Management of Psychiatric Disorders in Patients with Endocrine Disorders

Abstract

The neuropsychiatric symptoms and disorders among endocrine disorders are discussed in the context of current global and local epidemiological data. Neuropsychiatric symptoms, clinical differentials in hypothyroidism, hyperthyroidism, and parathyroid disorders, and relevant management protocols are described. HPT axis and its interaction with psychotropic usage are mentioned. Stress diathesis, depression, anxiety disorders, and severe mental illnesses and their respective association with diabetes, the relevant mechanisms, and management protocols are stated. The metabolic syndrome, its definition, and its relationship to psychotropic usage are laid out. Moreso, best clinical practices for scenarios such as hyperprolactinemia and psychiatric illnesses, and steroid-induced psychosis are mentioned.

INTRODUCTION

There is an intimate and complex relationship between endocrine disorders and mental illness with increasing evidence of a bidirectional relationship between the two, e.g., major depression with onset of diabetes and vice versa.[1]

Historically, Kraepelin had hypothesized dementia praecox to be an endocrine disorder due to lack of thyroxin during the early part of the development which caused impairment in the maturation of behavior.[2]

Endocrine disorders such as hypo and hyperthyroidism and diabetes mellitus are associated with prominent abnormalities in the mental status and mental illness. That treatment can affect the endocrine status, viz., lithium in thyroid functions or second-generation antipsychotics affect the blood sugars and precipitate the diabetes status. On this background, we will discuss the specific endocrine disorders associated with mental illness.

THYROID AND PSYCHIATRIC ILLNESS

The first confirmed relationship between thyroid disorder and psychiatric morbidity was reported way back in 1888 by the Committee of the Clinical Society of London.[3] Asher, roughly seven decades back, reported psychotic symptoms in 14 hypothyroid individuals and named the phenomenon myxedema madness.[4] This seminal case series laid the future ground for the definitive role of thyroid hormones (THs) in psychiatric disorders.[3]

Depression, anxiety, and cognitive difficulties are commonly reported neuropsychiatric symptoms (NPSs) in thyroid disorders.[3] Hypothyroidism symptoms could be mistaken for those of depression, whereas hyperthyroidism manifests as anxiety (up to 80%),[3] emotional lability, dysphoria, depression (up to 70%), and rarely mania.[4] Moreover, both hypothyroidism and hyperthyroidism are known to cause cognitive impairment citing which the recommendation is placed for screening of thyroid dysfunction in cognitive disorders.[5] Interestingly, there is no consensus on population screening for thyroid diseases. However, Garber et al. in the recent clinical practice guidelines (CPG) have endorsed the need for case finding (thyroid disease) in psychiatric disorders.[6]

Hypothyroidism

Overt hypothyroidism (OH) is when there are elevated serum thyroid-stimulating hormone (TSH) value and decreased serum thyroxin (T4) and/or triiodothyronine (T3) levels, with some clinical evidence of deficient TH action. The majority of affective disorder probands are euthyroid, but 1%–4% of these have OH and 4%–40% have subclinical hypothyroidism (SCH).[4] Moreover, up to 52% of refractory depression, probands may have evidence of SCH.[4,7] A recent meta-analysis revealed the odds of depression and anxiety in hypothyroidism to be significantly high, i.e., 3.56 and 2.32, respectively.[8] In addition, up to 25% of female rapid cycles have been found to have hypothyroidism.[5]

Neuropsychiatric symptoms

NPSs in OH are ill-defined, nonspecific, and insidious in onset.[3] Cognitive deficits such as attention, concentration, and memory issues would start manifesting at early stages. With chronicity, the inability to perform daily chores and slow processing speed ensue. The striking features are psychomotor retardation and increased fatigability. Specific difficulties in sustained mental exertion, comprehending complex questions, and learning new tasks are prevalent. Subsequent concern toward others and responsiveness is reduced. Along with these, the depressive effect has been frequently reported.[5] In severe cases, illusions and visual hallucinations (VHs) leading to paranoia are detected.[3] Psychosis in hypothyroidism has both admixture of affective and schizophrenia.[3]

Differential diagnosis

Because of reduced responsiveness, slowing of thoughts (and actions), and attention problems, diagnosis may resemble depression. Depression in OH is colored with irritability and might run a chronic course. Psychosis in OH may be laden with confusion, persistent cognitive disturbances, and VH.

Treatment

Treatment with levothyroxine (LT4) improves NPSs, though the complete resolution of symptoms is not consistently achieved. Attainment of TSH levels in the physiological range generally would suffice to achieve adequate neuropsychiatric function. However, despite adequate LT4 supplementation (up to 1.6 mcg/kg/day[6]), some patients may still have residual NPSs (e.g., long-standing dementia). Studies have attributed this residuum possibly to disease labeling effect or ascertainment bias.[4] There were initial reports of T3 (not available in India), augmentation of LT4, and improvement in residual NPSs.[4] However, subsequent controlled studies have shown inconsistent results and the combination needs further evidence.[9] McDermott[9] has suggested further evaluation for residual NPSs [Table 1].

