Lithium-induced hypothyroidism

Lithium-induced hypothyroidism occurs in 5 to 35% of people on lithium. It occurs more commonly among females; 30% of women on lithium have elevated levels of thyroid-stimulating hormone.

Mechanism

Lithium inhibits the action of thyroid-stimulating hormone, causing reduced synthesis and release of thyroxine. The pituitary gland releases the thyroid-stimulating hormone, which reaches and binds to its receptors on the thyroid gland and stimulates the production of thyroid hormones, thyroxine, and triiodothyronine, by the thyroid gland by binding to receptors on cells in the thyroid gland.

Brain Damage

Lithium causes organic brain damage at supratherapeutic doses because of its accumulation and action of lithium on the ion-transport, second messenger, and receptor signalling systems.

Interactions

1. Diuretics increase lithium levels. Loop diuretics are less likely to do so compared with thiazide diuretics. 
2. Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors also elevate lithium levels.
3. Caffeine discontinuation can increase levels. 
4. Non-steroidal anti-inflammatory drugs reduce the renal clearance of lithium. 
5. Combining antipsychotics with lithium increases the risk of extrapyramidal side effects and neuroleptic malignant syndrome. 

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>> Apart from the medications listed above, a low-salt diet, diarrhoea, vomiting, excessive sweating, systemic illness of any origin, and renal impairment may also elevate lithium levels. 

Side-Effects of Lithium by Body System
Body System	Side Effects
Neuromuscular	Fine tremor slowed cognition.
Gastrointestinal	Nausea, diarrhoea, weight gain.
Endocrine	Hypothyroid, hyperthyroid, raised thyroid-stimulating hormone.
Cardiovascular:	ST and T wave changes, sinus bradycardia, T wave depression.
Renal	Polyuria and polydipsia, diabetes insipidus, interstitial nephritis

Use of Lithium During Pregnancy

Risks of Continuing Lithium During Pregnancy  

1. Lithium use during pregnancy is associated with cardiac malformations, including Einstein’s anomaly.  
2. The risk of association is exceptionally low, about one additional case for hundred live births.  
3. The highest risk to the fetus is during weeks two to six of conception.  
4. Therefore, the exposure has already occurred in this case.  
5. Use during the last trimester may cause neonatal complications

Neonatal Complications of Third-trimester Lithium Use 

1. Hypotonia
2. Neonatal goitre
3. Hypotonia
4. Lethargy
5. Cardiac arrhythmias 

Studies associate lithium discontinuation with reduced responsiveness in the future.  

There is an elevated risk of relapse following lithium discontinuation.  

Patients often need heavy doses of mood stabilisers during an acute relapse, which may increase the risk of side effects and teratogenicity even further.  

The perinatal period is a very high-risk period, and the risk of relapse mania is about 70% in patients with bipolar disorder who stop lithium before conception.  

Alternate Options 

Mood stabilising antipsychotics as recommended by NICE.  

Lamotrigine is also a good option, but it is more effective for treating and preventing bipolar depression.  

Brief Answer Questions

1. How does lithium cause hypothyroidism?
2. What are the neuromuscular side effects of lithium? 
3. How does lithium cause organic brain damage?    

A 32-year-old obese woman, the mother of a 2-year-old son, presented to you in the outpatient department with an episode of psychomotor excitation, elated mood, and sleep disturbance for the last one week. Her detailed history confirmed the diagnosis of bipolar mood disorder, for which she has been under treatment. Her last relapse was 3 years back, after which she was taking lithium carbonate. She was doing well but stopped treatment to avoid "long-term adverse effects". Her lab investigations revealed HbA1c 6.1 and serum thyroid-stimulating hormone level of 6.2 m IU/L.  

1. What would be the risks and benefits of restarting therapy?  
2. How would you minimise her adverse-effect burden? 
3. For how long would you recommend she continue the treatment? 

