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

Bhat

History
A report appeared in 1800 describing the discovery of

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

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

was embraced by the general public in the form of mineral spring waters.

History
Lithium tabs: weakness and tremor in patients was

reported in 1898 and diarrhea, vomiting, and death were described in animals in 1903. 1948: 25% solution of lithium chloride for use as a salt substitute in patients on low-sodium diets, the dangers were not appreciated. By 1949, however, reports of severe lithium intoxication and death resulted in the removal of lithium products ---delayed acceptance of lithium by American psychiatry for many years.

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

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

History
Lithium is regarded as old news & less appealing to

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

Pharmacokinetics & Disposition

Lithium carbonate tabs & capsules, Lithium citrate &

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

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

Circadian rythms

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

 Not all patients with acute mania respond equally well

to lithium. 79% Less success when dealing with patients with: mixed or dysphoric mania, many prior episodes, poor inter-episode functioning rapid cycling, comorbid substance abuse, comorbid personality disorder, organicity. Whether another medication would be preferable to has not been established in well-designed studies.

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

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

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

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

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

2001)

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

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

Therapeutic indications
The maximum benefits of lithium maintenance may

not be immediate; with continued treatment, relapses sometimes become less severe and less frequent. Some patients appear to develop a tolerance to lithium after several years of successful use. Following discontinuation of successful lithium therapy, the risk of recurrence increases by 23 times.

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

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

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

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

Therapeutic indications
A 2007 Cochrane Collaboration review concluded:

there is no evidence that lithium on its own is effective for people with schizophrenia or schizoaffective disorder. There is some evidence for the effectiveness of lithium as an adjunctive treatment to antipsychotic drugs, but this result was inconclusive.

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

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

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

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

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

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

Use in special populations

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

Use in special populations

When and if to begin long-term lithium therapy is an

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

Use in special populations

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

Use in special populations

Whether the elderly as a group respond to lower serum

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

Use in special populations

With appropriate monitoring and compliant patients,

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

Use in special populations

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

Use in special populations

Fetal and maternal blood concentrations are similar, so

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

Use in special populations

The American Academy of Pediatrics Committee on

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

Use in special populations

The incidence of Ebstein's anomaly is between 1 and 2

per 1,000 which is 10 to 20 times greater than in the general population). Teratogenic risk: Li>Valproate> CBZ. Fetal echocardiography is advised to screen for cardiovascular malformations in women exposed to lithium during the first trimester of pregnancy.

Use in special populations

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

Adverse effects & Toxicology

Fewer than 20 percent of patients have no adverse

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

Adverse effects & Toxicology

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

Adverse effects & Toxicology

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

Adverse effects & Toxicology

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

Adverse effects & Toxicology

A worsening of tremor at any time during the course of

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

Adverse effects & Toxicology

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

Adverse effects & Toxicology

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

Lithium Intoxication
Primarily a neurotoxicity.

Cardiovascular, gastrointestinal, and renal

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

Adverse effects & Toxicology

There is no well-demarcated serum lithium

concentration below which intoxication never occurs and above which it is inevitable.

 Mild to moderate intoxication (lithium level = 1.5 to

2.0 mEq/L)
GI Vomiting Abdominal pain Dryness of mouth

Neurologic

Ataxia Dizziness Slurred speech Nystagmus Lethargy or excitement Muscle weakness

 Moderate to severe intoxication (lithium level = 2.0 to

2.5 mEq/L)
GI Anorexia Persistent nausea and vomiting

Neurologic

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

Severe lithium intoxication (lithium level >2.5 mEq/L) Generalized convulsions Oliguria and renal failure Death

Adverse effects & Toxicology

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

Adverse effects & Toxicology

In the presence of normal renal function, mild to

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

Adverse effects & Toxicology

Redistribution of lithium from tissues to blood after

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

Adverse effects & Toxicology

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

Adverse effects & Toxicology

Exophthalmos and hyperthyroidism have been

described during lithium therapy. Lithium-induced silent thyroiditis as a potential cause of thyrotoxicosis.

Adverse effects & Toxicology

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

Adverse effects & Toxicology

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

Adverse effects & Toxicology

After correcting for age, one study of 142 patients on

lithium for a minimum of 15 years found reduced GFR in 21 % and increased serum creatinine in 12 %. (Creatinine creep) Polyuria is the most clinically troublesome renal effect of lithium. As many as 35% of patients taking lithium. Leads to insomnia, weight gain, poor nutrition, and noncompliance; and potentially dangerous if dehydration occurs.

Adverse effects & Toxicology

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

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

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

Adverse effects & Toxicology

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

Administration & Dosing

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

Administration & Dosing

Both 300 mg of the carbonate and 5 mL of the citrate

contain about 8 mEq (mmol) of lithium. Lithium acetate, glutamate, gluconate, orotate, and sulphate preparations have been available or are currently available. Clinicians should be aware the lithium and lithium carbonate are not interchangeable (300 mg of lithium is equivalent to 1,597 mg of lithium carbonate).

Dosing Lithium therapy is initiated in divided doses. Once a patient is stabilized, single daily dosing is sometimes more convenient. In the presence of normal kidney function, a total daily dose of 1,200 to 1,800 mg of lithium carbonate generally produces an antimanic serum concentration of 0.8 to 1.2 mEq/L. Maintenance levels of 0.6 to 1 mEq/L can usually be attained with 900 to 1,200 mg daily. In general, a conservatively low dose is started, perhaps 300 mg two or three times daily, a serum concentration is obtained after steady state is reached (in 4 or 5 days), and the dose is adjusted accordingly.

Non-psychiatric uses
Neurological Epilepsy Headache (chronic cluster, hypnic, migraine, particularly cyclic) Mnire's disease (not supported by controlled studies) Huntington's disease Levodopa-induced hyperkinesias On-off phenomenon in Parkinson's disease

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

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

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

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

Non-psychiatric uses
Dermatological Genital herpes (controlled studies support topical and oral use) Eczematoid dermatitis Seborrheic dermatitis (controlled studies support) Gastrointestinal Cyclic vomiting Gastric ulcers Ulcerative colitis

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

Psychiatric uses

 Historical
Gouty mania

Well established (FDA-approved)

Manic episode Bipolar maintenance therapy Reasonably well established Bipolar disorder Depressive episode Bipolar II disorder Rapid-cycling bipolar I disorder Cyclothymic disorder Major depressive disorder Acute depression (as an augmenting agent) Maintenance therapy Schizoaffective disorder

Evidence of benefit in particular groups Schizophrenia Aggression (episodic), explosive behavior, and selfmutilation

Conduct disorder in children and adolescents Mental retardation Prisoners

Anecdotal, controversial, unresolved, or doubtful Alcohol and other substance-related disorders

Cocaine abuse Substance-induced mood disorder with manic features

Anxiety disorders Obsessive-compulsive disorder Phobias Posttraumatic stress disorder

 Attention-deficit/hyperactivity disorder Eating disorders Anorexia nervosa Bulimia nervosa Impulse-control disorders Mental disorders due to a GMC(e.g., mood disorder

due to a general medical condition with manic features) Periodic catatonia Periodic hypersomnia

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

emotionally unstable, schizotypal) Premenstrual dysphoric disorder Sexual disorders Transvestic fetishism Exhibitionism Pathological hypersexuality