Pharmacotherapy in Psychiatry Depression Depression Schizophrenia Schizophrenia Bipolar disorders Bipolar disorders

Pharmacotherapy in Pharmacotherapy in PsychiatryPsychiatry

DepressionDepressionSchizophreniaSchizophreniaBipolar disordersBipolar disorders

ContentsContents

Schizophrenia and antipsychoticsSchizophrenia and antipsychotics Depression and antidepressantsDepression and antidepressants Bipolar disorders and mood Bipolar disorders and mood

stabilizersstabilizers

Schizophrenia and antipsySchizophrenia and antipsychoticschotics

SchizophreniaSchizophrenia

Characterized by psychosis, Characterized by psychosis, hallucinations, delusions, hallucinations, delusions, cognitive defects, occupational cognitive defects, occupational and social dysfunctionand social dysfunction

Chronic psychotic illnessChronic psychotic illnessEpisodic exacerbations and

remissions with residual symptomsComplete remission is not common


EpidemiologyEpidemiologyLifetime prevalence is 1% in United

StatesOnset in late teens or early 20s in

males; sometime later in femalesSuicide rate comparable to

depressive illness (approx 10%)


EtiologyEtiologyExact etiology unknown

Genetic predisposition Intrauterine, birth or postnatal complications Viral CNS infections Environmental stressors (biochemical or soci

al)No evidence of association with poor par

enting


PathophysiologyPathophysiologyNo consistent neuropathology or

biomarkers for schizophrenia ? Increased dopamine in mesolimbic pathw

ays causes delusions and hallucinations ? Dopamine deficiency in mesocortical and

nigrostriatal pathways causes negative symptoms (apathy, withdrawal)

Hallocinogens produce effect through action on 5-HT2 receptors


Positive symptomsPositive symptoms Hallucinations Delusions Disordered thinking Disorganized

speech Combativeness Agitation Paranoia

Negative symptomsNegative symptoms Social withdrawal Emotional

withdrawal Lack of motivation Poverty of speech Blunted affect Poor insight Poor judgement Poor self-care


AntipsychoticsAntipsychoticsTypical / Conventional

antipsychoticsAtypical antipsychotics

Typical / conventional Typical / conventional antipsychoticsantipsychotics Chlorpromazine (Largactil®)Chlorpromazine (Largactil®) Flupenthixol (Fluanxol®)Flupenthixol (Fluanxol®) Haloperidol (Serenace®, Haldol®)Haloperidol (Serenace®, Haldol®) Pericyazine (Neulactil®)Pericyazine (Neulactil®) Pimozide (Orap®, Orap Forte®)Pimozide (Orap®, Orap Forte®) Sulpiride (Dogmatil®)Sulpiride (Dogmatil®) Thioridazine (Melleril®)Thioridazine (Melleril®) Trifluoperazine (Stelazine®)Trifluoperazine (Stelazine®) Thiothixene (Navane®)Thiothixene (Navane®)

Typical / conventional Typical / conventional antipsychoticsantipsychotics Refers to agents introduced in US Refers to agents introduced in US

before 1990before 1990 Also known as Also known as

“Dopamine receptor antagonists” Pharmacologic activity at blocking central

dopamine receptors (esp. D2 receptors) “Neuroleptics”

Due to tendency to cause neurologic Adverse effects

“Major tranquilizers” Inappropriate as these agents (esp. high

potency) can improve psychosis without sedating or making patients tranquil

Typical / conventional Typical / conventional antipsychoticsantipsychoticsDopamine receptors in various tracksDopamine receptors in various tracks

TrackTrack OriginOrigin InnervationInnervationss

FunctionFunction Antipsychotic Antipsychotic effecteffect

MesolimbicMesolimbic Midbrain,Midbrain,Ventral tegmeVentral tegmentalntal

Limbic strucLimbic structure, nucleuture, nucleus accumbens accumbenss

Emotional Emotional and and intellectualintellectual

HallucinationHallucinations, deulsions, diss, deulsions, disordered cognitiordered cognitionon

MesocorticaMesocorticall

Ventral tegmeVentral tegmentalntal

Frontal Frontal cortexcortex

NigrostriataNigrostriatall

Substantia niSubstantia nigragra

Basal Basal gangliaganglia

ExtrapyramidaExtrapyramidal system movel system movementment

Motor symptoMotor symptomatologymatology

Tubero-infuTubero-infundubularndubular

HypothalamHypothalamusus

Pituitary Pituitary glandgland

Regulate Regulate endocrine endocrine functionsfunctions

Plasma prolacPlasma prolactin levelstin levels

Typical / conventional Typical / conventional antipsychoticsantipsychotics Mechanism of actionMechanism of action

Blocks receptors for dopamine, acetylcholine, histamine and norepinephrine

Current theory suggests dopamine2 (D2) receptors suppresses psychotic symptoms

All typical antipsychotics block D2 receptors

Close correlation between clinical potency and potency as D2 receptor antagonists

Typical / conventional Typical / conventional antipsychoticsantipsychotics PropertiesProperties

Effective in reducing positive symptoms during acute episodes and in preventing their reoccurrence

Less effective in treating negative symptoms

Some concern that they may exacerbate negative symptoms by causing akinesia

Higher incidence of EPS / sedation / anticholinergic Adverse effects

Typical / conventional Typical / conventional antipsychoticsantipsychotics PotencyPotency

All have same ability to relieve symptoms of psychosis

Differ from one another in terms of potency

i.e. size of dose to achieve a given response

When administered in therapeutically equivalent doses, all drugs elicit equivalent antipsychotic response

Typical / conventional Typical / conventional antipsychoticsantipsychotics Low potencyLow potency

Chlorpromazine, thioridazine Medium potencyMedium potency

Perphenazine High potencyHigh potency

Trifluoperazine, thiothixene, fluphenazine, haloperidol, pimozide

Typical / conventional Typical / conventional antipsychoticsantipsychoticsPotencyPotency DrugDrug Equiv Equiv

oral oral dose dose (mg)(mg)

EPSEPS SedationSedation Anticholinergic Anticholinergic s/es/e

Low Chlorpromazine

100 Moderate

High Moderate

Pericyazine NA Low High Low

Thioridazine 100 Low High High

Moderate

Perphenazine 10 Moderate

Moderate Low

High Trifluoperazine

5 High Low Low

Thiotheixene 2 High Low Low

Fluphenazine 2 High Low Low

Haloperidol 2 High Low Low

Pimozide 0.5 High Moderate Moderate

Sulpiride 200 Low Moderate Low

Typical / conventional Typical / conventional antipsychoticsantipsychoticsComparison of representative antipsychoticsComparison of representative antipsychotics

