lithium clinical uses & adverse effects

8/13/2019 Lithium Clinical Uses & Adverse Effects

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Dr. Manu SharmaChairperson: Dr. V. K. Bhat


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History A report appeared in 1800 describing the discovery oftwo new minerals, petalite and spodumene, on theisland of Ut near Stockholm, Sweden.1817: Johan Arfwedson discovered a new alkali that wasnamed lithion by Jons Jacob Berzelius, his laboratorychief.1818: Humphrey Davy was the first to isolate lithiummetal.In 1843 Alexander Ure showed in vitro that a uric acidbladder stone lost weight in a lithium carbonatesolution.


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HistoryFrom the late 1880s through the early 1900s, lithium was embraced by the general public in the form ofmineral spring waters.


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HistoryLithium tabs: weakness and tremor in patients wasreported in 1898 and diarrhea, vomiting, and death were described in animals in 1903.1948: 25% solution of lithium chloride for use as a saltsubstitute in patients on low-sodium diets, thedangers were not appreciated.

By 1949, however, reports of severe lithiumintoxication and death resulted in the removal oflithium products ---delayed acceptance of lithium by American psychiatry for many years.


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John F. J. Cade, an Australian psychiatrist, wasobserving its antimanic effect.

Mogens Schou and others firmly established theeffectiveness of lithium for mania and for theprophylactic treatment of manic-depressive disorder.1970: U.S. FDA approved its labeling for the treatment

of mania.1974: for maintenance therapy in patients with ahistory of mania.


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HistoryLithium is regarded as old news & less appealing toresearchers.

Pharmaceutical companies were reluctant to producethis inexpensive drug that they couldnt patent.


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Pharmacokinetics & DispositionLithium 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 plasmaconcn.Steady state concn: 4-5 days


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Mechanism of actionInositol depletionGlycogen-synthase kinase inhibition

Effects on neurotransmitter systemsCircadian rythms


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Therapeutic indicationsBipolar 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)


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Not all patients with acute mania respond equally wellto 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 well-designed studies.


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Therapeutic indicationsLithium vs antipsychotics

To date there is no obvious effect-size difference

between any antipsychotic & Li.

Lithium vs. CCBLi appears to be superior to verapamil.

Lithium vs. ECTECT>Li in first 8 weeks. After 8 weeks-no difference


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Therapeutic indicationsLithium vs. anticonvulsants

Li, CBZ, divalproex- equal efficacy

Anticonvulsants better tolerated than Li.Neurological abnormalities may predict a betterresponse to anticonvulsants.Pts with EEG abnormalities respond better to valproate. (Reeves et al. 2001)Lamotrigine= Li in acute mania (Ichim et al. 2000)


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Therapeutic indicationsDosing

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 withtrough plasma level determination on Day 4 or Day 5. Watching for any signs of toxicity.

A lower starting dose and slower titration in olderpatients & those impaired renal function.


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Therapeutic indicationsBipolar Depression

Not FDA approved for the acute treatment of bipolar

depressive episodes.Sufficient research to support its effectiveness as afirst-line choice either alone or for more severedepressions in combination with an antidepressant or

another medication. APA (2002): 1st line Rx with Li or Lamotrigine.


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Therapeutic indicationsSuicide: 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 (Gelenberg2001)


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Therapeutic indicationsMaintenance therapy

Just exactly when to begin long-term lithium

treatment has not been fully resolved.Early initiation of maintenance therapy may benefitmany patients at the expense of some patients beingtreated unnecessarily.


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Therapeutic indicationsFactors associated with response to Lithium:

Psychotic Sx during manic episode- good response.

Pattern of mania-depression-euthymia: goodresponse.Poor response within first 6 monthsMore severe episodesManic episodes> Depressive episodesUnmarried, psychosocial stressors

Poor response


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Therapeutic indicationsThe maximum benefits of lithium maintenance maynot be immediate; with continued treatment, relapsessometimes become less severe and less frequent.Some patients appear to develop a tolerance to lithiumafter several years of successful use.Following discontinuation of successful lithium

therapy, the risk of recurrence increases by 23 times.


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Therapeutic indicationsLithium-discontinuation induced refractoriness

Some patients, who had responded well to lithiumprophylaxis may not respond again when lithium isreintroduced after a failed discontinuation trial.15% A decision to discontinue successful lithium

maintenance should not be taken lightly, but rathermust be weighed carefully against the continued riskof adverse effects and toxicity.


