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Lithium: Clinical

uses & adverse


effects
Dr. Manu Sharma
Chairperson: Dr. V. K. Bhat

History
A report appeared in 1800 describing the discovery

of two new minerals, petalite and spodumene, on


the island of Ut near Stockholm, Sweden.
1817: Johan Arfwedson discovered a new alkali
that was named lithion by Jons Jacob Berzelius, his
laboratory chief.
1818: Humphrey Davy was the first to isolate
lithium metal.
In 1843 Alexander Ure showed in vitro that a uric
acid bladder stone lost weight in a lithium
carbonate solution.

History
From the late 1880s through the early 1900s,

lithium was embraced by the general public in


the form of mineral spring waters.

History
Lithium tabs: weakness and tremor in patients

was reported in 1898 and diarrhea, vomiting,


and death were described in animals in 1903.
1948: 25% solution of lithium chloride for use
as a salt substitute in patients on low-sodium
diets, the dangers were not appreciated.
By 1949, however, reports of severe lithium
intoxication and death resulted in the removal
of lithium products ---delayed acceptance of
lithium by American psychiatry for many years.

John F. J. Cade, an Australian psychiatrist, was

observing its antimanic effect.


Mogens Schou and others firmly established
the effectiveness of lithium for mania and for
the prophylactic treatment of manicdepressive disorder.
1970: U.S. FDA approved its labeling for the
treatment of mania.
1974: for maintenance therapy in patients
with a history of mania.

History
Lithium is regarded as old news & less

appealing to researchers.
Pharmaceutical companies were reluctant to
produce this inexpensive drug that they
couldnt patent.

Pharmacokinetics &
Disposition
Lithium carbonate tabs & capsules, Lithium

citrate & SR forms.


Minimally protein bound.
Evenly distributed in total body water space.
Absorbed well from GIT, excreted unchanged
in urine.
Peak plasma concn: 1 to 2 hrs (4-5 hrs with
SR)
Brain levels: highest within 2 hrs of peak
plasma concn.
Steady state concn: 4-5 days

Mechanism of action
Inositol depletion
Glycogen-synthase kinase inhibition
Effects on neurotransmitter systems
Circadian rythms

Therapeutic indications
Bipolar Disorder
Mania
Lithium is accepted universally as an
antimanic drug with effectiveness greater
than placebo.
Its onset of action is relatively slow, with
clinical improvement usually occurring over
the first 1 to 3 weeks of treatment.
oral lithium loading: 20mg/kg/day (Keck et
al. 2001)

Not all patients with acute mania respond

equally well to lithium. 79%


Less success when dealing with patients with:
mixed or dysphoric mania,
many prior episodes,
poor inter-episode functioning
rapid cycling,
comorbid substance abuse,
comorbid personality disorder,
organicity.
Whether another medication would be
preferable to has not been established in welldesigned studies.

Therapeutic indications
Lithium vs antipsychotics
To date there is no obvious effect-size
difference between any antipsychotic & Li.
Lithium vs. CCB
Li appears to be superior to verapamil.
Lithium vs. ECT
ECT>Li in first 8 weeks. After 8 weeks-no
difference

Therapeutic indications
Lithium vs. anticonvulsants
Li, CBZ, divalproex- equal efficacy
Anticonvulsants better tolerated than Li.
Neurological abnormalities may predict a
better response to anticonvulsants.
Pts with EEG abnormalities respond better to
valproate. (Reeves et al. 2001)
Lamotrigine= Li in acute mania (Ichim et al.
2000)

Therapeutic indications
Dosing
Therapeutic plasma concentrations (sampled
12 hr after the last dose) between 0.8 and 1.2
mEq/L.
Lithium carbonate 300 mg four times daily
with trough plasma level determination on
Day 4 or Day 5.
Watching for any signs of toxicity.
A lower starting dose and slower titration in
older patients & those impaired renal function.

