Management of Cholinergic Rebound After Abrupt Withdrawal of Clozapine: A Case Report and Systematic Literature Review.

BACKGROUND: Cholinergic discontinuation symptoms, also known as "cholinergic rebound," from abrupt clozapine discontinuation are characterized by a range of somatic and psychiatric symptoms. OBJECTIVE: The objective of this study was to describe the clinical features and management options for clozapine withdrawal-associated cholinergic rebound syndrome (henceforth referred to as CWCRS) and present an illustrative case report. METHODS: Based on a literature search of the databases PubMed, OVID Medline, and Embase as well as reviewing reference lists of relevant past reviews, we carried out a systematic review of case reports on the management of CWCRS from 1946 to 2023. RESULTS: We identified 10 previously published articles on the clinical management of CWCRS, with a total of 18 patients (6 female, 12 male) with an average age of 43 years (standard deviation 14). Half of the patients had a history of tardive dyskinesia. The mean dose of clozapine before discontinuation was 351 mg/day, with duration of clozapine treatment ranging from 3 weeks to 9 years. Clozapine was the most effective treatment, followed by benztropine. CONCLUSIONS: Given the small number of cases and the nonexperimental nature of the available studies, this review could not provide reliable data to guide management of CWCRS. The findings, however, suggest that clozapine may be more effective than other commonly used treatment options. With the high rates of discontinuation among patients on clozapine, there is a pressing need for further research into the epidemiology, natural history, and management of clozapine withdrawal syndromes.

Alprazolam: Good for Some, Not Good for All!

BACKGROUND: Although alprazolam is approved only for use in panic disorder and generalized anxiety disorder, it is used for numerous other conditions, not only by psychiatrists but also by medical professionals in general. This commentary critically analyzes the use of alprazolam. METHODS: A narrative review approach was adopted, using relevant articles and textbooks, to compile pertinent literature for the aforementioned topic. RESULTS: Among all its adverse reactions, the most bothersome concern about the use of alprazolam is its potential for abuse and dependence. This can be attributed to certain unique pharmacokinetic and pharmacodynamic properties of this benzodiazepine. Also, the withdrawal triggered by use of alprazolam is challenging to treat. Alternate pharmacological and non-pharmacological strategies for use in anxiety and insomnia are available, which might be safer than alprazolam. Also, policy changes can serve as an answer to curb alprazolam abuse to some extent. Alprazolam might still be a good choice for individuals who do not have a history of abuse of other substances, with adequate psychoeducation and close monitoring of their usage pattern. CONCLUSION: There is a need to reconsider the need for long-term use of benzodiazepines in general, and alprazolam in particular. However, they still might be an appropriate choice in individuals where abuse and dependence are less likely.

Oxytocin effects on amygdala reactivity to angry faces in males and females with antisocial personality disorder.

The amygdala is a key region in current neurocircuitry models of reactive aggression as it is crucially involved in detecting social threat and provocation. An increased amygdala reactivity to angry faces has been reported in aggression-prone individuals and the neuropeptide oxytocin (OT) could dampen anger-related amygdala reactivity in a number of mental disorders. One example is the antisocial personality disorder (ASPD) which has so far only been studied in limited numbers. To address the question whether OT can normalize amygdala hyperreactivity to emotional faces, we conducted a functional magnetic resonance imaging experiment with 20 men and 18 women with ASPD and 20 male and 20 female healthy control (HC) participants in a double-blind, randomized, placebo (PLC)-controlled within-subject design. Participants were exposed to an emotion classification task (fearful, angry, and happy faces) after receiving an intranasal dose (24 IU) of synthetic OT or PLC. We found OT to attenuate right amygdala hyperactivity to angry faces in participants with ASPD to such an extent that the intensity of amygdala activity in the ASPD group in the OT condition decreased to the level of amygdala activity in the PLC condition in the HC group. There was also a trend that OT effects were generally larger in women than in men. These findings suggest that OT differentially modulates the amygdala following social threatening or provoking cues in dependence of psychopathology (ASPD vs. HC) and sex (male vs. female). Particularly female ASPD patients could benefit from OT in the treatment of reactive aggression.

