Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities

Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3 antagonist/5-HT1A partial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2 antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal® and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine’s efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.


CME Information
Released: July 25, 2019 CME credit expires: May 15, 2022 Learning Objectives After completing this activity, you should be better able to: • Differentiate the mechanisms of action of new and emerging antipsychotics • Evaluate the latest clinical data on new and emerging antipsychotics

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The Neuroscience Education Institute (NEI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. NEI designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits TM . Physicians should claim only the credit commensurate with the extent of their participation in the activity. A posttest score of 70% or higher is required to earn CME credits. The American Society for the Advancement of Pharmacotherapy (ASAP), Division 55 of the American Psychological Association, is approved by the American Psychological Association to sponsor continuing education for psychologists. ASAP maintains responsibility for this program and its content.
The American Society for the Advancement of Pharmacotherapy designates this program for 1.5 CE credits for psychologists. Nurses and Physician Assistants: for all of your CE requirements for recertification, the ANCC and NCCPA will accept AMA PRA Category 1 Credits™ from organizations accredited by the ACCME. The content of this activity pertains to pharmacology and is worth 1.5 continuing education hours of pharmacotherapeutics.

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Introduction
Schizophrenia is a still all-too-often chronic and debilitating psychiatric disorder that is characterized by a combination of positive and negative symptoms, cognitive dysfunction, affective and motor disturbances that often result in functional impairment and poor quality of life. 1,2 Current treatment guidelines suggest long-term treatment with antipsychotic medications in conjunction with psychological interventions, for people with first episode psychosis, an acute exacerbation or recurrence of psychosis. 3 Despite pharmacologic advances in recent years, an effective treatment of schizophrenia remains an issue, as knowledge about the pathophysiology of this complex disorder is lacking. 1,4 The most challenging components of treatment effectiveness are adherence and efficacy for negative and cognitive as well as residual positive symptoms and adverse effects. 1 Dopamine modulating antipsychotics remain the primary and only currently approved treatment for schizophrenia, and over the past years many different antipsychotics have been developed and tested for their efficacy and safety in reducing acute symptoms of schizophrenia and maintaining stability. [5][6][7][8][9] However, currently available drugs are mostly effective against positive symptoms (i.e., hallucinations, delusions, disorganized thought or speech, and bizarre behaviors). This situation leaves most patients with diverse residual symptoms relatively untreated, especially negative symptoms (lack of motivation, drive, enjoyment, social interactions) and cognitive dysfunction (deficits in attention, memory, executive functioning, grasp of social situations/interactions), which lead to poor quality of life outcomes and lifelong impairments, [10][11][12][13][14][15][16][17][18] as cognitive and negative symptoms persist for most of the patients' lives. 15,19 To date, there are no FDA-approved medications for negative and cognitive symptoms, and augmentation strategies have been largely disappointing so far. 20,21 Furthermore, as at least positive symptoms in schizophrenia have primarily been associated with dopamine dysfunction, all currently available effective antipsychotics have dopamine D 2 receptor occupancy as a key feature, which is also associated with a varying degree of adverse effects, including motor impairments and prolactin abnormalities, with additional dopamine or off-target receptor activity-related effects on sedation, weight gain, metabolic disturbances and cardiovascular risk factors, morbidity and mortality. [22][23][24][25][26][27][28][29] In addition, too much dopamine blockade has been associated with secondary negative and cognitive symptoms. 20 However, drugs with dopamine D 2 receptor occupancy have remained the only approved and effective pharmacologic treatment for schizophrenia, since its discovery in the 1950s. 16 Currently, only clozapine, which has considerable adverse effects, 30 has been found superior to other antipsychotics in treatment-resistant schizophrenia, 31 defined as a failure to at least two nonclozapine antipsychotics. 32 Thus, less side effect-prone agents in monotherapy or as augmentation are needed for patients with suboptimal positive symptom response or treatment-resistance.
Recent findings suggest that the core pathophysiology of schizophrenia may also involve dysfunction of glutamatergic, serotonergic, cholinergic, and gamma-aminobutyric acid (GABA) signaling, with an imbalance within any of these influencing the entire system. 33 Therefore, novel treatment approaches have also been focusing on molecular targets beyond the dopamine hypothesis, including glutamate, serotonin, acetylcholine, GABA, and inflammatory cytokines. 34,35 Due to the goal of maintenance treatment 8 and longstanding problems with adherence in schizophrenia, 36 long-acting injectable antipsychotics (LAIs) have been developed and largely shown benefits for prevention of relapse, hospitalization, and mortality in patients with schizophrenia. [37][38][39][40][41][42] Novel LAI formulations have emerged, aiming to improve acceptability and avoid the need for oral cotreatment or loading strategies. Therefore, this selective review aimed to (i) summarize the mechanisms of action and, if available, the results of novel, emerging, and currently investigated pharmacologic treatments for total, negative, and cognitive symptoms of schizophrenia, as well as residual and resistant positive symptoms, (ii) summarize the latest clinical data of newly approved formulations of LAIs, and (iii) evaluate the data for the addition of opioid receptor modulation to mitigate olanzapine-associated weight gain.

Results
Total symptoms of schizophrenia (including positive and negative symptoms) Although many first-and second-generation antipsychotics are available, all modulate dopamine with or without serotonergic transmission modulation, but additional mechanisms of actions conferring efficacy, either added on separately or combined with dopamineserotonin antagonism, are needed. Furthermore, improved safety and tolerability also remains a goal. Several agents are at different stages of testing.

Cannabidiol
While tetrahydrocannabinol (THC), the major component of cannabis, is pro-psychotic, the potential antipsychotic and precognitive properties of cannabidiol for schizophrenia and its efficacy for other neuropsychiatric disorders are actively being pursued. [43][44][45] In an exploratory 6-week, double-blind study, patients with schizophrenia were randomized to cannabidiol (n = 43) or placebo (n = 45) added to preexisting antipsychotics. 46 Although no differences between cannabidiol and placebo emerged regarding the Positive and Negative Syndrome Scale (PANSS) total or negative and general scale scores, cannabidiol had significantly lower PANSS positive scores at week 6. Furthermore, cannabidiol was superior to placebo in being rated as improved (Clinical Global Impressions-Improvement (CGI-I)) and as not severely unwell (CGI-Severity). However, cannabidiol was not superior to placebo on the Global Assessment of Functioning (GAF) Scale or the Brief Assessment of Cognition (BACS) ( Table 2). Cannabidiol was well tolerated, with similar adverse event frequencies between cannabidiol and placebo.

