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

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SECTION II
NEUROPHARMACOLOGY
antipsychotic switching, and history of response to
prior agents. Patients with refractory schizophrenia on
clozapine are not good candidates for switching because
they are resistant to other medications (see the definition
of refractory schizophrenia later in this section).
There are many reasons for psychotic relapse or inadequate
response to antipsychotic treatment in schizophrenia patients.
Examples are ongoing substance use, psychosocial stressors, inherent
refractory illness, and poor medication adherence. Outside of
controlled settings, the problem of medication nonadherence remains
a significant barrier to successful treatment, yet one that is not easily
assessed. Serum drug levels can be obtained for most antipsychotic
medications, but there is limited dose-response data for
atypical antipsychotic agents (except for clozapine), leaving clinicians
little guidance about the interpretation of antipsychotic drug
levels. Even low or undetectable levels may not reflect nonadherence,
but rather can be the result of genetic variation or induction of
hepatic CYPs that decrease drug availability, such as the high prevalence
of CYP2D6 ultrarapid metabolizers among individuals from
North Africa and the Middle East. Nevertheless, the common problem
of medication nonadherence among schizophrenia patients has
led to the development of long-acting injectable (LAI) antipsychotic
medications, often referred to as depot antipsychotics. They are more
widely used in the E.U. Only < 5% of U.S. patients receive depot
antipsychotic treatment. There are currently four available LAI
forms in the U.S.: decanoate esters of fluphenazine and haloperidol,
risperidone-impregnated microspheres, and paliperidone palmitate.
Patients receiving LAI antipsychotic medications show consistently
lower relapse rates compared to patients receiving comparable oral
forms and may suffer fewer adverse effects. LAI risperidone and
paliperidone palmitate are currently the only atypical antipsychotic
agents in depot form. However, clinical trials of LAI aripiprazole
and olanzapine are in progress and these agents should become available
in the near future. LAI risperidone is administered as biweekly
intramuscular (IM) injections of 25-50 mg. Based on extensive
kinetic modeling of clinical data, paliperidone palmitate therapy in
acute schizophrenia is initiated with IM deltoid loading doses of
234 mg at day 1 and 156 mg at day 8 to provide serum paliperidone
levels equivalent to 6 mg oral paliperidone during the first week,
obviating the need for oral antipsychotic supplementation. Serum
paliperidone levels from these two injections peak on day 15 at a
level comparable to 12 mg oral paliperidone. Maintenance IM doses
are given in deltoid or gluteus muscle every 4 weeks after day 8.
Unlike acute IM preparations or paliperidone palmitate, all other
LAI antipsychotic medications require several weeks to attain therapeutic
levels and months to reach steady state, necessitating the use
of oral medications for the initial 4 weeks of treatment.
Lack of response to adequate antipsychotic drug
doses for adequate periods of time may indicate treatmentrefractory
illness. Refractory schizophrenia is defined
using the Kane criteria: failed 6-week trials of two separate
agents and a third trial of a high-dose typical
antipsychotic agent (e.g., haloperidol or fluphenazine
20 mg/day). In this patient population, response rates to
typical antipsychotic agents, defined as 20% symptom
reduction using standard rating scales (e.g., Positive and
Negative Syndrome Scale [PANSS]), are 0%, and for
any atypical antipsychotic except clozapine, are < 10%
(Leucht et al., 2009). Due to the long titration involved
to minimize orthostasis, and to sedation and other tolerability
issues, adequate clozapine trials often require
6 months, but response rates in 26-week-long studies
are consistently 60% in refractory schizophrenia
patients. The therapeutic clozapine dose for a specific
patient is not predictable, but various studies have found
correlations between trough serum clozapine levels
> 327-504 ng/mL and likelihood of clinical response.
When therapeutic serum concentrations are reached,
response to clozapine occurs within 8 weeks.
In addition to agranulocytosis risk that mandates routine
ongoing hematological monitoring, clozapine has numerous other
adverse effects. Examples are high metabolic risk, dose-dependent
lowering of the seizure threshold, orthostasis, sedation, anticholinergic
effects (especially constipation), and sialorrhea related to muscarinic
agonism at M 4
receptors. As a result, clozapine use is limited
to refractory schizophrenia patients.
Electroconvulsive therapy is considered a treatment of last
resort in refractory schizophrenia and is rarely employed. Despite
widespread clinical use of combining several antipsychotic agents,
there is virtually no data supporting this practice, and metabolic risk
increases with use of multiple antipsychotic agents (Correll et al.,
2007). In one of few instances where a sound pharmacological
rationale exists for combination treatment, the addition of a potent D 2
antagonist (e.g., risperidone, haloperidol) to maximally tolerated
doses of clozapine (a weak D 2
blocker), the results have been decidedly
mixed. That multiple antipsychotic agents (“polypharmacy”)
are commonly used in clinical practice attests to the limitations of
current treatment. Lastly, antipsychotic drug therapy is the foundation
of schizophrenia treatment, yet adequate management of schizophrenia
patients requires a multimodal approach that also includes
psychosocial, cognitive, and vocational rehabilitation to promote
functional recovery.
Pharmacology of Antipsychotic Agents
Chemistry. In the past, the chemical structure of selected agents was
informative regarding their antipsychotic activity, since most were
derived from phenothiazine or butyrophenone structures.
Phenothiazines have a tricyclic structure in which two benzene rings
are linked by a sulfur and a nitrogen atom (Table 16–1). The chemically
related thioxanthenes have a carbon in place of the nitrogen at position
10 with the R 1
moiety linked through a double bond. Substitution
of an electron-withdrawing group at position 2 increases the antipsychotic
efficacy of phenothiazines (e.g., chlorpromazine). The nature
of the substituent at position 10 also influences pharmacological
activity, and the phenothiazines and thioxanthenes can be divided into
three groups on the basis of substitution at this site. Those with an
aliphatic side chain include chlorpromazine and are relatively low in
potency. Those with a piperidine ring in the side chain include thioridazine,
which has lower EPS risk, possibly due to increased central