Mood Stabilisers in Treatment of Bipolar Disorders

Types of Mood Stabilisers

1. Lithium

2. Sodium valproate

3. Carbamazepine

4. Lamotrigine

Lithium

Mechanism of action – unknown
     (possibly increase 5-HT function in the brain)

Pharmacokinetics

- onset: 5-7 days
- absorbed and excreted by kidney

- narrow therapeutic index (TI)

Caution!

1. conditions which raise lithium concentration

   - dehydration

   - sodium depletion, diarrhoea

   - thiazide therapy
2. conditions which is absolute/relatively contraindicated

   - CVS disease

   - acute infection

   - fever

   - pregnancy (teratogenicity)

Dosage

Acute mania: 0.8-1.5mmol/L

Prophylaxis/maintenance: 0.5-1.0mmol/L (or 1.2mmol/L)

Side Effects

Early
1. polyuria – dehydration (and risk of intoxication)

2. fine tremor (rx propranolol)

3. dry mouth

4. metallic taste

5. weakness and fatigue

Late

6. fine tremor

7. polydipsia (compensatory from polyuria)

8. hair loss

9. thyroid enlargement

10. hypothyroidism, cold intolerance

11. impaired concentration

12. weight gain

13. GI distress

14. sedation

15. acne

16. impaired memory

17. ECG changes (flattened T wave, widening of QRS)

Long Term

18. kidney failure – impaired concentrating ability

19. nephrogenic diabetes insipidus (interferes with ADH)

20. teratogenic (crosses placenta) – Ebsein’s anormaly

Toxicity Effect (>1.5mmol/L)

1. nausea, vomiting

2. diarrhea

3. coarse tremor

4. ataxia, dysarthria

5. muscle twitching, hyperreflexia

6. confusion, coma

7. convulsion

8. renal failure

9. cardiovascular collapse

Emergency Treatment of Lithium Toxicity

1. stop lithium immediately

2. high fluid intake

3. IV normal saline or hyperosmotic saline to stimulate osmotic diuresis

4. renal dialysis if necessary

Monitoring of Lithium Administration

1. baseline physical and laboratory assessment

2. hx and pe on CNS, GIT, metabolic, thyroid, renal

3. pregnancy test

4. ECG in patients >40yo

5. RP for BUN, serum creatinine, electrolyte, biannually

6. TFT – TSH biannually
7. serum lithium level measured after 4-7 days of administration

8. repeat weekly for x3/52

9. then repeat once every x3/12
10. repeat serum lithium when inefficacy or adverse effect

* timing of measurement must be 12 hours after last dose (at steady state level)

Drug Interactions

1. Increases lithium concentration in:

   - haloperidol

   - thiazide diuretics

   - muscle relaxants

   - antibiotics (metronidazole, spectinomycin)

   - anti-HT (ACEi, methyldopa)

2. Interactions with antipsychotics

   - potentiates extrapyramidal side effects

   - confusion, delirium

3. Interactions with SSRI or ECT

   - serotonin syndrome

Withdrawal Symptoms

1. irritability

2. emotional lability

3. relapse to mania

Indications

1. acute mania, classic features (rapid cycling ↓ efficacy)

2. bipolar maintenance

3. other mood disorder use

Sodium valproate

Mechanism of Action – increase GABA in CNS

Pharmacokinetics

- onset: 2-5 days

- metabolized in liver, excreted in kidney

Dosage

Starting: 250-500mg titrated upward by 250-500mg/day

Maintenance: 750-1250mg/day

Side Effects

1. sedation

2. tiredness, fatigue

3. tremor

4. GI disturbance

5. reversible hair loss (alopecia)

6. thrombocytopenia

7. weight gain

8. haemorrhagic pancreatitis

9. hepatotoxicity

10. teratogenic – neural tube defect
* monitor FBC and LFT for baseline and changes

Drug Interactions

1. Displacement of protein-bound drugs (antiepileptics)

   - increases plasma level

2. Inhibits metabolism of lamotrigine (give only 50% dose if combined treatment)

Indications

1. bipolar disorder, manic episode, rapid cycling

Lamotrigine

- effective in bipolar depression without inducing mania

- prevents depressive relapse in bipolar

Mechanism of Action – blocks sodium channel

Pharmacokinetics

- metabolized in liver, excreted in urine (65%), faeces (2%)

Dosage

Initial: 25mg/day for 2 weeks
Later: 50mg/day for next 2 weeks
Maximum dose: 100-300mg/day

Side Effects

1. skin reactions – rashes, SJ S, toxic epidermal necrolysis

2. nausea

3. headache, aseptic meningitis

4. tremor

5. dizziness

6. teratogenic (cleft palate)

Drug Interactions

1. Increases lamotrigine concentration in:

   - valproate

2. Combined lamotrigine-carbamazepine – Neurotoxicity

Carbamazepine

- fastest onset mood stabilizer (? citation needed)

- prevent recurrence of affective depression

- patients unresponsive to lithium

- rapidly recurring bipolar disorder

Mechanism of Action - blocks Na channels, inhibits AP

Pharmacokinetics

- onset: 5-7 days

- metabolized in liver

- excreted in urine (72%) and faeces (28%)

Dosage

Starting: 400mg/day, increased up to 800-1000mg/day

Side Effects

1. drowsiness

2. dizziness

3. nausea

4. diplopia (double vision)

5. skin rash

6. agranulocytosis, leukopenia, aplastic anaemia

7. hyponatraemia
8. elevated liver enzymes
9. teratogenic – neural tube defect

* monitor FBC, LFT for baseline and subsequent changes

Drug Interactions

1. increased metabolism of some drugs and OCP

Indications

1. bipolar disorder, mixed episode, rapid cycling

2. trigeminal neuralgia