LITHIUM

Maybe we just need a little lithium in the water and maybe some ketamine in the air 

An overview of Lithium for Psychiatrists. 

 

History:

It is a naturally occurring mineral which was initially used for gout, epilepsy and cancer in the 1900s. Also, part of the third in a certain part of cities in southern and eastern Europe and they found the crime rates and the suicide of that particular area was significantly lower than other areas. And In the roman empire, it is said that people who were edgy temperamental were ordered to bathe in the spring water. Later on, found to have increasing levels of lithium. 

Lithium was taken as a health supplement, put in energy drinks and they started parting increasing doses till they found that people were having kidney failures and thyroid issues and that energy drink was banned. 

Lithium came back around in 1948.  The drug was (re)discovered in modern times by the Australian psychiatrist John Cade in 1948. 

What I love about lithium is that it is inexpensive. Often called an orphan drug because there is no incentive for pharmaceuticals to invest in it. This drug remains underutilized, and its side effects incidence and prevalence is often overestimated.

Lithium being a mineral itself shares similarities to other electrolytes including Na, K, Mg, Ca which may hint at it’s inclination towards causing electrolyte imbalance and its effect at renal function and its ability to be a part of so many core intra cellular process in our body very similar to Ca.  

FDA approved for:

  • Mood Stabilizer
  • Gold Standard for Bipolar
  • Acute Mania of BP 1, Mized episodes and Maintenance phase of mania, BP1 . (> or = 7 rs)

Off Label:

  • Bipolar II
  • Unipolar depressio with other agents (Children and adolescents also)
  •  It is also beneficial in conjunction with antipsychotics for schizoaffective disorder, bipolar type.
  •  For women of child-bearing age with a history of bipolar disorder (the strongest risk factor for post-partum psychosis), lithium has demonstrated efficacy for the prevention of post-partum psychosis; it is often initiated on the first post-partum day (in non-breast-feeding mothers). If started sooner, increased monitoring of lithium levels is important given tremendous fluid shifts during childbirth, which increase the risk for lithium toxicity

Mechanism of Action (Still needs better understanding, complex, affects a lot of things)

 

  • Inhibits glycogen synthase kinase 3 beta, protein C, inositol leading to alteration in intracellular signaling. 

  • Increase inhibitory neurotransmission and decrease stimulatory neurotransmission.

  • NMDA receptor modulation

  • Increases BDNF

  • Alters metabolism of neurotransmitters including catecholamines and serotonin

  •  

 

Interesting point to note:

Response to long-term treatment with lithium (eg, decreased recurrences) may involve genetic factors. linked single nucleotide polymorphisms on chromosome 21 were associated with a good response to lithium.

 

Advantages:

  • Decrease risk of suicide in BP patient, after ECT

  • Neuroprotective, neurogenesis possible decrease in neurocognitive disorder.

  • Preserve gray matter volume and hippocampal volume in BP patients. 

Disadvantages:

 

  • . It is more effective in pure mania (i.e., with euphoria and grandiosity) than it is with mixed episodes, rapid-cycling disorders, or in bipolar patients with co-morbid substance abuse. 

Things to consider before starting Lithium:

 

  • RFTs (cr and urine specific gravity), TFT, Serum Electrolytes, Vital Signs

  • Concurrent Medications: Co-administration of several agents (e.g., ACE inhibitors, thiazide diuretics, non-steroidal anti-inflammatory drugs) increase serum lithium levels, whereas others (e.g., xanthines {e.g., caffeine)theophylline], and osmotic diuretics [e.g., mannitol) decrease serum lithium

  •  

    • Risk and benefits in a female of child- bearing potential

Side Effects: (mention percentage of each) Mnemonic: Lithium. 

  • L: Loose stools

  • I

  • T – Thyroid Dysfunction, : Goiter, Hypo, AI Thyroiditis and Hyper

  •  Patients with normal thyroid function initially should be reevaluated every 6 to 12 months for several years, and thyroid dysfunction should be treated if diagnosed. The development of thyroid dysfunction does not typically require discontinuation of lithium. If thyroid function is abnormal at the initial evaluation, lithium can still be given, if necessary, but the thyroid dysfunction should be treated.

  • Hypothyroidism is also common in lithium-treated patients. In a review of 11 reports (over 1700 patients), the prevalence of hypothyroidism ranged from 6 to 52 percent [11]. In addition, a meta-analysis of eight case-control studies showed more hypothyroidism in patients treated with lithium than in controls (odds ratio [OR] 5.78, 95% CI 2.00-16.67) [14]. Hypothyroidism may occur in the presence or absence of goiter, and it is usually subclinical, ie, the patient has a high serum TSH and normal T4 and T3 concentrations. A few patients have overt hypothyroidism with all of its usual symptoms and signs

  • Lithium increases intrathyroidal iodine content, inhibits the coupling of iodotyrosine residues to form iodothyronines (thyroxine [T4] and triiodothyronine [T3]), and inhibits release of T4 and T3. (See ‘Introduction’ above.)

