Despite the lack of a definitive cause-effect model to explain the significant relationship between depression and diabetes, reports on the effects of treatment for depression have shown promise on outcomes for both diseases. Treatment for depression in patients with diabetes has demonstrated benefits on glycemic control as well as mood and even insulin sensitivity (32, 77). There is evidence that both antidepressant medication and psychotherapeu-tic treatments can improve both depressive and diabetic outcomes in patients with both illnesses. Recently, collaborative care models in primary care using case management interventions for the treatment of depression have shown promise in improving outcomes in patients with diabetes (78, 79).
Antidepressants, as a group, are equally effective in the treatment of depression. For a given individual, however, one medication will be more effective and/or tolerable than another. In current practice, the choice of medication is primarily based on side effects one wants to avoid (such as urinary retention or confusion secondary to anticholinergic effects in patients with benign prostatic hypertrophy or cognitive symptoms) or side effects that are desirable (such as sedation in patients with significant reports of insomnia). Additional considerations in diabetic patients include avoiding antidepressant medications which can increase weight gain, or which dys-regulate glucose metabolism, and whether one wants to additionally target diabetic neuropathic pain. This has been recently reviewed (80). Most current evidence supports the use of serotonin-reuptake inhibitors to treat depression (81).
A limited open-label study of sertraline indicated that patients with diabetes (HgbAlc > 8) and depressive symptoms showed decreases in depressive symptoms and a statistically significant decrease in HgbAlc from an average 9.2 to 8.8 (82). Several studies of fluoxetine in patients with diabetes and depression have indicated reductions in weight and in HbAlc to near-normal levels (<7) (83), and significant reductions in depressive symptoms in diabetic patients have occurred in addition to improvement in glycemic control (23, 84). A double-blind placebo-controlled study of nor-triptyline showed considerable effect on depressive symptomatology while at the same time indicating significant improvement in glucose control in patients with diabetes and depression (85). In a recent open-label treatment trial, depressed, diabetic patients treated with bupropion had significantly reduced depressive symptomatology as well as improved glycemic control which was unrelated to improvements in self-care or weight loss (27).
Rubin and colleagues (2008) (1) recently reported that among participants in a diabetes prevention program, use of antidepressants significantly increased the risk of subsequently developing diabetes. The authors postulate that use of antidepressants could be a marker for the actual cause of increased diabetes risk, namely, severe, chronic depression (1). A meta-analysis conducted in Canada indicated that persons with depression and treated with antidepressants (both tricyclics and SSRIs) had an increased risk of developing type II diabetes, but persons treated with SSRIs only had a significantly reduced risk of developing diabetes (28).
More double-blind, controlled studies of antidepressant treatments need to be conducted on larger populations of patients with diabetes and depression in order to obtain an evidence-base with which to establish treatment guidelines for use. Currently, the evidence suggests that treatment of depression improves both depressive symptoms as well as diabetes symptoms at clinically, if not statistically, significant levels.
These agents act by increasing serotonergic functioning, which in turn increases insulin sensitivity and reduces plasma glucose. Most studies have investigated fluoxetine (doses up to 60mg/day) and sertraline. Patients' depressive symptoms responded, and they experienced weight loss, decreased fasting plasma glucose, and lowered HgbA1c levels. Cat-echolamines, on the other hand, are associated with insulin resistance and hyperglycemia. Depressed diabetic patients who were administered nor-triptyline, a norepinephrine-reuptake inhibitor, had poorer glycemic control. Other tricyclic antidepressants can increase food cravings, increase weight, and raise serum glucose levels. Because both catecholamines and serotonin have been implicated in diabetic neuropathy, dual-action antidepressants may be the preferred agents, particularly in non-depressed subjects.
One important finding is that treatment of depression seems to be able to halt atrophy of the hippocampus and may even lead to stimulation of neurogenesis of hippocampal cells (86). Similarly, antidepressants directly increase the expression and function of corticosteroid receptors in the brain, enhancing the negative feedback loop and reducing pathological HPA-axis hyperactivity.
The notion of targeting the HPA axis directly to treat depression in diabetes is intriguing. Three major pathways are currently under investigation and include administration of (1) CRH antagonists; (2) glucocorticoid receptor (GR) antagonists; (3) steroid-synthesis inhibitors.
CRH antagonists: CRH acts through CRH1 receptors to produce a number of anxiety- and depression-like symptoms, which have led to the consideration of CRH1 receptors as potential drug targets. Several small non-peptide molecules that are able to pass the blood-brain barrier have entered clinical development. One agent, NBI-30775/R121919, was reported to have a clinical profile comparable to paroxetine (87). This compound was administered to 24 patients with a major depressive episode primarily for a safety and tolerability study. The drug was found to be tolerated by patients and did not interfere with cortisol secretion at baseline or following an exogenous CRH challenge (88). Significant reductions in both patient- and clinician-rated depression and anxiety scores were found. Of interest is that mood symptoms worsened following drug discontinuation. CRH1 receptor antagonism for the treatment of depression has demonstrated potential therapeutic value and merits further examination.
