Unraveling the molecular basis of cannabidiolic acid methyl Ester's anti-depressive effects in a rat model of treatment-resistant depression.

Major depressive disorder (MDD) stands as a significant cause of disability globally. Cannabidiolic Acid-Methyl Ester (CBDA-ME) (EPM-301, HU-580), a derivative of Cannabidiol, demonstrates immediate antidepressant-like effects, yet it has undergone only minimal evaluation in psychopharmacology. Our goal was to investigate the behavioral and potential molecular mechanisms associated with the chronic oral administration of this compound in the Wistar Kyoto (WKY) genetic model of treatment-resistant depression. Male WKY rats were subjected to behavioral assessments before and after receiving chronic (14-day) oral doses of CBDA-ME (0.5 mg/kg), 15 mg/kg of imipramine or vehicle. At the end of the study, plasma corticosterone levels and mRNA expression of various genes in the medial Prefrontal Cortex and Hippocampus were measured. Behavioral outcomes from CBDA-ME treatment indicated an antidepressant-like effect similar to imipramine, as oral ingestion reduced immobility and increased swimming duration in the Forced Swim Test. Neither treatment influenced locomotion in the Open Field Test nor preference in the Saccharin Preference Test. The behavioral impact in WKY rats coincided with reduced corticosterone serum levels, upregulated mRNA expression of Cannabinoid receptor 1, Fatty Acid Amide Hydrolase, and Corticotropin-Releasing Hormone Receptor 1, alongside downregulation of the Serotonin Transporter in the hippocampus. Additionally, there was an upregulation of CB1 mRNA expression and downregulation of Brain-Derived Neurotrophic Factor in the mPFC. These findings contribute to our limited understanding of the antidepressant effects of CBDA-ME and shed light on its potential psychopharmacological mechanisms. This discovery opens up possibilities for utilizing cannabinoids in the treatment of major depressive disorder and related conditions.

Acute oral cannabidiolic acid methyl ester reduces depression-like behavior in two genetic animal models of depression.

BACKGROUND AND PURPOSE: Cannabidiolic acid methyl ester (HU-580) was recently shown to reduce stress-induced anxiety-like behavior in rats. The aim of this study was to examine the antidepressant effect of HU-580 in two different rat models of depression. EXPERIMENTAL APPROACH: Using the forced swim test (FST), we evaluated the effect of HU-580 in 43 Wistar-Kyoto (WKY) and 23 Flinders Sensitive Line (FSL) adult male rats. KEY RESULTS: 1 mg/kg HU-580 reduced immobility and increased swimming in WKY rats, compared to vehicle-treated controls (p < 0.05). This dose exerted similar effects in FSL rats (p < 0.05). CONCLUSION AND IMPLICATIONS: This is the first report of antidepressant efficacy of HU-580. These findings expand the very limited existent results, suggesting that HU-580 is a potent anxiolytic agent. Taken together with its chemical stability, HU-580 emerges as a candidate for a future antidepressant medication.

Psychological autopsy of seventy high school suicides: Combined qualitative/quantitative approach.

OBJECTIVE: Suicide is the leading cause of death among Israeli youths but data on causes are scarce. This study used psychological autopsies of 70 Israeli school students who committed suicide during 2004-2011, attempting to determine the causes. METHODS: Four narratives of the self were identified (qualitative analysis) and compared (quantitative analysis): (1) regressive: functioning and mood deteriorated continuously (45%); (2) tragic: doing well until rapid decline around suicidal crisis (20%); (3) unstable: peaks and crises throughout life (20%); and (4) stable: long lasting state of adverse living circumstances (15%). Functioning, mental disorders, stressful life events and substance abuse were examined. RESULTS: A representative profile of the suicide-completer emerged. Suicidality in the tragic narrative involved shorter crisis, fewer risk factors and less psychopathology than the other narratives, also better general functioning and better school performance. Though decrease in functioning was evident in all groups, in the tragic group it tended to be disregarded. CONCLUSION: This study presents an in-depth analysis of a unique suicide population of high school students. A combined methodology of qualitative and quantitative analyses reveals a distinct subpopulation of suicidal adolescents with little or no overt psychopathology that poses a challenge to suicide prevention strategies.

Dynamic occupation assessment of executive function in adolescents with schizophrenia spectrum disorders: An initial report.