DrugDrug AdvantagesAdvantages DisadvantagesDisadvantages

ChlorpromazinChlorpromazinee

Generic, Generic, inexpensiveinexpensive

Many adverse Many adverse effects (esp. effects (esp. autonomic) autonomic)

ThioridazineThioridazine Slight EPS, genericSlight EPS, generic Cardiotoxicity (QT Cardiotoxicity (QT prolongation)prolongation)

FluphenazineFluphenazine Generic, depot Generic, depot availableavailable

(?) increased (?) increased tardive dyskinesiatardive dyskinesia

ThiothixeneThiothixene (?) decreased (?) decreased tardive dyskinesiatardive dyskinesia

UncertainUncertain

HaloperidolHaloperidol Generic, injection Generic, injection and depot A/V, few and depot A/V, few autonomic s/eautonomic s/e

Prominent EPSProminent EPS

Typical / conventional Typical / conventional antipsychoticsantipsychoticsReceptor blockade and Adverse effectsReceptor blockade and Adverse effects

Receptor type Consequence of blockade

D2 dopaminergic Extrapyramidal symptoms; prolactin release

H1 histaminergic Sedation

Muscarinic cholinergic

Dry mouth, blurred vision, urinary retention, constipation, tachycardia

Alpha1-adrenergic Orthostatic hypotension; reflex tachycardia

5-HT2 serotonergic Weight gain

Typical / conventional Typical / conventional antipsychoticsantipsychotics Adverse effectsAdverse effects

Extrapyramidal symptoms (EPS) Early reactions – can be managed with drugs

Acute dystonia Parkinsonism Akathisia

Late reaction – drug treatment unsatisfactory Tardive dyskinesia (TD)

Early reactions occur less frequently with low potency drugs

Risk of TD is equal with all agents


Acute dystonia Develops within a few hours to 5 days after first dose Muscle spasm of tongue, face, neck and back Oculogyric crisis (involuntary upward deviation of

eyeballs) Opisthotonus (tetanic spasm of back muscles,

causing trunk to arch forward, while head and lower limbs are thrust backwards)

Laryngeal dystonia can impair respiration Management

Anticholinergics (Benztropine, diphenhydramine IM/IV) Lower or split dosing Switch agent Add scheduled benztropine / diphenhydramine with antipsy

chotic


Parkinsonism (neuroleptic induced) Occurs within first month of therapy Bradykinesia, mask-like facies, drooling, tremor,

rigidity, shuffling gait, cogwheeling, stooped posture

Shares same symptoms with Parkinson’s disease Management

Centrally acting anticholinergics (scheduled benztropine / diphenhydramine / benzhexol with antipsychotics) and amantadine

Avoid levodopa as it may counteract antipsychotic effects

Switch to atypical antipsychotics for severe symptoms


Akathisia Develop within first 2 months of therapy Compulsive, restless movement Symptoms of anxiety, agitation Management

Beta blockers (propranolol) Benzodiazepines (e.g. lorazepam) Anticholinergics (e.g. benztropine, benzhexol) Reduce antipsychotic dosage or switch to low

potency agent


Tardive dyskinesia (TD) Develops months to years after therapy Involuntary choreoathetoid (twisting,

writhing, worm-like) movements of tongue and face

Can interfere with chewing, swallowing and speaking

Symptoms are usually irreversible


Tardive dyskinesia (TD) Management

Some manufacturers suggest drug withdrawal at earliest signs of TD (fine vermicular movements of tongue) may halt its full development

Gradual drug withdrawal (to avoid dyskinesia) Use lowest effective dose Atypical antypsychotic for mild TD Clozapine for severe, distressing TD Inconsistent results with

Diazepam, clonazepam, valproate Propranolol, clonidine Vitamin E

Typical / conventional Typical / conventional antipsychoticsantipsychotics Other Adverse effectsOther Adverse effects

Neuroleptic malignant syndrome (NMS) Rare but serious reaction, 0.2% of patients on

neuroleptics High fever, autonomic instability, mental status

changes, leaden rigidity, elevated CK, WBC, myoglobinuria

Management Discontinue antipsychotic Paracetamol for hyperthermia IV fluids for hydration Benzodiazepines for anxiety Dantrolene for rigidity and hyperthermia Bromocriptine for CNS toxicity


Neuroleptic malignant syndrome (NMS)

After symptom resolutionSome suggest to wait for at least 2 weeks

before resumingUse lowest effective doseAvoid high potency agentsConsider atypical antipsychotics

However, NMS has been reported from patients taking clozapine, risperidone, olanzapine and quetiapine


Prolactinemia D2 receptor blockade decreases dopamine inhibitio

n of prolactin Results in galactorrhea, amenorrhea, loss of libido

Managed with bromocriptine Sedation

Administer once daily at bedtime Seizures

Haloperidol has a lower risk of seizures Anticonvulsants (beware or possible interaction

with antipsychotic)

Atypical antipsychoticsAtypical antipsychotics

Refers to newer agentsRefers to newer agents Also known asAlso known as

“Serotonin-dopamine antagonists” Postsynaptic effects at 5-HT2A and D2

receptors


Amisulpiride (Solian®)Amisulpiride (Solian®) Quetiapine (Seroquel®)Quetiapine (Seroquel®) Ziprasidone (Zeldox®)Ziprasidone (Zeldox®) Risperidone (Risperdal®)Risperidone (Risperdal®) Olanzapine (Zyprexa®)Olanzapine (Zyprexa®) Clozapine (Clozaril®)Clozapine (Clozaril®) Aripiprazole (Abilify®)Aripiprazole (Abilify®)


Mechanism of actionMechanism of action Similar blocking effect on D2 receptors Seem to be a little more selective, targeting th

e intended pathway to a larger degree than the others

Also block or partially block serotonin receptors (particularly 5HT2A, C and 5HT1A receptors)

Aripiprazole: dopamine partial agonist (novel mechanism)


PropertiesPropertiesAvailable evidence to show advantage

for some (clozapine, risperidone, olanzapine) but not all atypicals when compared with typicals

At least as effective as typicals for positive symptoms

May be more efficacious for negative and cognitive symptoms (still under debate)


PropertiesPropertiesLess frequently associated with EPSMore risk of weight gain, new onset dia

betes, hyperlipidemiaNovel agents, more expensive


PotencyPotencyAll atypical antipsychotics are equally ef

fective at therapeutic doses Except clozapine Most effective antipsychotic For resistant schizophrenia 2nd line due to life-threatening side effect


Relative receptor-binding of atypical Relative receptor-binding of atypical antipsychoticsantipsychotics

