Bpolar disorder (BD) is a severe and chronic psychiatric disorder it is the sixth leading cause of disability among all illnesses worldwide. With regard to causes of premature mortality, patients with BD are at very high risk of suicide. Whereas risk factors for suicidal behaviors are multiple and complex, hopelessness appears to be a major independent risk factor for suicidality in BD. Compelling evidence has also demonstrated that BD is frequently associated with circadian rhythms alteration, contributing to its vulnerability, pathogenesis, and manifestations. in particular in the desynchronization of sleep and social life, has been associated with the severity of BD. Indeed hopelessness has never been studid in relation to circadian rhythms in BD

To examine the role of chronobiological rhythm alterations in suicidal ideation and behaviors and its relation with hopelessness.

One hundred twenty-seven patients (77 females, mean age of 47.4 ± 12.5 years) with a major depressive episode and bipolar disorder (BD) type I or II (according to Structured Clinical Interview for DSM-5 assessment) were recruited in 2019 and assessed for depressive and manic symptoms (Beck Depression Inventory-II, Young Mania Rating Scale) and with the Biological Rhythms Interview of Assessment in Neuropsychiatry, Beck Hopelessness Scale, and Scale for Suicide Ideation. Univariate regression and mediation analyses were performed.

Forty-one patients (32.3%) showed clinically significant suicidal ideation and were more frequently affected by BD type I (P = .029) with mixed features (P = .022). Compared to nonsuicidal individuals, they had significantly more depressive symptoms (P = .019), higher emotional component of hopelessness (P = .037), and higher dysrhythmicity of sleep (P = .009), activities (P = .048), and social life (P = .019). Passive and active suicidal ideation and suicidal plans were best predicted by dysrhythmicity of sleep and social life. Dysrhythmicity of sleep and social life mediated the direct effect of depressive symptoms on passive and active suicidal ideation and also of active ideation on suicidal plans. The emotional component of hopelessness was related to dysrhythmicity of social life and mediated its effect on suicidal plans (P = .010).

Chronobiological alterations directly contributed to passive and active suicidal ideation and to suicidal preparation, with a key role of circadian rhythm alteration of sleep, activities, and social life. Chronobiological alterations also impacted the emotional component of hopelessness, hence indirectly contributing to suicidal ideations and plans. These findings call for the systematic screening of these dysrhythmicity dimensions when considering suicidal risk in individuals with BD.

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With stressors that are often associated with suicide increasing during the coronavirus disease 2019 (COVID-19) pandemic, there has been concern that suicide mortality rates may also be increasing. Our objective was to determine whether suicide mortality rates increased during the COVID-19 pandemic.

With stressors that are often associated with suicideincreasing during the coronavirus disease 2019 (COVID-19) pandemic,there has been concern that suicide mortality rates may alsobe increasing.

Our objective was to determine whether suicidemortality rates increased during the COVID-19 pandemic.

We conducted an interrupted time-series study using data from January 2019 through December 2020 from 2 large integrated health care systems. The population at risk included all patients or individuals enrolled in a health plan at HealthPartners in Minnesota or Henry Ford Health in Michigan. The primary outcome was change in suicide mortality rates, expressed as annualized crude rates of suicide death per 100,000 people in 10 months following the start of the pandemic in March 2020 compared with the 14 months prior. We conducted an interrupted time-series study using data fromJanuary 2019 through December 2020 from 2 large integrated health care systems. The population at risk included all patients or individuals enrolledin a health plan at HealthPartners in Minnesota or Henry Ford HealthSystem in Michigan. The primary outcome was change in suicide mortality rates, expressed as annualized crude rates of suicide death per 100,000 people in 10 months following the start of the pandemic in March2020 compared with the 14 months prior.

There were 6,434,675 people at risk in the sample, with 55% women and a diverse sample across ages, race/ethnicity, and insurance type. From January 2019 through February 2020, there was a slow increase in the suicide mortality rate, with rates then decreasing by 0.45 per 100,000 people per month from March 2020 through December 2020 (SE= 0.19, P=0.03). There were 6,434,675 people at risk in the sample, with 55% women and a diverse sample across ages, race/ethnicity, and insurance type. From January 2019 through February 2020, there was a slow increase in the suicide mortality rate, with rates then decreasing by 0.45 per 100,000 people per month from March 2020 through December 2020 (SE= 0.19, P=0.03).

Overall suicide mortality rates did not increase with the pandemic, and in fact slightly declined from March to December 2020. Our findings should be confirmed across other settings and, when available, using final adjudicated state mortality data. Overall suicide mortality rates did not increase with the pandemic, and in fact slightly declined from March to December 2020. Our findings should be confirmed across other settings and,when available, using final adjudicated state mortality data.

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Natural disasters adversely impact individuals living in places where they occur, resulting in emotional distress. The wildfire that occurred in Fort McMurray (FMM), Alberta in 2016 is no different.

This study aims to identify the prevalence and predictors of Generalized Anxiety Disorder (GAD) symptoms in residents of FMM five years after the devastating wildfires.

Data for the study were collected through a cross-sectional survey conducted online from the 24th of April to the 2nd of June 2021. A validated instrument, the GAD-7 scale, was used to collect information on anxiety.

Of the total number of 186 residents who took part in the study, the majority were females (85.5%), employed (94.1%), working at school boards (50.0%), and were either married, cohabiting, or partnered (71.0%). The prevalence of likely GAD among the study sample was 42.5%. Unemployed respondents were seventeen times more likely to develop GAD symptoms (OR = 16.62; 95% C.I. 1.23-223.67) while respondents who would like to receive mental health counseling were five times more likely to experience GAD symptoms (OR = 5.35; 95% C.I. 2.03-14.15). Respondents who suffered a loss of property because of the wildfire were two times more likely to develop GAD symptoms (OR = 2.36; 95% C.I. 1.01-22.62).

Formulators of policy may mitigate GAD symptoms, particularly after natural disasters, by making long-term mental health counseling available and a key component of post-disaster management, and by investing in the social capital of the people to build resilience and support to deal with the post-disaster mental health effects.

