European Journal of Pharmacology 740 (2014) 464473

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European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Review

Lithium: A review of pharmacology, clinical uses, and toxicity

Ramadhan Oruch a,n, Mahmoud A. Elderbi a, Hassan A. Khattab b, Ian F. Pryme c,
Anders Lund d
a
Department of Pharmacology and Toxicology, School of Pharmacy, Benghazi University, Postbox: 5341, Benghazi, Libya
b
Department of Pharmaceutical Chemistry, School of Pharmacy, Benghazi University, Benghazi, Libya
c
Department of Biomedicine, University of Bergen, Bergen, Norway
d
MoodNet Research Group, Psychiatric Clinic, Haukeland University Hospital, University of Bergen, Bergen, Norway

art ic l e i nf o a b s t r a c t

Article history: A radical drug treatment for bipolar affective disorder (BD) is currently unavailable. This is attributed to
Received 27 March 2014 the fact that the precise pathophysiology of this ailment is unclear though a genetic factor is an essential
Received in revised form element in etiology. Dissimilar to other serious psychiatric categories such as psychoses and major
20 June 2014
depression the forecast of this disease is unpredictable. There is a high suicidal risk among BD affected
Accepted 20 June 2014
Available online 30 June 2014
individuals. In this review we will consider lithium, the drug of choice in treatment of this disorder with
special emphasis on pharmacology and toxicity. We have also elucidated the alternatives to lithium,
since it has a wide spectrum of side-effects. Lithium is known to interact with many types of drugs used
Keywords:
to treat different ailments in humans. This could cause either augmentation or minimization of the
Lithium
Bipolar affective disorder therapeutic action, causing secondary undesired effects of the agent. This necessitates a search for other
Major depression alternatives and/or different combinations to lithium in order to decrease the range of unwanted effects
Valproate for which it has received discredit. These alternatives should be potent mood stabilizers as monotherapy
Lamotrigine so as to avoid polypharmacy. If not, one should nd the best combination of drugs (synergistic agents)
Carbamazepine such that the lithium dose can be minimized, thereby securing a more potent drug therapy. This study
Chemical compounds studied in this article: also focuses on the provision of instruction to psychiatric care givers, such as junior doctors in residency,
Lithium (PubChem CID 28486) nurses in psychiatric units, psychiatric emergency personnel and, additionally, medical and pharmacy
Valproate (PubChem CID 3121) students.
Lamotrigine (PubChem CID 3878) & 2014 Elsevier B.V. All rights reserved.
Carbamzepine (PubChem CID 2554)
Lurasidone (PubChem CID 213046)

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
1.1. Bipolar affective disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
1.2. Major depressive disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
1.3. Acute mania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
2. Clinical use (historic) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
3. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
4. Therapeutic doses of lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
5. Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
6. Side effects of lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
7. Pregnancy and breast-feeding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
8. Overdose and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
9. Management of lithium toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
9.1. Prelude . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
9.2. Impact of lithium serum levels on renal and cardiac functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
9.3. Treatment of an overdose and intoxication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
9.4. Steps in resuscitation and treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469

Abbreviations: BD, Bipolar affective disorder; BD, Bipolar mood disorder

n
Corresponding author. Tel.: 218 916879672; fax: 218 2231520.
E-mail address: oruchr@gmail.com (R. Oruch).

