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Thyroid issues and mood/behavioral issues
Jan 19, 2009
www.psychiatryweekly.com/aspx/article/ArticleDetail.aspxThe Mood Spectrum and Hypothalamic-Pituitary-Thyroid Axis
Focus Points
• Hyperthyroidism and hypothyroidism are associated with changes in mood and cognitive function.
• Thyroid dysfunction is more prevalent in patients with mood disorders than in the general population.
• Hypothyroidism is the most frequent disorder of thyroid dysfunction accompanied by depression-like symptoms; subclinical hypothyroidism is prevalent in approximately 15% of depressed patients.
• Although most bipolar patients are euthyroid, thyroid measures in the low-normal range or below-normal range seem to be relevant for the pathophysiology of bipolar disorders and may result in a less than optimal outcome.
• Thyroid measures in the low-normal or below-normal range seem to be correlated with time to recurrence of affective episodes.
• Thyroid hormones are used in the treatment of both depression and bipolar disorders in acceleration and augmentation strategies.
Abstract
Of the endocrine axes linked to the pathophysiology of bipolar disorder, the hypothalamic-pituitary-thyroid (HPT) axis has been extensively studied. Hyperthyroidism and hypothyroidism are associated with changes in mood and cognitive function. Abnormal thyroid indices, for example, are more prevalent in patients with mood disorders than in the general population. Most depressed patients are euthyroid, though subclinical hypothyroidism can be seen in approximately 15% of depressed patients. Furthermore, serum triiodothyronine (T3) levels are inversely correlated with time to recurrence of depressive episodes. Although most manic patients are euthyroid, thyroid measures in the low-normal range or below-normal range appear to be relevant in the pathophysiology of bipolar disorders and may result in suboptimal mood stabilization. Low thyroid function or frank clinical hypothyroidism has been associated with rapid-cycling bipolar disorder. In contrast to the T3/unipolar relapse, illness morbidity in bipolar disorder has more often been correlated with thyroxine (T4) indices. These observations have contributed to the clinical use of thyroid hormones both in acceleration and augmentation strategies. T3 has been mainly utilized in acute depression, while T4 has been used in lithium-maintained bipolar patients or in supraphysiological dosages in acute and maintenance treatment of bipolar depression, rapid cycling, and refractory depressive disorder.
Introduction
Thyroid dysfunction is more prevalent in patients with mood disorders than in the general population. The activity of the thyroid gland is essential for normal brain development and cognitive functioning. In patients with thyroid disease, cognitive, behavioral, and neurovegetative disturbances can all be observed.
The close relationship of thyroid economy and cognitive function has interested clinicians and researchers since the possible association between thyroid functioning and behavior was first described by Parry1 and Graves.2 They related “various nervous affectations” and symptoms of hysteria, restlessness, hyperactivity, and impaired concentration to the diagnosis of hyperthyroidism or thyrotoxicosis.1,2 In 1888, a report of the Clinical Society of London also noted a variety of mental disturbances associated with hypothyroidism.3
The most common psychiatric symptoms related to hypothyroidism are depression and cognitive dysfunction. In severe forms of hypothyroidism (ie, myxedema), psychotic and delusional symptoms may occur, and the syndrome may mimic melancholic depression and dementia.4 In a 1949 case series, Asher5 demonstrated the causative role of hypothyroidism in the psychopathology of these symptoms. Asher’s findings show that thyroid hormone deficiency may lead to depression and psychosis and may be reversed by desiccated thyroid administration.5
As synthetic thyroid hormones became available later in the century, studies of their use alone or preferably in combination with traditional treatment of mood disorders followed. Prange and colleagues,6 for example, found the accelerating effect of thyroid hormone in response to tricyclic antidepressants (TCAs).
More recently, researchers studying the hypothalamic-pituitary-thyroid (HPT) system have suggested that thyroid hormones play an important role in the pathophysiology of mood disorders.7,8 Thyroid hormones may interact with neurotransmitter systems and intracellular mechanisms and are capable of modulating the phenotypic expression of major affective illnesses.7,8 Depressive and bipolar disorders in particular often constitute a mood spectrum; HPT system abnormalities discussed in the following sections therefore pertain to this broad spectrum.
