Pharmacologic Considerations in
the Treatment of Schizophrenia and
Psychosis
Presented by: Ann M. Hamer, PharmD, BCPP
Date: 3/12/2015
Disclosures and Learning Objectives
• Learning Objectives
–
–
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Be able to discuss first-line treatment
recommendations for schizophrenia
Be able to discuss benefits and risks of
typical and atypical antipsychotics
Be able to identify differences between
available atypical antipsychotics
Disclosures: Dr. Ann Hamer has nothing to disclose.
Use of Antipsychotics in Primary Care
Results from a UK study:
•
47,724 individuals prescribed an AP
• 13,941 received traditional AP
• 27,966 received atypical AP
Rates of prescribing were higher among:
•
Females
•
Older people (80+)
•
Those from the most deprived areas
BMJ Open 2014;4:e006135. doi:10.1136/bmjopen-2014-006135
Use of Antipsychotics in Primary Care
Diagnoses:
•
Less than 50% of traditional AP users had a diagnosis
of psychosis/bipolar disorder
•
For AAP users, the numbers ranged from 4824 (36%)
for quetiapine to 7094 (62%) for olanzapine had a
diagnosis of psychosis/bipolar disorder.
In patients without psychosis/bipolar disorder, common
diagnoses included anxiety, depression, dementia, sleep
and personality disorders.
BMJ Open 2014;4:e006135. doi:10.1136/bmjopen-2014-006135
Schizophrenia: 6 Diagnostic Clusters
http://santabarbarastreetmedicine.org/wordpress/wp-content/uploads/2011/04/Schizophrenia-for-primary-careproviders-am-j-m-2012.pdf
Role of Antipsychotic Medications
Choosing an Antipsychotic
The choice of antipsychotic medication should be made by
the patient and provider together. Provide information
and discuss the likely benefits and possible side effects
of each drug, including:
• metabolic (including weight gain and diabetes)
• extrapyramidal (including akathisia, dyskinesia and dystonia)
• cardiovascular (including prolonging the QT interval)
• hormonal (including increasing plasma prolactin)
• other (including unpleasant subjective experiences)
www.nice.org.uk
Traditional Antipsychotics
Generic
Brand
Chlorpromazine
Thorazine
Thioridazine
Mellaril
Mesoridazine
Serentil
Loxapine
Loxitane
Molindone
Moban
Perphenazine
Trilafon
Thiothixene
Navane
Trifluoperazine
Stelazine
Haloperidol
Haldol
Fluphenazine
Prolixin
Droperidol
Inapsine
Prochlorperazine
Compazine
Atypical Antipsychotics
Generic
Brand
Aripiprazole
Abilify
Asenapine
Saphris
Clozapine
Clozaril
Iloperidone
Fanapt
Lurasidone
Latuda
Olanzapine
Zyprexa
Paliperidone
Invega
Quetiapine
Seroquel
Risperidone
Risperdal
Ziprasidone
Geodon
Receptor Binding Profiles of Antipsychotics
Traditional
Atypical
Effects from Receptor Blockade
Treatment Selection
CATIE
•
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)
•
Compared rates of all-cause discontinuation in 1432 patients
treated with either an SGA (olanzapine, quetiapine, risperidone, or
ziprasidone) or the FGA perphenazine.
•
Olanzapine showed a longer time to discontinuation for any reason
compared with the other antipsychotics (9.2 months for olanzapine
vs 3.5-5.6 months for the others).
•
This difference was not significant when compared with
perphenazine alone.
•
Perphenazine showed effectiveness comparable to that of the
other SGAs used in the study.
Treatment Selection
CATIE
•
Patients with schizophrenia treated with olanzapine experienced
higher rates of clinically significant weight gain (≥7% of body
weight) compared with the other antipsychotics (30% with
olanzapine vs 7% with ziprasidone, 12% with perphenazine, 14%
with risperidone, and 16% with quetiapine; P <.001) and had
greater increases in HbA1C, total cholesterol, and triglycerides.