Sniffing submissiveness? Oxytocin administration in severe psychopathy.

Psychopathy is a personality disorder associated with criminal behavior and violent recidivism, and therefore a burden to society. Social dominance is one of the characteristics of psychopathy that might contribute to these problems. Nevertheless, only few studies have objectively measured the relationship between socially dominant behavior and psychopathy. Therefore, the current study assessed performance of 21 forensic PCL-R confirmed psychopathic patients and 24 normal controls on a gaze aversion task, in which slower gaze aversion from masked angry faces compared to masked happy faces is a measure of reactive dominance. Moreover, the current study assessed the potential beneficial effects of the neuropeptide oxytocin. The results showed that psychopaths were not more dominant on the gaze aversion task compared to normal controls. However, the severity of psychopathy was positively correlated with reactive dominance. Crucially, a single nasal spray administration of oxytocin abolished the connection between psychopathy and reactive dominance. This implies that socially dominant psychopaths might benefit from oxytocin administration.

Inhibition of ecto-5'-nucleotidase and adenosine deaminase is able to reverse long-term behavioural effects of early ethanol exposure in zebrafish (Danio rerio).

The behavioural impacts of prenatal exposure to ethanol include a lower IQ, learning problems, anxiety and conduct disorders. Several components of the neurochemical network could contribute to the long-lasting effects of ethanol embryonic exposure. Adenosine is an important neuromodulator, that has been indicated to be affected by acute and chronic exposure to ethanol. Here, embryos of zebrafish exposed to 1% ethanol during the developmental stages of gastrula/segmentation or pharyngula exhibited anxiolytic effect, increased aggressiveness, and decreased social interaction. The exposure during pharyngula stage was able to affect all behavioural parameters analysed at 3 months-post fertilization (mpf), while the treatment during gastrula stage affected the anxiety and social interaction parameters. The aggressiveness was the only behavioural effect of early ethanol exposure that lasted to 12 mpf. The use of a specific inhibitor of adenosine production, the inhibitor of ecto-5'-nucleotidase (AMPCP/150 mg/kg), and the specific inhibitor of adenosine degradation, the inhibitor of adenosine deaminase, EHNA (100 mg/kg) did not affect the effects over anxiety. However, AMPCP at 3 mpf, but not EHNA, reversed aggressive parameters. AMPCP also recovered the social interaction parameter at 3 mpf in animals treated in both stages, while EHNA recovered this parameter just in those animals treated with ethanol during the gastrula stage. These results suggest that long-lasting behavioural effects of ethanol can be modulated by intervention on ecto-5'-nucleotidase and adenosine deaminase activities.

Pharmacological interventions for antisocial personality disorder.

