In view of the high rates of both depression and eating disorders and their medical consequences in girls and women with diabetes, regular screening for these problems should be incorporated into their primary medical care, beginning in the preteen years. Questions about persistent mood alterations, loss of interest in activities, lowering of motivation or energy level, or sleep problems, can reveal the presence of a mood disturbance. Enquiry about satisfaction with weight and shape, dieting, binge eating and weight-control behavior can uncover difficulties with body image and eating behavior. There are well-validated self-report screening measures for both depression and eating disorders that can be useful in the medical clinic setting. Scales commonly used to screen for depressive symptoms in this context include the Center for Epidemiologic Studies Depression Scale (122), the Beck Depression Inventory-II (123) and the PHQ-9 (124). Appropriate screening measures for eating disorders include the Eating Attitudes Test (125) and the modified Diagnostic Survey for Eating Disorders (DSED) (126), both of which have been used in individuals with diabetes. Diagnoses should be confirmed by clinical interview in those individuals whose scores on a self-report measure indicate the possibility of a clinically significant disturbance.
In women with diabetes, several warning signs may suggest the presence of either depression or an eating disorder. These include the following: overall deterioration in psychosocial functioning (including school attendance and performance, work functioning and interpersonal relationships); worsening in metabolic control; increasing neglect of diabetes management, including blood sugar monitoring, insulin titration and adherence to other medications; erratic clinic attendance; significant weight gain or weight loss; increased concern about meal planning and food composition; and somatic complaints, including low energy, fatigue, disrupted sleep and increased worries about physical health. In some cases, family members will raise concerns about depression or disturbed eating before the individual with diabetes does so. If worsening metabolic control is due to intentional insulin omission, the individual may appear surprisingly unconcerned, and may initially deny that she has engaged in this behavior. Such denial may allow the individual to avoid reactions of disappointment, criticism, fear, or anger from their family or their diabetes team. It may also help them to avoid the threat of weight gain often associated with improving metabolic control. Indeed, it is often challenging for family and care-givers to tolerate the knowledge that the individual with diabetes continues to engage in disturbed eating behavior, particularly insulin omission, with such dangerous health consequences. Although individuals with either depression or an eating disorder may be reluctant to seek treatment, defensiveness about or refusal of treatment has been more commonly described in association with eating disorders. Adopting a nonjudgmental stance and using motivation enhancement techniques to facilitate exploration of the benefits and dangers of an eating disorder and recovery is often more helpful than warnings or "scare tactics" to engage these individuals in treatment for their eating disorder. If an eating disorder is known or suspected to be present, early referral to a mental health professional with experience working with individuals with eating disorders is warranted.
Both antidepressant medication and some modalities of psychotherapy have proven useful in decreasing or eradicating binge eating and purging symptoms, in studies conducted in nondiabetic populations. There have been several positive randomized controlled trials of cognitive-behavioral therapy for bulimia nervosa and binge eating disorder (127). Cognitive-behavioral therapy is a time-limited psychotherapy, usually 16-20 1-hour sessions, which is intended to help the individual to better understand the links between distorted thought patterns, negative emotions, and maladaptive behavioral patterns. Through this intervention, patients learn and practice ways of challenging negative thoughts and altering their environment and behavior in order to stop engaging in eating disorder behavior. There is a strong focus in this intervention on normalizing eating patterns. This includes eating in a planned way and at regular intervals during the day, as well as incorporating a broad variety of foods into the meal plan, which serves to diminish food cravings and binge eating of "forbidden foods." In our clinical experience, having an explicit treatment contract (e.g., number of planned sessions, consultation with their endocrinologist, and use of urgent care services if necessary), with negotiated and concrete treatment goals (e.g., related to specific aspects of diabetes management, such as checking blood glucose regularly and taking insulin appropriately) is important. Interpersonal therapy is another time-limited (e.g., 16-20 1-hour sessions) psychotherapy in which the patient and her therapist choose a specific interpersonal area of current difficulty on which to focus throughout the therapy. The problem area is grouped into one of the four major themes (a) unresolved grief, (b) interpersonal role disputes, (c) role transitions, or (d) deficits in social relationships (128). The goal of therapy is to work toward resolving current difficulties in that interpersonal area by developing and practising skills in effective communication and conflict resolution, and by strengthening meaningful social relationships. Interestingly, in randomized controlled trials of interpersonal therapy, improvements in eating behavior occur even without overt focus on eating or body image (129). Those with more severe disturbances may require more intensive treatment, including either day hospitalization or inpatient hospitalization, to achieve full remission of bulimic symptoms. We have found that intensive treatment of more severe eating disorders associated with diabetes is most likely to achieve sustained optimization of blood sugar levels. There is a paucity of evidence for effective treatment of anorexia nervosa, although some of the most promising results have been obtained with family therapy for adolescents, with benefit sustained at 5-year follow-up (130). Treatment of anorexia nervosa generally focuses on medical stabilization, nutritional rehabilitation and weight gain into a healthy range, along with a variety of individual and family psychotherapeutic approaches (131), including motivation enhancement and cognitive-behavioral therapy.