•
Other adverse effects seen were generally consistent with those
observed in clinical practice. Risperidone was associated with the
greatest increase in prolactin (P <.001) and perphenazine had the
highest rate of discontinuation due to EPS, although there were no
significant differences in the rates of EPS between the different
treatment groups.
Treatment Selection
CUtLASS
• European Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia Study (CUtLASS 1).
• Examined improvement in quality of life as measured by the Quality
of Life Scale (QLS) in 185 patients who were treated over a period
of 1 year with either an FGA or an SGA.
• No significant difference was observed in the primary outcome
(QLS) in either treatment arm, nor in any of the secondary
outcomes, including symptom improvement, treatment adherence,
attitudes toward medication, or extrapyramidal side effects.
Treatment Selection
EUFEST
• European First Episode Schizophrenia Trial (EUFEST)
• Examined 498 first episode patients over 1 year of randomized
treatment with haloperidol, amisulpride, olanzapine, quetiapine, or
ziprasidone.
• More patients discontinued haloperidol for any reason than the other
antipsychotics (72% vs 40% for amisulpride, 33% for olanzapine,
53% for quetiapine, and 45% for ziprasidone; P <.001).
• There were no differences in symptom improvement or rates of
hospital admission between the treatment groups.
• Patients treated with haloperidol experienced the most EPSs, and
patients treated with olanzapine experienced the most weight gain.
Treatment Selection
CAFE
• Comparison of Atypicals for First Episode Schizophrenia (CAFE)
• Patients treated with either olanzapine, quetiapine, or risperidone
had similar all-cause discontinuation rates at 1 year, no differences
in overall symptom severity measures, and side effects similar to
those seen in other trials.
Treatment Selection
Treatment Selection
Considerations:
• patient preference
• prior treatment response (or first degree relative)
• side effect profile
• medical history and risk factors
• adherence history
Treatment Selection
• In patients with schizophrenia experiencing their FEP,
the SGAs are generally preferred for initial treatment.
• These patients are also particularly vulnerable to the
adverse effects of antipsychotic medications, such as
weight gain and EPS, and are generally more
responsive to lower doses than patients who have
experienced multiple episodes.
• Therefore, the lowest possible dose, typically about half
the dose used in patients with chronic schizophrenia,
should generally be used in these patients
Risperidone (Risperdal)
• The pharmacokinetics of the oral formulations are all equivalent,
with rapid absorption and 20-hour elimination half life.
• Risperidone has little activity at muscarinic receptors and no
anticholinergic effects.
• Drug-drug interactions are infrequent, but its serum levels are
modestly decreased by inducers of the cytochrome P450 system,
such as carbamazepine, and are increased by inhibitors such as
fluoxetine and ketoconazole.
• Although it is not necessary to adjust the dose of risperidone
whenever such a medication is added or withdrawn, clinicians
should be aware of the potential for a change in serum level with the
simultaneous use of these medications.
Risperidone (Risperdal)
• The drug is typically dosed once daily.
• Starting doses for adults are 1 to 2 mg/day, and maintenance doses
are typically in the 2 to 6 mg/day range, with 4 mg/day the average
dose in the community. Doses above 6 to 8 mg/day are associated
with higher rates of extrapyramidal symptoms.
• Titration should be done over the course of several days in order to
minimize the emergence of extrapyramidal symptoms or akathisia.
• For the elderly population, doses typically start at 0.25 to 0.5
mg/day, average about 1 mg/day, and do not usually exceed 2
mg/day.
Risperidone (Risperdal)
• Hepatic impairment results in increased serum levels and activity
due to a 35 percent greater free fraction of the drug. Renal
dysfunction reduces elimination of risperidone by 60%. Both
conditions may require dose reductions.
• The usual dose of the oral solution and rapid-disintegrating
formulation of risperidone for acute agitation is 1 to 2 mg every 30
minutes to two hours, to a maximum of 4 mg/day. The primary side
effects of risperidone are mild sedation, hypotension, akathisia,
prolactin elevation, and weight gain.
