James L. Levenson, M.D.
Alyson K. Myers, M.D.
The onset, course, and outcomes of endocrine disorders traditionally have been linked to psychological and social factors. A growing body of neuroendocrine research has begun to illuminate important biological mechanisms underlying the interplay of psyche and soma, with important clinical ramifications. In this chapter, we focus primarily on these latter pragmatic issues. Diabetes mellitus is the most common endocrine condition and is growing in epidemic proportions, so it has been given major emphasis. Other topics include disturbances in thyroid, parathyroid, adrenal, growth, prolactin, and gonadal hormones; pheochromocytomas; and metabolic disorders including electrolyte and acid–base disturbances, vitamin deficiencies, osteoporosis, and inherited disorders including the porphyrias.
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that affects an estimated 500,000 to 1 million people in the United States. It is most commonly diagnosed in children and young adults (see also Chapter 32, “Pediatrics”) but is also diagnosed in middle-aged and older adults (Thomas and Philipson 2015). The exact mechanism of T1DM is unknown; however, it appears that genetic and environmental factors trigger an autoimmune response, which attacks the insulin-producing beta cells of the pancreas.
The Diabetes Control and Complications Trial, a 9-year multicenter intervention study of nearly 1,500 persons with T1DM in the United States and Canada, established that tight glycemic control delays the onset and slows the progression of diabetic complications (Nathan et al. 1993). Therefore, treatment is aimed at lowering and stabilizing blood glucose to near-normal levels through dietary control, exercise, blood glucose monitoring, and insulin therapy. Intensive blood glucose management for T1DM can be achieved by the use of basal–bolus insulin injections or the use of a continuous subcutaneous insulin infusion pump, with the goal of mirroring as closely as possible the physiological patterns of insulin release. In 2014, the U.S. Food and Drug Administration (FDA) approved the use of continuous glucose monitoring (CGM) in lieu of fingerstick testing. CGM has been found to be noninferior to the use of a glucometer when blood sugars are 70–180 mg/dL (Aleppo et al. 2017).
In both T1DM and type 2 diabetes mellitus (T2DM), hemoglobin A1C (HbA1C) is used to assess glycemic control, reflecting average blood glucose concentrations over a 2- to 3-month period. The HbA1C can be falsely elevated in coexisting conditions of abnormal red blood cell turnover such as anemia, end-stage renal disease, pregnancy, or a recent blood transfusion (Nathan et al. 2007). For most patients, the target is an HbA1C level less than 7%, but the target may be higher in those who are very old or who have multiple medical comorbidities (American Diabetes Association 2017a).
Approximately 90% of all people with diabetes have T2DM, which is caused by insulin resistance leading to dysglycemia. Insulin resistance leads to progressively increased pancreatic insulin production to achieve normoglycemia. In the early stages, patients can have impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (Nathan et al. 2007). IFG is diagnosed when the fasting glucose is 100–125 mg/dL and the HbA1C is 5.7%–6.4%, whereas IGT is diagnosed when the postprandial glucose is 140–200 mg/dL 2 hours after a 75-g glucose load (oral glucose tolerance test [OGTT]). Once the fasting glucose is greater than 126 mg/dL and the HbA1C is greater than 6.5%, the diagnosis of diabetes can be made (American Diabetes Association 2017a). After 10–15 years of having T2DM, the pancreas can no longer meet the increased need of insulin production, and exogenous insulin therapy is required. Risk factors for T2DM include IFG/IGT; history of gestational diabetes mellitus (GDM); obesity; black, Hispanic, Native American, or Asian ethnicity; sedentary lifestyle; metabolic syndrome; and chronic use of medications such as corticosteroids or antipsychotics. Onset of T2DM is typically during middle age, but with growing rates of obesity at younger ages, children and adolescents are starting to develop the disease at higher rates.
The association between stress and diabetes is rooted in biological as well as behavioral causes (Pouwer et al. 2010). Those with high levels of stress tend to have a sedentary lifestyle as well as poor dietary habits. On a biological level, repeated stress leads to overstimulation of the hypothalamic-pituitary-adrenal (HPA) axis. This leads to increases in the cortisol and inflammatory cytokines that play a role in insulin resistance (Golden 2007; Kan et al. 2013). Several studies have shown that glycemic control is poorer in people with diabetes who report more stress (Garay-Sevilla et al. 2000; Lloyd et al. 1999). However, this finding may be limited to certain populations; for example, in the Whitehall II prospective study of workers older than 18 years, obese women with high psychosocial work stress were the only group to show an increased risk of diabetes (Heraclides et al. 2012). This association was not seen in men or in nonobese women. It is still unclear whether stress directly influences metabolic regulation or whether people under stress change their self-care behaviors.
The Diabetes Control and Complications Trial (DCCT) and U.K. Prospective Diabetes Study (UKPDS) research established that intensive management of T1DM and T2DM improves long-term health outcomes in diabetes (Nathan et al. 1993; U.K. Prospective Diabetes Study [UKPDS] Group 1998a, 1998b). However, the newer approach to diabetes management is to set glycemic targets based on patient goals, psychosocial factors, age, life expectancy, and comorbid conditions (Young-Hyman et al. 2016). For most patients, the goal of glycemic control is an HbA1C level less than 7%, but in persons with severe mental illness, this may not be attainable. Many patients have difficulty sustaining the burden of self-care over time—the stress of coping with a chronic disease is a major risk factor for psychopathology and nonadherence to complex treatment recommendations (Lustman et al. 2000a). There is a growing literature examining the relationship of T1DM and T2DM with psychiatric disorders, especially mood and eating disorders. In both types of diabetes, psychiatric disorders have been linked to treatment nonadherence, worse blood glucose control, and complications. Disease outcomes in diabetes are dependent on patient behaviors, attitudes, and cognitions; thus, optimal treatment is multidisciplinary, including primary care providers, endocrinologists, certified diabetes educators, psychiatrists, and other mental health care professionals.
The prevalence of depression in both T1DM and T2DM is two to three times higher than that found in the general population (Gendelman et al. 2009; Li et al. 2008). The International Prevalence and Treatment of Diabetes and Depression (INTERPRET-DD) study, currently ongoing in 16 countries, is examining the prevalence of diabetes and depression as well as diagnostic measures, treatment modalities, and clinical outcomes (Lloyd et al. 2015). The consequences of having both diabetes and depression include worse glycemic control (Brieler et al. 2016), more severe diabetic symptoms (Nguyen et al. 2015), and a heightened risk of major diabetic complications (Ciechanowski et al. 2000; de Groot et al. 2001). Complications such as painful neuropathy, sexual dysfunction, and renal disease increase the risk for development of depression (Holt et al. 2014).
However, there have also been studies showing no association between glycemic control and depression. In a population sample, there was no difference in attainment of individual HbA1C, blood pressure, or cholesterol goals between diabetic individuals with depression and those without depression; however, those without depression were more likely to reach goals for all three measures (Shah et al. 2015). In a cohort of Black and Latino elderly patients in New York, depression was not associated with worsened glycemic control (Palta et al. 2014).
The association between diabetes and depression is described as bidirectional (Holt et al. 2014), in that individuals with depression have been found to have a 60% increased risk of developing diabetes (Mezuk et al. 2008), which is due to genetic predisposition as well as poor health behaviors (Park and Reynolds 2015). The converse is also true, in that the stress of diabetes can lead to depression in individuals who have a biological or psychological predisposition to it. In a meta-analysis of 24 studies of depression, hyperglycemia, and diabetes, Lustman et al. (2000a) concluded that hyperglycemia is provoked by depression and also independently contributes to the exacerbation of depression.
