psychotic disorders, antipsychotic agents and their SE, Clozapine

What is psychosis?

- Loss of contact with reality.

- Severe disturbances in emotions, thinking and behaviour

FIVE DOMAINS

- Delusions

- Hallucinations

- Disorganized thinking & speech

- Disorganized/ abnormal behavior

- Negative symptoms

key types of psychotic disorders

Schizophrenia, schizoaffective disorder, substance/medication-induced psychotic disorder, brief psychotic disorder.

What is schizophrenia?

Chronic disabling mental illness characterized by disordered/change in mental function, thoughts, and perceptions.

- High rate of suicide and orther mental illness co-morbidities

What is the epidemiology of schizophrenia?

7 in 1000 people are affected, males are more likely to develop it, women have later onset (protective onset of estrogen- hypothesis)

What are some possible factors contributing to schizophrenia?

- Genetic vulnerability, developmental stressors

- Family history esp immediate family with mental health history

- Cannabis use

Other possible factors: maternal health, nutrition, infection, pregnancy and birth complications, place of birth, socioeconomic factors.

What is the dopamine hypothesis of schizophrenia?

Schizophrenia is caused by dopaminergic (DA) neuron overactivity. DA antagonists reduce anxiety, agitation, hallucinations. Evidence of abnormalities in the prefrontal cerebral cortex and increased DA receptor occupancy in schizophrenia.

positive symptoms of schizophrenia (overactive functioning)

- Hallucinations: false perception involving any of the five senses

- Delusions: false beliefs

- Disorganised thinking, speech or behaviour

TX: AP

negative symptoms of schizophrenia (loss of functioning)

- Avolition/apathy: lack of motivation

- Poor self care

- Blunted affect or inappropriate emotions

- Alogia: reduced speech output

- Anhedonia: loss of capacity for pleasure

- Social withdrawal

TX: NO PROVEN DRUG TX

Often harder to treat

Often 1st symptom to appear

Can occur at all stages of illness

Associated with long-term disability & poor functional outcomes

cognitive deficits of schizophrenia

- Impaired executive functioning: poor planning or problem solving

- Impaired memory and ability to concentrate

- Reduced mental flexibility

- Lack of insight

TX: NO PROVEN DRUG TX

diagnosis of Schizophrenia (DSM-V criteria)

2 present for a significant portion of time during 1-month period (at least one must be (1), (2), or (3):

1. Delusions

2. Hallucinations

3. Disorganized speech (e.g., frequent derailment or incoherence)

4. Grossly disorganized or catatonic behaviour

5. Negative symptoms (i.e., diminished emotional expression)

- Level of functioning in key areas below achieved prior to onset, for sig. portion of time

- Continuous signs of disturbance for at least 6 mths (with 1 mth active Sx)

- Other causes ruled out

What is the dopamine hypothesis of schizophrenia?

- Schizophrenia caused by overactivity of DA neurones

- DA hypothesis: DA antagonists (All APs) can reduce anxiety, agitation & hallucinations associated with psychoses

Evidence:

- all antipsychotics are DA antagonists:

reduce anxiety, agitation, hallucinations

- Amphetamine increases DA availability -> psychosis-like effect

-Imaging studies: increased DA receptor occupancy in schizophrenia

- evidence of brain abnormalities in the hippocampus and prefrontal cerebral cortex

Dopaminergic pathways in the brain

- Mesolimbic pathway:

overactivity of DA neurons mediate positive symptoms

- Mesocortical pathway deficient mediate negative symptoms

- Mesocortical and Mesolimbic: in some pt, there is an increase of DA levels in Mesolimbic but DA deficient in Mesocortical at the same time

- Nigrostriatal: involved in movement and run from the substantia nigra to the basal ganglia

- Tuberoinfundibular: reside in the hyppothalamus and plays a role in secretion of prolatin

- Dopamine balance in different pathways of the brain may be related to diffrent symptoms, cognitive symptoms are not related to DA at all

flaws of DA hypothesis in schizophrenia

- Antagonism of DA does not fully alleviate symptoms

- DA levels /metabolites /receptors are within normal limits in patients

- DA in the brain is more complex than a switch for psychotic symptoms.

