Role of thyroid hormone therapy in depressive disorders.

PURPOSE: The close association among thyroid metabolism, mood disorders and behavior has long been known. The old and modern uses of thyroid hormones to modulate the expression of depression and bipolar disorder and to improve clinical outcome when used in conjunction with psychotropic medications. METHODS: A literature search was performed to identify studies investigating the effects of thyroid hormone treatment in patient s with mood disorders. RESULTS: The successful modification of mood disorders with thyroid hormone underscores the association between endocrine and cerebral systems in these disorders. Thyroid hormones have a profound influence on behavior and appear to be capable of modulating the phenotypic expression of major mood disorders. In fact, there is evidence that triiodothyronine (LT3) may accelerate the antidepressant response to antidepressants, and studies suggest that LT3 also may augment the response to antidepressants in refractory depression. Add-on treatment with supraphysiologic doses of levothyroxine (LT4) has shown efficacy in open-label and in placebo-controlled studies, including in rapid cycling and prophylaxis-resistant bipolar disorder, and with acute refractory uni- or bipolar depression. Functional brain-imaging studies (PET) demonstrated that administration of supraphysiologic LT4 improves depressive symptoms in patients with bipolar depression by modulating cerebral activity in the anterior limbic network. CONCLUSION: The add-on administration of supraphysiologic doses of LT4 is a promising strategy in patients with refractory bipolar and depressive mood disorders.

Trajectories of adherence to mood stabilizers in patients with bipolar disorder.

BACKGROUND: Nonadherence with mood stabilizers is a major problem that negatively impacts the course of bipolar disorder. Medication adherence is a complex individual behavior, and adherence rates often change over time. This study asked if distinct classes of adherence trajectories with mood stabilizers over time could be found, and if so, which patient characteristics were associated with the classes. METHODS: This analysis was based on 12 weeks of daily self-reported data from 273 patients with bipolar 1 or II disorder using ChronoRecord computer software. All patients were taking at least one mood stabilizer. The latent class mixed model was used to detect trajectories of adherence based on 12 weekly calculated adherence datapoints per patient. RESULTS: Two distinct trajectory classes were found: an adherent class (210 patients; 77%) and a less adherent class (63 patients; 23%). The characteristics associated with the less adherent class were: more time not euthymic (p < 0.001) and female gender (p = 0.016). No other demographic associations were found. CONCLUSION: In a sample of motivated patients who complete daily mood charting, about one quarter were in the less adherent class. Even patients who actively participate in their care, such as by daily mood charting, may be nonadherent. Demographic characteristics may not be useful in assessing individual adherence. Future research on longitudinal adherence patterns in bipolar disorder is needed.

Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study.

Adding supraphysiologic doses of levothyroxine (L-T4) to standard treatment for bipolar depression shows promise, but the mechanisms underlying clinical improvement are unknown. In a previous pilot study, L-T4 treatment reduced depression scores and activity within the anterior limbic network. Here we extended this work in a randomized, double-blind, placebo-controlled study of patients with bipolar depression. Cerebral glucose metabolism was assessed with positron emission tomography and [F-18]fluorodeoxyglucose before and after 6 weeks of treatment with L-T4 (n=15) or placebo (n=10) in 12 volumes of interest (VOIs): the bilateral thalamus, amygdala, hippocampus, dorsal striatum and ventral striatum, and midline cerebellar vermis and subgenual cingulate cortex. Radioactivity in the VOIs, normalized to whole-brain radioactivity was taken as a surrogate index of glucose metabolism, and markers of thyroid function were assayed. Changes in brain activity and their association with clinical response were assessed using statistical parametric mapping. Adjunctive L-T4 treatment produced a significant decline in depression scores during the 6-week treatment. In patients treated with L-T4, we found a significant decrease in regional activity at P<0.05 after Bonferroni correction in the left thalamus, right amygdala, right hippocampus, left ventral striatum and the right dorsal striatum. Decreases in the left thalamus, left dorsal striatum and the subgenual cingulate were correlated with a reduction in depression scores (P<0.05 after Bonferroni correction). Placebo treatment was associated with a significant decrease in activity only in the right amygdala, and no region had a change in activity that was correlated with change in depression scores. The groups differed significantly in the relationship between the changes in depression scores and in activity in the thalamus bilaterally and the left ventral striatum. The findings provide evidence that administration of supraphysiologic thyroid hormone improves depressive symptoms in patients with bipolar disorder by modulating function in components of the anterior limbic network.

