110 140 Ordin Centre de Sanatate Mintala

Pharmacotherapy in
Psychiatry
Depression
Schizophrenia
Bipolar disorders
Contents
 Schizophrenia and antipsychotics

 Depression and antidepressants
 Bipolar disorders and mood stabilizers
Schizophrenia and antipsyc
hotics
Schizophrenia
 Characterized by psychosis,
hallucinations, delusions, cognitive
defects, occupational and social
dysfunction
 Chronic psychotic illness
 Episodic exacerbations and remissions
with residual symptoms
 Complete remission is not common
Schizophrenia
 Epidemiology
 Lifetime prevalence is 1% in United
States
 Onset in late teens or early 20s in males;
sometime later in females
 Suicide rate comparable to depressive
illness (approx 10%)
Schizophrenia
 Etiology
 Exact etiology unknown
 Genetic predisposition
 Intrauterine, birth or postnatal complications
 Viral CNS infections
 Environmental stressors (biochemical or social)
 No evidence of association with poor pare

nting
Schizophrenia
 Pathophysiology
 No consistent neuropathology or
biomarkers for schizophrenia
 ? Increased dopamine in mesolimbic pathway
s causes delusions and hallucinations
 ? Dopamine deficiency in mesocortical and ni
grostriatal pathways causes negative sympto
ms (apathy, withdrawal)
 Hallocinogens produce effect through action o
n 5-HT2 receptors
Schizophrenia
 Positive symptoms  Negative symptoms
 Hallucinations  Social withdrawal
 Delusions  Emotional withdrawal
 Disordered thinking  Lack of motivation
 Disorganized speech  Poverty of speech
 Combativeness  Blunted affect
 Agitation  Poor insight
 Paranoia  Poor judgement
 Poor self-care
Schizophrenia
 Antipsychotics
 Typical / Conventional antipsychotics
 Atypical antipsychotics
Typical / conventional
antipsychotics
 Chlorpromazine (Largactil®)
 Flupenthixol (Fluanxol®)
 Haloperidol (Serenace®, Haldol®)
 Pericyazine (Neulactil®)
 Pimozide (Orap®, Orap Forte®)
 Sulpiride (Dogmatil®)
 Thioridazine (Melleril®)
 Trifluoperazine (Stelazine®)
 Thiothixene (Navane®)
antipsychotics
 Refers to agents introduced in US before
1990
 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
antipsychotics
Dopamine receptors in various tracks
Track Origin Innervations Function Antipsychotic
effect
Mesolimbic Midbrain, Limbic struct Emotional and Hallucinations,
Ventral tegme ure, nucleus intellectual deulsions, disord
ntal accumbens ered cognition
Mesocortical Ventral tegme Frontal

ntal cortex
Nigrostriatal Substantia nig Basal ganglia Extrapyramidal Motor sympto
ra system movem matology
ent
Tubero-infun Hypothalamus Pituitary Regulate Plasma prolacti
dubular gland endocrine n levels
functions
antipsychotics
 Mechanism 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
antipsychotics
 Properties
 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
antipsychotics
 Potency
 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
antipsychotics
 Low potency
 Chlorpromazine, thioridazine
 Medium potency
 Perphenazine
 High potency
 Trifluoperazine, thiothixene, fluphenazine,
haloperidol, pimozide
antipsychotics
Potency Drug Equiv EPS Sedation Anticholinergic s/e
oral
dose
(mg)
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
antipsychotics
Comparison of representative antipsychotics
Drug Advantages Disadvantages
Chlorpromazine Generic, inexpensive Many adverse effects
(esp. autonomic)
Thioridazine Slight EPS, generic Cardiotoxicity (QT
prolongation)
Fluphenazine Generic, depot (?) increased tardive
available dyskinesia
Thiothixene (?) decreased tardive Uncertain
dyskinesia
Haloperidol Generic, injection and Prominent EPS
depot A/V, few
autonomic s/e
antipsychotics
Receptor 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
antipsychotics
 Adverse 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
antipsychotics
 Adverse 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 antipsychoti
c
antipsychotics
 Adverse 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
antipsychotics
 Adverse 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
antipsychotics
 Adverse effects
 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
antipsychotics
 Adverse effects
 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
antipsychotics
 Other 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
antipsychotics
 Neuroleptic malignant syndrome (NMS)
 After symptom resolution
 Some suggest to wait for at least 2 weeks before
resuming
 Use lowest effective dose
 Avoid high potency agents
 Consider atypical antipsychotics
 However, NMS has been reported from
patients taking clozapine, risperidone,
olanzapine and quetiapine
antipsychotics
 Prolactinemia
 D2 receptor blockade decreases dopamine inhibition 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 antipsychotics
 Refers to newer agents

