MOOD STABILIZERS

Definition

No consensus definition.

Any medication that is able to decrease vulnerability to subsequent episodes of mania or depression; and not exacerbate the current episode or maintenance phase of treatment. (Sachs -1996)

“There is no such thing as a mood stabilizer”

-FDA

Brief History

1817 – Lithium was discovered as a chemical element.

1871 – First recorded use as a treatment of mania. 1876 – Li2CO3 used in the prevention of

depression. By the beginning of 20th century - use of Lithium

largely abandoned due to its toxicity. 1949 – Use of Lithium for mania rediscovered by

John Cade. 1970- FDA approved use of Lithium for mania. 1995- Sodium valproate approved for acute

mania.

Trivia

Soft drink 7up had contained Lithium citrate from 1929-1950.

Marketed as good for relieving alcoholic hangouts.

Drugs used as Mood Stabilizers

Lithium

Anticonvulsants- Carbamazepine, Sodium Valproate, Lamotrigine, Gabapentin & Pregabalin, Topiramate etc.

Atypical antipsychotics - Olanzapine, Quetiapine, Risperidone, Aripiprazole .

Lithium

Indications for use: 1. Acute treatment of mania 2. Prophylaxis of bipolar affective

disorder ( More effective in preventing manic than depressive relapse)

3. Augmentation of antidepressants in resistant depression

4. Prevention of aggressive behaviour in patients with learning difficulties

Lithium and suicide

Estimated suicide rate in bipolar

patients : 10-15%

Lithium reduces both attempted and

completed suicide by , 80%

Lithium : Mechanism of action

May work by affecting signal transduction

1. Through inhibition of 2nd messenger enzymes (eg: inositole monophosphate)

2. By modulation of G proteins

3. By interaction at various sites within downstream signal transduction cascades. ( eg: inhibition of GSK3, PKC)

Exact mechanism of action is not certain.

Lithium : Pre-treatment tests

Renal functions

Thyroid functions

ECG for patients with risk factors / existing cardiac disease.

Lithium : Monitoring

Narrow therapeutic index

Essential to measure plasma concentrations during treatment. 1st- 4-7 days 2 weekly until the plasma level is satisfactory 6 weekly 3 monthly when plasma level is very stable

unless more frequent monitoring is indicated. GFR, TFT – 6 monthly

Lithium : Plasma levels

For prophylaxis Minimum effective level : 0.4 mmol/L Optimal range : 0.6 - 0.75

mmol/L

Treatment of acute mania 0.8 - 1.0 mmol/L

Lithium : Adverse effects Fine tremour/ Dry mouth/ Metallic taste/ Fatigue Weight gain (esp. women) Hair loss/ coarsening of hair texture Polyuria/ polydipsia ( due to blocking of ADH) Nephrogenic diabetes insipidus ( reversible in short to

medium term Rx) Reduction in GFR ( 1/3 of young patients – GFR < 60mL/min) Interstitial nephritis ( Rarely) Thyroid enlargement ( 5% - reversible ) Hypothyroidism ( 20% of women) Hyperparathyroidism – hypercalcaemia Reversible ECG changes : T wave flattening,

inversion/widening of QRS Reversible leucocytosis Fetal abnormalities (esp. cardiac – Ebstein anomaly)

Lithium during pregnancy

Human teratogen.

Continuation during pregnancy should be considered carefully ( with likelihood of relapse during pregnancy)

If continued, plasma levels should be monitored closely.

Lithium toxicity

> 1.5mmol/L - Early toxic effects Gastrointestinal effects (increasing anorexia,

nausea, diarrhoea) CNS effects (muscle weakness, drowsiness,

ataxia,coarse tremor, poor coordination, slurring of speech, confusion, muscle twitching)

> 2.0mmol/L – Serious toxic effects Disorientation Seizures Coma Death

Lithium : Risk factors for toxicity

Mostly involve reduced plasma Na levels Low salt diet Dehydration Drug interactions ▪ diuretics (esp. Thiazides)▪ NSAIDS▪ ACE inhibitors▪ Angio.2 receptor blockers▪ some antibiotics like metronidazole

Lithium : Management of toxicity

Stop lithium immediately.

High intake fluids.

Extra NaCl to stimulate osmotic diuresis.

If level > 3.0 mmol/L Peritoneal / haemodialysis is indicated.

Lithium : Discontinuation

Risk of manic relapse ( even in patients symptomless for 5 years)

Recommended not to start Lithium without an intention to continue for at least 3 years.

Discontinuation should done slowly at least over 1 month.

Carbamazepine

Indications in mood disorders1. Treatment of acute mania2. Prophylaxis of bipolar disorder

Effectiveness in prophylaxis of unipolar/ bipolar depression is not well established.

Overall efficacy is less than that of Lithium.

Carbamazepine : Mechanism of action

Blocks voltage sensitive Na+ channels (VSSC) -At a site within the channel on alpha subunit

Reduces glutamate release

Decreases turnover of norepinephrine and dopamine.

Facilitates 5HT neurotransmission.

