Peter C. Whybrow
Michael Bauer
The prevalence, nature, and clinical course of the behavioral and psychological changes that occur in adults with primary hypothyroidism were first described in the latter half of the nineteenth century (1,2,3,4). In 1888, the Clinical Society of London described myxedematous (hypothyroid) patients, most of whom had some mental disturbance, ranging from irritability and agoraphobia to dementia and melancholia (3). Subsequently, it became generally accepted that hypothyroidism had severe effects on brain function and could irreversibly damage the developing brain. In adults with hypothyroidism, the subtle behavioral and psychological changes, especially during the early stages of the illness, confounded the clinical diagnosis, and people with “myxedematous madness” were commonly found on careful evaluation of patients in mental hospitals (5). Objective laboratory tests have improved this situation enormously, but isolated case reports of patients with hypothyroidism who present with severe mental disturbance continue to appear, and it remains important that the clinician be aware of the wide range of behavioral disturbances that can occur in patients with hypothyroidism (6,7,8).
NEUROPSYCHIATRIC FEATURES
The initial behavioral and neuropsychological changes in adults with primary hypothyroidism are nonspecific and ill-defined complaints (e.g., weakness, fatigue) and disturbances in cognition. The latter include inattentiveness, inability to concentrate, slowing of thought processes, and inability to calculate and to understand complex questions. Memory for recent events is frequently poor, and eventually memory for remote events also may become impaired. Ability to perform everyday, routine tasks is decreased. The patient becomes less responsive to others, less interested in his or her surroundings, and less capable of learning and performing new tasks. There is a paucity of speech, frequently with perseveration. Motor functions are slowed. Alterations in the accuracy of perception with an increased tendency toward illusion formation may appear; still later, visual and other hallucinatory distortions may occur that result in bizarre behavior and paranoid ideas. We know from historical descriptions that as hypothyroidism becomes more severe, progressive drowsiness, with lethargy and difficulty in arousal, occurs. The patient may sleep for long periods during the day and, finally, may lapse into stupor and even coma (see Chapter 65) (9). Convulsions also can occur (10).
Because of slowing of thought and speech, decreased attentiveness, poor concentration, and diminished interest in and responsiveness to others, the diagnosis initially may be confused with that of a depressive mood state (Fig. 64.1). Indeed, hypothyroidism may induce a specific melancholic disorder in some patients (11), with crying, loss of appetite, constipation, insomnia, delusions of self-reproach, and suicidal ideation (7,12,13,14). The picture is not consistently one of depression; a disorganized agitated state also has been described. In case vignettes of hypothyroid patients with psychosis (5,15,16,17), insomnia, hyperactivity, irritability, anger, and both auditory and visual hallucinations are described. Other patients become fearful, suspicious, and delusional. Hence, although depressed mood seems to predominate, the specific mental state and thought content varies with the individual patient. Cognitive changes, however, with alterations in attention, concentration, perception, and speed of thought, appear to be the most common of the clinical manifestations.
FIGURE 64.1. The symptoms of hypothyroidism overlap with those of dementia, psychosis, and depression.
OBJECTIVE BEHAVIORAL ASSESSMENT
These clinical observations are confirmed by the few objective studies of behavior that have been conducted in patients with hypothyroidism. Taken together, the symptoms and signs are diverse, and the mental state of hypothyroid patients thus has much in common with other organic syndromes of brain dysfunction. The results of electroencephalographic studies reflect this, with low-voltage θ and δ waves predominating (18,19). Stages 3 and 4 of sleep may be reduced (13), and evoked responses also are slowed (20,21,22). The electroencephalographic changes can be correlated with the mental status examination and particularly with tests of cognitive function, such as mental arithmetic or short-term memory and attention (23). More recently, studies using positron emission tomography have revealed a reduction of brain activity in association with the behavioral symptoms in severe hypothyroidism, but with varying results in different regions of the brain (24,25,26).
