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• Schizophrenia is recognized as a
heterogeneous disorder linked to multiple genes
which individually exert relatively small effects
and which are believed to interact with
numerous environmental factors.
• Phenotype is similarly heterogeneous,
composed of at least four or five distinct
symptom clusters, including psychotic
symptoms, disorganization, negative
symptoms, cognitive deficits, and affective
symptoms . The pattern of symptom expression
is diverse within patient samples.
• Medications also differ in patterns of symptom
response. Future advances in drug development
first require identification of subgroups of
patients that share biological defects in
common and may also take into account
different pathogenic mechanisms associated
with different stages of the disease.
• Pharmacological interventions that target
specific symptoms may be necessary rather
• The classic pharmacological model,
stimulant intoxication, produces
delusions and hallucinations that
closely resemble psychotic
symptoms of schizophrenia and
generally can be fully attenuated by
dopamine antagonists. Stimulant
intoxication is less informative for
other symptoms of schizophrenia.
• A subgroup of schizophrenia patients
exhibit increased dopamine release
which positively correlates with
response to conventional
antipsychotic medication
• An additional pharmacological challenge of
interest to schizophrenia drug development
involves infusion of noncompetitive
antagonists that block the glutamatergic-
NMDA gated channel. Drugs such as
phencyclidine (PCP) and the lower-affinity
dissociative anesthetic, ketamine, produce a
broad spectrum of schizophrenia-like
symptoms in normal subjects, including
psychosis, negative symptoms and memory
deficits. Ketaminealso exacerbates
symptoms in schizophrenia patients who
have been stabilized on haloperidol—an
effect that is blocked by clozapine .
• Furthermore, the abnormality in
amphetamine-induced striatal dopamine
release characteristic of some patients with
schizophrenia can be reproduced in normal
• Several genes with biologically relevant
functions recently have been linked
preliminarily to schizophrenia.
• For example, a gene on chromosome 8p,
associated with expression of neureglin, has
been linked to schizophrenia. Neureglinplays a
role in brain development, particularly the
expression of NMDA receptors. Transgenic mice
heterozygous for the neureglin allele express
16% fewer NMDA receptors compared to normal
mice, and exhibit hyperactivity and abnormal
PPI; the abnormal behaviors respond to
• In a related finding, Mohnand colleagues
produced transgenic mice with an
approximately 95% reduction in functional
NMDA receptors (by deletion of the NMDAR1
subunit) and found that mice exhibited
hyperactivity, sterotypies, and social isolation.
Hyper-activity and stereotypy improved with
haloperidol, whereas only clozapine improved
• In addition, two genes involved in
expression and activation of D-amino acid
oxidase (DAAO) have also been linked to
schizophrenia. DAAO metabolizes D-serine,
a neurotransmitter believed to play an
important role in activating the glycineco-
agonist site of the NMDA receptor. It is
hypothesized that a polymorphism that
results in heightened activity of DAAO might
lower brain concentrations of D-serine,
decrease activation of NMDA receptors, and
hence place individuals at risk for
schizophrenia. An additional gene is
involved in expression of catecholamine-O-
methyl transferase (COMT), an enzyme that
metabolizes intrasynapticdopamine . While
the presence of a polymorphism that would
increase COMT activity and decrease
Dopamine: Future Directions
• Preservation of nigrostriatal dopaminergicfunction remains an
important goal for novel antipsychotics—one that can be partially
realized by addition of 5-HT 2A antagonism combined with careful
clinical titration of dose, or more successfully by a high
dissociation constant for binding to the D receptor, or by partial
agonist activity at the D2 receptor.
• It is also possible that atypical agents preferentially bind to D2
and D3 receptors in thalamus and temporal cortex compared to
striatum. While atypical agents appear to preserve
nigrostriatalfunction, depolarization blockade of A10 dopamine
neurons by atypical agents, which probably is necessary for
antipsychotic efficacy, may disrupt cognitive functions associated
with the phasic release of dopamine in the prefrontal cortex.
• Efforts to enhance dopaminergic release in prefrontal cortex have
included augmentation with psychostimulants. Preliminary
evidence suggests that stimulants (amphetamine) may improve
prefrontal cortical activation and negative symptoms when
administered as a single dose, but repeated dose trials of
stimulant augmentation have generally been negative.
• Alternative strategies could include antagonism of dopamine
metabolism (COMT or MAOI inhibitors) and augmentation with
selective D1 agonists. Clozapine, risperidone and olanzapinehave
been shown to increase dopamine release in prefrontal cortex, an
Dopamine: Future Directions
• Unfortunately, since the mechanism by which D2 blockade
produces antipsychotic effects remains unclear, it is difficult
to design strategies that will preserve or enhance
antipsychotic efficacy while minimizing side effects.
