Molecular Psychiatry (1999) 4, 418–428

 1999 Stockton Press All rights reserved 1359–4184/99 $15.00

MECHANISMS OF DRUG ACTION

Mechanisms of typical and atypical antipsychotic drug

action in relation to dopamine and NMDA receptor
hypofunction hypotheses of schizophrenia
GE Duncan1, S Zorn2 and JA Lieberman1
1
Department of Psychiatry and UNC Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill,
NC 27599; 2NS Discovery, Pfizer Inc, Central Research Division, Pfizer Inc, Groton, CT 06340, USA

Available evidence indicates that clozapine is the most effective antipsychotic currently used
for the pharmacotherapy of schizophrenia. Unfortunately, clozapine can cause serious side
effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is
poorly understood, and accordingly, it has been difficult to design new drugs with the advan-
tageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and ser-
otonergic receptor-blocking properties of clozapine account for its clinical efficacy, several
novel antipsychotic drugs have been introduced recently. There is currently insufficient data
to reach definitive conclusions regarding the efficacy of the newer ‘atypical’ antipsychotics in
comparison to clozapine. However, most published studies, and general clinical impressions,
suggest that none of the newer drugs are as effective as clozapine in treating patients resist-
ant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experi-
ence with the newer ‘atypical’ antipsychotic drugs and then discusses clinical and preclinical
data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor
hypofunction hypothesis of schizophrenia.
Keywords: clozapine; olanzapine; risperidone; ziprasidone; quetiapine; antipsychotic; schizophrenia;
dopamine; NMDA

The introduction of clozapine for the pharmacotherapy
of schizophrenia represented a significant advance in
the treatment of this devastating mental illness. Cloza-
pine is superior to typical neuroleptic drugs (eg
haloperidol) in treating positive and negative symp-
toms, and is effective in many patients who are refrac-
tory to typical antipsychotics.1–3 In addition, clozapine
does not induce the extrapyramidal side effects (EPS)
commonly caused by the typical agents. Because of
these properties, clozapine was termed atypical and
represents the prototype drug of this class. Although
clozapine is the most efficacious antipsychotic cur-
rently available, serious side effects induced by the
drug, including agranulocytosis, impose substantial
limitations on its use. Concerted research and develop-
ment efforts have been made to produce an antipsy-
chotic drug with the therapeutic advantages of cloza-
pine, without the properties contributing to its serious
side effects. However, the specific pharmacological
characteristics of clozapine that confer its therapeutic
properties are poorly understood. Clozapine binds to a
diverse number of neurotransmitter receptors (see
Correspondence: GE Duncan, PhD, Neuroscience Center, CB #
7250, University of North Carolina School of Medicine, Chapel
Hill, NC 27599–7250, USA. E-mail: gduncan얀css.unc.edu
Received 3 March 1999; revised and accepted 10 May 1999
Table 1) but it is unclear whether actions at specific
serotonin, dopamine, or adrenergic receptors, alone or
in combination, account for its clinical efficacy.
A number of specific hypotheses concerning mech-
anisms of action of clozapine have directed drug dis-
covery efforts and led to clinical trials of drugs with
widely different receptor-binding characteristics. The
clinical experience with drugs whose development
was inspired by clozapine will be briefly reviewed and
then actions of clozapine and other antipsychotic drugs
will be addressed in the context of the NMDA hypo-
function hypothesis of schizophrenia.
Clinical experience with clozapine-inspired
putative antipsychotics in relation to therapeutic
mechanisms of action
One of the earliest hypotheses of clozapine’s mech-
anism of action related to the D1 dopamine antagon-
istic properties of the drug.4 Clozapine binds to D1
receptors in vitro with modest affinity (see Table 1) and
at therapeutic doses occupies approximately 40–50%
of D1 receptors in humans.5 Based on the hypothesis
that the D1 antagonistic properties of clozapine dis-
tinguished it from the typical antipsychotic drugs,
selective D1 antagonists were developed as potential
antipsychotic agents. Unfortunately, such drugs were
not effective and there were indications that selective
 Antipsychotic drug action in schizophrenia
GE Duncan et al

419
Table 1 Affinity of antipsychotic drugs for human neurotransmitter receptors

Receptor Clozapine Risperidone Olanzapine Ziprasidone Quetiapine Haloperidol M-100907

(Ki, nM)

