Drugs in Psychiatry

Pharmacotherapy in
Psychiatry
Depression
Schizophrenia
Bipolar
disorders
Contents
Schizophrenia and antipsychotics

Depression and antidepressants
Bipolar disorders and mood
stabilizers
Schizophrenia and
antipsychotics
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

parenting
Schizophrenia
Pathophysiology
No consistent neuropathology or
biomarkers for schizophrenia
? Increased dopamine in mesolimbic
pathways 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
Schizophrenia
Positive symptoms
Hallucinations
Delusions
Disordered thinking
Disorganized
speech
Combativeness
Agitation
Paranoia
Negative symptoms
Social withdrawal
Emotional
withdrawal
Lack of motivation
Poverty of speech
Blunted affect
Poor insight
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
Innervation Function
s
Antipsychotic
effect
Mesolimbic Midbrain,
Ventral
tegmental
Limbic
Emotional
structure,
and
nucleus
intellectual
accumbens
Hallucination
s, deulsions,
disordered
cognition
Mesocortic
al
Ventral
tegmental
Frontal
cortex
Nigrostriat
al
Substantia
nigra
Basal
ganglia
Extrapyramid Motor
al system
symptomatolo
movement
gy
Tuberoinfundubul
ar
Hypothalam
us
Pituitary
gland
Regulate
endocrine
functions
Plasma
prolactin levels
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
oral
dose
(mg)
EPS
Sedation
Anticholinergic
s/e
Low
Chlorpromazi
ne
100
Moderat
e
High
Moderate
Pericyazine
NA
Low
High
Low
Thioridazine
100
Low
High
High
Moderat
e
Perphenazine
10
Moderat
e
Moderate Low
High
Trifluoperazin
e
High
Low
Low
Thiotheixene
High
Low
Low
Fluphenazine
High
Low
Low
Haloperidol
High
Low
Low
Pimozide
0.5
High
Moderate Moderate
antipsychotics
Comparison of representative antipsychotics
Drug
Advantages
Disadvantages
Chlorpromazin
e
Generic,
inexpensive
Many adverse
effects (esp.
autonomic)
Thioridazine
Slight EPS, generic
Cardiotoxicity (QT
prolongation)
Fluphenazine
Generic, depot
available
(?) increased
tardive dyskinesia
Thiothixene
(?) decreased
tardive dyskinesia
Uncertain
Haloperidol
Generic, injection
Prominent EPS
and 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
antipsychotic
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 Parkinsons 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)
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)
Mechanism of action
Similar blocking effect on D2 receptors
Seem to be a little more selective,
targeting the 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)
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
diabetes, hyperlipidemia
Novel agents, more expensive
Potency
All atypical antipsychotics are
equally effective 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 51
HT2
Clozapine
++ ++ +++ ++
+
Risperidone ++ +++ ++
+
+
Olanzapine ++ ++ +++ ++
Quetiapine
++
++
+
M1
H1
++
+
-
++
+
+
++
Comparison of representative atypical antipsychotics
Drug
Advantages
Disadvantages
Clozapine
For treatment-resistant
cases, little EPS
Risk of fatal agranulocytosis
Risperidone
Broad efficacy, little or no

EPS at low doses
EPS and hypotension at high

doses
Olanzapine
Effective with positive and Weight gain

negative symptoms, little
or no EPS
Quetiapine
Similar to risperidone,
maybe less weight gain
Dose adjustment with

associated hypotension, bd
dosing
Ziprasidone
Perhaps less weight gain

than clozapine, Inj A/V
QT prolongation
Aripiprazole Less weight gain, novel

mechanism potential
Uncertain
Relative incidence of Adverse effects
Drugs
Sedatio
n
EP
S
Anticholinerg
ic
Orthostas
is
Seizur
e
Prolacti
n
elevatio
n
Weight
gain
Clozapine
++++
++++
++++
++++
++++
Risperidon +++
e
++
+++
++
0 to ++
++
++
Olanzapin
e
+++
+++
++
++
+++
Quetiapin
e
+++
++
++
++
++
Ziprasidon ++
e
++
++
++
Aripiprazo
le
++
++
++
++
1st 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
2nd 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)
Clozapine
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)
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 oraldispersible 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

noncompliance
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 selfcare
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 interfere 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 depressive

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, hypothalamic-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)

Mechanism 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)

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
Monoamine-oxidase
inhibitors (MAOI)
Mechanism of action
Inhibit both MAO-A and MAO-B
Phenelzine, tranylcypromine
Selective & reversible inhibitor of

MAO-A
Moclobemide
Monoamine-oxidase
inhibitors (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
Monoamine-oxidase
inhibitors (MAOI)
Properties
Drug interactions
Other antidepressants should not be
started 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
inhibitors (MAOI)
Adverse effects
Hypertensive crisis
Severe occipital headache, photophobia,

palpitation, 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
Amphetamins
Pseudoephedrine
Monoamine-oxidase
inhibitors (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)
Selective serotonin
Mechanism of action
Inhibits reuptake of serotonin (5-HT)
presynaptic uptake
Increases availability of serotonin at
synapses
Selective serotonin
Properties
Overdose less likely to be fatal
Less anticholinergic side effects
But more GI side effects
Seems to be better tolerated
Selective serotonin
Properties
Fluoxetine
Most stimulating SSRI