Antibodies in autoimmune thyroiditis affect glucose metabolism of anterior cingulate.

BACKGROUND: Hypothyroidism induced by an autoimmune process is associated with neuropsychiatric symptoms and metabolic abnormalities in the brain. The aim of this study was to examine the relationship between autoimmune thyroiditis and regional brain function in hypothyroid patients. METHODS: Cerebral glucose metabolism, as an index of brain function, was assessed in regional whole-brain analyses using positron emission tomography (PET) and [18F]fluorodeoxyglucose in thirteen hypothyroid patients with autoimmune thyroiditis suffering from neuropsychiatric symptoms. The primary biological measures were radioactivity in pre-selected brain regions, relative to whole-brain radioactivity, as a surrogate index of glucose metabolism, and serum levels of thyroglobulin (TG) and thyroid peroxidase (TPO) antibodies as endocrine markers of autoimmune thyroiditis. RESULTS: Serum levels of anti-TG antibodies in hypothyroid patients were significantly correlated with glucose metabolism in the perigenual anterior cingulate cortex, a brain region previously shown to regulate affect and emotional homeostasis. CONCLUSION: Thyroid autoimmune processes may play an important role in the still poorly defined pathogenic correlates of disturbed function in brain regions critically involved in emotional processing in hypothyroid conditions.

Regularity in daily mood stabilizer dosage taken by patients with bipolar disorder.

OBJECTIVE: The aim of this study was to investigate regularity in the daily mood stabilizer dosage taken by patients with bipolar disorder, and identify factors associated with irregularity. METHODS: Self-reported daily mood and medication data were available from 206 patients who took the same mood stabilizer for ≥100 days. Approximate entropy (ApEn) was used to measure serial regularity in daily mood stabilizer dosage. Generalized estimating equations (GEE) were used to estimate if demographic or clinical variables were associated with ApEn. RESULTS: There was a wide range of regularity in the daily mood stabilizer dosage. The mean percent of days of missing doses was 13.6%. The number of psychotropic medications (p=0.007), pill burden (p=0.004) and percent of days with depressed mood (p=0.013) were associated with more irregularity, while the percent of days euthymic (p=0.014) was associated with less irregularity. The percent of days missing doses was not associated with the number of medications, pill burden or mood ratings. DISCUSSION: Patients may have irregularity in daily dosage in spite of a low percent of days missing doses. Psychotropic medication regimen complexity and depression are associated with increased dosage irregularity. Research is needed on how irregularity in daily dosage impacts the continuity of drug action of mood stabilizers.

Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.

In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.

Comparison of pre-episode and pre-remission states using mood ratings from patients with bipolar disorder.

Daily self-reported mood ratings from patients with bipolar disorder were analyzed to see if the 60 days before an episode of hypomania or depression (pre-episode state) could be distinguished from the 60 days before a month of euthymia (pre-remission state), and if a pre-hypomanic state could be distinguished from a pre-depressed state. Data were available from 98 outpatients with bipolar disorder, who returned about one year of daily data, and received treatment as usual. The approximate entropy (ApEn), mean mood and mood variability (standard deviation) were determined for 53 pre-hypomanic states, 42 pre-depressive states, and 65 pre-remission states.There was greater serial irregularity (ApEn) and greater variability in mood in the pre-episode than the pre-remission state. There was greater serial irregularity (ApEn) but no difference in variability in mood in the pre-hypomanic state when compared to the pre-depressed state. ApEn can distinguish between the pre-episode, pre-remission, pre-hypomanic and pre-depressive states. Using daily mood ratings, pre-episode changes were detected before the episode onset. Further investigation to relate the pre-episode and pre-remission states to other clinical and biological data is indicated.