Benefits of Restarting Lithium for in this case

• A good previous response shows that she is likely to respond to it.  
• Lithium is a safe and effective antimanic agent/mood stabiliser.  
• We can continue lithium in the long-term as the most effective prophylactic agent (with no switch to an alternative agent) 
• The risk of teratogenicity is lower compared to valproate and even carbamazepine 
• Relative to second-generation antipsychotics like olanzapine and valproate, weight gain and impairment of diabetic control may be less marked.  

Risks of Restarting Lithium in this case

• she may experience a recrudescence of symptoms because of poor adherence to lithium (Mander & Loudon, 1988) 
• Her illness may become resistant because of sudden lithium discontinuation. (Fornaro et al., 2016)  
• Worsening of hypothyroidism may precipitate rapid cycling disorder in the patient.  
• Weight gain and worsening of diabetic control (also occurs with valproate and several second-generation antipsychotics) 
• Risk of teratogenicity as she is of childbearing age.

Minimising the Adverse Effects of Lithium in this case

Monitoring with regular physical examination and laboratory investigations for the side effects of lithium.  For example, on each visit, we should inquire the patient about hypothyroidism symptoms. We should also examine her for hypothyroidism signs, including weight gain, thyroid gland, eyebrows, etc. Regular monitoring of thyroid function tests, renal function tests, electrocardiography, and baseline investigations on every visit helps to identify and treat these complications early. Educate the patient at the time of prescribing about the adverse effects risk of toxicity and the factors that increase the chances of these (for example increased risk of toxicity because of dehydration). Providing written material helps patients so they can read them at their ease.  

Minimum duration for lithium prophylaxis

We should continue lithium for the prophylaxis for at least three years. (Goodwin GM et al 1994).  

NICE 2014 recommends up to 5 years if there is a substantial risk of relapse.  

What are the indications for lithium?

Prophylaxis and treatment of mania. Prophylaxis of bipolar disorder, an augmentation strategy for patients with treatment-resistant depression.

What are the common signs of lithium toxicity?    

Thirst, polyuria, memory problems, tremor, weight gain, tiredness, diarrhea. Cognitive dysfunction is the most common symptom that leads to non-compliance. Side effects are dose-related.

What is the concentration at which toxic effects reliably occur?    

Toxic effects reliably occur at 1.5mmol/l but toxic effects can occur at MUCH LOWER LEVELS in many patients, especially in older patients, systemically ill patients, and in use of alcohol or other cans active meds

What are the two body systems most prone to lithium-induced injury?    

The thyroid gland and renal system are most prone to lithium-induced injury. 

What are the differences between the brands of lithium?

There are differences in the bioavailability of different formulations, and they advise to keep to the same brand. If changing the formulation of lithium is essential, monitor lithium levels closely until it reaches a steady-state in all cases.

What are the distinct forms of lithium found in different formulations?

The tablet form is lithium carbonate, while the liquid form is lithium citrate.

What is the best time to

We give it as a single daily dose at night.

What is the most suitable time to take a blood sample for serum lithium estimation?

We take the sample for lithium in the morning, 12 ± 1 hours after the last dose for patients on twice-daily dosing, and once-daily dosing in the evening.  Inform patients who are on twice-daily dosing, not to take the next dose unless they have given blood samples. See the review systematic review below. 

>> What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations Nolen - 2019 - Bipolar Disorders

What can increase serum lithium concentration?

How do we determine the dose of lithium? 

We determine the dose of lithium with serum levels. The target serum level of lithium depends on the underlying diagnosis, effects, and side effects.  

What is the therapeutic range of lithium?

Previously, 0.6 to 1.2 mmol/L was the recommended therapeutic range of lithium. Recent studies show lithium can be effective at doses as low as 0.4 mmol/L and that to above 1 mmol/L, side effect burden increases but with little-to-no benefits. 

The Recommended Dose of Lithium in Different Age Groups
Adults		0.60‐0.80 mmol/L
	Suitable response with poor tolerance	reduce to 0.40‐0.60 mmol/L
	Insufficient response and good tolerance	Increase it to 0.80‐1.00 mmol/L
Children and adolescents		Same as above
Elderly		0.40‐0.60 mmol/L
Max. dose in the elderly
	65‐79 year	0.70 or 0.80 mmol/L
	over 80 years	0.70 mmol/L

What kind of damage does lithium cause to the thyroid?

