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Research Overview Improving Current Treatments for Schizophrenia DDR DRUG DEVELOPMENT RESEARCH 00 : 00–00 (2016) Nadja P. Maric,1,2* Milica J. Jovicic,2 Marina Mihaljevic,2 and Cedo Miljevic1,3 1 School of Medicine, University of Belgrade, Belgrade, Serbia 2 Clinical Centre of Serbia, Clinic for Psychiatry, Belgrade, Serbia 3 Institute of Mental Health, Belgrade, Serbia Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I-III Regulatory, Quality, Manufacturing Postmarketing Phase IV ABSTRACT 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. V pies and more favorable outcomes. Drug Dev Res 00 : 000–000, 2016. Key words: antipsychotic; dopamine; NMDR; clinical trial; drug discovery INTRODUCTION 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. V (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 2 MARIC ET AL. 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. ANTIPSYCHOTICS: CURRENT STATE 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, 2010]: 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, FUTURE TREATMENTS FOR SCHIZOPHRENIA 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 3 suggested to improve schizophrenia treatment [Remington et al., 2013]. PIPELINE DRUGS FOR SCHIZOPHRENIA IN RECENTLY COMPLETED CLINICAL TRIALS 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., 2012]. 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. 4 MARIC ET AL. 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 modulator 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 regimen 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. Evaluation 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 Phase IV IV IV IV IV IV IV FUTURE TREATMENTS FOR SCHIZOPHRENIA 5 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 receptors 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 transporter Evaluation Phase Negative Symptoms (SANS) and Cognition in Schizophrenia (MATRICS). 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 effects. 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 IV III III Drug Dev. Res. 6 MARIC ET AL. TABLE 1. Continued Pipeline drug Mechanism of Action Evaluation 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 schizophrenia Agonist at glycine site on NMDA receptors 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 [http://phx.corporate-ir.net/phoenix. 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]. Phase III II/III II/III II/III 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 FUTURE TREATMENTS FOR SCHIZOPHRENIA 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]. PIPELINE DRUGS FOR SCHIZOPHRENIA IN ONGOING CLINICAL TRIALS A search of the www.clinicaltrials.gov 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 7 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 of Schizophrenia” [ClinicalTrials.gov 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. 8 MARIC ET AL. 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. FUTURE DIRECTIONS 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 neuroprotective. 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. CONCLUSION The various symptom dimensions and subtypes of schizophrenia(s) and several “critical windows” FUTURE TREATMENTS FOR SCHIZOPHRENIA 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. 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APPENDIX : LIST OF ABBREVIATIONS From text: 5HT AMPA CB1 DA FDA FGA FOLH1 GABA GluN2B GlyT1 IU mGluR2/3 NMDA SGA TGA : 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 epsilon-2 : Glycine transporter 1 : International unit : metabotropic glutamate receptors 2/3 : N-methyl-D-asparate : Second-generation antipsychotics : Third-generation antipsychotics From the table: CBT CDSS CGI EPS GLP-1 H2 IL-6 MATRICS PANSS SANS TNF-a : Cognitive-behavioural therapy : Calgary depression scale for schizophrenia : 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.