D1 290 580 52 130 1300 120 1800

D2 130 2.2 20 3.1 180 1.4 1800
D3 240 9.6 50 7.2 940 2.5
D4 47 8.5 50 32 2200 3.3
5-HT1A 140 210 2100 2.5 230 3600 ⬎4700
5-HT1Da 1700 170 530 2.0 ⬎5100 ⬎5000 ⬎5100
5-HT2A 8.9 0.29 3.3 0.39 220 120 0.3
5-HT2C 17 10 10 0.72 1400 4700 68
5-HT6 11 2000 10 76 4100 6000 7400
5-HT7 66 3.0 250 9.3 1800 1100 2000
␣1 4.0 1.4 54 13 15 4.7 68
␣2 33 5.1 170 310 1000 1200 2200
H1 1.8 19 2.8 47 8.7 440 83
m1 1.8 2800 4.7 5100 100 1600

Values are geometric means of at least three determinations.

a
Bovine.

D1 antagonists may have even exacerbated symptoms
of schizophrenia and induced extrapyramidal side
effects.6,7 Although selective D1 antagonists were not
effective, it is possible that D1 antagonistic properties
of clozapine, in combination with other actions of the
drug, contribute to, but are not sufficient for, its thera-
peutic effects.
Clozapine has relatively high affinity for 5HT2A
receptors and is a potent antagonist of 5HT2A receptor-
mediated responses in vivo.8,9 The hypothesis has been
advanced that the combination of relatively high affin-
ity for 5HT2A receptors, and lower affinity for D2
receptors, account for the atypical therapeutic actions
of clozapine and other atypical antipsychotics.10 The
balanced D2/5HT2 hypothesis was the driving force
behind development of risperidone, which is a potent
D2 and 5HT2 antagonist, but with greater relative
affinity for the 5HT2A receptor (Table 1). Consistent
with the receptor-binding characteristics of risperi-
done, high occupancy of D2 and 5HT2 receptors is
observed clinically at therapeutic doses.11
Although risperidone is an effective antipsychotic
agent, and has a favorable side effect profile in com-
parison to haloperidol, the general clinical impression
has been that risperidone is not as effective as cloza-
pine in schizophrenic patients resistant to treatment
with typical antipsychotics. However, there is insuf-
ficient clinical data available to unequivocally estab-
lish the superior efficacy of clozapine relative to risper-
idone (for review see 3). Flynn et al12 and Breier et al13
found that clozapine was more effective than risperi-
done in treatment-resistant patients. However, Bon-
dolfi et al found no difference between risperidone and
clozapine in treatment-resistant patients.14 In this latter
study, certain methodological issues may have led to
an overestimation of the efficacy of both clozapine and
risperidone in truly resistant patients.3 Consequently,
it is difficult to infer equal efficacy of the drugs from
the study of Bondolfi et al.14 Further investigation is
necessary to adequately compare the relative efficacy
of risperidone and clozapine in treatment-resistant
patients.
The reduced EPS side effects associated with low
dose risperidone treatment (4–6 mg day−1), even at high
levels of D2 receptor occupancy, may be due to the
5HT2A antagonistic properties of the drug.10,15 How-
ever, at higher doses, risperidone produces EPS, indi-
cating that 5HT2A receptor antagonism alone cannot
completely eliminate EPS associated with high D2
receptor blockade. The potential role of 5HT2A recep-
tor antagonism in therapeutic responses to atypical
antipsychotic drugs may become more apparent when
data from clinical trials are available for the selective
5HT2A antagonists M100907.
Risperidone, like clozapine, has relatively high
affinity for alpha-1 and alpha-2 adrenergic receptors.
The potential therapeutic significance of the adrenergic
receptor-blocking properties of clozapine and risperi-
done are uncertain. Addition of the alpha-2 antagonist
idazoxan to the regime of patients treated with the typi-
cal neuroleptic fluphenazine improved treatment
responses in patients refractory to treatment with flu-
phenazine alone.16 However, there has been no con-
firmation of the effects of alpha-2 antagonists as
adjuncts to typical neuroleptic treatment and it has
been suggested that alpha-2 agonists may actually be
useful for treating cognitive deficits of the disease.17
Based on findings of elevated D3 dopamine receptors
in drug-free schizophrenics, and a reduction in these
receptors in patients treated with antipsychotics, Gure-
vich et al18 have suggested that normalization of D3
receptors may be contribute to the efficacy of antipsy-
chotic drugs. While risperidone and haloperidol are
relatively potent D3 antagonists (Table 1), the affinity
 Antipsychotic drug action in schizophrenia
GE Duncan et al
420
of clozapine for the D3 receptor is even lower than that
for the D2 receptor. Thus antagonism of D3 receptors
by haloperidol and the newer ‘atypical’ drugs could
contribute to their therapeutic actions, but it is unlikely
that the antipsychotic actions of clozapine can be
explained on the basis of D3 receptor blockade.
D4 dopamine receptor antagonism has also been sug-
gested to contribute to the therapeutic action of cloza-
pine.19,20 Clozapine has a relatively high affinity for the
D4 receptor compared to the D2 receptor (Table 1),
which is enriched in the hippocampus and prefrontal
cortex. Furthermore, a number of clinically efficacious
antipsychotic drugs have high affinity for this receptor
site (Table 1). An initial clinical study with the selec-
tive D4 antagonist L-745 870 did not demonstrate effi-
cacy in the treatment of schizophrenia.21,22 However,
since only one small dose was tested, it is difficult to
