Pharmacology and ECT

Melvin Issac
Zaitul Ilham
Wen Tzien
ANTIPSYCHOTICS
 Antipsychotics
• Relieve symptoms of psychosis
• Alternative terms = Neuroleptics or major
tranquilisers

1. First Generation Antipsychotics Drugs/Typical

 treat positive symptoms
 dopamine antagonist

2. Second Generation Antipsychotics Drugs/Atypical

 treat positive and negative symptoms
 dopamine antagonist and serotonin antagonist
 Indications
 Schizophrenia
 Schizoaffective disorder
 Bipolar disorder (acute mania and mixed episodes)
 Psychotic depression
 Substance induced psychosis
 Organic psychosis
 Personality disorder with psychotic features

X They are not recommended for dementia or insomnia

unless other treatments have not worked.
X They are not recommended in children unless other
treatments are not effective.
First Generation Antipsychotics Drugs
• Chlorpromazine
• Haloperidol
• Flupenthixol
• Trifluoperazine
• Pimozide
• Sulpiride (highly selective D2 blocker)
• Fluphenazine
• Perphenazine
• Zuclopenthixol
Mechanism Of Action and Side Effects
 Chlorpromazine
Class Phenothiazines with aliphatic side chain
Dose 100 mg – 800 mg daily
Mechanism of High level of anticholinergic, anti-α1 adrenergic and antihistaminergic actions
action
Indications Schizophrenia
Contraindications • Cholestatic jaundice
• Addison’s disease
• Myasthenia gravis
• Glaucoma
• Bone marrow suppression
Side effects • Extra-pyramidal symptoms (akathisia, dystonia, muscle stiffness,
neuroleptic malignant syndrome, Parkinsonism, tardive dyskinesia)
• Most common: anti-cholinergic effects, sedation, weight gain, erectile
dysfunction, oligomenorrhoea or amenorrhoea
• Increase risk of cataract
• Galactorrhoea
• Hemolytic anemia/Agranulocytosis
• Leucocytosis/Leucopenia
• Cholestatic jaundice
• Prolonged QT interval
• Photosensitive rash
• Hyperglycaemia
 Haloperidol
Class Butyrophenones

Dose 5 mg to 10 mg daily

Mechanism of • Very potent D2 blocker

actions • Lower level of activity with the nigrostriatal pathway
• Little antimuscarinic, antihistaminergic and anti adrenergic
activity

Indications • Positive symptoms of schizophrenia

• Delirium
• Rapid tranquilisation (IM)
• Tourette’s syndrome

Contraindications • Parkinson’s disease

• Lewy body dementia

Side effects • High doses often lead to extrapyramidal symptoms,

akathisia and akinesia
 Flupenthixol
Class Thioxanthenes
Dose IM 20 mg once per month
Mechanism of • Antipsychotic effects caused by D2 and/or 5-HT2A antagonism
action • Antidepressant effect at lower doses mediated by preferential
D2/D3 autoreceptor blockade

Indications • Depot antipsychotics

• For people with schizophrenia who are non-compliant
• Not a recommended as a first line treatment for depression
Contraindications • Pheochromocytoma
• Prolactin-dependant tumors such as pituitary prolactinomas and
breast cancer
• Long QT syndrome
• Blood dyscrasia
• Parkinson’s disease
• Dementia with Lewy bodies
Side effects • Acute dystonia
• Extrapyramidal syndrome
• Long term use may lead to tardive dyskinesia
Second Generation Antipsychotics Drugs
• Clozapine
• Risperidone
• Quetiapine
• Olanzapine
• Aripiprazole
• Ziprasidone
• Paliperidone
• Asenapine
• Amisulpride
Mechanism Of Action and Side Effects
 Clozapine
Class Dibenzodiazepine
Dose 200 mg to 450 mg daily
Mechanism of • Higher antagonist affinity for non-dopamine than for dopamine
action receptor subtypes;
• moderate affinity for D2 receptors and a high affinity for 5-HT2A
receptors
• 5-HT1A partial antagonism with D2-like antagonism: may contribute
not only to mitigation of EPSE but also to enhancement of prefrontal
dopamine release and putative therapeutic effects
• Hypersalivation: due to antagonism of α2-adrenergic receptors and
agonism at the M4 receptor