http://dx.doi.org/10.1016/j.ejphar.2014.06.042
0014-2999/& 2014 Elsevier B.V. All rights reserved.
 R. Oruch et al. / European Journal of Pharmacology 740 (2014) 464473
9.5. Hospital admission and duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
10. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
1. Introduction
Lithium is a soft silver-white metallic element of the alkaline
group, having an atomic number of 3. Its name originates from the
Greek (lithos) meaning stone. It has a light atomic mass of 6.941 a.
m.u. In nature it never exists freely, but appears in ion form in
compounds (Lodders, 2003). Lithium is a monovalent cation (Li )
when it loses the only electron of the second orbital. It has two
stable isotopes 6Li and 7Li, the latter being more abundant in
nature. Its biological signicance is based on the use of its salts in
handling psychiatric disease. It is used mainly as a mood stabilizer
when dealing with bipolar mood disorders (BD) formerly (manic
depressive psychosis), and to a lesser extent in combination with
other antidepressants in treatment of major depression.
1.1. Bipolar affective disorder
Bipolar affective disorder is an episodic disturbance of mood
with swinging periods of mania (or hypomania) and depressed
mood. Men and women are equally affected and the onset is
usually in the teens. The life-time risk of developing BD is about 4%
(Ketter, 2010). The ailment is subcategorized into two major types:
bipolar I and bipolar II disorders. One can see DSM-5 or ICD-10
for details and subclass nomenclature of BD.
1.2. Major depressive disorders
Major depressive disorders have a prevalence of 5% in the
general population and 10% in chronically ill medical outpatients.
The disorder is characterized by a pervasive and persistent low
mood which is accompanied by low self-esteem and by a loss of
interest or pleasure in normally enjoyable activities (anhedonia).
The disease also has other somatic symptoms like reduced
appetite (and thus weight changes), fatigue, disturbed sleep, loss
of libido, motor retardation and bowel disturbance in addition to
other minor symptoms (Schacht et al., 2014; Sharpe and Lawrie,
2010). Patients with major depressive disorder have the risk of
developing a desire to commit suicide.
1.3. Acute mania
In addition to catatonic schizophrenia, melancholia (deep
depression, that might end in suicide), acute mania is also another
category of serious psychiatric emergency. This situation needs
active intervention from the psychiatrists and the whole team at
the emergency psychiatric unit. This is different from hypomania
in which the individual has a mild to moderate level of elevated
mood, optimism, pressure of speech and activity, and decreased
need for sleep. This a situation that does not inhibit general
function as mania does.
Mania is the identifying milestone of BD. It is a distinct period
of elevated or irritable mood, which can manifest itself as euphoria
that lasts for at least a week if the patient is not admitted to a
psychiatric unit. These individuals usually experience an increase
in energy and get little sleep (34 h per night) or may even not
sleep for many days. They become talkative and their attention
span is shallow and they could be easily distracted. Because their
judgment is impaired, they may indulge in substance abuse,
particularly alcohol or other depressants, cocaine or other
465
stimulants, or sleeping pills. They become aggressive, might not
be able to control sexual drive, may be intolerant, or intrusive.
They may have grandiose or delusional ideas. In extreme cases
they might experience psychosis and occasionally become violent
(Dean et al., 2007; Pompili et al., 2013; Volavka, 2014). A stage of
aura might precede the onset of a manic episode manifested as
anxiety, sleep and mood disturbances, psychomotor and appetite
changes. This can occur up to three weeks before a manic episode
develops (Mansell and Pedley, 2008).
Regarding the treatment of acute manic episodes, one can start
with haloperidol until the concomitantly given rst-line drugs
such as lithium or valproate show an effect. Olanzepine has also a
place in treatment of acute mania, it is indicated either as a
monotherapy or as co-therapy with lithium or valproate (Geoffroy
et al., 2012; Tohen et al., 2000b; Wong, 2011). Haloperidol and
olanzapine are superior to chlorpromazine because of the short
lag-period for onset of action which is 26 days compared to
chlorpromazine which takes 2 weeks to exert its effect (Tohen
et al., 2000a). (See Fig. 1 for structures).
In a recent review it was emphasized that lurasidone may be an
option in the management of depressive symptoms in patients
with bipolar 1 disorder, and it may be considered as a treatment
alternative for patients who are at high risk of metabolic abnorm-
alities (Woo et al., 2013).
According to the available evidence lithium is the drug of choice
in treatment of acute manic episodes (Chen et al., 2014; Mitchell,
2013; Poolsup et al., 2000; Vieta and Valenti, 2013) and preventing
mainly the relapses of manic attacks than hampering the depressive
episodes (Geddes et al., 2004). Another positive issue regarding
lithium is that it reduces the risk of self-harm, also in people with
BD (Cipriani et al., 2013b). The anticonvulsant sodium valproate has
become a commonly prescribed treatment for BD, and is also
effective in treating manic episodes (Macritchie et al., 2003).
Three other anticonvulsants are used in the treatment of manic
episodes and these are: 1. Carbamazepine which is effective in
treating manic episodes (Selle et al., 2014). 2. Lamotrigine has its
greatest benet in the treatment of more severe depression (Geddes
et al., 2009). 3. Topiramate has also been used in treatment of BD
(Peruzzolo et al., 2013). Anticonvulsants may be used in combination
with lithium or alone, depending on the severity of the case.
2. Clinical use (historic)
In the 19th century lithium was used to dissolve uric acid
crystals in urine obtained from patients with gout. In order to treat
gout with lithium, doctors had to give large oral doses of its salts,
which unfortunately proved to be toxic (Marmol, 2008). Later, Carl
Lange (Denmark) and W.A. Hammond (USA) separately used
lithium to treat mania; this was because at that time prevalent
theories linked high uric acid levels to many psychiatric disorders
such as depression and manic disorders (Lenox and Watson, 1994;
Mitchell and Hadzi-Pavlovic, 2000). Clinical expertise proved the
role of excess sodium intake as an important cause of hyperten-
sion and cardiovascular disease; therefore physicians prescribed
lithium salts for patients, replacing sodium chloride as a table salt.
Unexpectedly, this practice led to serious side effects and deaths
among those individuals that used lithium salts. Consequently the
sale of lithium salts was abandoned in 1949 (Marmol, 2008). It was
466 R. Oruch et al. / European Journal of Pharmacology 740 (2014) 464473
Fig. 1. Chemical structures of the drugs discussed in this review.
known that uric acid is a psychoactive substance because of its
stimulant actions on adenosine receptors of the neuronal mem-
brane. This fact led the Australian psychiatrist John Cade, to inject
lithium salts into rodents. Cade observed that lithium salts acted
as a tranquilizer. The next step was that Cade used lithium salts to
control mania in chronically hospitalized patients (Cade, 1949).
Psychiatrists in Europe and USA, and the rest of the world, thus
became aware of the therapeutic signicance of lithium salts in
treating BD and, furthermore, also its use as a maintenance drug to
prevent relapse (Geoffroy et al., 2014; Mitchell and Hadzi-Pavlovic,
2000). It is believed that lithium decreases the risk of suicide in
those who suffer from BD (Can et al., 2014; Cipriani et al., 2013b;
Foster, 2013) and treatment resistant depression (Carvalho et al.,
2014; Cipriani et al., 2013a; Edwards et al., 2013; Kohler et al.,
2014). This is a positive issue in favor of lithium, not demonstrated
by other similar remedies (Kovacsics et al., 2009; Muller-
Oerlinghausen et al., 2003).
3. Mechanism of action
Similar to the monovalent cation sodium (Na ), lithium under
in vitro conditions, replaces Na to produce a single action
potential in a neuron. In normal individuals lithium, dissimilar to
other antipsychotics, does not for example, produce euphoria. On
reviewing the pharmacodynamics of lithium to envision the
mechanism of its mood stabilizing action, one can make 9 postu-
lates that may or may not act together, and these are:
1. Because of a potential gradient between the inner and outer
leaets of the neuronal membrane, this membrane is electri-
cally excitable. Glutamate (an excitatory neurotransmitter)
could play a part in the effect of lithium in the same way as
with other anticonvulsant type mood stabilizers such as lamo-
trigine and valproate. It is believed that Li exerts an inuence
over glutamate. This possibility might also explain the biologi-
cal background of mania (Jope, 1999).
2. Lithium might have gene regulatory function via inducing
effects on nuclear receptors, which in turn may inuence either
up- or down-regulation of the biosynthesis of neurotransmit-
ters or their receptors (Lenox and Wang, 2003).
3. It may increase serotonin release by the neurons (Massot et al.,
1999). In a study on rats, neurons of the raphae nucleus treated
with Li , released serotonin during depolarization, while
untreated equivalents did not (Scheuch et al., 2009).
4. Lithium inhibits the enzyme GSK3 that phosphorylates Rev-
Erb (intracellular transcription factor protein), this in turn
increases the expression of ARNTL (Aryl hydrocarbon Receptor
 R. Oruch et al. / European Journal of Pharmacology 740 (2014) 464473 467