draw firm conclusions regarding the potential utility of
D4 antagonists as antipsychotic agents.23 Several other
selective D4 antagonists have shown promise in pre-
clinical pharmacological screens24–26 and are currently
being tested in patients with schizophrenia. Results of
the clinical studies could allow a more complete
assessment of the efficacy of D4 antagonists in the treat-
ment of schizophrenia.
Olanzapine is a drug closely related in chemical
structure to clozapine (Figure 1), and the two drugs
have many common receptor-binding characteristics
(Table 1). Olanzapine was selected for development in
large part because of its relatively potent antagonistic
effects at both D2 and 5HT2A receptors.27,28 Like cloza-
pine, olanzapine is more potent at 5HT2 than D2 recep-
tors. In addition, the pharmacologic profile of olanza-
pine in regard to other dopaminergic, serotonergic,
cholinergic, and adrenergic receptor subtypes is simi-
lar to clozapine, but there are also some notable differ-
ences (see Table 1). For example, clozapine has sub-
stantially higher affinity for 5HT1A and 5HT7
receptors in comparison to olanzapine. Extensive con-
trolled studies have proven olanzapine to be an effec-
tive antipsychotic that has very low EPS liability.29–32
EPS side effects are minimal even at doses that produce
D2 receptor occupancy of 70–80%.33,34 Although
olanzapine is highly effective in many patients, clinical
experience with currently suggested doses indicates
that it is not as effective as clozapine in patients refrac-
tory to effects of typical antipsychotics.35 There is
insufficient clinical data for ziprasidone, quetiapine,
and M-100907 to compare the efficacy of these newer
atypical antipsychotics with clozapine.
Potential relationships between D2 and 5HT2
receptor occupancy and therapeutic mechanisms
of atypical antipsychotic drugs
Although further studies are required to firmly estab-
lish the relative efficacy of the new generation of atypi-
cal antipsychotic drugs in comparison to clozapine,
general clinical impressions suggest that clozapine has
greater efficacy than new ‘atypical’ antipsychotic
drugs. The imaging studies showing that therapeutic
doses of risperidone and olanzapine produce high
occupancy of D2 receptors suggest that D2 receptor
antagonism could be a predominant mechanism of
action of these new ‘atypical’ drugs.11,33,36 Although
clozapine does not exhibit high levels of D2 receptor
occupancy as assessed by standard approaches, See-
man and Tallerico37 have suggested that the drug can
indeed occupy high levels of the D2 receptors when
competing with endogenous dopamine, and not the
radioligands used to assess in vivo receptor occupancy.
Seeman and Tallerico37 hypothesize that the low EPS
liability for clozapine is related to its relatively low
affinity for the D2 receptor and the antipsychotic effi-
cacy is due to effective antagonism of endogenous
dopamine. Although this theoretical position could
explain the lack of EPS in response to clozapine treat-
ment, it does not explain the greater efficacy of cloza-
pine in relation to other currently used antipsychotic
drugs. If a predominant action of clozapine is not D2
antagonism, this would provide an explanation for the
superior efficacy of clozapine in the patients resistant
to typical neuroleptics (as well as to olanzapine and
risperidone), for which D2 receptor antagonism may be
a predominant therapeutic mechanism of action.
The high level of 5HT2A receptor occupancy pro-
duced by ‘atypical’ antipsychotic drugs such as risperi-
done and olanzapine suggests that antagonism of this
receptor may be involved in their clinical
actions.5,11,33,36 Preclinical studies show that 5HT2A
receptor antagonists attenuate cataleptic effects of D2
receptor antagonists.38–41 These data suggest that the
5HT2A receptor antagonism may contribute to the low
EPS liability of risperidone and olanzapine, and also
the recently introduced drugs quetiapine and ziprasi-
done.
Clozapine, risperidone and olanzapine occupy
⬎80% of 5HT2A receptors in the therapeutic dose
range in humans.5,11,33,36,42 Although 5HT2A receptor
antagonism is likely to be involved in the low EPS liab-
ility of risperidone and olanzapine, the role of this mol-
ecular action in therapeutic responses to clozapine is
uncertain. If a high level of 5HT2A receptor antagon-
ism was responsible for the efficacy of clozapine, then
risperidone and olanzapine would be expected to be as
effective as clozapine in treatment-resistant patients,
but to date this has not been demonstrated.3,12,13,35
The available basic science and clinical data suggest
that antagonistic actions at D2/D3 and 5HT2A recep-
tors are insufficient to explain the superior therapeutic
efficacy of clozapine in relation to other antipsychotic
agents. Whether the combination of clozapine’s actions
at other serotonergic receptors (ie 5HT1A, 5HT2C,
5HT6, 5HT7) or adrenergic receptors is responsible for
the drug’s efficacy may become apparent when more
extensive clinical data are available for ziprasidone
and quetiapine, which exhibit widely varying affinities
for these receptors. No definite conclusions can be
reached regarding the relative efficacy of the new atypi-
cal antipsychotics, until adequately controlled clinical
studies are conducted that compare the new atypical