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Healthcare practitioners (HCPs) are facing a mental health crisis. Group therapies have long been used to treat symptoms associated with PTSD, anxiety and/or depression, however no studies have investigated the role of implementing group therapy with and without ketamine-assisted therapies (KaT).

The current study investigated the effects of the Roots to Thrive (RTT) group therapy intervention both with and without adjunctive KaT.

In the present study we conduct a secondary analysis of data derived from the 12-week group psychotherapy program to that of the same program with adjunct KaT. Participants were administered a series of validated psychiatric assessment tools before and after the 12-weeks. Inclusion criteria included a diagnosis of treatment resistant mental health condition (depression, PTSD and/or generalized anxiety disorder) and a score of 15 or greater on the PTSD Checklist for DSM-5 (PCL-5). To assess the effects of time x group interaction and calculate differences between the RTT only and RTT-KaT subgroups, a repeated measures ANOVA was conducted. Effect sizes were calculated through partial eta-squared.

Forty-nine HCPs with treatment-resistant PTSD, anxiety and/or depression were treated with the RTT group therapy model to target their symptoms. A total of 49 individuals (34 female, 10 male, 3 other) with a median age of 47 years old (SD 14.19) participated in the study. There were no statistically significant differences between RTT only (n=14) and RTT KaT (n=35) subgroups across gender [X2 (1, N=44) = 2.84, ns] or age [F (1, 36) = .257, p = .615]. From pre- to post-treatment, all patients showed significant reductions in scores of PTSD (from 39.3 to 20.99), depression (from 15.5 to 7.7) and anxiety (from 15.5 to 6.2). Two-way repeated measures ANOVA did not reveal any significant between-group differences between the RTT and RTT-KaT subgroups.

This observational study provides preliminary support for the potential of the RTT community of care model of group therapy and adds to a small but growing body of knowledge on the integration of group therapy and the broad category of psychedelic psychotherapies. Given the rapid proliferation and expansion of KaT clinics throughout North America, the finding that KaT did not appear to impact changes related to the RTT intervention suggests the need for further research to better explain the potential impacts of relational transference between the two groups, and the distinct contributions of ketamine administration in a group therapy context.

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Childhood trauma (CT) is associated with severe sequelae, including personality disorders and stress-related mental health disorders that can perpetuate long into adulthood.

We aimed to investigate (1) whether childhood trauma is associated with anger in adulthood, and, if so, (2) to explore which types of childhood trauma predominate in the prediction of anger, and (3) to explore whether the association is independent of psychopathology in a cohort that included participants without lifetime psychiatric disorders, with current or remitted depressive and anxiety disorders, or comorbid depressive and anxiety disorders.

In the Netherlands Study of Depression and Anxiety (NESDA), childhood trauma was assessed with a semi-structured Childhood Trauma Interview (CTI) at baseline, and analyzed in relation to anger as measured at 4-year follow-up with the Spielberger Trait Anger Subscale (STAS), the Anger Attacks Questionnaire, and cluster B personality traits (i.e., borderline, antisocial) of the Personality Disorder Questionnaire 4 (PDQ-4), using analysis of covariance (ANCOVA) and multivariable logistic regression analyses. Post-hoc analyses comprised cross-sectional regression analyses, using the Childhood Trauma Questionnaire – Short Form (CTQ-SF) obtained at 4-year follow-up.

Participants (n = 2,276) were on average 42.1 years (SD = 13.1), and 66.3% were female. Childhood trauma showed a dose-response association with all anger constructs. Zooming in, all types of childhood trauma except for sexual abuse were associated with higher levels of trait anger, and a higher prevalence of anger attacks and antisocial personality traits in adulthood, independently of depression and anxiety. Additionally, all types of childhood trauma were significantly associated with borderline personality traits. Cross-sectionally, the effect sizes were larger compared to the analyses with the childhood trauma measured four years prior to the anger measures.

Childhood trauma is linked with anger in adulthood, most strongly for trait anger and borderline personality traits. It is of clinical importance to explore childhood traumatic experience and start trauma-focused interventions when appropriate.

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Treatment resistant depression (TRD) affects a substantial proportion of patients with depression and carries a large unmet need. Esketamine nasal spray (NS), in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI), has been shown to reduce depressive symptoms and risk of relapse, in patients with TRD (Popova, V., et al. 2019. Am J Psychiatry; Daly, E.J., et al. 2019. JAMA Psychiatry). Esketamine NS has been authorised by European Medicines Agency as treatment for resistant depression since December 2019. ESKALE, is the first French observational study to describe TRD patients treated with Esketamine NS under real-world settings and to provide data on this innovative solution for patients.

To describe patients with TRD at Esketamine NS initiation and during the following 12-month period in real-world clinical practice.

ESKALE is a French, observational, multicentre, retrospective study of adult patients with moderate to severe TRD defined as a non-response to ≥ 2 oral antidepressant. Each patient was included in one of the 3 cohorts according to Esketamine NS start date: Temporary Authorisation for Use (ATUc) cohort, post-ATU cohort or post-launch period cohort. Data were collected from medical records of patients treated with Esketamine NS between 10-29-2019 and 06-14-2022. Primary objective is to describe patients’ profile and Esketamine NS conditions of use at esketamine initiation and during the 12-month period after esketamine initiation in real-world clinical practice (either patient had stop or not the treatment). Secondary objectives are to describe Esketamine NS management, safety profile and patient pathway.

Two standard descriptive statistical interim analysis were conducted and published in several conferences (Samalin L, et al. Presented at EPA Hybrid congress June 2022. P.2482; Samalin L, et al. Presented at ECNP Vienna, October 2022. P.0122). This final analysis describes the data collected from medical records of patients included in the study from 04-08-2020 to 06-30-2021. 157 patients were included from 26 French centers, the majority (>65%) of patients were females. Average age was 49 years old with 27 patients > 65 years old. Duration of the current depressive episode was up to 2,5 years (mean) with an average of more than three episode in the patient’s entire life (mean). At esketamine initiation, 3 patients out of 4 were clinically perceived to have severe depression with a MADRS score of 32.0 (median). Patients had mainly depression with anxious distress specifier. Esketamine NS dose at initiation was mainly 56mg.