Nuclear Translocator-Like) which dampens the circadian clock
(Yin et al., 2006). By this mechanism the master clock of the
hypothalamus is blocked and the body's natural cycle is
disturbed. This will affect many biological functions governed
by the brain such as metabolism, sleep (diurnal rhythm) and
body temperature. This will enable the brain to resettle its
functions in a more naturally harmonized manner.
5. Inhibition of PAP by lithium increases the level of 30 -5'phos-
phoadenosine phosphate, which in turn inhibits PARP-1
(Toledano et al., 2012).
6. In a series of animal studies by Ghasemi et al. (2008), (2009a)
and (2009b) with an emphasis on nitric oxide (NO) signaling
pathways in the CNS, it was shown that NO plays a crucial role
in neural plasticity (brain plasticity) and in extending the
antidepressant-like effects of lithium in rats. Results from the
same group indicated a possible involvement of N-Methyl
D-Aspartate (NMDA) receptor/NO signaling in the action of
lithium in these animal model systems.
7. Lithium inhibits the enzyme inositol monophosphatase, thus levels
of inositol triphosphate increase (Einat et al., 1998). This enzyme
dephosphorylates inositol monophosphate to free inositol and as a
result the inositol pool is depleted. This could then explain the
therapeutic function of lithium with minimal effects on physiolo-
gical behavior (Belmaker et al., 1996; Belmaker and Kofman, 1990).
This effect was enhanced further using an inositol triphosphate re-
uptake inhibitor. Disruption of the inositol pathway has been
linked to depression and memory problems.
8. Jope (1999), in an animal study, demonstrated for the rst time
a possible different mechanism related to the therapeutic
action of lithium, namely the modication by this cation of
brain arachidonic and docosahexaenoic metabolism in
lipopolysaccharide-induced neuroinamed rats. This study
demonstrated that lithium can increase 17-hydroxy-DHA for-
mation in the brain, indicating a new and potentially important
therapeutic action of lithium on metabolism in rats (Basselin
et al., 2009).
9. Lithium interacts with cAMP mediated processes and modies
them in a way such that the supersensitive catecholamine
receptors of the neurons of the CNS are blocked. In this
hypothesis it is proposed that the pathophysiology of BD is
related to the supersensitivity of catecholamine receptors
(Bunney et al., 1979).
4. Therapeutic doses of lithium
Lithium in the form of a carbonate salt is given as oral tablets
(0.42.0 g/day). This is dependent on renal function and concomi-
tant use of other drugs. Lithium serum levels rise following the
introduction of diuretics, dehydration and salt depletion. Lithium
clearance is 0.2 times that of creatinine (see Table 1); thus the dose
should be adjusted in the presence of renal impairment and in
elderly patients. Lithium interacts with other drugs that alter
sodium balance such as steroids (McCarthy et al., 2011), ACE
inhibitors (Handler, 2009) and NSAIDs (Faaij et al., 2009). The
drug potentiates the neurotoxicity of haloperidol and upentixol
(McKay and Waltes, 2013). For drug interactions see Table 2.
5. Pharmacokinetics
Lithium is rapidly and completely absorbed after oral admin-
istration. Being a cation it is not metabolized, excreted unchanged
by the renal system. Lithium has a half-life of 12 h. It is totally
distributed in the body uid (interstitial uid) and ultimately
slowly enters the cells (intracellular uid). Its level in serum
culminates at steady-state after 57 days. The therapeutic range
is 0.51.0 mmol/l (higher levels are needed to treat acute mania).
Levels exceeding this range can cause severe adverse effects, see
Table 1.
Concerning the bioavailabity of lithium carbonate supplied as
tablets, compared to lithium provided as citrate syrup, then these
are bioequivalent with respect to the maximum lithium serum
concentration achieved and the extent of drug absorption (Guelen
et al., 1992).
Monitoring serum lithium levels is pivotal from three aspects:

Table 1
1. To titer the therapeutic dose, to ensure that this results in
Important data in relation to lithium therapy (pharmacology).
properly controlled ranges for the patient of between 0.5 and
Therapeutic Titration Therapeutic Overdose Serum Li 1.3 mmol/l (Guo et al., 2013).
daily dose, starting serum level limits of levels of clearance 2. Accumulative values may achieve higher levels of up to
adults dose, (mmol/l) serum level lithium (plasma)
1.82.5 mmol/l in patients over time. Much higher values are
(gram) adults (mmol/l) toxicity vs. b CrCl
(gram) (mmol/l)
seen in victims of acute overdose where they may reach
310 mmol/l (Amdisen, 1978; Baselt, 2008 ).
a
0.42.0 0.4 0.51.0 1.82.5 310 0.2 that of 3. Because lithium has a narrow therapeutic/toxic ratio, prescrip-
CrCl tion should be restricted to psychiatrists in centers where
equipment to measure and monitor plasma concentration is
Data adapted from Guelen et al. (1992), Morena et al. (1977) and Sharpe and Lawrie
(2010). available. Patients should be carefully selected (with correct
a
Depends on the state of renal function. diagnoses). In the start phase the dose should be adjusted to
b
CrCl: is the volume of blood plasma that is cleared of creatinine per unit time yield a plasma concentration of 0.41.2 mmol/l (Solomon et al.,
and is a useful measure for approximating the GFR (Glomerular Filtration Rate). 1996). The lower end of this range i.e. 0.4 mmol/l should be

Table 2
Some known interactions of lithium with other drugs.

Drugs that increase lithium toxicity even at therapeutic doses Drugs that reduce lithium renal clearance Drugs that increase lithium renal clearance

Amitriptyline Diuretics: Thiazide, K sparing (e.g. Spiranolactone). Acetazolamide
Pancuronium Cisplatin
Antipsychotics NSAIDs: Ibuprofen, Ketoprufen, Naproxen Sodium bicarbonate
Succinylcholine Theophylline
Others: Tetracycline, Methyldopa, Phenytoin Verapamil

