Thyroid and Anti-thyroid drugs

Thyroid & Antithyroid Drugs 1
09-02-2021

09-02-2021
Thyroid & Anti-thyroid Drugs
Presentation by,
Dr Pooja S G
Guide: Dr Nirmala N Rege

Thyroid Drugs
Levothyroxine
• History
• Pharmacokinetics
• Pharmacodynamics
• Drug interactions
Liothyronine
Combination of T3:T4
Hypothyroidism
• Treatment &
Complications
Anti-thyroid drugs
Classification
• Thionamides
• Iodides
• Ionic inhibitors
• Radioactive-iodine
Hyperthyroidism
• Treatment &
Complications
09-02-2021 3
Flow of seminar
Thyroid drugs in Non-thyroidal illnesses
Introduction

Important Actions
• Metabolic actions
• Cellular respiration
• Metabolism of
Carbohydrates, proteins
and lipids.
• Growth & development
09-02-2021 Thyroid & Antithyroid Drugs 4
Introduction: Thyroid Physiology
Thyroxine (T4) and Triiodothyronine (T3)

09-02-2021
Thyroid Drugs

Levothyroxine (T4)
Liothyronine (T3)
Liotrix (T4:T3)
Thyroid Preparations

1891
1914
1926
1949
1962
History of Levothyroxine
Thyroid hormone was
used for first time
High yield synthetic
technique
C R Harrington
established its structure
Thyroxine discovered
by Edward C Kendall
Levothyroxine came
into the market

• Levothyroxine - an iodine-containing aminoacidic derivative
embedded in a glycoprotein (thyroglobulin).
• Synthetic preparations: Sodium salts
• Levothyroxine sodium is available as:
➢Tablets
➢Liquid-filled capsules for oral administration
➢Lyophilized powder for injection
➢Strength- 12.5,25,50,75,88,100,112,125,150,200,300
mcg
Levothyroxine is 2nd the most commonly prescribed
medication in the US; 22.3 million prescriptions in 2017.
Levothyroxine

Absorption
• Stomach and small intestine and is incomplete (~80% )
• Serum T4 peaks 2–4 h after oral ingestion
• Plasma t1/2 of about 7 days
Factors decreasing absorption:
• Antacids
• Bile acid sequestrants
• Malabsorption syndromes
• Calcium and Iron supplements
Pharmacokinetics of Levothyroxine

Distribution
➢ Thyroid Binding Globulin (TBG)
➢ Transthyretin (TTR)
➢ Albumin
The higher affinity of both TBG and TBPA for T4 partially explains
the higher serum levels, slower metabolic clearance, and longer
half-life of T4 compared to T3 .
Clofibrate, Estrogens ↑TBG
Androgens, Glucocorticoids
↓TBG

Metabolism
➢ De-iodination - iodothyronine deiodinases, D1,D2,D3
➢ Conjugation – Glucuronide and sulfate
➢ CYP3A4
Phenobarbital induce UGT
Rifampin, carbamazepine,
phenytoin, sertraline
Amiodarone

Elimination
• 80% - Kidney
• 20% -stools
Other drug interactions
• Anticoagulants
• Antidepressants
• Antidiabetic drugs
• Drug food interactions with Dietary fibres, soyabean
flour
Narrow therapeutic index

• Liothyronine sodium is the salt of T3 and is available in
tablets and in an injectable form.
• Absorption is nearly 100%, with peak serum levels 2–4 h
following oral ingestion.
• T1/2- 18-24 hours, requires BD/TID dosing
• Strengths : 5/25/50 mcg tablets
• Use: When more rapid onset of action is desired,
• Myxedema coma
• When preparing a patient with thyroid cancer for 131I
therapy.
Liothyronine

• Requires multiple daily dosing
• Expensive
• Transient elevation of TSH
• Tissues depending on local conversion of T3 – low
intracellular T3.
ATA – Long-term controlled clinical trials needed before
routine use
Disadvantages in exclusive T3 replacement

