The Relationship of Early Sleep Improvement With Response to Pharmacotherapy in Unipolar Psychotic Depression.

BACKGROUND: Since insomnia and depression are interrelated, improved sleep early in antidepressant pharmacotherapy may predict a positive treatment outcome. We investigated whether early insomnia improvement (EII) predicted treatment outcome in psychotic depression (PD) and examined if there was an interaction effect between EII and treatment type to assess if findings were treatment-specific. METHODS: This study is a secondary analysis of a randomized trial comparing 7 weeks treatment with the antidepressants venlafaxine, imipramine and venlafaxine plus the antipsychotic quetiapine in PD ( n = 114). Early insomnia improvement, defined as ≥20% reduced insomnia after 2 weeks, was assessed by the Hamilton Rating Scale for Depression (HAM-D-17). Associations between EII and treatment outcome were examined using logistic regressions. Subsequently, we added interaction terms between EII and treatment type to assess interaction effects. The predictive value of EII was compared with early response on overall depression (≥20% reduced HAM-D-17 score after 2 weeks). RESULTS: EII was associated with response (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.7-23.4; P = <0.001), remission of depression (OR, 6.1; 95% CI, 1.6-22.3; P = 0.009), and remission of psychosis (OR, 4.1; 95% CI, 1.6-10.9; P = 0.004). We found no interaction effects between EII and treatment type on depression outcome. Early insomnia improvement and early response on overall depression had a comparable predictive ability for treatment outcome. CONCLUSIONS: Early insomnia improvement was associated with a positive outcome in pharmacotherapy of PD, regardless of the medication type. Future studies are needed to confirm our findings and to examine the generalizability of EII as predictor in treatment of depression.

Mild early-life stress exaggerates the impact of acute stress on corticolimbic resting-state functional connectivity.

Abundant evidence shows that early-life stress (ELS) predisposes for the development of stress-related psychopathology when exposed to stressors later in life, but the underlying mechanisms remain unclear. To study predisposing effects of mild ELS on stress sensitivity, we examined in a healthy human population the impact of a history of ELS on acute stress-related changes in corticolimbic circuits involved in emotional processing (i.e., amygdala, hippocampus and ventromedial prefrontal cortex [vmPFC]). Healthy young male participants (n = 120) underwent resting-state functional magnetic resonance imaging (fMRI) in two separate sessions (stress induction vs. control). The Childhood Trauma Questionnaire (CTQ) was administered to index self-reported ELS, and stress induction was verified using salivary cortisol, blood pressure, heart rate and subjective affect. Our findings show that self-reported ELS was negatively associated with baseline cortisol, but not with the acute stress-induced cortisol response. Critically, individuals with more self-reported ELS exhibited an exaggerated reduction of functional connectivity in corticolimbic circuits under acute stress. A mediation analysis showed that the association between ELS and stress-induced changes in amygdala-hippocampal connectivity became stronger when controlling for basal cortisol. Our findings show, in a healthy sample, that the effects of mild ELS on functioning of corticolimbic circuits only become apparent when exposed to an acute stressor and may be buffered by adaptations in hypothalamic-pituitary-adrenal axis function. Overall, our findings might reveal a potential mechanism whereby even mild ELS might confer vulnerability to exposure to stressors later in adulthood.

The Additional Effect of Individualized Prescriber-Focused Feedback on General Guideline Instruction in Reducing Antipsychotic Polypharmacy in Inpatients.

PURPOSE/BACKGROUND: Antipsychotic polypharmacy (APP) is the concurrent use of more than one antipsychotic by a patient. Multiple antipsychotics are often prescribed, although all relevant guidelines discourage this practice. These recommendations are based on a lack of evidence for effectiveness and an increased risk of serious adverse events with APP. Studies on the effects of educational interventions targeted at physicians have demonstrated inconclusive results. Moreover, it is unclear how individualized these interventions need to be. In this study, we aimed to assess the effect of a general intervention and the additional impact of an individualized, prescriber-focused intervention on guidelines adherence, that is, the prescription of APP. METHODS/PROCEDURES: We conducted a 36-month 2-step serial intervention study with 4 stages of 9 months each (baseline, general intervention, addition of an individualized intervention, and follow-up) including all 20 inpatient units of one regional mental health organization. The primary outcome was the proportion of patients with regular prescriptions for APP ≥30 consecutive days across all patients with a prescription of at least one antipsychotic. The secondary outcome was the proportion of patient days on APP over the total number of patient days on at least one antipsychotic. FINDINGS/RESULTS: The general intervention was ineffective on both outcome measures. Addition of an individualized intervention decreased the proportion of patients with prescriptions for episodes of persistent APP significantly by 49.6%. The proportion of patient days on APP significantly decreased by 35.4%. IMPLICATIONS/CONCLUSIONS: In contrast to a general intervention, the addition of an individualized intervention was effective in improving adherence to guidelines with respect to APP prescription in inpatients.

