Module 1.5.2 (Management of Schizophrenia)

Question 1

What are 1st gen and 2nd gen antipsychotics

Answer 1

Question 2

What are high potency 1st gen antipsychotics?

↑EPSE ↓ Sedation ↓ orthostatic hypotension ↓ anticholinergic side effects

Answer 2

Droperidol Flupentixol Haloperidol Trifluoperazine Zuclopenthixol

Question 3

What are low potency 1st gen antipsychotics?

↓EPSE ↑sedation ↑ orthostatic hypotension ↑ anticholinergic side effects

Answer 3

Chlorpromazine and Pericyazine

Question 4

What to do if EPSE occurs?

Answer 4

ideally reduce antipsychotic dose or switch to alternative antipsychotic

Question 5

What treatment for the following EPSE?

A) Dystonias - stiffness, uncontrolled muscular spasms

B) Akathisia - inner restlessness, strong desire or compulsion to move

C) Parkinsonism - tremor and/or rigidity, mask- like face, shuffling gait, slow movements

D) Tardive Dyskinesia - involuntary abnormal movements of face, tongue, lips, hands or feet

Answer 5

A)

benzatropine (oral, inj), trihexyphenidyl (benzhexol)

B)

propranolol, clonazepam

C)

benzatropine, trihexyphenidyl

D)

Can be irreversible. Stop antipsychotic (preferred)

Treatment poor efficacy – tetrabenazine, Ginkgo biloba

anticholinergic MOA: Antagonizes acetylcholine and histamine receptors.it reduces the cholinergic effects significantly during Parkinson disease which becomes more pronounced in the nigrostriatal tract because of reduced dopamine concentrations.

Question 6

What is first line treatment in schizophrenia?

Answer 6

2nd Generation Antipsychotics (SGAs)

• More metabolic adverse effects
• More expensive

Question 7

How does cloazapine differ from other side effects of SGAs?

Answer 7

Increased sedation, weight gain and anticholinergic effects

Question 8

Pharmacalogy of aripiprazole? What is it used to agument?

Answer 8

Is a dopamine system stabiliser (increased dopamine output when conc are low and decreased dopamine output when conc. are high)

• Less sedation, weight gain and prolactin elevation
• Good 1st choice antipsychotic
• Doesn’t provide sedation if patient acutely unwell
• May cause insomnia, akathisia and/or activation

> Often used to augment other antipsychotics

To reduce weight gain – e.g. clozapine, olanzapine

To reduce prolactin – e.g. risperidone

Question 9

Pharmacology of brexpiprazole

Answer 9

Indicated only in schizophrenia

May have positive effects on mood

Well tolerated – little weight gain, prolactin elevation, akathisia

> best evidence of no EPSE side effects

Question 10

Pharmaclogy of lurasidone

Answer 10

Take with food to increase absorption

Low incidence weight gain, small rise in prolactin

Theorised to improve mood & be useful in bipolar

Reports of increased irritability/rage

Question 11

Pharmacology of olanzapine

Answer 11

Sedating – may be beneficial in acute psychosis

WEIGHT GAIN +++

• Metabolic syndrome major concern. For this reason falling out of favour as long term treatment

Question 12

Pharmacology of paliperidone

Answer 12

• 9-hydroxyrisperidone
• Active metabolite of risperidone
• Similar adverse effects to risperidone

Swallow tablets whole –> Cannot be halved, crushed –> Empty tablet may appear in stools

• always with food, or always on an empty stomach
• Oral not commonly used, but depot very common

Question 13

Pharmacology of Quietiapine

Answer 13

Commonly used antipsychotic

• Prone to abuse – watch for doctor shopping and picking up supply earlyn
• More sedating at lower doses
• To get antipsychotic effect, some patients require higher dose

Question 14

Pharmacology of risperidone

Answer 14

Adverse effects:

• Prolactin elevation – can be severe and problematic
• EPSE – dose related

cheaper than most SGAs

Question 15

Pharmacology of Amisulpride? How does its MOA change from low to higher doses?

Answer 15

Indicated for treatment of schizophrenia

• At low doses (50-300mg) it is more effective for negative symptoms
• At higher doses (400-800mg) it is more effective for positive symptoms
• Not metabolised in the liver; reduce dose in renal impairment
• Dose-related EPSE & hyperprolactinemia

Question 16

Pharmacology of Asenapine

Answer 16

Rarely used

Sublingual wafer –> do not eat or drink for 10 minutes after taking –> take after all other medications –> poor absorption if swallowed

• Tastes awful!! Makes mouth numb/tingly up to 1 hour after taking

Question 17

Pharmacology of Ziprasidone

Answer 17

Can cause QT prolongation, increase risk of arrythmia – monitor ECG

Little weight gain, prolactin elevation & sedation

Question 18

Clozapine pharmacology? Why is it not 1st line?

