The antithyroid actions of lithium were first investigated in detail when it was noted

that patients with psychiatric disease treated with lithium carbonate developed
hypothyroidism and goiter. Animal and human studies subsequently revealed that
lithium increases intrathyroidal iodine content, inhibits the coupling of iodotyrosine
residues to form iodothyronines (thyroxine [T4] and triiodothyronine [T3]) [1-3], and
inhibits release of T4 and T3 [2-4].

The mechanism by which lithium inhibits thyroid hormone release is not well

understood. In vitro, lithium decreases colloid droplet formation within thyroid
follicular cells, a reflection of decreased pinocytosis of colloid from the follicular
lumen [5]. The efficiency of proteolytic digestion of thyroglobulin within
phagolysosomes also may be impaired.

an cause goiter and hypothyroidism, and its use has been associated with both
thyroid autoimmunity and hyperthyroidism [6,7]. 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

Goiter is the most common thyroid abnormality in lithium-treated patients, occurring

in approximately 40 to 50 percent [8-11]. The inhibition of thyroid hormone
secretion that occurs during lithium treatment results in decreased serum T4 and
T3 concentrations, a compensatory increase in pituitary secretion of TSH and, in a
new steady state, secretion of a normal amount of thyroid hormone by an enlarged
thyroid gland

Chronic autoimmune thyroiditis — It is likely that many patients who develop

hypothyroidism during lithium treatment have underlying chronic autoimmune
thyroiditis [1,2,13]. They have a greater prevalence of antithyroid antibodies before
lithium is begun than those lithium-treated patients who remain euthyroid
Chronic lithium ingestion in patients with bipolar (manic depressive) illness has
been associated with several different forms of kidney injury [1]. Nephrogenic
diabetes insipidus (NDI) is the most common renal side effect of lithium therapy

Chronic lithium ingestion can lead to resistance to ADH, resulting in polyuria and

polydipsia in up to 20 to 40 percent of patients [4,9]. Lithium enters the principal
cells of the collecting duct through epithelial sodium channels in the luminal
membrane [9,10]. It then accumulates in these cells and interferes with the ability
of ADH to increase water permeability. 

Lithium may increase expression of cyclooxygenase-2 and therefore increase

urinary prostaglandin E2 excretion by medullary interstitial cells [13]. These
prostaglandins then act on principal cells to induce lysosomal degradation of AQP2
water channels and a decline in urine concentrating ability:

●Lithium may reduce AQP2 gene transcription, an effect that is prostaglandin

independent, leading to a further decrease in concentrating ability [13].
●Lithium induces collecting duct remodeling characterized by a decreased
population of principal cells relative to the number of intercalated cells, a
phenomenon that was previously presumed to be due to apoptosis [11,12].
However, lithium may actually lead to proliferation of principal cells, which then
undergo cell cycle arrest [15]. This may also be responsible for the
development of interstitial nephritis and renal fibrosis.

Major risk factors for nephrotoxicity appear to be the duration of lithium exposure

and the cumulative dose [7,39]. Other risk factors include episodes of acute
intoxication, increased age [34,39], other comorbid illnesses (eg, hypertension,
diabetes mellitus, hyperparathyroidism, and hyperuricemia), and concomitant use
of other antipsychotic medications. The degree of kidney function impairment is
variable [16,34,35,39,40].

Chronic interstitial nephritis usually presents as the insidious development of renal

insufficiency, with normal to only a mild degree of proteinuria, often in the setting of
nephrogenic diabetes insipidus (NDI). The degree of interstitial fibrosis on kidney
biopsy may be directly related to the duration and cumulative dose of lithium

HYPERPARATHYROIDISM AND HYPERCALCEMIA Another

complication of long-term therapy with lithium carbonate is hyperparathyroidism,

with associated hypercalcemia and hypocalciuria [45].

There are several mechanisms by which lithium may increase serum calcium

levels:
 ●Increasing the threshold for the calcium-sensing mechanism within the
parathyroid gland [46]. Thus, parathyroid hormone (PTH) secretion continues
despite the presence of hypercalcemia.
●Inducing PTH overproduction via inhibiting the action of glycogen synthase
kinase 3b (GSK-3b).
●Inhibiting calcium transport (influx) across cell membranes.

