Few studies have examined treatment response in adolescents with schizophrenia who are treatment-naive; and there is no placebo-controlled study that we are aware of in first episode treatment-naive patients with schizophrenia. The aim of this analysis was to evaluate the long-term efficacy of lurasidone in antipsychotic-naive adolescents with schizophrenia.

Patients aged 13–17 years with schizophrenia, and a PANSS total score ≥70 and <120, were randomized to 6 weeks of double-blind (DB) treatment with lurasidone (40 or 80 mg/day) or placebo. Six-week completers were eligible to enroll in a 2-year open-label extension phase receiving lurasidone flexibly dosed from 20–80 mg/day. In a post-hoc analysis, efficacy was evaluated for 2 patient groups based on treatment status prior to entering the initial 6-week DB study (treatment naïve [TN] vs. treated previously [TP]). Treatment-naïve was defined as never having received antipsychotic treatment. Efficacy measures included the PANSS total score and the Clinical Global Impression, Severity (CGI-S) score. Level of functioning was assessed using the Children’s Global Assessment Scale (CGAS), with a score of 70 representing normative levels of functioning.

A total of 50 TN and 221 TP patients completed the 6-week DB study and entered the extension study; and 30 (60.0%) TN and 126 (57.0%) TP patients completed 104 weeks. During the initial 6 weeks of DB treatment, mean change in PANSS total score at endpoint was greater for lurasidone vs. placebo in both the TN group (−25.0 vs. −14.4; P<0.02; effect size, 0.75), and in the TP group (−17.3 vs. −10.0; P<0.001; effect size, 0.45). During OL extension phase treatment with lurasidone, mean change from DB baseline in the PANSS total score for TN and TP patients, at week 52 was −32.6 (n=38) and −28.1 (n=151), respectively; and at week 104 was −33.6 (n=30) and −29.2 (n=126), respectively. Mean change from DB baseline in CGI-S score at both weeks 52 and 104 was −1.8 for TN patients and −1.5 for TP patients. At DB baseline mean CGAS scores indicated significant functional impairment in both the TN and TP patients (CGAS=48 and 43, respectively). During OL treatment with lurasidone, mean change (from DB baseline) in the CGAS score at Weeks 52 and 104, respectively, was +22.0 and +22.9 in TN patients, and +21.1 and +22.9 in TP patients. During OL treatment with lurasidone, mean observed change from DB baseline in the weight (in kg,) at Weeks 52 and 104, respectively, was +4.2 and +4.8 in TN patients, and +4.0 and +5.0 in TP patients. These weight increases are consistent with expected weight gains in adolescents during a 2-year period (based on CDC growth charts).

In this post-hoc analysis of a 2-year study, adolescents with schizophrenia who had received no previous antipsychotic therapy showed greater improvement compared to previously treated patients during both short- and long-term treatment with lurasidone.

Sunovion Pharmaceuticals Inc.

There is a burgeoning body of evidence suggesting that arginine vasopressin (AVP) acts as a neuromodulator of the stress response. AVP stimulates the release of adrenocorticotropic hormone, synergistic to corticotropin-releasing hormone, which might explain AVP’s role in resilience. Personal hardiness is the bedrock of resilience. Numerous studies have demonstrated elevated plasma levels of AVP in patients with major depressive disorder (MDD), suggesting an etiopathogenetic role as well as a novel therapeutic target.

The aim of this study was to examine the relationship between AVP and resilience in patients with MDD and to determine AVP levels in serum of patients with MDD.

Forty patients with MDD and 40 healthy control subjects were studied using the Dispositional Resilience (Hardiness) Scale by Barton, the Quality of Life Scale, the Social Readjustment Rating Scale, and the Beck Depression Inventory. Biochemical analysis of plasma levels of AVP, using the enzyme-linked immunosorbent assay (ELISA), was performed for all participants.

Levels of AVP were statistically significantly elevated in patients with MDD compared with healthy controls. Psychological hardiness was decreased in patients with MDD compared with healthy controls, a finding also statistically significant. There was a negative correlation between plasma AVP level and psychological hardiness.

AVP and psychological hardiness are negatively correlated, reflecting lower stress resilience. AVP levels are indeed higher in patients struggling with MDD.

Benzodiazepine (BZD) prescription rates have increased over the past decade in the United States. Available literature indicates that sociodemographic factors may influence diagnostic patterns and/or prescription behaviour. Herein, the aim of this study is to determine whether the gender of the prescriber and/or patient influences BZD prescription.

Cross-sectional study using data from the Florida Medicaid Managed Medical Assistance Program from January 1, 2018 to December 31, 2018. Eligible recipients ages 18 to 64, inclusive, enrolled in the Florida Medicaid plan for at least 1 day, and were dually eligible. Recipients either had a serious mental illness (SMI), or non-SMI and anxiety.

