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Clinical Applications of
Levothyroxine in Refractory Mood
Disorders
M Bauer,1,2* M Adli,1 T Bschor,3 A Heinz,1 N Rasgon,4 M Frye,2 H Grunze,5 R Kupka,6 and PC Whybrow2
1Department of Psychiatry and Psychotherapy, Humboldt University at Berlin, Charité University Hospital, Schumannstr. 20/21, 10117 Berlin, Germany (*for correspondence); 2Neuropsychiatric Institute and Hospital, Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles (UCLA), Los Angeles, CA, USA; 3Technische Universität Dresden, Germany; 4Department of Psychiatry, Stanford School of Medicine, Palo Alto, CA, USA; 5Ludwig-Maximilians-Universität Munich, Germany; 6University Medical Center Utrecht, The Netherlands E-mail: [email protected]
Received for publication: March 25, 2003 Accepted: April 14, 2003 A novel approach to refractory bipolar disorder is supplementing standard treatment regimens
with levothyroxine (L-T ). Open-label studies consistently demonstrate that augmentation
with thyroid hormone can improve the course of affective illness. Specifically, adjunctive
treatment with supraphysiologic doses of L-T may be an effective and well-tolerated strategy
for maintenance treatment of patients with rapid cycling and otherwise prophylaxis-resistant
bipolar disorders. Evidence has also shown that supraphysiologic doses of L-T may be an
effective augmentation agent for acute intervention in unipolar and bipolar patients with a
treatment-resistant major depressive episode. This article aims to review the evidence
pertaining to treatment of refractory affective disorders with supraphysiologic doses of L-T ,
and provide practice guidelines for its effective and safe use.
Key Words
Ⅲ Bipolar disorder Ⅲ Affective disorder Ⅲ Rapid cycling Ⅲ Prophylaxis-resistance Ⅲ Levothyroxine (L-T ) Ⅲ Supraphysiologic doses Interest in using thyroid hormones to treat affective disorders arose from observed associations between psychiatric symptoms and thyroid disease states,1–5 and thyroid hormones have been A series of open and controlled clinical trials have been conducted on therapeutic use of thyroid hormones in mood used as treatment since the early 20th century. In the 1930s and disorders8,9 since Prange’s classic triiodothyronine (T ) 40s, Norwegian physicians first used hypermetabolic doses of acceleration study in the late 1960s.10 There is good evidence desiccated sheep thyroid gland to successfully treat patients with that T may accelerate the response to tricyclic antidepressants11 cyclic disorders they called periodic catatonia.6,7 This success, and possibly also augments the response to tricyclic drugs in treatment-refractory patients, although results were coupled with reports of an increased frequency of thyroid axis inconsistent.12,13 There are a large number of studies of T3 dysfunction in affective illness, has prompted several groups to augmentation in acute depression, but augmentation with L-T4 administer the synthetic thyroid hormone levothyroxine (L-T ), to was rarely studied despite several advantages of using L-T4 instead of T . L-T has a longer half-life, better tolerability, is Clinical Approaches in Bipolar Disorders 2003; 2: 49–56
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easier to measure in blood, and is available in multiple strengths Studies using low, ‘replacement’ doses of L-T in A few single case reports,14–19 case series,20 or open trials of One larger study of the augmenting effects of L-T in acute unipolar depression23 directly compared the antidepressant literature review search of the National Library of Medicine augmenting effects of T versus L-T in patients not responsive MEDLINE database from February 1966 to February 2003 to an adequate trial of desipramine or imipramine. In this (summarized in Table 1). Most articles report use of adjunctive 3-week, randomized, double-blind study, nine out of 17 patients L-T in rapid cycling bipolar disorder in adults, but adolescent18 (response rate, 53%) responded to T , which was significantly and geriatric patients17 have been studied. A single case study more than those responding to L-T (four out of 21 patients; describes the repeated prolongation of response to sleep 19%). This result suggested that T should be the augmentation deprivation with concurrent administration of L-T thyroid hormone of choice in acute depression. Owing to the long 150 µg/day).21 Doses of L-T varied broadly from replacement16 half-life of L-T (1 week, leading to a steady-state approximately 3–4 weeks after the last increase) however, its therapeutic Table 1: Use of levothyroxine (L-T ) in affective disorders: review of augmentation and prophylactic studies
Duration of
group size
Thyroid status
Subjects
(gender F/M)
(µg/day)
Co-medication
treatment
responders
aDouble-blind, cross-over with lithium augmentation. bPlacebo substitution in 4 patients. cPreliminary results in Baumgartner et al.46AD, antidepressant; BD, bipolar disorder; CBZ, carbamazepine; CGI, Clinical Global Impression Scale; DB, double-blind; DMI, desipramine; IMI, imipramine; Li-X, cross-over study with lithium; MS, mood stabilizer; NLP, neuroleptic; NR, non-response; PR, partial response; R, response; RA, randomization; RC-BD, rapid cycling bipolar disorder; SA, schizoaffective disorder; T , triiodothyronine; UP, unipolar major depressive disorder.