Targeting D3 receptors is an interesting approach, since a
selective D3 antagonist might modulate limbic dopamine
activity without affecting ventral tegmental or nigrostriatal
neuronal firing.
• Amisulpiride has been reported to preferentially block D3
receptors, to which has been attributed its very favorable
clinical profile of efficacy for positive and negative
symptoms with minimal EPS. Other, more selective D3
antagonists are currently in development.
• Whether the combination of relatively weak D2 antagonism
with relatively strong D1 antagonism, as typified by
clozapine, is a model worth replicating in new agents also
requires further work. Despite considerable interest in D4
antagonists following the discovery of clozapine’shigh
• More recently, selective 5-HT2A antagonists have demonstrated
the ability to reverse some behavioral effects of NMDA
antagonism, possibly by increasing release of glutamate.
However, M100907, a selective 5-HT2A antagonist, was not
adequately effective compared with haloperidol in early clinical
trials to merit development as an antipsychotic agent. Antagonism
of 5-HT2A continues to be a desirable characteristic of
antipsychotic agents when combined with D2 antagonist effects.
• Serotonin5-HT1A partial agonists also appear to reverse
neurological side effects of D2 antagonists. In an open
augmentation study, the 5-HT1A partial agonist, buspirone,
improved ratings of EPS and tension when added to haloperidol.
Both ziprasidone and aripiprazoleexhibit agonist activity at the 5-
HT1A receptor—the potential contribution of this activity to
clinical response requires study.
• Serotonin-reuptake blockers have also demonstrated efficacy for
negative symptoms when added to conventional neuroleptics. This
finding has been relatively consistent with fluoxetine and
fluvoxamine, but less consistent with other selective serotonin
reuptake inhibitors (SSRIs)—the reason for this inconsistency is
Novel Serotonergic and
Dopaminergic Mechanisms
• Iloperidone is a compound in clinical
development with SDA properties, but it has
even more potent alpha 1 antagonist
properties. Mazapertine is a D2 antagonist, but
rather than 5HT2A antagonist properties, it has
5HT1A agonist actions. Nemonapride is a D2
(D3, D4) antagonist and 5HT1A agonist as well.
The selective 5HT2A antagonist MDL-100,907
was recently dropped from clinical
development, as was the 5HT2A/2C antagonist
ritanserinin prior years, both for lack of robust
efficacy in schizophrenia. However, there
remains some continuing interest in both 5HT2C
selective agonists and antagonists, several of
which are in early development. There are even
Novel Serotonergic and
Dopaminergic Mechanisms
• On the dopamine side of the equation, one of the most
promising agents in late clinical development is presynaptic
D2 autoreceptor agonist. This compound is postulated to
exert its antipsychotic actions in a manner far different from
serotonin-dopamine antagonism: that is, it may shut off the
presynaptic dopamine terminal and stop dopamine release
in the mesolimbic dopamine pathway by stimulating
presynaptic D2 receptors. The agents CI-1007 and DAB-452
may have a similar mechanism of action.
• Several selective D4 antagonists have been tested in
schizophrenia, with generally disappointing results,
although some trials are continuing. Such compounds,
some more selective for D4 receptors than others, include
YM-43611, nemonapride, fananserin, L-745,870, PNU-
101,387G, NGD-94-4, LU-111,995, and others.
• Several selective D3 antagonists are being developed,
because most known D2 antagonists block D3 receptors as
well. It is theoretically possible that pure D3 antagonists,
which increase psychomotor behavior in rodents, might
activate such behaviors in schizophrenia and thus reduce
negative symptoms.
• Antagonism of postsynaptic alpha 2
adrenoreceptorsappears to enhance release of
dopamine in prefrontal cortex and may have cognitive
benefits . The selective alpha 1 receptor antagonist,
prazosin is also reported to prevent depolarization
blockade of A9 dopamine neurons following
administration of conventional neuroleptics. While less
well studied than D2 and 5-HT2A receptors,
adrenergic antagonism is shared by most atypical
antipsychotics and may contribute to clinical benefit. It
is an intriguing hypothesis that extraordinarily high
concentrations of norepinephrine produced by
clozapinevia unclear mechanisms may reduce
sensitivity to environmental stress and hence protect
against relapse—an effect possibly also achieved by
adrenergic receptor blockade.

Glutamatergicapproaches have received considerable attention in
light of reported abnormalities of glutamatergicreceptor density
and subunit composition in schizophrenia brain, the production of
a broad range of symptoms characteristic of schizophrenia by
infusion of NMDA antagonists in normal subjects, and preliminary
success with agonists at the glycine site of the NMDA receptor.