Objective psychological testing has revealed impairment in cognitive function with deficits in memory and learning, attention, visuoperceptual and construction skills, and psychomotor slowing (27,28). In most patients the deficits in cognitive function improve markedly with treatment (14,27,29,30,31,32,33). Some investigators have suggested that treatment with a combination of thyroxine (T4) and triiodothyronine (T3) improves performance in cognitive tasks more than does treatment with T4 alone (34). Subsequent analysis suggested that the combination had a greater effect in those patients with thyroid carcinoma than in those with autoimmune thyroiditis (35). Subsequent studies, however, have not confirmed the benefit of combined T4 and T3 therapy (36,37). Not all cognitive dysfunction, however, is reversed by therapy, suggesting that chronic deficiency of thyroid hormone may induce irreversible deficits in central nervous system (CNS) function (14,27,28,38).
Few behavioral studies have been conducted in hypothyroid patients unselected for psychiatric disorder, and hence the incidence of psychosis in hypothyroidism is difficult to estimate. Among the hypothyroid patients studied in 1888, it was about 15% (3). A study in the 1920s described hallucinations in 26% of patients (39). Improvements in laboratory tests that aid in the early diagnosis of hypothyroidism have reduced the incidence substantially, probably to less than 5%.
ASSOCIATED PSYCHIATRIC SYNDROMES
Schizophrenic and Affective Psychoses
The psychoses that occur in patients with hypothyroidism are nonspecific, representing a final common path of neurobiologic disorganization. Thus, they may mimic schizophrenic, paranoid, and affective psychoses. Although a careful history and physical examination usually reveal at least a few stigmata of hypothyroidism, the florid and acute nature of the psychotic disturbance may distract the physician or preclude such detailed clinical examination. Of special importance in clarifying the differential diagnosis is the impairment of cognitive function that is found in hypothyroidism. Even though confusion occurs in acute schizophrenia, together with distractibility that may masquerade as poor memory, visual hallucinations with profound and persistent cognitive disturbance (including memory and orientation) are rare. Thus, formal neuropsychological testing can be helpful. The very low amplitude waves present on electroencephalography in patients with severe hypothyroidism suggest an underlying delirium (18), but this test cannot be considered a reliable differential diagnostic procedure.
In patients with affective psychoses, cognitive impairment or pseudodementia is more common, especially in elderly persons, in whom it may be dismissed as the dementia of old age. Indeed, the symptoms of hypothyroid psychosis may mimic so closely those of the severely psychotic affective states that routine thyroid screening should be performed in all patients over 60 years of age who present with the clinical syndrome of affective psychosis and intellectual impairment.
The Depressive Syndrome and Manic Depression
Several metabolic and behavioral disturbances are common to hypothyroidism and affective illness, even in the absence of psychosis, suggesting that changes in pituitary–thyroid secretion may play an important role in the modulation of mood (40,41).
Patients with depression have a spectrum of abnormalities in thyroid test results, the most common of which is a slightly high serum T4 concentration (40,41,42), with a decline during treatment that correlates with the clinical response to antidepressant drug therapy (42,43). The serum thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) is blunted in approximately 25% of patients with depression, even though their serum T4 concentrations are within normal limits (44,45). Finally, as part of the disturbed circadian endocrine profile, the nocturnal surge in serum TSH concentrations is lost in depression, but returns with recovery (46).
Hypothyroidism is a graded phenomenon, and changes in serum T4 and especially TSH concentrations can be detected before the appearance of any clinical evidence of hypothyroidism. About 10% of 250 consecutive patients referred to a psychiatric hospital for treatment of depression or anergia had evidence of subclinical hypothyroidism (high serum TSH concentrations alone) or overt hypothyroidism (high serum TSH and low T4 concentrations) (47).
