Download Figure1: graphic representation of the connecting positive and

Connecting positive and negative symptoms of schizophrenia via the NMDA and
Dopaminergic processes.
Abstract
Phillips and Silverstein largely exclude the presence of the positive schizophrenic
symptoms within their article. If it could be proven that NMDA receptor function and
dopamine synapse function were connected in one continuous system, then an
underlying cause for both positive and negative symptoms of schizophrenia may be
identifiable. The evidence for a potential link that the affects of the drug PCP creates
between the NMDA and dopamine systems may provide evidence for an underlying
influence which may then affect diagnosis and treatment of schizophrenia and similar
disorders. This theory expands on the NMDA receptor channel influences mentioned
in the Phillips and Silverstein (2003) target article and suggests further investigation.
Schizophrenia is one of the most well known mental disorders throughout the
western world. Many theories have been developed over time in an attempt to identify
both a cause and a cure for schizophrenia. Although these theories have aided the
continued advancement of research into the disease, a definitive underlying cause of
schizophrenia remains to be identified. Without knowing what the root cause of a
disease is, it is very difficult to either prevent or cure it entirely. Schizophrenia is
widely considered to be heterogeneous. The symptoms are varied and include
positive, negative and disorganized symptoms as the three most significant categories.
The target article by Phillips and Silverstein (2003) primarily considers NMDA (Nmethyl-D-aspartate) receptor hypofunction to be a causal influence on both
disorganised and negative schizophrenic symptoms. The most reliable evidence to
suggest the connection between hypoactive NMDA receptors and negative symptoms
of schizophrenia was collected by Javitt and Zukin (1991). Their research involved
the drug PCP which, when taken in doses large enough to cause PCP-psychosis,
shares many symptoms with schizophrenia.
However, Phillips and Silverstein largely exclude the presence of the positive
schizophrenic symptoms within their article. The Dopamine Hypothesis (Delay and
Deniker, 1952) suggests that the hyperactivity of Dopaminergic synapses can cause
the positive symptoms of schizophrenia. While the knowledge that NMDA receptor
hypofunction may influence negative symptoms, and dopaminergic synapse
hyperfunction may influence positive symptoms, there is very little evidence to
connect the two systems together. If it could be proven that NMDA receptor function
and dopamine synapse function were connected in one continuous system, then an
underlying cause for both positive and negative symptoms of schizophrenia may be
identifiable. The implications of this discovery would be to encourage further research
into the underlying cause of schizophrenia and eventually into a single treatment for
all major schizophrenic symptoms. It would also be evidence against the
heterogeneity and for the homogeneity of schizophrenia.
This commentary will provide a theory that suggests a coordinated system
connecting NMDA receptor function and dopaminergic synapse function, and
therefore both negative and positive symptoms of schizophrenia respectively. This
theory will be an extension on the NMDA receptor research within the Phillips and
Silverstein article, potentially providing areas for continued future research into the
underlying biological causes of schizophrenia. Future research may also apply to
mental disorders with similarities to schizophrenia, such as autism.
PCP- NMDA antagonist and
creates D. hypoactivity in PFC
Positive
Symptoms
Hyperactivity of
dopaminergic
Synapses in the
Nucleus accumbens.
Dopamine
hypoactivity
in PFC
NMDA receptor
hypofunction
Negative
Symptoms
Figure1: graphic representation of the connecting positive and negative
schizophrenic symptom process.
The reduced activity within the voltage dependant NMDA receptor channels causes or
influences the negative schizophrenic symptoms (Fig. 1). The negative symptoms can
be treated using NMDA agonists or glycine agonists that increase the NMDA function
and therefore prevent the receptor from becoming hypoactive. Schizophrenic patients
appear to have NMDA hypofunction as do patients who have suffered from PCPpsychosis. Drugs such as PCP and Ketamine can cause negative schizophrenic
symptoms as they perform as indirect or non-competitive antagonists for NMDA
receptors.
The positive symptoms appear to be influenced by the dopamine pathways in
the brain (Fig. 1). The dopaminergic synapses within the dorsolateral prefrontal
cortex usually create enough dopamine to inhibit dopamine creation within the
mesolimbic pathway, or more specifically the nucleus accumbens. It appears that in
schizophrenic patients of PCP-psychosis sufferers, a loss of neurons within the
prefrontal cortex causes dopaminergic hypoactivity (Jentsch et al., 1999). This limit of
dopamine within the prefrontal cortex reduces the inhibitory affect on dopamine
production in the nucleus accumbens. The hyperactivity of the dopaminergic synapses
in the nucleus accumbens creates the positive symptoms of schizophrenia.
Evidence for the connection between the two systems comes from the
similarities that PCP-psychosis has with schizophrenia. Treating either ketamine or
PCP-psychosis with drugs such as clozapine appears to alleviate both the positive and
the negative schizophrenic based symptoms (Kinon and Lieberman, 1996). This
immediately suggests a possible link between the NMDA and Dopaminergic
processes. Furthermore, not only does PCP treatment act as an antagonist for NMDA
receptors causing negative symptoms, but it also causes dopaminergic hypoactivity in
the prefrontal cortex (Fig. 1). This then causes dopaminergic hyperactivity in the
nucleus accumbens, and eventually the positive symptoms of both PCP-psychosis and
schizophrenia. The potential link that the affects of the drug PCP create between the
NMDA and dopamine systems may provide evidence for an underlying influence
governing both the positive and negative symptoms of schizophrenia.
Although this theory suggests a single process and possible underlying
biological influence for both positive and negative symptoms, any possible cognitive
or external causes cannot be ignored. As with most complex systems it should be
expected that many other influences have a potential affect on the disorder. At its least
this theory is an expansion on the biological coordination in schizophrenia that is
mentioned in the target article by Phillips and Silverstein (2003). More specifically it
expands on the NMDA receptor hypofunction theory by suggesting possible
interactions that may occur between the NMDA receptor channels and other
neurological mechanisms within the brain. At its most this theory may suggest areas
of further research that may provide evidence for one or more underlying influences
that connect all aspects of schizophrenia. This would suggest a more homogeneic
view of the disorder. The prospects for both drug and cognitive treatment for
schizophrenia may also be improved by further investigation into this theory.
Identification of an underlying cause would also impact on the diagnosis and
treatment of other similar disorders.
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Date of retrieval: 20/05/2005
http://gestalttheory.net/archive/wert1.html