Psychiatry
Depression
Schizophrenia
Bipolar
disorders
Contents
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)
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)
Typical / conventional
antipsychotics
Neuroleptics
Major tranquilizers
Typical / conventional
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
Typical / conventional
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
Typical / conventional
antipsychotics
Properties
Effective in reducing positive symptoms
during acute episodes and in preventing
their reoccurrence
Less effective in treating negative
symptoms
Typical / conventional
antipsychotics
Potency
All have same ability to relieve
symptoms of psychosis
Differ from one another in terms of
potency
Typical / conventional
antipsychotics
Low potency
Chlorpromazine, thioridazine
Medium potency
Perphenazine
High potency
Trifluoperazine, thiothixene,
fluphenazine, haloperidol, pimozide
Typical / conventional
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
Typical / conventional
antipsychotics
Comparison of representative antipsychotics
Drug
Advantages
Disadvantages
Chlorpromazin
e
Generic,
inexpensive
Many adverse
effects (esp.
autonomic)
Thioridazine
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
Typical / conventional
antipsychotics
Receptor blockade and Adverse effects
Receptor type
Consequence of blockade
D2 dopaminergic
Extrapyramidal symptoms;
prolactin release
H1 histaminergic
Sedation
Muscarinic
cholinergic
Alpha1-adrenergic
Typical / conventional
antipsychotics
Adverse effects
Extrapyramidal symptoms (EPS)
Typical / conventional
antipsychotics
Adverse effects
Acute dystonia
Typical / conventional
antipsychotics
Adverse effects
Typical / conventional
antipsychotics
Adverse effects
Akathisia
Typical / conventional
antipsychotics
Adverse 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
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
Typical / conventional
antipsychotics
Typical / conventional
antipsychotics
Typical / conventional
antipsychotics
Sedation
Seizures
Atypical antipsychotics
Atypical antipsychotics
Amisulpiride (Solian)
Quetiapine (Seroquel)
Ziprasidone (Zeldox)
Risperidone (Risperdal)
Olanzapine (Zyprexa)
Clozapine (Clozaril)
Aripiprazole (Abilify)
Atypical antipsychotics
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)
Atypical antipsychotics
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)
Atypical antipsychotics
Properties
Less frequently associated with EPS
More risk of weight gain, new onset
diabetes, hyperlipidemia
Novel agents, more expensive
Atypical antipsychotics
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
Atypical antipsychotics
Relative receptor-binding of atypical
antipsychotics
Drug
D1 D2 51
HT2
Clozapine
++ ++ +++ ++
+
Risperidone ++ +++ ++
+
+
Olanzapine ++ ++ +++ ++
Quetiapine
++
++
+
M1
H1
++
+
-
++
+
+
++
Atypical antipsychotics
Comparison of representative atypical antipsychotics
Drug
Advantages
Disadvantages
Clozapine
For treatment-resistant
cases, little EPS
Risperidone
Olanzapine
Quetiapine
Similar to risperidone,
maybe less weight gain
Ziprasidone
QT prolongation
Uncertain
Atypical antipsychotics
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
++
++
++
++
Atypical antipsychotics
Atypical antipsychotics
NICE recommendations
Atypical antipsychotics
Clozapine
Atypical antipsychotics
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
Atypical antipsychotics
Clozapine
Contraindication
History of clozapine-induced
agranulocytosis
Bone marrow suppression
On myelosuppressive drugs
Caution
Seizure disorders
Diabetes
2 atypicals
1 atypical
Antipsychotic injections
Available for
2 typicals
Chlorpromazine (Largactil)
Haloperidol (Haldol)
2 atypicals
Olanzapine (Zyprexa)
Ziprasidone (Zeldox)
Antipsychotic depot
injections
Available for
4 typicals
1 atypical
Non-antipsychotic agents
Benzodiazepines
Lithium
Non-antipsychotic agents
Carbamazepine
Valproate
Propranolol
Antipsychotics in
schizophrenia
Clozapine
2nd line treatment when other agents are
ineffective or not tolerated
Antipsychotics in
schizophrenia
Antipsychotics in
schizophrenia
Oral administration
Injections
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
6-8 weeks
Antipsychotics in
schizophrenia
Acute phase
Initiate therapy
Titrate as tolerated to average effective dose
Stabilization phase
Maintenance phase
Depression and
antidepressants
Depression
Depression
Epidemiology
Life prevalence 3-17%
Onset in late 20s
Highest in
25-44 years
Elderly in community
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
Depression
Depression
Etiology
Etiology unknown
Depression
Pathophysiology
Exact course unknown
Changes in receptor-neurotransmitter
relationship in limbic system
Serotonin, norepinephrine, sometimes dopamine
Antidepressants
Other antidepressants
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
Properties
Inexpensive, generic
Some with off-label use, e.g.