Mechanism of action
Pharmacodynamics

• 10- 15% of the thyroxine treated patients: persistent
symptoms
• 3 meta-analysis : No advantage.
• Other RCT’s : Improved compliance, weight reduction.
• Genetic polymorphism
• ATA and ETA guidelines: L-T4 remains the therapy of choice
in hypothyroidism :lack of long-term safety data
• Consider L-T4 and L-T3 as an experimental approach
• L-T4 and L-T3 are not recommended in pregnancy and in
patients with cardiac arrhythmias
Liotrix : Combination of T3 &T4
De Castro JPW, et al. Differences in hypothalamic type 2 deiodinase ubiquitination
explain localized sensitivity to thyroxine. J Clin Invest. 2015;125(2):769–81.

• Armour Thyroid: natural, porcine-derived. (1 grain=60 mg=88
mcg of T4))
(Prothyroid, Novothyral, Thyreotom, Thyrolar-3, and
Diotroxin)
• A mixture of levothyroxine and T3 around 4:1 by weight and
desiccated thyroid preparations with a similar T4:T3 ratio
also are available.
• Recent RCT:
• No improvement in QOL
• Increased weight loss
Hoang TD, et al. Desiccated thyroid extract compared with levothyroxine in the
treatment of hypothyroidism: a randomized, double- blind, crossover study. J Clin
Endocrinol Metab. 2013;98: 1982–1990. )

• Absorption of levothyroxine is enhanced by a lower gastric
pH.
• Rationale: Studies have demonstrated that gastric acid
secretion is at its circadian peak during the nighttime hours.
• 2 out of 4 studies ; Significant decrease in TSH.
Morning V/s bedtime dosages
Moore JG, Englert E Jr. Circadian rhythm of gastric acid secretion in man.
Nature. 1970; 226:1261-2.
Geer M, Potter DM, Ulrich H. Alternative schedules of levothyroxine
administration. Am J Health Syst Pharm. 2015 Mar 1;72(5):373-7.

• Soft gel Capsules1 - T4 dissolved Glycerin with a gelatin
capsule
• Oral liquid Solution2 – Ethanol and glycerol (Tirosint-SOL)
• TICO study
• Change from tablet to liquid – normalisation of TSH
• Switching back to tablets caused worsening of TSH
Newer formulations
1. Fallahi P, Ferrari SM, Antonelli A. Oral L-thyroxine liquid versus tablet in
patients with hypothyroidism without malabsorption: a prospective study.
Endocrine. 2016 Jun;52(3):597-601.
2. Fallahi P, Ferrari SM, Ruffilli I, Antonelli A. Reversible normalisation of serum
TSH levels in patients with autoimmune atrophic gastritis who received L-T4 in
tablet form after switching to an oral liquid formulation: a case series. BMC
Gastroenterol. 2016 Feb 24;16:22.

Kashiwagura Y, Uchida S, Tanaka S, Watanabe H, Masuzawa M,
Sasaki T, Namiki N. Clinical efficacy and pharmacokinetics of
levothyroxine suppository in patients with hypothyroidism. Biol
Pharm Bull. 2014;37(4):666-70.
• Rectal Suppository
• Low bioavailability
• 1.8 times higher dose than tablet
✓ Alternative in situations like dysphagia

Switching between formulations
FDA’s methods of establishing bioequivalence is flawed!!
✓ AUC
✓ Cmax
⌦ TSH
Endogenous factors that influence the Thyroxine bioavailability
are not taken into account.
Therefore, switching between the brands is not recommended.

Hypothyroidism
• Hypothyroidism is a clinical state resulting from
underproduction of the thyroid hormones T4 and T3.
• 95% are primary, 5% are secondary.
• Most common cause - Iodine deficiency, Autoimmune
disease
Clinical Manifestations:
Tiredness, weakness
Dry skin
Feeling cold
Hair loss
Difficulty concentrating
Constipation
Weight gain with poor appetite
Dyspnea
Hoarse voice
Paresthesia
Menstrual irregularities

Treatment
• Treatment is indicated in all symptomatic patients
• Goal: Reduction of symptoms and prevention of long-term
complications.
Treatment is to be given lifelong.
• Patients should be started on the full replacement dose of
levothyroxine.

