Dr Mohd Osman Ali
Scheme of Presentation
• Chemistry and Pharmacokinetics
• Therapeutic indications
• Adverse reactions and Intoxication
• Drug interactions
• Lab monitoring
• Dosage and administration
• Distribution and metabolism
• The elimination half-life
• It is a member of the group IA alkaline
metals together with sodium, potassium,
rubidium, cesium, and francium.
• Lithium follows hydrogen and helium on the
– making it the third simplest element(atomic
number 3, atomic weight 6.94)
– and the first solid element.
IN NORMAL HUMAN BEINGS
• Trace amounts of lithium are present in food
and water and hence in all living tissue.
• Whether lithium is essential to normal
human growth and development has not
been established, and there is no evidence of
a lithium deficiency state in humans.
• Experimentally produced lithium deficiency
in goats and rats led to reduced fertility,
retarded development, and reduced
• completely absorbed
• serum concentrations peaking
– in 1 to 1.5 hours with standard preparations
– and in 4 to 4.5 hours with the slow and controlled-release
• Equilibrium is reached after 5 to 7 days of
Distribution and Metabolism
•NO clinically important
THE RATE AND EXTENT OF ENTRY INTO TISSUES
• thyroid and renal concentrations exceed
serum level, whereas red blood cell, spinal fluid, and
brain concentrations do not.
• Lithium enters and leaves the central nervous
system (CNS) or crosses BBB slowly,which
– why acute overdoses with relatively high blood
levels are sometimes well tolerated
– why clinical manifestations of chronic
intoxications often persist long after blood levels
have decreased substantially.
The Elimination Half-life
• about 18 to 24 hours
• Age of the patient considerably longer in the elderly
because of the age-related decrease in GFR (and
correspondingly shorter in youth for the opposite
• Duration of treatment half-life as evidenced by a
small study that found it to be 1.3 days in those just
starting treatment but 2.4 days in those treated for
over a year.
• Obesity based on the observation that clearance
was almost 50 percent higher in obese subjects
than in normal-weight volunteers.
• almost entirely by the kidneys
– although small amounts are also lost in sweat
• A substantial amount of filtered lithium is
reabsorbed (primarily in the proximal
– so that renal lithium clearance is about one fifth
of creatinine clearance
• Excretion is complex during pregnancy,excretion increases
during pregnancy but decreases after delivery
In an overview of possible mechanisms of action,
Robert Lenox and Chang-Gyu Hahn concluded:
“We are currently still at the stage of
identifying the pieces of the lithium puzzle;
within the next 50 years, we will be putting
the puzzle together”
???? LITHIUM DEFICIENCY
•NOT the cause of bipolar
• The amounts required for its mood stabilizing
effects exceed the trace amounts normally
present in the body by about 100-fold.
• extremely difficult to ascertain the key
mechanism of action of lithium in regulating
– The ubiquitous nature of sodium in the
humanbody, and its involvement in a wide range
of biological process,
– and the potential for lithium to alter these
• Marmol F. lithium; bipolar disorder and neurodegenertive
disease possible cellular mechanism of the therapeutic
effects of lithium. Pro neur psychopharmacol biol psychiatry
• Ion transport theories
• The neurotransmitter arena
• Signal transduction pathways
• Alteration of nuclear transcription
factors and influence of gene
• Bipolarity virus
Ion Transport Theories
PERTURBATION OF SODIUM PUMP
• make use of lithium's similarities to both
monovalent (sodium, potassium) and divalent
(calcium, magnesium) cations
• neuronal transmembrane potential differences are
maintained by the Na, K-ATPase pump (also known
as the sodium pump),
• perturbations of this system are felt to cause
neurotransmitter aberrations that translate into
mania and depression.
MEMBRANE STABILISING ACTION
• Because lithium crosses cell membranes by
four independent mechanisms (sodium
pump, sodium leak channel, sodium-lithium
countertransport, and lithium-bicarbonate
• Synapse-specific accumulation of lithium has
been demonstrated in intracellular
The Neurotransmitter Arena
• Early investigations focused undue
optimism on the fashionable
acetylcholine, γ-aminobutyric acid
[GABA]) and found that lithium had
diverse effects on them all.
• Recent studies have implicated glutamatergic
excitotoxicity in the pathophysiology of bipolar
disorder, especially mania.
MODULATION OF NMDA AND AMPA RECEPTORS
• Some, but not all, research findings suggest that
lithium's antimanic effect might be related to
modulation of N-methyl-D-aspartate (NMDA) or
acid (AMPA) receptors
Signal Transduction Pathways
POSTTRANSLATIONAL MODIFICATIONS OF G PROTEINS
• there is evidence suggesting that “the effects of
chronic lithium may in part be mediated through
posttranslational modifications of G proteins that
affect its coupling to receptor and/or second
• Both the phosphoinositide and adenylyl cyclase
second-messenger systems are altered by lithium in
many ways.The activity of lithium in the adenylyl cyclase
second messenger system has generated a bimodal theory
to explain its action
THE INOSITOL DEPLETION HYPOTHESIS
• based on lithium's potent inhibition of
inositol monophosphatase, leading to
intracellular inositol depletion,
• has been difficult to validate
REDUCED HIPPOCAMPAL EXPRESSION OF PKC
• work done by Husseini Manji, Robert Lenox,
and others found reduced hippocampal cell
expression of two isozymes of PKC as well as
a substrate of PKC known as myristoylated
alanine-rich C kinase substrate (MARCKS)
• effects shared with valproate
Alteration of Nuclear Transcription
Factors and Influence of Gene Expression.
THE DNA BINDING ACTIVITY OF ACTIVATOR PROTEIN-1
• was increased by chronic lithium treatment,
• as were protein levels of immediate-early
genes, c-Fos and c-Jun
• similar effects were also found with
INHIBITION OF GLYCOGEN SYNTHASE KINASE-3 (GSK3)
• a protein kinase involved in several signal
• Among its many activities, GSK-3 regulates
phosphorylation of tau,
– the microtubule-associated protein involved in
the paired helical filaments of Alzheimer's
– Perhaps lithium may play a role in the treatment
of that disease by inhibiting abnormal
hyperphosphorylation of tau.
ADDITIONAL REGULATORY FACTORS
• that may play a role in the etiology and
treatment of bipolar disorder include
– brain-derived neurotrophic factor (BDNF),
– extracellular signal-regulated kinase (ERK),
– the neuroprotective protein Bcl-2,
– and other members of the neurotrophin family.
