Advertisement

ITI-007 for the Treatment of Schizophrenia: A 4-Week Randomized, Double-Blind, Controlled Trial

Open AccessPublished:August 31, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.08.026

      Abstract

      Background

      An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues. ITI-007 is a new molecular entity with a pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins.

      Methods

      A phase II randomized, double-blind, placebo-controlled, and active-controlled trial was conducted at eight sites in the United States with randomization of 335 acutely psychotic adults with schizophrenia. ITI-007 (60 mg and 120 mg), placebo, and risperidone, included for assay sensitivity, were evaluated as monotherapy for 4 weeks. The primary outcome measure was the Positive and Negative Syndrome Scale total score, with secondary analyses conducted on symptom subscales.

      Results

      ITI-007 60 mg (p = .017, effect size = .4) and risperidone (p = .013, effect size = .4) demonstrated antipsychotic efficacy superiority over placebo on the primary end point. The results of secondary analyses reflected improvements in negative and depressive symptoms by ITI-007 60 mg. ITI-007 120 mg did not separate from placebo. However, both doses of ITI-007 were well tolerated in this patient population, as evidenced by low discontinuation and adverse event rates, and were associated with a benign metabolic profile as evidenced by significantly lower levels of prolactin, fasting glucose, total cholesterol, and triglycerides than risperidone.

      Conclusions

      The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial. Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have expanded therapeutic efficacy in comparison with current antipsychotic drugs.

      Keywords

      Schizophrenia is a debilitating psychotic illness that affects approximately 1% of the population. Current antipsychotic drugs (APDs) have therapeutic effects in patients with schizophrenia predominantly against positive symptoms, such as hallucinations and delusions (
      • Kane J.M.
      • Correll C.U.
      Past and present progress in the pharmacologic treatment of schizophrenia.
      ), but leave most individuals with significant residual symptoms, diminished quality of life, and enduring functional impairment (
      • Vos T.
      • Flaxman A.D.
      • Naghavi M.
      • Lozano R.
      • Michaud C.
      • Ezzati M.
      • et al.
      Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010.
      ). Treatment early in the course of the disease and psychosocial support may improve outcome, but treatment options remain limited.
      Most APDs show only modest effectiveness, if any, in treating the nonpsychotic symptoms of schizophrenia that are believed to be responsible for the poor social and academic/vocational functioning characteristics of the illness, including social withdrawal, flattened affect, depression, and cognitive impairment (
      • Millan M.J.
      • Fone K.
      • Steckler T.
      • Horan W.P.
      Negative symptoms of schizophrenia: Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment.
      ). Additionally, all currently used APDs exhibit clinically significant side effects of varying types and severity. So-called first-generation APDs are commonly associated with extrapyramidal side effects (EPS) such as bradykinesia, rigidity, akathisia, tremor, and tardive dyskinesia, while many second-generation, or atypical, APDs frequently lead to weight gain and metabolic alterations such as hyperglycemia, insulin resistance, and dyslipidemia (
      • De Hert M.
      • Detraux J.
      • van Winkel R.
      • Yu W.
      • Correll C.U.
      Metabolic and cardiovascular adverse effects associated with antipsychotic drugs.
      ). Clozapine is arguably the most efficacious APD, yet is among the most prone to the aforementioned metabolic disturbances. It is also associated with an increased incidence of seizures and potentially lethal side effects of agranulocytosis and myocarditis (
      • Nielsen J.
      • Correll C.U.
      • Manu P.
      • Kane J.M.
      Termination of clozapine treatment due to medical reasons: When is it warranted and how can it be avoided?.
      ). Consequently, there is tremendous unmet medical need for safer treatments that are more effective and have a broader spectrum of efficacy across multiple symptom domains.
      ITI-007 is a new molecular entity with a unique pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins (
      • Li P.
      • Zhang Q.
      • Robichaud A.J.
      • Lee T.
      • Tomesch J.
      • Yao W.
      • et al.
      Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders.
      ). While it interacts with several targets that are common to some existing APDs, its full actions are complex and unique (
      • Snyder G.L.
      • Vanover K.E.
      • Zhu H.
      • Miller D.B.
      • O’Callaghan J.P.
      • Tomesch J.
      • et al.
      Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.
      ). ITI-007 is a high-affinity serotonin 2A (5-HT2A) receptor antagonist with lower, but clinically relevant, affinity for other neurobiological targets, including D2 receptors. While 5-HT2A receptor antagonism in addition to D2 receptor antagonism has been the hallmark of atypical APDs (
      • Meltzer H.Y.
      • Matsubara S.
      • Lee J.C.
      Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values.
      ), ITI-007 has a wider separation (sixtyfold) between its affinity for 5-HT2A receptors and D2 receptors than other APDs, allowing full saturation of 5-HT2A receptors, even at modest levels of dopamine receptor occupancies (
      • Snyder G.L.
      • Vanover K.E.
      • Zhu H.
      • Miller D.B.
      • O’Callaghan J.P.
      • Tomesch J.
      • et al.
      Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.
      ). Moreover, unlike most other antipsychotics that are antagonists at D2 receptors both presynaptically and postsynaptically and unlike aripiprazole and related compounds that are partial agonists at D2 receptors both presynaptically and postsynaptically, ITI-007 interacts with dopamine receptors in a unique way. At D2 receptors, ITI-007 is a presynaptic partial agonist and postsynaptic antagonist with functional mesolimbic/mesocortical selectivity (
      • Snyder G.L.
      • Vanover K.E.
      • Zhu H.
      • Miller D.B.
      • O’Callaghan J.P.
      • Tomesch J.
      • et al.
      Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.
      ). This allows for functional blockade of dopamine without increasing dopamine turnover and corresponds to antipsychotic efficacy without motor side effects (
      • Snyder G.L.
      • Vanover K.E.
      • Zhu H.
      • Miller D.B.
      • O’Callaghan J.P.
      • Tomesch J.
      • et al.
      Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.
      ). Above and beyond 5-HT2A and D2 receptor interactions, ITI-007 increases phosphorylation of mesolimbic GluN2B subunits of N-methyl-D-aspartate (NMDA) receptors (
      • Snyder G.L.
      • Vanover K.E.
      • Zhu H.
      • Miller D.B.
      • O’Callaghan J.P.
      • Tomesch J.
      • et al.
      Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.
      ). An increase in GluN2B increases synaptic NMDA activity via subcellular trafficking to plasma membranes (
      • Goebel-Goody S.M.
      • Davies K.D.
      • Alvestad Linger RM
      • Freund RK
      • Browning MD
      Phospho-regulation of synaptic and extrasynaptic N-methyl-d-aspartate receptors in adult hippocampal slices.
      ). To the extent that a deficit in glutamatergic function contributes to schizophrenia symptoms (
      • Laruelle M.
      • Frankle W.G.
      • Narendran R.
      • Kegeles L.S.
      • Abi-Dargham A.
      Mechanism of action of antipsychotic drugs: From dopamine D(2) receptor antagonism to glutamate NMDA facilitation.
      ,
      • Javitt D.C.
      Glutamate and schizophrenia: Phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions.
      ), indirect enhancement of glutamatergic NMDA function is predicted to reduce psychosis and improve cognitive function and negative symptoms. Although investigational therapeutics targeted solely at direct interaction with glutamate receptors or glycine transporters have not successfully translated into clear clinical benefit, it is recognized that the interaction between glutamate and dopamine modulation is important in schizophrenia (
      • Schwartz T.L.
      • Sachdeva S.
      • Stahl S.M.
      Glutamate neurocircuitry: Theoretical underpinnings in schizophrenia.
      ). At serotonin transporters, ITI-007 inhibits the serotonin transporter (
      • Snyder G.L.
      • Vanover K.E.
      • Zhu H.
      • Miller D.B.
      • O’Callaghan J.P.
      • Tomesch J.
      • et al.
      Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.
      ), an effect associated with many antidepressant drugs (
      • Meyer J.H.
      Imaging the serotonin transporter during major depressive disorder and antidepressant treatment.
      ). ITI-007 lacks significant activity at many receptors (e.g., H1, muscarinic, serotonin 2C) that are associated with deleterious effects experienced with many other APDs (i.e., clinically significant sleep induction, cognitive impairment, weight gain). Thus, by acting through serotonergic, dopaminergic, and glutamatergic signaling systems in a mechanistically and neuroanatomically selective manner, ITI-007 represents a novel approach to the treatment of schizophrenia and other neuropsychiatric disorders.
      This study evaluated the efficacy of ITI-007 in schizophrenia patients and included secondary outcomes of positive, negative, and depressive symptoms and symptoms associated with social function. We hypothesized that based on its pharmacologic profile and preliminary data that ITI-007 would be an effective APD with efficacy across a broader range of symptoms in patients presenting with an acute exacerbation of schizophrenia and excellent tolerability as compared with placebo and risperidone (one of the most commonly prescribed APDs).

