Medical Students

Hierarchy of Conditions

Role of drugs
Typical Antipsychotics

Thought to act by blocking specific brain receptors

e.g. mesolimbic D2 receptors

Receptor blockade takes hours yet clinical effect takes weeks.

Homovalinic acid levels takes weeks to fall

 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

Relative Times to achieve maximal

effects of antipsychotic drugs

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

1st Episode Schizophrenia

Start agreed antipsychotic
Titrate if necessary
1st onset of antipsychotic action 2/52
Assess at optimum dosage over 4-6 weeks
If successful, continue.
1-2 years treatment. Probably needed longer.
If not, change antipsychotic
If not successful, consider clozapine
8

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

Why do patients get acute

exacerbations?

10

High Dose Antipsychotic

Medication
Little proven advantage of using high doses or
polypharmacy in most clinical situations.
Royal College Statement. Consensus statement
on high dose antipsychotic medication.
Majority of the response likely within 3-4 weeks.
If no response by 6 - 8 weeks then raising
doses further usually of little benefit.
Early treatment associated with better
prognosis.
11

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.

If treatment stopped, relapse may be delayed.

The patient may feel better before relapse.

13

Typicals divided into:

Low potency (e.g. chlorpromazine 1952)
Less extrapyramidal side effects (EPSEs)
more sedative
increased postural hypotension
increased anticholinergic side effects
eg chlorpromazine and thioridazine.

High potency (e.g. haloperidol 1958)

the reverse
eg haloperidol and trifluoperazine.
14

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

Extrapyramidal Side Effects

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

This 29 year old women was the product of

a normal, full-term pregnancy and a vaginal
breech birth. She developed fairly normally
until the sixth grade, when she was found
to require special education classes. IQ
testing revealed a score of 37.
She stopped school at grade 9. At age 20,
she had episodic violent behavior, for which
she took haloperidol for 5 years and
risperidone for 3 years.
One year before evaluation, she had
involuntary pulling of the neck backward,
and tardive dystonia was diagnosed.
She obtained partial relief from oral
trihexiphenidyl, baclofen, clonazepam, and
tetrabenazine, in combination with
botulinum toxin injections.
She has severe cervical and oral dystonia.

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

EPSE-Tardive Dyskinesia (TD)

Involuntary hyperkinesia. increases with
anxiety,and relieved with sleep.
May be irreversible.
Symptoms include tics, choreas and
dystonias.
Repetitive, involuntary, purposeless
movements of : jaw, neck and tongue.
25

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

Is it a good idea to give patients

antimuscarinics/anticholinergics
regularly?

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

Other Side Effects

Hyperprolactinaemia.
Drowsiness.
Postural hypotension.
Weight gain.
Anticholinergic side effects.
Increased glucose levels.

34

What medical checks could

you do as safety precautions?

35

Atypical antipsychotics available in

United Kingdom

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.

Delaying treatment until after an

extended period with typical/ other
atypicals may reduce eventual
effectiveness of clozapine
38

Can cause reversible Neutopenia (3%). Can

progress to agranulocytosis (0.8%).
Not dose related. Risk higher in elderly and
those with lower baseline wbc counts.
Onset 8-10 weeks.
Treatment restricted by blood tests:
weekly (for 18 weeks).
Fortnightly (for 52 weeks).
monthly ever after.
39

Clozapine
Interactions inc.
Carbamazepine and various medicines
which cause neutropenia are
contraindicated.
Fluovoxamine in particular may increase
clozapine levels.
Smoking.
40

Clozapine Side Effects

inc.
Sore throat , fever Hypersalivation must be treated.
Constipation must be treated.
Seizures must be treated.
Urinary incontinence.
Drowsiness.
Hypotension.
41

Clozapine Side Effects inc.

Tachycardia investigate and treat if
necessary.
Weight gain potential long term
problems.
Raised glucose and cholesterol levels.
Pulmonary embolism.
Myocarditis.
Cardiomyopathy.
42

If Clozapine on its own does

not work augmentation with
A second antipsychotic.
Fish oils deficiency in fatty acids in cell
membranes.
Lamotrigine reduces release of
glutamate.
Check clozapine levels interpretation.

