Anti-manic drugsAnti-manic drugs

Anti-manic drugs or mood stabilizers are medications used suppress swings

between mania and depressionThey are effective in treating mania

and mood cycling, but are not effective in treating depression

Anti-manic Anti-manic drugsdrugs

Normal people have euthymic mood.Bipolar oscillate between mania and

depression

Anti-manic drugsAnti-manic drugs

1- Lithium2- Anticonvulsants

–Valproic acid [Depakote]–Carbamazepine [Tegretol]– Lamotrigine [Lamictal]

Classes of Anti-manic Classes of Anti-manic drugsdrugs

3- Atypical antipsychotics–Clozapine –Olanzapine –Risperidone

4- Benzodiazepines

LithiumLithium

Lithium ion, Li+, is the oldest and best known mood stabilizing drug

Lithium salts (carbonate, citrate) are the most commonly prescribed

60-80% success in reducing acute manic and hypomanic states

It reduces the risk of suicide related to bipolar disorder

Lithium: Therapeutic uses

1- Prophylaxis and treatment of mania 2- Prophylaxis of and maintenance treatment of bipolar

disorders (in combination with antidepressants) 3-Lithium augmentation (prophylaxis of recurrent

depression) in unipolar depression and schizophrenic in unipolar depression and schizophrenic patients who don't respond to treatment (i.e. used in patients patients who don't respond to treatment (i.e. used in patients who don’t have mania)who don’t have mania)

*** it can take up to a week for lithium to have an effect because it has a slow onset of action (3-4 days to act) so sedative drugs such as diazepam should be given

Pharmacokinetics

• Completely absorbed from the GIT• Peak plasma levels within 30 min to 2 hrs• Long plasma half-life (20 hr)• Not bound to plasma proteins• Not metabolized in the body• Distributed in all body fluids• Slow entry into intracellular compartment• Its concentration can be detected in plasma,

saliva, and urine.• Narrow therapeutic index – requires monitoring.

Lithium: Mechanism of Action

• Lithium has multiple actions and complex effects as it stabilizes neuronal activities:

• Lithium is a monovalent cation that can mimic the role of Na+ in excitable tissues, being able to permeate the voltage-gated Na+ channels that are responsible for action potential generation

• Lithium readjusts balances between excitatory & inhibitory neurotransmitters, and and

decreases glutamate activity decreases glutamate activity

Lithium: Mechanism of Action Lithium alters the cellular concentration

of the second messenger (IP3) second messenger (IP3) by iinhibiting inositol monophosphatase Lithium adjusts signaling activities

regulating transcription transcription

factors and gene expression factors and gene expression at at nuclear receptorsnuclear receptors

• Lithium salts have a narrow therapeutic / toxic ratio. Patients should know that:Patients should know that:

1- Plasma level monitoring is importantPlasma level monitoring is important. Doses are adjusted to achieve plasma concentrations of 0.4 to 0.4 to 1 mmol Li1 mmol Li++/liter /liter

2- Patients should know the early symptoms the early symptoms of toxicity; nausea, vomiting, diarrhea, ataxia, confusion, delirium

3- Monitoring of thyroid functionthyroid function4- - NSAIDs decrease lithium clearance in the

kidney

Lithium: Precautions

5- As lithium interferes with the regulation of sodium and water levels in the body it can cause dehydration. Patients must avoid dehydrationdehydration and heat and heat ,take plenty of fluids.

6- Concurrent use of thiazidesthiazides that inhibit the uptake of sodium by the distal tubule should be avoided. In mild cases, withdrawal of LiLi++ and administration of large amounts of sodium and fluid will reverse the toxicity

7- ContraindicatedContraindicated during pregnancy affects fetal heart development

Lithium: Precautions

Lithium: ToxicityLithium: Toxicity

Usually with serum lithium Usually with serum lithium concentrations of over 1.5 concentrations of over 1.5 mmol/Lmmol/L

1- GIT:1- GIT: anorexia, N & V, diarrhea **Earliest symptoms of toxicity

2-2-NeurologicalNeurological: tremors, ataxia, dysarthria, nystagmus and convulsions