Table 1.

Further workup of residual neuropsychiatric symptoms in overt hypothyroidism

Thorough physical examination

Obstructive sleep apnea screening

Blood biochemistry including metabolic panel

Vitamin D levels

Thyroid antibodies

Exercise

Dietary changes

Sleep hygiene

Change of brand of levothyroxine

Subclinical hypothyroidism

SCH is diagnosed when TSH levels are elevated with normal circulating free T4 and T3 concentrations. Frequent NPSs (depression, anxiety, and cognition) in SCH have been reported at a young age, while studies have been inconsistent regarding NPS prevalence.[4] Cardinal reasons for the inconsistencies are definitional issues (upper limit set for TSH) and age-related physiological rise. Importantly, it is pertinent to know the risk factors that would determine the progression from SCH to OH. Some of these risk factors are female gender, TSH >10 mIU/L, and presence of thyroid antibodies.[10] Presence of these risk factors emanate the need to start LT4 in order to prevent progression from SCH to OH. However, treatment outcomes of NPSs with LT4 have been modest and inconsistent enough to draw any conclusion.[11]

Hyperthyroidism/thyrotoxicosis

In hyperthyroidism, patient has a low TSH value (<0.1 mIU/L) and an increased serum TH concentration, with reports of excessive circulating TH action.[4] The most common etiology is Grave’s disease.[3] The majority of psychiatric symptoms in hyperthyroidism resemble those (and mistaken for) of primary mental disorders and are due to secondary hyperadrenergic.[5]

Neuropsychiatric symptoms onset

NPS onset is usually abrupt.[3] The patient would routinely complain of nervousness, fatigue, restlessness, irritability, overactivity, emotional lability, and poor frustration tolerance. The associated heightened arousal often leads to distractibility and impairment of concentration.[3] Severe hyperthyroidism may exhibit delirium but is rarely encountered. Excessive circulating TH may precipitate impending psychiatric illnesses such as anxiety or mania. An inflated sense of well-being akin to mania is often encountered in the early stages of hyperthyroidism. Depression, though more common in hypothyroidism, manifests in prolonged hyperthyroidism due to noradrenergic exhaustion.[5] Interestingly, T4 levels tended to correlate with several anxiety symptoms but not for depression.[4] Intriguingly, in the elderly, hyperthyroidism manifests as depression, lethargy, and mental slowing without the characteristic eye signs and is known as “apathetic hyperthyroidism.” Psychosis is uncommonly associated with hyperthyroidism and presents as an admixture of both affective and schizophrenia-like reactions.[3]

Differential diagnosis

An important differential diagnosis is anxiety states. Hyperthyroidism should be suspected if the patient complains of intolerance to heat and gives a preference for cold weather which is accompanied by classical eye signs, such as lid lag. Further, increase appetite despite persistent weight loss would be a key clinical differentiating feature from anxiety states where the appetite is reduced. Although stress precipitation is found in both conditions, it is more prevalent and exclusive in anxiety states.[3]

Treatment

The majority of hyperthyroid probands (50% complete; 35% partial) with NPSs do respond if rendered euthyroid.[4,5] Occasionally, additional psychotropics are needed for residual symptoms. Beta-blockers would bring prompt relief even if euthyroidism is not restored. Propranolol (usually 60–80 mg) is preferred due to its effect on hypermetabolism, i.e., peripheral conversion of T4 to T3[12] [Figure 1].

Figure 1.

Treatment algorithm for lithium induced thyroid dysfunction. Li: Lithium; Hypo: Hypothyroidism; Hyper: Hyperthyroidism; OHypo: Overt hypothyroidism; OHyper: Overt hyperthyroidism; SCH: Subclinical hypothyroidism; TSH: Thyroid stimulation hormone; T4: Thyroxin; T3: Triiodothyronin; LT4: Levothyroxine; WNL: Within normal limits

Nonthyroidal illness and psychiatric disorders

Nonthyroidal illness is characterized by deranged thyroid function that occurs as a consequence to an underlying medical or an acute psychiatric problem rather than an actual thyroid disease. Systemic medical illnesses may have low levels of T3 and T4 and, in more severe forms, suppressed TSH.[13] Contrastingly, acute psychiatric illnesses may exhibit hyperthyroxinemia (elevated T4) in acute psychosis (and mood disorders) and elevated TSH in substance use disorders. Reasons emanating these hormonal changes are largely unknown.[13]

Thyroid hormones and refractory depression

Depression is not strongly correlated with an overt thyroid disorder but is associated with subtle irregularities, such as elevated TSH, altered circadian rhythm of TH, and blunted TSH response to TRH. Interestingly, TSH of the upper quartile range of normal is associated with recurrent, severe, and poorly responding depression phenotype. Importantly, TSH level may not always accurately reflect brain TH levels, e.g., in D2 deiodinase-deficient allelic polymorphisms (Thr92Ala polymorphism); there is the impaired conversion of T4 to T3, resulting in brain hypothyroidism.[4] Thus, T4 or T3 (more studied) has been added (to either augment or accelerate the antidepressants response) in major depression even in the absence of any biochemical thyroid dysfunction.[14] Clearly, in the presence of SCH or OH, T4/T3 supplementation is warranted in case of refractory depression or rapid cycling states for clinical benefit.