BACKGROUND: Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death. Certain types of medication (drugs) may help people with AsPD. This review updates a previous Cochrane review, published in 2010. OBJECTIVES: To assess the benefits and adverse effects of pharmacological interventions for adults with AsPD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, 13 other databases and two trials registers up to 5 September 2019. We also checked reference lists and contacted study authors to identify studies. SELECTION CRITERIA: Randomised controlled trials in which adults (age 18 years and over) with a diagnosis of AsPD or dissocial personality disorder were allocated to a pharmacological intervention or placebo control condition. DATA COLLECTION AND ANALYSIS: Four authors independently selected studies and extracted data. We assessed risk of bias and created 'Summary of findings tables' and assessed the certainty of the evidence using the GRADE framework. The primary outcomes were: aggression; reconviction; global state/global functioning; social functioning; and adverse events. MAIN RESULTS: We included 11 studies (three new to this update), involving 416 participants with AsPD. Most studies (10/11) were conducted in North America. Seven studies were conducted exclusively in an outpatient setting, one in an inpatient setting, and one in prison; two studies used multiple settings. The average age of participants ranged from 28.6 years to 45.1 years (overall mean age 39.6 years). Participants were predominantly (90%) male. Study duration ranged from 6 to 24 weeks, with no follow-up period. Data were available from only four studies involving 274 participants with AsPD. All the available data came from unreplicated, single reports, and did not allow independent statistical analysis to be conducted. Many review findings were limited to descriptive summaries based on analyses carried out and reported by the trial investigators. No study set out to recruit participants on the basis of having AsPD; many participants presented primarily with substance abuse problems. The studies reported on four primary outcomes and six secondary outcomes. Primary outcomes were aggression (six studies) global/state functioning (three studies), social functioning (one study), and adverse events (seven studies). Secondary outcomes were leaving the study early (eight studies), substance misuse (five studies), employment status (one study), impulsivity (one study), anger (three studies), and mental state (three studies). No study reported data on the primary outcome of reconviction or the secondary outcomes of quality of life, engagement with services, satisfaction with treatment, housing/accommodation status, economic outcomes or prison/service outcomes.   Eleven different drugs were compared with placebo, but data for AsPD participants were only available for five comparisons. Three classes of drug were represented: antiepileptic; antidepressant; and dopamine agonist (anti-Parkinsonian) drugs. We considered selection bias to be unclear in 8/11 studies, attrition bias to be high in 7/11 studies, and performance bias to be low in 7/11 studies. Using GRADE, we rated the certainty of evidence for each outcome in this review as very low, meaning that we have very little confidence in the effect estimates reported. Phenytoin (antiepileptic) versus placebo One study (60 participants) reported very low-certainty evidence that phenytoin (300 mg/day), compared to placebo, may reduce the mean frequency of aggressive acts per week (phenytoin mean = 0.33, no standard deviation (SD) reported; placebo mean = 0.51, no SD reported) in male prisoners with aggression (skewed data) at endpoint (six weeks). The same study (60 participants) reported no evidence of difference between phenytoin and placebo in the number of participants reporting the adverse event of nausea during week one (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.06 to 16.76; very low-certainty evidence). The study authors also reported that no important side effects were detectable via blood cell counts or liver enzyme tests (very low-certainty evidence). The study did not measure reconviction, global/state functioning or social functioning. Desipramine (antidepressant) versus placebo One study (29 participants) reported no evidence of a difference between desipramine (250 to 300 mg/day) and placebo on mean social functioning scores (desipramine = 0.19; placebo = 0.21), assessed with the family-social domain of the Addiction Severity Index (scores range from zero to one, with higher values indicating worse social functioning), at endpoint (12 weeks) (very low-certainty evidence). Neither of the studies included in this comparison measured the other primary outcomes: aggression; reconviction; global/state functioning; or adverse events. Nortriptyline (antidepressant) versus placebo One study (20 participants) reported no evidence of a difference between nortriptyline (25 to 75 mg/day) and placebo on mean global state/functioning scores (nortriptyline = 0.3; placebo = 0.7), assessed with the Symptom Check List-90 (SCL-90) Global Severity Index (GSI; mean of subscale scores, ranging from zero to four, with higher scores indicating greater severity of symptoms), at endpoint (six months) in men with alcohol dependency (very low-certainty evidence). The study measured side effects but did not report data on adverse events for the AsPD subgroup. The study did not measure aggression, reconviction or social functioning. Bromocriptine (dopamine agonist) versus placebo One study (18 participants) reported no evidence of difference between bromocriptine (15 mg/day) and placebo on mean global state/functioning scores (bromocriptine = 0.4; placebo = 0.7), measured with the GSI of the SCL-90 at endpoint (six months) (very low-certainty evidence). The study did not provide data on adverse effects, but reported that 12 patients randomised to the bromocriptine group experienced severe side effects, five of whom dropped out of the study in the first two days due to nausea and severe flu-like symptoms (very low-certainty evidence). The study did not measure aggression, reconviction and social functioning. Amantadine (dopamine agonist) versus placebo The study in this comparison did not measure any of the primary outcomes. AUTHORS' CONCLUSIONS: The evidence summarised in this review is insufficient to draw any conclusion about the use of pharmacological interventions in the treatment of antisocial personality disorder. The evidence comes from single, unreplicated studies of mostly older medications. The studies also have methodological issues that severely limit the confidence we can draw from their results. Future studies should recruit participants on the basis of having AsPD, and use relevant outcome measures, including reconviction.

