Thyroid: Clinical relevance

in psychiatry.

Dr.Cijo Alex

Overview

• Introduction • Applied anatomy and physiology• Clinical features of thyroid disorders• Thyroid function tests• Role of thyroid in

-Depression-Psychosis-Cognitive dysfunction-MR- Anxiety

• Thyroid dysfunction induced by psychotropic medications

• Therapeutic indications ,dosing and clinical guidelines for thyroid replacement.

• Conclusion

Introduction

• Thyroid disorders are common , up to 5% of population.

• The thyroid axis is involved in the regulation of cellular differentiation and metabolism in virtually all nucleated cells , so that thyroid disorders have wide spread manifestations.

• Thyroid gland one of the most common endocrine glands related with psychiatric disorders

• Abnormal thyroid hormone levels are found in 33% of psychiatric patients compared to 5% in general population.

• Almost all thyroid abnormalities in psychiatric patients are in women.

Functional Anatomy & Physiology

• The thyroid is a highly vascular gland located in the neck ,anterior to trachea ,between cricoid cartilage and suprasternal notch.

• Consists of two elongated lateral lobes interconnected by an isthmus.

• The Thyroid gland secretes predominantly thyroxine(T4) and a small amount of triiodothyronine (T3).

• Iodide is the key substrate to maintain thyroid function.

The HPT Axis

The most common thyroid disorders include

1)Hypothyroidism

2)Subclinical hypothyroidism and

2)Hyperthyroidism.

Hypothyroidism : Inadequate synthesis of thyroid hormones

- Overt : Low T3 & T4 , High TSH : Symptomatic- Sub clinical : biochemical evidence of thyroid

hormone deficiency in patients with few or no apparent clinical features of hypothyroidism

N- T3 & T4 , High TSH : Asymptomatic

Clinical features of Hypothyroidism

• Weight gain, Fatigue,Cold intolerence• Constipation• Bradycardia,Hypertension• Malar flush,Myxoedema,Dry skin and Hair.• Menorrhagia,Infertility,Impotence

• Delayed DTR,Cerebellar Ataxia.• Depression,Psychosis(Myxoedema madness)

Grades of Hypothyroidism

I : Low T3 & T4, High TSH and TSH response to TRH - exaggerated.

II : Normal T3 & T4 Basal plasma TSH elevated, and TSH response to TRH - exaggerated.

III : Normal levels of T3, T4 and TSH TSH response to TRH - exaggerated

IV : Positive antithyroid antibodies but Normal T3, T4, TSH and TRH-induced TSH

response –Kaplan And Sadock’s Comprehensive Textbook of Psychiatry 9th Edition 2009

Clinical features of Hyperthyroidism

• Weight loss, Heat intolerance.

• Diarrhoea

• Tachycardia

• Sweating, Palmar erythema .

• Gynaecomastia , Impotence.

• Tremors,Hyperreflexia

• Anxiety, Irritability,Emotional lability.

Subclinical hypothyroidism

• By definition subclinical hypothyroidism refers to biochemicalevidence of thyroid hormone deficiency with no or few apparent clinical features.

• No universally accepted guidelines exist for managing this condition.

• However there is no risk in thyroxinesupplementation in such cases and may be useful in preventing a full blown hypothyroidism.

Neuropsychiatric manifestations

of thyroid disorders.• Primary thyroid disorders including both hypothyroidism and

hyperthyroidism may be accompanied by various neuropsychiatric manifestations ranging from mild depression and anxiety to overt psychosis.

• Dysphoria, anxiety, irritability, emotional lability, and impairment in concentration constitute the classical neuropsychiatric symptoms occurring in hyperthyroidism

• On the other hand, hypothyroid patients frequently demonstrate features of depression, cognitive dysfunction, apathy, and psychomotor slowing. In severe forms of hypothyroidism, clinical symptoms may mimic that of melancholic depression and dementia

-Dementia ( Cognitive Deficits-MC 50%)-Affective Disorders

-Depression(40%)-Acute Mania-Rare

-Anxiety Disorders (30%)-Psychosis ( Myxoedema madness)(<5%)

-

-Mental Retardation(cretinism)-Depersonalization & Derealization( Case reports )-Late Luteal Phase Dysphoric Disorder.

Neuropsychitry of Neurometabolic & Neuroendocrine Disorders –Kaplan And Sadocks Comprehensive Textbook of Psychiatry –Ch 2.14;612-13

Thyroid function tests

1) Measurement of thyroid hormones ─

TSH,Total T4 & T3, Free T4 & T3.

