Bipolar disorder involves mood swings between mania and depression. Drugs used to treat it include lithium, antiepileptics like valproate and carbamazepine, and atypical antipsychotics. Lithium is well-established as an antimanic and mood stabilizing drug. It works by altering signal transduction pathways and inhibiting enzymes like inositol monophosphatase. Lithium, valproate, and atypical antipsychotics are effective for acute mania, while lithium, lamotrigine, and some antipsychotics can help prevent future mood episodes as maintenance therapy. Careful monitoring of lithium levels is needed due to its narrow therapeutic window.

1. ANTIMANIC AND MOOD
STABILIZING
DRUGS
(Drugs for bipolar disorder)

2. Bipolar disorder (manic-depressive illness) is characterised by
mood changes which swing between mania and depression.
Severe mania
Severe Depression

3. Drugs For Bipolar disorder
• Lithium, an inorganic ion, taken orally as
lithium carbonate.
• Antiepileptic drugs (e.g., valproate,
carbamazepine, lamotrogine)
– - better side effect and safety profile.
• Atypical antipsychotic drugs (e.g. olanzapine,
risperidone, quetiapine, aripiprazole).

4. Lithium
• The psychotropic effect of lithium was
discovered in 1949 by Cade.
• Lithium is a monovalent cation that can mimic
the role of Na+ in excitable tissues.
• Lithium is established as the standard
antimanic and mood stabilizing drug.

5. Contd..
• Over the past 2 decades, several
anticonvulsants and atypical antipsychotics
have emerged as alternatives to lithium with
comparable efficacy.

6. Mechanism of action
1. Altering signal transduction pathways
2. Effect on electrolyte & ion transport
3. Inhibiting NT release.
Inhibiting inositol monophatase Inhibiting GSK3

7. Mechanism of action
• The biochemical effects of lithium are
complex, and it inhibits many enzymes that
participate in signal transduction pathways.
• Lithium is capable of altering G-protein
function.
• They use IP3 & DAG as second messengers.
• IP3 is metabolised to regenerate PIP2

8. Contd..
• Activity of these pathways is postulated to be
markedly increased during manic episodes
• The hyperactive neurons involved in the manic
state may be preferentially affected.
• Lithium inhibits the regeneration of PIP2 by
inhibiting an enzyme inositol monophosphatase
thereby decreasing the activity.

9. Inositol monophosphatase

10. Contd…
• Thus, lithium may ignore normally operating
receptors, but ‘search out’ and selectively,
though indirectly, dampen signal transduction
in the overactive receptors functioning
through phosphatidyl inositol hydrolysis.

11. Contd..
• Inhibition of glycogen synthase kinase 3
(GSK3) isoforms.
• GSK3 isoforms phosphorylate a number of key
enzymes involved in pathways leading to
apoptosis and degradation of BDNF.

12. MOA
2. Effect on electrolyte & ion transport
• Affect ionic fluxes across brain cells or modify
the property of cellular membranes.
3.Lithium decreases the presynaptic release of
NA and DA in the brain of treated animals
without affecting 5-HT release.

13. Other actions
• Lithium inhibits the action of ADH on distal
tubules in the kidney.
• An insulin-like action on glucose metabolism is
exerted
• Lithium inhibits release of thyroid hormones.
• Leukocyte count is increased by lithium
therapy.
Diabetes insipidus

14. Pharmacokinetics
• Well absorbed orally, but slowly.
• Attains uniform distribution in total body water
• The CSF concentration of Li+ is about half of
plasma concentration.
• Nearly 80% of the filtered Li+ is reabsorbed in the
proximal convoluted tubule.
• Initially rapid excretion, then slower in later
phase.
• T1/2 is about 24 Hrs
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15. Control of therapy
• Since the margin of safety is narrow,
monitoring of serum lithium
concentration(TDM) is essential for optimizing
therapy.
• On repeated medication, steady-state plasma
concentration is achieved in 5–7 days.
• Serum lithium level is measured 12 hours after
the last dose to reflect the steady-state
concentration

16. Contd..
• 0.5–0.8 mEq/L is considered optimum for
maintenance therapy in bipolar disorder
• 0.8–1.1 mEq/L is required for episodes of
acute mania.
• Exceed 1.5 mEq/L.- toxic symptoms

