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Research Overview
Improving Current Treatments for Schizophrenia
Nadja P. Maric,1,2* Milica J. Jovicic,2 Marina Mihaljevic,2 and Cedo Miljevic1,3
School of Medicine, University of Belgrade, Belgrade, Serbia
Clinical Centre of Serbia, Clinic for Psychiatry, Belgrade, Serbia
Institute of Mental Health, Belgrade, Serbia
Strategy, Management and Health Policy
Preclinical Development
Toxicology, Formulation
Drug Delivery,
Clinical Development
Phases I-III
Regulatory, Quality,
Phase IV
After the identification of the schizophrenia as an illness over a century ago, treatment of
affected individuals included unspecific, mostly very robust methods including deep insulin coma and
lobectomy/leucotomy. The first relatively specific treatment of schizophrenia started about 60 years ago
with the antipsychotic chlorpromazine. All currently approved antipsychotic drugs block dopamine
receptors, indicating that manipulation of dopaminergic function is fundamental to a therapeutic response
in psychosis. Despite refinements in their mechanism of action, the therapeutic effects of subsequent generations of antipsychotics are insufficient in claiming superiority over the first generation, with the possible exception of clozapine. Dopamine receptor blockade is necessary but not always sufficient for
antipsychotic response and improvements have been reported with molecules acting on other receptors
(glutamate, glycine, cannabidiol, estrogen), intracellular signaling proteins, or products of identified risk
genes. Here, we review the current status of drugs under investigation. In addition, we emphasize that
the development of the novel compounds to target the underlying cognitive dysfunction and negative
symptom dimension of full blown schizophrenia, or attenuated psychosis syndrome and specific endophenotypes related to the increased risk of psychosis in the general population, alongside efforts to
deconstruct the concept of schizophrenia(s), represent the best way to meet patient needs for better theraC 2016 Wiley Periodicals, Inc.
pies and more favorable outcomes. Drug Dev Res 00 : 000–000, 2016.
Key words: antipsychotic; dopamine; NMDR; clinical trial; drug discovery
At the beginning of the 20th century, Kraepelin
(Germany) and Bleuler (Switzerland) identified regular
patterns of symptoms that appeared together in clinical settings and termed these “schizophrenia” [Bleuler,
1950; Kraepelin, 1971]. These patterns of symptoms
were studied extensively and several multidimensional
models were identified. Although the construct of
schizophrenia as a unitary disorder was maintained
during the 20th century in the International Classification of Disease and Diagnostic and Statistical Manual
of Mental Disorders classification systems, most of the
considerations agree that “schizophrenia” has at least
three symptom dimensions (core features): negative
C 2016 Wiley Periodicals, Inc.
(poverty of speech, lack of spontaneous movement
and various aspects of blunting of affect); positive (particular types of delusions and hallucinations), and; disorganization/cognitive syndrome (inappropriate affect,
poverty of content of speech, and disturbances of the
form of thought) [Liddle, 1987; Maric et al., 2004].
*Correspondence to: Nadja P. Maric, Clinical Centre of
Serbia, Clinic for Psychiatry, Belgrade, Serbia. E-mail: nadja.
[email protected]
Received 0 Month 2016; Accepted 0 Month 2016
Published online in Wiley Online Library (wileyonlinelibrary.
com). DOI: 10.1002/ddr.21337
There is also increasing evidence that schizophrenia represents an even more complex, heterogeneous group of heritable disorders. These
disorders—the schizophrenias—are thought to be
caused by a limited number of separate genotypic
networks associated with several distinct clinical syndromes [Green et al., 2013; Arnedo et al., 2014;
Kranz et al., 2016]. For example, treatment-resistant
disease might be a distinct subtype of schizophrenia
and not merely a more severe form [Farooq et al.,
2013; Wimberley et al., 2016]. No doubt that the
identification of additional genetic associations [Farrell et al., 2015] and network models for biological
systems [Fornito and Bullmore, 2015] that underlie
psychopathological dimensions of psychosis will be of
particular interest in improving schizophrenia(s) therapy (and prevention) in the future, but these studies
are in flux and will take years or even decades, to
explore how particular constellation of symptoms
should be treated. For the purposes of the present
review, we will summarize the evolution of drugs for
the treatment schizophrenia as a unitary disorder and
emphasize future directions in drug development.
