Comorbid Substance Abuse Research Articles

Analysis of Hospitalization Length of Stay and Total Charges for Patients with Drug Abuse Comorbidity.

BackgroundDrug abuse has been on the increase over the last few years, contributing to the healthcare cost. An understanding of the overall impact of drug abuse hospitalizations is essential in combatting the drug abuse epidemic.ObjectiveTo evaluate inpatient outcomes of total charges and length of stay for patients with drug abuse comorbidity compared to non-drug abuse admissions.MethodThe Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample data was utilized. Drug abuse comorbidity was used as defined by HCUP. Various descriptive and inferential analyses were performed on the filtered data sets for the years 2010 to 2014.ResultsThe average hospitalization length of stay was 4.5 days for non-drug abuse and 5.5 days for drug abuse comorbidity (P < 0.001). Mean charges for drug abuse comorbidity were significant for claims to private insurance and Medicaid.ConclusionTotal charges and length of stay are higher for drug abuse than non-drug abuse cases. The results will aid as a reference for resource allocation and policy changes. Further research is needed for alternative and innovative interventions for conditions that are identified to be co-existing with drug abuse comorbidity.

The importance of clinical normative data for conceptualizing neuropsychological deficits in people with schizophrenia spectrum disorders

Objective To create clinical normative data tables for Norwegian patients with schizophrenia spectrum disorders, to examine whether clinical normative data from Norway differs from similar normative data from Canada and the U.S., and to illustrate the usefulness of such data. Method A nationally representative sample of 335 patients from psychiatric hospitals in Bergen, Norway was included. Inclusion criteria were 18–39 years of age, Norwegian as first language, and symptoms of schizophrenia, psychosis, or hallucinations. Comorbid substance abuse was recorded in 134 (40.0%). All completed the Norwegian version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results The average scores of patients with schizophrenia spectrum disorders were approximately one to two standard deviations below the mean for healthy adults. There were no significant differences in scores between patients with or without comorbid substance abuse. Men had higher scores than women. Clinical normative reference value look-up tables were created. Conclusions Clinical normative values were very similar to values from Canada and the U.S. Clinical normative data, as a supplement to standard healthy normative data, can be used to describe patients’ cognitive performance in terms of expectation for their peer group which can be useful for multidisciplinary treatment planning.

Restless Legs Syndrome in Women with Comorbid Psychiatric Disease

Restless legs syndrome (RLS) is a relatively common sleep disorder that affects many patients with psychiatric comorbidities. Also known as Willis-Ekbom disease, RLS is a neurologic sensorimotor disorder that was initially described in the 17th century. It is defined by four clinical features outlined by the International Restless Legs Syndrome Study Group, including (1) an urge to move typically associated with an abnormal sensation in the legs, (2) symptoms that occur at rest or are worsened by rest, (3) symptoms relieved by movement, and (4) symptoms that are more severe at night. Although the exact etiology of primary RLS is not known, current evidence suggests that RLS is related to decreased activity of dopaminergic function in specific central nervous system pathways. RLS can be triggered or exacerbated by a multitude of factors, including iron deficiency, uremia, pregnancy, heredity, caffeine use, alcohol use, smoking, nicotine use, and medications. Patients with psychiatric disease can have comorbid substance abuse and often are on medications that exacerbate RLS symptoms. [ Psychiatr Ann. 2019;49(12):514–517.]

Posttraumatic Stress Disorder and Incident Infections: A Nationwide Cohort Study.

