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

monitoring for agranulocytosis has prompted the use of
low doses of quetiapine, itself a very weak D 2
antagonist,
although the evidence for quetiapine’s efficacy in L-dopa
psychosis is not compelling. Anecdotal evidence also
exists for using low doses of the D 2
partial agonist aripiprazole
(1-5 mg/day) in L-dopa psychosis (Zahodne
and Fernandez, 2008).
The choice of antipsychotic agents for long-term
schizophrenia treatment is based primarily on avoidance
of adverse effects and, when available, prior history
of patient response. Since schizophrenia spectrum
disorders are lifelong diseases, treatment acceptability
is paramount to effective illness management. Whether
atypical antipsychotic agents are superior to typical
antipsychotic agents has been the subject of significant
and contentious debate. Large meta-analyses of predominantly
industry-funded studies find only minute
differences in relapse risk (Leucht et al., 2003).
Atypical antipsychotic agents offer significant advantages
related to reduced neurological risk, with longterm
tardive dyskinesia rates < 1%, or approximately
one-fifth to one-tenth of that seen with typical antipsychotic
drugs (for haloperidol, the annual incidence of
tardive dyskinesia is 4-5% in non-geriatric adult
patients; lifetime risk ~20%). This advantage of the
atypical agents is magnified in elderly patients, in
whom tardive dyskinesia incidence is 5-fold greater
than in younger patients, and for whom annual tardive
dyskinesia rates with typical antipsychotic agents
exceed 20% per year. The decreased affinity for D 2
receptors among atypical agents has also translated into
reduced concerns over hyperprolactinemia with most
atypical antipsychotic agents, although risperidone and
paliperidone (9-OH risperidone) are exceptions; both
agents cause dose-dependent increases in prolactin (see
“Adverse Effects and Drug Interactions” later in the
chapter).
While concerns over EPS and tardive dyskinesia
have abated with the introduction of the atypical
antipsychotic agents into clinical practice, there has
been increased concern over metabolic effects of
antipsychotic treatment: weight gain, dyslipidemia
(particularly hypertriglyceridemia), and an adverse
impact on glucose-insulin homeostasis, including
new-onset type 2 DM, and diabetic ketoacidosis
(DKA), with reported fatalities from the latter
(American Diabetes Association et al., 2004).
Clozapine and olanzapine have the highest metabolic
risk and are only used as last resort. Olanzapine has
been relegated in most treatment algorithms to thirdtier
status, and is considered only after failure of more
metabolically benign agents such as aripiprazole,
ziprasidone, asenapine, iloperidone, risperidone, and
paliperidone.
Acutely psychotic patients usually respond within
hours after drug administration, but weeks may be
required to achieve maximal drug response, especially
for negative symptoms, which respond much less
robustly to drug therapy. While 6 weeks of therapy has
been considered an adequate antipsychotic trial, analyses
of symptom response in clinical trials indicate that
the majority of response to any antipsychotic treatment
in acute schizophrenia is seen by week 4 (Agid et al.,
2003; Emsley et al., 2006). Failure of response after
2 weeks should prompt a clinical reassessment, including
determination of medication adherence, before a
decision is made to increase the current dose or consideration
of switching to another agent. First-episode
schizophrenia patients often respond to modest doses,
and more chronic patients may require doses that
exceed recommended ranges. While the acute behavioral
impact of treatment is seen within hours to days,
long-term studies indicate improvement may not
plateau for 6 months, underscoring the importance of
ongoing antipsychotic treatment in functional recovery
for schizophrenia patients.
Usual dosages for acute and maintenance treatment
are noted in Table 16–1. Dosing should be
adjusted based on clinically observable signs of
antipsychotic benefit and adverse effects. For example,
higher EPS risk is noted for risperidone doses that
exceed 6 mg/day in non-elderly adult schizophrenia
patients. However, in the absence of EPS, increasing
the dose from 6-8 mg would be a reasonable approach
in a patient with ongoing positive symptoms, albeit
with appropriate monitoring for emerging EPS symptoms.
Treatment-limiting adverse effects may include
weight gain, sedation, orthostasis, and EPS, which to
some degree can be predicted based on the potencies of
the selected agent to inhibit neurotransmitter receptors
(Table 16–2). The detection of dyslipidemia or hyperglycemia
is based on laboratory monitoring (Table 16–1).
Certain adverse effects such as hyperprolactinemia,
EPS, orthostasis, and sedation may respond to dose
reduction, but metabolic abnormalities improve only
with discontinuation of the offending agent and a
switch to a more metabolically benign medication. The
decision to switch stable schizophrenia patients with
antipsychotic-related metabolic dysfunction solely for
metabolic benefit must be individualized, based on
patient preferences, severity of the metabolic disturbance,
likelihood of metabolic improvement with
CHAPTER 16
PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
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