Mood stabilizers

Prepared by: Maryam Abdulwahid Tanya Muhammad Hawar Jarjees Hedi Hamid Supervised by:

Dr. Suzan

Mood stabilizers

• mood stabilizers are medicines used in treating mood disorders such as bipolar disorder and

depression.

Bipolar Disorder:•Bipolar disorder, also called manic depression, is characterized by severe mood swings from manic highs to depressive lows. These cycles can last for months at a time. symptoms of bipolar disorder can include:ManiaDepressionImpulsive behaviorsFeelings of hopelessnessHallucinationsDelusionsLethargyInability to focusImpaired judgmentSuicide risks

Types of bipolar disorder

– Bipolar disorder type IBipolar disorder type I is the classic form of the disease in which patients have periodic episodes of mania and depression.

– Bipolar disorder type IIIs the form in which patients do not develop severe mania but go through episodes of hypomania that alternate with milder depression.

– Rapid cycling bipolar disorder when patients exhibit more than four manic or depressive episodes.

Types of mood stabilizers

1. Lithium2. Anticonvulsant medicines3. Antipsychotic medicines

The goals

• 1) reduce residual symptoms• 2) prevent manic or depressive relapse• 3) reduce the frequency of cycling into the next manic or

depressive episode.• 4) improve functioning.• 5) reduce the risk of suicide.

How long do they take to work?

•Lithium may take a week or more to begin working.•Anticonvulsants such as valproate and the antipsychotics olanzapine and aripiprazole may work more rapidly to control a manic episode.•Until the mood stabiliser takes effect, other medicines such as anipsycotics or sedatives are initially used help control an episode of mania.• people with bipolar disorder continue treatment with mood stabilisers for extended periods of time (usually at least two years) to help prevent episodes of ill health.•Other medicines may be added when necessary, typically for shorter periods, to treat episodes of mania or depression that break through despite the mood stabiliser.•Some people with bipolar disorder do better with a combination of mood stabilisers to help prevent episodes of high and low mood. For example, lithium or valproate may be used together with an antipsychotic.

Lithium• Lithium was one of the first mood stabilizers used in the

treatment of bipolar disorder. • Lithium is a simple ion like sodium found in table salt (sodium

chloride). Lithium comes in two forms—lithium carbonate (Eskalith-CR, Lithobid Extended-Release) and lithium citrate.

• Lithium carbonate is available in immediate- and controlled-release capsules and tablets.

• Lithium also comes in a liquid preparation in the form of lithium citrate. Over several decades of clinical experience, lithium has been shown to be effective not only in treating mania but also in preventing relapse of mania and depression in bipolar disorder.

• Is clinically effective at plasma concentration of (0.5_1) mmol/l (narrow therapeutic limit).

• Above 1.5mmol/l produces toxic effects.• 1 mmol/l of lithium can produce many detectable

biochemical changes but it has no psychotropic effects

PHARMACOLOGICAL AND MECHANISM OF ACTION:

The therapeutic actions

1.Interference with inositol triphosphate formation:The phosphatidylinositol(pi)pathway is blocked at a point where inositol phosphate is hydrolyzed to free inositol.This step is required for the regeneration of PI in the membrane after it has been hydrolyzed by agonist action.Lithium thus causes depletion of membrane PI and accumulation of intracellular inositol phosphate. The result is inhibition of agonist stimulated inositol triphosphate formation(stimulates release of calcium) through various linked Pi linked receptors, therefore block of many receptor mediated effects.

2. interference with cAMP production: hormone induced cAMP production is reduced For example; The response of renal tubular cells to ADH and of thyroid to TSH

• Effect of lithium on these2 second messenger systems accounts for its therapeutic effects.

Pharmacokinetics and toxicity:

• Is given orally as carbonate salt two or three times daily during meals, often with a higher dosage in the evening. The sustained release formulation is taken only once in the evening.

• its excreted by kidney• Half of an oral dose is excreted with in 12 hours and the

remainder that represents the lithium taken up by cells is

excreted over the next 1_2 weeks. so the lithium is accumulated slowly with in that 2 weeks

before a steady state is reached.

Lithium toxicity

• Lithium therapy requires reaching plasma concentrations of lithium which are relatively close to the toxic concentration.

• depletion of sodium reduces the rate of excretion of lithium by increasing reabsorption of lithium from proximal tubule .

• Diuretics acting on proximal tubule have the same effect.• Renal diseases also predispose to lithium toxicity.

To prevent toxicity:

• adequate renal function and adequate salt and fluid intake are essential.

• a decision to initiate lithium therapy should be preceded by a thorough clinical examination and evaluation of each patient, including laboratory determinations, ECG, and a very careful assessment of renal function.

• monitoring of plasma concentration is needed especially

in case of renal disease, in patients who sweat profusely, experience diarrhea or vomiting, with infection or fever causing fluid loss.

Side effects of lithium

•Nausea, vomiting, and diarrhea.•Trembling.•Increased thirst and increased need to urinate.•Weight gain in the first few months of use.•Drowsiness.•A metallic taste in the mouth.•Abnormalities in kidney function.•Abnormalities in thyroid function.