Figure 1 Structures of clozapine, haloperidol and recently introduced ‘atypical’ antipsychotic drugs.
drugs in head to head comparison with each other and
with clozapine.
Potential new directions for antipsychotic drug
discovery
The interaction of clozapine with a diverse array of
neurotransmitter receptors complicates identification
of the molecular characteristics of the drug that confer
its atypical therapeutic properties. It is possible that
none of the newer ‘atypical’ drugs have the appropriate
combination and relative proportion of generally recog-
nized pharmacological actions of clozapine at specific
neurotransmitter receptors (Table 1). Alternatively, it is
possible that a currently unrecognized neurochemical
action of clozapine contributes to its therapeutic effi-
cacy and none of the newer ‘atypical’ drugs have been
modeled on the critical molecular property to create a
drug with an efficacy profile comparable to clozapine.
As noted above, the rationale for development of the
antipsychotic drugs recently introduced, and currently
under development, has been based predominantly on
dopamine and serotonin hypotheses of schizophrenia.
Antipsychotic drug action in schizophrenia
GE Duncan et al
421
The drugs were selected primarily for their antagonist
actions at dopamine and serotonin receptors and their
ability to antagonize dopamine- and serotonin-
mediated effects in pharmacological screens. Since that
strategy of drug development has apparently not
yielded an antipsychotic that is as efficacious as cloza-
pine, it may be prudent to consider other hypotheses
of schizophrenia to guide alternative strategies for the
discovery of novel antipsychotic agents. In this regard,
the NMDA receptor hypofunction hypothesis of
schizophrenia may provide a novel theoretical frame-
work for investigating mechanisms of action of antipsy-
chotic drugs.
The NMDA receptor hypofunction hypothesis of
schizophrenia
In early clinical investigations, the anesthetics PCP and
ketamine were observed to induced a state resembling
schizophrenia in 40–50% of individuals given the
drugs.43–48 In the 1970s, the abuse of PCP was fre-
quently associated with psychotic-like responses (for
review see49). In retrospective analyses of admission
 Antipsychotic drug action in schizophrenia
GE Duncan et al
422
records from PCP-induced adverse reactions, there was
little distinction between symptoms presented by these
patients and acute psychotic reactions in schizo-
phrenic patients. The discovery that ketamine and PCP
are non-competitive antagonists of the NMDA receptor
prompted the hypothesis that schizophrenia involves
reduced NMDA receptor function.49–52 Competitive
antagonists of the NMDA receptor also induced psych-
otomimetic effects,53 further supporting the hypothesis
that endogenous psychosis may result from reduced
NMDA function.
Recent studies with healthy human volunteers dem-
onstrated that ketamine induces a spectrum of
responses that resemble positive, negative, and cogni-
tive symptoms of schizophrenia.54–56 Furthermore, in
stabilized schizophrenic patients, ketamine can pre-
cipitate psychotic reactions that in some cases re-create
specific psychotic symptoms experienced during active
phases of their illness.57–59 These recent studies con-
firm the early clinical investigations and provide con-
vincing support for the hypothesis that symptoms of
schizophrenia may be associated with NMDA recep-
tor hypofunction.
The ‘psychotomimetic’ effects induced by NMDA
antagonists and psychostimulants (eg amphetamine)
are distinctly different. For example, unlike ketamine,
single injections of amphetamine rarely induced psy-
chotic reactions in healthy subjects. After repeated
treatments, amphetamine can induced positive schizo-
phrenic-like reactions in healthy individuals, such as
paranoia and hostility, but the withdrawal responses
and cognitive deficits induced by ketamine are not
observed.60,61 Similarly, in schizophrenic patients,
stimulants precipitate positive symptoms but do not
induce negative or cognitive symptoms.62 The ability
of ketamine and other NMDA antagonists to induce a