DrugDrug D1D1 D2D2 5-5-HT2HT2

11 M1M1 H1H1

ClozapineClozapine ++++ ++++ ++++++ ++++++

++++++

++

RisperidoneRisperidone -- ++++++

++++++ ++++++

-- ++

OlanzapineOlanzapine ++++ ++++ ++++++ ++++ ++++++

++++

QuetiapineQuetiapine -- ++ ++++ ++++++

++ ++

ZiprasidoneZiprasidone +/-+/- ++++ ++++++ ++++ -- ++

AripiprazoleAripiprazole ++ ++++++

++++ ++++ -- ++


Comparison of representative atypical antipsychoticsComparison of representative atypical antipsychotics

DrugDrug AdvantagesAdvantages DisadvantagesDisadvantages

ClozapineClozapine For treatment-resistant For treatment-resistant cases, little EPScases, little EPS

Risk of fatal agranulocytosisRisk of fatal agranulocytosis

RisperidoneRisperidone Broad efficacy, little or no Broad efficacy, little or no EPS at low dosesEPS at low doses

EPS and hypotension at high EPS and hypotension at high dosesdoses

OlanzapineOlanzapine Effective with positive and Effective with positive and negative symptoms, little negative symptoms, little or no EPSor no EPS

Weight gainWeight gain

QuetiapineQuetiapine Similar to risperidone, Similar to risperidone, maybe less weight gainmaybe less weight gain

Dose adjustment with Dose adjustment with associated hypotension, bd associated hypotension, bd dosingdosing

ZiprasidoneZiprasidone Perhaps less weight gain Perhaps less weight gain than clozapine, Inj A/Vthan clozapine, Inj A/V

QT prolongationQT prolongation

AripiprazoleAripiprazole Less weight gain, novel Less weight gain, novel mechanism potentialmechanism potential

UncertainUncertain


Relative incidence of Adverse effectsRelative incidence of Adverse effects

DrugsDrugs SedatioSedationn

EPEPSS

AnticholinergAnticholinergicic

OrthostasOrthostasisis

SeizurSeizuree

ProlactiProlactin n elevatioelevationn

Weight Weight gaingain

ClozapineClozapine ++++++++ ++ ++++++++ ++++++++ ++++++++ 00 ++++++++

RisperidonRisperidonee

++++++ ++ ++++ ++++++ ++++ 0 to ++0 to ++++++

++++

OlanzapinOlanzapinee

++++++ ++ ++++++ ++++ ++++ ++ ++++++

QuetiapinQuetiapinee

++++++ ++ ++++ ++++ ++++ 00 ++++

ZiprasidonZiprasidonee

++++ ++ ++++ ++++ ++++ 00 ++

AripiprazoAripiprazolele

++++ ++ ++++ ++++ ++++ 00 ++


11stst line atypical antipsychotics line atypical antipsychotics All atypicals except clozapine NICE recommendations

Atypical antipsychotics considered when choosing 1st line treatment of newly diagnosed schizophrenia

Treatment option of choice for managing acute schizophrenic episode

Considered when suffering unacceptable Adverse effects from a conventional antipsychotic

Changing to an atypical not necessary if typical controls symptoms adequately and no unacceptable Adverse effects


22ndnd line atypical antipsychotic line atypical antipsychotic Clozapine

Most effective antipsychotic for reducing symptoms and preventing relapse

Use of clozapine effectively reduce suicide risk 1% risk of potentially fatal agranulocytosis

Acute pronounced leukopenia with great reduction in number of neutrophil

NICE recommendations Clozapine should be introduced if schizophrenia

is inadequately controlled despite sequential use of 2 or more antipsychotic (one of which should be an atypical) each for at least 6-8 weeks)


ClozapineClozapine BNF 52 (September 2006)

Leucocyte and differential blood count normal before starting

Monitor counts Q week for 18 weeks, then at least Q 2 weeks after 1 year

At least Q 4 weeks after count stable for 1 year (for 4 more weeks after discontinuation)

If leucocyte count < 3000/mm3, or if ANC < 1500/mm3, discontinue immediately and refer to hematologist

Patient should report immediately symptoms of infection, esp. flu-like illness (fever, sore throat)


ClozapineClozapine Rare cases of myocarditis and

cardiomyopathy Fatal Most commonly in first 2 months CSM recommendations

Physical exam and medical history before starting Persistent tachycardia esp. in first 2 weeks should

prompt observation for cardiomyopathy If myocarditis or cardiomyopathy, stop clozapine Inform patients for unexplained fatigue, dyspnea,

tachypnea, chest pain, paipitation and ask them to report these signs and symptoms immediately


ClozapineClozapineContraindication

History of clozapine-induced agranulocytosis

Bone marrow suppression On myelosuppressive drugs

Caution Seizure disorders Diabetes

Antipsychotic oral-Antipsychotic oral-dispersible and solution dispersible and solution preparationspreparations Oral-dispersible preps available forOral-dispersible preps available for

2 atypicals Risperidone (Risperdal Quicklet®) Olanzapine (Zyprexa Zydis®)

Carefully peel off packing, allow tablet to dissolve on tongue and swallow

Do not break the tablet Some may be dispersed in fluids (consult manufacturer

literature) Solutions available forSolutions available for

1 typical Haloperidol (Haldol® drops)

1 atypical Risperidone (Risperdal® solution)

Very concentrated, avoid from contact with skin (dermatitis)

Antipsychotic injectionsAntipsychotic injections

Available forAvailable for2 typicals

Chlorpromazine (Largactil®) Haloperidol (Haldol®)

2 atypicals Olanzapine (Zyprexa®) Ziprasidone (Zeldox®)

Useful for acutely agitated patients

Antipsychotic depot Antipsychotic depot injectionsinjections Available forAvailable for

4 typicals Haloperidol decanoate (Haldol Decanoate®) Fluphenazine decanoate (Modecate®) Flupenthixol (Fluanxol®) Zuclopenthixol (Clopixol Depot®)

1 atypical Risperidone (Risperdal Consta®)

Used for chronic illness and history of noncompliance

Trial of oral meds first to assess tolerability

Non-antipsychotic agentsNon-antipsychotic agents

BenzodiazepinesBenzodiazepines Useful in some studies for anxiety, agitation,

global impairment and psychosis Schizophrenic patients are prone to BZD

abuse Limit use to short trials (2-4 weeks) for

management of severe agitation and anxiety LithiumLithium

Limited role in schizophrenia monotherapy Improve psychosis, depression, excitement,

and irritability when used with antipsychotic in some studies

Non-antipsychotic agentsNon-antipsychotic agents

CarbamazepineCarbamazepine Weak support when used alone and with antipsychotic Alters metabolism of antipsychotic NOT to be used with clozapine (risk of agranulocytosis)