Eskale is the first French cohort study generating real-world evidence on treatment resistant depression patients treated with Esketamine nasal spray. Results of the final analysis confirmed the 2 interim analysis results already published.

None Declared

Treatment resistant depression (TRD) is estimated to affect 10–30% of patients with major depressive disorder (Al‑Harbi et al. Patient Prefer Adherence 2012; 6 369–88). Esketamine nasal spray (NS), in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI), increases remission and response rates in patients with TRD compared with placebo plus SSRI/SNRI (Popova et al. Am J Psychiatry 2019; 176 428–38). ESCAPE-TRD (NCT04338321) is the first randomised clinical trial to compare esketamine NS to quetiapine extended-release (XR), an antipsychotic augmentation therapy for patients with TRD.

To explore the efficacy and safety of esketamine NS compared with quetiapine XR in TRD over 32 weeks (wks).

In the ESCAPE-TRD phase IIIb open-label, rater-blinded trial, patients were randomised 1:1 to esketamine NS (56/84 mg; twice per wk, weekly or every 2 wks) or quetiapine XR (150–300 mg daily) both in combination with an ongoing SSRI/SNRI. Remission (Montgomery-Åsberg Depression Rating Scale [MADRS] total score of ≤10) and response (≥50% improvement in MADRS total score from baseline or MADRS≤10) rates were analysed over time using last observation carried forward. MADRS change from baseline was analysed using Mixed Models for Repeated Measures (MMRM). The most common adverse events (AEs) leading to discontinuation are reported for patients who received ≥1 dose of study medication.

At baseline, 336 patients were randomised to esketamine NS and 340 to quetiapine XR. A significantly higher percentage of patients in the esketamine NS group achieved remission (at each visit from Wk6 [p=0.008] onward) and response (at each visit from Day 15 [p<0.001] onward) versus patients treated with quetiapine XR. Esketamine NS significantly improved MADRS score compared to quetiapine XR at each visit from Day 8 onwards, with an average difference over time in the least squares means total MADRS score change from baseline of -2.4 (Figure). The most common AEs leading to treatment discontinuation for esketamine NS were dizziness (n=2, 0.6%), dissociation (n=2, 0.6%) and vomiting (n=2, 0.6%), and for quetiapine XR were sedation (n=7, 2.1%), weight increased (n=6, 1.8%) and somnolence (n=5, 1.5%).

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Esketamine NS increased the percentage of patients achieving response and remission and improved MADRS total score over time compared with quetiapine XR. Rates of discontinuation arising from the most common AEs were generally lower with esketamine NS than quetiapine XR.

We thank participating patients and all who assisted with the study. This study was funded by Janssen; medical writing support was provided by Carolyn Walsh, PhD, Costello Medical, UK.

A. Reif Grant / Research support from: Medice, Consultant of: National Care Guidelines (NVL, S3) on major depression, bipolar disorder, ADHD and suicidal behaviour (aided in developing guidelines); board member of DGBS, DGPPN, ECNP and German Depression Foundation, Speakers bureau of: (and participated in advisory boards over the last 3 years) for Cyclerion, Janssen, Medice, SAGE/Biogen and Shire/Takeda; received speaker’s honoraria from Das Fortbildungskolleg; , A. E. Anıl Yağcıoğlu Grant / Research support from: Participated as an investigator for Janssen, Speakers bureau of: (and participated in advisory boards over the last 3 years) for Janssen and Abdi İbrahim Otsuka, A. Luts Speakers bureau of: (or participated in advisory boards for or participated as an investigator) for Janssen-Cilag, Asarina Pharma, Bristol Meyer Squibb, Dr August Wolff GmbH & Co, Eli Lilly, Lundbeck, Pfizer, Allergan, Sunovion and Regeneron., T. Messer Consultant of: National Care Guidelines (NVL, S3) on major depression (aided in developing guidelines), Speakers bureau of: (and participated in advisory boards) for Janssen-Cilag and Otsuka/Lundbeck, R. Nielsen Consultant of: Board member of DSAL and IGSLi, Speakers bureau of: (or participated in advisory boards, received research funds or participated as investigator over the last 3 years) for Boehringer Ingelheim, Compass Pharmaceuticals, Janssen-Cilag, Lundbeck, Otsuka, Sage and Teva Pharmaceuticals, J. Buyze Employee of: Janssen, T. Ito Employee of: Janssen, Y. Kambarov Employee of: Janssen, S. Mulhern Haughey Employee of: Janssen, B. Rive Employee of: Janssen, I. Usankova Employee of: Janssen, C. von Holt Employee of: Janssen, Y. Godinov Employee of: Janssen

COMP360 is a synthetic, proprietary, purified form of psilocybin in development for treatment-resistant depression (TRD) with FDA Breakthrough Therapy designation. In a recent phase IIb study, COMP360 psilocybin 25mg was superior to 1mg on change from baseline (CFB) to Week 3 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score (primary efficacy endpoint), when administered alongside psychological support. Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR16) total score (exploratory efficacy endpoint) showed similar results.

To analyse changes in specific depression symptoms after psilocybin treatment in the aforementioned study, as measured by individual item scores on the MADRS and QIDS-SR16 (range 0-6 and 0-3).

Participants with TRD were randomised to single doses of psilocybin 25mg (n=79), 10mg (n=75), or 1mg (n=79). A remote, blinded rater assessed the MADRS at Baseline, Day 2 (the day post-psilocybin), and Weeks 1, 3, 6, 9, and 12. The QIDS-SR16 was self-rated at Baseline, Day 1, Day 2, and Weeks 1, 2, 3, 6, 9, and 12. At each time point, descriptive statistics were calculated for each MADRS and QIDS-SR16 individual item score.

At Week 3, MADRS items with the largest differences in mean CFB in the 25mg arm were Inability to Feel, Apparent Sadness, Lassitude, and Reported Sadness. Greater improvement in the 25mg arm was apparent from Day 2 and remained to Week 12 (Lassitude remained to Week 6 only). On the QIDS-SR16, the item with the largest difference in mean CFB at Week 3 in the 25mg arm was in Feeling Sad and remained evident to Week 12 (Table 1).Table 1.