Following the identification of the schizophrenia
as an illness over a century ago, treatment of the
affected individuals included unspecific, mostly
robust methods like deep insulin coma, lobectomy/
leucotomy, and so on. The first relatively specific
treatment of schizophrenia as a unitary disorder was
identified some 60 years ago, after the discovery that
N-dimethylamino-prophylchlorophenothiazine (4560
RP) could be used against agitation in psychotic
patients [Delay et al., 1952]. Later, the fact that
dopamine receptor blockade was involved in the alleviation of psychosis symptoms by phenothiazine and
butyrophenone was described in 60s and 70s, alongside with the notion that exacerbation of schizophrenia symptoms was following increased dopamine and/
or norepinephrine activity [Seeman and Lee, 1975;
Snyder, 1976]. From that time, the evolution of the
dopamine hypothesis of schizophrenia—one of the
most enduring ideas in psychiatry, included several
reconceptualizations [Howes and Kapur, 2009].
Dopaminergic disruption in schizophrenia was first
considered as the result of excess transmission at
dopamine (postsynaptic) receptors, then as a result of
regionally specific prefrontal hypodopaminergic/subcortical hyperdopaminergic activity and most recently
as a final common pathway of the complex interaction
between genes and the environment (GxE) which
ends as a presynaptic striatal hyperdopaminergia
Drug Dev. Res.
[Kahn and Sommer, 2015]. Presynaptic striatal hyperdopaminergia may be secondary to pathophysiological
changes in other neurotransmitter systems (e.g., prefrontal glutamatergic or GABAergic systems) [McGowan et al., 2004]. There is also the possibility that
NMDA receptor hypofunction and low-grade inflammation of the brain probably antedate increased dopamine synthesis by many years [Kahn and Sommer,
2015]. However, there is no approved drug for prepsychotic symptoms and the only drugs focused on
normalizing excess dopamine transmission (mostly
postsynaptic) and/or to stabilize regionally specific prefrontal hypodopaminergia/subcortical hyperdopaminergia have been approved over the last 60 years. The
evolution of these molecules can be best described as
three consequent generations [Mailman and Murthy,
First Generation—FGA: dopamine antagonists
(low potency drugs—chlorpromazine; high potency
drugs—pimozide, haloperidol, fluphenazine);
Second Generation—SGA: dopamine-serotonin
antagonists (risperidone, paliperidone) and multitargeted antipsychotics (clozapine, olanzapine, ziprasidone, quetiapine, asenapine, iloperidone);
Third Generation—TGA: dopamine-functionally
selective (aripirazole, brexpiprazole, cariprazine).
While FGAs are primarily dopamine D2 antagonists, the SGAs act at other receptor sites, including
dopamine D1, D2, D3, and D4, adrenergic alpha1
and alpha2, serotonin 5HT2A and 5HT2C, histamine
and muscarinic receptors. TGAs are considered as
functionally selective/partial D2 agonists (“dopamine
stabilizers”) with possible actions on 5-HT1A and 5HT2A sites [Keck and McElroy, 2003]. Although the
increasing number of antipsychotic drugs [Maric
et al., 2011] may be considered an advantage, treatment of the disease remains far from optimal [Miyamoto et al., 2012].
Schizophrenia results in approximately 60% of
patients receiving disability benefits within the first
year after diagnosis [Ho et al., 1997] and it has been
estimated that current interventions can at most
reduce 25% of disease burden. A major issue with
the potent D2 antagonists i.e., the FGAs (haloperidol,
fluphenazine) is the limited ability to treat negative
and cognitive domains of the disease, alongside with
the risk of extrapyramidal symptoms. Similarly, the
major concern with drugs that act at other receptor
sites, including dopamine D1, D2, D3, and D4,
alpha1 and alpha2 adrenergic, 5HT2A and 5HT2C,
histamine and muscarinic receptors is the associated
weight gain, risk of metabolic syndrome [Maric et al.,
2007; Britvic et al., 2013], and loss of brain tissue,
suggesting careful risk-benefit review of the dosage
and duration of treatment for each patient [Ho et al.,
2011; Guo et al., 2015].
