1. Anti-manic drugs

2. 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

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

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

5. 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

6. 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

7. 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.

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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.

15. 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

16. 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

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

18. 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)

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

20. 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

21. 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

22. 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

23. 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

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

25. 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