Treatments For Schizophrenia: A Critical Review of Pharmacology and Mechanisms of Action of Antipsychotic Drugs

Molecular Psychiatry (2005) 10, 79–104
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FEATURE REVIEW
Treatments for schizophrenia: a critical review of

pharmacology and mechanisms of action of antipsychotic
drugs
S Miyamoto1, GE Duncan2, CE Marx3 and JA Lieberman2
1
Department of Neuropsychiatry, St. Marianna University School of Medicine, Kawasaki, Japan; 2Department of Psychiatry and
Mental Health and Neuroscience Clinical Research Center, School of Medicine, The University of North Carolina at Chapel Hill,
NC, USA; 3Department of Psychiatry and Behavioral Sciences, Duke University Medical Center and Durham VA Medical
Center, NC, USA
The treatment of schizophrenia has evolved over the past half century primarily in the context
of antipsychotic drug development. Although there has been significant progress resulting in
the availability and use of numerous medications, these reflect three basic classes of
medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all
of which, despite working by varying mechanisms of actions, act principally on dopamine
systems. Many of the second-generation (atypical and dopamine partial agonist) antipsycho-
tics are believed to offer advantages over first-generation agents in the treatment for
schizophrenia. However, the pharmacological properties that confer the different therapeutic
effects of the new generation of antipsychotic drugs have remained elusive, and certain side
effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic
drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of
treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not
been successful to date, though numerous development strategies continue to be pursued,
guided by various pathophysiologic hypotheses. This article provides a brief review and
critique of the current therapeutic armamentarium for treating schizophrenia and drug
development strategies and theories of mechanisms of action of antipsychotics, and focuses
on novel targets for therapeutic agents for future drug development.
Molecular Psychiatry (2005) 10, 79–104. doi:10.1038/sj.mp.4001556
Published online 3 August 2004
Keywords: antipsychotic; dopamine partial agonist; NMDA receptor; metabotropic glutamate
receptor; schizophrenia
The therapeutic armamentarium for the treatment of improvement in negative symptoms, cognitive impair-
schizophrenia has grown and diversified in the half ment, relapse prevention, functional capacity, and
century since the advent of chlorpromazine and the quality of life with fewer extrapyramidal symptoms
beginning of the pharmacologic era in psychiatry. Over (EPS), and less tardive dyskinesia (TD) (for a review,
the past decade, much of our attention regarding the see Miyamoto et al1). Accordingly, many clinicians are
treatment for schizophrenia and related psychotic prescribing these new antipsychotics as first-line
disorders has focused on a new class of antipsychotic agents for acute and maintenance therapy for schizo-
medications. The reintroduction of clozapine repre- phrenia.2–5 However, these advantages, thus far, have
sented a major step forward, and led to the prolifera- been regarded as incremental and not necessarily
tion of ‘atypical’ or second-generation antipsychotics substantial. In addition, concerns about side effects
(SGAs), including risperidone, olanzapine, quetiapine, such as EPS have been replaced by other distressing
ziprasidone, sertindole and zotepine. In fact, there is side effects, including weight gain, hyperglycemia and
growing evidence that most of the new medications dyslipidemia. At present, we are still in the process
can offer some advantages over ‘typical’ or first- of defining fully the clinical profiles of new agents
generation antipsychotics (FGAs) such as greater in terms of the extent of their therapeutic efficacy and
adverse effects, on a variety of other outcomes includ-
ing cognition, affect, suicide, subjective response,
Correspondence: Dr J Lieberman, Department of Psychiatry and social and vocational function, cost effectiveness, etc.6
Mental Health and Neuroscience Clinical Research Center, Although intensive research on the new antipsy-
University of North Carolina School of Medicine, CB #7160, chotic drugs has led to a greater understanding of the
7025 Neurosciences hospital, Chapel Hill, NC 27599-7160, USA. biochemical effects of these drugs, the pharmacologi-
E-mail: [email protected]
Received 04 February 2004; revised 11 June 2004; accepted 17 cal mechanisms underlying their various therapeutic
June 2004 properties remain to be identified. Moreover, an agent
Treatments for schizophrenia
S Miyamoto et al
80
like clozapine that was clinically superior to other psychotic symptoms either fail to respond to these
highly selective dopamine D2 antagonists demanded drugs or respond inadequately or partially.12 In
reconsideration of the principal mechanisms of action addition, they cause significant rates of undesirable
of antipsychotics as well as the pathophysiological acute and chronic adverse effects (for a review, see
mechanisms in schizophrenia.6,7 In addition, the Miyamoto et al9). At this time, the only groups of
limitations of existing antipsychotic drugs to alle- patients in which the FGAs are clearly preferable are
viate all of the pathologic dimensions of the illness those for whom there is a clear indication for short- or
(ie negative symptoms, cognitive deficits and social long-acting injectable preparations (this will quickly
disabilities) have produced an awareness that no change as injectable SGAs become more available), or
single treatment may be sufficient and prompted the who have a history of excellent response to a FGA
search for compounds that can be used adjunctively with minimal side effects.13,14
with antipsychotic drugs. Various adjunctive treat- Despite the superior clinical effectiveness and EPS
ments, including benzodiazepines, lithium, antic- profile of clozapine, its clinical utility is restricted by
onvulsants, antidepressants, beta-blockers and the propensity to cause agranulocytosis and manda-
dopamine agonists, have been used to enhance the tory hematological monitoring of patients. Newly
response to antipsychotic medications or to treat developed SGAs in addition to the benzamide
residual symptoms of chronic schizophrenia and antipsychotic drugs (sulpirides and amisulprides)
comorbid conditions with schizophrenia (for reviews, and aripiprazole, appear to provide important ad-
see Miyamoto et al5,8). However, despite the preva- vances in side effect profile and efficacy for this drug
lence of the use of adjunctive therapies in clinical class. However, a variety of side effects associated
practice, there are very few empirical data and with individual SGAs and the substituted benza-
theoretical rationale to support this practice. The mides still affect patient health and quality of life in
development of additional novel strategies to obtain addition to their limitations in efficacy. Consequently,
potentially new antipsychotic compounds and their there is a continuing need for new and better drugs.
adjuncts possessing unique pharmacological profiles Over the last few years, new routes of administra-
with few side effects is being pursued based on tion for SGAs have been developed. As of December
specific hypotheses, and actually more agents with 2003, besides oral tablet form of medication, risper-
antipsychotic efficacy are being developed. (for re- idone is available in a liquid form and long-acting
views, see Miyamoto et al5,9). This article provides a microsphere preparations in the US and some
brief review and critique of the current theory of European countries. Olanzapine is available as a
mechanisms of action of antipsychotic drugs, and rapidly disintegrating tablet (zydis) form and an
focuses on novel targets for therapeutic intervention intramuscular form in some countries. A short-acting
and potential strategies for future drug development. intramuscular parenteral form of ziprasidone is
available in the US and many European countries.15
These newly available routes of administration could
Current forms of treatment: first-generation anti-
enhance the usefulness of the SGAs significantly (for
psychotics and second-generation antipsychotics
a review, see Fleischacker16).
The strategies and forms of treatment for schizophre-
nia vary according to the phase and severity of the
Theories of mechanisms of action of antipsychotic
illness. Pharmacologic treatment is the cornerstone
drugs
and essential component of treatment for schizophre-
nia and its clinical management through the different First-generation antipsychotic agents
stages of the illness. Although various psychosocial The effect that is common to all FGAs is a high
therapies, such as cognitive behavior therapy, psy- affinity for dopamine D2 receptors,17 and there is a
choeducation and supported employment, are useful strong correlation between the therapeutic doses of
adjuncts to drug treatment,8,10,11 they all require these drugs and their binding affinity for the D2
pharmacologic treatment to be maximally effective. receptor.18–21 In vitro data show that FGAs such as
In particular, adequate pharmacotherapy during the haloperidol bind ‘tightly’ to the D2 receptor and
acute stage of the illness could set the stage for dissociate slowly.22 In vivo positron emission tomo-
subsequent long-term treatment. Although all avail- graphy (PET) and single photon emission computed
able pharmacological treatments have limitations in tomography (SPECT) studies have further demon-
their effectiveness and are associated with uncomfor- strated the importance of dopamine receptor occu-
table side effects, it is an established fact that pancy as a predictor of antipsychotic response and
antipsychotics can improve the psychotic symptoms adverse effects (for a review, see Remignton and
of schizophrenia and prevent their recurrence.10,11 At Kapur23). Such studies have demonstrated that anti-
present, a total of 11 different classes of antipsychotic psychotic effects are associated with a striatal D2
medications are available in the US. Among them are receptor occupancy of 65–70%,24–27 and D2 occu-
the currently available FGAs (phenothiazines, butyr- pancy greater than 80% significantly increases the
ophenones and thioxanthenes) which, although effec- risk of EPS.24 Recent imaging studies have also shown
tive, are far from being optimal treatments. Between that therapeutic doses of FGAs produce high blockade
30 and 60% of patients with acutely exacerbated of D2-like receptors equally in limbic cortical areas
Molecular Psychiatry
S Miyamoto et al
81
and the striatum.28,29 Thus, a threshold between 65 and whether it would occur in the intact nonanesthe-
and 80% D2 occupancy appears to represent the tized unrestrained animals.43–45 Nevertheless, a num-
therapeutic window to minimize the risk of EPS for ber of studies have demonstrated that FGA-induced
FGAs.23,27,30 However, this is not absolute as some dopamine cell depolarization block does occur in
patients can respond below this threshold, and nonanesthetized animals40,41,46,47 (for a review, see
nonresponders can be seen in spite of adequate D2 Grace et al48).