Side effects and the patient’s subjective perspective regarding the (moderate) effectiveness, particularly in negative and cognitive symptom domains
and in overall functionality, are associated with low
compliance with only half of patients treated with
SGAs adhering to their medications [Pogge et al.,
2005; Haddad et al., 2014]. It is theoretically possible
to use pharmacogenetic approaches to assign the
right drug, reach an effective dose earlier and ensure
patient safety [Maric et al., 2015]. Although there are
several commercial tests currently available, the use
of pharmacogenetics in the clinical setting is minimal
[Arranz et al., 2016].
The TGAs, notably aripiprazole, were introduced in 2002. This group also includes brexpiprazole and cariprazine. TGAs act as partial D2 agonists
with actions on 5-HT1A and 5-HT2A receptors. Partial
agonists can also act as antagonists, depending on the
endogenous concentration of dopamine [Tamminga,
2002]. With high dopamine concentrations (e.g., in
the mesolimbic areas involved in positive symptoms),
partial agonists compete with dopamine and cause
partial antagonism resulting in clinical improvement.
Conversely, if dopamine concentrations are low (e.g.,
in the prefrontal cortex), a partial agonist will stimulate dopamine receptors [Stahl, 2001]. Nevertheless,
data from different studies points to possibility that
these drugs work as functionally selective D2 ligands
where their intrinsic activity varies markedly depending on the signaling environment of the D2 receptor
(i.e., they possess functional activity as an antagonist
at postsynaptic D2 receptors and a partial agonist at
presynaptic striatal D2 receptors), which results in
antipsychotic activity with no motor side effects
[Mailman and Murthy, 2010; Snyder et al., 2015].
TGAs reduce prolactin levels and compared to other
antipsychotics do not produce menstrual disturbances, galactorrhea and prolactin-related side effects
[Maric, 2015]. Expected antipsychotic activity alongside with the lack of motor side effects and favorable
effects on prolactin level should result in better compliance with these drugs.
Despite refinements in the mechanism of
action, the therapeutic effects of the newer generations of antipsychotics are insufficient to claim superiority over FGAs, with the possible exception of
clozapine [Miyamoto et al., 2012]. Clozapine is now
the third line therapy in most of the guidelines
worldwide being restricted to those who have failed
first/second-line treatments. However, greater use of
clozapine earlier in the illness course is a strategy
suggested to improve schizophrenia treatment [Remington et al., 2013].
There is still an ongoing debate as to whether
drugs selective for a single molecular target (i.e.,
“magic bullets”) or drugs selectively nonselective for
several molecular targets (i.e., “magic shotguns”) will
lead to new and more effective medications for
schizophrenia [Roth et al., 2004; Miyamoto et al.,
Although all currently available antipsychotic
medications target dopamine D2 receptors, there are
several agents that have no direct effect on the dopamine system. For example, a number of agents with
direct or indirect activity on the glutamate system are
under investigation especially for their potential beneficial effects on cognitive and negative symptoms in
schizophrenia. These agents are in various phases of
development and include glycine agonists, glycine
transporter 1 inhibitors, metabotropic glutamate
receptor agonists, and AMPA/kainate receptor antagonists. These compounds have been studied either as
monotherapy or as add-ons to antipsychotics but
none have accomplished their primary goals. Results
from recent clinical trials of bitopertin, a noncompetitive GlyT1 inhibitor that enhances NMDA receptor
function, as an adjunct to antipsychotics failed to
confirm its efficacy in negative symptoms [BugarskiKirola et al., 2014]. Similarly, the development of
LY2140023 a prodrug of LY404039 (pomaglumetad),
an mGluR2/3 agonist was discontinued as the compound failed to show any clear benefit for the treatment of negative symptoms [Stauffer et al., 2013].