Emotional dysregulation and callous unemotional traits as possible predictors of short-term response to methylphenidate monotherapy in drug-naïve youth with ADHD.

BACKGROUND: Emotional dysregulation (ED) and callous unemotional (CU) traits can be associated with ADHD in youth, influencing its natural history and outcome, but their effect on medication efficacy is unexplored. We examined whether two measures of baseline ED and CU traits, the Child Behavior Checklist-Dysregulation Profile (CBCL-DP) and the Antisocial Process Screening Device (APSD), respectively, were predictors of change of ADHD-Rating Scale (ADHD-RS) after a 4-week methylphenidate (MPH) monotherapy. METHODS: 43 patients (37 males, 8-16 years, mean 9.9 ± 2.7 years) were included. Hierarchical linear regression models were used to explore whether CBCL-DP and APSD might predict ADHD-RS score, controlling for baseline severity. RESULTS: Baseline CBCL-DP predicted higher post-treatment ADHD-RS scores in total and hyperactivity-impulsivity, but not in inattention subscale. Baseline APSD was not significantly related to ADHD-RS scores at the follow-up. LIMITATIONS: Small sample size, lack of gender diversity, non-blind design and short period of observation. CONCLUSION: ED, assessed with that CBCL-DP, might be a negative predictor of change of hyperactive-impulsive symptoms after MPH treatment and should be systematically assessed at baseline.

Prevalence and correlates of suicide attempt among Chinese individuals receiving methadone maintenance treatment for heroin dependence.

To date, there have been very limited studies regarding the clinical epidemiology of attempted suicide in Chinese individuals with heroin-dependence. The objective of this study was to examine the prevalence and correlates of suicide attempt in Chinese individuals receiving methadone maintenance treatment for heroin dependence. Demographic, clinical, and psychosocial data of 603 methadone-maintained patients with heroin dependence were collected with a standardized self-administered questionnaire. The presence of suicide attempt and antisocial personality disorder was assessed by using a single question and the Mini-International Neuropsychiatric Interview 5.0. The one-month and lifetime prevalence rates of suicide attempt were 9.5% and 34.2%, respectively. In multivariable logistic regression, lifetime suicide attempt was significantly associated with female gender (OR = 2.81), being 20-39 years old (OR = 2.73), an education level of primary school or lower (OR = 2.07), poor economic status (OR = 3.06), injecting heroin before methadone maintenance treatment (OR = 2.92), depressive symptoms (OR = 3.46), anxiety symptoms (OR = 1.88), and antisocial personality disorder (OR = 2.85). Suicide attempt is very prevalent among Chinese individuals receiving methadone maintenance treatment for heroin dependence. Services for patients with heroin dependence in methadone maintenance treatment clinics in China should include psychosocial supports, periodic screening for suicide attempt and other suicidal behaviors and, when needed, psychiatric treatment and crisis intervention.

An Integrative Model and Dynamic Nosology of Personality Disorder: Part 2: Symptom-based pharmacotherapy.

This paper presents an integrative model of personality and personality disorder which incorporates psychoanalytic concepts with modern neuroscience. In addition, a dynamic, personalized, and context - and time-sensitive diagnosis of personality disorder is introduced. The authors cogently argue that all clinical variants of personality disorder share the same common deficit: fragmented basic units of experience at the nonconscious core of the mind (aka "partial object relations"). The fragmentation propagates through mental faculties (thought, motivation, emotion), as they self-organize into subsystems of personality, e.g., one's sense of self, identity, character, moral values, rendering them polarized into extreme and thus adaptively suboptimal. The syndrome of personality disorder arises as a nonconscious compensatory maneuver of the fragmented mind to organize itself through a defensive but unrealistic self-image (e.g., narcissistic, schizoid, antisocial, etc.), giving rise to a host of unique symptoms. Symptomatic pharmacotherapy of personality disorder is best organized around four empirically derived domains of symptoms, shared by all variants to a variable degree: i) mood and anxiety dysregulation; ii) impulsivity, aggression, and behavior dyscontrol; iii) emotional disinterest and detachment; and iv) cognitive distortions and brief reactive psychoses. Pharmacotherapy targeting the above domains is nonspecific, as medications affect multiple domains simultaneously. Modest empirical evidence and considerable clinical benefits continue to support the use of medications in the overall symptomatic treatment of personality disorder.