receptor blockade reflecting the limitations of the
receptor occupancy model.27,31 Interestingly, low Benzamides
doses of haloperidol (2–5 mg/day) would be expected Amisulpride, a substituted benzamide analogue of
to induce 60–80% dopamine D2 receptor occu- sulpiride, is a highly selective anatagonist of D2 and
pancy,25,32 while dosages five to 20 times as high are D3 receptors with little affinity for D1-like or non-
often prescribed in current clinical practice.33 This dopaminergic receptors (Table 1).49,50 Its congener,
may be partly accounted for by the fact that long-term sulpiride, demonstrates a generally similar pharma-
treatment with FGAs induces upregulation in D2 cological profile. Preclinical studies suggest that low
receptors in both animals34,35 and humans,36,37 which doses of amisulpride (and probably sulpiride) pre-
appears to be associated with dopamine D2-mediated ferentially block presynaptic D2-like autoreceptors,
supersensitivity,38,39 thus theoretically, increments in and thus lead to an increase in dopaminergic release
dose may be needed to produce the same effect on and neurotransmission, while higher doses reduce
dopaminergic transmission for chronic patients.27,31 certain postsynaptic dopamine receptor-mediated
It is important to acknowledge that the gradual and behaviors that predict antipsychotic efficacy, but with
time-dependant onset of therapeutic efficacy is not little or no induction of catalepsy that predicts low
consistent with the rapid striatal D2 receptor blockade EPS liability.31,50,51 Several PET and SPECT studies in
induced by antipsychotics. Preclinical studies de- schizophrenia demonstrated that amisulpride selec-
monstrating that chronic treatment of rodents with tively binds to temporal cortical D2/D3 receptors in a
FGAs can decrease the number of spontaneously dose-dependent fashion, but this extra-striatal selec-
active dopamine neurons in both the substantia nigra tivity is lost at higher doses as striatal D2/D3 receptor
pars compacta (A9) and the ventral tegmental area occupancy increases.52–54 Another PET study found
(A10) have given rise to the ‘depolarization inactiva- no significant binding to 5-HT2A receptors in amisul-
tion (or block) hypothesis’.40–42 Mereu et al,43–45 pride-treated patients.55 It is also characterized by the
however, have suggested that the depolarization rapid dissociation from the D2 receptor similar to
inactivation of dopamine neurons may be an artifact clozapine.56 Amisulpride is essentially devoid of 5-
produced by the use of general anesthetics, and HT2A antagonism, thus its moderate affinity for
thereby questioned the validity of this phenomenon striatal D2 receptors and preferential occupancy of
Table 1 Relative neurotransmitter receptor affinities for antipsychotics at therapeutic doses (adapted from Miyamoto et al1 and
modified)
Receptor Cloza- Risperi- Olanza- Quetia- Ziprasi- Sertin- Sulpi- Amisul- Zote- Aripipra- Halope-
pine done pine pine done dole ride pride pine zole ridol
D1 þ þ þþ þ þþ þ þ
D2 þ þþþ þþ þ þþþ þþþ þþþþ þþþþ þþ þþþþ þþþþ
D3 þ þþ þ þþ þþ þþ þþ þþ þþ þþþ
D4 þþ þþ þþ þ þ þ þþþ
5-HT1A þþþ þþ þþ
5-HT1D þ þþþ þ
5-HT2A þþþ þþþþ þþþ þþ þþþþ þþþþ þþþ þþþ þ
5-HT2C þþ þþ þþ þþþþ þþ þþ þ
5-HT6 þþ þþ þ þþ þ
5-HT7 þþ þþþ þþ þþ þþ
a1 þþþ þþþ þþ þþþ þþ þþ þþ þ þþþ
a2 þ þþ þ þ þþ þ
H1 þþþ þþþ þþ þ þþ þ
m1 þþþþ þþþ þþ þ
DA þþ þþ
transporter
NA þ þþ þþ þþ
transporter
5-HT þþ
transporter
¼ minimal to none; þ ¼ low; þ þ ¼ moderate; þ þ þ ¼ high; þ þ þ þ ¼ very high.
S Miyamoto et al
82
limbic cortical D2/D3 receptors may be reasons for its binding can act as an effective antipsychotic.6 The
therapeutic efficacy and low liability to induce EPS.54 question has been do pharmacologic effects on
dopamine-mediated pathways account for all of the
Second-generation antipsychotic agents clinical therapeutic effects of antipsychotic drugs.
Recent in vitro studies have demonstrated that
The serotonin–dopamine antagonism theory The antipsychotics dissociate from the D2 receptor at
‘serotonin–dopamine (S2/D2) antagonism theory’ very different rates, expressed as a koff value.22,74
promulgated by Meltzer et al57 suggests that a higher The SGAs have higher koff values as a group, that is
ratio of a drug’s affinity for serotonin 5-HT2A receptor faster dissociation rates, than the FGAs, but they
relative to dopamine D2 receptor affinity can predict differ among themselves on this dimension as well
‘atypicality’ and will explain the enhanced efficacy (e.g., quetiapine4clozapine4olanzapine4ziprasi-
and reduced EPS liability of SGAs (for reviews, see done4risperidone).6,56,75 Kapur and Seeman hypothe-
Miyamato et al,1 Lieberman,58 Duncan et al 59). sized that dissociation from the D2 receptor quickly
PET studies showing that therapeutic doses of makes an antipsychotic agent more accommodating of
risperidone, olanzapine and ziprasidone produce physiological dopamine transmission, permitting an
greater than 70% occupancy of D2 receptors suggest antipsychotic effect without EPS, hyperprolac-
that a specific threshold of D2 receptor antagonism tinemia, as well as conferring benefits along a
could be important in producing antipsychotic effects variety of clinical dimensions such as cognitive, affec-
of these drugs.60,61,391 Clozapine and quetiapine, tive and secondary negative symptoms.74 Accor-
however, exhibit lower levels of D2 receptor occu- dingly, they suggest that sustained D2 occupancy is
pancy (less than 70%) at therapeutically effective not necessary for antipsychotic action. However, this
doses (Table 1),24,61–63 suggesting that a threshold level theory cannot explain the greater therapeutic efficacy
of D2 receptor occupancy (and possibly antagonism) of clozapine compared with other SGAs, particularly
alone cannot fully explain the greater therapeutic in the management of treatment-resistant schizo-
efficacy of clozapine59 or for that matter serve as a phrenia. The rapid dissociation of clozapine and
model to predict antipsychotic efficacy. The low quetiapine from D2 receptors by endogenous
occupancy of striatal D2 receptors by clozapine dopamine may lead to more rapid clinical relapse
and quetiapine could account for its low EPS after discontinuation of these medications.75 At
liability.30,62–64 Interestingly, ziprasidone exhibits present, it remains unclear how long an antipsy-
high levels of D2 occupancy at doses of 20– chotic agent must bind to the D2 receptor to maximize
40 mg,65,66 doses that are substantially below the therapeutic efficacy while minimizing the risk of
therapeutically effective dose range (120–200 mg/ D2-related side effects.31 Another limitation of this
day).67,68 Thus, pharmacological properties other than model is that all antipsychotics have not been
a threshold level of D2 receptor antagonism (at least as studied with it, including the benzamides, low-
reflected by receptor occupancy levels) may account potency FGAs and partial dopamine agonists (e.g.
for the clinical efficacy of ziprasidone. aripiprazole).
Clozapine, risperidone, olanzapine and ziprasidone
occupy more than 80% of cortical 5-HT2A receptors Potential therapeutic significance of targeting other
in the therapeutic dose range in humans (Table neuroreceptors The SGAs, particularly clozapine,
1).24,60,61,63,69,70 Although 5-HT2A receptor antagonism have multiple sites of action other than dopamine D2
is likely to be associated with the low EPS liability of receptors, including dopamine (D1, D3, D4), serotonin
SGAs, risperidone at higher doses produces EPS,71 (5-HT1A, 5-HT2C, 5-HT6, 5-HT7), muscarinic
indicating that high levels of D2. antagonism cannot cholinergic and histamine receptor (Table 1). Among
be completely ameliorated by even maximal 5-HT2A them, it has been hypothesized that the partial agonist
receptor antagonism. Moreover, at this point, it is activity of clozapine at serotonin 5-HT1A receptors
unclear what clinical effects 5-HT2A antagonism may contribute to its efficacy against anxiety, depres-
confers, beyond mitigating the adverse effect of sion, cognitive and negative symptoms of schizo-
striatal D2 antagonism, and propensity to cause phrenia (Table 2).76–79 Preclinical studies have also
EPS.72 In particular, the role of 5-HT2A antagonism suggested that 5-HT1A agonists may potentiate the
in the superior therapeutic responses to clozapine antipsychotic activity of dopaminergic antagonists,80
awaits further clarification.59 The apparent lack of and activation of inhibitory 5-HT1A autoreceptors may
efficacy of monotherapy with the selective potential counteract the induction of EPS due to striatal D2
role of the 5-HT2A receptor antagonist M-10090773 receptor blockade.81 Furthermore, 5-HT1A agonism
indicates that 5HT2A antagonism alone cannot explain has been suggested to contribute to enhancement of
the efficacy of SGAs. Further studies examining prefrontal dopamine release.82 Indeed, clozapine,
combination therapy with D2 antagonist and M- and olanzapine and ziprasidone, but not haloperidol
100907 are necessary to evaluate the potential role or risperidone, can preferentially augment dopamine
of 5HT2A antagonism. and norepinephrine release in the prefrontal cortex
relative to the subcortical areas, which may be rela-
The ‘fast-off-D2’ theory To date, there is no evidence ted to their potential efficacy for negative symptoms
showing that an agent without some degree of D2 and cognitive dysfunction of schizophrenia.83 The
S Miyamoto et al
83
Table 2 Potential clinical efficacy and benefits related to the mechanisms of action of antipsychotics (adapted from Richelson6
in part and modified)
Mechanisms Potential clinical efficacy Potential consequences
D2R antagonism k positive symptoms EPS

mNegative symptoms
mCognitive symptoms
D2R partial agonism k positive symptoms Little or no EPS
k negative symptoms Behavioral activation
k cognitive symptoms
mDA and NE release in the PFC k negative symptoms Behavioral activation
k depressive symptoms
ACh release in the PFC k cognitive symptoms
5-HT2A antagonism k negative symptoms k EPS
5-HT1A partial agonism k negative symptoms

k anxiety symptoms
k depressive symptoms
Muscarinic R antagonism k EPS m Anticholinergic symptoms
e.g. dry mouth, constipation tachycardia
Muscarinic R agonism k psychotic symptoms
Glutamate modulation k positive symptoms
k negative symptoms
k illness progression
NE, norepinephrine; Ach, acetylcholine; PFC, prefrontal cortex; EPS, extrapyramidal symptoms.
