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.

129

Depression and its

Treatment

Audrey Coker

Senior Psychiatry Pharmacist

130

Contents

Introduction

Causes

Principles of treatment

Choice of drug

Drugs used

131

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

132

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.

133

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.

134

Principles of treatment

1) Eliminate contributory causes

e.g. other drugs, excessive caffeine intake, physical causes such as anaemia and hypothyroidism.

135

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.

136

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.

137

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.

138

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

139

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

140

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.

141

Side Effects of SSRIs

Insomnia.

Agitation.

Dystonia – paroxetine.

Increased risk of bleeding. This is additvie to that produced by aspirin and NSAIDs.

Sexual dysfunction.

142

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.

143

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.

144

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.

145

Side effects of TCAs

Anticholinergic side effects.

Arrhythmogenic properties.

Hypotension.

Drowsiness.

Sexual dysfunction.

146

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.

147

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.

148

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?

149

Serotonin Syndrome

May occur when two antidepressants are administered together.

May occur when crosstapering.

Other concurrent drugs may cause it e.g. tramadol.

150

Serotonin Syndrome

Restlessness.

Tremor.

Shivering.

Myoclonus.

Confusion.

Convulsions.

Death.

151

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.

152

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.

153

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.

154

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.

155

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.

156

St John’s Wort

May be effective in mild to moderate depression only.

Active component not yet determined.

Uncertainty about therapeutic dose.

157

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.

158

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.

159

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.

160

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.