OBJECTIVE: This study presents an initial evaluation of the psychometric properties of the Dynamic Occupation Assessment of Executive Function (DOAEF), a new tool designed to assess adolescents' executive function (EF) in daily situations and offering two levels of mediation through the administration process. METHOD: In the preliminary study, we tested 22 healthy adolescents. In the advanced stage, the instrument was administered to 105 healthy adolescents and to another 92 adolescents diagnosed with schizophrenia spectrum disorders. Information regarding EF was assessed by the DOAEF and Wisconsin Card Sorting Computer Version Test (WCST-CV-64). RESULTS: Inter-rater, test-retest and internal consistency indices were found to be satisfactory. Correlation between the DOAEF and the WCST-CV-64 scores supports the DOAEF's convergent validity. Significant differences were found between the healthy participants and the adolescents diagnosed with schizophrenia spectrum disorders, thus supporting the DOAEF's criterion validity. CONCLUSION: The DOAEF may be useful in assessing the level of mediation, which patients need for the comprehension of daily situations in which EFs are required.

Emotional regulation of mental pain as moderator of suicidal ideation in military settings.

BACKGROUND: In the Israel Defense Forces (IDF) as well as in most armies throughout the world, the leading cause of death during peace-time is suicide. This study examines emotional regulation of mental pain as a contributor to suicidal ideation in soldiers. METHODS: One hundred sixty-eight IDF soldiers (aged 18-21years, 59% males) completed the following self-report questionnaires: Scale for Suicide Ideation (SSI); Orbach & Mikulincer Mental Pain Scale (OMMP); and Emotional Regulation of Mental Pain questionnaire. Participants were divided into 3 groups: soldiers who attempted suicide (AS group, n=58), soldiers under treatment by a mental health professional and reporting no suicidal behavior (PT group, n=58), and controls (C group, n=50). RESULTS: Suicide ideation, mental pain, and low emotional regulation were significantly higher in the suicidal group as compared to the two other groups (P<0.001). Mental pain was significantly related to more suicide ideation in soldiers with low ability to regulate mental pain (P<.001 for the interaction). CONCLUSION: Emotional regulation of mental pain moderates the link between mental pain and suicide ideation. Soldiers with high mental pain and low regulation of mental pain exhibited higher suicidal ideation. These findings may assist in planning prevention programs in the army and similar settings.

Insight and satisfaction with life among adolescents with mental disorders: assessing associations with self-stigma and parental insight.

OBJECTIVE: The purpose of the current study was to assess the associations of illness perception-related variables with satisfaction with life (SwL) among adolescents with mental disorders. METHODS: Insight into mental disorder (SAI-E), Internalized stigma of mental illness (ISMI) and Multidimensional Students' Life Satisfaction Scale (MSLSS) were administrated to 30 adolescent patients. Adapted version for parents of the SAI-E was also administrated to 37 of their parents. RESULTS: Significant positive correlations were found between insight into the illness, self-stigma and parental insight. Insight and self-stigma were significantly negatively related to the total score of SwL and few of its dimensions while parental insight was significantly associated only with the SwL dimensions of school and self. Regression models revealed main negative effects of insight and self-stigma on SwL and no interaction effect. CONCLUSIONS: The possible independent contribution of insight and self-stigma to SwL should be addressed in interventions designed for family and adolescents coping with mental illness. Special attention should be given to the possible negative implications that insight possesses. In lack of support of the moderation role of self-stigma, reported in studies among adults with mental illness, future studies should trace other variables in order to further understand the insight paradox among adolescents.

Father-daughter relationship and the severity of eating disorders.

BACKGROUND: Mother-daughter relationship was the focus of studies on the development of eating disorders (ED) for many years. This study aimed to examine the association between the father-daughter relationship and ED and depressive symptoms. METHODS: Fifty-three women diagnosed with ED were compared to a psychiatric control group (n=26) and to healthy participants (n=60) regarding their perception of their fathers and the relationship with them. Assessments were done using the Parental Bonding Instrument, the Eating Disorders Questionnaire, the Body Shape Questionnaire, the Eating Attitude Test, and the Beck Depression Inventory as well as narrative-based methods. RESULTS: Fathers' negative attributes were significantly associated with ED and depressive symptom. Two profiles of father-daughter relationship were found, the "caring and benevolent" relationship and the "overprotective and avoidant" one. In the latter, patients displayed significantly higher levels of food-restraint, more concerns about eating and about their body shape and appearance, and higher levels of depression. DISCUSSION: Negative perception of the father's parenting style as well as the quality of the relationship with him are crucial for the understanding of the development and persistence of ED. Therapeutic programs for ED should focus not only on the relationship with the mother but must also address the relationship with the father.