• Adults age <50-60 years –
• levothyroxine: 1.6 mcg/kg/day orally,
• Adjust dose in increments of 12.5 to 25 micrograms to
normalize TSH.
• Pre-existing CAD or age >60 years –
• 25-50 mcg orally once daily,
• Adjust dose in increments of 12.5 to 25 micrograms every
6-8 weeks
TSH should be measured 4 to 6 weeks after initiation of therapy
or dosage change.
Confirmed overt Primary Hypothyroidism

• Angina – initial high dose
• Resistant hypothyroidism – Non adherence
• Atrial fibrillation - overtreatment
• Osteoporosis – overtreatment
• Rarely, pseudotumor cerebri in children. Presentation
appears to be idiosyncratic and occurs months after
treatment has begun.
Complications of Treatment
FDA warning : The use of thyroid hormones in the therapy of
obesity, alone or combined with other drugs, is unjustified
and has been shown to be ineffective.

• Incidence: 0.3% to 0.5% for overt hypothyroidism and 2% to
3% for subclinical hypothyroidism
• Increased risk of adverse neonatal outcomes
Preterm birth
Low birth weight
Increased perinatal morbidity and mortality.
• Screening:
Current thyroid therapy
Personal/Family history of autoimmune thyroid disease ,
Goiter
Previous delivery of infant with thyroid disease
Type 1 diabetes mellitus
Hypothyroidism in Pregnancy

• Reference range for TSH lower: cross-reactivity of the alpha
subunit of HCG with the TSH receptor.
• Goal of TSH : less than 2.5 mIU/L during T1
less than 3.0 mIU/L during T2 & T3
After delivery, thyroxine doses typically return to
prepregnancy levels
• 20%-40% increase in thyroid hormone requirement:
Increase in thyroid binding globulin
Increased volume of distribution of thyroid hormone
Placental transport and metabolism of maternal thyroxine

All pregnant women should ingest approximately 250 mcg
iodine daily.
Women with a history or high risk of hypothyroidism:
✓ Euthyroid prior to conception
✓ Thyroid function Tests:
✓ Immediately after pregnancy is confirmed
✓ every 4 weeks during the first half of the pregnancy
✓ less frequent testing after 20 weeks’ gestation

• Cretinism: Most common treatable cause of mental
retardation.
• May be transient, but permanent in majority.
• Neonatal Hypothyroidism
• Thyroid gland dysgenesis – 80-85%
• Inborn errors of metabolism – 10- 15%
• TSH-R antibody mediated – 5%
• Neonatal screening – TSH and T4 in heel prick blood
• Treatment should be started at L-T4 dose of 10 –15 µg/kg/d
Hypothyroidism In childhood

• Mortality rate : 20% - 40%
• Common precipitating factors :
Hypothermia,
Infections (particularly influenza, pneumonia, and sepsis),
trauma
Drugs (sedatives, anesthetics, antidepressants)
• Manifestations:
Depression of cerebral function,
Hypothermia
hyponatremia, hypoglycemia, respiratory acidosis
Low cardiac output, water retention –
hypoxia, hypercapnia, may lead to respiratory failure and
coma.
Myxedema Coma

✓ Thyroid hormone replacement
✓ Levothyroxine : Loading dose -500 µg IV bolus → 50–100
μg/d. (nasogastric)
✓ Liothyronine IV or nasogastric 10 to 25 μg every 8–12 h
✓ Supportive measures:
✓ O2 and mechanical ventilation
✓ Administration of iv fluids (5%–10% glucose in isotonic NaCl
solution resuscitation plus hydrocortisone;
✓ Hypothermia: External warming
✓ Hypoglycemia: Managed with dextrose infusion
✓ Hyponatremia may be treated with saline solution and loop
diuretics
✓ Parenteral hydrocortisone (50 mg every 6 h)

• Subclinical hypothyroidism is a state of usually asymptomatic,
mild thyroid failure, with normal levels of T4 and T3, and
minimal elevation of TSH.
• No universally accepted recommendations
• Treatment indicated when:
✓ Woman who is pregnant or wishes to conceive
✓ When TSH > 10 mIU/L.
✓ Elderly patients
Subclinical Hypothyroidism

