Mood Stabilisers Psychopharmacology

 The treatment of bipolar disorder may be divided into three overlapping phases –Acute manic episode –Depressive episode –Prophylactic treatment  Only 1/3 of bipolar patients experience adequate relief with a monotherapy.

How they work?  They have no clear effect on dopamine?? So why are they effective in mania?  They have no clear effect serotonin?? So why are they effective in depressive episodes?

Pregnancy categories

Lithium  First original mood stabiliser  Underutilised  Appears most effective in treating acute mania  First psychiatric drug that required blood level monitoring

Lithium  Manic episodes of bipolar disorder  Maintenance treatment for bipolar disorder  Bipolar depression  Major depressive disorder  Vascular headache  Neutropenia

Mechanisms  Generally unknown  Complex in action  Alters sodium transport across cell membranes  Alter metabolism of neurotransmitters catecholamines, serotonin, GABA and glutamate -May alter intracellular signalling through actions on second messenger systems

Second messenger systems  Method of cellular signalling  Cyclic adenosine monophosphate (cAMP)  intracellular signal transduction signal transductionsignal transduction  A different process of neurotransmission

Lithium  Effective within 1-3 weeks  Goal of treatment is a remission in symptoms  Many patients only have a partial response

Concept of Augmentation  the combination of two or more drugs to achieve better treatment results  Failure of monotherapy  Better tolerability

Pre-testing  Kidney function( should be repeated 1-2)  Thyroid function  ECG for patients over 50  Metabolic monitoring –Fasting plasma glucose level –Cholesterol and triglycerides –BMI

Side Effects  The reason to why lithium causes side effects is complex  Excessive actions at the same or similar sites that mediate actions  Renal side effects= acts on transportation of ions

Side Effects  Polyuria  Polydipsia  Diarrhoea  Nausea  Weight gain  Goiter  Acne, rash, alopecia  leukocytosis

Life Threatening Side Effects  Lithium toxicity  Renal impairment  Nephrogenic diabetes insipidus  Arrhythmias  Cardiovascular changes\sick sinus rhythm  Sick Sinus syndrome  Bradycardia  hypotension  T wave flattening and inversion

Toxicity  Toxic Levels are very close to therapeutic levels Symptoms; –Diarrhoea –Vomiting –Course tremor –Delerium –Coma –Seizures  Monitoring for dehydration

Dosing and Using  1800mg/day in divided doses (acute)  mg/day in divided doses( maintenance)  Dosage forms –450mg (slow release) –250mg tablets  start low and adjust dosage upward as indicated by plasma levels

Dosing  Slow release= less gastric irritation, lower peak plasma levels and peak dose side effects  Use the lowest dose of lithium associated with adequate therapeutic response  Go low in the elderly  Rapid discontinuation= increase relapse

Monitoring  Therapeutic Levels

Drug interaction Increase plasma levels;  NSAIDS  Diuretics  Angiotensin-converting enzymes  Anticonvulsants (carbemazepine and phenytoin)  Metronidazole  Calcium channel blockers Increase side effects  SSRI’s  Haloperidol

Special Populations  Elderly  Pregnancy  Breast feeding

Anticonvulsant medications  Sodium Valproate  Carbemazepine  Lamotrogine

Sodium Valproate  A first line treatment for bipolar disorder especially mixed state or rapid cycling bipolar.  Prescribed for; – Mania –Maintenance treatment of Bipolar Disorder –Seizures –Migraine prophylaxis

How does it work?  Blocks voltage- sensitive sodium channels  Increases brain concentrations of gamma-aminobutyric acid (GABA)  Relatively unknown why it does this

Sodium Valproate  Effects occur within a few days  Optimised at several weeks to one month  The goal is to see a remission in symptoms  Augmentation

Pre-testing  Platelet counts  Liver function testing  Coagulation tests  Metabolic monitoring

Sides Effects  Due to Excessive actions at voltage sensitive sodium channels Include; - Sedation- dyspepsia - Tremor- weight gain - ataxia - alopecia - tremor- polycystic ovarian syndrome - headache- hyperandrogenisam - Abdominal pain- hyperinsulinemia - nausea/vomiting- Lipid dysregulation - reduced appetite- decreased bone density - constipation

Life threatening/Dangerous Side Effects  Hepatotoxicity  Liver failure  Pancreatitis  Overdose –Restlessness –Hallucinations –Sedation –Heart block –Coma

Dosage and Use  Range;  Mania; mg/day  Migraine; mg/day  Epilepsy; 10-60mg/day  100mg, 200mg and 500mg tablets  Dosages are increased rapidly in the case of mania.  May need divided dose due to half life  Terminal mean half life of 9-16 hours  Metabolised by the liver

Drug interactions  Lamotrogine should be reduced by 50%  Plasma levels lowered by drugs such as;  Carbemazepine  Phenytoin  Plasma levels are increased by drugs such as;  Aspirin  Chlorpromazine  Fluoxetine  NSAIDS

Warnings  Hepatotoxicity  Malaise  Weakness  Lethargy  Facial edema  Anorexia  Vomiting  Jaundice skin and eyes  Pancreatitis  Abdominal pain  Nausea  vomiting

Special Populations  Elderly  Pregnancy  Breast feeding  Post partum issues

Carbamazepine  More commonly used to treat seizures  First anticonvulsant to be widely used in the treatment of Bipolar disorders  Potentially an advantage in treatment resistant bipolar and or psychotic disorders

How it works  Blocks voltage sensitive sodium channels  Interacts with the open channel conformation of sodium channels  Inhibits release of glutamate

Carbamazepine  Goal of treatment is remission of symptoms  Effect usually occur within a few weeks  Can be used a augment other medications

Pre testing  Blood count  Liver function  Kidney function  Thyroid function

Side effects  Sedation  Dizziness  Confusion  Unsteadiness  Headache  Nausea and vomiting  Diarrhoea  Blurred vision  Benign leukopenia  Rash  Weight gain

Dangerous side effects  Rare aplatic anemia  Agranulocytosis –Ususal bleeding –Infections –Fever –Sore throat  Steven Johnson syndrome (RASH)  Cardiac issues  SIADH

Dosage and Use  mg/day  Comes in slow release  Should always be taken with food

Pharmacokinetics  Metabolised in the liver by CYP450  Half life of hours initially then drops with repeated doses

Drug interactions  Other antiepileptic medications  Fluvoxamine, fluoxtetine  Decrease efficacy of benzodiazepines, clozapine, haloperidol, lamotrogine, epilum and warfarin  Can decrease effectiveness of the contraceptive pill  Lithium

Special Populations  Pregnancy Category D  Breast Feeding

Lamotrigine  Seems to be more effective in treating depressive episodes of bipolar  Used less than other anticonvulsants for Bipolar Disorder

How it works?  Voltage- gated sodium channel agonist  Inhibits the release of glutamate

Side effects  Benign rash (10%)  Sedation  Blurred vision  Dizziness  Ataxia  Headache  Tremor  Insomnia  Poor coordination  Fatigue  Nausea and vomiting  Can cause flu like symptoms in some people

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

Dosage and Use  Monotherapy mg/day  Halved if used with other medication  Monitor for rash

Pharmacokinetics  Elimination half life 33 hours  Higher if used concurrently with other anticonvulsant medication  Metabolised through the liver

Drug interactions  Depressive effects may be increased by other CNS depressants

Special populations  People with renal impairment  Hepatic Impairment  Elderly  Children and Adolescents  Pregnancy  Breast feeding

Atypical Antipsychotic Medication  Increasing use of antipsychotic medication  Olanzapine, Risperidone, Quetiapine, Ziprasidone and Aripripazole