• Preliminary data suggest that risperidone may be associated with an
increased incidence of pituitary adenomas compared to other
antipsychotic agents. At higher doses, the drug is associated with a
somewhat greater risk of extrapyramidal symptoms than other
atypicals.
Olanzapine (Zyprexa)
• Generic olanzapine is available in standard tablets and orally
disintegrating tablets
• Proprietary olanzapine is available in coated tablets, rapiddisintegrating tablets, short-acting injectable solution, and a longacting injectable (depot) formulation, olanzapine pamoate.
• The oral formulations have gradual absorption and 30-hour
elimination half life. The drug is usually given once a day.
• Olanzapine has significant activity at histaminic and muscarinic
receptors.
• Drug-drug interactions are not prominent with olanzapine, but
olanzapine is dependent upon CYP 1A2 for clearance.
Olanzapine (Zyprexa)
• Coadministration of medications that strongly inhibit or induce CYP
1A2 can alter olanzapine levels. Olanzapine levels are decreased
somewhat by cigarette smoking. This may be an issue when
patients are stabilized on a specific dose of olanzapine while on a
nonsmoking hospital unit and then resume smoking upon discharge,
reducing serum levels of the drug.
• For adults, the starting dose of olanzapine is usually 5 to 10 mg/day.
•
Maintenance doses of 15 to 30 mg/day are common and doses up
to 40 mg/day can be useful in selected cases, though exceeding the
manufacturer's recommended maximum of 20 mg/day.
Olanzapine (Zyprexa)
• Doses for most non-treatment-refractory patients should not exceed
20 mg/day, as data have suggested equivalent efficacy of 10, 20
and 40 mg/day, but worsened tolerability at doses of 40 mg
compared to 10 mg/day.
• The average dose for stable schizophrenia patients participating in
an 18-month effectiveness study was about 20 mg daily [12]. For the
elderly population, doses begin at 1.25 to 2.5 mg/day, average 5
mg/day, and may go up to 10 mg/day [13].
• The usual dose of oral olanzapine for acute agitation is 5 to 10 mg,
repeated every 30 minutes to two hours to a maximum of 20
mg/day. There is no significant absorption of the rapid-disintegrating
formulation of olanzapine across the oral mucosa.
Olanzapine (Zyprexa)
• An intramuscular injectable form of the medication is available for
the treatment of acute agitation. The recommended dose is 10 mg,
repeated at intervals of two to four hours, up to a total of 30 mg/day.
• The most common side effects of olanzapine are weight gain,
sedation, akathisia, hypotension, dry mouth, and constipation.
Weight gain, hyperglycemia, and hyperlipidemia are greater with
olanzapine than with other SGAs, and are particularly prominent in
adolescents. The FDA has recommended that olanzapine be used
with caution when treating this age group.
• No specific recommendations have been made regarding dosing
changes for patients with renal or hepatic impairment.
Quetiapine (Seroquel)
• Quetiapine is available as immediate or extended release tablets.
• The immediate release formulation is available as a generic
• It is rapidly absorbed and cleared with a six to seven hour
elimination half life.
• The extended release tablets give a peak concentration at six hours,
followed by a seven-hour clearance half life.
• For both formulations, an active metabolite, norquetiapine,
represents about half of the active drug in circulation and has a 12
hour elimination half time.
Quetiapine (Seroquel)
• Although the manufacturer recommends twice daily dosing for the
immediate release tablets, both formulations are commonly used in
the community on a once daily schedule without substantial
problems.
• The drug has strong histaminic, cholinergic, and alpha-1-adrenergic
binding, responsible for relatively high levels of sedation,
anticholinergic effects, and orthostatic hypotension.
• Drug-drug interactions are not common with quetiapine, but serum
levels are affected by induction or inhibition of the cytochrome P450
system by drugs including carbamazepine, fluoxetine, and
ketoconazole. In practice, dose adjustments with these medications
are not commonly required.
Quetiapine (Seroquel)
• The usual adult starting dose of immediate release quetiapine is 25
mg twice daily, followed by a relatively slow titration at the rate of 25
to 50 mg/day to a total dose of 300 to 600 mg/day.