• TSH – Immunoradiometric assay

• Free T4 & T3

Direct method• Competition with radiolabelled analogue

• Separation by ultracentrifugation or dialysis

Indirect method

Free T4 or T3 index -Harrison’s internal Medicine 17th edn; ch 335;2008

2) Determine the etiology of thyroid dysfunction- Antimicrosomal & Antithyroglobulin -

Autoimmune thyroid disease- Serum thyroglobulin .

3) Radioiodine uptake and thyroid dysfunction

4) Thyroid ultrasound-Nodular/ cystic thyroid disease

(Harrison’s internal Medicine 17th edn; vol-2,ch 335;2008)

What is free and total T3/T4

• Total thyroxine (T4). Most of the thyroxine (T4) in the blood is attached to a protein called thyroxine-binding globulin. Less than 1% of the T4 is unattached. A total T4 blood test measures both bound and free thyroxine. Free thyroxine affects tissue function in the body, but bound thyroxine does not.

• Free thyroxine (FTI or FT4). Free thyroxine (T4) can be measured directly (FT4) or calculated as the free thyroxine index (FTI). The FTI tells how much free T4 is present compared to bound T4. The FTI can help tell if abnormal amounts of T4 are present because of abnormal amounts of thyroxine-binding globulin.

• Triiodothyronine (T3). Most of the T3 in the blood is attached to thyroxine-binding globulin. Less than 1% of the T3 is unattached. A T3 blood test measures both bound and free triiodothyronine. T3 has a greater effect on the way the body uses energy than T4, even though T3 is normally present in smaller amounts than T4.

Thyroid function tests- reference ranges

• T3- 0.8 to 2.0 ng/mL

• T4- 4.0 to 12 ug/dL

• TSH- ?? 0.4 to 4.0 uIU/mL

The TSH debate.- To believe it or not.

“The consensus of thyroidologists decided in 1973 that the TSH (lab) was the blood test they had been looking for all through the years. This was about two years after I started practice. Having been taught how to diagnose hypothyroid conditions clinically, I was in a position to watch to see what the relation of the TSH was to the onset of hypothyroidism. What I found was many people would develop classic signs and symptoms of hypothyroidism but the TSH was ever so slow to become abnormal, rise and confirm the clinical diagnosis. Sometimes it never did. Finally I began treating patients with hypothyroid in the normal manner I was taught. I could not see why I had to wait for the TSH to rise for me to be able to treat them.”

TRH Stimulation test

• Indicated for patients with marginally abnormal TFT with suspected subclinical hypothyroidism.

• I.V injection of 500 mg of TRH is given which produces rapid rise in serum TSH levels,which are measured at 15,30,60 & 90 mins.

• An increase in TSH of 5 to 25mIU/mL above baseline is normal.

• An increase of less than 7 mIU/mL is considered blunted response and correlates with a diagnosis of subclinical hypothyroidism

Role of Thyroid in depression• Some studies have reported that upto 10% of patients with

depression are having hypothyroidism as a co morbidity. • As correctly said , its difficult to be euthymic unless some one is in

euthyroid state.• Thyroid supplementation can covert an antidepressant resistant

person into a responsive person.So it holds great role in treatment resistant depression, as an adjuvant to antidepressants.

• No evidence exists till now that correlates with thyroid function and its efficacy in augmentation therapy. Ie,irrespective of the thyroid function, thyroxine supplementation can be used as an adjuvant in treating depressed patients.

• However the MOA of thyroxine in treating depression is still not clear.

Ref:Consise textbook of clinical psychiatry ,Kaplan & Saddock,IIIrd Edition ,Pg:553

• Epidemiology-17.3%preexisting hypothyroidism 13.3% in general population. (Engum et al, 2002)

• Manifestations:– Subsyndromal depressive symptoms only

– Treatment resistant depression

– Rapid cycling affective disorder

– Atypical depression

• Clinical features:– Typical picture - mental lethargy & general dulling of personality

– Cognitive deficits - more prominent

– Typical mood change - towards apathy, irritability

– Usually family history of hypothyroidism is +ve

Subclinical Hypothyroidism and Depression

• Less severe • Doubles -Risk of major depression. • Reduce -efficacy of antidepressant treatment• Response to T3 augmentation better

-Kaplan And Sadock’s : Comprehensive Textbook of Psychiatry 9th Edition 2008

• Subclinical hypothyroidism - renamed as “Minimal Thyroid Insufficiency (MTI)”

• Approximately 5-15 % of patients with subclinical hypothyroidism progress to overt hypothyroidism per year (Wiersinga et al, 1995)

Many meta analyses and RCT have reconfirmed the role of thyroid supplementation in refractory depression.