Anxiety symptoms are also frequently reported by patients with diabetes and depression but may independently contribute to diminished quality of life (Collins et al. 2009). After accounting for depression, one study found that panic symptoms correlated with elevated HbA1C, higher rates of complications, and lower self-rated functional health (Ludman et al. 2006). In persons with T1DM, isolated anxiety regarding hypoglycemia may also be present, leading to manipulation of insulin dosing in order to maintain blood sugar above 150 mg/dL. Risk factors for fear of hypoglycemia (FOH) include duration of diabetes and history of hypoglycemia and of fluctuating blood sugars (Wild et al. 2007). FOH, as measured by the Hypoglycemia Fear Survey (HFS), is associated with greater symptoms of anxiety and depression (Gonder-Frederick et al. 2011).
Related research has shown that the number of diabetes symptoms reported by patients was more strongly associated with the number of depression symptoms reported than it was with measures of glycemic control and diabetes complications (i.e., HbA1C levels above 8.0% and two or more complications) (Ludman et al. 2004). Depression is associated with increased mortality in diabetes (Black et al. 2003; Katon et al. 2006) as well as an increased risk of self-harm or suicide (Myers and Trivedi 2017).
Diagnosing depression in individuals with diabetes can be complicated, as some symptoms of hyperglycemia overlap with those of depression, including fatigue, poor sleep, and inattention. Standard self-report scales such as the nine-item depression scale of the Patient Health Questionnaire (PHQ-9) or the Beck Depression Inventory–II (BDI-II) can be used for screening (Young-Hyman et al. 2016). In addition, “depressive” symptoms may not fulfill criteria for major depressive disorder; therefore, patients should also be assessed for diabetes distress (American Diabetes Association 2017b). The term diabetes distress conceptually recognizes that some patients are not depressed, but rather are distressed about their diagnosis of diabetes, and this distress leads to poorer glycemic control and worse health behaviors regarding diet and exercise (Fisher et al. 2012). Providers can use either the Diabetes Distress Scale (DDS) or the Problem Areas in Diabetes (PAID) questionnaire to pinpoint the exact areas of diabetes care that are most distressing to the patient (Young-Hyman et al. 2016).
Evidence is limited by small sample sizes and is somewhat contradictory regarding whether specific treatment of depression can lead to improvements in diabetes treatment adherence and glycemic control. Two small controlled studies reported that nortriptyline and fluoxetine are effective treatments for depression in diabetes. However, nortriptyline improved mood but did not improve glucose regulation, whereas fluoxetine was associated with improvements in mood and a nonsignificant trend for improved HbA1C levels (Lustman et al. 1997, 2000b). Sertraline maintenance also was shown to decrease the risk of recurrence of depression in younger patients with diabetes (Williams et al. 2007). HbA1C was found to improve slightly in relation to symptom improvement and to deteriorate with depression recurrence in those treated with sertraline (Lustman et al. 2006). Paroxetine in individuals with T2DM and mild depression led to statistically but not clinically significant improvement in HbA1C at 3 months of therapy; however, the effect was lost at 6 months (Paile-Hyvärinen et al. 2007). Compared with patients receiving diabetes education only, patients receiving cognitive-behavioral therapy (CBT) to address their depression symptoms showed significant improvements in HbA1C levels (Lustman et al. 1998). A similar study showed improved mood in response to CBT but no change in HbA1C levels either during treatment or 1 year later (Georgiades et al. 2007). In a study of sertraline versus group CBT, remission of depression was more likely for those treated with sertraline; however, despite the improvement in depressive symptoms, only minimal improvements were seen in glycemic control (Petrak et al. 2015). CBT was shown in a small study to improve pain symptoms in individuals with painful diabetic neuropathy, but with minimal change in depressive symptoms (Otis et al. 2013).
It appears that improving glycemic control involves addressing both depression and diabetes during therapy (van der Feltz-Cornelis 2013). As a result, collaborative care studies in which both diabetes and depression are addressed have become more popular. Katon et al. (2010) randomly assigned 214 people with depression and poorly controlled diabetes to care as usual with primary care versus bimonthly to monthly visits with nurses. The nurses were trained by physicians in motivational interviewing and adjusting medications for diabetes, depression, dyslipidemia, and hypertension. Unsurprisingly, the intervention group had better outcomes and satisfaction with care, but at a greater expense (average cost: $1,224 per person). This increased expense was in contrast to a previous study, the Improving Mood—Promoting Access to Collaborative Treatment (IMPACT) trial, which found that treatment of depression in older adults with diabetes contributed to significant clinical benefits without adding to health care costs (Katon et al. 2006). The Diabetes–Depression Care Management Adoption Trial (DCAT) demonstrated an improvement in depression but not glycemic control in participants who received interdisciplinary care by telephone and in person from physician, nurses, and social workers (Wu et al. 2014). Collaborative care interventions have also been delivered by telemedicine. Two studies delivering Web-based interventions targeting depression in adults with T1DM and T2DM reported improvement in both diabetes distress and depressive symptoms, with less-robust improvement in glycemia (Nobis et al. 2015; van Bastelaar et al. 2011).
In summary, the high prevalence of depression and its adverse effects in diabetes, combined with clinically proven treatments, argue for aggressive identification and treatment of depression as early as possible in diabetes. In a meta-analysis of studies delivering interventions with pharmacotherapy and/or psychotherapy, the effect on depression was greater than that on glycemic control (van der Feltz-Cornelis et al. 2010). As a result, there is a need for more research to improve both indices.
T2DM occurs with significantly increased prevalence in bipolar disorder and schizophrenia. Patients with these disorders have diabetes rates of 10%–15%, which is two to three times higher than rates in the general population (De Hert et al. 2009), and risks are greater in females than in males (Goff et al. 2005). Much of the association appears to be related to obesity—specifically central adiposity—secondary to overstimulation of the HPA axis; poor sleep; a sedentary lifestyle; poor dietary choices; and the metabolic effects of psychotropic medications (Holt 2015; Calkin et al. 2013). As a result, the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, and North American Association for the Study of Obesity partnered to develop screening guidelines for metabolic syndrome (MetS) in patients taking antipsychotics (American Diabetes Association et al. 2004). These guidelines specify that prior to initiating treatment with a second-generation antipsychotic, all persons should be assessed for family history of diabetes and the components of MetS: weight/body mass index (BMI), blood pressure, fasting glucose, and fasting lipids. Weight should be checked monthly for the first 3 months and then quarterly. Measurements of blood pressure and fasting glucose should be taken again at 12 weeks and then annually. Fasting lipids should be measured again at 12 weeks and then every 5 years. With several of the atypical antipsychotics, the onset of diabetes may occur suddenly, with emergent diabetic ketoacidosis or hyperglycemic hyperosmolar state (Buse 2002; Geller and MacFadden 2003).
Lifestyle or pharmacological interventions aimed at self-management of weight and glycemic targets in patients with schizophrenia and diabetes have shown mixed results. McKibbin et al. (2006) found that adults (>40 years of age) with schizophrenia who received a 24-week lifestyle intervention involving group diabetes education showed improved weight and HbA1C levels compared with control patients who received pamphlets on diabetes; however, those in the intervention had higher baseline levels of HbA1C. The STRIDE weight loss and lifestyle intervention study found that 40% of patients with schizophrenia in the treatment arm lost 5% or more of their initial weight; the number of sessions attended correlated with weight loss (Green et al. 2015). A similar result was seen in the ACHIEVE behavioral weight loss intervention study; however, participants completed the intervention at local psychiatric rehabilitation centers as opposed to being responsible for making weekly appointments on their own (Daumit et al. 2013). Other lifestyle interventions studied in this population group involved goals such as 150 minutes of physical activity per week, losing 5%–15% of weight, increasing fiber in the diet, and reducing dietary fat below 30% (Holt 2015).