What is the glutamate hypothesis of schizophrenia?

Schizophrenia is caused by NMDA receptor underactivity. (NMDA is a receptor of glutamate, the main excitatory neurotransmitter)

- PCP, an NMDA receptor antagonist, can induce psychosis-like effects.

- ↓ gene expression of messenger RNA for NMDA receptors

- Reduced glutamate in spinal cord

What are the diagnostic criteria for schizophrenia according to DSM?

Presence of at least 2 (positive/negative) symptoms for a significant portion of time during a 1-month period - where at least 1 symptom is positive

What are the consequences of schizophrenia?

Lifelong condition, significant impact on work, study, and relationships, high stigma, high rates of self-harm, and distressing for both individual and family.

What are the phases/episodes of schizophrenia?

Premorbid phase (at risk), prodromal phase (early signs and symptoms), acute psychotic phase (unwell), and recovery. RELAPSE

1) Premorbid - before onset, person at risk or showing subtle signs

2) Prodromal - early signs and symptoms

3) Acute Psychotic - acutely unwell: most severe symptoms - the acute/active phase

4) Recovery - periods of improvement in symptoms and functioning

5) Relapse - recurrence of symptoms after a period of improvement/stabilisation

Prognosis of Schizophrenia

1/3 respond to treatment with few residual side effects

1/3 continue to be functionally impaired

1/3 remain psychotic with increased hospitalization, homelessness, suicide, self-harm.

Management for schizophrenia

AIM: Reduce relapse/maintain maximum functional remission.

- increase quality of life

- better integration into society

- reduce hospitalization, suicide rate, substance abuse, social alienation, victimization, unemployment, incarceration, economic burden.

OPTIONS

- Medications (antipsychotics, mood stabilizers, antidepressants)

- Psychoeducation & psychotherapy (e.g. CBT)

- Family & social supports, housing & vocation support

- Public mental health services.

antipsychotic MOA

POSSIBLY: block D2 receptors in brain

- Mesolimbic pathway: positive symptoms

- Mesocortical pathway: negative symptoms

- Nigrostriatal pathway: antagonism of postsynaptic DA EPSE risk (long term blockade ->Tardive Dyskinesia)

- Tuberoinfundibular pathway: ↑ prolactin, endocrine AE

- Differential blockade of other dopamine receptors

- Antagonism of other receptors eg 5HT2 (improve negative symptoms)

- M-receptors antagonists (anticholinergic ADRs)

- ⍺-adrenergic antagonists (postural hypotension)

Anticholinergic for EPSE

Reasoning: EPSE is due to decrease DA and increase Ach creating imbalance

In the nigrostriatal pathway: DA neurons make post synaptic connections with the cholinergic neurons

DA is down at post synaptic receptor -> lillte acetyl choline being released on the other end -> D2 antagonism leads to increase of acetyl choline in post synaptic cleft (complex)

Anticholinergics: benztropine: selective M1 Ach antagonist, partially block cholinergic activity in the basal ganglia, increase DA availability and dopaminergic activity

Neuroleptic induced deficit syndrome

in the Mesocortical pathway:

antagonism of DA receptors leads to emotional blunting and cognitive SE

Neuroleptic induced deficit syndrome: apathy (no interest), lack of initiative, anhedonia (no joy), indifference (no concern), blunted affect

-> increase negative symptoms

typical antipsychotic (1st gen, conventional)

PUTATIVE D2 ANTAGONISTS

Chlorpromazine (tab)

Droperidol (IM)

Flupentixol (LAI)

Haloperidol (tab, IM, LAI)

Periciazine (tab)

Trifluoperazine (tab)

Zuclopenthixol (tab, IM, LAI)

atypical antipsychotic (2nd gen, serotonin dopamine antagonists (SDA)) (3rd gen)

Atypical/SGA (D2/5-HT2A antagonists)

Amisulpride (liquid)

Aripiprazole (LAI)

Asenapine (wafer)

Brexpiprazole

Cariprazine

Clozapine (liquid)

Lurasidone

Olanzapine (wafers, IM, LAI)

Paliperidone (IM)

Quetiapine (XR)

Risperidone (IM, LAI, liquid)