It can cause both hyper and hypothyroidism

What is the lag phase of lithium?

The lag phase of lithium is around 5-7 days. 

Lithium and Surgery

Lithium is safe in minor surgery, but usually, we discontinued it before a patient on lithium must undergo a major procedure; we restart it once electrolytes normalize. Consider the following points 

1. Lithium prolongs the action of muscle relaxant
2. Electrolyte imbalance and dehydration can precipitate lithium toxicity, 
3. Multiple factors including electrolyte imbalance put the patient at an increased risk of arrhythmia.

What are the neurochemical effects of lithium?

Enhances serotonergic activity, reduces cholinergic activity, and inhibits PI and cyclic AMP.

How is lithium transported across the cell membrane?

It is actively transported across membranes a voltage-sensitive sodium channel actively and sodium-potassium ATPase.

How does lithium affect signal transduction?

It increases inositol monophosphate. It depletes free inositol. Adrenergic, cholinergic, serotonergic, and dopaminergic receptors are coupled to Pi turnover in the CNS. There is a compensatory stabilization of biogenic amine imbalance. cAMP accumulation is inhibited. G proteins mediate all of this. Chronically, it may have effects through protein kinase C and expression of neuromodulator and components of secondary messenger systems.

Tell me about lithium's mechanism of action?

It affects serotonin precursor uptake, synthesis, release, storage, catabolism, receptors, and receptor effector interaction primarily presynaptically. It increases DA turnover, decreases DA formation, decreases striatal DA activity. Facilitates the release of NA through the pre-synaptic autoreceptor. Stimulates ACH synthesis and release.

What percentage of people relapse when on lithium? What percentage relapse on a placebo?    Thirty-four percent relapse on lithium, while 81% relapse on placebo.

What percentage relapse and after abrupt termination of lithium?

Fifty percent relapse within 5 months.

What can reduce the risk of relapse when you stop the lithium?    

Tapering slowly

What percentage of bipolar patients will show an inadequate response to lithium alone and will require an addition of ADT or anticonvulsant?

50%

What patterns of bipolar show reduced efficacy of lithium?

Rapid cyclers or mixed states. Studies also associate personality disorders and substance abuse with poorer response.

Is MDI better or DMI better in lithium treatment?

MDI pattern which is preceding depression responds better to lithium while DMI, which is when you get severe episodes of depression doesn't respond as well.

How long does lithium take to work in bipolar depression?

3-4 weeks

What percentage of bipolar patients respond to lithium as an antidepressant vs how many unipolar patients respond to it as an antidepressant?

Seventy-nine percent of bipolar patients and 36% of unipolar patients.

What percentage of treatment-refractory patients respond to lithium augmentation?    50%

What other ailments is lithium used to treat?

Schizoaffective disorders, cluster headache, preliminary use in HIV treated patients with zidovudine.

What are the important drug interactions of lithium?

What teratogenic effects does lithium have?

It has teratogenic effects on the cardiovascular system in the first trimester. Ebstein's anomaly.

What levels do you want lithium at?

6-.8 in maintenance level .8-1.2 in the acute manic state.

How would you begin with the dose of lithium? 

Recommend the patient to start lithium at a dose of 400-600 mg given at night. Increase its dose weekly depending on the results of serum monitoring to a maximum dose of 2g/day.

Describe how to monitor patients on lithium?

Check lithium level seven days after starting and seven days after each change of dose. Take blood samples 12 hours post-dose. Once the patient archives a therapeutic serum level, continue to check lithium level and eGFR every three months and thyroid function tests every six months.  Monitor the weight!

1.    Mander AJ, Loudon JB. RAPID RECURRENCE OF MANIA FOLLOWING ABRUPT DISCONTINUATION OF LITHIUM - The Lancet  1988/07/02/ 1988;332(8601):15-17. doi: https://doi.org/10.1016/S0140-6736(88)92947-9