Endocrine disorders often cause or co-occur with depression. Thyroid, parathyroid, and adrenal disease, as well as diabetes and abnormalities in the hypothalamic–pituitary–thyroid (HPT) and hypothalamic–pituitary–adrenal (HPA) axes, can all result in depression. Treatment of these endocrine conditions often ameliorates the depressive symptoms, but if persistent, they can be addressed with somatic, behavioral, and psycho therapies.

DESCRIPTION

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia that develops as a result of decreased secretion of insulin and/or impaired tissue response to insulin.¹ Type 1 diabetes is caused by autoimmune destruction of pancreatic beta cells, which leads to decreased insulin secretion. Type 2 diabetes—the most common form—is due to an impaired tissue response to insulin and decreased secretion of insulin. Untreated diabetes can lead to cardiovascular, renal, neurologic, and ophthalmologic damage. Diabetes is strongly associated with depression, as evidenced by the increased prevalence of depression in individuals with diabetes compared to the general adult population.² Untreated depression in those with diabetes can have a profound impact upon glycemic control and self-care behaviors, resulting in a greater risk of end-organ complications, disability, diminished quality of life, and increased mortality.

EPIDEMIOLOGY

In the United States, 29.1 million people (9.3% of the population) have diabetes. However, more than a quarter of them remain undiagnosed (Fig. 14-1).³ Type 1 diabetes accounts for 5% of all diagnosed cases,³ and type 2 diabetes accounts for 90% to 95% of all diabetes cases in the United States.³ It is being diagnosed more often in children and adolescents due to increasing rates of childhood obesity.³ Gestational diabetes affects 3% to 5% of pregnant women.⁴ Postpartum, women with gestational diabetes have a 17% to 63% risk of being diagnosed with type 2 diabetes within 5 to 16 years.⁵

In the United States, there are significant racial and ethnic differences in those who are 20 years or older and diagnosed with diabetes (Table 14-1).

Compared with the general population, the prevalence of depression is three times greater in individuals with type 1 diabetes and almost twice as high in those with type 2.⁶ Specifically, the point prevalence of depression is about 11%⁶ compared to 3% to 4% in the general population.² The point prevalence increases to 28.5% in those diabetics with a past history of depression.⁶ Women with diabetes have a higher prevalence of depression than men with diabetes.⁷

PATHOPHYSIOLOGY

Both types of diabetes cause impaired carbohydrate, fat, and protein metabolism. Gestational diabetes is characterized by glucose intolerance that is commonly diagnosed during the second or third trimester of pregnancy (Box 14-1).³

Other forms of diabetes include maturity onset of youth and latent autoimmune of adults. Patients with maturity-onset diabetes of youth have symptoms manifest before age 25 and have only impaired insulin secretion due to a monogenetic defect of beta cells with an autosomal dominant inheritance pattern.⁸Latent autoimmune diabetes in adults is characterized by a late diagnosis and the presence of pancreatic autoantibodies.⁹ Additional causes of diabetes include pancreatic disease, infections, medication side effects, and surgery.⁸ The risk for both type 1 and type 2 diabetes is increased in close relatives, suggesting a genetic predisposition, although no direct genetic link has been identified.¹

Although studies endorse a relationship between diabetes and depressive symptoms, the relationship is bidirectional and the pathophysiological mechanisms linking them remain uncertain.⁷ Lustman and Clouse have suggested that depression can induce hyperglycemia, especially in diabetic patients.¹⁰ Findings by Eaton et al.¹¹ and Kawakami et al.¹² support this, finding both major depressive disorder and depressive symptoms precede and may increase the risk of type 2 diabetes.