 Also known as
 “Serotonin-dopamine antagonists”
 Postsynaptic effects at 5-HT2A and D2
receptors
 Amisulpiride (Solian®)
 Quetiapine (Seroquel®)
 Ziprasidone (Zeldox®)
 Risperidone (Risperdal®)
 Olanzapine (Zyprexa®)
 Clozapine (Clozaril®)
 Aripiprazole (Abilify®)
 Similar blocking effect on D2 receptors
 Seem to be a little more selective, targeting the i
ntended pathway to a larger degree than the oth
ers
 Also block or partially block serotonin receptors
(particularly 5HT2A, C and 5HT1A receptors)
 Aripiprazole: dopamine partial agonist (novel me
chanism)
 Properties
 Available 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)
 Properties
 Less frequently associated with EPS
 More risk of weight gain, new onset diabe
tes, hyperlipidemia
 Novel agents, more expensive
 Potency
 All atypical antipsychotics are equally effe
ctive at therapeutic doses
 Except clozapine
 Most effective antipsychotic
 For resistant schizophrenia
 2nd line due to life-threatening side effect

Relative receptor-binding of atypical antipsychotics
Drug D1 D2 5-HT2 1 M1 H1
Clozapine ++ ++ +++ +++ +++ +
Risperidone - +++ +++ +++ - +
Olanzapine ++ ++ +++ ++ +++ ++
Quetiapine - + ++ +++ + +
Ziprasidone +/- ++ +++ ++ - +
Aripiprazole + +++ ++ ++ - +
Comparison of representative atypical antipsychotics
Drug Advantages Disadvantages
Clozapine For treatment-resistant cases, Risk of fatal agranulocytosis
little EPS
Risperidone Broad efficacy, little or no EPS EPS and hypotension at high
at low doses doses
Olanzapine Effective with positive and Weight gain
negative symptoms, little or
no EPS
Quetiapine Similar to risperidone, maybe Dose adjustment with associated
less weight gain hypotension, bd dosing
Ziprasidone Perhaps less weight gain than QT prolongation
clozapine, Inj A/V
Aripiprazole Less weight gain, novel Uncertain
mechanism potential
Relative incidence of Adverse effects
Drugs Sedation EPS Anticholinergic Orthostasis Seizure Prolactin Weight

elevation gain
Clozapine ++++ + ++++ ++++ ++++ 0 ++++
Risperidone +++ + ++ +++ ++ 0 to +++ ++

+
Olanzapine +++ + +++ ++ ++ + +++
Quetiapine +++ + ++ ++ ++ 0 ++
Ziprasidone ++ + ++ ++ ++ 0 +
Aripiprazole ++ + ++ ++ ++ 0 +
 1st line atypical antipsychotics
 All atypicals except clozapine
 NICE recommendations
 Atypical antipsychotics considered when choosing 1 st
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
 2nd line atypical antipsychotic
 Clozapine
 Most effective antipsychotic for reducing symptoms an
d preventing relapse
 Use of clozapine effectively reduce suicide risk
 1% risk of potentially fatal agranulocytosis
 Acute pronounced leukopenia with great reduction in nu
mber 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)
 Clozapine
 BNF 52 (September 2006)
 Leucocyte and differential blood count normal before s
tarting
 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/mm
3, discontinue immediately and refer to hematologist
 Patient should report immediately symptoms of infectio
n, esp. flu-like illness (fever, sore throat)
 Clozapine
 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
 Clozapine
 Contraindication
 History of clozapine-induced agranulocytosis
 Bone marrow suppression
 On myelosuppressive drugs
 Caution
 Seizure disorders
 Diabetes
Antipsychotic oral-dispersible
and solution preparations
 Oral-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 for
 1 typical
 Haloperidol (Haldol® drops)
 1 atypical
 Risperidone (Risperdal® solution)
 Very concentrated, avoid from contact with skin (dermatitis)
Antipsychotic injections
 Available for
 2 typicals
 Chlorpromazine (Largactil®)
 Haloperidol (Haldol®)
 2 atypicals
 Olanzapine (Zyprexa®)
 Ziprasidone (Zeldox®)
 Useful for acutely agitated patients