It is unknown whether posttraumatic stress disorder (PTSD) is associated with incident infections. This study's objectives were to examine (1) the association between PTSD diagnosis and 28 types of infections and (2) the interaction between PTSD diagnosis and sex on the rate of infections. The study population consisted of a longitudinal nationwide cohort of all residents of Denmark who received a PTSD diagnosis between 1995 and 2011, and an age- and sex-matched general population comparison cohort. We fit Cox proportional hazards regression models to examine associations between PTSD diagnosis and infections. To account for multiple estimation, we adjusted the hazard ratios (HRs) using semi-Bayes shrinkage. We calculated interaction contrasts to assess the presence of interaction between PTSD diagnosis and sex. After semi-Bayes shrinkage, the HR for any type of infection was 1.8 (95% confidence interval: 1.6, 2.0), adjusting for marital status, non-psychiatric comorbidity, and diagnoses of substance abuse, substance dependence, and depression. The association between PTSD diagnosis and some infections (e.g., urinary tract infections) were stronger among women, whereas other associations were stronger among men (e.g., skin infections). This study's findings suggest that PTSD diagnosis is a risk factor for numerous infection types and that the associations between PTSD diagnosis and infections are modified by sex.

African-American and Caucasian participation in postmortem human brain donation for neuropsychiatric research.

Increased African-American research participation is critical to the applicability and generalizability of biomedical research, as population diversity continues to increase both domestically and abroad. Yet numerous studies document historical origins of mistrust, as well as other barriers that may contribute to resistance in the African-American community towards participation in biomedical research. However, a growing body of more recent scientific evidence suggests that African-Americans value research and are willing to participate when asked. In the present study, we set out to determine factors associated with research participation of African-American families in postmortem human brain tissue donation for neuropsychiatric disorders as compared with Caucasian families, from same-day medical examiner autopsy referrals. We retrospectively reviewed brain donation rates, as well as demographic and clinical factors associated with donation in 1,421 consecutive referrals to three medical examiner’s offices from 2010–2015. Overall, 69.7% of all next-of-kin contacted agreed to brain donation. While Caucasian families consented to donate brain tissue at a significantly higher rate (74.1%) than African-American families (57.0%) (p<0.001), African-American brain donation rates were as high as 60.5% in referrals from Maryland. Neither African-American nor Caucasian donors differed significantly from non-donors on any demographic or clinical factors ascertained, including age, sex, diagnosis of the donor, or in the relationship of the next-of-kin being contacted (p>0.05). However, Caucasian donors were significantly older, had more years of education, were more likely to be referred for study due to a psychiatric diagnosis, more likely to have comorbid substance abuse, and more likely to have died via suicide, as compared with African-American donors (p<0.05). When African-American participants are identified and approached, African-American families as well as Caucasian families are indeed willing to donate brain tissue on the spot for neuropsychiatric research, which supports the belief that African-American attitudes towards biomedical research may be more favorable than previously thought.

CHALLENGES IN EATING DISORDER TREATMENT: INPATIENT, OUTPATIENT, COMORBID, AND BEYOND

Eating disorders are potentially fatal and highly impairing disorders that can present with medical and psychiatric acuity and complexity. Additionally, comorbidity is common. This Clinical Perspectives will explore specific challenges in treating eating disorders, including discussions from both medical and psychiatric inpatient and outpatient treatment settings, and the impact of comorbid substance abuse.

Nationwide Analysis of 30-Day Readmissions After Esophagectomy: Causes, Costs, and Risk Factors

Postsurgical readmissions are an increasingly scrutinized marker of health care quality. We sought to estimate the rate, risk factors, causes, and costs associated with readmissions after esophagectomy in a large, nationally representative cohort. We studied patients from the Nationwide Readmissions Database undergoing esophagectomy from 2010 to 2014. Data were collected on the prevalence and indications for readmission within 30 days as well as the hospital-, procedure-, and patient-level risk factors as determined by multivariable logistic regression. Among 13,282 cases, the rate of 30-day readmission was 19.4%, with the most common indications for readmission being pulmonary (20.6%) and gastrointestinal complications (20%). Median cost of readmission was $9660 (interquartile range, $5392 to $20,447), and pulmonary complications accounted for the greatest total cost burden at 25.8% of all readmission-related costs. Independent risk factors for readmission on multivariable analysis included perioperative blood transfusion (adjusted odds ratio [AOR] 1.33; 95% confidence interval [CI], 1.08 to 1.65; P= .008), discharge to a nursing facility (AOR 1.83; 95% CI, 1.41 to 2.39; P < .001), high illness severity based on All Patients Refined Diagnosis-Related Groups scoring (AOR 1.49; 95% CI, 1.21 to 1.84; P < .001), chronic renal failure (AOR 1.61; 95% CI, 1.13 to 2.29; P= .009), and comorbid drug abuse (AOR 2.19; 95% CI, 1.08 to 4.41; P= .029). Nearly 1 in 5 patients undergoing esophagectomy are readmitted within 30 days of discharge, at a median cost of $9660 per readmission. Pulmonary complications account for the greatest number of readmissions and the greatest total cost burden. Targeting the causes of readmission, especially pulmonary causes, may help significantly reduce the total morbidity and health care costs associated with esophagectomy.

