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Hierarchy of Conditions
Role of drugs
Typical Antipsychotics
Generally act by blocking dopamine receptors in particular D2. Can give rise to S/Es
Also can affect cholinergic, alpha adrenergic, histamine and serotonin receptors.
Possible Pathways
Involved
4 Dopamine Lines:
- Brainstem to Limbic System Too much Dopamine is
thought to be cause for POSITIVE symptoms
- Brainstem to Mesocortical System Too little dopamine is
thought to be cause for NEGATIVE symptoms
- Brainstem to Basal Ganglia Blocking Dopamine causes
movement disorders
- Brainstem to Hypothalamus Blocking Dopamine leads to
Hyperprolactinaemia
Acute Episodes
Drug induced illicit or prescription?
Pharmacological management is necessary
Informed choice
First line atypical monotherapy within BNF limits,
particularly if the patient cannot give informed consent
Atypicals if experiencing EPSEs, otherwise continue
with regular treatment
Advance Directives
Acute cases respond better than chronic patients
May require additional sedatives.
7
Acute Exacerbation
Continue/restart usual treatment
May consider a short term sedative
Avoid increasing antipsychotic dose
May switch to another antipsychotic if
appropriate
If ineffective, switch to clozapine
10
If no response review
symptoms e.g.
Affective symptoms? Concurrent mood
stabiliser?
Depressive symptoms? Concurrent
antidepressant?
Side effects e.g. akathisia.
Acceptability of side effects.
Compliance.
12
Relapse
Occurs in 80% of untreated cases.
20% who would not relapse cannot be identified.
Maintenance therapy significantly reduces relapse
rate.
13
Class of Antipsychotics
Phenothiazines Chlorpromazine, promazine,
pipothiazine, fluphenazine, trifluoperazine
Butyrophenones Haloperidol -potent D2
blocker, high level of EPSE. Depot formulation
Thioxanthenes Flupenthixol and
zuclopenthixol mainly used as depots
Diphenylbutylpiperidines pimozide fairly
dopamine specific. ECGs if dose higher than
16mg/day
15
Class of Antipsychotic
Sulpiride
-doses <800mg per day- main affinity is
for pre-synaptic D4 receptors -less
inhibition of dopamine release & more
dopamine available at the synapse.
doses, D2 affinity dominates resulting in
post synaptic blockade of D2 receptors
16
17
EPSE-Dystonia
Sustained involuntary muscle contractions.
Twisting of neck, limbs,trunk or face.
Acute form more likely in younger, more ill
patients.
Especially antipsychotic nave, with predominant
negative symptoms.
Can occur after a few doses or several years.
18
Treatment of Choice
Switch to an atypical or an atypical with
less risk of EPSEs
Parenteral anticholinergic e.g. procyclidine
IM or IV in acute situations
19
Dystonic Reaction
20
EPSE-Parkinsonian
Akinesia.
Rigidity.
Course tremor at rest but no pill rolling.
May occur within weeks.
Remit on withdrawal of drug.
21
Treatment
Switch to an atypical or an atypical with
less risk of EPSE.
If not an option, consider as required
procyclidine (oral).
22
EPSE-Akathisia.
Uncontrolled restlessness with feelings
of inability to keep still.
Constantly shifting posture, rocking
pacing the floor.
May resemble agitation or psychosis.
Use validated rating scale to assess
such as Barnes Akathisia Rating Scale.
23
Treatment
Switch to an atypical or an atypical with
less risk of EPSE.
If not an option, consider propranolol.
Procycline is less efficacious.
24
Treatment
Switch to an atypical or an atypical with
less risk of EPSE.
If necessary consider:
Tetrabenzine (licensed) or
Vitamin E liquid (not licensed) or
Clonazepam (not licensed).
26
Antimuscarinics
Benzatropine mesilate
Orphenadrine
hydrochloride
Procyclidine
hydrochloride
Trihexyphenidyl
hydrochloride
(Benzhexol)
27
Antimuscarinic Side
Effects
Dry mouth
Blurred vision
GI disturbance e.g.
constipation
Urinary retention
Tachycardia
Mental confusion
Contra-indicated in
untreated urinary
retention, glaucoma, GI
obstruction
28
29
Neuroleptic Malignant
Syndrome
Inc. Rigidity, fever, confusion, fluctuating
BP, tachycardia.