Total 125 463 cases were identified (i.e., received BZD or non-BZD prescription). Main effect of patient and prescriber gender was significant F(1, 125 459) = 0.105, P = 0 .745, partial η2 < 0.001. Relative risk (RR) of male prescribers prescribing a BZD compared to female prescribers was 1.540, 95% confidence intervals (CI) [1.513, 1.567], whereas the RR of male patients being prescribed a BZD compared to female patients was 1.16, 95% CI [1.14, 1.18]. Main effects of patient and prescriber gender were statistically significant F(1, 125 459) = 188.232, P < 0.001, partial η2 = 0.001 and F(1, 125 459) = 349.704, P < 0.001, partial η2 = 0.013, respectively.

Male prescribers are more likely to prescribe BZDs, and male patients are more likely to receive BZDs. Further studies are required to characterize factors that influence this gender-by-gender interaction.

All current antipsychotics have direct dopamine (DA) D2 receptor activity, which is associated with problems such as dysphoria, EPS, or prolactin elevation. Muscarinic receptor agonists have shown antipsychotic-like activity across preclinical models and clinical trials. This poster reviews preclinical evidence as to how muscarinic receptor agonists, such as the M1/M4 preferring agonist xanomeline, might have clinically relevant antipsychotic effects.

Highlight the novel mechanisms through which muscarinic receptor agonists are associated with antipsychotic effects without having any direct dopaminergic D2 receptor activity.

The muscarinic receptor family is composed of 5 G protein-coupled receptors (GPCRs). One of the leading hypotheses explaining the antipsychotic activity of muscarinic receptor agonists is preclinical studies of muscarinic receptor modulation of those DA circuits associated with psychosis. Both M1 and M4 receptors are expressed in DA neural circuits implicated in psychosis, and provide unique regulation of these circuits. Xanomeline has both functional M1 and M4 receptor agonist activity, and shows robust antipsychotic-like effects in several animal models that require the presence of functional M1 and M4 receptors. M4 receptors are autoreceptors on cholinergic neurons that regulate DA circuits in two locations: ventral tegmental area (VTA) and nucleus accumbens (NAc). Cholinergic-rich neurons from the hindbrain at the VTA, where they release acetylcholine (ACh) into DA-rich synaptic spaces. M4 autoreceptors are present on these neurons, and their activation reduces ACh release and lowers ambient synaptic ACh concentrations, leading to reduced DA cell firing. Cholinergic interneurons residing in the NAc also express M4 autoreceptors. These ACh interneurons regulate ACh release with M4 activation also turning off ACh release. Therefore, M4 receptors serve as DA regulators at VTA and NAc, both key sites for dopamine’s role in psychotic processes. M1 receptors regulate DA circuits in a different, “top down” manner. M1 receptors are found on cortical inhibitory interneurons. When activated, inhibitory drive onto excitatory output neurons is enhanced, which leads to reduced excitatory tone to VTA DA neurons.

Over the last 25 years, a growing body of evidence has shown potential for muscarinic receptor agonists to become a new class of medicines with potent antipsychotic activity. Preclinical data at micro-and macro-circuit levels suggest that the M1 and M4 receptor subtypes are most relevant in the regulation of DA circuits. The antipsychotic effects of muscarinic agonists effects may arise from influencing these key muscarinic receptor subtypes that are integral to the regulation of DA neural circuits. In summary, there has been great progress in understanding the potential for muscarinic receptor agonists for the treatment of psychosis.

Karuna Therapeutics

Obsessive-compulsive disorder (OCD) is a prevalent and disabling condition with frequent chronic course. Staging models applied to psychiatric disorders seek to define their extent of progression at a particular time-point and differentiate early, milder clinical phenomena from those characterizing illness progression and chronicity. In OCD patients, a staging model has been recently proposed but not tested yet. This was the aim of the present study.

From an overall sample of 198 OCD patients, recruited across two psychiatric clinics in Northern Italy, 70 patients on stable treatment completed a follow-up assessment ranging from 12 to 24 months. At follow-up initiation, patients had been divided into four staging groups, according to the model proposed by Fontenelle and Yucel. At the end of the follow-up, patients were subdivided into three groups (no stage change, improved stage, or worsened stage) compared with statistical analyses.

At the end of the follow-up, 67.1% patients showed no stage changes, 24.3% a stage improvement, and 8.6% a stage progression. Worsened patients showed higher rates of comorbid disorders and higher rates of unfavorable employment characteristics compared to the other subgroups (P < .05). Patients with worsened stage showed higher prevalence of somatic obsessions (P < .05), while patients with improved stage showed higher rates of magical thinking and violence/harm obsessions compared to other groups (P < .05).

