Peter C. Whybrow
When Parry first described the syndrome of hyperfunction of the thyroid gland in 1825, he attributed the disorder he observed in his young female patient to the fear she had experienced when caught in a runaway wheelchair (1). In 1835, in Graves' classic description of the disorder that now bears his name, he focused on the nervous dysfunction, suggesting a relationship of the thyroid gland to the syndrome of globus hystericus (2). In 1840, Basedow (3) provided the first description of the associated psychosis, but it was not until 1886 that a thyrotoxic syndrome of endocrine origin was clearly distinguished from the group of neuroses (4).
NEUROPSYCHIATRIC MANIFESTATIONS OF THYROTOXICOSIS
The neurobehavioral and psychological changes associated with thyrotoxicosis are multiple and varied (5,6,7,8). Patients complain of anxiety and dysphoria, emotional lability, insomnia, and, at times, intellectual dysfunction. Their ability to concentrate is particularly impaired; indeed, this may be the earliest disturbance, and it is often associated with increasing restlessness and tremulousness. Patients appear irritable, jittery, and easily moved to anger; some express ideas of reference and frank paranoia. Thoughts and words can come rapidly and are disjointed at times, suggesting a thought disorder.
Motor activity is increased, usually associated with agitation. Although this may mimic manic behavior, the fully developed psychiatric syndrome of mania is surprisingly rare in patients with thyrotoxicosis. Sleep disturbances including vivid dreams and nightmares are common, and daytime energy levels are often decreased. These features are an important distinction from mania, in which increased energy, irritability, and decreased sleep are the common presenting problems. When true mania and hypomania occur in patients with thyrotoxicosis (8,9,10,11,12,13), the patients typically have a previous diagnosis of bipolar disorder or a strong family history of that disorder.
Episodic anxiety, frequently in association with subjective awareness of tachycardia or arrhythmia, is a common symptom in patients with thyrotoxicosis. Indeed, some of these diffuse dysphoric feelings have been reported in normal subjects given high doses of thyroxine (14,15).
In rare patients, the behavioral dysfunction may progress to a nonspecific psychotic illness with bizarre delusional thoughts, often of a paranoid nature. A careful mental status examination in such patients usually reveals associated cognitive clouding, suggesting that the psychotic phenomena are directly correlated with this evidence of delirium (8,14). The few electroencephalographic recordings that have been obtained support these observations by revealing abnormal slow activity admixed with paroxysmal fast waves and an augmented response to photic stimulation (16,17). Epileptic seizures have been reported in thyrotoxicosis, although they are rare events (18). With the onset of thyrotoxic storm (also rare), delirium, restlessness, and agitation can appear acutely (19,20) (see Chapter 43).
In contrast to this picture is the mental state of patients with so-called apathetic thyrotoxicosis (21), an uncommon form of presentation of thyrotoxicosis, that mimics a depressive disorder and that usually occurs in elderly patients, although not exclusively so (8,22). This syndrome is characterized by apathy, lethargy, pseudodementia, weight loss, and depressed mood; the patients may be initially diagnosed as having melancholia. The true diagnosis can be overlooked, because many of the common manifestations of thyrotoxicosis in young people, such as tachycardia, hyperphagia, increased perspiration, warm skin, and goiter, are lacking (23). Thus, special vigilance for this type of thyrotoxic syndrome should be maintained. Apathetic thyrotoxicosis also has been described in young adults (24,25,26) and rarely in adolescents (27).
Because of the considerable overlap between mental and physical complaints, such as loss of energy and tremulousness, the true incidence of neuropsychiatric symptoms in patients with thyrotoxicosis is difficult to estimate. From 11 studies of unselected patients, however, certain trends emerge (6,7,28,29,30,31,32,33,34,35,36). Some behavioral change, perhaps best characterized as a tense dysphoria, appears ubiquitous; a subjective awareness of diminished intellectual function is also common. In comparison, overt psychiatric illness has been considered a rarity, probably occurring in about 10% of patients (6,28). In studies of patients with thyrotoxicosis using modern diagnostic criteria for psychiatric disorders, the prevalence rates for depressive disorders were 31% (35) and 69% (36), and the rates for anxiety disorders were 62% (35) and 61% (36).