• Several placebo- controlled trials have demonstrated improvement
of negative symptoms with the addition of the full agonists,
glycine and D-serine, or the partial agonist, D-cycloserine, to
antipsychotics other than clozapine. Because glycinepoorly
penetrates the blood-brain barrier, large doses (30–60 g/d) are
required to achieve clinical effects. Glycine reuptake inhibitors are
currently under development and represent a promising
alternative approach. D-Cycloserine, a partial agonist, has
produced improvement of negative symptoms over a narrow
therapeutic dose range; psychotic exacerbation has been reported
at higher doses and in approximately 10% of patients receiving a
typical therapeutic dose of 50 mg/d. Glycineand D-serine have
demonstrated a broader range of efficacy in preliminary studies;
negative symptoms, psychosis, and relatively rudimentary
measures of cognitive function have all improved in augmentation
• If found safe, D-serine is particularly attractive since it crosses the
blood-brain barrier more readily than glycine, is not removed from
the synapse as rapidly by active transport, and has been
implicated by recent genetic linkage studies between
• Trials of glycine site agonists added to
clozapinehave tended to find no clinical
improvement and the partial agonist, D-
cycloserine, worsened negative symptoms
when added to clozapine in two studies . The
relative efficacy of glycine site agonists when
added to other atypicalsis less well studied,
although a large clinical trial (the CONSIST
study) is currently underway to examine this
question.Thesefindings suggest that targeting
the glycine site may enhance efficacy of
mostantipsychotic drugs, but probably will not
improve upon clozapine’s efficacy. This further
raises the question of whether clozapine’s
superior efficacy may in part reflect activity at
• Metabotropic (mGlu) receptor agonists
have recently gained attention as a
promising new target for antipsychotic
development. mGlureceptor ligands
have been shown to modulate
dopamine neuronal activity in striatum
and nucleus accumbens. The group II
mGlureceptor agonists have been
demonstrated to selectively regulate
glutamate release in cortex and
hippocampus. In rat models, group II
mGlu receptor agonists attenuated
phencyclidine behavioral effects but did
• A final glutamatergic receptor class which may
hold promise as an area of drug development in
schizophrenia is the AMPA receptor. AMPA
receptor positive modulators, or “ampakines,”
are currently under development.
Ampakinesaugment opening of voltage-
dependent NMDA receptors by facilitating early
depolarization . In animal studies,
ampakineshave produced improvements in
learning and memory and have acted
synergistically when combined with low doses
of antipsychotics to attenuate rearing behaviors
in response to methamphetamine. In one very
preliminary placebo-controlled dose-finding
trial, addition of an ampakine to clozapine in 19
• Alpha-7-nicotinic cholinergic agonists
• Nicotinic acetylcholine receptors have also received considerable
attention for their possible role in cognitive deficits of
schizophrenia. Nicotine normalizes a sensory gating abnormality
measured by the inhibition of P50 evoked response to paired
stimuli; this deficit in information processing is found in about 85%
of schizophrenia patients and in about half of first degree relatives
and has been linked to the alpha 7 nicotinic receptor.
• The gene that expresses the alpha 7 nicotinic receptor, CHRNA7,
is decreased by approximately 50% in post-mortem hippocampus
from schizophrenia patients compared to normal controls . A
polymorphism in the promoter region of the CHRNA7 gene has
also been linked to schizophrenia. Pharmacological targeting of
the alpha 7 nicotinic receptor is complicated because it is highly
sensitive to down-regulation in response to agonists.
• Nicotine transiently normalizes P50 gating deficits, but this effect
is lost with repeated dosing. Clozapineuniquely appears capable of
improving P50 deficits, apparently via alpha 7 receptors, although
the mechanism remains uncertain. It has been suggested that
alpha 7 activation by clozapine might be mediated by serotonin 5-
HT 3agonist effects which enhance release of acetylcholine.
• A selective alpha 7 agonist, DMXB-A appears to produce sustained
improvement of P50 sensory gating with repeated dosing in
animal models. Trials in schizophrenia patients will be of great
interest to determine whether this compound enhances attention,
even in subjects prone to maintain high levels of nicotine from
• One of the few approaches to schizophrenia treatment
that do not focus upon receptor ligandsis based on the
conceptualization of schizophrenia as a brain lipid
disorder. In this model, first proposed by as a
prostaglandin deficiency , the focus is on alterations
of the physicochemical properties of the biomembrane
of the cell. In its simplest form, the theory posits an
aberrant composition of constituents of the cell
membrane leading to a multitude of biological
changes. The focus has been on phospholipids and
polyunsaturated fatty acids (PUFAs), especially
deficiency of omega-3 fatty acids . Clinical evidence
for the usefulness of supplementation with omega-3
fatty acids has been mixed, several small studies
showing excellent improvement, one double-blind trial
being negative
• The prototypical course of schizophrenia can be
characterized as a time-limited progression of
illness to a defect state . Possible targets
include neurotrophic factors that regulate
processes putatively disturbed in schizophrenia:
neuronal and glialdifferentiation, migration, and
proliferation. some aspect of schizophrenia can
be understood as a fault in synaptic pruning. A
clearer understanding of the cellular pathways
that maintain synaptic connectivity and control
apoptosis (such as the role of bcl-2) and their
role in schizophrenia. These pathways might
provide important targets for disease-
modifying treatments or at a minimum lead to
drugs that do not add additional neurotoxicity.