Therapeutic indications
Bipolar Depression
Not FDA approved for the acute treatment of
bipolar depressive episodes.
Sufficient research to support its effectiveness
as a first-line choice either alone or for more
severe depressions in combination with an
antidepressant or another medication.
APA (2002): 1st line Rx with Li or Lamotrigine.

Therapeutic indications
Suicide: is Lithium protective?
Fewer pts attempted or committed suicide
while they were on Li. (Tondo et al, 2001;
Baldessarini et al, 2006)
Methodological problems exist in studies

(Gelenberg 2001)

Therapeutic indications
Maintenance therapy
Just exactly when to begin long-term lithium
treatment has not been fully resolved.
Early initiation of maintenance therapy may
benefit many patients at the expense of some
patients being treated unnecessarily.

Therapeutic indications
Factors associated with response to Lithium:
Psychotic Sx during manic episode- good
response.
Pattern of mania-depression-euthymia: good
response.
Poor response within first 6 months
More severe episodes
Poor response
Manic episodes> Depressive episodes
Unmarried, psychosocial stressors

Therapeutic indications
The maximum benefits of lithium

maintenance may not be immediate; with


continued treatment, relapses sometimes
become less severe and less frequent.
Some patients appear to develop a tolerance
to lithium after several years of successful
use.
Following discontinuation of successful lithium
therapy, the risk of recurrence increases by 23
times.

Therapeutic indications
Lithium-discontinuationinduced
refractoriness
Some patients, who had responded well to
lithium prophylaxis may not respond again
when lithium is reintroduced after a failed
discontinuation trial.
15%
A decision to discontinue successful lithium
maintenance should not be taken lightly, but
rather must be weighed carefully against the
continued risk of adverse effects and toxicity.

Therapeutic indications
Dosing
Levels between 0.6 and 0.8 mEq/L are often
recommended for bipolar I maintenance.
Substantial variations in brain Li levels among
individuals with similar serum levels.
Once-daily bedtime dosing yields higher
brain-to-serum ratios than twice daily doses
(Soares et al. 2001)

Therapeutic indications
Unipolar Depression
The major value of lithium in major depressive
disorder patients with acute depression is as an
augmenting agent when antidepressants alone have
been ineffective.
About 50% of patients respond when lithium is added
to a wide variety of antidepressant drugs.
Benefit has been reported with most antidepressants,
but evidence is most convincing with TCADs.
When effective, augmentation should be maintained
for at least 12 months.

Therapeutic indications
Schizoaffective disorder & Schizophrenia
In general, the less affective and the more
schizophrenic an illness is, the less likely it is to
respond to lithium.
The same cannot be said of an episode because
the acute manifestations of mania and
schizophrenia may be indistinguishable.
Lithium is generally accepted to be of value,
especially in combination with antipsychotic
drugs, and especially if the affective component
is prominent.

Therapeutic indications
A 2007 Cochrane Collaboration review

concluded: there is no evidence that lithium


on its own is effective for people with
schizophrenia or schizoaffective disorder.
There is some evidence for the effectiveness
of lithium as an adjunctive treatment to
antipsychotic drugs, but this result was
inconclusive.

Therapeutic indications
Aggression & Impulsivity
Li reduced the frequency of aggressive & selfmutilative episodes in pts with intellectual
disability.
Controlled studies have found reduced
aggression in subjects recruited from prison
populations.
Countries with higher Li levels in drinking
water had lower rates of suicide, homicide,
rape (Schrauzer & Shrestha 1990)

Therapeutic indications
Decreases impulsive gambling.
Li has not been used extensively to treat

aggression associated with head trauma or


epilepsy, and the results have been mixed.
No work has been done to evaluate the effect
of lithium in intermittent explosive disorder.