The present results provide epidemiologic and clinical correlates of the first application of a staging model in a sample of OCD patients, encouraging further studies to assess the utility of this approach in the field.

Obsessive–compulsive disorder (OCD) is a chronic psychiatric disorder that results in significant disability and substantial compromise in the quality of life. Until now, the role of repetitive transcranial magnetic stimulation (rTMS) has been primarily explored in individuals with treatment-resistant OCD. In this study, we investigated the safety and efficacy of rTMS as an early augmentation strategy in drug-free patients with OCD.

This is a randomized double-blind, placebo-controlled study that involved the administration of a total of 20 sessions of rTMS (active/sham) to drug-naïve OCD patients using a standard protocol (1-Hz; 20 trains [80 pulses/train]; 1600 pulses per session at 100% resting motor threshold) at supplementary motor area. All patients (active and sham) were started on escitalopram 10 mg/d, which was subsequently increased to 20 mg/d after 10 days.

Out of the 24 patients, 13 received active and 11 received sham rTMS. At the end of rTMS therapy, there was a substantial reduction (P = .001) in total Yale-Brown Obsessive–Compulsive Scale, obsessions (P = .030) and compulsions (P = .001) between the groups. Only few patients (N = 8) reported mild side effect with rTMS, local pain, and headache being the commonest. The study revealed large effect size (Cohen’s d = 1.6) of rTMS as an early augmentation strategy in drug-free patients of OCD.

rTMS is a safe and effective early augmentation strategy in the management of OCD. Larger randomized controlled trials are required to establish the therapeutic role of rTMS as early augmentation in OCD.

Patients treated with antipsychotics, regardless of psychiatric diagnosis, are at risk for developing tardive dyskinesia (TD), a potentially debilitating drug-induced movement disorder. Valbenazine (INGREZZA; VBZ) is a novel vesicular monoamine transporter 2 (VMAT2) inhibitor approved to treat TD in adults. Data from KINECT 4 (NCT02405091) were analyzed to evaluate the long-term effects of VBZ in adults with schizophrenia/schizoaffective disorder (SZD) or mood disorder (MD) and moderate or severe TD.

KINECT 4 included open-label treatment (48weeks) followed by washout (4weeks). Entry requirements included: moderate or severe TD, qualitatively assessed at screening by a blinded, external reviewer; DSM diagnosis of SZD or MD; psychiatric stability (Brief Psychiatric Rating Scale score <50). Stable concomitant psychiatric medications were allowed. Dosing was initiated at 40mg, with escalation to 80mg at Wk4 if participants had a Clinical Global Impression of Change-TD score of ≥3 (minimally improved to very much worse) and tolerated 40mg. A reduction to 40mg was allowed if 80mg was not tolerated (80/40mg); participants unable to tolerate 40mg were discontinued. Safety was the primary focus, but the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7) was used to evaluate changes in TD. Mean changes from baseline (BL) in AIMS total score (rated by on-site investigators) were analyzed descriptively. Safety assessments included treatment-emergent adverse events (TEAEs) and psychiatric scales (Positive and Negative Syndrome Scale [PANSS], Calgary Depression Scale for Schizophrenia [CDSS], Montgomery-Åsberg Depression Rating Scale [MADRS], Young Mania Rating Scale [YMRS], and Columbia-Suicide Severity Rating Scale [C SSRS]).

Of 163 participants in the analyses, 103 completed the study. Adverse events (n=26) was the most common reason for discontinuation. Analyses included 119 participants with SZD (40mg=37; 80mg=76; 80/40mg=6) and 44 with MD (40mg=8; 80mg=31; 80/40mg=5). At Wk48, mean improvements from BL in AIMS total score were: SZD (40mg, –10.1; 80mg,–10.7); MD (40mg, 10.2; 80mg: –11.6). AIMS total scores at Wk52 (end of washout) indicated a return toward BL levels. Compared to SZD, the MD subgroup had a higher incidence of any TEAE (84% vs 61% [all doses]) but fewer TEAEs leading to discontinuation (7% vs 18%). Urinary tract infection was the most common TEAE in the MD subgroup (18%); somnolence and headache were most common in the SZD subgroup (7% each). Psychiatric status remained stable from BL to Wk48: SZD (PANSS positive, –0.7, PANSS negative, –0.6; CDSS, –0.7); MD (MADRS, –0.3; YMRS, –0.3). Most participants (95%) had no change in C-SSRS score during the study.

Sustained and clinically meaningful TD improvements were observed with VBZ, regardless of primary psychiatric diagnosis. VBZ was generally well tolerated and no notable changes in psychiatric status were observed.

Funding Acknowledgements: Supported by Neurocrine Biosciences, Inc.