Ziprasidone

NOTE:

Aripiprazole, cariprazine, prexipiprazole are also considered THIRD GEN

- partial D2 and 5-HT1A agonist, 5-HT2A and 5HT1B antagonist

Serotonin dopamine antagonists (SDA) MOA (2nd gen antipsychotic)

Antagonism of D2 receptors

- Reduce negative symptoms via antagonism of 5HT2a receptors

- 5HT opposes Da in the nigrostriatal and tuberoinfundibular pathways

- Decrease EPSE/tardive dyskinesia SE

- Some do not increase prolactin

SGA/SDA action on the mesocortical pathways

1. 5HT excess in mesocortical pathway leads to Da deficiency

2. SGAs selectively increase Da conc in mesocortical pathway

3. Reduced negative symptoms (oh wow amazing)

SGA/SDA action on the nigrostriatal pathways

1. 5HT regulates Da release: no 5HT at 5HT2a -> Da released

2. 5HT binds to 5HT2a receptors -> no Da

3. SGAs antagonise 5HT2 -> no more 5HT binding -> Da released

4. Da then competes with SGA for D2 receptors, reversing antagonism

- yay no EPSEs, drug doesnt get to bind too much to Da receptors

1st gen does not exhibit antagonism of 5HT2 therefore EPSE

rationale for antipsychotic use

- relief of symptoms such as hallucinations, deluions or abnormal behaviour/ thoughts

- sedative and tranquillising effects in very disturbed or aggressive pt

- help prevent relapse and keep pt well

treatment regimen for antipsychotic (UK)

1. Start on 2nd gen antipsychotic. Generally will also agree on choice of antipsychotic with pt or carer

2. Titrate to minimum effective dose

3. Adjust dose according to response and tolerability over 2-3 weeks

4a. if not effective, change drug and follow 1-3. Consider 2nd or 1st gen

4b. if not tolerated or poor compliance: discuss with pt and change drug

5. from 4a, if not effective, use clozapine (2nd gen). early use much more likely to be successful compared to anything else.

Treatment for first episode psychosis (AUs)

1. Psychiatric and physical assessment. no antipsychotics yet, can add benzos for symptoms control:

- Agitation/agression: diazepam

- Anxiety: lorazepam

- Sleep disturbances: temazepam

Differential diagnosis: bipolar 1 with psychotic features, major depressive disorder with psychotic features

2. Start low, go slow

1st choices:

- Amisulpride: start 50-100 mg/d, initial target dose 3-400mg d, highest dose 800mg/d

- Aripiprazole: start 5-10 mg/d, initial target dose 15-20mg d, highest dose 30mg/d

- Quetiapine: start 25-50 mg/d, initial target dose 3-400mg d, highest dose 750mg/d

- Risperidone: start 0.5-1 mg/d, initial target dose 2-3mg d, highest dose 6mg/d

- Ziprasidone: start 20-40 mg/d, initial target dose 80-120mg d, highest dose 160mg/d

no no for 1st choice: clozapine (reserved for treatment resistance Schiz), olanzapine (significant weight gain)

3a. if insufficient response after 3 weeks: increase dose over 2-3 weeks

3b. non-response 6-8 weeks: cross over switch to another SGA

3c. non-responsive to 2nd SGA -> consider olanzapine or clozapine

Consider non-adherence

4. Continue for at least 2-5 years

For which are antipsychotic drugs often effective?

- Positive symptoms: delusions, halucinations

- Disorganisation: speech, behaviour

- Mood symptoms are treated with antidepressants, mood stabilizers, and antipsychotics

* Negative and cognitive deficits are harder to treat as they dont response to pharmacological treatment.

Adverse Effects of antipsychotics (listing)

Extrapyramidal SE (EPSEs) - Dystonia, Akathisia, Parkinsonism, Tardive Dyskinesia

Sedation

Weight gain

Dyslipidaemia

Hypersalivation

Orthostatic hypotension

QT interval prolongation

Anticholinergic effects (to be further explained)

Sexual dysfunction

Blood dyscrasias

Antipsychotic SE (elaborating)

Antagonism of muscarinic cholinergic receptors (M1): constipation, blurred vision, dry mouth, sedation, incontinence

Antagonism of H1 receptors: weight gain, sedation. The greater affinity to H1, the more pronounce SE

Antagonism of adrenergic receptors (a1): orthostatic (postural) hypotension, dizziness, sedation

Extrapyramidal Side Effects (EPSEs) (Schizophrenia)

A) Acute Dystonic Reactions: sustained, increased muscle tone/spasm.