• Start with – Levothyroxine 1 microgram/kg/day orally
(usual dose 25–50 μg/d)
• Adjust dose in increments of 25 to 50 micrograms to
normalize TSH
• If levothyroxine is not given, thyroid function should be
evaluated annually.
Replacement when TSH < 10 mIU/L,
✓ Symptoms suggestive of hypothyroidism,
✓ Positive TPO antibodies
✓ Any evidence of heart disease.

09-02-2021
Anti-thyroid Drugs

Anti-thyroid drugs
Ionic
Inhibitors
Potassium
perchlorate
Potassium
Thiocyanate
Thioamide
derivatives
Propylthio
uracil
Carbimaz
ole
Methimaz
ole
Radioactive
iodine
131I
Iodides
Lugols
solution
Release
Inhibitors
Synthesis Inhibitors
SSKI:
Saturated
Solution of KI

Propylthiouracil, Methimazole, Carbimazole
Mechanism of action
Thionamides
Iodination
Coupling
• Inhibition of hormone synthesis
• Depletion of the Iodinated Tg
• Also reduce thyroid antibody
levels – mechanism unclear
• PTU – Blocks peripheral
conversion of T4 to T3

Pharmacological properties
Propylthiouracil Carbimazole
Plasma protein binding ~75% Nil
Plasma t1/2 1-2.5 ~6–9 h
Urinary excretion 35% 10%
Concentrated in thyroid Yes Yes
Metabolism of drug:
Severe liver disease
Severe kidney disease
Normal
Normal
Decreased
Normal
Dosing frequency 1–4 times daily
Once or twice
daily
Transplacental passage Low Low
Levels in breast milk Low Low

Initial Dose:
• 100-200 mg every 6-8 hours
Maintenance:
• 50 -100 mg
Initial Dose:
• 10-20 mg every 8-12 hours
Maintenance:
• 2.5 – 10 mg
Titration Regimen
Propylthiouracil Methimazole/Carbimazole
✓ Reviewed after 4–6 weeks and the dose is titrated based
on unbound T4 levels.
✓ TSH – not a sensitive marker for dose titration
✓ Response in 6-8 weeks

• Initial doses of anti-thyroid drug is continued
• T4 is adjusted for normal unbound T4 levels.
Remission rates:
• Titration regimen: Maximum remission rates (up to 30–60%
in some populations) are achieved by 12–18 months.
• Block-replace regimen: By 6 months.
• In case of relapse, RAI is the treatment of choice.
All patients should be followed closely for relapse during the
first year after treatment and at least annually thereafter.
Block & Replace Regimen

Untoward Reactions of Thionamides
• Incidence of side effects with both drugs is low.
• Most common reaction: mild urticarial papular rash
• Agranulocytosis – most serious reaction
• First few weeks of therapy
• Periodic monitoring of counts is not useful
• Reversible
• Instructions to patients
• Carbimazole- Congenital anomalies
• Others – pain and stiffness in joints, paresthesias, Drug fever,
Nephritis.
• Vasculitis: Antineutrophilic cytoplasmic anti-bodies (ANCA);
PTU>Methimazole

! FDA Black Box warning !
From 1969,
!! 34 cases of severe liver injury with propylthiouracil
!! 15 deaths, 12 liver transplantations
On April 21, 2010, after 63 years clinical use – Black box
warning for the label of PTU.
Methimazole : 5 cases of severe liver injury

• Oldest remedy, also quickest.
• MOA:
• Inhibition of hormone release
• Acute and transient inhibition of synthesis (Wolf-Chaikoff
effect)
• Decrease the size and vascularity of the gland
• Dose:
• Lugol solution- 16-36mg (2-6 drops of 5% - 10% soln) TID
• SSKI: 50-100 mg (1-2 drops) TID
Thyroshield: In radiation emergency, adult dose is 2 mL (130
mg) every 24 h.
Surgical preparation
Iodides
Logols Iodine and Saturated Solution of Potassium Iodide
Pregnancy

