Anti-manic drugs

Anti-manic drugs Anti-manic drugs or mood stabilizers are medications used suppress swings between mania and depression They are effective in treating mania and mood cycling, but are not effective in treating depression Normal people have euthymic mood. Bipolar oscillate between mania and depression

Anti-manic drugs 1- Lithium 2- Anticonvulsants Valproic acid [Depakote] Carbamazepine [Tegretol] Lamotrigine [Lamictal]

Classes of Anti-manic drugs 3- Atypical antipsychotics Clozapine Olanzapine Risperidone 4- Benzodiazepines

Lithium 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 patients who don't respond to treatment (i.e. used in patients 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 decreases glutamate activity

Lithium: Mechanism of Action Lithium alters the cellular concentration of the second messenger (IP3) by inhibiting inositol monophosphatase Lithium adjusts signaling activities regulating transcription factors and gene expression at nuclear receptors

Lithium: Precautions Lithium salts have a narrow therapeutic / toxic ratio. Patients should know that: 1- Plasma level monitoring is important. Doses are adjusted to achieve plasma concentrations of 0.4 to 1 mmol Li+/liter 2- Patients should know the early symptoms of toxicity; nausea, vomiting, diarrhea, ataxia, confusion, delirium 3- Monitoring of thyroid function 4- 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 dehydration and heat ,take plenty of fluids. 6- Concurrent use of thiazides that inhibit the uptake of sodium by the distal tubule should be avoided. In mild cases, withdrawal of Li+ and administration of large amounts of sodium and fluid will reverse the toxicity 7- Contraindicated during pregnancy affects fetal heart development

Lithium: Toxicity Usually with serum lithium concentrations of over 1.5 mmol/L 1- GIT: anorexia, N & V, diarrhea **Earliest symptoms of toxicity 2-Neurological: tremors, ataxia, dysarthria, nystagmus and convulsions 3- Renal impairment: polydipsia and polyuria (nephrogenic diabetes insipidus) 4- Psychotic effect: Mental confusion

Lithium: Toxicity 7-Skin: acne, hair loss, psoriasis 5- Changes in heart rhythm “sick sinus syndrome” 6-Thyrotoxicosis Enlargement of thyroid gland with decreased function (hypothyroidism) 7-Skin: acne, hair loss, psoriasis 8- Teratogenic effect

Atypical Antipsychotics 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 Antipsychotics Risperidone, clozapine, and olanzapine are used as mood stabilizers Risperidone is approved for the treatment of bipolar disease Olanzapine is approved for acute mania associated with bipolar disorder Clozapine is effective but have potential serious side effects ** Still lithium is superior in treatment of mania and hypomania

Anticonvulsant 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

Anticonvulsant Mood Stabilizers Carbamazepine, Tegretol Valproic acid, Depakote Lamotrigine, Lamictal

Second-line treatment for mania Carbamazepine Therapeutic uses As mood stabilizer, carbamazepine is superior to Li+ for rapid-cycling (bipolar) Second-line treatment for mania Drug of choice in partial seizures & Tonic-clonic seizures (also called grand-mal epilepsy)

Carbamazepine: mechanism of action Blockade of voltage-dependent sodium channels (↓cell excitability, suppresses neuronal firing) Attenuates glutamate (excitatory)

Carbamazepine: Side 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 because of narrow safety margin

Valproate sodium Therapeutic 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: Mechanism of action It acts by several mechanisms Blockade of Na+ channels Potentiation of GABA (increasing synthesis and release) Blocks T-type Ca2+ channels

Valproate sodium: Side effects Valproate is teratogenic, causing spina bifida and other neural tube defects Transient hair loss Hepatotoxicity Inhibition of P450 leading to interactions with other antiepileptic drugs

Lamotrigine Lamotrigine is effective in bipolar depression MoA: Blocks Na+ channels (like carbamazepine ) Inhibits the release of the excitatory amino acid “glutamate”

Benzodiazepines: in 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