NEUROTROPIC AND NEUROPROTECTIVE ACTIVITY
• Lithium also has both neurotropic and
• Possibly through its effects on NMDA
• that may further extend its spectrum of use
beyond bipolar disorder
• Literature pertaining to possible
neuroprotective effects of lithium reports
largely on either in vitro or animal studies.
The clinical literature is dominated by reports
• Lithium is an effective treatment for two
clinically episodic illnesses; namely genital
herpes simplex and bipolar disorder.It does
have well-documented inhibitory effects on
herpes simplex viral replication
• but whether it also inhibits a yet
unidentified virus that causes bipolar
disorder remains to be determined.
• A more speculative but not implausible theory
• Historical(gouty mania)
• Well established (FDA-approved)
• Reasonably well established
• Evidence of benefit in particular
• Anecdotal, controversial,
unresolved, or doubtful
• Non psychiatric uses
Bipolar Disorders-- Mania
• Currently it is but one of many FDA-approved
drugs for treating manic episodes, but it
continues to be listed among the first
• in rx of mania it is limited by
– Usually takes a week to achieve response and that the coadministration of antipsychotics may increase the risk of
neuroloigical side effects
– Monitoring can be problematic if the pt is uncooperative
ONSET OF ACTION OF ACTION OF LITHIUM
• Its onset of action is relatively slow, with
clinical improvement usually occurring over
the first 1 to 3 weeks of treatment.
• Although a small open study suggested that
oral lithium loading might produce
improvement in a few days, this approach
has yet to be substantiated.
• Instead, the concomitant use of a
benzodiazepine or an antipsychotic drug is
often necessary during the initial phase of
– Among antipsychotics, atypicals have largely
replaced conventionals in terms of preference.
– Since disturbed sleep may ignite or fuel a manic
episode, early treatment of insomnia with a
sedative may be useful.
RESPONSE OF LITHIUM TO ACUTE MANIA
• The response rate of 79 percent in the
initial research trials contrasts
• with findings of less success when
dealing with patients with
–mixed or dysphoric mania,
–comorbid substance abuse,
–or organicity(encephalopathy etc ).
FDA-APPROVED ANTIMANIC ALTERNATIVES
• include divalproex, carbamazepine, aripiprazole,
olanzapine, quetiapine, risperidone , and
ziprasidone. Combining lithium with one of these is
a common practice.
• in the United States, divalproex has become a preferred
initial treatment for dysphoric or true mixed mania).
• The effectiveness of lithium maintenance therapy is far
betterestablished than for any other drug, which may
sometimes weigh infavor of using lithium to treat the initial
Bipolar Disorders– Maintenance
• Long-term treatment does not cure bipolar
• Long-term treatment with lithium is an effective
way to reduce the frequency, severity, and duration
of manic and depressive episodes in patients with
• Lithium was somewhat more effective against
mania than against depression (although some
would debate this).
• Also effective treatment for persons with sever
RESPONSE TO LITHIUM MAINTENANCE
• Treatment response to lithium monotherapy
is usually less than complete, and
supplemental pharmacotherapies are often
necessary either intermittently or
• Nonetheless, there is growing evidence for a
major benefit from long-term lithium
therapy; namely, reduced mortality.
FAVORABLE RESPONSEWork by Paul Grof and
• episodic course with euthymic intervals,
• and the absence of rapid cycling were
the main predictors.
LESS THAN IDEAL RESPONSE factors have been
Mixed or dysphoric mania
rapid cycling (four or more episodes per year),
many prior episodes,
poor interepisode functioning,
an episode pattern of depression-maniaeuthymia,
• comorbid substance abuse
• and comorbid personality disorder.
ANTISUICIDAL EFFECTS OF LITHIUM
• the antisuicidal effect of lithium extends beyond its
mood stabilizing property (the beneficial role of
psychosocial support could also be a contributing
factor). SOP10th -- Reduces incidence by six fold or
• In general, bipolar disorder carries with it an increased risk
of premature death, particularly but not entirely from
• Studies comparing mortality rates in lithium-treated patients
to the general population, to patients following
discontinuation of lithium, and to patients treated with
alternative prophylactic medications all support the
mortality-lowering and suicide-reducing effect of lithium
• Lithium reduced by 80% the risk of both
attempted and completed suicide
– Baldessarini RJ et al. decreased risk of suicides and
attempts during long-term lithium treatment: a metaanalytical review. Bipolar disorder 2006;8:625– 39
• Studies comparing lithium and divalproex
– Goodwin FK et al. suicide risk in bipolar during treatment
with lithium and divalproex. JAMA2003;290: 1467--73
– Coolins JC et al. divalproex, lithium and suicide among
medical patients with bipolar disorder. J affect disorder
• The mechanism of this protective effect is
• In patients with unipolar depression, lithium
also seems to protect against suicide ; the
effect size being similar to that found in
– Guzzetta F et al. lithium reduces suicide risk in
recurrent major depressive disorder. J clin
WHEN TO BEGIN LONG-TERM LITHIUM
• Just exactly when has not been fully resolved,
• although most recommendations suggest earlier
rather than later—possibly after only one episode
of mania and certainly after two.
• There is growing concern that episodes beget
episodes (perhaps a form of kindling or behavioral
sensitization), and that each episode increases the
likelihood of the next and may shorten the interval
to the next; hence, the recent trend toward earlier
initiation of maintenance therapy.
• Obviously, many individual factors must be taken
into consideration, including
and frequency of episodes;
the presence of risk factors;
and attitudes toward medication.
• Early initiation of maintenance therapy may benefit
many patients at the expense of some patients
being treated unnecessarily
• The maximum benefits of lithium maintenance may
not be immediate; with continued treatment,
relapses sometimes become less severe and less
lithium maintenance is almost always indicated after
the second episode of bipolar 1 disorder depression or
And should be considered after first episode for
– For the persons who have family history of bipolar 1 disorder
Others who benefit from lithium maintenance are
– Those who have poor support system
– Had no precipitating factor for the first episode
– Or had a first episode of mania
TOLERANCE TO LITHIUM
• Some patients appear to develop a tolerance
to lithium after several years of successful
• this tolerance can sometimes be overcome by
the addition of divalproex, carbamazepine,
lamotrigine, or an atypical antipsychotic
BREAKTHROUGH DEPRESSION AND MANIA
• Just as breakthrough depression may
respond to a temporary increase in serum
lithium concentration, so too may
DISCONTINUATION OF SUCCESSFUL LITHIUM
• the risk of recurrence increases substantially
• In addition, rapid discontinuation of lithium
appears to be associated with a rebound
phenomenon characterized by increased risk
of early recurrence, especially mania.
