant issues. Very little information is currently available in guiding the treatment of depression in diabetes, and even less is known about treating women in this group. People with medical illness have often been excluded from participating in clinical trials investigating new antidepressant medications for market approval. Not infrequently, women have also been excluded from such trials for a variety of reasons: to avoid the confounding variable of the menstrual cycle, to avoid issues of fetal liability, to keep study populations homogeneous, and because of cost concerns.⁸⁵

In 1977, Weissman and Klerman¹² published their seminal review of gender differences in depression, and ironically in the same year the Food and Drug Administration (FDA) issued guidelines that restricted participation in early phases of clinical drug trials by women of childbearing age.⁸⁶ Such restrictions were influenced by the thalidomide and diethylstilbestrol (DES) catastrophes of the previous decade. A broad interpretation of these guidelines (i.e., researchers and investigational review boards tended to extend the policy to all phases of drug trials) resulted in somatic treatments being used in populations (namely women) for whom efficacy was not established.⁸⁷

The criteria for enrolling women in clinical trials changed during the late 1980s and gave more balanced consideration to the importance of both protecting women from undue risks and including them in outcome trials. Nevertheless, the knowledge gap regarding potential gender-related differences in pharmacokinetics and pharmacodynamics of psychotropic agents still exists.⁸⁸

In light of the scarcity of gender- and disease-specific treatment data, the clinical management of depression in women with diabetes is based heavily on what is known to be efficacious in depressed, medically well patients. Antidepressant medications and psychotherapy, alone or in combination, are currently the most often employed treatments for depression management. In general, both treatment modalities are equally effective, and the initial treatment relieves depression in 50-60% of patients.⁸⁹ Treatment choice is often guided by such factors as presenting symptoms, medical insurance and financial resources, availability of services, provider's clinical expertise, and patient preference. Individual aspects of each treatment approach have advantages and disadvantages for women with diabetes.

The antidepressant medications most commonly used, along with their dosages and side effects, are shown in Table 2.^90-92 Controlled studies in general psychiatric populations have determined similar efficacy rates for all categories of antidepressant medications (i.e., tricyclics, heterocyclics, and the selective serotonin reuptake inhibitors [SSRIs]).⁸⁹ In determining which medication to prescribe, clinicians consider the configuration of depression symptoms, coexisting medical conditions, concomitant medications and the potential for drug interactions, and side effects of the antidepressant.

Tricyclic antidepressants (TCAs) have been used for more than 40 years and are particularly useful in restoring sleep. TCAs may also be beneficial for depressed women whose symptoms include reduced appetite, weight loss, and agitation. The TCAs have had a long history of successful use in treating diabetic neuropathic pain,⁹³ and they cost considerably less than the newer SSRIs. These advantages must be balanced against the potential of TCA-related weight gain, sedation, orthostatic hypotension, cardiac arrhythmia, and anticholinergic side effects.

We recently reported a placebo-controlled trial that established the efficacy of nortriptyline for the treatment of depression in diabetes.⁹⁴ Depression remission was achieved in ~60% of the nortriptyline-treated patients versus 35% in the placebo-treatment group. There were no gender differences in treatment response or side effects in this female-predominant (61%) group and no side effects (e.g., sedation, increased appetite) or expected adverse events (e.g., weight gain) during 8 weeks of treatment. Although treatment with nortriptyline improved depression, it had measurable hyperglycemic effects.

Path analysis was used to determine the independent effects of nortriptyline and depression improvement on glycemic control. The analysis showed that improvement in depression had a significant beneficial effect on glycemic control. A complete remission of depression was associated with a 0.8-1.2% improvement in glycated hemoglobin over the 8-week study period. The finding that improving mood can improve glycemic control has stimulated investigation into the newer antidepressant agents such as the SSRIs, for which animal evidence suggests serotonin may have a hypoglycemic effect.⁹⁵

In general, the SSRIs have fewer side effects than do the TCAs, and this more favorable profile makes them an attractive treatment option for depression in diabetes.^95,96 The SSRIs often have anorectic effects and fewer anticholinergic side effects than do the TCAs, and this suggests a usefulness for women with depression characterized by significant lethargy, hypersomnia, and increased appetite. With little risk for cardiovascular side effects, SSRIs are the treatment of choice for women with heart disease.⁹⁶

The use of SSRIs in diabetes must include consideration of the potential for gastrointestinal distress and sexual dysfunction. Sexual dysfunction is not as frequently reported with the use of the newer antidepressant nefazodone or of buproprion, a heterocyclic antidepressant. Use of the heterocyclic trazodone may be helpful in restoring sleep and mood in depressed women with diabetes and does not cause sexual dysfunction. Medications are often used in combination to achieve maximum efficacy and reduce problematic side effects (e.g., amitriptyline or trazodone may be added at bedtime to restore sleep in the fluoxetine-treated woman). Alleviating depression symptoms with psychotropic agents and minimizing medication side effects requires careful monitoring and good communication between patient and physician.

