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History
A report appeared in 1800 describing the discovery
History
From the late 1880s through the early 1900s,
History
Lithium tabs: weakness and tremor in patients
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
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)
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
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
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
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
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
Use in special
populations
With appropriate monitoring and compliant
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
Use in special
populations
The American Academy of Pediatrics
Use in special
populations
The incidence of Ebstein's anomaly is
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.
Only about 30 percent have more than minor
complaints.
Recognizing and minimizing adverse effects
can do much to enhance compliance with
lithium treatment.
Lithium Intoxication
Primarily a neurotoxicity.
Cardiovascular, gastrointestinal, and renal
Vomiting
Abdominal pain
Dryness of mouth
Neurologic
Ataxia
Dizziness
Slurred speech
Nystagmus
Lethargy or excitement
Muscle weakness
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)
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.
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
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
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
Manic episode
Bipolar maintenance therapy
Reasonably well established
Bipolar disorder
Depressive episode
Bipolar II disorder
Cyclothymic disorder
Major depressive disorder
Acute depression (as an augmenting agent)
Maintenance therapy
Schizoaffective disorder
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
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