Download - 03.1A Psychopharmacology
1
Medical Students
2
Hierarchy of Conditions
3
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
4
Generally act by blocking dopamine receptors in particular D2. Can give rise to S/E’s
Also can affect cholinergic, alpha adrenergic, histamine and serotonin receptors.
5
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
6
Relative Times to achieve maximal
effects of antipsychotic drugs
7
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.
8
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
9
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
Why do patients get acute
exacerbations?
11
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.
High Dose Antipsychotic
Medication
12
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.
13
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.
14
Typicals divided into:
Low potency (e.g. chlorpromazine 1952)
Less extrapyramidal side effects (EPSE’s)
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.
15
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
16
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
17
Extrapyramidal Side Effects
18
EPSE-Dystonia
Sustained involuntary muscle contractions.
Twisting of neck, limbs,trunk or face.
Acute form more likely in younger, more ill patients.
Especially antipsychotic naïve, with predominant negative symptoms.
Can occur after a few doses or several years.
19
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
20
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.
21
EPSE-Parkinsonian
Akinesia.
Rigidity.
Course tremor at rest but no pill rolling.
May occur within weeks.
Remit on withdrawal of drug.
22
Treatment
Switch to an atypical or an atypical with less risk of EPSE.
If not an option, consider as required procyclidine (oral).
23
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.
24
Treatment
Switch to an atypical or an atypical with less risk of EPSE.
If not an option, consider propranolol.
Procycline is less efficacious.
25
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.
26
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).
27
Antimuscarinics
Benzatropine mesilate
Orphenadrine hydrochloride
Procyclidine hydrochloride
Trihexyphenidyl hydrochloride (Benzhexol)
28
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
29
Is it a good idea to give patients antimuscarinics/anticholinergics regularly?
30
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.
31
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.
32
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.
33
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.
34
Other Side Effects
Hyperprolactinaemia.
Drowsiness.
Postural hypotension.
Weight gain.
Anticholinergic side effects.
Increased glucose levels.
35
What medical checks could
you do as safety precautions?
36
Atypical antipsychotics available in
United Kingdom
Atypical Neuroleptics
Clozapine Olanzapine Zotepine Aripripazole Amisulpride Risperidone Quetiapine
37
Atypical antipsychotics.
Better tolerated than Typicals ?
EPSE’s and prolactin elevation less frequent.
Efficacy in negative symptoms.
Care in patients with cardiovascular disease, epilepsy or Parkinson's.
S/E’s- weight gain, dizziness, postural hypotension, EPSE’s (mild and transient, respond to dose reduction), NMS rarely, Occasionally TD.
38
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
39
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.
40
Clozapine
Interactions inc.
Carbamazepine and various medicines which cause neutropenia are contraindicated.
Fluovoxamine in particular may increase clozapine levels.
Smoking.
41
Clozapine – Side Effects
inc.
Sore throat , fever -
Hypersalivation – must be treated.
Constipation – must be treated.
Seizures – must be treated.
Urinary incontinence.
Drowsiness.
Hypotension.
42
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.
43
If Clozapine on it’s 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.
44
Are all atypical
antipsychotics equivalent?
45
Alternative Strategies for
TRS
Little evidence base:
High dose olanzapine (30-60mg per day).
High dose quetiapine.
Omega – 3- Triglycerides augmentation.
46
Depot Antipsychotics
Haloperidol decanoate
Pipotiazine palmitate
Fluphenazine decanaote
Flupentixol decanoate
Zuclopenthixol decanoate
Risperidone long acting injection (atypical)
Paliperidone depot
Olanzapine pamoate depot (atypical)
47
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.
48
Advantages AND Disadvantages
of depot medication
49
Physical Health Checks
Weight gain.
Diabetes.
Hyperprolactinaemia.
Cardiovascular risk factors.
Side effects of medication.
Lifestyle factors – smoking.
Cannabis.
50
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.
51
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.
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 non-pharmacological 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 TTA’s
• 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 non-pharmacological 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 TTA’s
• Be observant with regular use
• If long term use, withdrawal must be very
gradual
Bipolar Mood Disorders-
Medication
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 70-80% 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 Disorders-
Medication
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 70-80% 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.
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Depression and its
Treatment
Audrey Coker
Senior Psychiatry Pharmacist
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Contents
Introduction
Causes
Principles of treatment
Choice of drug
Drugs used
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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
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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, NSAIDs, -blockers.
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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.
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Principles of treatment
1) Eliminate contributory causes
e.g. other drugs, excessive caffeine intake, physical causes such as anaemia and hypothyroidism.
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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.
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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.
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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.
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Duration of Treatment For
Major Depression
Age
<39
40-49
>50
1st episode 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
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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
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Selective Serotonin Reuptake
Inhibitors SSRI’s
Drugs of choice but for cost.
Low risk in overdose, safety in heart conditions, better s/e profile.
Cost more per day than TCA’s but may be cheaper in the long run.
e.g. fluoxetine, paroxetine, sertraline, citalopram.
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Side Effects of SSRIs
Insomnia.
Agitation.
Dystonia – paroxetine.
Increased risk of bleeding. This is additvie to that produced by aspirin and NSAIDs.
Sexual dysfunction.
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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.
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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.
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Tricyclic antidepressants
TCA’s
Doses of 125-150mg/day effective.
No evidence supporting <75mg.
In community 88% of doses < accepted effective levels.
Older TCA’s high doses cause more s/e’s.
e.g. amitriptyline, clomipramine, dothiepin, lofepramine.
Dangerous in overdose.
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Side effects of TCAs
Anticholinergic side effects.
Arrhythmogenic properties.
Hypotension.
Drowsiness.
Sexual dysfunction.
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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.
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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.
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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?
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Serotonin Syndrome
May occur when two antidepressants are administered together.
May occur when crosstapering.
Other concurrent drugs may cause it e.g. tramadol.
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Serotonin Syndrome
Restlessness.
Tremor.
Shivering.
Myoclonus.
Confusion.
Convulsions.
Death.
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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.
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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.
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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.
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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.
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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.
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St John’s Wort
May be effective in mild to moderate depression only.
Active component not yet determined.
Uncertainty about therapeutic dose.
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St John’s Wort
S/Es – dry mouth, nausea, dizziness, photosensitivity.
May cause hypomania (like other antidepressants).
Reduces levels of e.g. CoCs, antiretrovirals and warfarin.
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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.
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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.
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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.