Indicated for premenstrual dysphoric disorder
(PMDD) (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
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
Selective serotonin
Adverse effects
Somnolence or insomnia
Dose in morning for insomnia
Increase in anxiety, agitation,

akathisia early in treatment (esp.
fluoxetine)
Agitation or nervousness
Sexual dysfunction
Selective serotonin
Adverse effects
Serotonergic syndrome
Rare but potentially fatal interaction between 2

or more 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
reuptake inhibitor (SNRI)
Duloxetine (Cymbalta)
Venlafaxine (Efexor, Efexor
XR)
Mechanism of action
Inhibits norepinephrine and
serotonin reuptake
Potentiates neurotransmitter activity
in the 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,
hypertension (when > 300mg/day)
Mixed serotonin
norepinephrine effects
Mirtazapine (Mirtazon,
Remeron, Remeron SolTab)
Mechanism of action
Presynaptic 2-antagonist
Increases central noradrenergic and
serotonergic neurotransmission
Mixed serotonin
norepinephrine effects
Mirtazapine (Mirtazon,
Remeron, Remeron SolTab)
Fewer anticholinergic effects
Marked sedation during initial
treatment
Stimulating as dose increases
Increased appetite and weight gain
Constipation, dry mouth
Norepinephrine dopamine
reuptake inhibitor (NDRI)
Bupropion (Wellbutrin SR)

Mechanism of action
Inhibits weakly the neuronal uptake
of dopamine, norepinephrine and
serotonin
Does not inhibit monoamine oxidase
Norepinephrine dopamine
reuptake inhibitor (NDRI)
Bupropion (Wellbutrin SR)

Properties and side effects
GI side effects, confusion, dizziness,
headache, insomnia, tremor
Seizure risk at high doses
Minimal risk of sexual dysfunction
Also licensed for smoking cessation
(Zyban)
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
refractory 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
Antidepressants in
depression
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
Antidepressants in
depression
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
Antidepressants in
depression
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 major depression that cause marked
impairment 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

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 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 depressive 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 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

prefrontal cortical areas, striatum, and
amygdala predate illness onset
Bipolar disorders
Signs and symptoms

Mania
Distractability
Insomnia
Grandiosity or inflated
self-esteem
Flight of ideas or
subjective experience
that thoughts are
racing
Agitation or increase in
goal-directed activity
Speech pressured/more
talkative than usual
Taking risks
Hypomania
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 disorders
Signs and symptoms

Mixed episode
Simultaneous
occurrence of manic
and depressive
symptoms nearly every
day for aat least 1
week
Poorer prognosis
More seen in younger
and older patients
Less likely to respond
to mood stabilizer
monotherapy
Rapid cyclers
> 4 major depressive
or manic episodes
(manic, mixed or
hypomanic for 12
months)
Frequent and severe
episodes of
depression
Poorer prognosis
Often require
combination therapies
Mood stabilizers
Lithium
Anticonvulsants
Valproate
Carbamazepine
Lamotrigine
Antipsychotics, antidepressants
and others
Lithium
Mechanism 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
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
Early, dose related

Adverse effects
GI distress
Sedation, weight gain
Muscle weakness
Polyuria, polydipsia
Impaired cognitive
funciton
Tremor
Tolerance may develop

Management
Take with meal

Beta blocker for
tremor
Late Adverse effects

Psoriasis / acne
exacerbation
Nephrogenic
diabetes insipidus
Hypothyroidism
Cardiac
T-wave flattening or
inversion
Bradycardia
AV block
Leukocytosis
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
Severe toxicity
(< 1.6 mmol/L) toxicity
(> 2.5 mmol/L)
(< 2.5 mmol/L)
Apathy
Irritability
Lethargy
Muscle
weakness
Nausea
Blurred vision
Confusion
Drowsiness
Progressing
tremor
Slurred speech
Unsteady gait
Cardiovascular
collapse
Coma
Seizure
Lithium
Toxicity
Discontinue lithium
NaCl infusion, rehydration, electrolyte
Monitor lithium level q3h
Electrolyte panel, renal function labs
Hemodialysis if patient not clearing
lithium 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 CR)
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 depression
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
bleeding
Syndrome of inappropriate antidiuretic

hormine (SIADH)
Cardiac conduction abnormalities
(sometimes arrhythmia)
Lamotrigine
Properties
Approved for maintenance of bipolar I
disorder
To delay the time to occurrence of mood episodes