To improve cognition and sensory gating, agents
that enhance brain cholinergic activity have been
examined. These including acetylcholinesterase inhibitors (e.g., galanthamine), partial muscarinic agonists
(e.g., xanomeline), nicotinic receptor agonists and
allosteric potentiators of nicotinic receptor function.
Preclinical and clinical studies showed that the
diminished suppression of P50 auditory evoked
potentials in patients with schizophrenia may be associated with a decreased density of a7 nAChRs in the
brain [Hashimoto, 2015]. However, a7 agonists (TC5619 [Walling et al., 2016] and encenicline [Preskorn
et al., 2014]) failed to show any benefit on either cognitive or negative symptoms.
Another important monoamine—5HT has been
extensively studied in schizophrenia for the last 30
years. Agonists of the 5-HT2C receptor have been
hypothesized to have therapeutic potential in a wide
Drug Dev. Res.
TABLE 1. Pipeline Drugs for Schizophrenia in the Ongoing Phase III and IV Clinical Trials
Pipeline drug
Mechanism of Action
1) Raloxifene Hydrochloride, (FDA
approved for treatment and
prevention of osteoporosis/
reduction in breast cancer risk
in postmenopausal women)—
add on
Selective estrogen receptor
2) Vortioxetine (approved for
Major depressive disorder)—
add on
Agonist at 5-HT1A, partial
agonist at 5-HT1B, antagonist at
5-HT3, 5-HT1D, 5-HT3, 5-HT7
3) Tocilizumab, (approved for
different forms of arthritis)—
add on
Humanized IL-6 receptor monoclonal antibody
4) D-cycloserine (approved
antibiotic for pulmonary and
extrapulmonary tuberculosis)—add on to CBT and stable antipsychotic drugs
Partial agonist at the glycine site of
the NMDA receptor
Other: enhancement of learning
and neuroplasticity
5) Minocycline, (approved
antibiotic for infections caused
by susceptible gram positive
and gram negative strains of
microorganisms)—add on
Semisynthetic tetracycline. Acts
via modulation of microglial
activity and the subsequent
release of pro-inflammatory
cytokines IL1b, IL6, and TNF-a
6) MMFS-202-302, add on
Induces an increase in intracellular
Mg concentration, upregulates
the expression of NR2B-containing NMDAR, boosts mitochondrial membrane potential, and
increases functional synapse
density in neuronal cultures
[Sun et al., 2016].
7) Exenatide (approved for type 2
diabetes mellitus)—add on
Glucagon-like peptide-1 agonist
(GLP-1 agnost); incretin mimetic
Drug Dev. Res.
Pilot results:
Oral adjunctive raloxifene treatment (120 mg/day) has beneficial
effects on attention/processing
speed and memory in both men
and women with schizophrenia.
Thus, raloxifene may be useful as
an adjunctive treatment for cognitive deficits associated with schizophrenia [Weickert et al., 2015].
No results published.
Outcome Measures: Change in
Negative Symptom Assessment
Scale (NSA-16) total score from
baseline to endpoint. Randomization stratified by illness duration
(i.e., </55 years and >5 years) to
examine whether earlier illness
moderates greater negative and/or
cognitive symptom reduction in
response to vortioxetine.
Pilot results:
The findings suggest that tocilizumab may be a viable adjunctive
treatment for cognitive impairment
in schizophrenia, although safety
and cost are important considerations regarding its clinical utility
[Miller et al., 2016].
Pilot results:
Improvements in delusional severity, distress, and belief conviction
after two sessions of a CBT (cognitive-behavioral therapy) exercise in
subjects who received
D-cycloserine with the first session
[Gottlieb et al., 2011].
Pilot results: Addition of minocycline
to atypical antipsychotic drugs in
early schizophrenia had significant
efficacy on negative symptoms, but
had a slight effect on the attention
domains of patients with schizophrenia. It may be considered as a
new adjunct treatment for negative
symptoms of schizophrenia [Liu
et al., 2014].
No results published.
Hypothesis: As augmentation of
SGA—to improve specific domains
of cognitive function, e.g., attention, executive function, declarative memory, negative symptoms of
schizophrenia, positive symptoms
of schizophrenia, and working
memory, as measured by a neuroimaging paradigm.