Outcomes of Direct-Acting Antiviral Treatment of Psychiatric Patients with Comorbid Hepatitis C Virus Infection

Background: The highest burden of hepatitis C virus (HCV) infection is seen in patients with psychiatric disorders who have been excluded from traditional treatments with Interferon due to treatment-emergent neuropsychiatric adverse effects. The goal of this study is to determine the tolerability, treatment retention, and efficacy of direct-acting antivirals with psychiatric disorders and comorbid substance use disorders in real-life settings. Methods: This is a retrospective cohort observational study of HCV patients treated with direct-acting antivirals between January 2016 and December 2018. Patients were stratified and sub-stratified based on their psychiatric diagnosis and substance use. The primary assessment was the sustained virologic response at 12 weeks post-treatment (SVR12). Results: Among the 291 patients analyzed, patients with psychiatric diagnosis and non-psychiatric patients made up 51.2% (n = 149) and 48.8% (n = 142) respectively. Majority of the patients included in the study were African-Americans (68.7%, n = 200). Overall, 95.3% (142/149) and 94.4% (134/142) of psychiatric and non-psychiatric patients, respectively, achieved SVR12 and treatment response was similar between the groups (p = 0.72). Among psychiatric patients, only the prior treatment status was identified as a predictor of treatment response (OR 0.153, 95% CI 0.03–0.79; p = 0.05). No statistical difference was observed among the patients with SVR12 based on their primary psychiatric diagnoses or by comorbid substance abuse. Conclusion: The results of our study show that direct-acting antiviral treatments are well tolerated in psychiatric patients, and an overwhelming majority of patients achieved SVR12. Our study highlights the need to integrate HCV screening with treatment linkage in psychiatry and primary care practice.

227. Does baseline substance use predict subsequent development of mental health disorders in adolescent idiopathic scoliosis patients?

BACKGROUND CONTEXT MHD prevalence in patients with substance abuse history has been well-described. However, the impact of current or historical substance abuse/dependence in adolescent idiopathic scoliosis (AIS) patients on risk of subsequent development of new-onset mental health disorders (MHDs) is unknown. PURPOSE This study evaluated the: (1) demographics and (2) new-onset diagnosis of MHD among AIS patients with baseline substance abuse/dependence. The goal of this study was to determine whether substance abuse among AIS patients increases the odds of subsequent new-onset development of a MHD. STUDY DESIGN/SETTING Retrospective review of prospectively collected data. PATIENT SAMPLE Using the NYS Statewide Planning and Research Cooperative System (SPARCS), we identified age, gender, race, and Charlson/Deyo-index propensity-score matched cohorts of AIS patients with or without prior/current substance abuse. AIS patients with comorbid substance abuse were included from 2009-11, with minimum 2-year follow-up. A total of 386 AIS patients (n=193 in each group) were included. OUTCOME MEASURES Demographic information, length of stay, hospital charges, new-onset MHD diagnosis at 2-year follow-up METHODS The NYS Statewide Planning and Research Cooperative System was reviewed to identify all 10-25 year-old AIS patients with prior or concurrent substance abuse (AIS-Sub: alcohol, tobacco, cannabis, amphetamine, opioid or polysubstance) from 2009-11 to ensure two-year follow-up. Patients with prior or concurrent MHD(s) were excluded. AIS-Sub were 1:1 propensity score-matched by age, sex, race and Charlson/Deyo index to AIS patients without substance abuse (AIS-NoSub). Cohorts were compared for subsequent incidence/development of individual and overall MHDs (depressive, anxiety, stress, sleep and/or eating disorder). Binary stepwise logistic regressions were utilized to calculate odds ratios (OR) of developing individual or any MHDs based on baseline substance abuse. RESULTS A total of 386 AIS patients were included (n=193 each in AIS-Sub and AIS-NoSub). AIS-Sub and AIS-NoSub patients had comparable age (both 20.8 years), sex (62.2 vs 62.7% male), race (54.9 vs 52.8% white), insurance (55.4 v 45.6% Medicaid), and Charlson-Deyo (0.29 vs 0.37) respectively. AIS-Sub patients had higher rates of new-onset subsequent overall MHDs (16.1% vs 3.6%), with only depressive disorder higher among individual MHDs (10.9% vs 0.5%), both p CONCLUSIONS AIS patients with prior or current substance abuse/dependence were at increased two-year risk of developing any new-onset MHD, specifically depressive disorders. This data may guide preoperative screening and optimization efforts for scoliosis surgeons, as MHDs have been associated with poor outcomes following spine surgery. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