OBJECTIVE BEHAVIORAL ASSESSMENT
Several groups of investigators have sought to quantify the behavioral changes in patients with thyrotoxicosis, both by comparing patients with matched normal subjects and by studying patients during their illness and after recovery (7,31,33,34,35,36,37,38,39,40). In general, the studies confirm the clinical descriptions reviewed earlier.
In an early study of seven women and three men with thyrotoxicosis evaluated before and after treatment and various matched control groups, the patients' performance when thyrotoxic most closely approximated that of a control group with proven structural or physiologic disturbances of the brain; after treatment, the results were similar to those of normal subjects (38). In a study in which 16 patients seen in a medical clinic were studied using the Clyde mood scale to document affective changes, more than half the patients reported depression of mood, but the mean Clyde score was similar to that of normal subjects (34). The patients' jittery score was increased and corresponded with reports of anxiety, bouts of tachycardia, and restlessness. The score for clear thinking was reduced, reflecting subjective disorganization of cognition.
A thorough psychological study of middle-class Turkish women with thyrotoxicosis revealed multiple abnormalities (37). Although the range of educational background of the study and control groups was broad, some being illiterate and some having had 12 years of schooling, the groups were well matched for this variable and for age and socioeconomic status. Of the 23 women with thyrotoxicosis, 10 were retested after treatment. Before treatment, their responses to visual stimuli were slow, but they were normal after treatment. The auditory reaction times were also slow, but did not return to normal after treatment. Their visuomotor coordination was less accurate, less steady, slower, and more readily fatigued, as compared with that of the normal subjects, and they made more mistakes on mirror-drawing tests.
This impairment of cognition, directly correlated with the thyrotoxic state, also was found in two subsequent studies. In these studies, thyrotoxic patients performed poorly on the Porteus maze and trail-making tests (7), and performance on those tasks that require concentration and memory was impaired in proportion to the degree of increase in their serum thyroxine (T4) concentrations (31).
In both of these studies the Minnesota Multiphasic Personality Inventory (MMPI) was used as part of the assessment. The mean corrected raw scores for the clinical scales of somatic distress, depression, anxiety, and schizophrenia were all high, although not extraordinarily so. With treatment, the scores declined, but the profile of the test results did not change. Of the 19 women with thyrotoxicosis in the second study, all complained of nervousness, 16 of jumpiness, and 15 of restlessness and tension. More than half noted anxiety and irritability. This constellation of symptoms, which perhaps is best described as tense dysphoria, appears to be characteristic of the affective state of thyrotoxicosis. These findings were recently confirmed in a study of 15 patients with thyrotoxicosis caused by Graves' disease, in whom treatment resulted in improvement of the dysphoric mood and cognitive ability (41). The patients reported being more relaxed and less anxious after treatment, had better comprehension, and were more capable of abstraction.
One study was undertaken to assess the degree of mental and cognitive impairment in patients with subclinical thyrotoxicosis, patients with overt thyrotoxicosis, and normal subjects (42). Both patient groups reported increased anxiety and irritability and decreased vitality and activity, as compared with the normal subjects, indicating that mental disturbances are already present in patients with subclinical thyrotoxicosis (see Chapter 79). Depressive affect also occurs in thyrotoxicosis, but usually it is intermixed with the more common complaint of anxiety; this is an important distinction from hypothyroidism, in which depressive symptoms are dominant, more florid, and may merge into the syndrome of melancholia (7). Unfortunately, there has been no careful study of mental status in patients with apathetic thyrotoxicosis, in whom a depressive mood disturbance appears dominant.