The predominant form of chronic kidney disease associated with lithium therapy is

a chronic tubulointerstitial nephropathy

Monitoring Parameters
Renal function including BUN and SCr (baseline, every 2 to 3 months during the
first 6 months of treatment, then once a year in stable patients or as clinically
indicated); pediatric patients may require more frequent checks); serum
electrolytes (baseline, then periodically), serum calcium (baseline, 2 to 6 weeks
after initiation, then every 6 to 12 months; repeat as clinically indicated) (Broome
2011); thyroid (baseline, 1 to 2 times with in the first 6 months of treatment, then
once a year in stable patients or as clinically indicated); beta-hCG pregnancy test
for all females not known to be sterile (baseline); ECG with rhythm strip (baseline
for all patients over 40 years or if underlying cardiac risk factors, repeat as clinical
indicated), CBC with differential (baseline, repeat as clinically indicated); serum
lithium levels (twice weekly until both patient's clinical status and levels are stable,
then repeat levels every 1 to 3 months or as clinically indicated); weight (baseline,
then periodically) (APA 2002; Mehta 2017); polyuria.
Reference Range
Monitor symptom improvement in conjunction with serum concentrations to guide
dose adjustments. Obtain 2 consecutive serum concentrations in the therapeutic
range during the acute phase, then monitor regularly (ie, every 3 to 6 months).

Timing of serum samples: Draw trough just before next dose (8 to 12 hours after
previous dose) ~5 days after a dosage adjustment (CANMAT [Yatham 2018]).

Therapeutic concentrations:

Bipolar disorder:

Acute mania: 0.8 to 1.2 mEq/L (SI: 0.8 to 1.2 mmol/L); some guidelines
recommend lower target serum concentrations (eg, 0.4 to 0.8 mEq//L
[SI: 0.4 to 0.8 mmol/L]) for older adults.

Maintenance: 0.6 to 1 mEq/L (SI: 0.6 to 1.0 mmol/L); a higher rate of

relapse is described in subjects who are maintained at <0.6 mEq/L
(SI: 0.6 mmol/L) (CANMAT [Yatham 2018]).
 Major depressive disorder: 0.6 to 1 mEq/L (SE: 0.6 to 1 mEq/L) (VA/DoD
2016).

Toxic concentrations

>1.5 mEq/L (SI: >1.5 mmol/L): Early signs and symptoms of intoxication may
include marked tremor, nausea, diarrhea, blurred vision, vertigo,
confusion, and decreased deep tendon reflexes (APA 2002).

>2.5 mEq/L (SI: >2.5 mmol/L): Intoxication symptoms may progress to include
severe neurological complications, seizures, coma, cardiac dysrhythmia,
and permanent neurological impairment (APA 2002).

>3.5 mEq/L (SI: >3.5 mmol/L): Potentially lethal toxicity (Mitchell 2001).

Note: A 10% to 26% increase of a 12-hour serum concentration can be expected

with once-daily dosing compared to a 12-hour serum concentration checked of
an equal dose that is given twice daily (Mitchell 2001; Singh 2011).
Mechanism of Action
The precise mechanism of action in mood disorders is unknown. Traditionally
thought to alter cation transport across cell membranes in nerve and muscle cells,
influence the reuptake of serotonin and/or norepinephrine, and inhibit second
messenger systems involving the phosphatidylinositol cycle (Ward 1994). May also
provide neuroprotective effects by increasing glutamate clearance, inhibiting
apoptotic glycogen synthase kinase activity, increasing the levels of antiapoptotic
protein Bcl-2 and, enhancing the expression of neurotropic factors, including brain-
derived neurotrophic factor (Sanacora 2008).
Pharmacodynamics and Pharmacokinetics
Absorption: Rapid and complete

Distribution: Vd: Initial: 0.307 L/kg; Vdss: 0.7 to 1 L/kg; decreased in elderly patients
(Ward 1994)

Protein binding: Not protein bound

Metabolism: Not metabolized (Ward 1994)

Bioavailability: 80% to 100% (Ward 1994)

Half-life elimination:

Pediatric patients 7 to 17 years: t1/2(beta): 27 hours (Findling 2010)

Adults: 18 to 36 hours; prolonged in elderly patients (~28.5 hours) (Ward

1994)
Time to peak, serum: Immediate release: ~0.5 to 3 hours; Extended release: 2 to 6
hours; Solution: 15 to 60 minutes

Excretion: Urine (primarily; unchanged drug); sweat, saliva, and feces (negligible
amounts)

Clearance: 80% of filtered lithium is reabsorbed in the proximal convoluted

tubules; decreased in elderly patients secondary to age-related decreases
in renal function (Ward 1994)
Pharmacodynamics and Pharmacokinetics: Additional
Considerations
Pediatric: In pediatric patients, great variability in clearance was found across
subjects with linear pharmacokinetics correlated to fat-free mass (Findling
2010).

