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Psychiatric Disorders Presenting in the Elderly With Type 2 Diabetes Mellitus
CRITICAL REVIEW ARTICLE
Psychiatric Disorders Presenting in the Elderly With Type 2 Diabetes Mellitus Kannayiram Alagiakrishnan, M.D., M.P.H., F.R.C.P.(C)., Anne Sclater, M.D., F.R.C.P.(C), F.A.C.P.
Diabetes mellitus (DM) is one of the major health problems of the elderly. Developed countries face an epidemic of Type 2 DM. Healthcare providers should be aware of the frequent coexistence of psychiatric conditions in elderly patients with DM. Dementia, depression, and anxiety are commonly seen in addition to other psychiatric conditions. The relationship between diabetes and psychiatric disorders is complex. Evidence suggests that common mechanisms may play a role in both the pathogenesis of DM and several psychiatric illnesses. Possible mechanisms, diagnosis, and management options are reviewed and discussed. Common mechanisms of psychiatric illness involving brain-derived neurotrophic factor, insulin resistance, and inflammatory cytokines are throwing new light that these psychiatric illnesses could be due to the complications of Type 2 DM. Periodic screening should be done in DM patients to identify the psychiatric complications. Healthcare professionals should routinely screen for psychiatric complications of DM in addition to the microvascular and macrovascular complications of DM. It is important to screen all diabetic elderly patients for mental health issues as these may interfere with self-care and the overall management of DM. Recognition and management of psychiatric disorders will help to optimize the diabetes management. Good diabetes control can also reduce the mental health complications in these patients. (Am J Geriatr Psychiatry 2012; 20:645–652) Key Words: Dementia, depression, diabetes mellitus, elderly, psychiatric disorders
D
iabetes Mellitus (DM) is a common metabolic disorder in the elderly. Both the prevalence and incidence of DM increase with aging. It is seen in 10%–25% of the elderly population.1 DM is a metabolic vascular risk factor associated with atherosclerotic disease. The resultant microvascular
and macrovascular complications can lead to serious morbidity and mortality and increased costs of care. Psychiatric conditions are seen frequently in people with DM.2 This article highlights the common psychiatric conditions that can coexist or be seen as a complication due to DM. It also reviews the mechanisms
Received October 3, 2010; revised May 12, 2011; accepted June 6, 2011. From the Division of Geriatric Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (KA); and Division of Geriatric Medicine, Department of Medicine, Memorial University, St. John’s, Newfoundland, Canada (AS). Send correspondence and reprint requests to Kannayiram Alagiakrishnan, M.D., M.P.H., F.R.C.P.(C)., B139N Clinical Sciences Building, 8440-112 Street, University of Alberta, Edmonton, Alberta, Canada T6G 2G3. e-mail: [email protected] Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.AJGPonline.org). C 2012 American Association for Geriatric Psychiatry DOI: 10.1097/JGP.0b013e31823038db
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Psychiatric Disorders in Aging Adults With Type 2 DM and common pathogenesis of the two conditions and recommends an approach to the diagnosis and management of these mental health conditions.
REVIEW CRITERIA A peer reviewed literature search was conducted using MEDLINE, PubMed, Scopus, and PsycINFO databases from 1990 to 2010. The following keywords were used: diabetes, elderly, psychiatric disorders, cognitive impairment, dementia, depression, delirium, eating disorders, self-neglect, schizophrenia, and anxiety. Articles were limited to the English language literature.
COMMON PSYCHIATRIC COMPLICATIONS IN DIABETES MELLITUS The common psychiatric complications seen in diabetes are dementia, depression, anxiety disorders, delirium, and eating disorders (disinhibited or binge eating). Some of the symptoms of diabetes may overlap with the symptoms of psychiatric disorders and thus cause problems in the correct diagnosis of certain clinical situations. The symptoms of weight loss and lethargy can occur with both diabetes and depression; whereas, symptoms such as sweating, tremor, and palpitations can occur with both hypoglycemia and anxiety. The clues for suspecting psychiatric complication or illness in diabetic patients are shown in Table 1.
DIABETES AND COGNITIVE IMPAIRMENT/DEMENTIA Mild hyperglycemia, impaired glucose tolerance, and diabetes in the elderly have been associated with accelerated cognitive aging, the development of mild
TABLE 1. Clues for Psychiatric Illness in Diabetic Patients 1. Decreased self-care 2. Missed appointments 3. Decreased satisfaction with care 4. Poor adherence to medication management 5. Increased frequency of hospitalization 6. Behavioral problems
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cognitive impairment (MCI), as well as the progression of MCI to dementia. The risk of cognitive impairment is doubled in women with impaired fasting glucose and diabetes.3 A recent study has also shown that high blood glucose may affect other cognitive functions in addition to memory.4 DM is associated with deficits in multiple domains of cognition including learning, speed of information processing, executive function, and complex motor skills.5 The association between Type 2 DM and cognitive impairment/dementia is supported by many epidemiological (Table 2)6–11 and some imaging studies. However, some studies did not show an association. The study from Honolulu found no association between midlife diabetes and Alzheimer disease (AD) at later age (RR = 0.98, 95% CI: 0.48–1.99), and VD, RR = 1.48, 95% CI: 0.79– 2.78) in Japanese Americans.12 Similarly Kungsholmen study from Sweden, showed an association with VD, hazard ratio (HR): 2.6, 95% CI: 1.2–6.1, but no association with AD, HR: 1.3, 95% CI: 0.9–2.15.13 A systematic review by Biessels et al.14 showed the overall incidence of dementia, both Alzheimer disease and vascular was increased by 50%–100%, with more risk for vascular dementia.14 Another study points out, if patients had diabetes and comorbid depression the risk of developing dementia was higher (HR: 2.69, 95% CI: 1.77–4.07) when compared with patients with diabetes alone.15 Diabetes may also accelerate the conversion of MCI to dementia (HR: 2.9, 95% CI: 1.1–7.3).16 A systematic review of brain imaging studies (CT, MRI, SPECT, PET) in diabetic patients, showed a 30% increased risk for infarcts in diabetic patients relative to controls, in population based study cohorts, odds ratio (OR): 1.3 (95% CI: 1.1–1.6) and 120% increased risk, OR: 2.2 (95% CI: 1.9–2.5) in cohorts of patients with vascular disease. In the early stages of AD, MRI findings showed atrophy of the median temporal lobe predominantly, whereas in diabetic patients having AD, atrophy seems to be generalized.17
MECHANISMS OF DM IN CAUSING MCI TO DEMENTIA Several biochemical and pathogenetic mechanisms are suggested in different studies, but the precise mechanism is still unclear.18 Recurrent hypoglycemic
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Alagiakrishnan and Sclater
TABLE 2. Selected Studies Showing Positive Association of DM With MCI/Dementia Studies
Age Group
Type of Study/Follow-up
MCI/Dementia Risk
Study of osteoporotic fractures research group U.S.A.6 Washington–Heights Inwood Columbia Aging Project7 Shanghai Community Brain Health Initiative8 Rotterdam Study9
65 years or older
Longitudinal study (5–6 years)
Cognitive decline RR = 1.63, 95% CI: 1.20–2.23
65 years or older
Longitudinal study (4 years)
Mild cognitive impairment RR = 1.4, 95% CI: 1.1–1.8
Mean age 74 years
Cross-sectional study
Dementia RR = 1.83, 95% CI: 1.09–3.08.