- Dose related

- Greatest risk in 1st gen

- Young male at increase risk

- Tx - benztropine IM/IV

B) Parkinsonism: Tremor, bradykinesia, rigidity

- FGA, occurs early in tx, some SGA (Paliperidone, risperidone)

- Treat with benztropine or benzhexol po (Cease after weeks)

C) Akathisia - Unpleasant state of motor restlessness & agitation:

- Can cause insomnia

- Associated with increased suicide risk

- flupenthixol, fluphenazine, zuclopenthixol, haloperidol (FGA)

- Reduce dose, switch agent, anticholinergic +/- alternate pharmacotherapy

D) Tardive Dyskinesia: Involuntary repetitive shaking that persist/ worsen after drug ceased

- Prevention and early detection essential

- FGA (esp LAIs) but can occur with SGA

- Withdraw causative drug, switch agent (clozapine, quetiapine > olanzapine, aripiprazole), adjunctive pharmacotherapy (benzos,propranolol, ?vitamin E)

in 1st gen: More sedating -> least EPSEs

Hyperprolactinemia in antipsychotic

amisulpride, quetiapine, risperidone, paliperidone

D2 receptor antagonism (in tuberoinfundibular) -> ↑ prolactin elevation -> inhibit GnRH and therefore oestrogen & progesterone release -> galactorrhoea (milk production in both men and women), amenorrhoea (absent of menses), gynaecomastia (swollen breast tissue in men), impotence (inability to achieve an erection)

- Common and neglected adverse effect (45% men, 75% women)

- Avoid use if <25 yrs, history of Hr+ Breast Cancer

Monitor:

- Actively ask pt about symptoms every 3 months and monitor prolactin levels

- Treat based of symptoms and long term risk

- Dose reduction, switch agent, add aripiprazole ( ↓ prolactin)

- Contraception (COCP or other) in women of fertile

age with amenorrhoea 1y duration

- ?Da receptor agonist: can worsen psychosis

Neuroleptic Malignant Syndrome (antipsychotics)

EMERGENCY!!!!

- Rare (0.5-1%) but potentially fatal, especially in 1st gen

- Develops anytime during treatment, esp in high or rapidly increasing doses

Symptoms: high temp (>38.5°C), muscle rigidity, confusion, altered consciousness, autonomic instability (unstable pulse & BP), raised WBC, raised creatinine kinase (from muscle breakdown), dehydration, cardiac arrest, liver failure, death

Sedation/CNS depression in antipsychotics

- Greatest with initiation and dose titration

- Effects often temporary → reassure will decrease over 1-2 weeks

- Greatest with chlorpromazine, clozapine > olanzapine, quetiapine

- Least with aripiprazole, brexpiprazole, cariprazine

Anticholinergic effects in antipsychotics

- Sedation, tachycardia, dry mouth,

blurred vision, confusion, retention,

constipation

- Greatest with chlorpromazine,

clozapine > olanzapine > haloperidol,

quetiapine

- Depending on adverse effect may opt to treat, reduce dose or switch agen

Orthostatic (postural) hypotension in antipsychotics

- All antagonise postsynaptic ∝1 receptors → postural hypotension

- Upon initiation, subsides within a few days

- Consider age, concurrent medications

- Greatest with chlorpromazine, clozapine > paliperidone, quetiapine, risperidone

- If severe or persisting cease and switch to: aripiprazole, amisulpride, trifluoperazine

sexual dysfunction (antipsychotics)

30-60% of patients

Influenced by:

- Pharmacology- receptor binding,

passage across BBB, metabolites

- Other- eg. sedation, effect on T/prolactin

Reduce dose, switch agent

(prolactin sparing), add PDE5I

cardiometabolic effects side effects (antipsychotics)