Medications have also been used to improve glycemic control in individuals with prediabetes. Salsalate has been used in some small studies as a short-term therapy, because its anti-inflammatory properties can decrease the levels of inflammatory markers that contribute to insulin resistance in patients with or without schizophrenia (Goldfine et al. 2008; Keller et al. 2013). In the Diabetes Prevention Program (DPP) study, the insulin sensitizer metformin was found to reduce the onset of diabetes in prediabetic patients by 31% in comparison with placebo; unfortunately, patients with severe mental illness were excluded from this study (Knowler et al. 2002). Acarbose and thiazolidinediones have also been used to reduce the risk of diabetes in prediabetic individuals, although studies have not been conducted in patients with schizophrenia (Holt 2015). Glucagon-like peptide 1 (GLP-1) agonists are another class of drugs being studied for diabetes prevention in patients with schizophrenia treated with olanzapine or clozapine (Larsen et al. 2014). These agents are an attractive option because they induce early satiety.
Antipsychotics as well as mood stabilizers have been implicated in insulin resistance and weight gain through several proposed mechanisms; these include carbohydrate cravings and antagonism of histamine and serotonin2A and serotonin2C receptors (Calkin et al. 2013). In patients with known diabetes, antipsychotics with lower propensities to cause weight gain and glucose intolerance, such as perphenazine, molindone, aripiprazole, and ziprasidone, should be favored (Meyer et al. 2008) (see Chapter 36, “Psychopharmacology,” for a full discussion). Unsurprisingly, patients who are adherent to their antipsychotic medications are more likely to adhere to their diabetes medications (Hansen et al. 2012); therefore, good glycemic control warrants a multidisciplinary effort from mental health care professionals, primary care physicians, and diabetologists.
Insulin is an anabolic hormone that aids in glycemic control at the expense of weight gain; therefore, a negative side of intensive diabetes management is weight gain (see also Chapter 13, “Eating Disorders”). Disturbed eating behavior (DEB) is common among adolescent girls and young women in the general population, and those with T1DM are more likely than their peers without diabetes to have two or more disturbed eating behaviors (Colton et al. 2004). Olmsted et al. (2008) defined DEB as eating disorder symptomatology not yet at the level of frequency or severity to merit a formal diagnosis; such behaviors include dieting for weight loss, binge eating, calorie purging through self-induced vomiting, laxative or diuretic use, excessive exercise, and insulin restriction (in the case of T1DM). Studies of the natural history of DEB in T1DM indicate that these behaviors persist and increase in severity over time, becoming more common in young adulthood (Colton et al. 2004; Peveler et al. 2005). Evidence suggests that in comparison with women without diabetes, women with T1DM have 2.4 times the risk of developing an eating disorder and 1.9 times the risk of developing subthreshold eating disorders (Jones et al. 2000). Predisposing factors for DEB in adolescents with T1DM, as identified by Peterson et al. (2015), included a preoccupation with food due to the need for teens to count their carbohydrates, weight gain due to the use of insulin, and overeating after episodes of hypoglycemia caused by restrictive behaviors. Other characteristics associated with DEB include valuing others’ opinions or needs before one’s own (Young-Hyman and Davis 2010), having high levels of diabetes distress, having fears of hypoglycemia, and having poor diabetes self-care behaviors (Goebel-Fabbri et al. 2008). As noted for mood disorders, practitioners should screen patients with T1DM for comorbid eating disorders. In females ages 13–53 years, the Eating Disorders Inventory–3 (Garner 2004) can be used (Young-Hyman et al. 2016).
Women with T1DM may manipulate insulin (e.g., taking reduced insulin doses or omitting necessary doses altogether) as a means of caloric purging. Intentionally induced glucosuria—known as “diabulimia” (Shaban 2013)—is a powerful weight loss behavior and a symptom of eating disorders unique to T1DM. Diabulimia is not intended to describe the subset of people who may omit insulin for reasons other than weight loss (e.g., fear of hypoglycemia) (Weinger and Beverly 2010). Questions such as “Do you ever change your insulin dose or skip insulin doses to influence your weight?” or “How often do you take less insulin than is prescribed?” can be helpful in screening for insulin omission, especially for patients who present with persistently elevated HbA1C levels, repeated episodes of diabetic ketoacidosis, frequent hospitalizations, drastic weight changes, or amenorrhea (Gagnon et al. 2012).
Intermittent insulin omission or dose reduction for weight loss purposes has been found to be a common practice among women with T1DM. As many as 31% of women with T1DM report intentional insulin restriction, with rates of this disturbed eating behavior peaking in late adolescence and early adulthood (40% of women between the ages of 15 and 30 years) (Polonsky et al. 1994). Even subthreshold disturbed eating behaviors can lead to significant medical and psychological consequences in the context of diabetes (Verrotti et al. 1999). In one study, use of insulin restriction was associated with a threefold increased risk of death over the 11-year follow-up period (Goebel-Fabbri et al. 2008).
Binge-eating disorder (BED) with or without inappropriate compensatory behavior is a common problem seen in T2DM. If the binge is accompanied by certain behaviors, then the diagnosis becomes that of bulimia. Behaviors used to compensate for overeating in persons with T1DM include skipping meals, misusing diuretics and/or diet pills, underdosing insulin to induce glucosuria, and self-inducing vomiting (Gagnon et al. 2012). Obesity is a significant risk factor in T2DM, and recurrent binge eating may increase the risk of obesity development (Striegel-Moore et al. 2000). Initial studies of BED and T2DM relied on small, nonrepresentative samples. Kenardy et al. (1994) found that 14% of the patients with newly diagnosed T2DM experienced problems with binge eating, compared with 4% of individuals in the age-, sex-, and weight-matched control group. In a study of Brazilian middle-aged, low-educated individuals with T2DM, there was a 10% prevalence of BED (Papelbaum et al. 2005). Those with both conditions tended to have a family history of mood disorders and a personal history of anxiety disorder. Another study showed higher rates of both depression and anxiety in those with T2DM and BED compared with those with just BED, but the difference was not statistically significant, and HbA1C levels did not differ between the two groups (Crow et al. 2001).
Night-eating symptoms also have been associated with obesity and poor diabetes control. In a survey of adults with T2DM, increased symptoms of night eating were associated with poorer glycemic control and disruptions in eating, sleep, and mood, including a significantly increased likelihood of having HbA1C levels greater than 7% (Hood et al. 2014). In the largest study of its kind to date, more than 5,000 patients with T2DM were evaluated to determine whether binge eating was related to weight loss after a 1-year intervention. Larger weight losses were observed in those patients who never endorsed binge eating or who reported that they were no longer binge eating at 1-year follow-up (Gorin et al. 2008). Thus, recurrent binge eating and night eating symptoms can be expected to make it difficult to control diabetes and weight.
A multidisciplinary team approach, including a diabetologist, nurse educator, nutritionist with eating disorder and diabetes training, and mental health care practitioner, is ideal for the treatment of comorbid eating disorders and diabetes (Kahn et al. 2005; Mitchell et al. 1997). At this time, little research has examined treatment efficacy for eating disorders in the context of diabetes; however, a large research literature on treatment outcomes in bulimia nervosa supports the use of CBT in combination with antidepressant medications as the most effective treatment (Peterson and Mitchell 1999; Walsh and Devlin 1995).
Early in treatment, intensive glycemic management of diabetes is not an appropriate target for a person with diabetes and an eating disorder. Overly intensive diabetes management may actually aggravate obsessional thinking about food and weight in patients with eating disorders. The first goal should focus on medical stabilization. Gradually, the team can build toward increasing doses of insulin, increases in food intake, greater flexibility of meal plans, regularity of eating routine, and more frequent blood glucose monitoring.