• The titration of the drug may be even slower if the patient develops
hypotension or excessive sedation.
• The manufacturer suggests a starting dose of quetiapine extended
release to be up to 300 mg/day, with titration to 600 mg/day by Day
2, and 800 mg/day by Day 3.
• Final doses of the two formulations are equivalent. The
manufacturer recommends a maximum dose of 800 mg/day, but
doses as high as 1200 mg/day have been used and appear to be
well tolerated.
Quetiapine (Seroquel)
• For the elderly population, doses usually start at 12.5 to 25 mg twice
daily and are titrated to doses substantially lower than for younger
adults.
• The drug does not require renal function for clearance, but patients
with hepatic impairment may experience an increase in serum levels
necessitating dose adjustment.
• The main side effects of quetiapine are sedation, orthostatic
hypotension, akathisia, dry mouth, and weight gain.
• Sedation is most often noted early in treatment and seems more
closely related to treatment duration than to dose, so patients may
find their sedation improving after several days, even if the
medication dose is still being titrated.
Quetiapine (Seroquel)
• Quetiapine causes QT prolongation in combination with other
factors prolonging the QT interval; use of the drug should be
avoided in conjunction with other medications that prolong the QT
interval or patient risk factors for QT prolongation.
• Quetiapine appears to cause less extrapyramidal symptoms than
other antipsychotics, with the exception of clozapine or iloperidone,
and is less likely to increase prolactin levels.
Ziprasidone (Geodon)
• Ziprasidone is available in capsules and as a sterile solution for
intramuscular injection.
• A generic preparation of the oral medication is also available.
• The oral formulation is absorbed slowly and cleared with an
elimination half life of seven hours.
• The drug is approved for twice daily dosing, but once daily
administration is commonly used in the community without apparent
problem.
• Bioavailability in the absence of food is inconsistent. It has been
estimated to be 50 percent lower than when ziprasidone is taken
with the recommended ≥500 calorie meal.
Ziprasidone (Geodon)
• The drug has low histaminic and no appreciable muscarinic activity.
• Drug-drug interactions are of two types.
•
First, serum levels respond modestly to concurrent treatment with inhibitors and
inducers of the cytochrome P450 system, such as carbamazepine, fluoxetine,
and ketoconazole .
•
Second, the drug causes mild QT prolongation, not usually clinically significant in
isolation, but use of the drug with other medications that prolong the QT interval
is contraindicated.
• The recommended adult starting dose of oral ziprasidone is 20 to 40
mg twice daily, followed by titration over two to five days to the
manufacturer's highest recommended dose of 80 mg twice daily.
Ziprasidone (Geodon)
• In practice, doses up to 240 mg/day are common and well tolerated.
A dose of at least 120 mg/day is believed to be necessary to
achieve sufficient dopamine D2 blockade for therapeutic efficacy.
• The oral drug is not affected by renal impairment, but a component
of the intramuscular preparation is cleared through the kidney,
leading to the manufacturer’s recommendation that it be used with
caution in that population.
• Hepatic impairment causes mild increases in serum levels and
clearance time that may require dose adjustment.
• Injectable ziprasidone has been FDA-approved for acute agitation. It
is recommended in 20 mg doses every four hours or 10 mg doses
every two hours to a maximum of 40 mg/day.
Ziprasidone (Geodon)
• Side effects include mild sedation early in treatment, nausea,
weakness, nasal congestion, and mild QT prolongation.
• Ziprasidone appears to cause less weight gain, hyperglycemia, and
hyperlipidemia than other second-generation antipsychotics.
• There are rare reports of severe hypersensitivity, including drug
reaction with eosinophilia and systemic symptoms (DRESS), a
potentially life-threatening reaction that begins as a rash.
• Despite the report of QT prolongation in clinical trials, this has not
emerged as a clinically significant problem in post-marketing
surveillance.
Aripiprazole (Abilify)
• Aripiprazole is unique among the SGA in its pharmacology and
pharmacokinetics, but is similar in clinical efficacy.
