Emotion dysregulation (ED) is increasingly recognized as a transdiagnostic factor in adolescent psychopathology and suicidal ideation and behavior. This study examined the association between ED and recent suicide attempts (SAs) in a clinically referred adolescent sample (n = 182; mean age = 15.70 ± 1.44 years; 80.8% female). We compared adolescents with recent SAs (n = 41) to psychiatric controls (n = 141) on diagnostic and dimensional variables, including the RIPoSt-Y, a novel measure of ED. Adolescents with SAs had higher rates of major depressive episodes (MDEs), depressive symptoms, and significantly elevated RIPoSt-Y interpersonal sensitivity and affective instability. Sequential logistic regressions revealed that both MDE diagnosis and interpersonal sensitivity independently predicted recent SAs, with the latter showing incremental predictive value beyond depressive symptoms. Mediation analysis using structural equation modeling indicated that interpersonal sensitivity had both a significant direct effect and a smaller indirect effect mediated by MDE and depressive symptoms. The total model explained 32.7% of the variance. Findings support the role of interpersonal sensitivity as a dispositional vulnerability of adolescent suicidal behavior, partially mediated by depression. This is the first study to demonstrate the predictive value of RIPoSt-Y dimensions for SAs in youth, underscoring the clinical importance of ED assessment in suicide risk evaluation.

Background: Emotional dysregulation (ED) is a transdiagnostic construct implicated in a broad range of psychiatric conditions. However, the influence of gender on ED remains understudied, particularly among adolescents with severe mood and behavioral disorders. Furthermore, few studies have controlled for confounding effects of specific psychiatric diagnoses. Methods: We assessed 182 adolescents (80.8% female; mean age 15.7 years) referred to our clinical institution. Participants completed the Cyclothymic-Hypersensitive Temperament Questionnaire (CHTQ), the Reactivity, Intensity, Polarity, and Stability Questionnaire (RIPoSt-Y), and the K-SADS-PL interview. Results: Females reported significantly higher levels of CHTQ mood lability (7.53 vs. 5.94, p = 0.012), RIPoSt-Y affective instability (62.33 vs. 53.31, p = 0.023), and interpersonal sensitivity (30.80 vs. 24.97, p < 0.001). They also exhibited higher rates of cyclothymic-hypersensitive temperament (46.6% vs. 14.7%, p = 0.001). Regression analysis revealed that gender and specific psychiatric diagnoses exerted significant independent effects on ED dimensions. Mood lability/hypersensitivity was significantly predicted by bipolar disorder (p = 0.001), depressive disorder (p = 0.002), and female sex (p = 0.025). Affective instability was independently predicted by bulimia nervosa (p = 0.019), depressive disorder (p = 0.004), and female sex (p = 0.033). Significant predictors for interpersonal sensitivity included female sex (p = 0.002), depressive disorder (p = 0.008), bulimia nervosa (p = 0.044), and the absence of conduct disorder (p = 0.048). Conclusions: Female adolescents with severe psychiatric presentations exhibited higher levels of ED, specifically regarding mood lability, affective instability, and interpersonal sensitivity. These associations persisted independently of current mood disorder diagnoses or comorbidities. While findings from this clinical cohort may not be fully generalizable to the general population, they highlight the need for gender-informed clinical interventions for adolescents characterized by severe ED.