• Some patients, approaching 15 percent, who
had responded well to lithium prophylaxis
may not respond again when lithium is
reintroduced after a failed discontinuation
• 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.
reasonably well established
Bipolar II disorder
Rapid-cycling bipolar I disorder
Major depressive disorder
Acute depression (as an augmenting agent)
Bipolar Disorders-- Depression
• Although lithium is not approved by the FDA for the acute
treatment of bipolar depressive episodes (in contrast to
quetiapine and olanzapine/fluoxetine combination
• there is 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
• Therapeutic blood concentrations have not been well
established for the antidepressant effects of lithium but
appear to be in the same general range as for mania.
ROLE OF LAMOTRIGINE
• Recent studies of lamotrigine (Lamictal) have
questioned its effectiveness as monotherapy for
• and the effectiveness of other anticonvulsants such
as carbamazepine, oxcarbazepine (Trileptal), and
divalproex for treating bipolar depression is not
• Since lamotrigine is beneficial for prevention of
recurrent bipolar depression with long-term
treatment, combining it with lithium has
ROLE OF ANTIDEPRESSANTS
• Treating bipolar depression with a conventional
antidepressant alone does not protect against mania and
may even precipitate mania or rapid cycling.
• Consequently, the presence of a mood stabilizer is a
necessity in all but occasional low-risk bipolar II patients.
• Although tricyclic drugs can be effective, they have fallen by
the wayside because of poor tolerability and higher switch
rates to mania than newer antidepressants.
• Preferred antidepressants for bipolar depression are
bupropion, SSRIs,and venlafaxine, with an edge toward
bupropion in all but the most severe cases.
• All in all, the role that antidepressants should or should not
play in the treatment of bipolar disorder remains a matter of
ROLE OF ECT
• is an effective treatment for bipolar depression,
although it tends to be used only after
medications have failed.
• Concern has been expressed that the presence of
lithium during ECT increases the risk and severity
of cognitive dysfunction, but whether this is true
DURATION OF ANTIDEPRESSENT AND LITHIUM
• if an antidepressant is combined successfully with lithium,
• it was once recommended that it be discontinued shortly
after remission to reduce the risk of antidepressant-induced
mania or rapid cycling.
• In practice, however, some patients seem to both require
and tolerate the long-term use of lithium and an
• At present, some experts suggest continuing the
antidepressant for 2 to 6 months after remission of a first
episode of bipolar depression.
• If breakthrough depression occurs during
– lithium-induced hypothyroidism,
– poor compliance,
– and substance abuse must be considered as
possible causes or contributors.
• If there is a margin of safety and tolerability,
increasing the serum lithium level may be
sufficient to bring the episode under control.
• even if results of thyroid function testing are
within normal limits, supplementing with thyroid
hormone may be of value.
• There is some evidence that bipolar depression
responds more slowly to antidepressant treatment in
patients who have a lower free thyroxine index (FTI)
and higher thyroid-stimulating hormone (TSH) levels,
even within the range of normal.
• If optimizing the lithium blood level is
ineffective, an antidepressant, a second mood
stabilizer, or an atypical antipsychotic could be
Major Depressive Disorder
• Although episodes of major depressive
disorder may respond to lithium alone,
traditional antidepressant medications are
considerably more effective and are the
• The major value of lithium in major
depressive disorder patients with acute
depression is as an augmenting agent when
antidepressants alone have been ineffective.
AUGMENTATION OF ANTIDEPRESSANTS
• On average, about 50 percent of patients respond
when lithium carbonate, usually 300 mg three times
daily (less in the elderly), is added to a wide variety
of antidepressant drugs.
• Occasionally, a dramatic response is noted in 24 to
48 hours, but improvement is more likely to occur
gradually over several weeks.
• Benefit has been reported with most all
antidepressants, but evidence is most convincing
• When effective, augmentation should be
maintained for at least 12 months.
• research support for a true augmenting interaction
is quite persuasive.
• Indeed, most studies have found lithium to be more
effective than placebo and as effective as antidepressant
drugs for the long-term management of major depressive
disorder.(esp those with marked cyclicity)
– This may reflect the conceptualization that highly recurrent major
depressive disorder and bipolar disorder are both components of
• Lithium has not, however, demonstrated clear
advantages over conventional antidepressant drugs,
and since long-term treatment is most likely to
involve the drug that ended the acute episode (an
antidepressant), lithium maintenance for major
depressive disorder is likely to be reserved for
antidepressant treatment failures.
– On the other hand, a recent meta-analysis found
support for antisuicidal effects of lithium in
patients with recurrent major depressive
Evidence of benefit in particular
Aggression (episodic), explosive
behavior, and self-mutilation
Conduct disorder in children and
Schizoaffective Disorder and
• lithium is generally accepted to be of value
for treating this condition, especially in
combination with antipsychotic drugs, and
especially if the affective component is
– In general, the less affective and the more
schizophrenic an illness is, the less likely it is to
respond to lithium
• The addition of lithium to an antipsychotic
– remains a treatment strategy for antipsychoticresistant schizophrenia, although the availability
of atypical antipsychotics makes this less
– In addition, while several small early studies
suggested benefit from lithium augmentation of
antipsychotic medication, more recent data have
been less convincing.
– Should there be a coexisting mood disorder,
lithium might play a more prominent role.
• Lithium appears to have antiaggressive effects
independent of its mood-stabilizing action.
• Behavioral dyscontroland self-mutilation in
intellectual disabled patients have also been
successfully treated with lithium
• No work has been done to evaluate the effect of
lithium in those patients defined by DSM-IV-TR as
having intermittent explosive disorder.