Mean age 73 years
Longitudinal study (2.1 years)
Honolulu—Asia Aging Study10
Mean age 77 years
Longitudinal study (3 years)
Cardiovascular Health Study11
Mean age 74 years
Longitudinal study (5.4 years)
Alzheimer dementia RR = 1.90, 95% CI: 1.2–3.1 Alzheimer dementia RR = 1.8, 95% CI: 1.1–2.9 Vascular dementia RR = 2.3, 95% CI: 1.1–5.0 DM alone-mixed Alzheimer dementia RR = 1.75, 95% CI: 1.00–3.04. DM with APOE—Alzheimer dementia RR = 4.99, 95% CI: 2.70–9.20.
attacks are one of the causes for cognitive impairment in the elderly. Longitudinal cohort study demonstrated the attributable risk of dementia when compared in individuals with and without a history of hypoglycemia was 2.39% per year, 95% CI: 1.72%– 3.01%.19 Advanced glycosylation products due to chronic hyperglycemia cause neuronal damage and have been found on specific cell-surface receptors for beta amyloid.20 Longitudinal studies have demonstrated that the risk of incident AD was higher in patients with hyperinsulinemia due to insulin resistance. Peripheral hyperinsulinemia may inhibit brain insulin production which, in turn, results in impaired amyloid clearance and a higher risk of AD.21,22 Reduced level of insulin, insulin-like growth factor 1 polypeptide gene and receptors are seen in advanced AD. Glucose utilization and energy metabolism in the brain are regulated by insulin and insulin-like growth factor, and studies had shown that cognitive impairment may be improved by insulin administration. Choline acetyl transferase expression increases with insulin or insulin-like growth factor 1 stimulation.23 There is also a direct mechanism linking insulin resistance and AD. Insulin resistance was related to decrease in glucose uptake in regions known to be predictive of AD.24 Microvascular changes also leading to chronic diffuse ischemia results in atrophy and lacunar infarcts in diabetes patients.25 In elderly men with metabolic syndrome, whom had evidence of inflammation, cognitive perfor-
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mance declined significantly over a 5-year period, indicating the role of inflammatory cytokines in cognitive decline.26 Brain-derived neurotrophic factor (BDNF) is released from the human brain and is negatively regulated by high plasma glucose levels. BDNF plays a regulatory role in neuronal differentiation and synaptic plasticity. A low level of BDNF was seen in patients with impaired glucose tolerance and DM.27 In Type 2 DM subjects, decreased serum BDNF was seen and was also associated with cognitive decline.28
CLINICAL FEATURES AND MANAGEMENT Decreased cognitive function in diabetic elderly has been associated with poor adherence to diabetic self-care activities, need for increased personal care services and increased frequency of hospitalization. Routine screening of cognition in older subjects with diabetes is recommended.29 Common screening test for dementia in clinical practice include the MMSE.30 The diagnosis of dementia is made using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia.31 Two small intervention studies have suggested that improved glycemic management may improve cognitive function among patients with DM.32,33 Beeri et al.34 showed that combination therapy of insulin and oral diabetic agents is associated with a substantially lower neuritic plaque density in several areas of the AD brain.34 Another study by Plastino et al35 suggested a significant slowing
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Psychiatric Disorders in Aging Adults With Type 2 DM
TABLE 3. Possible Common Mechanisms of Some Psychiatric Disorders in DM Dementia Recurrent hypoglycemia Ischemic cerebrovascular disease Advanced glycosylation products Inflammatory cytokines Hyperinsulinemia Insulin resistance BDNF Depression BDNF Higher cortisol levels HPA dysregulation Inflammatory cytokines Insulin resistance Anxiety Stress hormones Disruption of self-care mechanisms Insulin resistance BDNF HPA dysregulation Inflammatory cytokines Delirium Neurotransmitter defects Higher cortisol levels Impairment of cerebral oxidative mechanisms Inflammatory cytokines Disruption in blood-brain barrier HPA dysregulation
in cognitive decline after 12 months in the group treated with insulin and oral antidiabetic medication. Intranasal insulin has been shown to improve memory and cognitive abilities in early AD patients.36 Decreasing peripheral hyperinsulinemia and increasing brain insulin levels may have a beneficial effect on AD. Insulin promotes the cell membrane expression of NMDA receptors, which in turn can increase neuronal calcium influx, presumably by activating calcium dependent enzymes and strengthening neuronal synaptic association37 and increasing CSF norepinephrine.38 Rosiglitazone, a TZD, preserved memory function in patients with amnestic MCI and early AD on a 6 months trial.39 Another small randomized double-blind trial showed improvement in cognitive function in mild to moderate AD patients who were not carriers of the APOE–e4 allele.40 However, a recent Phase III trial in mild-to-moderate AD failed to show a benefit.41 Rosiglitazone decreases insulin resistance and decreases peripheral insulin levels and shows beneficial effect in AD. Also, intranasal insulin delivered with direct access to the brain without accessing the periphery has a similar effect.42 Interventions addressing cerebral
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glucose, insulin and energy metabolism may evolve as future candidates for treatment of dementia in diabetes patients, independent of their antidiabetic effect. In addition preventing hypoglycemia, which can contribute to cognitive impairment, is important. At this point, there is no clear-cut evidence that diabetes treatment will reduce AD, but more evidence is emerging that diabetes treatment will improve cognitive function. Therefore, the most practical approach to prevent cognitive decline is to optimize glycemic control, prevent hypoglycemic episodes, and control other vascular risk factors. In established cases of dementia, treatment with cholinesterase inhibitors or NMDA receptors should be considered. Diabetes and Depression Depression is perceived as a mental health problem triggered by social stressors, but biological factors such as diabetes can also lead to depression. Patients with DM are 2 to 4 times more likely to be diagnosed with a major depressive disorder.43 In the Health, Aging, and Body Composition study, elderly diabetic subjects had an increased incidence of depressive mood symptoms when compared with those without diabetes by 30%, HR 1.31 (95% CI: 1.07– 1.61).44 Diabetic patients with depression have greater functional disability than their nondiabetic counterparts. The adjusted OR for functional disability was 7.2 for subjects with diabetes and depression; whereas, OR was 2.4 for subjects with diabetes alone and 3.0 for subjects who have major depression alone.45 A study of Medicare patients showed that total annual healthcare costs was 4.5 times more in patients with comorbid depression and diabetes, when compared with diabetic patients without depression.46
MECHANISMS Lowered hippocampal volume is seen in depressed patients.47 Hippocampal serotonin 5–HT2A receptors are upregulated during depression and this can cause decreased BDNF.48 Decreased BDNF, a regulator of dopamine pathway, can play a role in depression. Stress, activation of the hypothalamic-pituitaryadrenal axis and inflammatory mechanisms have also