For information on diabetes and sexual function, see Chapter 15, “Sexual Dysfunctions.”
Older persons with diabetes are at increased risk of both cognitive impairment and dementia, and their risk is 50%–100% greater than that in persons without diabetes (Mayeda et al. 2015). Cognitive impairment in diabetes is influenced by glycemic control as well as control of comorbid conditions such as hypertension and dyslipidemia. Most of the studies of cognition have been in T2DM. The American Diabetes Association (2017c) recommends screening persons older than 65 years for mild cognitive impairment with the Mini-Mental State Examination and the Montreal Cognitive Assessment. Managing patients with cognitive dysfunction and diabetes can be difficult, as they may be unable to participate in self-care behaviors such as adhering to a diabetic diet, testing blood sugars, or taking medications. Some of these issues can be mitigated by using alternative methods of nutrition, giving meal insulin after the patient eats, using long-acting medications, or scheduling medication administration/glucose testing for times when the patient is more cooperative (Munshi et al. 2016).
Some risk factors for dementia in diabetic individuals are similar to those in the general population: low level of education, unmarried status, depression, and older age. Some of these risk factors are more common in those with diabetes: chronic severe hyper/hypoglycemia, history of diabetic ulcer or limb amputations, retinopathy, and coronary artery disease (Bruce et al. 2014). The diabetes-specific dementia risk score can be used to predict the 10-year risk of developing dementia in persons with T2DM (Exalto et al. 2013). The most common types of dementia are Alzheimer’s and vascular, or a combination of the two (Strachan et al. 2008).
Neurocognitive decline in diabetes is thought to be mediated by chronic hyperglycemia and insulin resistance contributing to the formation of free radicals, inflammation, and advanced glycation end products. These agents then contribute to the formation of neurofibrillary tangles and beta-amyloid deposition, and micro/macrovascular disease, leading to cognitive decline with eventual dementia (Mayeda et al. 2015). Recurrent episodes of hypoglycemia also have been implicated in cognitive decline. In a longitudinal study of elderly persons with T2DM, each visit to the emergency department for hypoglycemia increased the risk of eventual dementia by 2.39% (Whitmer et al. 2009). This study did not track episodes of hypoglycemia that did not require an emergency department visit, so the risk may be even greater. Interestingly enough, the same association is not seen in persons with T1DM, who are at even greater risk of hypoglycemia. In both the DCCT and the Epidemiology of Diabetes Interventions and Complications (EDIC) studies (N=1,144), patients randomly assigned to either intense or conventional treatment arms did not have cognitive deficits noted on extensive neuropsychological testing (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group et al. 2007). When the data were reanalyzed after elimination of cohorts with visual impairment, stroke, or severe renal disease, patients in the conventional treatment group showed worsening of psychomotor speed. Another cause of cognitive impairment in diabetes is depression, especially in the elderly (Park and Reynolds 2015). Vitamin B12 deficiency should also be considered as a cause of cognitive dysfunction in patients treated with metformin, which decreases B12 absorption in the terminal ileum (Biemans et al. 2015). Statins were previously believed to be associated with cognitive dysfunction, but subsequent studies have disproved this association (Ott et al. 2015).
Hyperthyroidism and hypothyroidism are accompanied by a variety of physiological, psychiatric, and cognitive symptoms. Patients with psychiatric disorders, especially depression, have elevated rates of thyroid disease (Farmer et al. 2008). However, routine screening of psychiatric inpatients for thyroid dysfunction is not warranted, given that cases of dysfunction are not common in the absence of physical signs of hypo- or hyperthyroidism (Garnier et al. 2016).
Hyperthyroidism is accompanied by a host of physiological symptoms, including nervousness, sweating, fatigue, heat intolerance, weight loss, and muscle weakness. The most common cause of hyperthyroidism is Graves’ disease. Less common causes include toxic nodular goiter and thyroid-stimulating hormone (TSH)–secreting pituitary tumors. Graves’ disease is an autoimmune disorder that also causes ophthalmopathy and infiltrative dermopathy (pretibial edema). Some evidence shows that stress can precipitate Graves’ disease (Vita et al. 2015) and can aggravate treated disease (Fukao et al. 2003). The presentation of hyperthyroidism can vary depending on the age of the patient. In younger patients, hyperthyroidism typically manifests as hyperactivity or anxious dysphoria, whereas in the elderly, it can manifest as apathy or depression (referred to as “apathetic hyperthyroidism”). The best screening test for hyperthyroidism is measurement of serum TSH, but a low TSH level should be followed by a free thyroxine (T4) test to confirm the diagnosis. Treatment options for hyperthyroidism include antithyroid medications, thyroidectomy, and radioactive iodine.
Patients with hyperthyroidism often present with anxiety, hypomania, depression, and cognitive difficulties. There are many case reports of mania or psychosis in patients with extreme hyperthyroidism (thyrotoxicosis) (Brownlie et al. 2000). Ironically, lithium can precipitate hyperthyroidism. Psychiatric symptoms correlate poorly with thyroid hormone levels (Vogel et al. 2007), and typically resolve with antithyroid therapy or with use of beta-blockers (Trzepacz et al. 1988). Consequently, psychiatric drugs may not be needed and should be reserved for severe mood or psychotic symptoms, or for psychiatric symptoms that persist despite effective antithyroid treatment, as is not uncommon (Cramon et al. 2016). Hyperthyroidism may increase risk for future psychopathology. A Danish study that followed 2,631 patients with hypothyroidism and matched control subjects without the disorder over 6 years found that the patients were more likely than controls to receive psychiatric medications and to be psychiatrically hospitalized by study end (Brandt et al. 2013). A Taiwanese cohort study in 21,574 hyperthyroid patients and matched control subjects found more than twice the risk of bipolar disorder in patients compared with controls (Hu et al. 2013). Even subclinical hyperthyroidism (low TSH, normal T4) may increase risk for depression (Kvetny et al. 2015).
Hyperthyroid patients have been reported to have a variety of cognitive impairments (e.g., Yuan et al. 2015), although subjective cognitive complaints are not supported by objective evidence (Vogel et al. 2007). A recent meta-analysis of prospective studies concluded that even subclinical hyperthyroidism may be associated with an elevated risk for cognitive decline in the elderly (Rieben et al. 2016), but there is no evidence that antithyroid treatment prevents such decline.
Hypothyroid patients often experience weakness, fatigue, somnolence, cold intolerance, weight gain, constipation, hair loss, hoarseness, stiffness, and muscle aches. The most common cause of hypothyroidism is autoimmune thyroiditis (Hashimoto’s thyroiditis). Hypothyroidism is also a side effect of lithium. Radioactive iodine, the most commonly used modality for treating hyperthyroidism (such as in Graves’ disease), may cause hypothyroidism, which may go undiagnosed for several years after treatment for hyperthyroidism.
The symptoms of hypothyroidism overlap with retarded depression, and the diagnosis is easy to miss in patients who already have a depression diagnosis. Physical signs of hypothyroidism include weakness, bradycardia, facial puffiness, weight gain, hair loss, hoarseness, and slowed speech. The best screening test for hypothyroidism is measurement of serum TSH concentration, but an elevated TSH level should be followed by a free T4 determination to confirm the diagnosis. A serum TSH determination will be misleading in patients with secondary hypothyroidism caused by pituitary or hypothalamic disease. In such a patient, a free T4 measurement is usually diagnostic.