Lack of correspondence between the reactive proactive questionnaire and the impulsive premeditated aggression scale among forensic psychiatric outpatients.

The most studied bimodal classifications of aggressive behavior are the impulsive/premeditated distinction measured with the Impulsive Premeditated Aggression Scale and the reactive/proactive distinction measured with the Reactive Proactive Questionnaire. The terms of these classifications are often used interchangeably, assuming that reactive aggression is equivalent to impulsive aggression and that proactive aggressive behavior is the same as premeditated aggression. The correspondence or discrepancy between both aggression classifications/questionnaires, however, is understudied. Therefore, the current study investigated the correspondence between the RPQ and IPAS in a sample of 161 forensic psychiatric outpatients (FPOs) with severe aggressive behavior. Correlation analysis revealed a limited correspondence between the RPQ and IPAS. Cluster analyses derived three clusters from the RPQ as well as the IPAS: these clusters did not match in 60.3% of the cases. Furthermore, the notion that the RPQ measures trait aggression whereas the IPAS assesses state aggression could not be verified. The present study indicates that aggression subtypes as measured by use of the RPQ and IPAS correspond only partially and should not be used interchangeably. Furthermore, it was suggested that RPQ focuses more on actual aggressive behavior and the IPAS more on emotions and their regulation. Future research is needed to elucidate the applicability of both questionnaires in further detail.

Generalized hostile interpretation bias regarding facial expressions: Characteristic of pathological aggressive behavior.

Individuals with aggression regulation disorders tend to attribute hostility to others in socially ambiguous situations. Previous research suggests that this "hostile attribution bias" is a powerful cause of aggression. Facial expressions form important cues in the appreciation of others' intentions. Furthermore, accurate processing of facial expressions is fundamental to normal socialization. However, research on interpretation biases in facial affect is limited. It is asserted that a hostile interpretation bias (HIB) is likely to be displayed by individuals with an antisocial (ASPD) and borderline personality disorder (BPD) and probably also with an intermittent explosive disorder (IED). However, there is little knowledge to what extent this bias is displayed by each of these patient groups. The present study investigated whether a HIB regarding emotional facial expressions was displayed by forensic psychiatric outpatients (FPOs) and whether it was associated with ASPD and BPD in general or, more specifically, with a disposition to react with pathological aggression. Participants of five different groups were recruited: FPOs with ASPD, BPD, or IED, non-forensic patients with BPD (nFPOs-BPD), and healthy, non-aggressive controls (HCs). Results suggest that solely FPOs with ASPD, BPD, or IED exhibit a HIB regarding emotional facial expressions. Moreover, this bias was associated with type and severity of aggression, trait aggression, and cognitive distortions. The results suggest that a HIB regarding facial expressions is an important characteristic of pathological aggressive behavior. Interventions that modify the HIB might help to reduce the recurrence of aggression. Aggr. Behav. 43:386-397, 2017. © 2017 Wiley Periodicals, Inc.

Examining the reactive proactive questionnaire in adults in forensic and non-forensic settings: A variable- and person-based approach.

The Reactive Proactive Questionnaire (RPQ) was originally developed to assess reactive and proactive aggressive behavior in children. Nevertheless, some studies have used the RPQ in adults. This study examines the reliability of the RPQ within an adult sample by investigating whether reactive and proactive aggression can be distinguished at a variable- and person-based level. Male adults from forensic samples (N = 237) and from the general population (N = 278) completed the RPQ questionnaire. Variable-based approaches, including factor analyses, were conducted to verify the two-factor model of the RPQ and to examine alternative factor solutions of the 23 items. Subsequently, a person-based approach, i.e., Latent Class Analysis (LCA), was executed to identify homogeneous classes of subjects with similar profiles of aggression in the observed data. The RPQ proved to have sufficient internal consistency. Multiple-factor models were examined, but the original two-factor model was statistically and theoretically considered as most solid and in line with previous research. The multi-level LCA identified three different classes of aggression severity (class 1 showed low aggressive behavior; class 2 subjects displayed modest aggression levels; and class 3 exhibited the highest level of aggressive behavior). In addition, class 1 and 2 showed more reactive than proactive aggression, whereas class 3 displayed comparable levels of reactive/proactive aggression. The RPQ appears to have clinical relevance for adult populations in the way that it can distinguish severity levels of aggression. Before the RPQ is implemented in adult populations, norm scores need to be developed. Aggr. Behav. 43:155-162, 2017. © 2016 Wiley Periodicals, Inc.