Adapted from Baselt (2008), Lenox and Wang (2003) and Sharpe and Lawrie (2010).
468 R. Oruch et al. / European Journal of Pharmacology 740 (2014) 464473
Fig. 2. Chemical structures of different lithium salts discussed in this review.
applied as a maintenance dose, also for patients in the geriatric
age group, and the upper value (1.2 mmol/l) for adolescent and
pediatric patients, provided the samples are drawn routinely
12 h after the last oral dose.
The lithium salt most often prescribed by psychiatrists is the
carbonate form (Li2CO3), followed by lithium citrate (Li3C6H5O7).
Alternative to these two salts are the sulfate (Li2SO4), orotate
(C5H3LiN2O4) and aspartate (C4H5Li2NO4) salts (See Fig. 2). Con-
cerning the halogenated salt of lithium, bromide (LiBr), this fell out
of use because it proved to be toxic. The other salts such as
chloride (LiCl), uoride (LiF), and iodide (LiI) have never been
evaluated for their pharmacological effects since these have been
presumed to be toxic as well. Sustained release tablets of carbo-
nate and citrate salts are also available for therapeutic uses.
It is important to mention that these salts vary tremendously in
their bioavailability, thus one has to be cautious when prescribing
different formulations of these salts, in other words to prefer use
of citrate rather than carbonate, for example, is very difcult to
evaluate, simply because the carbonate salt is most frequently
used.
6. Side effects of lithium
Most side effects of lithium are dose-dependent. The lowest
effective dose should be used to limit the risk of side effects
(Albert et al., 2014; Bschor and Bauer, 2013).
Fine hand tremor, which might disappear in certain patients, is
otherwise generally present throughout the period of treatment
(Bohlega and Al-Foghom, 2013; Chan et al., 2012). Lithium
is a well-known cause of downbeat nystagmus (Lee and Lessell,
2003) which could be permanent or need several months before
improvement is seen after abstinence (Chan et al., 2012; Williams
et al., 1988).
Other minor side effects such as nausea and headache can be
generally overcome by increased uid intake. Being an electrolyte,
lithium causes unbalance of the interstitial uid and consequently
affects the electrolytes in the intracellular compartment. To
counteract this electrolyte misbalance, an increased water intake
is recommended.
Many studies have shown that lithium intake can cause
hypothyroidism (Ozerdem et al., 2014; Sierra et al., 2014); this is
the reason behind the development of clinical depression in these
individuals (Kibirige et al., 2013). Lithium therapy can also rarely
cause hyperthyroidism by an unknown mechanism (Siyam et al.,
2013). Other unwanted metabolic effects of lithium therapy are
weight gain (Grandjean and Aubry, 2009) and hypercholesterole-
mia (Choong et al., 2012). Hyperparathyroidism and hypercalcemia
can result and prove to be undesired consequences of lithium
therapy (Albert et al., 2013). Nephrogenic diabetes insipidus
(polyuria) is another endocrine dysfunction that can be attributed
to medication with lithium; this is because lithium competes with
ADH receptors in the kidney (Gahr et al., 2014; Ibbeken et al.,
2012). There are indications of permanent renal damage as a rare
complication of lithium therapy (Bendz et al., 2009; de Groot et al.,
2014).
Most of the peripheral side effects of lithium are attributed to
its tendency to inhibit the enzyme prostatic acid phosphatase
(PAP), causing its accumulation. The increase in PAP affects several
cellular processes such as RNA processing (Shaldubina et al., 2001).
Another important factor which is believed to contribute to its
dose dependant side-effects is inhibition of glycogen synthase
kinase-3, an enzyme that is involved in a wide spectrum range of
signal transduction pathways (Brown and Tracy, 2013; Cui et al.,
1998; Manji et al., 1999; Summers et al., 1999).
7. Pregnancy and breast-feeding
Bipolar depressive illness is diagnosed in many women of
childbearing age; thus they are candidates for lithium therapy.
Since lithium has the most clearly documented teratogenic effect
of all the psychotropic drugs, special care must be taken by the
psychiatrist, obstetrician and patient when considering its use
during this period of life (Chapman, 1989; Hosseini et al., 2010;
Nguyen et al., 2009). Controversial results from different cohort,
prospective and retrospective studies, and also some case reports,
indicate that lithium is a weak teratogen in humans (Giles and
Bannigan, 2006). Other case reports and retrospective studies have
demonstrated a possible increase of Ebstein's congenital heart
defects (tricuspid valve defect and enlargement of right atrium)
among children of mothers taking lithium preparations for ther-
apeutic reasons (Oyebode et al., 2012; Yacobi and Ornoy, 2008).
Because of this there is an indication to perform routine echocar-
diography on the fetus (between 18 and 22 weeks of gestation) to
exclude these anomalies. Close monitoring of lithium levels
throughout pregnancy is therefore mandatory. Alternatives to
the use of lithium during pregnancy to avoid teratogenicity are
the anticonvulsants lamotrigine (Yacobi and Ornoy, 2008) or
gabapentin (Montouris, 2003) or the benzodiazepine agent, clo-
nazepam (Weinstock et al., 2001). Since the anticonvulsants
valproate and carbamazepine are known teratogenic agents, they
are thus contraindicated as alternatives to lithium.
Lithium should not be used during breast-feeding, the only
exception is when it is strongly indicated, such as in women who