Elevated creatine kinase.
? Dopamine deficiency.
Risk factors inc. high potency drugs,
rapid dose changes, agitation,
dehydration, abrupt withdrawal of
anticholinergics, concurrent lithium.
30
Treatment
Life threatening.
Withdraw antipsychotic immediately.
Monitor TPR.
May need to be admitted to A&E.
Rehydrate, artificial ventilation.
Sedate with benzodiazepines.
Dantrolene muscle relaxant.
Bromocriptine dopamine agonist.
ECT for psychosis.
31
Subsequent treatment of
Psychosis
No antipsychotics for at least 5 days.
Wait for symptoms to resolve inc. CPK.
Use small doses of an unrelated
antipsychotic, preferably not a long acting
one and one with low dopamine affinity.
Monitor for symptoms of NMS TPR, CPK.
32
Psychotropic Related QT
prolongation
Some antipsychotics block cardiac potassium
channels and are linked to the cardiac QT
prolongation which is a risk factor for ventricular
arrhythmias.
Some are assoc. with an extremely low risk of
sudden death.
Risk factors cardiac, low K, Ca & Mg, stress,
physical exertion , anorexia nervosa.
Particularly relevant in RT and with high doses.
33
34
35
Atypical Neuroleptics
Clozapine
Olanzapine
Zotepine
Aripripazole
Amisulpride
Risperidone
Quetiapine
36
Atypical antipsychotics.
Better tolerated than Typicals ?
EPSEs and prolactin elevation less frequent.
Efficacy in negative symptoms.
Care in patients with cardiovascular disease,
epilepsy or Parkinson's.
S/Es- weight gain, dizziness, postural
hypotension, EPSEs (mild and transient,
respond to dose reduction), NMS rarely,
Occasionally TD.
37
Pharmacology of clozapine
Clozapine discovered 1966.
Indicated for treatment resistance. Considered more
effective in all aspects of schizophrenia.
Effective in 30-50% treatment resistant cases. May
reach 60% if adequate dosing for 12 weeks.
Clozapine
Interactions inc.
Carbamazepine and various medicines
which cause neutropenia are
contraindicated.
Fluovoxamine in particular may increase
clozapine levels.
Smoking.
40
43
44
45
Depot Antipsychotics
Haloperidol decanoate
Pipotiazine palmitate
Fluphenazine decanaote
Flupentixol decanoate
Zuclopenthixol decanoate
Risperidone long acting
injection (atypical)
Paliperidone depot
Olanzapine pamoate
depot (atypical)
46
Depot Antipsychotics
Slow onset of action several weeks
48
50
51
52
Rapid Tranquillisation
and
Benzodiazepines
Audrey Coker
Camden and Islington
Mental Health Foundation
Trust
What is RT?
Rapid tranquillisation has a limited evidence
base because clinical trials are difficult to
conduct.
It is a pharmacological strategy used to
manage a high risk of imminent violence.
Tranquillisation means calming without
sedating.
The Dilemma .
The Aim
To manage an agitated,
irritable, hostile or
violent episode.
To calm the patient so
they can be safely
managed and be safe to
others.
To alleviate disturbing
symptoms.
BENZODIAZEPINES
Used as better
tolerated
COMBINATION
Some evidence that
this works
synergistically
Also can mean
giving less of more
toxic
antipsychotics
Routes
Always offer tablets, syrup or
fast dissolving tablets first
The IM route should only be
used if the patient will not
accept oral medication or has
not responded to it lorazepam,
haloperidol, aripiprazole
SIDE EFFECTS
Acute dystonia
Hypotension
Neuroleptic
Malignant
Syndrome (NMS)
Arrhythmias
Respiratory
depression
Monitoring
Requirements
After IM medication
Alertness
Temperature
Pulse
Blood pressure
Respiratory rate
Continuous pulse oximetry
every 15 minutes for 2 hours
then
every 30 minutes until patient is
ambulatory
then
continue to monitor alertness,
mental state and behaviour
Clopixol Acuphase
Drugs of abuse
Tolerance
Hangover effect
Disinhibition
Confusion
Respiratory
Depression
Be Firm!!