• Aggressive outbursts are also treated with
medications such as anticonvulsants, βadrenergic receptor antagonists, benzodiazepines,
buspirone (BuSpar), antipsychotics, and
– The relative ranking of lithium among those
other drugs must be determined on an individual
• To both treat and prevent steroid induced
• To raise the white blood cell counts in pts
unresolved, or doubtful
• Alcohol and other substance-related
Substance-induced mood disorder with manic features
– that found reduced alcohol intake in rodents
receiving lithium. Efforts to establish lithium as a
useful treatment for alcoholism have been
– Although not all research reports have been that
discouraging, lithium is unlikely to play a major
role in the treatment of alcoholism
• Anxiety disorders
– Posttraumatic stress disorder
• Attention-deficit/hyperactivity disorder
• Eating disorders
– Bulimia nervosa
• Impulse-control disorders
• Klein-Levin syndrome
• Mental disorders due to a general medical
condition (e.g., mood disorder due to a
general medical condition with manic
• Periodic catatonia
• Periodic hypersomnia
• Personality disorders (e.g., antisocial,
borderline, emotionally unstable,
– it is likely that a comorbid mood disorder has responded
followed by indirect improvement in personality
– Today, the substantial mood component of borderline
personality disorder suggests a role for lithium in its
treatment, but controlled trials have not been conducted
• Premenstrual dysphoric disorder
• Sexual disorders
Exhibitionism Pathological hypersexuality
• children and adolescents
• elderly patients
• pregnant patients
• Lactating patients
• medically ill patients
• rapid cycling patients
Children and Adolescents
• lithium is FDA-approved for treating mania
in adolescents (ages 12 years and older).
• The range of serum lithium concentrations in
adolescents is similar to that in adults (although
its elimination half-life may be shorter)
• and the likelihood of responding appears the
THE ADVERSE EFFECT PROFILE OF LITHIUM IN
• is also the same across age groups,
• although in view of adolescent concern about
body image,adverse events such as acne and
weight gain may be poorly tolerated.
• Also, nontoxic cognitive dulling induced by
therapeutic amounts of lithium may impact
negatively on academic performance.
WHEN TO BEGIN LONG-TERM LITHIUM THERAPY IN CHILDREN
• 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 must be balanced against the potentially
deleterious adverse effects of long-term lithium.
The following factors may be predictive of a bipolar
outcome and influence early treatment with lithium or
another mood stabilizer:
– rapid onset with psychosis and psychomotor retardation,
– family history of bipolar disorder, and
– antidepressant-induced hypomania
• In the absence of organicity and substance abuse,
most evidence suggests that advanced age alone
does not compromise responsiveness to lithium.
FACTORS COMPLICATING IN ELDERLY
associated medical illnesses
age-related reduction in GFR,
• and increased sensitivity to adverse effects.
SERUM LITHIUM LEVELS IN ELDERLY
• Whether the elderly as a group respond to
lower serum concentrations of lithium than
do their younger counterparts is not known.
– Increased sensitivity to adverse effects and
toxicity confine many elderly patients to
relatively low doses and blood concentrations,
which may prevent them from benefiting from
the drug. However, this is not always the case
THE ELIMINATION HALF-LIFE OF LITHIUMIN ELDERLY
• in increases with age, and the time required
to reach steady state is much longer in the
– If lithium is stopped, serum levels fall more
slowly and the resolution of adverse effects and
toxicity may be prolonged
THE PUTATIVE NEUROPROTECTIVE EFFECTS OF
• have practical utility in this population
remains open to question.
• in general, the elderly
– should be started on lower-than-usual dosages,
with dosage changes occurring less frequently
than in younger patients
– With appropriate monitoring and compliant
patients, lithium use in the elderly can be both
safe and effective.
• FDA pregnancy category D
• drugs for which there is evidence of human
fetal risk, but whose potential benefits may
outweigh the risk in some pregnant women.
• incidence of Ebstein's anomaly is between 1 and 2
per 1,000 which is 10 to 20 times greater than in the
• fetal echocardiography is advised to screen for
cardiovascular malformations in women exposed to
lithium during the first trimester of pregnancy.
• Although the teratogenic risk of lithium is still greater than
that found in the general population, it is lower than that
posed by carbamazepine and valproate.
• in a pregnant woman taking lithium was
ascribed to lithium-induced fetal polyuria.
• Physiological changes accompanying pregnancy
alter maternal lithium metabolism
• Complications of pregnancy, such as hypertension
and edema and their treatments, may further
complicate lithium therapy.
• Following delivery, the altered renal physiology of
pregnancy returns rapidly to normal.
– These factors and their variability among
individual patients dictate that lithium use during
pregnancy be closely supervised.
• Fetal and maternal blood concentrations are similar,
so women should receive minimum effective
SHORTLY BEFORE DELIVERY.
• To reduce the risk of toxicity in the newborn,
clinicians should markedly reduce or possibly
temporarily discontinue the drug
• In view of evidence that abrupt or rapid discontinuation of
lithium is associated with a high risk of relapse (which may
be increased further postpartum), dosage reduction rather
than discontinuation may be more appropriate as delivery
• Full prophylactic concentrations should be reestablished
• because this is a time of great vulnerability to
• Because lithium appears in breast milk and in the blood of
breast-fed babies, the American Academy of Pediatrics
Committee on Drugs feels that lithium should be used with
caution in nursing mothers.
• The merits of breastfeeding are considerable, and actual
reports of infant lithium toxicity are limited to one or two
• consequently, in some situations the benefits may outweigh
• Signs of lithium toxicity in infants include lethargy, cyanosis,
abnormal reflexes, and sometimes hepatomegaly
Medically Ill Patients
• Untreated or inadequately treated mania or
depression can adversely affect a medical illness
(e.g., mania and congestive heart failure) and
decrease treatment adherence,
• and lithium may be more difficult or impossible to
use in the presence of a medical illness (e.g., severe
• Also, because medically ill patients are receiving
other medications, the risk of adverse drug
interactions is increased.
• result in increased serum lithium concentrations
and may cause lithium intoxication unless the
dosage of lithium is reduced.
DIETS THAT SEVERELY RESTRICT FLUID INTAKE
• place patients at risk for dehydration and
subsequent lithium intoxication.
• Should be used with caution in diabetic person,
who should monitor their blood glucose
concentratios carefully to avoid diabetic
Rapid Cycling Patients
• Rapid cycling
– has been defined as four or more mood disorder
episodes per year.
– Up to 20 percent of bipolar disorder patients are rapid
cyclers and the majority of them are women.
– Rapid cycling may not be a persistent condition in many
who experience it.
• Ultra-rapid cyclers
– have 24- to 48-hour cycles,
– and the concept of ultra-ultra rapid cycling has been
introduced to describe patients with frequent mood
shifts within a 24-hour period.
• Risk factors associated with rapid cycling
– a depression-hypomania course,
– antidepressant drug therapy (some controversy
remains about this). Also, because
antidepressants may induce rapid cycling, merely
discontinuing the antidepressant agent may be
sufficient to slow the cycling pattern (although at
times a rather nasty depression is the result).
– thyroid abnormalities,
– and neurological disease.
