Antimanic (Mood Stabilizing) Drugs

ANTIMANIC (MOOD STABILIZING) DRUGS

Lithium Carbonate

Lithium is a small monovalent cation. In 1949, it was found to be sedative in animals and to exert beneficial effects in manic patients.

In the 1960s and 1970s the importance of maintaining a narrow range of serum lithium concentration was realized and unequivocal evidence of its efficacy was obtained. Lithium is a drug of its own kind to suppress mania and to exert a prophylactic effect in bipolar manic depressive illness (MDI) at doses which have no overt CNS effects. Lithium is established as the standard antimanic and mood stabilizing drug. Over the past 2 decades, several anticonvulsants and antipsychotics have emerged as alternatives to lithium with comparable efficacy.

Actions And Mechanism

1. CNS

Lithium has practically no acute effects in normal individuals as well as in MDI patients. It is neither sedative nor euphorient; but on prolonged administration, it acts as a mood stabiliser in bipolar disorder. Given to patients in acute mania, it gradually suppresses the episode taking 1–2 weeks; continued treatment prevents cyclic mood changes. The markedly reduced sleep time in manic patients is normalized.

The mechanism of antimanic and mood stabilizing action of lithium is not known. It has been argued that:

a) Li+ partly replaces body Na+ and is nearly equally distributed inside and outside the cells (contrast Na+ and K+); this may affect ionic fluxes across brain cells or modify the property of cellular membranes.

b) Lithium has been found to decrease the release of NA and DA in the brain of treated animals without affecting 5HT release. This may correct any imbalance in the turnover of brain monoamines.

c) The above hypothesis cannot explain why Li+ has no effect on people not suffering from mania.

An attractive hypothesis has been put forward based on the finding that lithium inhibits hydrolysis of inositol1phosphate by inositol monophosphatase. As a result, the supply of free inositol for regeneration of membrane phosphatidylinositides, which are the source of IP₃ and DAG, is reduced (Fig. 32.1). The hyperactive neurones involved in the manic state may be preferentially affected, because supply of inositol from extracellular sources is meagre. Thus, lithium may ignore normally operating receptors, but ‘search out’ and selectively, though indirectly, dampen signal transduction in the overactive ones.

2. Other Actions

Lithium inhibits the action of ADH on distal tubules and causes a diabetes insipidus like state.

It has some insulin-like action on glucose metabolism.

Leukocyte count is increased by lithium therapy. Lithium reduces thyroxine synthesis by interfering with iodination of tyrosine.

Pharmacokinetics And Control Of Therapy

Lithium is slowly but well absorbed orally and is neither protein bound nor metabolized. It first distributes in the extracellular water and then gradually enters cells and slowly penetrates into the CNS, ultimately attaining a rather uniform distribution in total body water; apparent volume of distribution at steady state averages 0.8 L/kg.

Lithium is handled by the kidney in much the same way as Na+. Most of the filtered Li+ is reabsorbed in the proximal convoluted tubule. When Na+ is restricted, a larger fraction of filtered Na+ is reabsorbed, so is Li+. After a single dose of Li+ urinary excretion is rapid for 10–12 hours, followed by a much slower phase lasting several days. The t½ of the latter phase is 16–30 hours. Renal clearance of lithium is 1/5 of creatinine clearance. On repeated medication steady state plasma concentration is achieved in 5–7 days. Levels are higher in older patients and in those with renal insufficiency.

There is marked individual variation in the rate of lithium excretion. Thus, with the same daily dose, different individuals attain widely different plasma concentrations. However, in an individual the clearance remains fairly constant. Since the margin of safety is narrow, monitoring of serum lithium concentration is essential for optimal therapy. Serum lithium level is measured 12 hours after the last dose to reflect the steady state concentration; 0.5–0.8 mEq/L is considered optimum for maintenance therapy in bipolar disorder, while 0.8–1.1 mEq/L is required for episodes of mania. Toxicity symptoms occur frequently when serum levels exceed 1.5 mEq/L.

Peaks in plasma lithium level over and above the steadystate level occur after every dose. Divided daily dosing in 2–4 portions is needed to avoid high peaks. Lithium is excreted in sweat and saliva also. Lithium is secreted in breast milk. Mothers on lithium should not breastfeed.

Adverse Effects

Side effects are common, but are mostly tolerable. Toxicity occurs at levels only marginally higher than therapeutic levels.

1. Nausea, vomiting and mild diarrhoea occur initially, can be minimized by starting at lower doses.

2. Thirst and polyuria are experienced by most, some fluid retention may occur initially, but clears later.

3. Fine tremors and rarely seizures are seen even at therapeutic concentrations.

4. CNS toxicity manifests as plasma concentration rises—coarse tremors, giddiness, ataxia, motor incoordination, nystagmus, mental confusion, slurred speech, hyperreflexia. Overdose symptoms are regularly seen at plasma concentration above 2 mEq/L. In acute intoxication these symptoms progress to muscle twitchings, drowsiness, delirium, coma and convulsions. Vomiting, severe diarrhoea, albuminuria, hypotension and cardiac arrhythmias are the other features.

Treatment

It is symptomatic. There is no specific antidote. Osmotic diuretics and sod. bicarbonate infusion promote Li+ excretion. Haemodialysis is indicated if serum levels are > 4 mEq/L.

1. On long-term use, some patients develop renal diabetes insipidus. Goiter has been reported in about 4%. This is due to interference with iodination of tyrosine → decreased thyroxine synthesis. However, hypothyroidism is rare. Thyroxine administration inhibits TSH and reverses thyroid enlargement.