A single administration of COMP360 psilocybin therapy rapidly and dose-relatedly improved symptoms of depressed mood and anhedonia – the two key symptoms of depression. As anhedonia is predictive of poorer treatment response, and improvements in anhedonia correlate with improvements in functioning, it is important to understand the impact of treatments on this symptom.

G. Goodwin Shareolder of: COMPASS Pathways, P1Vital, and P1Vital products , Employee of: COMPASS Pathways, L. Marwood Shareolder of: COMPASS Pathways, Employee of: COMPASS Pathways, S. Mistry Employee of: COMPASS Pathways, A. Nowakowska Employee of: COMPASS Pathways, H. Simmons Employee of: COMPASS Pathways, J. Tsai Employee of: COMPASS Pathways, S. Williams Employee of: COMPASS Pathways, M. Young Shareolder of: COMPASS Pathways, Employee of: COMPASS Pathways, E. Malievskaia Employee of: COMPASS Pathways

Depression is a leading cause of disability worldwide despite dozens of approved antidepressants. There are currently no clear guidelines to assist the physician in their choice of drug, with existing tools limited to pharmacogenetics that have shown suboptimal response prediction outcomes resulting in a subscription process that is largely a trial and error one. Consequently, the majority of depressed patients do not respond to their first prescribed antidepressant, with >30% not responding to subsequent drugs. We report here on molecular readouts from an in vitro-based platform that provides patient-specific information on antidepressant mechanisms using cortical neurons derived individually from each patient.

To assess gene expression differences in prefrontal cortex neurons derived from responders and non-responders to two commonly used antidepressants, the selective serotonin reuptake inhibitor Citalopram and the atypical antidepressant Bupropion.

Patient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study with known response to Citalopram or Bupropion were reprogrammed and then differentiated to cortical neurons. Differential gene expression analysis was preformed to identify genes that are differentially expressed between drug responders and non-responders.

Significant differential expression was shown in 359 genes between Bupropion responders and non-responders (Fig1A) and 12 genes between Citalopram responders and non-responders (Fig1B). Clustering on the differentially expressed genes showed high agreement with the known response to both drugs (Fig1). Functional enrichment analysis revealed biologically relevant pathways that differ between responders and non-responders in Bupropion versus Citalopram.

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Figure 1.

Heatmap of the expression of genes that show significant differential expression between neurons derived from Bupropion (A) and Citalopram (B) responders and non-responders. Color is the scaled gene expression; lines are genes and columns are samples. Column side colors represent the known response of the patient. Colum and line dendrograms are unsupervised hierarchical clustering.

Gene expression patterns of neurons derived from patients with depression differ according to their response to two common antidepressants from different groups. The identification of distinct drug response dependent expression patterns in derived neurons can help elucidate mechanisms underlying antidepressant activity, supporting new drug development and response prediction.

None Declared

Tricyclic antidepressants (TCAs) have an important role in pharmacotherapy of Major Depressive Disorder (MDD). TCA dosing is aimed at achieving a concentration in the therapeutic window. Due to inter-individual differences in activity of Cytochrome P450 (CYP) 2D6 and 2C19, (enzymes involved in TCA metabolism) patients require an individualized dose. Currently, finding of a suitable dosage is a process of trial-and-error, including multiple drug concentration measurements and dose adjustments. A starting dose based on a patient CYP2D6 and CYP2C19 metabolizer phenotype may contribute to achieving a therapeutic concentration more quickly, possibly resulting in higher treatment efficacy and the occurrence of fewer adverse effects.

We aimed to study whether genotype-informed dosing in TCAs leads to faster attainment of therapeutic plasma concentrations, a higher reduction of depression severity symptoms and less adverse effects.

We conducted a double-blind randomized clinical trial, in which patients (18-65 years) diagnosed with severe MDD and eligible for treatment with a TCA were randomized in two treatment arms: The intervention arm (Pharmacogenetics Informed Treatment; PIT) and standard treatment (Treatment As Usual; TAU). Patients were treated with nortriptyline, clomipramine or imipramine for seven weeks and depressive symptom severity and adverse effects were monitored weekly. The primary outcome measure, time needed to attain a therapeutic drug concentration, was analyzed using Kaplan-Meier analyses. The secondary outcome measures, reduction in depressive symptoms and adverse effects, were analyzed with mixed model linear regression.

In total, we randomized 111 patients. The PIT group (n=56) reached a therapeutic plasma concentration significantly faster (Kaplan Meier, X2 (1) = 4.3, p=0.039) compared to TAU (n=55), especially for patients treated with nortriptyline. On average depressive symptoms decreased relatively more in PIT than in TAU, although this was not significantly different: F(6) = 0.45, p = 0.84. The severity of adverse events during the study period differed significantly between PIT and TAU (F(6)=3.10, p=0.008). PIT experienced fewer adverse effects than TAU, especially in the last two weeks of the study.

Genotype-informed dosing leads to faster attainment of therapeutic TCA concentrations and does not lead to more adverse effects. Although we were not able to demonstrate that genotype-informed dosing leads to a significantly better response, we conclude that pharmacogenetics can contribute to the optimization of pharmacological treatment. Future research may focus on subgroups for which pharmacogenetics may be of great value, such as specific antidepressants or patients with an abnormal pharmacogenetic profile.

None Declared

Rapid-acting therapies remain an unmet need in the treatment of major depressive disorder (MDD) and postpartum depression (PPD). Zuranolone (ZRN) is being evaluated as a once-daily, oral, 14-day treatment for adult patients with MDD and PPD.

To evaluate the efficacy (assessed by Montgomery–Åsberg Depression Rating Scale [MADRS]) and safety of ZRN versus placebo across clinical studies with MDD and PPD.

In 5 completed Phase 2/3 placebo-controlled randomised studies of once-daily ZRN 30 or 50 mg in adults with MDD or PPD, improvement in depressive symptoms was assessed at Day 15 (end of 14-day treatment) by change from baseline in MADRS total score and the percentage of patients achieving MADRS response (≥ 50% improvement from baseline in total score) and remission (total score ≤ 10). Safety was assessed throughout.