Contraindications of lithium

• renal or cardiovascular disease• sodium depletion• dehydration• patients on diuretics • during pregnancy and lactation

Anticonvulsants

• Carbamazepine(Carbatrol, Tegretol, and Tegretol-XR)

• valproic acid (Depakene) • divalproex (Depakote)• lamotrigine (Lamictal )• gabapentin (Neurontin )• topiramate (Topamax)• oxcarbazepine (Trileptal)

• these medications are more recently being used to treat bipolar disorder.

• about 40% of bipolar pts. are not helped by Li or cannot tolerate the Li SEs…thus, need an alternative treatment.

Valproate

• Is a simple monocarboxylic acid.• now the 1st choice for treatment of mania (even over Li)• actually less effective than Li in treating mania, but does also

help decrease depression more effectively than Li• Effective in 71% of patients.• Is especially good for treatment of acute mania (alone or with

antipsychotic meds)• Has low toxicity and lacks sedation.

MECHANISM OF ACTION:

• a GABA agonist (enhances synthesis/release of GABA)• Is aweak inhibitor of GABA transaminase and succinic semi

aldehyde dehydrogenase.• a glutamate antagonist• 50% plasma protein bound• is a liver enzyme inhibitor (of P450 enzymes)

Carbamazepine

• Carbamazepine (Carbagen SR, Tegretol, Tegretol retard) was the first anticonvulsant to be discovered as an effective mood stabiliser as well as a treatment for epilepsy.

• It tends to cause more side effects than valproate and is less effective than lithium. It is usually only used in people who have been unresponsive to lithium, however it may be better for rapid cycling bipolar illness.

• Many people find that carbamazepine causes unwanted side-effects, and it can also interact with several other medicines. Oxcarbazepine (Trileptal) is related to carbamazepine, but has less potential to affect other medicines and so may sometimes be used instead.

pharmacokinetics:

• Is well absorbed.• 75% protein bound.• Plasma half life is about 30 hours when given as a single

dose and shortens to 15 hours when given repeatedly.• is a liver enzyme inducer (CYP-3A4 especially)

Side effects

DrowsinessDizzinessAtaxiaWater retentionGastrointesinal distressCardiovascular side effectsBone marrow suppression leading to neutropenia(rarely)decrease the amount of platelets.

Contraindication • Pregnant women should not take anticonvulsants

without consulting with their doctor because they may increase the risk of birth defects.

• Many anticonvulsants can cause problems with the liver over the long term. Also, anticonvulsants can interact with other drugs, even aspirin and cause serious problems.

Antipsychotics

A. Typical Antipsychotics: Are blockers of dopamine D2 postsynaptic receptors, includes:• Phenothiazines :, fluphenazine, trifluoperazine,

thioridazine,Chlorpromazine• Thioxanthines : chlorprothixene, thiothixene• Butyrophenones : haloperidol, droperidol, Others :loxapine,

molindone, pimozide

B.Atypical Antipsychotic Drugs:

Lower relative blockade of D2 receptors, no or low Extra pyramidal effects.

Includes:• Clozapine • Risperidone • Olanzapine • Quetiapine : Similar to clozapine• Sertindole• Aripiprazole

MECHANISM OF ACTION:

•Antipsychotic effects correlate with effect on mesolimbic/mesocortical dopamine pathway.

• There are two classes of dopamine receptors: D1 includes D1 and D5 receptors and D2 include D2, D3, and D4 receptors.

• D2 receptors are the main targets for the antipsychotic activity. If the 80% of the D2 receptors get occupied, then it causes the antipsychotic activity.

• Most of them also block other monoamine receptors especially5-HT2 receptor. Clozapine also blocks D4 receptor.• Many of antipsychotics also block cholinergic,adrenergic, and histaminergic receptors (resulting in side effects).• antipsychotic drugs takes some week to show their action even though they bind as soon as they are administered.

PHARMACOKINETICS:

• The levels of the antipsychotics in the plasma and their effect is not related.

• incompletely absorbed.• Significannt 1st pass metabolism.• Most are highly lipid soluble.• Most are highly protein bounded(92_98 %)• High volume of distribution.• the toxicity caused by these drugs is very less.• Plasma half life : 15 to 30 hours• Route of administration : oral route or IM injection

Side effects:

A.EXTRAPYRAMIDAL MOTOR DISTURBANCE: by blockage of niigrostriatal pathway.

B. On endocrine system: Neurons present in the tuberohypophyseal pathway liberatedopamine which is stops the prolaction secretion. Soantiphychotics disturbs this process and more amount of prolactin

is produced .

• Sedation , weight gain and hypotension are also common.

• dry mouth, blurred vision• Obstructive jaundice with phenothiazine some times• With clozapine leucopenia is common requiring

routine monitoring.• Antipsychotic malignant syndrome is rare but

potentially dangerous.

Side effects:continued

Contraindications •hypersensitivity •blood dyscrasias•Parkinson’s disease •severe hypotension

Reference • Rang & Dale’s Pharmacology, 6th Edition, Chapter 38 (John A. Harvey, Ph.D.)• http://www.webmd.com/bipolar-disorder/mood-stabilizi

ng-medications-for-bipolar-disorder• http://www.pharmainfo.net/sivaganesh/blog/

antipsychotics• http://

support4hope.com/medications/mood_stabilizers/index.htm

• http://en.wikipedia.org/wiki/Lithium_pharmacology

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