The complex impact of five years of stress related to life-threatening events on pregnancy outcomes: a preliminary retrospective study.

OBJECTIVE: To study the impact of chronic, life-threatening stressors in the form of daily missile attacks, for five consecutive years, on pregnancy outcomes. METHOD: Charts of deliveries from two neighboring towns in the south of Israel, covering the years 2000 and 2003-2008, were reviewed retrospectively. One city had been exposed to missile attacks, while the other was not. For each year, 100 charts were chosen at random. RESULTS: Significant association was found between exposure to stress and frequency of pregnancy complications (P=0.047) and premature membrane rupture (P=0.029). A more detailed analysis, based on dividing the stressful years into three distinct periods: early (2003-2004), intermediate (2005-2006) and late (2007-2008), revealed that preterm deliveries were significantly more frequent (P=0.044) during the intermediate period, as was premature membrane rupture during the late period (P=0.014). CONCLUSION: Exposure to chronic life-threatening stress resulted in more pregnancy complications and in particular more premature membrane ruptures. The impact was most significant during the middle period of the 5-year-exposure to the stressor. Hence it seems that factors of duration and habituation may play a role in the impact of chronic, life-threatening stressors on pregnancy.

Religiosity is a protective factor against self-injurious thoughts and behaviors in Jewish adolescents: findings from a nationally representative survey.

PURPOSE: Few studies have investigated the association between religiosity and self-injurious thoughts and behaviors specifically in adolescents, yielding inconsistent results. To date, no study has examined this relationship in a Jewish adolescent cohort. METHODS: Self-injurious thoughts and behaviors, as well as depression, were assessed in a nationally representative sample of Jewish adolescents (n=620) and their mothers, using the Development and Well-Being Assessment Inventory (DAWBA) structured interview. Degree of religiosity was obtained by a self-report measure. RESULTS: Using multivariate analysis, level of religiosity was inversely associated with self-injurious thoughts and behaviors (Wald χ(2)=3.95, P=0.047), decreasing the likelihood of occurrence by 55% (OR=0.45, 95% CI 0.2-0.99), after adjusting for depression and socio-demographic factors. This model (adjusted R(2)=0.164; likelihood ratio χ(2)=7.59; df=1; P<0.047) was able to correctly classify 95.6% of the patients as belonging either to the high or low risk groups. CONCLUSION: This is the first study demonstrating religiosity to have a direct independent protective effect against self-injurious thoughts and behaviors in Jewish adolescents. This finding has clinical implications regarding risk assessment and suicide prevention. Further research can potentially elucidate the complex relationship between religiosity, self-injury and suicide in this population.

The neurobiology of autism spectrum disorders.

Data is progressively and robustly accumulating regarding the biological basis of autism. Autism spectrum disorders (ASD) are currently considered a group of neurodevelopmental disorders with onset very early in life and a complex, heterogeneous, multifactorial aetiology. A comprehensive search of the last five years of the Medline database was conducted in order to summarize recent evidence on the neurobiological bases of autism. The main findings on genetic influence, neuropathology, neurostructure and brain networks are summarized. In addition, findings from peripheral samples of subjects with autism and animal models, which show immune, oxidative, mitochondrial dysregulations, are reported. Then, other biomarkers from very different systems associated with autism are reported. Finally, an attempt is made to try and integrate the available evidence, which points to a oligogenetic, multifactorial aetiology that converges in an aberrant micro-organization of the cortex, with abnormal functioning of the synapses and abnormalities in very general physiological pathways (such as inflammatory, immune and redox systems).

Gender differences in emotional and behavioral disorders and service use among adolescent smokers: a nationwide Israeli study.

