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1. Atypical Antipsychotics
MED IV & III

2. PHARMACOECONOMICS
In general, SGAs still within patent are more likely to be expensive
agents.
However, the approval of generic forms of risperidone,
olanzapine, quetiapine, ziprasidone, and aripiprazole may change
the cost differential between FGAs and SGAs
At this time, no generic forms of SGA LAls are available on the
market.
Additional/imitations to literature analysis include differences
between availability/cost/other factors for different countries
studied and variability of methods used for different evaluations.
Head-to head comparisons are limited.

3. • A 28-year-old with a diagnosis of schizophrenia and benign ethnic
neutropenia was started on clozapine three weeks ago at the outpatient
clozapine clinic. The patient's current dose of clozapine is 100 mg every
morning and 300 mg every evening. The patient has experienced a
reduction in positive symptoms and is less aggressive. The patient's
most recent absolute neutrophil count laboratory results were 1300µg/L.
A review of the medical chart shows the following absolute neutrophil
count results: 4400 µg/L (baseline/3 weeks ago}t 2800 µg/L (2 weeks
ago}, and 1900 µg/L (1week ago}.
Based upon these results, what action would you take?
a. Decrease clozapine dose and add filgrastim
b. Increase monitoring interval to three times weekly
c. Continue current clozapine dose and monitoring schedule
d. Switch to a different second-generation antipsychotic

4. answer
C. Continue current clozapine dose and monitoring schedule:
As this patient has benign ethnic neutropenia, the monitoring
recommendation is to continue therapy and regular monitoring
interval. Had this patient been in the general population,
increasing the monitoring interval to three times weekly until the
patient's ANC was in usual range would be indicated. There is no
indication to reduce the dose of clozapine or switch to a different
second generation antipsychotic

5. When educating a patient on a new prescription for ziprasidone,
which statement would be considered the most appropriate
regarding taking the medication?
a. Take the dose just prior to bedtime to obtain the best effect
b. Use caution when being outdoors in hot weather for prolonged
periods of time
c. All side effects are short-lived and will resolve within 4 weeks
d. Make sure to take dose with a meal of at least 350 calories

6. answer
• B. Use with caution when being out doors in hot weather for
prolonged periods of time:
Changes in body temperature regulation can occur with any of the
antipsychotics. Ziprasidone should be taken with meals of at
least 500 calories to ensure adequate absorption. Time of
administration does not impact the effectiveness of ziprasidone.
Although many side effects may resolve, others may persist.

7. Mechanism of Action
A.
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•
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Clinical
1. "Atypical" antipsychotics, or SGAs, were first identified as
having less risk of EPS vs. FGAs at doses producing
antipsychotic effects
a. Originally thought to be better for negative symptoms
because of effects on the mesocortical dopamine pathway in
the midbrain ventral tegmental, although this has not been
proven in clinical trials
b. May be due to not causing secondary negative symptoms as
compared to having positive effects on negative symptoms

8. a.
b.
2. Four different mechanisms of action may contribute to th
e "atypical" profile of an SGA, though not all SGAs possess all
criteria:
Serotonin type 2 (5HT2) and DA antagonism: A common feature
of most "atypical "antipsychotics; most FGAs do not have
significant effects at 5HT receptors at usual doses.
D2 antagonism with rapid dissociation
i. FGAs have long receptor occupancy times on D2 receptors
ii. Lower potency SGAs have faster dissociation/weaker affinity binding
(e.g., quetiapine and clozapine) than higher potency SGAs (e.g.,
Risperidone and Paliperidone)

9. C. D2 partial agonism (Aripiprazole, Brexipiprazole, Cariprazine)
i. Stabilization of DA neurotransmission by reduction of D2
hyperactivity in mesolimbic DA neurons
ii. Limited reduction/partial agonism of DA activity in nigrostriatal
system allows some signal transduction through D2 receptors so
as to reduce EPS symptoms
D. Cariprazine has high potency at the D3 receptor which
potentially may be a benefit in terms of cognition and negative
symptoms

10. •
•
•
E. Serotonin 1A (5HT,1A) partial agonism
i. May increase the release of DA in the prefrontal cortex which
in turn may have a beneficial effect on cognition
ii. Can also potentially reduce the risk of EPS and improve mood
iii. Clozapine, quetiapine, and ziprasidone have some 5HT,1A
partial agonism effect but newer antipsychotics (Aripiprazole,
Brexipiprazole, and Cariprazine) appear to have a more potent
effect on this receptor

11. Dosing
Initial Adult Dosing, Titration, and Maximum Dosing
•
•
A. Initiation of a SGA should be done at a low dose and titrated in
order to improve tolerability
B. Patients can be titrated up to the approved maximum dose
based upon tolerability and response
C. The lower half of the recommended dose range should be the
initial goal dose for first episode schizophrenia: E.g.:
Risperidone 3-4 mg/day, Olanzapine 10 mg/day) due to
increased responsiveness and sensitivity to adverse effects.
Quetiapine is the exception to this general guideline and often
will need to be titrated to 500-600 mg/day to be effective

12. D. It is recommended that clozapine be dosed between 300-800
mg/day for at least eight weeks as an adequate trial in treatment-
resistant schizophrenia
E. Information specific to both oral and parenteral administration
is similar to FGAs.