Rapid Tranquillisation
and
Benzodiazepines
Audrey Coker
Camden and Islington
Mental Health Foundation
Trust
What is RT?
Rapid tranquillisation has a limited evidence
base because clinical trials are difficult to
conduct.
It is a pharmacological strategy used to
manage a high risk of imminent violence.
Tranquillisation means calming without
sedating.
The Dilemma .
The Aim
To manage an agitated,
irritable, hostile or
violent episode.
To calm the patient so
they can be safely
managed and be safe to
others.
To alleviate disturbing
symptoms.
BENZODIAZEPINES
Used as better
tolerated
COMBINATION
Some evidence that
this works
synergistically
Also can mean
giving less of more
toxic
antipsychotics
Routes
Always offer tablets, syrup or
fast dissolving tablets first
The IM route should only be
used if the patient will not
accept oral medication or has
not responded to it lorazepam,
haloperidol, aripiprazole
SIDE EFFECTS
Acute dystonia
Hypotension
Neuroleptic
Malignant
Syndrome (NMS)
Arrhythmias
Respiratory
depression
Monitoring
Requirements
After IM medication
Alertness
Temperature
Pulse
Blood pressure
Respiratory rate
Continuous pulse oximetry
every 15 minutes for 2 hours
then
every 30 minutes until patient is
ambulatory
then
continue to monitor alertness,
mental state and behaviour
Clopixol Acuphase
Drugs of abuse
Tolerance
Hangover effect
Disinhibition
Confusion
Respiratory
Depression
Be Firm!!
Mood
Mode of Action
Li+ may reduce higher intracellular conc.
of Na and Ca, reduce activity of Na
dependent I/C 20 messenger systems,
protein kinase C? Neuroprotective via
NMDA pathways? Modulate dopamine and
serotonin pathways. Reduced turnover of
arachidonic acid.
Carbamazepine blocks voltage
dependent sodium channels, inhibiting
repetitive neuronal firing, reduces
glutamate release and the turnover of
dopamine and noradrenaline.
Valproate inhibits the catabolism of
GABA, reduced turnover of arachidonic
acid, reduced levels of protein kinase C,
inhibition of voltage gated Na channels,
promote brain derived neurotrophic factor.
Lithium
Generally 70-80%
effective in aborting an
acute manic or
hypomanic episode.
Takes 7-14 days after
starting therapy.
Prophylactic lithium
therapy required in 7080% to prevent
recurrences of mania,
hypomania or depression.
Adverse effects:
Short Term
GI upset, Nausea, Polydipsia, Polyuria,
Nocturia, dry mouth, fine hand tremor,
leukocytosis, muscle weakness, difficulty
concentrating, impaired memory,
Long Term
weight gain, altered taste, decreased libido,
hypothyroidism, rash, acne, psoriasis,
alopecia, non specific T wave changes,
premature ventricular beats, nephrogenic
diabetes insipidus, nephrotoxicity, fine hand
tremor
Toxic > 1.5mmol/l
Severe drowsiness, coarse hand tremor,
muscle twitching, myoclonus, cogwheel
rigidity, vomiting, loss of appetite, ataxia,
nystagmus, seizures, coma & death
Lithium Preparations
Keep to same brand/
preparation because of
bioavailability.
Write Rx in proprietary
format (brand name).
Monitor more frequently
when changing between
brands & formulation.
Carbonate not
equivalent to citrate
Pre-lithium Work Up
ECG, TFTs, Us&Es inc. serum creatinine
and urea.
Starting Dose: 400mg per day.
Elderly: 200mg per day.
Levels in 5-7 days 12 hours post dose
Range: 0.4 1.0mmol/l.
A salt free diet is contraindicated.
