Schizophrenia 3 Flashcards
Adverse Effects of Antipsychotics
M1 receptor blockade
Anticholinergic effects:
Constipation, dry mouth, dry
eye, sedation, dizziness,
blurred vision, tachycardia,
urinary retention, confusion
Change agent
Drink water
Bowel regimen
Eye drops
Dose at bedtime
Risk management
Beta blocker
Bethanecol
Adverse Effects of Antipsychotics
H1 receptor blockade
Sedation
Metabolic changes (weight
gain/increased appetite,
increased risk of
hypertension,
hypercholesterolemia, type 2
diabetes)
Tolerance develops
Switch agent
Dietician consult
Exercise regimen
Regular monitoring (BMI, waist circumference, BP, lipid panel, A1C)
–3 months, 6 months, annually
If metabolic condition develops (e.g., hyperlipidemia, HTN,
diabetes) – treatment as per guidelines
Metformin/GLP-1 RAs can be considered for weight management
(independent of diabetes management)
Adverse Effects of Antipsychotics
a1 receptor blockade
d2 in tubueroinfundibular tract
d2 in nigrostriatal tract
α1 Orthostatic hypotension, reflex
tachycardia, dizziness
Risk management
Tolerance may develop (2-3 months)
Drink water
Sodium supplementation if needed
In some cases, tachycardia treated w/ beta blocker
D2 in
tuberoinfundibular
tract (TI)
Hyperprolactinemia (gynecomastia,
galactorrhea, menstrual
irregularities, infertility, reduced
libido, erectile/ejaculatory
dysfunction, risk of osteoporosis)
Screen for sx at 1 month, 3 months, 6 months, 12
months, annually; Prolactin level if indicated
Change agent
Add aripiprazole (dopamine partial agonist)
Calcium, vitamin D supplementation
No evidence for adding DA agonists
D2in Nigrostriatal
tract (NS)
Extrapyramidal symptoms (EPS) –
dystonia, dyskinesia, akathisia
See antipsychotics slides (Dr. Chue
Compliance
- 1 - 10 days per year of non-adherence doubles hospitalization rates
- Adherence rates
- chronic disease medications - 76%
- antipsychotics - 58%
- Many potential reasons for noncompliance: poor insight into illness,
finances, medication side effects, substance use, impaired
memory/forgetfulness, etc… - Role of the pharmacist!!!
Adverse effects adverse effect management, switch agent*
Memory compliance aids (e.g., blister packs, long-acting injections),
daily administration (e.g., at pharmacy or with community teams)
Intentional noncompliance long-acting injections, community
treatment orders (CTO) (if appropriate)
Finances compassionate care programs, special authorization, liaise
with social work supports
Treatment-Resistant Schizophrenia (TRS)
- ~30% of individuals do not response adequately to antipsychotics
Consensus criteria defined by TRRIP Working Group: - Current symptoms:
- Persistent psychotic symptoms of at least moderate severity*
- At least moderate functional impairment*
- Minimum of 2 failed antipsychotic trials
- Adequate duration (≥ 6 weeks)
- Therapeutic dose
- Adequate adherence: ≥80% of prescribed doses taken
Clozapine
- Treatment of choice for TRS
- Demonstrated superior efficacy compared with other antipsychotics
in patients with TRS - Demonstrated reduction in suicidality
- One of three drugs that has evidence for this indication
CATIE 2E
* Included patients from phase 1 who discontinued treatment due to
inefficacy. respond to olanzapine, risperidone, ziprasidone, quetiapine
* Median time to discontinuation 10.5 months for clozapine vs.
risperidone (3.3 months), quetiapine (3.3 months) or olanzapine (2.7
months)
* NS for olanzapine
* Time to discontinuation for inadequate therapeutic effect was
significantly longer for clozapine
* At 3 months clozapine showed significant improvement in PANSS
compared to risperidone and quetiapine
Clozapine has superior efficacy to other anti-psychotics.
Clozapine MOAO, AE
- Lower D2 binding ↓ risk:
- EPS
- hyperprolactinemia
- ↑ risk:
- Weight gain and metabolic side effects (H1)
- Sedation (H1)
- Orthostatic hypotension (a1, a2)
- Tachycardia (a1, a2)
- Anticholinergic side effects (M1): constipation (+++), blurred vision, dry mouth, etc..