Conversely, hyperglycemia may induce dysphoria.^11,12 In addition, antidepressant medications, such as SSRIs, influence metabolic function through weight loss or gain, and hydrazine monoamine oxidase inhibitors increase insulin sensitivity. Lustman and Clouse point out that antidepressants may also ameliorate hyperglycemia by virtue of improved antidiabetic medication adherence and dietary compliance.¹⁰

CLINICAL PRESENTATION

Typical presenting symptoms of diabetes include polyuria, polydipsia, weight loss, polyphagia, and blurred vision (Box 14-2).¹³ Chronic hyperglycemia during childhood and adolescence may cause growth retardation and decreased resistance to infections.¹³ Glucose control is essential, as uncontrolled diabetes may result in life-threatening hyperglycemia with ketoacidosis or the nonketotic hyperosmolar syndrome.¹³

There are no studies to suggest that the clinical presentation of depression differs in those with or without diabetes. However, depression in patients with type 1 and 2 diabetes is significantly associated with hyperglycemia and may interfere with glycemic control.¹⁴ In type 1 diabetes a direct relationship has been found between depressive symptoms and mortality risk.¹⁵ In type 2 diabetes, depressive symptoms may not necessarily be indicative of a DSM disorder, but may instead reflect a depressive reaction to this stressful disease that requires demanding and extensive self-management. The stress of living with, adjusting to, and managing diabetes has been referred to as “diabetes distress.”¹⁵

COURSE AND NATURAL HISTORY

Control of blood glucose is essential to reduce the risk of cardiovascular disease and stroke, renal dysfunction, lower limb amputations, peripheral neuropathy, nonalcoholic liver disease, periodontal disease, hearing loss, erectile dysfunction, and diabetic retinopathy and blindness.³ Patients with diabetes and comorbid major depression who have poor glycemic control are at increased risk for retinopathy,¹⁶ microvascular complications, and mortality.^17,18 Conversely, hypoglycemia can lead to seizures, loss of consciousness, and death. In 2010, diabetes was the seventh leading cause of death in the United States, and may be vastly underreported.³ After adjusting for population age differences, all-cause mortality is approximately 1.5 times higher among adults with diabetes than among those without the disease.³

As in the general population, depression is a remitting and relapsing disorder for those with diabetes.¹⁰ Even though most individuals will recover from the first episode of depression, there is a high likelihood of relapse¹⁰ and its course has been described as “chronic and severe.”¹⁰ Maintenance of antidepressant medication appears to be effective in reducing recurrence rates.¹⁰ In cross-sectional studies, glycemic control is significantly worse in those with depression than in those without.¹⁹

The depressive diagnosis more often follows rather than precedes the diagnosis of type 1 diabetes.¹⁰ Longitudinal studies suggest that major depression may increase the probability of developing type 2 diabetes.²⁰ This may be due to several different mechanisms, including the “… hyperglycemic effects of antidepressant medications, changes in diet and weight, and physical inactivity associated with chronic depression.”¹¹ It is also possible that due to increased release of counter-regulatory hormones, depression may impair the disposition of carbohydrate loads and increase the chances of developing of type 2 diabetes. In addition, hyperglycemia may cause arousal states with greater risk to environmental stress and depression.

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

Patients presenting with diabetes are often over 45 years old, overweight, and have unexplained weight loss, polydipsia, and polyuria. The diagnosis is confirmed by a fasting plasma glucose level >126 mg/dL, a random plasma glucose level >200 mg/dL with characteristic symptoms, a hemoglobin A_1C level > 6.5%, or a 2-hour plasma glucose level >200 mg/dL following an oral glucose challenge (Boxes 14-3 and 14-4).²¹ Patients presenting with hypertension or hyperlipidemia should be screened for diabetes. During pregnancy, women are at increased risk of developing diabetes and those with gestational diabetes are at increased lifelong risk for type 2 diabetes.

Although depression in diabetes is similar to major depression in general, certain risk factors may point to a diagnosis of depression, as outlined in Box 14-5.

The use of screening tools to identify and monitor depression in diabetes is also highly recommended.¹⁰ These include self-report questionnaires such as the Beck Depression Inventory, the 9-Item Patient Health Questionnaire (PHQ-9), and the Depressive Cognition Scale, as well as interviewer-administered scales, such as the Hamilton Rating Scale for Depression, the Diagnostic Interview Schedule, and the Structured Clinical Interview—DSM IV.