Dyslipidaemia, weight gain, Diabetes Mellitus & impaired glucose tolerance , hypertension

- Metabolic syndrome in ~50% patients with psychosis

- Consider weight, CVD risk, fHx DM/hypertension, smoking

- Clozapine, olanzapine > chlorpromazine, quetiapine> paliperidone,risperidone

- Most favourable: aripiprazole, brexpiprazole, cariprazine, lurasidone,ziprasidone

- Monitor: weight, BMI, waist circumference, BP, fBSL/HBA1c, lipids

- Other: education (lifestyle, diet, smoking cessation)

Dyslipidemia (antipsychotics)

Phenothiazines ↑Triglycerides (TG) & LDLC, ↓HDLC

- Atypicals have the most profound effect on TG

Clozapine: after 5y Rx, TG double & TC ↑10%

Olanzapine: ↑TG in ~2/3 patients; 40% ↑TG over 3-4/12; 5x risk ↑TG cf conventional agents

- Olanzapine > risperidone, quetiapine > aripiprazole, ziprasidone

- Monitor: ↑ freq if clozapine, olanzapine, quetiapine, phenothiazines

- Treatment includes switch agent (aripiprazole), dietary advice/lifestyle changes, statin if TC >4mmol/L or fish oil/fibrates to ↑ TG

Weight gain (antipsychotics)

- Concerning ADR for patients and clinicians

Due to appetite stimulation:

- H1 antagonism induces appetite stimulation through effects athypothalamic sites

- 5HT2C antagonism promotes weight gain for drugs with highH1 affinity (but not without)

- Little evidence is due to ↓ activity or sedation

- Monitor weight, BMI & waist circumference + behavioural interventions

- Switch to weight neutral agent (aripiprazole, ziprasidone)

- Pharmacotherapy: metformin, GLP-1 agonists (exenatide,liraglutide), samidorphan

Diabetes Mellitus & impaired glucose tolerance

QT prolongation (antipsychotics)

Blockade of cardiac K channels → QT prolongation, MAY increase risk of ventricular arrhythmia torsade de pointes (TdP)

- Differences between antipsychotics on QT are rarelystatistically significant

- Likely dose related, but absolute risk is low

- QT measurement complicated by: Physiological variation, variation in [drug]

- Highest risk for haloperidol, amisulpride, ziprasidone

- Risk factors: cardiac, metabolic, other meds: antibiotics, antiarrhythmics, antimalarials, CYPs that may ↑ conc of drugs that affect QT

Monitor:

- Lowest effective dose, avoid polypharmacy and PK that ↑ risk

- Monitor serial ECGs, especially on starting.

- Smoking, obesity and impaired glucose tolerance increase the risk of arrhythmia/ sudden cardiac death MORE than QT changes

SGA less potential for weight gain (3)

Asenapine: less potential for sedation

Ziprasidone: may prolong QT interval

Amisulpride: less sedation, prolong QT also, hyperprolactinaemia may be a problem

SGA less potential for hyperprolactinaemia (4)

Aripiprazole may decrease it, may cause insomnia

quetiapine: sedating, moderate weight gain, vasoactive

Brexipiprazole, cariprazine.

SGA with weight gain potential (3)

Quetiapine: moderate

Clozapine: serious ADR

- blood dyscrasias, seizures, orthostatic hypotension, sedation, myocarditis, cardiomyopathy

Olanzapine: sedation, oedema, dislipidaemia, increase blood glucose

SGA with hyperprolactinaemia potential (3)

amisulpride

risperidone, paliperidone: increase risk of stroke, sexual/ ejaculatory problems, hypotension

Antipsychotic practicepoint

- Lowest dose possible should be used

- Use a single antipsychotic

- SHOULD NOT be used as "prn" sedative

- Need close monitoring (BP, pulse ECG, glucose, lipids, weight, FBC, urea, electrolytes, prolactin, CK, LFTs)

Long-Acting Injectable 1st Gen Antipsychotics

- 1st gen (FGA) LAIs are esters of common FGAs with long chain fatty acids

- Once esterified they become fat soluble and can be dissolved in oils such as sesame oil