- Clozapine-specific concerns: neutropenia, myocarditis, cardiomyopathy,
seizure risk
Extremely anticholinergic
Clozapine Monitoring
Hematological:
* Higher risk of agranulocytosis neutropenia (absolute risk of agranulocytosis is
low – 1%)
* Manufacturer specific monitoring, e.g., GenCAN, CSAN, etc…
* Monitor ANC: baseline, weekly x 26wks, biweekly x 26 weeks, q4wks
thereafter
Clozapine – Neutropenia
Exceptions/Accommodations:
* Benign Ethnic Neutropenia
* Certain ethnicities have
lower baseline ANC
* BEN Guidelines
* Special guidelines:
* Patients with demonstrated
low ANC independent to
clozapine
* Purpose: reduce
interruption to therapy
Clozapine – other monitoring considerations
- Cardiomyopathy, myocarditis
- Consider monitoring CRP, troponin x 4 weeks (some guidelines recommend longer
duration of monitoring) - cardiac monitoring that can be considered but are not mandatory. - Flu-like symptoms, respiratory symptoms, persistent tachycardia, chest pain, syncope
- Rare (≤3%), life threatening (fatality 10-30%)
- Seizures
- Absolute risk is LOW
- No established dose-related or level associated risk
- Constipation
- +++ common
- Monitor often!!
- Majority of patients require laxatives (many require multiple)
- Bowel protocols used in hospitals
absolute risk of seizure it with clozapine might be overstated. You might hear it a lot, but the absolute risk is very low and there’s no established dose-related, dose-related or level related risks.
Clozapine and Smoking
Clozapine: major metabolite of CYP1A2
* Tobacco: Tobacco smoke contains polycyclic aromatic hydrocarbons
induce CYP1A2
* Smoking tobacco ↑ metabolism of clozapine ↓concentration, efficacy
* Dose related
* Recall: up to 90% of patients with schizophrenia smoke
* Risk:
* Admission to hospital abrupt discontinuation of tobacco smoking ↑ clozapine
concentration ↑ risk of toxicity
* Discharge from hospital abrupt resumption of tobacco smoking ↓ clozapine
concentration ↑ risk psychiatric decompensation
Smoking is an important interaction. It’s clinically important. Just know that the risk with cause pain and smoking is not with the nicotine itself. It’s what the hydrocarbons that come from tobacco smoke. So this is not relevant with nRT.
up to 90% of patients with schizophrenia smoke. So this is important to note because patients when they’re admitted to hospital, they might not be smoking at all.
Back in community, if they smoke anywhere anymore than seven cigarettes per day, this will result in a reduction in the plasma concentration and possibly a decompensation of their psychiatric status.
Ultra-Resistant Schizophrenia (URS)
- Aka clozapine-resistant schizophrenia (CRS)
- Of patients that are treatment resistant, only 30-60% respond
adequately to clozapine - Ultra-Resistant Schizophrenia:
- Patients with schizophrenia that meet criteria for TRS, and
- Have demonstrated inadequate treatment response to adequate treatment
with clozapine - No one strategy that has produced robust effects
- Mood stabilizers (conflicting evidence)
- Additional antipsychotic (only aripiprazole and amisulpride have evidence)
- ECT (most promising at this time)
Prognosis
- 80% relapse within first 5 years
- 75% have recurrent relapse,
continued disability - 15% hospitalized and unimproved
- Mortality is 50% above general
population - Cardiovascular events, metabolic,
COPD, certain cancers, HIV, hepatitis C,
tuberculosis - Higher rate of smoking, less exercise,
poor nutrition - 10% die (mostly by suicide)
- Earlier death: Males 20y, females 15y
After 10 years, of the people diagnosed
with schizophrenia: - 25% completely recover
- 25% are much improvement and
relatively independent - 25% improved but continue to require
extensive support - Many have acceptable QOL despite
symptoms
Factors Influencing Course
Positive Impact
* Early Intervention
* Multidisciplinary treatment
* Appropriate pharmacotherapy
and consistent adherence
Negative Impact
* Longer duration of untreated
illness
* External stressors
* Significant negative symptomology
* Medication noncompliance
* Poorer outcomes earlier in illness
* Insufficient medication
management
* Substance use
Barriers to Treatment
- Patient
- Stigma
- Substance use
- Complex psychosocial stressors
- Compliance
- Limited insight
- Adverse effects of medications
- Clinician
- Difficult to navigate/sparse evidence base
- Heterogeneity of the condition
- Clinician attitudes