Patients in the ZRN arm achieved improvements in depressive symptoms, as assessed by MADRS. Improvements in MADRS total score at Day 15 were observed in all 5 studies and were nominally significant (p < 0.05) versus placebo in 4 studies (Fig. 1). Percentage of patients achieving response and/or remission in the ZRN arm was numerically greater than placebo in all MDD studies and significantly greater than placebo in the PPD studies (Fig. 2 and 3). ZRN was generally well tolerated with consistent safety and tolerability profiles across studies. The most common treatment-emergent adverse events (≥5 % in ZRN treatment arm) were headache, somnolence, dizziness, nausea, sedation, diarrhea, upper respiratory tract infection, fatigue, and COVID-19.

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In the 5 completed clinical studies, rapid improvement in depressive symptoms assessed by MADRS was observed across studies of adults with MDD and PPD who received a 14-day treatment of once-daily ZRN. In all studies, ZRN was generally well tolerated. These data support further development of ZRN as a potential oral, rapid-acting treatment for patients with MDD or PPD.

The MDD-201B, MOUNTAIN, and ROBIN studies were sponsored by Sage Therapeutics, Inc.; the WATERFALL and SKYLARK studies were sponsored by Sage Therapeutics, Inc. and Biogen Inc. Medical writing and editorial support were provided by MediTech Media, Ltd, and funded by Sage Therapeutics, Inc. and Biogen Inc.

A. Clayton Shareolder of: Royalties from Ballantine Books/Random House, the Changes in Sexual Functioning Questionnaire, and Guilford Publications; and restricted stock in Euthymics, Mediflix LLC, and S1 Biopharma., Grant / Research support from: Daré Bioscience, Janssen, Otsuka, Praxis Precision Medicines, Relmada Therapeutics, Inc., and Sage Therapeutics, Inc, Consultant of: AbbVie, Inc., Brii Biosciences, Inc., Fabre-Kramer, Janssen Research & Development, LLC, Mind Cure Health, Ovoca Bio plc, Praxis Precision Medicines, PureTech Health, Reunion Neuroscience (formerly Field Trip Health) S1 Biopharma, Sage Therapeutics, Inc., Takeda/Lundbeck, Vella Bioscience, Inc., and WCG MedAvante-ProPhase, K. Deligiannidis Shareolder of: Royalties from an NIH employee invention outside of the submitted work. , Grant / Research support from: Received grants from from NIH and Vorso Corporation. Grants awarded to Zucker Hillside Hospital/Feinstein Institutes for Medical Research during the conduct of the brexanolone injection and zuranolone clinical trials (Sage Therapeutics), Consultant of: Sage Therapeutics, Inc., Brii Biosciences, Inc., and GH Research Ireland Limited, J. A. Ramos-Quiroga Grant / Research support from: The Department of Mental Health chaired by him received unrestricted educational and research support from the following companies in the last 3 years: Janssen-Cilag, Shire, Oryzon, Roche, Psious, and Rubió. Dr Ramos-QuirogaReceived travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire, Takeda, Shionogi, Bial, and Medice., Consultant of: Was on the speaker’s bureau and/or acted as consultant for Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogi, Sincrolab, Novartis, BMS, Medice, Technofarma, Rubió and Raffo in the last 3 years., Speakers bureau of: Was on the speaker’s bureau and/or acted as consultant for Janssen-Cilag, Novartis, Shire, Takeda, Bial, Shionogi, Sincrolab, Novartis, BMS, Medice, Technofarma, Rubió and Raffo in the last 3 years., R. Lasser Shareolder of: May hold stock and/or stock options of Sage Therapeutics, Inc. , Employee of: Employee of Sage Therapeutics, Inc., A. Sankoh Shareolder of: May hold stock and/or stock options of Sage Therapeutics, Inc., Employee of: Employee of Sage Therapeutics, Inc. , B. Leclair Shareolder of: May hold stock of Biogen Inc., Employee of: Employee of Biogen Inc., M. Kotecha Shareolder of: May hold stock of Biogen Inc., Employee of: Employee of Biogen Inc., J. Doherty Shareolder of: May hold stock and/or stock options of Sage Therapeutics, Inc., Employee of: Employee of Sage Therapeutics, Inc.

Antidepressant discontinuation may cause withdrawal syndrome in some cases. However, evidence on this syndrome related to individual antidepressants is limited, as well as about individual risk factors for severe reactions.

To ascertain whether each individual antidepressant is associated with an increased reporting of withdrawal syndrome as compared with other medications, and to examine clinical risk factors for severe reactions.

We conducted a pharmacovigilance study, with a case/non-case design. We included reports of antidepressant-related withdrawal syndrome from the VigiBase, the WHO global database of individual case safety reports of suspected adverse drug reactions. We performed a disproportionality analysis (calculating reporting odds ratio (ROR) and the Bayesian information component (IC)) of reports of antidepressant-related withdrawal syndrome, comparing antidepressants to all other drugs and to buprenorphine (as a positive control). Antidepressants with significant disproportionate reporting were ranked in terms of clinical priority. We compared serious versus non-serious reactions to determine clinical risk factors for severe reactions.

Based on 31,688 reports of antidepressant-related withdrawal syndrome, we detected a disproportionate reporting for 23 antidepressants. The ROR for antidepressants altogether, compared to all other drugs, was 14.26 (95%CI:14.08-14.45), 17.01 for other antidepressants (95%CI:16.73-17.29), 13.65 for SSRIs (95%CI:13.41-13.90) and 2.8 for tricyclics (95%CI:2.59-3.02). Based on clinical priority ranking, the strongest signals were found for paroxetine, duloxetine, venlafaxine and desvenlafaxine (figure 1), being comparable to buprenorphine. Severe reactions were more frequently reported in males, adolescents, persons with multiple medications, and with longer treatment duration.

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Antidepressants are associated with increased reporting of withdrawal syndrome compared with other medications, with differences between individual antidepressants. Clinicians should be aware of such differences, when prescribing and discontinuing these drugs, as well as of the risk to experience more severe withdrawal symptoms in specific cases.