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Alagiakrishnan and Sclater been postulated in the development of depression in diabetes.49 A low level of BDNF was seen in patients with impaired glucose tolerance and DM. Decreased BDNF was also seen in patients with dementia and depression. This explains a possible common pathogenic mechanism of DM causing both dementia and depression.27 Diabetic and metabolic syndrome patients have high levels of inflammatory cytokines-like TNF-α and interleukin-6. Patients with major depression also have high levels of inflammatory cytokines.50 Inflammatory cytokines cause increased cortisol levels with stimulation of the hypothalamic-pituitary-axis.51 The insulin resistance of metabolic syndrome may play a role in depression. Insulin resistance enhances cortisol neurotoxicity in the hippocampus and may affect both mood and cognition. Insulin resistance in the brain contributes to the causation and progression of depression disorders and AD.52
MANAGEMENT Some of the symptoms of diabetes including weight loss, lethargy, and loss of libido overlap with the symptoms of depression itself. In depressed patients with diabetes due to amotivation, fatigue, anhedonia, lack of concentration, and hopelessness, diabetes self-management may become a difficult task. The screening test for depression is the Geriatric Depression Scale. It has 15 yes/no items and a score above 7 suggests depression.53 The diagnosis is usually done in clinical practice using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for depression.31 Nonpharmacological: Walking and improving physical activity have been shown to improve outcomes in patients with diabetes and depression.54 Treatment of depression improves the functional state and state of low well-being of diabetic patients, and can result in an increased number of exercise days.55 A recent systematic review showed that with nonpharmacological treatment, the improvement of glycemic control did not parallel the improvement in depression.56 Pharmacological: There are scarce clinical trials on treatment of depression in diabetic elderly. The PROSPECT trial, which is a randomized controlled trial of a depression treatment program for older adults based in primary care, showed elderly de-
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pressed diabetic patients who had depression care management, including treatment with the antidepressant Citalopram, were less likely to die over 5 years, when compared with depressed diabetic elderly in usual care practices (Adjusted HR: 0.49 (95% CI: 0.24–0.98).57 A double-blind randomized placebo controlled trial with Paroxetine therapy in mildly depressed Type 2 diabetic patients showed a significant benefit at 3 months, whereas at 6 months there was no significant benefit.58 An Austrian, observational, open label study, which included elderly patients, showed that Milnacipran therapy over a period of 6 months results in a significant improvement in both depressive symptoms and metabolic parameters.59 However, a post hoc secondary analysis of a study using Sertraline as maintenance therapy did not delay recurrence of major depressive disorder in elderly diabetes when compared with younger diabetic subjects.60 Collaborative care (with antidepressants and/or psychotherapy) for depression in diabetic elderly patients, over a period of 12 months, showed improvement in mood and function, but had no significant effect on glycemic control.55 Depression is associated with insulin resistance. Few depression remission studies with Mirtazapine, Venlafaxine, Amitriptyline, and Paroxetine improved insulin sensitivity with depression remission in nondiabetic patients.61,62 Prodiabetic effect of antidepressants has been shown in the study by Anderson et al.63 Long-term use of tricyclic antidepressants in moderate to high dose has been shown to increase the risk of diabetes by 77% and selective serotonin reuptake inhibitors by 106%. But in this study, remission of depression has not been taken into account.63 In a randomized controlled trial on diabetic patients, depression recovery and sustained remission with Sertraline was associated with improvement in Glycemic control.64,65 Overall, the studies point out that depression remission rather than depression treatment per se is associated with improved insulin resistance. Taken together, the successful treatment of depression with remission improves insulin resistance and glucose tolerance; whereas, antidepressant treatment without remission may further increase diabetes risk. Depression in diabetic patients may result in poor compliance with home blood glucose monitoring adherence, health providers’ follow-up, as well as poor adherence to dietary instructions and medications
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Psychiatric Disorders in Aging Adults With Type 2 DM management. So, healthcare providers should monitor for depression and, when found, should be effectively managed in these patients. Diabetes and Anxiety Anxiety is also a common problem seen in DM patients. The few studies that have included elderly patients also showed that anxiety was seen more in Type 2 DM patients. In a longitudinal study, Type 2 diabetic patients had higher rates of anxiety disorders over time when compared with community nondiabetic patients (123% for generalized anxiety disorder and 85% for panic disorder).66 In insulin treated patients, injection related anxiety or needle phobia is seen and it may interfere with the management of DM. Needle phobia causes some people to avoid needed medical care.67 Anxiety is associated with decreased function and quality of life. Kohen et al68 showed that anxiety, in addition to depression, was significantly associated with poor self-reported quality of life in patients with Type 2 diabetes. Mechanisms: Anxiety disorders can occur by an interaction of biopsychosocial factors. The major neurotransmitters, which can cause anxiety, include norepinephrine, serotonin, gamma-amino butyric acid, and neuropeptides. Anxiety in diabetes could be due to disturbances in the cerebral cortex, especially the limbic system.69 Anxiety may also increase blood glucose levels through the effect of stress hormones, such as catecholamines and cortisol and by the disruption of self-care behaviors. Anxiety leads to sympathetic hyperactivation, which can also contribute to insulin resistance.70 Low BDNF may contribute to anxiety like behaviors.71 Depression and anxiety disorders are related to stress and this can cause stress-induced inflammation, which can result in cell damage.72
CLINICAL FEATURES AND MANAGEMENT Patients may ignore important hypoglycemic symptoms or may misinterpret anxiety symptoms as hypoglycemic symptoms. Anxiety and depression can also coexist in the same patient. The diagnostic instrument one can use is the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for anxiety disorder.31
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A study on insulin treatment in diabetes showed improved mental health and social functioning scores using the SF-36 Quality-of-Life instrument and well being in elderly Type 2 patients.73 This study also showed that oral administration of an anxiolytic, Fludiazepam 0.25 mg, three times daily orally for 12 weeks significantly reduced glycosylated hemoglobin (8.4 to 7.3, p < 0.0001).74 A small study from Thailand showed sitting breathing meditation exercises in Type 2 DM patients (age range 42– 80 years) had a significant reduction in postprandial blood glucose in 3 weeks’ time.75 For additional information, please see Supplemental Digital Content 1 (http://links. lww.com/AJGP/A24).