Brain glucose metabolism in hypothyroidism: a positron emission tomography study before and after thyroid hormone replacement therapy.

CONTEXT: Hypothyroidism is frequently associated with subtle behavioral and psychiatric symptoms. The consequences of inadequate thyroid hormone availability to brain metabolism are poorly understood. OBJECTIVE: This study assessed the relationships between neuropsychiatric symptoms and changes in relative regional cerebral glucose metabolism in hypothyroid patients undergoing thyroid hormone replacement therapy. DESIGN, SETTING, AND OUTCOME MEASURE: Relative regional cerebral glucose metabolism was compared in 13 previously untreated hypothyroid patients and 10 healthy control participants. Effects of thyroid hormone replacement therapy (levothyroxine, 3 months) were assessed using neuropsychiatric measures and positron emission tomography with [(18)F]fluorodeoxyglucose. RESULTS: Before treatment, hypothyroid patients exhibited lower regional activity than control subjects in the bilateral amygdala, hippocampus, and perigenual anterior cingulate cortex (ACC), left subgenual ACC, and right posterior cingulate cortex. Severity of depressive symptoms covaried negatively with pretreatment activity in the bilateral middle frontal gyrus and right subgenual and dorsal ACC. Thyroid hormone replacement therapy abolished pretreatment group differences in regional activity, robustly increased activity in the ventral ACC, and significantly reduced both clinician-rated and self-rated behavioral and psychiatric symptoms. Increased activity within the ventral ACC was associated with reduced somatic complaints, whereas increased activity within the dorsal ACC was associated with reduced depressive symptoms. CONCLUSIONS: Reduction of the behavioral complaints during thyroid hormone therapy is associated with a restoration of metabolic activity in brain areas that are integral to the regulation of affect and cognition. The findings suggest that thyroid hormone modulates regional glucose metabolism and psychiatric symptoms in the mature brain.

The thyroid-brain interaction in thyroid disorders and mood disorders.

Thyroid hormones play a critical role in the metabolic activity of the adult brain, and neuropsychiatric manifestations of thyroid disease have long been recognised. However, it is only recently that methodology such as functional neuroimaging has been available to facilitate investigation of thyroid hormone metabolism. Although the role of thyroid hormones in the adult brain is not yet specified, it is clear that without optimal thyroid function, mood disturbance, cognitive impairment and other psychiatric symptoms can emerge. Additionally, laboratory measurements of peripheral thyroid function may not adequately characterise central thyroid metabolism. Here, we review the relationship between thyroid hormone and neuropsychiatric symptoms in patients with primary thyroid disease and primary mood disorders.

Do antidepressants influence mood patterns? A naturalistic study in bipolar disorder.

This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.

Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression.