Therapeutic indications
Personality Disorders
In pts with emotionally unstable personality
disorders with mood swings and chronically
maladaptive behavior.
5 cases of BPD showed clinical improvement
(LaWall & Wesselius, 1982)
When favorable outcomes do occur, it is likely
that a comorbid mood disorder has responded
followed by indirect improvement in
personality.

Therapeutic indications
Alcohol use disorders
The close association between mood
disorders and alcohol-use disorders and in
part on animal research that found reduced
alcohol intake in rodents receiving lithium.
Efforts to establish lithium as a useful
treatment for alcoholism have been largely
unsuccessful.

Therapeutic indications
Anxiety Disorders
PTSD (Forster et al. 1995)
Refractory panic disorder (Feder 1988)
Refractory OCD (Golden et al. 1988)

Use in special
populations
Children & Adolescents
FDA approved for bipolar disorder in 12 yrs and above.
The range of serum lithium concentrations in
adolescents is similar to that in adults (although its
elimination half-life may be shorter)
The likelihood of responding appears the same.
The adverse effect profile of lithium is also the same
across age groups.
Cognitive dulling induced by therapeutic amounts of
lithium may impact negatively on academic
performance.

Use in special
populations
When and if to begin long-term lithium

therapy is an even more difficult decision


when treating young patients than when
treating adults.
The markedly disruptive effects of episodes in
youth and the highly recurrent nature of
bipolar disorder. (Risk vs. Benefit)

Use in special
populations
Elderly patients
Advanced age alone does not compromise
responsiveness to lithium.
Use of lithium in the elderly is complicated by
associated medical illnesses and medications,
special diets,
age-related reduction in GFR, and
increased sensitivity to adverse effects.

Use in special
populations
Whether the elderly as a group respond to

lower serum concentrations of Li than do their


younger counterparts is not known.
The elderly should be started on lower-thanusual dosages, with dosage changes occurring
less frequently than in younger patients.
The elimination t of Li increases with age,
and the time required to reach steady state is
much longer in the elderly.
If Li is stopped, serum levels fall more slowly
and the resolution of adverse effects and
toxicity may be prolonged.

Use in special
populations
With appropriate monitoring and compliant

patients, Li use in the elderly can be both safe


and effective.
There continues to be a lack of randomized
controlled studies of any medication in elderly
bipolar patients.
Whether the putative neuroprotective effects
of Li would have practical utility in this
population remains open to question.

Use in special
populations
Pregnancy & Lactation
Lithium is in FDA pregnancy category D.
Physiological changes accompanying pregnancy
alter maternal lithium metabolism:
The GFR increases 30 to 50% over baseline
Plasma volume increases by 50%.
The filtered sodium load increases markedly,
as does the renal tubular reabsorption.
Polyhydramnios : lithium-induced fetal
polyuria.

Use in special
populations
Fetal and maternal blood concentrations are

similar, so women should receive minimum


effective dosages.
To reduce the risk of toxicity in the newborn,
clinicians should markedly reduce or possibly
temporarily discontinue the drug shortly
before delivery.
Reduction rather than discontinuation may be
more appropriate as delivery approaches.

Use in special
populations
The American Academy of Pediatrics

Committee on Drugs feels that lithium should


be used with caution in nursing mothers.
One study of ten breastfeeding infants found
infant serum levels to average 0.16 mEq/L
(range 0.05 to 0.23).
The merits of breastfeeding are considerable,
and actual reports of infant Li toxicity are
limited to one or two cases; consequently, in
some situations the benefits may outweigh
the risks.

Use in special
populations
The incidence of Ebstein's anomaly is

between 1 and 2 per 1,000 which is 10 to 20


times greater than in the general population).
Teratogenic risk: Li>Valproate> CBZ.
Fetal echocardiography is advised to screen
for cardiovascular malformations in women
exposed to lithium during the first trimester of
pregnancy.

Use in special
populations
Medical comorbidity
Untreated or inadequately treated mania or
depression can adversely affect a medical
illness.
Decreased treatment adherence.
Li may be more difficult or impossible to use
in the presence of a medical illness.
Risk of adverse drug interactions is increased.