TREATMENT

Treatment of diabetes begins with patient/family education, glucose-lowering medication, and the self-care practices of salutary dietary intake, regular physical activity, and weight control. Other crucial lifestyle changes include reducing the cardiovascular risk factors by controlling hypertension and hyperlipidemia, and curtailing nicotine use. Individuals with type 1 diabetes require life-sustaining insulin administered as multiple daily injections or as a continuous infusion supplied by a pump. Type 2 glucose levels can be controlled with similar behavioral interventions and the use of insulin and oral medications.³

Two-thirds of depressed diabetics do not receive treatment of their mood disorder (Box 14-6).²² Yet, simply implementing glycemic control by diet, insulin, or oral hypoglycemic agents is beneficial.²³ When diagnostic criteria for major depressive disorder are met, evidence-based somatic therapy with or without cognitive behavioral therapy (CBT) is recommended.¹⁰ CBT is effective in treating depression in type 2 diabetes patients with major depression, and results in moderate improvements in glycemic control as well.²⁴ Fluoxetine decreased depressive symptoms in an RCT of patients with major depression and either type 1 or type 2 diabetes.²³ In this study glycemic control improved, and this was associated more with fluoxetine’s hypoglycemic affects than with remission of depressive symptoms suggesting a possible insulin sensitizing effect of fluoxetine.²³ Selective serotonin reuptake inhibitors may exacerbate hypoglycemia in diabetic patients by impairing hormonal counter-regulatory responses.²⁵

Oral medications for type 2 diabetes have different interactions with commonly prescribed SSRIs (Box 14-7). Metformin has no interaction, but sulfonylurea drugs such as glimepiride, glyburide, glipizide, the meglitinides including repaglinide, and D-phenylalanine derivatives, such as nateglinide, may interact in a clinically significant manner requiring monitoring and dosage adjustments.

Interventions to improve diabetes self-management are also important. These include online diabetes self-management programs, assistance in problem solving, personalized health risk information, and educational material.¹⁶

SUMMARY

Most cases of diabetes mellitus are classified as type 1 or type 2. Diabetes can also be the result of pancreatic disease, infections, medication side effects, or surgery. The diagnosis is based on measurement of hemoglobin A_1C level, fasting or random plasma glucose level, or the results of oral glucose tolerance testing. Depression is common in both type 1 and type 2 diabetes, and due to its chronic and severe nature has significant effects on the course and outcome of diabetes. Untreated depression can result in decreased adherence to treatment, poor metabolic control, higher complication rates, decreased quality of life, increased healthcare use and costs, increased disability and lost productivity, and increased risk of death. SSRIs, particularly fluoxetine, and/or CBT are effective treatments. Glycemic control and the use of insulin may also improve depressed mood and sense of well-being. Depression in type 2 diabetes may often be a form of “diabetes distress” rather than a major depression. As such, it responds to self-management, assisted problem solving, and education.

DESCRIPTION

Hypercortisolism (Cushing syndrome) is caused by endogenous chronic overproduction of cortisol or by prolonged exposure to exogenous glucocorticoids used in the treatment of other medical conditions. Laboratory tests confirm the diagnosis, and a variety of treatment modalities target the specific cause of Cushing syndrome. Depression is the most common psychiatric disorder affecting patients with Cushing syndrome.²⁶ Cushing disease is the pituitary ACTH-dependent form of Cushing syndrome.

EPIDEMIOLOGY

Endogenous Cushing syndrome is a rare disorder. Its precise incidence is difficult to determine because large numbers of patients are prescribed glucocorticoids and many others have subclinical features. In one Danish study the estimated annual incidence was 2–3 per million, of which benign adrenal adenomas accounted for 0.6 per million.²⁷ The female-to-male ratio was 3:1, and the median age for first hospitalization was 41.²⁷ Preliminary data suggest that patients with type 2 diabetes or osteoporosis may account for a large number of cases of subclinical Cushing syndrome.²⁸ The incidence of Cushing disease (pituitary ACTH-dependent Cushing syndrome) is five to six times more common than ACTH-independent adrenal Cushing syndrome caused by the secretion of excessive cortisol from benign or malignant adrenal tumors.²⁹

The prevalence of depression in Cushing syndrome is high, and 50% to 70% of these patients experience a major depressive syndrome.²⁶

PATHOPHYSIOLOGY

The production of cortisol is mediated by the HPA axis. The hypothalamus, located in the ventral diencephalon, sends corticotropin-releasing hormone (CRH) to the pituitary gland (Box 14-1). CRH then causes the pituitary to secrete adrenocorticotropin hormone (ACTH), which stimulates the adrenal glands that in turn release cortisol into the bloodstream.

