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

SECTION II
NEUROPHARMACOLOGY
422 Schizophrenia. The immediate goals of acute antipsy-
Schizophrenia patients have a 2-fold higher prevalence of
metabolic syndrome and type 2 diabetes mellitus (DM) and 2-fold
greater cardiovascular (CV) related mortality rates than the general
population (Meyer and Nasrallah 2009). For this reason, consensus
guidelines recommend baseline determination of serum glucose,
lipids, weight, blood pressure, and when possible, waist circumference
and personal and family histories of metabolic and CV disease
(American Diabetes Association et al., 2004). This cardiometabolic
risk assessment should be performed for all schizophrenia patients
despite the low metabolic risk for certain agents. With the low EPS
risk among atypical antipsychotic agents, prophylactic use of
anti-parkinsonian medications (e.g., benztropine, trihexyphenidyl) is
not necessary; however, acute dystonic reactions can occur (see
Table 16–4), typically among patients who have never before taken
antipsychotic drugs, adolescents, and young adults. Lower dosages
are recommended in these individuals. Drug-induced parkinsonism
can also occur, especially among elderly patients exposed to antipsychotic
agents that have high D 2
affinity (e.g., typical antipsychotic
drugs, risperidone, paliperidone); recommended doses are ~50% of
those used in younger schizophrenia patients. (See also “Use in
Pediatric Populations” and “Use in Geriatric Populations” later in
the chapter.)
chotic treatment are the reduction of agitated, disorganized,
or hostile behavior, decreasing the impact of
hallucinations, the improvement of organization of
thought processes, and the reduction of social withdrawal.
Doses used are often higher than those required
for maintenance treatment of stable patients. Despite
considerable debate, newer atypical antipsychotic
agents are not more effective in the treatment of positive
symptoms than typical agents (Rosenheck et al.,
2006; Sikich et al., 2008), although there may be small
but measurable differences in effects on negative symptoms
and cognition (Leucht et al., 2009).
Newer, atypical antipsychotic agents do offer a
better neurological side-effect profile than typical
antipsychotic drugs. Clinically effective doses of atypical
agents show markedly reduced EPS risk (or nearly
absent in the case of quetiapine and clozapine) compared
to typical antipsychotic agents. Excessive D 2
blockade, as is often the case with the use of highpotency
typical agents (e.g., haloperidol), not only
increases risk for motor neurological effects (e.g., muscular
rigidity, bradykinesia, tremor, akathisia), but also
slows mentation (bradyphrenia), and interferes with
central reward pathways, resulting in patient complaints
of anhedonia. Rarely used are low-potency typical
agents (e.g., chlorpromazine), which also have high
affinities for H 1
, M, and α 1
receptors that cause many
undesirable effects (sedation, anticholinergic properties,
orthostasis). Concerns regarding QT c
prolongation
(e.g., thioridazine) further limit their clinical usefulness.
In acute psychosis, sedation may be desirable, but the
use of a sedating antipsychotic drug may interfere with
a patient’s cognitive function and social reintegration.
Clinicians often prefer using nonsedating antipsychotic
agents, and add low doses of benzodiazepines as necessary.
As a result of the improved neurological risk profile
and aggressive marketing, atypical antipsychotic
agents have essentially replaced typical antipsychotic
drugs in clinical practice in the U.S.
Since schizophrenia requires long-term treatment,
antipsychotic agents with greater metabolic liabilities,
especially weight gain (discussed later),
should be avoided as first-line therapies (Meyer et al.,
2008). Ziprasidone and aripiprazole are the most
weight and metabolically neutral atypical agents, with
asenapine and iloperidone also having favorable metabolic
profiles. Ziprasidone and aripiprazole are available
in IM form, thus permitting continuation of same
drug treatment initiated parenterally in the emergency
room.
Long-Term Treatment
The need for long-term treatment poses issues almost
exclusively to the chronic psychotic illnesses, schizophrenia
and schizoaffective disorder, although longterm
antipsychotic treatment is sometimes used for
manic patients, for ongoing psychosis in dementia
patients, for L-dopa psychosis, and for adjunctive use in
SSRI-unresponsive major depression. Safety concerns
combined with limited long-term efficacy data have
dampened enthusiasm for extended antipsychotic drug
use in dementia patients (Jeste et al., 2008). The goal
should be to optimize clinical and behavioral aspects
of treatment in order to minimize the need for antipsychotic
drugs in the dementia population. Justification
for ongoing use, based on documentation of patient
response to tapering of antipsychotic medication, is
often mandated in long-term care settings. L-dopa psychosis
represents a thorny clinical problem, as clinicians
are caught between the Scylla of treatment-induced
psychotic symptoms and the Charybdis of motoric
worsening as a result of exposure to antipsychotic
drugs. Parkinson disease patients who present with
L-dopa psychosis usually have advanced disease and
cannot tolerate reductions in dopamine agonist treatment
without significant motoric worsening and on-off
phenomena (Chapter 22). They are exquisitely sensitive
to minute amounts of D 2
blockade (Zahodne and
Fernandez, 2008). Clozapine, used in doses ranging
from 6.25-50 mg/day, has the most extensive clinical
evidence base. The necessity for routine hematological