Monitoring of patients on
Lithium
Lithium blood levels - every 3
months (patients on established
treatment)
Blood sample at same time interval
post dose (ideally 12-18 hours)
On a 6 monthly
basis the following should be
checked: urea & electrolytes, renal
function, thyroid function, weight, bp,
pulse, ECG
Certain patients may require more
frequent monitoring, eg elderly,
those on interacting drugs, medical co
morbidity such as renal, thyroid,
cardiac disease.
Drug Interactions
Haloperidol or Carbamazepine may
cause neurotoxicity occasionally.
SSRIs may cause CNS toxicity.
Stopping Lithium
Reduce slowly over at least a month,
preferably 3 months even if another mood
stabiliser is added.
Carbamazepine &
Valproate
Carbamazapine
DRUG INTERACTIONS!!
Valproate
Carbamazepine &
Valproate
Carbamazepine.
Autoinducer low
initial doses.
Check levels in 2-4
weeks.
Dose of at least
600mg per day and a
serum level of 7mg/l
(range: 4-12mg/l).
Valproate.
Level of 50-125mg/l.
Side effects are often
dose related.
Carbamazepine &
Valproate
Carbamazepine
Interactions
Antipsychotic
Antidepressants
Methadone
Benzodiazepines
Washout with MAOIs
C/I - clozapine
Valproate
Interactions
Warfarin protein
binding displacement
Increase levels of
lamotrigine
Valproate levels
increased by
erythromin, fluoxetine
Other Options
Lamotrigine bipolar depression.
Clozapine resistant bipolar illness (not
licensed).
Prophylaxis
1st line lithium, olanzapine and valproate
Rx for 2yrs or longer.
Antidepressants may be used on combn
with an antimanic agent for acute
depressive episodes.
Rapid cyclers lithium + valproate.
Bipolar Depression
Initial use of an SSRI + an anti manic
agent.
Or Quetiapine (if not antipsychotic already
prescribed).
Mirtazapine or venlafaxine may be used
as the antidepressant.
Or add quetiapine, olanzapine or lithium
to the antidepressant.
Mood
Mode of Action
Li+ may reduce higher intracellular conc.
of Na and Ca, reduce activity of Na
dependent I/C 20 messenger systems,
protein kinase C? Neuroprotective via
NMDA pathways? Modulate dopamine and
serotonin pathways. Reduced turnover of
arachidonic acid.
Carbamazepine blocks voltage
dependent sodium channels, inhibiting
repetitive neuronal firing, reduces
glutamate release and the turnover of
dopamine and noradrenaline.
Valproate inhibits the catabolism of
GABA, reduced turnover of arachidonic
acid, reduced levels of protein kinase C,
inhibition of voltage gated Na channels,
promote brain derived neurotrophic factor.
Lithium
Generally 70-80%
effective in aborting an
acute manic or
hypomanic episode.
Takes 7-14 days after
starting therapy.
Prophylactic lithium
therapy required in 7080% to prevent
recurrences of mania,
hypomania or depression.
Adverse effects:
Short Term
GI upset, Nausea, Polydipsia, Polyuria,
Nocturia, dry mouth, fine hand tremor,
leukocytosis, muscle weakness, difficulty
concentrating, impaired memory,
Long Term
weight gain, altered taste, decreased libido,
hypothyroidism, rash, acne, psoriasis,
alopecia, non specific T wave changes,
premature ventricular beats, nephrogenic
diabetes insipidus, nephrotoxicity, fine hand
tremor
Toxic > 1.5mmol/l
Severe drowsiness, coarse hand tremor,
muscle twitching, myoclonus, cogwheel
rigidity, vomiting, loss of appetite, ataxia,
nystagmus, seizures, coma & death
Lithium Preparations
Keep to same brand/
preparation because of
bioavailability.
Write Rx in proprietary
format (brand name).
Monitor more frequently
when changing between
brands & formulation.
Carbonate not
equivalent to citrate
Pre-lithium Work Up
ECG, TFTs, Us&Es inc. serum creatinine
and urea.