PSYCHOTROPICS AND THYROID DYSFUNCTION

Lithium generally impedes the secretion of TH into blood circulation, decreases iodine trapping, and inhibits the synthesis of TH within the gland. The lithium-induced thyroid dysfunction varies substantially across studies reflecting both heterogeneous geography and varying definitions. Lithium-induced goiter prevalence varies from 2.5% to 50%, is nontender, and may occur within a few weeks.[15]

Lithium-induced OH and SCH have estimated prevalence rates of 8%–19% and up to 23%, respectively.[16] The presence of antithyroid antibodies, female gender, old age, and family history positive of thyroid dysfunction are the most important risk factors for lithium-induced hypothyroidism.[16] Studies have found a mean weighted difference of TSH 4.00 mIU/L on lithium therapy than those without over the mean of 70 months.[15] Given the substantial morbidity, at least TSH assessments are recommended at baseline and thereafter at least biannually or depending upon clinical discretion.[16] Whether the dose and the length of lithium therapy increase the incidence of hypothyroidism is unclear. Importantly, it is pertinent to remember that hypothyroidism never justifies lithium discontinuation.[16] Thyroid supplementation is required in OH and SCH if TSH >10 mIU/L[17] [Figure 1]. Interestingly, in the case if TH is stopped after lithium is discontinued, the re-emergence of hypothyroidism is reported. Therefore, lithium may accelerate the underlying thyroiditis or SCH.[16,17]

As per the retrospective data, lithium may counterintuitively result in hyperthyroidism years after the therapy. Lithium-induced hyperthyroidism is more common in females and is short-lived painless thyroiditis. Treatment principles remain identical to those treating hyperthyroidism and a course of antithyroid drugs such as carbimazole shall be initiated[15] [Figure 1]. Many patients may go on to develop hypothyroidism.[15] Interestingly, lithium carbonate is used as a short-lived add-on therapy to radioiodine in the treatment of hyperthyroidism.[18] Lithium may rarely result in an increase in blood calcium (by 10%) and parathyroid hormone (PTH) levels lending guidelines to make it prudent to assess calcium also along with TFT.[16]

Other mood stabilizers

Carbamazepine (CBZ) may reduce the levels of free T4 within 2 months without inducing clinical hypothyroidism. This TH suppression is usually reversible and does not warrant precautious monitoring. However, valproate and CBZ combination warrants precautious monitoring of TH citing suppression of free T4 levels and increase of TSH.[17]

Other psychotropics

Tricyclic antidepressants (TCAs) and phenothiazines via formation of drug–iodide complexes may induce clinical hypothyroid state and thereby would require regular monitoring of thyroid function.[17] Moreover, among antipsychotics, those with a higher propensity to increase prolactin might derange TFT more than those without. Euthyroid hyperthyroxinemia (high T4 but normal TSH) has been reported with methadone and stimulant use.[13,17] Benzodiazepine does not seem to affect thyroid function parameters.

Hyperparathyroidism

Hyperparathyroidism is prevalent in around 0.1% of the population and is more in aged females. Primary hyperparathyroidism (PHPT) is when there are increased PTH levels, calcium levels, and hypophosphatemia.[3] Classical symptoms of hypercalcemia such as fatigue, lethargy, or loss of appetite may resemble primary psychiatric morbidity. Onset may be insidious and gradually progress to coma. Hyperparathyroidism may give rise to abdominal cramps (“moans”), bone disease (“bones”), and renal stones (“stones”). Today, it is possible to detect hyperparathyroidism early due to routine biochemical screening.[3] Apart from reasons such as head and neck radiation therapy, an important plausible etiology is lithium therapy. Lithium may stimulate PTH secretion and result in hypercalcemia in around 10% of cases.[16] Though fortunately, lithium-induced hypercalcemia is associated with a lower incidence of renal stones. Importantly, hypercalcemia shall be considered as a differential in lithium-treated probands with atypical psychopathology or nonresponse to treatment.[19]

