Contemporary pathways to adolescent pregnancy in Indonesia: A qualitative investigation with adolescent girls in West Java and Central Sulawesi.

In the last decade, reduction in adolescent fertility rates in Indonesia has slowed despite national programmes and policies focused on addressing child marriage. Indonesia currently has the highest number of births to adolescent girls aged 15-19 years in Southeast Asia. There is a need to develop a more nuanced understanding of the drivers of adolescent pregnancy in Indonesia to inform programmes and policies tailored to young people's needs and priorities. This study explored adolescent girls' pathways to pregnancy across two provinces (Central Sulawesi and West Java) in Indonesia. We conducted participatory timeline interviews with 79 girls aged 15-21 years from urban, peri-urban, and rural communities and inquired about their relationships and life experiences leading up to pregnancy. We conducted follow-up interviews with 19 selected participants to validate and clarify preliminary findings. We identified six pathways to adolescent pregnancy which were broadly differentiated by the timing of pregnancy relative to marriage. Three pregnancy pathways within marriage were further differentiated by the main motivation for marriage-financial reasons, protecting the girl and family's reputation, or to progress a romantic relationship. Three pregnancy pathways outside marriage were distinguished by the nature of the sexual relationship preceding pregnancy-consensual sex, unwanted or pressured sex, and forced sex. Drivers of adolescent pregnancy include the acceptability of child marriage and stigma surrounding premarital pregnancy, family and social expectations of pregnancy following marriage, harmful gender-based norms and violence, and lack of sexual and reproductive health information and access to services. Adolescents follow varied pathways to pregnancy in Indonesia. The idealisation and acceptance of child marriage is both a catalyst and outcome of adolescent pregnancy, which is occurring amid stigma surrounding premarital sex and pregnancy, harmful gender-based norms and violence, and barriers to contraceptive access and use. Our findings emphasise that there are many drivers of adolescent pregnancy and different pathways will require intervention approaches that address child marriage alongside other key contributors.

Simulation in thoracic surgery-A mini review of a vital educational tool to maximize peri-operative care and minimize complications.

Thoracic surgery is an increasingly expanding field, and the addition of national screening programs has resulted in increasing operative numbers and complexity. Thoracic surgery overall has an approximately 2% mortality and 20% morbidity with common specific complications including persistent air leak, pneumothorax, and fistulas. The nature of the surgery results in complications being unique to thoracic surgery and often very junior members of the surgical team feel underprepared to deal with these complications after very little exposure during their medical school and general surgical rotations. Throughout medicine, simulation is being increasingly used as a method to teach the management of complicated, rare, or significant risk occurrences and has shown significant benefits in learner confidence and outcomes. In this mini review we explain the learning theory and benefits of simulation learning. We also discuss the current state of simulation in thoracic surgery and its potential future in aiding complication management and patient safety.

An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity.

Diamond-Blackfan anemia (DBA) is a genetic blood disease caused by heterozygous loss-of-function mutations in ribosomal protein (RP) genes, most commonly RPS19. The signature feature of DBA is hypoplastic anemia occurring in infants, although some older patients develop multilineage cytopenias with bone marrow hypocellularity. The mechanism of anemia in DBA is not fully understood and even less is known about the pancytopenia that occurs later in life, in part because patient hematopoietic stem and progenitor cells (HSPCs) are difficult to obtain, and the current experimental models are suboptimal. We modeled DBA by editing healthy human donor CD34+ HSPCs with CRISPR/Cas9 to create RPS19 haploinsufficiency. In vitro differentiation revealed normal myelopoiesis and impaired erythropoiesis, as observed in DBA. After transplantation into immunodeficient mice, bone marrow repopulation by RPS19+/- HSPCs was profoundly reduced, indicating hematopoietic stem cell (HSC) impairment. The erythroid and HSC defects resulting from RPS19 haploinsufficiency were partially corrected by transduction with an RPS19-expressing lentiviral vector or by Cas9 disruption of TP53. Our results define a tractable, biologically relevant experimental model of DBA based on genome editing of primary human HSPCs and they identify an associated HSC defect that emulates the pan-hematopoietic defect of DBA.