      Methods and Materials

      Study Design

      This was a randomized, double-blind, placebo- and active-controlled, multicenter phase II clinical trial (ITI-007-005) conducted at eight sites in the United States from December 2011 to November 2013. Subjects (n = 335) were randomized in a 1:1:1:1 ratio across parallel groups to receive ITI-007 (60 mg, 120 mg), placebo, or risperidone (4 mg) as oral monotherapy once daily in the morning for 4 weeks. Individuals randomized to 120 mg ITI-007 or risperidone received a single day dose titration (60 mg to 120 mg ITI-007 on day 2; 2 mg to 4 mg risperidone on day 2); 60 mg ITI-007 required no dose titration. Doses of 60 mg and 120 mg ITI-007 were selected based on estimated striatal D2 receptor occupancy of approximately 50% and 70%, respectively, modeled from the D2 receptor occupancies determined in a positron emission tomography study at lower doses in healthy volunteers (
      • Davis R.E.
      • Vanover K.E.
      • Zhou Y.
      • Brasic J.R.
      • Guevara M.
      • Bisuna B.
      • et al.
      ITI-007 demonstrates brain occupancy at serotonin 5-HT and dopamine D receptors and serotonin transporters using positron emission tomography in healthy volunteers.
      ). A dose of risperidone of 4 mg was selected as a positive control for assay sensitivity based on its mean modal effective dose determined by the Clinical Antipsychotic Trials of Intervention Effectiveness (
      • Lieberman J.A.
      • Stroup T.S.
      • McEvoy J.P.
      • Swartz M.S.
      • Rosenheck R.A.
      • Perkins D.O.
      • et al.
      Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
      ) and its well-characterized efficacy and safety profile as one of the most prescribed antipsychotics in the United States. The risperidone dose and titration schedule are also within the recommendations of the US Food and Drug Administration approved label for this drug. Assignment of a randomization number across the study was via an automated central randomization and trial supply management system using a computer-generated sequence. The randomization assigned a numbered kit containing visually matched capsules to keep subjects, clinical site staff, and study oversight team blinded.

      Participants

      Patients, 18 to 55 years of age, with a diagnosis of schizophrenia confirmed by a Structured Clinical Interview for DSM Disorders–Clinical Trials Version (
      • First M.B.
      • Williams J.B.W.
      • Spitzer R.L.
      • Gibbon M.
      Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Clinical Trials Version (SCID-CT)..
      ) were eligible for participation if experiencing an acute exacerbation of psychosis defined as a score of ≥40 on the 18-item Brief Psychiatric Rating Scale (item range 1–7) with a score of ≥4 on ≥2 of the positive symptom items: suspiciousness, conceptual disorganization, hallucinatory behavior, or unusual thought content. The current acute episode was required to have started within 4 weeks of screening with an independent informant verifying that symptom severity represented an acute exacerbation for a given individual. Individuals were required to have shown previous treatment response to APD therapy and thus be neither treatment-naïve nor treatment-resistant. Diagnosis and symptom severity at screening were rated by study investigators and confirmed by independent psychiatrists or clinical psychologists to ensure inclusion of an appropriate patient population (Clintara LLC, Boston, Massachusetts) (
      • Targum S.D.
      • Pendergrass J.C.
      • Toner C.
      • Asgharnejad M.
      • Burch D.J.
      Audio-digital recordings used for independent confirmation of site-based MADRS interview scores.
      ). Patients who met any of the following exclusion criteria were not included in the study: unable to provide informed consent; pregnant/breastfeeding; dementia/delirium/mental retardation/epilepsy/drug-induced psychosis/brain trauma; schizoaffective disorder/bipolar disorder/acute mania/major depression with psychotic features; imminent danger to self or others; suicidal ideation/behavior; unstable living environment; use of depot antipsychotic within one treatment cycle before baseline; use of any APD within screening period; use of specific agents with known interaction with 5-HT2A receptors; clinically significant abnormal laboratory values or clinical findings; uncontrolled angina/recent history of myocardial infarction/clinically significant cardiac arrhythmia; hematological/renal/hepatic/endocrinological/neurological/cardiovascular disease; history of neuroleptic malignant syndrome; human immunodeficiency virus; hepatitis B or C with evidence of active liver disease; substance abuse/dependence; positive drug/alcohol screen; likely drug allergy/sensitivity; prior participation in a study with ITI-007 or recent exposure to any investigational product; unable to be safely discontinued from current antipsychotic or other psychotropic medications; and any patient judged by the investigator to be inappropriate for study participation.
      All candidates for the study with signed informed consent were admitted to an inpatient unit. Baseline efficacy measures were assessed on day 1, following the ≤7-day drug-free screening period and before randomization on day 1. Those who met eligibility criteria were randomized to treatment and maintained as inpatients throughout the 28-day treatment period. Following the treatment period, patients were stabilized on standard of care APDs for 5 days before discharge and returned to the clinic for a follow-up safety visit 2 weeks following the last dose of study medication.
      The study was conducted in compliance with the principles of the Good Clinical Practice guidelines of the Food and Drug Administration and International Conference on Harmonization. The protocol, informed consent document, and other study-specific materials were approved by a central Institutional Review Board. All subjects provided written informed consent before study-specific procedures were conducted. The study was completed as originally designed, without protocol amendment.