ValproateValproate Concurrent administration with risperidone and

olanzapine resulted in early psychotic improvement in recent investigation

PropranololPropranolol Research showed improvement in chronic aggression Treat aggression or enhance antipsychotic response Reasonable trial 240mg/day

Antipsychotics in Antipsychotics in schizophreniaschizophrenia Selection of typical antipsychoticsSelection of typical antipsychotics

Equally efficacious Chosen by side effect profile

Atypical antipsychotics may be Atypical antipsychotics may be appropriate if appropriate if Adverse effect is a particular concern Additional benefits for negative and cognitive

symptoms required ClozapineClozapine

2nd line treatment when other agents are ineffective or not tolerated

Antipsychotics in Antipsychotics in schizophreniaschizophrenia Depot antipsychotic preparationsDepot antipsychotic preparations

Useful for noncompliant patients with poor insight

Antidepressents and mood stabilisersAntidepressents and mood stabilisers In schizoaffective disorders Patients with secondary mood symptoms

or aggressivity Differentiate between adverse effects Differentiate between adverse effects

and signs of disease progressionand signs of disease progression E.g. Parkinsonism vs. psychotic hysteria,

Akathisia vs. exacerbation of psychosis

Antipsychotics in Antipsychotics in schizophreniaschizophrenia Oral administrationOral administration

Divided daily doses at initial phase Once daily at bedtime when stabilized

Promoting sleep and reducing daytime sedation Smallest effective dose employed

Oral-dispersible and solution preparationsOral-dispersible and solution preparations For unreliable patients

InjectionsInjections Usually deltoid or gluteal muscle (or according to

manufacturer) Depot injectionsDepot injections

At intervals of 1 to 4 weeks Generally not more than 2-3ml oily injection at one site Correct injection technique (z-track) and injection site

rotation

Antipsychotics in Antipsychotics in schizophreniaschizophrenia Treatment responseTreatment response

First 7 days Decreased agitation, hostility, combativeness,

anxiety, tension and aggression Normalization of sleep and eating habits

First 2-3 weeks Increased socialization, improvement in self-

care

6-8 weeks Improvement in formal thought disorder

Antipsychotics in Antipsychotics in schizophreniaschizophrenia Acute phaseAcute phase

Initiate therapy Titrate as tolerated to average effective dose

Stabilization phaseStabilization phase Dose titration within the therapeutic range

Maintenance phaseMaintenance phase Therapy should be continued for at least 12

months after remission of 1st episode Good treatment responders should be treated for

at least 5 years Continuous lifetime maintenance required in the

majority of patients to prevent relapse Lowest effective and tolerable dose

Depression and Depression and antidepressantsantidepressants

DepressionDepression

Depressed mood and/or decrease in interest Depressed mood and/or decrease in interest in things that used to give pleasurein things that used to give pleasure

Sadness severe enough or persistent enough to iSadness severe enough or persistent enough to interfere with functionnterfere with function

DSM-IV:DSM-IV: Major depressive disorder / major depression Dysthymia

Depression for most of the day, more days than not Depressive disorder not otherwise specified Depressive disorder due to a general physical condition Substance-induced depressive disorder


EpidemiologyEpidemiologyLife prevalence 3-17%Onset in late 20sHighest in

25-44 years Elderly in community

Female vs male = 2:1 Female 10-25% lifetime risk Male 5-12% lifetime risk


EpidemiologyEpidemiology 4th most common reason to visit family

physician Most common in elderly and difficult to

diagnose Coexists with dementia or delirium frequently Recurrence rate of major depression

After single episode = 50% After second episode = 70% After third episode = 90%

Approx 10-15% of patients with major depressive or bipolar disorder complete suicide


Signs and symptomsSigns and symptoms Depressed mood Sleep (insomnia or hypersomnia) Loss of interest (including libido) Guilt Energy loss Concentration loss Appetite (loss or gain) Psychomotor (agitation or retardation) Suicide (ideation)


EtiologyEtiology Etiology unknown

Uncertain with heredity History of child abuse or other major life stresses Changes in neurotransmitter/neurohormone levels

Cholinergic, noradrenergic/dopaminergic and serotonergic neurotransmission

Deregulation with hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis and growth hormone

Life stresses (e.g. Separation and losses)


PathophysiologyPathophysiologyExact course unknown

Changes in receptor-neurotransmitter relationship in limbic system

Serotonin, norepinephrine, sometimes dopamine Increased pump uptake of neurotransmitter

Reabsorption into neuronDestroyed by monoamine oxidase in

mitochondriaLack of neurotransmitters

AntidepressantsAntidepressants

Tricyclic and related antidepressants (TCA)Tricyclic and related antidepressants (TCA) E.g. amitriptyline, imipramine, doxepin,

mianserin, trazodone Monoamine-oxidase inhibitors (MAOI)Monoamine-oxidase inhibitors (MAOI)

E.g. moclobemide, phenelzine, isocarboxazid, tranylcypromine

Selective serotonin reuptake inhibitors Selective serotonin reuptake inhibitors (SSRI)(SSRI) E.g. fluoxetine, paroxetine, sertraline,

citalopram Other antidepressantsOther antidepressants

E.g. mirtazapine, venlafaxine, duloxetine, flupentixol

Tricyclic and related Tricyclic and related antidepressants (TCA)antidepressants (TCA) Amitriptyline (Saroten®)Amitriptyline (Saroten®) Clomipramine (Anafranil®)Clomipramine (Anafranil®) Dothiepin (a.k.a. dosulepin, Dothiepin (a.k.a. dosulepin,

Prothiaden®)Prothiaden®) Doxepin (Sinequan®)Doxepin (Sinequan®) Imipramine (Tofranil®)Imipramine (Tofranil®) Mianserin (Tolvon®)Mianserin (Tolvon®) Nortriptyline (Nortrilen®)Nortriptyline (Nortrilen®) Trazodone (Trittico®)Trazodone (Trittico®) Trimipramine (Surmontil®)Trimipramine (Surmontil®)

Tricyclic and related Tricyclic and related antidepressants (TCA)antidepressants (TCA) Mechanism of actionMechanism of action

Blocks neuronal uptake or norepinephrine and serotonin

Initial response develops in 1-3 weeks Maximal response develops in 1-2 months Older tricyclics

Marked anticholinergic Adverse effects Risk of cardiotoxicity

Tricyclic-related drugs (e.g. trazodone) Fewer anticholinergic Adverse effects Sedation, dizziness, priapism (persistent penile

erection accompanied by pain and tenderness)

Tricyclic and related Tricyclic and related antidepressants (TCA)antidepressants (TCA) PropertiesProperties

Inexpensive, generic Some with off-label use, e.g.