BEHAVIORAL SYNDROMES THAT MAY MIMIC THYROTOXICOSIS
In most patients, the diagnosis of thyrotoxicosis presents little difficulty. Problems may arise, however, in older patients, as noted above, who are apathetic and in whom behavioral and psychological symptoms and signs (i.e., anxiety, agitation, lowered attentiveness, irritability, depressed mood with poorly defined ideas of persecution, insomnia, or depression) are prominent. They may be diagnosed as having an agitated major depression or involutional paranoid psychosis, if other manifestations of thyrotoxicosis are overlooked.
The most frequent misdiagnosis is that of anxiety state or neurosis. A questionnaire study of neuropsychiatric complaints in 137 patients with thyrotoxicosis caused by Graves' disease confirmed that psychiatric symptoms, especially anxiety and irritability, were common (43). Thus, the differentiation between thyrotoxicosis and an anxiety state may not be easy, especially in the early stages of either disorder (44). Unlike thyrotoxicosis, which is usually progressive, the intensity of anxiety states tends to vary over time. There also may be a history of other adjustment difficulties, and the anxiety state itself may be associated with specific fears of objects or situations.
Panic attacks may present a particular difficulty in differential diagnosis, especially because of the rapid heart rate and palpitations that accompany them. Patients who have panic attacks often awaken in the middle of the night with these symptoms. Their resting pulse rates, however, usually are not high, unlike in thyrotoxicosis; the hands and feet are usually cold and clammy, whereas they are warm and moist in patients with thyrotoxicosis. Also, although both anxious and thyrotoxic patients may have difficulty sleeping and may eat more than usual, the former usually do not lose weight, nor do they have the progressive disturbances of memory, calculation, and problem-solving ability that characterize thyrotoxicosis.
The relationship of thyrotoxicosis to mania is complex. Motor acceleration, pressure of speech, and disorganization of thought content are found in patients with thyrotoxicosis. However, the constellation of symptoms that is necessary to fulfill the criteria for secondary mania (45) is far less common (10,13,46); it usually is not a diagnostic problem. Initiation of high doses of thyroid hormone in hypothyroid patients can precipitate classic mania (47), especially in patients with a family history of affective illness. This possibility should be considered in a patient who exhibits bizarre or hyperactive behavior while receiving thyroid hormone.
Thyrotoxicosis factitia is the term used to describe thyrotoxicosis caused by surreptitious ingestion of high doses of thyroid hormones (48). Patients attempting suicide by taking T4 or other thyroid hormone preparations usually suffer from psychiatric illness and should be referred for psychiatric consultation. The disorders that may be associated with thyrotoxicosis factitia include Munchausen's syndrome (a disorder characterized by the intentional production or feigning of physical or psychological symptoms and signs) and neurotic disorders in patients with poor body image and concerns regarding their weight and sexual identity (48,49).
THE ROLE OF PSYCHOLOGICAL FACTORS IN THE PATHOGENESIS OF THYROTOXICOSIS
The role of psychosocial strain and trauma in the pathogenesis of Graves' disease, which is the most common cause of thyrotoxicosis, has been the subject of considerable debate. Although anecdotal reports and a considerable body of clinical opinion seem to support an association, objective evidence remains elusive. One problem in assessing any temporal association between the two is determining the precise onset of thyrotoxicosis. The speed of onset of symptoms is variable, and the thyrotoxicosis is probably subclinical for weeks or months before symptoms appear, so that it may already have been present at the time of the supposed precipitating event. Similarly, the psychological reaction to the event may be a reflection of already present thyrotoxicosis, rather than causing it. Information distinguishing these points is virtually impossible to obtain by retrospective study.
Prospective studies would undoubtedly offer better information, but are difficult to conduct. However, in one such study, subjects from the general population who had hyperfunctioning regions on thyroid scintiscans were followed carefully with independent psychological and thyroid evaluations. Among 239 women followed for 12 years, the hyperfunctioning regions appeared to wax and wane in a direct relationship with life stress, and some women developed clinical thyrotoxicosis during conditions of severe or prolonged life strain (50,51).
