Can Phillips & Silversteins’ (2003) model explain why atypical antipsychotics
reduce the disorganized symptoms of schizophrenia? What implications might this
have for treating the condition?
A robust phenomenon to emerge from studies of schizophrenic individuals is that
atypical antipsychotic medication can help reduce the disorganized symptoms of the
disorder. The reasons for this, however, are largely unknown. Phillips & Silverstein
(2003) argue that a range of cognitive disturbances in schizophrenia result from a
deficit in cognitive coordination attributable to NMDA receptor dysfunction. They
suggest that some atypical drugs may enhance NMDA receptor activity and that this
may improve cognitive symptoms. They also suggest that this may lead to future
medications that can improve cognition in schizophrenia. If this were to be the case it
would add further support to their model. Here we briefly review findings in this area
and, as way of contrast, an alternative view of why atypical drugs may have positive
cognitive effects for schizophrenic patients.
Phillips & Silverstein (2003) present an intriguing model for schizophrenia extending
four levels of abstraction: molecules, cells, cognition and syndrome. The authors
focus primarily on the disorganized symptoms of schizophrenia. Their basic
argument can be summarised as follows: if the activity of NMDA glutamate receptors
in the cortex is below normal, the neural coordination within and between regions is
decreased, this in turn implies decreased cognitive coordination, such as
disambiguation and dynamic grouping; this will then be the direct cause of the
symptoms of schizophrenia, such as impairments of perception, preattentive gating,
selective attention, working memory and long term memory.
A question raised by Phillips & Silverstein (2003, p.89) is why do some atypical
antipsychotic medications reduce cognitive disorganization? This has proven a fairly
robust finding (see Meltzer & McGurk, 1999 for a review). Phillips & Silverstein
(2003, p.81) cite Mechri, Saoud, Khiari, d’Amato, Darley, Gaha (2001) who
concluded that colzapine significantly reduces ketamine induced positive symptoms
in some schizophrenic patients. More recently, Revely & Libretto (2004) concluded
that risperidone significantly improved cognitive deficits in schizophrenic patients.
Despite numerous findings like these, relatively little is known about the mechanisms
that mediate the cognitive enhancing effect of atypical antipsychotics. Phillips &
Silverstein (2003, p.81) provide a plausible explanation for these findings. They
suggest that atypical antipsychotics differ from traditional antipsychotics in that they
enhance NMDA receptor activity and, in line with their model, thus reduce cognitive
disorganization. They cite a study by Goff & Coyle (2001) as support for this idea.
These researchers concluded that the effects of some atypical antipsychotics
such as clozapine and olanzapine on NMDA receptors differentiate them from typical
antipsychotics, such as haloperidol. At least three general lines of evidence further
support Phillips & Silversteins’ (2003) ideas which can be summarized as follows: (1)
beyond Goff & Coyle (2001), other accumulating basic science data demonstrate that
presently used conventional and atypical neuroleptics affect differently various
aspects of glutamatergic neurotransmission, (2) indirect evidence stemming from the
principles of the phencyclidine (PCP) model of schizophrenia, suggest that
conventional neuroleptics cannot counter all aspects of schizophrenia
symptomatology, while a more favourable treatment would be expected, theoretically,
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with the use of agents that target glutamatergic transmission and (3) the results of the
first decade of clinical research with glutamatergic agents targeting the NMDA
receptor indicate that these types of compounds have efficacy and side-effects
different from those of presently used antipsychotics and may actually represent a
new class of atypical antipsychotic medication.
If enhancement of NMDA medicated neurotransmission represents one of the
mechanisms by which atypical antipsychotics have their cognitive enhancing effects,
then the addition of glycine site agonists, which act as an NMDA agonists, to the
treatment of patients receiving atypical drugs should be less beneficial than adding
glycine site agonists to those on traditional neuroleptics. Unfortunately, few studies
have studied the effects of glycine agonists with traditional antipsychotics, probably
as their use is rapidly in decline. However, Levy (2003) reviews those which have
and concludes that glycine agonists have much more profound effects on those treated
with typical as opposed to atypical medication. It is worthy of note, however, that
benefits were more significant for positive and negative than disorganized symptoms.
Phillips & Silverstein (2003) remark that if pharmological interventions at glutamate
receptors can improve disorganized symptoms, this may provide a new line of
medical treatment for schizophrenia. They leave this line of enquiry very much open.