The Hierarchy of the HPT Axis
The thyroid gland produces two hormones, the prohormone thyroxine (T4) and the biologically active triiodothyronine (T3). The predominant T4 is converted to the biologically active T3 by special deiodinases (ie, type-I to type-III deiodinases). The rate of synthesis of the thyroid hormones is regulated by the pituitary thyrotropin-stimulating hormone (TSH), which is stimulated by hypothalamic thyrotropin-releasing hormone (TRH). Thyroid hormones are necessary for the regulation of various metabolic functions and homeostasis. They exert a negative feedback on thyroid hormone release at hypothalamic and pituitary levels (Figure 1).9
Thyroid hormones enter the central nervous system (CNS) mainly in the form of T4,10 which is catalyzed to T3 by specific deiodinases. In the adult brain, the process of deiodination is different from that in peripheral tissue and is associated with a region-specific expression of type-II and type-III isoenzymes in the brain and amygdala.11,12 After the coupling of T3 to nuclear receptors, the transcriptionally active complex binds to thyroid-hormone responsive elements and thus alters gene expression and, accordingly, synthesis of messenger ribonucleic acid and proteins (Figure 2).13 Thyroid hormones affect neuronal processing and integration, glial cell proliferation, myelination, and synthesis of key enzymes required for neurotransmitter synthesis.14,15
Effects of a Disturbed Thyroid System on the Premature and Mature Brain
In the perinatal period, thyroid deficiency results in irreversible brain damage and mental retardation. This syndrome is referred to as cretinism.14 Similar consequences, such as variable degrees of irreversible brain damage, can be associated with clinical hypothyroidism in early childhood, but are generally less severe than cases detected by neonatal screening tests. The neurologic symptoms do not seem to be progressive but are irreversible, despite T4 treatment.16 Delayed growth following childhood hypothyroidism is restored rapidly with treatment.17
The symptoms of thyroid hormone abnormalities in adults primarily manifest as alterations in metabolism. In addition, they also change the synthesis and degradation rates of a variety of other growth factors and hormones.9,18 Nuclear thyroid hormone receptors are widely distributed in the mature brain.19,20
Thyroid Illness and Clinical Symptoms
Thyrotoxicosis is the clinical syndrome of hypermetabolism resulting from increased serum concentrations of T4, T3, or both. Subsequently, the secretion of TSH is suppressed, resulting in decreased serum TSH concentrations. Thus, the term hyperthyroidism refers to an increase in thyroid hormone biosynthesis and secretion by the thyroid gland.8,21 Hyperthyroidism or thyrotoxicosis is accompanied by symptoms including dysphoria, anxiety, restlessness, emotional lability, and impaired concentration. In elderly patients, depressive symptoms, such as apathy, lethargy, pseudodementia, and depressed mood, can also occur.22,23 Approximately 60% of thyrotoxic patients suffer from anxiety disorder and 31% to 69% suffer from depressive disorders.24,25 However, overt psychiatric illness only occurs in approximately 10% of thyrotoxic patients.26,27 Patients developing mania while in a thyrotoxic state typically have a diagnosis of an underlying mood disorder or a positive family history.28-30
Hypothyroidism is the most frequent disorder of thyroid dysfunction.31 In hypothyroid patients, depression-like symptoms frequently occur; they include psychomotor retardation, decreased appetite, fatigue, and lethargy.31 Neurocognitive dysfunction and depression, as well as impaired perception with paranoia and visual hallucinations, may develop.32,33 Severe hypothyroidism mimics melancholic depression and dementia. The neurocognitive deficits reverse rapidly on return to a euthyroid state (Figure 3).34
Thyroid Indices in Mood Disorders
Thyroid function abnormalities are classified following the system devised by Wenzel and colleagues.35 Grade I hypothyroidism is defined as decreased serum T4 level, grade II as an increased serum basal TSH with normal serum T4 level, and grade III as the presence of an isolated exaggeration of the TSH response to TRH stimulation, with normal basal TSH levels.35
Most depressed patients are euthyroid, although subclinical hypothyroidism can be seen in approximately 15% of depressed patients.36,37 Gold and colleagues36 reported grade-II or grade-III hypothyroidism in 8% of depressed patients admitted to a psychiatric hospital. Subclinical hypothyroidism may be a risk factor for depression in women.38
The time to recurrence of depressive episodes was found to be inversely correlated with serum T3 but not T4 levels in patients with unipolar depression.39 Studying the HPT axis, investigators have found abnormal TSH response to TRH stimulation in depressed patients.38,40-42 The peak response was blunted in 25% to 30% of patients43 and exaggerated in 10%.44 Elevated levels of cerebrospinal fluid (CSF) TSH have also been reported in depressed patients.45
Although most bipolar patients are euthyroid, thyroid measures in the low-normal or below-normal range seem to be relevant for the pathophysiology of bipolar disorders and may result in a less than optimal outcome. Frye and colleagues46 reported an association of low levels of T4, within the normal range, with greater mood instability and depression severity during prophylactic lithium treatment in bipolar patients. Cole and colleagues47 found poorer treatment response in bipolar patients with lower free T4 index values and higher TSH values within the normal range.