No results published.
Outcome Measures: Change in
Scale for the Assessment of
TABLE 1. Continued
Pipeline drug
8) Curcumin – add on
9) DSP-5423P
(transdermal patch formulation
of blonanserin)
Approved in Japan (2008) and
Korea (2009)
10) ITI-007 (Lumateperone)
Mechanism of Action
Polyphenolic compound extracted
from green tea and Ginkgo biloba
Activity mediated through various
signal transduction pathways, e.g.
cyclooxygenases (COX) inhibition, STAT3 and NF-jB signaling
pathways modulation, etc [Shehzad and Lee, 2013].
Antagonist at D2/3 and 5HT2A
High-affinity serotonin 5-HT2A
receptor antagonist; presynaptic
partial agonist and postsynaptic
antagonist at D2 receptor with
functional mesolimbic/mesocortical selectivity; increases phosphorylation of mesolimbic
GluN2B subunits of NMDA
receptors; inhibits the serotonin
Negative Symptoms (SANS) and
Cognition in Schizophrenia
No results published on schizophrenia.
Primary Outcome Measures:
PANSS up to 24 weeks.
Secondary Outcome Measures:
CGI, Calgary Depression Scale for
Schizophrenia (CDSS) and Side
As effective as risperidone for the
treatment of schizophrenia, but
associated with a higher incidence
of EPS compared to risperidone [Li
et al., 2015].
Significant improvements in several
subscales on the Subjective Wellbeing under Neuroleptic treatment
scale, the Schizophrenia Quality of
Life Scale, and the Brief Assessment of Cognition in Schizophrenia, and in all factor scores on the
PANSS. Improvement in depressive
symptoms positively correlated
with improvements in subjective
well-being and subjective quality
of life, as well as verbal memory
[Ninomiya et al., 2014].
Meta-analysis results: There were
no significant differences in the
PANSS total score, positive, negative, and general psychopathology
subscale scores, nor response rate
between blonanserin and other
pooled antipsychotics, but blonanserin had greater efficacy in PANSS
negative subscale scores compared
with haloperidol. Lower risk of
hyperprolactinemia, higher risk of
akathisia than other comparators
[Kishi et al., 2013].
Pilot results:
At dose 60 mg demonstrated significant improvements in negative
and depressive symptoms compared to placebo. ITI-007 at dose
120 mg did not separate from placebo [Lieberman et al., 2015].
Based on a large, placebo and risperidone controlled Phase-II trial,
dose of 60 mg was effective in
reducing symptoms in patients with
acutely exacerbated schizophrenia.
It was associated with minimal
safety risk compared to risperidone.
A second 6-week, placebo and
risperidone-controlled Phase-III trial
in acutely exacerbated
Drug Dev. Res.
TABLE 1. Continued
Pipeline drug
Mechanism of Action
11) Ondansetron (approved for
prevention of nausea and
vomiting associated with
chemotherapy, radiotherapy,
and postoperative nausea
and/or vomiting)—add on
5-HT3 receptor antagonist
12) Famotidine (approved for
treatment of gastric ulcers)—
add on
H2 receptor antagonist
13) ALKS 3831
(Samidorphan 1
olanzapine)designed to attenuate olanzapine-induced
metabolic side effects, that
is, e.g., weight gain, in
patients with schizophrenia
and to have utility in the
treatment of schizophrenia in
patients with alcohol use
l-opioid receptor antagonist
14) D-serine—add on for tardive
dyskinesia and for cognitive
remediation in patients with
Agonist at glycine site on NMDA
range of psychiatric disorders based on data from
preclinical animal models. However, Phase II trials
with the selective 5-HT2C receptor agonist, vabicaserin (SCA-136) suggested it had limited benefit in
Drug Dev. Res.
schizophrenia is ongoing [Davis
and Correll, 2016].
Pilot results:
Improvement in CGI scores, total
PANSS scores and positive, negative, and general symptoms subscales [Hema et al., 2016].
Reduction in symptoms compared
with treatment as usual on PANSS
total score, not statistically significant [Chaudhry et al., 2014].