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Therapeutic indicationsUnipolar DepressionThe major value of lithium in major depressivedisorder patients with acute depression is as anaugmenting agent when antidepressants alone havebeen ineffective. About 50% of patients respond when lithium is addedto 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 maintainedfor at least 12 months.


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Therapeutic indicationsSchizoaffective disorder & Schizophrenia

In general, the less affective and the moreschizophrenic an illness is, the less likely it is torespond to lithium.The same cannot be said of an episode because theacute manifestations of mania and schizophrenia may

be indistinguishable.Lithium is generally accepted to be of value, especiallyin combination with antipsychotic drugs, andespecially if the affective component is prominent.


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Therapeutic indications A 2007 Cochrane Collaboration review concluded:there is no evidence that lithium on its own iseffective for people with schizophrenia orschizoaffective disorder. There is some evidence for theeffectiveness of lithium as an adjunctive treatment toantipsychotic drugs, but this result was inconclusive.


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Therapeutic indications Aggression & Impulsivity

Li reduced the frequency of aggressive & self-mutilative episodes in pts with intellectual disability.Controlled studies have found reduced aggression insubjects recruited from prison populations.Countries with higher Li levels in drinking water had

lower rates of suicide, homicide, rape (Schrauzer &Shrestha 1990)


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Therapeutic indicationsDecreases impulsive gambling.Li has not been used extensively to treat aggressionassociated with head trauma or epilepsy, and theresults have been mixed. No work has been done to evaluate the effect oflithium in intermittent explosive disorder.


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Therapeutic indicationsPersonality DisordersIn pts with emotionally unstable personality disorders with mood swings and chronically maladaptivebehavior. 5 cases of BPD showed clinical improvement (LaWall& Wesselius, 1982)

When favorable outcomes do occur, it is likely that acomorbid mood disorder has responded followed byindirect improvement in personality.


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Therapeutic indications Alcohol use disordersThe close association between mood disorders andalcohol-use disorders and in part on animal researchthat found reduced alcohol intake in rodents receivinglithium.Efforts to establish lithium as a useful treatment for

alcoholism have been largely unsuccessful.


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Therapeutic indications Anxiety DisordersPTSD (Forster et al. 1995)

Refractory panic disorder (Feder 1988)Refractory OCD (Golden et al. 1988)


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Use in special populationsChildren & AdolescentsFDA approved for bipolar disorder in 12 yrs and above.The range of serum lithium concentrations in adolescentsis similar to that in adults (although its elimination half-lifemay be shorter)The likelihood of responding appears the same.The adverse effect profile of lithium is also the same acrossage groups.Cognitive dulling induced by therapeutic amounts oflithium may impact negatively on academic performance.


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Use in special populations When and if to begin long-term lithium therapy is aneven more difficult decision when treating youngpatients than when treating adults.The markedly disruptive effects of episodes in youthand the highly recurrent nature of bipolar disorder.(Risk vs. Benefit)


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Use in special populationsElderly patients Advanced age alone does not compromiseresponsiveness to lithium.

Use of lithium in the elderly is complicated byassociated medical illnesses and medications,special diets,age-related reduction in GFR, andincreased sensitivity to adverse effects.


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Use in special populations Whether the elderly as a group respond to lower serumconcentrations of Li than do their youngercounterparts is not known.

The elderly should be started on lower-than-usualdosages, with dosage changes occurring less frequentlythan in younger patients.The elimination t of Li increases with age, and the

time required to reach steady state is much longer inthe elderly.If Li is stopped, serum levels fall more slowly and theresolution of adverse effects and toxicity may beprolonged.


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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 controlledstudies 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.


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Use in special populationsPregnancy & LactationLithium is in FDA pregnancy category D.

Physiological changes accompanying pregnancy altermaternal lithium metabolism:The GFR increases 30 to 50% over baselinePlasma volume increases by 50%.

The filtered sodium load increases markedly, as doesthe renal tubular reabsorption.Polyhydramnios : lithium-induced fetal polyuria.


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Use in special populationsFetal and maternal blood concentrations are similar, so women should receive minimum effective dosages.To reduce the risk of toxicity in the newborn, cliniciansshould markedly reduce or possibly temporarilydiscontinue the drug shortly before delivery.Reduction rather than discontinuation may be more

appropriate as delivery approaches.