CONCLUSION DM is one of the chronic medical conditions, and needs a high degree of patient self-management to ensure optimal outcomes. Psychiatric disorders associated with DM may interfere with adherence to diet, taking medications, exercise, and self-monitoring of blood glucose and health providers follow-up. Because DM and psychiatric illness may share common pathogenic mechanisms, mental health consequences should be considered in the assessment and prevention of diabetic complications. In the care of patients with DM, healthcare providers should address the physical, psychological, and social aspects of the patient. Evaluating for mental health on a regular basis might provide optimal treatment. Periodic screening using valid instrument scales may help to improve the care provided to these patients, especially their compliance to treatment. Recognition and management of psychiatric disorders will help to optimize the diabetes management. Good diabetes control can also reduce the mental health complications in these patients. In the future, guideline development for diabetes management in the elderly should stress the need to screen for psychiatric complications in addition to the routine primary care screening for microvascular and macrovascular complications. The authors have no conflict of interest or financial disclosure to report. All the authors contributed to the drafting and revision of the manuscript and approved the final draft of the article.
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Alagiakrishnan and Sclater
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Psychiatric Disorders in Aging Adults With Type 2 DM 39. Watson GS, Cholerton BA, Reger MA, et al: Preserved cognition in patient with early Alzheimer Disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 2005; 13:950–958 40. Risner ME, Saunders AM, Altman JF, et al: Efficacy of Rosiglitazone in a genetically defined population with mild to moderate Alzheimer’s Disease. J Pharmacogenomics 2006; 6:246–254 41. Gold M, Alderton C, Zvartau Hind M, et al: Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s Disease: results from a randomized, double-blind, placebo-controlled phase III study. Demen Geriatr Cogn Disord 2010; 30(2):131–146 42. Reger MA, Watson GS, Frey WH, et al: Effects of intranasal insulin on cognition in memory—impaired older adults: modulation by APOE type genotype. Neurobiol Aging 2006; 27(3):451–458 43. Anderson RJ, Freedland KE, Clouse RE, et al: The prevalence of comorbid depression in adults with diabetes-a meta-analysis. Diab Care 2001; 24:1069–1078 44. Maraldi C, Volpato S, Pennix BW, et al: Diabetes Mellitus, glycemic control and incident depression symptoms among 70-79 year old persons: the Health, Aging, and Body Composition study. Arch Intern Med 2007; 167:1137–1144 45. Egede LE: Diabetes, major depression, and functional disabilities among the U.S. adults. Diab Care 2004; 27:421–428 46. Egede LE, Zheng D, Simpson K: Comorbid depression is associated with increased healthcare use and expenditures in individuals with diabetes. Diab Care 2002; 25:464-470 47. den Heijer T, Vermeer SE, van dijk EJ, et al: Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 2003; 46:1604–1610 48. Sheline YL, Minton MA, Barch DM, et al: Decreased hippocampal 5-HT2A receptor binding in older depressed patients using the Altanserin positron emission tomography. Neuropsychopharmacology 2004; 29:235–241 49. Katholokuta JK, Haynes SN, Grandinetti A, et al: Biological, psychosocial and sociodemographic variables associated with depressive symptoms in persons with type 2 diabetes. J Behave Med 2003; 26:435–458 50. Sluzewska A, Rybakowski J, Bosmans E, et al: Indicators of immune activation in major depression. Psychiatry Res 1996; 64:161–167 51. Raison CL, Capuron L, Miller AH: Cytokines sing the blues; inflammation and the pathogenesis of depression. Trends Immunol 2006; 27:25–31 52. Rasgon NL, Kenna HA: Insulin resistance in depressive disorders and Alzheimer’s disease: revisiting the missing link hypothesis. Neurobiol Aging 2005; 26(suppl 1):103–107 53. Greenberg SA: The geriatric depression scale: short form. Am J Nurs 2007; 107(10):60–70 54. Strawbridge WJ, Deleger S, Roberts RE, et al: Physical activity reduces the risk of subsequent depression in older adults. Am J Epidemiol 2002; 156:328–334 55. Williams JW Jr, Katon W, Lin EH: The effectiveness of depression care management on diabetes- related outcomes in older patients. Ann Intern Med 2004; 140:1015–1024 56. Wang MY, Tsai PS, Chou KR, et al: A systematic review of the efficacy of non-pharmacological treatments for depression on glycemic control in type 2 diabetes. J Clin Nurs 2008; 17:2524– 2530 57. Bogner HR, Morales KH, Post EP, et al: Diabetes, depression, and death. a randomized controlled trial of a depression treatment program for older adults based in primary care (PROSPECT). Diab Care 2007; 30(12):3005–3010
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58. Paile-Hyv¨arinen M, Wahlbeck K, Eriksson JG: Quality of life and metabolic status in mildly depressed patients with type 2 diabetes treated with Paroxetine: a double-blind randomized placebo controlled 6-month trial. BMC Fam Pract 2007; 8:34 59. Abrahamian H, Hofmann P, Prager R, et al: Diabetes Mellitus and co-morbid depression: treatment with Milnacipran results in significant improvement of both diseases (results from the Austrian MDDM study group). Neuropsychiatr Dis Treat 2009; 5(1):261– 266 60. Williams MM, Clouse RE, Mix BD, et al: Efficacy of Sertraline in prevention of depression recurrence in older versus younger adults with diabetes. Diab Care 2007; 30(4):801–806 61. Weber-Hemann B, Gilles M, Schilling C, et al: Improved insulin sensitivity in 51 nondiabetic depressed in patients remitting with Mirtazaoine