INTRODUCTION:Bipolar Disorder (BD) presents with heterogeneous longitudinal cycling patterns, including Manic-Depressive-free Interval (MDI), Depressive-Manic-free Interval (DMI), and Irregular (IRR) cycles. Studies investigating how these cycle types affect clinical course remain limited. This study aimed to examine a large, well-characterised sample of patients with BD types I (BD-I) and II (BD-II). METHODS:Life charts were used to determine the type of cycle, collecting information on first affective episode type, hospitalisations (presence or absence), suicidal ideation/attempts, psychiatric family history, seasonality, agitated depression, predominant polarity, and diagnostic subtype (BD-I vs. BD-II). The impact of cycle type on clinical course was analysed through univariate and multivariate models. RESULTS:Of 378 BD patients, 140 (37.0%) had MDI cycles, 92 (24.3%) had DMI cycles, and 146 (38.6%) had IRR cycles. Multivariate analyses showed MDI patients were more likely to have a manic onset compared to DMI and IRR (p < 0.001). They also showed a higher likelihood of hypomanic onset compared to DMI (p < 0.001). Conversely, DMI was associated with a depressive onset relative to MDI and IRR (p < 0.001). Seasonality was more frequent in patients with regular cycles (MDI and DMI) compared to IRR (p < 0.001). Hospitalisations were more frequent in MDI and DMI cycles compared to IRR, but the association survived only for MDI in multivariate analysis. MDI patients had a higher prevalence of manic predominant polarity and lower rates of depressive predominant polarity compared to both DMI and IRR (p < 0.001). A BD-II diagnosis was significantly more frequent in DMI and IRR (p < 0.001), and a BD-I diagnosis was more prevalent in MDI (p < 0.001). DISCUSSION:Cycle type affected the BD clinical course, with MDI tending to show more frequent hospitalisations, BD-I diagnosis, and manic predominant polarity, while DMI and IRR patients had more BD-II diagnoses. CONCLUSION:Findings underscore the importance of classifying BD based on cycle patterns and suggest that taking into account these patterns may support more personalised treatment planning and improve clinical outcomes.

Background: Antidepressant tolerance/ tachyphylaxis (AT) is defined as initial response (≥ 50% improvement) to antidepressant treatment followed by relapse while on the same adequate dose. The impact of AT as prognostic indicator for response to subsequent antidepressant treatment is unknown. Objective: To test the efficacy of esmethadone (REL-1017) in a subgroup of patients with major depressive disorder (MDD) and AT. Methods: A phase 3, double-blind, randomized, placebo-controlled trial of esmethadone was conducted in adult outpatients with MDD. Prior to randomization, AT was independently assessed by clinicians from the Massachusetts General Hospital Clinical Trials Network and Institute using the MGH Antidepressant Treatment Response Questionnaire. Data for the primary efficacy end point were analyzed using mean difference in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to primary end point (Day 28) in the AT subgroup from the intent to treat (ITT) population, the per-protocol (PP) population, and in patients with severe depression (baseline MADRS ≥35). Results: Among 227 ITT patients, 87 experienced AT. For this subgroup, there was a nominally statistically significant mean difference of 5.4 (P=.023, Cohen effect size 0.53) for esmethadone vs placebo in MADRS total score change from baseline to primary end point (Day 28). Additionally, there was a nominally statistically significant difference in response rate (P=.0004). Consistent results were seen in the PP population with AT and in the severely depressed subgroup of patients with AT. Conclusions: These post hoc analyses, based on data collected independently pre-randomization, suggest that esmethadone may be an effective adjunctive treatment for patients with AT. These results need to be confirmed in larger prospective clinical trials.

Background:Sex differences in psychiatric symptoms among children and adolescents with a major depressive episode (MDE) are less studied than among adults. Previous non-recent studies reported a greater severity in adolescent girls and small differences between sexes in specific symptoms. We aim to explore the differences between male and female patients in the diagnoses, comorbidities, and psychiatric symptoms in a large cohort of pediatric patients referred to a tertiary center for child and adolescent psychiatry. Methods:We collected cross-sectional data on 382 consecutively referred patients (age 6-18 years; 73.8% female patients) with current MDEs (unipolar or bipolar) thoroughly evaluated with clinician (Children's Depression Rating Scale-Revised; K-SADS Mania Rating Scale; Columbia Suicide Severity Rating Scale) and self and parent report (Children's Depression Inventory-2; Multidimensional Anxiety Scale for Children-2; Child Behavior Checklist) standardized measures. Bivariate analyses were followed by a logistic regression model to assess significant predictors of the MDE phenotype of female (vs. male) patients. Results:Female patients were more likely to show severe MDEs (41.5% vs. 26.0%; p = 0.006), suicidal ideation (63.9% vs. 47.0%; p < 0.001) and behaviors (29.4% vs. 13.0%; p = 0.001), and non-suicidal self-injury (58.5% vs. 27.0%; p < 0.001). Male patients were more frequently diagnosed with bipolar disorder (21% vs. 11%; p = 0.012) and/or comorbid ADHD/behavior disorders (20% vs. 8.9%; p = 0.003). Male patients also had more frequently significant mixed hypo/manic symptoms (17% vs. 7.7%; p = 0.01) and were younger at the onset of the first psychiatric symptom (6.32 vs. 7.75 years; p = 0.003), onset of mood disorder (11.3 vs. 12.5 years; p = 0.005), and evaluation (14.0 vs. 15.2 years; p = 0.001). Several symptoms were significantly and independently associated with female patients diagnosed with a current MDE, including a) excessive weeping (OR 1.53; p < 0.001), b) mood lability (OR 1.50; p = 0.014), c) excessive fatigue (OR 1.38; p = 0.002), d) appetite disturbance (OR 1.28; p = 0.041), and e) attention problems (OR 1.07; p = 0.001). Distractibility (OR 0.55; p = 0.009) and conduct problems (OR 0.93; p = 0.001) were in turn correlated with MDE among male patients. Discussion:The study confirms that female patients with MDEs exhibit more severe affective symptoms, while male patients present with more externalizing behaviors and comorbidities. We further report more mixed symptoms and bipolar disorder diagnoses in male patients, who also have an earlier onset of psychiatric symptoms. These findings are discussed also considering implications for the diagnosis of pediatric bipolar disorder. A high clinical sensitivity is needed for highlighting subtle mixed and/or atypical features in severe MDEs among girls.