RESOPONSE OF RAPID CYCLERS TO LITHIUM
• less responsive to lithium
• Prior treatment with antidepressant drugs may
predict a poorer response to lithium.
WHAT TO DO
• Correcting thyroid abnormalities is an important
aspect of treating rapid cycling.
– Preliminary research suggests that
hypermetabolic doses of thyroid hormone may
be useful in dealing with treatment-resistant
• If lithium alone is ineffective,
– treatment considerations include some anticonvulsants
(particularly lamotrigine and valproate) either alone or
combined with lithium.
– Atypical antipsychotics are additional considerations, as
is ECT in more extreme cases.
• Adverse effects are to be expected during lithium
• Fewer than 20 percent of patients have no adverse
effects, but only about 30 percent have more than
• Most side effects are dose related
Neurological Adverse Effects
• Benign, nontoxic:
– lack of spontaneity,
– slowed reaction time,
– memory difficulties
– occasional extrapyramidal
Coarse tremor dysarthria,
seizures, coma, death
• Miscellaneous: rarely with
benign intracranial hypertension (pseudotumor cerebri),
a myasthenia gravis–like syndrome,
and lowering of the seizure threshold.
• Creativity has been variously enhanced, impaired,
and unaltered by lithium therapy.
BENIGN, NONTOXIC NEUROLOGIC
• These are
– lack of spontaneity,
– slowed reaction time,
– intellectual inefficiency,
– and spotty impairment of memory.
• Although these complaints may be subtle,
they are a common cause of poor
• The following must also be considered as
possible causes of these complaints:
– Breakthrough depression,
– lithium-induced hypothyroidism or
– other illnesses,
– and other drugs.
• Single daily dosing at bedtime or a dosage
reduction may be helpful, although switching
to another mood stabilizer may be necessary.
• Postural, occasional extrapyramidal
• The most common tremor associated with lithium
use is a benign postural tremor with a frequency of
8 to 12 Hz in the hands (which is similar to the
tremor seen with valproate).
• Because the tremor worsens during activities
requiring fine motor control, it can be socially
embarrassing and occupationally troublesome.
• With long-term lithium therapy, a tremor with
parkinsonian characteristics may occur occasionally.
MANAGEMENT OF TREMOR
• A nontoxic tremor often improves spontaneously,
• but if it does not, benefit may be obtained from
use of a slow-release lithium preparation,
elimination of dietary caffeine,
discontinuation of other medications,
and treatment of associated anxiety.
• Medications useful in treating lithium tremor
– β-adrenergic receptor antagonists such as propranolol
– as well as primidone (Mysoline),
– and possibly gabapentin (Neurontin).
IMPORTANCE OF TREMOR
• A worsening of tremor at any time during the
course of lithium therapy may be an
indication of impending lithium intoxication,
• and COARSE tremor should be considered
due to lithium toxicity until proven
Endocrine Adverse Effects
– Goiter, hypothyroidism,
– hyperthyroidism (rare)
TRANSIENT MILD ABNORMALITIES
• are common early in the course of lithium treatment
• but are usually of little or no clinical consequence.
normalize without treatment.
• more than usually susceptible are
– Women, esp during first two years of treatment
– those with preexisting thyroid dysfunction
– and those from iodine deficient areas, .
Among lithium's many effects on thyroid function, most
importantly it impedes the release of hormone from the
• elevated TSH, normal free thyroxine
• is considerably more common than clinical
• Nonetheless, subclinical hypothyroidism may not be
asymptomatic, and it may be associated with a
slower response of bipolar depression to
conventional treatment; consequently it may
require treatment with supplemental thyroxine.
• occurs in at least 4 percent of patients taking
• Once diagnosed, it can be treated with
supplemental levothyroxine (Synthroid) at a
dosage that returns the TSH concentration to
• has been described in about 5 percent of
patients taking lithium (prevalence figures
• is rarely of cosmetic or obstructive
MONITORING FOR THYROID FUNCTIONS
• Baseline assessment (including antithyroid antibody
titers) and periodic monitoring of thyroid function is
an integral part of lithium therapy
• usually measurement
– of serum TSH concentration
– with or without triiodothyronine [T3] and thyroxine [T4]
• Whether it is done routinely (every 6 or 12 months)
or only when clinical suspicion is aroused is a
matter of preference.
• Lithium induced hypothyroidism should be
considered when evaluating depressive episode
during lithium therapy
• Whether these occur more often than in the
general population remains a matter of
• One study implicated lithium-induced silent
thyroiditis as a potential cause of
HYPERPARATHYROIDISM AND HYPERCALCEMIA
• several possible mechanisms
– antagonism of the calcium sensing receptor, direct
stimulation of parathyroid hormone production, and
decreased renal calcium excretion
Hypercalcemia is usually mild, but there have been reports of
surgery being required to treat parathyroid hyperplasia or adenoma
• Clinical consequences of chronically increased serum calcium
include– renal stones, osteoporosis, dyspepsia, hypertension
and renal impairment
• Some authorities advise baseline and periodic monitoring of
serum calcium levels.
Cardiovascular Adverse Effects
• Benign T-wave changes, are common during lithium
therapy and are of no clinical consequence.
– Resemble those of hyopokalemia on the ECG
– Caused by the displacement of intracellular potassium by
the lithium ion
• can impair sinus node function,
– Contraindicated in persons with sick sinus syndrome
– Cause sinus dysrhythmias, sometimes associated with
syncopal episodes, have been reported in a few patients.
• Varying degrees of heart block and
bradyarrhythmias as well as QTc prolongation
and T-wave inversion have been reported
during lithium intoxication and occasionally
during its therapeutic use.
• Lithium does not have clinically important
effects on blood pressure.
• Although the drug is not contraindicated in
the presence of cardiovascular disease, it
should be used with caution.
– Low-salt diets,
– certain diuretics,
– angiotensin-converting enzyme inhibitors,
– angiotensin II receptor type-1 antagonists,
– fluid-electrolyte imbalances,
– and impaired renal function
• all predispose to lithium toxicity.
Renal Adverse Effects
polyuria (nephrogenic diabetes insipidus),
syndrome, renal tubular acidosis
– Progression of renal insufficiency has been described
despite discontinuation of lithium, but it is not clear if
this suggests an alternative etiology or if lithium has
ignited an irreversible event.
MONITORING FOR RENAL ADVERSE EFFECTS
• For most patients,
– the periodic measurement of serum creatinine,
– a urinalysis,
– and a clinical estimate of urine volume will
• Equation-based estimations of GFR are in
common use but may be inaccurate at higher
levels of kidney function.
