DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

and dosage adjustment can minimize development of subtherapeutic
or supratherapeutic levels.
Use in Pediatric Populations. Both risperidone and aripiprazole
have indications for child and adolescent bipolar disorder (acute
mania) for ages 10-17, and for adolescent schizophrenia (ages 13-17).
Risperidone and aripiprazole are FDA-approved for irritability associated
with autism in child and adolescent patients ages 5-16. As discussed
in the sections on adverse effects, antipsychotic drug-naïve
patients and younger patients are more susceptible to EPS and to
weight gain. Use of the minimum effective dose can minimize EPS
risk; aripiprazole and ziprasidone have the lowest risk, olanzapine
the highest. Risperidone’s effects on prolactin must be monitored by
clinical inquiry, but long-term follow-up studies indicate some tolerance
to hyperprolactinemia, with levels after 12 months of exposure
significantly lower than peak levels, and close to baseline.
Delayed sexual maturation was not seen in adolescents in clinical
trials with risperidone, but should nevertheless be monitored.
Use in Geriatric Populations. The increased sensitivity to EPS,
orthostasis, sedation, and anticholinergic effects are important issues
for the geriatric population, and often dictate the choice of antipsychotic
medication. Avoidance of drug-drug interactions is also
important, as older patients on numerous concomitant medications
have multiple opportunities for interactions. Dose adjustment can
offset known drug-drug interactions, but clinicians must be attentive
to changes in concurrent medications and the potential pharmacokinetic
consequences. Vigilance must also be maintained for the additive
pharmacodynamic effects of α 1
adrenergic, antihistaminic, and
anticholinergic properties of other agents. Elderly patients have an
increased risk for tardive dyskinesia and parkinsonism, with TD rates
~5-fold higher than those seen with younger patients. With typical
antipsychotics, the reported annual TD incidence among elderly
patients in 20-25% compared to 4-5% for younger patients. With
atypical antipsychotic, the annual TD rate in elderly patients is much
lower (2-3%). Increased risk for cerebrovascular events and all-cause
mortality is also seen in elderly patients with dementia (see “Increased
Mortality in Dementia Patients”). Compared to younger patients,
antipsychotic-induced weight gain is lower in elderly patients.
Use During Pregnancy and Lactation. Antipsychotic agents carry
pregnancy class B or C warnings. Human data from anecdotal case
reports and manufacturer registries indicate limited or no patterns of
toxicity and no consistent increased rates of malformations.
Nonetheless, the use of any medication during pregnancy must be
balanced by concerns over fetal impact, especially first-trimester
exposure, and the mental health of the mother. Haloperidol is often
cited as the agent with the best safety record based on decades of
accumulated human exposure reports, but newer antipsychotic drugs,
such as risperidone, have not generated any signals of concern
(Viguera et al., 2009). As antipsychotic drugs are designed to cross
the blood-brain barrier, all have high rates of placental passage.
Placental passage ratios are estimated to be highest for olanzapine
(72%), followed by haloperidol (42%), risperidone (49%), and quetiapine
(24%). Neonates exposed to olanzapine, the atypical agent
with highest placental passage ratio, exhibit a trend towards greater
neonatal intensive care unit admission (Viguera et al., 2009). Use in
lactation presents a separate set of concerns due to the low level of
infant hepatic catabolic activity in the first 2 postpartum months.
While breast milk presents an important source of protective antibodies
for the baby, the inability of the newborn to adequately metabolize
xenobiotics presents a significant risk for antipsychotic drug toxicity.
The available data do not provide adequate guidance on choice
of agent.
Major Drugs Available in the Class
In the U.S., atypical antipsychotic drugs have largely
replaced older agents, primarily due to their more favorable
EPS profile, although typical agents are widely
used throughout the world. Table 16–1 describes the
acute and maintenance doses for adult schizophrenia
treatment based on consensus recommendations.
Acute IM forms exist for many typical antipsychotic drugs,
and also for aripiprazole, ziprasidone, and olanzapine, with the latter
being the most sedating due to its antihistaminic and anticholinergic
properties. The standard IM doses are 9.75 mg for aripiprazole,
10 mg for olanzapine, and 20 mg for ziprasidone (Altamura et al.,
2003). The 20-mg IM ziprasidone dose generates serum levels that
exceed those from 160 mg/day orally, but has not been associated
with reports of torsade de pointes or cardiac dysrhythmia. There are
numerous LAI (long-acting injectable) formulations of typical
antipsychotics, but in the U.S., the only available LAI typical agents
are fluphenazine and haloperidol (as decanoate esters), with usual
dosages 12.5-25 mg IM every 2 weeks and 50-200 mg (not to exceed
100 mg as the initial dose) IM monthly, respectively. Haloperidol
decanoate has more predictable kinetics, while fluphenazine
decanoate’s serum level can increase within days after administration
and induce adverse effects (Altamura et al., 2003). EPS remains a
significant barrier for using these agents. LAI risperidone was studied
at doses of 25, 50, and 75 mg IM biweekly, but the higher dose
was found to be without increased efficacy and with greater EPS
rates. Current available doses, all distributed as complete, singledose
kits, are 12.5, 25, 37.5, and 50 mg, given as a 2-mL water-based
injection. LAI risperidone is impregnated into organic microspheres
that require several weeks to liberate free drug. The impact of any
dosage change (or missed dose) of LAI risperidone is seen 4 weeks
later. LAI paliperidone has recently become available, and dosing is
initiated with two loading IM deltoid injections given at days 1 (234
mg) and 8 (156 mg), followed by injections every 4 weeks starting
at day 36. This loading strategy can be omitted if transitioning
patients from another LAI antipsychotic, with LAI paliperidone
given in lieu of the next injection, and the every 4 weeks thereafter.
The package insert provides detailed information on dose equivalency
with oral paliperidone, and on handling missed injections.
ODT forms are available for aripiprazole, clozapine, olanzapine, and
risperidone, and are the only form for asenapine. These ODT preparations
are commonly used in emergency and inpatient settings
where patients may be prone to cheeking or spitting out oral tablets.
Clinical Summary: Treatment
of Psychosis
The pharmacological profile of newer, atypical antipsychotic
drugs has expanded the uses of antipsychotic
medications during the last decade to include adjunctive
use for major depression and bipolar depression, with
CHAPTER 16
PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
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