Marked gender differences have been identified in cigarette smoking. In this study, we aimed to identify the gender-specific emotional and behavioral disorders among adolescent smokers and their consequent utilization of mental health services. We performed a nationwide survey study of an Israeli representative sample of 906 adolescents and their mothers. Mental disorders were assessed using the Development and Well-Being Assessment (DAWBA) Inventory. Levels of emotional and behavioral difficulties were evaluated using the Strengths and Difficulties Questionnaire (SDQ). Mental health services use and smoking habits were also assessed. Among non-smoker adolescents there were significant gender differences in almost all SDQ scales: emotional problems, pro-social, hyperactivity/inattention and conduct problems, whereas in the smoker group there was a difference only in the SDQ emotional problems scale (both self- and maternal-rated, P<0.001 and P=0.002, respectively). Only marginal difference was noted between males and females in help-seeking for emotional or behavioral problems. Over 50% of both male and female smokers in the study had untreated mental disorders (non-significant gender difference). The well-established gender differences in psychiatric symptomatology narrowed markedly in adolescent smokers; the typical gender difference in disruptive behaviors was lost in the adolescent smoking population. The implications of these findings are particularly relevant to developing more effective gender-specific programs to prevent youth smoking, to facilitate quitting and prepare primary care practitioners to identify mental disorders and behavioral problems in adolescents with a smoking history.

The use of mental health services by adolescent smokers: a nationwide Israeli study.

In this study, we aimed to evaluate the utilization of mental health services by adolescent smokers, the presence of untreated mental disorders in this young population and the associated emotional and behavioral difficulties. We performed a nationwide survey study of an Israeli representative sample of 906 adolescents and their mothers. Mental disorders were assessed using the Development and Well-Being Assessment (DAWBA) Inventory. Emotional and behavioral difficulties were evaluated using the Strengths and Difficulties Questionnaire (SDQ). Mental health services use and smoking habits were evaluated by relevant questionnaires. Adolescent smokers were using significantly more mental health services than non-smokers (79% vs. 63%, respectively, P<0.001), independently of their mental health status or ethnic group. Adolescent smokers also reported more emotional and behavioral difficulties in most areas (P<0.001), which are consistent with their mothers' reports, except in the area of peer relationships. The treatment gap for the smoking adolescents was 53% compared to 69% in the non-smokers (P<0.001). This is the first study characterizing the use of mental health services and the related emotional and behavioral difficulties in a nationally-representative sample of adolescents. The findings of a wide treatment gap and the rates of the associated emotional and behavioral difficulties are highly relevant to the psychiatric assessment and national treatment plans of adolescent smokers.

Self versus maternal reports of emotional and behavioral difficulties in suicidal and non-suicidal adolescents: an Israeli nationwide survey.

UNLABELLED: There is relatively little research addressing parent-adolescent agreement as regards to reporting on adolescent suicidal behavior in general and their behavioral and emotional difficulties in particular. The objective of this study was to compare maternal and adolescents' reports on behavioral and emotional difficulties among adolescents with and without suicidal behavior. This nationally-representative sample included 906 adolescents and their mothers. The mothers and adolescents were interviewed and evaluated separately using the Development and Well-Being Assessment Inventory (DAWBA) and the Strengths and Difficulties Questionnaire (SDQ). Self-rated SDQ scores of the suicidal adolescents were significantly higher in all SDQ problem scales compared to the non-suicidal participants. In contrast, maternal-rated SDQ assessments failed to discriminate between these groups, except the Hyperactivity scale. We demonstrated that mothers of suicidal adolescents in the community hardly recognize the emotional and behavioral difficulties of their offsprings. CONCLUSION: The mental examination of the adolescent patient should be maintained as the central and most reliable source of information regarding the suicidal adolescent. Mental health services planning of national suicide prevention programs should take into account these poor mother-adolescent agreement findings.

The European Psychiatric Association (EPA) guidance on suicide treatment and prevention.