Starting Dose: 400mg per day.
Elderly: 200mg per day.
Levels in 5-7 days 12 hours post dose
Range: 0.4 1.0mmol/l.
A salt free diet is contraindicated.
Monitoring of patients on
Lithium
Lithium blood levels - every 3
months (patients on established
treatment)
Blood sample at same time interval
post dose (ideally 12-18 hours)
On a 6 monthly
basis the following should be
checked: urea & electrolytes, renal
function, thyroid function, weight, bp,
pulse, ECG
Certain patients may require more
frequent monitoring, eg elderly,
those on interacting drugs, medical co
morbidity such as renal, thyroid,
cardiac disease.
Drug Interactions
Haloperidol or Carbamazepine may
cause neurotoxicity occasionally.
SSRIs may cause CNS toxicity.
Stopping Lithium
Reduce slowly over at least a month,
preferably 3 months even if another mood
stabiliser is added.
Carbamazepine &
Valproate
Carbamazapine
DRUG INTERACTIONS!!
Valproate
Carbamazepine &
Valproate
Carbamazepine.
Autoinducer low
initial doses.
Check levels in 2-4
weeks.
Dose of at least
600mg per day and a
serum level of 7mg/l
(range: 4-12mg/l).
Valproate.
Level of 50-125mg/l.
Side effects are often
dose related.
Carbamazepine &
Valproate
Carbamazepine
Interactions
Antipsychotic
Antidepressants
Methadone
Benzodiazepines
Washout with MAOIs
C/I - clozapine
Valproate
Interactions
Warfarin protein
binding displacement
Increase levels of
lamotrigine
Valproate levels
increased by
erythromin, fluoxetine
Other Options
Lamotrigine bipolar depression.
Clozapine resistant bipolar illness (not
licensed).
Prophylaxis
1st line lithium, olanzapine and valproate
Rx for 2yrs or longer.
Antidepressants may be used on combn
with an antimanic agent for acute
depressive episodes.
Rapid cyclers lithium + valproate.
Bipolar Depression
Initial use of an SSRI + an anti manic
agent.
Or Quetiapine (if not antipsychotic already
prescribed).
Mirtazapine or venlafaxine may be used
as the antidepressant.
Or add quetiapine, olanzapine or lithium
to the antidepressant.
129
Contents
Introduction
Causes
Principles of treatment
Choice of drug
Drugs used
130
Abnormalities in monoamine
neurotransmission in depression
5-HT
Decreased plasma tryptophan
Blunted 5-HT neuroendocrine
responses
Clinical relapse after tryptophan
depletion
Noradrenaline
Blunted noradrenaline-mediated
growth hormone release
Dopamine
Decreased homovanillic acid (HVA)
levels in CSF
131
Role of Antidepressants
Virtually all available
antidepressants are
equally effective if given at
an adequate dose for a
sufficient time
Most cases resolve with time
Antidepressants hasten
recovery and reduce suffering.
Indicated for a major
depressive disorder that is
moderate to severe.
133
Principles of treatment
1) Eliminate contributory causes
e.g. other drugs, excessive caffeine intake,
physical causes such as anaemia and
hypothyroidism.
134
135
Principles of Treatment
Discuss with the patient, choice of drug and non
pharmacological options.
Explain it does not work immediately.
Prescribe a dose of antidepressant likely to be
effective.
Is episode continue for 4-6 moths after
recovery.
Reduce slowly to reduce discontinuation rxns.
136
Rx Options
1st line SSRI assess over 4-6 weeks.
If successful continue for 6 mths.
If not - ineffective/poorly tolerated another antidepressant for 4-6 weeks.
If no effect refractory Rx options.
No evidence that any antidepressant
works faster.