Supplementation of standard treatment with high-dose levothyroxine (L-T(4)) is a novel approach for treatment-refractory bipolar disorders. This study tested for effects on brain function associated with mood alterations in bipolar depressed patients receiving high-dose L-T(4) treatment adjunctive to ongoing medication (antidepressants and mood stabilizers). Regional activity and whole-brain analyses were assessed with positron emission tomography and [(18)F]fluorodeoxyglucose in 10 euthyroid depressed women with bipolar disorder, before and after 7 weeks of open-label adjunctive treatment with supraphysiological doses of L-T(4) (mean dose 320 microg/day). Corresponding measurements were acquired in an age-matched comparison group of 10 healthy women without L-T(4) treatment. The primary biological measures were relative regional activity (with relative brain radioactivity taken as a surrogate index of glucose metabolism) in preselected brain regions and neuroendocrine markers of thyroid function. Treatment-associated changes in regional activity (relative to global activity) were tested against clinical response. Before L-T(4) treatment, the patients exhibited significantly higher activity in the right subgenual cingulate cortex, left thalamus, medial temporal lobe (right amygdala, right hippocampus), right ventral striatum, and cerebellar vermis; and had lower relative activity in the middle frontal gyri bilaterally. Significant behavioral and cerebral metabolic effects accompanied changes in thyroid hormone status. L-T(4) improved mood (remission in seven patients; partial response in three); and decreased relative activity in the right subgenual cingulate cortex, left thalamus, right amygdala, right hippocampus, right dorsal and ventral striatum, and cerebellar vermis. The decrease in relative activity of the left thalamus, left amygdala, left hippocampus, and left ventral striatum was significantly correlated with reduction in depression scores. Results of the whole-brain analyses were generally consistent with the volume of interest results. We conclude that bipolar depressed patients have abnormal function in prefrontal and limbic brain areas. L-T(4) may improve mood by affecting circuits involving these areas, which have been previously implicated in affective disorders.

Thyroid, brain and mood modulation in affective disorder: insights from molecular research and functional brain imaging.

The efficacy resulting from adjunctive use of supraphysiological doses of levothyroxine has emerged as a promising approach to therapy and prophylaxis for refractory mood disorders. Most patients with mood disorders who receive treatment with supraphysiological doses of levothyroxine have normal peripheral thyroid hormone levels, and also respond differently to the hormone and tolerate it better than healthy individuals and patients with primary thyroid diseases. Progress in molecular and functional brain imaging techniques has provided a new understanding of these phenomena, illuminating the relationship between thyroid function, mood modulation and behavior. Thyroid hormones are widely distributed in the brain and have a multitude of effects on the central nervous system. Notably many of the limbic system structures where thyroid hormone receptors are prevalent have been implicated in the pathogenesis of mood disorders. The influence of the thyroid system on neurotransmitters (particularly serotonin and norepinephrine), which putatively play a major role in the regulation of mood and behavior, may contribute to the mechanisms of mood modulation. Recent functional brain imaging studies using positron emission tomography (PET) with [ (18)F]-fluorodeoxyglucose demonstrated that thyroid hormone treatment with levothyroxine affects regional brain metabolism in patients with hypothyroidism and bipolar disorder. Theses studies confirm that thyroid hormones are active in modulating metabolic function in the mature adult brain, and provide intriging neuroanatomic clues that may guide future research.

The electronic assessment of the longitudinal course of bipolar disorder: the ChronoRecord software.

Longitudinal studies are the optimal approach when investigating the highly variable course of bipolar disorder, but such studies are expensive, prone to reporting errors and to missing data. Automation of data collection may reduce such errors and improve data quality. The ChronoRecord, validated software that patients can install on a home computer to report mood, medications, sleep, life events, weight and menstrual data, has been designed to achieve such automation. In the trial of the ChronoRecord reported here, 80 of 96 (83 %) patients with bipolar disorder showed high acceptance of this computer-based system for self-report, entering daily recordings for a period of 3-months. This new technology, in addition to providing an accurate longitudinal record for research purposes, also facilitates on-going patient feedback and accurate study monitoring.

Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain.

The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly. Interaction of the thyroid and monoamine neurotransmitter systems has been suggested as a potential underlying mechanism of action. While catecholamine and thyroid interrelationships have been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal of this article is to review the literature on the relationships between thyroid hormones and the brain serotonin (5-HT) system, limited to studies in adult humans and adult animals. In humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-HT responsiveness that is reversible with thyroid replacement therapy. In adult animals with experimentally-induced hypothyroid states, increased 5-HT turnover in the brainstem is consistently reported while decreased cortical 5-HT concentrations and 5-HT2A receptor density are less frequently observed. In the majority of studies, the effects of thyroid hormone administration in animals with experimentally-induced hypothyroid states include an increase in cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT1A receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermore, there is some indication that thyroid hormones may increase cortical 5-HT2 receptor sensitivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact on the brain serotonin system. Thus it is postulated that one mechanism, among others, through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission, specifically by reducing the sensitivity of 5-HT1A autoreceptors in the raphe area, and by increasing 5-HT2 receptor sensitivity.