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effects may not be evident in a 3-week trial (as suggested by the treatment regimen, the patients’ mean score on the Hamilton Rating Scale for Depression (HRSD, 21 items) was 11.6, compared with 26.6 before addition of L-T . Eight patients were Studies using high, ‘supraphysiologic’ doses of in full remission (defined as a ≥50% reduction in HRSD-21 score and an end score of ≤8) after 8 weeks of treatment and two other patients were in full remission after 12 weeks.26 Prophylaxis studies in refractory unipolar and bipolar disorder Spoov and Lahdelma27 compared lithium augmentation, an Studies using supraphysiologic doses (defined as ≥200 µg/day) established strategy for patients not responding to of L-T aim to elevate thyroid hormone levels beyond the normal antidepressants, with L-T augmentation (L-T dose, 200 µg/day) (reference) range. Administering supraphysiologic doses of in a group of unipolar depressed patients non-responsive to L-T (up to 500 µg/day) as prophylactic medication (Table 1), 4-weeks of treatment with an antidepressant. The percentage Stancer and Persad22 reported that rapid cycling ceased in five reduction in depression ratings was significantly greater in out of eight women with bipolar disorder, but not in two men.
Later, a study using adjunctive supraphysiologic doses of L-T to The effects of open-label, add-on L-T medication (mean treat 11 patients (10 women [of whom nine were pre- dose 320 µg/day) for 7 weeks were investigated in euthyroid, menopausal] and one man) with refractory rapid cycling bipolar young women with refractory bipolar depression.28 L-T4 illness was described.24 L-T treatment was initiated after stable treatment improved mood as indicated by a reduction of the ‘therapeutic’ blood levels of mood stabilizing medications had HRSD-21 score from 23.2 to 6.0, and reduction of the Beck been reached, and the physiological criteria for optimum Depression Inventory score from 33.4 to 11.6, at study end (P<0.001 for both). Of the 10 patients enrolled, seven women approximately 150% of normal. Adjunctive treatment with L-T were full responders to augmentation with L-T (reduction in reduced the manic and depressive phases in both amplitude and HRSD-21 score of >50%; end score ≤7), and three women were frequency, and led to remittance in some patients. Four patients partial responders (reduction in HRSD-21 score of >50%; also underwent single- or double-blind placebo substitution: endpoint score ≥8). Similarly, Rudas et al.29 reported that three patients relapsed, after switching to placebo, into augmentation with high-dose L-T (mean dose, 235 µg/day) showed antidepressant effects in six out of seven patients with In a recently published, 8-year long-term study, adjunctive chronic depression and dysthymia in an 8-week open-label study.
