Increased burden of rare protein-truncating variants in constrained, brain-specific and synaptic genes in extremely impulsively violent males with antisocial personality disorder.

The genetic correlates of extreme impulsive violence are poorly understood, and there have been few studies that have characterized a large group of affected individuals both clinically and genetically. We performed whole exome sequencing (WES) in 290 males with the life-course-persistent, extremely impulsively violent form of antisocial personality disorder (APD) and analyzed the spectrum of rare protein-truncating variants (rPTVs). Comparisons were made with 314 male controls and publicly available genotype data. Functional annotation tools were used for biological interpretation. Participants were significantly more likely to harbor rPTVs in genes that are intolerant to loss-of-function variants (odds ratio [OR] 2.06; p < 0.001), specifically expressed in brain (OR 2.80; p = 0.036) and enriched for those involved in neurotransmitter transport and synaptic processes. In 60 individuals (20%), we identified rPTVs that we classified as clinically relevant based on their clinical associations, biological function and gene expression patterns. Of these, 37 individuals harbored rPTVs in 23 genes that are associated with a monogenic neurological disorder, and 23 individuals harbored rPTVs in 20 genes reportedly intolerant to loss-of-function variants. The analysis presents evidence in support of a model where presence of either one or several private, functionally relevant mutations contribute significantly to individual risk of life-course-persistent APD and reveals multiple individuals who could be affected by clinically unrecognized neuropsychiatric Mendelian disease. Thus, Mendelian diseases and increased rPTV burden may represent important factors for the development of extremely impulsive violent life-course-persistent forms of APD irrespective of their clinical presentation.

Should Behavior Harmful to Others Be a Sufficient Criterion of Mental Disorders? Conceptual Problems of the Diagnoses of Antisocial Personality Disorder and Pedophilic Disorder.

Generally, diseases are primarily harmful to the individual herself; harm to others may or may not be a secondary effect of diseases (e.g., in case of infectious diseases). This is also true for mental disorders. However, both ICD-10 and DSM-5 contain two diagnoses which are primarily defined by behavior harmful to others, namely Pedophilic Disorder and Antisocial (or Dissocial) Personality Disorder (ASPD or DPD). Both diagnoses have severe conceptual problems in the light of general definitions of mental disorder, like the definition in DSM-5 or Wakefield's "harmful dysfunction" model. We argue that in the diagnoses of Pedophilic Disorder and ASPD the criterion of harm to the individual is substituted by the criterion of harm to others. Furthermore, the application of the criterion of dysfunction to these two diagnoses is problematic because both heavily depend on cultural and social norms. Therefore, these two diagnoses fall outside the general disease concept and even outside the general concept of mental disorders. We discuss whether diagnoses which primarily or exclusively ground on morally wrong, socially inacceptable, or criminal behavior should be eliminated from ICD and DSM. On the one side, if harming others is a sufficient criterion of a mental disorder, the "evil" is pathologized. On the other side, there are practical reasons for keeping these diagnoses: first for having an official research frame, second for organizing and financing treatment and prevention. We argue that the criteria set of Pedophilic Disorder should be reformulated in order to make it consistent with the general definition of mental disorder in DSM-5. This diagnosis should only be applicable to individuals that are distressed or impaired by it, but not solely based on behavior harmful to others. For ASPD, we conclude that the arguments for eliminating it from the diagnostic manuals overweigh the arguments for keeping it.

Rare copy number variation in extremely impulsively violent males.

The genetic correlates of extreme impulsive violence are poorly understood, and there have been no studies that have systematically characterized a large group of affected individuals both clinically and genetically. We performed a genome-wide rare copy number variant (CNV) analysis in 281 males from four Czech prisons who met strict clinical criteria for extreme impulsive violence. Inclusion criteria included age ≥ 18 years, an ICD-10 diagnosis of Dissocial Personality Disorder, and the absence of an organic brain disorder. Participants underwent a structured psychiatric assessment to diagnose extreme impulsive violence and then provided a blood sample for genetic analysis. DNA was genotyped and CNVs were identified using Illumina HumanOmni2.5 single-nucleotide polymorphism array platform. Comparing with 10851 external population controls, we identified 828 rare CNVs (frequency ≤ 0.1% among control samples) in 264 participants. The CNVs impacted 754 genes, with 124 genes impacted more than once (2-25 times). Many of these genes are associated with autosomal dominant or X-linked disorders affecting adult behavior, cognition, learning, intelligence, specifically expressed in the brain and relevant to synapses, neurodevelopment, neurodegeneration, obesity and neuropsychiatric phenotypes. Specifically, we identified 31 CNVs of clinical relevance in 31 individuals, 59 likely clinically relevant CNVs in 49 individuals, and 17 recurrent CNVs in 65 individuals. Thus, 123 of 281 (44%) individuals had one to several rare CNVs that were indirectly or directly relevant to impulsive violence. Extreme impulsive violence is genetically heterogeneous and genomic analysis is likely required to identify, further research and specifically treat the causes in affected individuals.

Childhood hyperkinetic disorder/attention deficit disorder grown up.

There is growing evidence for the validity of the diagnosis of Attention Deficit Hyperkinetic Disorder (ADHD) in adults, as well as evidence that conduct disorder in adolescents and dissocial personality disorder in adult life are linked to ADHD in childhood. Methylphenidate is an effective treatment of ADHD in adolescents and young adults and it is possible that dissocial personality disorder will respond to methylphenidate. There is no evidence that methylphenidate reduces symptoms of conduct disorder in adolescents or of dissocial personality disorder in young adults, because no studies have evaluated methylphenidate in these conditions. We recorded a dramatic improvement in symptoms, predominantly of conduct disorder, in an adolescent with a previous history of ADHD. Trials of methylphenidate are required in adolescents with conduct disorder and young people with dissocial personality disorder, when there is a past history of probable ADHD.