Furthermore, T3 given as an adjunct to tricyclic antidepressant drug treatment speeds recovery in some patients with depression (48), especially women (43,49). Some depressed patients resistant to therapeutic doses of antidepressant drugs may respond when T3 or high doses of T4 are added to the therapeutic regimen (50,51,52,53). Other patients with subclinical hypothyroidism complain of anergia and depressive-like symptoms that fall short of the classic depressive syndromes (see Chapter 78). However, the effect of T4 therapy on these symptoms in patients with subclinical hypothyroidism has been mixed (54,55,56,57,58).
Among women with postpartum depression, some also have postpartum thyroiditis, which occurs in about 5% of postpartum women (see Chapter 27). Each of these disorders can occur separately, but postpartum women with high serum antithyroid antibody concentrations are more likely to be depressed. In a study of 145 women who had high serum antithyroid antibody concentrations 6 weeks postpartum, 47% later had significant depressive symptoms, as compared with 32% of women with normal serum antibody concentrations (59). In a randomized double-blind placebo-controlled trial of 446 thyroid antibody–positive women, however, administration of 100 µg of T4 per day failed to diminish the incidence of depressive symptomatology (60).
Thyroid dysfunction is particularly important in the clinical course of manic-depressive (bipolar) illness, especially in rapid cycling, a severe form of the illness. Patients with the rapid cycling pattern, 70% to 90% of whom are women, by definition have more than four episodes of bipolar illness per year (61). They have a much higher incidence (~25%) of hypothyroidism than depressed patients in general (2%–5%) or those taking lithium carbonate (9%) (62,63). Administration of therapeutic doses of lithium carbonate, an established drug for the prophylaxis of bipolar disorder that also has antithyroid properties (64), resulted in significantly higher serum TSH responses to TRH stimulation in otherwise untreated patients with rapid cycling bipolar disease, as compared with normal subjects (65). This difference suggests that small degrees of hypothyroidism play a key role in the development of a rapid cycling pattern in patients with bipolar disorder. High doses of T4 added to the established treatment with lithium and other psychotropic drugs can reverse the rapid cycling pattern (66,67) and reduce the number of episodes in otherwise refractory bipolar disorder (68,69).
In addition to its antithyroid activity (70), lithium may inhibit type 2 deiodinase activity, the predominant deiodinase in the brain and pituitary (see Chapter 7) (71,72). Hence, the treatment of bipolar illness with lithium may impair brain thyroid economy and thus complicate the clinical course of the mood disturbance itself (73). Conversely, in some hypothyroid patients with a family history of bipolar affective illness, rapid replacement with T4 can induce mania (74). Tricyclic antidepressant drugs, which can precipitate rapid cycling disease (62,74), may also inhibit T4 conversion to T3 in the brain (75).
Taken together, these studies suggest that thyroid abnormalities, including overt and subclinical hypothyroidism, may contribute to psychiatric disability. Therefore, thyroid screening by measurement of serum TSH is warranted in all patients with syndromes of affective illness, especially women, who are resistant to antidepressant drugs and in those with atypical psychoses with a substantial cognitive disorder.
PATHOPHYSIOLOGY OF BEHAVIORAL DYSFUNCTION IN HYPOTHYROIDISM
The specific pathophysiology responsible for the behavioral disturbances of patients with hypothyroidism is unknown. It is probable that the general decline in cognitive and behavioral function is an integral part of the hypometabolic state characteristic of the disorder.
It has long been recognized that thyroid hormone is essential for the normal development of the central nervous system (see Chapter 74) (76,77). T4 is taken up avidly by the developing rat brain, and brain T3 content in these animals is higher than in mature animals (10). During development, T4 and T3 determine the rate and completeness of neuronal cell division and stimulate the activity of many enzyme systems in the brain, by exerting major effects on both nucleic acid and protein synthesis (78).
In an early study in adults with hypothyroidism, cerebral blood flow was reduced 38% below normal, as were oxygen and glucose consumption (27% below normal), and cerebrovascular resistance was increased twofold (79). All of the patients in this study had evidence of cognitive impairment. The three patients studied after treatment had normal values for those measurements. These changes, coupled with the electroencephalographic disturbances noted earlier (13,18,20,21,22), suggest delirium as the nonspecific final common path to mental dysfunction in patients with hypothyroidism.