• Aripiprazole acts as a partial agonist at dopamine D2 receptors,
activating the receptor but eliciting a reduced response compared to
the natural neurotransmitter. The drug is also a partial agonist at
serotonin 5HT1a receptors, but an antagonist at 5HT2a, H1, and
alpha-1-adrenergic receptors.
• Aripiprazole is available as a standard and orally disintegrating
tablet, as a sterile solution for intramuscular injection, and as a longacting intramuscular formulation for monthly administration.
Aripiprazole (Abilify)
• Oral aripiprazole is absorbed slowly and cleared with a 75-hour
elimination half life.
• The injectable preparation shows significant clinical efficacy within
45 minutes, and reaches peak serum levels in one to three hours. Its
long elimination half life has the advantage of creating relatively
steady serum levels throughout the day, even with an occasional
missed dose, but may slow the impact of a dose adjustment or
transition to a different medication.
• Drug-drug interactions have not commonly been reported with
aripiprazole, but it is metabolized via the cytochrome P450 system.
A two-fold increase in dosing in the presence of metabolic inducers,
and a 50%reduction in dose with cytochrome P450 inhibitors, such
as fluoxetine, quinidine, or ketoconazole.
Aripiprazole (Abilify)
• Clinical trials of adults with schizophrenia started the drug at 10 to
15 mg daily, administered in a single dose. This dose proved to be
adequate for many patients, but doses up to 30 mg daily have been
approved. The manufacturer's clinical trials for bipolar disorder
started patients at 30 mg daily and lowered the dose only for side
effects.
• The manufacturer does not recommend dose adjustment for
patients with hepatic or renal insufficiency .
• The most common side effects of aripiprazole are headache,
nausea, vomiting, insomnia, tremor, and constipation. Weight gain
has been minimal in short and long-term trials. The drug has a lower
risk of extrapyramidal symptoms, increases in lipid or prolactin
levels, and sedation, compared to other atypicals in a small number
of comparative trials.
Aripiprazole (Abilify)
• Aripiprazole may be a cause of QT prolongation, based on a case
report. Avoidance of aripiprazole is suggested in patients with
congenital prolonged QT syndrome.
• Rates of akathisia are substantially higher for patients receiving
aripiprazole for major depressive disorder and bipolar disorder
compared to patients receiving aripiprazole for schizophrenia.
• The use of aripiprazole in conjunction with other antipsychotic
medications is not generally recommended, because the
combination of a partial agonist with an antagonist leads to
unpredictable levels of receptor activity.
• Switching patients to aripiprazole should be done slowly because of
aripiprazole’s exceptionally high affinity for dopamine D2 receptors
in the face of its partial agonism at this receptor.
Paliperidone (Invega)
• Paliperidone is available in an osmotic delivery capsule to be
swallowed whole, not crushed or chewed, and requires several days
to achieve steady-state kinetics. It is also available as a LAI.
• The bioavailability of paliperidone is increased by about 50% when
taken with a high calorie meal.
• Once absorbed, paliperidone has a 23-hour elimination half time.
• About 60% is excreted unchanged in the urine, with the remainder
metabolized by cytochrome P450 isoenzymes. The high level of
urinary excretion of unmetabolized paliperidone makes it unique
among antipsychotics in not requiring intact hepatic function for
clearance.
• Thus, in contrast to other antipsychotics, paliperidone requires no
dose adjustment with hepatic impairment. Significant drug-drug
interactions have not been identified.
Paliperidone (Invega)
• For non-elderly adults, paliperidone is typically started at 6 mg once
daily and, if needed, can be increased in 3 mg/day increments at
five day intervals. For elderly patients, or those with renal
impairment, 3 mg per day may be used.
• The most common side effects are extrapyramidal symptoms,
including parkinsonism, dystonia, dyskinesia, and akathisia. Other
side effects include prolactin elevation and tachycardia.
• Paliperidone has a mild to moderate risk of weight gain; comparative
trials found that the increase in weight was less than that caused by
olanzapine.
• Paliperidone can prolong the QT interval, and should not be used
with other drugs with similar effects.