Antipsychotic depot injections
 Available for
 4 typicals
 Haloperidol decanoate (Haldol Decanoate®)
 Fluphenazine decanoate (Modecate®)
 Zuclopenthixol (Clopixol Depot®)
 1 atypical
 Risperidone (Risperdal Consta®)
 Used for chronic illness and history of noncomplia
nce
 Trial of oral meds first to assess tolerability
Non-antipsychotic agents
 Benzodiazepines
 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
 Lithium
 Limited role in schizophrenia monotherapy
 Improve psychosis, depression, excitement, and
irritability when used with antipsychotic in some
studies
Non-antipsychotic agents
 Carbamazepine
 Weak support when used alone and with antipsychotic
 Alters metabolism of antipsychotic
 NOT to be used with clozapine (risk of agranulocytosis)
 Valproate
 Concurrent administration with risperidone and olanzapine
resulted in early psychotic improvement in recent
investigation
 Propranolol
 Research showed improvement in chronic aggression
 Treat aggression or enhance antipsychotic response
 Reasonable trial  240mg/day
Antipsychotics in
schizophrenia
 Selection of typical antipsychotics
 Equally efficacious
 Chosen by side effect profile
 Atypical antipsychotics may be appropriate if
 Adverse effect is a particular concern
 Additional benefits for negative and cognitive
symptoms required
 Clozapine
 2nd line treatment when other agents are
ineffective or not tolerated
Antipsychotics in
schizophrenia
 Depot antipsychotic preparations
 Useful for noncompliant patients with poor
insight
 Antidepressents and mood stabilisers
 In schizoaffective disorders
 Patients with secondary mood symptoms or
aggressivity
 Differentiate between adverse effects and
signs of disease progression
 E.g. Parkinsonism vs. psychotic hysteria,
Akathisia vs. exacerbation of psychosis
Antipsychotics in
schizophrenia
 Oral 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 preparations
 For unreliable patients
 Injections
 Usually deltoid or gluteal muscle (or according to manufacturer)
 Depot 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
schizophrenia
 Treatment 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
schizophrenia
 Acute phase
 Initiate therapy
 Titrate as tolerated to average effective dose
 Stabilization phase
 Dose titration within the therapeutic range
 Maintenance 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
antidepressants
Depression
 Depressed mood and/or decrease in interest in
things that used to give pleasure
 Sadness severe enough or persistent enough to int
erfere with function
 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
Depression
 Epidemiology
 Life prevalence 3-17%
 Onset in late 20s
 Highest in
 25-44 years
 Elderly in community
 Female vs male = 2:1