Tetrahydrocannabinol in Behavioral Disturbances in Dementia: A Crossover Randomized Controlled Trial.

OBJECTIVES: Neuropsychiatric symptoms (NPS) are highly prevalent in dementia, but effective pharmacotherapy without important side effects is lacking. This study aims to assess the efficacy and safety of oral tetrahydrocannabinol (THC) in the treatment of NPS in dementia. DESIGN: Randomized, double-blind, placebo-controlled, repeated crossover trial, consisting of six treatment blocks of 2 weeks each. SETTING: Two hospital sites in The Netherlands, September 2011 to December 2013. PARTICIPANTS: Patients with dementia and clinically relevant NPS. INTERVENTION: Within each block THC (0.75 mg twice daily in blocks 1-3 and 1.5 mg twice daily in blocks 4-6) and placebo were administered in random order for 3 consecutive days, followed by a 4-day washout. MEASUREMENTS: Primary outcome was change in Neuropsychiatric Inventory (NPI) score. Analyses were performed intention-to-treat. Data from all subjects were used without imputation. Sample size required for a power of 80% was 20 patients, because of repeated crossover. RESULTS: 22 patients (15 men, mean age 76.4 [5.3] years) were included, of whom 20 (91%) completed the trial. THC did not reduce NPI compared to placebo (blocks 1-3: 1.8, 97.5% CI: -2.1 to 5.8; blocks 4-6: -2.8, 97.5% CI: -7.4 to 1.8). THC was well tolerated, as assessed by adverse event monitoring, vital signs, and mobility. The incidence of adverse events was similar between treatment groups. Four non-related serious adverse events occurred. CONCLUSIONS: This is the largest randomized controlled trial studying the efficacy of THC for NPS, to date. Oral THC did not reduce NPS in dementia, but was well tolerated by these vulnerable patients, supporting future higher dosing studies.

Establishing the dopamine dependency of human striatal signals during reward and punishment reversal learning.

Drugs that alter dopamine transmission have opposite effects on reward and punishment learning. These opposite effects have been suggested to depend on dopamine in the striatum. Here, we establish for the first time the neurochemical specificity of such drug effects, during reward and punishment learning in humans, by adopting a coadministration design. Participants (N = 22) were scanned on 4 occasions using functional magnetic resonance imaging, following intake of placebo, bromocriptine (dopamine-receptor agonist), sulpiride (dopamine-receptor antagonist), or a combination of both drugs. A reversal-learning task was employed, in which both unexpected rewards and punishments signaled reversals. Drug effects were stratified with baseline working memory to take into account individual variations in drug response. Sulpiride induced parallel span-dependent changes on striatal blood oxygen level-dependent (BOLD) signal during unexpected rewards and punishments. These drug effects were found to be partially dopamine-dependent, as they were blocked by coadministration with bromocriptine. In contrast, sulpiride elicited opposite effects on behavioral measures of reward and punishment learning. Moreover, sulpiride-induced increases in striatal BOLD signal during both outcomes were associated with behavioral improvement in reward versus punishment learning. These results provide a strong support for current theories, suggesting that drug effects on reward and punishment learning are mediated via striatal dopamine.

Short-term antidepressant administration reduces default mode and task-positive network connectivity in healthy individuals during rest.

Resting-state studies in depressed patients have revealed increased connectivity within the default mode network (DMN) and task-positive network (TPN). This has been associated with heightened rumination, which is the tendency to repetitively think about symptoms of distress. Here, we performed a pharmacological neuroimaging study in healthy volunteers to investigate whether short-term antidepressant administration could reduce DMN connectivity. We recorded resting-state functional magnetic resonance imaging (fMRI) scans in twenty-three healthy volunteers after two week intake of the combined serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine in a double-blind, placebo-controlled, crossover study. Duloxetine improved mood in part as a result of increased resilience to the mood-worsening effects of scanning and reduced DMN and TPN connectivity. Within the DMN, duloxetine reduced connectivity between the medial prefrontal cortex (MPFC) and the lateral parietal cortex (LPC) and uncoupled the MPFC from the dorsolateral prefrontal cortex (DLPFC). Within the TPN, duloxetine uncoupled the intraparietal sulcus (IPS) from the inferior occipital gyrus. These results show that two-week antidepressant administration reduces DMN and TPN connectivity in healthy volunteers, which may contribute to their antidepressant effects in depression.

