Fifty years ago, when the ACNP was first convened, it was
an exciting time for new treatment development in
psychiatry. In schizophrenia, a new era of treatment was
ushered by the fortuitous finding that chlorpromazine and
other phenothiazines showed dramatic effects in control of
psychosis. Implementation of these treatments permitted
deinstitutionalization of large numbers of patients with
schizophrenia, and allowed a substantial number of
chronically disabled patients to resume relatively normal
lives. This was followed shortly thereafter with seminal
findings linking effective doses of antipsychotic drugs to
blockade of the recently discovered D2-type dopamine
receptor (Seeman et al, 1975; Creese et al, 1976).
Pharmaceutical companies quickly exploited these findings
by developing large families of phenothiazine and nonphenothiazine
antipsychotics, all showing similar efficacy
and with side effect profiles modulated by binding profile
across a wide variety of receptor types.
Fifty years later, pharmacological treatment of schizophrenia
remains virtually unchanged (Lieberman et al,
2005). The most efficacious antipsychotic drug is clozapine,
developed in 1961. All attempts to develop an equally
effective compound free of its hematological and orthostatic
side effects so far have failed. The failure is most obvious in
the case of negative symptoms and cognitive deficits, which
remain as key predictors of functional disability.
However, even positive symptoms of schizophrenia
persist despite an aggressive antipsychotic treatment in a
significant number of individuals (Foussias and Remington,
2010). Perhaps most disappointingly, not only have compounds
directed at D2 receptors failed to ameliorate core
symptoms of schizophrenia in a great many individuals, but
even compounds directed at some of the most obvious
closely related sites, such as serotonin 5-HT2A receptors,
have no or inferior efficacy compared with typical antipsychotics
such as haloperidol (Geyer et al, 1999b; Meltzer
et al, 2004; Marder, 1999).
A half century after the initial
discovery of antipsychotics, the field finds itself in need not
only of alternative medications but also alternative targets
(Abbott, 2010). Selection of these targets must be guided by
sound etiological theories, as well as by practical considerations
such as ‘drug ability’ and stability of effect.
The glutamate synapse has emerged as one of the most
prominent targets in this context (Javitt, 2004; Moghaddam,
2004). This is due in part to the fact that biological evidence
at several levels supports an involvement for glutamate
neurotransmission in the etiology and pathophysiology
of the disease. More importantly, the glutamate synapse
is a target-rich environment containing a large number
of presynaptic, postsynaptic, and regulatory proteins
that represent appropriate targets for drug development
(Moghaddam, 2003; Marek et al, 2010). Here, we review the
progression of scientific discovery and theoretical thinking
that has moved the glutamate hypothesis of schizophrenia
from a neurotransmitter theory into the practical arena of
target identification and animal modeling
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