had already earlier been on lithium during pregnancy (Nielsen and
Damkier, 2012).
The effect of lithium on the lactation process per se, is that it
increases serum prolactin levels, thus causing galactorrhea, which
is an abnormal increase in milk production (Basturk et al., 2001).
Almost all conventional antipsychotics also exert this unwanted
effect, among others, in a wide spectrum of side effects. Galactor-
rhea usually ceases upon discontinuation of lithium therapy
(Ohishi and Higashimura, 1983).
Lithium is contraindicated during breast-feeding. This is
because lithium secreted in the milk will affect the neonate. One
should therefore seek other forms of therapy e.g. electroconvulsive
therapy (ECT) as a valid alternative option (if indicated), both
during pregnancy and breast-feeding (Nielsen and Damkier, 2012).
 R. Oruch et al. / European Journal of Pharmacology 740 (2014) 464473
Another study came to the controversial conclusion that gave
support to women taking lithium during pregnancy and lactation,
that they can also breast-feed (Bogen et al., 2012). Generally
though, it is accepted that lithium is considered as contraindicated
in breast-feeding women (Davanzo et al., 2011).
8. Overdose and toxicity
Accidental or intentional intake of excessive amounts of
lithium, or the accumulative high levels during ongoing chronic
therapy are the general causes of overdose and toxicity. The
symptoms and signs of which include the following:
GIT: nausea, vomiting, and diarrhea.
CNS: confusion, lethargy, seizures, and coma (syndrome of
irreversible Lithium-Effected Neurotoxicity: SILENT), these are
attributed to cerebellar dysfunction (Adityanjee et al., 2005).
Musculoskeletal: coarse tremor, and muscle twitching (Chan
et al., 2012).
Renal: polyuria and renal failure (Adityanjee et al., 2005).
Endocrine: one of the chronic sequels of lithium therapy is
hypothyroidism, goiter and even myxedema coma (Nishikawa et
al., 2012). Hypercalcemia is a result of hyperparathyroidism where
parathormone mobilizes calcium from the bones to the circulation
(Nair et al., 2013). Transient hyperglycemia may also occur
(Thomas et al., 2010).
Cardiovascular: ECG changes in the form of T wave inversion (ST
segment depression in chronic toxicity), conduction disturbances
and arrhythmias are less common (Prencipe et al., 2013). SA node
dysfunction may occur, leading to sinus bradicardia or sinoatrial
block. The AV node can also be affected and AV node dissociation
and junctional rhythms can occur (Morena et al., 1977). Peripheral
edema, hypotension and cardiovascular collapse may also arise.
Hematological: leukocytosis in the form of increased neutrophil
and eosinophil counts (Mazaira, 2008).
Dermatology: psoriasis, dermatitis and edema (Wakelin et al.,
1996).
Ophthalmological: burning, tearing, nystagmus, exophthalmos
and papilledma can be seen in chronic cases (Ullrich et al., 1985).
These manifestations of toxicity occur when the plasma con-
centration exceeds 1.5 mmol/l.
We have to bear in mind that serum levels of more than
2.5 mmol/l could be fatal and such individuals should therefore be
promptly treated immediately after stopping lithium treatment
(Gadallah et al., 1988). Coexisting hyponatremia because of the use
of diuretics can exaggerate the toxicity. This is because diuretics
such as thiazide (Chakraborty and Dan, 2012) increase the reab-
sorption of lithium in the proximal tubules, leading to increased
serum lithium to potentially toxic levels (Timmer and Sands,
1999), see Table 2.
The signs of acute toxicity can be summarized as follows:
tremor, ataxia, dysarthria, nystagmus, renal insufciency, confu-
sion, and convulsions (Amdisen, 1978).
9. Management of lithium toxicity
9.1. Prelude
Lithium poisoning occurs frequently, since it is used by indivi-
duals at high risk of taking an overdose. In mild cases, withdrawal
of lithium and administration of large amounts of sodium and
uid will reverse the toxicity.
It is important to keep in mind that when toxic concentrations
are reached there may be a delay of one or two days before the
symptoms actually appear (latent effect). Therefore the clinical
469
presentation of acute lithium intoxication may not reect the
blood level and vice versa (Edokpolo and Fyyaz, 2012). Further-
more, lithium has a relatively narrow therapeutic index that
predisposes patients on maintenance treatment to poisoning with
relatively minor changes in medication or health status.
9.2. Impact of lithium serum levels on renal and cardiac functions
1. Because lithium cannot be detected by the majority of urinary
screening tests and, moreover, it can mislead the diagnosis,
quantitative lithium blood level measurements by atomic
absorption should be ordered. In cases of acute ingestion, signi-
cant signs and symptoms may not become obvious before the
level is above 4.0 mmol/l. In cases of chronic toxicity, espe-
cially in the elderly, these may manifest signicant symptoms
even with mild elevations in the serum concentration. This fact
demonstrates the importance of integration of clinical symp-
toms with serum lithium levels in order to settle diagnosis of
toxicity (Groleau, 1994).
2. Renal function tests should also be performed. Blood urea
nitrogen (BUN)/serum creatinine ratio of 20:1 indicates uremia
(azotemia), possibly due to dehydration. This situation often
responds to extensive rehydration by intravenous uids.
Patients exhibiting ratios of 10:1 are less likely to improve
following intravenous rehydration, and almost certainly will
require hemodialysis (Hauger et al., 1990).