Bone mineral density in pre-and post-menopausal women with affective disorder treated with long-term L-thyroxine augmentation.

BACKGROUND: Augmentation with TSH-suppressive L-thyroxine (T4) has been shown to improve the course of illness in otherwise refractory affective disorders. This collaborative study investigates whether T4 augmentation for a minimum of 12 months decreases bone mineral density (BMD) in 26 pre- and post-menopausal women with affective disorder. METHODS: We measured BMD at the femoral neck, Ward's triangle, trochanter and lumbar vertebrae (L1-L4) in 13 premenopausal and 13 postmenopausal women with affective disorder using dual energy X-ray absorptiometry. BMD was expressed as g/cm(2) and as a Z-score, calculated using bone density data from the international reference population standard. RESULTS: The Z-scores for the pre- and post-menopausal women were within the reference range of the age and sex matched population standard. BMD for the composite group also did not differ either from the population standard. BMD in the lumbar spine and hip did not differ significantly between the pre- and post-menopausal groups. However, there were a relatively high number of postmenopausal patients with BMDs one S.D. lower than the population standard. LIMITATIONS: This is a cross-sectional study with a relatively small sample size. CONCLUSIONS: The study demonstrates that T4 augmentation treatment does not reduce BMD to a clinically significant degree in many women with affective disorder. However, the resilience of bone structure to T4 treatment may vary with site and menopausal status. This study underscores the need for regular assessment of BMD during adjunctive thyroid treatments for affective disorder, especially in postmenopausal women.

Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature.

OBJECTIVE: The delayed onset of therapeutic response to antidepressants remains a major problem in the treatment of depression. Among the strategies to accelerate response to treatment, the early addition of thyroid hormone to antidepressants has been suggested as a viable method. The authors performed a meta-analysis of the literature on the use of thyroid hormone supplementation to accelerate the treatment of depression to determine whether there is sufficient evidence to support the clinical efficacy of this strategy. METHOD: Both a computer-aided search of the National Library of Medicine MEDLINE and an intensive search by hand were conducted to identify all double-blind, placebo-controlled studies assessing the concomitant administration of thyroid hormone and antidepressant to accelerate clinical response in patients with nonrefractory depression. RESULTS: Six studies were identified. All were conducted with triiodothyronine (T(3)) and a tricyclic antidepressant. Five of the six studies found T(3) to be significantly more effective than placebo in accelerating clinical response. The pooled, weighted effect size index was 0.58, and the average effect was highly significant. Further, the effects of T(3) acceleration were greater as the percentage of women participating in the study increased. CONCLUSIONS: This meta-analysis supports the efficacy of T(3) in accelerating clinical response to tricyclic antidepressants in patients with nonrefractory depression. Furthermore, women may be more likely than men to benefit from this intervention.

Subjective response to and tolerability of long-term supraphysiological doses of levothyroxine in refractory mood disorders.