Neuropathy with amitriptyline Refractory skin diseases with doxepin

Very dangerous in overdose Life threatening Lethal dose only 8 times average daily dose Acutely depressed patients should not be given

more than 1-week TCA supply at one time

Tricyclic and related Tricyclic and related antidepressants (TCA)antidepressants (TCA) Adverse effectsAdverse effects

Orthostatic hypotension Reduced by moving slowly when assuming upright

posture Sit or lie down if symptoms (dizziness,

lightheadedness) occur Divided doses and slow titration

Anticholinergic effects Dry mouth, blurred vision, photophobia, constipation,

urinary retention, tachycardia Tolerance may develop as treatment persists Divided doses and slow titration

Sedation Dose at bedtime

Tricyclic and related Tricyclic and related antidepressants (TCA)antidepressants (TCA) Adverse effectsAdverse effects

Cardiac toxicity Arrhythmias and heart block ECG recommended before initiation Do not use in heart block

Seizures Lowered seizure threshold

Hypomania (mild mania) Elevated mood Patient should be evaluated to determine dose

reduction or bipolar disorder Diaphoresis

Paradoxical effect

Tricyclic and related Tricyclic and related antidepressants (TCA)antidepressants (TCA) Drug interactionsDrug interactions

CNS depressants Narcotics, benzodiazepines Additive CNS depression

Anticholinergics Additive anticholinergic effects

P450 enzyme inducers/inhibitors

Monoamine-oxidase Monoamine-oxidase inhibitors (MAOI)inhibitors (MAOI) Moclobemide (Aurorix®)Moclobemide (Aurorix®) Not registered in Hong KongNot registered in Hong Kong

PhenelzineIsocarboxazidTranylcypromine

Monoamine-oxidase Monoamine-oxidase inhibitors (MAOI)inhibitors (MAOI) Mechanism of actionMechanism of action

Inhibit both MAO-A and MAO-B Phenelzine, tranylcypromine

Selective & reversible inhibitor of MAO-A

Moclobemide

Monoamine-oxidase Monoamine-oxidase inhibitors (MAOI)inhibitors (MAOI) PropertiesProperties

Useful in atypical depression (somnolence and weight gain), refractory disorders and certain types of anxiety disorders

Less prescribed than tricyclics, SSRIs and other antidepressants

Danger of dietary and drug interactions

Monoamine-oxidase Monoamine-oxidase inhibitors (MAOI)inhibitors (MAOI) PropertiesProperties

Drug interactions Other antidepressants should not be starte

d for 2 weeks after MAOI has been stopped (3 weeks for clomipramine or imipramine)

MAOI should not be started for 7-14 days after a tricyclic or related antidepressant (3 weeks for clomipramine or imipramine)

MAOI should not be started for at least 2 weeks after a previous MAOI

Monoamine-oxidase Monoamine-oxidase inhibitors (MAOI)inhibitors (MAOI) Adverse effectsAdverse effects

Hypertensive crisis Severe occipital headache, photophobia, p

alpitation, sharply increased in BP due to additive effect between MAOI and adrenergic stimulants

Tyramine-rich food e.g. cheese, wine, smoked/aged/picked meat or fish, alcohol

AmphetaminsPseudoephedrine

Monoamine-oxidase Monoamine-oxidase inhibitors (MAOI)inhibitors (MAOI) Adverse effectsAdverse effects

Orthostatic hypotensionInsomniaWeight gainSexual dysfunction

Selective serotonin Selective serotonin reuptake inhibitors (SSRI)reuptake inhibitors (SSRI) Fluoxetine (Prozac®)Fluoxetine (Prozac®) Fluvoxamine (Faverin®)Fluvoxamine (Faverin®) Paroxetine (Seroxat®)Paroxetine (Seroxat®) Sertraline (Zoloft®)Sertraline (Zoloft®) Citalopram (Cipram®)Citalopram (Cipram®) Escitalopram (Lexapro®)Escitalopram (Lexapro®)

Selective serotonin Selective serotonin reuptake inhibitors (SSRI)reuptake inhibitors (SSRI) Mechanism of actionMechanism of action

Inhibits reuptake of serotonin (5-HT) presynaptic uptake

Increases availability of serotonin at synapses

Selective serotonin Selective serotonin reuptake inhibitors (SSRI)reuptake inhibitors (SSRI) PropertiesProperties

Overdose less likely to be fatalLess anticholinergic side effectsBut more GI side effectsSeems to be better tolerated

Selective serotonin Selective serotonin reuptake inhibitors (SSRI)reuptake inhibitors (SSRI) PropertiesProperties

Fluoxetine Most stimulating SSRI Indicated for premenstrual dysphoric disorder (PMD

D) (as Sarafem®) Long half-life, ensure 5 week washout before MAOI

(2 week for other SSRI) Some SSRIs also indicated for

Obsessive-compulsive disorder (OCD) Panic disorder Eating disorders Social phobia Post traumatic stress disorder (PTSD)

Selective serotonin Selective serotonin reuptake inhibitors (SSRI)reuptake inhibitors (SSRI) Adverse effectsAdverse effects

HeadacheGI

Nausea, diarrhoea, loss of appetite Titrate dose to minimize side effect May be taken with food

Anticholinergic Adverse effects Fever than TCA Tend to see more with paroxetine


Somnolence or insomnia Dose in morning for insomnia

Increase in anxiety, agitation, akathisia early in treatment (esp. fluoxetine)

Agitation or nervousnessSexual dysfunction


Serotonergic syndrome Rare but potentially fatal interaction between 2 or m

ore drugs that enhance serotonin Anxiety, shivering, diaphoresis, tremor, hyperflexia,

autonomic instability (BP, pulse) Fatal if malignant hyperthermia Management

Mild: resolve in 24-48 hours after discontinuing offending agent

Severe: 5-HT antagonist, cyproheptidine, propranolol, methysergide, dantrolene (hyperthermia)

Serotonin norepinephrine rSerotonin norepinephrine reuptake inhibitor (SNRI)euptake inhibitor (SNRI) Duloxetine (Cymbalta®)Duloxetine (Cymbalta®) Venlafaxine (Efexor®, Efexor XR®)Venlafaxine (Efexor®, Efexor XR®) Mechanism of actionMechanism of action

Inhibits norepinephrine and serotonin reuptake

Potentiates neurotransmitter activity in the CNS

Serotonin norepinephrine rSerotonin norepinephrine reuptake inhibitor (SNRI)euptake inhibitor (SNRI) Duloxetine (Cymbalta®)Duloxetine (Cymbalta®) Properties and Adverse effectsProperties and Adverse effects