Adverse effects &


Toxicology
Fewer than 20 percent of patients have no

adverse effects.
Only about 30 percent have more than minor
complaints.
Recognizing and minimizing adverse effects
can do much to enhance compliance with
lithium treatment.

Adverse effects &


Toxicology
Laboratory monitoring
APA practice guidelines:
Medical history
Serum urea & creatinine
TFTs
ECG (in pts >40 yrs)
RFT should be assessed every 2-3 months
TFTs every once in 2 months during first 6
months.
Then, RFT & TFT once every 6-12 months.

Adverse effects &


Toxicology
Neurological reactions
Dysphoria, lack of spontaneity, slow reaction
times, intellectual inefficiency, and spotty
impairment of memory.
Other causes of these complaints:
Breakthrough depression, lithium-induced
hypothyroidism or hypercalcemia, other
illnesses, and other drugs.

Adverse effects &


Toxicology
Tremor
Benign postural tremor with a frequency of 8
to 12 Hz in the hands.
4%-65% pts.
It worsens during activities requiring fine
motor control, it can be socially embarrassing
and occupationally troublesome.
It decreases with time.

Adverse effects &


Toxicology
A worsening of tremor at any time during the

course of lithium therapy may be an indication


of impending lithium intoxication, and severe
tremor should be considered due to
lithium toxicity until proven otherwise.
A nontoxic tremor often improves
spontaneously, but if it does not:
dose reduction,
use of a slow-release lithium preparation,
elimination of dietary caffeine,
discontinuation of other medications, and
treatment of associated anxiety.

Adverse effects &


Toxicology
Medications useful in treating lithium tremor:
-adrenergic receptor antagonists such as
propranolol, as well as primidone, and
possibly gabapentin.
With long-term lithium therapy, a tremor with
parkinsonian characteristics may occur
occasionally.
Delirium: Li + Haloperidol

Adverse effects &


Toxicology
Other Nontoxic Effects
rarely peripheral neuropathy,
downbeat nystagmus,
benign intracranial hypertension
(pseudotumor cerebri),
a myasthenia gravislike syndrome, and
lowering of the seizure threshold.
Creativity has been variously enhanced,
impaired, and unaltered by lithium therapy.

Lithium Intoxication
Primarily a neurotoxicity.
Cardiovascular, gastrointestinal, and renal

manifestations may also be present.


Factors associated with toxicity:
excessive intake (accidental or deliberate),
reduced excretion, kidney disease,
low-sodium diet,
drug interaction,
reduced volume of distribution (dehydration),
and
individual sensitivity (the elderly and the
organically impaired).

Adverse effects &


Toxicology
There is no well-demarcated serum lithium

concentration below which intoxication never


occurs and above which it is inevitable.

Mild to moderate intoxication (lithium level =

1.5 to 2.0 mEq/L)


GI

Vomiting
Abdominal pain
Dryness of mouth

Neurologic

Ataxia
Dizziness
Slurred speech
Nystagmus
Lethargy or excitement
Muscle weakness

Moderate to severe intoxication (lithium level

= 2.0 to 2.5 mEq/L)


GI

Anorexia
Persistent nausea and vomiting

Neurologic

Blurred vision
Muscle fasciculations
Clonic limb movements
Hyperactive deep tendon reflexes
Choreoathetoid movements
Convulsions
Delirium
Syncope
Electroencephalographic changes
Stupor
Coma
Circulatory failure (lowered BP, cardiac
arrhythmias, and conduction abnormalities)

Severe lithium intoxication (lithium level >2.5


mEq/L)
Generalized convulsions
Oliguria and renal failure
Death

Adverse effects &


Toxicology
Management
Stop Li immediately.
Serum Li levels and RFT
After an overdose, gastric lavage is indicated
and may have to be repeated.
Polystyrene sulfonate (Kayexalate), a cation
exchange resin, or whole bowel irrigation with
polyethylene glycol solution (GoLYTELY).