3. An ECG should also be carried out to check heart block, T wave
inversion and ST segment changes (Canan et al., 2008).
9.3. Treatment of an overdose and intoxication
There is no known antidote for lithium. The aims of treatment
should actually focus on two axes, these being: rst, to decrease
the serum lithium concentration, and second, to correct the uid
and electrolyte imbalance to prevent the sequels of potential
chronic neurological complications caused by toxicity (Meltzer
and Steinlauf, 2002).
9.4. Steps in resuscitation and treatment
1. Airway: should be assessed and protected accordingly (if
necessary).
2. Gastrointestinal decontamination
A: ipecac syrup (emetic) or gastric lavage (Hall et al.,
1979). In cases of acute toxication (2 h or less) deconta-
mination should be performed as quickly as possible. The
use of ipecac should be avoided in cases of CNS depres-
sion, or impending CNS depression, caused by the con-
comitant use of drugs (coingestants).
B: activated charcoal should be used even though it will
not absorb lithium (Hall et al., 1979). It may help,
however, by removing other possible toxic coingestants.
C: whole bowel irrigation with a balanced electrolyte
uid, such as polyethylene glycol (PEG) solution, until
the rectal efuent is clear. This could be useful in over-
dose cases caused by sustained-release preparations
(Bretaudeau Deguigne et al., 2013). 2 L/h in adults and
500 ml/h in children is recommended.
3. Fluids: lithium poisoning causes water depletion and electro-
lyte imbalance. Hydration (0.9% saline) is needed to improve
the impaired renal function. Several liters of isotonic uid
might be needed for severely water-depleted patients
(Boltan and Fenves, 2008). A change to one half-normal saline
should be evaluated once the initial stage of rehydration is
470 R. Oruch et al. / European Journal of Pharmacology 740 (2014) 464473
accomplished. In patients with impaired renal function hemo-
dialysis should be considered as an early measure of treatment.
4. Diuretics: hydrochlorothiazide and loop diuretics (frusemide)
should be avoided because these diuretics may aggravate
dehydration and sodium depletion, which is likely to increase
lithium retention even further (Juurlink et al., 2004).
Osmotic diuretics (such as mannitol), carbonic anhydrase
inhibitors (like acetazolamide) and phosphodiesterase inhibi-
tors (e.g., theophylline) increase lithium secretion, but they can
also cause water depletion in such a way they can actually
worsen the degree of intoxication (Finley et al., 1995).
5. Hemodialysis
Why do we perform hemodialysis? The aims are as follows:
rst, to shorten the exposure of different tissues of the body to
the elevated lithium concentration, second, to lower the serum
lithium levels to below 1.0 mmol/l.
Before performing this aggressive technique both the labora-
tory data and the clinical condition of the individual should
be evaluated. Patients with severe dehydration should rst
be resuscitated with intravenous uid, and, if they improve
clinically, then they might not require hemodialysis.
According to (Mohandas and Rajmohan, 2007), the candidates
for hemodialysis should be considered according to the following
criteria:
I. Compromized renal function, this also includes the elderly
whose GFR is already decreased.
II. Patients with severe (irreversible) neurological symptoms,
such as hyperreexia and clonus have clear indications for
hemodialysis.
III. The serum lithium level is also a good guide-line regarding
dialysis, but the clinical condition of the patients must still be
taken into consideration.
In acute ingestion, hemodialysis should be considered when
the symptoms are clear and serum lithium levels are above
4.0 mmol/l.
In chronic toxicities, hemodialysis is performed when lithium
levels exceed the therapeutic values with a clearly manifested
clinical picture. The duration of hemodialysis recommended
by most nephrologists is a 36 h run. Prolonged periods of
812 h, however, may sometimes be necessary and useful.
Clinicians should take into consideration the rebound effect after
the equilibrium is reached between the intra and extracellular
compartments.
Clinical recovery may not occur in a linear fashion when using
hemodialysis, because it might lag behind the decreased lithium
level due to the extensive compartmentalization of lithium in the
brain tissues. Continuous arteriovenous blood ltration has proved
to be successful, though the experience with this modality is
limited. Peritoneal dialysis has proved to be ineffective.
9.5. Hospital admission and duration
Asymptomatic patients, 46 h post-ingestion, with normal
serum lithium levels can leave the intensive care unit (hospital),
this applies to the users of regular release lithium preparations.
Patients who have ingested sustained release tablets might need
to be hospitalized for longer periods. Cases of chronic intoxication
should be admitted to a psychiatric hospital such that the lithium
doses can be readjusted.
10. Discussion
The state of our knowledge reviewed here indicates that there
is no radical medicinal treatment for BD. All we actually have at
hand are palliative measures that only treat the symptoms/signs of
the disease and not the cause. The worst scenario concerning
psychiatric diseases is the fact that these ailments are inherited,
with different genes playing pivotal roles in the etiology. Advanced
paternal age has been linked to this, representing a factor that is
consistent with increased new genetic mutation (DOnofrio et al.,
