A comprehensive evaluation of adverse childhood experiences, social-emotional impairments, and neurodevelopmental disorders in cannabis-use disorder: Implications for clinical practice.

BACKGROUND: Adverse childhood experiences (ACEs), social-emotional impairments (SEIs), and neurodevelopmental disorders (NDs) are frequent in psychiatric disorders, including substance-use disorders. We aimed to determine the prevalence of ACE, SEI, or ND in individuals with cannabis-use disorder (CUD). We compared individuals with preCUD-onset ACE, SEI, or ND to those without. METHODS: We crosssectionally studied 323 inpatients or outpatients with a history of past or current CUD, aged 12-35 years (mean age 22.94 ± 4.79), 64.5% of whom were male. The sample was divided into two groups: the non-premorbid (N = 52) and the premorbid ACE/SEI/ND group (N = 271). Within the premorbid group, further subgroups were based on ACEs, SEI, and NDs. We also analyzed other substance use and psychiatric symptoms/diagnoses based on the non-premorbid-premorbid dichotomy in the CUD sample. RESULTS: Pre-CUD ACE-SEI-ND had higher prevalence of bipolar, schizoaffective, borderline personality, and attention-deficit/hyperactivity disorders, and a history of agitation, hallucinations, and self-injury. The ACE group had higher rates of agitation, depression, delusions, hallucinations, eating disorders, and use of cocaine, amphetamines, and hallucinogens than the SEI or ND. Patients in the premorbid group initiated cannabis use at an earlier age, experienced the first comorbid psychiatric episode earlier, and were hospitalized earlier than those in the non- premorbid ACE-SEI-ND group. CONCLUSIONS: PreCUD-onset ACE, SEI, or ND conditions in individuals with CUDare linked to earlier onset of comorbid mental illness. Furthermore, ACEs contribute to significant and potentially severe clinical symptoms, as well as the use of substances other than cannabis.

Differential Response to Three Antidepressants in Patients with Major Depressive Episode Who Suffered Covid-19-Related Trauma.

BACKGROUND: The Covid 19 pandemic might have impacted response to drug treatment in major depressive episode (MDE). We compared responses to three different antidepressant drugs, i.e., vortioxetine, sertraline, and trazodone, in outpatients with MDE during Major Depressive Disorder (MDD), Bipolar Disorder (BD), or schizophrenia and related psychoses (SSOPDs) during two time periods, i.e., before and after suffering Covid-19-related trauma. METHODS: We conducted an observational study on clinically stabilised for at least 6 months outpatients with MDE during the course of MDD (N=58), BD (N=33), or SSOPDs (N=51). Patients, whose baseline assessments of Montgomery-Åsberg Rating Scale (MADRS), Hamilton Anxiety Rating Scale (Ham-A), Brief Psychiatric Rating Scale (BPRS), Visual Analogue Scale for Craving (VAS-crav) and World Health Organization Quality of Life, Brief version (WHOQOL-BREF) were available, were recruited at the time they suffered Covid-19-related traumas. Fifty patients, prior to the pandemic, when they were clinically stable, were treated with 15 mg/die vortioxetine, 44 with 450 mg/die trazodone, and 48 with 150 mg/die sertraline. After experiencing a major Covid-19-related personal trauma, patients showed clinical worsening which required dosage adjustment (20 mg/day vortioxetine; 600 mg/day trazodone, and 200 mg/day sertraline) and, for some of them, hospitalisation. Scores on the MADRS, Ham-A, BPRS, VAS-crav and WHOQOL-BREF were compared drug-wise and genderwise with Student's t test for continuous variables and Χ2 for categorical variables. RESULTS: The sample consisted of 142 outpatients (age, mean 39.63 ± 16.84; 70 men and 72 women); women were older than men (mean age 43.18 ± 17.61 vs. 35.98 ± 15.30; p=0.01). The two genders did not differ on other variables. For all treatments, worsening symptoms were observed at the time of trauma, followed by slow recovery with treatment readjustment. Trauma-related worsening in patients on vortioxetine was less intense than patients on the other two antidepressants and recovery was faster. All drugs were associated with an improvement in QoL. The vortioxetine group showed a lower hospitalisation rate (24%) than sertraline (35.4%) and trazodone (38.6%), but this was not significant (p=0.27). CONCLUSION: All drugs improved symptoms of Covid-19 trauma in patients with MDE, with vortioxetine showing a small advantage. No differences between vortioxetine, sertraline and trazodone were found as concerning the need for hospitalisation.

Disorganization domain as a putative predictor of Treatment Resistant Schizophrenia (TRS) diagnosis: A machine learning approach.