Pilot results:
The PANSS Total score and the
General CGI subscore showed significantly greater change than in
the placebo group. There was a
reduction in the SANS Scale that
did not reach statistical significance
[Meskanen et al., 2013].
Press release:
Data from completed study support
and extend the initial positive
results showing ALKS 3831’s favorable efficacy and mean weight gain
profile and show for the first time
that switching patients from olanzapine to ALKS 3831 resulted in a
cessation of mean weight gain
zhtml?c592211&p5irol-corporateNewsArticle&ID5 2032249].
Pilot results:
D-serine as antipsychotic monotherapy in treatment-resistant
schizophrenia was inferior compared to high-dose olanzapine
regarding effect on PASS scores.
However, within group analysis
demonstrated that among study
completers D-serine resulted in
improved total and negative symptom PANSS scores without a worsening of psychotic features
[Ermilov et al., 2013].
High doses of D-serine add-on
(60 mg/kg/d) seem effective in
treatment of both persistent symptoms and neurocognitive dysfunction in patients with schizophrenia
or schizoaffective disorder [Kantrowitz et al., 2010].
treating schizophrenia [Liu et al., 2014]. Ondansetron, a 5-HT3 receptor antagonist approved for the
nausea and vomiting associated with chemotherapy,
is in Phase III trials (Table 1) to evaluate its efficacy
in the combination with antipsychotics in main symptom domains and global functioning.
There is also data that endocannabinoids are
involved in schizophrenia. The selective CB1 receptor antagonist, rimonabant (approved in the EU for
weight loss) failed to show improvements in global
cognitive function in [Boggs et al., 2012]. However, a
study of an oily solution containing cannabidiol—
GWP42003 as adjunctive therapy for schizophrenia
reported that 500 mg bid for 5 weeks reduced positive symptoms of psychosis in patients stabilized on
antipsychotic therapy [McGuire et al., 2016]. Additional Phase II studies using cannabinoids are recruiting patients with acute psychosis.
The lack of pharmacological add-on treatments
for cognitive deficits led to a focus on novel therapeutic agents that could improve this symptom
dimension which is of particular interest for functional recovery in schizophrenia, including social cognition. A clinical trial with oxytocin (40 IU intranasally)
in 23 male veterans with schizophrenia showed
improved performance in several social cognitive
tasks as compared to placebo, which encouraged further studies into the therapeutic potential of oxytocin
in schizophrenia [Davis et al., 2013]. However, randomized, double blind study with daily administration
of intranasal oxytocin which measured its effect on
emotional intelligence and performance on measures
of social cognition in schizophrenia/schizoaffective
patients found no treatment group differences in any
symptom measures [Lee et al., 2016].
Trials testing folate with Vitamin B12 as the
add-on therapy in outpatients with chronic schizophrenia taking stable doses of antipsychotic medications improved negative symptoms compared with
placebo but only when the folate hydrolase genotype
FOLH1 (rs202676) was present. Changes in positive
and total symptoms did not differ between treatment
groups. Folate is a B vitamin that provides methyl
donors for biosynthetic methylation reactions and
contributes to gene expression via methylation of
DNA and histones. The investigators concluded that
folate plus vitamin B12 supplementation can improve
negative symptoms of schizophrenia, however, the
response is influenced by genetic variation in folate
absorption [Roffman et al., 2013].
A search of the website
on May 4th, 2016, focused on recruiting phase I–IV
studies of schizophrenia, identified 48 clinical trials.
For the purposes of the present overview, the focus
was on compounds involved in Phase III (6) or Phase
IV (8) clinical trials. These are summarized in Table
1 in terms of preliminary data on efficacy or, if there
were no data, the expected outcomes of the studies.
Two agents could be singled out as potential
drugs for schizophrenia, both of which are being tested as monotherapy: blonanserine and ITI-007.