Two studies explored the onset of Graves' thyrotoxicosis using a controlled retrospective methodology. In a case control study, patients developing Graves' thyrotoxicosis reported more negative life events, such as divorce, bereavement, and educational and occupational failure, than did control subjects (52). Similar results were obtained in a consecutive sample of 70 patients attending an endocrine clinic and matched for age and sex with normal subjects (53). In this study the patients had greater life change, both positive and negative, in the year preceding the diagnosis of Graves' thyrotoxicosis than did the control subjects; however, raters unaware of the subjects' study group judged only negative life events to be significantly greater in the patients than in the control subjects.
There is also support for the notion that environmental stress plays a role in the exacerbations and relapses of established thyrotoxicosis. In a longitudinal study of patients receiving antithyroid drug therapy, the course of thyrotoxicosis seemed to be related to the patient's ability to cope with life stress psychologically, especially when confronted with loss (such as financial difficulty) or bereavement (54). If successful solutions were found, the illness subsided; if not, the exacerbation progressed. Individual case reports provide supporting evidence (55). For example, in a woman with Graves' thyrotoxicosis, surgical biopsy for a benign breast tumor was followed by a rapid increase in thyroid secretion. In another instance, a woman who had been treated successfully for Graves' thyrotoxicosis had a recurrence within 2 months after the death of two young members of her family.
In summary, psychological stress may be associated with the onset of symptoms of thyrotoxicosis and may influence its clinical course.
FACTORS AFFECTING THE PATHOPHYSIOLOGY OF THYROTOXICOSIS
Family studies suggest a strong although complex contribution of genetic factors to Graves' disease (56,57,58) (see Chapter 20). However, how these factors are linked to the development of thyrotoxicosis, even in genetically predisposed people, is not known.
Many studies have explored the response of the brain–thyroid axis to environmental challenge, but most were conducted before sensitive and specific assays for thyroid hormones and thyrotropin (TSH) were available. For example, in a study of five normal subjects and seven treated thyrotoxic patients, the serum protein–bound iodine concentrations (an early indirect measurement of serum T4) in both groups were higher after viewing an emotionally disturbing film than after viewing a travelogue. In both the normal subjects and treated patients, the concentrations decreased after the film ended, but the rate of decline was slower in the thyrotoxic patients (59).
The results of two studies of the effects of chronic psychological stress on thyroid function in humans suggest that long-term dysregulation of thyroid axis function may occur under adverse conditions. In a group of male veterans with post-traumatic stress disorder, a condition in which mental disturbances follow exposure to extreme stress, serum total T4, total and free triiodothyronine (T3), and thyroxine-binding globulin concentrations, but not serum free T4 or TSH concentrations, were higher than in age-matched normal men (60). In a study of hypothalamic–pituitary–thyroid function and psychiatric disturbances in 84 refugees, the serum concentrations of total and free T4, total and free T3, reverse T3, and TSH were significantly lower than were those in control subjects, and thyroid function did not correlate with psychiatric diagnosis (61).
In animals, serum protein–bound iodine concentrations increase in response to the challenge of restraint and the avoidance of foot shock (62). Thyroid hormones and catecholamines are intimately involved in the response to cold in animals (63), and serum TSH concentrations increase rapidly in response to cold and other challenges in humans (64,65,66). Although these changes may be of adaptive benefit and important in understanding the brain mechanisms in some psychiatric syndromes (67)—and possibly exacerbations in clinical symptomatology in thyrotoxicosis—it is unlikely that they play a major role in the genesis of thyrotoxicosis.