The 2nd to 4th digit ratios (2D:4D) in patients with bipolar disorder

BackgroundThe ratio of the index finger to the ring finger (2D:4D) is a reflection of the intrauterine hormonal environment and a lower ratio has been shown to be associated with male gender, impulsive behaviors, substance abuse, and aggression. Bipolar illness is characterized by increased impulsivity and increased rates of co-morbid substance abuse, but the 2D:4D ratios have not been examined in this disorder. MethodsWe measured digit length of both hands in subjects with bipolar disorder and age- and gender-matched non-bipolar controls (n = 50 in each group). Diagnosis was confirmed with structured diagnostic interviews (MINI) and all subjects also completed Barratt Impulsivity Scale-version 11. ResultsThe patients did not vary significantly from the controls in demographic variables. Subjects with bipolar disorder had a higher right hand 2D:4D ratio compared to controls (0.967 ± .029 vs. 0.953 ± .035, t = 2.18, p = .03). Despite clearly higher measures of impulsivity in the bipolar group, no relationship could be documented between digit ratio and measures of impulsivity in either group. However, the right hand 2D:4D ratios and total impulsivity scores predicted bipolar disorder diagnosis status. LimitationsThe predominantly white racial composition of the study sample may limit generalizability to other groups. Only three patients were diagnosed with bipolar type 2, limiting the generalizability of the findings to all bipolar disorder types. ConclusionsThe data confirm previous observations of increased measures of impulsivity in euthymic bipolar individuals, and suggest that the mechanism of this increased impulsivity is different than in impulsivity seen in other conditions such as personality disorders.

Addressing the Co-morbidity of HIV, Substance Abuse and Trauma: Exploring an Integrated Intervention

Given the high incidence of comorbid conditions of Post-Traumatic Stress Disorder (PTSD) and Substance Use Disorder (SUD) among women living with the human immunodeficiency virus (HIV), there is a critical need to develop integrated interventions to address the comorbidity of HIV/AIDS, PTSD and SUD. This paper discusses a study conducted with African American women living with HIV/AIDS and histories of substance abuse and trauma in a major metropolitan city in the U.S. The purpose was to have women respond to a presentation on the acceptability of an integrated intervention entitled Trauma Affect Regulation: Guide for Education and Therapy (TARGET). The women also generated ideas on how to adapt the intervention for African American women. Participants responded favorably to TARGET and indicated that a holistic focus on the stigma of HIV/AIDS, and disclosure of HIV/AIDS to children and sexual partners were important considerations to include in an integrated PTSD/SUD treatment intervention.

