Mood StabilisersMood Stabilisers

Psychopharmacology Psychopharmacology

Mood StabilisersMood Stabilisers

The treatment of bipolar disorder The treatment of bipolar disorder may be divided into three may be divided into three overlapping phasesoverlapping phases

– Acute manic episodeAcute manic episode– Depressive episode Depressive episode – Prophylactic treatmentProphylactic treatment

Only 1/3 of bipolar patients Only 1/3 of bipolar patients experience adequate relief with a experience adequate relief with a monotherapy.monotherapy.

How they work?How they work?

They have no clear effect on They have no clear effect on dopamine?? So why are they dopamine?? So why are they effective in mania?effective in mania?

They have no clear effect serotonin?? They have no clear effect serotonin?? So why are they effective in So why are they effective in depressive episodes?depressive episodes?

Pregnancy categoriesPregnancy categories

LithiumLithium

First original mood stabiliserFirst original mood stabiliser Underutilised Underutilised Appears most effective in treating Appears most effective in treating

acute maniaacute mania First psychiatric drug that required First psychiatric drug that required

blood level monitoringblood level monitoring

LithiumLithium

Manic episodes of bipolar disorderManic episodes of bipolar disorder Maintenance treatment for bipolar Maintenance treatment for bipolar

disorderdisorder Bipolar depressionBipolar depression Major depressive disorderMajor depressive disorder

Vascular headacheVascular headacheNeutropeniaNeutropenia

MechanismsMechanisms Generally unknownGenerally unknown Complex in actionComplex in action Alters sodium transport across cell Alters sodium transport across cell

membranesmembranes Alter metabolism of Alter metabolism of

neurotransmitters catecholamines, neurotransmitters catecholamines, serotonin, GABA and glutamate serotonin, GABA and glutamate

- May alter intracellular signalling through actions May alter intracellular signalling through actions on second messenger systemson second messenger systems

Second messenger systemsSecond messenger systems

Method of cellular signallingMethod of cellular signalling Cyclic adenosine monophosphateCyclic adenosine monophosphate

((cAMPcAMP)) intracellular signal transduction intracellular signal transduction A different process of A different process of

neurotransmissionneurotransmission

LithiumLithium

Effective within 1-3 weeksEffective within 1-3 weeks Goal of treatment is a remission in Goal of treatment is a remission in

symptomssymptoms Many patients only have a partial Many patients only have a partial

responseresponse

Concept of AugmentationConcept of Augmentation

the combination of two or more the combination of two or more drugs to achieve better treatment drugs to achieve better treatment results results

Failure of monotherapyFailure of monotherapy Better tolerabilityBetter tolerability

Pre-testingPre-testing

Kidney function( should be repeated Kidney function( should be repeated 1-2)1-2)

Thyroid functionThyroid function ECG for patients over 50ECG for patients over 50 Metabolic monitoringMetabolic monitoring

– Fasting plasma glucose levelFasting plasma glucose level– Cholesterol and triglyceridesCholesterol and triglycerides– BMIBMI

Side EffectsSide Effects

The reason to why lithium causes The reason to why lithium causes side effects is complexside effects is complex

Excessive actions at the same or Excessive actions at the same or similar sites that mediate actionssimilar sites that mediate actions

Renal side effects= acts on Renal side effects= acts on transportation of ionstransportation of ions

Side EffectsSide Effects

PolyuriaPolyuria PolydipsiaPolydipsia DiarrhoeaDiarrhoea NauseaNausea Weight gainWeight gain GoiterGoiter Acne, rash, alopeciaAcne, rash, alopecia leukocytosisleukocytosis

Life Threatening Side EffectsLife Threatening Side Effects Lithium toxicityLithium toxicity Renal impairmentRenal impairment Nephrogenic diabetes insipidusNephrogenic diabetes insipidus ArrhythmiasArrhythmias Cardiovascular changes\sick sinus Cardiovascular changes\sick sinus

rhythm rhythm Sick Sinus syndromeSick Sinus syndrome BradycardiaBradycardia hypotension hypotension T wave flattening and inversionT wave flattening and inversion

ToxicityToxicity Toxic Levels are very close to Toxic Levels are very close to

therapeutic levelstherapeutic levels

Symptoms;Symptoms;– DiarrhoeaDiarrhoea– VomitingVomiting– Course tremor Course tremor – DeleriumDelerium– ComaComa– SeizuresSeizures

Monitoring for dehydrationMonitoring for dehydration

Dosing and UsingDosing and Using

1800mg/day in divided doses (acute)1800mg/day in divided doses (acute) 900-1200mg/day in divided 900-1200mg/day in divided

doses( maintenance)doses( maintenance) Dosage formsDosage forms

– 450mg (slow release)450mg (slow release)– 250mg tablets250mg tablets

start low and adjust dosage upward start low and adjust dosage upward as indicated by plasma levelsas indicated by plasma levels

Dosing Dosing

Slow release= less gastric irritation, Slow release= less gastric irritation, lower peak plasma levels and peak lower peak plasma levels and peak dose side effectsdose side effects