Deconstructing resilience in patients at high risk for suicidal behavior.

BACKGROUND: Resilience represents coping abilities to overcome exposure to psychopathological risk. In the context of risk factors for suicidal behavior, it is unknown if this attribute is deficient in suicide attempters, how it relates to other measures of risk, and where it may overlap with other risk factors associated with suicidal behavior. METHODS: The present study examined the performance on the Connor-Davidson Resilience Scale (CD-RISC) in three groups of individuals with familial risk for both mood disorder and suicidal behavior, as well as a healthy comparison group. Other risk factors for suicidal behavior, such as depression severity, hopelessness, and lifetime impulsiveness were examined as well to determine if these mediated group differences in CD-RISC scores. RESULTS: CD-RISC scores differed between groups, with lowest scores in the past attempter group. However, CD-RISC scores were strongly correlated with other common risk factors for suicide attempt, including hopelessness, subjective depression, and reasons for living, which together explained 68 % of the CD-RISC variance. Group differences in CD-RISC scores were eliminated when the model included these covariates. LIMITATIONS: Sample sizes were modest, and depression severity was low overall and significantly higher in the past suicide attempter group. CONCLUSIONS: The CD-RISC has demonstrated utility for predicting risk for depression, but appears to overlap with other known risk factors for suicidal behavior, especially hopelessness and subjective depression. Though it encapsulates variance from multiple risk factors in a single scale, it may not provide additional predictive power above and beyond these other risk factors for suicidal behavior.

Mood Disorders and Aggressive Traits Mediate Effects of Reported Childhood Adversity on Suicide Attempt Risk.

BACKGROUND: Childhood adversity (CA) is linked to suicidal behavior as well as to mood disorders and aggressive traits. This raises the possibility that depression and aggressive traits mediate the relationship of childhood adversity to suicide risk. Moreover, it is not known if they operate independently or interactively. AIMS: To determine whether, and how, mood disorders and aggressive traits mediate the effects of reported physical and sexual abuse on future suicidal behavior. METHODS: Five hundred and forty-eight subjects, offspring of parents with mood disorders, were interviewed at baseline and at yearly follow-ups with questionnaires assessing aggression, mood disorders, and suicidal behavior. The mediation analysis involved a three-step process, testing the relationships between (1) CA and attempt; (2) CA and putative mediators; and (3) putative mediators and suicide attempt, adjusting for CA. RESULTS: Aggressive trait severity and mood disorder onset each mediated the relationship between CA and future suicide attempts. Greater aggression severity also raised the hazard of the development of a mood disorder. If aggressive trait severity was clearly elevated, then onset of mood disorder did not increase further the hazard of the suicide attempt. Including family as a random effect had a much bigger effect on attempt outcome for physical abuse compared with sexual abuse. CONCLUSIONS: Amelioration of aggressive traits and treatment of mood disorders in CA-exposed offspring of a parent with a mood disorder may prevent future suicide attempts and may reduce the risk of mood disorder. Familial factors influence the impact of childhood physical abuse but not sexual abuse. HIGHLIGHTSChildhood Adversity (CA) predicted future mood disorder and aggression severity.Depression and aggression mediate the relationship between CA and suicide attempts.When one mediator is present, the presence of the other does not increase the hazard.Between family variation contributed much more to suicidal behavior outcomes relative to the effect of physical abuse, but sexual abuse contributed to suicidal outcomes more than family variation.

Deficiency of ribosomal protein S26, which is mutated in a subset of patients with Diamond Blackfan anemia, impairs erythroid differentiation.

