PRESENTOR : DR.DHEERAJ KUMAR

MODERATOR: DR.CHANDRASEKHAR A.L

NEUROPSYCHIATRIC MANIFESTATIONS

OF ENDOCRINE DISORDERS

INTRODUCTION

It has long been known that endocrine disorders are associated with neuropsychiatric symptoms

In 1786, Parry described psychotic symptoms associated with hyperthyroidism,

Graves first lectured on the psychiatric complications of hyperthyroidism in 1834.

Psychiatric symptoms can precede or present concurrently with the more typical physical symptoms of endocrine disease

These secondary disorders can be impossible to distinguish from primary psychiatric disorders, such as depression, mania,psychosis, anxiety, delirium, or dementia

When psychiatric symptoms are thought to be secondary to endocrine disease, the primary treatment focus remains correcting the endocrine disorder.

That being said, there are times when the psychiatric symptoms are severe enough to warrant immediate

intervention like mania, psychosis, and severe depression that could be life-threatening

THYROID DISORDERS

HYPERTHYROIDISM (THYROTOXICOSIS)

Numerous neuropsychiatric symptoms have been noted in patients with hyperthyroidism and include psychosis,depression, mania, anxiety, and cognitive dysfunction.

These can occur with either

primary hyperthyroidism (Graves disease)

toxic nodular goiter or

excessive consumption of exogenous thyroid hormone

Brownlie and colleagues (2000) reported a series of 18 patients: of which

Mania – 7 patients

Depression – 7 patients

Psychosis – 3 patients

Delerium – 1 patient

Thus the range of neuropsychiatric symptoms seen with hyperthyroidism is quite broad.

The presenting neuropsychiatric symptoms of hyperthyroidism include emotional lability

poor impulse control,

crying spells

euphoria

irritability

Distractibility

reducedattention, impaired recall, and psychosis (delusions and hallucinations)

A minority of patients can present with symptoms of depression,apathy, or lethargy

HYPOTHYROIDISM (MYXEDEMA)

Neuropsychiatric symptoms include:

cognitive dysfunction,

affective disorders, and psychosis

The psychiatric presentation may be indistinguishable from a primary psychiatric disorder, thus reinforcing the importance of ruling out medical causes of psychiatric disorders.

The onset of symptoms of hypothyroidism is often gradual, and slow progression is common, especially in the elderly, mimicking the development of a degenerative dementia

Common symptoms include slowed comprehension and impairment in attention, recent memory, and abstract thinking.

In contrast to cortical dementias such as Alzheimer’s disease and frontotemporal degeneration, the

cognitive disorder of myxedema does not present

with discrete cortical syndromes like aphasia, anomia, apraxia, and frontal disinhibition.

The most common affective disorder seen with hypothyroidism is depression, manifested most often as reduced mood, psychomotor retardation, sleep and appetite disturbances, anhedonia, reduced libido, and emotional lability. Suicidal thinking, delusions, and hallucinations can be present in more advanced illness.

hypothyroidism had a greater risk of being admitted for the treatment of depression or bipolar disorder, and that this risk was greatest in the first year

A meta-analysis of individuals with treatment resistant depression demonstrated that approximately 50% had subclinical hypothyroidism, and the response to antidepressant therapy is known to be reduced if the thyroid disease is not treated.

Although it is generally believed that treatment of the underlying hypothyroidism will treat the neuropsychiatric symptoms, Demartini et al. (2010) found that thyroid replacement alone was not effective in producing remission of the depressive symptoms.

Compared to depression, mania is a much less common manifestation of hypothyroidism; however, there are a number of reported cases of hypothyroidism presenting with symptoms of mania

Patients can present with elevated mood and energy, irritability, psychomotor agitation, decreased need for sleep, increased goal-directed behavior, pressured speech, flight of ideas, grandiosity, hallucinations,and delusions.

Hypothyroidism has been associated with psychosis (myxedema madness), and there is no typical presentation of psychotic symptoms which can include delusions (paranoia), auditory and visual hallucinations, perseveration, and thought disorganization

Psychosis has been noted in 5–15% of patients with hypothyroidism

ADRENAL DISORDERS

HYPERCORTISOLEMIA (CUSHING’S SYNDROME)

Psychiatric disturbances are common with Cushing’s syndrome.

major depression was on average 57%, with a range of 50–80% across studies

Patients with depression appeared to have a more severe clinical presentation and have higher cortisol levels than patients with increased cortisol without depression.

Mania in Cushing’s syndrome presents less commonly than depression, though approximately 30% of patients present with hypomanic or manic symptoms, subclinical mood fluctuations being more common.