behavioral state that resembles several dimensions of
schizophrenia suggests that paradigms involving
assessment of behavioral and neurochemical conse-
quences of NMDA antagonists administration may con-
stitute valid experimental models of some aspects of
schizophrenia.
Neurobiological consequences of NMDA
antagonist administration
Ketamine and PCP block NMDA receptors by binding
to a site within the calcium channel of the receptor.
Although, this molecular action of ketamine and PCP
is well documented, mechanisms responsible for trans-
lation of this cellular and molecular action into the
psychotomimetic effects of the drugs are poorly under-
stood. The electrophysiological consequences of sys-
temic administration of ketamine are complex, with
some regions showing inhibition and other regions
exhibiting excitation that can progress to seizure-like
activity.47,63,64 By contrast, iontophoretic application of
ketamine to neurons uniformly antagonizes NMDA-
evoked excitatory responses.65–68 The well documented
ability of ketamine to inhibit excitatory actions of
NMDA at the cellular level, and induce excitatory
responses after systemic administration, suggests that
the excitatory effects of ketamine result from disrup-
tion of inhibitory neural circuits (ie from
disinhibition).
Consistent with excitatory effects demonstrated in
electrophysiological investigations, NMDA antagonists
have been observed to induce neuroanatomically selec-
tive activation of brain glucose utilization. In response
to anesthetic doses of ketamine, increased 2-deoxyglu-
cose (2-DG) uptake was observed in the hippocampus,
and decreased uptake observed in the medial genicu-
late, inferior colliculus and isocortical regions.69,70
Since subanesthetic doses of ketamine induce schizo-
phrenic-like reactions, we examined subanesthetic
doses of the NMDA antagonist on 2-DG uptake in rats.
Robust increases in 2-DG uptake were observed in spe-
cific hippocampal subregions, limbic cortical regions
(medial prefrontal, cingulate, retrosplenial cortices),
nucleus accumbens, anterior ventral thalamic nucleus,
and basolateral nucleus of the amygdala.71,72 In
addition, laminar patterns of 2-DG uptake in isocortical
regions were dramatically altered. In contrast to the
marked activation of limbic brain regions after subane-
sthetic doses of ketamine, 2-DG uptake was substan-
tially reduced in the inferior colliculus, medial genicu-
late, and auditory cortex. The effects of subanesthetic
doses of ketamine on 2-DG were almost identical to
those induced by the more specific antagonist MK-
801,73,74 indicating that the effects observed for keta-
mine were due to the NMDA antagonistic properties of
the drug. These findings of increased functional
activity in limbic regions, and decreased activity in
sensory pathways, suggest a dramatic remodeling of
functional circuitry in response to a subanesthetic dose
of ketamine.
Functional imaging studies in humans after subanes-
thetic doses of ketamine have also shown neuroana-
tomically specific functional activation. Lahti et al57
found that ketamine increased blood flow in the
anterior cingulate cortex and Breier et al75 demon-
strated increased 18F-flurodeoxyglucose (FDG) in the
prefrontal cortex after infusion of subanesthetic doses
of ketamine. Vollenweider et al76,77 observed global
increases in FDG uptake in response to subanesthetic
doses of ketamine, but found greater increases in pre-
frontal cortex in comparison to other regions. Thus,
studies in rats and humans indicate that subanesthetic
doses of ketamine can alter patterns of brain activity
and suggest a functional neuroanatomical basis for psy-
chotomimetic effects of reduced NMDA receptor func-
tion.
Potential mechanisms for NMDA antagonist-
induced functional activation
One potential mechanism by which NMDA receptor
antagonism could result in functional activation would
be to reduce excitation of inhibitory neurons. In sup-
port of a disinhibitory action involving GABAergic
transmission, NMDA receptors on hippocampal inhibi-
tory interneurons were demonstrated to be more sensi-