Introduction: Diamond Blackfan anemia (DBA) is a rare congenital disease characterized by defective maturation of the erythroid progenitors in the bone marrow, for which treatment involves steroids, chronic transfusions, or hematopoietic stem cells transplantation. Diamond Blackfan anemia is caused by defective ribosome biogenesis due to heterozygous pathogenic variants in one of 19 ribosomal protein (RP) genes. The decreased number of functional ribosomes leads to the activation of pro-apoptotic pathways and to the reduced translation of key genes for erythropoiesis. Results and discussion: Here we characterized the phenotype of RPS26-deficiency in a cell line derived from human umbilical cord blood erythroid progenitors (HUDEP-1 cells). This model recapitulates cellular hallmarks of Diamond Blackfan anemia including: imbalanced production of ribosomal RNAs, upregulation of pro-apoptotic genes and reduced viability, and shows increased levels of intracellular calcium. Evaluation of the expression of erythroid markers revealed the impairment of erythroid differentiation in RPS26-silenced cells compared to control cells. Conclusions: In conclusion, for the first time we assessed the effect of RPS26 deficiency in a human erythroid progenitor cell line and demonstrated that these cells can be used as a scalable model system to study aspects of DBA pathophysiology that have been refractory to detailed investigation because of the paucity of specific cell types affected in this disorder.

Twenty-six years of psychosocial interventions to reduce suicide risk in adolescents: Systematic review and meta-analysis.

BACKGROUND: During adolescence, suicide risk increases; effective treatments are needed to reduce risk. METHODS: Databases were searched (1995-2020) for randomized controlled trials (RCTs) concerning psychosocial treatments for suicide prevention in adolescents (10-18 yrs). Data were extracted from the timepoint closest to 6 months. Cohen's ds were estimated for reducing suicidal ideation (SI), self-harming behaviors (SHB) excluding strictly non-suicidal self-injury, and suicide attempts (SA) and analyzed using generalized least square regression. Meta-analytic innovations included within-person correlations to reflect trait suicidality; annualization to control for exposure; estimated lifetime risk based on ages; and modeling inclusion/exclusion criteria. Alternate approaches included relative risk and comparison of intervention and control treatments to baseline. RESULTS: Of 30 RCTs, 6 assessing SHB (4 measuring SA), and 7 assessing SI demonstrated treatment effectiveness. Overall, interventions decreased SI (n = 25) with low effect size (d = 0.08, p = 0.01), non-significant after controlling for publication bias (d = 0.05, p = 0.1); interventions were non-significant for SHB (n = 25, d = 0.001, p = 0.97) or SA (n = 18, d = 0.03, p = 0.52). To prevent one SHB, the number needed to treat (NNT) was 45[26,156]; for SA, NNT=42[24,149]. Non-superiority may relate to effectiveness of control treatments. Thus, experimental and control treatments also were compared to baseline: both reduced SI (p < 0.0001), and effectiveness improved for SHB (NNT=12) and SA (NNT=11). LIMITATIONS: Study heterogeneity and inconsistent statistical reporting limited meta-analysis. CONCLUSIONS: Psychosocial interventions for suicide risk in adolescents showed little effectiveness compared with control treatments; suicide outcomes improved in both groups compared to baseline. Different approaches may be needed, including precision medicine methodologies and standardized statistical reporting criteria.

High-resolution dietary reconstruction of victims of the 79 CE Vesuvius eruption at Herculaneum by compound-specific isotope analysis.

The remains of those who perished at Herculaneum in 79 CE offer a unique opportunity to examine lifeways across an ancient community who lived and died together. Historical sources often allude to differential access to foodstuffs across Roman society but provide no direct or quantitative information. By determining the stable isotope values of amino acids from bone collagen and deploying Bayesian models that incorporate knowledge of protein synthesis, we were able to reconstruct the diets of 17 adults from Herculaneum with unprecedented resolution. Significant differences in the proportions of marine and terrestrial foods consumed were observed between males and females, implying that access to food was differentiated according to gender. The approach also provided dietary data of sufficient precision for comparison with assessments of food supply to modern populations, opening up the possibility of benchmarking ancient diets against contemporary settings where the consequences for health are better understood.

Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles.