F17464
F17464 is an oral, selective D 3 antagonist/5-HT 1A partial agonist that is developed for the treatment of schizophrenia. 47 In a phase-II, double-blind, randomized, placebocontrolled, parallel-group 6-week trial, 48 patients (n = 134) with acute exacerbation of schizophrenia were randomized to 40 mg/day F17464 or placebo. The F17464 group was significantly superior to placebo in reducing the PANSS total score, PANSS positive and general subscale score, and of the PANSS Wallwork factors, which correspond to cognitive functioning. However, F17464 did not differentiate from placebo on the PANSS negative and CGI-S scores ( Table 2). 48 Adverse events were comparable to placebo. Overall, results of this phase-II study demonstrated therapeutic efficacy in improving total, positive, and PANSS-derived cognitive symptoms in acutely exacerbated schizophrenia patients, with a favorable safety profile. 48 Lumateperone (ITI-007) Lumateperone, also known as ITI-007, is an investigational agent with simultaneous modulation of serotonin, dopamine, and glutamate, which is being developed for the treatment of schizophrenia, bipolar depression, and other neuropsychiatric/ neurodegenerative diseases. The FDA has accepted the new drug application (NDA) for lumateperone for the treatment of acutely exacerbated schizophrenia in December 2018.
Lumateperone acts as a presynaptic partial agonist and postsynaptic antagonist at dopamine D 2 receptors with functional mesolimbic/mesocortical selectivity. 49 In addition, it has potent serotonin 5-HT 2A receptor antagonism, serotonin transporter inhibition, and stimulates phosphorylation of glutamatergic N-methyl-Daspartate (NMDA) GluN 2B receptors, likely downstream of dopamine D 1 receptor intracellular signaling. 49 Recently, the additional and unique increase of AMPA currents via the mTOR protein pathway has been described. 50 At the therapeutic dose of 60 mg/day, lumateperone fully saturates 5-HT 2A receptors, at modest levels of dopamine receptor occupancies (30-40%), at least partially due to its wider separation (60-fold) between its affinity for 5-HT 2A receptors and D 2 receptors, compared to other second-generation antipsychotics, including risperidone (12-fold) and aripiprazole (0.18-fold). 51 Lumateperone has been investigated in three placebocontrolled trials of acutely exacerbated schizophrenia, two of which included risperidone for assay sensitivity as an active comparator, and all conducted in the USA only. 52 In a 4-week, phase-IIb clinical trial (n = 335; ITI-007-005), ITI-007 showed statistically significant efficacy vs. placebo in improving schizophrenia symptoms, measured with the PANSS total score and its subscale scores at a dose of 60 mg/day (but not at 120 mg/day), and at a similar effect size as risperidone. 52 Compared to risperidone 4 mg/day, ITI-007 was superior at reducing negative symptoms, as well as on key safety and tolerability measures including prolactin, body weight, and glucose and lipid levels. 52 In a first 4-week, phase-III trial (n = 440; ITI-007-301), lumateperone 60 mg/day separated from placebo regarding schizophrenia symptoms both in PANSS total and CGI-S. 50 Notably, although lumateperone 40 mg/day was not superior to placebo regarding PANSS total scores, the 40 mg/day group was significantly superior regarding the CGI-S and PANSS positive subscale score (although not formally tested as the primary outcome did reach statistical significance), like the 60 mg/day group (Table 2). In a second phase-III trial lasting 6 weeks (n = 695; ITI-007-302), however, lumateperone 60 mg/day as well as 20 mg/day did not separate from placebo regarding schizophrenia symptoms, while risperidone 4 mg/day did ( Table 2). 50 Nevertheless, although risperidone separated from placebo, it also had the greatest dropout rate, with patients dropping out early being potentially the less responsive patient subgroup, and the placebo effect was much larger than in the other two trials, making the results less reliable than in the first two trials. In terms of adverse effects, lumateperone separated on few symptoms from placebo, including only somnolence, sedation,      Negative study: Sodium nitroprusside failed to separate from placebo on the primary endpoint (PANSS total).

TAK-063
Macek and fatigue (Table 1). However, these adverse effects were generally only mild or moderate, and lumateperone was associated with low and placebo-like discontinuation rates. 50 Finally, in phase 1 of a recently completed study (n = 302, ITI-007-303), 53 investigating the safety of ITI-007 in an open-label setting in patients with stable schizophrenia switching from standard-of-care (SOC) antipsychotics to lumateperone, 6 weeks of treatment with lumateperone led to significant improvements in both schizophrenia symptoms and key cardiometabolic parameters, such as LDL-cholesterol and triglycerides as well as prolactin levels. After only 2 weeks of switching back to SOC antipsychotics, the safety variables that had significantly improved trended back to pre-lumateperone baseline and were not significantly improved anymore. 54 Interestingly, in this study program, lumateperone was dosed in the evening, and the already-low adverse event rates seen in the acute studies in which AM dosing had been applied were further reduced.
In phase 2 of the same study (n = 603, ITI-007-303) 54 patients were enrolled for a planned treatment duration of up to 1 year. As the study is ongoing, data reflect an interim data cut that includes observed cases for those subjects who have had completed each visit (300 days, n = 184). After 300 days of treatment, lumateperone led to significant improvements in both schizophrenia symptoms ( Table 2) and key cardiometabolic parameters, such as body weight and total cholesterol, LDL-cholesterol as well as prolactin levels. 54 These results imply that patients with stable symptoms on other antipsychotics may further improve when switched to lumateperone. 54 Overall, lumateperone represents a novel approach, with a unique mechanism of action, which seems to be promising in enhancing efficacy with a favorable safety profile.