Indications • Should be offered in treatment resistant schizophrenia (despite the use

of adequate doses and duration of at least 2 different antipsychotics)
• Severe Tardive dyskinesia after treated with first generation
antipsychotics
Contraindications • Potential lethal combination with carbamazepine or sulphonamide
(blood dyscrasia)
• If take with lithium will have high risk of seizure, confusion, dyskinesia
and NMS
Side Effects • Agranulocytosis 1 in 10 000 (FBC weekly basis for first 18 weeks,
fortnightly until the end of the year, monthly after 1 year)
• Pulmonary embolism 1 in 4500
• Myocarditis 1 in 1300
• Weight gain, metabolic syndrome
• Hypotension, tachycardia and ST segment changes
• Hypersalivation, constipation and urinary incontinence
• Incidence of seizure in people with schizophrenia taking clozapine at
more than 600 mg per day is roughly 15%
 Risperidone (Risperdal®)
Class Benzisoxazole
Dose • 1 mg to 6 mg daily
• Riperdal consta (IM depot) 37.5 mg to 50 mg every two weeks
Mechanism of • D2-like high-affinity antagonist of 5-HT2
action • α-Adrenergic antagonism
• Allows more dopaminergic transmission compared to conventional
antipsychotics because
• the normal inhibitory action of serotonin on dopamine neurons is
inhibited due to
• antagonism of the 5HT2A heteroreceptor
• Affinity of risperidone for D2 receptors is approximately 50-fold
greater than that of
• clozapine and 20%-50% of haloperidol.
Indications • Schizophrenia
• Bipolar disorder in manic episode
• Behavioral problems in dementia and autism
Contraindications • Patients reported EPS with risperidone
Side effects • At higher doses: hyperprolactinaemia and EPS
• At a low dose range of 2-6 mg, EPS is reduced
• Insomnia, dizziness, anxiety, menstrual disturbances, weight gain
 Quetiapine (Seroquel®)
Class Dibenzothiazepine
Dose 200 mg to 800 mg daily
Mechanism of • High affinity for muscarinic receptors
action • High affinity for 5-HT1A receptors may increase dopamine levels in
the hypoactive mesocortical dopaminergic pathway and improve
negative symptoms
• Lower affinity for all receptors compared to clozapine
Indications • Schizophrenia patients who cannot tolerate EPS
• Parkinson disease patients with psychotic features after taking
levodopa
Contraindications • Hypersensitivity reaction to quetiapine or to any excipients in the
Seroquel formulation (anaphylactic reaction)
Side effects • Sedation (17.5%)
• Dizziness (10%)
• Constipation (9%)
• Postural hypotension
• No difference from placebo in terms of EPSE and prolactin level
• Less weight gain compared to olanzapine and clozapine (clozapine =
olanzapine > risperidone> quetiapine > ziprasidone)
 Olanzapine (Zyprexa®)
Class Thienobenzodiazepine
Dose 5 mg to 15 mg daily
Mechanism of • High affinity for D2 and 5HT2A but low affinity for D1 receptors
action • Similar chemical structure to clozapine, but only partially selective
for D2 receptors
• Smoking increases CYP1A2 activity and increases the metabolism of
olanzapine.
• When a patient stops smoking, olanzapine metabolism reduces, they
are more susceptible to side effects, and hence they may require a
lower dose of olanzapine
Indications • Schizophrenia
• Schizoaffective disorder
• Bipolar mania
Contraindications • Stroke patients
• Diabetes patient
• Obese patients
• Narrow angle glaucoma due to anticholinergic effect
Side effects • Increase in appetite, Weight gain, High risk of diabetes, Sedation,
Dizziness, EPS (mild), Low rate of tardive dyskinesia
• Anticholinergic side effects: dry mouth and constipation
 Aripiprazole
Dose 15 mg to 30 mg daily
Mechanism of • D2 and 5-HT1A partial agonist
action • 5HT2A antagonist
• High affinity for D3 receptors; moderate affinity for D4, 5HT2C, 5-
HT7, adrenergic, and histaminergic receptors
• No significant difference in outcomes compared to 1st and 2nd
generation antipsychotics