Dorsal Amygdala Neurotrophin-3 Decreases Anxious Temperament in Primates

BackgroundAn early-life anxious temperament (AT) is a risk factor for the development of anxiety, depression, and comorbid substance abuse. We validated a nonhuman primate model of early-life AT and identified the dorsal amygdala as a core component of AT's neural circuit. Here, we combine RNA sequencing, viral-vector gene manipulation, functional brain imaging, and behavioral phenotyping to uncover AT's molecular substrates. MethodsIn response to potential threat, AT and brain metabolism were assessed in 46 young rhesus monkeys. We identified AT-related transcripts using RNA-sequencing data from dorsal amygdala tissue (including central nucleus of the amygdala [Ce] and dorsal regions of the basal nucleus). Based on the results, we overexpressed the neurotrophin-3 gene, NTF3, in the dorsal amygdala using intraoperative magnetic resonance imaging–guided surgery (n = 5 per group). ResultsThis discovery-based approach identified AT-related alterations in the expression of well-established and novel genes, including an inverse association between NTRK3 expression and AT. NTRK3 is an interesting target because it is a relatively unexplored neurotrophic factor that modulates intracellular neuroplasticity pathways. Overexpression of the transcript for NTRK3's endogenous ligand, NTF3, in the dorsal amygdala resulted in reduced AT and altered function in AT's neural circuit. ConclusionsTogether, these data implicate neurotrophin-3/NTRK3 signaling in the dorsal amygdala in mediating primate anxiety. More generally, this approach provides an important step toward understanding the molecular underpinnings of early-life AT and will be useful in guiding the development of treatments to prevent the development of stress-related psychopathology.

The influence of substance use on the effectiveness of antipsychotic medication: a prospective, pragmatic study

Background: Psychosis is associated with a high prevalence of substance use, leading to worsened prognosis. Less is known about how comorbid substance abuse may influence the effectiveness of antipsychotic medications. The aim of this study was to compare the effectiveness of second generation antipsychotics in patients with psychosis with and without substance use.Methods: All patients (n = 226) were aged >18 years old had symptom level scores of ≥4 on selected psychosis items on the Positive and Negative Syndrome Scale and met ICD-10 diagnostic criteria for psychosis. Information on substance use was collected based on the Clinician Drug Use Scale. Patients were grouped at baseline according to the presence of substance use, medication history and diagnosis group. Clinical symptoms at baseline and changes at follow-up were assessed with the PANSS.Results: At baseline about 30% of the patients used substances, most frequently cannabis followed by methamphetamine. About half (47%) of the patients had no prior exposure to antipsychotic medication at inclusion. Patients who had consumed substances showed no substantial differences in the PANSS score reduction as a result of antipsychotic medication compared to patients without substance. There were, however, some group differences in relation to pattern of change that were influenced by medication history. Substance use was found to be related to stronger reduction of positive symptoms from week 4 to week 27.Conclusion: Substance use alone did not influence antipsychotic effectiveness in this sample of patients with psychosis.

Reversibility of psychotropic medication induced weight gain among children and adolescents with bipolar disorders

ObjectiveTo assess the reversibility of weight gain associated with psychotropic medications in children. MethodsA retrospective cohort study was conducted using an ambulatory electronic medical records database. Individuals under 18 years of age were identified if they were initiating a new course of second generation/atypical antipsychotics (SGA) or mood stabilizers (MS) following a bipolar disorder diagnosis and subsequently discontinued treatment within 24 months of treatment initiation. ResultsOf the 297 children who had experienced positive BMI percentile increase (mean±SD: 8.71±11.94) during the treatment of SGA and/or MS, treatment discontinuation led to an average of 1.88 (±13.41) unit decrease in BMI percentile during a 12-month period since the treatment discontinuation. Repeated measure mixed model analysis showed that the reduction of BMI percentile after treatment discontinuation was neither associated with the treatment regimens patients previously received, nor associated with time since the treatment discontinuation. The three statistically significant predictors were baseline BMI percentile, BMI percentile gained during the treatment, and comorbid substance abuse disorder. ConclusionChildren with bipolar disorder were able to lose a fraction of weight gained during pharmacotherapy after the treatment discontinuation, however, their BMI percentile may not return to the prior treatment level within a year post-medication discontinuation.