Neuropsychiatric symptoms

NPS in hyperparathyroidism is largely cited by case reports and case series. The most frequent psychopathology reported is depression (up to 62%) and anxiety (up to 53%). Cognitive symptoms of ensuing depression are marked but only in the elderly population. The presence of apathy, irritability (up to 51%), or fatigue (“psychiatric overtones”) should be alerting and has been associated with mild-to-moderate hypercalcemia.[20] Overt delirium and coma have been reported when calcium levels are markedly elevated, i.e., above 14 mg/dl. Psychosis is a rarely described phenotype. Recently, the major neurocognitive syndrome has been reported to be associated (though weakly) with long-lasting hyperparathyroidism.[21] With chronicity, seclusion and withdrawn behavior ensue.[19]

Most studies have found improvement in NPS postsuccessful surgical treatment unless the disease chronicity has set in. However, the measured improvement of NPS specifically in mild PHPT cases has been of uncertain clinical significance. Therefore, in overt hypercalcemic hyperparathyroidism with NPS, surgical removal of parathyroid glands is a definitive and straightforward treatment option. However, in probands with mild PHPT with NPS, surgical treatment is not recommended option as per the international workshop on PHPT.[20]

Hypoparathyroidism

The most common cause of hypoparathyroidism is iatrogenic, i.e., either removal or interference with the blood supply of parathyroids during neck surgeries. Resulting hypocalcemia does present with neuromuscular irritability, cramps, paresthesias, facial grimacing, and seizures. These may again resemble a neuropsychiatric condition.[19]

NPS is present in around half of the probands who developed hyperparathyroidism after surgery and may even be higher in idiopathic ones.[3] Delirium is expected in the postsurgery period as a complication due to the associated biochemical disturbances. Several psychiatric disturbances such as anxiety, depression, and emotional lability have been found in idiopathic hypoparathyroidism. Probands have been reported to suffer from irritability, socially awkward behavior, and nervousness. Intriguingly, descriptions of the psychotic symptoms in clear consciousness have been uncommon. Cognitive deficits (subtle and major neurocognitive) have been reported, but severity increases with chronicity of the endocrine disease. Basal ganglia calcifications are common in hypoparathyroidism and are related to poor quality of life. NPSs developing in the background of intracranial calcifications are reported to be more refractory. Hypoparathyroidism is frequently associated with velocardiofacial syndrome (VCF syndrome; 22q. 11.2 deletion syndrome). VCF syndrome would present as schizophrenia and mood disorder in adults. Hypoparathyroidism pathogenesis is mainly due to hypocalcemia. NPSs such as depression and anxiety would appear episodically in “partial parathyroid insufficiency” due to frequent instances of calcium deprivation. Anxiety is known to provoke hyperventilation which can in turn precipitate tetany in hypoparathyroid patients.[19]

Correction of the underlying biochemical disturbances helps nonchronic hypoparathyroidism cases.

Depression and anxiety symptoms would remit in the majority of cases. Short-term benzodiazepines can be considered if the anxiety is debilitating. Postsurgical delirium would resolve spontaneously. Almost half of the cases with cognitive impairment would improve with serum biochemistry correction barring those with intracranial calcification or long-standing cases. There are some reports of enhanced sensitivity to neuroleptics in hypoparathyroidism.[19]

Largely, organic psychiatry syndromes due to thyroid and parathyroid disorders require merely endocrine treatment unless the NPS persists after 4 weeks of adequate treatment or is severe in intensity. NPSs in thyroid and parathyroid disorders and their clinical relevance are described in Table 2.

Table 2.

Neuropsychiatric symptoms in thyroid and parathyroid disorders

NPS	Hypothyroidism	Hyperthyroidism	Hypoparathyroidism	Hyperparathyroidism
Onset	Insidious	Abrupt	Postoperative	Insidious
Depression	++	++/30%–70%	+	++/up to 62%
Apathy	+	Apathetic hyperthyroidism	+
Anxiety	+	+++	+	++/up to 53%
Delirium	+	+	++	++/2%–5%
Cognitive decline	+++	++	+	++
	Cretinism
MNCD	++	+/-	+/-	+
Others	Slowing/psychomotor retardation/mania (treatment-induced)	Overactivity/inflated sense of well-being/irritability	Social withdrawal/neurotic behavior/poor quality of life if basal ganglia calcifications	Irritability (up to 51%) or fatigue

+/+++ – Clinical relevance; NPS – Neuropsychiatric symptoms; MNCD – Major neurocognitive disorder

DIABETES AND PSYCHIATRIC ILLNESS

Introduction

Diabetes mellitus is a chronic medical condition that has hazardous consequences not only on the various organ systems of the body but also affects the emotional well-being of patients.[22] There is an increasing trend of the disorder seen globally with nearly 77 million cases in the adult population of India. The prevalence is also showing an increasing trend among the urban (19%) and rural (15%) areas of India for both diabetes and prediabetes.[23] Nearly 422 million people are affected with diabetes worldwide.[22] The prevalence of diabetes in India is expected to rise with presumably 101 million people being affected by 2030 and 134 million by 2045, which will be a huge burden. Apart from this, India also has nearly 43.9 million people who are undiagnosed diabetics and ranks second globally in the world following China who has a population of about 65.2 million undiagnosed diabetics.[23]