43

Are all atypical

antipsychotics equivalent?

44

Alternative Strategies for

TRS
Little evidence base:
High dose olanzapine (30-60mg per day).
High dose quetiapine.
Omega 3- Triglycerides augmentation.

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

10-12 weeks to steady state.

Removal from the body also takes a long time
several weeks.
Concurrent oral antipsychotics.
Olanzapine depot e-learning programme due
to low incidence of sedation, confusion,
disorientation, convulsions.
47

Advantages AND Disadvantages

of depot medication

48

Physical Health Checks

Weight gain.
Diabetes.
Hyperprolactinaemia.
Cardiovascular risk factors.
Side effects of medication.
Lifestyle factors smoking.
Cannabis.
49

How and When to Stop

Treatment
Risk Benefit Analysis.
Abrupt withdrawal is more likely to lead to
a relapse within the first six months.
Careful surveillance.

50

What the Patient needs to

Know
Antipsychotics do not cure schizophrenia.
Long term treatment is required to
prevent relapses.
Side effects should be discussed.
Antipsychotics should not be stopped
suddenly.

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 of RT is not to

treat any underlying illness
or disorder.
This must proceed
alongside RT, but is
distinct from RT.
Violence need not be
associated with psychosis
for RT to be an appropriate
therapy.
Violence that is associated
with psychosis may
respond to nonpharmacological
intervention.

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.

Providing the lowest

side effect load.
Using the lowest,
most effective dose.
Being cost-effective.

What drugs do we use?

ANTIPSYCHOTIC
Traditionally
Haloperidol
Atypical
Antipsychotics
may be used and
may be better
tolerated

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

 Would you give all patients a

combination of an antipsychotic
and a benzodiazepine?

SIDE EFFECTS
Acute dystonia
Hypotension
Neuroleptic
Malignant
Syndrome (NMS)
Arrhythmias
Respiratory
depression

 What would you do if a patient

had a history of NMS or dystonia
to haloperidol?

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

ECG Fluid balance & electrolyte balance

Clopixol Acuphase

Onset of action 2 hours

Peak sedative action: 12 hours
Lasts 72 hours
May be increased minimum of every
24 hrs to a maximum of 4 injections
and 400mg in total in two weeks
Monitoring vital signs over the
period.

 Would you give someone

clopixol acuphase if he/she
experienced dystonia to
haloperidol?

Adverse Effects of Long Term

Benzodiazepine Use:

Drugs of abuse
Tolerance
Hangover effect
Disinhibition
Confusion
Respiratory
Depression

Be Firm!!

Offer alternatives where available

Be strict with TTAs
Be observant with regular use
If long term use, withdrawal must be very
gradual

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 of RT is not to

treat any underlying illness
or disorder.
This must proceed
alongside RT, but is
distinct from RT.
Violence need not be
associated with psychosis
for RT to be an appropriate
therapy.
Violence that is associated
with psychosis may
respond to nonpharmacological
intervention.

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.

Providing the lowest

side effect load.
Using the lowest,
most effective dose.
Being cost-effective.

What drugs do we use?

ANTIPSYCHOTIC
Traditionally
Haloperidol
Atypical
Antipsychotics
may be used and
may be better
tolerated

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

 Would you give all patients a

combination of an antipsychotic
and a benzodiazepine?

SIDE EFFECTS
Acute dystonia
Hypotension
Neuroleptic
Malignant
Syndrome (NMS)
Arrhythmias
Respiratory
depression

 What would you do if a patient

had a history of NMS or dystonia
to haloperidol?

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

ECG Fluid balance & electrolyte balance

Clopixol Acuphase

Onset of action 2 hours

Peak sedative action: 12 hours
Lasts 72 hours
May be increased minimum of every
24 hrs to a maximum of 4 injections
and 400mg in total in two weeks
Monitoring vital signs over the
period.