Indications • Schizophrenia patients who developed weight gain, metabolic

syndrome, galactorrhoea, EPS, prolonged QT associated with other
antipsychotics

Contraindications • Patient with a history of hypersensitivity reaction to aripiprazole

ranged from pruritus/urticaria to anaphylaxis

Side effects • Excellent safety and tolerability profile

• Most common: headache, insomnia, agitation and anxiety
• Less likely to cause elevation in prolactin compared to other
antipsychotics
ANTIDEPRESSANTS
 Antidepressants
• Tricyclic antidepressants (TCAs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin and noradrenaline reuptake
inhibitors (SNRIs)
• Noradrenergic and specific serotonergic
antidepressants (NaSSAs)
• Monoamine oxidase inhibitors (MAOIs)
 Tricyclic antidepressants (TCA)
• TCA block norepinephrine and serotonin reuptake into the neuron by
competition for the binding site of the amine transporter
• Improvement of emotional symptoms due to an enhancement of serotonin
mediated transmission
• The TCA are no longer considered first-line agents in the treatment of
depression because of their prominent side effects and the need to
monitor drug blood levels to avoid toxicity

• Therapeutic Drug Monitoring

 Safe and effective use of the TCA drugs requires monitoring of serum
levels.
 The importance of this monitoring is based on the relatively narrow
range between therapeutic and toxic doses (therapeutic index of 3) of
each agent.

• TCAs are also used to treat neuropathic pain

Indications:
• treating moderate to severe major depression
• patients with panic disorder
• Imipramine : used to control bed-wetting in children (older than 6 years)
by causing contraction of the internal sphincter of the bladder.
• Amitriptyline : used to treat migraine headache and chronic pain
syndromes (e.g. : neuropathic pain)

Adverse Effects :
• Anticholinergic (e.g. constipation, blurred vision, urinary retention, dry
mouth, dizziness, syncope, postural hypotension, sedation)
• Histaminergic and dopaminergic blockade : nausea, vomiting, weight
gain, sedation
• Sexual dysfunction
• Hyponatraemia
• Cardiac : arrhythmias, ECG changes (QT prolongation), tachycardia, heart
block
• Overdose may lead to delayed ventricular conduction time, dilated
pupils and acidosis due to central respiratory depression and fall in pH
reducing protein binding
Contraindications:
• Cardiac diseases (e.g. post-myocardial infarction,
arrhythmias)
• Epilepsy
• Severe liver disease
• Prostatic hypertrophy
• Mania

Examples:
• Amitriptyline (25mg to 150mg/day): most potent
anticholinergic effect (usually use by anaesthetic)
• Clomipramine (100mg to 225mg/day): most potent TCA at
D2 receptors, more selective inhibitor of serotonin
reuptake (usually use to treat OCD)
• Dothiepin
• Imipramine
• Lofepramine
 Selective serotonin reuptake inhibitors
(SSRIs)
• Fluoxetine
• Escitalopram
• Paroxetine
• Sertraline
• Fluvoxamine
Mechanism of Action
• Selectively block reuptake of serotonin at presynaptic nerve
terminals
• Increase synaptic serotonin concentration

Indications:
• Depressive disorder (first-line treatment over TCAs)
• Anxiety disorders
• Obsessive compulsive disorder
• Bulimia nervosa (fluoxetine)
• Premature ejaculation

Contraindications:
• Absolute: mania
• Relative: prior to surgery if clotting factors are deranged
(believed to inhibit platelet aggregation)
 Side effects
• Gastrointestinal effects: nausea, dyspepsia, bloating,
flatulence, diarrhea, weight gain except paroxetine
• Neuropsychiatry effects: insomnia, daytime somnolence,
agitation, tremor, restlessness, irritability, headache,
extrapyramidal side effects (Parkinsonism and akathisia)
• Other effects: sexual dysfunction, sweating, dry mouth, skin
rashes, increase risk of upper GI bleeding, long term use
will increase risk of osteoporotic fracture
• Serotonin syndrome : In combination with MAOIs, SSRIs can
cause a 'serotonin syndrome' characterised by tremor,
hyperthermia and cardiovascular collapse, from which
deaths have occurred (can give BDZ such as
diazepam(Valium) or lorazepam(Ativan), if still not working,
consider cyproheptadine)