More potent than venlafaxineAlso indicated for diabetic neuropathyInsomnia, nausea, headache

Serotonin norepinephrine rSerotonin norepinephrine reuptake inhibitor (SNRI)euptake inhibitor (SNRI) Venlafaxine (Efexor®, Efexor XR®)Venlafaxine (Efexor®, Efexor XR®) Properties and Adverse effectsProperties and Adverse effects

Also for anxiety disordersLacks sedative and anticholinergic effec

ts predominant with TCAsNausea, dizziness, sexual dysfunction, h

ypertension (when > 300mg/day)

Mixed serotonin norepinephMixed serotonin norepinephrine effectsrine effects Mirtazapine (Mirtazon®, Remeron®, RMirtazapine (Mirtazon®, Remeron®, R

emeron SolTab®)emeron SolTab®) Mechanism of actionMechanism of action

Presynaptic α2-antagonistIncreases central noradrenergic and ser

otonergic neurotransmission

Mixed serotonin norepinephMixed serotonin norepinephrine effectsrine effects Mirtazapine (Mirtazon®, Remeron®, RMirtazapine (Mirtazon®, Remeron®, R

emeron SolTab®)emeron SolTab®) Properties and Adverse effectsProperties and Adverse effects

Fewer anticholinergic effectsMarked sedation during initial treatmen

tStimulating as dose increasesIncreased appetite and weight gainConstipation, dry mouth

Norepinephrine dopamine rNorepinephrine dopamine reuptake inhibitor (NDRI)euptake inhibitor (NDRI) Bupropion (Wellbutrin SR®)Bupropion (Wellbutrin SR®) Mechanism of actionMechanism of action

Inhibits weakly the neuronal uptake of dopamine, norepinephrine and serotonin

Does not inhibit monoamine oxidase

Norepinephrine dopamine rNorepinephrine dopamine reuptake inhibitor (NDRI)euptake inhibitor (NDRI) Bupropion (Wellbutrin SR®)Bupropion (Wellbutrin SR®) Properties and side effectsProperties and side effects

GI side effects, confusion, dizziness, headache, insomnia, tremor

Seizure risk at high dosesMinimal risk of sexual dysfunctionAlso licensed for smoking cessation (Zy

ban®)

Other antidepressantsOther antidepressants

Flupenthixol (Fluanxol®)Flupenthixol (Fluanxol®)Typical antipsychoticAntidepressant effect at low doses

Antipsychotic dose: 3-9mg twice daily Antidepressant dose: 1-3mg daily

Combined with another antidepressant as Deanxit®

Flupenthixol 0.5mg + melitracen 10mg For depression and anxiety

Non-antidepressantsNon-antidepressants

AnxiolyticsAnxiolytics AntipsychoticsAntipsychotics

Use may mask the true diagnosis Used with caution But are still useful adjuncts in agitated

patients Lithium and thyroidLithium and thyroid

To potentiate effect of antidepressants in refractory cases

Lithium: plasma level 0.4-0.8mEq/L Thyroid supplement: 25mcg/day

Antidepressants in Antidepressants in depressiondepression Choice of agentsChoice of agents

All are equally efficacious for depression

Selection based on Side effect profile Potential drug interaction

Response failure to an antidepressant does not predict response to another drug class or another drug within class

Antidepressants in Antidepressants in depressiondepression GeriatricsGeriatrics

Reduce initial dose by half Gradual dose titration

Risk of dizziness and syncope Hyponatremia

PediatricsPediatrics Decrease initial dose by half Recent evidence links SSRIs with suicide in

adolescents

Antidepressants in Antidepressants in depressiondepression Treatment responseTreatment response

Weeks 1-2 Physical responses

Improvement in appetite and sleep

Weeks 3-4 Energy and cognitive responses

Improvement in energy Improvement in guilt, concentration

Weeks 5-6 Emotional responses

Improvement in mood

Antidepressants in Antidepressants in depressiondepression Continuation therapyContinuation therapy

To prevent relapse 4-9 months after complete remission of

symptoms At therapeutic doses

Lifelong maintenance therapyLifelong maintenance therapy Recommended by some investigators for

patients at greater risk or reoccurrence < 40 years with ≥ 2 prior episodes Any age with ≥ 3 prior episodes

Bipolar disorders and Bipolar disorders and mood stabilizersmood stabilizers

Bipolar disordersBipolar disorders

Cyclic disorder with recurrent fluctuations Cyclic disorder with recurrent fluctuations in mood, energy and behaviour, “mood sin mood, energy and behaviour, “mood swings”wings”

Episodes of mania and/or hypomania, and Episodes of mania and/or hypomania, and major depression that cause marked impamajor depression that cause marked impairment and/or hospitalizationirment and/or hospitalization

Devastating long term illnessDevastating long term illness Deterioration in functioning Suicidal ideation Substance abuse Noncompliance to meds


DSM-IV:DSM-IV: Bipolar I disorder

≥1 manic or mixed episode Bipolar II disorder

Recurrent major depressive episodes with hypomanic episodes

Bipolar disorder not otherwise specified Cyclothymic disorder

Both hypomanic and depressive episodes not meeting criteria for a major depressive epidose

Mood symptoms have persisted for 2 years without > 2 months of remission at a time

Bipolar disorder due to their general physical condition Substance-induced bipolar disorder


EpidemiologyEpidemiologyPrevelance 1-2%Male = femaleAverage age of onset 20 to 3010-15% rate of suicide


EpidemiologyEpidemiology5-15% of adults diagnosed with major d

epressive disorder eventually meet criteria for bipolar I disorders

60-70% of manic or hypomanic episodes occur immediately before or after major depressive episode

Period of euthymia (normal mood)


EtiologyEtiologyExact cause unknown

Genetic predisposition Life stressors Can occur with several physical

disorders As adverse effects of many drugs As part of several mental disorders


PathophysiologyPathophysiologyNeurotransmitters known to be involved

Serotonin Norepinephrine Dopamine

Brain structures most involved MRI findings suggests abnormalities in prefr

ontal cortical areas, striatum, and amygdala predate illness onset


Signs and symptomsSigns and symptoms ManiaMania

Distractability Insomnia Grandiosity or inflated sel

f-esteem Flight of ideas or subjecti

ve experience that thoughts are racing

Agitation or increase in goal-directed activity

Speech pressured/more talkative than usual

Taking risks

HypomaniaHypomania Distinct period of

persistently elevated, expansive, or irritable mood

Lasting throughout at least 4 days

< 1 week for mania Different from usual

non-depressed mood But not severe enough

to cause marked impairment in social or occupational functioning


Signs and symptomsSigns and symptoms Mixed episodeMixed episode

Simultaneous occurrence of manic and depressive symptoms nearly every day for aat least 1 week