      Assessments

      Participating subjects underwent baseline and weekly assessment with the Positive and Negative Syndrome Scale (PANSS), a well-validated 30-item scale used to measure symptoms of schizophrenia (
      • Kay S.R.
      • Fiszbein A.
      • Opler L.A.
      The positive and negative syndrome scale (PANSS) for schizophrenia.
      ). Individuals were rated on this scale by remote central raters (MedAvante, Inc., Trenton, New Jersey) using audiovisual communication; central raters were mental health professionals trained to a high degree of interrater reliability and blinded to study design, treatment, and time point of assessment (
      • Sharp I.R.
      • Kobak K.A.
      • Osman D.A.
      The use of videoconferencing with patients with psychosis: A review of the literature.
      ). Calgary Depression Scale for Schizophrenia (CDSS) was used to assess symptoms of depression. Safety end points included assessment of adverse events, motor function (Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale), suicidal ideation and behavior (Columbia Suicide Severity Rating Scale), clinical laboratory assessments, vital signs, and electrocardiograms. The CDSS and safety scales were rated by site raters after receiving training for standardization across sites.

      Statistical Analysis

      The primary efficacy end point, defined a priori, was change from baseline to day 28 (or end point) on the PANSS total score. The primary treatment effect comparison was performed using a mixed-effect model repeated measures (MMRM) method, also defined a priori, with the Bonferroni correction applied to adjust for multiple comparisons; each comparison (60 mg ITI-007 vs. placebo; 120 mg ITI-007 vs. placebo) was tested at two-sided significance level α = .05. The treatment effect was analyzed using the MMRM method, including change from baseline to day 28 as the response variable and terms of treatment, baseline variable, time point (treated as a categorical variable), as well as interaction between treatment and time point. An unstructured covariance matrix was used to model the correlation among repeated measurements. The Kenward-Roger adjustments were used with restricted maximum likelihood to make proper statistical inferences. The primary analysis was conducted in the modified intent-to-treat (ITT) population, defined as having a valid baseline PANSS assessment and at least one valid postdose assessment. Determination of exclusion of subjects from the ITT population was made on blinded data before database lock. In addition, a sensitivity analysis, also defined a priori, was performed using analysis of covariance (ANCOVA) with last observation carried forward (LOCF) to assess the main effect of treatment, adjusted for baseline score. A responder analysis, defined a priori, calculated the percent of subjects with ≥30% reduction on PANSS total score (subtracting 30 from the PANSS score so that a complete response is represented by 100% decrease; p value computed using Cochran Mantel-Haenszel test).
      Secondary (post hoc) analyses included the PANSS subscales analyzed using ANCOVA with LOCF in the ITT sample. In addition, a priori defined subgroup analyses were conducted in patients completing 28 days of treatment for those symptoms such as negative symptoms and depression that are thought to require longer treatment duration to detect a response. These subgroup analyses were not powered to detect statistically significant differences but designed to illustrate magnitude of response as indicated by the effect size (ES). ES (Cohen’s d) was calculated by dividing the difference of the means in change from baseline to end point (treatment – placebo) by the common standard deviation. Treatment effects were examined in a patient subgroup with prominent negative symptoms at baseline (a priori defined as having a score of ≥4 on ≥3 items on the PANSS negative symptoms subscale at baseline, i.e., blunted affect, emotional withdrawal, poor rapport, passive apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking) and a subgroup with depression symptoms at baseline (a priori defined as having a CDSS score >6 at baseline). In addition, a post hoc analysis was conducted on the ITT sample to determine the effects of ITI-007 on a PANSS-derived prosocial factor (
      • Purnine D.M.
      • Carey K.B.
      • Maisto S.A.
      • Carey M.P.
      Assessing positive and negative symptoms in outpatients with schizophrenia and mood disorders.
      ) that consists of PANSS items: G16: Active Social Avoidance, N2: Emotional Withdrawal, N4: Passive Social Withdrawal, N7: Stereotyped Thinking, P3: Hallucinatory Behavior, and P6: Suspiciousness/Persecution.
      Safety analyses were conducted in all patients who were randomized and received at least one dose of study medication. Treatment-emergent adverse events were summarized and relative risk (ratio of frequency of treatment-emergent adverse events on drug relative to placebo), the associated 95% confidence interval, and the p value using Fisher’s exact test were reported. A post hoc comparison of ITI-007 with risperidone on key safety measures was conducted using t tests for difference in means in independent treatment groups based on change from baseline in patients completing 28 days of treatment. Placebo-adjusted by site mean weight gain was calculated by the sum of all sites for (placebo-adjusted mean in site × number of subjects in site)/sum of all sites for (number of subjects in site).