 Would you give someone

clopixol acuphase if he/she
experienced dystonia to
haloperidol?

Adverse Effects of Long Term

Benzodiazepine Use:

Drugs of abuse
Tolerance
Hangover effect
Disinhibition
Confusion
Respiratory
Depression

Be Firm!!

Offer alternatives where available

Be strict with TTAs
Be observant with regular use
If long term use, withdrawal must be very
gradual

Bipolar Mood DisordersMedication

Audrey Coker
Senior Pharmacist Mental
Health Services

Camden and Islington

Mental Health Foundation
Trust

Mood

Acute Mania (No prior

medication)
Stop any antidepressant.
Consider an antipsychotic particularly if
severe behavioural problems or
Valproate (avoid in women of child
bearing age).
Lithium (if future adherence is likely)
Antipsychotic + valp. Or li.
Consider a short term benzodiazepine.

Why should antidepressants

be stopped

Why are antipsychotics used?

Acute Mania previous

antimanic medication
If taking an antipsychotic:Compliance.?
Increase dose if necessary. Consider
adding lithium or valproate.
If taking lithium or valproate, check
plasma levels. Increase dose to levels of
up max. +/- antipsychotic.

Acute Mania previous

antimanic medication
Carbamazepine consider adding an
antipsychotic (higher doses may be
needed).
Short term benzodiazepines may be
added.

If a patient presented in a depressive

phase after a period of non
compliance what could you
prescribe?

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.

Changes in Lithium Levels

Situations that may increase plasma
lithium levels
Decreased sodium intake or increased sodium excretion
Low sodium diet
Diuretics, ACEIs, Angiotensin antagonists
Excessive exercise/sweating
Protracted diarrhoea/ vomiting
Salt deficiency
Decrease water intake or increased water excretion
Dehydration
Diuretics (thiazide and potassium sparing)
Fever
Physical illness (flu, surgery, diarrhoea, vomiting)
Postpartum fluid changes
Slimming diets
Renal disease or decreased renal blood flow
Renal dysfunction
Nonsteroidal anti-inflammatory agents

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

Neurological adverse effects:

dizziness, fatigue, ataxia,
blurred vision, nystagmus,
dysarthria, confusion.
GI side effects
Mild to severe rashes
Agranulocytosis, aplastic
anaemia
SIADH
Liver enzymes elevation
Neutropenia

DRUG INTERACTIONS!!

Valproate

GI upset and sedation

ataxia, lethargy, fine tremor,
alopecia, pruritus, prolonged
bleeding, liver enzymes
increase, weight gain,
thrombocytopenia
Established teratogen must
discuss with women of child
bearing age folate

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).

Rapid Cycling BAD

Withdraw antidepressants.
Consider precipitants e.g. thyroid
dysfunction.
Optimise mood stabilisers e.g. lithium +
valproate.
If no response options with a smaller
evidence base may be considered e.g.
clozapine, lamotrigine, thyroxine.

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.

Bipolar Mood DisordersMedication

Audrey Coker
Senior Pharmacist Mental
Health Services

Camden and Islington

Mental Health Foundation
Trust

Mood

Acute Mania (No prior

medication)
Stop any antidepressant.
Consider an antipsychotic particularly if
severe behavioural problems or
Valproate (avoid in women of child
bearing age).
Lithium (if future adherence is likely)
Antipsychotic + valp. Or li.
Consider a short term benzodiazepine.

Why should antidepressants

be stopped

Why are antipsychotics used?

Acute Mania previous

antimanic medication
If taking an antipsychotic:Compliance.?
Increase dose if necessary. Consider
adding lithium or valproate.
If taking lithium or valproate, check
plasma levels. Increase dose to levels of
up max. +/- antipsychotic.

Acute Mania previous

antimanic medication
Carbamazepine consider adding an
antipsychotic (higher doses may be
needed).
Short term benzodiazepines may be
added.

If a patient presented in a depressive

phase after a period of non
compliance what could you
prescribe?

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.

