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

of substance-induced psychoses, removal of the offending
agent results in prompt improvement of psychotic symptoms
with no further need for antipsychotic therapy. This
may not apply to advanced Parkinson’s disease patients,
for whom L-dopa cannot be stopped and for whom
ongoing antipsychotic treatment may be necessary
(Chapter 22). Patients with psychosis related to mood disorders,
in particular manic patients, may have antipsychotic
treatment extended for several months after
resolution of the psychosis, since antipsychotic medications
are effective in controlling mania symptoms. Chronic
psychotic symptoms in dementia patients may also be
amenable to drug therapy, but potential benefits must be
balanced with the documented risk of mortality and cerebrovascular
events associated with the use of antipsychotic
medications in this patient population (Jeste et al., 2008).
Delusional disorder, schizophrenia, and schizoaffective disorder
are chronic diseases that require long-term antipsychotic treatment,
although there are few reliable studies of treatment outcomes
for delusional disorder patients. Individuals with monosymptomatic
delusions (e.g., paranoia, marital infidelity) do not have neurocognitive
dysfunction and may continue to perform work and social functions
unaffected by their illness, aside from behavioral consequences
related to the specific delusional belief (American Psychiatric
Association, 2000). These patients often have limited or no psychiatric
contact outside of mandated legal interventions, thus limiting
the opportunity for clinical trials. For schizophrenia and schizoaffective
disorder, the goal of antipsychotic treatment is to maximize
functional recovery by decreasing the severity of positive symptoms
and their behavioral influence, improving negative symptoms,
decreasing social withdrawal, and remediating cognitive dysfunction.
That only 15% of chronic schizophrenia patients are employed
in any capacity and 11% are married has been attributed to the relatively
limited effect of treatment on core negative and cognitive
symptoms of the illness (Lieberman et al., 2005). Nonetheless, continuous
antipsychotic treatment reduces 1-year relapse rates from
80% among unmedicated patients, to ~15%. Poor adherence to
antipsychotic treatment increases relapse risk, and is often related
to adverse drug events, cognitive dysfunction, substance use, and
limited illness insight.
Regardless of the underlying pathology, the
immediate goal of antipsychotic treatment is a decrease
in acute symptoms that induce patient distress, particularly
behavioral symptoms (e.g., hostility, agitation)
that may present a danger to the patient or others. The
dosing, route of administration, and choice of antipsychotic
depend on the underlying disease state, clinical
acuity, drug-drug interactions with concomitant
medications, and patient sensitivity to short- or longterm
adverse effects. With the exception of clozapine’s
superior efficacy in treatment-refractory schizophrenia
(Leucht et al., 2009), neither the clinical presentation
nor biomarkers predict the likelihood of response to a
specific antipsychotic class or agent. As a result, avoidance
of adverse effects based upon patient and drug
characteristics, or exploitation of certain medication
properties (e.g., sedation related to histamine H 1
or
muscarinic antagonism) are the principal determinants
for choosing initial antipsychotic therapy.
All commercially available antipsychotic drugs
reduce dopaminergic neurotransmission (Figure 16–1).
This finding implicates D 2
blockade (or, in the case of
aripiprazole, modulation of DA activity) as the primary
therapeutic mechanism. Chlorpromazine and other early
low-potency typical antipsychotic agents are also profoundly
sedating, a feature that used to be considered
relevant to their therapeutic pharmacology. The development
of the high-potency typical antipsychotic agent
haloperidol, a drug with limited H 1
and M 1
affinity and
significantly less sedative effects, and the clinical efficacy
of intramuscular forms of nonsedating newer
antipsychotic drugs, aripiprazole and ziprasidone,
demonstrate that sedation is not necessary for antipsychotic
activity, although at times desirable.
Short-Term Treatment
Delirium and Dementia. Disease variables have considerable
influence on selection of antipsychotic agents.
Psychotic symptoms of delirium or dementia are generally
treated with low medication doses, although
doses may have to be repeated at frequent intervals initially
to achieve adequate behavioral control (Lacasse
et al., 2006). Despite widespread clinical use, not a single
antipsychotic drug has received approval for dementiarelated
psychosis. Moreover, all antipsychotic drugs
carry warnings that they may increase mortality in this
setting (Jeste et al., 2008). Because anticholinergic drug
effects may worsen delirium (Hshieh et al., 2008) and
dementia, high-potency typical antipsychotic drugs
(e.g., haloperidol) or atypical antipsychotic agents with
limited antimuscarinic properties (e.g., risperidone)
are often the drugs of choice (Jeste et al., 2008; Lacasse
et al., 2006).
The best-tolerated doses in dementia patients are one-fourth
of adult schizophrenia doses (e.g., risperidone 0.5-1.5 mg/day),
although extrapyramidal neurological symptoms (EPS), orthostasis,
and sedation are particularly problematic in this patient population
(Chapter 22). Significant antipsychotic benefits are usually seen in
acute psychosis within 60-120 minutes after drug administration.
Delirious or demented patients may be reluctant or unable to swallow
tablets, so oral dissolving tablet (ODT) preparations for risperidone,
aripiprazole, and olanzapine, or liquid concentrate forms of
risperidone or aripiprazole, are options. The dissolving tablets adhere
CHAPTER 16
PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
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