      Results

      Subject Characteristics

      A total of 335 patients with schizophrenia were randomized across four treatment groups. There were no systematic differences in prior antipsychotic therapy; all APDs, in patients who were receiving them, were discontinued at the start of the screening period. The safety population (n = 334) included all subjects who received ≥1 dose of study medication; one subject was randomized but withdrew before receiving study medication and was excluded from the safety population. The ITT population included 311 subjects. Exclusions from the ITT population included a few instances in which there was no predose baseline assessment of the PANSS, in error, or subjects who withdrew consent before the first postdose assessment of the PANSS was conducted and refused all end-of-study procedures. Demographics and baseline characteristics were similar across treatment groups (Table 1). Eighty-one percent of the 335 subjects completed study treatment and very few patients were lost to follow-up after discharge from the inpatient unit, providing a study completion rate of 74% (Figure 1).
      Table 1Subject Demographics and Baseline Characteristics
      PlaceboITI-007 60 mgITI-007 120 mgRisperidone 4 mg
      Demographics (Safety Population)n = 85n = 84n = 83n = 82
       Male, n (%)65 (76.5)66 (78.6)72 (86.7)73 (89.0)
       Age (years, mean ± SD), percent ≤40 years40.5 ± 9.8, 47.138.3 ± 10.0, 54.841.1 ± 8.9, 43.440.7 ± 9.3, 43.9
       Race, n (%)
        Black65 (76.5)70 (83.3)62 (74.7)64 (78.0)
        White17 (20.0)13 (15.5)16 (19.3)16 (19.5)
        Asian1 (1.2)002 (2.4)
        Other
      Other race includes American Indian/Native Alaskan, Native Hawaiian/Other Pacific Islander, or Other.
      2 (2.4)1 (1.2)5 (6.0)0
       Non-Hispanic, n (%)81 (95.3)81 (96.4)76 (91.6)80 (97.6)
      Baseline (ITT Population)n = 80n = 76n = 80n = 75
       Paranoid schizophrenia, n (%)78 (97.5)74 (97.4)76 (95.0)71 (94.7)
       Years since first diagnosis, mean ± SD16.7 ± 10.416.0 ± 9.417.0 ± 10.215.2 ± 9.4
       Screening BPRS, mean ± SD56.5 ± 8.055.6 ± 7.055.5 ± 7.756.6 ± 8.2
       Baseline PANSS, mean ± SD86.3 ± 13.188.1 ± 11.084.6 ± 11.686.1 ± 12.2
        Positive symptoms subscale, mean ± SD24.6 ± 4.624.8 ± 4.223.8 ± 4.524.2 ± 4.1
        Negative symptoms subscale, mean ± SD19.8 ± 4.821.0 ± 4.119.8 ± 4.120.7 ± 5.1
        General psychopathology subscale, mean ± SD41.9 ± 7.042.2 ± 7.041.0 ± 6.941.3 ± 6.6
      Baseline (Subgroup With Prominent Negative Symptoms)n = 29n = 33n = 25n = 33
       Negative symptoms subscale, mean ± SD23.3 ± 4.223.5 ± 3.123.9 ± 3.023.2 ± 3.9
      Baseline (Subgroup With Depression Symptoms)n = 14n = 7n = 13n = 11
       Baseline PANSS91.9 ± 10.995.1 ± 11.185.3 ± 15.492.7 ± 12.5
       CDSS, mean ± SD9.3 ± 2.88.0 ± 1.08.9 ± 1.79.8 ± 2.6
      BPRS, Brief Psychiatric Rating Scale; CDSS, Calgary Depression Scale for Schizophrenia; ITT, intent to treat; PANSS, Positive and Negative Syndrome Scale.
      a Other race includes American Indian/Native Alaskan, Native Hawaiian/Other Pacific Islander, or Other.
      Figure thumbnail gr1
      Figure 1Study flow diagram and patient disposition.

