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MOOD STABILIZERS

Mood stabilizers

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An overview of commonly used mood stabilizers.

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Page 1: Mood stabilizers

MOOD STABILIZERS

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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

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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.

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Trivia

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

Marketed as good for relieving alcoholic hangouts.

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Drugs used as Mood Stabilizers

Lithium

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

Atypical antipsychotics - Olanzapine, Quetiapine, Risperidone, Aripiprazole .

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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

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Lithium and suicide

Estimated suicide rate in bipolar

patients : 10-15%

Lithium reduces both attempted and

completed suicide by , 80%

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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.

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Lithium : Pre-treatment tests

Renal functions

Thyroid functions

ECG for patients with risk factors / existing cardiac disease.

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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

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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

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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)

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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.

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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

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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)

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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.

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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.

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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)

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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.

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Widely used combinations Atypical antipsy. + Lithium

Atypical antipsy. + Valproate

Lithium + Valproate

Lamotrigine + Valproate

Lamotrigine + Lithium

Lamotrigine + Lithium + Valproate

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Dangerous combinations

Lithium + Carbamazepine

Neurotoxicity Lamotrigine + Carbamazepine

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