treatment of prophylaxis-resistant unipolar and bipolar patients In summary, the diagnostic group within affective disorders, (21 women, five men) with supraphysiologic doses of L-T age of study participants, indication for L-T augmentation, and prevented affective episodes in approximately 60% (for details L-T dose used in the case reports and studies varied greatly see Table 1). There was a significant reduction in number of (Table 1). The results, however, indicate that augmentation with affective recurrences and morbidity indexes during treatment, supraphysiologic doses of L-T is a viable treatment strategy for compared with the same time period before L-T administration patients with refractory affective disorders. Augmentation with (mirror-image method). A substantial number of these refractory has not yet been studied in a double-blind, placebo- patients also experienced full remission. The mean length of controlled trial in affective illness, but studies to date (Table 1) adjunctive treatment with L-T was 51.4 months, and mean L-T describe beneficial effects, and in some refractory patients L-T augmentation studies of major depressive episodes Evidence emerging from acute intervention studies suggests that add-on treatment with supraphysiologic doses of L-T is also effective in reducing depression in treatment-refractory patients with a major depressive episode. An open-label study was conducted on 17 severely treatment-resistant, acutely depressed bipolar (n=12) and unipolar (n=5) patients, who had failed to In studies using supraphysiologic doses of L-T , a striking finding respond to at least two adequate treatment trials with was that patients tolerated the high doses of thyroid hormone antidepressants. Eight weeks after addition of L-T surprisingly well.22,24–26,30 The low rate of side effects contrasts Clinical Approaches in Bipolar Disorders 2003; 2: 49–56
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with that typically seen in patients with primary thyroid disorders, or healthy controls, treated with higher than replacement doses of Thyrotoxicosis is associated also with an increased risk of L-T .31 Despite increased serum thyroid hormone levels cardiovascular changes, including atrial fibrillation.
(‘hyperthyroxinemia’), patients with affective disorders reported Cardiovascular assessment, including 12-lead electrocardiograms only minimal side effects. Increased sweating, tremor, pulse and monitoring blood pressure and body weight in patients increase, and increase in agitation were most commonly reported.
receiving supraphysiologic doses of L-T detected no significant No serious adverse events were observed, even after treatment with changes or adverse effects during long-term treatment.25,26,34 In supraphysiologic doses of L-T over a period of several years,24,25,30 some patients, there was an increase in pulse rate (typical but the total patient numbers are small.
increase, 10–20 beats/minute; rarely beyond 100 beats/minute) Patients’ subjective response and attitude to supraphysio- that usually subsided after a decrease in L-T dose. The long- logic L-T treatment was favorable. In a study of 16 patients, term effects of treatment with supraphysiologic doses of L-T on none expressed a negative response, and the majority felt this other cardiovascular functions, e.g. ventricular function, cardiac output, and systemic vascular resistance, have not been The mechanism behind tolerability of supraphysiologic doses of L-T in patients with affective disorders remains speculative.
Treating mood disorders with high dose L-T , however, does not result in excessive peripheral levels of T (the hormone with the highest biologic activity),24–26,31 in contrast with endogenous production of thyroid hormone secondary to hyperthyroidism. It has been speculated that a low thyroid reserve may contribute also to the excellent tolerability to L-T supplementation of Treatment with supraphysiologic doses of L-T should be reserved for patients with refractory mood disorders because of limited evidence from controlled data and potential hazards. Overall, there is more evidence on L-T efficacy in bipolar disorder, but A concern over long-term prophylactic treatment with thyroid some evidence that it works in unipolar depressive disorders.
hormone is the increased risk of bone density loss and Specifically, augmentation with L-T is indicated in patients consequent osteoporosis. Thyrotoxicosis – the clinical syndrome of hypermetabolism, when serum concentrations of free thyroxine (fT ), free T (fT ), or both are increased – causes a Prophylaxis-resistant bipolar and unipolar affective disorders decrease in bone mass. A history of thyrotoxicosis is a known Treatment-resistant major depressive episodes (with or risk factor for osteoporosis. In two cross-sectional studies, without a history of mania or hypomania).