      Antipsychotic Efficacy of ITI-007

      ITI-007 60 mg significantly improved schizophrenia symptoms on the primary end point, change from baseline on the total PANSS to day 28, compared with placebo (least squares [LS] mean change −13.2 points vs. −7.4 points; p = .017, MMRM, ES = .4) (Table 2). ITI-007 120 mg did not significantly separate from placebo on the total PANSS at day 28 (LS mean change −8.3 vs. −7.4; p = .708). Risperidone (4 mg) differed from placebo on the total PANSS, demonstrating assay sensitivity (LS mean change −13.4 points vs. −7.4 points; p = .013, MMRM, ES = .4). The sensitivity analysis by ANCOVA LOCF confirmed the results of the MMRM analysis (Table 2). The responder analysis indicated that a similar proportion of patients (40%) randomized to 60 mg ITI-007 or risperidone improved on the PANSS total by ≥30% (Table 2).
      Table 2Primary and Secondary Analyses Demonstrated Antipsychotic Efficacy of ITI-007 at a Dose of 60 mg Including Prospective Subgroup Analyses That Demonstrated a Differentiating Response Profile of ITI-007 at a Dose of 60 mg and a Post Hoc Analysis of a PANSS-Derived Prosocial Factor
      LS Mean (± SEM) Change From Baseline on Day 28LS Mean Difference From Placebo (Rounded)p ValueEffect Size
      Total PANSS (MMRM) – Primary
       Placebo (n = 80)−7.4 ± 1.68n/an/an/a
       60 mg ITI-007 (n = 76)−13.2 ± 1.69−5.8.017.42
       120 mg ITI-007 (n = 80)−8.3 ± 1.68−.9.708.07
       4 mg Risperidone (n = 75)−13.4 ± 1.72−6.0.013.44
      Total PANSS (ANCOVA-LOCF) – Sensitivity
       Placebo (n = 80)−6.3 ± 1.6n/an/an/a
       60 mg ITI-007 (n = 76)−12.3 ± 1.7−6.0.011.41
       120 mg ITI-007 (n = 80)−7.7 ± 1.6−1.4.558.09
       4 mg Risperidone (n = 75)−12.6 ± 1.7−6.3.008.43
      PANSS Positive Subscale (ANCOVA-LOCF)
       Placebo (n = 80)−2.3 ± .5n/an/an/a
       60 mg ITI-007 (n = 76)−4.7 ± .5−2.4.002.50
       120 mg ITI-007 (n = 80)−3.2 ± .5−.8.272.17
       4 mg Risperidone (n = 75)−4.8 ± .5−2.4.002.51
      PANSS Negative Subscale (ANCOVA-LOCF)
       Placebo (n = 80)−.3 ± .5n/an/an/a
       60 mg ITI-007 (n = 76)−1.2 ± .5−.9.230.19
       120 mg ITI-007 (n = 80).5 ± .5.7.319.16
       4 mg Risperidone (n = 75)−.4 ± .5−.1.914.02
      PANSS General Psychopathology Subscale (ANCOVA-LOCF)
       Placebo (n = 80)−3.6 ± .9n/an/an/a
       60 mg ITI-007 (n = 76)−6.3 ± .9−2.6.040.33
       120 mg ITI-007 (n = 80)−5.0 ± .9−1.4.271.17
       4 mg Risperidone (n = 75)−7.5 ± .9−3.8.003.48
      n (%)Rate Difference % (95% CI)p Value
      Total PANSS Responder Analysis ≥ 30% Reduction
       Placebo (n = 80)18 (22.5)n/an/a
       60 mg ITI-007 (n = 76)31 (40.8)18.3 (3.9, 32.6).014
       120 mg ITI-007 (n = 80)20 (25.0)2.5 (−10.7, 15.7).711
       4 mg Risperidone (n = 75)30 (40.0)17.5 (3.1, 31.9).019
      Mean (± SEM) Change From Baseline on Day 28Mean Difference From Placebo (Rounded)p ValueEffect Size
      PANSS Negative Subscale in Subgroup With Prominent Negative Symptoms at Baseline
       Placebo (n = 29)−1.3 ± .92n/an/an/a
       60 mg ITI-007 (n = 33)−3.0 ± .88−1.6.206.34
       120 mg ITI-007 (n = 25)−1.1 ± .93.2.8650
       4 mg Risperidone (n = 33)−1.2 ± .80.2.8930
      Total PANSS in Subgroup With Depression Symptoms at Baseline
       Placebo (n = 14)−12.4 ± 3.89n/an/an/a
       60 mg ITI-007 (n = 7)−31.7 ± 7.31−19.4.0181.13
       120 mg ITI-007 (n = 12)−14.2 ± 3.51−1.8.736.14
       4 mg Risperidone (n = 11)−20.6 ± 3.89−8.3.152.60
      CDSS in Subgroup With Depression Symptoms at Baseline
       Placebo (n = 14)−5.4 ± 1.00n/an/an/a
       60 mg ITI-007 (n = 7)−7.7 ± .42−2.4.044.99
       120 mg ITI-007 (n = 13)−5.6 ± .74−.3.839.09
       4 mg Risperidone (n = 11)−7.2 ± 1.31−1.8.271−.48
      LS Mean (± SEM) Change From Baseline on Day 28LS Mean Difference From Placebo (Rounded)p ValueEffect Size
      Post Hoc Analysis of PANSS-Derived Prosocial Factor (ANCOVA-LOCF)
       Placebo (n = 80)−2.5 ± .5n/an/an/a
       60 mg ITI-007 (n = 76)−5.0 ± .5−2.5<.001.59
       120 mg ITI-007 (n = 80)−3.3 ± .5−0.8.243.19
       4 mg Risperidone (n = 75)−4.2 ± .5−1.7.01.42
      ANCOVA, analysis of covariance; CDSS, Calgary Depression Scale for Schizophrenia; CI, confidence interval; LOCF, last observation carried forward; LS, least squares; MMRM, mixed-effects model repeated measures; n/a, not applicable; PANSS, Positive and Negative Syndrome Scale; SEM, standard error of the mean.
      ITI-007 60 mg and risperidone significantly reduced positive symptoms and general psychopathology relative to the placebo group on the PANSS subscales; ITI-007 120 mg reduced positive symptoms and general psychopathology, but the improvement relative to the placebo group did not reach statistical significance (Figure 2). The effect of the interaction between treatment and time point on change from baseline in PANSS total score and in PANSS positive subscale was not statistically significant (F9,783.2 = 1.56, p = .123 and F9,845.5 = 1.27, p = .252, respectively). Negative symptoms improved only with 60 mg ITI-007, though the improvement did not reach statistical significance (Table 2), likely due to relatively low negative symptomatology at baseline in this acute population (Table 1). Risperidone and 120 mg ITI-007 did not improve negative symptoms.
      Figure thumbnail gr2
      Figure 2ITI-007 at a dose of 60 mg demonstrated antipsychotic efficacy as measured by the primary end point, least squares (LS) mean (standard error of the mean [SEM]) change from baseline in Positive and Negative Syndrome Scale (PANSS) total score (mixed-effects model repeated measures [MMRM]). *p < .05 vs. placebo. ITT, intent to treat.

      Results From Subgroups of Patients With Negative and Depression Symptoms

      Approximately a third of the patients met the criteria for prominent negative symptoms at baseline and were included in an exploratory a priori specified subgroup analysis of treatment effects on negative symptoms in this acutely exacerbated population (Table 1). In this subgroup, 60 mg ITI-007 reduced the severity of symptoms as reflected by the PANSS negative symptoms subscale (ES = .34). In contrast, the improvement in negative symptoms with risperidone was minimally less than that with placebo (ES = −.02) (Table 2).
      Thirteen percent of patients met the criteria of comorbid symptoms of depression at baseline and were included in this subgroup analysis (Table 1). ITI-007 60 mg significantly reduced the total PANSS score and the CDSS score in this subgroup with an ES of approximately 1 on both measures, while risperidone showed substantially smaller ESs (Table 2).
      Because this differential response profile for ITI-007 is related to improved social function, we added a post hoc analysis of the PANSS-derived prosocial factor, a cluster of symptoms corresponding to social function (
      • Purnine D.M.
      • Carey K.B.
      • Maisto S.A.
      • Carey M.P.
      Assessing positive and negative symptoms in outpatients with schizophrenia and mood disorders.
      ). ITI-007 (60 mg) significantly (p < .001) improved prosocial behavior as defined as a reduction in the PANSS prosocial factor with an ES of .6, suggesting that 60 mg ITI-007 might be particularly effective against this cluster of symptoms. In contrast, risperidone had a lower ES of .4 (p < .01) similar to its ES on the PANSS total score (Table 2).