 Less cardiotoxicity than TCA, lack anticholinergic effects and

non-sedative
 Fluoxetine (Prozac)
Dose 20 mg to 80 mg per day orally
Indications • Major depressive disorder (MDD)
• Obsessive compulsive disorder (OCD)
• Bulimia nervosa
• Panic disorder with or without agoraphobia
• Acute treatment in depressive episode of Bipolar 1 Disorder
• Treatment resistant depression ( MDD in patient who not respond to 2
separate trials of different adequate dose and duration in the current
episode)
Side effects • Anxiety
• Agitation
• Delayed ejaculation
• Hypersomnolence in high doses
• Nausea
• Dry mouth
 Escitalopram (Lexapro)
Dose 10 mg – 20 mg per day
Indications • Acute and maintenance treatment of MDD in adults and adolescents 12
to 17 years of age
• Acute treatment for generalized anxiety disorder (GAD)

Side effects • Nausea and vomiting (20%)

• Increased sweating (18%)
• Dry mouth and headache (17%)
• Anorgasmia and ejaculatory failure
• Dose-dependent QT prolongation (higher risk than other SSRIs, but lower
risk than antipsychotics)
• No significant effect on cardiac conduction and repolarisation
Serotonin-Noradrenaline Reuptake
Inhibitor (SNRIs)
• Generally, similar to TCAs but lack major receptor-
blocking actions, so fewer side effects.
• Less risk of cardiac effects, so safer in overdose
than tricyclic antidepressants.
• Can be used to treat other disorders:
 anxiety disorders (venlafaxine, desvenlafaxine
and duloxetine)
 neuropathic pain and fibromyalgia (duloxetine
and milnacipran)
 urinary incontinence (duloxetine)
 Venlafaxine hydrochloride (Effexor XR)
Dose
Indications • Major depressive disorder
• Generalised anxiety disorder
• Social anxiety disorder
• Panic disorder
Mechanism of • Low dose blocks serotonin reuptake
action • Moderate dose blocks noradrenaline reuptake
• High dose blocks noradrenaline, dopamine and serotonin
reuptake
Side effects • Nausea (35%)
• Sustained hypertension (dose-related, 50% remits
spontaneously)
• Dry mouth
• Constipation
• Sexual dysfunction
• Toxic interaction with MAOIs leading to serotonin syndrome
(most severe drug interaction involving venlafaxine)
 Duloxetine (Cymbalta)
Dose 30 mg – 120 mg daily
Indications • Major depressive disorder
• Generalized anxiety disorder
Mechanism of action Exerts a more marked influence on noradrenaline reuptake
than on serotonin
Reuptake

Side effects • Common: nausea, dry mouth, dizziness, headache,

somnolence, constipation, fatigue
• Small but significant increase in heart rate
• Low rate of sexual dysfunction
 Noradrenergic and specific
serotonergic antidepressant (NaSSAs)
Mechanism of action:
• Act by antagonizing the α2-adrenergic receptor and
certain serotonin receptors such as 5-HT2A and
5HT2C
• Enhance adrenergic and serotonergic
neurotransmission in the brain involved in mood
regulation by blocking the α2-adrenergic
autoreceptors and heteroreceptors.
• The blockade of certain serotonin receptors causes
serotonergic neurotransmission to be less
facilitated in unwanted areas (so less side effects
compared to SSRI)
 Mirtazapine (Remeron)
Dose 15 mg – 45 mg daily
Mechanism of action • Potent antagonism of central α2-adrenergic
autoreceptors enhanced norepinephrine release
• Antagonism of 5-HT2 and 5-HT3 receptors enhanced
serotonin release results in a net increase in 5-HT1-
mediated neurotransmission

Indications Insomnia, agitation, depression with cachexia

Side effects • CNS : somnolence, dizziness, seizure

• Endocrine : increase cholesterol and triglyceride
• GI : constipation, increase alt
 Monoamine oxidase inhibitors
(MAOIs)
• MAO is located intracellularly, mostly associated with mitochondria, and has two
main functions:
i.Within nerve terminals, MAO regulates the free intraneuronal concentration of
noradrenaline or serotonin
ii.MAO is important in the inactivation of endogenous and ingested amines such as
tyramine that would otherwise produce unwanted effects

• Monoamine oxidase isozymes-MAO-A (mainly metabolizes serotonin and

noradrenaline) and MAO-B (mainly metabolize dopamine)