• MOA: Competitive inhibition of NIS. (Iodide entry)
• Dose : potassium perchlorate – 600-800 mg , maintenance
dose- 200-400 mg daily.
• Perchlorate causes nephrotic syndrome and fatal aplastic
anemia.
• Indications:
• Used in patients allergic to thionamides.
• Amiodarone induced Thyrotoxicosis
Ion Inhibitors
Potassium Thiocyanate, Potassium perchlorate

Acute effects:
• Angioedema, Laryngeal edema – Suffocation
• Thrombotic thrombocytopenic purpura & fatal periarteritis
nodosa
Chronic Intoxication:
• Iodism- Brassy taste, burning of mouth and throat.
• Increased salivation, coryza, swelling of eyes
• Parotid & submaxillary gland enlargement –Mumps parotitis
• Rarely, fatal eruptions – Ioderma
Symptoms disappear within few days of stopping the drug
Untoward Reactions of Iodine therapy

• Isotopes – 123I and 131I (Stable isotope- 127 I)
• 123I is a short-lived 𝛄-emitter with a t1/2 of 13 h; diagnostic
studies.
• 131I has a t1/2 of 8 days and emits both 𝛄 rays and β particles.
used therapeutically for,
• Destruction of an overactive or enlarged thyroid
• Thyroid cancer for thyroid ablation and treatment of
metastatic disease.
• Dose – 10-15 mCi
Radioactive Iodine

Indications
• Comorbidities increasing
surgical risk
• Previously operated or
externally irradiated necks
• lack of access to a high-
volume thyroid surgeon
• patients with
contraindications to ATD
use
• Cardiovascular risk factors
Contraindications
• Pregnancy is strictly
contraindicated.
Conception safe after 6
months.
• Nursing mothers
• Children - Relative

Incorporates into the thyroid hormones and
Thyroglobulin
• Follicles – Necrosis; bizarre cell forms
and nuclear pyknosis
• Destruction of small vessels
• Edema and fibrosis of the interstitial
tissue
Mechanism of action of RAI
After few weeks

• Beta blockers
• Iodides – 3 to 7 days after RAI.
• Prior therapy of ATD’s.
• Lithium – High rate of cure, fast response and prevention of
post-treatment hormone release.
• Glucocorticoids – Thyroid ophthalmopathy1
Role of Adjunctive therapy with RAI
Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for
hyperthyroidism and the course of Grave’s ophthalmopathy. N Engl J Med
1998;338(2): 73-78.

• Acute effects: mild tenderness and dysphagia
• High incidence of delayed hypothyroidism
• Slight increase in cancer stomach, kidney, and breast.
• Radiation thyroiditis/thyrotoxic crisis
• Exaggeration of Thyroid Ophthalmopathy - Prednisone, 40
mg/d, at the time of radioiodine treatment, tapered over 6–
12 weeks.
• Alterations in reproductive function
Sioka C, Totopoulos A. Effects of I-131 therapy on gonads and pregnancy outcome in
patients with thyroid cancer. Fertil Steril 2011. 95:1552-9.
Complications of Radioiodine

• Condition of excess thyroid function.
• Thyrotoxicosis is defined as the state of thyroid hormone
excess and is not synonymous with hyperthyroidism.
• Common causes of primary hyperthyroidism are:
Graves Disease(60-80%)
Toxic multinodular goiter
Toxic adenoma
Thyroid carcinoma
Hyperthyroidism

Clinical features
Hyperactivity, irritability,
Dysphoria
Heat intolerance
Palpitations
Fatigue
Diagnosis: Clinical + Laboratory Subnormal (TSH) + ↑↑ T3 +/ T4.
Weight loss with increased appetite
Diarrhea
Polyuria
Oligomenorrhea
loss of libido.
Treatment options:
1. Antithyroid drugs
2. Radioactive iodine
3. Surgery