- Delivered by deep IM injection. Pain at inj site

- Slow onset: months to reach steady state and slow elimination period

- FGA LAIs: fluphenazine,flupentixol, zuclopenthixol, haloperidol

- Approximate equivalent doses of some LAIs:

flupentixol 40 mg every 2 weeks

haloperidol 100 mg every 4 weeks

zuclopenthixol 200 mg every 2 weeks

2nd Gen LAIs

Risperidone 1st developed

- Microsphere delivery rather than oil-based with FGAs

- Faster onset

-FGAs caused muscle pain at injection site, SGAs do not

- Some have lag time, oral supplementation required (e.grisperidone), others work from Day 1 (e.g. paliperidone)

- Gluteal or deltoid muscle injection

- Dose range varies fortnightly to 6 monthly

Antipsychotic LAIs practice points

- For chronic treatment and once stable on oral

- Useful when pt is forgetful or non-adherent

- Monitor carefully for ADR and effectiveness

Why is Olanzapine LAI not recommended

- Olanzapine LAI comes in the salt form pamoate, which is a poorly soluble salt of olanzapine

- Risk of post injection syndrome (dizziness, weakness, altered speech, hypertension)

- Given 2-4 weekly but has a complicated dosing regimen

Role of LAIs in Schizophrenia

- May help with persistent non-adherence

- For persistent symptoms: disorganisation, cognitive impairment, lack of community support

- May be a requirement as part of hospital discharge order, involuntary pt (ethical cocerns)

- Pt unable to take oral med

Switching antipsychotic agents

- Common to switch due to AE or poor response

- Non-acute: Slow cross-taper over 1-4 weeks + adjuncts

- Lag time when switching from LAI to oral - caution

WATCH FOR:

- Movement disorders

- Increased risk of pregnancy

- Cholinergic rebound symptoms

- Activation syndrome

- Changes in QT interval

Anticipate problems - withdrawal/discontinuation, AEs

Patient education (time lag & problems) to not compromise adherence

5 problems with switching antipsychotics

Problems...

DOPAMINERGIC REBOUND - Replacing high D2 affinity drug with low D2 affinity drug, rapid dissociation drug or partial D2 agonist (eg haloperidol to aripiprazole) = ↑ risk psychosis, implications for EPS

CHOLINERGIC REBOUND - Replace high affinity cholinergic antagonist with low affinity drug (eg chlorpromazine to ziprasidone) = Flu-like syndrome: malaise, myalgia, runny nose, vomiting/diarrhoea, sweating, insomnia, agitation

HISTAMINERGIC REBOUND - Replacing high affinity histamine antagonist with low affinity drug = ↓ sedation, rebound insomnia, ↓ weight gain

ACTIVATION SYNDROME - Initiating less sedating agent (aripiprazole, amisulpride) = Restless overactivity, insomnia, N&V

↓ PROLACTIN LEVELS DURING SWITCHING = ↑ risk unplanned pregnancy due to ↓ blood [prolactin]

• Switching from amisulpride, paliperidone, risperidone

• Ensure adequate contraception

Use of antipsychotic in females of childbearing age

- Pregnancy does not protect against relapse

- Risk vs benefit discussed

- Avoid abrupt cessation of meds upon discovering pregnancy

- Discuss contraception as many psychotropic meds cross placenta

- Some AP increase blood prolactin conc and reduce fertility (risperidone, amisulpride) -> risk of pregnancy increase if ceased

- Avoid switching agents during pregnancy

- Use AP with most safety data (clozapine, haloperidol, olanzapine, quetiapine, risperidone)

- Little data available: amisulpride, aripiprazole, chlorpromazine, periciazine, ziprasidone, zuclopenthixol

- No published data on others: asenapine, brexpiprazole, lurasidone, paliperidone

- Taking APs during pregnancy: monitor for excessive weight gain and gestational diabetes

Adherence with antipsychotics

Poor adherence = relapse

- Each relapse/new episode has further cognitive impacts

- 4-fold ↑ suicide risk

- Even partial adherence increases relapse risk (i.e. few missed doses)

- Re-trying same AP again, may not be as beneficial

Role of other meds in Schizophrenia

- Mental health comorbidities

- May see use of: antidepressants, anticholinergic, BDZ, mood stabilisers

Clozapine (indication)