Analysis of risk factors and outcomes in psychiatric inpatients with tardive dyskinesia: A nationwide case-control study

ObjectiveTo analyze comorbidities and outcomes in patients with tardive dyskinesia (TD) during psychiatric inpatient management. MethodsWe conducted a case-control study using the Nationwide Inpatient Sample. It included 77,022 adult inpatient admissions for mood disorders and schizophrenia. Cases had a secondary diagnosis of TD, and controls without TD were matched for age. Multivariable logistic regression was used to generate odds ratio (OR). ResultsMajority of TD patients were older age adults (50–64 years; 40%), and were in nearly equal proportions of men and women. African Americans had two-fold higher odds of TD. TD patients had a higher likelihood for cardio-metabolic comorbidities-obesity (OR 1.61, 95% CI 1.481–1.756), hypertension (OR 1.78, 95% CI 1.635–1.930) and diabetes (OR 1.54, 95% CI 1.414–1.680) compared to controls. They also had 1.5-fold increased risk of comorbid drug abuse. Patients with schizophrenia and bipolar disorder (depressive) had four-fold higher odds of TD. TD patients had about six-fold higher odds of severe morbidity. They had a higher likelihood of extended hospitalization stay by 6.36 days (95% CI 6.174–6.550) and higher cost by $20,415 (95% CI 19537–21293) compared to controls. ConclusionPsychiatric inpatients with TD have greater severity of illness, and those with schizophrenia and bipolar disorders are at highest risk. Presence of TD portends poor hospital outcomes and need for higher acute inpatient care.

Mass murders in Germany – classification of surviving offenders based on the examination of court files

ABSTRACTPersonality, psychopathology, and motives of 44 surviving offenders committing mass murder in Germany over 25 years (1984–2009) were analyzed using court files and psychiatric expertises. Initially, 123 mass murders in Germany were detected in the time period 1980–2010 (inclusive deceased offenders). Using a data entry form based on ViCLAS (Violent Crime Linkage Analysis System), we categorized the 44 surviving mass murderers into three prototypes using the ‘TwoStep Cluster’-method (separation of the offenders in different groups depending on their similarity of specific items): 1. Narcissistic or aggressive men suffering from addiction or affective disorder, committing mass murder out of rage/hate when being intoxicated by alcohol, 2. Psychotic offenders with schizophrenia and comorbid substance abuse. 3. Aggressive, narcissistic or anxious adolescents, half of them suffering from affective disorder or ADHD, committing mass murder out of rage/hate. Not included are such events where the offenders died and therefore no court files or psychiatric expertises were available. Classification and subtyping of the offenders’ personalities and psychopathological conditions might help to improve the chances for an early detection of persons at risk.

Prevalence, predictors, and patterns of mechanical restraint use for inpatients with dual diagnosis.

This study examined the prevalence, predictors, and patterns of mechanical restraint in an inpatient dual diagnosis population. Data were longitudinally collected from patients affected by severe mental illness and comorbid substance abuse that were hospitalized in three large wards from 2006 to 2012. In a sample of 1698 hospitalizations, the use of mechanical restraint ranged between 1% and 4% per year. The diagnosis of schizophrenia (odds ratio [OR], 2.64; 95% confidence interval [CI], 1.29-5.40), the use of stimulant substances (OR, 5.68; 95% CI, 2.78-11.59) and male sex (OR, 3.22; 95% CI, 1.12-9.27) were associated with an increased risk of being exposed to mechanical restraint. Specialized interventions targeting people at risk of mechanical restraint may further reduce the incidence of restraint and improve treatment outcomes.

An on-site health home for homeless men in addiction recovery.