2. Lithium is contraindicated during pregnancy: foetal goiter and other congenital abnormalities, especially cardiac, can occur; the newborn is often hypotonic.

3. Lithium is contraindicated in sick sinus syndrome.

Interactions

1.   Diuretics (thiazide, furosemide) by causing Na+ loss promote proximal tubular reabsorption of Na+ as well as Li+ → plasma levels of lithium rise.

2.   Tetracyclines, NSAIDs and ACE inhibitors can also cause lithium retention.

3.   Lithium reduces pressor response to NA.

4.   Lithium tends to enhance insulin/sulfonylurea induced hypoglycaemia.

5.   Succinylcholine and pancuronium have produced prolonged paralysis in lithium treated patients.

6.   Neuroleptics, including haloperidol, have been frequently used along with lithium without problem; sometimes, the combination of haloperidol and lithium produces marked tremor and rigidity. The neuroleptic action appears to be potentiated by lithium.

Use

Lithium is used as its carbonate salt because this is less hygroscopic and less gastric irritant than LiCl or other salts. It is converted into chloride in the stomach.

LICAB, LITHOSUN 300 mg tab, 400 mg SR tab.

It is generally started at 600 mg/day and gradually increased to yield therapeutic plasma levels; mostly 600– 1200 mg/day is required.

1. Acute Mania (inappropriate cheerfullness or irritability, motor restlessness, nonstop talking, flight of ideas, little need for sleep and progressive loss of contact with reality; sometimes violent behaviour): though lithium is effective, response is slow and control of plasma levels is difficult during the acute phase. Most prefer to use a neuroleptic, generally by i.m. route, with or without a potent BZD like clonazepam/ lorazepam, and start lithium after the episode is under control. Maintenance lithium therapy is generally given for 6–12 months to prevent recurrences.

2.  Prophylaxis In Bipolar Disorder

Lithium has proven efficacy in bipolar disorder: is gradually introduced and maintained at plasma concentration between 0.5–0.8 mEq/L. Such treatment lengthens the interval between cycles of mood swings: episodes of mania as well as depression are attenuated, if not totally prevented. Bipolar disorder is the most common and definite indication of lithium. Risks and benefits of prolonged (almost indefinite) lithium therapy are to be weighed in individual cases. Patients have been maintained on lithium therapy for over a decade. Most cases relapse when lithium is discontinued. Withdrawal, when attempted should be gradual over months.

Recurrent unipolar depression also responds to lithium therapy. Combination of antidepressant + lithium is often used initially, and lithium alone is continued in the maintenance phase.

3. Lithium is being sporadically used in many other recurrent neuropsychiatric illness, cluster headache and as adjuvant to antidepressants in resistant nonbipolar major depression.

4. Cancer chemotherapy induced leukopenia and agranulocytosis: Lithium may hasten the recovery of leukocyte count.

5. Inappropriate ADH secretion syndrome: Lithium tends to counteract water retention, but is not dependable.

Alternatives To Lithium

Approximately 50% patients of mania and bipolar disorder (especially rapidly cycling cases) show incomplete or poor response to lithium. Many do not tolerate it, or are at special risk of toxicity.

Alternatives are:

1. Carbamazepine

Soon after its introduction as antiepileptic, carbamazepine (CBZ) was found to prolong remission in bipolar disorder. Its efficacy in mania and bipolar disorder has now been confirmed and is rated almost equal to lithium. Patients who relapse on lithium therapy or those prone to rapid cycling of mood state do better on combined lithium + CBZ treatment. Since CBZ therapy is easier to manage and better tolerated than lithium, it is being increasingly used as firstline/adjunctive treatment for acute mania as well as bipolar illness. The dose and effective plasma concentration range is the same as for treatment of epilepsy. However, its efficacy in long-term prophylaxis of bipolar illness and suicides is less well established.

2. Sodium Valproate

A reduction in manic relapses is noted when valproate is used in bipolar disorder. It is now a first line treatment of acute mania in which high dose valproate acts faster and is an alternative to antipsychotic ± benzodiazepine. It can be useful in those not responding to lithium or not tolerating it. Patients with rapid cycling pattern may particularly benefit from valproate therapy. A combination of lithium and valproate may succeed in cases resistant to monotherapy with either drug. Valproate has a favourable tolerability profile. Dosage guidelines are the same as for epilepsy.

3. Lamotrigine

This newer anticonvulsant is now an approved drug for bipolar disorder, but is not recommended for acute mania. It is especially useful in rapidly cycling bipolar depression. Randomized trials have demonstrated its efficacy, both as monotherapy as well as adjuvant to lithium. It carrys minimal risk of inducing mania. The tolerability profile of lamotrigine is favourable.

4. Topiramate

 Few open studies have found it to be useful as adjunctive therapy of bipolar disorder, but efficacy needs to be established.

Gabapentin also has shown some prophylactic effect in bipolar disorder.

5. Atypical antipsychotics:

Olanzapine, risperidone and newer atypical antipsychotics aripiprazole, quetiapine, with or without a BZD, are now the first line drugs for control of acute mania, except cases requiring urgent parenteral therapy, for which the older neuroleptics are still the most effective.

Olanzapine is also approved for maintenance therapy of bipolar disorder. Because it carrys a low risk of inducing extrapyramidal side effects or agranulocytosis, it is being increasingly used as adjuvant/alternative to lithium for prophylaxis of cyclic mood swings. The usefulness of other atypical antipsychotics as prophylactic in bipolar illness is not established, but there are reports of beneficial effect.