Severe hypothyroidism is relatively rare, although milder hypothyroidism is common. Patients with overt hypothyroidism are usually symptomatic and have elevated TSH and low free T4 concentrations. Patients with subclinical hypothyroidism typically have either mild or no symptoms of hypothyroidism, and have an elevated TSH level and a normal free T4 level. Subclinical hypothyroidism is fairly common, affecting 5%–10% of the population, mainly women, and occurs in 15%–20% of women older than 45 years. Subclinical hypothyroidism is particularly common in elderly women.
A variety of cognitive functions may be impaired in overt hypothyroidism, including attention, memory, reaction time, and performance on speeded tests (Miller et al. 2007; Smith et al. 2015). One possible explanation is that cognitive inefficiency in hypothyroidism is a result of secondary depression. However, in some cases, patient perceptions of cognitive difficulty (rather than actual cognitive dysfunction) may be a result of depression or fatigue.
Earlier studies found subtle signs of cognitive dysfunction in patients with subclinical hypothyroidism, but more recent research has generally been less supportive of subclinical hypothyroidism as a cause of cognitive dysfunction (Pasqualetti et al. 2015; Rieben et al. 2016). Whether and when to treat subclinical hypothyroidism remains controversial (Garber et al. 2012).
Hypothyroidism is a known cause of secondary depression. Concurrent symptoms of depression are extremely common in patients with hypothyroidism (Bathla et al. 2016) but typically do not include reported guilt and lowered self-esteem (Smith et al. 2015). Depressive symptoms are also increased in patients with subclinical hypothyroidism (Blum et al. 2016; Demartini et al. 2010). Whether subclinical hypothyroidism is a risk factor for depression is controversial (de Jongh et al. 2011; Yu et al. 2016).
Triiodothyronine (T3) has long been used to augment the effects of antidepressants in treatment-resistant depression.
Patients with bipolar disorder with either rapid cycling or mixed episodes have particularly high rates of subclinical hypothyroidism. In one study, almost 40% of rapid-cycling or mixed-episode bipolar patients were found to have subclinical hypothyroidism (Joffe et al. 1988). Although lithium-induced thyroid dysfunction may be the cause in some cases, subclinical hypothyroidism is common in bipolar patients receiving other mood stabilizers (Lambert et al. 2016). Every patient with rapid-cycling bipolar disorder should be evaluated for (subclinical) hypothyroidism and should receive T4 if TSH levels are elevated. High-dose thyroid supplementation has been advocated in the treatment of bipolar disorder, even if patients are euthyroid, and studies have found that this treatment does not increase the risk of adverse cardiac effects or osteoporosis (Kelly et al. 2016).
Untreated hypothyroidism can result in psychosis, so-called myxedema madness. This condition was fairly common—reported in up to 5% of all hypothyroid patients (Kudrjavcev 1978)—before the widespread use of modern thyroid function tests. It is now rare, although cases continue to be reported. Psychotic symptoms typically remit when TSH and T4 levels return to normal. Another rare possibility in hypothyroid patients is Hashimoto’s encephalopathy, a delirium with psychosis, seizures, and focal neurological signs, which is associated with high serum antithyroid antibody concentrations, responsive to corticosteroids, and thought to be an autoimmune disorder. Most cases of Hashimoto’s encephalopathy are euthyroid or mildly hypothyroid (Montagna et al. 2016).
Congenital hypothyroidism usually occurs as a result of thyroid agenesis or dysgenesis, although inherited defects in thyroid hormone synthesis also may play a role. From a global perspective, iodine deficiency is the most common cause of congenital hypothyroidism. Newborns with untreated hypothyroidism develop the syndrome of cretinism, characterized by mental retardation, short stature, poor motor development, and a characteristic puffiness of the face and hands. Because early treatment is essential to prevent permanent mental retardation, all infants born in the United States are screened for hypothyroidism at birth (American Academy of Pediatrics et al. 2006). Treatment with thyroid hormones before age 3 months can result in normal intellectual development in most infants.
Hyperparathyroidism can cause bone disease, kidney stones, and hypercalcemia via oversecretion of parathyroid hormone. Symptoms of hypercalcemia include anorexia, thirst, frequent urination, lethargy, fatigue, muscle weakness, joint pain, constipation, and, when severe, depression and eventually coma.
The prevalence of hyperparathyroidism is 0.1%. It is three times more common in women than in men, and its prevalence increases with age. Hyperparathyroidism may occur as a consequence of radiation therapy to the head and neck and is an underrecognized side effect of long-term lithium therapy (Albert et al. 2015). Cessation of lithium often does not correct the hyperparathyroidism, necessitating parathyroidectomy.
With mild hypercalcemia, patients may show personality changes, lack of spontaneity, and lack of initiative. Moderate hypercalcemia (serum calcium concentration = 10–14 mg/dL) may cause dysphoria, anhedonia, apathy, anxiety, irritability, and impairment of concentration and recent memory. In severe hypercalcemia (serum calcium concentration >14 mg/dL), confusion, disorientation, catatonia, agitation, paranoid ideation, delusions, auditory and visual hallucinations, and lethargy progressing to coma may occur. Symptoms of depression, anxiety, and cognitive impairment are very common prior to parathyroidectomy and resolve in most patients following surgery (Kahal et al. 2012; Liu et al. 2016; Weber et al. 2013).
Patients with hypoparathyroidism present with hypocalcemia causing increased neuromuscular irritability. Typical symptoms include paresthesias, muscle cramps, carpopedal spasm, and (less commonly) facial grimacing and seizures. Complications include calcification of the basal ganglia and pseudotumor cerebri. Psychiatric symptoms may include anxiety, emotional irritability, and lability. Severe hypocalcemia causes tetany and seizures. Hypoparathyroidism is caused by inadequate parathyroid hormone secretion, most often as a result of parathyroid or thyroid surgery. Hypoparathyroidism is also common in the 22q11.2 deletion syndrome (velocardiofacial syndrome), in which psychosis is common in adults and mood, anxiety, attentional, and behavior disorders are common in children (Radoeva et al. 2017).
Cognitive and neurological deficits, which are common in patients with long-standing hypoparathyroidism, may be irreversible but do not always correlate with the extent of intracranial calcification (Aggarwal et al. 2013).
Osteoporosis is a metabolic disturbance of bone resulting in low bone mass, reduced bone strength, and increased risk of fractures. Osteoporosis occurs most commonly in postmenopausal women. The association between depression and osteoporosis is bidirectional; there is evidence that depression is a risk factor for osteoporosis in both women and men (Lee et al. 2015). The causal relationship between depression and osteoporosis is unclear. Some of the association may be the result of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), which as a class are associated with reduced bone mineral density and increased fracture risk (Bruyère and Reginster 2015). Other risk factors for osteoporosis in depression include hypercortisolism, smoking, alcohol consumption, and physical inactivity. An increased risk of osteoporosis might be expected in patients receiving long-term augmentation of antidepressant therapy with T3, but whether chronic augmentation of antidepressants with T3 increases risk of osteoporosis has not been studied. Osteoporosis is common in people with schizophrenia, although the extent to which osteoporosis is due to antipsychotic-induced hyperprolactinemia is unclear (De Hert et al. 2016).
Cushing’s syndrome results from abnormally high levels of cortisol and other glucocorticoids. The most common cause is the pharmacological use of corticosteroids, followed by excessive corticotropin secretion (most commonly by a pituitary tumor, referred to as Cushing’s disease) and adrenal tumors. Symptoms and signs of Cushing’s syndrome include truncal obesity and striae, diabetes, hypertension, hyperglycemia, muscle weakness, osteopenia, skin atrophy and bruising, increased susceptibility to infections, and gonadal dysfunction.
