Neurochemical Theories
Dopamine
is the most extensively investigated neurotransmitter system in schizophrenia.
In 1973 it was proposed that schizo-phrenia is related to hyperactivity of
dopamine. This proposition became the dominant pathophysiological hypothesis
for the next 15 years. Its strongest support came from the fact that all
com-mercially available antipsychotic agents have antagonistic effects on the
dopamine D2 receptor
in relation to their clinical potencies (Creese et al., 1975). In addition, dopamine
agonists, such as am-phetamine and methylphenidate, exacerbate psychotic
symptoms in a subgroup of patients with schizophrenia. Moreover, as noted
earlier, the most consistently reported postmortem finding in the literature of
schizophrenia is elevated D2
receptors in the striatum.
The
dopamine hyperactivity hypothesis and the primacy of D2 antagonism for antipsychotic drug action were seriously ques-tioned
largely because of the advent of clozapine, an atypical an-tipsychotic drug.
Clozapine has proved to be the most efficacious treatment for chronic
schizophrenia and yet it has one of the lowest levels of D2 occupancy of all antipsychotic drugs. This started an extensive search
for explanations underlying the extraordinary ef-ficacy of clozapine. However,
new information from PET studies has once again highlighted the central role
that the dopaminergic system plays in treatment of psychosis. The typical and
atypical antipsychotics are effective only when their D2 receptor occupancy exceeds 65%, reinforcing the importance of D2 antagonism in pro-ducing antipsychotic effects. However, an important
difference between typical and atypical antipsychotics is in their affinity for
the D2
receptors. Medications like clozapine attach loosely to and dissociate rapidly
from the dopamine D2
receptors compared with typical antipsychotic agents (like haloperidol) which
have strong affinity for and bind tightly to these receptors.
Five subtypes of dopamine receptor have now been dis-covered, D1, D2, D3, D4 and D5, and interest in dopamine
recep-tors other than the D2 receptor has arisen. Reduced levels of D1-like dopamine receptors in the
prefrontal cortex of patients with schizophrenia including in those never
exposed to antipsy-chotic agents have been reported. The D1 receptors are expressed
predominantly by pyramidal neurons on their dendritic spines, where they
possibly modulate glutamate-mediated inputs to these neurons – inputs that
mainly come from other pyramidal and thalamic neurons. Thus the reduced D1-like receptors seen in the
prefrontal cortex of schizophrenia patients may underlie aspects of cognitive
dysfunction and severity of negative symp-toms (Nestler, 1997).
Clinical trials of dopamine agonists have resulted in im-provements in
the negative symptoms of schizophrenia. A new model of dopamine dysfunction was
proposed which stated that deficits in dopamine, perhaps in the prefrontal
cortex, may result in negative symptoms and that concomitant dopamine
dysregula-tion in the striatum, perhaps related to faulty presynaptic control
of dopamine release, may be involved in positive symptoms. This bidirectional
model is under investigation.
The DA hypothesis of schizophrenia has been critical in guiding
schizophrenia research for several decades. Until re-cently, a main shortcoming
of this hypothesis was absence of di-rect evidence linking DA dysfunction to
schizophrenia. Sophis-ticated in vivo
techniques have provided fascinating data directly implicating dopamine in
developing psychosis. It is also becom-ing clear that dopamine works closely
with serotonin, glutamate and other systems such that changes in one system
affects the balance of the other systems too.
Clozapine
has a relatively high affinity for specific serotonin (5-hydroxytryptamine
[5-HT]) receptors (5-HT2A and 5-HT2C) and risperidone, has even greater serotonin
antagonistic properties. Clozapine, risperidone, olanzapine, quetiapine and
ziprasidone, the novel antipsychotic agents, have a greater ratio of serotonin
5-HT2A to
dopamine D2 binding
affinity. This has led to the hypoth-esis that the balance between serotonin
and dopamine may be altered in schizophrenia. Serotonin 5-HT2A (and other serotonin) receptor occupancy by the
antipsychotic drugs, depending on the areas of the brain involved, could be
associated with improve-ment in cognition, depression and D2 receptor mediated EPS.
There has been an explosion of new information about the structure and
function of 5-HT receptors. To date, 15 serotonin receptor subtypes have been
identified. Two receptors, 5-HT6 and 5-HT7, have been proposed as candidates for atypical drug ac-tion and are
therefore reasonable targets for pathophysiological studies of schizophrenia.
It is clear that the field is in the early stages of understanding the possible
involvement of serotonin in schizophrenia.
Glutamate is a major brain excitatory amino acid neurotrans-mitter and
is critically involved in learning, memory and brain development. Interest in
glutamate and the NMDA receptor in schizophrenia arose because of the
similarity between phencycli-dine (PCP) psychosis and the psychosis of
schizophrenia. PCP is a noncompetitive antagonist of the NMDA receptor and
produces a psychotic state that includes conceptual disorganization, audi-tory
hallucinations, delusions and negative symptoms. PCP pro-duces more symptoms
that are similar to those of schizophrenia than most other pharmacological
agents.
PCP and other highly potent NMDA receptor antagonists cause neuronal
damage and therefore are not used as research tools in clinical populations.
However, ketamine, a widely used dissociative anesthetic, is another
noncompetitive NMDA antag-onist and, at subanesthetic doses, produces a
PCP-like psychosis resembling schizophrenia. The glutamate hypothesis of
schizo-phrenia is one of the most active areas of research currently. The NMDA
receptor is reported to play a critical role in guiding axons to their final
destination during neurodevelopment. Also, abnormalities with glutamate
transmission is reported in many areas of the brain such as frontal cortex,
hippocampus, limbiccortex, striatum and thalamus. Moreover, there are changes
re-ported in the gene expression in these areas, Hypoglutamatergia in
schizophrenia may have very important downstream modu-latory effects on
catecholaminergic neurotransmission and play a critical role during
neurodevelopment. It also plays an impor-tant role in synaptic pruning and
underlies important aspects of neurocognition.
