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K E Y R E V I E W 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
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M Bauer et al.
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. Clinical Approaches in Bipolar Disorders 2003; 2: 49–56
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Levothyroxine in Refractory Mood Disorders
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
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M Bauer et al.
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
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Levothyroxine in Refractory Mood Disorders
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). Clinical Approaches in Bipolar Disorders 2003; 2: 49–56
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M Bauer et al. 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
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Levothyroxine in Refractory Mood Disorders
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,
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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
Dear Sir or Madam! Good morning/afternoon and welcome to our hotel. We are pleased that you decided to stay with us. If you have spent at least one night in our hotel we kindly ask you to participate in a survey which will help us make your future stay here even more pleasant. The interview will take about 10-15 minutes and is conducted anonymously. 1. How did you arrive to Slovenia? (mark the ap
Why Differentiate Instruction? A single seventh grade English language class at your College is likely to include students who can read and comprehend as well as most college learners; students who can barely decode words, comprehend meaning, or apply basic information; and students who fall somewhere between these extremes. There are students whose primary interests lie in science, sports