17. Adverse effects
• Gastrointestinal s/e can be seen during initiation of
therapy.
– Fine tremors and polyuira are frequent.
 CNS
– Mental confusion, coarse tremors, ataxia, nystagmus,
seizures etc..
– Occurs mainly when plasma level is high (2mEq/L)
- In acute intoxication these symptoms may progress to
coma and death. In association with hypotension &
cardiac arrhythmias,vomiting & diarrhoea

18. Treatment of acute toxicity
• It is symptomatic. There is no specific
antidote.
• Osmotic diuretics and sod. bicarbonate
infusion promote Li+ excretion.
• Haemodialysis is indicated if serum levels are
> 4 mEq/L.

19. Adverse effect
Renal:
– On long term use Nephrogenic Diabetes
Insipidus.
– Loss of ability of collecting tubules to conserve
water by influence of ADH (G protein).

20. Contd..
3.Cardiac Effects: Sick-sinus syndrome –
contraindicated – flattening of T wave
4. Thyroid Function: Decrease in thyroid
Function – goitre (G protein)
5. Pregnancy – contraindicated
– Foetal goitre, congenital abnormalities (cardiac
Ebstein’s anomaly )

21. Drug interaction
• Diuretics: Lithium clearance is reduced by 25%
with Diuretic e.g. furosemide, Thiazides.
• Tetracyclines, NSAIDs and ACE inhibitors can
also cause lithium retention.
• The neuroleptic action appears to be
potentiated by lithium.
• Lithium tends to enhance insulin/sulfonylurea
induced hypoglycaemia

22. Uses
1. Acute mania:
• lithium is effective in controlling acute mania, but
the effect develops after 1-2 wks.
• Initially with a second generation antipsychotic
such as olazapine/ Risperidone / aripiprazole in
conjuction with or without benzodiazepine.
• Start lithium/valproate after the episode is under
control.
• Maintenance lithium therapy is generally given for
6–12 months to prevent recurrences.

23. 2. Prophylaxis in Bipolar disorder
• Li+ is the mood stabilizer with the most robust
data on suicide reduction in bipolar patients.
• Li can reduce the frequency of manic or
depressive episodes in the bipolar patient and
therefore is considered a mood-stabilizing agent.
• Type I (mania episodes only or both manic and
depressive phases), Type II (cycles of hypomania
alternating with major depression)
• Lithium appear to work best in patients with
classic bipolar 1 disorders.(CMDT 2018)

24. Contd..
• Li+ is also efficacious in unipolar depressive
patients who respond inadequately to
antidepressant therapy.

25. Alternative to Lithium
Sodium Valproate:
– 1st line in acute mania.
• Patients with rapid cycling pattern may
particularly benefit from valproate therapy.
– Lithium resistance cases.
– Lithium + Valproate – resistance to
monotherapy

26. Carbamazepine
• Its efficacy in mania and bipolar disorder has
now been confirmed.
• Carbamazepine is less effective than lithium or
valproate in acute mania.
• It is a valuable alternative/adjunct to lithium.

27. Lamotrigine
• Lamotrigine-Prophylaxis of depression in
bipolar disorder.
• It is now extensively used in the maintenance
therapy of type II bipolar disorder
• Used as monotherapy as well as with Lithium

28. Atypical antipsychotics:
• Olanzapine, risperidone, aripiprazole,
quetiapine, with or without a BZD, are now
preffered drugs for control of acute mania.
• Aripiprazole has recently emerged as the
favoured drug for treatment of mania in
bipolar I disorder

29. MCQs
1.Drug of choice for rapid cyclers in manic –
depressive psychosis is:
A)Carbamazepine
B)Valproate
C)Phenytoin
D) Lithium
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30. 2.Drugs having proven efficacy in bipolar
depression is:
A)Carbamazepine
B)Valproate
C)Tiagabine
D) Lamotrigine
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31. Just to remember
• L- leucocytes
• I – Increased
• T – Tremors
• H- Hypothyroidism
• I- Increased
• U- Urine
• M- should be avoided in expectant MOTHER
as it causes Ebstein’s anomaly
Diabetes Insipidus

32. Thank you