Geriatric: Elderly patients receiving lithium may have a decreased glomerular

filtration rate and decrease in renal plasma clearance (13.7 mL/minute) (Ward
1994).
Las reacciones adversas al litio son fundamentalmente del SNC, gastrointestinales o
renales. Durante los primeros días de tratamiento con litio puede aparecer ligero temblor de
manos, sed, poliuria, náuseas y malestar general. Por lo general los síntomas remiten a lo
largo del tratamiento, o con la disminución de la dosis o suspensión temporal del mismo.

Trastornos endocrinos: Frecuentes: Hipotiroidismo. Bocio. Poco frecuentes:

Hiperparatiroidismo primario leve. Trastornos del metabolismo y de la nutrición: Muy
frecuentes: Síntomas de diabetes insípida nefrogénica: poliuria y polidipsia. Hipercalcemia
Poco frecuentes: Pérdida de peso o aumento de peso. Trastornos del sistema nervioso: Muy
frecuentes: somnolencia, cansancio, debilidad muscular, hiperirritabilidad muscular
(fasciculaciones, movimientos clónicos de las extremidades), temblor, cefalea, confusión,
palabra gangosa, ligera dificultad para concentrarse. Todos ellos aparecen al inicio del
tratamiento, suelen ser benignos, transitorios y reversibles mientras continúa el tratamiento
con litio. El temblor ocurre en las manos, es fino e intencional. Una agravación del temblor
o su extensión hacia otras partes del cuerpo pueden indicar intoxicación por litio.
Frecuentes: Síntomas extrapiramidales tales como rigidez en “rueda dentada”,
hiperreflexia, hipertonía. Poco frecuentes: mareo, vértigo, trastornos de la acomodación,
pérdida de conciencia transitoria, estupor, coma, intranquilidad, retardo psicomotor,
distonía aguda, nistagmus vertical, convulsiones, movimientos coreoatetoides. Se han
descrito casos aislados de pseudotumor cerebral (aumento de la presión intracraneal y
papiledema) en pacientes tratados con litio, que en caso de no detectarse puede resultar en
un agrandamiento de la mancha ciega, constricción de las fibras ópticas y eventual ceguera
debida a atrofia del nervio óptico. En tales casos, se interrumpirá el tratamiento con litio.

5.2 Propiedades farmacocinéticas El litio se absorbe de forma rápida y completa por vía
oral. Los comprimidos de Plenur se presentan con una formulación de cesión modificada a
fin de retrasar y prolongar la liberación del principio activo. Por ello, los valores de Tmax
(>5 horas) son muy superiores a los de las formas convencionales (30 minutos
aproximadamente). La biodisponibilidad del litio a partir de los comprimidos de Plenur es
del 60-90%. No se une a las proteínas plasmáticas. El litio se distribuye por todo el
organismo, alcanzando mayor concentración en tiroides, hueso y tejido cerebral. Atraviesa
la barrera placentaria y puede pasar a la leche materna. El tiempo preciso para que aparezca
inicialmente la acción terapéutica es de unos 5-7 días. La mejoría clínica aparece en un
período entre 1 y 3 semanas. No se metaboliza y es eliminado mayoritariamente de forma
inalterada por la orina en un 90-95% y en una pequeña cantidad por las heces y el sudor. Su
semivida de eliminación es de 20 a 24 h en caso de función renal normal; de unas 24 a 48
horas en pacientes sometidos a largas terapias; de unas 36 horas en pacientes geriátricos y
de unas 40-50 h. en casos de insuficiencia renal. El litio es eliminable mediante diálisis,
tanto hemodiálisis como diálisis peritoneal.

Sustained-release formulation may

reduce gastric irritation, lower peak lithium
plasma levels, and diminish peak dose side
effects (i.e., side effects occurring 1–2
hours after each dose of standard lithium
carbonate may be improved by sustainedrelease formulation)