This is therefore a source of concern as the socioeconomic costs of diabetes are escalating, and it is causing a burden on healthcare resources and infrastructure to cater to the diabetes-related complications, repeated admissions, emergency care, renal failure, amputations, etc.[24] All this has caused an increase in psychological and social problems with nearly one-third of the patients expressing inability to self-manage their diabetes. An interrelationship between diabetes and mental illness has already been studied where the psychological status of the patients could impact the need for glycemic control and the further development of complications, disability, or mortality associated with diabetes. Another area of concern is the increased prevalence of noninsulin-dependent diabetes mellitus due to metabolic side effects caused by psychotropics given to psychiatric patients.[24] There is enough literature examining the relationship between diabetes and psychiatric illness seen in both type 1 and type 2 diabetic patients [Figure 2].

Figure 2.

Diabetes and psychiatric disorders

Stress and diabetes

The impact of stress directly on the physiology of glucose metabolism is not very clear, though previous research has shown an association between stress and poor glycemic control in patients of diabetes.[25]

Depression and diabetes

There are several views as to whether depression is the cause or effect of diabetes. The exact direction of the association has not been determined through several researchers who have reported both. Lustman et al. reported that the relationship was reciprocal with hyperglycemia either being provoked by depression or contributing to the exacerbation of depression.[26] Several meta-analytic studies have reported the rates of depression in diabetes to increase twofold or threefold as compared to the general population.[27] Lustman et al. in their findings got a strong association of HbA1c values and presence of depression.[26]

There is also a lot of inconsistency in what methodological parameters were used to diagnose the depressive symptoms. Researchers have pointed out that the mere presence of symptoms may not constitute a depressive disorder as several studies use scales such as PHQ without using clinical interviews. This probably could result in a high prevalence compared to the general population. Lloyd et al. in their INTERPRET-DD study in 14 countries revealed the prevalence of current major depressive disorder as per the MINI to be 10.6%, but a higher number of moderate-to-severe depressive symptoms as per the PHQ were reported by 17% of the patients. Golden et al. reported minor depression in 13% of the diabetic patients, suggesting that other depressive disorders are equally prevalent.[28]

It is often seen that the presence of depressive symptoms such as reduced motivation, lack of initiative and energy, reduced interest, weakness, and feelings of hoplessness and helplessness could lead to poor compliance with nonadherence to the antidiabetic medication, which further worsens the glycemic control and could lead to diabetes-related complications.[24]

Both lifestyle factors and biological mechanisms could be responsible for depressive symptoms in diabetics. Insulin resistance is now recognized as an important regulator of mood and causes an increase in cytokines, which results in a proinflammatory state. Inflammation has also been linked to depressive symptoms, and there is a poor response to antidepressants in those patients who have elevated inflammatory markers.[24] This has also led to the hypothesis that depression could lead to diabetes because depression affects the hypothalamic–pituitary axis, resulting in increased cortisol production and other counter-regulatory hormones, leading to insulin resistance.[24] Other risk factors in depressed patients include decreased physical activity, eating high caloric fatty foods, and indulging in smoking or drinking which again put them at risk for diabetes [Figure 3].

Figure 3.

Depression and diabetes: Mechanisms and risk factors

Assessment of patients

Every patient with diabetes and depression should be evaluated for the following [Figure 4].

Figure 4.

Parameters to evaluate in depression and diabetes

Management of depression in diabetes

Management of depression can be done with a holistic approach [Figure 5].

Figure 5.

Treatment arms in depression and diabetes

Use of antidepressants [Table 3]

Table 3.

Choice of antidepressants in diabetes

Choice of antidepressant medication in depression with diabetes	Effect on diabetes
SSRIs	All SSRIs are preferred among antidepressants due to their efficacy, lower side effect profile
Fluoxetine	Fluoxetine was much better in causing hypoglycemia, weight loss, decreased body fat, and better glycemic control compared to the other SSRIs
Sertraline	Can be the first drug of choice
Paroxetine
Escitalopram
Bupropion	Reduction in BMI, body fat, and HbA1c levels
	Can be considered
TCAs	Can cause hyperglycemic effect, no change in HbA1c levels
Nortriptyline	Can cause hyperglycemic effects
Imipramine	Can cause weight gain, inconclusive effects on glucose metabolism
Amitriptyline	The use of TCAs requires regular glucose monitoring
SNRI	Inconclusive evidence on glucose metabolism
Venlafaxine	Can cause weight loss
Duloxetine	Regulates body weight, safe in stable diabetic patients but interferes with glucose metabolism
Mirtazapine
SARI	No evidence on glycemic control
Trazodone

BMI – Body mass index; TCAs – Tricyclic-antidepressants; HbA1c – Hemoglobin A1c; SSRI – Selective serotonin reuptake inhibitors; SNRI – Serotonin and norepinephrine reuptake inhibitors; SARI – Serotonin antagonist and reuptake inhibitors

• All antidepressants have a favorable outcome on depressive symptoms which then improves self-care behavior, resulting in improved glycemic control[24,29]

• All groups of antidepressants can be given safely in diabetes

• Both SSRIs and bupropion improve the depressive symptoms in diabetics; they also stabilize or lower glucose levels

• TCAs such as nortriptyline and imipramine could increase glucose levels, and hence, regular glycemic monitoring is required.