Cushing’s syndrome patients commonly experience a range of psychiatric symptoms, including depression, anxiety, hypomania or frank mania, psychosis, and cognitive dysfunction (Pivonello et al. 2015; Starkman 2013), with rates varying widely across studies. Depression is the most prevalent psychiatric disturbance in Cushing’s syndrome. A full depressive syndrome has been reported in 50%–80% of cases, accompanied by irritability, insomnia, crying, decreased energy and libido, poor concentration and memory, and suicidal ideation (Pivonello et al. 2015). Although antidepressants are less effective than in regular major depressive disorder, they are helpful until definitive treatment of Cushing’s syndrome can be provided. Mood symptoms generally improve with resolution of hypercortisolemia (Pivonello et al. 2015) but may persist in remitted patients (Valassi et al. 2017). There are many case reports of Cushing’s syndrome patients presenting with a variety of psychotic symptoms, usually as part of a manic or depressive syndrome (Arnaldi et al. 2003), leading to misdiagnosis of bipolar disorder or a schizophrenia spectrum disorder. Chronic hypercortisolism can impair cognition, with effects on attention, executive performance, and nonverbal memory (Forget et al. 2016) that are not attributable to depression. Cushing’s disease causes reduction in hippocampal volume and cerebral atrophy, which may not be entirely reversible after cortisol levels return to normal (Andela et al. 2015). The data are mixed on whether cognitive deficits improve or persist after treatment of Cushing’s syndrome (Arnaldi et al. 2003).
The primary treatment for corticotropin-dependent Cushing’s syndrome is surgery. However, medical therapies—including inhibitors of steroidogenesis (e.g., etomidate) and glucocorticoid receptor antagonists (e.g., mifepristone)—have a role in reducing psychiatric and other symptoms (Fleseriu et al. 2012).
Insufficient production of adrenal corticosteroids can be caused by several mechanisms. Primary adrenal insufficiency, or Addison’s disease, results in deficient secretion of mineralocorticoids and glucocorticoids. The major causes of Addison’s disease are autoimmune adrenalitis, metastatic cancer, and infection (e.g., tuberculosis, HIV). The most common cause of secondary adrenal insufficiency is suppression of corticotropin (adrenocorticotropic hormone [ACTH]) secretion by chronic glucocorticoid administration. Less common secondary causes include diseases that result in pituitary destruction. In secondary adrenal insufficiency, ACTH levels are low, whereas in Addison’s disease, the deficiency in cortisol results in an increase in ACTH. This increase in ACTH can cause hyperpigmentation. The decrease in mineralocorticoid levels results in contraction of the extracellular volume, leading to postural hypotension. Individuals with adrenal insufficiency are prone to hypoglycemia when stressed or fasting. Although electrolytes can be normal in mild Addison’s disease, hyponatremia and hyperkalemia are typical. Other manifestations of adrenal insufficiency include anemia, anorexia, nausea, vomiting, diarrhea, abdominal pain, weight loss, and muscle weakness.
Psychiatric symptoms such as apathy, social withdrawal, fatigue, anhedonia, poverty of thought, and negativism are common in patients with Addison’s disease. Nonspecific symptoms such as weakness, fatigue, and anorexia often appear before more specific findings, making it difficult to attribute the cause to adrenal insufficiency. Cognitive impairment, especially memory loss, is often present but ephemeral and varying in severity (Tiemensma et al. 2016). During Addisonian crisis, patients may experience delirium, disorientation, confusion, and even psychosis (Anglin et al. 2006). Adrenal insufficiency is particularly likely to be misdiagnosed as primary major depression in patients with chronic medical illness who previously received high doses of corticosteroids, resulting in unrecognized secondary adrenal insufficiency. Another possible psychiatric misdiagnosis is anorexia nervosa.
Although the diagnosis of adrenal insufficiency may be suspected on the basis of a low morning serum cortisol level, definitive diagnosis requires a corticotropin stimulation test. This is typically performed with cosyntropin, a synthetic ACTH analogue. An increase in the serum cortisol concentration to greater than 20 ng/dL following cosyntropin injection excludes the diagnosis of adrenal insufficiency.
The cause of depression in patients with Addison’s disease is not clear. Regardless of the etiology of adrenal insufficiency, urgent treatment is indicated. Both glucocorticoid and mineralocorticoid replacement are usually necessary in the treatment of Addison’s disease, whereas glucocorticoid replacement alone is sufficient in secondary adrenal insufficiency.
Adrenal insufficiency is also a feature in adrenoleukodystrophy, a rare, X-linked inherited metabolic disease, which also leads to leukoencephalic myeloneuropathy. Adult onset is rare but commonly presents with psychiatric symptoms, including mania, psychosis, and cognitive dysfunction (Rosebush et al. 1999).
Acromegaly is a disease of excess growth hormone (GH) secretion. Deficiency of GH in children results in short stature, as discussed in Chapter 32, “Pediatrics.” The most common cause of acromegaly is a GH-secreting adenoma of the anterior pituitary. Clinical manifestations of acromegaly include headache, cranial nerve palsies, acral enlargement (frontal bossing), increased hand and foot size, prognathism, soft tissue overgrowth (macroglossia), glucose intolerance, and hypertension.
Psychiatric disturbances associated with acromegaly include mood disorders, anxiety, and personality changes, which may persist after treatment (Tiemensma et al. 2010). Psychiatric symptoms and impairment in quality of life have been attributed both to the endocrine disorder itself and to the psychosocial stress of disfigurement (T’Sjoen et al. 2007). However, studies have found that body-image perceptions and quality of life are more reflective of emotional state than of objective measures of the disease (Dimopoulou et al. 2017; Geraedts et al. 2015). Personality changes described in acromegalic patients include loss of initiative and spontaneity, with marked lability in mood (Pantanetti et al. 2002). Cognitive impairments in attention, memory, and executive function are common (Sievers et al. 2012).
Treatment of acromegaly may include surgery, medication, and radiation.
Pheochromocytomas are rare catecholamine-secreting tumors derived from the adrenal medulla and sympathetic ganglia. The clinical signs and symptoms arise from the release of catecholamines, which leads to increased heart rate, blood pressure, myocardial contractility, and vasoconstriction, resulting in paroxysmal hypertension, headache, palpitations, diaphoresis, anxiety, tremulousness, pallor (rarely flushing), chest and abdominal pain, and often nausea and vomiting (Manger 2009). Because these are nonspecific symptoms, pheochromocytomas may be suspected in patients who actually have anxiety disorders (especially panic disorder), migraine or cluster headaches, stimulant abuse, or alcohol withdrawal. Among patients tested for pheochromocytoma, fewer than 2% are found to have the tumor (Eisenhofer et al. 2008). Many of those with negative tests have unexplained severe symptomatic paroxysmal hypertension, often referred to as “pseudopheochromocytoma,” which appears to be triggered by anxiety (Pickering and Clemow 2008). Cases of classic panic attacks in patients with pheochromocytoma have been reported in both adults and children (Manger 2009). There are reports of cases in which antidepressants have “unmasked” silent pheochromocytomas, presumably by inhibiting neuronal intake of circulating catecholamines.
There is still no consensus as to the “best test” for the diagnosis of pheochromocytoma. Some centers rely on 24-hour urine measurement of increased excretion of catecholamines and metanephrines. Plasma metanephrine determinations have an extremely high sensitivity (approaching 99%) and overall specificity (in the 85%–90% range) (Lenders et al. 2002). The finding of elevated urinary catecholamine levels is not specific to pheochromocytoma and can lead to misdiagnosis. Psychological and physiological stressors can elevate levels of urinary catecholamines. Substances that can interfere with testing include drugs (e.g., tricyclic antidepressants, buspirone, L-dopa, antipsychotics, stimulants, decongestants) as well as certain foods.