prefrontal cortex contains high densities of 5-HT1A experimentally induced NMDA receptor hypo-
and 5-HT2A receptors located on affrents to and on function at the cellular and behavioral levels,96–100
pyramidal neurons.84 It has been suggested that which provides support for the NMDA receptor
activation of 5-HT2A receptors increases the release hypofunction hypothesis. For example, clozapine
of glutamate onto pyramidal cells,85 whereas sero- and olanzapine, but not haloperidol or raclopride,
tonin, possibly via activation of 5-HT1A receptors, inhibit the electrophysiological effects of PCP in brain
inhibits the release of glutamate.86 Thus, compounds slices,99,101,102 and attenuate NMDA antagonist-
with 5-HT2A antagonism and/or 5-HT1A agonism like induced deficits in prepulse inhibition (PPI)96,103
clozapine could regulate the physiological balance and social behavior.97 In addition, ketamine-induced
between excitatory and inhibitory inputs onto brain metabolic activation is blocked by acute
prefrontal pyramidal neurons.78,84 Some SGAs, parti- administration of clozapine and olanzapine, but not
cularly ziprasidone, can also increase serotonin haloperidol in rats.98,100 The well-documented
activity in the frontal cortex by virtue of their effects of the SGAs on responses to NMDA
affinity for the serotonin transporter.87,88 In addition, antagonists raise the possibility that the therapeutic
some of the SGAs, but not FGAs, can increase the mechanisms of action of these agents may be
release of acetylcholine in the prefrontal cortex, which associated with counteracting the effects of NMDA
could be a possible factor contributing to improve receptor hypofunction.104 However, since none of
cognition in schizophrenia.89 the SGAs have direct affinity for any of the
glutamate receptors including the NMDA receptor,
Antipsychotic interactions with the glutamate the mechanism by which these effects are mediated
system The ability of noncompetitive N-methyl- is poorly understood. A recent report by Sur et al.105
D-aspartate (NMDA) receptor antagonists, such as could help to elucidate this question. They have
phencyclidine (PCP) and ketamine, to induce a shown that clozapine’s biologically active metabolite,
spectrum of positive, negative and cognitive schizo- N-desmethylclozapine, which is a potent, allosteric
phrenia-like symptoms has led to the hypothesis that agonist at muscarinic M1 receptors, can potentiate
hypofunction of NMDA receptors is involved in the hippocampal NMDA receptor currents through M1
pathophysiology of schizophrenia.90–95 In a wide receptor activation.105 Thus, clozapine’s unique thera-
range of preclinical paradigms, some of the SGAs, peutic profile may be, at least in part, attributed to
but not the FGAs, selectively antagonize the effects of N-desmethylclozapine through potentiation of NMDA
S Miyamoto et al
84
receptor function mediated by M1 receptors. Further pancies appear to be due to different treatment
studies are needed to determine whether the regimens, brain regions examined and the method of
inhibition of the effects of NMDA antagonists by the assessment. Thus, it is unclear whether such changes
SGAs involves molecular modifications in glutamate reflect increased or decreased function of different
receptors or altered other neurotransmitter–glutamate glutamate receptors after chronic antipsychotic treat-
interactions. ments.
In contrast to the acute effects, chronic administra-
tion of haloperidol can block not only PCP-induced Microarray analysis of gene expression induced by
deficits in PPI,106,107 but also ketamine-induced brain antipsychotic drug treatment Microarray expression
metabolic activation.108 Thus, adaptive changes eli- profiling appears to be a useful strategy to iden-
cited by chronic treatment with both the FGAs and tify candidate target genes that may be relevant to
the SGAs appear to attenuate the effects of NMDA the mechanisms of action of antipsychotic drugs.
antagonists.108 To date, numerous animal studies have Kontkanen et al124 have found that acute clozapine
reported increases, decreases, or no change in binding treatment induces the gene expression of chromo-
sites of glutamate receptors in various brain regions granin A and calcineurin A, and decreases synapto-
after chronic administration of antipsychotics109–115 tagmin V mRNA in the rat frontal cortex. In addition,
(Table 3). At the molecular level, inconsistent and chronic administration of clozapine induced the
often opposite findings have also been reported in the differential mRNA expression patterns of chromo-
gene expression of subunits composing different granin A, son of sevenless, and Sec-1 in the cortex.
glutamate receptors following long-term treatment In contrast, chronic exposure to haloperidol regula-
with both the FGAs and SGAs.116–123 These discre- ted the gene expression of inhibitor of DNA-binding
Table 3 Major findings in studies examining effects of chronic antipsychotics treatment on glutamate receptor binding and
mRNA expression (adapted from109123)
Antipsychotics NMDA-R AMPA-R KA-R Metabotropic-R
Haloperidol MK-801binding - k m (cortex) 3H- AMPA binding - m (cortex) KA binding - Group II mRNA
CGP-39653 binding m (striatum, AMPA mRNA m (GluB & (cortex) KA2 - (cortex)
cortex) MK-801binding - m GluC) (hippocampus) mRNA m
(striatum, hippocampus) MK- Subunits mRNA - (Acb, (cortex,
801binding m (Acb) striatum) GluR1 protein striatum,
m(cortex) GluR2 mRNA m k hippocampus)
(cortex, striatum) GluR4
mRNA k (cortex, striatum)
NR1 protein m (striatum) NR1
mRNA m k (striatum, cortex) NR1
mRNA m (hippocampus) NR2A-C
mRNA m (striatum) NR2A mRNA k
(cortex, hippocampus)
Clozapine MK-801binding - k (cortex) 3H- AMPA binding - (cortex) KA binding - Group II mRNA
CGP-39653 binding m (cortex) MK- AMPA mRNA m (GluB & (cortex) GluR7 m (cortex)
801binding k (striatum) MK- GluC) (hippocampus) GluC mRNA m
801binding m (Acb) mRNA k (Acb) GluR1 protein (cortex,
m (cortex) GluR2 mRNA - striatum) KA2
(striatum) GluR3 mRNA k mRNA m
(cortex, striatum) GluR4 (striatum)
mRNA k (striatum)
NR1 mRNA m k (Acb) NR1 mRNA
- (cortex, striatum, hippocampus)
NR1 protein - (striatum) NR2A
mRNA k (cortex, hippocampus)
NR2C mRNA k (cortex, Acb)
Olanzapine MK-801binding - (cortex) AMPA mRNA m (GluB & KA binding - Subunits mRNA
GluC) (hippocampus) AMPA (cortex) - (striatum,
binding m Subunits mRNA - hippocampus)
(cortex, striatum)
MK-801binding k Subunits mRNA
- (cortex, striatum, hippocampus)
Acb, nucleus accumbens.
S Miyamoto et al
85
2 (ID-2) and Rab-12. Moreover, the expression of Aripiprazole neither conforms to the standard 5-
visinin-like proteins was regulated by chronic HT2A/D2 antagonist nor the fast dissociation theories
treatments with both agents in various brain regions. of atypicality. It has a very high affinity for the D2
Chromogranin A and synaptotagmin V have been receptor (greater than its 5-HT2A affinity) and this is
suggested to play roles in presynaptic vesicle forma- unlikely to have a fast koff. Similarly, the compound
tion and secretion.125,126 Calcineurin A, a Ca2 þ / has a long half-life and is therefore unlikely to show
calmodulin-dependent protein phosphatase, and transient receptor occupancy. PET studies in normal
visinin-like proteins are involved in the regulation humans indicate that although aripiprazole occupies
of intracellular Ca2 þ metabolism (for reviews, see up to 90% of striatal D2-like dopamine receptors at
Bultynck et al127 and Braunewell and Gundefinger128). clinical doses, it does not cause EPS, suggesting that
Thus, it is possible that both antipsychotics may its inherent agonism may provide a mechanism that
modulate neurotransmitter vesicle release and protects against excessive blockade of the D2 sys-
presynaptic organization as well as the regulation tem.139 This underlines aripiprazole’s unique me-
of intracellular Ca2 þ in the cortex.124 Interestingly, chanism of action as a partial dopamine receptor
altered expression of genes involved in presynaptic agonist,79,134 and possibly a novel form of treatment
function has been observed in the prefrontal cortex of for schizophrenia.
the postmortem brains of schizophrenics.129 However,
Bauer et al.130 failed to detect any significant changes
Clinical pharmacological profiles of antipsychotic
in cortical synaptic protein levels or their enco-
drugs
ding mRNAs after chronic haloperidol adminis-
tration in rats. Furthermore, several genes involved First-generation antipsychotic agents
in the presynaptic function were not altered after Although the FGAs (eg, chlorpromazine and haloper-
chronic haloperidol treatment in the prefrontal idol) vary in potency, their pharmacological proper-
cortex of monkeys.129 The effects of chronic anti- ties, and their propensity to induce side effects, they
psychotic administration on presynaptic function are equally effective in the treatment of positive
at the molecular and cellular levels require further symptoms of schizophrenia and in preventing their
study. recurrence (for reviews, see Miyamoto et al8,9, Davis
et al140 and American Psychiatric Assocoation141).