tive to an NMDA antagonist, in comparison to NMDA
receptors on CA1 pyramidal neurons.78 In addition,
benzodiazepines, which potentiate GABA-mediated
neurotransmission, are effective in reducing adverse
emergence reactions following ketamine anesthesia.79
However, ketamine-induced psychosis was not attenu-
ated by subhypnotic doses of lorazepam, and cognitive
deficits induced by ketamine were worsened by the
benzodiazepine.80 Thus, components of ketamine-
induced behavioral effects may be due in part, but not
wholly, to disinhibitory effects via reduced activity of
GABA-containing neurons.
In addition to disinhibition of GABAergic neurons,
reduced autoregulation of glutamate release by antag-
onism of presynaptic NMDA receptors is another
potential mechanism for ketamine-induced functional
activation. In support of this latter possibility, Liu and
Moghaddam81 found that local infusion of NMDA
antagonists into the striatum and hippocampus
increased extracellular glutamate, suggesting a tonic
inhibitory role of NMDA receptors on glutamate
release. Also, systemic administration of ketamine and
PCP increased glutamate release in the prefrontal cor-
tex.82,83 This excessive release of glutamate could then
activate non-NMDA glutamate receptors (ie AMPA and
kainate receptors). A role for increased glutamate
release in the actions of NMDA antagonists is suggested
by the observations that AMPA/kainate receptor antag-
onists partially block behavioral effects induced by the
drugs.82,84–86 Furthermore, a metabotropic Group II/III
agonist, that inhibits glutamate release, antagonized
behavioral activation induced by PCP.83
Effects of antipsychotic drugs on responses to
NMDA antagonists in preclinical paradigms
Effects of typical and atypical drugs on
neurotoxicological and behavioral responses to
NMDA antagonists
There is an increasing body of evidence that atypical
antipsychotic drugs can antagonize effects of ketamine
and other NMDA antagonists. Although ketamine and
the more selective NMDA antagonist MK-801 have
neuroprotective effects in ischemic conditions, these
drugs can induce neuronal damage in select brain
regions.87–89 Both typical and atypical antipsychotic
drugs can antagonize MK-801-induced neurotoxic
responses.90,91 In addition, MK-801-induced locomotor
activation can be blocked by typical and atypical anti-
psychotics.92–94 However, certain behavioral responses
induced by NMDA antagonists are differentially affec-
ted by atyptical drugs. For example, clozapine and
olanzapine blocked PCP-induced deficits in social
interactions, whereas haloperidol and risperidone were
ineffective.92 Also, clozapine, quetiapine and olanza-
pine blocked NMDA antagonists-induced deficits in
prepulse inhibition.95–97 While both typical and atypi-
cal antipsychotics can reverse disrupting effects of
dopamine agonists on prepulse inhibition,98 the typical
drugs do not block effects of NMDA antagonists in
this paradigm.99
Antipsychotic drug action in schizophrenia
GE Duncan et al
423
Differential effects of typical and atypical
antipsychotics on NMDA antagonist-induced
alterations in brain metabolic activity
We have demonstrated dramatic differences in the
effects of clozapine in comparison to other antipsy-
chotic drugs on ketamine-induced alterations in 2-DG
uptake. Clozapine blocked the effects of the NMDA
antagonist on 2-DG uptake in all brain regions, whereas
haloperidol did not block, and in fact potentiated the
metabolic activation in most brain regions.71 Pretreat-
ment of rats with risperidone did not block the effects
of ketamine on 2-DG uptake, but unlike haloperidol,
did not potentiate the effects of the NMDA antagon-
ist.100 In preliminary studies, olanzapine (5 mg kg−1)
effectively blocked ketamine-induced increases in 2-
DG uptake in the medial prefrontal cortex, but not in
the hippocampus (Duncan et al, unpublished
observations). However, at a dose of 10 mg kg−1 olanza-
pine blocked the effects of ketamine in all brain
regions. At a dose of 5 mg kg−1 of olanzapine, there
would be a maximally effective blockade of 5HT2 and
D2 receptors.101 Therefore an action of olanzapine
other than D2 or 5HT2 receptor blockade may be
involved in the drug’s effect on ketamine-induced 2DG
uptake. The results we have obtained with different
classes of antipsychotic drugs suggest that the para-
digm of ketamine-induced alterations in brain 2-DG
uptake may constitute a promising model to explore
mechanisms of action of atypical antipsychotic drugs,
and to discriminate drugs with clozapine-like
properties.
Differential effects of typical and atypical
antipsychotics on electrophysiological responses to
NMDA and NMDA antagonists
Electrophysiological studies examining the effects of
clozapine indicate that the atypical antipsychotic may
potentiate NMDA-mediated responses. Clozapine was
shown to potentiate electrophysiological activation of
neurons in the medial prefrontal cortex induced by
stimulation of the forceps minor of the corpus callo-
sum.102 By contrast, haloperidol inhibited responses in
the same experimental paradigm. These data are con-
sistent with the opposite effects of colzapine on keta-
mine-induced 2-DG uptake. However, when effects of
haloperidol and clozapine were examined on
responses induced by direct application of NMDA,
both haloperidol and clozapine potentiated NMDA-
evoked responses, although clozapine was more potent
in this action.102 The differential effects observed in the
NMDA-evoked responses, in comparison to excitation
induced by stimulation of the corpus callosum, was
explained by the observation that haloperidol, but not
clozapine, inhibited AMPA-activated responses.
In accord with the action of clozapine to potentiate
NMDA-evoked electrophysiological responses are the
findings that the atypical antipsychotic was able to
reverse the inhibitory effect of PCP in the prefrontal
cortex.103 However, haloperidol and raclopride (a
potent D2 antagonist) did not prevent the PCP-induced
inhibition of NMDA-mediated electrophysiological
 Antipsychotic drug action in schizophrenia
GE Duncan et al