and Venlafaxine. J Clin Psychopharmacol 2008; 28:581– 584 62. Weber-Hemann B, Gilles M, Schilling C, et al: Improved insulin sensitivity in 80 nondiabetic patients with MDD after clinical remission in a double-blind, randomized trial of Amitriptyline and Paroxetine. J Clin Psychiatry 2006; 67:1856–1861 63. Andersohn F, Schade R, Suissa S, et al: Long-term use of antidepressants for depressive disorders and the risk of diabetes mellitus. Am J Psychiatry 2009; 166(5):591–598 64. Lustman PJ, Louse RE, Mix BD, et al: Sertraline for prevention of depression recurrence in diabetes mellitus; a randomized, doubleblind, placebo controlled trial. Arch Gen Psychiatry 2006; 63:521– 529 65. Wagner J, Allen NA, Swallen LN, et al: Depression, depression treatment and insulin sensitivity in adults at risk for type 2 Diabetes. Diabet Res Clin Pract 2009; 86(2):96–103 66. Fisher L, Skaff MM, Mullan JT, et al: A longitudinal study of affective and anxiety disorders, depressive affect and diabetes distress in adults with type 2 diabetes. Diabet Med 2008: 25(9): 1096–1101 67. Zambanini A, Newson RB, Maisey M, et al: Injection related anxiety in Insulin-treated Diabetes. Diabet Res Clin Pract 2001; 46:239– 246 68. Kohen D, Burgess AP, Catalan J, et al: The role of anxiety and depression in quality of life and symptom reporting in people with diabetes mellitus. Qual Life Res 1998; 7:197–204 69. Johnson MR, Lynard RB: The neurobiology of anxiety disorders. Psychiatric Clin North Am 1995; 18(4):681–725 70. Narita K, Murata T, Hamada T: Association between trait anxiety, insulin resistance and atherosclerosis in the elderly: a pilot crosssectional study. Psychoneuroendocrinology 2008; 33:305–312 71. Martinowich K, Manji H, Lu B: New insights into BDNF function in depression and anxiety. Nature Neuroscience 2007; 10(9):1089– 1093 72. Garcia-Bueno B, Caso JR, Leza JC: Stress as a neuroinflammatory condition in brain: damaging and protecting mechanisms. Neurosci Biobehav Rev 2008; 32(6):1136–1151 73. Reza M, Taylor C, Towse K, et al: Insulin improves well being for selected elderly type 2 diabetic subjects. Diabet Res Clin Pract 2002; 55(9):201–207 74. Okada S, Hamada H, Iski K, et al: Factors related to stress in patients with non-insulin dependent diabetes mellitus. J Int Med Res 1995; 23(6):449–457 75. Chaiopanont S: Hypoglycemic effect of sitting breathing meditation exercise on type 2 diabetes at Wat Khae Nok Primary Health Center in Nonthaburi province. J Med Assoc Thai 2008; 91(1): 93–98
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Psychiatric Disorders Presenting in the Elderly With Type 2 Diabetes Mellitus Kannayiram Alagiakrishnan, M.D., M.P.H., F.R.C.P.(C)., Anne Sclater, M.D., F.R.C.P.(C), F.A.C.P.
Diabetes mellitus (DM) is one of the major health problems of the elderly. Developed countries face an epidemic of Type 2 DM. Healthcare providers should be aware of the frequent coexistence of psychiatric conditions in elderly patients with DM. Dementia, depression, and anxiety are commonly seen in addition to other psychiatric conditions. The relationship between diabetes and psychiatric disorders is complex. Evidence suggests that common mechanisms may play a role in both the pathogenesis of DM and several psychiatric illnesses. Possible mechanisms, diagnosis, and management options are reviewed and discussed. Common mechanisms of psychiatric illness involving brain-derived neurotrophic factor, insulin resistance, and inflammatory cytokines are throwing new light that these psychiatric illnesses could be due to the complications of Type 2 DM. Periodic screening should be done in DM patients to identify the psychiatric complications. Healthcare professionals should routinely screen for psychiatric complications of DM in addition to the microvascular and macrovascular complications of DM. It is important to screen all diabetic elderly patients for mental health issues as these may interfere with self-care and the overall management of DM. Recognition and management of psychiatric disorders will help to optimize the diabetes management. Good diabetes control can also reduce the mental health complications in these patients. (Am J Geriatr Psychiatry 2012; 20:645–652) Key Words: Dementia, depression, diabetes mellitus, elderly, psychiatric disorders
D
iabetes Mellitus (DM) is a common metabolic disorder in the elderly. Both the prevalence and incidence of DM increase with aging. It is seen in 10%–25% of the elderly population.1 DM is a metabolic vascular risk factor associated with atherosclerotic disease. The resultant microvascular
and macrovascular complications can lead to serious morbidity and mortality and increased costs of care. Psychiatric conditions are seen frequently in people with DM.2 This article highlights the common psychiatric conditions that can coexist or be seen as a complication due to DM. It also reviews the mechanisms
Received October 3, 2010; revised May 12, 2011; accepted June 6, 2011. From the Division of Geriatric Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada (KA); and Division of Geriatric Medicine, Department of Medicine, Memorial University, St. John’s, Newfoundland, Canada (AS). Send correspondence and reprint requests to Kannayiram Alagiakrishnan, M.D., M.P.H., F.R.C.P.(C)., B139N Clinical Sciences Building, 8440-112 Street, University of Alberta, Edmonton, Alberta, Canada T6G 2G3. e-mail: [email protected] Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.AJGPonline.org). C 2012 American Association for Geriatric Psychiatry DOI: 10.1097/JGP.0b013e31823038db
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Psychiatric Disorders in Aging Adults With Type 2 DM and common pathogenesis of the two conditions and recommends an approach to the diagnosis and management of these mental health conditions.