• These side effects are dose-dependent, more prominent at doses
above 6 mg per day.
Iloperidone (Fanapt)
• Iloperidone has antagonist activity at dopamine D2 and serotonin
5HT2a receptors, similar to other SGAs.
• Short-term studies of varying doses found optimal efficacy at 12 to
24 mg daily.
• Because of the propensity for orthostatic hypotension, dosing should
be initiated at 1 mg BID with gradual titration, reaching 6 mg BID by
Day 4.
• The elimination half life is 18 to 33 hours.
• Plasma levels increase with CYP 2D6 and CYP3A4 inhibitors,
leading to the recommendation that dose be reduced by 50% in the
presence of medications such as fluoxetine.
Iloperidone (Fanapt)
• Side effects include dizziness, orthostatic hypotension, tachycardia,
weight gain, dry mouth, and sedation.
• Compared to other antipsychotics, iloperidone caused relatively few
extrapyramidal symptoms, an intermediate degree of weight gain,
and above average QT prolongation, though not to a degree that
cardiac monitoring or avoidance of other drugs that prolong the QT
interval has been recommended.
• The drug is not affected by renal insufficiency or mild hepatic
impairment. Moderate hepatic impairment is associated with
increased levels of drug metabolites, suggesting a lower dose may
be needed. The manufacturer recommends against its use in
patients with severe hepatic impairment, which has not been
studied.
Asenapine (Saphris)
• Asenapine has a broad range of receptor activities, including
antagonism of dopamine, serotonin, adrenergic, and histaminic
receptors, but minimal muscarinic activity.
• It is rapidly absorbed and has a 24-hour elimination clearance halftime.
• Its major route of metabolism is through CYP 1A2 and
glucuronidation, with no major active metabolites.
• Drug interactions tend to be mild and generally do not require an
adjustment in dose.
• Asenapine is unique among antipsychotics in its sublingual
administration, necessitated by its poor GI absorption.
Asenapine (Saphris)
• Both the starting and maintenance doses of the medication are 5 to
10 mg BID. The maximum recommended dose is 10 mg BID.
• The drug dissolves and is absorbed quickly, but the patient should
not eat or drink within 10 minutes of administration.
• The most common side effects are sedation, weight gain, dizziness,
EPS (especially akathisia), and oral hypoesthesia. Weight gain is
intermediate among the SGAs.
• QT prolongation was limited to 2 to 5 milliseconds at doses as high
as 20 mg BID, a level not expected to be of clinical significance.
• Prolactin levels do not differ from those seen with placebo.
Asenapine (Saphris)
• Rare reports of serious hypersensitivity reactions, including
anaphylaxis, caused the issuance of a safety communication and
product warnings by the FDA. Eight of 52 cases described in the
communication occurred after only one dose of asenapine and 19
prompted emergency intervention or hospitalization.
• Systematic studies of asenapine in geriatric patients have not been
reported, but caution is recommended early in treatment because of
a mildly elevated risk of orthostatic hypotension and syncope.
• No data on use in children or adolescents have been reported.
• Severe hepatic dysfunction caused a 7-fold increase in serum levels
of asenapine, leading the manufacturer to recommend against its
use in that population.
• Renal impairment has no impact on drug levels or clearance.
Lurasidone (Latuda)
•
Lurasidone shows high affinity for dopamine D2 and serotonin 5HT2A receptors, as is characteristic of other second-generation
antipsychotics.
•
It also has potent antagonism at 5-HT7 receptors of unclear
significance.
•
It has moderate affinity for 5-HT1A and alpha2 adrenergic
receptors, and minimal binding at alpha1 adrenergic, histamine H1,
and muscarinic M1 receptors.
•
Absorption of the drug occurs over one to three hours, followed by
a serum half-life of 18 to 37 hours.
Lurasidone (Latuda)
•
Bioavailability increases two to three-fold when the drug is taken
with a 350 calorie meal, but is not dependent on the fat content of
the meal.
•
Its major route of metabolism is via CYP3A4, which produces both
active and inactive metabolites. Medications that are strong
inhibitors or inducers of CYP3A4 substantially alter serum levels of
lurasidone and their coadministration is contraindicated.
