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

418 glutamate receptor. Advances in treatment have
emerged from exploration of alternative (non-dopaminergic)
mechanisms for psychosis and from experience
with atypical antipsychotic agents such as clozapine.
These newer antipsychotics potently antagonize the
5-HT 2
receptor, while blocking D 2
receptors less
potently than older typical antipsychotic agents, resulting
in the atypical clinical profile of antipsychotic efficacy
with limited extrapyramidal side effects. Also
promising are medications that target glutamate and
5-HT 7
receptor subtypes, receptors for γ-aminobutyric
acid (GABA) and acetylcholine (both muscarinic and
nicotinic), and even peptide hormone receptors (e.g.,
oxytocin) (Carpenter and Koenig, 2008).
SECTION II
NEUROPHARMACOLOGY
Review of Relevant Pathophysiology
Not all psychosis is schizophrenia, and the pathophysiology
relevant to effective schizophrenia treatment may not
apply to other psychotic disorders. The effectiveness of
dopamine D 2
antagonists for the positive symptoms of
psychosis seen in most psychotic disorders suggests a
common etiology for these symptoms related to excessive
dopaminergic neurotransmission in mesolimbic
dopamine pathways. In substance-induced psychotic disorders,
the substance may directly increase postsynaptic
DA activity through increased presynaptic neurotransmitter
release (amphetamine), inhibition of presynaptic
DA reuptake (methylphenidate, cocaine, and amphetamine),
or increased DA availability (L-dopa). The
NMDA antagonists phencyclidine and ketamine indirectly
act to stimulate DA availability by decreasing the
glutamate-mediated tonic inhibition of DA release in the
mesolimbic DA pathway.
The psychoses related to delirium and dementia, particularly
dementia of the Alzheimer type, may share a common etiology: the
deficiency in cholinergic neurotransmission, either due to anticholinergic
properties of medications (Chew et al., 2008), age- or diseaserelated
neuronal loss, or both (Barten and Albright, 2008; Hshieh
et al., 2008). Among hospitalized elderly patients, increased plasma
concentrations of anticholinergic medications are directly associated
with increased delirium risk (Flacker and Lipsitz, 1999); however,
unlike in Alzheimer’s dementia, where psychotic symptoms are
directly related to cholinergic neuronal loss and may respond to
acetylcholinesterase therapy, delirium may have numerous precipitants
besides medication-associated anticholinergic properties, all of
which require specific treatment (e.g., infection, electrolyte imbalance,
metabolic derangement) in addition to removal of offending
anticholinergic medications.
Schizophrenia is a neurodevelopmental disorder with complex
genetics and incompletely understood pathophysiology. Certain
environmental exposures confer an increased risk of developing
schizophrenia, including fetal second-trimester viral and nutritional
insults, birth complications, and substance abuse in the late teen or
early adult years (Fanous and Kendler, 2008). Rather than being the
result of a single gene defect, mutations or polymorphisms of many
genes appear to contribute to the risk for schizophrenia. Implicated
are genes that regulate neuronal migration and synaptogenesis
(neuregulin 1), synaptic DA availability (Val{108/158}Met polymorphism
of catechol-O-methyltransferase, which increases DA catabolism),
glutamate and DA neurotransmission (dystrobrevin binding
protein 1 or dysbindin, particularly with schizophrenia patients
with prominent negative symptoms), nicotinic neurotransmission
(α7-receptor polymorphisms), and cognition (disrupted-inschizophrenia-1)
(Porteous, 2008). Schizophrenia patients also have
increased rates of genome-wide DNA microduplications termed
copy number variants (Need et al., 2009) and epigenetic changes,
including disruptions in DNA methylation patterns in various brain
regions (Porteous, 2008). This genetic variability is consistent with
the clinical disease heterogeneity, and suggests that any one specific
mechanism is unlikely to account for large amounts of disease risk.
In addition to increased mesolimbic DA activity related to positive
symptoms, schizophrenia patients have decreased DA D 1
activity in
the dorsolateral and ventromedial prefrontal cortex (PFC) that is
associated with cognitive deficits and negative symptoms (Buchanan
et al., 2007).
Cognitive dysfunction is the greatest predictor of poor functional
outcome in schizophrenia and shows limited response to
antipsychotic treatment. Experimental studies have provided new
insights into the mechanisms of cognitive dysfunction. Glutamate
NMDA receptor stimulation is involved in tonic inhibition of
mesolimbic DA release, but facilitates mesocortical DA release
(Sodhi et al., 2008). Ketamine infusion studies in animals and
healthy volunteers demonstrate that decreased NMDA function
results in a picture that more accurately encompasses all aspects of
schizophrenia, including positive, negative, and cognitive symptoms,
and social withdrawal. Several of the newer antipsychotic drugs
remediate not only the positive psychotic symptoms but also the cognitive
disruption induced by ketamine and other potent NMDA
antagonists such as MK-801 (dizocilpine). These results have
prompted the clinical investigation of agents without affinity for DA
receptors, but with potent agonist properties at metabotropic glutamate
receptor subtypes (Patil et al., 2007).
Review of Psychosis Pathology and
the General Goals of Pharmacotherapy
Common to all psychotic disorders are positive symptoms,
which may include hallucinatory behavior, disturbed
thinking, and behavioral dyscontrol. For many psychotic
disorders the state of psychosis is transient, and antipsychotic
drugs are only administered during and shortly after
periods of symptom exacerbation. Patients with delirium,
dementia, mania or major depressive disorder with psychotic
features, substance-induced psychoses, and brief
psychotic disorder will typically receive short-term
antipsychotic treatment that is discontinued after resolution
of psychotic symptoms, although the duration may
vary considerably based upon the etiology. In the majority