Currently, there is no way to measure the effects of thyroid hormone on brain metabolism, but novel brain imaging techniques for evaluating the relationship between cerebral metabolism and thyroid status are being developed. In a study of hypothyroid patients using phosphorus 31 magnetic resonance spectroscopy, frontal lobe phosphate metabolism increased during T4 (80). Data from studies using positron emission spectroscopy also indicate a close relationship between thyroid status and cerebral blood flow and cerebral glucose metabolism in depression. Serum TSH concentrations were inversely related to both global and regional cerebral blood flow and cerebral glucose metabolism, a relationship that was most pronounced in the prefrontal cortex and independent of the severity of depression (81). More recently, positron imaging of blood flow using [18F]-fluorodeoxyglucose in patients with hypothyroidism has confirmed frontal lobe dysfunction, which improved when the patients were treated with T4 (25,82) (Fig. 64.2).
FIGURE 64.2. Positron emission tomography scans after administration of [18F]-fluorodeoxyglucose in a 35-year-old woman with hypothyroidism before and after thyroxine treatment. Note increase in frontal lobe uptake of the fluorodeoxyglucose (arrows), indicative of increased metabolic activity, during treatment.
Both T4 and T3 regulate cellular function in most organs, including the brain (83). T3 nuclear receptors are prominent in brain tissue, particularly in neurons, but they are not evenly distributed; high concentrations are found in the amygdala and hippocampus—regions of importance in the modulation of mood—and low concentrations in the brainstem and cerebellum (84). T3 receptor complexes regulate expression of various proteins (83) and, in the brain, T3 receptor binding is sensitive to the local thyroid hormone economy (see Chapter 8) (85).
About half of the T3 in brain nuclei is produced within the neurons by deiodination of T4, a reaction catalyzed by type 2 deiodinase (see Chapter 7) (85). The activity of this enzyme is increased in hypothyroidism and decreased in thyrotoxicosis. This precise autoregulatory mechanism not only underscores the importance of T4 and its deiodination to optimal brain function, but also suggests that minor changes in local T3 production can lead to major changes in behavior (86). Thus, in hypothyroidism, intracerebral generation of T3 from T4 increases as serum T4 declines, but intracellular T3 concentrations decline little until serum T4 is virtually exhausted (87).
Are changes in thyroid economy in the brain important to the aberrant behavior of patients with hypothyroidism and psychiatric disease? Until brain T4 and T3metabolism can be quantified in vivo, this question cannot be answered; however, strong clinical evidence in support of such speculation exists. This evidence includes the role of mild hypothyroidism in depressive illness and in postpartum depressive states associated with thyroiditis, the association of the rapid cycling variant of bipolar illness with hypothyroidism, the adjunctive therapeutic role of thyroid hormones in both depression and rapid cycling bipolar illness, and the profound disturbances that are found in hypothyroidism.
The depressive mood disturbances that occur in patients with hypothyroidism are of great interest to psychiatrists because they suggest the possibility of a common pathophysiology of the affective disorders and thyroid disease. The biogenic amines, putatively disturbed in both disorders, may form a linkage (41). The interaction of thyroid state and sympathetic nervous system activity has been recognized for many years (88,89). The biochemical activity of noradrenergic neurons and thyroid function are inversely related. For example, in hypothyroid rats, norepinephrine synthesis from tyrosine in increased in the heart, spleen, and adrenal tissue, as compared with normal rats (90). Conversely, in rats given T4 for 10 days, norepinephrine synthesis in the heart and brain is decreased by 30% and 15%, respectively (91). The activity of the enzyme dopamine β-hydroxylase also decreases in response to thyroid hormone in animals and humans (92).