C. Gastaldon: None Declared, G. Schoretsanitis Consultant of: Dr. Schoretsanitis has served as a consultant for HLS Therapeutics, E. Arzenton : None Declared, E. Raschi : None Declared, D. Papola: None Declared, G. Ostuzzi: None Declared, U. Moretti: None Declared, E. Seifritz Grant / Research support from: Dr. Seifritz has received educational grants, consulting fees and lecture honoraria from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Ricordati, Vifor, Sunovion, Schwabe and Mepha, Consultant of: Dr. Seifritz has received educational grants, consulting fees and lecture honoraria from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Ricordati, Vifor, Sunovion, Schwabe and Mepha, J. Kane Shareolder of: LB Pharmaceuticals and Vanguard Research Group, Consultant of: Dr. Kane has been a consultant and/or advisor for or has received honoraria from Alkermes, Allergan, LB Pharmaceuticals, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson and Johnson, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Reviva, Roche, Sumitomo Dainippon, Sunovion, Takeda, Teva and UpToDate, G. Trifirò Grant / Research support from: he was the scientific director of a Master program on pharmacovigilance, pharmacoepidemiology and real-world evidence which has received non-conditional grant from various pharmaceutical companies; he coordinated a pharmacoepidemiology team at the University of Messina until Oct 2020, which has received funding for conducting observational studies from various pharmaceutical companies (Boehringer Ingelheim, Daichii Sankyo, PTC Pharmaceuticals). He is also scientific coordinator of the academic spin-off “INSPIRE srl” which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.)., Consultant of: Dr. Trifirò has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen;, Speakers bureau of: Dr. Trifirò has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen;, C. Barbui: None Declared

Evidence on neonatal withdrawal syndrome following antidepressant intrauterine exposure is limited, particularly for antidepressants other than selective serotonin reuptake inhibitors (SSRIs).

To ascertain whether maternal antidepressant treatment may be associated with withdrawal syndrome in neonates, investigating the comparative reporting between individual antidepressants and classes.

We performed a case/non-case pharmacovigilance study, searching reports of withdrawal syndrome in newborns in the VigiBase, the WHO database of suspected adverse drug reactions. Disproportionality analysis was performed, estimating reporting odds ratio (ROR) and the Bayesian information component (IC). Antidepressants were compared to all other medications, to methadone, and within each class of antidepressants (SSRIs, tricyclics (TCA) and other antidepressants). Antidepressants were ranked in terms of clinical priority, based on a semiquantitative score.

We retrieved 406 reports of neonatal withdrawal syndrome in 379 neonates related to 15 antidepressants. Compared to all other drugs, disproportionate reporting was detected for antidepressants altogether (ROR: 6.18, 95%CI:5.45-7.01), for TCAs (10.55, 95%CI:8.02-13.88), other antidepressants (ROR: 5.90, 95%CI:4.74-7.36) and SSRIs (ROR: 4.68, 95%CI:4.04-5.42). All antidepressants showed a significant disproportionality, apart from bupropion (figure 1). We did not find any disproportionate reporting for any antidepressant compared to methadone. The clinical priority ranking showed moderate clinical priority for all antidepressants, with the exception four, that had a weak one (figure 1). Most frequently reported symptoms were respiratory symptoms (n=106), irritability/agitation (n=75), tremor (n=52) and feeding problems (n=40).

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Exposure to antidepressants in utero is associated with moderate signals of disproportionate reporting for neonatal withdrawal syndrome for most antidepressants. Clinicians should pay extra attention to neonates with antidepressant-treated mothers.

C. Gastaldon: None Declared, E. Arzenton : None Declared, E. Raschi: None Declared, O. Spigset: None Declared, D. Papola: None Declared, G. Ostuzzi: None Declared, U. Moretti: None Declared, G. Trifirò Grant / Research support from: he was the scientific director of a Master program on pharmacovigilance, pharmacoepidemiology and real-world evidence which has received non-conditional grant from various pharmaceutical companies; he coordinated a pharmacoepidemiology team at the University of Messina until Oct 2020, which has received funding for conducting observational studies from various pharmaceutical companies (Boehringer Ingelheim, Daichii Sankyo, PTC Pharmaceuticals). He is also scientific coordinator of the academic spin-off “INSPIRE srl” which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.)., Consultant of: has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen, Speakers bureau of: has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen, C. Barbui: None Declared, G. Schoretsanitis Consultant of: Dr. Schoretsanitis has served as a consultant for HLS Therapeutics and Thermo Fisher Scientific.

Accumulating studies have pointed out that gut-blood and blood-brain barrier dysfunctions due to the alterations in permeability may play a role in the pathophysiology of neurodevelopmental disorders. Tight junctions are crucial components of these barriers and some peptides including claudin-5, occludin, zonulin and tricellulin are important components of these structures.

This study aimed to investigate the relationship between these molecules and attention deficit hyperactivity disorder (ADHD) in children and adolescents.

A total of 57 children with ADHD and 60 controls aged between 6 and 12 years were included in the study. The severity of ADHD symptoms was assessed through a parent-rated questionnaire and Conner’s Continuous Performance Test. Serum levels of biochemical variables were measured using enzyme-linked immunosorbent assay kits.

Serum claudin-5 and tricellulin levels were significantly lower in the ADHD group compared to the control group. The difference between the groups in terms of serum claudin-5 and tricellulin levels remained significant after controlling for confounding factors such as age, gender and autistic characteristics. There was no significant difference between the groups in terms of serum zonulin and occludin levels. (Table 1)Table 2.

Serum claudin-5, occludin, zonulin and tricellulin levels of ADHD and controls

These results suggest that claudin-5 and tricellulin may be involved in the etiopathogenesis of ADHD. Alterations in these peptides may affect the brain by leading a dysregulation in intestinal or blood-brain barrier permeability that eventually affects the gut-brain axis. The causal relationship between these peptides and ADHD requires further investigation.

None Declared

Social isolation in childhood can be detrimental to physical and mental health. Children with neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD), may be particularly at risk for becoming socially isolated. Similarly, isolated children have limited opportunities to observe, model, and learn age-appropriate interpersonal interactions with other children which could increase ADHD behaviours.