Phosphodiesterase 10A (PDE10A) inhibitors
Phosphodiesterase 10A (PDE10A) inhibitors are expected to modulate via cAMP-and cGMP-dependent mechanisms both the dopamine D 1 -direct and D 2 -indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. 55 Therefore, studies of PDE10 inhibitors are expected to target both dopaminergic and glutamatergic dysfunction in schizophrenia.
Several PDE10A inhibitors are currently investigated, including TAK-063 and MK-8189 for total schizophrenia symptoms.
TAK-063 56 has shown mixed results. In a phase-II, 6-week, randomized, placebo-controlled study, subjects with an acute exacerbation of schizophrenia were randomized to TAK-063 20-mg/day (n = 83) or placebo (n = 81). Although in this sample, TAK-063 failed to separate from placebo on total PANSS at study endpoint, the effect size was small (0.308) ( Table 2). Consistent with previous phase-I studies, TAK-063 was well tolerated, with higher rates of akathisia and dystonia vs. placebo. 57 In addition, one recent negative study read out for MK-8189. In a placebo-and active-controlled, 4-week study of patients (n = 224) with an acute exacerbation of schizophrenia, MK-8189 (n = 90) was compared with placebo (n = 89) and with risperidone (n = 45). At study endpoint MK-8189 did not separate from placebo or risperidone on the PANSS total score. Conversely, risperidone significantly separated from placebo on the PANSS total score (Table 2). Furthermore, MK-8189 did not separate from placebo in other secondary outcomes (adverse events and study discontinuation). 58

Sodium nitroprusside (nitric oxide donor)
Nitric oxide may be implicated in the pathophysiology of schizophrenia, as it is a gas that mediates the release of neurotransmitters, and seems to be involved in learning, memory, and neurodevelopment. 59 As a nitric oxide donor, sodium nitroprusside may thus improve symptoms of schizophrenia.
The original randomized, double-blind, placebocontrolled study of sodium nitroprusside, conducted in Brazil, examined the effectiveness and safety of a single intravenous administration of sodium nitroprusside (0.5 μg/kg/min for 4 hours) for the improvement of positive, negative, anxiety, and depressive symptoms in 20 patients with schizophrenia who were within the first 5 years of schizophrenia and who were taking antipsychotics. 60 After the adjunctive infusion of sodium nitroprusside, a rapid improvement of symptoms was observed within 4 hours, with significant superiority of sodium nitroprusside vs. placebo on the 18-item Brief Psychiatric Rating Scale total score and subscale scores, which persisted for 4 weeks after infusion ( Table 2). 60 However, three recent studies were unable to replicate these original study results. In one study, 42 adults with schizophrenia were randomized to two placebo or sodium nitroprusside infusions (0.5 μg/kg per min for 4 h) during a 1-week interval. 61 The authors failed to find any significant effect of sodium nitroprusside vs. placebo on psychotic symptoms or cognitive functions, although sodium nitroprusside seemed relatively well tolerated. In a second study, 20 patients with a diagnosis of schizophrenia or schizoaffective disorder were randomized to an infusion of sodium nitroprusside (0.5 μg/kg per min for 4 h) or placebo and reassessed for symptoms and cognitive performance immediately after the infusion, and 4 weeks later ( Table 2). 62 Similarly, the authors failed to observe any significant advantage of sodium nitroprusside vs.
KEEPING UP WITH THE THERAPEUTIC ADVANCES IN SCHIZOPHRENIA  placebo for reducing psychotic symptoms or improving spatial working memory vs. placebo. Finally, in a third, 2-week acute treatment study, 63 patients (n = 52) were randomized to one of three treatment sequences (sodium nitroprusside þ sodium nitroprusside; placebo þ sodium nitroprusside; placebo þ placebo), without separation of sodium nitroprusside from placebo in this study (Table 2). Consistent with the results of the two prior studies, no differences emerged in safety or tolerability measures. 63 However, as in the original, positive study patients were younger, in an earlier illness phase and more severely ill than in the negative trials, patient features that may enhance the efficacy of sodium nitroprusside may need to be considered in future trials. 64 Trace amine-associated receptor 1 (TAAR-1) agonists Trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptor that belongs to the TAAR family. Discovered in 2001, TAARs have been found in several tissues, including the central nervous system and olfactory epithelium. 65,66 TAAR1 is activated by endogenous trace amines that are structurally related to monoaminergic neurotransmitters. TAAR1 agonists include amphetamine and methamphetamine, and TAAR1 seems to be most selective to dopamine, being less responsive to the endogenous tryptamine, norepinephrine, and serotonin, although glutamatergic transmission may also be modulated. In turn, these receptor features make TAAR1 agonists attractive targets for the treatment of schizophrenia. 65,66 Currently two TAAR1 agonists are being evaluated for schizophrenia. These include SEP-363856 67,68 and RO5263397 66,69 (for which wide variations in blood levels have been described based on genotype and ethnicity). 70 While for RO5263397, phase-II study results have to our knowledge not been publicly reported, results of a phase-IIb study of SEP-363856 have been presented as a poster. 71 In a phase-II, randomized, double-blind, placebo-controlled 4-week, flexible dose study, SEP-363856 50 mg/day or 75 mg/day (n = 120, modal dose=75 mg/day) was superior to placebo (n = 125) for PANSS total scores, PANSS positive, PANSS negative, and PANSS general psychopathology subscale score, CGI-S, Brief Negative Symptom Scale (BNSS), and the Montgomery-Asberg Depression Rating Scale (MADRS). All-cause discontinuation (approximately 20%) and intolerability-related discontinuation (<10%) were similar to placebo (Table 2). Moreover, changes in body weight, blood glucose, lipids, and prolactin levels were comparable to placebo. Adverse effects ≥2% and at a maximum 1-2.5% greater than with placebo included somnolence, nausea, diarrhea, and dyspepsia. 71

Negative symptoms
After a positive phase-II study, 72 the bitopertin program of a GLYT-1 inhibitor was stopped due to following negative studies, 73 leaving again negative symptoms a highly desirable and sorely needed indication for the treatment of schizophrenia. Several different agents are currently investigated for this indication.