UNLABELLED: Suicide is a major public health problem in the WHO European Region accounting for over 150,000 deaths per year. SUICIDAL CRISIS: Acute intervention should start immediately in order to keep the patient alive. DIAGNOSIS: An underlying psychiatric disorder is present in up to 90% of people who completed suicide. Comorbidity with depression, anxiety, substance abuse and personality disorders is high. In order to achieve successful prevention of suicidality, adequate diagnostic procedures and appropriate treatment for the underlying disorder are essential. TREATMENT: Existing evidence supports the efficacy of pharmacological treatment and cognitive behavioural therapy (CBT) in preventing suicidal behaviour. Some other psychological treatments are promising, but the supporting evidence is currently insufficient. Studies show that antidepressant treatment decreases the risk for suicidality among depressed patients. However, the risk of suicidal behaviour in depressed patients treated with antidepressants exists during the first 10-14 days of treatment, which requires careful monitoring. Short-term supplementary medication with anxiolytics and hypnotics in the case of anxiety and insomnia is recommended. Treatment with antidepressants of children and adolescents should only be given under supervision of a specialist. Long-term treatment with lithium has been shown to be effective in preventing both suicide and attempted suicide in patients with unipolar and bipolar depression. Treatment with clozapine is effective in reducing suicidal behaviour in patients with schizophrenia. Other atypical antipsychotics are promising but more evidence is required. TREATMENT TEAM: Multidisciplinary treatment teams including psychiatrist and other professionals such as psychologist, social worker, and occupational therapist are always preferable, as integration of pharmacological, psychological and social rehabilitation is recommended especially for patients with chronic suicidality. FAMILY: The suicidal person independently of age should always be motivated to involve family in the treatment. SOCIAL SUPPORT: Psychosocial treatment and support is recommended, as the majority of suicidal patients have problems with relationships, work, school and lack functioning social networks. SAFETY: A secure home, public and hospital environment, without access to suicidal means is a necessary strategy in suicide prevention. Each treatment option, prescription of medication and discharge of the patient from hospital should be carefully evaluated against the involved risks. TRAINING OF PERSONNEL: Training of general practitioners (GPs) is effective in the prevention of suicide. It improves treatment of depression and anxiety, quality of the provided care and attitudes towards suicide. Continuous training including discussions about ethical and legal issues is necessary for psychiatrists and other mental health professionals.

Low self-awareness of ADHD in adults using a self-report screening questionnaire.

INTRODUCTION: Awareness of attention deficit hyperactivity disorder (ADHD) in adults has been growing over the last decade. One of the most interesting issues related to this topic is these adults' self-awareness of their ADHD symptoms and their estimation of their own impairments. Our hypothesis while studying young adult ADHD populations was that there would be a significant difference between their self-report and their clinical assessment. METHOD: One hundred and three students volunteered for this study. In order to validate our ADHD screening questionnaire (ADHD-SQ), and to assess the level of awareness they have of their own symptoms, participants underwent a complete clinical assessment for ADHD. They were divided into a control group (n=24), and an ADHD study group (n=79), which in turn was composed of two sub-groups, one comprising 24 ADHD predominantly inattentive (ADHD-I) and the other 55 ADHD combined type (ADHD-C). RESULTS: Factor analysis yielded two factors explaining 41% of the variance. The Inattention (IA) subscale score tended to be higher in both ADHD sub-groups as compared to the control group (6.5 ± 2.1 vs. 2.34 ± 2.3 with P<0.001), with no significant difference between the two ADHD sub-groups. Hyperactivity Impulsivity (HI) subscale was significantly higher for the ADHD-C sub-group than in the ADHD-I sub-group, whose score was similar to that of the control group (control: 1.6 ± 2.1; ADHD-I: 1.55 ± 1.0; ADHD-C: 4.5 ± 2.6, P<0.0001). Receiver Operating Characteristics (ROC) analysis showed similar results. The area under the curve (AUC) of IA subscale score was 0.90 (95% confidence: 0.83-0.96) and for HI subscale score was 0.75, (95% confidence: 0.63-0.86). Classification into groups used a cut-off point of 3+ items out of nine, in the SQ and 6+ items out of nine in the clinical assessment. These two classifications showed 68% agreement (46% sensitivity and 95% specificity). In both ADHD sub-groups, the self-reported average number of positive symptoms per student was relatively low for both clusters; this phenomenon was pronounced in the specific subtypes. The self-rated HI cluster score was considerably low in the ADHD-C sub-group (4.5 ± 2.6), and the IA one was particularly low in the ADHD-IADHD-I sub-group (5.9 ± 1.9). CONCLUSION: This study's results indicate that ADHD symptoms are under-reported for both inattentive and hyperactive-impulsive clusters, indicating that adults with ADHD tend to under-estimate their own ADHD-related impairments. We suggest that this questionnaire may be used both in research and academic settings to help counsellors and students to obtain early indication of ADHD and to refer students suspected of having ADHD to full clinical assessment.

Rate of readmission and mortality risks of schizophrenia patients who were discharged against medical advice.