Use the lowest dose of lithium Use the lowest dose of lithium associated with adequate therapeutic associated with adequate therapeutic responseresponse

Go low in the elderlyGo low in the elderly Rapid discontinuation= increase Rapid discontinuation= increase

relapserelapse

MonitoringMonitoring

Therapeutic LevelsTherapeutic Levels

Drug interactionDrug interaction

Increase plasma levels;Increase plasma levels; NSAIDS NSAIDS DiureticsDiuretics Angiotensin-converting enzymesAngiotensin-converting enzymes Anticonvulsants (carbemazepine and phenytoin)Anticonvulsants (carbemazepine and phenytoin) MetronidazoleMetronidazole Calcium channel blockersCalcium channel blockers

Increase side effectsIncrease side effects SSRI’sSSRI’s HaloperidolHaloperidol

Special PopulationsSpecial Populations

ElderlyElderly PregnancyPregnancy Breast feedingBreast feeding

Anticonvulsant medicationsAnticonvulsant medications

Sodium ValproateSodium Valproate CarbemazepineCarbemazepine LamotrogineLamotrogine

Sodium ValproateSodium Valproate

A first line treatment for bipolar A first line treatment for bipolar disorder especially mixed state or disorder especially mixed state or rapid cycling bipolar.rapid cycling bipolar.

Prescribed for;Prescribed for;– ManiaMania– Maintenance treatment of Bipolar DisorderMaintenance treatment of Bipolar Disorder– SeizuresSeizures– Migraine prophylaxisMigraine prophylaxis

How does it work?How does it work?

Blocks voltage- sensitive sodium Blocks voltage- sensitive sodium channelschannels

Increases brain concentrations of Increases brain concentrations of gamma-aminobutyric acid (GABA)gamma-aminobutyric acid (GABA)

Relatively unknown why it does thisRelatively unknown why it does this

Sodium ValproateSodium Valproate

Effects occur within a few daysEffects occur within a few days Optimised at several weeks to one Optimised at several weeks to one

monthmonth

The goal is to see a remission in The goal is to see a remission in symptomssymptoms

AugmentationAugmentation

Pre-testingPre-testing

Platelet countsPlatelet counts Liver function testingLiver function testing Coagulation tests Coagulation tests Metabolic monitoringMetabolic monitoring

Sides EffectsSides Effects Due to Excessive actions at voltage sensitive Due to Excessive actions at voltage sensitive

sodium channelssodium channelsInclude;Include;

- Sedation- Sedation - dyspepsia- dyspepsia- Tremor- Tremor - weight gain- weight gain- ataxia - ataxia - alopecia- alopecia- tremor- tremor - - polycystic ovarian polycystic ovarian

syndromesyndrome- headache- headache - - hyperandrogenisamhyperandrogenisam- Abdominal pain- Abdominal pain - - hyperinsulinemiahyperinsulinemia- nausea/vomiting- nausea/vomiting - - Lipid dysregulationLipid dysregulation- reduced appetite- reduced appetite - - decreased bone densitydecreased bone density- constipation - constipation

Life threatening/Dangerous Side Life threatening/Dangerous Side EffectsEffects

HepatotoxicityHepatotoxicity Liver failureLiver failure PancreatitisPancreatitis OverdoseOverdose

– RestlessnessRestlessness– HallucinationsHallucinations– Sedation Sedation – Heart block Heart block – ComaComa

Dosage and UseDosage and Use Range; Range;

Mania; 1200-1500mg/dayMania; 1200-1500mg/dayMigraine; 500-1000mg/dayMigraine; 500-1000mg/dayEpilepsy; 10-60mg/dayEpilepsy; 10-60mg/day

100mg, 200mg and 500mg tablets100mg, 200mg and 500mg tablets Dosages are increased rapidly in the Dosages are increased rapidly in the

case of mania. case of mania. May need divided dose due to half lifeMay need divided dose due to half life

Terminal mean half life of 9-16 hoursTerminal mean half life of 9-16 hoursMetabolised by the liverMetabolised by the liver

Drug interactionsDrug interactions

Lamotrogine should be reduced by 50% Lamotrogine should be reduced by 50% Plasma levels lowered by drugs such as;Plasma levels lowered by drugs such as;

CarbemazepineCarbemazepine PhenytoinPhenytoin

Plasma levels are increased by drugs such Plasma levels are increased by drugs such as;as;

AspirinAspirin ChlorpromazineChlorpromazine FluoxetineFluoxetine NSAIDSNSAIDS

WarningsWarnings

HepatotoxicityHepatotoxicity MalaiseMalaise WeaknessWeakness LethargyLethargy Facial edemaFacial edema AnorexiaAnorexia VomitingVomiting Jaundice skin and eyesJaundice skin and eyes

PancreatitisPancreatitis Abdominal painAbdominal pain NauseaNausea vomitingvomiting

Special PopulationsSpecial Populations

ElderlyElderly PregnancyPregnancy Breast feedingBreast feeding Post partum issues Post partum issues

CarbamazepineCarbamazepine

More commonly used to treat More commonly used to treat seizuresseizures

First anticonvulsant to be widely First anticonvulsant to be widely used in the treatment of Bipolar used in the treatment of Bipolar disordersdisorders