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Use in special populationsThe American Academy of Pediatrics Committee onDrugs feels that lithium should be used with cautionin nursing mothers.One study of ten breastfeeding infants found infantserum levels to average 0.16 mEq/L (range 0.05 to0.23).

The merits of breastfeeding are considerable, andactual reports of infant Li toxicity are limited to one ortwo cases; consequently, in some situations thebenefits may outweigh the risks.


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Use in special populationsThe incidence of Ebstein's anomaly is between 1 and 2per 1,000 which is 10 to 20 times greater than in thegeneral population).Teratogenic risk: Li>Valproate> CBZ.Fetal echocardiography is advised to screen forcardiovascular malformations in women exposed to

lithium during the first trimester of pregnancy.


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Use in special populationsMedical comorbidityUntreated or inadequately treated mania or depressioncan adversely affect a medical illness.Decreased treatment adherence.Li may be more difficult or impossible to use in thepresence of a medical illness.

Risk of adverse drug interactions is increased.


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Adverse effects & ToxicologyFewer than 20 percent of patients have no adverseeffects.Only about 30 percent have more than minorcomplaints.Recognizing and minimizing adverse effects can domuch to enhance compliance with lithium treatment.


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Adverse effects & ToxicologyLaboratory monitoring APA practice guidelines:

Medical historySerum urea & creatinineTFTsECG (in pts >40 yrs)RFT should be assessed every 2-3 monthsTFTs every once in 2 months during first 6 months.Then, RFT & TFT once every 6-12 months.


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Adverse effects & ToxicologyNeurological reactionsDysphoria, lack of spontaneity, slow reaction times,intellectual inefficiency, and spotty impairment ofmemory.Other causes of these complaints: Breakthroughdepression, lithium-induced hypothyroidism or

hypercalcemia, other illnesses, and other drugs.


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Adverse effects & ToxicologyTremorBenign postural tremor with a frequency of 8 to 12 Hzin the hands.4%-65% pts.It worsens during activities requiring fine motorcontrol, it can be socially embarrassing and

occupationally troublesome.It decreases with time.


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Adverse effects & Toxicology A worsening of tremor at any time during the course oflithium therapy may be an indication of impendinglithium intoxication, and severe tremor should beconsidered due to lithium toxicity until provenotherwise.

A nontoxic tremor often improves spontaneously, but ifit does not:

dose reduction,use of a slow-release lithium preparation,elimination of dietary caffeine,discontinuation of other medications, and treatment of associated anxiet .


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Adverse effects & ToxicologyMedications useful in treating lithium tremor: -adrenergic receptor antagonists such aspropranolol, as well as primidone, and possibly gabapentin.

With long-term lithium therapy, a tremor with

parkinsonian characteristics may occur occasionally.

Delirium: Li + Haloperidol


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Adverse effects & ToxicologyOther Nontoxic Effectsrarely peripheral neuropathy,

downbeat nystagmus,benign intracranial hypertension (pseudotumorcerebri),a myasthenia gravis like syndrome, and

lowering of the seizure threshold.Creativity has been variously enhanced, impaired, andunaltered by lithium therapy.


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Lithium Intoxication

Primarily a neurotoxicity.Cardiovascular, gastrointestinal, and renalmanifestations 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).


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Adverse effects & ToxicologyThere is no well-demarcated serum lithiumconcentration below which intoxication never occursand above which it is inevitable.


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Mild to moderate intoxication (lithium level = 1.5 to2.0 mEq/L)

GI Vomiting Abdominal painDryness of mouth

Neurologic AtaxiaDizzinessSlurred speechNystagmusLethargy or excitement

Muscle weakness

Moderate to severe intoxication (lithium level = 2 0 to


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Moderate to severe intoxication (lithium level = 2.0 to2.5 mEq/L)

GI AnorexiaPersistent nausea and vomiting

Neurologic Blurred visionMuscle fasciculationsClonic limb movements

Hyperactive deep tendon reflexesChoreoathetoid movementsConvulsionsDeliriumSyncopeElectroencephalographic changesStuporComaCirculatory failure (lowered BP, cardiac arrhythmias,and conduction abnormalities)


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Severe lithium intoxication (lithium level >2.5 mEq/L)Generalized convulsions

Oliguria and renal failureDeath


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Adverse effects & ToxicologyManagementStop Li immediately.