Changes in Lithium Levels

Situations that may increase plasma
lithium levels
Decreased sodium intake or increased sodium excretion
Low sodium diet
Diuretics, ACEIs, Angiotensin antagonists
Excessive exercise/sweating
Protracted diarrhoea/ vomiting
Salt deficiency
Decrease water intake or increased water excretion
Dehydration
Diuretics (thiazide and potassium sparing)
Fever
Physical illness (flu, surgery, diarrhoea, vomiting)
Postpartum fluid changes
Slimming diets
Renal disease or decreased renal blood flow
Renal dysfunction
Nonsteroidal anti-inflammatory agents

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

Neurological adverse effects:

dizziness, fatigue, ataxia,
blurred vision, nystagmus,
dysarthria, confusion.
GI side effects
Mild to severe rashes
Agranulocytosis, aplastic
anaemia
SIADH
Liver enzymes elevation
Neutropenia

DRUG INTERACTIONS!!

Valproate

GI upset and sedation

ataxia, lethargy, fine tremor,
alopecia, pruritus, prolonged
bleeding, liver enzymes
increase, weight gain,
thrombocytopenia
Established teratogen must
discuss with women of child
bearing age folate

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).

Rapid Cycling BAD

Withdraw antidepressants.
Consider precipitants e.g. thyroid
dysfunction.
Optimise mood stabilisers e.g. lithium +
valproate.
If no response options with a smaller
evidence base may be considered e.g.
clozapine, lamotrigine, thyroxine.

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.

Depression and its

Treatment
Audrey Coker
Senior Psychiatry Pharmacist

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

Drugs which are depressogenic

Cardiovascular Drugs: -blockers, calcium
channel blockers, digoxin, methyldopa, statins.
Hormones: corticosteroids, oestrogens,
progestogens.
Drugs acting on CNS: alcohol, amphetamine
(withdrawal), amantadine, benzodiazepines,
carbamazepine, levodopa, phenothiazines.
Antibacterials: sulphonamides, ciprofloxacin.
Miscellaneous: disulfiram, interferon-,
isotretinoin, mefloquine, metoclopramide,
132
NSAIDs, -blockers.

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

Factors to consider when

choosing an antidepressant
Previous response to class of antidepressants.
Tolerability and adverse effects of previous antidepressants.
Effects of antidepressants on co-morbidity.
Lethality in overdose.
Concurrent physical illness or condition.
Associated psychiatric disorder that may specifically respond to a
particular class of antidepressant.
(eg, obsessive compulsive disorder and serotonin reuptake inhibitors)
Patient preference.

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

Duration of Treatment For

Major Depression

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

Third or subsequent 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

Selective Serotonin Reuptake

Inhibitors SSRIs
Drugs of choice but for cost.
Low risk in overdose, safety in heart
conditions, better s/e profile.
Cost more per day than TCAs but may be
cheaper in the long run.
e.g. fluoxetine, paroxetine, sertraline,
citalopram.
140

Side Effects of SSRIs

Insomnia.
Agitation.
Dystonia paroxetine.
Increased risk of bleeding. This is additvie
to that produced by aspirin and NSAIDs.
Sexual dysfunction.

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

Side effects of TCAs

Anticholinergic side effects.
Arrhythmogenic properties.
Hypotension.
Drowsiness.
Sexual dysfunction.

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.

ARE ANTIDEPRESSANTS ADDICTIVE?

148

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

30-80% of `treatment resistant cases are under

treated.
50% of these respond to improved dosing.
True resistance:
treated with higher doses.
logical combinations.
Augmentation.
assuring compliance.
152

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

Key Points Patients Should

Know
A single episode of depression should be
treated for 6 months after recovery.
The risk of recurrence of depressive
illness is high and increases with each
episode.
Those with multiple episodes may require
long term treatment.
Treatment doses are required.
158

Key Points Patients Should

Know
Antidepressants are:
Effective.
Non addictive.
Not known to lose efficacy over time.
Not known to cause long term effects.
Medication should be reduced slowly
under the supervision of a doctor.
159

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