Treatment-refractory schizophrenia (TRS): 30-40% of pts

- Non-responsive/intolerant to 6-12 weeks on optimal doses of at least 2 different AP

OTHER: recurrent suicidal ideation, severe persistent EPSE, aggressive behaviour, severe comorbid substance abuse, intolerance to other AS

OFF-LABEL: bipolar disorder, psychosis associated with Parkinson's Disease

Clozapine efficacy in schizophrenia

TRS POSITIVE SYMPTOMS: more effective than other FGA/SGA short-term AND long-term

TRS NEGATIVE SYMPTOMS: more effective than other FGA/SGA short-term (but same as other AP long-term)

AP use NOT associated with increased hospitalization due to somatic or CV reasons

AP use decreased risk of all-cause, CV & suicide mortality - CLOZAPINE MOST BENEFICIAL

Clozapine has lowest cumulative mortality rates

Clozapine role in schizophrenia

Underutilised, delayed access & reluctance to prescribe

40% TRS respond to monotherapy

Clozapine Augmentation: add aripiprazole OR fluoxetine OR sodium valproate to ↑ efficacy

First AP with less EPSE

CONCERNS: adherence, tolerance, blood test compliance, neutropenia/agranulocytosis

Clozapine MOA and dose

BDZ derivatives

Complex MOA & remains unclear

Similar structure to olanzapine & quetiapine

Actions at 5HT2A and D2 (+more)

Immunomodulatory actions

Start @ 12.5mg, increase by 25mg at a time - therapeutic range 250-400mg d

MISSED DOSE -> Risk of rapid-onset psychosis

- >48h but <72h - contact prescriber, re-titrate from 12.5mg, no extra monitoring

- >72h - contact prescriber, re-titrate, weekly monitoring for 6 weeks

- >28 days - restart like a new patient with all associated monitoring

moinitoring of Clozapine

ON INITIATION: FBC, U&E, LFT, TFT, glucose, lipids, troponin, ECG, echocardiogram, physical measurements

- Weekly for first 18 weeks (usually hospital) + at least monthly + 1 month after tx

- Regular ECG and CK / troponin monitoring

Haematological Monitoring - Neutropenia/Agranulocytosis

- WCC > 3.5X10^9/L - monitor weekly first 18 weeks, then monthly after

- NC > 2.0 x 10^9/L

Clozapine CYPs interactions

CYP1A2, CYP2D6

Carbamazepine (CYP1A2 inducer), fluvoxamine (CYP1A2 inhibitor)

Carbamazepine (mood stabiliser)- additional neutropenia risk

Caffeine - CYP3A4 substrate, CYP1A2 inhibition, increases serum clozapine: significant changes in caffeine consumption can affect clozapine levels

Smoking - Polycyclic Aromatic Hydrocarbons induce CYP1A2 (clozapine metabolism) NOT NICOTINE

- Lower plasma conc (up to 50%), hence dose may have to increase for smokers

- 5 cigarettes/day may need drug dose increase

CESSATION: rapid ↓ CYP activity, ↑ plasma conc, new steady reached ~1 week:

- High serum clozapine = sedation, hypotension, seizure risk

NSW health guidance:

- Close monitoring (TDM) and dose reduction

- Immediate decrease clozapine dose - ↓10% daily for 4 days

- Blood/clinical monitoring 6 mths

- TDM for individual variation

Contraceptives: increases serum clozapine, use alternative contraception

- DO NOT USE: COC, POP, vaginal ring, etonogestrel implant

OTHER FACTORS AFFECTING SERUM CLOZAPINE: age, gender, other medications

counselling for antipsychotics

Listen non-judgmentally

Speak slowly, clearly and in short sentences & don't try to reason with acute psychoses

Be guided by their baseline level of understanding

Explain simply and repeat it

Adherence extremely important: "How can you help remember" - write down, demonstrate

NB: person is usually their own self-expert - ask what has worked in the past etc