Adverse effects &


Toxicology
In the presence of normal renal function, mild

to moderate toxicity often responds to


correcting dehydration and maintaining
proper fluid and electrolyte balance.
Whether forced diuresis provides additional
benefit is open to debate.
Hemodialysis is the treatment of choice for
severe intoxication (peritoneal dialysis is
considerably less efficient).

Adverse effects &


Toxicology
Redistribution of lithium from tissues to blood

after dialysis usually results in a rebound


increase in its blood level; this may
necessitate further dialysis.
Hemodialfiltration has also been used,
sometimes in conjunction with hemodialysis to
minimize the likelihood of rebound.

Adverse effects &


Toxicology
Thyroid Reactions
Li impedes the release of hormone from the
gland.
Women with preexisting thyroid dysfunction
and those from iodine deficient areas, are
more than usually susceptible.
Clinical hypothyroidism occurs in at least 4
percent of patients taking lithium.
Subclinical hypothyroidism is more common.
Issues with subclinical hypothyroidism

Adverse effects &


Toxicology
Exophthalmos and hyperthyroidism have

been described during lithium therapy.


Lithium-induced silent thyroiditis as a
potential cause of thyrotoxicosis.

Adverse effects &


Toxicology
Cardiovascular Reactions
Benign, reversible T-wave changes.
AV block has been reported.
Bradyarrythmia, T wave inversion, QTc
prolongation.
Not C/I in pts with cardiovascular disease.
Keep in mind drug interactions.
Monitor PR & ECG in >50 yrs. Risk of SA node
dysfunction.

Adverse effects &


Toxicology
Renal Reactions
Li impairs renal concentrating ability, which in
itself is of no clinical importance.
A nonspecific interstitial fibrosis, although a
lithium-distinctive microcystic lesion has also
been described.
A major issue that has still not been resolved
fully is the extent to which nontoxic use of
lithium is associated with renal insufficiency.
Progression of renal insufficiency has been
described despite discontinuation of lithium.

Adverse effects &


Toxicology
After correcting for age, one study of 142

patients on lithium for a minimum of 15 years


found reduced GFR in 21 % and increased
serum creatinine in 12 %. (Creatinine creep)
Polyuria is the most clinically troublesome
renal effect of lithium.
As many as 35% of patients taking lithium.
Leads to insomnia, weight gain, poor
nutrition, and noncompliance; and potentially
dangerous if dehydration occurs.

Adverse effects &


Toxicology
adequate fluid replacement,
using the lowest effective dosage,
and counteractive medications such as

thiazides or potassium sparing diuretics, or


indomethacin.
inositol, potassium supplementation, and
desmopressin.
Polyuria does not always resolve following
discontinuation of lithium.

Other Reactions
Weight gain
May be due to the drug's complex effects on
carbohydrate metabolism.
Other possible causes include lithium-induced
hypothyroidism, fluid retention, and increased
caloric intake from thirst-quenching beverages.
Gastrointestinal adverse effects- may portend
impending lithium intoxication.
Granulocytosis (Neutrophilia), thrombocytosis.
Hypercalcemia and hyperparathyroidism.
Sexual dysfunction: decreased libido and
erectile difficulties.

Adverse effects &


Toxicology
Dermatological adverse effects:
the first occurrence or worsening of acne,
psoriasis, and
follicular keratosis,
scattered reports of rashes of various types,
and hair loss (only occasionally related to
lithium-induced hypothyroidism).

Administration & Dosing


Lithium Preparations Available
Lithium carbonate capsules 150, 300, 600 mg
Lithium carbonate tablets 300 mg
Lithium carbonate controlled-release tablets
450 mg
Lithium carbonate slow-release tablets 300
mg
Lithium citrate syrup 8 mEq/5 mL

Administration & Dosing


Both 300 mg of the carbonate and 5 mL of the

citrate contain about 8 mEq (mmol) of lithium.