The idea that thyroid hormones act as modulators in affective illnesses is further strengthened by studies of the relationship between thyroid function and the clinical course of rapid-cycling bipolar disorder, which affects 10% to 15% of all bipolar patients. Treatment-resistant rapid cycling is much more common in women than men.48 Studies7,49-51 have found associations of low thyroid function or clinical hypothyroidism with rapid cycling. The incidence of grade-II hypothyroidism is 25% higher in rapid cyclers than in depressed patients in general (2% to 5%) or depressed patients taking lithium (9%).7,52
In a study by Gyulai and colleagues,53 bipolar patients received 4 weeks of treatment with lithium carbonate followed by stimulation with TRH. Rapid-cycling patients showed a higher increase of TSH after stimulation with TRH than healthy controls, although at baseline (without lithium treatment) no differences in response to the stimulation had been found.
It can be argued that latent hypofunction of the HPT system is present in rapid-cycling bipolar patients and manifests following antithyroid stress (eg, as induced by lithium treatment). This could explain the reversion of the rapid-cycling pattern and the reduction in number of episodes in refractory bipolar disorder following high dosage T4 treatment additive to established pharmacotherapy.54-56
Antithyroid antibodies are present in autoimmune thyroiditis, a major cause of hypothyroidism, and are useful to identify subclinical hypothyroid states. Anticolloid antibodies mainly react with thyroglobulin; anticytoplasmic antibodies react with components in the microsomal fraction of the thyrocytes (antimicrosomal antibodies) and are specific for the enzyme thyroid peroxidase.57,58 TSH receptor antibodies influence the function and growth of the gland.59
Studies are inconsistent as to whether thyroid antibodies are elevated in bipolar patients, with reported rates ranging from 0% to 43%, and as to whether lithium exposure is associated with the occurrence of thyroid antibodies.60-63 Kupka and colleagues64 found a higher prevalence of thyroid peroxidase antibodies in bipolar patients than in the general population or in nonbipolar psychiatric patients. A positive antibody status was associated with an increased risk for lithium-induced hypothyroidism but not with current or former lithium treatment.64
Approximately 30% to 40% of patients insufficiently respond to antidepressant treatment. This could be due in part to altered thyroid hormone availability in the CNS. Sullivan and colleagues65 reported lower CSF transthyretin (ie, thyroid hormone-binding globulin) levels in depressed patients than in healthy controls despite normal peripheral blood thyroid hormone measures. Reduced levels of central transthyretin—responsible for the uptake of T4 across the blood-brain barrier and its distribution throughout the brain—could attenuate trafficking of thyroid hormones within the blood-brain barrier despite functioning thyroid hormone feedback to the hypothalamus and anterior pituitary.65
Effects of Pharmacologic and Nonpharmacologic Treatment on the HPT System
Antidepressant treatment with TCAs, tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), carbamazepine, and lithium is followed by a decrease in peripheral T4 serum concentrations which is correlated with clinical effectiveness.42,66,67 A decrease in T4 could also be observed following nonpharmacologic treatment, such as sleep deprivation, light therapy,68 electroconvulsive therapy, and psychotherapy.69 After establishing the antidepressant effect of rapid transcranial magnetic stimulation (rTMS) on prefrontal cortex regions, George and colleagues70 found an increase in TSH when applying rTMS over the prefrontal but not the occipital or cerebellar cortex.
A variety of brain imaging techniques offer the chance to evaluate the relationship between the brain, thyroid hormones, and behavior in healthy subjects and patients with mood disorders. Using positron emission tomography, Marangell and colleagues71 demonstrated that serum TSH was inversely related to both global and regional cerebral blood flow and glucose metabolism, with prefrontal areas showing maximal negative correlations in patients with bipolar and unipolar depression. Treating bipolar patients with supraphysiological dosages of T4, Bauer and colleagues34 found significant cerebral metabolic effects in frontal, limbic, and subcortical regions accompanying mood improvement.