Poorer prognosis More seen in younger a

nd older patients Less likely to respond t

o mood stabilizer monotherapy

Rapid cyclersRapid cyclers > 4 major depressive or

manic episodes (manic, mixed or hypomanic for 12 months)

Frequent and severe episodes of depression

Poorer prognosis Often require combina

tion therapies

Mood stabilizersMood stabilizers

LithiumLithium AnticonvulsantsAnticonvulsants

ValproateCarbamazepineLamotrigine

Antipsychotics, antidepressants and Antipsychotics, antidepressants and othersothers

LithiumLithium

Mechanism of actionMechanism of action Not fully understood

Mood-stabilizing effect has been postulated to reduction of catecholamine neurotransmitter concentration

Possibly related to Na-K-ATPase to improve membrane transport of Na ion

Alternative postulate that Li may decrease cyclic AMP concentrations, which would decrease sensitivity of hormonal-sensitive adenylcyclase receptors

LithiumLithium

PropertiesProperties Manic episode

Approved for manic episodes and maintenance therapy

About 70% patients show at least partial reduction of mania

Full effect takes 1-2 weeks Depressive episode

As adjunct to antidepressant for refractory patients Onset 4-6 weeks

Long term use reduces suicide risk and mortality

Narrow therapeutic index

LithiumLithium

DosingDosingStart with low divided doses to minimiz

e Adverse effectsGradual titrationAdjusted to achieve serum lithium

Acute manic episode: 1.0-1.5 mmol/L Maintenance: 0.6-1.2 mmol/L

LithiumLithium

Adverse effectsAdverse effects Early, dose related Adv

erse effects GI distress Sedation, weight gain Muscle weakness Polyuria, polydipsia Impaired cognitive fu

nciton Tremor

Tolerance may develop Management

Take with meal Beta blocker for trem

or

Late Adverse effectsLate Adverse effects Psoriasis / acne exacer

bation Nephrogenic diabetes i

nsipidus Hypothyroidism Cardiac

T-wave flattening or inversion

Bradycardia AV block

Leukocytosis

LithiumLithium

Adverse effectsAdverse effects Nephrogenic diabetes insipidus (DI)

Reduced renal response to aldosterone (ADH) Low osmolality polyuria

> 3L urine output per day Urine specific gravity < 1.005

Management Lowest effective dose Adequate hydration Once-daily bedtime dose Thiazides (lithium dose to 50%) or amiloride

LithiumLithium

Lithium toxicity (serum level > 1.5-2.5 mmol/L)Lithium toxicity (serum level > 1.5-2.5 mmol/L)Mild toxicityMild toxicity(< 1.6 mmol/L)(< 1.6 mmol/L)

Moderate toxicitModerate toxicityy(< 2.5 mmol/L)(< 2.5 mmol/L)

Severe toxicitySevere toxicity(> 2.5 mmol/L)(> 2.5 mmol/L)

ApathyApathy

IrritabilityIrritability

LethargyLethargy

Muscle Muscle weaknessweakness

NauseaNausea

Blurred visionBlurred vision

ConfusionConfusion

DrowsinessDrowsiness

Progressing Progressing tremortremor

Slurred speechSlurred speech

Unsteady gaitUnsteady gait

Cardiovascular Cardiovascular collapsecollapse

ComaComa

SeizureSeizure

LithiumLithium

ToxicityToxicityDiscontinue lithiumNaCl infusion, rehydration, electrolyteMonitor lithium level q3hElectrolyte panel, renal function labsHemodialysis if patient not clearing lithi

um well or lithium level > 3 mmol/LSupportive care

LithiumLithium

InteractionsInteractionsNumerous drug interactions!Dietary sodium, soda, coffee, tea,

caffeine lithium clearanceAcute mania lithium clearance

LithiumLithium

FormulationFormulation Regular release tablets

As lithium carbonate 250mg and 400mg (e.g. Camcolit®)

More adverse effects due to higher peak levels More convenient for small dose increments

Sustained release tablets As lithium sulphate 660mg (e.g. Lithiofor®) Fewer Adverse effects More expensive

AnticonvulsantsAnticonvulsants

Carbamazepine (Tegretol®, Tegretol Carbamazepine (Tegretol®, Tegretol CR®)CR®)

Lamotrigine (Lamictal®)Lamotrigine (Lamictal®) Valproate (Epilim EC®, Epilim ChronoValproate (Epilim EC®, Epilim Chrono

®)®)

CarbamazepineCarbamazepine

PropertiesProperties Approved for acute mania and mixed episodes

in bipolar I disorder As Equetro® extended-release capsules

Preferred when response to lithium is poor Rapid cyclers Mixed mania episodes

Not recommended as monotherapy for bipolar depression

P450 enzyme inducer


Adverse effectsAdverse effectsWeight gainNeurotoxicity

Diplopia, drowsiness, blurred vision, vertigo Transient and reversible with dose reductio

nMild elevation of liver enzymesHypersensitivity rash

Uncommon


Adverse effectsAdverse effects Hematologic effects

Rare: agranulocytosis, blood dyscrasia Discontinue when

Fever, sore throat, rash, mouth ulcers, bruising or bleeding

Syndrome of inappropriate antidiuretic hormine (SIADH)

Cardiac conduction abnormalities (sometimes arrhythmia)

LamotrigineLamotrigine

PropertiesProperties Approved for maintenance of bipolar I disorde

r To delay the time to occurrence of mood episodes

(depression, mania, hypomania, mixed episodes) Significant antidepressant effect without incre

ase in cycling May not be effective for severe mania Significant drug interactions with other antico

nvulsants


Dosing of lamotrigine in bipolar disordersDosing of lamotrigine in bipolar disordersWeeks 1-Weeks 1-22

Weeks 3-Weeks 3-44

Week 5Week 5 MaintenancMaintenance dosee dose

Lamotrigine Lamotrigine monotherapmonotherapyy

25mg qd25mg qd 50mg qd50mg qd 100mg qd100mg qd 200mg/day200mg/day

Lamotrigine Lamotrigine added to valadded to valproateproate

25mg qod25mg qod 25mg qd25mg qd 50mg qd50mg qd 100mg/day100mg/day

Lamotrigine Lamotrigine added to enadded to enzyme inducezyme inducers w/o valprrs w/o valproateoate

50mg qd50mg qd 100mg/100mg/day in day in divided divided dosesdoses

200mg/day 200mg/day for 1 week, for 1 week, then then 300mg/day 300mg/day for 1 week for 1 week (both in (both in divided doses divided doses ))

