Since the publication of the Clinical Society of London’s “Report on Myxoedema” in 1888, it has been recognized that thyroid disease may give rise to psychiatric disorders that can be corrected by reestablishment of normal thyroid hormone levels. Later, Asher reemphasized that patients with profound hypothyroidism may present with depressive psychosis. As outlined in Table 41-1, the symptoms of hypothyroidism often mimic those of depression, whereas those of hyperthyroidism include anxiety, dysphoria, emotional lability, and intellectual dysfunction, as well as mania or depression, the latter especially characteristic among elderly patients presenting with apathetic thyrotoxicosis.

Because patients with thyroid disease may manifest frank psychiatric disorders that are reversible with endocrine therapy, the thyroid axis has been extensively studied in patients presenting with a wide variety of behavioral disturbances. Various abnormalities of thyroid function have been identified, particularly in depression. In most depressed subjects, the basal serum thyroid-stimulating hormone (TSH), thyroxine (T₄), and triiodothyronine (T₃) levels are within the normal range, although in one report, a third of such patients were observed to have suppressed TSH levels.

A “blunted” TSH response to TRH administration (defined as a TSH rise < 5 mU/L) is seen in approximately 25% of depressed subjects. The blunted TSH response is said to be observed more often in unipolar than bipolar depression, but differentiating these disorders with TRH testing has been disappointing. The blunted TSH response is a “state” marker that normalizes on recovery from depression.

The mechanism for the blunted TSH response in affective disorders is not known; however, glucocorticoids, known to inhibit the hypothalamic-pituitary-thyroid axis, are elevated in depression and could be responsible. This suppressed TSH response is not specific to depression and may be observed in alcohol withdrawal, starvation, normal male aging, renal failure, acromegaly, Cushing’s syndrome, and hypopituitarism. The blunting may also result from medications such as T₄, glucocorticoids, growth hormone, somatostatin, dopamine, and phenytoin, all of which have been reported to diminish this response.

In normal subjects, TSH begins to rise in the evening before the onset of sleep and reaches a peak between 11:00 pm and 4 am. In depression, the nocturnal TSH surge is frequently absent, resulting in reduced thyroid hormone secretion. This finding supports the view that functional central hypothyroidism may occur in some depressed subjects. Sleep deprivation, which has an antidepressant effect, returns the TSH circadian rhythm to normal. The mechanism for the impaired nocturnal TSH rise is unknown.

Although the blunted TSH response is well recognized in depression, it is less clearly appreciated that an enhanced TSH response may occur in up to 15% of depressed subjects with normal baseline thyroid function tests. Most such patients have antithyroid antibodies, a finding suggesting that the TSH hyperresponse may indicate latent hypothyroidism caused by autoimmune thyroiditis. When autoimmunity is tested using the antithyroid peroxidase antibody (anti-TPO) rather than the less specific antimicrosomal antibody, the prevalence of autoimmune thyroid disease is even higher. Not all studies, however, have found an increased prevalence of antithyroid antibodies in depressed subjects when compared with matched control groups.

Approximately 20% of patients admitted to a hospital with acute psychiatric presentations, including schizophrenia and major affective disorders, but rarely dementia or alcoholism, may demonstrate mild elevations in their serum T₄ levels and, less often, T₃ levels. The basal TSH is usually normal but may demonstrate blunted TRH responsiveness in up to 90% of such patients. These findings do not appear to represent thyrotoxicosis, and the abnormalities spontaneously resolve within 2 weeks without specific therapy. Such phenomena may be secondary to central activation of the hypothalamic-pituitary-thyroid axis resulting in enhanced TSH secretion with consequent elevation in circulating T₄ levels.

In depressed patients, the most consistent abnormality of the thyroid axis may be an increase in serum total or free T₄ levels, although usually within the conventional reference range. This elevation generally regresses following successful treatment of the depression.

Thyroid function test abnormalities are common in older individuals. In otherwise normal female patients who are more than 60 years old, the prevalence of elevated TSH values and/or positive antithyroid antibodies is 10% or more. Subjecting apparently asymptomatic individuals with slight elevations of serum TSH but normal T₄ and T₃ levels to a battery of psychological tests has revealed significant differences from control subjects on scales measuring memory, anxiety, somatic complaints, and depression in many but not all studies reported. It is becoming increasingly recognized that depression is much more common in elderly individuals. Whether borderline hypothyroidism plays a role in these behavioral disturbances requires clinical attention. Further investigation should also be directed at studying the outcomes of intervention with levothyroxine.