REVIEW CRITERIA A peer reviewed literature search was conducted using MEDLINE, PubMed, Scopus, and PsycINFO databases from 1990 to 2010. The following keywords were used: diabetes, elderly, psychiatric disorders, cognitive impairment, dementia, depression, delirium, eating disorders, self-neglect, schizophrenia, and anxiety. Articles were limited to the English language literature.
COMMON PSYCHIATRIC COMPLICATIONS IN DIABETES MELLITUS The common psychiatric complications seen in diabetes are dementia, depression, anxiety disorders, delirium, and eating disorders (disinhibited or binge eating). Some of the symptoms of diabetes may overlap with the symptoms of psychiatric disorders and thus cause problems in the correct diagnosis of certain clinical situations. The symptoms of weight loss and lethargy can occur with both diabetes and depression; whereas, symptoms such as sweating, tremor, and palpitations can occur with both hypoglycemia and anxiety. The clues for suspecting psychiatric complication or illness in diabetic patients are shown in Table 1.
DIABETES AND COGNITIVE IMPAIRMENT/DEMENTIA Mild hyperglycemia, impaired glucose tolerance, and diabetes in the elderly have been associated with accelerated cognitive aging, the development of mild
TABLE 1. Clues for Psychiatric Illness in Diabetic Patients 1. Decreased self-care 2. Missed appointments 3. Decreased satisfaction with care 4. Poor adherence to medication management 5. Increased frequency of hospitalization 6. Behavioral problems
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cognitive impairment (MCI), as well as the progression of MCI to dementia. The risk of cognitive impairment is doubled in women with impaired fasting glucose and diabetes.3 A recent study has also shown that high blood glucose may affect other cognitive functions in addition to memory.4 DM is associated with deficits in multiple domains of cognition including learning, speed of information processing, executive function, and complex motor skills.5 The association between Type 2 DM and cognitive impairment/dementia is supported by many epidemiological (Table 2)6–11 and some imaging studies. However, some studies did not show an association. The study from Honolulu found no association between midlife diabetes and Alzheimer disease (AD) at later age (RR = 0.98, 95% CI: 0.48–1.99), and VD, RR = 1.48, 95% CI: 0.79– 2.78) in Japanese Americans.12 Similarly Kungsholmen study from Sweden, showed an association with VD, hazard ratio (HR): 2.6, 95% CI: 1.2–6.1, but no association with AD, HR: 1.3, 95% CI: 0.9–2.15.13 A systematic review by Biessels et al.14 showed the overall incidence of dementia, both Alzheimer disease and vascular was increased by 50%–100%, with more risk for vascular dementia.14 Another study points out, if patients had diabetes and comorbid depression the risk of developing dementia was higher (HR: 2.69, 95% CI: 1.77–4.07) when compared with patients with diabetes alone.15 Diabetes may also accelerate the conversion of MCI to dementia (HR: 2.9, 95% CI: 1.1–7.3).16 A systematic review of brain imaging studies (CT, MRI, SPECT, PET) in diabetic patients, showed a 30% increased risk for infarcts in diabetic patients relative to controls, in population based study cohorts, odds ratio (OR): 1.3 (95% CI: 1.1–1.6) and 120% increased risk, OR: 2.2 (95% CI: 1.9–2.5) in cohorts of patients with vascular disease. In the early stages of AD, MRI findings showed atrophy of the median temporal lobe predominantly, whereas in diabetic patients having AD, atrophy seems to be generalized.17
MECHANISMS OF DM IN CAUSING MCI TO DEMENTIA Several biochemical and pathogenetic mechanisms are suggested in different studies, but the precise mechanism is still unclear.18 Recurrent hypoglycemic
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Alagiakrishnan and Sclater
TABLE 2. Selected Studies Showing Positive Association of DM With MCI/Dementia Studies
Age Group
Type of Study/Follow-up
MCI/Dementia Risk
Study of osteoporotic fractures research group U.S.A.6 Washington–Heights Inwood Columbia Aging Project7 Shanghai Community Brain Health Initiative8 Rotterdam Study9
65 years or older
Longitudinal study (5–6 years)
Cognitive decline RR = 1.63, 95% CI: 1.20–2.23
65 years or older
Longitudinal study (4 years)
Mild cognitive impairment RR = 1.4, 95% CI: 1.1–1.8
Mean age 74 years
Cross-sectional study
Dementia RR = 1.83, 95% CI: 1.09–3.08.
Mean age 73 years
Longitudinal study (2.1 years)
Honolulu—Asia Aging Study10
Mean age 77 years
Longitudinal study (3 years)
Cardiovascular Health Study11
Mean age 74 years
Longitudinal study (5.4 years)
Alzheimer dementia RR = 1.90, 95% CI: 1.2–3.1 Alzheimer dementia RR = 1.8, 95% CI: 1.1–2.9 Vascular dementia RR = 2.3, 95% CI: 1.1–5.0 DM alone-mixed Alzheimer dementia RR = 1.75, 95% CI: 1.00–3.04. DM with APOE—Alzheimer dementia RR = 4.99, 95% CI: 2.70–9.20.