Thyroid Hormone Mechanisms of Action
To date, the mechanisms of thyroid hormone effects on the brain are not fully known. Besides influencing brain metabolism, they seem to modulate gene expression and affect intracellular signaling pathways and neurotransmitter systems, including the noradrenergic, serotonergic,72 and g-aminobutyric acid (GABA) systems. Downstream of receptors, thyroid hormones appear to exert important influences on the activity and synthesis of G-proteins in the adult brain. Lack of this hormone leads to an impairment in adenylate cyclase and phosphoinositide-based signaling pathways.72
Treatment Strategies
The close association between the HPT system and mood disorders has led to different approaches for the therapeutic use of thyroid hormones (ie, T3 and levothyroxine [L-T4]) in affective disorders.
T3 is mainly applied in the treatment of acute depression. One strategy is acceleration, which is speeding up the response to antidepressants. A recent meta-analysis,73 which included studies where T3 was initiated within 5 days after starting TCAs, found T3 to be significantly more effective than placebo in accelerating response to the antidepressant.73 Women especially benefited from a primary combination of an antidepressant with T3.74,75 The treatment was generally well-tolerated. Another approach is the augmentation strategy in refractory depression. In a meta-analysis, Aronson and colleagues76 evaluated the effect of T3 augmentation. They found that subjects were twice as likely to respond under T3 augmentation compared to placebo.76 No data are available so far for long-term T3 treatment of affective disorders.
L-T4 has been investigated in augmentation approaches for treatment-resistant depression. An open-label trial by Bauer and colleagues77 found promising results in unipolar and bipolar patients given L-T4 as add-on therapy to antidepressants or mood-stabilizers; side effects were surprisingly mild in this trial.77 In a recent case series78 observing unipolar and bipolar subjects with refractory depression, investigators again found a high remission rate.78 Successful treatment with supraphysiological doses of L-T4 has also been reported in several case reports of rapid-cycling bipolar disorder.79,80 An open-label study81 in prophylaxis-resistant non–rapid-cycling subjects did show significantly decreased relapse rates and fewer hospitalizations. Only mild side effects were reported.81
Whether the promising data of the use of T3 and T4 in acceleration and augmentation strategies extend to their use in combination with SSRIs is still to be studied since almost all data relate to the combination with TCAs.82-84
Thyroid hormone treatment alone in affective disorders has only rarely been studied. Wilson and colleagues85 compared T3 alone with imipramine alone in depressed patients in a double-blind study. At a dose of 50 µg/day, T3 alone was as effective as imipramine. However, the study had to be terminated because of signs of mild thyrotoxicity when T3 doses reached 62.5 µg/day.85 In patients with primary major depressive disorder without apparent thyroid dysfunction, 50–100 µg/day of T4 alone for 2 weeks showed only modest average effects, although some patients improved markedly.86
Treatment approaches using TRH showed promising antidepressant effects by intrathecal infusion87 and longer-term intravenous or subcutaneous injection.88 Prange and colleagues89 found that when TSH was administered intramuscularly in addition to TCAs the response rate was twice that of placebo; however, this approach has not been pursued by others and thus the findings have not been replicated.
Conclusion
Since the 19th century, observations of behavioral and mood changes in patients suffering from thyroid disorders have stimulated research to understand the relationship between thyroid function, behavior, and mood.
Both excess and inadequate thyroid hormones can induce disturbances of behavior that mimic depression, mania, and dementia. The neurocognitive impairments accompanying these dysfunctions are generally reversible following return to euthyroid status.
Thyroid hormones appear to be capable of modulating the phenotypic expression of major affective illness. Research aims to answer the question of whether changes in the functioning of the HPT system play a role in the pathophysiology of mood disorders. Furthermore, stress asserts inhibiting effects on the HPT axis. Pharmacologic, as well as nonpharmacologic, antidepressant treatment influences thyroid hormone levels in relation to treatment response. Beginning in the early 20th century, thyroid hormones were studied as a treatment option in depression and bipolar disorders. Data so far show good response rates in augmentation strategies in severely ill patients (ie, those with rapid-cycling bipolar disorder and refractory depression) with surprisingly mild side effects.
The mechanisms of thyroid hormone effects on the brain are still not fully known. Besides influencing brain metabolism, they seem to modulate gene expression and affect intracellular signalling pathways and neurotransmitter systems, including catecholamine, serotonin, and GABA systems.72
As clinicians gain more profound knowledge about the interactions of thyroid hormones, behavior, and mood, they advance their understanding of the pathophysiology and treatment options for bipolar disorder and depression. Additional research with rigorous scientific designs is still needed to confirm the efficacy, safety, and feasibility of thyroid hormone therapy in severely ill patients. PP
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