Hypomania or mania may be some of the earliest signs of illness onset

Anxiety can be commonly associated with Cushing’s syndrome.

The rate of generalized anxiety disorder has been noted to be as high as 79%, and panic disorder as high as 53%.

Cognitive dysfunction has been noted in approximately two-thirds of patients with Cushing’s syndrome. The major impairments seen are :

nonverbal, visual-ideational, visual-memory, and spatial-constructional abilities

MANAGEMENT:

Although the successful control of hypercortisolismcan result in a progressive improvement of psychiatric symptoms and cognitive function, this is not always the case; Pereira et al. (2010) describe a Cushing’s syndrome cohort comprising 33 patients, with 67% having significant psychopathology (primarily depression) Of which After cure of Cushing’s syndrome,the prevalence of diagnosed psychopathology was

54% at three months,

36% at six months, and

24% at one year.

They also report a 74-patient cohort that continued to experience impairments in memory and executive function despite long-term cure of the Cushing’s disease.

Thus they required treatment with antidepressants though the primary disease is taken care of.

ADRENAL INSUFFICIENCY (ADDISON’S DISEASE)

Addison’s disease, which results in deficiencies in glucocorticoids and mineralocorticoids

Mild disturbances in mood, motivation, and behavior were described as core clinical symptoms.

Psychosis and extensive cognitive changes, including delirium, were less common and associated with more severe disease.

Catatonia and self-mutilation were still more rarely seen

Adrenal insufficiency is generally treated by replacing hydrocortisone.

Thomsen et al. (2006) note that patients with adrenal insufficiency may be at risk for developing severe affective disorders, and in particular may be at risk for developing elevated mood symptoms in the context of receiving hormone replacement.

HYPERPITUITARISM

The most common type of pituitary tumor is a prolactin-secreting adenoma (prolactinoma). Hyperprolactinemia can result in a wide variety of

symptoms, including galactorrhea, gynecomastia, amenorrhea, decreased libido, and sexual dysfunction

Categories of drugs associated with inducing hyperprolactinemia include

antipsychotics (phenothiazines, butyrophenones, and risperidone),

antidepressants (amitriptyline, imipramine, amoxapine), and

dopamine-receptor antagonists (metoclopramide, domperidone, sulpiride).

Of the atypical neuroleptics, risperidone has the greatest capacity for stimulating prolactin secretion

As a class, however, the atypical neuroleptics have less tendency to be associated with increased serum prolactin than the typical agents

A common clinical dilemma is the psychotic patient

on a neuroleptic drug who develops menstrual dysfunction, galactorrhea, or

gynecomastia (in males) associatedwith an elevated serum prolactin concentration

Treatment requires a careful balancing between the decreasing prolactin and maintenance of adequate control of the psychotic disorder. In such cases, it is reasonable to consider a

switch to an alternative antipsychotic, such as quetiapineor

Olanzapine which is less likely to exacerbate hyperprolactinemia

Consideration could also be given to the use of aripiprazole, which might actually decrease prolactin due to its mixed dopaminergic antagonism and agonism.

If the serum prolactin level returns to normal when the offending agent is stopped, the possibility of a pituitary tumor is virtually excluded.

The use of a dopamine agonist such as bromocriptineor cabergoline is potentially risky, as these may theoretically—though rarely—lead to worsened psychotic symptoms despite the patient’s remaining on an antipsychotic.

Acromegaly is the clinical syndrome that results from sustained hypersecretion of growth hormone, most often the result of a pituitary adenoma depression, pathological gambling, psychosis, amotivational syndrome , harm avoidance, neurosis,anticipatory worry, pessimism, and reduced impulsivity and less novelty-seeking behaviors

A relatively recent examination of acromegalic patientsrevealed “increased lifetime rates of affective disorders,”especially major depression and dysthymia, but not anxietydisorders, which persisted even after curative surgery.

One pharmacological intervention, octreotide, has very few psychiatric side effects, although according to the package insert it may cause depressive symptoms in 1–4% of patients

In fewer than 1% of patients, may cause anxiety, decreased libido , paranoia, or amnesia

The infundibular-hypothalamic anatomy is relatively fragile, especially traumatic brain injury(TBI), subarachnoid hemorrhage, or brain tumors increase

The risk of patients’ developing hypopituitarism, including the first and most common sign of pituitary impairment,growth hormone deficiency

Regardless of etiology, the primary issue is the decreased hormonal output, and use of psychotropic agents directed at the nature of the presenting symptom (e.g., antidepressantsfor depression, anxiolytics for anxiety, or antipsychotics for psychosis) is suggested only after correction of the endocrine abnormality.