attacks are one of the causes for cognitive impairment in the elderly. Longitudinal cohort study demonstrated the attributable risk of dementia when compared in individuals with and without a history of hypoglycemia was 2.39% per year, 95% CI: 1.72%– 3.01%.19 Advanced glycosylation products due to chronic hyperglycemia cause neuronal damage and have been found on specific cell-surface receptors for beta amyloid.20 Longitudinal studies have demonstrated that the risk of incident AD was higher in patients with hyperinsulinemia due to insulin resistance. Peripheral hyperinsulinemia may inhibit brain insulin production which, in turn, results in impaired amyloid clearance and a higher risk of AD.21,22 Reduced level of insulin, insulin-like growth factor 1 polypeptide gene and receptors are seen in advanced AD. Glucose utilization and energy metabolism in the brain are regulated by insulin and insulin-like growth factor, and studies had shown that cognitive impairment may be improved by insulin administration. Choline acetyl transferase expression increases with insulin or insulin-like growth factor 1 stimulation.23 There is also a direct mechanism linking insulin resistance and AD. Insulin resistance was related to decrease in glucose uptake in regions known to be predictive of AD.24 Microvascular changes also leading to chronic diffuse ischemia results in atrophy and lacunar infarcts in diabetes patients.25 In elderly men with metabolic syndrome, whom had evidence of inflammation, cognitive perfor-
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mance declined significantly over a 5-year period, indicating the role of inflammatory cytokines in cognitive decline.26 Brain-derived neurotrophic factor (BDNF) is released from the human brain and is negatively regulated by high plasma glucose levels. BDNF plays a regulatory role in neuronal differentiation and synaptic plasticity. A low level of BDNF was seen in patients with impaired glucose tolerance and DM.27 In Type 2 DM subjects, decreased serum BDNF was seen and was also associated with cognitive decline.28
CLINICAL FEATURES AND MANAGEMENT Decreased cognitive function in diabetic elderly has been associated with poor adherence to diabetic self-care activities, need for increased personal care services and increased frequency of hospitalization. Routine screening of cognition in older subjects with diabetes is recommended.29 Common screening test for dementia in clinical practice include the MMSE.30 The diagnosis of dementia is made using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for dementia.31 Two small intervention studies have suggested that improved glycemic management may improve cognitive function among patients with DM.32,33 Beeri et al.34 showed that combination therapy of insulin and oral diabetic agents is associated with a substantially lower neuritic plaque density in several areas of the AD brain.34 Another study by Plastino et al35 suggested a significant slowing
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Psychiatric Disorders in Aging Adults With Type 2 DM
TABLE 3. Possible Common Mechanisms of Some Psychiatric Disorders in DM Dementia Recurrent hypoglycemia Ischemic cerebrovascular disease Advanced glycosylation products Inflammatory cytokines Hyperinsulinemia Insulin resistance BDNF Depression BDNF Higher cortisol levels HPA dysregulation Inflammatory cytokines Insulin resistance Anxiety Stress hormones Disruption of self-care mechanisms Insulin resistance BDNF HPA dysregulation Inflammatory cytokines Delirium Neurotransmitter defects Higher cortisol levels Impairment of cerebral oxidative mechanisms Inflammatory cytokines Disruption in blood-brain barrier HPA dysregulation
in cognitive decline after 12 months in the group treated with insulin and oral antidiabetic medication. Intranasal insulin has been shown to improve memory and cognitive abilities in early AD patients.36 Decreasing peripheral hyperinsulinemia and increasing brain insulin levels may have a beneficial effect on AD. Insulin promotes the cell membrane expression of NMDA receptors, which in turn can increase neuronal calcium influx, presumably by activating calcium dependent enzymes and strengthening neuronal synaptic association37 and increasing CSF norepinephrine.38 Rosiglitazone, a TZD, preserved memory function in patients with amnestic MCI and early AD on a 6 months trial.39 Another small randomized double-blind trial showed improvement in cognitive function in mild to moderate AD patients who were not carriers of the APOE–e4 allele.40 However, a recent Phase III trial in mild-to-moderate AD failed to show a benefit.41 Rosiglitazone decreases insulin resistance and decreases peripheral insulin levels and shows beneficial effect in AD. Also, intranasal insulin delivered with direct access to the brain without accessing the periphery has a similar effect.42 Interventions addressing cerebral
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glucose, insulin and energy metabolism may evolve as future candidates for treatment of dementia in diabetes patients, independent of their antidiabetic effect. In addition preventing hypoglycemia, which can contribute to cognitive impairment, is important. At this point, there is no clear-cut evidence that diabetes treatment will reduce AD, but more evidence is emerging that diabetes treatment will improve cognitive function. Therefore, the most practical approach to prevent cognitive decline is to optimize glycemic control, prevent hypoglycemic episodes, and control other vascular risk factors. In established cases of dementia, treatment with cholinesterase inhibitors or NMDA receptors should be considered. Diabetes and Depression Depression is perceived as a mental health problem triggered by social stressors, but biological factors such as diabetes can also lead to depression. Patients with DM are 2 to 4 times more likely to be diagnosed with a major depressive disorder.43 In the Health, Aging, and Body Composition study, elderly diabetic subjects had an increased incidence of depressive mood symptoms when compared with those without diabetes by 30%, HR 1.31 (95% CI: 1.07– 1.61).44 Diabetic patients with depression have greater functional disability than their nondiabetic counterparts. The adjusted OR for functional disability was 7.2 for subjects with diabetes and depression; whereas, OR was 2.4 for subjects with diabetes alone and 3.0 for subjects who have major depression alone.45 A study of Medicare patients showed that total annual healthcare costs was 4.5 times more in patients with comorbid depression and diabetes, when compared with diabetic patients without depression.46
MECHANISMS Lowered hippocampal volume is seen in depressed patients.47 Hippocampal serotonin 5–HT2A receptors are upregulated during depression and this can cause decreased BDNF.48 Decreased BDNF, a regulator of dopamine pathway, can play a role in depression. Stress, activation of the hypothalamic-pituitaryadrenal axis and inflammatory mechanisms have also
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Alagiakrishnan and Sclater been postulated in the development of depression in diabetes.49 A low level of BDNF was seen in patients with impaired glucose tolerance and DM. Decreased BDNF was also seen in patients with dementia and depression. This explains a possible common pathogenic mechanism of DM causing both dementia and depression.27 Diabetic and metabolic syndrome patients have high levels of inflammatory cytokines-like TNF-α and interleukin-6. Patients with major depression also have high levels of inflammatory cytokines.50 Inflammatory cytokines cause increased cortisol levels with stimulation of the hypothalamic-pituitary-axis.51 The insulin resistance of metabolic syndrome may play a role in depression. Insulin resistance enhances cortisol neurotoxicity in the hippocampus and may affect both mood and cognition. Insulin resistance in the brain contributes to the causation and progression of depression disorders and AD.52