• If appropriate, a 24-hour urine volume,
protein, and creatinine clearance will provide
more comprehensive information.
(nephrogenic diabetes insipidus)
• Them most common adverse effect with seconday
polydysia and also the most clinically troublesome
renal effect of lithium.
• a 24-hour urine volume of more than 3 L (1 to 2 L is
normal) has been reported in as many as 35 percent
of patients taking lithium.
• Lithium increases urine volume primarily by
inhibiting the effect of antidiuretic hormone on the
– although additional renal (including disruption of the
aquaporin-2 shuttle) and CNS mechanisms have been
• The effect is usually reversible in the short to
medium term but may be irreversible after
longterm (>15 years)
• When severe, polyuria can be
– socially and occupationally compromising;
– a cause of insomnia,
– weight gain (through consumption of high-calorie
– poor nutrition,
– and noncompliance;
– and potentially dangerous if dehydration occurs.
• Polyuria does not always resolve following
discontinuation of lithium.
TREATMENT CONSIDERATIONS FOR POLYURIA
adequate fluid replacement,
Shifting to single daily dosing
using the lowest effective dosage,
and counteractive medications such as thiazides or
potassium sparing diuretics, or indomethacin
• Amiloride (Midamor) or an amiloridehydrochlorothiazide combination (Moduretic) is
preferred to minimize the risk of hypokalemia.
– Whether single-daily dosing is beneficial remains
controversial, as do treatments such as inositol,
potassium supplementation, and desmopressin (DDAVP).
• In the majority of patients, lithium impairs
renal concentrating ability, which in itself is
of no clinical importance.
• The concentrating defect is not always
reversible after lithium discontinuation,
suggesting that both functional and structural
changes have occurred in the distal tubules
and collecting ducts.
• The most common finding is a nonspecific
interstitial fibrosis,-- the most serious renal adverse
effect and associate with chronic use
• although a lithium-distinctive microcystic lesion has
also been described.
• In the absence of lithium intoxication and renal
insufficiency, the morphological changes attributed
to lithium tend to be mild, especially when
compared with appropriately selected controls.
Dermatological Adverse Effects
• the first occurrence or worsening of
– and follicular keratosis,
• scattered reports of rashes of various types,
• and hair loss that is only occasionally related
to lithium-induced hypothyroidism.
• If tetracycline is used for rx of acne it can
cause lithium retention
Gastrointestinal Adverse Effects
• common but usually mild
– Appetite loss,
• Severe gastrointestinal symptoms
– may portend impending lithium intoxication.
• These can be diminished by
– Dividing the dosage
– Administration of lithium with food
– Or switching to another lithium preparation
• The lithium preparation
– least likely to cause diarrhea is lithium citrate
– Because ofSome preparations contain lactose
– More With slow release preparations , because of
unbsorbed medication in the lower part of GI,
– may experience less with standard release preparations
– Diarrhoea may respond to loperamide, bismuth
subsalicylate, or diphenoxylate with atropine
• The most common hematological effect of lithium is
– a benign, reversible, and usually mild granulocytosis
– induced by stimulation of granulocyte production.
• An increase in platelet count is noted occasionally,
• but there are no clinically important effects on red
blood cell count.
• Weight gain is a common adverse effect of
• and may be due to
– the drug's complex effects on carbohydrate
– Other possible causes include lithium
• induced hypothyroidism,
• fluid retention,
• and increased caloric intake from thirst-quenching
Sexual Adverse Effects
• Sexual dysfunction, including decreased
libido and erectile difficulties, has been
attributed to lithium,
• but well-documented cases are quite
• Factors associated with toxicity
• Symptoms and signs
• Toxic Serum lithium levels
Factors Associated with Toxicity
excessive intake (accidental or deliberate),
Changes in sodium levels-low-sodium diet,dehydration
and individual sensitivity (the elderly and the organically
• Antipsychotic drug-induced sedation impaired ability to
• Uncommon physical illness– Addisons disease
Toxic Serum Lithium levels
• There is no well-demarcated below which
intoxication never occurs and above which it
– Severe toxicity has been described in patients
whose serum concentrations were within the socalled therapeutic range of .5 to 1.5 mEq/L.
• In general, however, the higher the
concentration and the longer the exposure,
the more serious the intoxication
• mild to moerate intoxication(1.5-2 meq/l)
• moderate to severe intoxication (2-2.5meq/
• severe lithium intoxication(>2.5 meq/l)
• Toxic effects reliably occur at levels > 1.5 m mol/L
– Usually consists of gastrointestinal effects – increasing
anorexia, nausea and diarrhoea
– and CNS effects– muscle weakness, drowsiness, ataxia,
course tremor and muscle twitching
• Above 2 m mol /L
– Increased disorientation and seizures usually occur which
can progress to coma and ultimaley death
• Individuals vary in their susceptibility to symptoms
Symptoms and signs
• Lithium intoxication is primarily a neurotoxicity
• that can lead to death
• or permanent neurological damage often
cerebellar as characterized by
– dysarthric speech,
– and wide-based gait.
Cardiovascular, gastrointestinal, and renal manifestations may also be
EARLY CLINICAL MANIFESTATIONS
• gastrointestinal upset,
• and coarse tremor.
• impaired consciousness,
• neuromuscular irritability (fasciculations,
• and coma
MILD TO MOERATE INTOXICATION(1.5-2 mEq/L)
– Abdominal pain
– Dryness of mouth
Lethargy or exciteent
MODERATE TO SEVERE INTOXICATION (2-2.5meq/ lit)
Persistent nausea and voiting
Clonic limb movements
Hyperactive deep tendon reflexes
SEVERE LITHIUM INTOXICATION(>2.5 MEQ/L)
• Some cases of lithium intoxication have
– Creutzfeldt-Jakob disease,
– nonconvulsive status epilepticus,
– or neuroleptic malignant syndrome.
• Absorption can be delayed substantially if
slow-release preparations are involved.
• is directed at the removal of lithium from the
• In mild cases, nothing more may be
necessary than discontinuation of intake.
• Dehydration treated
GASTRIC LAVAGE AFTER AN OVERDOSE
• is indicated and may have to be repeated.
