Mood Stabilisers

Psychopharmacology

Mood Stabilisers

 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  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)  900-1200mg/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 - ataxia - tremor - weight gain - alopecia polycystic ovarian syndrome - headache - Abdominal pain - nausea/vomiting - reduced appetite - constipation hyperandrogenisam hyperinsulinemia Lipid dysregulation decreased bone density

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

Dosage and Use

    Range;  Mania; 1200-1500mg/day  Migraine; 500-1000mg/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

 400-1200 mg/day  Comes in slow release  Should always be taken with food

Pharmacokinetics

 Metabolised in the liver by CYP450  Half life of 26-65 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 100- 200 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