Abstract Background Elevated rates of suicidal behavior were reported during the COVID-19 pandemic. However, information is scarce on patients’ profiles during this period. Studies evoke the potential adverse effects of the mandatory lockdown, but they remain relatively speculative. Methods We monitored fluctuations in suicide attempts (SA) in six European countries. We gathered data, retrospectively for under 18-year-old SA episodes (1 January 2018 to 31 December 2021), through records of psychiatric emergency services. We collected clinical profiles individually. We extracted environmental indicators by month, as provided by Oxford COVID-19 Government Response Tracker (OxCGRT). We used the Pruned Exact Linear Time (PELT) method to identify breakpoints in SA episodes reported for each country, and logistic regressions to estimate changes in patients’ characteristics after the breakpoints. Finally, we used a univariate and multivariate negative binomial model to assess the link between SA and OxCGRT indicators, accounting for the delay (lag) between the interventions and their impact on SA. Results The study comprised 2,833 children and adolescents (mean age = 15.1 years (SD 1.6); M: F sex-ratio = 1:5.4). A significant increase in SA was found either 6 or 10 months after the beginning of the pandemic, varying by country. Patients were more likely to be girls (aOR = 1.77 [1.34; 2.34]) and used SA methods “other than self-poisoning” (aOR = 1.34 [1.05; 1.7]). In the multivariate model, an association was found between SA and the contact tracing indicator with an 11 months delay, and the number of COVID-19 deaths with a 3-months delay. Conclusions Findings confirmed a delayed increase in SA during the COVID-19 pandemic in children and adolescents as well as changes in patients’ profiles. The duration and severity of the pandemic emerged as the strongest predictor in the rise of SA. If faced with a similar pandemic in the future, the gap between the onset of pandemic and the increase in suicide attempts presents an opportunity for prevention.

Objective: To identify childhood psychopathological features that predict the onset of adolescent Bipolar (BD) versus Unipolar Major Depressive Disorder (UD) during adolescence. Method: We analyzed clinical data from 495 juveniles diagnosed with DSM-5 UD (n = 359), and BD (n = 136), using bivariate analysis and multivariate logistic regression model. Results: BD subjects exhibited earlier onset of any psychiatric feature compared to UD. Antecedents associated with later BD were: oppositional defiant > specific phobias > ADHD > obsessive compulsive (OCD). Antecedents selectively associated with later UD were: social anxiety and separation anxiety. Factors significantly and independently associated with later BD diagnosis were: [a] emotional dysregulation at onset of the mood disorder; [b] first depressive episode with mixed features; [c] antecedent ADHD; [d] antecedent OCD, and [e] antecedent oppositional-defiance. Conclusion: Identifying developmental differences in BD and UD symptoms can aid clinicians in early identification and treatment planning for bipolar disorder in youth.