• Although activated charcoal is not helpful
following an acute lithium overdose,
• preliminary reports using polystyrene
sulfonate (Kayexalate), a cation exchange
• or whole bowel irrigation with polyethylene
glycol solution (GoLYTELY) have been
Rx OF MILD TO MODERATE TOXICITY
• In the presence of normal renal function,
often responds to correcting dehydration and
maintaining proper fluid and electrolyte
• Whether forced diuresis provides additional
benefit is open to debate.
Rx OF SEVERE INTOXICATION (> 3 m eq/ lit)
• Hemodialysis is the treatment of choice
for severe intoxication (peritoneal
dialysis is considerably less efficient)
• Lithium is removed effectively by dialysis because it
is water soluble, unbound to plasma
protein,without metabolites, and of simple
chemical structure (an element).
• 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
tominimize the likelihood of rebound.
• Because of the drug's tissue-toxic effects and its
gradual removal from the CNS, clinical
improvement may lag many days behind the
lowering of serum concentration.
• ACE inhibitors and Angiotensin II receptor
• Calcium channel inhibitors
• Miscellaneous drugs
• Psychiatric drugs
– and ECT
• Most clinically significant interactions are
with drugs that alter renal sodium handling
Lithium ₊ ACE inhibitors or
Angiotensin II antagonists
• ACE inhibitors– captopril, cilazapril,
enalapril,fosinopril, imidapril, lisinopril,
moexipril, perinopril, quinapril, ramipril and
• Angiotensin receptor antagonists–
candesartan, eposartan, irbesartan, losartan,
olmesertan, telmesartan, and valsartan
• both of these drug classes are used
extensively to treat cardiovascular disease,
• Ace inhibitors can reduce thirst which can lead to
– mild dehydration and increase renal Na loss leading to
– increased Na reabsorption by the kidney leading to an
increase in lithium plasma levels
• The magnitude of this effect is variable; from no
increase to a fourfold increase
• The full effect can take several weeks to develop
• In elderly, ACE inhibitors increase seven fold the risk
of hospitalisation due lithium toixicity
• ACE inhibitors can also precipitate renal failure
Lithium ₊ Diuretics
• Diuretics can reduce the renal clearance of
lithium, the magnitude of this effect being
greater with thiazide than loop dieuretics
– Drugs are bendroflumethiazide, chlorthalidone,
cyclopenthiazide, idapamide, metolazone, and
– Lithium levels usually rise within 10 days of a
thiazide diuretic being prescribed
– Magnitude of rise is unpredictable and can vary
from 25% to 400%
– Well-documented reduced renal lithium
clearance and increased serum concentration.
– Toxicity reported
– If a thiazide is prescribed, lithium dosage
reduction is often necessary.
– If a thiazide is discontinued, lithium dosage may
need to be increased to avoid subtherapeutic
– Drugs are– bumetamide,furosemide, and
– lithium clearance unchanged (some case reports
of increased lithium concentration).
– Pt are on low sodium diet this may inrease the
– Loop diuretics are safer any effect will be
apparent in the first month
– Limited data, may increase lithium
• Osmotic (mannitol, urea)
– Increase renal lithium clearance and decrease
• Xanthine (aminophylline, caffeine,
– increase renal lithium clearance and decrease
• Carbonic anhydrase inhibitors
– Increase renal lithium clearance (acetazolamide)
• Because diuretics are often given to patients
who are medically ill with unstable fluidelectrolyte status, interactions with lithium
may not be predictable, and close monitoring
Lithium ₊ NSAIDs
• Inhibit synthesis of renal prostaglandins,
thereby renal blood flow and possibly
increasing renal re-absorption of sodium and
• reduce renal lithium clearance and increase
the serum lithium concentration
– in a way that is clinically important and
• Among the drugs that cause this interaction
– indomethacin (Indocin),
– phenylbutazone (Butazolidine),
– diclofenac (Voltaren),
– ketoprofen (Orudis),
– meloxicam (Mobic),
– oxyphenbutazone (Tandearil),
– ibuprofen (Motrin, Advil, Nuprin),
– piroxicam (Feldene),
– and naproxen (Naprosyn).
• Aspirin and possibly sulindac (Clinoril) appear to be
• The newer cyclooxygenase-2 (COX-2) inhibitors,
such as celecoxib (Celebrex) and rofecoxib (Vioxx,
no longer available), are no exception.
• Risk factors include
– high doses of the anti-inflammatory drug, increased age,
– and renal impairment.
• Because many of these drugs are now available
without prescription, it is especially important that
patients be aware of the possibility of an
Lithium ₊ Calcium channel
• Case reports of neurotoxicity; no consistent
Lithium ₊ Miscellaneous drugs
• Succinylcholine, pancuronium
– Reports of prolonged neuromuscular blockade.
– Increased lithium concentration.
– Few reports of neurotoxicity.
• Sodium bicarbonate
– Increased renal lithium clearance.
– Additive antithyroid effects.
– Used for lithium tremor. Possible slight increase
in lithium concentration.
Lithium ₊ Antipsychotics
CASE REPORTS OF ENCEPHALOPATHY
• Lithium and antipsychotic drugs have been used together
safety and effectively for years;
• however, concern has been expressed that the combination
may cause an encephalopathy in certain persons.
• Although the interaction has been reported most frequently
with haloperidol (Haldol), a number of other antipsychotic
drugs have also been implicated.
• A clear cause-and-effect relationship has not been
established;nonetheless, caution is advised, and the
simultaneous use of high doses of the two drugs should be
• worsening of extrapyramidal adverse effects,
and neuroleptic malignant syndrome.
• Inconsistent reports of altered red blood cell
and plasma concentrations of lithium,
antipsychotic drug, or both.
• With quetiapine can cause somnolence, but
is otherwise well tolerated
• With ziprasidone – may modestly increase
Lithium ₊ Anticonvulsants
• combinations helpful for treatment
• When two drugs are used together,. In
addition, lithium offers some protection
granulocytopenia, although whether it does the same
for the rare agranulocytosis and aplastic anemia is unknown
• No significant pharmacokinetic interactions.
• Occasional reports of; but are usually
avoidable with careful clinical management
• CBZ can cause hyponatremia, which in turn
lead to lithium retention and toxicity
SHARED ADVERSE EFFECTS
• may be more pronounced; for example,
tremor and weight gain from lithium and
Lithium ₊ Antidepressants
• In general, lithium and antidepressant
combinations are safe and effective, although
there have been occasional reports of a
serotonin-like syndrome when lithium was
combined with potent SSRIs.