13. Contraindications
A. General contraindications as a class - known hypersensitivity to
the agent
B. Clozapine - myeloproliferative disorders, uncontrolled epilepsy,
paralytic ileus, history of clozapine-induced Agranulocytosis or
severe granulocytopenia, severe CNS depression or comatose
states, and not to be used in combination with other agents
known to cause Agranulocytosis
C. Lurasidone - concomitant use with a strong CYP3A4 inhibitor or
inducer

14. Warnings/Precautions
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General warnings and precautions include:
Increased mortality in elderly patients with dementia-related psychosis
Increased incidence of cerebrovascular adverse events in elderly patients
with dementia-related psychosis.
Falls which may be caused by postural hypotension, somnolence, and/or
impairment in motor and sensory stability,NMS. TD.
Metabolic changes such as:
Hyperglycaemia, diabetes mellitus, dyslipidaemia, and weight gain that
may increase risk of cardiovascular or cerebrovascular events.

15. •
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Hyperprolactinaemia, leukopenia, neutropenia, and
Agranulocytosis, orthostatic hypotension and syncope.
Seizures
Potential for cognitive/motor impairment
Changes in body temperature regulation,
Suicide, and dysphagia.

16. Adverse Events and Management
A. Agranulocytosis
1. Less than 1% incidence worldwide with clozapine but may be
as low as 0.05%.
2. Risk is greatest in the first year with increased risk in females,
older adults, and those patients taking multiple psychotropic
medications
3. Case reports with the other SGAs

17. B. QTc prolongation
1. Medications with a high risk of causing a prolonged QTc
interval should be avoided or used with caution in patients with
congenital long QT, history of arrhythmias, bradycardia,
hypokalemia,hypomagnesemia, or when there is concurrent use
of other QTc prolonging agents:

18. •
C. Hyperprolactinaemia
1. Bone mineral density (BMD) is decreased in patients with
schizophrenia as compared to persons without the disease with
osteoporosis being nearly three times more prevalent in this
population.
This may be because of lifestyle factors and/or the use of antipsychotic
medications.
2. A recent meta-analysis found a significant difference in BMD in
patients receiving prolactin raising versus prolactin-sparing
antipsychotics
3. Risperidone and Paliperidone have the highest risk of causing
hyperprolactinaemia
4. Clozapine and quetiapine only transiently increase prolactin
5. Aripiprazole lowers prolactin secondary to partial agonist activity

19. D. Weight gain
1. Besides the antipsychotics and dose, other factors for
increased risk for weight gain include young age, antipsychotic
naive, low BMI before treatment initiation, and polypharmacy
2. Nearly 50% of patients with first-episode schizophrenia
spectrum disorders (FES) are obese or overweight which is likely
from the interplay among the disease, antipsychotic medications
used to treat the disease, and unhealthy lifestyles
3. Behavioural interventions, including health coaching, appear to
be most beneficial in managing weight loss

20. a.
b.
c.
4. Pharmacological interventions
Topiramate has been shown to result in weight loss although it
is generally not considered first-line treatment for weight gain
Current data for the use of metformin to prevent or manage
weight gain or metabolic parameters are limited although
there may be some possible benefit in terms of weight loss
when metformin is used for antipsychotic-induced weight gain,
in particular olanzapine
Orlistat has been shown to result in weight loss for men with
clozapine or olanzapine-induced weight gain but not in women

21. 5. Women taking a SGA may gain more weight during pregnancy
raising the risk of gestational diabetes (case reports with
clozapine and olanzapine)
6. Changing to an antipsychotic with less propensity for weight
gain should be considered in patients who have gained equal to
or greater than 5% of baseline weight if clinically possible based
upon individual patient symptoms and drug therapy response

22. E. Glucose intolerance
1. Prevalence of adult-onset diabetes in patients with
schizophrenia (most of whom are likely treated with
antipsychotics) is approximately twice the population rate (13%)
2. Impaired fasting glucose tolerance has been noted in
medication-naive patients with schizophrenia

23. F. Lipid abnormalities
1. Dyslipidaemia was observed in 56.5% of patients with FES in
the RAISE-ETP study
2. Monitoring for lipids is recommended for all anti psychotics
regardless of risk
3. Triglyceride changes generally observed clinically more often
than other lipid changes
4. Statins may be used but risk versus benefit including drug-drug
interactions and adverse effects must be considered

24. Patient Education
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•
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Patients should be educated regarding recommended metabolic
monitoring to be done routinely, including blood pressure, HgbA 1c,
fasting blood glucose, lipid profile, weight, and waist circumference
Early in drug therapy, the patient should be given information
regarding the risk of weight gain and lifestyle changes that may be
initiated to prevent or reduce this risk.
Administration with food or beverages
1. Ziprasidone should be taken with a meal containing a minimum of
500 calories
2. Lurasidone should be taken with a meal containing a minimum of
350 calories
3. Patients should refrain from eating or drinking for at least 10
minutes after taking sublingual Asenapine