424
activation.103 These electrophysiological findings are treatment blunted ketamine-induced increases in
consistent with the ability of clozapine (but not thought disturbance in schizophrenic patients.105
haloperidol) to block ketamine-induced increases in 2- These findings in humans parallel the observed effects
DG uptake. of haloperidol and clozapine on responses to NMDA
antagonists in preclinical models, and provide support
Potential mechanisms for clozapine-induced for the contention that such preclinical paradigms may
alterations in responses to NMDA antagonists have utility for understanding the therapeutic basis of
Further study is required to determine whether the atypical antipsychotic drugs action.
action of clozapine to alter brain metabolic and
electrophysiological effects induced by NMDA antag- Therapeutic potential of agonists of the glycine
onists results from direct modulatory actions on site on the NMDA receptor in schizophrenia
NMDA receptors, or involves interactions with other patients
neurochemical systems and circuits. Although there is
Glycine is a positive allosteric modulator and co-agon-
no evidence for direct effects of clozapine on MK-801
ist at the NMDA receptor (for review see106). The allo-
binding, Banerjee et al104 found that clozapine
steric glycine regulatory site on the NMDA receptor
enhanced glycine-stimulated MK-801 binding to stria-
represents a potential target for drugs to augment
tal membranes, indicating that the drug could potenti-
NMDA-mediated neurotransmission. There have been
ate NMDA-induced responses. Haloperidol produced a
a number of clinical studies to test effects of different
similar effect so it is difficult to explain the differences
glycine site agonists in schizophrenic patients. The
in clinical and preclinical effects of these prototype
earliest studies in this regard used glycine in doses of
typical and atypical antipsychotic drugs by that action.
5–15 g day−1 and obtained inconsistent results.107,108 In
It will be of interest to compare effects of different anti-
more recent work with glycine, higher doses were
psychotics on glycine-stimulated MK-801 binding in
administered (30–60 g day−1) and more robust and con-
regions other than the striatum, such as medial pre-
sistent effects were found, primarily in the improve-
frontal cortex and hippocampus.
ment of negative symptoms.109–111 d-Cycloserine, a par-
In regard to the observed effects of clozapine on
tial agonist at the glycine regulatory site on the NMDA
electrophysiological responses to NMDA and PCP,
receptor, has also been tested in schizophrenic
the selective 5HT2A receptor antagonist M100907
patients. In a very narrow dose range, d-cycloserine
produces similar effects as clozapine.103 Those data
was demonstrated to improve negative symptoms
suggest that the 5HT2A antagonistic properties of
when administered alone112 and when added to con-
clozapine could account for the observed electrophysi-
ventional neuroleptic treatment regimes.113,114 How-
ological effects of the drug. Results of ongoing clinical
ever, when d-cycloserine was administered in conjunc-
trials with M100907 will determine the therapeutic
tion with clozapine, the negative symptoms of the
potential of selective 5HT2A antagonism for schizo-
patients were worsened.115,116 A similar worsening of
phrenia.
negative symptoms in schizophrenic patients who
The ability of clozapine to block the brain metabolic
were treated with clozapine was observed after admin-
effects of ketamine in vivo may not relate directly to
istration of glycine.117 Defining mechanisms that
5HT2A antagonism, since risperidone did not mimic
account for the worsening of negative symptoms after
the effects of clozapine in that paradigm.100 However,
administration of glycine and d-cycloserine to cloza-
it is possible that the 5HT2A blocking properties of clo-
pine-treated patients could contribute to the under-
zapine contribute to its action, perhaps in concert with
standing of clozapine’s therapeutic mechanism of
other pharmacological properties of the drug. Assess-
action.
ment of the effects of M100907, alone and in combi-
The poor penetration of the blood–brain barrier by
nation with other drugs selective for specific dopamine
glycine, and the partial agonistic properties of d-cyclo-
and serotonin receptors, could resolve the importance
serine, make these agents less than optimal for provid-
of various receptor-blocking properties of clozapine on
ing pharmacological agonism of the glycine regulatory
the robust antagonism of ketamine-induced metabolic
site on the NMDA receptor. d-Serine is a full agonist
activation.
of the glycine regulatory site118 and has recently been
demonstrated to improve both positive and negative
Effects of clozapine and haloperidol on responses symptoms when given in conjunction with antipsy-
to ketamine in schizophrenia patients chotic medication in treatment-resistant patients.119
These data, together with the results of the clinical
Although limited information is available from human
investigations with glycine and d-cycloserine, offer
studies, reported effects of antipsychotic drugs on
promise for the therapeutic potential of enhancing
responses to ketamine in schizophrenic patients are
NMDA receptor function as a strategy for the pharma-
consistent with results from experimental animals,
cotherapy of schizophrenia.
indicating that clozapine selectively modifies
responses to NMDA antagonists. Patients on haloperi-
dol exhibited greater increases in ketamine-induced Conclusions
psychosis ratings relative to baseline, compared to a A number of antipsychotic drugs designated as ‘atypi-
haloperidol-free condition.58 By contrast clozapine cal’ have been introduced, or are in advanced stages of