Among alcoholic patients and those suffering from anorexia nervosa, suppressed T₃ levels with elevations in reverse T₃ and normal TSH values are consistent with the euthyroid sick syndrome. These findings likely result from caloric deprivation.

Medications commonly used to treat psychiatric illness have been shown to affect thyroid function tests (Table 41-2).

Lithium carbonate, used to treat bipolar disorders, interferes with both the release and organification of thyroid hormone. Therapeutic lithium levels diminish both T₃ and T₄ release from the thyroid gland, whereas at higher (probably toxic) levels, iodine uptake and organification may also be inhibited. Following a 3-week therapeutic course of lithium carbonate, suppression of serum T₄ and T₃ levels and associated elevations of basal serum TSH values and exaggerated TSH responses to TRH administration may be noted; these abnormalities generally return to normal within 3 to 12 months, even if the medication is continued.

Goiter is the most common thyroid disorder in lithium-treated patients. Hypothyroidism can also occasionally develop, particularly in patients who have thyroid glands that have been compromised by disorders such as Hashimoto’s thyroiditis and Graves’ disease previously treated with 131-iodine therapy. However, it is uncommon for hypothyroidism to occur if pretreatment thyroid function was completely normal and patients are thyroid antibody negative. If considered clinically necessary, lithium may be continued and T₄ added to treat patients who develop goiter or hypothyroidism.

The effects of phenytoin (Dilantin), occasionally used for bipolar disorder, on thyroid function are quite complex. Suppressed values of total T₄ and, occasionally, free T₄ are observed in a significant minority of patients who are treated on a long-term basis with phenytoin alone and in more than 75% of patients in whom the drug is combined with carbamazepine (Tegretol). The lower total T₄ levels are likely secondary to displacement of T₄ from thyroxine-binding globulin (TBG), whereas the reduced free T₄ levels result from enhanced clearance of T₄ through phenytoin-induced hepatic microsomal oxidative enzyme activity. Generally, the suppressed T₄ levels are accompanied by normal T₃ and free T₃ levels and normal TSH concentrations. Normal basal TSH values with diminished TSH responses to TRH have been attributed to potential phenytoin agonism at the T₃ receptor. However, other studies have suggested that this may be an assay artifact because free T₄ values have been found to be normal or mildly elevated in analyses using undiluted serum.

Carbamazepine (Tegretol) is used increasingly in bipolar disorder. Long-term use with maintenance of therapeutic serum levels suppresses serum T₄ values in more than 50% of patients. This may be the result of enhanced hepatic metabolism of T₄. TRH stimulation testing before and after initiation of carbamazepine therapy reveals that TSH responsiveness is reduced by the addition of this drug; this finding has led to speculation that carbamazepine may inhibit thyroid function through effects on the pituitary gland. Displacement of T₄ from TBG, similar to that seen with phenytoin, has additionally been cited as a potential effect.

Both phenobarbital and valproic acid are reported to lower serum levels of T₄ in patients treated on a long-term basis, the former via enhanced hepatic T₄ clearance and the latter likely from protein binding changes. Heroin, methadone, and perphenazine commonly increase serum TBG levels and therefore may elevate serum total T₄ levels, although TSH and free T₄ values remain normal. Amphetamines induce hyperthyroxinemia through enhanced secretion of TSH, an effect that appears to be centrally mediated.

Antidepressants do not generally cause abnormal peripheral thyroid hormone levels but may affect thyroid hormone metabolism in the central nervous system (CNS). Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) appear to promote activity of type 2 deiodinase (D2), which increases conversion of T₄ into T₃ in the brain. However, peripheral circulating total T₄ and free T₄ levels, often show a modest decline, though still within the normal range after treatment with various pharmacologic classes of antidepressants, or electroconvulsive therapy (ECT). There are case reports of sertraline-, paroxetine-, and escitalopram-related asymptomatic hypothyroidism, but more recent studies evaluating fluoxetine and sertraline have shown no clinically significant change in thyroid function test results.

The use of TCAs in thyrotoxic patients should be pursued with caution because cardiac dysrhythmias may be exacerbated or precipitated. Further, the monoamine oxidase (MAO) inhibitors may cause hypertension in thyrotoxic patients, although these drugs generally do not affect thyroid function or serum thyroid hormone levels.