LuAF-11167
Since PDE10A inhibitors have not reliably separated from placebo in acutely exacerbated schizophrenia, 57,58 LuAF-11167 is currently being developed for the treatment of negative symptoms. 74 Since, possibly, dopamine blockade due to accompanying antipsychotic treatment in the adjunctive trial programs for acutely exacerbated schizophrenia patients may interfere with the optimized effects of a PDE10A inhibitor for negative symptoms, an ongoing study evaluates LuAF-11167 in monotherapy vs. placebo. Results are not available for this phase-II study. 74 Pimavanserin Pimavanserin is a 5-HT 2A inverse agonist approved for the treatment of psychosis associated with Parkinson's disease. In one prior study of schizophrenia patients, 75 pimvanserin added to lower risperidone doses (2 mg/ day) was equally efficacious as higher risperidone doses (6 mg/day); also pimavanserin augmentation seemed to reduce EPS. Currently, the ongoing ADVANCE study is a phase-II, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adjunctive pimavanserin for the treatment of negative symptoms of schizophrenia. 76 This 26-week study compares three doses of pimavanserin (34 mg, 20 mg, or 10 mg) plus background antipsychotic vs. placebo plus background antipsychotic, with the primary outcome measure being the Negative Symptom Scale-16 (NSA-16). Results are expected later in 2019.

Roluperidone (MIN-101)
Roluperidone, also known as MIN-101, is a cyclic amido derivative, with affinities for sigma-2, 5-HT 2A , and alpha1-adrenergic receptors, developed to target negative symptoms and cognitive dysfunction in schizophrenia patients. MIN-101 has low affinity for dopaminergic, muscarinic, cholinergic, and histaminergic receptors. Recent studies have shown that MIN-101 is an antagonist at sigma-2 and 5-HT 2A . 77,78 Reportedly, an unpublished phase-IIa study 79 was positive for negative symptoms in schizophrenia, which was replicated in a phase-IIb trial. 78 In that 12-week study, 234 patients who had been symptomatically stable for at least ≥3 months and who had predominant negative symptoms (score ≥20 on the PANSS negative subscale, baseline mean = 26.8) were randomized to roluperidone 32 mg/day or 64 mg/day or placebo. At 12 weeks, MIN-101 32 mg/day and 64 mg/day were statistically significantly superior in the PANSS negative factor score (pentagonal structure model). In addition, positive results were also reported for PANSS negative symptom, total, and activation factor scores, CGI-S, and the BNSS (Table 3). 78 In addition, roluperidone was safe, without clinically significant changes in vital signs, routine laboratory values, body weight, metabolic parameters, or neuromotor scale scores. Adverse events included headache, anxiety, insomnia, schizophrenia symptoms, asthenia, nausea, and somnolence. 78 Results of secondary analyses from this trial also suggested that roluperidone may also have an enhancing effect on cognitive functioning. 77 The BACS token motor, verbal fluency, and composite z scores improved significantly vs. placebo in the 32 mg roluperidone group, but not the 64 mg/day group, although the efficacy for negative symptoms was greater for the higher dose, and although negative correlations were seen for improvements in certain cognitive symptom domains and negative symptom reduction even in the 64 mg/day group (Table 3). Thus, it is important to note that dose-related effects of roluperidone diverged between negative and cognitive symptom improvement. Moreover, results do not yet indicate whether similar results would be observed for patients with a different range of schizophrenia symptoms. 77 Nevertheless, roluperidone represents an innovative mechanism of action, which seems to be promising in improving the treatment of negative symptoms, as well as cognitive dysfunction while having a favorable safety profile. The ongoing phase-III trial program will have to confirm these initial results. 80

TAK-831
D-serine is an endogenous ligand for the glycine modulatory binding site on the NR1 subunit of NMDA receptors in the brain, whose agonist functioning is thought to improve negative symptoms of schizophrenia. 81 Since D-serine is degraded by the flavoenzyme DAAO, DAAO inhibitors may improve NMDA functioning and negative symptoms in schizophrenia.
TAK 831 is an oral, highly selective and potent DAAO inhibitor that is undergoing phase-II testing for the treatment of negative symptoms in schizophrenia. 82 In this 12-week, placebo-controlled trial, three different doses (50 mg/day, 125 mg/day, 500 mg/day) are tested using the PANSS negative symptoms factor score as the primary outcome.

Cognitive impairment
Since the negative results for encenicline, an alpha-7 nicotinic acetylcholine receptor agonist for cognition, in schizophrenia, 83 activity in this area has slowed down considerably. Since glycine is involved in glutamatergic NMDA transmission, which seems to be relevant for both negative and cognitive symptoms in schizophrenia, 84 GLYT-1 agonists may also improve cognitive dysfunction.

BI-425809
BI 425809 is a GLYT-1 inhibitor that was well tolerated in a phase-1 study in healthy male volunteers, displaying an adverse event profile suggestive of GLYT1-inhibiting effects. 85 BI 425809 is currently undergoing phase 2 testing for cognitive dysfunction in schizophrenia. 86 In this 12-week, placebo-controlled study, four doses of once daily oral BI 425809 are evaluated for their effect on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) total score, with everyday functional capacity, measured by Schizophrenia Cognition Rating Scale (SCoRS), being the key secondary outcome. 86 Another 12-week, phase-II, placebo-controlled proof of concept study with the same outcomes is being planned that aims to explore the effect of oral once daily BI 425809 on cognition administration in patients with schizophrenia on stable antipsychotic treatment and adjunctive computerized cognitive training. 87 Cannabidiol Cannabidiol has also been investigated for the treatment of cognitive dysfunction in schizophrenia. In a 6-week, randomized, placebo-controlled, fixed-dose study targeting cognition, oral cannabidiol (600 mg/day) added on to background antipsychotics was not superior to placebo in 36 stable chronic schizophrenia patients on either the MATRICS CCB or the PANSS total score (Table 3). 88 Similarly, in another 6-week study of 88 patients with schizophrenia focusing on total PANSS that separated on positive symptoms and CGI-I and CGI-S, there was no significant benefit of adjunctive cannabidiol (1000 mg/day) for the secondary outcome of cognition measured with the Brief Assessment of Cognition in Schizophrenia. 46

Residual and treatment-resistant positive symptoms
Residual and refractory symptoms of schizophrenia remain a major unmet need in schizophrenia. Only clozapine is indicated for this indication, and few agents are being studied in this area.

