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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
SchizophreniaSchizophrenia
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%)
SchizophreniaSchizophrenia
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
SchizophreniaSchizophrenia
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
SchizophreniaSchizophrenia
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
SchizophreniaSchizophrenia
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
Typical / conventional Typical / conventional antipsychoticsantipsychotics Adverse effectsAdverse effects
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
Typical / conventional Typical / conventional antipsychoticsantipsychotics Adverse effectsAdverse effects
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
Typical / conventional Typical / conventional antipsychoticsantipsychotics Adverse effectsAdverse effects
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
Typical / conventional Typical / conventional antipsychoticsantipsychotics Adverse effectsAdverse effects
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
Typical / conventional Typical / conventional antipsychoticsantipsychotics Adverse effectsAdverse effects
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
Typical / conventional Typical / conventional antipsychoticsantipsychotics Other Adverse effectsOther Adverse effects
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
Typical / conventional Typical / conventional antipsychoticsantipsychotics Other Adverse effectsOther Adverse effects
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
Atypical antipsychoticsAtypical antipsychotics
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®)
Atypical antipsychoticsAtypical antipsychotics
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)
Atypical antipsychoticsAtypical antipsychotics
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)
Atypical antipsychoticsAtypical antipsychotics
PropertiesPropertiesLess frequently associated with EPSMore risk of weight gain, new onset dia
betes, hyperlipidemiaNovel agents, more expensive
Atypical antipsychoticsAtypical antipsychotics
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
Atypical antipsychoticsAtypical antipsychotics
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 ++ ++++++
++++ ++++ -- ++
Atypical antipsychoticsAtypical antipsychotics
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
Atypical antipsychoticsAtypical antipsychotics
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 ++
Atypical antipsychoticsAtypical antipsychotics
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
Atypical antipsychoticsAtypical antipsychotics
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)
Atypical antipsychoticsAtypical antipsychotics
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)
Atypical antipsychoticsAtypical antipsychotics
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
Atypical antipsychoticsAtypical antipsychotics
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
DepressionDepression
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
DepressionDepression
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
DepressionDepression
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)
DepressionDepression
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)
DepressionDepression
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
Selective serotonin Selective serotonin reuptake inhibitors (SSRI)reuptake inhibitors (SSRI) Adverse effectsAdverse effects
Somnolence or insomnia Dose in morning for insomnia
Increase in anxiety, agitation, akathisia early in treatment (esp. fluoxetine)
Agitation or nervousnessSexual dysfunction
Selective serotonin Selective serotonin reuptake inhibitors (SSRI)reuptake inhibitors (SSRI) Adverse effectsAdverse effects
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
Bipolar disordersBipolar disorders
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
Bipolar disordersBipolar disorders
EpidemiologyEpidemiologyPrevelance 1-2%Male = femaleAverage age of onset 20 to 3010-15% rate of suicide
Bipolar disordersBipolar disorders
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)
Bipolar disordersBipolar disorders
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
Bipolar disordersBipolar 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
Bipolar disordersBipolar disorders
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
Bipolar disordersBipolar disorders
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
CarbamazepineCarbamazepine
Adverse effectsAdverse effectsWeight gainNeurotoxicity
Diplopia, drowsiness, blurred vision, vertigo Transient and reversible with dose reductio
nMild elevation of liver enzymesHypersensitivity rash
Uncommon
CarbamazepineCarbamazepine
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
LamotrigineLamotrigine
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
LamotrigineLamotrigine
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
LamotrigineLamotrigine
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
Mood stabilizers in bipolar Mood stabilizers in bipolar disordersdisorders Acute manic or mixed episodeAcute manic or mixed episode
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
Mood stabilizers in bipolar Mood stabilizers in bipolar disordersdisorders Acute manic or mixed episodeAcute manic or mixed episode
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
Mood stabilizers in bipolar Mood stabilizers in bipolar disordersdisorders Depressive episodeDepressive episode
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
Mood stabilizers in bipolar Mood stabilizers in bipolar disordersdisorders Depressive episodeDepressive episode
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
Questions & AnswersQuestions & Answers