Multiple cases of factitious pheochromocytoma have been reported and include cases involving vanilla extract ingestion, phenylpropanolamine abuse, injection of catecholamines, and Valsalva maneuvers (Stern and Cremens 1998).
The rare possibility of a pheochromocytoma should be considered in patients with panic attacks, headaches, and labile hypertension, particularly those who do not respond to treatment. It is not necessary to screen for pheochromocytoma in patients who have only psychiatric symptoms; elevated catecholamines are common and likely to be false-positive results. Some psychotropic drugs may cause hypertensive reactions that mimic pheochromocytoma, and in rare cases the drugs may be unmasking an unsuspected pheochromocytoma.
Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome. The differential diagnosis of hyperprolactinemia includes pituitary adenomas, physiological causes (pregnancy and lactation), medication effects, chronic renal failure, primary hypothyroidism, and lesions of the pituitary stalk and the hypothalamus. Clinical signs in women include galactorrhea, menstrual irregularities, infertility, and decreased libido. Men present with diminished libido and rarely with galactorrhea.
Stress induces an increase in prolactin levels. Hyperprolactinemia has been associated with increased depression and anxiety, which resolve with treatment of hyperprolactinemia (Kars et al. 2007). In patients with treatment-resistant depression who have galactorrhea and/or amenorrhea, hyperprolactinemia should be considered as a possible causal factor (Holroyd and Cohen 1990).
Medication-induced hyperprolactinemia has been associated with antipsychotics and, to a lesser extent, antidepressants. Serum prolactin levels in patients taking therapeutic doses of typical antipsychotics are increased six- to tenfold from mean baseline prolactin levels (Arvanitis and Miller 1997). Atypical antipsychotics vary in their effects on prolactin (Ajmal et al. 2014; Peuskens et al. 2014). Most atypicals either cause no increase in prolactin secretion or increase prolactin transiently, but sustained hyperprolactinemia can occur in patients taking risperidone, paliperidone, and amisulpride. Haloperidol raises the serum prolactin concentration by an average of 17 ng/mL, while risperidone may raise it by 45–80 ng/mL, with larger increases in women than in men (David et al. 2000). Aripiprazole may reduce prolactin levels, and several clinical trials have demonstrated that switching from risperidone to aripiprazole, or adding it adjunctively, promptly reduced previously elevated prolactin levels (Chen et al. 2015).
Antidepressants with serotonergic activity, including SSRIs, monoamine oxidase inhibitors, and some tricyclic antidepressants, can cause modest elevations in prolactin (Ajmal et al. 2014) and may further elevate prolactin levels in patients also taking prolactin-elevating antipsychotics.
Patients on long-term regimens of prolactin-elevating antipsychotics are at risk of osteoporosis and should be educated about—and regularly monitored for—signs and symptoms of hyperprolactinemia.
For information on premenstrual disorders and disorders of menopause, readers are referred to Chapter 31, “Obstetrics and Gynecology.”
Polycystic ovary syndrome (PCOS) is a common disorder, affecting 5%–10% of women of childbearing age. Clinical manifestations include amenorrhea or oligomenorrhea, infrequent or absent ovulation, increased levels of testosterone, infertility, truncal obesity or weight gain, alopecia, hirsutism, acanthosis nigricans, hypertension, and insulin resistance. The cause of the disorder is unknown. The risk of developing PCOS is increased during treatment with valproate and seems to be higher in women with epilepsy than in women with bipolar disorder (Bilo and Meo 2008).
There are adverse psychosocial consequences of PCOS. Elevated rates of clinically significant anxiety and depression in women with PCOS have been documented in numerous studies, including meta-analyses (Barry et al. 2011; Blay et al. 2016; Dokras et al. 2012) and a Taiwanese national cohort study involving more than 5,000 women with PCOS (Hung et al. 2014). Increased risk for a much wider array of psychiatric disorders and suicidality was found in a Swedish national cohort study involving more than 24,000 women with PCOS (Cesta et al. 2016). Possible causal factors—including BMI, insulin resistance (e.g., Greenwood et al. 2015), hormonal differences (e.g., Annagür et al. 2013), hyperlipidemia, hirsutism, acne, infertility, body image, sexual functioning, and relationship satisfaction—have been examined, primarily with respect to depression. Studies to date have been relatively small, and no consistent associations have been found. Although the causal link between psychiatric symptoms and PCOS is not resolved, the frequency of these symptoms points to the importance of screening all PCOS patients for psychiatric syndromes, especially depression.
Testosterone deficiency in men can result from diseases affecting the testes, pituitary gland, or hypothalamus. Consequences of testosterone deficiency vary depending on the stage of sexual development. Testosterone production declines naturally with age, so that a relative testosterone deficiency occurs in older men. Hypogonadal disorders of the testes (primary hypogonadism) are most commonly caused by Klinefelter’s syndrome, mumps orchitis, trauma, tumor, cancer chemotherapy, or immune testicular failure (see Chapter 26, “Infectious Diseases,” for a discussion of hypotestosteronism in HIV infection). Pituitary lesions caused by tumors, hemochromatosis, sarcoidosis, or cranial irradiation can lead to secondary hypogonadism. The classic cause of hypothalamic hypogonadism is Kallmann’s syndrome (hypogonadotropic hypogonadism with hyposmia, sensorineural hearing loss, oral clefts, micropenis, and cryptorchidism). Hypogonadism in childhood is characterized by failure of normal secondary sexual characteristics to develop and diminished muscle mass. In adult men, typical complaints are sexual dysfunction, diminished energy, decreased beard and body hair, muscle loss, and breast enlargement.
Decreasing testosterone levels as men age appear to be associated with changes in mood and cognition, but no clear relation between psychiatric syndromes and testosterone levels has been established. Men with lower testosterone levels are more likely to be depressed (Westley et al. 2015) or to become depressed (Ford et al. 2016), but there are many potential explanations for this finding. The concept of a male climacteric with related mood, anxiety, and cognitive disorders is controversial.
Evidence supports the use of testosterone replacement in hypogonadal men for improvement of body composition and sexual function. Questions remain about the value of testosterone replacement in age-related testosterone decline as well as in the treatment of depressive disorder in hypogonadal men. In some but not all studies, testosterone does seem to improve mood in hypogonadal men. However, results from randomized controlled clinical trials do not support testosterone treatment for major depressive disorder. The risks associated with physiological doses of testosterone appear to be small. The possible increased risk of prostate cancer remains a concern, but the evidence to date does not substantiate it.
Although some studies have found that testosterone deficiency in women is associated with impaired sexual function, low energy, and depression, other studies have found that higher testosterone levels increase the risk of depression (Milman et al. 2015). What level represents deficiency, as well as the indications, risks, and benefits of replacement, is even less well defined in women than it is in men (see Chapter 15, “Sexual Dysfunctions”).
Hyponatremia’s principal manifestations are neuropsychiatric, and their severity is related to both the degree and the rapidity with which the disorder develops. Patients may have lethargy, stupor, confusion, psychosis, irritability, and seizures. Hyponatremia has many different causes, but those of particular psychiatric relevance are the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which can be caused by many psychotropic drugs (especially carbamazepine and oxcarbazepine, but also SSRIs, tricyclic antidepressants, and antipsychotics); and psychogenic polydipsia. Polydipsia leading to hyponatremia in patients with schizophrenia is mediated by a reduced osmotic threshold for the release of vasopressin and by a defect in the osmoregulation of thirst. Acute-onset symptomatic hyponatremia may require emergent treatment with hypertonic (3%) saline. In chronic cases, correction should be gradual to minimize the risk of pontine myelinolysis, relying on fluid restriction and vasopressin receptor antagonists (Siegel 2008).