GR antagonists: One drug in this group has been studied, although with only small samples and case reports. The medication, mifepristone, is a powerful progesterone and glucocorticoid receptor antagonist, also known as RU-486. One case of Cushing's disease was successfully treated, and an incidental finding was the patient's suicidal depression resolved (89). A small brief, double-blind, placebo-controlled cross-over study demonstrated substantial improvements in depression symptoms when mifepristone was administered (90). Because of controversies associated with the abortifa-cient effects of this drug, however, its clinical utility for the treatment of depression is limited.
Steroid-synthesis inhibitors: In the 1970s, depressed Cushing's patients were treated with metyrapone, which blocks the synthesis of cortisol and causes a compensatory increase in ACTH secretion. A subsequent case report using metyrapone and two small double-blind studies on ketoconazole (which also blocks cortisol synthesis) in non-Cushing's depressed patients suggested that steroid-synthesis inhibition might be an effective treatment strategy. Recently, a double-blind trial investigated the use of metyrapone for augmentation treatment in depression (91). Metyrapone induced increases of plasma ACTH and the cortisol precursor 11-deoxycortisol and the neu-rosteroid DHEA (which itself has anxiolytic and antidepressant properties). Added to selective serotonin inhibitor antidepressants, more patients in the metyrapone-treated group responded and showed an earlier onset of action, in some cases beginning in the first week. Metyrapone-enhanced antide-pressant efficacy occurred independently of basal morning plasma cortisol concentrations. The mechanism of action of this effect remains unknown, but metyrapone decreases cortisol levels in both the plasma as well as the brain. Inhibition of cortisol synthesis in the hippocampus leads to up-regulation of mineralocorticoid receptors (MR), a finding demonstrated for many antidepressant medications (92). Increased MR in the hippocampus leads to decreased CRH mRNA in the hypothalamus and resetting of the HPA axis. Additionally, metyrapone increases cell numbers in the dentate gyrus of the hippocampus of mice, possibly mediated through the production of DHEA, facilitating hippocampal feedback restoration to the HPA axis.
Pharmacogenomics: In the not too distant future, we may be able to select antidepressants based on pharmacogenomic profiles. For example, the most studied polymorphism in the pharmacogenomics of antidepressant response is 5-HTTLPR, located in a repeat region of the promoter of the serotonin transporter gene. In Caucasian and Chinese subjects, most studies on the effect of 5-HTTLPR on response to selective serotonin-reuptake inhibitors (SSRIs) in unipolar depressed patients have shown significant associations of the "long" variant (L allele) of the polymorphism with better treatment outcome. Associations with response to antidepressants other than SSRIs have been mostly negative. Knowing that an individual has the L allele may favor the initiation of an SSRI. Ongoing pharmacogenomic projects are evaluating the idea that genetic variations in pharmacokinetic targets may be used to develop drug recommendations that aim at decreasing adverse drug reactions (ADRs) and at increasing remission of depressive symptoms by antidepressant treatment. It is possible that genetic screening for metabolizing enzymes could help improve treatment outcome and lower health care costs if treatment assignment avoids drugs that would be out of the therapeutic window.
Aversive experiences both in utero and the neonatal period in rodents resulted in elevated HPA responses to subsequent stress (93). This is similar to the long-lasting effects on the stress response in humans who experienced early traumatic events. Interestingly, nurturing experiences can up-regulate glucocorticoid receptors in the hippocampus, thus terminating the stress response (94). This suggests a possible biological mechanism of action for the psychotherapeutic experience.
Current clinical research has also indicated benefits from psychological therapies. The introduction or inclusion of various types of behavioral interventions into the management of diabetes has been demonstrated to improve metabolic control as well as quality of life. To date, however, there has been little empirical support for the successful use of non-pharmacological therapies (psychotherapies, relaxation) for the management of depression specifically in persons with diabetes. Non-pharmacologic interventions are particularly useful in the initial management of patients who may have mild depressive symptoms and are concerned about taking medications or in older adults who may take multiple medications for co-occurring illnesses.
Other forms of psychotherapy, specifically cognitive-behavioral psychotherapy have been shown useful in the treatment of depression in persons with diabetes. Cognitive-behavioral therapy (CBT) is characterized by implementing behavioral strategies to engage patients in social and physical activities as well as employing problem-solving and cognitive methods to identify and replace maladaptive thought patterns with more adaptive and useful thoughts. Several studies have demonstrated that individuals who received CBT have reduced cortisol response which is a measure of HPA-axis activity (95). Further, Lustman and colleagues (1998) (96) performed a randomized, controlled investigation of the use of cognitive-behavioral therapy for depression in patients with type II diabetes. CBT was found to be an effective treatment for depression and also led to a significant decrease in HgbAlc levels compared to the control group.
Collaborative care models have used case management, in conjunction with problem-solving therapy, for the treatment of depression in diabetic populations (9). Systematic, between-visit patient monitoring appears to be essential for improving outcomes in patients with depression and diabetes, as these patients are more likely to require regular monitoring and follow up, and collaborative care models adhere to systematic monitoring. Several of these models, which integrate mental health and primary care, have specifically targeted persons with diabetes and depression (IMPACT, pathways) (97-100). Both of these models report significantly improved depressive outcomes in patients with diabetes and minimal improvement in hemoglobin A1C levels (98, 99). Another collaborative care model, PROSPECT, which was initiated as a suicide prevention program in primary care, recently reported that persons with diabetes and depression who participated in the collaborative care intervention were significantly less likely to die than depressed diabetic patients who did not participate in the intervention (100).
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