IntroductionSevere depression is a prevalent psychiatric illness in children and adolescents associated with high levels of morbidity, disability, and a high risk of suicidal behavior. Cognitive factors associated with depression severity in juveniles have been poorly reported. MethodsWe investigated the relationship between depression severity and intelligence quotient (IQ)with its subscales in 65 juveniles (aged 10–17 years) with a current major depressive episode evaluated at the Mood Disorder Program of Bambino Gesù Children’s Hospital in Rome. Pearson’s correlation analyses were followed by a Benjamini–Hochberg correction and linear multivariable regression model. ResultsDepression severity measured with the total score of the Children’s Depression Rating Scale-Revised (CDRS-R) was positively associated with the Verbal Comprehension Index (VCI; Pearson’s r = 0.309 [0.042−0.534]; p = 0.024). The CDRS-R subscales positively associated with VCI by Pearson’s correlation were depressed feelings, suicidal ideation, excessive weeping, and reduced facial expressions. Suicidal ideation was the only factor independently and significantly associated with higher VCI in the multivariable linear regression model.DiscussionSuicidal ideation was significantly and independently associated with higher verbal comprehension, indicating that depressed juveniles with better verbal ability may be at a greater risk of showing suicidal ideation.

Objective: The relationship between the duration of major depressive disorder (MDD) and therapeutic response to standard antidepressant treatment (SAT) is unknown. N-methyl- D-aspartate receptor uncompetitive antagonists are emerging drugs for MDD. We investigated whether the antidepressant effect of esmethadone (REL-101 7) could be related to the duration of depression. Methods: We analyzed data from a Phase 2a study of adjunctive treatment with esmethadone in MDD patients ( DSM-5 ) with inadequate response to ongoing SAT (May 2018-August 2019). Patients were randomized to treatment with esmethadone 25 mg, esmethadone 50 mg, or placebo for 7 days, followed by an observation period (Days 7-14). Duration of depression was derived from 2 measures: (1) time from onset (TFO), calculated as the difference in years between age at trial enrollment and age at the onset of the first major depressive episode (MDE), and (2) TFO index, calculated by computing the years of illness duration (number of years from the beginning of MDD), divided by age and multiplied by 100. First, bivariate correlations between TFO and change from baseline (CFB) were calculated by Spearman rho. Linear mixed-model analyses were also conducted. Results: A total of 62 patients participated in the trial. The median values of time from MDD onset for the 62 patients were 11 years (absolute value) and 22% (percentage of life-years). Duration of depression was significantly correlated with Montgomery-Asberg Depression Rating Scale (MADRS) CFB on Day 14, even when controlling for the effect of current depression severity (MADRS baseline). In the linear mixed-model analyses, we found a significant effect of duration on reduction in MADRS score from T0 to subsequent assessments (P< P < .05). Number of previous MDEs and effect of esmethadone 50 mg when compared to 25 mg were not significant. Conclusion: Esmethadone 25 and 50 mg were more effective in reducing MADRS scores in patients with shorter time from first MDE onset.

Objective: The relationship between the duration of major depressive disorder (MDD) and therapeutic response to standard antidepressant treatment (SAT) is unknown. N-methyl-D-aspartate receptor uncompetitive antagonists are emerging drugs for MDD. We investigated whether the antidepressant effect of esmethadone (REL-1017) could be related to the duration of depression.Methods: We analyzed data from a Phase 2a study of adjunctive treatment with esmethadone in MDD patients (DSM-5) with inadequate response to ongoing SAT (May 2018-August 2019). Patients were randomized to treatment with esmethadone 25 mg, esmethadone 50 mg, or placebo for 7 days, followed by an observation period (Days 7-14). Duration of depression was derived from 2 measures: (1) time from onset (TFO), calculated as the difference in years between age at trial enrollment and age at the onset of the first major depressive episode (MDE), and (2) TFO index, calculated by computing the years of illness duration (number of years from the beginning of MDD), divided by age and multiplied by 100. First, bivariate correlations between TFO and change from baseline (CFB) were calculated by Spearman ρ. Linear mixed-model analyses were also conducted.Results: A total of 62 patients participated in the trial. The median values of time from MDD onset for the 62 patients were 11 years (absolute value) and 22% (percentage of life-years). Duration of depression was significantly correlated with Montgomery-Asberg Depression Rating Scale (MADRS) CFB on Day 14, even when controlling for the effect of current depression severity (MADRS baseline). In the linear mixed-model analyses, we found a significant effect of duration on reduction in MADRS score from T0 to subsequent assessments (P < .05). Number of previous MDEs and effect of esmethadone 50 mg when compared to 25 mg were not significant.Conclusion: Esmethadone 25 and 50 mg were more effective in reducing MADRS scores in patients with shorter time from first MDE onset.Trial Registration: ClinicalTrials.gov identifier: NCT03051256.