Recent studies exploring this area have tended to examine the role of NMDA
enhancing properties along with atypical antipsychotics, presumably to show that they
have effects above and beyond those of atypical antipsychotics. Most seem to broadly
support Phillips & Silversteins’ ideas.
Jarvitt (cited in Philips & Silverstein, 2003, p.93) provides data which suggests that
glycine reverses impairments on the MMN and AX-CPT paradigms, suggesting that
agents that enhance NMDA activity can improve cognitive coordination. Since
Phillips & Silversteins' (2003) article, several other findings have been made. Tsai,
Lane, Yang, Chong, Lange (2004) report that surcosine (which enhances NMDA
activity through a complex interaction with glycine) improves cognitive function in
schizophrenic patients. Coyle (2004) reports that D-cycloserine (a partial NMDA
agonist) and glycine have proven partially successful in reducing negative and
cognitive symptoms in schizophrenia. Heresco-Levy, Ermilov, Lichtenberg, Bar &
Javitt (2004) report a 9 reduction in cognitive symptoms when glycine was added to
risperidone or olanzapine. Heresco-Levy, Javitt, Ebstien, Vass, Lichenberg, Bar,
Catinari, Ermilov (2005) point out potential problems with D-cycloserine and glycine,
namely that both may affect other receptor sites. They studied the effect of D-Serine,
which is not known to interact with any other neurotransmitter system except NMDA,
along with risperidone or olanzapine and reported an 11% reduction in cognitive
symptoms. Most recently, Kremer, Vass, Gorelik, Bar, Blanaru, Javitt, Heresco-Levy
(2005) reported that lamotrigine, a novel anticonvulsant drug which enhances NMDA
activity, had the effect of reducing cognitive symptoms, although not to a significant
level, when added to clomzapine.
Unfortunately, despite the promise of the above findings in terms of producing a new
line of medication aimed at reducing disorganized symptoms in schizophrenia, Jarvitt
& Coyle (2004) point out that none of the agents studied to date have the properties
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needed for commercialisation because, for example, for many the doses required are
simply to high.
Despite the above findings, which seem to offer some support for Phillips &
Silversteins’ (2003) model, it should be noted that other proposals have been put
forward to explain why atypical antipsychotics reduce disorganized symptoms. For
example, it has been argued that the preponderance of serotonin (5-HT)-2A
antagonism over dopamine (DA)-2 blockade excerted by atypical antipsychotics may
enhance dopamengeric output in the pre-frontal cortex and this may account, at least
in part, for their beneficial cognitive effects in schizophrenia (Ruiu, Marchese, Saba,
Gessa, Pani, 2000). There is some support for this hypothesis. Poyurovsky, Koren,
Gonopolsky, Schniedman, Fuchs, Weizman & Weizman (2003) concluded that that
the addition of mianserin, a 5-HT2A antagonist, to atypical antipsychotics added
significantly to their cognitive enhancing effect. Chaudhry, Soni, Hellewell & Deakin
(2002) using a different cognitive battery and 5-HT2A antagonist, cypohepadine,
reached similar conclusions with chronic neuroleptic treated patients. These findings
seem to be most easily accommodated by the model by Braver, Barch & Cohen
(1999) who suggest that some of the cognitive deficits in schizophrenia arise from
reduced dopamengeric modulation in the pre-frontal cortex. Phillips & Silverstein
would no doubt interject here and point out that as the glutamatergic system closely
interacts with and modulates other systems, NMDA hypofunction may well effect
dopamine dysregulation. Therefore, 5-HT2A antagonists may be simply modulating a
effect of NMDA hypofunction. Whilst the intricacies of the above argument are
beyond the scope of this review it serves to make a good point. Drug development for
schizophrenia needs to advance in the direction of targeting complex, interactive
neurotransmitter systems like glutamate and dopamine. By manipulating the
physiological and biochemical mechanisms that are proximal to the underlying
disease, we are more likely to obtain therapeutic results that significantly enhance
cognitive performance. In addition, as Levy (2003) indicates, with regard to the
relationship between atypical antipsychotics and NMDA receptor agonists, future
studies need to compare full versus partial agonists of the glycerine site and, perhaps
more importantly, include the assessment of glycerine site modulators as mono versus
add-on therapy.
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