Answer 18

• The most effective antipsychotic
• 50% of non-responders will improve with clozapine
• Particularly effective for negative symptoms

Not 1st line due to serious adverse effects (Immune mediated, rather than dose-dependent)

• Agranulocytosis
• Neutropenia
• Cardiomyopathy
• Myocarditis
• Gastrointestinal Hypomotility – i.e. constipation = highest risk of mortality

Question 19

Why is clozapine more effective than all other antipsychotic agents?

Answer 19

Clozapine differs from other neuroleptics by antagonising D1, D2 and D4 dopamine receptors, with less affinity for D2 receptors, so it is less apt to induce extrapyramidal side effects.

Clozapine also antagonises 5-HT2, α1-adrenoreceptors and histamine H1 receptors –> It has been suggested it is more effective than all other antipsychotics, particularly in the treatment of negative symptoms or in treatment resistant patients

Question 20

What is the condition of clozapine being used?

Answer 20

Must have trialled ≥2 antipsychotics prior to clozapine initiation

• Not effective or not tolerated
• At least 1 must be atypical antipsychotic

Question 21

What is done before treatment of clozapine can be done (monitoring)?

Answer 21

Monitoring systems record WCC and neutrophil count

• Clopine Connect
• Clozaril Patient Monitoring Service

Pre-treatment

• FBP, CRP, troponin, ECG, echocardiogram ( pregnancy test)
• Desired: LFTs, U&Es, lipids, weight, BSL/HbA1c, weight, waist circumferance,

Question 22

What ongoing monitoring for clozapine?

Answer 22

Ongoing monitoring. Medication only supplied until next blood test

• FBP weekly for first 18 weeks
• CRP, troponin weekly for 4 weeks

> Monthly (every 4 weeks) thereafter

Question 23

Clozapine dosing/drug concentration

Answer 23

Slow dose titration to avoid/reduce dose dependent adverse effects

• Target drug concentration: 350-1000mcg/L

Question 24

For clozapine;

A) What to use to treat hypersalivation

B) What to use to treat GI hypomotility (constiaption)

Answer 24

A)

• Atropine 1% eye drops sublingually
• Hyoscine wafers
• Ipratropium MDI sublingually
• Moclobemide, metoclopramide

B)

• Macrogol first line and BE AGGRESSIVE!
• Docusate/senna first line for prophylaxis

Question 25

Why is medication used in acute agitation and arousal in patients with schizophrenia? What drugs to use?

Answer 25

Medication is used to calm/lightly sedate the patient and reduce the risk to self and/or others \> Verbal de-escalation * Oral benzodiazepine (lorazepam, clonazepam, diazepam) * Oral antipsychotic (olanzapine, risperidone, quetiapine, haloperidol) * IM medication (lorazepam, olanazapine, ziprasidone, haloperidol, droperidol, midazolam, clonazepam) * IV med --\> used in EDs, not used in psychiatric inpatient wards

Question 26

Outline why certain IM medication is not used for acute agitation. Which one is preferred?

Answer 26

M diazepam not recommended as absorption is poor & erratic IM chlorpromazine not recommended due to risk of abscess formation & catastrophic hypotension IM clonazepam not an approved route of administration – absorption erratic \> **IM lorazepam available under SAS – more predictable absorption & effect --\> refrigerate, 3 months shelf life once out of fridge**

Question 27

What is needed when benzodiazepines used IM/IV? When to use?

Answer 27

Have flumazenil available when benzodiazepines used IM/IV * Use if respiratory rate falls below 10/minute * Caution in patient with epilepsy & on long term benzos * Has short half life (shorter than diazepam) so respiratory function may recover then deteriorate again

Question 28

Pharmacology of Zuclopenthixol acetate. When are they used?

Answer 28

* NOT a rapid tranquilising agent * Can only be written as a stat dos * **Used if other short-acting treatment options for acute agitation and arousal have been ineffective** * IM administration. Intermediate-acting injection. * Not for long-term use. Duration of Tx cannot exceed 2 weeks, 400mg or 4 injections * Max conc at about 8 hours. Effects persist for 3 days \> Paroxetine and fluoxetine are known potent inhibitors of CYP2D6, and these SSRIs apparently reduce zuclopenthixol metabolism --\> increase AE of zuclopenthixiol \> Raised zuclopenthixol concentrations with the addition of fluoxetine may also increase the risk of adverse events such as movement disorders and increased risk of QT prolongation. It is also possible that the risk is greater due to additive, similar side effects.

Question 29

When is long acting (depot) antipsychotics used? How is it used?

Answer 29

Antipsychotic long-acting injections (LAIs) used where non-adherence to oral treatment is problematic, or patient prefers this formulation type Deep intramuscular injection (gluteal or deltoid) Medication slowly released into bloodstream, providing steady supply of medication. LAIs do not ensure adherence: they assure awareness of adherence Allow regular assessment of patient (due to regular injections)

Question 30

Advantages and disadvantages of LAI antipsychotics?

Answer 30

**Advantages** Proven reduction in relapse Improved adherence Fewer hospitalisations Less fluctuation in drug concentration Regular contact with clinicians Less risk of overdose Avoids first pass metabolism **Disadvantages** Pain at injection site Cannot be withdrawn quickly (E.g. side effects) Patient loses control of treatment Less dosing flexibility Monitoring required (olanzapine)

Question 31

How is LAI antipsychotics formulated? Where is it injected?

