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

Pharmacotherapy of Psychosis
and Mania
Jonathan M. Meyer
TREATMENT OF PSYCHOSIS
Psychosis is a symptom of mental illnesses characterized
by a distorted or non-existent sense of reality. Psychotic disorders
have different etiologies, each of which demands a
unique treatment approach. Common psychotic disorders
include mood disorders (major depression or mania) with
psychotic features, substance-induced psychosis, dementia
with psychotic features, delirium with psychotic features,
brief psychotic disorder, delusional disorder, schizoaffective
disorder, and schizophrenia. Schizophrenia has a worldwide
prevalence of 1% and is considered the prototypic
disorder for understanding the phenomenology of psychosis
and the impact of antipsychotic treatment, but
patients with schizophrenia exhibit features that
extend beyond those seen in other psychotic illnesses.
Hallucinations, delusions, disorganized speech, and disorganized
or agitated behavior comprise the types of psychotic
symptoms found individually, or rarely together, in
all psychotic disorders, and are typically responsive to pharmacotherapy.
In addition to positive symptoms, schizophrenia
patients also suffer from negative symptoms (apathy,
avolition, alogia), and cognitive deficits, particularly
deficits in working memory, processing speed, social cognition,
and problem solving that test 1.5-2 standard deviations
below population norms (Green et al., 2004).
Cognitive dysfunction is the strongest predictor of functional
impairment among schizophrenia patients, yet negative
symptoms and cognitive deficits show limited
improvement with antipsychotic treatment (Buchanan
et al., 2007). That schizophrenia is not identical to other
psychoses is important for appreciating the differential
impact of antipsychotic medications on psychotic
symptomatology, and for understanding the rationale for
non-dopaminergic antipsychotic drugs based on the
underlying pathophysiology of schizophrenia (Carpenter
and Koenig 2008).
The Dopamine Hypothesis. The development of our understanding
of the neurobiology and pharmacotheorapy of psychoses profited from
the synthesis of chlorpromazine in 1950 and of haloperidol in 1958.
The DA hypothesis of psychosis derived from the fortuitous discovery
of chlorpromazine’s therapeutic efficacy in schizophrenia, and the
subsequent elucidation by Carlsson that postsynaptic DA D 2
receptor
antagonism was the common mechanism that explained antipsychotic
properties. Reserpine, derived from Rauwolfia, exhibited antipsychotic
properties by decreasing dopaminergic neurotransmission; however,
unlike D 2
receptor antagonists, reserpine exerted its effects through
depletion of monoamines from presynaptic nerve terminals. The
dopamine theory of psychosis was reinforced by the high risk for druginduced
psychosis among substances that directly increased synaptic
dopamine availability, including cocaine, amphetamines, and the
Parkinson’s disease treatment L-dopa (Carlsson, 1978).
The dopamine (DA) overactivity hypothesis has
led to the development of the first therapeutic class of
antipsychotic agents, now referred to as typical or firstgeneration
antipsychotic drugs. These medications differed
in potency, but shared the common mechanism of
significant DA D 2
blockade and associated risk for
extrapyramidal side effects. In the past, the term “neuroleptic”
was also employed to refer to typical antipsychotic
drugs, literally meaning to “take hold of the
nerves” in Greek, but this has been dropped from contemporary
usage (as has the term “major tranquilizer”)
in favor of “antipsychotic drug,” a term that more accurately
reflects the primary clinical use of these agents.
While the DA hypothesis is an advance over earlier
conceptualizations of psychosis, it has limitations,
and does not account for the cognitive deficits associated
with schizophrenia that appear to be related to
decreased DA signaling in the prefrontal cortex. The
DA hypothesis also does not explain the psychotomimetic
effects of agonists of other pathways
(e.g., d-lysergic acid, a potent serotonin 5-HT 2
receptor
agonist), or the effects of phencyclidine and ketamine,
antagonists of the N-methyl-D-aspartate (NMDA)