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?
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
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