Beta Blockers
In an RCT with Methimazole alone v/s Methimazole + Beta
blockers
After 4 weeks of therapy,
✓ Lower heart rate
✓ Less shortness of breath and fatigue
✓ Imroved score on SF-36 questionnaire
Propranolol – 10-40 mg TID is preferred.
If Beta blckers are contraindicated,
✓ Calcium channel blockers
Tagami T, Yambe Y, Tanaka T,et al. BBGD Study Group. Short- term effects of beta-
adrenergic antagonists and methimazole in new-onset thyrotoxicosis caused by
Graves’ disease. In- tern Med. 2012; 51:2285–2290

Subclinical Hyperthyroidism
When to treat?
• TSH Below lower limit of reference range with normal T3,T4.
• Risk of atrial fibrillation and all cause mortality.
• Increased hip fractures in postmenopausal women
• >65 yreas whem TSH <0.1 mIU
• <65 years – Depends on CVS risk factors.
• ATD’s are preferred.

• Hyperthyroidism is less common than hypothyroidism, with an
approximate incidence of 0.2%.
• Graves disease:
• Exacerbation in T1.
• Monthly Fetal USG.
• Thyroid autoantibodies – should be measured at end of T2.
Hyperthyroidism in Pregnancy
1. Carney LA, Quinlan JD, West JM. Thyroid disease in pregnancy. Am Fam
Physician. 2014 Feb 15;89(4):273-8.
Subclinical : One large prospective study of more than
25,000 pregnant women with subclinical hyperthyroidism
showed no increase in adverse pregnancy outcomes;
therefore, treatment is not recommended in these cases.1

• Lowest possible dose of antithyroid drugs should be used.
• The goal of treatment is a serum free T4 level
at, or moderately above the normal range for pregnancy.
• First trimester: PTU
• Second Trimester: Carbimazole/methimazole
• If discontinued because of side effects: second-trimester
thyroidectomy is the only other option for symptomatic
patients.
• Radioactive iodine is contraindicated in pregnancy.
Choice of therapy in pregnancy

• TFT should be monitored 3 months after initiation and 3
monthly thereafter.
• AIT type 1: Iodine induced excessive thyroid hormone
synthesis, especially in patients with underlying thyroid
disease.
• AIT type 2: destructive thyroiditis in previously normal
thyroid gland with release of thyroid hormones into
circulation
• Unresponsive: Thyroidectomy
Amiodarone Induced Thyrotoxicosis
Rx Carbimazole
Rx Corticosteroids

Choice of therapy
✓ Remission possible; Carbimazole therapy for 1 year is first-line
of choice. Dose :0.2–0.5 mg/kg daily.
Majority of pediatric patients with GD will eventually require
either RAI or surgery.
Hyperthyroidism in Children
If remission is not achieved after a course of therapy with ATDs,
RAI or surgery should be considered.
Or
ATD therapy may be continued long term or until the child
is considered old enough for surgery or RAI.

Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association
Guidelines for Diagnosis and Management of Hyperthyroidism and Other
Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421.
✓ RAI
• Should be avoided in <5 yrs
• 5-10 yrs – The calculated activity is <10 mCi.
❑ No evidence suggests that children or adults treated for GD with
more than 150 µCi/g (5.55 MBq/g) of RAI have an increased risk
of thyroid cancer directly attributable to RAI.
❑ If a small risk exists, a sample size of more than 10,000 children
who were treated at <10 years of age would be needed to
identify the risk, likely exceeding the number of such treated
children.
✓ Thyroidectomy
Definitive treatment:

• Sudden severe
exacerbation of
hyperthyroidism.
• Precipitating factors:
Stress
Infection
Following radio iodine
Trauma
Pregnancy.
Thyroid Storm
• Clinical features:
Hyperthermia
Tachycardia
Delirium
Hypotension
Vomiting
Diarrhoea
Mortality rate: 30%, due to cardiac failure, arrhythmia, or
hyperthermia