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
Anticholinergic effects
Sedation
Dose at bedtime
Adverse effects
Cardiac toxicity
Seizures
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
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
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
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
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
reuptake inhibitors (SSRI)
Mechanism of action
Inhibits reuptake of serotonin (5-HT)
presynaptic uptake
Increases availability of serotonin at
synapses
Selective serotonin
reuptake inhibitors (SSRI)
Properties
Overdose less likely to be fatal
Less anticholinergic side effects
But more GI side effects
Seems to be better tolerated
Selective serotonin
reuptake inhibitors (SSRI)
Properties
Fluoxetine
Selective serotonin
reuptake inhibitors (SSRI)
Adverse effects
Headache
GI
Nausea, diarrhoea, loss of appetite
Titrate dose to minimize side effect
May be taken with food
Selective serotonin
reuptake inhibitors (SSRI)
Adverse effects
Somnolence or insomnia
Selective serotonin
reuptake inhibitors (SSRI)
Adverse effects
Serotonergic syndrome
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
Serotonin norepinephrine
reuptake inhibitor (SNRI)
Duloxetine (Cymbalta)
Properties and Adverse effects
More potent than venlafaxine
Also indicated for diabetic
neuropathy
Insomnia, nausea, headache
Serotonin norepinephrine
reuptake inhibitor (SNRI)
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)
Properties and Adverse effects
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)
Norepinephrine dopamine
reuptake inhibitor (NDRI)
Other antidepressants
Flupenthixol (Fluanxol)
Typical antipsychotic
Antidepressant effect at low doses
Antipsychotic dose: 3-9mg twice daily
Antidepressant dose: 1-3mg daily
Non-antidepressants
Anxiolytics
Antipsychotics
Use may mask the true diagnosis
Used with caution
But are still useful adjuncts in agitated
patients
Antidepressants in
depression
Choice of agents
All are equally efficacious for
depression
Selection based on
Side effect profile
Potential drug interaction
Antidepressants in
depression
Geriatrics
Reduce initial dose by half
Gradual dose titration
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
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
Bipolar disorders
Bipolar disorders
DSM-IV:
Bipolar I disorder
Bipolar II 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
Bipolar disorders
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
Bipolar disorders
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
Lithium
Properties
Manic episode
Depressive episode
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
GI distress
Sedation, weight gain
Muscle weakness
Polyuria, polydipsia
Impaired cognitive
funciton
Tremor
T-wave flattening or
inversion
Bradycardia
AV block
Leukocytosis
Lithium
Adverse effects
Nephrogenic diabetes insipidus (DI)
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
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
Rapid cyclers
Mixed mania episodes
Carbamazepine
Adverse effects
Weight gain
Neurotoxicity
Diplopia, drowsiness, blurred vision, vertigo
Transient and reversible with dose
reduction
Uncommon
Carbamazepine
Adverse effects
Hematologic effects
Lamotrigine
Properties
Approved for maintenance of bipolar I
disorder
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
Lamotrigine
Adverse effects
GI
Asthenia, pain
Ataxia, dizziness, headache,
somnolence
Valproate
Properties
Substance abusers
Rapid cyclers
Mixed mania episodes
Valproate
Adverse effects
GI: anorexia, indigestion, nausea,
vomiting, heartburn, diarrhoea
Valproate
Adverse effects
Neutropenia and thrombocytopenia
Sedation, tremor
Decrease dose
Beta blocker for tremor
Other anticonvulsants
Oxcarbazepine (Trileptal)
Topiramate (Topamax)
No FDA approval
Tested in some clinical studies
Less used than carbamazepine,
lamotrigine and valproate
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
Antipsychotics
Olanzapine
Risperidone
Aripiprazole
Ziprasidone
Quetiapine
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
Benzodiazepines
As adjunct to treat acute agitation,
anxiety and insomnia
For severely ill patients
Short term use only
Depressive episode
Mild to moderate
Depressive episode
Moderate to severe
Depressive episode
Moderate to severe
Initial therapy
Maintenance therapy
Lifelong prophylaxis
Consider with mood stabilizers for
End
Questions & Answers