      Safety of ITI-007

      ITI-007 was safe and well tolerated in individuals with schizophrenia. There were no serious adverse events associated with ITI-007. Two treatment-emergent serious adverse events (worsening of schizophrenia/psychotic disorder) occurred during the trial, one in a patient randomized to risperidone and one patient randomized to placebo. Five patients discontinued study treatment due to an adverse event: two patients randomized to ITI-007 (one dry mouth and one worsening of schizophrenia) and three patients randomized to risperidone (two cases of akathisia and one blood creatine phosphokinase increase). The relative risk of any treatment-emergent adverse event for 60 mg ITI-007 (1.14; 95% confidence interval: .89, 1.46) did not differ from placebo (p = .346). The relative risk was 1.30 for 120 mg ITI-007 (p = .024) and 1.25 for risperidone (p = .077). The most frequent adverse event reported in the study was somnolence/sedation (placebo = 13%, 60 mg ITI-007 = 17%, risperidone = 21%, and 120 mg ITI-007 = 32.5%) (Table 3). Neither dose of ITI-007 was associated with EPS as measured by the Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale (Supplemental Table S1). Notably, whereas risperidone caused akathisia as a treatment-emergent adverse event in 7% of subjects, ITI-007 at both doses was similar to placebo at 1% to 2%. Similarly, benztropine was allowed as a rescue medication for EPS and was used in seven patients in the risperidone group (9.3%) during the 28-day treatment period, in contrast to 1 to 2 subjects in each of the ITI-007 or placebo groups (1.3% to 2.5%). Weight gain for placebo subjects varied considerably from site to site, ranging from an average loss of 4.5 kg to an average gain of 4.8 kg (Supplemental Table S2), suggesting median weight gain might be more representative than mean changes. Median weight gain (change from screening at day −7 to day 28) was about 1 kg for patients randomized to placebo, 60 mg ITI-007, or 120 mg ITI-007 and about 2.5 kg for patients randomized to risperidone (Table 3). Placebo-adjusted mean weight gain by site (change from screening at day −7 to day 28) indicated a gain of .3 to .4 kg for both doses of ITI-007 and a gain of 2.3 kg for risperidone. Despite the site-to-site variability, post hoc analyses indicated a trend toward significantly less weight gain in ITI-007 groups than for risperidone (p = .087 for 60 mg vs. risperidone; p = .074 for 120 mg vs. risperidone). In post hoc comparisons to risperidone (Figure 3), ITI-007 showed statistically significantly lower prolactin levels (ITI-007 60 mg and 120 mg, p < .001 vs.risperidone), fasting glucose (ITI-007 60 mg, p = .007; ITI-007 120 mg, p = .023), total cholesterol (ITI-007 60 mg, p = .012; ITI-007 120 mg, p = .004), and triglycerides (ITI-007 60 mg, p = .074; ITI-007 120 mg, p = .002). Levels of insulin, glucose, triglycerides, and prolactin remained low while subjects were on ITI-007 but increased when switched to standard of care antipsychotic medication for stabilization after the 28-day study treatment period (Supplemental Figure S1).
      Table 3Adverse Event and Safety Profile (Safety Population)
      Placebo (n = 85)ITI-007 60 mg (n = 84)ITI-007 120 mg (n = 83)Risperidone 4 mg (n = 82)
      TEAEs Occurring in at Least 5% of Subjects in Either ITI-007 Treatment Group and Considered at Least Possibly Related to Study Drug, n (%)
       Sedation/somnolence11 (12.9)14 (16.7)27 (32.5)17 (20.7)
       Dry mouth2 (2.4)4 (4.8)7 (8.4)5 (6.1)
       Nausea1 (1.2)5 (6.0)4 (4.8)4 (4.9)
       Dizziness1 (1.2)4 (4.8)7 (8.4)1 (1.2)
      Other TEAEs Common With Risperidone, n (%)
       Akathisia2 (2.3)1 (1.2)2 (2.4)6 (7.3)
       Tachycardia01 (1.2)04 (4.9)
      Change From Screening (Day −7) to Day 28 (All Inpatient) on Body Weight (kg)
       Mean (SD).8 (3.46)2.0 (3.10)1.9 (3.35)3.0 (3.69)
       Median.81.01.12.5
       Placebo-adjusted by site meann/a.4.32.3
      Proportion With >7% Increase From Screening in Body Weight
       x/n completing 28 days (%)4/67 (6.0)9/69 (13.0)12/69 (17.4)13/68 (19.1)
       Difference from placebo, p valuen/a.162.039.022
      n/a, not applicable; TEAEs, treatment-emergent adverse events.
      Figure thumbnail gr3
      Figure 3Effects of ITI-007 on blood levels of metabolic parameters and prolactin (safety population).
      There were no serious adverse events related to ITI-007. There were no clinically meaningful changes in safety measures with ITI-007, including cardiovascular safety issues.