26 pre-menopausal and postmenopausal women and men with Prophylaxis- and treatment-resistance is usually defined as mood disorders received supraphysiologic L-T treatment for 12 months or longer. No significant loss of bone mineral density failure to respond to two medication trials given at adequate (BMD) was measured by dual-energy X-ray absorptiometry.32,33 doses for an appropriate duration.25,26 Initiation of L-T4 In a prospective, longitudinal study of 21 patients (16 women, treatment is not recommended during a manic or hypomanic five men), BMD measurement was performed after patients episode due to the lack of experience and risk of worsening the had received thyroid stimulating hormone (TSH)-suppressive manic state.3 In rare cases, however, manic states may be therapy with L-T (mean dose 411 µg/day) for an average of associated with hypothyroid conditions;3 in such cases, 16.4 months, and again after 33.6 months (mean dose supplementation with thyroid hormone is indicated in addition 416 µg/day). Comparison of BMD after treatment with an age- to standard antimanic drug treatment.
matched reference population found no significant bone loss (Bauer M, personal communication, 2003). Regular assessment Investigations prior to and during L-T treatment of BMD during long-term supraphysiologic thyroid hormone The experimental nature of supraphysiologic L-T treatment must treatment is recommended, however, particularly for be recognized. Careful examination of patients to identify postmenopausal women and those with a history of thyroid potential hazards and exclude conditions that place a patient at Clinical Approaches in Bipolar Disorders 2003; 2: 49–56
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that patients with bipolar disorder tolerated this approach Table 2: Contraindications for use of supraphysiologic
doses of levothyroxine in patients with refractory affective
unusually well. In discussions with medical consultants, the suicide risk of a patient with refractory mood disorder should beconsidered and weighted against the risks of L-T treatment Ⅲ Current hyperthyroidismⅢ Previous or current thyroid adenoma Pre-treatment thyroid status determines the dosing regimen (summarized in Table 4). The speed by which the L-T dose can be increased varies with the patient’s pre-treatment thyroid status, and tolerability to the agent during the initial treatment phase.
Generally, the dose should be increased more slowly in Postmenopausal women with evidence of osteopenia/osteoporosis, patients with overt and subclinical hypothyroidism. In and without concurrent protection for bone loss hypothyroid patients, the appropriate speed of treatment depends on duration and severity of hypothyroidism, and presence of other associated medical disorders. The initial dosemay range from 25–50 µg/day, to a full replacement dose based A series of investigations are recommended for baseline on age, weight, cardiac status, and severity of hypothyroidism.35 (pre-treatment) medical evaluation of the patient and during Once a euthyroid state is established, we recommend a ‘wait and treatment, which are summarized in Table 3. If pre-treatment see’ approach for 4–8 weeks before deciding if additional investigations show abnormal findings, or if any medical supraphysiologic L-T treatment would be beneficial.
A faster speed of dose increase is recommended for baseline endocrinologist or internist is recommended.
euthyroid patients (see bottom row in Table 4). If side effects In the past, many endocrinologists and internists hesitated occur (most often sweating or tremor), a reduction in dose or or resisted treating psychiatric patients with L-T . Experience slower speed of dose increase usually helps. The target dose of has shown that it is wise to provide such consultants, before L-T is a matter of debate, but our experience suggests that discussing a patient, with copies of reprints documenting 250–400 µg/day is the preferred range, depending on experience with this treatment in psychiatry and the observation Table 3: Recommended investigations prior to and during treatment with supraphysiologic doses of levothyroxine (L-T )
Investigationa
Pre-L-T treatment
Every 3 months
Every 12 months
Thyroid function tests (thyroid stimulating hormone, thyroid hormonesd) (liver enzymes, white and red blood cell count, electrolytes, creatinine) Bone mineral density (dual-energy X-ray absorptiometry) aConsider additional radiological investigations in patients with history or suspected thyroid disorder (e.g. sonography or scintigraphy of the thyroid gland). bIf pre-treatment shows abnormalities. cConsider 24-h electrocardiography recording if history of arrhythmia. dTotal T4, free T4, and total T3 levels; optional free T3 levels and thyroid antibodies (TPO antibodies).
eOnly in case of tolerability problems or side effects. fOnly in patients who receive L-T prophylactically (≥3 months).