White matter abnormalities can be seen with
diffusion MRI and recently abnormal expression
of genes involved in myelination has been
found in schizophrenia brain. It is of interest
• Current drug targets are generally focused on
extracelluar receptors. As a
result,pharmacological approaches remain
limited to influencing neuronal systems through
manipulating the initiation phase rather than
the adaptation phase. Very likely, future
understanding of pathophysiology will shift the
focus from receptors to downstream (post
receptor) signal transduction pathways located
inside the cell and more specifically influencing
gene expression. A case in point is the
phosphoprotein DARPP-32 which integrates
dopaminergic and other signaling pathways. Its
central position in dopamine signaling makes it
an attractive target for disorders of dopamine
regulation. and the more speculative goal of
producing drugs that influence brain
development, perhaps by enhancing
myelination-stimulating neurotrophic factors, or
Novel Neurotransmitter
Mechanisms Other Than
• Sigma antagonists
• Originally categorized as one type of opiate
receptor, they are now associated with the
actions of the psychotomimetic agent
phencyclidine (PCP) and the activity of the N-
methyl-d-aspartate (NMDA) subtype of
glutamate receptors. Theoretically, a sigma
antagonist could block any PCP-like actions
occurring in schizophrenia. Although early
testing of the sigma antagonist BMY-14,802 in
schizophrenia was not impressive, other
antagonists with greater selectivity, especially
SR31742A, have been developed and have
entered testing. A combined sigma/5HTlA
agonist/5HT reup-take inhibitor, OPC14523, is
Cannabinoid antagonists.
• An antagonist to cannabinoid 1 (CB1)
receptors, SR141716A, reduces the
activity of mesolimbic dopamine
neurons in animal models,
suggesting possible antipsychotic
actions in schizophrenia and leading
to testing in schizophrenic patients.
Neurotensin antagonists.
• Neurotensin is a peptide
neurotransmitter, which is colocalized
with dopamine in the mesolimbic
dopamine pathway, but is much lower
in concentration in the nigrostriatal and
mesocortical dopaminergic pathways. A
non-peptide antagonist SR-142948 is in
clinical testing in schizophrenia as a
theoretical agent that could reduce
positive symptoms without producing
EPS by exploiting differential actions on
the mesolimbic rather than nigrostriatal
dopamine system.
• Cholecystokinin (CCK) is also
colocalized with dopaminergic
neurons and has two receptor
subtypes, CCK-A being predominantly
outside of and CCK-B within the
central nervous system. Studies of
CCK agonists and antagonists to date
have not given clear clues as to their
potential for therapeutic actions in
Substance P and the
• The substance P and neurokinin
family of peptide neurotransmitters
was extensively discussed in Chapter
5 (see Figs. 5—69 through5—73).
Antagonists to all three neurokinin
receptors (i.e., NK-1, NK-2, and NK-3)
are now in clinical testing for a
variety of indications, predominantly
depression. Several are being tested
in schizophrenia as well.
Future Combination
Chemotherapies for
• psychopharmacological treatments for psychotic disorders in the
future will use multiple drugs simultaneously to attain therapeutic
synergy. Combination chemotherapy uses the approach of adding
together several independent therapeutic mechanisms. When
successful, this results in a total therapeutic response that is
greater than the sum of its parts. This approach often has the
favorable consequence of simultaneously diminishing total side
effects, since adverse experiences of multiple drugs are mediated
by different pharmacological mechanisms and therefore should not
be additive. Clinical trials with multiple therapeutic agents working
by several mechanisms can be quite difficult to undertake, but it
may be an approach that should be applied to complex
neurodegenerative disorders with multiple underlying disease
mechanisms, such as schizophrenia. Thus, schizophrenia
treatments of the future will combine an atypical antipsychotic for
positive and negative symptoms and for mood, cognition, and
hostility, without causing EPS, tardive dyskinesia, or
hyperprolactinemia, with some sort of booster treatment to attain
even better relief of negative symptoms and cognitive symptoms.
Possibly an additional neuroprotective agent will be helpful if
stopping future psychotic episodes alone is not sufficient to arrest
the downhill course of illness. In the long run, some sort of
molecular-based therapy to prevent genetically programmed