      Discussion

      ITI-007 60 mg demonstrated a statistically and clinically significant reduction in schizophrenia symptoms in comparison with placebo, meeting the primary end point of this trial. Its therapeutic effect on total PANSS was comparable with risperidone, a widely used APD, with an ES of .4 in the range of other effective antipsychotics tested in 4-week treatment trials (
      • Turner E.H.
      • Knoepflmacher D.
      • Shapley L.
      Publication bias in antipsychotic trials: An analysis of efficacy comparing the published literature to the US Food and Drug Administration database.
      ). In addition, individuals treated with 60 mg ITI-007 exhibited improvement across a broad range of symptoms, beyond psychosis, including general psychopathology and negative and depressive symptoms, the latter two of which are believed to be associated with social function. Importantly, the change in negative symptoms was independent of improvement in positive symptoms, depression, or EPS. This is supported by the fact that risperidone’s improvement of positive symptoms occurred without corresponding improvement and even a worsening of some negative symptoms, and there was no correlation between change from baseline on positive symptoms and change from baseline on negative symptoms in the overall ITT population (R2 = .06). Moreover, improvement of negative symptoms with ITI-007 did not correspond to change in depression or EPS. However, a severely ill subset of patients with schizophrenia and comorbid depression (defined a priori by explicit criteria, with higher baseline PANSS scores than the entire ITT sample), exhibited a robust response to ITI-007 60 mg including improved depressive and psychotic symptoms. Improvement in the PANSS-derived prosocial factor reflects an improvement of symptoms related to emotional and social withdrawal and suspiciousness. ITI-007 60 mg showed a tolerability and safety profile similar to placebo and significantly better than risperidone on several clinically relevant outcomes in a post hoc head-to-head comparison for those subjects completing 28 days of treatment.
      These results indicate significant therapeutic effect and favorable side effect profile of ITI-007, in contrast to currently approved APDs that are thought to exhibit safety issues that include EPS, weight gain, changes in glucose and lipid metabolism, hyperprolactinemia, and cardiovascular and cerebrovascular risks (
      • Ballon J.S.
      • Pajvani U.
      • Freyberg Z.
      • Leibel R.L.
      • Lieberman J.A.
      Molecular pathophysiology of metabolic effects of antipsychotic medications.
      ,
      • Hennekens C.H.
      • Hennekens A.R.
      • Hollar D.
      • Casey D.E.
      Schizophrenia and increased risks of cardiovascular disease.
      ,
      • Peuskens J.
      • Pani L.
      • Detraux J.
      • De Hert M.
      The effects of novel and newly approved antipsychotics on serum prolactin levels: A comprehensive review.
      ). Young and first-episode patients with schizophrenia are at a particularly increased risk for obesity, dyslipidemia, and cardiovascular disease with many of the currently used APDs (
      • Vancampfort D.
      • Wampers M.
      • Mitchell A.J.
      • Correll C.U.
      • De Herdt A.
      • Probst M.
      • De Hert M.
      A meta-analysis of cardio-metabolic abnormalities in drug naive, first-episode and multi-episode patients with schizophrenia versus general population controls.
      ). It is also of interest with respect to cardiovascular safety that ITI-007 at both doses did not prolong corrected QT intervals and did not cause sustained heart rate elevations.
      It is puzzling that the higher dose of 120 mg ITI-007 was not as therapeutically effective as 60 mg ITI-007 in this study. Without a clear reason to explain this result, we can only speculate that the lack of apparent therapeutic efficacy of the 120 mg dose could be due to a higher frequency of side effects, specifically somnolence/sedation. Although somnolence/sedation was mostly mild and did not result in early discontinuations, the occurrence of somnolence/sedation might have affected patients’ behavior and subjective reports and thus obscured therapeutic effects and the ability of centralized rating procedures to accurately assess the extent of patients’ symptoms. Another possibility is that the lack of improvement in negative symptoms associated with higher sedation/somnolence could have contributed to the lack of separation of 120 mg ITI-007 on the total PANSS despite some improvements on positive symptoms and general psychopathology. Although unlikely, it is also possible that varying receptor affinities occurring at the higher (120 mg) dose alters ITI-007’s therapeutic activity.
      The broader spectrum of ITI-007’s therapeutic effects that are suggested based on secondary analyses of negative and depressive symptom enriched, albeit small, subgroups (defined a priori) must be confirmed in future studies. Caution is warranted in making such conclusions pending further investigation, as such claims have been made in the past only to not be born out subsequently (
      • Miyamoto S.
      • Miyake N.
      • Jarskog L.F.
      • Fleischhacker W.W.
      • Lieberman J.A.
      Pharmacological treatment of schizophrenia: A critical review of the pharmacology and clinical effects of current and future therapeutic agents.
      ). The current design in the acute phase of the illness was not intended to definitively address improvements on symptoms other than positive symptoms. Further investigations are warranted to examine the effects of ITI-007 on primary negative or depressive symptoms in stable patients with predominant/persistent negative symptoms or depression, respectively, to extend the findings of improvement in these symptom domains in patients with acute symptoms.
      In summary, ITI-007 is a mechanistically novel investigational new drug that was found to be safe, well tolerated, and effective for symptoms associated with schizophrenia in a rigorously designed and executed 28-day clinical trial.

      Acknowledgments and Disclosures

      This clinical trial was funded by Intra-Cellular Therapies, Inc. (ITI). ITI-007-005 Phase 2 Study Investigators included J. Aukstuolis, Little Rock, AR; D. Brown, Austin, TX; S. Glass, Marlton, NJ; R. Litman, Rockville, MD; R. Mofsen, St. Louis, MO; M. Novitsky, Philadelphia, PA; R. Riesenberg, Atlanta, GA; and D. Walling, Garden Grove, CA.
      We thank L. Ereshefsky for input on the study design; M. Roessner and M. Weingart for their input on the statistical design and analysis, respectively; M. Bussel for medical oversight during the trial; and the subjects who participated in the trial. This manuscript was written entirely and solely by Drs. Lieberman, Vanover, Davis, and Mates, with each co-author making substantial contributions on drafts and revisions. No professional medical writing services were used in the writing of the manuscript.
      Dr. Lieberman is an unpaid advisor to ITI; reports additional consulting/advising for EnVivo and Pear Therapeutics; has received research grants from Biomarin, EnVivo, Genentech, Lilly, Novartis, Psychogenics, and Sunovion; and holds a patent for Repligen. Dr. Davis is a paid consultant to ITI. Dr. Correll reports financial relationships as a consultant/advisor for Eli Lilly and Company; Genentech, Inc.; Gerson Lehrman Group; ITI; Janssen/Johnson & Johnson; Lundbeck, Inc.; MedAvante; Pfizer, Inc.; ProPhase; Otsuka Pharmaceuticals Co., Ltd.; Roche; Sunovion; Supernus; and Takeda Pharmaceuticals North America, Inc. Dr. Correll has served as a speaker for Bristol-Myers Squibb Company, Janssen/Johnson & Johnson, ProPhase, and Otsuka Pharmaceuticals Co., Ltd. Dr. Correll has received research grants from Bristol-Myers Squibb Company, Novo Nordisk, AstraZeneca Pharmaceuticals LP, and Otsuka Pharmaceuticals Co., Ltd., and served as member of the Data Safety Monitoring Board of Eli Lilly and Company; Cephalon; Janssen; Lundbeck, Inc.; Pfizer, Inc.; and Takeda Pharmaceuticals North America, Inc. Dr. Goff is an unpaid advisor to ITI. Dr. Kane reports consulting fees for Alkermes, Bristol-Myers Squibb, Eli Lilly, Forrest, Forum, Genentech, ITI, Janssen, Johnson and Johnson, Lundbeck, Novartis, Otsuka, Roche, Sunovion, Reviva, and Pierre Fabre. Dr. Tamminga reports having received consulting fees from Astellas, Eli Lilly, ITI, Kay Scholer LLC, Lundbeck, and Pfizer. Drs. Mates and Vanover are full-time employees of ITI.