  • Lithium can cause goiter and hypothyroidism, and its use has been associated with both thyroid autoimmunity and hyperthyroidism. Goiter and hypothyroidism are more common, occurring in approximately 40 to 50 and 20 to 30 percent, respectively, of patients treated with lithium. (See ‘Thyroid disease in lithium-treated patients’ above.) Because of the high incidence of thyroid dysfunction that occurs during lithium treatment, patients should have a careful thyroid physical examination and determination of serum thyroid-stimulating hormone (TSH) and antithyroid peroxidase antibody titers before lithium treatment is begun. Patients with normal thyroid function initially should be reevaluated every 6 to 12 months for several years, and thyroid dysfunction should be treated if diagnosed. The development of thyroid dysfunction does not typically require discontinuation of lithium. If thyroid function is abnormal at the initial evaluation, lithium can still be given if necessary, but the thyroid dysfunction should be treated. (See ‘Thyroid disease in lithium-treated patients’ above.

  • Because of its ability to inhibit thyroid secretion, lithium has been used in the treatment of several thyroid diseases. However, it is not used as first-line therapy, because of side effects and the availability of other antithyroid drugs. 

  • Nausa: divided doses, sustained relaease with food. Might be related to peak levels.

  • Weight gain : RR:1.9

  • Cognitive dulling: – smaller doses, modafinil?, polypharmacy- X

  • Cardiac: arrhythmia get baseline ekg

  • Sexual dysfunction: 37% , important cause of non adherence.

  • Diarrhoea: Loose stools/diarrhea — Lithium-induced loose stools/diarrhea is seen in up to 10 percent of patients [44]. Higher serum lithium concentrations (eg, greater than 0.8 mEq/L [0.8 mmol/L]) may correlate with loose stools/diarrhea; thus, management strategies include

  • Using an immediate-release formulation of lithium (to avoid distal absorption of the drug).

  • Treatment with a second drug. (See “Approach to the adult with chronic diarrhea in resource-abundant settings”, section on ‘Symptomatic therapy’.)

  • Reducing the daily dose.

  • Tremors –   Lithium tremor is common; pooled results from multiple studies suggest that the prevalence is approximately 25 percent .
  • Watchful waiting is a reasonable approach to lithium tremor because it often is relatively mild and resolves over time [44,58]. Management of lithium tremor that is troublesome and/or persistent starts with modifying aggravating factors (eg, decreasing caffeine intake). In addition, it may help to change the lithium preparation from long acting to short acting, or to a different salt (ie, from carbonate to citrate), or to divide the daily dose to take smaller amounts more often.
  • For lithium tremor that still persists and causes moderate to severe functional problems, we suggest add-on pharmacotherapy (eg, beta blockers such as propranolol) [44,58]. Alternatively, the total daily dose of lithium can be reduced if feasible. 
  • Thirsty
  • H – Heart Anomaly (Ebstein) – 1 in 20k (link) Lithium use during the first trimester of pregnancy has been associated with the development of Ebstein’s anomaly (congenital downward displacement of the tricuspid valve into the right ventricle). All women of child-bearing age beginning treatment with lithium should be advised of this risk. Ebstein’s anomaly occurs in 1 in 20,000 live births in the general population; with newborns exposed to lithium, the incidence appears higher (i.e., as much as 400- fold higher according to some studies). However, a systematic review and metaanalysis failed to show any increase in congenital malformations in lithiumexposed pregnancies. This suggests the association between Ebstein’s anomaly and lithium is lower than what earlier reports indicated. Moreover, the risk is probably much lower than the risks of neural tube defects associated with the use of anticonvulsant mood stabilizers (e.g., divalproex, carbamazepine) in pregnancy; thus, in the severely manic patient who requires treatment, lithium use might be necessary, ideally after the first trimester whe n drugs are considered safer for the fetus. As always, a careful risk–benefit analysis should be done before prescribing lithium treatment during pregnancy. . However, the increased absolute risk of congenital abnormalities (7 per 1000) is considered small [51].

  • In addition, infants exposed to lithium were compared with infants who were not exposed to either lithium or lamotrigine (n >1,000,000); right ventricular outflow tract obstruction defects were more common in lithium exposed infants than controls (0.6 versus 0.2 percent).