137
1st episode
Age
<39
40-49 >50
6-9 m 6-9 m Indef
2nd
6-9 m 4-5 y
Indef
2nd + complication
4-5 y
Indef
Indef
Indef
Indef
138
Classes of antidepressants
TCAs and related compounds
Amitriptyline, amoxapine, clomipramine, desipramine, doxepin,
imipramine, nortriptyline, protriptyline, trazodone, lofepramine
MAOIs
Isocarboxazid, phenelzine, tranylcypromine
SSRIs
Citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
Miscellaneous antidepressants
Venlafaxine, nefazodone, mirtazapine, reboxetine, moclobemide
139
141
Mirtazapine
Often used as a second line agent after
an SSRI.
Relatively safe in overdose, but not yet
considered as safe SSRIs.
Drowsiness.
Weight gain.
Rare cases of neutropenia.
142
Venlafaxine
Often used as a 2nd / 3rd line agent and
also in patients acknowledged treatment
resistant depression.
Care in patients with CVS problems.
BP at higher doses.
Not as safe as SSRIs, but not as
dangerous as TCAs.
143
Tricyclic antidepressants
TCAs
Doses of 125-150mg/day effective.
No evidence supporting <75mg.
In community 88% of doses < accepted
effective levels.
Older TCAs high doses cause more s/es.
e.g. amitriptyline, clomipramine,
dothiepin, lofepramine.
Dangerous in overdose.
144
145
Monoamine Oxidase
Inhibitors
Hardly ever used.
Used for atypical depression.
Patient has to be counselled about diet
and over the counter medicines and
prescribed medicines.
Also dangerous in overdose.
146
Hyponatraemia
Most antidepressants cause this.
Risk factors old age, female LBW, low
baseline Na, concurrent medication,
hypothyroidism, diabetes, warm weather.
May need to be clinically managed.
SSRIs are more likely to cause it.
Lofepramine, reboxetine and
moclobemide are less likely. ECT.
147
Withdrawal Syndrome
GI & somatic distress, sleep disturbances,
movement disorders, hypomania.
Due to cholinergic / adrenergic overdrive.
Appears 1-14 days after cessation, lasts 7
14 days. Differs to relapse.
Treat with low doses, or leave to resolve
and reassure.
Serotonin Syndrome
May occur when two antidepressants are
administered together.
May occur when crosstapering.
Other concurrent drugs may cause it e.g.
tramadol.
149
Serotonin Syndrome
Restlessness.
Tremor.
Shivering.
Myoclonus.
Confusion.
Convulsions.
Death.
150
Cross Tapering
Guidelines in the Maudsley.
MAOIs cheese reaction.
With monoamine oxidase inhibitors, wait
for 2 weeks after stopping the MAOI
before starting another.
If switching to an MAOI, the washout
period depends on the T1/2 of the
previous antidepressant.
151
Resistant depression
Treatment Resistant
Depression
Venlafaxine inhibits serotonin reuptake at
low doses and also noradrenaline at high
doses. Supported by NICE.
ECT.
Lithium (low doses) added to an
antidepressant.
SSRI + mirtazapine or mianserin (NICE).
Phenelzine failure to respond to others.
153
Resistant Depression
Add tri-iodothyronine less popular, but now
supported by STAR*D.
Add an antipsychotic to the antidepressant.
Psychotic depression may require an
antipsychotic as well. TCAs best evidence base
as antidepressant.
Venlafaxine + mirtazapine (Maudsley Guide)
Others are less widely used either due to
toxicity MAOI and a TCA or poor evidence base
addition of tryptophan.
154
Psychotic Depression
TCAs are probably more effective.
But response rate is poorer than in patients with
non psychotic major depression.
A combn of an antipsychotic + an
antidepressant is more effective than an
antipsychotic alone.
ECT may be indicated.
155
St Johns Wort
May be effective in mild to moderate
depression only.
Active component not yet determined.
Uncertainty about therapeutic dose.
156
St Johns Wort
S/Es dry mouth, nausea, dizziness,
photosensitivity.
May cause hypomania (like other
antidepressants).
Reduces levels of e.g. CoCs,
antiretrovirals and warfarin.
157
Summary
Depression is a common psychiatric illness
especially in primary care.
Antidepressants hasten recovery and
reduce suffering.
It is important to give them in adequate
doses for adequate periods.
Care is needed when switching
antidepressants.
160