However, approximately 30% of patients with acutely
Partial dopamine agonists exacerbated psychotic symptoms, however, have little
Aripiprazole (OPC-14597), approved for clinical use or no response to FGAs, and up to 60% of patients
in the US and more recently in Europe, is the first of a have only a partial response to medication.12,142 FGAs
possible ‘next- generation antipsychotics’ with a are generally less effective against negative than
mechanism of action that differs from currently positive symptoms of schizophrenia (for a review,
marketed FGAs and SGAs.79 It is a partial dopamine see Miyamoto et al8). They also produce small and
agonist with a high affinity for D2 and D3 receptors,131–133 inconsistent effects on cognitive functioning.143–145
and demonstrates properties of a functional agonist Some studies report worsening, improvement, or no
and antagonist in animal models of dopaminergic change in cognitive function with FGAs treatment.144
hypoactivity and hyperactivity, respectively.131,134 The discrepancies may be due, in part, to differences
Aripiprazole acts on both postsynaptic D2 receptors in patient populations, specific tests used, and the
and presynaptic autoreceptors. Partial agonist activity differential response of psychopathology to antipsy-
at D2 receptors could stabilize the dopamine system chotics.144 Cognitive impairment may also be wor-
while avoiding the hypodopaminergia that may limit sened by adjunctive anticholinergic medications,
the efficacy and tolerability of FGAs.135 In addition, which are frequently required to treat EPS caused by
aripiprazole displays 5-HT1A partial agonism and 5- FGAs.146
HT2A antagonism.136 The distinction, pharmacologi- In addition, the prophylactic efficacy of FGAs for
cally, between aripiprazole and the SGAs in this relapse prevention is limited by poor treatment
regard is that aripiprazole’s affinity for the D2 compliance and the fact that even with full compli-
receptors exceeds that for serotonin by an order of ance approximately 20% of patients may re-
magnitude.6,137 It also has very modest affinity lapse.147,148 Other dimensions of treatment
for alpha1-adrenergic, histamine (H1), 5-HT6, and limitations are functional capacity, quality of life,
5-HT7 receptors, and no appreciable affinity for D1, prevention of illness progression and improvement of
histaminergic or cholinergic muscarinic receptors long-term outcome.
(Table 1).132,137 The clinical significance of these in In terms of adverse effects, all of the FGAs can
vitro receptor-binding affinities as well as its partial 5- produce EPS at therapeutic doses, including parkin-
HT1A agonism has not been determined apart from sonism, dystonia, akathisia and tardive dyskinesia to
their obvious association with side effects.138 It has a varying degree, and increase serum prolactin
also been proposed that aripiprazole induces ‘func- concentration in the usual clinical dose range.149
tionally selective’ activation of D2 receptors coupled When present, these EPS side efffects can be
to diverse G proteins (and hence different functions), unpleasant for the patient and frequently an impor-
thereby explaining its unique clinical effects.132,137 tant reason for noncompliance with medication.150
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Benzamides clozapine, risperidone, and olanzapine were 0.49,
A meta-analysis of 11 randomized controlled trials of 0.25 and 0.21, respectively, and each was signifi-
acutely ill schizophrenic patients comparing amisul- cantly greater than those of FGAs. Importantly, there
pride with FGAs or placebo found amisulpride to be was no evidence that the FGA dose affected the
consistently more effective than FGAs for global results. With respect to comparisons of efficacy
schizophrenic symptoms and negative symptoms.151 among SGAs, Geddes et al155 asserted that the SGAs
However, the mean effect size of amisulpride for are equally efficacious as a homogeneous group, but
change in the Brief Psychiatric Rating Scale (BPRS) Davis et al157 concluded that some SGAs (clozapine,
score was relatively small (0.11). In four studies of risperidone and olanzapine) are superior to other
patients with primary or predominantly negative SGAs (sertindole, quetiapine, ziprasidone and remox-
symptoms, amisulpride was more effective than ipride). It should be noted that these three meta-
placebo, but not more effective than FGAs.151 The analyses did not include data currently available to
agent also demonstrated its therapeutic benefit with evaluate the other clinical dimensions (eg, cognition,
little or no EPS, lower use of antiparkinsonian affect, quality of life) now receiving more attention.6
medication and fewer dropout rates due to adverse Moreover, the fact that most studies included in these
effects than FGAs.151 Its main side effect is substantial reviews were pharmaceutical industry-sponsored
elevations of prolactin. Additional research is neces- trials,158 used limited types of assessment measures
sary for clarifying whether amisulpride is really more and methods of data analysis (eg, last-observation-
effective for primary negative symptoms. carried-forward analyses)155 and were relatively short
in duration could limit the ability to fully evaluate the
Second-generation antipsychotic agents comparative effects of the two drug classes.158
Investigations of SGAs in very large samples and
Efficacy There have been numerous double-blind with head-to-head comparisons to each other, such as
studies comparing the efficacy and tolerability of the Clinical Antipsychotic Trials of Intervention
SGAs with FGAs for acute and maintenance therapy Effectiveness (CATIE), could provide adequate infor-
for schizophrenia. Such an expansive review is, mation regarding the role of SGAs in efficacy and
however, beyond the scope of this paper; thus, the effectiveness.158
reader is referred to other sources.1,5,152 In general,
although the proportion of patients who improve and Efficacy on negative symptoms Although SGAs have
the magnitude of therapeutic effects vary greatly, been shown to be more effective than FGAs in treating
SGAs appear to be at least as effective for psychotic negative symptoms, there is a continuing debate as to
symptoms as FGAs (for reviews, see Markowitz whether these ostensible therapeutic effects are
et al153 and Remington and Kapur154). However, secondary to a reduction in EPS or other symp-
there has been considerable debate with regard to toms, or to a direct effect on primary negative
the clinical superiority of SGAs over FGAs. symptoms.71,154,159–162 Secondary negative symptoms
Geddes et al conducted a systematic review and may be associated with positive symptoms, EPS,
meta-analyses of 52 randomized trials comparing new depression and environmental deprivation,163,164 but
antipsychotics (clozapine, olanzapine, risperidone, most clinical studies of SGAs do not distinguish
quetiapine, sertindole and amisulpride) with FGAs between primary and secondary negative symptoms
(haloperidol or chlorpromazine).155 There was no and generally involve acutely symptomatic patients
difference in efficacy between FGAs and SGAs, in undergoing treatment for their psychosis.165
trials that used a dose of an SGA in haloperidol Moreover, the effect sizes of improvement on
equivalents of 12 mg/day or less. For example, the negative symptoms for SGAs are usually moderate
advantages of SGAs in terms of efficacy and dropout to small in comparison with placebo or FGAs.156,166,167
rates were not seen if haloperidol is used at doses of Path analyses, however, have suggested that both
12 mg/day or less, although SGAs still caused fewer risperidone and olanzapine exert direct effects on
EPS.155 They concluded that the observed superior (primary) negative symptoms independent of diffe-
efficacy of some SGAs may be due to the negative rences in psychotic, depressive or extrapyramidal
effects on efficacy of the excessively high dose of the symptoms.168,169 Nevertheless, these path analytical
FGA comparator. statistical approaches were performed post hoc, and
Leucht et al156 also performed a meta-analysis and only the most effective doses of the SGAs were
concluded that SGAs have efficacy and tolerability chosen. Thus, prospective studies on stable patients
advantages over FGAs, although the benefits of new with predominant primary negative symptoms are
agents in terms of total, positive and negative necessary to draw conclusions on this issue.170 A
symptoms are modest at best. However, they did not collaborative working group concluded that SGAs are
attempt to address dose in the same fashion as Geddes superior in terms of the ‘totality’ of negative
et al.155 symptoms, but their impact on specific components
A third meta-analysis was performed by Davis is still under investigation.164
et al157 on 124 randomized controlled studies with
efficacy data on 10 SGAs vs FGAs, and 18 trials of Efficacy on cognition Studies of the effect of SGAs
comparisons between SGAs. The effect sizes of on cognition have been limited, and the findings have
S Miyamoto et al
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been inconsistent.171–173 It is unclear whether this FGAs in terms of overall psychopathology, EPS, and
effect is dependent on or independent of treatment compliance rate. There are several controlled, double-
effects on psychotic symptoms.2 Anticholinergic and blind trials comparing SGAs with FGAs in treatment-
sedative effects as well as the propensity to induce refractory schizophrenia, but the relative efficacy of
EPS associated with antipsychotic medications may other new agents is modest or less clear (for a review,
have detrimental effects on some (but not all) areas of see Miyamoto et al1). Volavka et al389 in a double-
cognition.174–176 Improvement in global cognitive blind PET found clozapine and olanzapine but not
functioning with SGAs may be secondary to less risperidone superior to haloperidol. Sequential
EPS liability and greater efficacy in the treatment of controlled trials of the newer agents in treatment-
negative symptoms.173 In general, the SGAs have resistant patients will be necessary to fully examine
demonstrated superior efficacy compared to FGAs on this issue.
tests of verbal fluency, digit-symbol substitution, fine
motor function, and executive function.171,172,177 Safety The major difference of the SGAs compared
Measures of learning and memory were least to the FGAs is their lower incidence of EPS and TD.