Correct classification of irritability is extremely important to assess prognosis and treatment indications of juvenile mood disorders. We assessed factors associated with low versus high parent- and self-rated irritability using the affective reactivity index (ARI) in a sample of 289 adolescents diagnosed with a bipolar or a major depressive disorder. Bivariate analyses were followed by multilinear logistic regression model. Factors significantly and independently associated with high versus low parent-rated ARI score were: more severe emotional dysregulation and bipolar disorders diagnosis. Factors significantly and independently associated with high versus low self-rated ARI score were: lower children depression rating scale (CDRS-R) difficulty of having fun item score, greater children depression inventory (CDI-2) self-report score, more severe emotional dysregulation, and greater CDRS-R appetite disturbance item score. High parent-rated irritability was strictly related with a bipolar disorder diagnosis, whereas high youth-rated irritability was related to depressive phenotype characterized by appetite/food-intake dysregulation, mood lability, and less anhedonia and apathy.

Introduction Suicidal attempts (SAs) in youth have been increasing during the last decades. Methods We studied consultations, SA, and suicidal ideation (SI) in a pediatric emergency department (ED). Results From 1 January 2011 to 31 May 2022, 606,159 patients accessed the ED, 8,397 of who had a child psychiatry consultation (CPC). CPCs increased significantly by 11 times in the last decade (155 in 2011 vs. 1,824 in 2021, p < 0.001); CPCs for SA increased significantly by 33 times, from 6 in 2011 to 200 in 2021 (3.9% of total CPC vs. 11%, p < 0.001). While total CPCs increased constantly during the entire period (annual percent change (APC) of 21.7 from 2011 to 2021 in a 0 joinpoint model), CPCs for SA increased significantly from 2011 to 2016, were approximately stable from 2016 to 2020, and then had a peak in 2021 after the COVID-19 pandemic (APC from 2011 to 2016 of 64.1, APC of 1.2 from 2016 to 2020, and APC of 230 after 2020 in a 2-joinpoint model). Discussion Total CPCs in ED as well as evaluation for SA and SI increased significantly during the last decade. CPCs for SA had an additional increase after the COVID-19 pandemic. This picture warrants timely and efficient improvements in emergency settings and mental health resources.

Objective: Improvement of cognitive function in patients with major depressive disorder (MDD) is an important treatment outcome. REL-1017 (esmethadone HCl) is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and a potentially rapidly acting antidepressant. The objective of this study was to define the effects of REL-1017 on subjective cognitive measures in patients with MDD.Methods: Post hoc analysis was conducted of subjective cognitive measures from the Montgomery-Asberg Depression Rating Scale (MADRS) and the Symptoms of Depression Questionnaire (SDQ) from a randomized, double-blind, placebo-controlled, Phase 2a study. The study, designed to assess the safety, tolerability, and efficacy of 2 dosages (25 mg and 50 mg) of REL-1017 as an adjunctive treatment in patients with MDD unresponsive to standard antidepressants, included 62 patients. We analyzed subjective cognitive measures derived from the MADRS and SDQ scales at baseline and up to day 14, 7 days after the last dose of study drug. We developed 2 composite indexes that included subjective cognitive measures selected from the MADRS and SDQ.Results: The subanalysis of single measures and the 2 composite indexes derived from the MADRS and SDQ measures showed clinically meaningful and statistically significant improvements in cognitive function (P < .05).Conclusions: In a Phase 2a clinical trial, REL-1017 improved subjective measures of cognitive impairment, in addition to improving total MADRS and SDQ scores. These results need to be confirmed in larger and longer studies in MDD that include objective measures of cognitive function. Phase 3 studies of REL-1017 for MDD are currently underway.Clinical Trials Registration: ClinicalTrials.gov identifier: NCT03051256.