LuAF-35700
LuAF-35700 is a D 1 -preferring D 1 and D 2 antagonistic investigational antipsychotic agent that is also an antagonist at serotonin 5-HT 2A and 5-HT 6   Positive study: Roluperidone was significantly superior to placebo on the PANSS negative factor score (pentagonal structure model). In addition, positive results were reported for secondary outcomes (PANSS negative, total and activation factor score, CGI-S, and BNSS). No difference in PANSS positive or depression scores.   affinity. Due to its relatively lower dopamine D 2 occupancy, it is expected to have less antidopaminergic-related adverse effects, including EPS, prolactin elevation, dysphoria or anhedonia, and depressed mood, than most currently available antipsychotics. The FDA granted fasttrack designation for LuAF-35700 in November 2015.
Currently, this novel antipsychotic is in phase-III of its clinical development, evaluating two doses (10 mg/day and 20 mg/day) in the Daybreak 89 and one dose (10 mg/day) in the ANEW 90 study programs.
In the DAYBREAK study, 1098 patients who had failed at least one prior well-documented antipsychotic treatment trial without satisfactory clinical improvement were enrolled and underwent a single-blinded, prospective, 6-week treatment period with either risperidone (4-6 mg/day) or olanzapine (15-20 mg/day) to confirm antipsychotic treatment resistance. Those failing to adequately respond to prospective treatment with risperidone or olanzapine were randomized to either stay on this treatment or switch to LuAF-35700 for another 10 weeks. In a press release from on October 25, 2018, Lundbeck announced that in the DAYBREAK study LuAF-35700 was not superior, but as effective as olanzapine or risperidone for treatment-resistant patients ( Table 4). The drug was well tolerated and safe at both doses. 91 Due to these results, the ANEW was terminated that had a similar design, except for evaluating a single dose of 10 mg/day of LuAF-35700 vs. placebo and for stratifying randomization for treatment-resistant schizophrenia developing either within the first 5 years or after 10 years of the illness. Final results in a relatively small number of randomized patients are currently awaited.

Pimavanserin
Since a first augmentation study of risperidone with pimavanserin had shown that enhancing 5-HT 2A receptor blockade by adding pimavanserin to a sub-effective risperidone dose provided faster onset of action, and at endpoint, equal efficacy and better safety, compared to standard dose risperidone, while reducing EPS, 75 a program for schizophrenia patients with suboptimal positive symptom response was initiated.
The recently completed ENHANCE-1 study is a phase-III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of adjunctive pimavanserin for the treatment of schizophrenia with residual positive symptoms. 92 This international, 6-week study (n = 396, mean age = 37.2 years) compared pimavanserin (starting dose 20 mg, with adjustments possible to 34 mg or 10 mg) plus background antipsychotic vs placebo plus background antipsychotic (risperidone = 39.1%, olanzapine = 35.7%, aripiprazole = 21.3%). 93 Despite numerical advantages, pimavanserin augmentation missed statistical separation from placebo for the primary outcome, PANSSS total score (p = 0.0940). A positive trend was also observed on the key secondary endpoint, the CGI-S score (p = 0.0543). In a pre-specified subgroup analysis by region, significant separation from placebo was seen in the European sites (>80% of the sample) both for the PANSS total score (unadjusted p = 0.0234), and the CGI-S score (unadjusted p = 0.0214). Furthermore, in the entire sample, pimavanserin reduced negative symptoms significantly more than placebo, both regarding the PANSS negative symptoms scale sub-score (unadjusted p = 0.0474) and the PANSS Marder negative factor score (unadjusted p = 0.0362).
Approximately 88% of pimavanserin and 96% of placebo patients completed the study. Additionally, pimavanserin was well-tolerated with low and similar rates of adverse events in the adjunctive pimavanserin (40.4%) and adjunctive placebo (36.9%) groups. Adverse events reported in at least 5% of patients in the pimavanserin group included headache, somnolence, and insomnia. Discontinuations due to adverse effects were low, being 2.5% for pimavanserin vs. 0% for placebo. 93

Sodium benzoate
Not only dopaminergic hyperactivity but also NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia, possibly especially in patients resistant to treatment with dopamine antagonizing agents. 32 In addition to NMDA partial or full agonists, NMDA functioning can be increased by raising d-amino acid levels via blockade of their metabolism. Sodium benzoate, a DAAO inhibitor and common food preservative, has this mechanism. In two placebo-controlled trials, sodium benzoate had beneficial efficacy and acceptable tolerability. 94,95 In the first randomized, double-blind, placebocontrolled trial, 95 52 patients with chronic schizophrenia stabilized with antipsychotics for ≥3 months were randomized to 6 weeks of add-on treatment of 1 g/day of sodium benzoate vs. placebo. Sodium benzoate produced a 21% improvement in PANSS total score, and with large effect sizes (range = 1.16-1.69). Sodium benzoate was significantly superior to placebo in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression. In addition, neurocognition subtests improved significantly, including the domains of processing speed and visual learning (Table 4). Sodium benzoate was well tolerated without significant adverse effects.
In the second randomized, double-blind, placebocontrolled trial, 94 60 inpatients with schizophrenia stabilized with clozapine were randomized to 6 weeks of add-     on treatment with 1 g/day sodium benzoate, 2 g/day sodium benzoate, or placebo. At 6 weeks, 2 g/day sodium benzoate was associated with significantly greater improvement than placebo in PANSS total score, PANSS positive subscore, and Quality of Life Scale. Furthermore, both the 1 mg/day and 2 mg/day sodium benzoate were associated with significantly greater improvement in the Scale for the Assessment of Negative Symptoms vs. placebo (Table 4). Sodium benzoate was well tolerated without relevant adverse effects. Furthermore, as an indication of the mechanism involved in the significant results, changes of the antioxidant catalase differed among the three groups and were correlated with the improvement of PANSS total score and PANSS positive score in the sodium benzoate group.

Agents targeting antipsychotic non-adherence
Non-adherence remains a serious issue with schizophrenia as with many other psychiatric and medical disorders. 36 Although several second-generation LAIs have been approved, 96 several have required oral cotreatment for several weeks until therapeutic antipsychotic levels have been reached. Moreover, historically, all LAIs were injected deep intramuscularly. Four innovative LAI formulations have been developed to avoid the need for loading or booster injections and/or oral cotreatment. Furthermore, two LAI formulations have received recent FDA approval, one being the first subcutaneously injected LAI.