Management of thyroid storm
✓ Intensive monitoring and supportive care
✓ Treat precipitating cause
✓ Reduce Thyroid hormone synthesis
➢Propylthiouracil (500–1000 mg loading dose → 250 mg
every 4 hrly orally or by nasogastric tube or per rectum;
➢Methimazole can be used in doses up to 30 mg 12 hrly
➢5 drops SSKI every 6 h /ipodate or iopanoic acid (500
mg per 12 h) / Sodium iodide, 0.25 g IV every 6 h
✓ Propranolol 60–80 mg PO every 4 h; or 2 mg IV every 4 h
✓ Hydrocortisone 300 mg IV bolus, then 100 mg every 8 h
✓ Antibiotics if infection is present
✓ Oxygen, IV fluids

Thyroid Hormones in Non-thyroidal illness

• Thyromimetics : Subtype selective, potent TR agonists and
antagonists.
• Sobetirome: Selective for TRb1.
• It preferentially accumulates in liver.
• Experimental data: It reduced LDL-cholesterol, fat mass and
hepatic steatosis without increasing heart rate .
• Sobetirome achieved orphan drug status for X-linked
adrenoleukodystrophy. (VLCFA accumulation)
Thyroid hormones in Dyslipidemia
Hartley MD, Kirkemo LL, Banerji T, Scanlan TS. A Thyroid Hormone-Based
Strategy for Correcting the Biochemical Abnormality in X-Linked
Adrenoleukodystrophy. Endocrinology. 2017 May 1;158(5):1328-1338.

• Depression is associated with neuronal death.
• T3 increases gene expression by increasing levels of TRH,CRH
and BDNF.
• Increased levels of 5-HT levels.
• STAR*D trial – T3 better than lithium in augentation of
antidepresent effect.
T3 in Depression
Nierenberg AA, et al. A comparison of lithium and T(3) augmentation following two
failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006
Sep;163(9):1519-30.

Garlow SJ, Dunlop BW, Ninan PT,et al. The combination of
triiodothyronine (T3) and sertraline is not superior to
sertraline monotherapy in the treatment of major depressive
disorder. J Psychiatr Res. 2012 Nov;46(11):1406-13.
• 8 week Double blind ,RCT of 153 patients between 18 and
60 yrs with DSM-IV Major depressive disorder.
---No difference in the treatment arm

Touma KTB, Zoucha AM, Scarff JR. Liothyronine for Depression:
A Review and Guidance for Safety Monitoring. Innov Clin
Neurosci. 2017 Apr 1;14(3-4):24-29.
• Most trials were published earlier than 10 years ago
• Small samples of patients, and there are limited data available
for liothyronine’s efficacy with newer antidepressants
• Larger studies of longer duration are needed to evaluate T3’s
efficacy with newer and other classes of antidepressants.

Summary
✓ Hypothyroidism is most often due to iodine deficiency or
autoimmune disorder known as Hashimoto’s thyroiditis.
✓ The drug of choice for replacement therapy in
hypothyroidism is levothyroxine.
✓ Studies of combination therapy with levothyroxine and
liothyronine have not shown reproducible benefits. This
approach to treatment requires further study.
✓ Monitoring therapy is achieved by observing clinical signs
and symptoms and by measuring the serum TSH level.

✓ Hyperthyroidism may be treated with antithyroid drugs
such as Carbimazole or propylthiouracil, radioactive iodine
(RAI) or surgical removal of the thyroid gland;
✓ Selection of the initial treatment approach is based on
patient characteristics such as age, concurrent physiology
(eg, pregnancy), comorbidities (eg, chronic obstructive lung
disease), and convenience.
✓ Response to MMI and PTU is seen in 4 to 6 weeks and
therefore β-blocker therapy may be concurrently initiated to
reduce adrenergic symptoms.
✓ Therapy is monitored by clinical signs and symptoms and by
measuring the serum concentrations of TSH and free
thyroxine (T4).

✓ Adjunctive therapy with β-blockers controls the adrenergic
symptoms of thyrotoxicosis; iodine may also be used
adjunctively in preparation for surgery and acutely for
thyroid storm.
✓ Many patients choose to have ablative therapy with 131I
rather than undergo repeated courses of ATD treatment;
most patients receiving RAI eventually become hypothyroid
and require thyroid hormone supplementation

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