•
•
Dose reduction is recommended in the presence of moderate CYP3A4
inhibitors, such as diltiazem.
The drug is supplied as 20, 40, 80 and 120 mg tablets intended for
once daily dosing with a meal.
Lurasidone (Latuda)
• The suggested initial dose is 40 mg daily for most patients; dose
titration was not employed in the efficacy studies. The maximum
daily dose of 160 mg received approval based upon results of a 6
week efficacy trial. However, results of an unpublished trial that
included 120 mg daily showed no benefit over and more adverse
effects than 80 mg per day.
• Dose reduction is needed in the setting of moderate or severe renal
or hepatic insufficiency.
• Common side effects include somnolence, akathisia, nausea, and
parkinsonism. Less commonly reported adverse effects include
acute dystonia, agitation, anxiety, and dizziness.
Lurasidone (Latuda)
• Weight gain was mild in short-term studies and was not observed in
open-label extension studies of 24 to 52 weeks. Fasting glucose is
more likely to be elevated with lurasidone (10 to 14% of patients
compared to 8.6% on placebo), but lipid levels show little difference
compared to placebo treatment.
• Prolactin elevation occurs in 8.3% of women and 1.9% of men on
the drug, compared to 0.6 to 1% of those on placebo.
• The mean change in QT interval was -1.2 milliseconds in the initial
clinical trial and no other ECG abnormalities were reported
subsequently
• The drug has not been tested in children or adolescents.
• Its pharmacokinetics appear unchanged in the elderly population,
but no studies of its efficacy or safety in that group are available
Role of Clozapine
• For patients who have failed treatment with adequately dosed trials
(generally 4-6 weeks) of more than 1 antipsychotic medication, the
most evidence-based treatment strategy is to initiate clozapine.
• Clozapine may be instituted earlier in the treatment of patients with
schizophrenia who have persistent suicidality, aggression, or
hostility, as these patient populations in particular seem to benefit
from clozapine (as in 1 meta-analysis which demonstrated a 3-fold
reduction in suicidal behaviors compared with other antipsychotics).
• The high risk of weight gain and other metabolic effects, and the risk
for agranulocytosis, myocarditis, orthostatic hypotension, seizures,
and other adverse effects limit the use of clozapine, but many
experts agree that the agent is likely underutilized.
Schizophr Res. 2005;73(2-3): 139-145.
Antipsychotic Comparison
Antipsychotic Comparison
Cost Comparison
Drug
Usual Dosage
Cost of 30 day supply
First Generation Antipsychotics
Chlorpromazine
200mg BID
$140
Fluphenazine
10mg QD
$11
Haloperidol
5mg BID
$14
Loxapine
60 – 100mg in 2-4
divided doses
$129
Perphenazine
24mg/day in 2-3 divided
doses
$139
Thioridazine
100-200mg BID
$24
Thiothixene
10mg BID
$26
Trifluoperazine
10mg BID
$57
Cost Comparison
Drug
Usual Dosage
Cost of 30 day supply
Second Generation Antipsychotics
Abilify
10-30mgQD
$669
Abilify Discmelt
10mg QD
$797
Saphris (sl tab)
5mg BID
$690
Clozapine
100-300mg TID
$218
Clozapine ODT
100-300mg TID
$589
Fazaclo
100-300mg TID
$783
Fanapt
6-12mg BID
$697
Latuda
40-160mg QD
$553
Olanzapine
10-20mg QD
$23
Olanzapine ODT
10-20mg QD
$340
Cost Comparison
Drug
Usual Dosage
Cost of 30 day supply
Second Generation Antipsychotics
Invega
6-12mg QD
$604
Quetiapine
300-800mg in 2-3
divided doses
$72
Seroquel XR
400-800mg QD
$585
Risperidone
4-8mg QD
$42
Risperidone ODT
4-8mg QD
$362
Ziprasidone
60-80mg BID
$292
The End!
Next Week:
EPS and
Metabolic
Abnormalities