Download Pharmacotherapy 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®)
Typical / conventional
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
Typical / conventional
antipsychotics
Dopamine receptors in various tracks
Track
Origin
Innervations
Function
Antipsychotic
effect
Mesolimbic
Midbrain,
Ventral
tegmental
Limbic
structure,
nucleus
accumbens
Emotional and
intellectual
Hallucinations,
deulsions,
disordered
cognition
Mesocortical
Ventral
tegmental
Frontal
cortex
Nigrostriatal
Substantia
nigra
Basal ganglia Extrapyramidal
system
movement
Motor
symptomatology
Tuberoinfundubular
Hypothalamus
Pituitary
gland
Plasma
prolactin levels
Regulate
endocrine
functions
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

Some concern that they may exacerbate negative
symptoms by causing akinesia
 Higher incidence of EPS / sedation /
anticholinergic Adverse effects
Typical / conventional
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
Typical / conventional
antipsychotics

Low potency
Chlorpromazine, thioridazine

Medium potency
Perphenazine

High potency
Trifluoperazine, thiothixene, fluphenazine,
haloperidol, pimozide
Typical / conventional
antipsychotics
Potency
Drug
Low
Equiv
oral
dose
(mg)
EPS
Sedation
Anticholinergic s/e
Chlorpromazine 100
Moderate
High
Moderate
Pericyazine
NA
Low
High
Low
Thioridazine
100
Low
High
High
Moderate
Perphenazine
10
Moderate
Moderate
Low
High
Trifluoperazine
5
High
Low
Low
Thiotheixene
2
High
Low
Low
Fluphenazine
2
High
Low
Low
Haloperidol
2
High
Low
Low
Pimozide
0.5
High
Moderate
Moderate
Sulpiride
200
Low
Moderate
Low
Typical / conventional
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
available
(?) increased tardive
dyskinesia
Thiothixene
(?) decreased tardive
dyskinesia
Uncertain
Haloperidol
Generic, injection and Prominent EPS
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 Dry mouth, blurred vision, urinary
retention, constipation, tachycardia
Alpha1-adrenergic
Orthostatic hypotension; reflex
tachycardia
5-HT2 serotonergic
Weight gain
Typical / conventional
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
Typical / conventional
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
Typical / conventional
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
Typical / conventional
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
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
 Tardive dyskinesia (TD)

Management
 Some manufacturers suggest drug withdrawal at earliest
signs of TD (fine vermicular movements of tongue) may
halt its full development
 Gradual drug withdrawal (to avoid dyskinesia)
 Use lowest effective dose
 Atypical antypsychotic for mild TD
 Clozapine for severe, distressing TD
 Inconsistent results with
 Diazepam, clonazepam, valproate
 Propranolol, clonidine
 Vitamin E
Typical / conventional
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
Typical / conventional
antipsychotics

Other Adverse effects
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
Typical / conventional
antipsychotics

Other Adverse effects
 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
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
5-HT2 1
Clozapine
++
++
+++
Risperidone
-
+++ +++
+++ -
Olanzapine
++
++
+++
++
Quetiapine
-
+
++
+++ +
+
Ziprasidone
+/-
++
+++
++
-
+
Aripiprazole
+
+++ ++
++
-
+
M1
H1
+++ +++ +
+
+++ ++
Atypical antipsychotics
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 EPS and hypotension at high
at low doses
doses
Olanzapine
Effective with positive and
negative symptoms, little or
no EPS
Weight gain
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
Atypical antipsychotics
Relative incidence of Adverse effects
Drugs
Sedatio
n
EPS
Anticholinergic
Orthostasis
Seizure
Prolactin
elevation
Weight
gain
Clozapine
++++
+
++++
++++
++++
0
++++
Risperidone
+++
+
++
+++
++
0 to
++++
++
Olanzapine
+++
+
+++
++
++
+
+++
Quetiapine
+++
+
++
++
++
0
++
Ziprasidone
++
+
++
++
++
0
+
Aripiprazole
++
+
++
++
++
0
+
Atypical antipsychotics

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
Atypical antipsychotics

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)
Atypical antipsychotics

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)
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

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®)
Flupenthixol (Fluanxol®)
Zuclopenthixol (Clopixol Depot®)
 1 atypical

Risperidone (Risperdal Consta®)
 Used for chronic illness and history of
noncompliance
 Trial of oral meds first to assess tolerability
Non-antipsychotic 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
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®)
Tricyclic and related
antidepressants (TCA)

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)
Tricyclic and related
antidepressants (TCA)

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
Tricyclic and related
antidepressants (TCA)

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
Tricyclic and related
antidepressants (TCA)

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
Tricyclic and related
antidepressants (TCA)

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 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



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 reuptake
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

Selective serotonin reuptake
inhibitors (SSRI)

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 reuptake
inhibitors (SSRI)

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
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)


Venlafaxine (Efexor®, Efexor XR®)
Properties and Adverse effects
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 α2-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)


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

Flupenthixol (Fluanxol®)
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 selfesteem
 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 nondepressed 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 toxicity Severe toxicity
(< 1.6 mmol/L) (< 2.5 mmol/L) (> 2.5 mmol/L)
Apathy
Blurred vision
Cardiovascular
collapse
Irritability
Confusion
Coma
Lethargy
Drowsiness
Seizure
Muscle weakness Progressing
tremor
Nausea
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
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 1-2
Weeks 3-4
Week 5
Maintenance
dose
Lamotrigine
monotherapy
25mg qd
50mg qd
100mg qd
200mg/day
Lamotrigine
added to
valproate
25mg qod
25mg qd
50mg qd
100mg/day
Lamotrigine
added to
enzyme
inducers w/o
valproate
50mg qd
100mg/day
in divided
doses
200mg/day for Increase up
1 week, then
to
300mg/day for 400mg/day
1 week (both in
divided doses )
Lamotrigine

Adverse effects
Skin rash
Stevens-Johnson’s Syndrome, toxic epidermal
necrosis, hypersensitivity syndrome
 Consider withdrawal if rash or signs of
hypersensitivity occur

 Increased risk of serious skin reactions with
 Concomitant use of valproate
 Initial lamotrigine doses higher than
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 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
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
Other drugs for bipolar
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
Other drugs for bipolar
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
Other drugs for bipolar
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
Mood stabilizers in bipolar
disorders

Acute manic or mixed episode
Moderate to severe

1) Stabilize with lithium / valproate PLUS
antipsychotic for short term adjunctive
treatment (e.g. olanzapine, quetiapine,
risperidone)
 Alternative anticonvulsant: carbamazepine,
lamotrigine or oxcabazepine

2) If inadequate response, adjunctive
benzodiazepines for anxiety or insomnia
 Lorazepam recommended for catatonia
Mood stabilizers in bipolar
disorders

Acute manic or mixed episode
 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
 α2-adrenergic agonist, calcium channel blockers
(nimodipine, verapamil), newer anticonvulsants (e.g.
gabapentin, topiramate)
Mood stabilizers in bipolar
disorders

Depressive episode
Mild to moderate

Stabilize with lithium or lamotrigine
 Alternative anticonvulsant: carbamazepine,
oxcabazepine or valproate
Mood stabilizers in bipolar
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
Mood stabilizers in bipolar
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
 α2-adrenergic agonist, calcium channel blockers
(nimodipine, verapamil), newer anticonvulsants (e.g.
gabapentin, topiramate)
Mood stabilizers in bipolar
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)
Mood stabilizers in bipolar
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
Questions & Answers