• Therapeutic efficacy by selective MAO-A inhibitors (such as clorgyline or

moclobemide) in major depressions strongly suggests that MAO inhibition at central
serotonin or norepinephrine synapses or both is responsible for the antidepressant
properties of these agents.
Adverse effects:
• Hepatotoxicity is likely to occur with isocarboxazid or phenelzine, since
hydrazine compounds can cause damage to hepatic parenchymal cells.
• Other side effects : tremors, orthostatic hypotension, ejaculatory delay, dry
mouth, fatigue, and weight gain, are common at therapeutic doses of
MAOIs.
• Dietary tyramine : induced hypertensive crisis
 Patients who take a MAOI should not eat food rich in tyramine or other
biologically active amines. Normally, these amines are rapidly
metabolized by MAO-A during gastric absorption by the mucosal cells
of the intestinal wall and by MAO-A and MAO-B during passage
through the liver parenchyma.
 If both isozymes of MAO are inhibited, elevated circulating levels of
tyramine will be free to interact with the sympathetic noradrenergic
nerve terminals innervating cardiac and vascular smooth muscle tissue
to produce a pressor effect.
 In these conditions, tyramine can cause an acute elevation in blood
pressure, sometimes leading to a hypertensive crisis.
 Cheeses, wine, and a whole host of other foods rich in tyramine must
be avoided.
 Moclobemide
Dose 5 mg to 225 mg per day
Indications • Atypical depression
• Depression with predominant anxiety symptoms (e.g. social
anxiety)
• Hypochondriasis
Contraindications • Acute confusional state
• Phaeochromocytoma
Mechanism of • Reversible MAOI
action • Monoamine oxidase A acts on noradrenaline, serotonin,
dopamine and tyramine
Side effects • Visual changes
• Headache
• Dry mouth
• Dizziness
• Gastrointestinal symptoms
* With moclobemide, hypertensive crisis (due to tyramine containing
food such as aged cheese) is much reduced because it inactivates
only MAO-A and does so in a reversible manner.
* Serotonin syndrome with SSRIs
MOOD STABILISERS
 Lithium
• Lithium was one of the first mood stabilizers used
in the treatment of bipolar disorder.
• Lithium is a simple ion like sodium found in table
salt (sodium chloride). Lithium comes in two
forms—lithium carbonate and lithium citrate.
• Lithium carbonate is available in capsules and
tablets. Lithium also comes in a liquid preparation
in the form of lithium citrate
• Good for manic phase but not good in depressive
phase
INDICATION:

• First-line treatment in bipolar disorder

• Often used with antidepressants and other
mood stabilisers in bipolar depression
• Reduces suicidal ideation in bipolar patients
• Inexpensive
 Side effects

COMMON LONG TERM DERMATOLOGICAL

• Metallic taste • Hypothyroidism • Worsen psoriasis

• Nausea • Renal Failure
• Polydipsia
• Polyuria
• Oedema
• Weight gain
• Fine tremor
 Sodium Valproate
• Enhances GABA function and produces
neuroinhibitory effects on mania
• Indication
– Can combine with antipsychotics in treatment of
mania (lower dose)
– Effective in maintenance treatment to prevent mood
episodes
– Renal failure (eliminated by liver)
– Rapid cycling disorder
– Contraindicated in liver failure
Side effects

Common Serious

Weight gain Thrombocytopenia

Nausea Polycystic ovary
Gastric irritation syndrome
Diarrhoea
Hair loss
 Carbamazepine
• Carbamazepine was the first anticonvulsant to
be discovered as an effective mood stabiliser
• Generally effective in maintenance treatment
to prevent mood episodes
• Does not cause weight gain (Can be used by
patients with bipolar disorder who are
concerned about weight gain caused by
lithium or valproate)
• Side effects

COMMON UNCOMMON

• Dizziness • Ataxia
• Somnolence • Diplopia
• Nausea • Nystagmus
• Dry mouth • Serious exfoliative
• Oedema dermatological
• Hyponatremia reactions
• Increase ALP and • Agranulocytosis
GGT • Leucopenia
• Aplastic anaemia
BENZODIAZEPINE
• Benzodiazepines enhance the effect of
the neurotransmitter GABA, resulting
in sedative, hypnotic, anxiolytic, anticonvulsant,
and muscle relaxant properties
• Benzodiazepines slow the activity of the brain. In
doing so, they can help treat
mania, anxiety, panic disorder, and seizures.
• Some of the benzodiazepines prescribed are:
– lorazepam (Ativan)
– Midazolam
– Alprazolam (Xanax)
– clonazepam
– diazepam (Valium)
• Side Effects
 Drowsiness or dizziness
 Urinary retention, low libido
 Fatigue
 Blurred vision
 Slurred speech
 Memory loss
 Muscle weakness