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Table 4: Recommended dosing regimens for the use of supraphysiologic doses of levothyroxine (L-T ) in patients with
Projected thyroid
axis status for
Target treatment
start dose
(µg/day)
supraphysiologic
(µg/day)a
increasea
(µg/day)
L-T doses
Patients with subclinical hypothyroidismb aSingle morning dose (approximately 30 min before breakfast). bSlower L-T dose increase and closer monitoring recommended. cAppropriate dose increase after 6–8 weeks of treatment to achieve euthyroid status; for details see guidelines of the American Association of Clinical Endocrinologists.35 Duration and discontinuation of treatment with Thyroid hormone receptors are widely distributed in the brain, Duration of L-T treatment is determined by clinical indication and thyroid hormones have multiple effects on the central of use. In patients with treatment-resistant depression, nervous system (CNS).36,37 This action includes the limbic system augmentation with L-T should be administered for at least structures that have been implicated in the pathogenesis of 8 weeks, to allow assessment of the patient’s response. This time mental disorders, and where thyroid hormone receptors are period is necessary because with a half-life of 1 week, a steady- prevalent.36 The specific neurochemical basis and functional state is not reached until approximately 3–4 weeks after the last pathways of thyroid hormones that underlie therapeutic effects dose increase. If the patient responds, L-T should be continued on mood are unknown.37 Influence of the thyroid system on as long as antidepressant medication is required.
neurotransmitters that putatively play a major role in regulating The recommended minimum duration of treatment for mood and behavior, particularly serotonin and norepinephrine, patients with rapid cycling bipolar disorder is 6 months, and may contribute to the mechanisms of action.37–39 However, it is should be 12 months for patients with other prophylactic- not clear whether these are the seminal disturbances accounting resistant bipolar disorder. If the patient responds, prophylactic for mood modulation and behavioral change. Furthermore, within treatment may need to be continued for long periods (as long as the CNS, the regulatory cascade, through which thyroid no severe adverse effects develop), but a minimally effective hormones exert their effects, is not well understood: thyroid duration is recommended because of cardiac and bone risks.
hormone transport into the CNS, deiodinase activity in the brain, Discontinuation of treatment is recommended when the nuclear binding to genetic loci, and ultimately protein synthesis, patient does not respond to this intervention. Due to the long may all be involved.40,41 For instance, reduced levels of half-life of L-T , discontinuation can be performed over transthyretin (TTR), as detected in the cerebrospinal fluid of 1–2 weeks, or even immediately (depending on the reason for depressed patients,42 might disrupt delivery of thyroid hormones discontinuation), without adverse effects.
to regions inside the blood–brain barrier despite feedback to the Clinical Approaches in Bipolar Disorders 2003; 2: 49–56
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hypothalamus and pituitary to maintain peripheral thyroid using more rigorous scientific designs (e.g. randomized, double- hormone levels. One hypothesis for depression is that lack of TTR blind, placebo-controlled), to confirm these optimistic results is accounts for ‘brain hypothyroidism’, with normal peripheral now planned. Acute treatment and prophylaxis of bipolar (serum) thyroid hormone concentration, and thus contributes to patients with L-T appears to be a most promising strategy for the failed response to standard antidepressive treatments.42 severely ill patients with affective disorders.