3- Renal impairment3- Renal impairment: : polydipsia and polyuria (nephrogenic diabetes insipidus)

4- Psychotic effect: 4- Psychotic effect: Mental confusion

Lithium: ToxicityLithium: Toxicity

5-5- Changes in heartChanges in heart rhythm rhythm ““sick sinus syndrome”

6-Thyrotoxicosis Enlargement of thyroid gland with decreased

function (hypothyroidismhypothyroidism)

7-Skin: Skin: acne, hair loss, psoriasis

8- Teratogenic effectTeratogenic effect

Some atypical antipsychotics have mood stabilizing effects and are thus commonly prescribed even when

psychotic symptoms are absent •They affect glucose and lipid levels

and cause weight gain.

Atypical Atypical AntipsychoticsAntipsychotics

Atypical AntipsychoticsAtypical Antipsychotics

• Risperidone, clozapine, and olanzapine are used as mood stabilizers

• Risperidone is approved for the treatment of bipolar disease

• Olanzapine is approved for acute maniaassociated with bipolar disorder

• Clozapine is effective but have potential serious side effects

** Still lithium is superior in treatment of mania and hypomania

AnticonvulsantAnticonvulsant Mood Stabilizers Mood Stabilizers

• It is unclear how anticonvulsants work to stabilize mood

• However, some theories indicate that these drugs work in the same way that they act to control seizure activity

• The only difference is that they work on different parts of the brain

AnticonvulsantAnticonvulsant Mood Stabilizers Mood Stabilizers

•Carbamazepine, TegretolTegretol•Valproic acid, DepakoteDepakote• Lamotrigine, LamictalLamictal

Carbamazepine Carbamazepine

Therapeutic usesTherapeutic uses• As mood stabilizer, carbamazepine is

superior to LiLi++ for rapid-cycling rapid-cycling (bipolar)(bipolar)

• Second-line treatment for mania• Drug of choice in partial seizures & Tonic-

clonic seizures (also called grand-mal epilepsy)

Carbamazepine: Carbamazepine: mechanism of actionmechanism of action

Blockade of voltage-dependent sodium channels (↓cell excitability,

suppresses neuronal firing)Attenuates glutamate (excitatory)

Carbamazepine:Carbamazepine:Side effectsSide effects

• GIT upset, sedation, ataxia

• Induction of hepatic P450 : efficacy of other drugs e.g. failure of oral

contraceptive pills, oral anticoagulants “warfarin”• Severe bone marrow depression

(agranulocytosis , aplastic anemia) so contraindicated with clozapine

• Therapeutic drug monitoring is required Therapeutic drug monitoring is required because of narrow safety marginbecause of narrow safety margin

Valproate sodium Valproate sodium

Therapeutic usesTherapeutic uses– Acute mania– Maintenance / prophylaxis of bipolar

disease – More effective than lithium in rapid cycling

and mixed bipolar states– Adjuvant treatment in schizophrenia– It is effective for all forms of epilepsy

Valproate sodium: Valproate sodium: Mechanism of actionMechanism of action

It acts by several mechanismsBlockade of Na+ channels Potentiation of GABA (increasing synthesis and release)Blocks T-type Ca2+ channels

Valproate sodium: Valproate sodium: Side effects Side effects

1. Valproate is teratogenic, causing spina bifida and other neural tube defects

2. Transient hair loss3. Hepatotoxicity

4. Inhibition of P450 leading to interactions with other

antiepileptic drugs

Lamotrigine Lamotrigine Lamotrigine is effective in bipolar depression

MoA: Blocks Na+ channels (like carbamazepine )

Inhibits the release of the excitatory amino acid “glutamate”

Benzodiazepines:Benzodiazepines:in acute maniain acute mania

• In state of extreme mood elevation• Give rapid sedation• Useful until the effects of Lithium take place

Ex: Diazepam – long acting (~ 2 days) MOA: potentiate GABA-A receptors and

open Cl- channels → improve neuronal firing impulses