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

increase in cycling
May not be effective for severe mania
Significant drug interactions with other
anticonvulsants
Lamotrigine
Dosing of lamotrigine in bipolar disorders
Weeks 12
Weeks 34
Week 5
Maintenanc
e dose
Lamotrigine 25mg qd
monothera
py
50mg qd
100mg qd
200mg/day
Lamotrigine 25mg
added to
qod
valproate
25mg qd
50mg qd
100mg/day
Lamotrigine 50mg qd
added to
enzyme
inducers
w/o
valproate
100mg/da
y in
divided
doses
200mg/day
Increase up
for 1 week,
to
then
400mg/day
300mg/day
for 1 week
(both in
divided doses
Lamotrigine
Adverse effects
Skin rash
Stevens-Johnsons 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
recommended 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

disorder
As divalproex sodium (Depakote and

Depakote ER)
Delayed release (Depakote): manic episode
Extended release (Depakote ER): acute mania
and mixed 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,
vomiting, heartburn, diarrhoea
Decrease dose, antacid or H2antagonist
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 ovaries is posssible
Transient alopecia
Other anticonvulsants
Oxcarbazepine (Trileptal)
Topiramate (Topamax)
No FDA approval
Tested in some clinical studies
Less used than carbamazepine,
lamotrigine 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
nonpsychotic mania, but effectiveness
of mood stabilization in maintenance
phase not well established

diseases
Antipsychotics
Olanzapine
Risperidone
FDA approval: acute mania, mixed episodes,

maintenance
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 and 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 or oxcabazepine
2) If inadequate response, adjunctive

benzodiazepines for anxiety or insomnia
3) If still inadequate response, consider two-drug
therapy
Lithium + anticonvulsant / antipsychotic
Anticonvulsant + anticonvulsant / antipsychotic

disorders

Moderate to severe
1) Stabilize with lithium / valproate PLUS

antipsychotic for short term adjunctive
treatment (e.g. olanzapine, quetiapine,
risperidone)
lamotrigine or oxcabazepine
2) If inadequate response, adjunctive

benzodiazepines for anxiety or insomnia
Lorazepam recommended for catatonia

disorders

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

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

disorders
Depressive episode
Mild to moderate
Stabilize with lithium or lamotrigine

oxcabazepine or valproate

disorders
Depressive episode
Moderate to severe
1) Stabilize with 2-drug therapy

Lithium / lamotrigine PLUS antidepressant
Lithium PLUS lamotrigine
Alternative anticonvulsant:
carbamazepine, oxcabazepine or valproate
2) If inadequate response, short-term

adjunctive atypical antipsychotic if
needed

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

disorders
Initial therapy
If first line agent(s) not effective for 2-4 weeks, add

a second agent to augment mood stabilization
Maintenance 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
maintenance therapy for 12 months
Gradually taper off over several months (usually 6

months after 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

No evidence of association with poor

Refers to agents introduced in US before

Pharmacologic activity at blocking central

Due to tendency to cause neurologic Adverse

Inappropriate as these agents (esp. high potency)

Some concern that they may exacerbate

Higher incidence of EPS / sedation /

i.e. size of dose to achieve a given

When administered in therapeutically

Slight EPS, generic

Dry mouth, blurred vision,

Orthostatic hypotension; reflex

5-HT2 serotonergic Weight gain

Early reactions can be managed with drugs

Late reaction drug treatment unsatisfactory

Early reactions occur less frequently with low

Develops within a few hours to 5 days after first dose

Anticholinergics (Benztropine, diphenhydramine IM/IV)

Parkinsonism (neuroleptic induced)

Occurs within first month of therapy

Develop within first 2 months of therapy

Tardive dyskinesia (TD)

Other Adverse effects

Neuroleptic malignant syndrome (NMS)

Rare but serious reaction, 0.2% of patients on

Other Adverse effects

After symptom resolution

Other Adverse effects

D2 receptor blockade decreases dopamine

Administer once daily at bedtime

Haloperidol has a lower risk of seizures

Refers to newer agents

Postsynaptic effects at 5-HT2A and D2

Risk of fatal agranulocytosis

Broad efficacy, little or no

EPS and hypotension at high

Effective with positive and Weight gain

Dose adjustment with

Perhaps less weight gain

Aripiprazole Less weight gain, novel

1st line atypical antipsychotics

Atypical antipsychotics considered when choosing

2nd line atypical antipsychotic

Most effective antipsychotic for reducing

Clozapine should be introduced if schizophrenia

BNF 52 (September 2006)

Leucocyte and differential blood count normal

Antipsychotic oraldispersible and solution

Risperidone (Risperdal Quicklet)

Carefully peel off packing, allow tablet to dissolve on tongue

Solutions available for

Haloperidol (Haldol drops)

Risperidone (Risperdal solution)

Very concentrated, avoid from contact with skin (dermatitis)

Useful for acutely agitated patients

Haloperidol decanoate (Haldol Decanoate)

Risperidone (Risperdal Consta)

Used for chronic illness and history of

Useful in some studies for anxiety, agitation,

Limited role in schizophrenia monotherapy

Weak support when used alone and with antipsychotic

Concurrent administration with risperidone and