2014; Frans et al., 2008). These genetic factors are usually triggered
by causative environmental events that hand in hand obviate the
classical clinical picture of BD. These include childhood adversity
and highly conictual families. It was an accidental event that led
psychiatrists to the nding that lithium can be used in the
treatment of BD, as has been stated elsewhere in this review. But
what makes lithium different from other monovalent cations (e.g.
Na ) in order to exert this mood stabilizing effect? We do not have
a convincing answer to this question. In this review we have listed
all known available theories/postulations and scientic facts con-
cerning how lithium exerts its effects at the cellular level. Another
issue we have to consider is the 9 postulates mentioned under the
subtopic mechanism of lithium action: are they actually therapeu-
tic functions or are they the reason behind the wide spectrum of
side effects that lithium can cause? This is a difcult question to
answer.
Lithium, antipsychotics and anticonvulsants are actually drugs
that belong to three different categories, used to treat different
neuropsychiatric diseases. What makes these three different
groups of drugs benecial in treatment of BD? The fact is that
we do not know exactly what they do separately as in mono-
therapy or together as in polypharmacy, with respect to affecting
the neurons of the CNS. The 9 postulates cited above by which
lithium is believed to function as a mood stabilizer are accepted in
one way or another only because we do not know exactly what is
the real pathophysiology behind BD. The majority of these have
only become known during the course of the last decade. The vast
majority of studies in this era were conducted to identify the
neuroprotective and neurotrophic effects of this element. Lithium
nave BD patients can exhibit reduced cerebral and hippocampal
brain sizes in comparison to normal control individuals (Hajek
et al., 2012), a nding shared by other psychiatric disorders such as
major depressive disorder (Ota et al., 2014). As stated above, a
genetic factor is the corner stone of the etiology. We cannot
manipulate the genes present in the chromatin of neuronal nuclei.
However, it may be possible to do something at the level of the
neuronal membrane. In addition to psychotherapy and medica-
tions belonging to different classes, we should seriously consider
the potential role of dietary poly unsaturated fatty acids (PUFAs)
which can be readily obtained from sh, olives and different leafy
vegetables. It is highly likely that through PUFAs one can achieve a
sound and integrated neuronal membrane, enabling drugs to have
a more selective, and thus a more potent effect, on the neuronal
receptors (Oruch et al., 2011).
All in all, lithium is in fact the best agent available, currently being
the mood stabilizing drug of choice to treat and prevent manic and
depressive attacks occurring in BD (Calkin and Alda, 2012; Mohandas
and Rajmohan, 2007; Timmer and Sands, 1999; Vieta and Valenti,
2013; Young and Hammond, 2007). The choice of medicinal therapy
for treating any psychiatric disease is monotherapy, that is using one
drug, but in fact this is often inapplicable in BD. Monotherapy is often
not sufciently effective for acute and/or maintenance therapy, thus
many psychiatrists prefer to prescribe combination remedies.
A combination therapy (polypharmacy) is superior to monotherapy
especially in the manic phase of BD, particularly in terms of potency
and prevention of relapse (Geoffroy et al., 2012).
 R. Oruch et al. / European Journal of Pharmacology 740 (2014) 464473
It is a fact that during the last decade the number of pharma-
cological agents available for treating patients with BD has
increased signicantly. Some psychiatrists believe it may be best
to treat BD by agents other than lithium. However, we have to
admit that lithium continues to be the most effective and best-
tolerated treatment option for many patients. Thus psychiatrists
should continue to include this efcacious mode of treatment in
their armamentarium when confronted with the BD disorder.
Lithium is different to other drugs in this context because it can
restore the reduced brain volume seen in BD individuals to
normal. The volumetric reduction of brain size is frequently found
in lithium nave BD individuals (Hallahan et al., 2011). As stated
above, anticonvulsants and other antipsychotic agents mentioned
elsewhere in this review are also accessory agents that are useful
in treatment by polypharmacy. In other words any combination of
psychotropic drugs usually includes one or another type of lithium
salt. It is worth mentioning that there are some general measures
which might help to prevent/reduce the frequency of occurrence
of depressive episodes including healthy balanced nutrition, train-
ing in the form of regular moderate exercise, reducing stress both
at home and work as much as possible, allocating a enough time
for sleep, and avoiding alcohol and illegal drugs (psychedelics,
stimulants). A convincing radical medicinal treatment for curing
BD is currently unavailable, and will almost certainly not become
so until a complete understanding of the real pathophysiology of
this ailment has been accomplished. In order to achieve this goal
concentrated efforts of neuropsychiatric scientists, psychotropic
drug designers, and experts in bioassay will be required, and in
addition, economic funds and international willpower (e.g. by
WHO) will be required.
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