 Female 10-25% lifetime risk
 Male 5-12% lifetime risk
Depression
 Epidemiology
 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 depressiv
e or bipolar disorder complete suicide
Depression
 Signs 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)
Depression
 Etiology
 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, h
ypothalamic-pituitary-thyroid axis and growth hormone
 Life stresses (e.g. Separation and losses)
Depression
 Pathophysiology
 Exact course unknown
 Changes in receptor-neurotransmitter
relationship in limbic system
 Serotonin, norepinephrine, sometimes dopamine
 Increased pump uptake of neurotransmitter
 Reabsorption into neuron
 Destroyed by monoamine oxidase in mitochondria
 Lack of neurotransmitters
Antidepressants
 Tricyclic and related antidepressants (TCA)
 E.g. amitriptyline, imipramine, doxepin, mianserin,
trazodone
 Monoamine-oxidase inhibitors (MAOI)
 E.g. moclobemide, phenelzine, isocarboxazid,
tranylcypromine
 Selective serotonin reuptake inhibitors (SSRI)
 E.g. fluoxetine, paroxetine, sertraline, citalopram
 Other antidepressants
 E.g. mirtazapine, venlafaxine, duloxetine,
flupentixol
Tricyclic and related
antidepressants (TCA)
 Amitriptyline (Saroten®)
 Clomipramine (Anafranil®)
 Dothiepin (a.k.a. dosulepin, Prothiaden®)
 Doxepin (Sinequan®)
 Imipramine (Tofranil®)
 Mianserin (Tolvon®)
 Nortriptyline (Nortrilen®)
 Trazodone (Trittico®)
 Trimipramine (Surmontil®)
 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)
 Properties
 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
 Adverse 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
 Adverse 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
 Drug interactions
 CNS depressants
 Narcotics, benzodiazepines
 Additive CNS depression
 Anticholinergics
 Additive anticholinergic effects
 P450 enzyme inducers/inhibitors
Monoamine-oxidase inhibitors
(MAOI)
 Moclobemide (Aurorix®)
 Not registered in Hong Kong
 Phenelzine
 Isocarboxazid
 Tranylcypromine
(MAOI)
 Inhibit both MAO-A and MAO-B
 Phenelzine, tranylcypromine
 Selective & reversible inhibitor of MAO-A
 Moclobemide
(MAOI)
 Properties
 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
(MAOI)
 Properties
 Drug interactions
 Other antidepressants should not be started f
or 2 weeks after MAOI has been stopped (3
weeks for clomipramine or imipramine)
 MAOI should not be started for 7-14 days aft
er a tricyclic or related antidepressant (3 wee
ks for clomipramine or imipramine)
 MAOI should not be started for at least 2 wee
ks after a previous MAOI
(MAOI)
 Adverse effects
 Hypertensive crisis
 Severe occipital headache, photophobia, palpi
tation, sharply increased in BP due to additive
effect between MAOI and adrenergic stimulan
ts
 Tyramine-rich food e.g. cheese, wine, smoked/age
d/picked meat or fish, alcohol
 Amphetamins
 Pseudoephedrine
(MAOI)
 Adverse effects
 Orthostatic hypotension
 Insomnia
 Weight gain
 Sexual dysfunction
Selective serotonin reuptake
inhibitors (SSRI)
 Fluoxetine (Prozac®)
 Fluvoxamine (Faverin®)
 Paroxetine (Seroxat®)
 Sertraline (Zoloft®)
 Citalopram (Cipram®)
 Escitalopram (Lexapro®)
inhibitors (SSRI)
 Inhibits reuptake of serotonin (5-HT) pres
ynaptic uptake
 Increases availability of serotonin at syna
pses
inhibitors (SSRI)
 Properties
 Overdose less likely to be fatal
 Less anticholinergic side effects
 But more GI side effects
 Seems to be better tolerated
inhibitors (SSRI)
 Properties
 Fluoxetine
 Most stimulating SSRI
 Indicated for premenstrual dysphoric disorder (PMDD)
(as Sarafem®)
 Long half-life, ensure 5 week washout before MAOI (2 w
eek for other SSRI)
 Some SSRIs also indicated for
 Obsessive-compulsive disorder (OCD)
 Panic disorder
 Eating disorders
 Social phobia
 Post traumatic stress disorder (PTSD)
inhibitors (SSRI)
 Adverse effects
 Headache
 GI
 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
inhibitors (SSRI)
 Adverse effects
 Somnolence or insomnia
 Dose in morning for insomnia
 Increase in anxiety, agitation, akathisia e
arly in treatment (esp. fluoxetine)
 Agitation or nervousness
 Sexual dysfunction
inhibitors (SSRI)
 Adverse effects
 Serotonergic syndrome