Use of cognitive behavioral therapy for treatment of depression and improving glycemic control

• Mild depressive cases do well with cognitive behavioral therapy (CBT)[30,31]

• CBT can improve diabetes-related distress

• CBT improved depression than diabetes-related distress in some studies as interventions were not tailored in problem areas of self-care[30,31]

• Short-term reduction in mean HbA1c due to CBT was seen

• CBT can help in changing diabetes self-care behaviors by changing the negative beliefs about the illness which can then result in better glycemic control

• Short-term benefits >long-term effects.

Use of internet-guided self-help interventions

Some studies have reported the efficacy of using internet-guided measures which give a short-term benefit for depression and diabetes and can be done easily by integrating into the diabetes self-care program.[32]

Lifestyle modifications

Healthy eating, regular exercise, yoga, relation, and breathing techniques go a long way in improving both physical and mental outcomes.

Anxiety and diabetes

Anxiety disorders are quite prevalent in type 2 diabetes and can also lead to poor diabetes-related self-care, glycemic control, and an increase in diabetes-related complications. The most prevalent anxiety disorders in diabetes include generalized anxiety and panic disorders, with a higher prevalence of subsyndromal anxiety.[24,33] Rechenberg et al. in their review of 15 correlational studies found that the presence of underlying anxiety or depressive symptoms impacted glycemic control due to repeated fears about hypoglycemia or increased worrying about the same which affected the blood glucose monitoring and quality of life in these patients.[34] Three studies also looked at interventions to reduce anxiety in type 1 diabetes like participation in a summer camp for a week, which improved attitude toward diabetes and reduced trait anxiety, CBT which identified the maladaptive thoughts with a focus on restructuring these distorted cognitions and improving problem-solving, whereas continuous glucose monitoring did not affect anxiety.[34] Early management of the anxiety by using either pharmacological and/or nonpharmacological therapies would help in improving the disease-related burden and complications.

Bipolar disorder and diabetes

A prevalence of 10%–26% of diabetes has been seen in bipolar disorders more commonly due to the weight gain due to psychotropics, obesity, shared genetic risk, and psychiatric and medical comorbidities.[35] Reducing the risk with proper monitoring of patients on psychotropics and lifestyle modifications needs to be followed.[24]

Schizophrenia and diabetes

Several studies have pointed out that patients of schizophrenia are at a higher risk for developing diabetes. The most common risk factors include sedentary lifestyles, associated with nicotine use, increased appetite, and eating high carbohydrate caloric food, and metabolic side effects of atypical antipsychotics which cause hyperlipidemia, glucose intolerance, insulin resistance, and weight gain. As atypical antipsychotics are usually preferred due to their reduced extrapyramidal side effects, there is a surge in their use which has resulted in metabolic syndrome (MetS). The following should be done when doing management of schizophrenia and diabetes[24,36] [Table 4].

Table 4.

Management of diabetes in schizophrenia

Before initiation of antipsychotic medication check for glucose intolerance

Do both fasting and postprandial assessment; HBA1c if sugars deranged

Evaluate for the history of

Gestational diabetes

Obesity

Family history of diabetes

Check for hyperlipidemia

The choice of antipsychotic with a lower propensity for weight gain and metabolic alterations includes

Ziprasidone

Lurasidone

The other antipsychotics as per their effect on glucose metabolism, lipid dysregulation, weight gain in descending order include

Aripiprazole

Risperidone

Amisulpride

Quetiapine

Paliperidone

Asenapine

Haloperidol

Antipsychotics to be avoided in patients with risk factors and causing weight gain

Olanzapine

Clozapine

Sertindole

No current consensus on monitoring of glucose and lipids when atypical antipsychotics are prescribed

Use of pre/probiotics in diet can reduce gut dysbiosis and metabolic syndrome

HbA1c – Hemoglobin A1c

Eating disorders and diabetes

Researchers have reported that the aggressive management for diabetes control often results in weight gain, which then becomes difficult to lose. This often results in undue weight watching, attention to food portions, and blood sugars which may trigger health consciousness more in women with type 1 diabetes which may then cause eating disorders.[24] Body image concerns and a phenomenon called insulin manipulation are seen in these patients where women with type 1 diabetes omit or reduce insulin doses which are akin to caloric purging and a symptom of eating disorder-specific to type 1 diabetes. This also places them at a higher risk for ketoacidosis and retinopathy with higher HbA1c levels. About 7% of adolescents with type 1 diabetes may have eating disorders and this is also known as diabulimia.[37]

Many a times, these patients often go undiagnosed as they do not manifest symptoms of self-induced vomiting or laxative abuse. Dietary restriction, binge eating is common, but classical anorexia nervosa is rare. Obesity being a risk factor for type 2 diabetics, recurrent binge eating is often seen.[24] Management of diabetic patients with eating disorders should be done as shown in Table 5.