Benzodiazepines should be used short-term as they can

lead to tolerance, dependence (addiction) and abuse
Electroconvulsive therapy (ECT) uses a small electric current to produce a
generalized cerebral seizure under general anesthesia

ELECTROCONVULSIVE THERAPY
 Indications
• Urgent need of response
– Severe depressive disorder which does not respond to
an adequate trial of antidepressants, high suicide risk,
self harm, nutritionally compromised
– Severe mania that impaired decision-making,
impulsive or risky behavior, substance abuse, and
psychosis
– Agitation and aggression in people with
dementia, which can be difficult to treat and
negatively affect quality of life.
– in puerperal psychiatric disorders when it is important
that the mother should resume the care of her baby
as quickly as possible.
• Treatment resistant
– Depression, failure to respond to antidepressants
of adequate dosage and adequate period of time
– Schizophrenia, failure to respond to antipsychotics
– Bipolar disorder, severe or treatment resistance
manic or mixed episodes
• Rare case
– Depressive stupor
– Catatonia schizophrenia, that does not respond to
lorazepam
– Neuroleptic malignant syndrome
– Depression associated with Parkinson’s disease
– Acute confusion psychosis

• Others
– Some medications that will harm the foetus, used in
pregnancy
– Safe for elderly
– When ECT has been successful in the past treatments
 Contraindication
• No absolute contraindication
 Contraindication
• Relative contraindication
– Elevated ICP eg SOL, hydrocephalus
– Recent myocardial infarction
– Heart failure
– Severe hypertension
– Phaeochromocytoma
– Recent stroke
– Unruptured aneurysm
– Arteriovenous malformation
– Potential source of bleeding
 Drugs to stop before ECT
• Anticonvulsants
• Clozapine
• Lithium
• Benzodiazepines
 Side effects
• headaches (which could be severe and “indescribable”)
• jaw ache
• memory loss surrounding their treatment time/
retrograde amnesia
• Disorientation
• Fatigue
• confused
• nausea
• drooling
• muscle stiffness
• inability to eat
• hallucinations
 Procedures
• Consent
– Informed consent. A full explanation is given about
the procedure and its risks and benefits, before asking
for consent.
– Seek for a second opinion and discusses the situation
with relatives if patient refuse/unable to give consent.
• Fasting the night before the procedure.
• Removes ring, dentures or anything that may get
in the way of drug administration or emergency
aid during ECT.
• General anaethesia. Commonly used –
methotixal, propofol, alfentanyl, etomidate.
• Equipments – to monitor vital signs and
provide initial management in medical
emergencies. (Eg: stethoscope, ECG, pulse
oximetry, sphygmomanometer, supplies for
anaesthesia induction and resuscitaion)
• Neuromuscular blockers – succinylcholine
• Anticholinergic
 During the procedure
• Anesthetic team present
• IV access for anesthesia and muscle relaxant
• Monitor vitals (BP, oximetry, ECG)
• Bite block prevent biting on the tongue
• Positioning of the electrodes. Common sites –
bifrontotemporal, right unilateral and bifrontal
positions.
• Deliver electrical stimulus through electrodes
placed on patient's head
• At the same time record EEG during seizure.
• Methods used to determine stimulus intensity
and dosing:
– Empirical titration
– Formula-based titration – factors: age, gender,
electrode placement
– Fixed dosage
 Seizure quality
• If the seizure duration is less than 15 seconds
in motor and EEG manifestation, the seizure
was very likely limited by insufficient electrical
stimulation.
• The EEG is used to confirm seizure activity and
to document seizure duration
 Number and frequency of ECT
• It is most commonly performed 3 times per
week.
• The typical number of treatment is 6-12.
• Some may respond after a few treatments.
Some may not respond until after 10
treatments.
• Treatment is stopped when maximal
improvement is reached.
Thank you