Mood Stabilisers

1. Mood Stabilisers Psychopharmacology Vicki Smith MHPDU 06/07/2011

2. Mood Disorder - What Is It? Sustained disturbances of emotion Characterised by a full or partial manic or depressive syndrome not caused by any other physical of mental disorder

3. Mood Stabilisers • Antipsychotics • Lithium Carbonate • Lithicarb • QuilonumSR • Quetiapine • Seroquel • Seroquel • Olanzapine • Zyprexia • (IM, tablets, wafers) • Risperidone • RisperidalConsta • Risperidal • (tablets, quicklets) Anticonvulsants • Sodium Valproate • Epilim, Valpro, Valproate • Carbamazepine • Tegretol, Carbamazepine, Tegretol CR • Lamotrigine • Lamictal • Clonazepam • Paxam, Rivotril

4. Indications • Prevention & treatment of Manic episodes • Augmentation anti-depressants • Schizophrenia • Schizoaffective Disorder • Prevention of depression • Severe Aggression / Impulse Disorders • Personality Disorders

5. Lithium • First original mood stabiliser • Naturally occurring metallic element • First psychiatric drug that required blood level monitoring • Narrow therapeutic index (small margin between therapeutic dose & toxicity) • Effective within 1 – 3 weeks

6. Lithium - Actions • Generally unknown • Blocks voltage sensitive sodium channels • Alter metabolism of neurotransmitters catecholamine's, serotonin, GABA and glutamate • Metabolized by kidneys

7. Lithium Levels • < 0.5 mmol/L • Sub therapeutic • 0.8 to 1.2mmol/L • Therapeutic level • > 1.5 mmol/L • Adverse effects

8. Lithium – Adverse Effects 0.6-1.2mmol/L • Fine tremor in < 80% • > 30% have following: • Polydipsia • Polyuria (50-70%) • Weight gain • ECG changes • Fatigue, sedation 1.2 - 1.5 mmol/L • As for 0.6-1.2 mmol/L, together with: • Hypothyroidism (5%) reversible on stopping lithium • Rare: hyperparathyroidism • 1.5-2.0 mmol/L • Nausea & vomiting, dry mouth, abdominal pain, muscle weakness • Ataxia, dizziness, arousal / lethargy, nystagmus, slurred speech

9. Lithium – Toxicity 2.0-3.0 mmol/L • Anorexia, nausea & vomiting, circulatory collapse • Acute confusion, blurred vision, choreo-athetosis, clonic movements, deep tendon reflexes hyperactive, EEG changes, muscle fasciculations, seizures Treatment: • Gastric lavage if presenting early • Haemodialysis

10. Lithium levels - Toxicity >3.0 mmol/L • Life threatening • Coma and death may ensue

11. Toxicity Prevention • Avoid crash diets, diuretics, NSAID, Eno or Dexal • Adequate dietary salt & fluid intake • Take after meals to avoid G.I. upset • Replace lost fluid & salt (exercise, hot weather, G. I. Upset) • If dose forgotten, never double up, just take next due dose when due • Regular blood tests

12. Lithium - Drug interaction Increase plasma levels: • NSAIDS • Diuretics • Angiotensin-converting enzymes • Anticonvulsants (carbemazepine and phenytoin) • Metronidazole • Calcium channel blockers Increase side effects: • SSRI’s • Haloperidol

13. Unstable Lithium Levels Decrease in levels: • Missed doses • Drug interactions • Timing of blood test • Increased salt intake Increase in levels: • Increased dose • Drug interactions • Salt deficiency • Renal disease • Fluid loss: • Dehydration,  sweating, diarrhoea, vomiting, weight loss diets • Timing of blood test • Pregnancy

14. Sodium Valproate • A first line treatment for bipolar disorder especially mixed state or rapid cycling bipolar. • Blocks voltage- sensitive sodium channels • Increases brain concentrations of gamma-aminobutyric acid (GABA) • Effectiveness occurs within a few days • Optimised at several weeks to one month

15. Sodium Valproate - Actions • Generally unknown • Complex in action • Blockade of voltage dependent Na+ channels • Increased brain levels of gamma-aminobutyric acid (GABA) • The GABA-ergic effect is also believed to possibly contribute towards the antimanic properties of sodium valproate.