PURPOSE: To compare the readmission and the mortality rates of schizophrenia patients who were discharged against medical advice (AMA) and patients who were discharged by physician recommendation. METHODS: The records (1984-2005) of all consecutive admissions (n=12,937) of schizophrenia patients (n=8,052) were reviewed. Out of this group, 673 (8.3%) refused to remain in the hospital and signed a hospital form for discharge AMA. Their records were analyzed for rates of re-hospitalization and mortality at study closure. The records of AMA patients were compared to those of patients with regular discharge (n=1345). RESULTS: AMA patients were younger at admission (P<0.001), comprised more males (P<0.01), more were single (P<0.0001), and had a shorter duration of illness than the controls (P<0.05). A total of 49.9% of AMA events occurred within the first 2 weeks of hospitalization. The readmission rate was significantly higher for AMA patients than for the controls (P<0.001). The mortality rate as a result of suicide (P<0.0001) and accidents (P<0.05) was higher for AMA patients compared to controls. CONCLUSION: The schizophrenia patients discharged AMA have a higher readmission rate and a higher mortality rate due to suicide and accidents compared to non-AMA discharged patients. Patients with AMA discharge warrant special community surveillance to improve outcome.

Parental bonding in severely suicidal adolescent inpatients.

Family environment has a clear role in suicidal behavior of adolescents. We assessed the relationship between parental bonding and suicidal behavior in suicidal (n=53) and non-suicidal (n=47) adolescent inpatients. Two dimensions of parental bonding: care and overprotection, were assessed with the Parental Bonding Instrument. Results showed that adolescents with severe suicidal behavior tended to perceive their mothers as less caring and more overprotective compared to those with mild or no suicidal behavior. A discriminant analysis distinguished significantly between adolescents with high suicidality and those with low suicidality [χ2 (5) = 15.54; p=0.01] in 71% of the cases. The perception of the quality of maternal bonding may be an important correlate of suicidal behavior in adolescence and may guide therapeutic strategies and prevention.

Trends in prescribing of psychotropic medications for inpatient adolescents in Israel: a 10 years retrospective analysis.

We examined the trends in prescribing psychotropic drugs to children and adolescents within an inpatients adolescent psychiatric ward in Israel. Data of 414 subjects, ranging from 12- to 22-year-old, covering the years 1997, 2002 and 2007, was examined retrospectively. Analyzed variables included the number and type of drug prescriptions per patient at discharge, the subjects' age at discharge and the number of diagnoses per patient at discharge. Analysis of variance (ANOVA) with repeated measures was used to evaluate changes between the three calendar years, along the 10-year study period, while Pearson χ(2) test was performed for categorical variables. Over the study period the mean age at discharge decreased significantly, by about a year and a half, the mean number of diagnoses increased significantly, from 1.6 to 2.4 diagnoses per patient and the total number of drugs prescribed at discharge increased significantly from 1.48 to 1.93 per patient. Overall, the number of patients who were prescribed mood stabilizers increased by 14%, those who were prescribed antidepressants increased by almost 24%, almost 16% in antipsychotics prescriptions and 51.5% in prescriptions of atypical antipsychotics. Typical antipsychotic prescriptions decreased by 35.5% and accordingly, the number of patients who were prescribed agents for the treatment of extra-pyramidal side effects decreased by almost 24%. Due to a low number of inpatients with attention deficit and hyperactivity disorder (ADHD), no significant statistical conclusion could be drawn regarding trends in psychostimulant prescriptions. Our findings agree with other published studies from the last two decades. The growing use of psychotropic agents in children and adolescents merit a continuous concern with regard to their effects on the developing brain and impact on quality of life and to authorizing these drugs for use in specific young age subgroups.

Timing is critical: gene, environment and timing interactions in genetics of suicide in children and adolescents.

Suicidal behavior runs in families and is prevalent in adolescence. Case-control and family-based studies in this age group failed to find a genetic association that survived replications. Gene environment approach gave new hope for possible associations especially with the short allele of the serotonin transporter promoter polymorphism (5-HTTLPR). However, a recent meta-analysis raised doubts about the consistency of these findings. Some new structural and functional imaging data may shade light on the age-related and gender-related development of the brain. This review suggests a new approach to gene by environment and timing interaction to understand the interplay that leads to suicidality in adolescents and young adults.