This study examined longitudinal associations between ADHD symptoms and social isolation across childhood. We tested the direction of this association across time, while accounting for pre-existing characteristics, and assessed whether this association varied by ADHD presentation, informant, sex, and socioeconomic status.

Participants included 2,232 children from the Environmental Risk (E-Risk) Longitudinal Twin Study. ADHD symptoms and social isolation were measured at ages 5, 7, 10, and 12. We used random-intercept cross-lagged panel models to assess the directionality of the association across childhood.

Children with increased ADHD symptoms were consistently at increased risk of becoming socially isolated later in childhood, over and above stable characteristics (β=0.05-0.08). These longitudinal associations were not bidirectional; isolated children were not at risk of worsening ADHD symptoms later on. Children with a hyperactive ADHD presentation were more likely to become isolated, compared to an inattentive presentation. This was evident in the school setting, as observed by teachers, but not by mothers at home.

Our findings highlight the importance of enhancing peer social support and inclusion for children with ADHD, particularly in school settings. We add explanatory value over and above traditional longitudinal methods as our results represent how individual children change over time, relative to their own pre-existing characteristics.

None Declared

To study the effects of geography on risk for suicidal ideation and suicide attempts among commercially insured children and youth in the US

Effects of geography on risk for suicidal ideation and suicide attempts among commercially insured children and youth in the US

Few studies have examined the impact of geography on risk factors for suicidal ideation (SI) and suicide attempts (SA). This study used a national representative sample to study how geography may influence the relationships of risk factors for SI and SA in commercially insured children and youth.

The sample was a nationwide retrospective cohort study of 124,424 patients <25 years using commercial claims from four major insurance companies (Aetna, Humana, Kaiser Permanente, and UnitedHealthcare) in the US. The index visit was a mental health or substance use (MH/SUD) outpatient encounter between January 2014 and June 2015. SI and SA were defined by having an ICD-9 diagnosis code within one year after the index visit. Risk factors in the models were demographic and clinical risk factors, including prior psychiatric diagnoses, prescriptions, and healthcare services utilization. Patients’ geographic regions were assigned to one of the nine divisions defined by the US Census Bureau. We used survival analysis to evaluate the effects of geography on risk factors for SI and SA.

At each follow-up time period (post 7-, 30-, 90-, 180-, and 365-day), rates of SI and SA varied by geographic division (p<0.001). The Mountain Division consistently had the highest rates for both SI and SA (5.44%-10.26% for SI; 0.70%-2.82% for SA). Having MH emergency department (ED) visits in the past year increased the hazard ratio of SI by 28%-65% for children and youth residing in the New England, Mid-Atlantic, East North Central, West North Central, and East South Central Divisions. The main effects of geographic divisions were significant for SA (p<0.001). Risk of SA was lower in New England, Mid-Atlantic, South Atlantic, and Pacific (HRs=0.57, 0.51, 0.67, and 0.79, respectively) and higher in the Mountain Division (HR=1.46).

Children and youth residing in the Mountain Division had the highest prevalence of SI and SA and the highest risk of SI after having MH ED visits. Studies of indicators of access to MH ED care and other social determinants of health may clarify the reasons for SI and SA geographic differences.

None Declared

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder affecting 1-2% of the population worldwide. Recent large-scale whole-exome sequencing (WES) studies identified hundreds of rare, highly penetrant genetic variations associated with ASD. Many of these genetic variations underlie particular genetic syndromes characterized by a variety of congenital anomalies in addition to the core ASD symptoms. Recently, we reported about certain ultrasonography fetal anomalies (UFAs) associated with later development of ASD (Regev et al. Brain 2022).

To identify genetic mutations associated with UFAs in children with ASD.

We conducted a cross-sectional study of all children diagnosed with ASD registered at the Azrieli National Centre for Autism and Neurodevelopment (ANCAN) who have both fetal ultrasound and WES data. We used an integrative in-house bioinformatics pipeline specifically designated to identify gene-disrupting variants (GDVs) in a panel of >1200 genes associated with ASD according to SFARI gene database. Then, we compared the prevalence of GDVs in these genes between children with and without UFAs. Finally, we applied the Gene Analytics tool to disrupted genes in children with specific fetal anomalies to identify biological pathways associated with both ASD and these fetal anomalies.

Overall, 115 ASD children were included in this study, of which 49 (42.6%) of them had UFAs in their ultrasound scans (Figure 1). Children with and without UFAs did not differ in their sociodemographic and clinical characteristics except for a significantly lower proportion of males in the UFA group (63.4% vs. 84.8%, respectively; p=0.011). Notably, children with UFAs were more likely to carry GDVs in ASD genes than their counterparts even after adjustment to the sex differences between the groups (aOR=2.27, 95%CI: 1.05-4.93), and this association was the most prominent with GDVs in the most notable ASD genes (i.e., those with SFARI gene score=1). Also, the study shows higher prevalence of children with GDVs in most anatomical systems, with UFAs in fetal size (14.8% vs. 1.6%, p=0.012, cases vs. controls) and the head&brain (16.7% vs. 4.9%, p=0.040, cases vs. controls) being the most prominent (Figure 2). In addition, children with UFAs had significantly more co-occurring mutations, and the number of mutations in a single fetus was significantly correlated with the number of UFAs (r=0.20, p=0.035).

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Our findings suggest distinct genetic mechanisms for ASD subtypes that are characterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing. Our findings suggest distinct genetic mechanisms for ASD subtypes that arecharacterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing.

None Declared

Autism spectrum disorder is a heterogeneous group of disorders that affects virtually every population, regardless of their ethnic or socioeconomic origin. In recent years, the attention of researchers has been drawn to the participation of the oxytocinergic and vasopressinergic systems in the development of autism spectrum disorders. A relatively large number of studies have investigated the association of SNPs in these genes with the development of ASD, however, there is a lack of studies in the literature focusing on their actual effect on expression and on the effect of their expression on the risk of ASD.

The aim of this study was to assess the levels of expression of OXTR and AVPR1a genes and evaluate their links with both risk of ASD and genotypes of the most studied polymorphisms.