IKZF1 encodes Ikaros, a zinc finger-containing transcription factor crucial to the development of the hematopoietic system. Germline pathogenic variants in IKZF1 have been reported in patients with acute lymphocytic leukemia and immunodeficiency syndromes. Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid hypoplasia, associated with a spectrum of congenital anomalies and an elevated risk of certain cancers. DBA is usually caused by heterozygous pathogenic variants in genes that function in ribosomal biogenesis; however, in many cases the genetic etiology is unknown. We identified a germline IKZF1 variant, rs757907717 C > T, in identical twins with DBA-like features and autoimmune gastrointestinal disease. rs757907717 C > T results in a p.R381C amino acid change in the IKZF1 Ik-x isoform (p.R423C on isoform Ik-1), which we show is associated with altered global gene expression and perturbation of transcriptional networks involved in hematopoietic system development. These data suggest that this missense substitution caused a DBA-like syndrome in this family because of alterations in hematopoiesis, including dysregulation of networks essential for normal erythropoiesis and the immune system.

Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond Blackfan Anemia.

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of a class of disorders known as ribosomopathies. Most cases result from loss of function mutations or deletions in 1 of 23 genes encoding either a small or large subunit-associated ribosomal protein (RP), resulting in RP haploinsufficiency. DBA is characterized by red cell hypoplasia or aplasia, poor linear growth and congenital anomalies. Small case series and case reports demonstrate DBA to be a cancer predisposition syndrome. Recent analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified the cancer risk in DBA. These studies reveal the most prevalent solid tumor, presenting in young adults and in children and adolescents, to be colorectal cancer (CRC) and osteogenic sarcoma, respectively. Of concern is that these cancers are typically detected at an advanced stage in patients who, because of their constitutional bone marrow failure, may not tolerate full-dose chemotherapy. Thus, the inability to provide optimal therapy contributes to poor outcomes. CRC screening in individuals over the age of 50 years, and now 45 years, has led to early detection and significant improvements in outcomes for non-DBA patients with CRC. These screening and surveillance strategies have been adapted to detect familial early onset CRC. With the recognition of DBA as a moderately penetrant cancer risk syndrome a rational screening and surveillance strategy will be implemented. The downstream molecular events, resulting from RP haploinsufficiency and leading to cancer, are the subject of significant scientific inquiry.

Less NMDA Receptor Binding in Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex Associated With Reported Early-Life Adversity but Not Suicide.

BACKGROUND: Glutamate is an excitatory neurotransmitter binding to 3 classes of receptors, including the N-methyl, D-aspartate (NMDA) receptor. NMDA receptor binding is lower in major depression disorder and suicide. NMDA receptor blocking with ketamine can have antidepressant and anti-suicide effects. Early-life adversity (ELA) may cause glutamate-mediated excitotoxicity and is more common with major depression disorder and in suicide decedents. We sought to determine whether NMDA-receptor binding is altered with suicide and ELA. METHODS: A total 52 postmortem cases were organized as 13 quadruplets of suicide and non-suicide decedents matched for age, sex, and postmortem interval, with or without reported ELA (≤16 years). Tissue blocks containing dorsal prefrontal (BA8), dorsolateral prefrontal (BA9), or anterior cingulate (BA24) cortex were collected at autopsy. Psychiatrically healthy controls and suicide decedents underwent psychological autopsy to determine psychiatric diagnoses and details of childhood adversity. NMDA receptor binding was determined by quantitative autoradiography of [3H]MK-801 binding (displaced by unlabeled MK-801) in 20-µm-thick sections. RESULTS: [3H]MK-801 binding was not associated with suicide in BA8, BA9, or BA24. However, [3H]MK-801 binding with ELA was less in BA8, BA9, and BA24 independent of suicide (P < .05). [3H]MK-801 binding was not associated with age or postmortem interval in any brain region or group. CONCLUSIONS: Less NMDA receptor binding with ELA is consistent with the hypothesis that stress can cause excitotoxicity via excessive glutamate, causing either NMDA receptor downregulation or less receptor binding due to neuron loss consequent to the excitotoxicity.

Rare ribosomopathies: insights into mechanisms of cancer.