Background Gender differences have been reported in the severity and psychopathological features of major depressive disorders among adults but are poorly reported in adolescent samples. Objective This study aimed to examine gender differences in the psychopathology of mixed depression among adolescents. Methods We analyzed 341 outpatients with the current major depressive episode (MDE) retrospectively to identify patients with DSM-5 MDE with mixed features. We compared examiner-rated depressive and (hypo)manic symptoms and self- and parent-reported symptoms between sexes. Results We identified 76 patients with an MDE with mixed features (67.1% females, 32.9% with bipolar disorder). Depression severity was significantly greater in females versus males (CDRS-R total score 56.2 vs. 48.2, p = 0.014). Depressive symptoms were significantly and independently found to be more severe among females in a logistic regression model, including excessive fatigue (OR 1.68; p = 0.025), low self-esteem (OR 1.67; p = 0.04), excessive weeping (OR 1.62; p = 0.021), and CBCL AAA index (OR 1.04; p = 0.015). None of the depressive symptoms scored greater in males. Males had higher levels of motor activity (2.12 vs. 1.69; p = 0.048) and pressured speech (1.80 vs. 1.24; p = 0.004). Self-rated anxiety (69.3 vs. 56.8, p = 0.047) and CBCL AAA index (207 vs. 189; p = 0.007) were higher in females. Conclusion Adolescent depression with mixed features is more severe in women, with a higher expression of core affective symptoms and excessive fatigue. While in males, slightly higher levels of psychomotor activation are reported, in females, emotional dysregulation and excessive weeping may subtend a difference in a broader spectrum of mixed features.

Access to the emergency department (ED) for acute psychiatric problems, especially for suicide attempts (SA), has increased in the last decade. This increase has exceptionally accelerated after the COVID-19 pandemic. The aim of this project was to study the increase in acute psychiatric care demand of children and adolescents in the short and medium term after the pandemic, in relation to public health measures and in comparison with a pre pandemic reference period. We retrospectively studied 5445 child psychiatric (CP) consultations requested for any reason and for suicide attempt (SA), suicidal ideation (SI) and non-suicidal self-injury (NSSI) in a pediatric ED during three different pandemic periods in Italy (from March 2020 to May 2022) and compared them to a pre-pandemic reference period (from January 2018 to February 2020). Monthly CP consultations for any reason increased significantly by 2.2 times from 70.9 in 2018 to 157 in 2022 (p < 0.001). During the pandemic, monthly CP consultations for any reason increased significantly from 75/month in the first lockdown to 153/month in the second lockdown, remaining stable in the following year. CP consultations for SA increased significantly from 5/month in the first lockdown to 16/month in the second. Consultations for SI increased gradually but significantly from the pre-pandemic period to the end of the pandemic. Juveniles evaluated for SA during the pandemic vs. pre-pandemic more frequently attempted suicide by self-poisoning and less frequently by precipitation, and they were more likely to be diagnosed with a major depressive disorder. CP consultations for any reason and for suicide attempts significantly increased in the decade before the pandemic and peaked in the second lockdown period in Italy.