Others describe-

amotivation, dysphoria, disturbed sleep pattern,

personality change, affective blunting, and auditory

visual hallucinations

cognitive impairment, including visual and verbal memory impairment

decreased quality of life (Battisetty, 2008)

In one study,

nearly half of patients with post-traumatic hypopituitarism

(as measured by hormone-level output) expressed symptoms

of mild to moderate depression, and scales reflecting somatization

and paranoid ideation were inversely correlated with

pituitary hormone levels.

MANAGEMENT

Many neuropsychiatric symptoms

significantly improved with hormone replacement

DISORDERS OF GLUCOSE METABOLISM

DIABETES MELLITUS

It is generally acknowledged that the presence of psychiatric illness in the context of diabetes mellitus can affect patient motivation and compliance with treatment recommendations.

As such, psychiatric comorbidity is associated with decreased quality of life, increased cost of care, elevated glycosylated hemoglobin (HbA1c), and greater end organ damage

Diabetes Mellitus and Depression

Depression is nearly twice as common in individuals with diabetes as in those without.

Having diabetes may increase one’s risk of developing depression, and having depression may increase the likelihoodof developing diabetes, especially type II diabetes

The risk of developing diabetes appears to be greatest when the preexisting depression is non-severe, persistent,and untreated.

The association involves both health-related behavior and physiological abnormalities in the hypothalamic-pituitary-adrenal & sympathoadrenal systems that increase insulin resistance

Successful detection& treatment of depression may prevent the development of type II diabetes in patients at risk.

Treatment of depression in diabetics is much the same as in non-diabetics, though one must be aware that antidepressants may affect appetite and blood glucose.

Likewise, once depressive symptoms are treated, the patient may reengage in physical activity, which may further influence glycemic control.

The selective serotonin-reuptake inhibitors (SSRIs) are the preferred treatment for depression in diabetics due to their lack of effect on glucose metabolism, lower incidence of weight gain and carbohydrate craving, as well as the lower,but not absent, risk of anticholinergic and cardiac side effects

However, SSRIs can suppress appetite,enhance insulin sensitivity, and lead to hypoglycemia if diet and medication (oral hypoglycemics, insulin) are not adjusted accordingly.

Tricyclic antidepressants should be avoided in the treatment of depression in patients with diabetes, as studies show a correlation with impaired fasting glucose as well as increased appetite and carbohydrate craving

Treatment for diabetes in light of mental illness should be considered carefully, recognizing that cognitive disorders and symptoms of depression, including low motivation andsuicidal ideation, may affect a patient’s ability and willingness to comply with recommendations.

Likewise, patients with diabetes are at greater risk for suicide than the general population, raising the question about the safety of insulin or oral hypoglycemics for disease management.

Among antidiabetic agents used with lethal intent, sulfonylureas were responsible for the greatest number of deaths, though this may be related to the larger type II population,rather than to greater lethality. Medications should be monitored carefully in depressed diabetics, and some studies suggest discontinuation of insulin pumps during acute episodesof depression with suicidal ideation

Diabetes Mellitus and Anxiety

The prevalence of anxiety disorders, specifically generalized anxiety disorder (GAD), in diabetics is two to three times that in non-diabetics

As with depression, the presence of comorbid anxiety and diabetes mellitus is associated with elevated HbA1c levels

It is important to note that the symptoms of anxiety disorders and depressive disorders often overlap, making a very distinct differentiation quite difficult. In most cases, though,treatment is very similar.

Risk factors associated with more severe anxiety in diabetics include:

1. female gender,

2. presence of diabetes complications,

3. insulin use, unemployment, smoking, and past/presentmisuse of alcohol.

Protective factors include:

1. older age,

2. structured medical care, private medical insurance, and

3. patient perception of adequate glycemic control

Caution, however, should be used with pharmacotherapy, such as benzodiazepines and beta blockers, as they may mask the physiological symptoms of hypoglycemia, including tachycardia

Studies suggest selective serotonin reuptake inhibitors are used with greatest frequency, owing to their potential synergistic effects they have been found to provide adequate control of mood and anxiety symptoms while also improving diabetes self-care

Diabetes, Eating Disorders, and EatingDisordered Behavior

Many studies have shown that diabetics engaging in eating disordered behaviors, particularly insulin omission or underuse,are at particularly elevated risk of experiencing physical complications of diabetes

Treatment of eating disorders

using a team approach, including physicians, diabetes educators, nutritionists, and therapists

Diabetes Mellitus and Cognitive Changes

Many studies have shown an association between diabetes, both type I and type II, and the presence of cognitive decline

The exact cause of these cognitive changes remains unclear, and some studies have failed to reveal an association with HbA1c.