Serum Li levels and RFT After an overdose, gastric lavage is indicated and mayhave to be repeated.Polystyrene sulfonate (Kayexalate), a cation exchange

resin, or whole bowel irrigation with polyethyleneglycol solution (GoLYTELY).


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Adverse effects & ToxicologyIn the presence of normal renal function, mild tomoderate toxicity often responds to correctingdehydration and maintaining proper fluid andelectrolyte balance. Whether forced diuresis provides additional benefit isopen to debate. Hemodialysis is the treatment of choice for severeintoxication (peritoneal dialysis is considerably lessefficient).


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Adverse effects & ToxicologyRedistribution of lithium from tissues to blood afterdialysis usually results in a rebound increase in itsblood level; this may necessitate further dialysis.Hemodialfiltration has also been used, sometimes inconjunction with hemodialysis to minimize thelikelihood of rebound.


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Adverse effects & ToxicologyThyroid ReactionsLi impedes the release of hormone from the gland.

Women with preexisting thyroid dysfunction andthose from iodine deficient areas, are more thanusually susceptible.Clinical hypothyroidism occurs in at least 4 percent of

patients taking lithium.Subclinical hypothyroidism is more common.Issues with subclinical hypothyroidism


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Adverse effects & ToxicologyCardiovascular ReactionsBenign, 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 nodedysfunction.


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Adverse effects & ToxicologyRenal ReactionsLi impairs renal concentrating ability, which in itself isof 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 isassociated with renal insufficiency.Progression of renal insufficiency has been describeddespite discontinuation of lithium.


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Adverse effects & Toxicology After correcting for age, one study of 142 patients onlithium for a minimum of 15 years found reduced GFRin 21 % and increased serum creatinine in 12 %.(Creatinine creep) Polyuria is the most clinically troublesome renal effectof lithium. As many as 35% of patients taking lithium.Leads to insomnia, weight gain, poor nutrition, andnoncompliance; and potentially dangerous ifdehydration occurs.


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Adverse effects & Toxicologyadequate fluid replacement,using the lowest effective dosage,and counteractive medications such as thiazides orpotassium sparing diuretics, or indomethacin.inositol, potassium supplementation, anddesmopressin.

Polyuria does not always resolve followingdiscontinuation of lithium.


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Other Reactions

Weight gainMay be due to the drug's complex effects on

carbohydrate metabolism.Other possible causes include lithium-induced

hypothyroidism, fluid retention, and increased caloricintake from thirst-quenching beverages.

Gastrointestinal adverse effects- may portendimpending lithium intoxication.Granulocytosis (Neutrophilia), thrombocytosis.Hypercalcemia and hyperparathyroidism.Sexual dysfunction: decreased libido and erectile

difficulties.


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Adverse effects & ToxicologyDermatological 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).


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Administration & DosingBoth 300 mg of the carbonate and 5 mL of the citratecontain about 8 mEq (mmol) of lithium.Lithium acetate, glutamate, gluconate, orotate, andsulphate preparations have been available or arecurrently available.Clinicians should be aware the lithium andlithium carbonate are not interchangeable (300mg of lithium is equivalent to 1,597 mg of lithiumcarbonate).


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Non-psychiatric usesNeurologicalEpilepsyHeadache (chronic cluster, hypnic, migraine,particularly cyclic)Mnire's disease (not supported by controlled studies)Huntington's diseaseLevodopa-induced hyperkinesiasOn-off phenomenon in Parkinson's disease


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Non-psychiatric usesDermatologicalGenital herpes (controlled studies support topical andoral use)Eczematoid dermatitisSeborrheic dermatitis (controlled studies support)

Gastrointestinal

Cyclic vomitingGastric ulcersUlcerative colitis


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Non-psychiatric usesRespiratory Asthma (controlled study did not support)Cystic fibrosis

OtherBovine spastic paresis


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Psychiatric uses


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Evidence of benefit in particular groupsSchizophrenia Aggression (episodic), explosive behavior, and self-mutilation

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


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Attention-deficit/hyperactivity disorder

Eating disorders Anorexia nervosa Bulimia nervosa

Impulse-control disordersMental disorders due to a GMC(e.g., mood disorderdue to a general medical condition with manicfeatures)Periodic catatoniaPeriodic hypersomnia


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

emotionally unstable, schizotypal)Premenstrual dysphoric disorderSexual disorders

Transvestic fetishism

Exhibitionism Pathological hypersexuality


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lithium clinical uses & adverse effects

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