Carbamazepine : Adverse effects Drowsiness, dizziness, ataxia, diplopia,

nausea – common at the beginning of treatment

Agranulocytosis – Rare -1:10000 to 1:25000. Relative lecopenia – common. Rashes – 5% . Exfoliative dermatities- Rare. Elevation of LFT. Hepatitis – Rare. Disturbance of cardiac conduction. Teratogenicity ( Neural tube defects) Reduces plasma thyroxin level – clinical

hypothyroidism is rare.

Carbamazepine :

Pre-treatment tests : Baseline FBC, BU, SE, LFT - Recommended. Baseline weight.

Monitoring: Repeat FBC, BU, SE, LFT and Weight

measurement in 6 months. Use in women of childbearing age :

If cannot be avoided , adequate contraceptive method should be used.

Prophylactic folic acid 5mg/daily.

Oxcarbazepine

Structurally related to carbamazepine. Prodrug. Active form - eslicarbazepine. Mechanism of action – similar to

carbamazepine. Less sedating , less BM toxicity and less

hepatic enzyme inducing than carbamazepine.

Mood stabilizer effects not proven. Used off label due to better tolerability than

carbamazepine. (esp. for mania)

Sodium Valproate

Indications in mood disorders:1. Treatment acute mania2. Prophylaxis of bipolar disorder

Shown to be useful for patients unresponsive to Lithium and carbamazepine .

Believed to be more effective than Lithium in treating rapid cycling and mixed episodes of mania.

Sodium Valproate :Mechanism of action

Exact mechanism of action is uncertain.

Three possibilities:1. Inhibition of voltage-sensitive Na+

channels (VSSC) – Diminish excitatory glutamate neurotransmission.

2. Enhancing actions of GABA – promote inhibitory neurotransmission.

3. Regulating downstream signal transduction cascades – promote neuroprotection and long term plasticity.

Sodium Valproate : Adverse effects GI disturbances, tremour, sedation, tiredness –

common. Weight gain Transient hair loss Elevation of liver enzymes Thrombocytopenia Inhibition of platelet aggregation Acute pancreatitis Rashes Polycystic ovarian disease Teratogenicity – (Spina bifida, ASD, cleft palate,

hypospadias, polydactyly, craniosynostosis)

Sodium Valproate :

Pre- treatment tests: Baseline FBC, LFTs and weight.

Monitoring: Repeat FBC, LFTs after 6 months. Monitoring of BMI.

Use in women of childbearing age : should not be routinely used to treat bipolar

illness in women of childbearing age. If used, lowest possible dose is advisable. Prophylactic folic acid 5mg/daily.

Lamotrigine

Indications in mood disorders1. Acute treatment of bipolar depression2. Prophylaxis for bipolar depression

Used alone, it does not have significant acute or prophylactic anti-manic actions.

Lamotrigine : Mechanism of Action

Similar to carbamazepine

1. Blocks voltage sensitive Na+ channels (VSSC) -At a site within the channel on alpha subunit

2. Reduces excitatory glutamate neurotransmission.

Lamotrigine : Adverse effects

Rarely, serious side effects: Angioedema Steven Johnson syndrome Toxic epidermal necrolysis

Use in women of childbearing age : Risk of cleft palate – (low

risk)

Skin rashes – 3% , usually maculopapular

Nausea/headache/diplopia/blurred vision/dizziness/ataxia/tremor

Gabapentine & Pregabalin

Structural analogues of GABA. Mechanism of action :

inhibition of alpha-2 delta subunit of voltage-gated Ca++ channels.

Not considered to be effective mood stabilizers.

Anxiolytic, sedative and analgesic properties.

May be useful as adjunctive treatments to other mood stabilizers.

Topiramate

Anticonvulsant and antimigraine drug.

Not clearly effective as a mood stabilizer.

Mechanism of action: Enhance GABA function and Reduce

glutamate function by interfering with Na+ and Ca++ channels.

Useful as an adjunctive treatment in bipolar disorder by reducing weight gain, insomnia and anxiety.

Atypical antipsychotics as mood stabilizers Atypical antipsychotics proved to be

effective in preventing recurrence of mania.

New data suggest certain atypical antipsychotics are effective in , treating bipolar depression preventing recurrence of depression.

Proposed mechanisms

5HT2A antagonism Reduces glutamate hyperactivity – Action

shared by several anticonvulsants used as mood stabilizers.

Increasing trimonoamine neurotransmitters

(5HT, NA, DA) Important in improving mood in

depression.

Mood stabilizer Combinations

Majority of bipolar patients need treatment with several medications. Doses of each agent can be lowered to

tolerable levels . Synergy among agents provides greater

efficacy than a single agent in high dose.

Widely used combinations Atypical antipsy. + Lithium

Atypical antipsy. + Valproate

Lithium + Valproate

Lamotrigine + Valproate

Lamotrigine + Lithium

Lamotrigine + Lithium + Valproate

Dangerous combinations

Lithium + Carbamazepine

Neurotoxicity Lamotrigine + Carbamazepine