affected by SGAs.171 Because these tests all measure Most of the SGAs have little or no EPS, while
performance during a timed trial, enhanced risperidone has less at low doses but at higher doses
performance with SGAs could result, in part, from can cause EPS comparable to that of FGAs.189
reduced parkinsonian side effects 171. In a double- However, the individual SGAs have unique adverse
blind trial in the treatment of cognitive impairment in effects that were less of an issue with FGAs, are of
early-phase schizophrenia, risperidone (mean dose potential concern and undermine claims of safety
6 mg/day) and olanzapine (mean dose 11 mg/day) advantages for the SGAs. There is mounting evidence
produced significantly greater improvement in of the increased risk of weight gain, diabetes mellitus,
verbal fluency compared to haloperidol (mean dose prolonged QTc interval and possible secondary
10 mg/day), and olanzapine was superior to both cardiovascular complications.6 These side effects are
haloperidol and risperidone in effects on motor skills, associated with potential long-term health risks of
nonverbal fluency and immediate recall.178 This patients as well as decreased adherence to treatment
finding is, however, complicated by the high regimens, and eventually may lead to relapse.189
incidence of anticholinergic administration prior to Among SGAs, clozapine and quetiapine have been
the final cognitive assessment, and other problems in shown to carry minimal to no risk for EPS or
methodology.179,180 In a recent double-blind 14-week hyperprolactinemia within the therapeutic dosage
trial in chronic schizophrenia,181 olanzapine and range.185,190,191 Risperidone, however, can produce
risperidone were superior to haloperidol on global dose-related EPS (Z6 mg/day).192,193 With the excep-
cognitive function, but not different from each other tion of akathisia,194 the incidence of EPS or hyper-
or from clozapine. Average effect sizes for prolactinemia with olanzapine and ziprasidone is not
improvement with the SGAs were in the small to significantly different from that with placebo.195,196
medium range. Importantly, their results did not The relative liability of the individual SGAs to
appear to be mediated by changes in symptoms, side produce EPS will become apparent only when they
effects, or blood levels of medications. In contrast, have been directly compared with each other in
Green et al182 have found no cognitive advantage prospective clinical trials such as the NIMH ¼ CATIE
for risperidone (mean dose 6 mg/day) over low doses trials.390
of haloperidol (mean dose 5 mg/day) in stable schizo- Marked differences in liability for weight gain,
phrenic outpatients over a 2-year period.182 There is diabetes, or hyperlipidemia are seen between the
continued debate as to whether SGAs have pro-cogni- different SGAs. Analyses consistently report the
tive efficacy or have reduced cognitive liability.183,184 largest increases in weight gain with clozapine and
As in efficacy studies for negative symptoms, dose olanzapine, intermediate increases with risperidone
equivalence is an important factor in trials comparing and quetiapine, and minimal weight gain with
cognitive effects of SGAs, particularly since excessive ziprasidone.197–199
doses can impair performance on time-sensitive tasks
and can increase anticholinergic exposure. Keefe et Aripiprazole: efficacy and safety
al171 reported a meta-analysis which found a Several short-term double-blind, placebo-controlled
significant advantage for SGAs on cognitive test trials of aripiprazole (2–30 mg/day) demonstrated
performance. efficacy greater than placebo, and similar to haloper-
idol (10 mg/day) and risperidone (6 mg/day) against
Efficacy for treatment-resistant schizophrenia positive and negative symptoms in patients with
Clozapine has been consistently shown to have acute exacerbations of schizophrenia or schizoaffec-
efficacy against psychotic symptoms in well-defined tive disorder200,201 (for a review, see Bowles and
treatment refractory patients over FGAs and as Levin138). These studies suggest that aripiprazole
compared to other SGAs.185–187 Chakos et al,188 in a doses in the range of 15–30 mg/day are effective. It
review and meta-analysis of seven controlled trials can be started at a full dose without an initial titration
comparing clozapine to FGAs in treatment-resistant period. Two long-term double-blind studies showed
schizophrenia, found that clozapine is superior to that aripiprazole (15 or 30 mg/day) is superior to
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88
placebo, and comparable or superior to haloperidol ments for negative and cognitive symptoms of
(10 mg/day) in maintaining antipsychotic response schizophrenia.9,21,218–221
and relapse prevention.202,203 All of the short- and
long-term studies have shown that aripiprazole has a Dopamine D4 receptor antagonist There are several
favorable safety and tolerability profile, with low lines of evidence suggesting that selective dopamine
liability for EPS, TD, weight gain, sedation, hyper- D4 receptor antagonists may be potential novel
prolactinemia, or QTc prolongation, and a lack of antipsychotic drugs. For example, not only
adverse effects on glucose and lipid metabolism.204 clozapine but also a number of clinically efficacious
However, it should be noted that the agent exhibits a antipsychotics have a relatively high affinity for the
lack of a predictable dose–response relationship for D4 receptors222 (Table 1). In addition, an increase in D4
efficacy and adverse events.201,204 Further clinical receptors has been reported in the schizophrenic
studies are needed to determine the efficacy and brains.223,224 The selective D4 antagonist,
safety in special populations, including suicidal and sonepiprazole (U-101387 or PNU-101387G)
treatment-resistant patients with schizophrenia, el- attenuates apomorphine-induced impairment of
derly and children, dementia, agitation, autism and prepulse inhibition,225 and antagonizes the decrease
other disease status in which antipsychotic use is in c-fos expression in the medial prefrontal cortex and
helpful.138 Long-term effectiveness studies are also neurotensin mRNA in the nucleus accumbens
necessary, particularly those examining the relative produced by repetitive amphetamine administration
effects of aripiprazole and different SGAs on negative in rats.226 However, most of the in vivo pharma-
symptoms, cognitive function, relapse prevention, cological studies of sonepiprazole indicates the
treatment adherence, disease progression, function, lack of effects in at least traditional preclinical
quality of life and use of health services.205 models of antipsychotic activity.227,228 Nevertheless,
it entered Phase II clinical trials in patients with
schizophrenia, but no further data are currently
Future strategies of drug development available.228
Dopaminergic agents An initial clinical trial with another highly selec-
tive D4 antagonist, L-745,870 failed to demonstrate
Dopamine D1 receptor antagonist or agonist Evidence any antipsychotic activity in the treatment of schizo-
suggests an important role for D1-like dopamine phrenia.229,230 While the single dose tested and the
receptors in the pathophysiology of small number of patients make it difficult to draw
schizophrenia.206,207 Earlier preclinical studies firm conclusions regarding the potential efficacy of D4
demonstrated that selective D1-like antagonists were antagonists as antipsychotic agents,231 this drug
active in most traditional functional models held to seemed to cause a worsening of symptoms.230 Simi-
predict antipsychotic activity (for a review, see larly, NGD-94-1 and the D4/5-HT2A antagonist finan-
Waddington208). A clinical trial of the selective D1- serin (RP62203) also did not show clinical efficacy in
like antagonist SCH39166,209,210 and NNC 01-0687,211 limited trials in schizophrenics.228,232 Therefore, these
however, demonstrated no antipsychotic activity, and data cast doubt as to whether D4 antagonism alone is
instead may have aggravated psychoses in some responsible for the antipsychotic efficacy of cloza-
patients.209 pine, and that selective D4 antagonists could indeed
In contrast to the ineffectiveness of D1-like antago- have therapeutic potential in schizophrenia (for
nists in the treatment of schizophrenia, low doses of reviews, see Miyamoto et al5, Waddington et al31
selective full D1-like receptor agonists, such as and Rowley et al233).
dihydrexidine, A77636 and SKF81297, have been
reported to have cognitive-enhancing actions in non- Dopamine D3 antagonist or partial agonist Dopamine
human primates.212–214 In drug-naı̈ve schizophrenics, D3 receptor is a D2-like dopamine receptor that is
Okubo et al215 found decreased D1-like receptor localized in the mesolimbic areas of the brain, and for
binding using PET in the frontal cortex and basal which most antipsychotics have relatively high
ganglia, and correlation between the reduction in affinity (for a review, see Schwartz et al234). In
prefrontal D1-like receptors and the severity of addition, a post-mortem study demonstrated
negative symptoms and cognitive disturbance. Such elevation of D3 receptor levels in the limbic striatum
data are consistent with the fact that pyramidal of drug-free patients with schizophrenia, whereas D3
neurons in the prefrontal cortex postulated to be receptor expression was normal in subjects treated
involved in working memory express a high degree of with antipsychotic drugs.235 These findings have
D1-like dopamine receptors.207,216 It is postulated that prompted much interest in the D3 receptor as a
either insufficient or excessive D1-like receptor potential novel therapeutic target for antipsychotic
stimulation is deleterious to cognitive function of activity.31 A dopamine D3 receptor agonist, ( þ )-PD
the prefrontal cortex, thus an ‘optimal’ level of D1-like 128,907, can block stereotypy produced by NMDA
receptor activation is necessary for normal cognitive antagonists in mice, suggesting its antipsychotic
function.216,217 The finding that full D1-like receptor profile.236 So far, partial agonists at D3 receptors are,
agonists can improve working memory suggests that however, supposed to be beneficial only when
such class of drugs might be novel potential treat- administered to drug abusers or in Parkinson’s
S Miyamoto et al
89
disease (for review, see Hacking and Stark237). The control the extracellular glycine concentration.252
novel selective dopamine D3 antagonists such as Thus, blockade of the GLYT-1 transporter would
S33084, SB-277011-A, and AVE5997 have been deve- increase NMDA receptor-mediated transmission.
loped for the treatment of psychosis like schizo- Although there is some controversy as to whether
phrenia. While S33084 was not active in traditional the glycine regulatory site on the NMDA receptor is
models of antipsychotic activity in the manner of D2 saturated under physiological conditions, preclinical
antagonists,238 SB-277011-A can produce an increase data demonstrate that N-(3-(40 -fluorophenyl)-3-
in extracellular levels of dopamine, norepinephrine (40 -phenylphenoxy)propyl) sarcosine, a selective and
and acetylcholine in the rat anterior cingulate cortex, potent GLYT-1 reuptake inhibitor, can potentiate
similar to the effects of SGAs, clozapine and electrophysiological effects of NMDA.252,253 Further-
olanzapine, but not haloperidol.239 At present, the more, the glycine reuptake inhibitor glycyldo-
role of D3 antagonism in antipsychotic activity decylamide attenuated PCP-induced hyperactivity
remains unclear, and only controlled clinical trials more potently than glycine.254,255 These preclinical
with selective D3 antagonists in schizophrenia will data suggest that inhibition of glycine reuptake could
eventually clarify this issue.31 represent a feasible approach to potentiate NMDA
receptor-mediated neurotransmission and, possibly,
Glutamatergic agents treat schizophrenic patients.
NMDA receptor positive allosteric modulators If Glutamate reuptake inhibitors Glutamate trans-
reduced NMDA receptor function is involved in the porters (excitatory amino-acid transporters (EAATs)),
pathophysiology of schizophrenia, then drugs that normally expressed in both glia (EAAT1 and EAAT2)
enhance NMDA receptor function could be and neurons (EAAT3 and EAAT4), can control
therapeutic agents and potentially improve upon, or glutamatergic neurotransmission by removal of
supplement, current antipsychotic treatments glutamate from the synaptic cleft (for a review, see
(for reviews, see Miyamoto et al8, Duncan et al59, Danbolt256). EAAT3 (called EAAC1 in the rodent) is
Abi-Saab et al240 and Goff and Coyle241). Direct predominantly expressed in the cerebral cortex, basal
agonists of the NMDA receptor, however, may not be ganglia and hippocampus.257 Post-mortem studies in
feasible candidates in this regard, because of the schizophrenic patients revealed alterations in gene
propensity of such drugs to produce excessive expression of glutamate transporters.258,259 In
excitation and seizures. addition, preclinical studies demonstrated that
Glycine is a positive allosteric modulator and chronic treatment with clozapine or haloperidol can
obligatory co-agonist at the NMDA receptor.242 This downregulate EAAT3 in the infralimbic cortex and
allosteric regulatory site represents a potential target hippocampal CA2.260 Thus, glutamate reuptake
for drugs to augment NMDA-mediated neurotransmis- inhibitors such as EAAT3 antagonists could increase
sion. The glycine site agonists, including glycine, the synaptic availability of glutamate, and increase
D-cycloserine and D-serine, appear to be effective in glutamatergic action at the postsynaptic neuron, and
reducing negative symptoms and cognitive impair- thereby might produce therapeutic effects on some
ment in patients with schizophrenia when they are symptom dimensions following the model of
added to ongoing antipsychotic treatment, with the diminished glutamate activity in schizophrenia.