 Rare but potentially fatal interaction between 2 or mor
e drugs that enhance serotonin
 Anxiety, shivering, diaphoresis, tremor, hyperflexia, aut
onomic instability (BP, pulse)
 Fatal if malignant hyperthermia
 Management
 Mild: resolve in 24-48 hours after discontinuing offendin
g agent
 Severe: 5-HT antagonist, cyproheptidine, propranolol, m
ethysergide, dantrolene (hyperthermia)
Serotonin norepinephrine reu
ptake inhibitor (SNRI)
 Duloxetine (Cymbalta®)
 Venlafaxine (Efexor®, Efexor XR®)
 Inhibits norepinephrine and serotonin reu
ptake
 Potentiates neurotransmitter activity in th
e CNS
 Duloxetine (Cymbalta®)
 Properties and Adverse effects
 More potent than venlafaxine
 Also indicated for diabetic neuropathy
 Insomnia, nausea, headache
 Venlafaxine (Efexor®, Efexor XR®)
 Also for anxiety disorders
 Lacks sedative and anticholinergic effects
predominant with TCAs
 Nausea, dizziness, sexual dysfunction, hy
pertension (when > 300mg/day)
Mixed serotonin norepinephri
ne effects
 Mirtazapine (Mirtazon®, Remeron®, R
emeron SolTab®)
 Presynaptic α2-antagonist
 Increases central noradrenergic and serot
onergic neurotransmission
Mixed serotonin norepinephri
ne effects
 Mirtazapine (Mirtazon®, Remeron®, R
emeron SolTab®)
 Fewer anticholinergic effects
 Marked sedation during initial treatment
 Stimulating as dose increases
 Increased appetite and weight gain
 Constipation, dry mouth
Norepinephrine dopamine reu
ptake inhibitor (NDRI)
 Bupropion (Wellbutrin SR®)
 Inhibits weakly the neuronal uptake of do
pamine, norepinephrine and serotonin
 Does not inhibit monoamine oxidase
Norepinephrine dopamine reu
ptake inhibitor (NDRI)
 Bupropion (Wellbutrin SR®)
 Properties and side effects
 GI side effects, confusion, dizziness, head
ache, insomnia, tremor
 Seizure risk at high doses
 Minimal risk of sexual dysfunction
 Also licensed for smoking cessation (Zyba
n®)
Other antidepressants
 Typical antipsychotic
 Antidepressant 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-antidepressants
 Anxiolytics
 Antipsychotics
 Use may mask the true diagnosis
 Used with caution
 But are still useful adjuncts in agitated patients
 Lithium and thyroid
 To potentiate effect of antidepressants in refract
ory cases
 Lithium: plasma level 0.4-0.8mEq/L
 Thyroid supplement: 25mcg/day
Antidepressants in depression
 Choice 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
 Geriatrics
 Reduce initial dose by half
 Gradual dose titration
 Risk of dizziness and syncope
 Hyponatremia
 Pediatrics
 Decrease initial dose by half
 Recent evidence links SSRIs with suicide in
adolescents
 Treatment 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
 Continuation therapy
 To prevent relapse
 4-9 months after complete remission of
symptoms
 At therapeutic doses
 Lifelong 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 mood
stabilizers
Bipolar disorders
 Cyclic disorder with recurrent fluctuations in
mood, energy and behaviour, “mood swings”
 Episodes of mania and/or hypomania, and m
ajor depression that cause marked impairme
nt and/or hospitalization
 Devastating long term illness
 Deterioration in functioning
 Suicidal ideation
 Substance abuse
 Noncompliance to meds
Bipolar disorders
 DSM-IV:
 Bipolar I disorder
 ≥1 manic or mixed episode
 Bipolar II disorder
 Recurrent major depressive episodes with hypomanic episod
es
 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 mont
hs of remission at a time
 Bipolar disorder due to their general physical condition
 Substance-induced bipolar disorder
Bipolar disorders
 Epidemiology
 Prevelance 1-2%
 Male = female
 Average age of onset 20 to 30
 10-15% rate of suicide
Bipolar disorders
 Epidemiology
 5-15% of adults diagnosed with major de
pressive disorder eventually meet criteria
for bipolar I disorders
 60-70% of manic or hypomanic episodes
occur immediately before or after major d
epressive episode
 Period of euthymia (normal mood)
Bipolar disorders
 Etiology
 Exact 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 disorders
 Pathophysiology
 Neurotransmitters known to be involved
 Serotonin
 Norepinephrine
 Dopamine
 Brain structures most involved