There is growing evidence, from clinical research, that thyroid hormone levels below or at the lower end of the normal range (thyroid hypofunction), may be especially relevant to the Supported in part by a grant from The Stanley Medical Research pathophysiology of bipolar disorder and may result in a Institute (Grant 02T-238 to Dr Bauer).
suboptimal outcome. Frye et al.43 reported that a low level of fT , even if within the ‘normal’ range, was associated with moreaffective episodes and greater severity of depression during Key Points
prophylactic lithium treatment in patients with bipolar disorder.
It appears, therefore, that a higher fT level is advantageous for Clinical Applications of Levothyroxine in Refractory
treatment with lithium. Lower free thyroxine index values and Mood Disorders
higher TSH values (but within the normal range) were alsosignificantly associated with poorer treatment response in ■ Many individuals with refractory mood disorder do not bipolar patients during an acute depressed phase.44 A 4-week respond adequately to standard medications challenge study, with therapeutic doses of lithium (aprophylactic agent with established ‘antithyroid’ properties), ■ Adjunctive treatment with supraphysiologic doses of L-T4 found significantly higher delta TSH levels after thyroid releasing appears to be effective and well tolerated in maintenance hormone stimulation in unmedicated rapid cycling bipolar treatment of some patients with rapid cycling and patients compared with healthy controls.45 The investigators otherwise prophylaxis-resistant bipolar disorders postulated that if ‘central’ thyroid hypofunction is induced by ■ Supplementation of antidepressant and/or mood stabilizer lithium treatment, or any other mechanism, increasing the treatments with supraphysiologic doses of L-T may be availability of thyroid hormone to the brain may be therapeutic, effective in patients with bipolar disorder during a phase of with consequent modification of the mood state and improved refractory depression, and in patients with chronic unipolar ■ The therapeutic and prophylactic effects of adjunctive supraphysiologic L-T doses in refractory mood disorders are Open-label studies have consistently demonstrated that the promising, but remain experimental. Further research, using behavioral expression of bipolar disorder can be modified by a rigorous scientific designs is planned to confirm these change in thyroid status. In many instances, the course of illness is improved through use of supraphysiologic doses of L-T . The therapeutic and prophylactic effects of adjunctive ■ Acute treatment and prophylaxis of bipolar patients with supraphysiologic L-T doses in refractory mood disorders are L-T appears to be a most promising strategy for severely ill promising, but remain experimental due to the open study design applied in severely ill patient populations. Further research, References
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Key Paper
protein kinase. A number of GSK-3 substrates are involved in neuronal function and organization, and therefore present Harwood AJ, Agam G
plausible targets for therapy. Valproic acid (VPA) is an Biochem Pharmacol 2003; 66: 179–189
antiepileptic drug with mood-stabilizing properties. It may indirectly reduce GSK-3 activity, and can up-regulate gene Manic-depression, or bipolar affective disorder, is a prevalent expression through inhibition of histone deacetylase. These mental disorder with a global impact. Mood stabilizers have effects, however, are not conserved between different cell acute and long-term effects and at a minimum are prophylactic types. VPA also inhibits inositol signaling through an inositol- for manic or depressive poles without detriment to the other.
depletion mechanism. There is no evidence for GSK-3 inhibition Lithium has significant effects on mania and depression, but by carbamazepine, a second antiepileptic mood stabilizer. In may be augmented or substituted by some antiepileptic drugs.
contrast, this drug alters neuronal morphology through an The biochemical basis for mood-stabilizer therapies or the inositol-depletion mechanism as seen with lithium and VPA.
molecular origins of bipolar disorder is unknown. One approach Studies on the enzyme prolyl oligopeptidase and the sodium to this problem is to seek a common target of all moodstabilizers. Lithium directly inhibits two evolutionarily myo-inositol transporter support an inositol-depletion conserved signal transduction pathways. It both suppresses mechanism for mood stabilizer action. Despite these intriguing inositol signaling through depletion of intracellular inositol and observations, it remains unclear how changes in inositol inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional signaling underlie the origins of bipolar disorder.
Clinical Approaches in Bipolar Disorders 2003; 2: 56

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