The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients.

OBJECTIVE: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. METHODS: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. RESULTS: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. CONCLUSIONS: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.

Exogenous glucocorticoids to improve extinction learning for post-traumatic stress disorder patients with hypothalamic-pituitary-adrenal-axis dysregulation: a study protocol description.

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients - potentially with substantial exposure to early-life adversity (ELA) - show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories.Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration.Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts.Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies.Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

This protocol reports a proof-of-concept study for glucocorticoids as an enhancer for PTSD treatment.The study examines whether glucocorticoids enhance the strength and generalization of extinction memory.A further aim is to identify HPA-axis-related PTSD subgroups that may particularly benefit.

A genetic risk score to predict treatment nonresponse in psychotic depression.

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = -0.32, p = 0.0023, n = 88) and remission (r = -0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.

Neural basis of recollection in first-episode major depression.

BACKGROUND: Patients with major depressive disorder (MDD) display impairments in recollection, which have been explained by both hippocampal and prefrontal dysfunction. Here, we used an event-related fMRI design, to dissociate hippocampal and prefrontal contributions to the neural processes involved in recollection success and recollection attempt early in the course of MDD. METHODS: To disentangle state- and trait-effects of depression, we included 20 medication-naive patients with a first depressive episode, 20 medication-free patients recovered from a first episode, and 20 matched, healthy controls in an event-related fMRI study using a source recollection paradigm. RESULTS: Group comparisons revealed that during the acute state of depression there is an increase in left prefrontal activity related to recollection attempt, while there were no differences in neural correlates of successful recollection. CONCLUSIONS: Our results indicate that in the early course of depression, depressive state is associated with increased left prefrontal activation during the attempt to recollect source information suggesting an increased need for executive control during recollection in MDD. In this sample of first-episode MDD patients we found no evidence for hippocampal dysfunction.

Reversal deficits in individuals with psychopathy in explicit but not implicit learning conditions.

BACKGROUND: Psychopathy is a severe personality disorder that has been linked to impaired behavioural adaptation during reinforcement learning. Recent electrophysiological studies have suggested that psychopathy is related to impairments in intentionally using information relevant for adapting behaviour, whereas these impairments remain absent for behaviour relying on automatic use of information. We sought to investigate whether previously found impairments in response reversal in individuals with psychopathy also follow this dichotomy. We expected response reversal to be intact when the automatic use of information was facilitated. In contrast, we expected impaired response reversal when intentional use of information was required. METHODS: We included offenders with psychopathy and matched healthy controls in 2 experiments with a probabilistic cued go/no-go reaction time task. The task implicated the learning and reversal of 2 predictive contingencies. In experiment 1, participants were not informed about the inclusion of a learning component, thus making cue-dependent learning automatic/incidental. In experiment 2, the instructions required participants to actively monitor and learn predictive relationships, giving learning a controlled/intentional nature. RESULTS: While there were no significant group differences in acquisition learning in either experiment, the results revealed impaired response reversal in offenders with psychopathy when controlled learning was facilitated. Interestingly, this impairment was absent when automatic learning was predominant. LIMITATIONS: Possible limitations are the use of a nonforensic control group and of self-report measures for drug use. CONCLUSION: Response reversal deficits in individuals with psychopathy are modulated by the context provided by the instructions, according to the distinction between automatic and controlled processing in these individuals.

COMT Val158Met modulates the effect of childhood adverse experiences on the risk of alcohol dependence.

Genetic factors and childhood adverse experiences contribute to the vulnerability to alcohol dependence. However, empirical data on the interplay between specific genes and adverse experiences are few. The COMT Val158Met and DRD2/ANKK1 Taq1A genotypes have been suggested to affect both stress sensitivity and the risk for alcohol dependence. This study tested the hypothesis that genetic variation in COMT Val158Met and DRD2/ANKK1 Taq1A interacts with childhood adverse experiences to predict alcohol dependence. Male abstinent alcohol-dependent patients (n = 110) and age-matched healthy male controls (n = 99) were genotyped for the COMT Val158Met and the DRD2/ANKK1 Taq1A genotypes. Childhood adverse events were measured using three self-report questionnaires. Alcohol dependence severity, age of onset and duration of alcohol dependence were analyzed as secondary outcome measures. Statistical analysis involved logistic regression analysis and analysis of variance. Alcohol-dependent patients reported increased childhood adversity. The interaction between childhood adversity and the COMT Val158Met genotype added significantly to the prediction model. This gene-environment interaction was confirmed in the analysis of the secondary outcome measures, i.e. alcohol dependence severity, age of onset and duration of alcohol dependence. The DRD2/ANKK1 Taq1A genotype was not related to alcohol dependence, nor did it interact with childhood adversity in predicting alcohol dependence. This study provides evidence for a gene-environment interaction in alcohol dependence, in which an individual's sensitivity to childhood adverse experience is moderated by the COMT genotype. Exposed carriers of a low-activity Met allele have a higher risk to develop severe alcohol dependence than individuals homozygous for the Val allele.