MANAGEMENT Some of the symptoms of diabetes including weight loss, lethargy, and loss of libido overlap with the symptoms of depression itself. In depressed patients with diabetes due to amotivation, fatigue, anhedonia, lack of concentration, and hopelessness, diabetes self-management may become a difficult task. The screening test for depression is the Geriatric Depression Scale. It has 15 yes/no items and a score above 7 suggests depression.53 The diagnosis is usually done in clinical practice using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for depression.31 Nonpharmacological: Walking and improving physical activity have been shown to improve outcomes in patients with diabetes and depression.54 Treatment of depression improves the functional state and state of low well-being of diabetic patients, and can result in an increased number of exercise days.55 A recent systematic review showed that with nonpharmacological treatment, the improvement of glycemic control did not parallel the improvement in depression.56 Pharmacological: There are scarce clinical trials on treatment of depression in diabetic elderly. The PROSPECT trial, which is a randomized controlled trial of a depression treatment program for older adults based in primary care, showed elderly de-
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pressed diabetic patients who had depression care management, including treatment with the antidepressant Citalopram, were less likely to die over 5 years, when compared with depressed diabetic elderly in usual care practices (Adjusted HR: 0.49 (95% CI: 0.24–0.98).57 A double-blind randomized placebo controlled trial with Paroxetine therapy in mildly depressed Type 2 diabetic patients showed a significant benefit at 3 months, whereas at 6 months there was no significant benefit.58 An Austrian, observational, open label study, which included elderly patients, showed that Milnacipran therapy over a period of 6 months results in a significant improvement in both depressive symptoms and metabolic parameters.59 However, a post hoc secondary analysis of a study using Sertraline as maintenance therapy did not delay recurrence of major depressive disorder in elderly diabetes when compared with younger diabetic subjects.60 Collaborative care (with antidepressants and/or psychotherapy) for depression in diabetic elderly patients, over a period of 12 months, showed improvement in mood and function, but had no significant effect on glycemic control.55 Depression is associated with insulin resistance. Few depression remission studies with Mirtazapine, Venlafaxine, Amitriptyline, and Paroxetine improved insulin sensitivity with depression remission in nondiabetic patients.61,62 Prodiabetic effect of antidepressants has been shown in the study by Anderson et al.63 Long-term use of tricyclic antidepressants in moderate to high dose has been shown to increase the risk of diabetes by 77% and selective serotonin reuptake inhibitors by 106%. But in this study, remission of depression has not been taken into account.63 In a randomized controlled trial on diabetic patients, depression recovery and sustained remission with Sertraline was associated with improvement in Glycemic control.64,65 Overall, the studies point out that depression remission rather than depression treatment per se is associated with improved insulin resistance. Taken together, the successful treatment of depression with remission improves insulin resistance and glucose tolerance; whereas, antidepressant treatment without remission may further increase diabetes risk. Depression in diabetic patients may result in poor compliance with home blood glucose monitoring adherence, health providers’ follow-up, as well as poor adherence to dietary instructions and medications
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Psychiatric Disorders in Aging Adults With Type 2 DM management. So, healthcare providers should monitor for depression and, when found, should be effectively managed in these patients. Diabetes and Anxiety Anxiety is also a common problem seen in DM patients. The few studies that have included elderly patients also showed that anxiety was seen more in Type 2 DM patients. In a longitudinal study, Type 2 diabetic patients had higher rates of anxiety disorders over time when compared with community nondiabetic patients (123% for generalized anxiety disorder and 85% for panic disorder).66 In insulin treated patients, injection related anxiety or needle phobia is seen and it may interfere with the management of DM. Needle phobia causes some people to avoid needed medical care.67 Anxiety is associated with decreased function and quality of life. Kohen et al68 showed that anxiety, in addition to depression, was significantly associated with poor self-reported quality of life in patients with Type 2 diabetes. Mechanisms: Anxiety disorders can occur by an interaction of biopsychosocial factors. The major neurotransmitters, which can cause anxiety, include norepinephrine, serotonin, gamma-amino butyric acid, and neuropeptides. Anxiety in diabetes could be due to disturbances in the cerebral cortex, especially the limbic system.69 Anxiety may also increase blood glucose levels through the effect of stress hormones, such as catecholamines and cortisol and by the disruption of self-care behaviors. Anxiety leads to sympathetic hyperactivation, which can also contribute to insulin resistance.70 Low BDNF may contribute to anxiety like behaviors.71 Depression and anxiety disorders are related to stress and this can cause stress-induced inflammation, which can result in cell damage.72
CLINICAL FEATURES AND MANAGEMENT Patients may ignore important hypoglycemic symptoms or may misinterpret anxiety symptoms as hypoglycemic symptoms. Anxiety and depression can also coexist in the same patient. The diagnostic instrument one can use is the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for anxiety disorder.31
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A study on insulin treatment in diabetes showed improved mental health and social functioning scores using the SF-36 Quality-of-Life instrument and well being in elderly Type 2 patients.73 This study also showed that oral administration of an anxiolytic, Fludiazepam 0.25 mg, three times daily orally for 12 weeks significantly reduced glycosylated hemoglobin (8.4 to 7.3, p < 0.0001).74 A small study from Thailand showed sitting breathing meditation exercises in Type 2 DM patients (age range 42– 80 years) had a significant reduction in postprandial blood glucose in 3 weeks’ time.75 For additional information, please see Supplemental Digital Content 1 (http://links. lww.com/AJGP/A24).
CONCLUSION DM is one of the chronic medical conditions, and needs a high degree of patient self-management to ensure optimal outcomes. Psychiatric disorders associated with DM may interfere with adherence to diet, taking medications, exercise, and self-monitoring of blood glucose and health providers follow-up. Because DM and psychiatric illness may share common pathogenic mechanisms, mental health consequences should be considered in the assessment and prevention of diabetic complications. In the care of patients with DM, healthcare providers should address the physical, psychological, and social aspects of the patient. Evaluating for mental health on a regular basis might provide optimal treatment. Periodic screening using valid instrument scales may help to improve the care provided to these patients, especially their compliance to treatment. Recognition and management of psychiatric disorders will help to optimize the diabetes management. Good diabetes control can also reduce the mental health complications in these patients. In the future, guideline development for diabetes management in the elderly should stress the need to screen for psychiatric complications in addition to the routine primary care screening for microvascular and macrovascular complications. The authors have no conflict of interest or financial disclosure to report. All the authors contributed to the drafting and revision of the manuscript and approved the final draft of the article.
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