GABA is the major inhibitory neurotransmitter in brain. Sup-port for
GABA’s involvement in schizophrenia comes from two lines of investigation.
First, clinical trials have demonstrated that benzodiazepines, administered
both in conjunction with antipsychotic drugs and as the sole treatment, are
effective at reducing symptoms in subgroups of schizophrenia patients.
Benzodiazepines are agonists at GABAA receptors. Secondly, postmortem studies have found a deficit in GABA
interneurons in the anterior cingulum and prefrontal cortex and decreased GABA
uptake sites in the hippocampus. GABAergic neurons are especially vulnerable to
glucocorticoid hormones and also to glutamatergic excitotoxicity.
Several peptides have been hypothesized to play a pathophysi-ological
role in schizophrenia. Interest in neurotensin arose be-cause of the discovery
that it is colocalized in some dopaminergic neurons and acts as a
neuromodulator of this and other neuro-transmitters. In preclinical studies,
neurotensin was found to have effects that resembled those of antipsychotic
drugs (Kasckow and Nemeroff, 1991. In addition, schizophrenia patients were
found to have lower cerebrospinal fluid neurotensin levels than healthy control
subjects and other patients with neuropsychiatric disor-ders. Other peptides
that are under consideration for a patho-physiological role in schizophrenia
are somatostatin, dynorphin, substance P and neuropeptide Y.
Heightened noradrenergic function has been implicated in psychotic relapse
in subgroups of schizophrenia patients (van Kammen et al., 1990). In addition, clozapine, but not other neu-roleptic
drugs, consistently produces increases in central and pe-ripheral indices of
noradrenergic function, and one study found
significant relationship between
increases in plasma norepine-phrine and improvement in positive symptoms.
Carlsson and colleagues (2001) provide a multineurotransmitter theory of
schizophrenia which improves upon previous biochem-ical theories of
schizophrenia. Accumulating evidence suggests that hyperdopaminergia in
schizophrenia is probably second-ary to some other phenomena. The data
involving glutamater-gic system suggests that NMDA receptor antagonism enhances
the spontaneous and amphetamine-induced release of dopamine and thus raises the
possibility that hypoglutamatergia
could be related to the hyperdopaminergia.
Carlsson and colleagues propose that psychotogenesis depends on an interaction
between dopamine and glutamate pathways projecting to the striatum from the
lower brain stem and cortex respectively. These neu-rotransmitters are
predominantly antagonistic to each other, the former being inhibitory and the
latter stimulatory when acting on striatal GABAergic projection neurons. These
GABAergic neurons belong to striatothalamic pathways, which exert an inhibitory
action on thalamocortical glutamatergic neurons, thereby filtering off part of
the sensory input to the thalamus to protect the cortex from a sensory overload
and hyperarousal. Hyperactivity of dopamine or hypofunction of the
corticostriatal glutamate pathway should reduce this protective influence and
could thus lead to confusion or psychosis. As a result, the in-direct
striatothalamic pathways have an inhibitory influence on the thalamus with the
corresponding direct pathways exerting an opposite and excitatory influence.
Both pathways are controlled by glutamatergic corticostriatal pathways enabling
the cortex to regulate the thalamic gating in opposite directions. Thus,
accord-ing to Carlsson and colleagues they appear to serve as brakes and accelerators.
It has been suggested that the activity of the direct path-ways is
predominantly phasic and of the indirect pathways is mainly tonic. This
difference could have important consequences for a different responsiveness of
the direct and indirect pathways to drugs. Thus the NMDA receptor antagonists
are behavioral stimulants. AMPA receptor antagonists act in the same direction
as NMDA antagonists in some and opposite direction in other experiments. The
relationship between glutamate and serotonin is very important and interesting.
Serotonin appears to play a more important role than dopamine in the behavioral
stimula-tion induced by hypoglutamatergia. Serotonin may play a more prominent
role than dopamine in the behavioral stimulation in-duced by hypoglutamatergia.
Schizophrenia is a syndrome of heterogeneous etiology and pathology. If one
neurotransmitter is disturbed, it will inevitably have an impact on other
neurotrans-mitters (Carlsson et al.,
2001).
Neurodevelopmental hypotheses of schizophrenia posit that a disruption
in normal development causes the illness (Wein-berger, 1987). Thus, the
“lesion” occurs well before the onset of the illness and interacts with
maturation events such as neu-ronal precursor, glial proliferation and
migration; axonal and dendritic proliferation; myelination of axons; programmed
cell death and synaptic pruning and is in all likelihood a nonpro-gressive
disease process. Support for the neurodevelopment hypothesis includes the fact
that the majority of patients with schizophrenia do not have a course of
illness marked by progres-sive deterioration such as found in dementias. In
addition, brain morphological abnormalities commonly found in this illness,
such as enlarged ventricles and reduced mesolimbic structures, do not appear to
be progressive and, in fact, are present at the on-set of the illness.
Moreover, gliosis, which occurs during active pathological processes as part of
the cellular reparative process in mature brains, is not commonly found in postmortem
studies of schizophrenia.
That illness onset typically occurs in the teenage years and early
twenties, as opposed to earlier in life when the pro-posed pathogenic insult
occurs, has been explained by the fact that brain regions implicated in this
illness, such as prefrontal cortex, are still undergoing myelination during the
adolescent years and are therefore not fully functional until that time. Thus,
an early lesion involving this region could remain silent until adolescence,
when its normal functional capacity is expected to be realized. However, these
assumptions have proven to be controversial.
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