The study included 132 people, 77.5% of whom were male (n = 100). 113 participants (85.6%) were diagnosed with autism spectrum disorders confirmed by the ADOS-2 test conducted by a certified diagnostician. In this group, men constituted 76.1% of the population (n = 77). The remaining 28 people did not have a diagnosis of autism spectrum disorders, and in the ADOS-2 study they obtained the result below the cut-off level. The mean age in the whole group was 14.4 years (95% CI: 13.92-14.93).

Significant decrease in expression of the OXTR gene was found in case of rs53576 where presence of the alternative allele (G) was linked to the 20% decrease in expression (2^(-ΔΔCt) = 0.8). In case of AVPR1a alternative allele (T) of SNP rs10877969 was linked to the 20% increase in the gene expression(2^(-ΔΔCt) = 1.197). SNPs rs2254298 (2^(-ΔΔCt) = 0.97) and rs7294536 (2^(-ΔΔCt) = 0.97) did not influence expression of the appropriate genes in significant way. In comparison between the test and control group in participants with confirmed diagnosis of ASD 13% lower expression of AVPR1a was found (2^(-ΔΔCt) = 0.87).

Genotype of SNPs rs53576 and rs10877969 significantly influenced the levels of expression of the genes OXTR and AVPR1a respectively. In case of rs2254298 and rs7294536 observed effects were negligible. Presence of ASD diagnosis was linked to the 13% lower expression of AVPR1a. Abnormalities in AVPR1a expression seem to be more important for the development of autistic traits than the more attention-grabbing gene abnormalities for the oxytocinergic system.

None Declared

Substance use during adolescence is linked to adverse biopsychosocial events, including poor mental health, cognitive deficits, low academic performance, and delinquency (Deas & Brown J Clin Psych 2006; 67 18; Armstrong & Costello JCCP 2002; 70 1224; Cox et al. JSH 2007; 77 109-115; Chassin JJSU 2008; 165-183). Identifying risks for these events is critical, given they are associated with adverse outcomes in adulthood.

Post-pandemic, rates of adolescent depression and anxiety have more than doubled (Racine et al. JAMA Ped 2021; 175 1142-1150). Adolescents often use substances, most commonly alcohol and cannabis, to manage mental health (Colder et al. JCCP 2019; 87 629).

Cannabis is increasingly viewed by adolescents as safe, while alcohol is viewed negatively (SAMHSA 2021). Non-disordered alcohol use (ND-AU), alcohol use below diagnostic criteria level, has adverse developmental impacts for adolescents, including increased risk-taking behavior and heavy substance use in adulthood (Marshall Alcohol Alcohol. 2014; 49 160-164).

With growing normalization of cannabis use, important questions still remain whether non-disordered cannabis use (ND-CU) among adolescents is linked to adverse life events.

Using data from the 2018-2020 National Survey on Drug Use and Health (NSDUH), an annual US representative survey on substance use and mental health, we compared associations among common adolescent substance use and adverse life events.

Responses from adolescents aged 12-17 (N=32,407) from the 2018-2020 NSDUH were analyzed. Logistic regression was used to evaluate associations between substance use disorder (SUD) diagnoses and adverse adolescent life events. Adjusted odds ratios (aOR) were obtained while controlling for age, sex, and race/ethnicity. Analyses included sampling weights to account for the US population. Adolescents in ND-CU and ND-AU groups were defined by either past-month or past-year use without their respective SUD diagnosis.

Approximately 5% of adolescents had any SUD, and 1.3% had more than one SUD (Table 1). All SUD variables, including cannabis use disorder (CUD) and alcohol use disorder (AUD), were significant for all adverse adolescent life events (Table 2). Adolescents with a SUD were nearly 3 times more likely to have major depression in the past year, 2.5 times more likely to have a C+ or below grade average, and 10 times more likely to be arrested, than controls. These risks increased with more than one SUD (Table 2). Adverse events were similar between ND-CU and ND-AU. (Figure 1).

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Given the biopsychosocial risks to ND-CU and ND-AU in adolescents, there may be reason to reevaluate whether the DSM adequately captures the population of youth affected by their cannabis and alcohol use. Clinicians can use these nationally representative data to stratify risks and direct to appropriate treatment.

None Declared

ASD is a multifactorial disease. They arise from the interaction of various genetic and environmental factors. These factors affect specific neuronal circuits, oxidative stress, neuroinflammation, mitochondrial dysfunction. This disrupts the development of the nervous system, the formation of synapses, the connection between brain regions, and the size of the brain. Almost 80% of patients with ASD suffer from mitochondrial dysfunction. Therefore, mitochondrial dysfunction plays a crucial role in the pathogenesis of ASD.

Deficiency of adenosine-triphosphate (ATP) and abnormal levels of Reactive oxygen species (ROS) cause mitochondrial dysfunction in ASD. This leads to metabolic disorders, disorders of synaptic plasticity and disorders of the immune response

The negative association between pathogenic mtDNA mutations and IQ is specific for children with ASD / MD. The overall prevalence of these abnormalities is 1.2 times higher in ASD / MD. ASD, researchers reaffirm that autistic probands carry the burden of mutations in mtDNA, especially mutations that are prone to deleterious effects on OXPHOS. According to a number of researchers, all children with ASD should be screened for MD, given: the high prevalence of abnormal markers of mitochondrial function in ASD compared with the control group; relatively high prevalence of MD in ASD; some children with ASD who have MD may be phenotypically indistinguishable from typical children with ASD; the potential clinical significance of MD in children with ASD.

According to a number of researchers, all children with ASD should be screened for MD, given: the high prevalence of abnormal markers of mitochondrial function in ASD compared with the control group; relatively high prevalence of MD in ASD; some children with ASD who have MD may be phenotypically indistinguishable from typical children with ASD; the potential clinical significance of MD in children with ASD.

The pathophysiological mechanisms of ASD are multifactorial. They are largely unclear. But the mitochondrial hypothesis of the pathogenesis of ASD is being clarified. Mitochondrial dysfunction has been identified as a hallmark of diseased neurons in ASD patients, suggesting a critical role for mitochondrial dysfunction in the pathogenesis of ASD and allowing the development of ASD correction by normalizing mitochondrial functions.

None Declared