 MRI findings suggests abnormalities in prefron
tal cortical areas, striatum, and amygdala pre
date illness onset
Bipolar disorders
 Mania  Hypomania
 Distractability  Distinct period of
 Insomnia persistently elevated,
 Grandiosity or inflated self- expansive, or irritable
mood
esteem
 Lasting throughout at least
 Flight of ideas or subjective
4 days
experience that thoughts a
re racing  < 1 week for mania
 Agitation or increase in goa  Different from usual non-
l-directed activity depressed mood
 Speech pressured/more tal  But not severe enough to
kative than usual cause marked impairment
in social or occupational
 Taking risks functioning
Bipolar disorders
 Mixed episode  Rapid cyclers
 Simultaneous occurrenc  > 4 major depressive or
e of manic and depressi manic episodes (manic,
ve symptoms nearly eve mixed or hypomanic for
ry day for aat least 1 we 12 months)
ek  Frequent and severe epi
 Poorer prognosis sodes of depression
 More seen in younger an  Poorer prognosis
d older patients  Often require combinati
 Less likely to respond to on therapies
mood stabilizer monothe
rapy
Mood stabilizers
 Lithium
 Anticonvulsants
 Valproate
 Carbamazepine
 Lamotrigine
 Antipsychotics, antidepressants and ot
hers
Lithium
 Not fully understood
 Mood-stabilizing effect has been postulated to reductio
n 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 c
oncentrations, which would decrease sensitivity of hor
monal-sensitive adenylcyclase receptors
Lithium
 Properties
 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
Lithium
 Dosing
 Start with low divided doses to minimize
Adverse effects
 Gradual titration
 Adjusted to achieve serum lithium
 Acute manic episode: 1.0-1.5 mmol/L
 Maintenance: 0.6-1.2 mmol/L
Lithium
 Adverse effects  Late Adverse effects
 Early, dose related Adve  Psoriasis / acne exacerb
rse effects ation
 GI distress  Nephrogenic diabetes in
 Sedation, weight gain sipidus
 Muscle weakness  Hypothyroidism
 Polyuria, polydipsia  Cardiac
 Impaired cognitive fun  T-wave flattening or in
citon version
 Tremor  Bradycardia
 Tolerance may develop  AV block
 Management  Leukocytosis
 Take with meal
 Beta blocker for tremor
Lithium
 Adverse 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
Lithium
Lithium toxicity (serum level > 1.5-2.5 mmol/L)
Mild toxicity Moderate toxicity Severe toxicity
(< 1.6 mmol/L) (< 2.5 mmol/L) (> 2.5 mmol/L)
Apathy Blurred vision Cardiovascular
Irritability Confusion collapse
Lethargy Drowsiness Coma
Muscle weakness Progressing Seizure
Nausea tremor
Slurred speech
Unsteady gait
Lithium
 Toxicity
 Discontinue lithium
 NaCl infusion, rehydration, electrolyte
 Monitor lithium level q3h
 Electrolyte panel, renal function labs
 Hemodialysis if patient not clearing lithiu
m well or lithium level > 3 mmol/L
 Supportive care
Lithium
 Interactions
 Numerous drug interactions!
 Dietary sodium, soda, coffee, tea,
caffeine  lithium clearance
 Acute mania  lithium clearance
Lithium
 Formulation
 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
Anticonvulsants
 Carbamazepine (Tegretol®, Tegretol C

