Influence of Functional Variant of Neuronal Nitric Oxide Synthase on Impulsive Behaviors in Humans
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WEB-ONLY CONTENT Influence of Functional Variant of Neuronal Nitric Oxide Synthase on Impulsive Behaviors in Humans Andreas Reif, MD; Christian P. Jacob, MD; Dan Rujescu, MD; Sabine Herterich, PhD; Sebastian Lang, MD; Lise Gutknecht, PhD; Christina G. Baehne, Dipl-Psych; Alexander Strobel, PhD; Christine M. Freitag, MD; Ina Giegling, MD; Marcel Romanos, MD; Annette Hartmann, MD; Michael Rösler, MD; Tobias J. Renner, MD; Andreas J. Fallgatter, MD; Wolfgang Retz, MD; Ann-Christine Ehlis, PhD; Klaus-Peter Lesch, MD Arch Gen Psychiatry. 2009;66(1):41-50. SUPPLEMENTAL METHODS Personality Disorder A total of 403 inpatients and outpatients of the Department of SAMPLE DESCRIPTIONS Psychiatry and Psychotherapy, University of Würzburg, with personality disorders according to DSM-IV criteria partici- Control A pated in the study (43.2% male; mean [SD] age, 36 [13] years; mean number of Axis II diagnoses, 1.67 [1.15]; Axis I comor- A total of 284 control subjects (150 male and 134 female) con- bidity, 73.2%). Patients were drawn from the general popula- sisting of healthy blood donors originating from Würzburg, Ger- tion of hospital patients; every patient with a clinical diagno- many, were enrolled. The sample was not screened for psychiat- sis of personality disorder treated in the department from 2000 ric disorders; however, all subjects were free of medication, and to 2002 was approached and asked to participate in the study. the study was explained to them, so that the likelihood of severe Inclusion criteria were personality disorder (PD) according to psychiatric disorders in the control sample was low. The mean DSM-IV (antisocial, histrionic, borderline, narcissistic, avoid- (SD) age of controls was 35 (13) years. An additional 356 sub- ant, dependent, and obsessive-compulsive personality disor- jects (174 male and 182 female) were recruited and screened for der) and age between 18 and 60 years. Exclusion criteria were absence of psychiatric disorders by conducting a Structured Clini- medical conditions and lifetime diagnosis of schizophrenia or cal Interview for DSM-IV (SCID-I) interview. These subjects were other psychotic disorders. The sample was divided into sub- recruited by local advertisements, from hospital staff, and from samples of patients with an exclusive diagnosis on either per- medical students. The mean (SD) age of this sample was 30 (9) sonality disorder cluster B or C (ie, cluster B patients with his- years. All participants originated from the catchment area of Lower trionic PD had no cluster C diagnosis). In the cluster B subsample Franconia, a part of Bavaria (southern Germany). (n=322; 43.2% male; mean [SD] age, 35 [13] years), 31.1% had no Axis I diagnosis, whereas F3x (15.2%) and F4x (37.3%) di- Control B agnoses were the 2 most frequent comorbid Axis I disorders. In the cluster C subsample (n=81; 42.0% male; mean [SD] age, Unrelated healthy volunteers of German descent (ie, both of their 38 [13] years; mean [SD] number of Axis II diagnoses, 1.42 parents were German) were randomly selected from the general [0.68]), 12.4% had no Axis I diagnosis, 30.9% had an F3x di- population of Munich, Germany, and contacted by mail. To ex- agnosis, and 42.0% had an F4x diagnosis. Individuals with life- clude subjects with neuropsychiatric disorders or subjects who time diagnosis of schizophrenia or other psychotic disorders had first-degree relatives with neuropsychiatric disorders, we con- were excluded. ducted further screenings before the volunteers were enrolled in The SCID-II was used to diagnose PDs, and PDs were allo- the study. First, subjects who responded were initially screened cated to cluster B and C operationalized as follows: cluster B by telephone. Detailed medical and psychiatric histories were as- (dramatic-emotional) encompasses antisocial, borderline, his- sessed for both themselves and their first-degree relatives by using trionic, and narcissistic PDs. Cluster C (anxious-fearful) in- systematic forms. Second, they were invited to a comprehensive cludes avoidant, dependent, and obsessive-compulsive PDs. The interview including the SCID-I and SCID-II to evaluate their life- assessment of the PDs, including all psychometric testing, was time Axis I and II disorders. Psychiatric diagnoses among their performed by a single experienced psychiatrist (C.P.J.). first-degree relatives were also assessed by means of the Family History Assessment Module.11 Subjects with relevant somatic dis- eases or a lifetime history of any Axis I or II psychiatric disorders Adult Attention-Deficit/Hyperactivity Disorder or suicidal behavior were excluded. Subjects who had first- degree relatives with a lifetime history of a mental disorder or sui- A total of 383 inpatients and outpatients (54.3% male; mean cidal behavior were also excluded. Finally, 1314 healthy sub- [SD] age, 34 [10] years) of the Department of Psychiatry, jects (of whom 601 were male) were included. Their mean (SD) University of