Prescribing Trends of Atypical Antipsychotic Drugs in an Outpatient Unit of a Child and Adolescent Clinic in Turkey.

OBJECTIVE: Use of antipsychotic agents in the management of various psychopathologies in Child and Adolescent Psychiatric practice is gradually increasing. This study aimed to evaluate the sociodemographic and clinical features of children and adolescents who applied to an outpatient clinic of child and adolescent psychiatry department in Turkey and were prescribed atypical antipsychotics. METHOD: Patients with prescription codes of ATC N05A (except N05AN lithium) were accepted to denote those with atypical antipsychotic treatment. Sociodemographic and clinical variables, pharmacological mechanisms and groups and use of multiple agents for 212 patients with atypical antipsychotic treatment were collected and recorded. RESULTS: Patients (6.6%) evaluated within a year were prescribed antipsychotic agents (APs). The majority of the sample consisted of adolescents and especially females. The most common diagnoses managed with atypical antipsychotic were attention-deficit/hyperactivity disorder, MDD, and mental retardation/intellectual disability in decreasing frequency. Males with attention-deficit/hyperactivity disorder, CD, and autism spectrum disorders and females with MDD and PTSD were more frequently prescribed APs. Most common indications were irritability, impulsivity, and self-harming behaviors. Most common agents were risperidone, aripiprazole, and quetiapine in decreasing order of frequency. Most common adverse effects were reported as sedation, increased appetite, and hyperprolactinemia. CONCLUSIONS: Our results support the prevalence of off-label use of AP agents in managing various childhood psychopathologies also in Turkey. Further studies from multiple centers and using reliable and valid measurements are needed to determine the extent and predictors of AP use in outpatient samples from different child and adolescent centers.

Classification and treatment of antisocial individuals: From behavior to biocognition.

Antisocial behavior is a heterogeneous construct that can be divided into subtypes, such as antisocial personality and psychopathy. The adverse consequences of antisocial behavior produce great burden for the perpetrators, victims, family members, and for society at-large. The pervasiveness of antisocial behavior highlights the importance of precisely characterizing subtypes of antisocial individuals and identifying specific factors that are etiologically related to such behaviors to inform the development of targeted treatments. The goals of the current review are (1) to briefly summarize research on the operationalization and assessment of antisocial personality and psychopathy; (2) to provide an overview of several existing treatments with the potential to influence antisocial personality and psychopathy; and (3) to present an approach that integrates and uses biological and cognitive measures as starting points to more precisely characterize and treat these individuals. A focus on integrating factors at multiple levels of analysis can uncover person-specific characteristics and highlight potential targets for treatment to alleviate the burden caused by antisocial behavior.

Effects of adjunctive fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia: A 12-week, randomized, double-blind, placebo-controlled study.