Blonaserine is a D2/3/5HT2A antagonist (affinity
for D2 receptors higher than that for 5-HT2A receptors, thus blonanserin is pharmacologically closer to
an FGA) that in short-term, double-blind clinical trials had efficacy equal to haloperidol and risperidone
on positive symptoms in chronic schizophrenia and
was also superior to haloperidol in improving negative symptoms (Kishi et al., 2013; Tenjin et al., 2013;
Ninomiya et al., 2014; Li et al., 2015). Blonanserin
has been registered in Japan and Korea. It is currently in Phase III as a transdermal patch, DSP5423P
with an estimated completion date of February 2017.
ITI-007 (Lumateperone) acts not only via DA
and 5HT related mechanisms, but also increases
phosphorylation of the mesolimbic GluN2B NMDA
receptor subunit. It has been compared to placebo/
other antipsychotics in Phase III trials that provided
insights into its efficacy on positive symptoms, safety
and tolerability. A dose-related improvement in
symptoms of schizophrenia was reported [ Davis and
Correll, 2016; Lieberman et al., 2016; Vanover et al.,
2016]. Trials to assess the antipsychotic efficacy of
ITI-007 with 6 weeks of treatment should be completed around August 2016.
The other agents listed in Table 1 belong to different drug classes and are being explored as add-on
to antipsychotics, mostly for cognitive and negative
symptom domains. It is still an open question which
of these drugs (registered for the treatment of osteoporosis, depression, arthritis, tuberculosis, infections,
type 2 diabetes, nausea and vomiting, gastric ulceration) may improve treatment outcomes in subjects
with schizophrenia.
Schizophrenia has been associated with immune
system dysfunction and inflammatory responses to
viral or bacterial infections. An ongoing study “AntiInflammatory Combination Therapy for the Treatment
NCT01514682] is exploring the effects of an add-on
anti-inflammatory combination therapy (salsalate, fluvastatin, and omega-3-fatty acid (EPA/DHA)) in
depressive and negative symptoms.
A growing body of evidence suggests that estrogen plays a beneficial role in the brain, supporting
growth and neuroprotection, and that this helps
explain why women tend to present with first episodes of schizophrenia later in life, present less
Drug Dev. Res.
frequently than men, and, sometimes have a better
prognosis and treatment response. Raloxifene (Table
1) is increasingly being considered as an adjunct
treatment for postmenopausal women with schizophrenia [Kulkarni et al., 2010] and in treatmentresistant cases [Kulkarni et al., 2015] being part of
schizophrenia care in patients of any age or sex.
All currently approved antipsychotics block
dopamine receptors, indicating that manipulation of
dopaminergic function is fundamental to a therapeutic response in psychosis. However, adequate D2
blockade by antipsychotic drugs is necessary but not
always sufficient for antipsychotic response [Howes
et al., 2009]. For this reason, further attempts to
design efficient and safe molecules is focused on targets other than DA receptors (5HT, AMPA, NMDA,
GlyT, CB1, etc.). In parallel with the new drug
design, schizophrenia treatment will benefit from
some additional considerations.
First, since both FGAs and SGAs mainly block
postsynaptic dopamine transmission [Natesan and
Kapur, 2011] these drugs decrease the basal synaptic
dopamine which together with the postsynaptic
blockade, results in DA receptor upregulation and
reduced effectiveness. If there is agreement that
treating presynaptic dysfunctionality to balance DA
transmission in schizophrenia is an optimal scenario
for therapy [Howes and Kapur, 2009; Kahn and
Sommer, 2015], then FGAs and SGAs that act by
blocking a postsynaptic neurotransmission might be
considered as inducers of “mismatch” in the dopaminergic pathways in the brain. The possibility that
treatment with the most of the registered antipsychotics does not optimally target the synapse has
been questioned [Natesan and Kapur, 2011]. This
raises intriguing questions e.g.,: what does this say
about the long-term use of antipsychotics? are they
potentially harmful? are they necessary for an individual’s entire lifetime? and so on. There is also evidence that some individuals with schizophrenias have
more prominent neurodegenerative processes which
is a matter of great debate [Zipursky et al., 2013]. If
the progression of brain tissue loss seen in some
patients is due to antipsychotic treatment and not
any additional pathological process [Ho et al., 2011],
this would require the search for agents that are also
Second, the current approach in drug discovery
remains target-centric [Enna and Williams, 2009]),
with the goal to optimize compounds with high affinity and selectivity for a specific target [Geppert and
Drug Dev. Res.