Würzburg, referred for diagnostic assessment age was 46 (16) years (range, 19-79 years). and treatment of adult attention-deficit/hyperactivity disor- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 66 (NO. 1), JAN 2009 WWW.ARCHGENPSYCHIATRY.COM E1 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 der (aADHD), were examined with SCID-I. Again, SCID-II cases. The educational and professional status of most of the was used to diagnose PDs, and patients were assessed for subjects was low (special education, school dropout, 13.4%; personality traits by the revised NEO Personality Inventory– junior high school/Յ8 classes, 70.1%; high school/Ͼ8 classes, Revised (NEO-PI-R) Questionnaire. Inclusion criteria were 16.5%; completed professional training, 55.5%; no profes- aADHD according to DSM-IV, onset before the age of 7 sional training, 44.5%), and the rate of unemployment was high years, lifelong persistence, current diagnosis, and age at (employment rate, 39.3%). All subjects underwent a semistruc- recruitment between 18 and 65 years. Exclusion criteria tured psychiatric interview by well-trained psychiatrists (W.R. were a current diagnosis of not withdrawn drug/alcohol and M.R.) and neurologic examination. abuse/dependence, a lifetime diagnosis of bipolar I disorder, schizophrenia, or any other psychotic disorder, and mental Ͻ retardation (IQ 80). Patients were also excluded if the Familial ADHD appearance of symptoms was restricted to the duration of any other Axis I disorder. Details on the sample can be The study included 151 inpatients and outpatients aged 8 to obtained from Jacob et al.12 18 years who had been referred to the Department of Child and Adolescent Psychiatry, University of Würzburg, and Suicide Attempters phenotypically characterized by a team of experienced psy- chiatrists (C.P.J., M.R., and T.J.R.) in the outpatient unit of Suicide attempters were recruited among patients consecu- the clinic according to DSM-IV criteria. Furthermore, tively referred to general psychiatric wards of the Department included children were characterized by a standardized full of Psychiatry, Ludwig-Maximilians-University, Munich. Only interview (Schedule for Affective Disorders and Schizophre- patients of German descent (ie, both of their parents were Ger- nia for School-Age Children–Present and Lifetime Version man) were enrolled in the study. The sample has been par- [K-SADS-PL]) with a parent. Mothers received (1) the tially published for investigations on other gene variants.13 The unstructured Introductory Interview, (2) the Diagnostic current and lifetime diagnoses of mental disorders were as- Screening Interview, and (3) the Supplement Completion sessed close to discharge by applying the SCID-I interview. Pa- Checklist and, on fulfillment of screening criteria, the appro- tients with mental disorders due to a general medical condi- priate diagnostic supplements. The child was interviewed tion or with dementia were excluded. The study included 189 with the screening interview of the K-SADS and, in cases of suicide attempters (61 of them male) with a clear suicide at- positive screening for mood or anxiety disorders, with the tempt. Their mean (SD) age was 40 (14) years (range, 16-73 respective supplements of the K-SADS-PL. In addition, we years). The DSM-IV lifetime diagnoses of mental disorders among used the Child Behavior Checklist and a German teachers’ the patients were as follows: affective spectrum (n=131), schizo- report on ADHD symptoms according to DSM-IV. phrenia spectrum (n=30), and borderline PD (n=28). The sample included 118 male and 33 female children from 102 families; the mean (SD) age of the affected chil- Forensic dren was 12 (4) years. In all families, both parents were ascertained. The index patient was required to be older than One hundred eighty-two adult male volunteers were enrolled 8 years, and to fulfill DSM-IV criteria for the combined sub- who had been referred for a forensic examination to the Insti- type, other affected siblings in the family had to be older tute of Forensic Psychiatry of the Saarland University, Hom- than 6 years. Exclusion criteria were birth weight less than burg, Germany, by legal authorities for a forensic examination 2000 g, IQ less than 85, neurologic or severe somatic disor- (evaluation of legal responsibility or risk assessment). The mean ders, potentially confounding psychiatric diagnoses such as (SD) age was 34.1 (11.7) years. Criminal offenses of the par- schizophrenia, any pervasive developmental disorder, ticipants of the study comprised homicide, physical injury, and Tourette disorder, primary mood or anxiety disorders, drug robbery (n=75); property offenses and fraud (n=41); sexual of- abuse or autistic disorder, history of any acquired brain fenses (n=33); drug offenses (n=12); and others (n=67). Sub- damage or evidence of the fetal alcohol syndrome, prema- jects with a diagnosis of current substance dependence, acute ture deliveries, and maternal reports of severe prenatal, peri- schizophrenia, major depression/bipolar disorder, or any other natal, or postnatal complications.