Aristada Initio)
Aripiprazole lauroxil (AL) (Aristada ® ) is an extendedrelease, intramuscular long-acting injectable (LAI) aripiprazole prodrug with high dosage and considerable dosing interval flexibility (441, 662, and 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 8 weeks). However, due to being a prodrug and slow release, therapeutic drug levels are achieved only gradually, so that oral aripiprazole supplementation for 21 consecutive days is required after the first intramuscular injection. In order to achieve faster efficacy and significantly shorten or eliminate oral supplementation during the initiation phase, a 1-day intramuscular initiation regimen for aripiprazole lauroxil (Aristada Initio™) was approved by the FDA on July 2, 2018. 97 The single injection comprises the same prodrug used in aripiprazole lauroxil but with smaller particles, known as the nanocrystalline milled dispersion of aripiprazole lauroxil. The smaller nanoparticle size enables faster dissolution of aripiprazole lauroxil, resulting in faster release of aripiprazole into plasma. 98 Simultaneous administration of the 1day initiation regimen with all approved aripiprazole lauroxil dosing regimens is predicted to achieve the correct blood levels within 4 days. 99 A recent phase-III, double-blind, placebo-controlled study compared a 1-day initiation regimen with the 21-day oral coverage regimen. Patients (n = 161) randomized to the 1-day initiation regimen received a 675 mg injection of aripiprazole lauroxil NanoCrystal ® Dispersion (AL NCD ), a single 30 mg oral aripiprazole tablet, and then an aripiprazole lauroxil injection (441 mg or 882 mg). Subjects randomized to the 21-day oral coverage regimen received 15 mg oral aripiprazole and an aripiprazole lauroxil injection (441 mg or 882 mg) on day 1, followed by 20 days of 15 mg oral aripiprazole. The 1-day regimen groups had comparable aripiprazole exposure to the corresponding 21-day groups ( Table 5). The most common side effects were injection pain, headache, weight gain, insomnia, dyspepsia, and anxiety in both therapies. 100 Therefore, aripiprazole lauroxil NCD Technology can offer an alternative aripiprazole lauroxil initiation regimen that ensures therapeutic aripiprazole levels during the first 21 days of treatment 100 and has a comparably side effect profile, faster efficacy, and might positively affect adherence due to a very minimized (1 day) oral supplementation.

Paliperidone 6-monthly formulation
After developing a once-monthly and a 3-monthly intramuscular injectable formulation of paliperidone, 101 Janssen is currently conducting phase III trial for a 6-monthly formulation of paliperidone palmitate. Results are still outstanding.

Perseris™ risperidone for subcutaneous injection (RBP-7000)
Risperidone has been available since 1993 to treat schizophrenia and bipolar disorders. Risperidone blocks serotonergic 5-HT 2A and dopaminergic D 2 receptors with greater affinity to the 5-HT 2A receptor. In addition, there is a much less affinity to other receptors such as alpha-1-and alpha-2-adrenergic receptors as well as H1-histaminergic receptors. 102 Up until 2018, risperidone LAI was only available in a microsphere formulation that had to be injected deep intramuscularly every 2 weeks and that required a 21-day oral risperidone supplementation phase at the initiation of risperidone microsphere treatment. 96 RBP-7000 (Perseris™) is a recently (July 27, 2018) FDA-approved subcutaneous LAI formulation of risperidone 103 that requires no oral supplementation and is the first antipsychotic available as a subcutaneously (intraabdominally) administered LAI. 104 The once monthly injected depot formulation uses the ATRIGEL© administration system. After injection, the delivery system solidifies upon contact with bodily fluids, and the  resulting biodegradable implant delivers the drug for a longer period depending on the dose strength and the injection volume. 105 Pharmacokinetic population analyses reported optimized occupancy of the dopamine D 2 receptor for RBP-7000 after repeated doses of 90 mg/day and 120 mg/day and a potentially improved side effect profile compared to oral risperidone. 106,107 An 8-week, pivotal phase-III double-blind, placebo-controlled trial in acutely exacerbated patients with schizophrenia demonstrated the efficacy, safety, and tolerability of RBP-7000 (90 mg/day and 120 mg/day). [108][109][110] Common treatment-related side effects were injection site pain, headache, sedation/ somnolence, and weight gain. Mean subject-reported injection site pain, as measured by the Visual Analog Scale scores (0 = no pain to 100 = unbearably painful), was similar in all treatment groups following both injections, with pain scores decreasing from a mean of 27 at 1 min after the first dose to a range of 3-7 at 30-60 min postdose. Moreover, de novo patients were recruited, and completers from the double-blind placebo-controlled study were transferred to a 1-year open-label study in which they received monthly injections of RBP-7000 (120 mg/day). In general, the safety achieved with 12 monthly injections of RBP-7000 was comparable to that of oral risperidone (Table 5). In addition, symptoms continued to improve in completers of the placebo-controlled trial who moved on to the long-term study. 111 RBP-7000 has fast efficacy without the need for loading or booster injections or oral cotreatment and the subcutaneous injection route, which is hoped to be associated with less injection pain improved convenience, acceptance, and adherence. However, like risperidone microspheres, RBP-7000 needs to be refrigerated; furthermore, it needs to be reconstituted, and a large bore needle (18 G 5/8-inch length needle) is required for the subcutaneous intrabdominal injection. 104 Risperidone extended release for subcutaneous injection (TV-46000) Currently, risperidone extended release (TV-46000) is being studied in different dose regimens administered subcutaneously in patients with schizophrenia aged 13-65 years. One placebo-controlled study evaluates the efficacy, safety, and tolerability of two dose regimens of TV-46000 as relapse prevention treatment of patients who are clinically stabilized and eligible for risperidone treatment. 112 One TV-46000 dose-controlled study evaluates the long-term safety and tolerability of two dose regimens and will last up to 80 weeks (including a 4-week screening period, 12-week oral conversion/stabilization stage, 56-week double-blind maintenance stage, and 8week follow-up period). 113 Results are expected in the middle or end of 2020.