Table 5.

Management of diabetes in eating disorders

A multidisciplinary approach with an endocrinologist/diabetologist, a trained nutritionist with diabetes and eating disorder experience, mental health professional, and counselor to deal with the problem

Medical stabilization of diabetes

Increasing dose of insulin

Increasing food intake

Flexible meal plan

Regular eating routine

Regular glucose monitoring

Evaluation of comorbid psychopathology

Use of CBT to address issues of insulin omission and manipulation

Use of antidepressants

CBT – Cognitive behavioral therapy

Sexual dysfunction and diabetes

Sexual dysfunctions occur in diabetic males due to increasing age, duration of diabetes, and diabetic complications. The various sexual dysfunctions in males include primarily erectile dysfunction, loss of sexual interest, and ejaculatory disturbances.[38] Women with type 1 and type 2 diabetes reported loss of libido and arousal with reduced vaginal lubrication.[39]

For the assessment and management of these patients kindly refer to the chapter on Psychosexual Health and Sexual Medicine in Consultation–Liaison Psychiatry.

Cognitive functioning and diabetes

Hyper/hypoglycemia in children or adolescents with type 1 diabetes have:[40]

• Learning difficulties

• Reduced speed of processing

• Attention deficits

• Short-term memory difficulties.

Hence, children should be regularly assessed for the same and parents counseled.

Similarly, in adults with type 2 diabetes, a long time exposure to chronic hyperglycemia, uncontrolled sugars, and micro and macrovascular changes in the brain increase the risk of cognitive decline and dementia.[24]

Regular monitoring of the sugars to prevent ischemic changes is the only preventive strategy.

It is recommended that to rule out complications, all patients of type 2 diabetes should have an annual:

• Complete physical examination

• Foot examination

• Eye checkup.

METABOLIC SYNDROME

MetS is not a disease but a condition associated with cardiometabolic problems occurring worldwide due to lifestyle changes along with genetic vulnerability. It is now a major public health concern due to increased mortality due to its risk for cardiac diseases. Patients with psychiatric disorders such as schizophrenia, depression, and bipolar disorders have an increased risk for developing MetS in comparison to the general population.[41,42]

MetS is a condition in which there is the presence of abdominal obesity, insulin resistance or glucose intolerance, deranged lipid profile such as increased triglycerides with decreased high density lipoprotein cholesterol levels and hypertension[41,42] [Table 6].

Table 6.

Definition criteria of metabolic syndrome (adapted from Huang)

Parameters	Revised NCEP ATP III (2005)	IDF (2005)	WHO (1998)	EGIR (1999)
Definition	Any three of the following 5 features	Increased waist circumference Men ≥90 cm, Women ≥80 cm along with any 2 of the following features	Insulin resistance or diabetes plus 2 of the 5 criteria	Hyperinsulinemia (plasma insulin >75th percentile) plus two of the 4 criteria below
Elevated waist circumference	≥102 cm in men ≥88 cm in women		Waist–hip ratio: >0.90 (male); >0.85 (female) or BMI >30 kg/m2	Increased waist circumference Men ≥94 cm, Women ≥80 cm
Triglyceride	≥1.7 mmol/l or TG treatment		TG >150 mg/dl or HDL-C: <35 mg/dl (male), <39 mg/dl (female)	TG >177 mg/dl or HDL-C: <39 mg/dl
HDL-C	Men <1.03 mmol/l or women <1.29 mmol/l or HDL-C treatment
Blood pressure	Systolic ≥130 mmHg or Diastolic ≥85 mmHg or hypertension treatment or previously diagnosed hypertension		>140/90 mmHg	>140/90 mmHg
Fasting blood glucose	≥5.6 mmol/l or 100 mg/dl treatment for elevated glucose or previously diagnosed type 2 diabetes		Insulin resistance already required	Insulin resistance already required
Others			Microalbuminuria

NCEP ATP – National cholesterol education program adult treatment panel; IDF – International Diabetes Foundation; EGIR – European Group for the Study of Insulin Resistance; BMI – Body mass index; HDL-C – High-density lipoprotein cholesterol; TG – Triglyceride

The risk posed by psychotropics in the causation of MetS is inconsistent whether a trial is given with a single drug or polypharmacy is done or reduction of weight with the use of aripiprazole is considered [Table 7].[42]

Table 7.