Cortisol is an essential factor in the human stress response. Stress leads to rapid (seconds to minutes) activation of the sympathetic nervous system with the release of noradrenaline and adrenaline from the adrenal medulla.³⁰ These trigger increased vigilance, alertness, arousal, and attention. Slower (minutes to hours) stimulation of the mineralocorticoid and glucocorticoid receptors also takes place.³¹

Chronic stress results in a cumulative burden of behavioral adaptations, or “allostatic load,” which interferes with homeostasis and ultimately results in neurodegenerative changes and cognitive impairment. Thus, persistently elevated circulating glucocorticoids due to maladaptive coping can lead to depression, as well as increased abdominal obesity, osteoporosis, and cardiovascular disease.³² The hypercortisolemia of Cushing disease and Cushing syndrome results in depression and a concomitant reduction in hippocampal volume.³³ Depression is associated with increased glucocorticoid signaling via the glucocorticoid receptors.³⁴ In the glucocorticoid signaling insufficiency hypothesis, hypercortisolemia is the result of primary glucocorticoid receptor resistance. This is in contrast to the glucocorticoid signaling overactivity hypothesis that suggests up-regulation at glucocorticoid receptors.³⁵

CLINICAL PRESENTATION

The presentation of Cushing syndrome (Table 14-2) depends upon the duration and level of hypercortisolism and its cause, for example, adrenal adenomas that slowly secrete increasing amounts of cortisol that lead to gradual development of manifestations versus adrenal carcinomas that secrete markedly excessive amounts of cortisol over shorter intervals, often in combination with masculinizing androgens (Box 14-2). Gender and age also play a role in the clinical manifestations of hypercortisolism. Females commonly have dysmenorrhea or amenorrhea as well as facial, neck, chest, abdominal, and thigh hirsutism. Males may experience decreased or absent libido, erectile dysfunction, and infertility. Children of either sex experience impaired growth rates and obesity.³⁶

The depression accompanying hypercortisolemia does not differ in clinical presentation from the depression co-occurring with other medical disorder.

COURSE AND NATURAL HISTORY

The course of hypercortisolism is variable and depends on its etiology as well as the patient’s age at time of presentation. Excluding cases caused by exogenous glucocorticoids, 70% of Cushing syndrome cases are due to benign, single pituitary adenomas that secrete ACTH.³⁹ Cortisol-producing adrenal tumors are rare and usually take the form of nonmalignant adrenal adenomas that are more likely found in women with an age of onset of about 40. Cushing disease occurs most frequently in women of reproductive age. Primary pigmented micronodular adrenal disease with tumors that produce cortisol is a condition that is usually diagnosed in children and young adults. In familial or inherited Cushing syndrome, cortisol-secreting tumors are found in the pituitary and adrenal glands as well as ectopically.⁴⁰ The least common cause of hypercortisolism is adrenocortical carcinomas, which also secrete androgens and account for rapid development of debilitating symptoms.

ASSESSMENT AND DIFFERENTIAL DIAGNOSIS

Diagnosis involves history, physical examination, and laboratory tests including imaging studies to locate pituitary or adrenal tumors. Tests to diagnose Cushing syndrome include 24-hour urinary free cortisol levels and/or lack of cortisol suppression after low-dose dexamethasone induction, as well as late-night salivary cortisol measurements. Dexamethasone-CRH testing is used to rule out elevated cortisol levels associated with morbid obesity, uncontrolled diabetes, and alcoholism, depression, and anxiety disorders. To distinguish between pituitary, adrenal, or ectopic sources of hypercortisolemia, ACTH levels, CRH stimulation testing, high-dose dexamethasone testing, and imaging studies are conducted.³⁷ The differential diagnosis for these patients should include metabolic syndrome and polycystic ovary syndrome, which can also cause aberrant menses, obesity, hirsutism, and insulin resistance.