Risperidone ISM ® or Doria ®
Recently, positive topline results of the PRISMA-3 trial, a multicenter, randomized, placebo-controlled phase-III study of once-monthly intramuscular Doria ® or Risperidone ISM ® , were announced. 114 ISM ® is a technology for the release of drugs that is based on the in-situ formation of biodegradable matrices after the administration of a liquid carrier. Due to its special characteristics, therapeutic antipsychotic blood levels are achieved without requirement of initial oral antipsychotic coadministration or initial loading or booster injections. In the PRISMA-3 study 115 of 438 acutely exacerbated patients with schizophrenia, once-monthly injections of 75 mg and 100 mg of Risperidone ISM ® each showed statistically significant improvement (p < .0001) vs. placebo injections in the total score of the PANSS as well as in the CGI-Severity scale at 12 weeks, the pre-specified primary and key secondary efficacy endpoints (Table 5). 114 A long-term, open label study that evaluates the safety, tolerability, and durability of the long-term effects of Risperidone ISM ® is under way.

Amelioration of antipsychotic-related adverse effects
The recent FDA approval of the vesicular monoamine transporter-2 (VMAT-2) inhibitors valbenazine and deutetrabenazine for the effective amelioration of tardive dyskinesia associated with antidopaminergic medications in schizophrenia 116 was the first indication of a novel mechanism molecule specifically for the management of an adverse effect of antipsychotic medications. Currently, ALKS3831 is under study to ameliorate weight gain associated with olanzapine treatment.

Olanzapine-related weight gain
Most currently available antipsychotics are associated with considerable weight gain and cardiometabolic adverse effects. 22,23,117 These adverse effects are relevant for cardiovascular morbidity and mortality, 27 and are especially prominent early on in treatment and especially with clozapine and olanzapine. [118][119][120] Since both clozapine and olanzapine have been associated with efficacy advantages, 120,121 mitigating the weight gain and/or metabolic burden is of high clinical importance.

Fixed-dose combination of olanzapine and samidorphan (ALKS3831)
Samidorphan is an opioid antagonist, which originally has been investigated for the treatment of addiction and which is now examined for its mitigating or preventing effect of olanzapine-induced weight gain. Samidorphan (ALKS33) binds with high affinity to human μ-, k-, and ∂-opioid receptors and functionally acts as an μ-opioid receptor antagonist with low intrinsic activity at k-and KEEPING UP WITH THE THERAPEUTIC ADVANCES IN SCHIZOPHRENIA  ∂-opioid receptors. 122 By blocking opioid receptors involved in the brain reward pathway augmentation is decreased and cravings are reduced. 123 Results of a phase-I trial in healthy volunteers indicated that combining olanzapine with samidorphan (ALKS3831) did not affect the pharmacokinetic profile of either drug. 124 Similarly, in a phase-I proof of concept study in healthy volunteers, samidorphan in combination with olanzapine was associated significantly with less weight gain than olanzapine alone. 123 In recent studies, the combination drug ALKS3831 has been investigated, comprising a flexible dose of olanzapine and a fixed dose (10 mg/day) of samidorphan.
Results of a 12-week, phase-II trial (ENLIGHTEN-1) suggested mitigating effects of ALKS3831 on olanzapineinduced weight gain in schizophrenia patients across all dose-ranges of olanzapine, with equivalent efficacy to olanzapine and with a similar safety profile, except for significantly less weight gain. 125 This study had a 1-week open-label olanzapine lead-in period, which was followed by 12 weeks of double-blind treatment with olanzapine plus placebo (n = 75) or olanzapine plus 5 mg (n = 80), 10 mg (n = 86), or 20 mg (n = 68) of samidorphan. Treatment with ALKS3831 was associated with statistically significant lower weight gain (37% lower weight gain vs. olanzapine plus placebo) ( Table 5). Adverse events reported at a frequency ≥5% in any of the ALSK3831 groups and occurring at least two times more frequently than with olanzapine plus placebo included somnolence, sedation, dizziness, and constipation. Since all patients received a 1-week olanzapine monotherapy run-in treatment and since olanzapine alters metabolic glucose and lipid parameters within a week, this study was not designed to assess metabolic effects of ALKS 3831.
These positive results have recently been replicated in a 6-month study (ENLIGHTEN-2) where ALKS-3831 was associated with statistically significant advantages over olanzapine plus placebo for both primary endpoints, percentage change in body weight at 6 months and proportion of patients gaining ≥10%, as well as for the key secondary endpoint, the proportion of patients gaining ≥7%. 126 At 6 months, weight increased with ALKS3831 (n=266) by 4.21% vs. 6.59% with olanzapine (n=272), translating into a 57% lower mean percent weight change (p=0.003). Similarly, weight gain ≥10% ALKS3831 occurred in 17.8% with ALKS 3831 vs. 29.8% for olanzapine (p = .003, number-needed-to-treat (NNT)=9). Finally, weight gain ≥7% ALKS3831 occurred in 27.5% with ALKS 3831 vs. 42.7% with olanzapine (Table 5). For weight gain ≥2%, ≥5%, and ≥15% at six months, similar results were observed, each favoring ALKS3831. In the ENLIGHTEN-2 study, there was no significant difference between ALKS3831 and olanzapine at the end of 6 months in any of the investigated glucose and lipid metabolism parameters. However, somewhat surprisingly, the mean increases in fasting glucose, insulin, HbA1C and lipids were relatively small, which may have reduced the power to differentiate ALKS 3831 from Olanzapine. The most common adverse events with ALKS3831 were weight gain, somnolence, and dry mouth; the most common adverse events with olanzapine were weight gain, somnolence, and increased appetite. 127 Finally, in a 4-week, phase-III, randomized, doubleblind active (olanzapine monotherapy) and placebocontrolled trial in patients experiencing acute exacerbation of schizophrenia, ALKS3831 was investigated to demonstrate that addition of the centrally active samidorphan to olanzapine in ALKS3831 does not reduce olanzapine's efficacy. This study showed superior antipsychotic efficacy of ALKS3831 compared to placebo, with almost identical efficacy as olanzapine monotherapy (Table 5). 128 ALKS3831 was generally well tolerated, with a safety profile similar to olanzapine. Adverse events leading to study discontinuation included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia. In this short, 4-week study, body weight gain was not dissimilar between olanzapine and ALKS3831. Nevertheless, the results must be seen within the study's limitations, including baseline difference between groups with regard to BMI, the acute nature of the study population, inpatient treatment, and a short duration of the trial, making it difficult to compare weight gain between the three groups, as ALKS3831 is known to exert its weight gain mitigating effect only after 3 weeks of treatment. 128 Overall, ALKS 3831 has proven to be effective in the treatment of schizophrenia and has been associated with significantly less olanzapine-induced weight gain. 128 Questions still remain regarding the potential of ALKS3831 to also mitigate olanzapine's adverse effects on glucose and lipid parameters, and on oxidative stress and inflammation that are generally associated with significant body weight gain.