Koeppen, 2014]. At present, there are no definite
molecular targets/complex networks identified for any
of the dimensions of schizophrenia or its subtypes.
Conversely, approved antipsychotics have been tested
in patients diagnosed on the basis of the unitary concept of schizophrenia. This underestimates the fact
that distinct subtypes of schizophrenias require specific drug profiles beyond D2 receptor antagonism
for the currently unaddressed symptom dimensions.
Novel targets for which there is theoretical rationale
(glutamate receptors, intracellular signaling proteins,
or products of the risk genes are under investigation
and their application in different subpopulations,
instead of investigation in the heterogeneous group
of schizophrenias appears promising.
Third, it is important to note that at the time
when the first psychotic symptoms are diagnosed, the
neurobiological processes underlying the illness have
already been ongoing for years. Therefore, we need
to intervene before the “window of opportunity” is
closed, and the deterioration, mainly cognitive, is
mostly irreversible. According to Kahn and Sommer
[2015], the key for the future research will be to
determine deviations in DA synthesis, NMDAR dysfunction and proinflammatory status of the brain. For
example, NMDAR dysfunctions associated with
altered GABA-ergic signaling should be a possible
target for the intervention before full-blown symptoms appear. In addition, interventions which will
include anti-inflammatory agents tested in carefully
identified individuals during the critical prodromal
(or subthreshold) periods should be developed. The
pilot studies of minocycline [Chaves et al., 2015]
have shown that it may protect against gray matter
loss and, as an add-on treatment, may be effective in
the early stages of schizophrenia to ameliorate clinical
deterioration and brain alterations observed.
One of the crucial questions about the future
pharmacotherapy of schizophrenia(s) is should we try
to find one drug that will address all these issues, or
should we rely on drug combinations (polypharmacy)
to target different phenotypes and symptom domains?
The latter approach is already applied in other complex and chronic disease states in oncology, cardiology,
and so on, where treatment advances have been made
using combinations of the several agents. The concern
regarding the polypharmacology, which is sometimes
essential for the therapeutic effect [Peters, 2013] is
related to increased risk of side effects.
The various symptom dimensions and subtypes
of schizophrenia(s) and several “critical windows”
associated with specific, time limited, neurobiological
oscillations during neurodevelopment make the search
for more effective and better-tolerated antipsychotic
agents urgent. The development of novel compounds
interacting with molecular targets underlying cognitive
dysfunction, negative symptom dimensions, attenuated
psychosis syndrome, at risk mental states, and/or specific endophenotypes related to the increased risk of
psychosis in general population is expected. In parallel, efforts to deconstruct the concept of
“schizophrenia” [Braff et al., 2007] and to imply the
staging model of the illness should be encouraged.
Although many may say that today’s treatments are
not good enough and that the rate of progress in
schizophrenia treatment is slow, care for diagnosed
individuals has improved significantly over the last few
decades. We still have much to learn but progress in
brain research holds a great promise that the next few
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From text:
: 5-hydroxytryptamine (serotonin)
: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
: Cannabinoid receptor type 1
: Dopamine
: Food and Drug Administration
: First-generation antipsychotics
: Folate hydrolase (prostate-specific
membrane antigen) 1
: Gamma-aminobutyric acid
: Glutamate [NMDA] receptor subunit
: Glycine transporter 1
: International unit
: metabotropic glutamate receptors 2/3
: N-methyl-D-asparate
: Second-generation antipsychotics
: Third-generation antipsychotics
From the table:
: Cognitive-behavioural therapy
: Calgary
: Clinical Global Impressions Scale
: Extrapyramidal syndrome
: Glucagon-like peptide-1
: Histamine H2 receptor
: Interleukin 6
: Measurement and Treatment Research
to Improve Cognition in Schizophrenia
: Positive and negative syndrome scale
: Assessment of Negative Symptoms
: Tumor necrosis factor alpha
Drug Dev. Res.