Risk of metabolic syndrome with psychotropics

Increased risk for MetS with the type of antipsychotics

Clozapine (47.2%)

Quetiapine (37.3%)

Olanzapine (36.2%)

The lowest risk for MetS with the type of antipsychotics

Aripiprazole (19.4%)

Amisulpride (22.8%)

The risk for MetS with antidepressants is still unclear. Some studies postulate that antidepressants with H1 receptor antagonist function can be responsible for the causation of MetS

Mirtazapine, paroxetine, TCAs cause weight gain/obesity

SNRIs, bupropion, TCAs may cause hypertension

TCAs increase the risk for diabetes

Adding antipsychotic medication for augmenting the action of antidepressants can also be a risk factor

Among mood stabilizers

Lithium and valproate may cause weight gain/obesity and dyslipidemia

Valproate has a greater risk for diabetes as compared to lithium, lamotrigine, oxcarbazepine

Lamotrigine/topiramate do not affect obesity

TCAs – Tricyclic-antidepressants; MetS – Metabolic syndrome

Management of metabolic syndrome

Management of MetS includes lifestyle changes to prevent health problems such as a heart attack or stroke [Figure 6].

Figure 6.

Management of metabolic syndrome

HYPERPROLACTINEMIA AND PSYCHIATRIC ILLNESS

Psychological stressors associated with hyperprolactinemia are one of the explanations for hyperprolactinemia in drug-naïve patients.[43,44,45] Galactorrhea is more common in females with hyperprolactinemia in comparison to males[46] and is found in almost 10%–20% of females treated with the first-generation antipsychotics.[47]

Clinical presentation with hyperprolactinemia

Serum prolactin level of 99.6 ng/mL is associated with hypogonadism, amenorrhea, and galactorrhea. A level of 50.8–74.7 ng/mL is associated with oligomenorrhea. A level of 30.9–49.8 ng/mL is associated with reduced libido. The risk of osteoporosis and malignancy in hyperprolactinemia is associated with severe mental illness. There is nearly a 2–4 times risk of developing osteoporosis with nearly 70% risk of developing fractures in patients of schizophrenia compared to the general population.[48] Women are at a higher risk of developing malignancy, especially breast carcinoma if they are having hyperprolactinemia.[49]

Management of antipsychotic-induced hyperprolactinemia

• Pretreatment prolactin level of more than 1000 IU/L needs further evaluation before starting the treatment [Figure 7]

• Hyperprolactinemia in asymptomatic patients with serum level of less than 2500 IU/L does not require any further investigation or treatment

• Serum prolactin level of more than 2500 IU/L requires a low dose of bromocriptine of cabergoline and further endocrine referral.

Figure 7.

Flowchart of clinical evaluation of hyperprolactinemia

STEROIDS AND PSYCHOSIS

Steroid-induced psychosis is categorized as substance or medication-induced psychosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. To diagnose steroid-induced psychosis, operational criteria have to be met. The diagnostic criteria include exposure to medication that can induce psychotic symptoms such as delusions and hallucinations which cannot be explained by other nonmedication-induced psychotic disorders. The symptoms should not occur only when patient is delirious and they should be significant to cause distress or impairment in functioning of the patient.

The incidence of severe NPSs (including psychosis) due to steroids has been estimated to be around 6%.[50] Although the effects of steroids are unpredictable, the administered dose within 2 weeks is the most significant risk factor for the development of NPSs. Interestingly, symptoms can occur any time and even after cessation of therapy. The pathophysiology is poorly understood, but the preferential selection of glucocorticoids over mineralocorticoids stimulation is said to lead to emotional changes.

Management

Prevention hinges on using lower dosages and not prolonging the duration of the treatment. Treatment is reassuring with reduction or stopping of steroids and addition of antipsychotics. Haloperidol is the most frequent antipsychotic used.[51]

CONCLUSION

This CPG looks at the most common endocrine disorders seen in practice and associated psychiatric comorbidities. Understanding the connection between hormones and human behavior and liaison by the treating physicians would entail a better quality of life and medical outcomes for the patient. The impact of stress on the immune response and the hypothalamic–pituitary–adrenal axis is important to address in consultation–liaison. We have provided an approach to the management of the psychiatric conditions associated with endocrine dysfunctions such as depression, anxiety, cognitive dysfunction, psychosis, and delirium. The patient with endocrine dysfunction may either present with psychiatric symptoms and the endocrine dysfunction may often go undiagnosed or psychiatric symptoms may occur anytime during illness. An early diagnosis and appropriate referral may go a long way in improving the health-related outcomes and coping of the patient. Further reading for specific disorders is suggested in references, as it would otherwise be very exhaustive.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.