16. Sodium Valproate – Adverse Effects Common: • Nausea and Vomiting • Abdominal cramps • Anorexia • Diarrhoea • Indigestion • Increased appetite • Weight gain • Sedation • Tremor • Transient hair loss • Thrombocytopenia • Elevated liver transaminase levels Uncommon: • Severe hepatic dysfunction • Pancreatitis • Extrapyramidal syndrome • Hyperammonaemic encephalopathy • Hepatotoxicity • Liver failure • Pancreatitis

17. Carbamazepine • More commonly used to treat seizures • First anticonvulsant to be widely used in the treatment of Bipolar disorders • Blocks voltage sensitive sodium channels • Interacts with the open channel conformation of sodium channels • Inhibits release of glutamate • Effectiveness usually occurs within a few weeks, but may take several weeks to months for optimal mood stabilisation

18. Carbamazepine – Adverse Effects Common: • Dry mouth • Vomiting • Diarrhoea • Anorexia • Constipation • Abdominal pain • Dizziness • Headache • Ataxia • Drowsiness • Blurred vision • Diplopia • Rash Uncommon: • Agranulocytosis • aplastic anaemia • Severe skin reactions (including Stevens–Johnson syndrome) • SIADH (syndrome of inappropriate antidiuretic hormone secretion) • Arrhythmias • Orofacialdyskinesias • Hepatitis

19. Stevens Johnson’s Syndrome • Rare, serious rash • Bullae on the skin • Acute fever • Ulcers on the mucous membranes on lip, eyes, mouth and nasal passages • Management • Stop medication • Monitor and investigate organ involvement • May require admission

20. Lamotrigine • Used less than other anticonvulsants for Bipolar Disorder • Stabilises presynaptic neuronal membranes by blockade of voltage-dependent sodium channels, preventing the release of excitatory neurotransmitters, particularly glutamate and aspartate

21. Lamotrigine – Adverse Effects Common: • Dry mouth • Nausea and Vomiting • Diplopia • Dizziness • Ataxia • Blurred vision • Headache • Irritability • Somnolence • Tremor • Asthenia • Insomnia • Maculopapular rash • Arthralgia Uncommon: • Hepatic failure • Blood dyscrasias • Lupus-like reaction • Severe skin reactions: - Stevens–Johnson syndrome - Lyell syndrome

22. Clonazepam • Clonazepam is an anticonvulsant, which exhibits several pharmacological properties characteristic of the benzodiazepine class of medicines. • The exact site and mode of the anticonvulsant action of clonazepam is unknown. • Benzodiazepines enhance the polysynaptic inhibitory processes at all levels of the central nervous system. • Clonazepam is more effective in blocking spread of electrical activity in the lesion itself.

23. Clonazepam – Adverse Effects More common • Drowsiness • Somnolence • Ataxia • Behaviour problems • Hypersalivation • Fatigue • Muscle weakness • Vertigo • Lightheadedness • Tiredness • Lassitude • Dizziness Less common reactions • Agitation • Excitability • Irritability • Aggressive behaviour • Disturbances of concentration • Depression • Confusion • Bronchial • Hypersecretion • Anterograde amnesia • Restlessness • Disorientation

24. Use In Pregnancy - Category D It is recommended that: • women on antiepileptic drugs (AEDs) receive pre-pregnancy counselling with regard to the risk of foetal abnormalities • AEDs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication • if appropriate, folic acid supplementation (5 mg) should be commenced four weeks prior to and continue for 12 weeks after conception; specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered. • Patients should be counselled regarding the possibility of an increased risk of malformations and specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.

25. Use In Pregnancy - Category D • Lithium • Enters the foetal circulation and cases of disturbance of thyroid function of the newborn infant have been reported • Lithium during pregnancy may cause malformations of the cardiovascular system • Sodium valproate • If taken in the first trimester of pregnancy, is suspected of causing an increased risk of neural tube defects in the exposed foetus.

26. Use In Pregnancy - Category D • Carbamazepine • Although carbamazepine has been known to produce malformations in one animal species (the rat), the significance of this in humans is not known. • Lamotrigine • A weak inhibitor of dihydrofolatereductase and studies in rats have shown a decrease in folic acid during pregnancy. There is a theoretical risk of human foetal malformations when the mother is treated with a folate inhibitor during pregnancy.

27. Use In Pregnancy – Category B3 Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.

28. Use In Pregnancy – Category B3 • Quetiapine • The safety and efficacy of quetiapine during human pregnancy have not been established. • Olanzapine • Should be used in pregnancy only if the potential benefits justify the potential risk to the foetus. • Risperidone • The safety during human pregnancy has not been established. Reversible extrapyramidal symptoms in the neonate were observed following postmarketinguse of risperidone during the last trimester of pregnancy.

29. Use In Pregnancy – Category B3 • Clonazepam • Benzodiazepine • Crosses the placenta and appears in the foetus and may, after continuous administration during a large part of pregnancy, give rise to hypotonia, reduced respiratory function and hypothermia in the newborn child. • Withdrawal symptoms in newborn infants have occasionally been reported with this class of medicines.

30. References • MIMS Online (2011) • Therapeutic Guidelines (eTG complete) • The pharmacological treatment of bipolar disorder in primary care. The Medical Journal of Australia MJA 2010; 193 (4): S24-S30 • Bipolar disorder in adults - Treatment - Details - rapid-cycling and non-pregnant. BMJ Evidence Centre