Page 526 - Basic _ Clinical Pharmacology ( PDFDrive )

512 SECTION V Drugs That Act in the Central Nervous System

separate disorders but rather to be part of a continuum of brain 5-HT receptors leads to inhibition of cortical and limbic dopa-
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disorders with psychotic features. mine release. Many atypical antipsychotic drugs, eg, clozapine,
asenapine, and olanzapine, are 5-HT inverse agonists. 5-HT
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Nature of Psychosis & Schizophrenia agonists are currently being studied as antipsychotic agents.
The term “psychosis” denotes a variety of mental disorders that
are characterized by the inability to distinguish between what is THE DOPAMINE HYPOTHESIS OF
real and what is not: the presence of delusions (false beliefs); vari- SCHIZOPHRENIA
ous types of hallucinations, usually auditory or visual, but some-
times tactile or olfactory; and grossly disorganized thinking in a The dopamine hypothesis for schizophrenia was the second
clear sensorium. Schizophrenia is a particular kind of psychosis neurotransmitter-based concept to be developed but is no longer
characterized mainly by a clear sensorium but a marked thinking considered adequate to explain all aspects of schizophrenia, especially
and perceptual disturbance. Schizophrenia is the most common the cognitive impairment. Nevertheless, it is still highly relevant to
psychotic disorder, present in about 1% of the population and understanding the major dimensions of schizophrenia, such as posi-
responsible for approximately half of long-term psychiatric hos- tive (hallucinations, delusions) and negative symptoms (emotional
pitalizations. Psychosis is not unique to schizophrenia and is not blunting, social withdrawal, lack of motivation), cognitive impair-
present in all patients with schizophrenia at all times. ment, and possibly depression. It is also essential to understanding the
Schizophrenia is considered to be a neurodevelopmental disor- mechanisms of action of most and probably all antipsychotic drugs.
der. This implies that structural and functional changes in the brain Several lines of evidence suggest that excessive limbic dopami-
are present even in utero in some patients, or that they develop dur- nergic activity plays a role in psychosis. (1) Many antipsychotic
ing childhood and adolescence, or both. Twin, adoption, and fam- drugs strongly block postsynaptic D receptors in the central
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ily studies have established that schizophrenia is a genetic disorder nervous system, especially in the mesolimbic and striatal-frontal
with high heritability. No single gene is involved. Current theories system; this includes partial dopamine agonists, such as aripiprazole,
involve multiple genes with common and rare mutations, including brexpiprazole, and bifeprunox. (2) Drugs that increase dopaminer-
large deletions and insertions (copy number variations), combining gic activity, such as levodopa, amphetamines, and bromocriptine
to produce a very variegated clinical presentation and course. and apomorphine, either aggravate schizophrenia psychosis or pro-
duce psychosis de novo in some patients. (3) Dopamine-receptor
density has been found postmortem to be increased in the brains
THE SEROTONIN HYPOTHESIS OF of schizophrenics who have not been treated with antipsychotic
SCHIZOPHRENIA drugs. (4) Some but not all postmortem studies of schizophrenic
subjects have reported increased dopamine levels and D -receptor
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The discovery that indole hallucinogens such as LSD (lysergic acid density in the nucleus accumbens, caudate, and putamen. (5) Imag-
diethylamide) and mescaline are serotonin (5-HT) agonists led to ing studies have shown increased amphetamine-induced striatal
the search for endogenous hallucinogens in the urine, blood, and dopamine release, increased baseline occupancy of striatal D recep-
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brains of patients with schizophrenia. This proved fruitless, but tors by extracellular dopamine, and other measures consistent with
the identification of many 5-HT-receptor subtypes led to the piv- increased striatal dopamine synthesis and release.
otal discovery that 5-HT -receptor and possibly 5-HT stimu- However, the dopamine hypothesis is far from a complete
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lation was the basis for the hallucinatory effects of these agents. explanation of all aspects of schizophrenia. Diminished cortical or
It has been found that 5-HT -receptor blockade is a key factor hippocampal dopaminergic activity has been suggested to underlie
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in the mechanism of action of the main class of second-generation the cognitive impairment and negative symptoms of schizophrenia.
antipsychotic drugs, of which clozapine is the prototype and which Postmortem and in vivo imaging studies of cortical, limbic, nigral,
includes, in order of their introduction around the world, melp- and striatal dopaminergic neurotransmission in schizophrenic sub-
erone, risperidone, zotepine, blonanserin, olanzapine, quetiapine, jects have reported findings consistent with diminished dopaminer-
ziprasidone, aripiprazole, sertindole, paliperidone, iloperidone, gic activity in these regions. Decreased dopaminergic innervation in
asenapine, lurasidone, cariprazine, and brexpiprazole. These drugs medial temporal cortex, dorsolateral prefrontal cortex, and hippo-
are inverse agonists of the 5-HT receptor; that is, they block the campus, and decreased levels of DOPAC, a metabolite of dopamine,
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constitutive activity of these receptors. These receptors modulate in the anterior cingulate have been reported in postmortem studies.
the release of dopamine, norepinephrine, glutamate, GABA, Imaging studies have found increased prefrontal D -receptor levels
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and acetylcholine, among other neurotransmitters in the cortex, that correlated with working memory impairments.
limbic region, and striatum. Stimulation of 5-HT receptors The fact that several of the atypical antipsychotic drugs have
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leads to depolarization of glutamate neurons, but also stabiliza- much less effect on D receptors and yet are effective in schizo-
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tion of N-methyl-d-aspartate (NMDA) receptors on postsynaptic phrenia has redirected attention to the role of other dopamine
neurons. It has been found that hallucinogens can modulate the receptors and to nondopamine receptors. Serotonin receptors—
and NMDA receptors. -receptor subtype—may mediate synergis-
stability of a complex consisting of 5-HT 2A particularly the 5-HT 2A
5-HT -receptor stimulation provides a further means of mod- tic effects or protect against the extrapyramidal consequences of
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ulating cortical and limbic dopaminergic activity. Stimulation of D antagonism. As a result of these considerations, the direction
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