This paradox, in which the biochemical activity of the adrenergic nervous system is apparently inversely related to thyroid state, whereas physiologic activity is directly related, is possibly explained by changes in adrenergic receptor function. In the heart and adipose tissue, increasing thyroid activity increases the number of β-adrenergic receptors, whereas the number of α-adrenergic receptors declines; decreasing thyroid hormone activity leads to the reverse (93). In rat brain, both the serotonergic and noradrenergic systems are responsive to changes in hypothalamic–pituitary–thyroid function (94,95,96). Thyroidectomy decreases ligand binding to β- and α2-adrenergic receptors in the limbic regions of the brain, and increases ligand binding to 5-hydroxytryptamine (5-HT)1Areceptors in the cortex and hippocampus, changes that can be reversed by the administration of T4. In in vivo microdialysis studies in rats, coadministration of the tricyclic antidepressant drug clomipramine and T3 raised 5-hydroxytryptamine concentrations in the frontal cortex more than either alone (97). Furthermore, the decrease in 5-hydroxytryptamine concentrations in the frontal cortex induced by an injection of a receptor agonist was significantly less in rats given T3 compared with control animals (97). In challenge experiments with d -fenfluramine, a centrally acting 5-hydroxytryptamine agonist, T4 increased central serotonergic activity in hypothyroid patients (98). Thus, a careful review of the available animal and human studies suggests that T3 may act presynaptically in the brainstem through the inhibition of 5-HT1A receptors to increase serotonergic activity in the cerebral cortex and hippocampus (95) (Fig. 64.3).
FIGURE 64.3. Increased availability of thyroid hormone decreases 5-hydroxytryptamine (5-HT)1A receptor sensitivity in the brainstem, thus stimulating the synthesis and release of serotonin (5-HT) in the cortex and hippocampus.
These results from animal and human studies suggest that there are neuromodulatory links among the serotonergic and adrenergic systems and thyroid state. Furthermore, thyroid hormones may also influence affective state through postreceptor mechanisms, for example, changes in guanine- nucleotide-binding (G) protein synthesis and adenylyl cyclase activity, that facilitate signal transduction (99,100). The sensitivity of Purkinje neurons in the cerebellum of hypothyroid rats to iontophoretically applied norepinephrine is decreased in association with decreased adenylyl cyclase activity and returns to normal after the administration of T3 (101). Whether these changes in serotonergic and adrenergic brain mechanisms are the principal pathway mediating the melancholic symptoms that commonly occur in patients with hypothyroidism remains to be determined.
TREATMENT AND OUTCOME
The behavioral disturbances of hypothyroidism in adults respond to adequate T4 replacement therapy unless there is underlying depression unrelated to the hypothyroidism, in which case cognition may improve, but the depressed mood persists (17,37). Exacerbation of the psychosis may occur soon after T4treatment is initiated (18), and thus, ideally, severely disturbed patients should be hospitalized. Therapy with a major tranquilizing drug may be necessary in a few patients, but the drug should be given with great caution and in conjunction with T4 to avoid precipitating myxedema coma. Haloperidol or other dopamine-blocking agents are the preferred drugs to be used in the treatment of the psychosis. The patients should be monitored carefully for cardiac arrhythmias, especially in those patients given a phenothiazine; there is a case report of cardiac arrest in such a situation (102).
When a patient with hypothyroidism has a strong family history of affective disorder, especially bipolar in character, the initiation of T4 treatment may precipitate manic excitement (73). In such a patient, it may be necessary to add lithium or an anticonvulsant drug to the treatment regimen. Parenthetically, when a patient who is receiving lithium develops a severe depressive state, cognitive confusion, and anergy, the clinician should think of the possibility of lithium-induced hypothyroidism (see Chapter 50).
When hypothyroidism is mild and complicating a predominantly depressive syndrome, the therapeutic goal is to provide sufficient T4 to reduce the serum TSH concentration to normal. However, when the melancholia persists, an antidepressant drug or even electroconvulsive therapy may be necessary.
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