OBJECTIVE: Numerous studies have demonstrated that fluvoxamine has considerable pharmacokinetic and pharmacodynamic interactions with clozapine. We conducted a 12-week, randomized, double-blind, placebo-controlled study to evaluate the effects of fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia. METHODS: We recruited 85 patients who received a DSM-IV diagnosis of schizophrenia. Eligible patients were randomized to receive fluvoxamine 50mg/day plus clozapine 100mg/day or clozapine 300mg/day. We studied metabolic parameters, psychopathology, and drug levels at baseline and 4, 8, and 12weeks after the intervention. Plasma levels of clozapine, norclozapine, clozapine N-oxide, and fluvoxamine were determined using high-performance liquid chromatography with ultraviolet detection. RESULTS: No significant difference was observed in baseline characteristics between the two groups. Clozapine-fluvoxamine combined treatment significantly attenuated the increments in body weight, insulin resistance, and levels of insulin, glucose, and triglycerides compared with clozapine monotherapy. Both groups exhibited significant improvements in their Positive and Negative Syndrome Scale (PANSS) total and negative scores. The combined treatment group showed significant reduction in the PANSS general psychopathology scores compared with the monotherapy group. No difference was observed in the plasma clozapine level between the two groups. The monotherapy group showed higher levels of norclozapine and clozapine N-oxide than the combined group. CONCLUSIONS: Compared with clozapine monotherapy, treatment with adjunctive fluvoxamine with clozapine for 12weeks can alleviate body weight gain and metabolic abnormalities in patients with schizophrenia, without sacrificing the clinical effect. Clinicians should interpret these findings cautiously considering the short duration of this study. The study was registered at www.clinicaltrials.gov (NCT01401491).

[The efficacy and tolerability of pericyazine in the treatment of patients with schizotypal disorder, organic personality disorders and pathocharacterological changes within personality disorders]. / Éffektivnost' i perenosimost' terapii peritsiazinom bol'nykh shizotipicheskim rasstroistvom, organicheskim rasstroistvom lichnosti i patsientov s patokharakterologicheskimi narusheniiami v ramkakh rasstroistv lichnosti.

AIM: To assess the efficacy and tolerability of pericyazine in the treatment of patients with mental disorders manifesting with psychopathic-like symptoms and correction of pathocharacterological disorders in patients with personality disorders during the short-term admission to the hospital or the long-term outpatient treatment. MATERIAL AND METHODS: Sixty-three patients with schizotypal personality disorder and organic personality disorder with psychopathic-like symptoms and pathocharacterological changes within the diagnosis of dissocial personality disorder and borderline personality disorder were examined. Patients received pericyazine during the short-term admission to the hospital (6 weeks) or the long-term outpatient treatment (6 month). Efficacy, tolerability and compliance were assessed in the study. RESULTS AND CONCLUSION: Treatment with pricyazine was effective in all patients. The improvement was seen in patients with organic personality disorders and patients with personality disorders (psychopathy). The maximal effect was observed in inpatients and this effect remained during outpatient treatment. The improvement of mental state of patients with schizotypal personality disorder achieved during inpatient treatment with pericyazine continued during the long-term outpatient treatment. Side-effects were restricted to extrapyramidal symptoms, the frequency of metabolic syndrome was low. During outpatient treatment, the compliance was higher if the patient was managed by the same psychiatrist during inpatient- and outpatient treatment.

Oxytocin improves facial emotion recognition in young adults with antisocial personality disorder.

Deficient facial emotion recognition has been suggested to underlie aggression in individuals with antisocial personality disorder (ASPD). As the neuropeptide oxytocin (OT) has been shown to improve facial emotion recognition, it might also exert beneficial effects in individuals providing so much harm to the society. In a double-blind, randomized, placebo-controlled crossover trial, 22 individuals with ASPD and 29 healthy control (HC) subjects (matched for age, sex, intelligence, and education) were intranasally administered either OT (24 IU) or a placebo 45min before participating in an emotion classification paradigm with fearful, angry, and happy faces. We assessed the number of correct classifications and reaction times as indicators of emotion recognition ability. Significant group×substance×emotion interactions were found in correct classifications and reaction times. Compared to HC, individuals with ASPD showed deficits in recognizing fearful and happy faces; these group differences were no longer observable under OT. Additionally, reaction times for angry faces differed significantly between the ASPD and HC group in the placebo condition. This effect was mainly driven by longer reaction times in HC subjects after placebo administration compared to OT administration while individuals with ASPD revealed descriptively the contrary response pattern. Our data indicate an improvement of the recognition of fearful and happy facial expressions by OT in young adults with ASPD. Particularly the increased recognition of facial fear is of high importance since the correct perception of distress signals in others is thought to inhibit aggression. Beneficial effects of OT might be further mediated by improved recognition of facial happiness probably reflecting increased social reward responsiveness.