exception of clozapine.243–249 Their beneficial effects
on positive and depressive symptoms are less robust. Metabotropic glutamate receptors agonists
The poor penetration of the blood–brain barrier by Metabotropic glutamate (mGlu) receptors (mGluR),
glycine, and the partial agonistic properties of D- of which there are eight subtypes (mGluR1–8), are
cycloserine, appear to make these agents less than categorized into three groups according to their
optimal for providing pharmacological agonism of the agonist pharmacology, sequence similarity and signal
glycine regulatory site on the NMDA receptor.59 Of transduction pathways (for a review, see Rowley et
these glycine agonists, D-serine appears to be the most al233). NMDA antagonists induce hyperlocomotion
promising agent. It is a full agonist on the strychnine- and stereotypy, accompanied by an increase in
insensitive glycine site of NMDA receptor250 and is glutamate release in several brain regions of rats,261
more permeable than glycine at the blood–brain suggesting that pharmacological agents that decrease
barrier, thus requiring a lower dosage. In an 8-week glutamate release should block the effects of the
clinical trial, D-serine added to neuroleptic treatment drugs. Group II mGluR (mGluR2/3) are located
in treatment-resistant patients with schizophrenia presynaptically on glutamate terminals where they
demonstrated significant improvements not only in may act as autoreceptors regulating glutamate release
negative and cognitive symptoms but also an in in vivo (for reviews, see Rowley et al233 and Chavez-
positive symptoms, which is different from glycine.251 Noriega et al262). Administration of a group II mGluR
agonist, LY-354740, blocks both behavioral activation
Glycine reuptake inhibitors Glycine transporters, and increased glutamate (but not dopamine) release
GLYT-1 and GLYT-2, have been identified on both provoked by PCP in rats.263 Thus, group II mGluR
neuronal and glial cells in the central nervous system. agonists could be beneficial in the treatment of
A function of these transporters has been suggested to schizophrenia, although LY-354740 cannot attenuate
S Miyamoto et al
90
PCP-induced disruptions in prepulse inhibition (PPI) Glutathione prodrugs Glutathione is the principal
of acoustic startle responses. On the other hand, nonenzymatic endogenous antioxidant, and plays a
one of the effects induced by activation of group I critical role in protecting cells from damage by
mGluR (mGluR1/5), particularly of mGluR5, is a reactive oxygen species generated by dopamine
significant potentiation of NMDA receptor func- metabolism.274,275 A glutathione deficit can leave the
tion, suggesting that mGluR5 agonists may display brain susceptible to oxidation, and oxidative stress-
antipsychotic activity (for review, see Chavez-Noriega mediated cell damage has been considered in one of
et al262). the pathophysiologies of schizophrenia. Indeed, a
decrease of glutathione levels was observed in the
cerebrospinal fluid and the medial prefrontal cortex
AMPA/kainate receptor antagonists The increased in drug-naı̈ve schizophrenic patients.274 Its deficit
release of glutamate observed in response to NMDA would lead to degenerative processes in the
antagonists could mediate some of the behavioral surrounding of dopaminergic terminals, resulting in
actions of the drugs by activation of non-NMDA loss of connectivity.274 Glutathione also potentiates
receptors, including a-amino-3-hydroxy-5-methy-iso- the NMDA receptor response to glutamate via its
xazole-4-propionic acid (AMPA) and kainate recep- redox modulatory site.276 Taken together, although
tors.261 In support of the hypothesis that behavioral speculative, glutathione supplementation by gluta-
effects of NMDA antagonists relate to increased thione prodrugs could be an interesting treatment
glutamate release, administration of an AMPA/ strategy for schizophrenia in terms of preventing
kainate receptor antagonist, LY-293558, partially re- oxidative stress and enhancing neurotransmission at
versed impairment of working memory induced by NMDA receptors in the brain.
subanesthetic doses of ketamine in rats.261.Furthermore,
AMPA/kainate receptor antagonists reduce NMDA Noradrenergic agents
antagonist-induced hyperlocomotion264–266 and neuro-
degeneration.267 Systemic administration of other Alpha-2 adrenergic receptor agonist or anta-
AMPA receptor antagonists GYKI52466 and LY- gonist Norepinephrine plays an important role in
326325 can suppress conditioned avoidance response cognitive function of the prefrontal cortex (PFC) by its
in rats.268 These data suggest that AMPA/kainate actions at alpha-2 adrenergic receptors (Ars) located
receptor antagonists may possess an antipsychotic in the principal sulcus of the PFC (for reviews, see
effect, and have utility for treatment of cognitive Goldman-Rakic et al277, Arnsten et al278 and Friedman
deficits in which NMDA receptor hypofunction is et al279,280). Indeed, the alpha-2 agonist clonidine has
suspected.261 been shown to improve performance on working
memory tasks in young monkeys with noradrenergic
depleting lesions of the PFC, presumably through its
Ampakines (CX-516) In apparent contrast to the drug actions at post-synaptic alpha-2 Ars in the
postulated utility of AMPA/kainate receptor anta- PFC.281 In schizophrenia, clonidine also improves
gonists as antipsychotics, ampakines, a class of com- PFC-mediated cognitive dysfunction.282 In addition,
pounds that allosterically enhance AMPA receptor guanfacine, a selective alpha-2A agonist,283 improves
function, have also been suggested to represent poten- PFC-mediated working memory in aged non-human
tial adjunctive treatments for schizophrenia. primates, but without the significant adverse effects
Ampakines and AMPA potentiators enhance excita- associated with clonidine (eg, sedation, hypoten-
tory (glutamatergic) transmission, facilitate long-term sion).284 A 4-week, placebo-controlled, double-blind
potentiation, learning and memory in rodents,269,270 study demonstrated the efficacy and safety of guan-
and have synergistic effects with FGAs and SGAs on facine as adjunctive treatment of cognitive impair-
blocking behavioral effects of methamphetamine.271 In ment in schizophrenia.285 Those patients receiving
addition, preliminary results suggest that chronic guanfacine plus risperidone showed significant
administration of an ampakine (CX-516) can improve improvement on tasks of working memory and atten-
negative and cognitive symptoms in schizophrenia tion compared with patients receiving FGAs plus
patients that also receive clozapine.272 Thus, such guanfacine.285 The potential ability of alpha-2
findings are paradoxical with regard to the hypo- agonists to improve cognitive performance on tasks
thesis that excessive glutamate release may be dependent on PFC function appears to be of great
involved in behavioral effects of reduced NMDA importance in the search for a new pharmacologic
receptor function. In a recent double-blind placebo- approach for schizophrenia.
controlled small study of patients with schizophrenia Clozapine and risperidone have potent antagonist
who were partially refractory to treatment with the properties at alpha-2 Ars. Millan et al286 have
FGAs, CX516 as a sole agent did not produce drama- postulated the significance of the alpha-2 Ars antag-
tic effects on positive symptoms and cognitive impair- onistic activity for the antipsychotic effects of neuro-
ment.273 In the case of AMPA ligands, it seems at leptics. Blockade of inhibitory alpha-2-AR heterocep-
present unclear if agonists, antagonists or partial tors on terminals of dopaminergic fibers can enhance
agonists/modulators have potential therapeutic frontocortical dopaminergic transmission compared
application. with subcortical dopaminergic pathways.287 Litman
S Miyamoto et al
91
et al288 reported that combined treatment with as 3-2,4-dimethoxybenzylidene anabaseine (DMXB-A
idazoxan, a highly selective alpha-2-AR antago- or GTS-21) can normalize the auditory gating deficits
nist, and the FGA fluphenazine can produce a in rodents.303 Alpha-7 nAChR agonists are currently
‘clozapine-like’ profile of antipsychotic activity. under development for clinical trial in schizophrenia,
Antagonist properties of alpha-2-Ars appear to be although it is unclear whether such agonists have
implicated in the functional actions of clozapine in beneficial effects on symptoms other than the
humans,289 and contribute to an improvement in auditory gating deficit. Moreover, long-term use of
mood.286 such agents might induce desensitization of nAChRs,
leading to tolerance and therefore limiting the
duration of efficacy.
COMT inhibitors Considerable data suggest that
catechol-O-methyl transferase (COMT), a postsynap- Alpha4–beta2 nicotinic receptor agonist It has been
tic methylation enzyme that metabolizes released suggested that alpha4–beta2 nAChRs affect auditory
dopamine, is primarily responsible for synaptic sensorimotor gating.304 They are considered to
dopamine inactivation in the prefrontal cortex, and represent more than 90% of the high-affinity
that variation in COMT activity may affect prefrontal nicotine-binding sites in rat brain,305 and appear to
cortical activity, especially during working memory play an important role in many of the behavioral
tasks.290,291 Interestingly, studies of COMT-deficient actions of nicotine. SIB-1553A, an alpha4–beta2
mice have demonstrated that dopamine levels are subtype-selective nicotinic receptor agonist, appears
increased in the prefrontal cortex but not in the to produce enhanced performance in a variety of
striatum, and that memory performance is en- models of cognitive impairment in areas such as
hanced.292 Abnormalities of prefrontal dopamine spatial and nonspatial working and reference memory
function associated with working memory appear to in aged rodents and monkeys.306,307 Interestingly, SIB-
be prominent features of schizophrenia, and certain 1553A has also been shown to stimulate the release of
alleles of the COMT gene run in families with a high dopamine, norepinephrine and acetylcholine in the
incidence of the illness.293 Tolcapone, a reversible, frontal cortex and hippocampus in rats.306 These data
selective inhibitor of COMT has been reported to suggest that the use of alpha4–beta2 nicotinic
improve working memory in rodents,294 and receptor agonists could produce therapeutic benefit
tolcapone as adjunct to L-dopa therapy has been for the treatment of cognitive deficits in schizo-
shown to improve cognitive dysfunction in patients phrenia.