BACKGROUND: Treatment Resistant Schizophrenia (TRS) is the persistence of significant symptoms despite adequate antipsychotic treatment. Although consensus guidelines are available, this condition remains often unrecognized and an average delay of 4-9 years in the initiation of clozapine, the gold standard for the pharmacological treatment of TRS, has been reported. We aimed to determine through a machine learning approach which domain of the Positive and Negative Syndrome Scale (PANSS) 5-factor model was most associated with TRS. METHODS: In a cross-sectional design, 128 schizophrenia patients were classified as TRS (n = 58) or non-TRS (n = 60) after a structured retrospective-prospective analysis of treatment response. The random forest algorithm (RF) was trained to analyze the relationship between the presence/absence of TRS and PANSS-based psychopathological factor scores (positive, negative, disorganization, excitement, and emotional distress). As a complementary strategy to identify the variables most associated with the diagnosis of TRS, we included the variables selected by the RF algorithm in a multivariate logistic regression model. RESULTS: according to the RF model, patients with higher disorganization, positive, and excitement symptom scores were more likely to be classified as TRS. The model showed an accuracy of 67.19%, a sensitivity of 62.07%, and a specificity of 71.43%, with an area under the curve (AUC) of 76.56%. The multivariate model including disorganization, positive, and excitement factors showed that disorganization was the only factor significantly associated with TRS. Therefore, the disorganization factor was the variable most consistently associated with the diagnosis of TRS in our sample.

Relationships between early age at onset of psychotic symptoms and treatment resistant schizophrenia.

AIM: Early age at schizophrenia onset (EOS) has been associated with a worse clinical course, although previous studies reported substantial heterogeneity. Despite the relevance of the subject, the relationship between the age of onset and treatment resistant schizophrenia (TRS) is less clear. METHODS: We screened 197 non-affective psychotic patients. Of these, 99 suffered from schizophrenia and were putative TRS and were included in a prospective 4-to-8-week trial to assess their response to antipsychotics. According to status (TRS/nonTRS) and age-at-onset (early: ≤18 years, EOS; adult: >18 years, adult onset schizophrenia [AOS]) patients were subdivided in EOS-TRS, EOS-nonTRS, AOS-TRS, AOS-nonTRS. Multiple clinical variables were measured and compared by analysis of covariance (ANCOVA), using age as a covariate. Two-way analysis of variance (ANOVA) was used to assess whether significant differences were attributable to TRS status or age-at-onset. RESULTS: The rate of TRS patients was significantly higher in EOS compared to AOS. At the ANCOVA, EOS-TRS had significantly worse clinical, cognitive, and psychosocial outcomes compared to the other groups. Overall, EOS-TRS were more impaired than EOS-nonTRS, while significant differences with AOS-TRS were less consistent, albeit appreciable. Two-way ANOVA demonstrated that, in the majority of the investigated variables, the significant differences among groups were attributable to the TRS status effect rather than to age-at-onset or combined effects. CONCLUSIONS: These results suggest that refractoriness to antipsychotics may be strongly linked to the early onset of psychotic symptoms, possibly as a result of common neurobiology.

Treatment-resistant schizophrenia: Addressing white matter integrity, intracortical glutamate levels, clinical and cognitive profiles between early- and adult-onset patients.

BACKGROUND: Treatment-resistance in schizophrenia is 30-40%. Its neurobiology remains unclear; to explore it, we conducted a combined spectrometry/tractography/cognitive battery and psychopathological rating study on patients with treatment-resistant schizophrenia (TRS), dividing the sample into early-onset (N = 21) and adult-onset TRS (N = 20). Previous studies did not differentiate between early- (onset 13-18 years) and adult-onset (>18 years at formal diagnosis of schizophrenia) TRS. METHODS: We evaluated cross-sectionally 41 TRS patients (26 male and 15 female) and 20 matched healthy controls (HCs) with psychopathological and cognitive testing prior to participating in brain imaging scanning using magnetic resonance spectroscopy and diffusion tensor imaging to determine the relationship between their symptoms and their glutamate levels and white matter integrity. RESULTS: TRS patients scored lower than HCs on all cognitive domains; early-onset patients performed better than adult-onset patients only on the Symbol Coding domain. TRS correlated with symptom severity, especially negative symptoms. Glutamate levels and glutamate/creatine were increased in anterior cingulate cortex. Diffusion tensor imaging showed low fractional anisotropy in TRS patients in specific white matter tracts compared to HCs (bilateral anterior thalamic radiation, cortico-spinal tract, forceps minor, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, and right uncinate fasciculus). CONCLUSIONS: We identified specific magnetic resonance spectroscopy and diffusion tensor imaging alterations in TRS patients. Adult-onset TRS differed little from early-onset TRS on most measures; this points to alterations being present since the outset of schizophrenia and may constitute a biological signature of treatment-resistance.

Vortioxetine vs. Other Antidepressants in Patients with Major Depressive Episode With or Without Substance Use Disorder.