Answer 31

All fomulated in oil Test doses required to test tolerability to antipsychotic and oil --\> Regular dosing commence 4-10 days after test dose * • Injected into gluteal muscle sometimes deltoid

Question 32

Pharmacology of paliperidone palmitate? Strengths: 25mg, 50mg, 75mg, 100mg, 150mg

Answer 32

once monthly (every 4 weeks) --\> **IM** * Must trial oral risperidone or paliperidone prior to initiation --\> To test tolerability to medication * Two initiation doses, so oral administration not required once injection has commenced. * Deltoid gives approx 28% higher peak concentration

Question 33

Pharmacology of paliperidone palmitate? Strengths: 175mg, 263mg, 350mg, 525mg

Answer 33

3-monthly injection Deltoid or gluteal muscle **For patients who are clinically stable on paliperidone 1-monthly for at least 4 months** Recommended the last two injections are same dose \> Give the 1st dose in place of next 1-monthly injection

Question 34

Pharmacology of risperidone

Answer 34

First SGA long-acting injection Refrigerate. Remove from fridge 30 minutes prior to admin Risperidone coated in polymer to form microspheres Must be suspended in aqueous base immediately before use Test dose of oral risperidone Requires oral treatment (full dose) for 3-4 weeks Takes 3-4 weeks for 1st injection to produce therapeutic plasma levels

Question 35

Pharmacology of aripiprazole LAI?

Answer 35

Gluteal or deltoid muscle Oral test doses of aripiprazole Oral antipsychotic required for 14 days after LAI is commenced Indicated for treatment of: * Schizophrenia * BPAD – maintenance treatment (not PBS) Favourable metabolic and prolactin-sparing effects

Question 36

What is post injection syndrome? What are the symptoms? What type of IM drug does it occur in? How to prevent it?

Answer 36

Post-injection syndrome (PIS) presents with signs and symptoms of olanzapine overdose * Sedation (mild to coma), delirium, dizziness, agitation, hypotension, weakness, confusion \> Possibly due to inadvertent intravascular injection (more soluble in blood than muscle) * **The risk is present for every injection of olanzapine pamoate --\>** maintenance treatment of schizophrenia * Deep IM GLUTEAL site only --\> less vascular than deltoid * Must monitor for 2 HOURS after every injection * Visual, have conversation every 30 minutes * Cannot drive for rest of the day

Question 37

All antipsychotics can reduce the seizure threshold/ What antipsychotics to avoid?

Answer 37

Clozapine, chlorpromazine – most epileptogenic \> Depot antipsychotics – cannot be withdrawn

Question 38

What are the effects of smoking and smoking cessation with antipsychotics?

Answer 38

Cigarette smoking induces CYP1A2 * Reduces plasma levels of drugs eg BZD, clozapine, olanzapine * Significant effects with clozapine and olanzapine Smoking cessation --\> increased drug plasma levels --\> consider dose reduction

Question 39

What to use for smoking cessation?

Answer 39

NRT has been used effectively for smoking cessation * But does not affect CYP enzymes \> Varenicline – Champix® - pschiatric adverse effects reported, but can be used with careful monitoring \> Bupropion – Zyban® - not routinely used in psychiatric setting. Lowers seizure threshold

Question 40

What are effects of caffeine on antipsychotic drugs?

Answer 40

Patients with mental illness have been reported to drink large amounts of caffeinated drinks * Caffeine can increase drug levels --\> possibly due to competitive CYP1A2 inhibition

Question 41

Why does NMS occur (Neuroleptic Malignant Syndrome)?

Answer 41

Thought to be due to a sudden over-blockade of dopaminergic function * A very rare life-threatening syndrome that can occur with any antipsychotic medication **antipsychotics that act on stronger dopamine receptors**

Question 42

Symptoms of NMS (Neuroleptic Malignant Syndrome)? How to treat?

Answer 42

Characterised by fever, muscle stiffness, altered consciousness and problems with the autonomic nervous system * Can be fatal if left untreated * Treatment is symptomatic and antipsychotic should be ceased

Question 43

Concerns with elderly patients?

Answer 43

More susceptible to adverse effects including EPSE and TD Lower starting doses of medications are used There is some concern that olanzapine and risperidone may increase the chance of a stroke Elderly patients more likely to have other illness or be on other medications

Question 44

How to deal with side effects A) Akathisia B) Sedation C) nausea D) constipation some more not relate to questions above **Weight gain – combination of good diet and exercise – prevention better than treatment** **metformin can reduce weight gain** **Augmentation with aripiprazole --\> can reduce weight gain**

Answer 44

A) stretching & exercise B) take medication at night (if once daily dose) e.g. clozapine small dose in morning and large dose at night C) take with or after food D) balanced diet, increase fibre and fluid intake Coloxyl & Senna, Movicol