Potentially an advantage in Potentially an advantage in treatment resistant bipolar and or treatment resistant bipolar and or psychotic disorderspsychotic disorders

How it worksHow it works

Blocks voltage sensitive sodium Blocks voltage sensitive sodium channelschannels

Interacts with the open channel Interacts with the open channel conformation of sodium channelsconformation of sodium channels

Inhibits release of glutamateInhibits release of glutamate

CarbamazepineCarbamazepine

Goal of treatment is remission of Goal of treatment is remission of symptomssymptoms

Effect usually occur within a few Effect usually occur within a few weeksweeks

Can be used a augment other Can be used a augment other medicationsmedications

Pre testingPre testing

Blood countBlood count Liver functionLiver function Kidney functionKidney function Thyroid functionThyroid function

Side effectsSide effects Sedation Sedation DizzinessDizziness ConfusionConfusion UnsteadinessUnsteadiness HeadacheHeadache Nausea and vomitingNausea and vomiting DiarrhoeaDiarrhoea Blurred visionBlurred vision Benign leukopeniaBenign leukopenia RashRash Weight gainWeight gain

Dangerous side effectsDangerous side effects

Rare aplatic anemiaRare aplatic anemia AgranulocytosisAgranulocytosis

– Ususal bleedingUsusal bleeding– InfectionsInfections– FeverFever– Sore throatSore throat

Steven Johnson syndrome (RASH)Steven Johnson syndrome (RASH) Cardiac issuesCardiac issues SIADHSIADH

Dosage and UseDosage and Use

400-1200 mg/day400-1200 mg/day Comes in slow release Comes in slow release Should always be taken with foodShould always be taken with food

PharmacokineticsPharmacokinetics

Metabolised in the liver by CYP450Metabolised in the liver by CYP450 Half life of 26-65 hours initially then Half life of 26-65 hours initially then

drops with repeated dosesdrops with repeated doses

Drug interactionsDrug interactions

Other antiepileptic medicationsOther antiepileptic medications Fluvoxamine, fluoxtetineFluvoxamine, fluoxtetine Decrease efficacy of Decrease efficacy of

benzodiazepines, clozapine, benzodiazepines, clozapine, haloperidol, lamotrogine, epilum and haloperidol, lamotrogine, epilum and warfarinwarfarin

Can decrease effectiveness of the Can decrease effectiveness of the contraceptive pillcontraceptive pill

LithiumLithium

Special PopulationsSpecial Populations

Pregnancy Category DPregnancy Category D Breast FeedingBreast Feeding

LamotrigineLamotrigine

Seems to be more effective in Seems to be more effective in treating depressive episodes of treating depressive episodes of bipolarbipolar

Used less than other anticonvulsants Used less than other anticonvulsants for Bipolar Disorderfor Bipolar Disorder

How it works?How it works?

Voltage- gated sodium channel Voltage- gated sodium channel agonist agonist

Inhibits the release of glutamateInhibits the release of glutamate

Side effectsSide effects Benign rash (10%)Benign rash (10%) SedationSedation Blurred vision Blurred vision DizzinessDizziness AtaxiaAtaxia HeadacheHeadache Tremor Tremor InsomniaInsomnia Poor coordinationPoor coordination FatigueFatigue Nausea and vomitingNausea and vomiting Can cause flu like symptoms in some peopleCan cause flu like symptoms in some people

Stevens Johnson’s SyndromeStevens Johnson’s Syndrome

Rare serious rashRare serious rash Acute feverAcute fever Bullae on the skinBullae on the skin Ulcers on the mucous Ulcers on the mucous

membranes on lip, membranes on lip, eyes, mouth and nasal eyes, mouth and nasal passagespassages

ManagementManagement Stop medicationStop medication Monitor and Monitor and

investigate organ investigate organ involvementinvolvement

May require admissionMay require admission

Dosage and UseDosage and Use

Monotherapy 100- 200 mg/dayMonotherapy 100- 200 mg/day Halved if used with other medicationHalved if used with other medication

Monitor for rash Monitor for rash

PharmacokineticsPharmacokinetics

Elimination half life 33 hoursElimination half life 33 hours Higher if used concurrently with Higher if used concurrently with

other anticonvulsant medicationother anticonvulsant medication Metabolised through the liver Metabolised through the liver

Drug interactionsDrug interactions

Depressive effects may be increased Depressive effects may be increased by other CNS depressantsby other CNS depressants

Special populationsSpecial populations

People with renal impairmentPeople with renal impairment Hepatic ImpairmentHepatic Impairment ElderlyElderly Children and AdolescentsChildren and Adolescents PregnancyPregnancy Breast feedingBreast feeding

Atypical Antipsychotic MedicationAtypical Antipsychotic Medication

Increasing use of antipsychotic Increasing use of antipsychotic medicationmedication

Olanzapine, Risperidone, Quetiapine, Olanzapine, Risperidone, Quetiapine, Ziprasidone and AripripazoleZiprasidone and Aripripazole