In addition, it is thought that a state of hyperinsulinemia, seen in type II diabetics, may contribute to microvascular damage and may interfere with amyloid precursor protein metabolism, leading to cerebral beta amyloid deposits.

HYPOGLYCEMIA

Symptoms of hypoglycemia may be broken down into two distinct constellations

Autonomic

Neuroglycopenic

The autonomic effects are typically defined as adrenergic or catecholamine-mediated symptoms, including

tachycardia,

diaphoresis, tremor, weakness, hunger, irritability,

Palpitations

these hyperadrenergic symptoms can mimic a panic attack.

An inadequate supply of glucose to

the central nervous system (CNS), or neuroglycopenia, may

result in faintness, headache, blurred vision, lethargy, confusion,

dizziness, weakness, incoordination, bizarre reversible focal neurological findings, seizures, and coma,

which typically abates with normalization of glucose levels

The differential diagnosis of fasting hypoglycemia must include surreptitious administration of either insulin or an oral hypoglycemic agent

Factitious hypoglycemia secondary to one of these agents must be considered prior to pancreatic exploration for an islet cell tumor in any patient with hyperinsulinism.

The presence of anti-insulin antibodies or low C-peptide levels at the time of hypoglycemia strongly suggests a factitious etiology

Screening of urine or blood for sulfonylureas

is available for patients suspected of surreptitious oral hypoglycemic-agent ingestion.

An important issue in the psychopharmacological management of patients with hypoglycemia is the risk of beta-blocker therapy

Early misdiagnosis of hypoglycemia as

an anxiety disorder and treatment with agents whose action

blocks the normal response to hypoglycemia may prevent

the subjective experience of potentially lethal hypoglycemia

Additionally, there is some suggestion that the use of antidepressants can impair glycemic control leading to hyperglycemia or hypoglycemia (Khoza, 2011),

So serum glucose levels should be monitored more closely if any medication is added

DEVIATIONS IN GONADAL HORMONES

MALE HYPOGONADISM

Male hypogonadism of any etiology may cause significant psychological distress and impaired social adjustment

Low self-esteem and self-confidence and feelings of inadequacy,isolation, and alienation are common.

PRE-MENSTRUAL DYSPHORIC DISORDER

Diagnosis of PMDD requires five or more of 11 possible symptoms present during the late luteal phase, approximately days 21–28 of the menstrual cycle

At least one of the five symptoms must be depressed mood, anxiety, affective lability, or irritability

Derangements and dysregulation of the serotonergic

system are the most probable causes of PMDD

Treatment studies also support the serotonin hypothesis of PMDD causality, as SSRIs have proven efficacious in decreasing symptoms

summary

The onset of symptoms of hypothyroidism is often gradual and, especially in the elderly, mimics the development of a degenerative dementia. In contrast to cortical dementias such as Alzheimer’sdisease and frontotemporal degeneration, the cognitive disorder of myxedema does not present with discrete cortical syndromes like aphasia, anomia, apraxia, and frontal disinhibition.

In Cushing’s syndrome, depression is extremely common,and persistent elation rare.

The majority of cases of primary hyperparathyroidism are asymptomatic (Benge et al., 2009).

The diagnosis of Addison’s disease commonly is delayed.In one cohort of 216 patients with adrenal insufficiency,41% received a false diagnosis of a psychiatric illness(Bleiken et al., 2010).

Risperidone is the atypical antipsychotic most likely tocause hyperprolactinemia.

Acromegaly is associated with depression, psychosis, and amotivational syndrome

Those with insulin-dependent diabetes and eating disorders frequently turn to insulin omission or underuse as a means to prevent weight gain and to promote weight loss.

Beta-blocker therapy may prevent the normal sympathetic response to potentially lethal hypoglycemia in insulin-dependent diabetics.

In Klinefelter’s syndrome, XXY, boys with hypogonadism, cognitive and learning difficulties are seen most often in verbal IQ scores, speech and language acquisition and recognition, as well as in memory

REFERENCES

PSYCHIATRIC CARE OF THE MEDICAL PATIENT-

BARRY S.FOGEL & DONNA B. GREENBERG .

HARRISONS 19th edition

WILLIAMS TEXT BOOK OF ENDOCRINOLOGY 13TH edition