To the Editors Dissociative disorders (DDs) and dissociative states coexisting with other psychiatric disorders are highly prevalent in the psychiatric population and may be underdiagnosed. In an outpatient psychiatric population, the prevalence of DDs was 29%, and only 5% had previously received a DD diagnosis.1 Dissociative symptoms often coexist with depressive symptoms in patients with major depressive disorder (MDD),2 and there is a relationship between depression severity and dissociative symptoms in bulimic patients.3 Dissociative symptoms may precede the onset of mood disorders, could be a risk factor for their development, and may be added to those more traditionally considered as prodromal in depression.4–7 Uncompetitive N-methyl-d-aspartate receptor (NMDAR) channel blockers have been proposed as a treatment for posttraumatic stress disorder (PTSD). Ketamine, an NMDAR antagonist with antidepressant efficacy, has shown efficacy in PTSD.8 REL-1017 (esmethadone), the opioid-inactive (S)-enantiomer of methadone, is a novel, low potency NMDAR channel blocker,9 which currently is in phase 3 clinical trials for MDD. In phase 1 and phase 2 trials, REL-1017 showed very favorable safety, tolerability, and pharmacokinetic profiles and rapid, robust, and sustained antidepressant efficacy without clinically meaningful opioid-like effects or dissociative effects.10–12 We report 2 patients enrolled in a phase 2a trial11 experiencing a current major depressive episode and with clinically meaningful dissociative symptoms evaluated on the Clinician-Administered Dissociative States Scale (CADSS).13 Both patients had been diagnosed with MDD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and had inadequate responses to 1 to 3 courses of antidepressant treatment as defined by the Antidepressant Treatment Response Questionnaire.14 They were admitted to a clinical research unit for approximately 10 days, where they received REL-1017 or placebo daily, for 7 consecutive days as adjunctive treatment for MDD. Both patients gave written informed consent to publish their cases. Case 1 A 31-year-old White male patient who had been diagnosed with MDD at age 18 years and who had a history of recurrent depressive episodes during his lifetime and no other psychiatric history was randomized to the REL-1017 25-mg subgroup in June 2019. In October 2018, he was first started on trazodone 300 mg, which was suspended after 3 months for lack of efficacy. At study entry, the patient had been taking bupropion 300 mg once daily for 11 months. On day 1 before and after the first dose of REL-1017, the total CADSS scores were 22 and 2, respectively, showing a clinically meaningful improvement in dissociative symptoms. This improvement was sustained on day 7 (2 hours after dose) with a CADSS total score of 6 and after treatment discontinuation, on day 9, with a complete resolution of symptoms (a CADSS total score of 0; Table 1). The baseline depressive symptoms total score, the Montgomery-Åsberg Depression Rating Scale (MADRS) was 18. On day 2 (before dose) and on day 4, the MADRS scores were 15 and 19, respectively. The measurement on day 7 was 17, and the value was not available at day 14 because the patient was lost to follow-up after discharge. The patient reported no adverse events except for mild constipation resolving spontaneously without any treatment. TABLE 1 - Clinician-Administered Dissociative States Scale Total Score and Item Scores for the 2 Patients at 4 Evaluation Time Points: Day 1 Predose, Day 1 Postdose, Day 7 Post–Last Dose, and Day 9 Patient 1(Assigned to REL-1017 25 mg, 75-mg Loading Dose on Day 1) Patient 2(Assigned to REL-1017 50 mg, 100-mg Loading Dose on Day 1) CADSS (total score) at each time point 22, 2, 6, 0 35, 14, 9, 0 Single itemDefinition and score for the 2 patients 1) Do things seem to be moving in slow motion? 2/0/0/0 3/1/1/0 2) Do things seem to be unreal, as if you are in a dream? 0/0/0/0 3/1/1/0 3) Do you have some experiences that separates you from what is happening; for instance, do you feel as you are in a movie or a play, or as if you are a robot? 0/0/0/0 3/1/0/0 4) Do you feel as if you are looking at things from outside of your body? 0/0/0/0 3/1/0/0 5) Do you feel as if you are watching the situation as an observer or spectator? 2/0/0/0 3/1/1/0 6) Do you feel disconnected from own body? 1/0/0/0 3/1/0/0 7) Does sense of your own body feel changed: for instance, does your own body feel changed unusually large or unusually small? 2/0/0/0 1/1/0/0 8) Do people seem motionless/dead or mechanical? 0/0/0/0 3/1/0/0 9) Do objects look different than you would expect? 0/0/0/0 1/0/0/0 10) Do colors seem to be diminished in intensity? 