Practice points for Clozapine

Develop a good relationship with prescriber & community mental health

Need to assess bloods before every dispensing

Individual pharmacist must be registered with monitoring system

Maximum 28 days supply

Stick with one brand

Challenges: missing forms, wrong dose, non-adherence, run out of meds

Prescribing requirements for clozapine

Authorised GPs and eligible community prescribers can prescribe maintenance Clozapine

All community pharmacies can dispense Clozapine, with an authority streamline prescription, for maintenance therapy & with monitoring

-> Improved patient access, all medicines from one place, increase GP involvement, decrease stigma, decrease burden on hospital staff & carers, improved communication for physical & mental illness management

Clozapine adverse effects and management

Sedation: occurs in 1st few months but usually wears off. Management: smaller dose in morning, reduce dose if possible

Hypersalivation: paradoxical reaction caused by stimulation of parasympathetic system. Management:

- Non-pharm - sugar free/dentist approved gum to promote swallowing during daytime

- Pharm- α2adrenergic agonists (e.g. clonidine) or anticholinergics (e.g. atropine or hyoscine 300ug), BUT limited evidence and more side effects

NB: anticholinergics worsen constipation/cognition

Constipation: Clozapine-induced gastrointestinal hypomotility. Usually persists, can lead to ileus impaction intestinal obstruction, faecal impaction. Implicated in more deaths than agranulocytosis. Not well understood or managed. PROACTIVE management - regular discussions with pts. Proactive laxative use recommended (softeners, stimulants, osmotics)

Hypotension, Hypertension: 1st 4wks, slowdown rate of increase dose, atenolol 25mg d for high bp

Tachycardia: 1st 4wks, usually benign - bisoprolol, atenolol, ivabradine (if no BBs). May indicate myocarditis, stop if w/ chest pain or HF

Weight gain: 10-20kg 1st yr, diet counselling essential, refer

Fever: 1st 3 wks, inflammatory response, panadol, FBC for neutropenia, reduce rate of titration

Seizures: Related to dose - plasma level, rapid escalation

Consider prophylactic lamotrigine, gabapentin, valproate of high dose (≥500mg d). can occur at any stage

Nausea, Nocturnal Enuresis, GORD

Reasons for disparities in health outcomes for pt with schizophrenia

Greater exposure to known risk factors

• Reduced access to services

• Impacts of treatments

• Policy related factors

• Lack of recognition of risks or clinical signs

Disparities in care in schizophrenia - Multifactorial

• Antipsychotics

• Lifestyle factors

• Poor access to care

• Stigma - impacts: relationships, employment, healthcare services (non-mental health), social media à perceived & anticipated discrimination common

Challenges for pt with schizophrenia (care, exercise, nutrition)

ACCESSING CARE:

• Often don't have a regular GP

• Polypharmacy

• Mental health care can become the focus and physical health issues may be 'invisible'

• Impact of symptoms: Disorganised thinking, poor organisational skills/memory, fear of doctors

• Other barriers: Lack of $$, stigma from HCP/public

EXERCISE: Negative symptoms and low mood can contribute to -

• Low activity levels

• Less incidental exercise

• Structured exercise first to go when stress

• Disconnections from social networks (sporting teams)

NUTRITION:

• Low fruit & veg intake

• High caffeine intake, High intake of take-away, soft drinks, high fat/sugar foods

• Poor health literacy

• Inactive lifestyles

• Increased appetite, large portions

How to support people living with a mental illness

POLICY IMPLEMENTATION - e.g. Equally Well Consensus Statement

1) Holistic, person-centred approach to physical and mental health and wellbeing

2) Effective promotion, prevention, and early intervention

3) Equity of access to all services

4) Improved quality of health care

5) Care coordination and regional integration

6) Monitoring of progress towards improved physical health and wellbeing

Opportunities for pharmacists across the spectrum of mental illness

1) Health promotion

2) Supporting early detection & intervention

3) Minimising illness

4) Maximising recovery

Pharmacists: supporting people with physical health

Be aware of impact of mental health symptoms on the person's ability for self-care:

• Reminders for appointments

• Regular monitoring of symptoms E.g. use of inhalers

• Be proactive with interventions to address modifiable risk factors e.g. smoking

• Offer practical tips to improve adherence and use of medicines e.g. dose administration aids, inhaler technique