• Serum lithium concentrations are not altered
in any substantial way by antidepressant
Lithium ₊ ECT
• Concern has been expressed that the presence of
lithium during ECT increases the risk and severity of
cognitive dysfunction, but whether this is true
• SOP 10th -- a person taking lithium who is
about to undergo ECT should discontinue
taking lithium 2 days before beginning ECT to
reduce the risk of delirium
• Sample material
• Method of sample collection
• Types of tests available
• Interpretation of results
• Plasma lithium levels
• Lithium has been measured in virtually every
• but only blood (serum or plasma) is used in
– Despite considerable research, red blood cell,
saliva, and tear lithium measurements and ratios
such as red blood cell to plasma have failed to
gain widespread acceptance.
Method of Sample Collection
THE 12-HOUR INTERVAL SAMPLE
• the blood should be drawn in the morning,
12 hours (± 30 minutes) after the last dose
• a multiple-dose regimen should be used
• a steady-state condition should exist after 5
days (skipped or extra doses within 4 or 5
days should be avoided).
• 12-hour serum concentrations will be higher
with single as opposed to multiple daily
– The difference may range between 10 and 30
percent and cannot be easily predicted.
– Consequently, treatment is usually initiated with
at least twice-daily dosing, although switching
later to single-daily dosing may have the
advantage of improved compliance and fewer
Types of Tests Available
• Methods used to measure serum lithium include
and ion-selective electrode analysis
• More recently, colorimetric assays have been
developed. One uses finger stick blood and returns a plasma lithium
level within minutes.
The analyzers used in clinical laboratories are usually not
capable of measuring the low levels of naturally occurring
lithium in the blood
Interpretation of Results
• it should always be combined with sound
– Clinical toxicity, especially in the elderly, has been well
documented within this so-called therapeutic range.
– The dose–blood level relationship may vary considerably
from patient to patient.
• Essential to interpreting serum lithium levels
– is knowing the sampling interval (the time between the
last dose and the drawing of blood),
– the dose form, and the dosage schedule.
• the serum level may fluctuate from
measurement to measurement, reflecting
factors such as
– dietary sodium intake,
– mood state,
– activity level,
– body position,
– and improper sample collection (use of a lithiumheparin anticoagulant will increase the
concentration by more than 1 mEq/L).
– Aging of the lithium ion-selective electrode(can
cause inaccuracies uptl 0-5 mEq/L)
Plasma Lithium Levels
The U.S. package inserts
• for mania
– between 1.0 and 1.5 mEq/L (usually achieved
with 1,800 mg of lithium carbonate daily)
• and for long-term maintenance
– between 0.6 and 1.2 mEq/L (usually achieved
with 900 to 1,200 mg of lithium carbonate daily).
• Minimum effective plasma level for
prophylaxis is 0.4 m mol/L
• Optimal range being 0.6—0.75 m mol/ L
• Levels above 0.75 m mol / L offer additional
protection only against manic symptoms
• Optimal plasma range for patients who have
unipolar depression is less clear
• Pretreatment evaluation
• Preparations available
• Dosage prediction
• Starting dose
• Maintenance dose
• Patient education
• associated illnesses
• and the presence of other drugs
• consequently, a thorough medical history is
essential. The history determines the need
for and the extent of physical and laboratory
TESTS TO BE DONE
• All patients should have renal(serum
creatinine, CUE ) and thyroid(T3,T4,TSH)
• A pregnancy test would be appropriate for
women of childbearing potential
• an ECG in older patients.(maudsley10 th in
• A baseline measurement of weight is also
On Treatment Monitoring
• Plasma lithium should be checked every 3
• E GFR and TFTs should be checkded every 6
• More frequent tests may be
required in those
who are prescribed interacing dugs
Weignt or BMI should also be monitored ECG
IN THE UNITED STATES
– immediate release generic lithium carbonate,
– slow release (Lithobid and generic lithium carbonate),
– controlled release (generic lithium carbonate),
– and lithium citrate syrup.
ELSEWHERE IN THE WORLD
– lithium acetate,
– and sulphate
• There are no parenteral forms.
• Both 300 mg of the carbonate and 5 mL of
the citrate contain about 8 mEq (mmol) of
• 5.4 m mol/5ml of lithium citrate is equivalent
to 200 mg of lithium carbonate
• 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).
• giving a single dose of lithium carbonate and
using the serum concentration after a given
interval (usually 24 hours) to predict the
• measuring renal lithium clearance;
• and the use of mathematical models.
• Thus far, prediction techniques have not been
• and most clinicians continue to adjust the
– on the patient's clinical condition
– and previous blood concentrations.
• Initiated in divided doses.
– Once a patient is stabilized, single daily dosing is
sometimes more convenient.
• In general, a conservatively low dose is
started, perhaps 300 mg two or three times
– a serum concentration is obtained after steady
state is reached (in 4 or 5 days), and the dose is
• 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
• Maudsley 10th-start at 400 mg at night(200 mg
elderly). Plasma levels after 7 days, then 7 days
after every dose change until the desired level is
• Patients vary widely in the dose required to
reach a desired blood concentration,
• the elderly usually require lesser amounts.
• Is best to follow maxim “ treat the patient ,
not the laboratory results”
LOADING THE LITHIUM
• to produce a more rapid onset of action
• has become more appealing because of
economic pressures to minimize the length of
• patients must be evaluated clinically
• lithium levels determined periodically
• and appropriate laboratory tests performed
at regular intervals.
• Monthly visits are common early in
treatment if the clinical course is
uncomplicated. Patients who have been
stable for extended periods may be seen at
intervals of 3, 4, or even 6 months.
• Lithium should be discontinued if it is ineffective or
– Patients may stop the drug for other reasons, such as a
perceived or real loss in creativity, feeling cured, or a
dislike for feeling controlled by a medicine.
• After a period of stability with maintenance
therapy, a trial off lithium may be considered,
– although the risk of recurrence is substantial (especially
if there have been several prior episodes),
– and there have been reports of failure to respond to
lithium when treatment is reinstituted.
• Discontinuation should be gradual over many
– because more abrupt discontinuation appears to
be associated with a higher likelihood of early
recurrence, especially of mania.
– Maudsley 10 th-reduce slowly over at least 1
month. Avoid intermittent reduction in plasma
levels of > o.2 m mol/L
• Teaching patients and significant others to
recognize early signs of recurrence is an
important part of the discontinuation
• plays an important role in ensuring safe,
effective, and compliant long-term
• written materials
• and support programs, such as those by the
Depression and Bipolar Support Alliance
(DBSA) (formerly the National Depressive and
Manic Depressive Association),