      Appendix A. Supplementary Materials

      References

        • Kane J.M.
        • Correll C.U.
        Past and present progress in the pharmacologic treatment of schizophrenia.
        J Clin Psychiatry. 2010; 71: 1115-1124
        • Vos T.
        • Flaxman A.D.
        • Naghavi M.
        • Lozano R.
        • Michaud C.
        • Ezzati M.
        • et al.
        Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the Global Burden of Disease Study 2010.
        Lancet. 2012; 380: 2163-2196
        • Millan M.J.
        • Fone K.
        • Steckler T.
        • Horan W.P.
        Negative symptoms of schizophrenia: Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment.
        Eur Neuropsychopharmacol. 2014; 24: 645-692
        • De Hert M.
        • Detraux J.
        • van Winkel R.
        • Yu W.
        • Correll C.U.
        Metabolic and cardiovascular adverse effects associated with antipsychotic drugs.
        Nat Rev Endocrinol. 2012; 8: 114-126
        • Nielsen J.
        • Correll C.U.
        • Manu P.
        • Kane J.M.
        Termination of clozapine treatment due to medical reasons: When is it warranted and how can it be avoided?.
        J Clin Psychiatry. 2013; 74: 603-613
        • Li P.
        • Zhang Q.
        • Robichaud A.J.
        • Lee T.
        • Tomesch J.
        • Yao W.
        • et al.
        Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders.
        J Med Chem. 2014; 57: 2670-2682
        • Snyder G.L.
        • Vanover K.E.
        • Zhu H.
        • Miller D.B.
        • O’Callaghan J.P.
        • Tomesch J.
        • et al.
        Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.
        Psychopharmacology (Berl). 2015; 232: 605-621
        • Meltzer H.Y.
        • Matsubara S.
        • Lee J.C.
        Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values.
        J Pharmacol Exp Ther. 1989; 251: 238-246
        • Goebel-Goody S.M.
        • Davies K.D.
        • Alvestad Linger RM
        • Freund RK
        • Browning MD
        Phospho-regulation of synaptic and extrasynaptic N-methyl-d-aspartate receptors in adult hippocampal slices.
        Neuroscience. 2009; 158: 1446-1459
        • Laruelle M.
        • Frankle W.G.
        • Narendran R.
        • Kegeles L.S.
        • Abi-Dargham A.
        Mechanism of action of antipsychotic drugs: From dopamine D(2) receptor antagonism to glutamate NMDA facilitation.
        Clin Ther. 2005; 27: S16-S24
        • Javitt D.C.
        Glutamate and schizophrenia: Phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions.
        Int Rev Neurobiol. 2007; 78: 69-108
        • Schwartz T.L.
        • Sachdeva S.
        • Stahl S.M.
        Glutamate neurocircuitry: Theoretical underpinnings in schizophrenia.
        Front Pharmacol. 2012; 3: 195
        • Meyer J.H.
        Imaging the serotonin transporter during major depressive disorder and antidepressant treatment.
        J Psychiatry Neurosci. 2007; 32: 86-102
        • Davis R.E.
        • Vanover K.E.
        • Zhou Y.
        • Brasic J.R.
        • Guevara M.
        • Bisuna B.
        • et al.
        ITI-007 demonstrates brain occupancy at serotonin 5-HT and dopamine D receptors and serotonin transporters using positron emission tomography in healthy volunteers.
        Psychopharmacology (Berl). 2015; 232: 2863-2872
        • Lieberman J.A.
        • Stroup T.S.
        • McEvoy J.P.
        • Swartz M.S.
        • Rosenheck R.A.
        • Perkins D.O.
        • et al.
        Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
        N Engl J Med. 2005; 353: 1209-1223
        • First M.B.
        • Williams J.B.W.
        • Spitzer R.L.
        • Gibbon M.
        Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Clinical Trials Version (SCID-CT)..
        Biometrics Research, New York State Psychiatric Institute, New York2007
        • Targum S.D.
        • Pendergrass J.C.
        • Toner C.
        • Asgharnejad M.
        • Burch D.J.
        Audio-digital recordings used for independent confirmation of site-based MADRS interview scores.
        Eur Neuropsychopharmacol. 2014; 24: 1760-1766
        • Kay S.R.
        • Fiszbein A.
        • Opler L.A.
        The positive and negative syndrome scale (PANSS) for schizophrenia.
        Schizophr Bull. 1987; 13: 261-276
        • Sharp I.R.
        • Kobak K.A.
        • Osman D.A.
        The use of videoconferencing with patients with psychosis: A review of the literature.
        Ann Gen Psychiatry. 2011; 10: 14
        • Purnine D.M.
        • Carey K.B.
        • Maisto S.A.
        • Carey M.P.
        Assessing positive and negative symptoms in outpatients with schizophrenia and mood disorders.
        J Nerv Ment Dis. 2000; 188: 653-661
        • Turner E.H.
        • Knoepflmacher D.
        • Shapley L.
        Publication bias in antipsychotic trials: An analysis of efficacy comparing the published literature to the US Food and Drug Administration database.
        PLoS Med. 2012; 9: e1001189
        • Ballon J.S.
        • Pajvani U.
        • Freyberg Z.
        • Leibel R.L.
        • Lieberman J.A.
        Molecular pathophysiology of metabolic effects of antipsychotic medications.
        Trends Endocrinol Metab. 2014; 25: 593-600
        • Hennekens C.H.
        • Hennekens A.R.
        • Hollar D.
        • Casey D.E.
        Schizophrenia and increased risks of cardiovascular disease.
        Am Heart J. 2005; 150: 1115-1121
        • Peuskens J.
        • Pani L.
        • Detraux J.
        • De Hert M.
        The effects of novel and newly approved antipsychotics on serum prolactin levels: A comprehensive review.
        CNS Drugs. 2014; 28: 421-453
        • Vancampfort D.
        • Wampers M.
        • Mitchell A.J.
        • Correll C.U.
        • De Herdt A.
        • Probst M.
        • De Hert M.
        A meta-analysis of cardio-metabolic abnormalities in drug naive, first-episode and multi-episode patients with schizophrenia versus general population controls.
        World Psychiatry. 2013; 12: 240-250
        • Miyamoto S.
        • Miyake N.
        • Jarskog L.F.
        • Fleischhacker W.W.
        • Lieberman J.A.
        Pharmacological treatment of schizophrenia: A critical review of the pharmacology and clinical effects of current and future therapeutic agents.
        Mol Psychiatry. 2012; 17: 1206-1227

      Linked Article

      • Evaluating New Pharmacotherapies for Schizophrenia
        Biological PsychiatryVol. 79Issue 12
        • Preview
          In this issue of Biological Psychiatry, Lieberman et al. (1) report a clinical trial for a new compound testing efficacy for psychosis in persons with a diagnosis of schizophrenia. Over the past 25 years, there have been many reports with numerous compounds, and most have been disappointing. Novel mechanisms have failed efficacy tests, and the compounds with a dopamine mechanism have an efficacy profile similar to established antipsychotic medications. Advancing clinical care is mainly based on selecting a drug with the most benign adverse effect profile for the individual patient.
        • Full-Text
        • PDF