R®)
 Lamotrigine (Lamictal®)
 Valproate (Epilim EC®, Epilim Chrono
®)
Carbamazepine
 Properties
 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 de
pression
 P450 enzyme inducer
Carbamazepine
 Adverse effects
 Weight gain
 Neurotoxicity
 Diplopia, drowsiness, blurred vision, vertigo
 Transient and reversible with dose reduction
 Mild elevation of liver enzymes

 Hypersensitivity rash
 Uncommon
Carbamazepine
 Adverse effects
 Hematologic effects
 Rare: agranulocytosis, blood dyscrasia
 Discontinue when
 Fever, sore throat, rash, mouth ulcers, bruising or bleedi
ng
 Syndrome of inappropriate antidiuretic hormine
(SIADH)
 Cardiac conduction abnormalities (sometimes arr
hythmia)
Lamotrigine
 Properties
 Approved for maintenance of bipolar I disorder
 To delay the time to occurrence of mood episodes (de
pression, mania, hypomania, mixed episodes)
 Significant antidepressant effect without increase
in cycling
 May not be effective for severe mania
 Significant drug interactions with other anticonv
ulsants
Lamotrigine
Dosing of lamotrigine in bipolar disorders
Weeks 1-2 Weeks 3-4 Week 5 Maintenance
dose
Lamotrigine 25mg qd 50mg qd 100mg qd 200mg/day
monotherapy
Lamotrigine a 25mg qod 25mg qd 50mg qd 100mg/day
dded to valpr
oate
Lamotrigine a 50mg qd 100mg/day 200mg/day for Increase up
dded to enzy in divided 1 week, then to
me inducers doses 300mg/day for 400mg/day
w/o valproat 1 week (both in
e divided doses )
Lamotrigine
 Adverse effects
 Skin rash
 Stevens-Johnson’s Syndrome, toxic epidermal
necrosis, hypersensitivity syndrome
 Consider withdrawal if rash or signs of hyperse
nsitivity occur
 Increased risk of serious skin reactions with
 Concomitant use of valproate
 Initial lamotrigine doses higher than recommend
ed dose
 Dose escalation more rapid than recommended
Lamotrigine
 Adverse effects
 GI
 Abdominal pain, indigestion, nausea, vomiting
 Asthenia, pain
 Ataxia, dizziness, headache, somnolence
Valproate
 Properties
 Approved for treatment of mania in bipolar disor
der
 As divalproex sodium (Depakote® and Depakote® ER)
 Delayed release (Depakote®): manic episode
 Extended release (Depakote® ER): acute mania and mix
ed episodes
 Preferred when response to lithium is poor
 Substance abusers
 Rapid cyclers
 Mixed mania episodes
 P450 enzyme inhibitor
Valproate
 Adverse effects
 GI: anorexia, indigestion, nausea, vomitin
g, heartburn, diarrhoea
 Decrease dose, antacid or H2-antagonist
 Irreversible but rare hepatotoxicyt
 Weight gain, increased appetite
 Decrease dose, monitor weight
Valproate
 Adverse effects
 Neutropenia and thrombocytopenia
 Sedation, tremor
 Decrease dose
 Beta blocker for tremor
 Menstrual disturbances and polycystic ova