Lithium acetate, glutamate, gluconate,
orotate, and sulphate preparations have been
available or are currently available.
Clinicians should be aware the lithium
and lithium carbonate are not
interchangeable (300 mg of lithium is
equivalent to 1,597 mg of lithium carbonate).

Dosing
Lithium therapy is initiated in divided doses.
Once a patient is stabilized, single daily
dosing is sometimes more convenient.
In the presence of normal kidney function, a
total daily dose of 1,200 to 1,800 mg of
lithium carbonate generally produces an
antimanic serum concentration of 0.8 to 1.2
mEq/L.
Maintenance levels of 0.6 to 1 mEq/L can
usually be attained with 900 to 1,200 mg daily.
In general, a conservatively low dose is started,
perhaps 300 mg two or three times daily, a
serum concentration is obtained after steady

Non-psychiatric uses
Neurological
Epilepsy
Headache (chronic cluster, hypnic, migraine,

particularly cyclic)
Mnire's disease (not supported by controlled
studies)
Huntington's disease
Levodopa-induced hyperkinesias
On-off phenomenon in Parkinson's disease

Non-psychiatric uses
Spasmodic torticollis
Tardive dyskinesia (not supported by

controlled studies, and pseudo-parkinsonism


has been reported)
Tourette's disorder
Pain (facial pain syndrome, painful shoulder
syndrome, fibromyalgia)
Periodic paralysis (hypokalemic and
hypermagnesic but not hyperkalemic)

Non-psychiatric uses
Hematological
Aplastic anemia
Cancerchemotherapy-induced and radiotherapy-

induced neutropenia
Drug-induced neutropenia (e.g., from
carbamazepine, antipsychotics,
immunosuppressives, and zidovudine)
Felty's syndrome
Leukemia
Endocrine
Thyroid cancer, as adjunct to radioactive iodine
Thyrotoxicosis
SIADH
Cardiovascular

Non-psychiatric uses
Dermatological
Genital herpes (controlled studies support

topical and oral use)


Eczematoid dermatitis
Seborrheic dermatitis (controlled studies
support)

Gastrointestinal
Cyclic vomiting
Gastric ulcers
Ulcerative colitis

Non-psychiatric uses
Respiratory
Asthma (controlled study did not support)
Cystic fibrosis
Other
Bovine spastic paresis

Psychiatric uses

Historical
Gouty mania

Well established (FDA-approved)

Manic episode
Bipolar maintenance therapy
Reasonably well established
Bipolar disorder

Depressive episode

Bipolar II disorder

Rapid-cycling bipolar I disorder

Cyclothymic disorder
Major depressive disorder
Acute depression (as an augmenting agent)
Maintenance therapy
Schizoaffective disorder

Evidence of benefit in particular groups


Schizophrenia
Aggression (episodic), explosive behavior, and selfmutilation
Conduct disorder in children and adolescents
Mental retardation
Prisoners

Anecdotal, controversial, unresolved, or doubtful


Alcohol and other substance-related disorders
Cocaine abuse
Substance-induced mood disorder with manic features

Anxiety disorders
Obsessive-compulsive disorder
Phobias
Posttraumatic stress disorder

Attention-deficit/hyperactivity disorder
Eating disorders
Anorexia nervosa
Bulimia nervosa

Impulse-control disorders
Mental disorders due to a GMC(e.g., mood

disorder due to a general medical condition


with manic features)
Periodic catatonia
Periodic hypersomnia

Personality disorders (e.g., antisocial, borderline,

emotionally unstable, schizotypal)


Premenstrual dysphoric disorder
Sexual disorders
Transvestic fetishism
Exhibitionism
Pathological hypersexuality

THANK YOU

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