BACKGROUND: Although supplementation with supraphysiological doses of levothyroxine (T4) has been an effective treatment for refractory affective disorders in open studies, questions remain as to the tolerability of this treatment. This is the first study to investigate subjective patient response and tolerability to long-term treatment with adjunctive T4. METHODS: Of 24 patients with refractory affective disorders or schizoaffective disorder who were consecutively included into an open trial with supraphysiological T4, 16 were eligible for this study. Four measures were used to rate tolerability to T4 treatment. Subjective response was graded on a scale ranging from -33 (maximal negative response) to +33 (maximal positive response). Positive and negative effects were assessed on a structured questionnaire. Clinical tolerance was assessed with the clinician-rated Thyroid Symptom List and the self-rated Von Zerssen Complaint Lists. Outcome was assessed with the CGI for prophylactic ratings (CGI-BP). RESULTS: At the time of assessment, patients had been treated with supraphysiological T4 (mean dose 368 microg/d) for a mean of 54 months. The total subjective response score was +25.2. Positive subjective response and observer-rated treatment success were moderately correlated. Ratings on the Thyroid Symptom List indicated an overall favorable side effect profile. General physical and mental symptoms were only slightly higher than in the general population. LIMITATIONS: This was an open, cross-sectional study that only included responders and partial responders to T4 treatment. CONCLUSIONS: Subjective response and side-effect tolerability of long-term supraphysiological doses of T4 is favorable in patients with refractory mood and schizoaffective disorders who respond to the intervention.

Thyroid hormone, neural tissue and mood modulation.

The successful treatment of affective disorders with thyroid hormone exemplifies the suggested inter-relationship between endocrine and neuronal systems in these disorders. Thyroid hormones have a profound influence on behaviour and appear to be capable of modulating the phenotypic expression of major affective illness. Specifically, there is good evidence that triiodothyronine (T3) may accelerate the antidepressant response to tricylic antidepressants, and some studies suggest that T3 may augment the therapeutic response to antidepressants in refractory depressed patients. Open studies have also indicated that adjunctive supraphysiological doses of thyroxine (T4) can ameliorate depressive symptomatology and help stabilize the long-term course of illness in bipolar and unipolar patients, especially women refractory to standard medications. Despite acceptance of the essential role of thyroid hormone on brain maturation and differentiation, and the clinical and therapeutic observations in association with mood disorders, the molecular action that may underlie the mood-modulating properties of thyroid hormone in the adult brain has only recently become the focus of research. The identification of nuclear T3 receptors, the region-specific expression of deiodinase isoenzymes and the molecular analyses of thyroid-responsive genes in the adult brain have provided the biological bases for a better understanding of thyroid hormone action in mature neurons. Also the influence of thyroid hormones on the putative neurotransmitter systems that regulate mood and behaviour, serotonin and norepinephrine, may be helpful in explaining their mood-modulating effects.

Differential expression of thyroid hormone receptor isoforms by thyroid hormone and lithium in rat GH3 and B103 cells.

BACKGROUND: The interaction between lithium, a mood stabilizer, and the thyroid axis has been extensively studied; however, the regulation of thyroid hormone receptors by lithium is yet to be investigated. METHODS: To test whether lithium affects thyroid hormones at the receptor level, we examined the effects of lithium in combination with triiodothyronine (T3) on gene expression of thyroid hormone receptor isoforms in GH3 and B103 cells. RESULTS: The pattern of expression as well as the magnitude of regulation of the different thyroid hormone receptor isoforms appeared to be cell line specific. Whereas T3 regulated all four isoforms in GH3 cells at both time points, T3 did not alter thyroid hormone receptor TR alpha 1 and TR alpha 2 mRNA in B103 cells. Addition of lithium to thyroid hormone-deficient GH3 cells decreased TR alpha 1, alpha 2, and beta 2 expression without affecting TR beta 1 expression at 2 but not 5 days. Addition of lithium to T3-treated GH3 cells did not further modulate gene expression of TR alpha 1, alpha 2, beta 1, or beta 2 when compared to cells treated with T3 alone. The effects of lithium in B103 cells appeared to be isoform specific as well as time dependent, since TR alpha 1 expression was selectively decreased in B103 cells, when treated with T3 in the presence of lithium. CONCLUSIONS: The present study provides direct evidence that T3 and/or lithium regulate TR gene expression in vitro in a both time-dependent and cell line-specific manner.