0/0/0/0 0/0/0/0 11) Do you see things as if you are in a tunnel, or looking through a wide-angle photographic lens? 0/0/0/0 2/0/0/0 12) Does this experience seem to take much longer than you would expected? 0/0/0/0 1/1/1/0 13) Do things seem to be happening very quickly, as if there is a lifetime in a moment? 0/0/1/0 0/0/0/0 14) Do things happen that you later cannot account for? 2/0/0/0 1/1/0/0 15) Do you space out, or in some other way lose track of what is going on? 0/0/0/0 1/1/1/0 16) Do sounds almost disappear or become much stronger than you would have expected? 0/0/0/0 0/0/1/0 17) Do things seem to be very real, as if there is a special sense of clarity? 3/0/2/0 0/0/1/0 18) Does it seem as if you are looking at the world through a fog, so that people and objects appear far away or unclear? 2/0/0/0 1/1/0/0 19) Do colors seem much brighter than you would have expected? 0/0/0/0 0/0/0/0 20) Do you feel confused about who you really are? 2/0/0/0 2/0/1/0 21) Do feel there are different parts of yourself, which do not fit together? 2/0/0/0 1/1/0/0 22) Do you have gaps in your memory? 3/2/3/0 2/1/1/0 23) Do you feel like you have more than one identity? 1/0/0/0 1/0/0/0 Case 2 A 39-year-old African American male patient first diagnosed with MDD at age 21 years was randomized to the REL-1017 50-mg subgroup. The patient had a history of recurrent depressive episodes during his lifetime and no other psychiatric history. In April 2018, he was started on sertraline 100 mg once a day orally, which was suspended in January 2019 because of lack of efficacy. At study entry, the patient had been taking bupropion 300 mg once daily for 6 months. On day 1 before the study drug administration and on day 1 after the first dose, the total CADSS scores reported by the patient were 35 and 14 showing a clinically meaningful improvement in dissociative symptoms. This improvement was sustained on day 7 (2 hours after dose) with a CADSS total score of 9, and after treatment discontinuation on day 9, with a complete resolution of symptoms (a CADSS total score of 0; Table 2). The baseline depressive symptoms total score evaluated on MADRS scale was 31. On day 2 (before dose) and on day 4, the total MADRS scores were 24 and 22, respectively. The measurements on day 7 and on day 14 were 24 and 23, respectively. The patient reported no adverse events except for a mild constipation spontaneously resolved without any treatment. These case reports suggest a potential therapeutic role for NMDAR uncompetitive antagonists in patients with overlapping symptomatology of depression and dissociation with poor response to standard antidepressant treatments. Different hypotheses have been proposed concerning the nature and role of dissociation in the context of MDD.2,15 Dissociative symptoms have been related to childhood trauma or traumatic adult life events and are considered risk factors for developing psychiatric disorders and an indicator of severity for MDD, as proposed by the depersonalization item in the Hamilton Rating Scale for Depression.2 Given the strong polygenic association of major depressive disorder and PTSD,16 an overlap in pharmacological treatments for these 2 conditions is conceivable. These preliminary data signal that REL-1017 may potentially determine rapid improvement in dissociative symptoms in patients with MDD experiencing dissociative symptoms with a temporal association to acute changes in mood, which needs further investigations. These preliminary results need to be replicated in larger and longer trials. Ongoing phase 3 clinical trials with REL-1017 could generate additional data supporting the initiation of future clinical studies on REL-1017 for the treatment of PTSD. Clotilde Guidetti, MDGiulia Serra, MD Child and Adolescent Neuropsychiatry Unit Department of Neurological and Psychiatric Science Bambino Gesù Children’s Hospital Rome, ItalyLuca Pani, MD Department of Psychiatry and Behavioral Sciences University of Miami School of Medicine Miami, FL Department of Biomedical Metabolic and Neural Sciences University of Modena and Reggio Emilia, ItalyMarco Pappagallo, MD Relmada Therapeutics Coral Gables FL Department of Anesthesiology Albert Einstein College of Medicine Bronx, NYGino Maglio, MDMonia Trasolini, MD Child and Adolescent Neuropsychiatry Unit Department of Neurological and Psychiatric Science Bambino Gesù Children’s Hospital Rome, ItalySara De Martin, PhDAndrea Mattarei, PhD Department of Pharmaceutical and Pharmacological Sciences University of Padova Padova, ItalyFrancesco Bifari, MD, PhD Department of Medical Biotechnology and Translational Medicine University of Milan Milan, ItalyFranco Folli, MD, PhD Department of Health Science University of Milano Milan, ItalyPaolo L. Manfredi, MD Relmada Therapeutics Coral Gables, FL [email protected]Maurizio Fava, MD Department of Psychiatry Massachusetts General Hospital Boston, MA