Summary and Conclusion
This targeted and selective review (i) differentiated the mechanisms of action of new and emerging antipsychotics and medications with novel mechanisms targeting total, positive, negative, and cognitive symptoms of schizophrenia, as well as residual and treatment-resistant positive symptoms, non-adherence, and olanzapinerelated weight gain, and (ii) evaluated the latest clinical data on these agents inasmuch as these are already available. Successful phase-III and/or phase-II trial programs have included (i) new formulations of aripiprazole lauroxil LAI and risperidone LAI that have been able to avoid the need for oral cotreatment, as well as, in the case of the two risperidone LAI formulations, loading/booster injections in the initial phases of LAI treatment, 100,111,114 leading to FDA approval of Aripiprazole Lauroxil NanoCrystal ® Dispersion (AL NCD ; Aristada Initio) and once-monthly subcutaneously injected Perseris™ Risperidone (RBP-7000); (ii) the treatment of acutely exacerbated schizophrenia with lumateperone, a novel antipsychotic modulating dopamine, serotonin and, via D 1 agonism, glutamatergic transmission 50 that is currently being evaluated by the FDA for approval for acutely exacerbated schizophrenia, and (iii) the combination of samidorphan plus olanzapine in one pill for the reduction of body weight gain with ALKS3831 at 3 and 6 months, 123,125,126 while maintaining olanzapine's efficacy. 124,127,128 The other selectively reviewed agents have had either suggestive or mixed or, even, negative findings, or are at different stages of phase-II or phase-III development for different symptom domains of schizophrenia. Suggestive and encouraging results exist for monotherapy with roluperidone (MIN-101) for negative symptoms, 78 and the TAAR1 agonist SEP-363856, 71 D 3 antagonist/5HT 1A partial agonist F17464, cannabidiol, and sodium benzoate for total psychotic symptoms. Negative findings have been reported for total symptom reduction with PDE10A inhibitors (e.g., MK-8189 and TAK-063) and sodium nitroprusside given adjunctively with background antipsychotics in acutely/severely ill patients, for cannabidiol targeting cognitive dysfunction in schizophrenia, and for monotherapy with the D 1 -preferring D 1 /D 2 -antagonist LuAF-35700 for treatment-resistant schizophrenia. The pimavanserin trial for residual positive symptoms was negative for the primary and key secondary outcome in the overall sample, but showed significant separation from placebo in the prespecified regional analysis of the European sites that had enrolled >80% of the sample, and showed significant separation from placebo for negative symptoms in the overall analysis set. 93 Relevant data are expected soon for pimavanserin augmentation of antipsychotics for predominant negative symptoms. Trials are under way, but in the early stages for the DAAO inhibitor TAK-831 given adjunctively with antipsychotics and the phosphodiesterase 10A inhibitor LuAF-11167 in monotherapy for negative symptoms, as well as the GLYT-1 inhibitor BI-425809 targeting cognitive dysfunction in schizophrenia.
Of note, the findings of lumateperone showing that the lower 40 mg dose was significantly superior to placebo for positive symptoms and CGI-S, but not for total symptoms, 50 suggest that in future studies of novel agents that have minimal adverse effects, the broad-spectrum endpoint of total PANSS may be better exchanged for the more specific PANSS positive subscale when targeting the reduction of psychotic symptoms.
Interestingly, since dopamine blockade of background antipsychotic treatment may possibly interfere with the efficacy of novel, non-dopamine receptor targeting agents that focus on the improvement of negative symptoms, two trial programs attempt the testing of monotherapy of a non-dopaminergic mechanism molecular entity. These include the phase-II -PDE-10 inhibitor LuAF-11167 trial program 74 and the 5HT2 A /sigma 2 antagonist roluperidone (MIN-1010). 78 While data from the ongoing phase-II PDE10A inhibitor LuAF-11167 trial program are not available, roluperidone has already shown in one phase-II trial superiority vs. placebo for negative symptoms. 78 Although this superiority did not seem to have been accompanied by too many psychotic exacerbations (surprisingly both in the roluperidone and in the placebo arm), despite withdrawal of the antipsychotic for the 3-month study period (plus an up to 4week washout period), concern remains as to the safety of both roluperidone and LuAF-11167 that may not be sufficiently antipsychotic in and of themselves to protect patients from a psychotic relapse. It will be important to observe longer-term data with each of these agents and to identify characteristics of patients with relevant levels of negative symptoms who could possibly be sufficiently stable to be switched safely to a non-dopamine targeting novel agent. These studies will need to prove that, in fact, such non-dopamine modulating agents can improve negative symptoms while maintaining positive symptom stability, despite the removal of the prior dopamine modulating antipsychotic agent that at one point was needed to reduce schizophrenia symptoms.
Even 66 years after the serendipitous discovery of chlorpromazine as the first "antipsychotic" agent, the most challenging issue in the pharmacological management of this complex and multifactorial disorder is the need for increased efficacy, reduced side effects, and exploring novel approaches to effectively treat negative symptoms, cognitive dysfunction, and residual/treatment-resistant positive symptoms, which currently remain the biggest gaps in the management of schizophrenia. 130 Although emerging data exist, results from important trial programs are still outstanding and further highquality trials are required to evaluate the efficacy and tolerability of novel pharmacological approaches to the management of different domains of schizophrenia. Unfortunately, to date, only limited progress has been made in the exploration of novel psychopharmacological treatment targets for schizophrenia that go beyond the D 2 hypothesis. Therefore, the need for novel treatment approaches, which target the entire range of complex symptoms in schizophrenia, remains urgent. Nevertheless, part of the limited success for the search of novel treatments for schizophrenia remains the limited understanding of the pathophysiology of schizophrenia. 1 Therefore, a better understanding of pathophysiological mechanism and biomarkers is indispensable to ensure improved drug development for schizophrenia.