ries is posssible
 Transient alopecia
Other anticonvulsants
 Oxcarbazepine (Trileptal®)
 Topiramate (Topamax®)
 No FDA approval
 Tested in some clinical studies
 Less used than carbamazepine, lamotrigin
e and valproate
Other drugs for bipolar
diseases
 Antipsychotics
 Effective as adjunctive treatment of acute
mania
 Should be used when patient is psychotic
 Novel ones preferred
 Monotherapy may be used in acute nonps
ychotic mania, but effectiveness of mood
stabilization in maintenance phase not we
ll established
diseases
 Antipsychotics
 Olanzapine
 Risperidone
 FDA approval: acute mania, mixed episodes, maintenan
ce
 Aripiprazole
 Ziprasidone
 FDA approval: acute mania, mixed episodes
 Quetiapine
 FDA approval: acute mania, depressed phase
diseases
 Antidepressants
 May improve acute depression in short term
 Ineffective for long term
 Monotherapy (TCAs in particular) can precipitate
manic episodes or rapid cycling
 May be used as adjunct with mood stabilizers if
patient has a history of refractory depression an
d manic episodes that are relatively responsive
diseases
 Benzodiazepines
 As adjunct to treat acute agitation,
anxiety and insomnia
 For severely ill patients
 Short term use only
Mood stabilizers in bipolar
disorders
 Acute manic or mixed episode
 Mild to moderate
 1) Stabilize with lithium / valproate / antipsycotic (e.g.
olanzapine, quetiapine, risperidone)
 Alternative anticonvulsant: carbamazepine, lamotrigine o
r oxcabazepine
 2) If inadequate response, adjunctive benzodiazepines
for anxiety or insomnia
 3) If still inadequate response, consider two-drug thera
py
 Lithium + anticonvulsant / antipsychotic
 Anticonvulsant + anticonvulsant / antipsychotic
disorders
 Moderate to severe
 1) Stabilize with lithium / valproate PLUS anti
psychotic for short term adjunctive treatment
(e.g. olanzapine, quetiapine, risperidone)
 Alternative anticonvulsant: carbamazepine, lamotri
gine or oxcabazepine
 2) If inadequate response, adjunctive benzodi
azepines for anxiety or insomnia
 Lorazepam recommended for catatonia
disorders
 3) If still inadequate response, consider 2-drug therapy
 Lithium + anticonvulsant / antipsychotic
 Anticonvulsant + anticonvulsant / antipsychotic
 4) If still inadequate response, electroconvulsive thera
py or add clozapine for refractory illness
 5) If still inadequate response, consider adjunctive ther
apies
 α2-adrenergic agonist, calcium channel blockers (nimodi
pine, verapamil), newer anticonvulsants (e.g. gabapentin
, topiramate)
disorders
 Mild to moderate
 Stabilize with lithium or lamotrigine
 Alternative anticonvulsant: carbamazepine, oxcaba
zepine or valproate
disorders
 1) Stabilize with 2-drug therapy
 Lithium / lamotrigine PLUS antidepressant
 Lithium PLUS lamotrigine
 Alternative anticonvulsant: carbamazepine, oxc
abazepine or valproate
 2) If inadequate response, short-term adjunct
ive atypical antipsychotic if needed
disorders
 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 psychosi
s or catatonia
 5) If still inadequate response, consider adjunctive thera
pies
 α2-adrenergic agonist, calcium channel blockers (nimodipi
ne, verapamil), newer anticonvulsants (e.g. gabapentin, t
opiramate)
disorders
 Initial therapy
 If first line agent(s) not effective for 2-4 weeks, add a sec
ond agent to augment mood stabilization
 Maintenance therapy
 Maintain with a mood stabilizer for both bipolar I and II di
sorders 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 mainten
ance therapy for 12 months
 Gradually taper off over several months (usually 6 months aft
er complete remission)
disorders
 Lifelong 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 antidepressants
End
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Pharmacotherapy in

 Schizophrenia and antipsychotics

 Viral CNS infections

 Environmental stressors (biochemical or social)

 No evidence of association with poor pare

Mesocortical Ventral tegme Frontal

 Refers to newer agents

 For resistant schizophrenia

 2nd line due to life-threatening side effect

Drugs Sedation EPS Anticholinergic Orthostasis Seizure Prolactin Weight

Clozapine ++++ + ++++ ++++ ++++ 0 ++++

Risperidone +++ + ++ +++ ++ 0 to +++ ++

Olanzapine +++ + +++ ++ ++ + +++

 Useful for acutely agitated patients

 Female vs male = 2:1

 Anticholinergic Adverse effects

 Combined with another antidepressant as

 Response failure to an antidepressant

 Can occur with several physical disorders

 As adverse effects of many drugs

 As part of several mental disorders

 Brain structures most involved

 Carbamazepine (Tegretol®, Tegretol C

 Mild elevation of liver enzymes

 Menstrual disturbances and polycystic ova

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