The use of psychotropic medication in treating depressed women who are pregnant or lactating is a complex issue that deserves additional scientific attention given the high prevalence of female depression during childbearing years. Little definitive data concerning embryotoxicity and/or the teratogenic effects of antidepressant medication are available to guide clinicians who must consider both maternal well-being and fetal safety.⁹⁷ This risk-benefit assessment is further hampered by the lack of information regarding the morbidity and mortality of untreated depression in pregnancy. In addition, the FDA has not approved any psychotropic medications for use during pregnancy. It is clear that research in this area is sorely needed.

One study of antidepressant use during pregnancy was recently reported.⁹⁸ Eighty children of mothers who received TCAs during pregnancy and 55 children of mothers who received the SSRI fluoxetine during pregnancy were compared to 84 children whose mothers had not been exposed to antidepressants during pregnancy. Global IQ scores and language development, as well as the temperament, mood, arousability, activity level, distractibility, and behavioral problems of the children were assessed between 16 and 86 months of age. There were no significant differences in the measured variables between the three groups of children. The authors concluded that in utero exposure to either TCAs or fluoxetine does not adversely affect global IQ, language development, or behavioral development in preschool children.

Pharmacotherapy for depression treatment in some women may be medically contraindicated, poorly tolerated, or ineffective. Additionally, some women may personally object to taking medication for depression. Psychotherapy is a nonpharmacological treatment option that goes beyond supportive counseling and applies a proven set of techniques for removing depression symptoms and restoring functioning.

Cognitive-behavioral therapy (CBT) and interpersonal therapy (IPT) are proven effective treatments in medically well patients.^99,100 CBT is based on the premise that distorted thought processes and physical inactivity cause and maintain depressed mood. Depression is removed though a systematic process of identifying and changing erroneous thinking patterns and modifying behavior. IPT is based on the premise that depression occurs in a psychosocial and interpersonal context, regardless of biological vulnerability or personality traits.⁸⁹ Therapy addresses interpersonal difficulties such as role disputes and transitions, social isolation, and grief reactions.

The one available study examining the efficacy of psychotherapy for depression treatment in diabetes compared CBT plus intensive behavioral diabetes management to intensive behavioral management alone.¹⁰¹ Depression improvement was significantly greater in patients treated with cognitive therapy, both in terms of reduction in depression symptoms per the BDI (18.9 vs. 6.5, P < 0.001) and in the percentage of patients achieving depression remission (83.3% vs. 27.3%, P < 0.0001). There were no gender differences in treatment response in this group of 51 adults (29 females).

Psychotherapy has a distinct advantage in that there are no known medical contraindications or adverse physical side effects that might limit its use. For women of childbearing age who are pregnant, lactating, or purposely pursuing conception, psychotherapy provides a greater measure of safety. Psychotherapy is often more successful in women who prefer it to medication, especially when commitment and motivation to change are strong.

These advantages should be weighed against the facts that psychotherapy is costly in terms of time and money and is not as readily available as antidepressant medication. The physical mobility or mental acuity of the depressed woman may limit treatment efficacy in psychotherapy. For the small percentage of women who are suicidal or have severe depressions, psychotherapy should be used whenever possible in combination with antidepressant medication.

Conclusion
In psychiatry, there is growing awareness of the recurrent character of major depression. Even successful treatment does not confer lasting euthymia, and episodic recurrences are the norm and not the exception.⁹⁰ Similarly, depression in diabetes is a recurring condition, and patients have an average of one episode annually.³⁶ Recurrent depression is important because each new episode carries an additional risk for suicide. Women with diabetes and depression are at increased risk for suicide because of their depression; the presence of diabetes does not independently alter this risk.¹⁵

Recognizing depression in women with diabetes is an integral part of comprehensive clinical care. Proper treatment can produce dramatic improvements in mood and quality of life and thus may result in improved glycemic control.

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Linda S. Griffith, MSW, LCSW, and Patrick J. Lustman, PhD, are faculty members at Washington University School of Medicine in St. Louis, Mo. Ms. Griffith is an instructor of social work in the Department of Psychiatry and a lecturer at the George Warren Brown School of Social Work at Washington University. Dr. Lustman is an associate professor of medical psychology in the Department of Psychiatry and a counseling psychologist at the Department of Veterans Affairs Medical Center in St. Louis.

Acknowledgment: This work was supported by grant RO1 DK 36452 from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and by a Clinical Research Grant from the American Diabetes Association.

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