Long thought to be too big and too ubiquitous to fail, we now know that human cells can fail to make sufficient amounts of ribosomes, causing a number of diseases collectively known as ribosomopathies. The best characterized ribosomopathies, with the exception of Treacher Collins syndrome, are inherited bone marrow failure syndromes, each of which has a marked increase in cancer predisposition relative to the general population. Although rare, emerging data reveal that the inherited bone marrow failure syndromes may be underdiagnosed on the basis of classical symptomology, leaving undiagnosed patients with these syndromes at an elevated risk of cancer without adequate counselling and surveillance. The link between the inherited ribosomopathies and cancer has led to greater awareness that somatic mutations in factors involved in ribosome biogenesis may also be drivers in sporadic cancers. Our goal here is to compare and contrast the pathophysiological mechanisms underpinning ribosomopathies to gain a better understanding of the mechanisms that predispose these disorders to cancer.

Author Correction: Lymphoblastoid cell lines from Diamond Blackfan anaemia patients exhibit a full ribosomal stress phenotype that is rescued by gene therapy.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Effects of anxiety on suicidal ideation: exploratory analysis of a paroxetine versus bupropion randomized trial.

It is unclear whether anxiety increases or decreases suicidal risk. This may contribute to the lack of guidance on which antidepressant medications are best for suicidal depressed patients who present with high anxiety. This study explored whether anxiety predicts suicidal ideation in depressed individuals treated with paroxetine or bupropion. An 8-week double-blind trial comparing controlled-release paroxetine (N=36) versus extended-release bupropion (N=38) for effect on suicidal ideation and behavior in depressed patients with suicidal ideation, past attempt, or both found an advantage for paroxetine, but anxiety effects were not investigated. This secondary analysis explored the relationship, measured at baseline and weekly, of anxiety with suicidal ideation. Anxiety severity measured weekly correlated with suicidal ideation severity irrespective of treatment (P=0.012). Patients with high baseline anxiety showed a trend toward faster reduction of suicidal ideation with paroxetine compared with bupropion treatment (standard P=0.047; bootstrap P=0.077). The latter finding, if confirmed in larger samples, could enhance choice of antidepressant medication for suicidal, depressed patients presenting with high levels of anxiety.

A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare genetic hypoplasia of erythroid progenitors characterized by mild to severe anemia and associated with congenital malformations. Clinical manifestations in DBA patients are quite variable and genetic testing has become a critical factor in establishing a diagnosis of DBA. The majority of DBA cases are due to heterozygous loss-of-function mutations in ribosomal protein (RP) genes. Causative mutations are fairly straightforward to identify in the case of large deletions and frameshift and nonsense mutations found early in a protein coding sequence, but diagnosis becomes more challenging in the case of missense mutations and small in-frame indels. Our group recently characterized the phenotype of lymphoblastoid cell lines established from DBA patients with pathogenic lesions in RPS19 and observed that defective pre-rRNA processing, a hallmark of the disease, was rescued by lentiviral vectors expressing wild-type RPS19. Here, we use this complementation assay to determine whether RPS19 variants of unknown significance are capable of rescuing pre-rRNA processing defects in these lymphoblastoid cells as a means of assessing the effects of these sequence changes on the function of the RPS19 protein. This approach will be useful in differentiating pathogenic mutations from benign polymorphisms in identifying causative genes in DBA patients.

Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis.

Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation.

Sudden Unexpected Death in Epilepsy: Incidence, Risk Factors, and Proposed Mechanisms.

Epilepsy is a common neurological disorder associated with increased morbidity and mortality, including premature death from different causes. Sudden unexpected death in epilepsy, or SUDEP, is one of the most common causes of death in people with epilepsy and originally brought to light by medical examiners. It accounts for 5% to 30% of all deaths in individuals with epilepsy and up to 50% in individuals with medically refractory epilepsy. It is commonly associated with a history of generalized tonic-clonic seizures and may be mitigated by other electroclinical risk factors, such as postictal electroencephalographic suppression, prone position, altered heart rate variability, conduction abnormalities, gender, or antiepileptic medications, to name a few. More recently, potential neuroimaging biomarkers have also been identified. Still, despite the increased mortality risk in people with epilepsy due to SUDEP, little is known about its underlying pathophysiology. The pathogenesis is likely to be multifactorial, resulting in neurogenic pulmonary edema or, in some cases, fatal cardiac arrhythmias. Medical examiners can provide an important role in our understanding of the magnitude of the problem and ongoing research into the underlying mechanisms. In this review, we discuss diagnostic criteria, incidence, risk factors, and current theories regarding the pathophysiology of SUDEP.