GE Duncan et al
clinical development. The rationale for the develop-
ment of these drugs was to mimic the favorable actions
of clozapine, while minimizing its adverse side effects.
The discovery strategy which led to this new and
emerging class of atypical drugs has been based largely
on antagonistic activity at D2 and 5HT2A receptors.
Although insufficient data are available to reach
definitive conclusions, the clinical experience with ris-
peridone and olanzapine to date suggests that neither
drug is as efficacious as clozapine in treatment-resist-
ant schizophrenic patients. Risperidone and olanza-
pine are highly effective antipsychotics with low EPS
liability at appropriate doses, but available data suggest
that these new ‘atypical’ drugs are not as effective as
clozapine.13,35,120 Since olanzapine and risperidone are
potent antagonists at D2 and 5HT2 receptors, it is
unlikely that those same properties of clozapine
account for its superior therapeutic efficacy. There is
currently insufficient clinical data to compare efficacy
of clozapine with the newer ‘atypicals’ such as ziprasi-
done, M-100907, and quetiapine.
A growing body of data implicates involvement of
NMDA receptors in the etiology of schizophrenia and
mechanisms of action of clozapine. Exploration of the
effects of antipsychotic drugs in experimental animal
and human models of reduced NMDA receptor func-
tion may be useful for defining mechanisms of atypical
antipsychotic drug action, and distinguishing drugs
with clozapine-like qualities. Furthermore, if reduced
NMDA receptor function is a component of the patho-
physiology of schizophrenia, new therapeutic
approaches could involve potentiating NMDA-
mediated responses using allosteric modulators such
as glycine site agonists119,121,122 or other approaches
such as inhibition of glycine uptake.123
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