Elevated cortisol levels are also seen in individuals with depression. Subsequent cortisol nonsuppression with the dexamethasone suppression test (DST) is found in both unipolar depression and bipolar disorders. In a meta-analysis of 144 studies, baseline DST status did not predict response to antidepressant treatment or outcome after hospital discharge. Persistent nonsuppression after treatment was associated with high risk of early relapse and poor outcome after discharge. The test lacks sufficient specificity and sensitivity to be useful.⁴¹ Cushing syndrome should be part of the differential diagnosis when a medical etiology is considered in the presence of new or persistent psychopathology (Box 14-3).³⁴ Depression, anxiety, mood instability, and less commonly hypomania, psychosis, and mania^42,43 require careful assessment to rule out primary psychiatric disorders. If they are refractory to psychopharmacological interventions, then hypercortisolism should be considered as a possible etiology.³⁴ When atypical depression is associated with hypercortisolism, it often remits with treatment of the hypercortisolism.

TREATMENT

Treatment of hypercortisolism depends upon its etiology. If the cause is exogenous glucocorticoids, titration downward to the lowest effective dose doubled on alternate days may ameliorate symptoms. Another strategy is to switch to noncorticosteroid therapy. If an ACTH-secreting pituitary adenoma is the cause, trans-sphenoidal resection can be curative. Focused radiation therapy, or stereotactic radiosurgery, may be used to treat refractory cases. For ectopic ACTH syndrome, surgery, radiation, chemotherapy, immunotherapy, or combination therapy may be indicated. Cortisol-inhibiting medication or bilateral adrenalectomy is reserved for intractable cases. Cortisol-secreting adrenal tumors can usually be surgically removed.

In some depressed patients, cortisol level reductions result in significant symptom reduction.⁴⁴ In one study of Cushing syndrome, 67% of patients had a psychiatric diagnosis (52% atypical depression and 12% major depressive disorder [MDD]) prior to treatment; after successful treatment, only 24% manifested depression.⁴⁵ However, even with aggressive treatment directed toward reducing hypercortisolism, psychiatric and cognitive problems may persist.³⁷ Data are not yet available to guide the treatment of refractory MDD associated with hypercortisolism that does not remit upon treatment of the hypercortisolism. Dorn et al. suggest psychiatric and endocrinologic collaborative follow-up of such patients with treatment tailored to each individual patient.⁴⁵ Hippocampal volume loss occurs in Cushing syndrome.⁴⁶ Rodent studies indicate that tianeptine, an SSRI, or electroconvulsive therapy (ECT) have effects on the hippocampus that should counter those reported in major depression, increasing adult hippocampal neurogenesis.^47,48

SUMMARY

Hypercortisolism is the result of overproduction of cortisol due to benign pituitary adenomas (70%) that secrete ACTH, benign or malignant “ectopic” tumors that produce ACTH, or mostly benign adrenal tumors that secrete cortisol. Depression, which is the most common comorbid psychiatric disorder, as well as mood dysregulation, anxiety, and irritability are important presenting symptoms.

Data are not yet available to guide the treatment of MDD associated with hypercortisolism that does not remit upon treatment of the hypercortisolism.

DESCRIPTION

Adrenal insufficiency can be primary (Addison disease) or secondary, representing diminished ACTH secretion due to disruption of pituitary corticotroph function, and tertiary adrenal insufficiency to represent diminished ACTH secretion due to hypothalamic suppression of CRH secretion due to exposure to exogenous glucocorticoids. Although the diagnosis of adrenal insufficiency, which has the potential to be life-threatening, is primarily made through laboratory testing, it may initially present with psychiatric symptoms.

EPIDEMIOLOGY

Addison disease affects 110 to 144 of every 1 million people in developed countries⁴⁹ and has an incidence of 4.7 to 6.2 per million per year in Caucasians with the age of diagnosis peaking during the fourth decade.² However, secondary adrenal insufficiency is much more common than Addison disease with a prevalence estimated at 150 to 280 per million, with the incidence peaking in the sixth decade.⁵⁰ Women account for the majority of cases of primary and secondary adrenal insufficiency. There is a paucity of recent literature describing the epidemiology of psychiatric symptoms in Addison disease. However, mid-century reports found their prevalence to be between 64% and 84%.^51–54 Anglin et al.⁵⁵ reviewed these studies and concluded that the primary presenting psychiatric symptoms of Addison disease are mild disturbances in mood, motivation, and behavior. Severe Addison disease and the presenting symptoms of an addisonian crisis can be psychosis, cognitive impairment, and delirium.⁵⁵