Evidence-based treatment guidelines for the management of both depression and eating disorders have been published, including those from the American Psychiatric Association (131) and the Canadian Psychiatric Association (132). However, there is limited evidence regarding the effectiveness and efficacy of the various treatment modalities to support the application of these guidelines in special populations, such as women with diabetes. There are few treatment studies in this population; although a small, uncontrolled study of cognitive-behavioral therapy for an eating disorder in women with DM1 (133) suggested that treatment may be more difficult in women with DM1 and an eating disorder than in those without DM1. A small study of "integrated inpatient treatment" of individuals with DM1 and an eating disorder showed promising reductions in eating disorder symptoms (134) maintained at 3-year follow-up. However, validation of these results would require a study with a larger sample and with inclusion of a control group. Our group conducted the first randomized controlled treatment study for disturbed eating attitudes and behavior in individuals with diabetes (135). We found that a brief psychoeducational intervention offered to girls 12-19 years of age with DM1 was associated with reductions in dieting, body dissatisfaction, and preoccupation with thinness and eating, and that these improvements were maintained at 12-month follow-up. However, the intervention did not result in significant improvements in metabolic control or insulin omission for weight control.
There is some evidence for the effectiveness of the treatment of depression in association with diabetes. Antidepressant medication, cognitive-behavioral therapy and problem-solving therapy have been shown to improve depression outcomes in individuals with diabetes (136-139), as they have in general population studies (132). Those with depression and more severe medical complications may benefit most from collaborative care, which may better allow the multiple needs of these patients to be addressed (140). Collaborative care, including a stepped care approach delivered by specialized nurses, has also been shown to be associated with a reduction of healthcare costs in the context of an organized healthcare system (141). Lustman and colleagues (137) demonstrated in patients with DM2 that an intervention that included cognitive-behavioral therapy and diabetes education produced more than a 3-fold higher remission rate from depression, compared to a control condition. This treatment was associated with a significant improvement in metabolic control 6 months after the end of treatment. There is also some evidence that fluoxetine may help to improve metabolic control in patients with diabetes (138).
There are no published guidelines regarding choice of antidepressant therapy for individuals with DM1 or DM2. However, differences in metabolic side effects, including changes in weight, insulin sensitivity, and lipid profile, can guide medication choice to some extent. The selective serotonin reuptake inhibitors (SSRIs), the serotonin and norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine and duloxetine), mirtazapine, moclobemide, monoamine oxidase inhibitors, tricyclic agents and bupropion are all indicated for the treatment of depression (132). The SSRIs and SNRIs are also first-line agents for the treatment of anxiety disorders, and so these agents should likely be used in cases that involve both depression and an anxiety disorder (132).
Of the antidepressants currently in widespread clinical use, venlafaxine and duloxetine appear to be, on average, weight-neutral, while bupropion is often associated with no weight gain or a small amount of weight loss. SSRIs are weight-neutral or promote only small amounts of weight gain, with the exception of paroxetine, which appears to promote more weight gain than the other agents in this class. Mirtazapine, monoamine oxidase inhibitors and tricyclic agents are the most likely to promote weight gain, and so are not ideal first-line agents in individuals with diabetes (142, 143). Differential effects of various antidepressants on lipid profile have been little studied, but available findings to date suggest that those medications most strongly associated with weight gain (tricyclic agents, mirtazapine as well as paroxetine) are also associated with a less favorable lipid profile (144).
Individuals with diabetes should be counseled to be vigilant in monitoring their blood sugar levels when antidepressants are initiated or their dosage changed, as some of these medications affect glucose homeostasis (145). A synthesis of the available literature (146) indicated that SSRIs tend to increase insulin sensitivity and reduce hyperglycemia, so that individuals with DM1 overall require less insulin. Some tricyclic agents can decrease insulin sensitivity and thereby raise blood sugar levels and insulin requirements. SNRIs and bupropion do not usually affect glucose metabolism, while monoamine oxidase inhibitors are sometimes associated with hypoglycemia (146).
Antipsychotic agents are occasionally used in individuals with depression, either to augment a primary antidepressant's effectiveness or in the treatment of depression with psychotic features. Atypical antipsychotics (i.e., risperidone, olanzapine, clozapine, quetiapine, aripiprazole and ziprasidone) are now used more frequently than older antipsychotic medication. It has become clear that these medications can have significant negative effects on weight, lipid metabolism, and glucose homeo-stasis, contributing to the constellation of cardiac risk factors that constitutes metabolic syndrome (147). Of these medications, aripiprazole and ziprasidone appear to be least likely to promote weight gain, and, to date, have not been found to be associated with an increased risk of worsening glucose homeostasis, although there have been occasional case reports of sudden onset diabetic ketoacidosis or worsening of the lipid profile (147). Both risperidone and quetiapine have an intermediate propen sity to promote weight gain, with some potential to precipitate new-onset diabetes or to worsen lipid profiles. Olanzapine and clozapine are associated with the highest weight gain, on average in the range of 4-10 kg (148), and appear to confer the highest risk of worsening lipid profiles and precipitating diabetes in nondiabetic individuals. There are clear clinical guidelines for clinicians to adequately monitor these metabolic risk factors in individuals taking these medications. This involves assessing weight, waist circumference, blood pressure, fasting glucose and fasting lipid profile at baseline and at regular intervals during treatment (147). Given these findings, when an antipsychotic medication is warranted in an individual with DM1, first-line choices should include the medications less likely to contribute to a metabolic syndrome namely, quetiapine, risperidone, aripiprazole or ziprasidone, and the individual's cardiac risk factors should be closely monitored.
Antidepressant medication, cognitive-behavioral or interpersonal therapy, or a combination of these modalities, all appear to be appropriate treatment approaches in women with diabetes and depression. However, there is an urgent need to evaluate and tailor interventions to prevent and treat depression and eating disorders in girls and women with diabetes because of the adverse effects of these conditions on metabolic control and on diabetes-related health outcomes. Further, close collaboration between diabetes and mental healthcare providers is crucial in helping individuals with diabetes and depression and/ or an eating disorder to integrate both the psychological and behavioral changes needed to improve overall well-being as well as diabetes management.
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