The signs of hypernatremia are also predominantly neuropsychiatric and include cognitive dysfunction, delirium, seizures, and lethargy progressing to stupor and coma. Similar symptoms are seen with any hyperosmolar state, such as extreme hyperglycemia. Hypernatremia is usually caused by dehydration, with significant total body water deficits. A rare cause is adipsia, the absence of thirst even in the presence of water depletion or sodium excess, usually caused by a hypothalamic lesion (which may result in other psychopathology) (Harrington et al. 2014).
Hypokalemia produces muscular weakness and fatigue and, if severe, may cause severe paralysis (hypokalemic periodic paralysis), but central nervous system functions typically are not affected. Nevertheless, patients with symptomatic hypokalemia sometimes receive the misdiagnosis of depression. Hypokalemia is very common in eating disorders (see Chapter 13, “Eating Disorders,” for a full discussion of the metabolic complications of eating disorders), chronic alcoholism, and alcohol withdrawal. The adverse effects of hyperkalemia are mainly cardiac, but severe muscle weakness also may occur.
Hypocalcemia and hypercalcemia were described earlier in this chapter in the “Parathyroid Disorders” section. Magnesium levels usually rise and fall in concert with calcium levels. Hypomagnesemia can cause anxiety, irritability, tetany, and seizures. Low magnesium levels are very common in alcoholic patients and in refeeding starving patients (including those with anorexia nervosa and catatonia). Cyclosporine causes hypomagnesemia, which can contribute to its neuropsychiatric side effects. Hypermagnesemia is much less common, usually resulting from excessive ingestion of magnesium-containing antacids or cathartics, and causes central nervous system depression.
Hypophosphatemia causes anxiety, hyperventilation, irritability, weakness, delirium, and, if severe, seizures, coma, and death, in addition to symptoms in many other organ systems. Hypophosphatemia occurs in the same settings as hypomagnesemia.
Metabolic acidosis results in compensatory hyperventilation. When the acidosis is severe and acute, as in diabetic ketoacidosis, fatigue and delirium are present and may progress to stupor and coma. Acute metabolic acidosis is a complication of a wide variety of overdoses and toxic ingestions. Patients with chronic metabolic acidosis appear depressed, with prominent anorexia and fatigue. Patients with severe metabolic alkalosis present with apathy, confusion, and stupor. Respiratory acidosis results from ventilatory insufficiency, and respiratory alkalosis results from hyperventilation (see Chapter 18, “Lung Disease”).
Deficiencies of vitamin B12 and folate are discussed in Chapter 23, “Hematology.”
Pellagra, originally thought to be a deficiency of niacin, is now recognized to be a complex deficiency of multiple vitamins and amino acids. The classic triad of symptoms is dermatitis, dementia, and diarrhea, but irritability, anxiety, depression, apathy, and psychosis all have been reported (Prakash et al. 2008). Pellagra is now rare in the developed nations, but cases are still reported in anorexia nervosa, inflammatory bowel disease, and alcoholism.
Thiamine deficiency (beriberi) causes cardiac and neuropsychiatric syndromes, including peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Wernicke’s consists of vomiting, nystagmus, ophthalmoplegia, fever, ataxia, and confusion that can progress to coma and death. Korsakoff’s is a dementia with amnesia, impaired ability to learn, confabulation, and often psychosis. Improvement usually occurs with thiamine replacement but may be slow. Giving intravenous glucose to a thiamine-deficient patient without coadministering thiamine may precipitate acute beriberi. Thiamine deficiency is well known and most frequent in alcoholic patients, but it also occurs in patients undergoing chronic dialysis, patients refeeding after starvation (including patients with anorexia nervosa), and individuals on fad diets.
Pyridoxine (vitamin B6) deficiency causes peripheral neuropathy and neuropsychiatric disorders, including reports of seizures, migraine, chronic pain, depression, and psychosis. Homocysteine is elevated in B6 deficiency and may play a role in accelerating vascular disease and dementia. Pyridoxine deficiency is common because many drugs act as its antagonist. Clinical trials of B6 supplementation in healthy elderly persons and in cognitively impaired subjects to date have not shown improvements in mood or cognition.
Vitamin E deficiency can cause areflexia, ataxia, and decreased vibratory and proprioceptive sensation. Although lower levels of vitamin E have been reported in major depressive disorder, there is no evidence that vitamin E supplementation benefits mood or cognition.
The porphyrias are a group of rare disorders of heme biosynthesis that can be inherited or acquired. Neuropsychiatric manifestations occur in the two neuroporphyrias (acute intermittent porphyria and plumboporphyria) and two neurocutaneous porphyrias (hereditary coproporphyria and variegate porphyria). Acute intermittent porphyria is the most common. Recurrent acute attacks are typical in all four, with variable manifestations. In acute porphyria, the cardinal signs are abdominal pain, peripheral neuropathy, and psychiatric symptoms, which can be the sole presenting symptoms, including anxiety, depression, psychosis, and delirium. Seizures, autonomic instability, dehydration, electrolyte imbalance, and dermatological changes also may occur. Symptoms may vary considerably among patients and in the same patient over time, and they can mimic symptoms of other psychiatric and medical disorders, making diagnosis a challenge (Kumar 2012). Stress has long been considered a precipitant of acute episodes, but data are lacking. The diagnosis is made by measuring porphyrins and their metabolites in stool and urine during an acute episode. Between episodes, porphyrin levels return to normal. Diagnosis is more likely to be made when the clinician has a high index of suspicion. The diagnosis may be especially difficult because neuropsychiatric symptoms may continue well after the end of an acute episode. Therapy is primarily supportive and includes identification of precipitants. Although barbiturates clearly can trigger attacks, evidence is inadequate regarding the role of other psychotropic drugs. A comprehensive rating of drugs’ risk for porphyrinogenicity is available at the Drug Database for Acute Porphyria (www.drugs-porphyria.org).
Inborn errors of metabolism usually presenting in neonates or young children may in rare cases first present in adolescence or adulthood as a psychiatric disorder. Such a possibility may be suspected because of family history or because psychiatric symptoms present as part of a more complex clinical picture with systemic, cognitive, or motor signs (Sedel et al. 2007). Such a diagnostic possibility also should be considered when a psychiatric disorder presents atypically with subtle “organic” signs and responds poorly to standard treatments. Some of these disorders present with acute and recurrent attacks of confusion, which may be misdiagnosed as acute psychosis. Examples include urea cycle disorders (e.g., ornithine transcarbamylase deficiency) and homocysteine remethylation defects (e.g., hyperhomocysteinemia). Others may produce chronic psychiatric symptoms (e.g., catatonia, hallucinations), including homocystinuria, Wilson’s disease, adrenoleukodystrophy, and some lysosomal disorders (e.g., Gaucher’s disease). Mild intellectual disability and late-onset behavioral or personality changes may be a manifestation of homocystinuria, cerebrotendinous xanthomatosis, monoamine oxidase A deficiency, succinic semialdehyde dehydrogenase deficiency, or creatine transporter deficiency. Recognition of such disorders in an adult with only psychiatric symptoms may be very difficult, but earlier recognition and specific intervention can prevent irreversible nervous system (and other organ) injury.
Endocrine and metabolic disorders frequently occur in conjunction with common psychiatric conditions. The causal linkages and mechanisms vary widely. In some situations, the endocrine state manifests in part as a psychiatric condition. In other instances, the psychiatric condition may be a complex biopsychosocial and/or biological response to the endocrine disorder. Psychiatric conditions and their treatment with psychotropic drugs may also increase risk of endocrine disorders.
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