Patients with comorbid substance abuse, mental health disorders, and chronic health conditions face difficult challenges when attempting to access health care. A large gospel rescue mission developed an onsite wellness center, based on an integrated, embedded practice health home model, to promote health care access among homeless men in addiction recovery. The center model integrated primary care with behavioral health, specialty care referrals, and wellness services to address the multifaceted needs of the population. Standardized health care performance measures and resident and staff feedback support the effectiveness of the model in promoting improved health care access and treatment adherence. Future directions for program expansion include infrastructure development, expanded community outreach, and evaluation of effectiveness of the onsite health home through systematic program evaluation and research.

General and Specific Predictors of Comorbid Substance Use and Internalizing Problems from Adolescence to Age 33.

The current study examines the continuity in comorbidity between substance use and internalizing mental health problems from adolescence to adulthood and investigates the general and specific predictors of comorbidity across development. Participants were drawn from the Seattle Social Development Project (N= 808), a gender-balanced, ethnically diverse longitudinal panel. Structural equation modeling was used to examine risk factors for comorbid substance use and internalizing problems in family and peer social environments; substance use- and mental health-specific social environments (family tobacco, alcohol, and marijuana use; family history of depression); and individual risk factors (behavioral disinhibition). Latent factors were created for comorbid substance use and mental health problems at ages 13-14 and comorbidity of substance abuse and dependence symptoms and mental health disorder symptoms at ages 30-33 and included indicators of anxiety, depression, alcohol, tobacco, and marijuana problems. Comorbid problems in adolescence predicted later comorbidity of disorders in adulthood. In addition, family tobacco environment and behavioral disinhibition predicted adolescent comorbidity, while family history of depression was associated with adult comorbidity. Finally, family and peer substance use in adolescence predicted substance use (alcohol, tobacco, and marijuana) both in adolescence and adulthood. The pattern of results suggests that comorbidity in adolescence continues into adulthood and is predicted by both general and behavior-specific environmental experiences during adolescence. Findings clarify the etiology of comorbid internalizing and substance use problems and suggest potential preventive intervention targets in adolescence to curb the development of comorbidity in adulthood.

Revisiting the Concept of Subjective Tolerability to Antipsychotic Medications in Schizophrenia and its Clinical and Research Implications: 30 Years Later.

Schizophrenia is a long-term psychiatric disorder that impacts important mental functions and requires indefinite treatment, as well as psychosocial and economic support. The introduction of chlorpromazine, the first antipsychotic, and the subsequent development of a long list of similar dopamine-blocking antipsychotic medications, has changed the treatment of schizophrenia as medications have become the cornerstone of clinical management. The enthusiasm that greeted the introduction of antipsychotics was soon tempered by the realisation that they induced significant side effects, such as extrapyramidal and autonomic symptoms. A less-recognized side effect at the time was the emergence of subtle subjective side effects that led patients to dislike medications and eventually discontinue them, with serious consequences of frequent relapses requiring hospitalization, poor outcomes and more health costs. The development of our dedicated programme for research into subjective tolerability to medications over the past 30years has allowed us to establish the validity of the construct of 'subjective tolerability' to antipsychotics, applying research methodologies that are required for any scientific inquiry. We clarified definitions, developed reliable measuring tools, and constructed psychosocial and neurobiological conceptual models. We also documented the serious consequences of negative subjective tolerability to antipsychotics: poor medication adherence behaviour, impaired quality of life, and worse clinical and functional outcomes. More recently, using neuroimaging techniques, we and other international research groups were able to clearly elucidate the neurobiology of dysphoric negative subjective responses, linking it to low dopamine functioning in the striatal region of the brain. Such a discovery for the first time allowed us to also link the development of comorbid drug abuse in schizophrenia, which is a common occurrence, to the development of neuroleptic dysphoria, since both relate to the low dopamine function in the striatum. As an already validated scientific concept that has serious consequences, subjective tolerability to antipsychotics can serve as a model for patient-centered outcomes that really matter. Our long-serving research programme also illustrates the value of clinical observations to the development of important clinical research studies, i.e. from the bedside to the research bench, and back to the bedside.