with advanced Parkinson’s disease.295 At present,
Egan and Weinberger are conducting a trial of COMT Allosteric modulators of nicotinic receptor and
inhibitors in schizophrenia and healthy controls with acetylcholinesterase inhibitor Galantamine is a
and without the high-risk combination of COMT positive allosteric modulator of nAChRs and an
alleles.296 However, tolcapone was withdrawn from inhibitor of acetylcholinesterase (AchE), the enzyme
the market in Europe and Canada due to the risk of responsible for catabolizing acetylcholine (Ach) (for a
serious hepatic dysfunction,297 and in the US review, see Maelicke et al308). The allosteric inter-
restrictive liver enzyme monitoring measures are action amplifies the actions of Ach at pre- and post-
necessary, which severely limits the use of the synaptic nAChR.309 Presynaptic nAChRs are capable
agent.298 of modulating the release of Ach, and other neuro-
transmitters, such as glutamate, serotonin, and
Cholinergic agents GABA, which may contribute to the symptoms of
schizophrenia.310 Galantamine has been shown to
Alpha-7 nicotinic receptor agonist Cognitive improve cognitive and global function in placebo-
impairments are cardinal features of schizophrenia. controlled trials in Alzheimer’s disease patients (for a
Nicotinic acetylcholine receptors (nAChRs) have review, see Coyle and Kershaw311). Results from case
been implicated in cognitive function and reports suggest that adjuvant galantamine adminis-
formation of sensory processing (for a review, see tration improves negative symptoms in patients with
Rezvani and Levin299). In particular, auditory gating treatment-refractory schizophrenia.312,313 The extent
is modulated by the alpha-7 nAChR subtype, which to which the clinical benefits of galantamine are
is a rapidly desensitizing low-affinity nAChR (for attributable specifically to its nicotinic effects is
a review, see Simosky et al300). Genetic studies linking unclear, and prospective double-blind data are
the alpha-7 nAChR gene to sensory processing defi- required.
cits in schizophrenia, together with reductions of this Several case studies and an open-label trial of
receptor in discrete regions of the brains of schizo- adjunctive donepezil, a reversible AchE inhibitor,
phrenia patients, suggest that the alpha-7 nAChR may demonstrate some of its beneficial effects on cogni-
be a relevant therapeutic target in schizophrenia (for tive impairment in schizophrenia.314–316 However, a
review, see Adler et al301). Interestingly, clozapine, recent double-blind controlled trial of donepezil
but not haloperidol, can improve deficient inhibitory added to risperidone did not show any positive
auditory processing through stimulation of alpha-7 effects on cognitive deficit associated with schizo-
nAChRs in mice.302 Agonists at alpha-7 nAChRs such phrenia.317
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Muscarinic receptor agonist There is a large body of tor antagonist, SR141716, can reduce hyperactivity
anatomical and pharmacological evidence for induced in gerbils by various stimulant drugs,
potential modulation of dopamine and glutamatergic including cocaine, D-amphetamine, morphine and
neurons by cholinergic muscarinic receptors (for Win 55212-2, known to produce or exacerbate
a review, see Bymaster318). Recent findings that schizophrenic symptoms.329 In addition, SR141716
partial agonists of muscarinic receptors are active in dose-dependently alters Fos protein and neurotensin
animal models are predictive of antipsychotic expression in a manner comparable to that observed
activity, and the SGAs clozapine and olanzapine are with the SGAs.330 These findings suggest that
partial agonists for cholinergic M1, M2 and M4 selective CB1 receptor antagonists may be effective
receptors. Recently, the N-desmethyl metabolite of in the pharmacological treatment of schizophrenia.
clozapine was reported to preferentially bind to M1
muscarinic receptors with an IC50 of 55 nM, and was Neurokinin 3 antagonist Neurokinin 3 (NK3)
a more potent partial agonist (EC50, 115 nM and 50% tachykinin receptors appear to regulate midbrain
of acetylcholine response) at this receptor than dopamine neuronal activity.331 Preclinical studies
clozapine.105 Furthermore, pharmacological and site- have shown that a potent and selective nonpeptide
directed mutagenesis studies suggested that N- NK3 antagonist, osanetant (SR-142801), selectively
desmethylclozapine preferentially activated M1 inhibits dopamine release in certain brain regions (for
receptors by interacting with a site that does not a review, see Kamali332). Several NK3 compounds are
fully overlap with the acetylcholine orthosteric site. currently in development (eg, osanetant (Sanofi-
Moreover, N-desmethylclozapine is able to potentiate Synthélabo) and talnetant (Glaxo Smith Kline)) as
hippocampal NMDA receptor currents through M1 potential treatments for schizophrenia. Preliminary
receptor activation. In addition, muscarinic agonists clinical trials have demonstrated that osanetant is
have activity in animal models of negative symptoms, superior to placebo on global assessment of efficacy
cognitive dysfunction and affective disorders, and measures of positive symptoms in
suggesting the potential usefulness of muscarinic schizophrenia.333 Whether NK3 antagonist adminis-
agonists in the treatment of schizophrenia (for tration in schizophrenia may serve as novel anti-
reviews, see Rowly et al233 and Bymaster et al319). psychotics merits further investigation.
Examples of these agents are the muscarinic M1/M4
agonist xanomeline, and the muscarinic M2/M4 Neurotensin agonist Neurotensin (NT) is a
agonists PTAC, and BuTAC (for a review, see neuropeptide that regulates the function of
Bymaster318). Xanomeline has been demonstrated to mesolimbic dopamine neurons,334 and has been
have positive effects on cognitive and psychotic-like implicated in the pathophysiology of schizophrenia
symptoms (eg, hallucinations and delusions) in (for a review, see Binder et al335). The central
Alzheimer’s disease.320 Accumulating data suggest administration of NT induces behavioral and
that muscarinic partial agonists might be efficacious biochemical effects that are very similar to the
in treating not only positive, but also negative and effects of antipsychotic drugs.336 Thus, there is
cognitive symptoms in schizophrenia.319,321,322 much interest in the potential use of NT agonists
as novel antipsychotics. In vitro studies indicate
Other agents that NT behaves as an agonist at NT1 receptors and
as an antagonist at NT2 receptors.337 Systematic
Cannabinoid CB1 antagonist Acute cannabis administration of metabolically stable NT analogues
intoxication can produce schizophrenia-like such as PD-149163 and NT69L can attenuate
symptoms, including hallucinations, altered amphetamine- or NMDA antagonist-induced
judgment, false beliefs and cognitive dysfunction,323 hyperactivity and PPI without inducing catalepsy
and long-term cannabis use often induces negative or affecting baseline startle responses.338,339 NT1
schizophrenia-like symptoms.324 In addition, canna- receptor agonists, however, may have problems in
bis can precipitate psychotic symptoms in schizo- clinical use, since NT can produce autonomic adverse
phrenia, and may increase the risk of developing the effects. Chronic administration of SR-48692, which
illness.325 Several reports also demonstrated elevated is a nonpeptide and a high-affinity NT1 receptor
levels of the endogenous cannabinoids (anandamide antagonist with agonist activity at NT2 receptors,
and palmitylethanolamide) in both the cerebrospinal can decrease methamphetamine-induced dopamine
fluid and the blood of schizophrenic patients when release in the nucleus accumbens,340 suggesting this
compared to normal controls.326,327 These accu- compound could also have antipsychotic-like effects.
mulating evidences have led to ‘a cannabinoid
hypothesis of schizophrenia’ in which cannabinoid MAO B inhibitors It has been suggested that negative
receptors, the pharmacological target of cannabis- symptoms of schizophrenia may be manifestations
derived drugs, and their accompanying system of of regionally deficient dopaminergic activity in the
endogenous activators may be dysregulated in brain, thus augmentation of dopaminergic neurotrans-
schizophrenia.328 The endogenous cannabinoid sys- mission could be a beneficial treatment strategy.
tem comprises at least two cannabinoid receptors, Selegiline (deprenyl) is a monoamine oxidase
the CB1 and CB2 receptors. A selective CB1 recep- (MAO)-B inhibitor that selectively enhances
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dopaminergic activity. Selectivity for inhibition of Neurosteroids Dehydroepiandrosterone: Dehydro-
MAO-B without inhibition of MAO-A is clinically epiandrosterone (DHEA) and its sulfate derivative
important, since MAO-A inhibition is responsible for (DHEA-S) are neuroactive neurosteroids that repre-
most of the side effects of MAO inhibitors.341 sent steroid hormones synthesized de novo in the
Although several case series reported the beneficial brain and acting locally on nerve cells.356 Although
effects of selegiline on negative symptoms of DHEA and DHEA-S are the most abundant circulating
schizophrenia,342–344 one double-blind, controlled steroid hormones in humans, their precise physio-
study of the agent as adjunct to antipsychotic logical roles remain uncertain. In vitro data suggest
treatment failed to offer therapeutic benefit.345 The that DHEA and DHEA-S enhance neuronal and glial
selective irreversible MAO-B inhibitors, selegiline survival and differentiation.357–359 In addition, DHEA-
and rasagiline, have been shown to possess S shows marked neuroprotective ability against the
neuroprotective activities in cell culture and in vivo glutamate-induced toxicity360 and oxidative stress.361
models of Parkinson’s disease (for a review, see Interestingly, DHEA has been demonstrated to
Maruyama et al346). For example, these agents can potentiate neuronal responses at the NMDA
prevent experimentally induced apoptotoic DNA receptor.359,362,363 The enhancement of physiological
damage, and induce pro-survival genes.347 Thus, the response to NMDA by DHEA has also been suggested
MAO-B inhibitors may rescue degenerating dopamine to result from agonistic actions at ó1 receptors in the
neurons through inhibiting death signal transduction, brain.363 Consistent with a positive modulatory action
but clinical trials failed to confirm it.346 So far, no of DHEA at the NMDA receptor, the neurosteroid
solid conclusions could be drawn from the data enhances memory,364–367 and DHEA-S attenuates
regarding the effects of the MAO-B inhibitors on NMDA receptor antagonist MK-801-induced learning
schizophrenia. impairment in mice.368 In chronic schizophrenics,
significantly lower morning levels of plasma
DHEA were observed.369 Further, there are a number
PDE10 inhibitors PDE10A is a recently identified of earlier case reports suggesting that DHEA may
cyclic nucleotide phosphodiesterase expressed at be useful in the treatment of schizophrenia, espe-
high levels in the brain and more specifically in the cially for negative symptoms.370–372 A recent double-
medium spiny neurons of the striatum and associated blind study of DHEA as adjunct to antipsychotic
nucleus accumbens and olfactory tubercle.348 treatment in chronic schizophrenic patients with
Papaverine, a potent and selective PDE10A prominent negative symptoms suggests that it can
inhibitor, can dose-dependently attenuate hyper- improve negative, depressive and anxiety symp-
activity induced by both amphetamine and PCP in toms of the illness, especially in women.373
rats.349 The agent does not affect extracellular Although the mechanism of action of DHEA and
dopamine in the striatum nor alter PCP-induced DHEA-S has still to be further characterized, the
dopamine release in the nucleus accumbens. possibility that these compounds may have efficiency
Papaverine can also produce a dose-dependent in schizophrenia should be further investigated.