Increase up Increase up to to 400mg/day400mg/day


Adverse effectsAdverse effectsSkin rash

Stevens-Johnson’s Syndrome, toxic epidermal necrosis, hypersensitivity syndrome

Consider withdrawal if rash or signs of hypersensitivity occur

Increased risk of serious skin reactions with Concomitant use of valproate Initial lamotrigine doses higher than recomm

ended dose Dose escalation more rapid than recommend

ed


Adverse effectsAdverse effectsGI

Abdominal pain, indigestion, nausea, vomiting

Asthenia, painAtaxia, dizziness, headache,

somnolence

ValproateValproate PropertiesProperties

Approved for treatment of mania in bipolar disorder

As divalproex sodium (Depakote® and Depakote® ER)

Delayed release (Depakote®): manic episode Extended release (Depakote® ER): acute mania and mi

xed episodes Preferred when response to lithium is poor

Substance abusers Rapid cyclers Mixed mania episodes

P450 enzyme inhibitor

ValproateValproate

Adverse effectsAdverse effectsGI: anorexia, indigestion, nausea, vomiti

ng, heartburn, diarrhoea Decrease dose, antacid or H2-antagonist

Irreversible but rare hepatotoxicytWeight gain, increased appetite

Decrease dose, monitor weight

ValproateValproate

Adverse effectsAdverse effectsNeutropenia and thrombocytopeniaSedation, tremor

Decrease dose Beta blocker for tremor

Menstrual disturbances and polycystic ovaries is posssible

Transient alopecia

Other anticonvulsantsOther anticonvulsants

Oxcarbazepine (Trileptal®)Oxcarbazepine (Trileptal®) Topiramate (Topamax®)Topiramate (Topamax®)

No FDA approvalTested in some clinical studiesLess used than carbamazepine, lamotri

gine and valproate

Other drugs for bipolar Other drugs for bipolar diseasesdiseases AntipsychoticsAntipsychotics

Effective as adjunctive treatment of acute mania

Should be used when patient is psychotic

Novel ones preferredMonotherapy may be used in acute nonp

sychotic mania, but effectiveness of mood stabilization in maintenance phase not well established

Other drugs for bipolar Other drugs for bipolar diseasesdiseases AntipsychoticsAntipsychotics

Olanzapine Risperidone

FDA approval: acute mania, mixed episodes, maintenance

Aripiprazole Ziprasidone

FDA approval: acute mania, mixed episodes Quetiapine

FDA approval: acute mania, depressed phase

Other drugs for bipolar Other drugs for bipolar diseasesdiseases AntidepressantsAntidepressants

May improve acute depression in short term Ineffective for long term Monotherapy (TCAs in particular) can precipita

te manic episodes or rapid cycling May be used as adjunct with mood stabilizers i

f patient has a history of refractory depression and manic episodes that are relatively responsive

Other drugs for bipolar Other drugs for bipolar diseasesdiseases BenzodiazepinesBenzodiazepines

As adjunct to treat acute agitation, anxiety and insomnia

For severely ill patientsShort term use only

Mood stabilizers in bipolar Mood stabilizers in bipolar disordersdisorders Acute manic or mixed episodeAcute manic or mixed episode

Mild to moderate 1) Stabilize with lithium / valproate / antipsycotic (e.

g. olanzapine, quetiapine, risperidone) Alternative anticonvulsant: carbamazepine, lamotrigi

ne or oxcabazepine 2) If inadequate response, adjunctive benzodiazepin

es for anxiety or insomnia 3) If still inadequate response, consider two-drug th

erapy Lithium + anticonvulsant / antipsychotic Anticonvulsant + anticonvulsant / antipsychotic


Moderate to severe 1) Stabilize with lithium / valproate PLUS a

ntipsychotic for short term adjunctive treatment (e.g. olanzapine, quetiapine, risperidone)

Alternative anticonvulsant: carbamazepine, lamotrigine or oxcabazepine

2) If inadequate response, adjunctive benzodiazepines for anxiety or insomnia

Lorazepam recommended for catatonia


Moderate to severe 3) If still inadequate response, consider 2-drug thera

py Lithium + anticonvulsant / antipsychotic Anticonvulsant + anticonvulsant / antipsychotic

4) If still inadequate response, electroconvulsive therapy or add clozapine for refractory illness

5) If still inadequate response, consider adjunctive therapies

α2-adrenergic agonist, calcium channel blockers (nimodipine, verapamil), newer anticonvulsants (e.g. gabapentin, topiramate)

Mood stabilizers in bipolar Mood stabilizers in bipolar disordersdisorders Depressive episodeDepressive episode

Mild to moderate Stabilize with lithium or lamotrigine

Alternative anticonvulsant: carbamazepine, oxcabazepine or valproate


Moderate to severe 1) Stabilize with 2-drug therapy

Lithium / lamotrigine PLUS antidepressantLithium PLUS lamotrigine

Alternative anticonvulsant: carbamazepine, oxcabazepine or valproate

2) If inadequate response, short-term adjunctive atypical antipsychotic if needed


Moderate to severe 3) If still inadequate response, consider 3-drug therapy

Lithium + anticonvulsant + antipsychotic Lamotrigine + anticonvulsant + antidepressant

4) If still inadequate response, electroconvulsive therapy (ECT) for refractory illness and depression with psychosis or catatonia

5) If still inadequate response, consider adjunctive therapies

α2-adrenergic agonist, calcium channel blockers (nimodipine, verapamil), newer anticonvulsants (e.g. gabapentin, topiramate)

Mood stabilizers in bipolar Mood stabilizers in bipolar disordersdisorders Initial therapyInitial therapy

If first line agent(s) not effective for 2-4 weeks, add a second agent to augment mood stabilization

Maintenance therapyMaintenance therapy Maintain with a mood stabilizer for both bipolar I and II

disorders for 6-month continuation phase First line: lithium or valproate Alternative: carbamazepine, lamotrigine, oxcabazepine

Taper off adjunctive therapy and discontinue Patient with only 1 manic episode should continue mai

ntenance therapy for 12 months Gradually taper off over several months (usually 6 months

after complete remission)

Mood stabilizers in bipolar Mood stabilizers in bipolar disordersdisorders Lifelong prophylaxisLifelong prophylaxis

Consider with mood stabilizers for Patients after 2 manic episodes After 1 severe episode Strong family history of bipolar disorder Frequent episodes (> 1 per year) Rapid onset of manic apisodes Bipolar II After 3 hypomanic episodes Patients who become hypomanic with antidepressa

nts

EndEnd

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