Proapoptotic Requirement of Ribosomal Protein L11 in Ribosomal Stress-Challenged Cortical Neurons.

While impaired ribosomal biogenesis is observed in neurodegenerative diseases, its pathogenic contributions are not clear. For instance, it is well established that in rodent neurons, genetic inhibition of RNA-polymerase 1 that transcribes rRNA results in structural disruption of the nucleolus, neuronal apoptosis, and neurodegeneration. However, in most neurodegenerative diseases, nucleolar morphology is unaffected. It is reported here that in primary cortical neurons from newborn rats, inhibition of ribosomal biogenesis by shRNA-mediated knockdowns of several ribosomal proteins including S6, S14, or L4 resulted in p53-mediated apoptosis despite absence of structural disruption of the nucleolus. Conversely, knockdown of the RP L11, which in nonneuronal systems mediates p53 activation downstream of ribosomal stress, protected neurons against inhibition of ribosomal biogenesis but not staurosporine. Moreover, overexpression of L11 enhanced p53-driven transcription and increased neuronal apoptosis. In addition, inhibition of p53, or L11 knockdown, blocked apoptosis in response to the RNA analog 5-fluorouridine which perturbed nucleolar structure, inhibited ribosomal synthesis, and activated p53. Although the DNA double-strand break (DSB) inducer etoposide activated p53, nucleolar structure appeared intact. However, by activating the DNA damage response kinase ATM, etoposide increased 47S pre-rRNA levels, and enhanced nucleolar accumulation of nascent RNA, suggesting slower rRNA processing and/or increased Pol1 activity. In addition, shL11 reduced etoposide-induced apoptosis. Therefore, seemingly normal morphology of the neuronal nucleolus does not exclude presence of ribosomal stress. Conversely, targeting the ribosomal stress-specific signaling mediators including L11 offers a novel approach to uncover neurodegenerative contributions of deregulated ribosomal synthesis as exemplified in DSB-challenged neurons.

Suicidal ideation declines with improvement in the subjective symptoms of major depression.

BACKGROUND: Suicidal ideation appears to be more strongly associated with subjective rather than neurovegetative symptoms of depression. Effective treatment, then, should produce reductions in suicidal ideation to the degree that these subjective symptoms are alleviated relative to treatment effects on other symptoms. METHODS: In a randomized clinical trial comparing paroxetine and bupropion for treatment of depression in patients with either suicidal ideation or past attempt, depression severity and suicidal ideation were assessed weekly during the 8-week study. Depression rating scales - the 24-item Hamilton Depression Rating Scale [HDRS] and the Beck Depression Scale [BDI] - were decomposed into symptom clusters based on our published factor analyses, and their change over time compared to changes on the Beck Scale for Suicidal Ideation [SSI]. RESULTS: Improvement in factor scores associated with subjective symptoms of depression - HDRS Psychic Depression, BDI Subjective Depression, and BDI Self-Blame - were the best predictors of declining scores on the SSI regardless of type of drug treatment. BDI Subjective Depression was the best single predictor in the context of all other significant univariate predictors, accounting for 31.4% of the variance in the change in SSI. The three factors together accounted for 35.3%. LIMITATIONS: This is a secondary analysis of clinical trial data, with fixed treatments. CONCLUSIONS: Effective treatments to reduce suicidal ideation are associated with the reduction of the subjective symptoms of depression, which may not always decline in synchrony with improvement in neurovegetative symptoms. This asynchrony may result in a period of elevated risk after the initiation of therapy. Data indicate that subjective depression symptoms should be a primary target in the treatment of depressed suicidal patients.