reduction in conditioned avoidance responding in Pregnenolone: Intensive studies in animals estab-
rodents. These data suggest the possibility that lished that neuroactive steroids such as pregnenolone
selective inhibitors of PDE10 may provide a target (PREG) and pregnenolone sulfate (PREGS) display
for the development of a new class of antipsychotic neuronal actions and influence behavioral func-
drugs.349 tions.374 For example, PREG and PREGS exhibit
memory-enhancing properties in aged rodents (for a
review, see Vallee et al375). It has also been suggested
NNOS inhibitor Nitric oxide (NO) is a diffusible gas that PREGS can ameliorate MK-801-induced memory
and an important inter- and intracellular messenger in impairment by acting as ó1 receptor agonists.376 In
the central nervous system. NO activates guanylyl addition, PREGS can attenuate the conditioned fear
cyclase and increases the synthesis of cyclic stress response via ó1 receptors.377 Albeit speculative,
GMP. Nitric oxide synthase (NOS) converts arginine these findings suggest that PREG and PREGS may
into NO and citrulline in response to increased intra- have therapeutic potential for improving cognitive
cellular calcium levels (for a review, see Rowley et deficit observed in schizophrenia.
al233). Preclinical studies demonstrated that inhi-
bition of NOS activity with methylene blue, L- Neurotrophic factors The role of neurotrophic
NOARG, L-NAME, or 7-nitroindazole can attenuate factors in the pathophysiology of schizophrenia is
hyperactivity and disruption of PPI produced by rapidly becoming an important and exciting focus of
NMDA antagonists but not amphetamine.350–354 In investigation. A more recent pathophysiologic theory
treatment-refractory schizophrenia, methylene blue of schizophrenia suggests that it involves a limited
moderately improved symptoms.355 However, it neurodegenerative process reflected by the
should be noted that all available NOS inhibitors progressive and deteriorating clinical course of the
can produce serious side effects including hyper- illness.378 Recent longitudinal neuroimaging studies
tension and cognitive dysfunction, which may be of first-episode schizophrenia have demonstrated
due to poor selectivity for different NOS isoforms.233 morphological changes in cortical gray matter and
S Miyamoto et al
94
ventricular volumes that have been suggested to reviews, see Basile et al385 and Arranz and Kerwin388).
reflect pathological processes of developmental In addition, a more long-term approach may be to take
maturation and/or illness progression.379–381 The advantage of information from clinical imaging (sMRI,
neurotrophic factors such as nerve growth factor structural magnetic resonance imaging; MRS, mag-
(NGF), brain-derived neurotrophic factor (BDNF) netic resonance spectroscopy; fMRI, functional MRI)
and neurotrophin (NT)-3/4/5 play a decisive role in and electrophysiologic (ERP, event-related potential)
a neurodevelopmental process, including neuronal studies that are becoming increasingly sophisticated,
and glial differentiation, migration, proliferation providing more detailed information of the individual
and regeneration.382 They are not only active during brain morphologic changes, pathways and circuits
embryo- and organogenesis but also influence the involved in various aspects and stages of schizophre-
synaptic organization and the synthesis of neuro- nia.233 These measures can also serve to define bio or
transmitters in the adult brain, and are therefore surrogate markers of treatment effects.
involved in the maintenance of neural plasticity.382 As yet no drug that did not have some affinity
Thus, pathological alterations of the neurotrophic for and activity at the dopamine D2 receptor has
factor system may lead to neural maldevelopment, been proven to have antipsychotic efficacy. Thus,
migration deficits and dysconnections, which are the development of novel compounds targeting
proposed to be the characteristic pathogenetic other systems than dopamine will likely be employed
features of the neurodevelopmental hypothesis of as adjunctive or combined treatments in addition
schizophrenia.382,383 If neurotrophic factors salvage to whatever monotherapeutic applications they may
degenerating cells, facilitate desirable synaptic have.
connections, and hence, halt the progression of With the improvements in pharmacological treat-
neurodegenerative process of schizophrenia, drugs ment seen over the last decade, the focus of therapy
that selectively stimulate the production of neuro- for schizophrenia has shifted from the relief of
trophic factors could represent a new approach to psychotic symptoms to other pathological domains
forestall the progression of schizophrenia and prevent including negative and mood symptoms, cognitive
morbidity from increasing.384 Although neurotrophic deficits and the functional impairment that under-
factors are unable to cross the blood–brain barrier, mines patients’ capacities for daily functioning,
potential strategies for the administration of these reintegration into society, and recovery. At present,
factors are transplantation of neurotrophic factor- much remains to be done in terms of developing
producing cells, direct transfection of neurotrophic treatment strategies and the determination of its
factor gene and development of compounds which optimal use in conjunction with psychosocial and
modulate endogenous neurotrophic factor homeo- adjunctive therapies.
stasis and/or the influence their signal transduction
mechanisms.382 The augmentation therapy with
Conclusion
neurotrophic factors suggests novel and innovative
pharmacotherapeutic, but as yet unproven, strategies Psychopharmacological research efforts have focused
for schizophrenia. on developing compounds with unique combinations
of effects at different perisynaptic neurotransmitter
sites as described above.189 Future efforts must move
Future directions
beyond strategies that develop drugs which solely
Although a recent meta-analysis suggests that some target the modulation of chemical neurotransmission
SGAs are more efficacious than FGAs,157 one cannot at synapses to the development of agents that can
reliably predict which patient will respond best to a affect other cellular functions including signal trans-
particular antipsychotic medication.205 Significant duction, signaling pathways and gene expression,
differences between the new antipsychotics are and that underlie mechanisms of cell develop-
emerging so that drug choice needs to be tailored for ment, plasticity and resilience. In addition, efforts
individual patients.152 Recent developments in si- to identify genetic mechanisms that underlie mental
multaneous profiling of gene transcripts (gene chips) illnesses will reveal new targets for drug develop-
and gene products (proteomics) will allow definition ment. Such efforts could offer a more powerful
of the genes and proteins that are affected by method for identifying the neural and molecular
antipsychotic medication. It is very likely that mechanisms causing schizophrenia, and for develop-
individual genetic differences are important deter- ing animal models and novel therapeutic approaches.
mining factors in the efficacy and side effect profiles One of the important goals of pharmacological
of antipsychotic medication.385 Therefore, it is possi- research should be to develop new ideal antipsycho-
ble to improve drug response at the level of the tic drugs with low associated risk, rapid onset of
individual patient by detecting single-nucleotide action, a more effective treatment for negative,
polymorphism in patients’ DNA.386,387 Knowledge of cognitive and affective symptoms, in better efficacy
the relationship between specific genetic polymorph- against positive symptoms, and improved relapse
isms of genes involved in a drug’s pharmacokinetics rates and reduction or even reversal of cumulative
and pharmacodynamics may lead to better drug morbidity.189 The hope for further progress relies
design and to individualized pharmacotherapy (for upon development of a number of different basic and
S Miyamoto et al
95
clinical neuroscience strategies, but with these in- 14 Schulz C, McGorry P. Traditional antipsychotic medications:
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15 Breier A, Wright P, Birkett M, Meehan K, David, Brook S. A
Competing interests double-blind dose response study comparing intramuscular
olanzapine, haloperidol and placebo in acutely agitated schizo-
The following financial interests by coauthors in-
phrenic patients, ACNP 39th Annual Meeting Abstract. American
clude consultant fees, honoraria and/or research College of Neuropsychopharmacology: Puerto Rico, 2000.
funds. 16 Fleischhacker WW. New developments in the pharmaco-
Seiya Miyamoto: Eli Lilly Japan therapy of schizophrenia. J Neural Transm 2003; 64(Suppl):
Gary E Duncan: Eli Lilly 105–117.
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This work was supported in part by the UNC schizophrenia. Synapse 1987; 1: 133–152.
Schizophrenia Research Center, an NIMH Silvio O. 21 Miyamoto S, Mailman RB, Lieberman JA, Duncan GE. Blunted
Conte Center for the Neuroscience of Mental Dis- brain metabolic response to ketamine in mice lacking D1A
orders (MH064065)(JL), and the Foundation of Hope dopamine receptors. Brain Res 2001; 894: 167–180.
of Raleigh North Carolina (JL, GD). We thank Mr Kenji 22 Kapur S, Seeman P. Antipsychotic agents differ in how fast
they come off the dopamine D2 receptors. Implications for
Seo and Ms Yoshiko Suzuki for preparing some atypical antipsychotic action. J Psychiatry Neurosci 2000; 25:
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Treatments For Schizophrenia: A Critical Review of Pharmacology and Mechanisms of Action of Antipsychotic Drugs

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Molecular Psychiatry (2005) 10, 79–104

Treatments for schizophrenia: a critical review of

¼ minimal to none; þ ¼ low; þ þ ¼ moderate; þ þ þ ¼ high; þ þ þ þ ¼ very high.

Mechanisms Potential clinical efficacy Potential consequences

D2R antagonism k positive symptoms EPS

5-HT1A partial agonism k negative symptoms

Antipsychotics NMDA-R AMPA-R KA-R Metabotropic-R

Acb, nucleus accumbens.

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