Antisocial behaviour and conduct disorders in children and young people: recognition and management

This guideline covers recognising and managing antisocial behaviour and conduct disorders in children and young people aged under 19. It aims to improve care by identifying children and young people who are at risk and when interventions can prevent conduct disorders from developing. The guideline also makes recommendations on communication, to help professionals build relationships with children and young people and involve them in their own care. In April 2017, 4 research recommendations were identified as out of date in the surveillance review, and were deleted.

Tryptophan via serotonin/kynurenine pathways abnormalities in a large cohort of aggressive inmates: markers for aggression.

Aggressive behavior is one of the most challenging symptoms in psychiatry, and biological markers for aggression lack of large sample validations. Serotonin (5-HT) and other neuroactive compounds deriving from Tryptophan (Trp), including kynurenine (Kyn), have not yet been investigated in large cohorts of aggressive individuals to validate their potential as biomarkers of aggression. In 361 male inmates we measured serum levels of Trp, 5-hydroxytryptophan, 5-HT, Kyn, the ratios 5-HT/Trp∗1000 and Kyn/Trp∗1000, and performed Structured Clinical Interview for DSM-IV Axis-I and -II Disorders (SCID-I and -II), global assessment of functioning (GAF), and scales for aggressive behavior, impulsivity, adult attention-deficit/hyperactivity disorder (ADHD), and intelligent quotient (IQ). Aggressive compared to non-aggressive inmates exhibited lower Trp and Kyn serum levels but higher levels of 5-HT and 5-HT/Trp∗1000, higher levels of impulsivity and ADHD indices, lower IQ and GAF, higher prevalence of mood disorders, drug abuse/dependence, and borderline, conduct and antisocial behaviors. Interestingly, Kyn/Trp∗1000 was positively correlated to the number of severe aggressive acts (r=0.593, P<0.001). After adjusting for confounding factors, logistic regression analysis indicated that 5-HT/Trp∗1000, antisocial behavior, and GAF were predictors of aggressive behavior. The model combining these three predictors had an area under the ROC curve of 0.851 (95% CI 0.806-0.895). This study indicates that while circulating Trp is reduced in aggressive individuals, the combination of biological (5-HT/Trp ratio) and psychopathological (antisocial behavior and GAF) markers discriminates between aggressive and non-aggressive behavior suggesting the potential of a multi-marker approach in psychiatry given the heterogenic nature of mental diseases.

Neuropsychological Impairment and Its Association with Violence Risk in Japanese Forensic Psychiatric Patients: A Case-Control Study.

BACKGROUND: In Japan, the legislation directing treatment of offenders with psychiatric disorders was enacted in 2005. Neuropsychological impairment is highly related to functional outcomes in patients with psychiatric disorders, and several studies have suggested an association between neuropsychological impairment and violent behaviors. However, there have been no studies of neuropsychological impairment in forensic patients covered by the Japanese legislation. This study is designed to examine the neuropsychological characteristics of forensic patients in comparison to healthy controls and to assess the relationship between neuropsychological impairment and violence risk. METHODS: Seventy-one forensic patients with psychiatric disorders and 54 healthy controls (matched by age, gender, and education) were enrolled. The CogState Battery (CSB) consisting of eight cognitive domains, the Iowa Gambling Task (IGT) to test emotion-based decision making, and psychological measures of violence risk including psychopathy were used. RESULTS: Forensic patients exhibited poorer performances on all CSB subtests and the IGT than controls. For each group, partial correlational analyses indicated that poor IGT performance was related to psychopathy, especially antisocial behavior. In forensic patients, the CSB composite score was associated with risk factors for future violent behavior, including stress and noncompliance with remediation attempts. CONCLUSION: Forensic patients with psychiatric disorders exhibit a wide range of neuropsychological impairments, and these findings suggest that neuropsychological impairment may increase the risk of violent behavior. Therefore, the treatment of neuropsychological impairment in forensic patients with psychiatric disorders is necessary to improve functional outcomes as well as to prevent violence.