Ref:R. Aronson, H. J. Offman, R. T. Joffe, and C. David Naylor, “Triiodothyronine augmentation in the treatment of refractory depression: a meta-analysis,” Archives of General Psychiatry, vol. 53, no. 9, pp. 842–848, 1996.

Depression Vs Hypothyroidism : When depression starts in the Neck.

• When someone develops depression, the brain usually becomes the focus of attention. But it can be in fact only hypothyroidism which also shares some clinical features of depression.

• Although researchers aren't entirely sure why there is a link between hypothyroidism and depression, it is likely that some people are taking antidepressants when they should really be taking thyroid medication alone.

• Ie, Hypothyroidism can be the sole cause of low mood. So can we call it depression or is it just a feature of hypothyroidism?

• This question gains importance especially when the biological underpinnings of depression is being under covered.

Ref: http://www.health.harvard.edu/newsletters/Harvard_Mental_Health_Letter/2011/July/when-depression-starts-in-the-neck

Role of thyroid in psychosis

• Studies have shown that 5 to 15% of myxedematous patients show psychotic features.

• Asher in 1949 first described myxedemamadness.

• Psychosis usually emerges years after onset of physical findings

• C/F include delusions, visual and auditory hallucinations , perseveration , loosening of associations and paranoia.

• Onset - acute/subacute, fluctuating, paranoid

• Perceptual abnormality - visual and other hallucinatory distortions

• Associated mental slowing & cognitive impairment (esp., recent memory)

• Rapidly developing myxedema - agitation, irritability, alternate periods of restlessness and lethargy, hyper sexuality psychosis

(Hall et al, 1983)

Case review:

Role in cognitive dysfunction

• Hypothyroidism can lead to impaired consciousness , memory disturbances and psychomotor slowing.

• Most commonly affected- working memory and executive function.

• Elderly - Progressive dementia (Pseudo dementia) • Improve with thyroid supplements

• Chronic thyroid hormone deficiency - not always reversible -Irreversible damage in the CNS

Role of thyroid in MR

• Neonatal hypothyroidism can result in MR (Cretinism)and is preventable if diagnosis is made at birth.

• Seen in children who live in the iodine deficient regions

• Prevalence: 1 in 3000 to 4000 newborns.

• Often born to mothers with Iodine deficiency.

• C/F: Majority are normal at birth

• In <10% diagnosis is based on prolonged jaundice, feeding problems, enlarged tongue, delayed bone maturation & umbilical hernia.

• Mental and growth retardation

• Permanent neurological damage- If treatment delayed.

• Diagnosis based on the measurement of the TSH & T4.

• Early & adequate treatment - Normal IQ levels.

• Iodine deficiency- One of the most common causes of the preventable mental deficiency (Harrison-text book of internal medicine 17th edn; Ch 335;)

Psychiatric disorders due to

hyperthyroidism• Depression• Anxiety Disorders(10-20%)• Hyperthyroid dementia (Cognitive

impairment)(5-10%)• Hypomania or mania(2-5%)• Psychosis(2-5%)

Neuropsychitry of Neurometabolic & Neuroendocrine Disorders –Kaplan And Sadocks Comprehensive Textbook of Psychiatry –Ch 2.14;612-13

• Delirium• Insomnia

Role of Thyroid in anxiety

Hyperthyroidism can lead to features of anxiety.

Rarely hypothyroidism can also cause anxiety.

Many experts believe that imbalances in serotonin, dopamine, and GABA in the brain are potential causes of anxiety features and thyroid may be playing a vital role in their regulation

Ref:http://www.mayoclinic.com/health/thyroid-disease/AN00986

Prevalence rate 62% (Kathol et al, 1986 )

– Anxiety disorders dominate in hyperthyroidism

– Generalized anxiety syndrome : 40% of thyrotoxicPatients. (Hall et al, 1986)

– Episodic anxiety, with subjective awareness of tachycardia or arrhythmia

– Correlation exists with both the physical symptoms of hyperthyroidism and the level of the circulating thyroid hormone unlike depressive symptoms (Kathol et al.,1986)

Thyroid Abnormality in other

Psychiatric conditions.

