Sodium valproate was discovered in 1882 as a component of valerian plant juice and was later found to have anti-convulsant and anti-manic properties. It is effective in treating acute mania and preventing manic relapse in bipolar disorder, though has little effect on bipolar depression. Common side effects include gastrointestinal issues, sedation, and potential impacts on renal, hepatic and endocrine system function. Careful monitoring is required due to risks including teratogenicity, hepatotoxicity and hyponatremia. It has a rapid onset of action in mania but is generally considered a second-line option for bipolar prophylaxis.

1. Role of Sodium Valproate in
Bipolar Disorder
Dr. Ahsan Aziz
Assistant Registrar, NIMH

2. Discovery
Separated from juice of
Valeriana plant in 1882.
Anti-convulsant property
In 1963 and Anti-manic
property in 1968.

3. Compounds available
Valeric acid in plant
Valproate is the chemically synthesized form
Valproic Acid
Sodium Valproate (Na.Val:Valproic acid = 2:1)
Semi-Sodium Valproate (1:1)

4. Pharmacokinetics
Branch carboxylic acid. Rapidly and completely
absorbed in 1-2hrs. Valproate reaches peak in 4-5hrs.
Half life 10 to 16 hrs.
Highly protein bound. Metabolized by glucuronidation
and beta-oxidation.
Excreted mainly through urine.

5. Pharmacodynamics
Increases release or decreases reuptake and
breakdown of GABA.
Blockage of voltage sensitive sodium channel.
Decreases Inositol concentration.
Inhibit Histone deacetylase.

6. Pharmacodynamics
Valproate treats acute mania.
Valproate prevents manic relapse.
Valproate has little anti-depressant effect and
little efficacy in preventing depressive
relapse.

7. Dosage
 10-60mg/kg body weight
 Serum conc. level 50-125mg/L
 Once daily dose can be given with CR preparation

8. Bipolar disorder
 Bipolar ¼ : Unipolar depression responds
rapidly
 Bipolar ½ : Schizoaffective
 Bipolar I Disorder
 Bipolar II Disorder
 Bipolar III Disorder : Medication induced
hypo/Mania

9. Bipolar Disorders:
 Bipolar IV Disorder: Hyperthymic personality with
depression
 Bipolar V Disorder: Depression with mixed
hypomania
 Bipolar VI Disorder : With dementia

10. Bipolar Disorder Rx:
Acute mania or hypomania:
Step 1: Antipsychotic or valproate or lithium
Step 2: Combination
Use benzodiazepine
Bipolar Depression:
Olanzapine+ fluoxetine; Lamotrigine, Lurasidone,
Quetiapine, Valproate or Lithium plus SSRI

11. Bipolar Disorder Rx:
Prophylaxis in bipolar disorder:
First line: Lithium
Second line: Valproate, Olanzapine,
Aripiprazole, Risperidone, Quetiapine
Third line: Carbamazepine, Lurasidone,
Lamotrigine

12. Valproate in Bipolar Disorder:
Acute mania
Bipolar depression as add on therapy to anti-
depressants, lamotrigine etc
Prophylaxis treatment
Rapid cycling
Mania with dysphoric state or Mixed episode
Substance use

13. Side effects
GIT: Anorexia, nausea, vomiting, diarrhea
 Due to synthesis of valproic acid in the stomach
 First month of treatment
 Rapid dose escalation
 Less with enteric coated tablet

14. Side effects
Neuropsychiatric: Sedation, drowsiness,
tremor, ataxia, dysarthria, nystagmus, diplopia
Possible mechanism could be decrease dopamine
level
DA and NE imbalance
Degeneration of substantia nigra cell in mice

15. Side effects
Renal/fluid balance: Hyperammonia,
Hyponatremia
Interfere with urea cycle
Inappropriate secretion of ADH
Reversible with dose reduction or stoppage

16. Side effects
Endocrine: Menstrual disturbance, weight gain,
PCOS, hirsutism, acne
Hyperinsulinemia and Insulin resistance
Stimulate androgen biosynthesis in the gonad via
inhibition of histone deacetylases
Aromatase inhibitor; decreases oestrogen
concentration

17. Side effects
Hair loss, curly hair
3.5-12% cases
Dose related. Occurs when serum conc. Exceeds
100 µg/ml
Hair regrowth within 3 months of drug stoppage
Biotin, zinc, selenium deficiency may be
responsible.

18. Side effects
Low platelet count, abnormal platelet
aggregation
5-20% of patients receiving high dose of
valproate
Reversible
Increase risk of stroke in old age

19. Side effects
Hepatitis: hyperammonia, elevated liver
enzyme and acute failure
Pancreatitis (1 in 1,000)
Encephalopathy
Teratogenicity (20 times increased risk)
Histone deacetylase inhibition
Folate antagonism

20. Monitoring:
Pretreatment:
Weight, FBC, LFTs
On-treatment:
FBC, LFTs
Others:
USG of Abdomen, Pregnancy test, Ammonia
level, Serum electrolyte

21. Drug interactions
Lithium: Increased tremor ( Rx B-blocker)
Antipsychotics: Increased sedation
Lamotrigine: Increased risk of rash
Anti-coagulant: Increased risk of bleeding

22. Contraindications:
Pregnancy
Hepatic impairment
Inflammation of pancreas
Bleeding Disorder
Cautious use in child, elderly, renal
impairment, suicidal patient.

23. Comparison
Drug name Valproate Lithium Anti-psychotics
Onset of action 1-4 days
1 day with
loading dose
7-10 days 2-14 days
Anti-manic effect Yes Best Olanzapine is
better than
valproate
Manic relapse
prevention
Yes Yes Yes
Depressive
relapse
prevention
Little effect Little or no effect Quetiapine –Yes
Olanzapine –
Probably
Tolerability 75% discontinue
within 12 months
75% discontinue
within 25 months
75% discontinue
within 13 months

24. Key Points
Valproate is rapidly effective in acute mania
and can stabilize the patient in 5-7 days.
Valproate has little effect in bipolar depression,
usually used in combination with another drug.
2nd line choice in Bipolar prophylaxis.

25. ! Thank You !