It seems more likely that the mechanisms whereby loss, bereavement, and perhaps the subsequent depression may help precipitate Graves' thyrotoxicosis lie in a complex interaction between the genetics of the immune system and the general neuroendocrine response to stress (68). In Graves' disease, TSH receptor–stimulating antibodies cause the thyroid hyperfunction (see section Pathogenesis in Chapter 23). These antibodies may be produced as a result of a defect in immunologic surveillance (68). A reduction in the activity of suppressor lymphocytes secondary to environmental stress is one proposed mechanism whereby the genetic propensity for Graves' disease may be expressed (68,69). Bereaved and particularly depressed people often have sustained elevations of serum cortisol concentrations, reflecting a disturbance of the regulation of the brain–adrenocortical axis (70,71,72). A reduction of lymphocyte function in bereaved people also has been described (73,74). A rapidly expanding body of knowledge now suggests intimate links between immune function, the brain, and the hypothalamic–pituitary–adrenal axis, so that hormones of the pituitary and adrenal glands may exert control over immune function, and vice versa (75,76). Recently, inhibition of corticotropin secretion by a fragment of the prohormone of thyrotropin-releasing hormone was described in rats (77). It is these bits of information that at present form the basis for any speculation that may link genetics, the environment, and the onset of Graves' thyrotoxicosis.
Once the thyrotoxic state is established, interactions between biogenic amines, particularly catecholamines, and thyroid hormones clearly have an important role in determining mental state. Catecholamines and thyroid hormones share the amino acid tyrosine as precursor and have synergistic actions in many metabolic processes, including those in the brain (67) (see Chapter 38). Animals with thyrotoxicosis have increased adrenergic activity and are especially vulnerable to the toxic effects of drugs, including psychoactive drugs, that increase catecholamine activity (78). The turnover of catecholamines is decreased, but the number of β-adrenergic receptors is increased (67). These changes may underlie the increased activity, sleeplessness, and anxiety that occur in patients with thyrotoxicosis. The reduction of these symptoms by a β-adrenergic antagonist drug such as propranolol supports this contention. Similarly, the synergism of thyroid hormones and catecholamines may explain the development of mania in predisposed people (67).
TREATMENT AND OUTCOME
Successful treatment of thyrotoxicosis usually leads to resolution of the major mental disturbances associated with it (7,39,79). Treatment consistently reduces nervousness, anxiety, emotional withdrawal, and motor tension (7). Those patients who have cognitive difficulty improve. The results of MMPI testing also improve, but there is no change in personality characteristics (7). Some studies, however, suggest that patients with thyrotoxicosis do not achieve complete psychopathological and neuropsychological recovery after becoming euthyroid (80,81).
Treatment with a β-adrenergic antagonist drug such as propranolol can be useful in controlling the anxiety associated with thyrotoxicosis. In acutely psychotic patients, dopamine blockade may be required to reduce excitement. Haloperidol or other dopamine blocking agents also can be given, although the latter may increase tachycardia, and there is one report of haloperidol precipitating thyrotoxic storm (82). A combination of propranolol and propylthiouracil was found to be effective in controlling manic psychosis secondary to thyrotoxicosis (46).
Particularly important is an awareness that if the patient's thyrotoxicosis was misdiagnosed and treated as psychosis or an affective state of other origin, some psychotropic medications may be harmful. In the rare thyrotoxic patient who has psychiatric symptoms simulating bipolar mania, lithium carbonate may be given with subsequent masking of the thyrotoxic state (83). Lithium has antithyroid actions (84,85), and its administration can result in improvement of thyrotoxicosis (86), but with exacerbation of thyrotoxicosis, as well as ophthalmopathy, when the lithium is discontinued (12,87,88).
When the thyrotoxicosis is apathetic, mimicking depression, administration of a tricyclic antidepressant drug can be hazardous (89). The sensitivity to both the anticholinergic and adrenergic effects of these drugs is increased in patients with thyrotoxicosis, and serious cardiotoxic effects may occur, especially in elderly patients.
Conversely, in rare instances, successful treatment of thyrotoxicosis may reveal a depressive illness, which in turn requires intervention. In one depressed patient, whenever the thyrotoxicosis was treated, remissions induced by imipramine were negated (90).
Finally, it is worth noting that the synergism of the adrenergic and thyroid systems has been successfully used in the treatment of depression (91). In some depressed patients, especially women (92), and those who are poorly responsive to antidepressant drug therapy, administration of T3 (93,94,95) or T4 (96) may substantially increase the efficacy of an antidepressant drug.
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