• Periodic Catatonia: periodic catatonia

(Gjessing et al, 1935)

• Premenstrual Syndrome: Study of baseline and TRH-stimulated thyroid function in 45 healthy women

- 13.3%- subclinical hypothyroidism

(Korzekwa et al.1996)

• ADHD: Increased prevalence of thyroid abnormalities in children with ADHD than controls.

(Weiss et.al 93)

• Post partum: – At six weeks following delivery 43% of antibody positive women

experience mild to moderate depressive episode compared to 28% of antibody negative women in a double blind study 145 antibody positive women and 229 antibody negative women.

(Harris et al, 1992)

• Post traumatic stress disorder– Persistent and disproportionate elevation in both total and free T3 in

relation to free T4. (Mason et al 1994)

• Eating disorder: Studies of the effects of reduced caloric intake on healthy adult female noticed Euthyroid profile (normal plasmaT4 & decreased plasma T3).

(Fichter et al.,1986)

Psychotropic drugs causing Thyroid

dysfunction

• Lithium

• Carbamazepine

• TCA’s

• Quetiapine

Role of thyroid in Li therapy

• Li is a drug used as a mood stabilizer and an adjuvant antidepressant .

• It can cause reversible hypothyroidism.

• So TFT is advisable before initiating and during Li therapy.

Endocrine effects of Lithium

• Clinical Hypothyroidism- 2 to 15%• Subclinical- 19%• Chemical- 50%• Goitre- 5%• Hyperthyroidism- 0.7%

-Mohandas et.al.,Lithium use in Special Populations.Indian Journal of Psychiatry 49(3);Jul-Sep,2007

Management of Lithium Induced Hypothyroidism

CBZ

- Increases T4 and T3 metabolism through induction of hepatic microsomal enzyme

- Negligible incidence of clinical hypothyroidism

- Thyroid supplementation : Rarely needed.

TCAs - Blocking uptake of thyroid hormone into the neurons.

-Kaplan And Sadock’s : Comprehensive Textbook of Psychiatry 9th Edition 2008

Therapeutic indications and guidelines of

Thyroid supplementation

• Thyroid hormones are indicated as adjuvant antidepressants and in rapid cycling BP 1 disorder.

• Also used in replacemnt therapy for patients with Li treatment.

• Common AE.-Unusual at the augmention doses.-Headache,increase in BP,sweating ,tremors

• C/I -Cardiac diseases, HTN

• Most trials with tricyclic antidepressant.

• Case – reports with SSRI.

• First placebo controlled trial – by Prange & his colleagues in 1969/70; by adding T3 to imipramine in the depressed patient.

• T3 has been evaluated more extensively than T4 as an augmentation strategy for treatment resistant depression.

Kaplan And Sadock’s : Comprehensive Textbook of Psychiatry 9th Edition 2008

Comparison of lithium & Triiodothyronine augmentation of TCA’s

Joffe et al, 1993• 50 outpatients; unipolar non psychotic depression; failed 5

weeks of TCA (Desipramine or Imipramine)• Randomized double blind, placebo controlled study of 2

wks duration • Both liothyronine & lithium were effective than placebo• ≥ 50% reduction in HDRS Baumgartner et al 1994 • Open case series of 6 non-RCAD Patient’s who were

treatment refractory• Excellent prophylactic response on adding high dose T4

Dosing and clinical guidelines.

Usual augmentation dose – 25 to 50 ug.

An adequate trial should last for 2-3 weeks.

If successful,should be continued for 2 months.

T3– Started at 25µg/day single dose• After 1 week- insufficient response, no side effect

increase to 37.5- 50µg/ day in divided doses • After 2 weeks

• Responders- Continue for 2 months and then taper it off

• Non responders- Taper 12.5µg every 3-7 daysT4– Started at 100µg/day

• After 1 week –insufficient response increase by 25-50µg every week

• Maximum 500µg/day• Response usually within 2weeks. If none taper by 50µg

every 3 days

Common Adverse effects

– Abrupt discontinuation– Iatrogenic hypothyroidism.

– Minor side effect (usually reported) warmth, Flushing ,sweating, palpitation weakness, diarrhea insomnia, anxiety.

– More severe – cardiac decompensations, arrhythmias, CHF .(Caution in Elderly)

– Long term – muscle wasting, weight loss,

osteoporosis

Conclusion

• Role of thyroid in psychiatry remains only partially known.

• Until there are large randomized treatment trials that address the important clinical questions involved in the diagnosis and management of sub clinical thyroid disease, we will have to rely on imperfect and necessarily vague recommendation.

Thank You