BACKGROUND: Major Depressive Episodes (MDEs) may characterise many psychiatric disorders. Its pharmacotherapy is laid with unmet needs, rendering the testing of new drugs necessary. OBJECTIVE: To compare the effects of vortioxetine with those of other antidepressants (OADs) in a 1-year naturalistic setting. METHODS: We included 126 adult patients with anMDE in the course of major depressive (MDD), bipolar (BD), or schizophrenia spectrum disorders (SSOPDs), with or without substance use disorder (SUD), who received 5-20 mg/day oral vortioxetine, and compared them with 100 patients receiving OADs at baseline and after 1, 3, 8, and 12 months on their scores on the MADRS, the CGIS, the 24-item BPRS, the YMRS, the Hamilton Anxiety Rating Scale, a Visual Analogue Scale for craving, the Columbia-Suicide Severity Rating Scale, and the WHOQOL-BREF. RESULTS: Patients on vortioxetine improved similarly to those on OADs on all measures, independently from having or not a comorbid SUD. However, they improved with time better than their OADcounterparts if affected by BD or SSOPDs, but not MDD, on the CGI-S, BPRS depression, anxiety, and manic symptoms. SUD hampered the response of anxiety to treatment. Men improved on depression with time better than women. CONCLUSION: MDEs responded to vortioxetine similarly to OADs by improving in depression, general psychopathology, anxiety, suicidal thinking, and quality-of-life, independently from SUD comorbidity. MDEs of patients with BD or SSOPDs on vortioxetine responded better than that of patients on OADs. Clinical Trial Registration No. 17354N.

Developmental trajectories in psychiatric disorders: does substance/alcohol use moderate the effects of affective temperaments as moderators of age at onset? A study in post-acute, hospitalized patients with psychotic or DSM-5 bipolar or major depressive disorders.

BACKGROUND: Age-at-onset (AAO) affects psychiatric disorder outcome; substance (SUDs) or alcohol use disorders (AUDs) may influence their onset. Affective temperaments may affect early AAO and drug-use proneness. Objectives: To investigate whether SUD/AUD moderated temperamental effects in determining AAO of mental disorders. Methods: We included 300 post-acute inpatients with schizophrenia-spectrum and other psychotic (SSOPDs), major depressive (MDD) or bipolar (BD) disorders (168 men; mean age, 40.63 years ± 11.82 men, 43.21 years ± 12.69 women) with (N = 110) or without (N = 190) SUD/AUD. Patients completed cross-sectionally TEMPS-A. We carried moderation analysis with each regression-significant TEMPS temperament as independent variable, SUD/AUD presence/absence as dichotomous moderator, and AAO as dependent variable. Significance was set at p < 0.05. Results: AAO was lower in patients with SUD/AUD diagnosis than in patients without (23.74 ± 10.09 vs. 27.73 ± 10.35, respectively, p = 0.001, η2 = 0.034). SUD/AUD patients scored higher on the hyperthymic (10.22 ± 4.08, p < 0.001, η2 = 0.069) and irritable (8.26 ± 4.69, p < 0.01, η2 = 0.026) temperaments than nonSUD/AUD patients. Moderation analysis showed only direct effects of irritable (ß = -0.55, p < 0.005) and hyperthymic (ß = -0.95, p < 0.001) temperaments on AAO and no significant SUD/AUD and interaction effects. Limitations. Cross-sectional design. Conclusions: When irritable and hyperthymic traits prevail over other temperaments, AAO is earlier in SSOPDs, MDD, and BD. SUD/AUD presence/absence does not moderate the relationship between temperament and AAO.

Disease Severity in Treatment Resistant Schizophrenia Patients Is Mainly Affected by Negative Symptoms, Which Mediate the Effects of Cognitive Dysfunctions and Neurological Soft Signs.

This post-hoc study was aimed at assessing whether disease severity was higher in a sample of Treatment Resistant Schizophrenia patients (TRS) compared to schizophrenia patients responsive to antipsychotics (non-TRS). Determinants of disease severity were also investigated in these groups. Eligible patients were screened by standardized diagnostic algorithm to categorize them as TRS or non-TRS. All patients underwent the following assessments: CGI-S; PANSS; DAI; NES; a battery of cognitive tests. Socio-demographic and clinical variables were also recorded. TRS patients exhibited significantly higher disease severity and psychotic symptoms, either as PANSS total score or subscales' scores. A preliminary correlation analysis ruled out clinical and cognitive variables not associated with disease severity in the two groups. Hierarchical linear regression showed that negative symptoms were the clinical variable explaining the highest part of variation in disease severity in TRS, while in non-TRS patients PANSS-General Psychopathology was the variable explaining the highest variation. Mediation analysis showed that negative symptoms mediate the effects of verbal fluency dysfunctions and high-level neurological soft signs (NSS) on TRS' disease severity. These results show that determinants of disease severity sharply differ in TRS and non-TRS patients, and let hypothesize that TRS may stem from cognitive disfunctions and putatively neurodevelopmental aberrations.