The Course of Psychiatric Symptoms During Remand Imprisonment.

Imprisonment may pose a risk for unintended effects such as deterioration of psychiatric symptoms. Therefore, it is pivotal to understand the relation between imprisonment and the course of psychiatric symptoms, but previous studies are inconclusive. The current study followed up the psychiatric symptoms of newly admitted remand prisoners to one Dutch remand prison using the Brief Psychiatric Rating Scale (BPRS) and also studied possible related pre-existing variables. On average we found an overall slight-yet clinically marginal-improvement of psychiatric, in particular affective symptoms. One in three prisoners deteriorated and prisoners with psychotic disorders less often deteriorated. Other variables were not related. Overall, psychiatric symptoms remain stable over time during early remand imprisonment independent of most psychiatric disorders. The context in the Dutch prison studied appears to be adequately organized in terms of handling psychiatric stability, but we notice that prison contexts may vary to a large extend.

Psychopathology in female offenders of terrorism and violent extremism: a systematic review.

Introduction: Terrorism and violent extremism are major social threats worldwide and are committed not only by men but also by women. Previous research has shown indications of psychopathology, among other personal and contextual factors, as a potential risk factor for perpetrating terrorist and violent extremist crimes. Despite the fact that women have engaged in acts of terrorism and violent extremism throughout history, the vast majority of literature on psychopathology so far has been mainly focused on men with terrorist and violent extremist behavior. As women's engagement in terrorism and violent extremism is increasing, and gender differences in psychopathology in offenders of terrorism or violent extremism may exist based on empirical evidence for such differences in offenders of violence, gender-informed research into psychopathology as a potential risk factor for offending is of pivotal importance for improving the effectiveness of counter-terrorism interventions. The present systematic review was designed to examine what empirical knowledge exists on the presence and potential contributing role of psychopathology in female perpetrators of terrorism or violent extremism. Methods: A literature search was conducted to identify primary source studies in PsycINFO, PubMed, Embase, Web of Science, and Sociological Abstracts. ASReview as an artificial intelligence software was used to screen references. Results: In total, eight studies were included, of which only two studies distinguished prevalence rates and types of psychopathology separately for women, indicating personality disorder as most common. All four out of the eight studies that reported on the relationship between psychopathology and terrorism and violent extremism assumed psychopathology to be a contributing factor in engaging in terrorist or violent extremist acts. However, none of these four studies reported on potentially present female-specific mechanisms of the role of psychopathology in offenses. Discussion: The present systematic review draws the striking conclusion that there is a lack of clearly described empirical studies on psychopathology in female perpetrators of terrorism and violent extremism and emphasizes the importance of more future empirically based inquiries on this topic by the forensic psychiatric field. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=275354, identifier: CRD42021275354.

Methylphenidate undermines or enhances divergent creativity depending on baseline dopamine synthesis capacity.

Catecholamine-enhancing psychostimulants, such as methylphenidate have long been argued to undermine creative thinking. However, prior evidence for this is weak or contradictory, stemming from studies with small sample sizes that do not consider the well-established large variability in psychostimulant effects across different individuals and task demands. We aimed to definitively establish the link between psychostimulants and creative thinking by measuring effects of methylphenidate in 90 healthy participants on distinct creative tasks that measure convergent and divergent thinking, as a function of individuals' baseline dopamine synthesis capacity, indexed with 18F-FDOPA PET imaging. In a double-blind, within-subject design, participants were administered methylphenidate, placebo or selective D2 receptor antagonist sulpiride. The results showed that striatal dopamine synthesis capacity and/or methylphenidate administration did not affect divergent and convergent thinking. However, exploratory analysis demonstrated a baseline dopamine-dependent effect of methylphenidate on a measure of response divergence, a creativity measure that measures response variability. Response divergence was reduced by methylphenidate in participants with low dopamine synthesis capacity but enhanced in those with high dopamine synthesis capacity. No evidence of any effect of sulpiride was found. These results show that methylphenidate can undermine certain forms of divergent creativity but only in individuals with low baseline dopamine levels.

Evidence for absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity.

Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity, and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, 'off-the-shelf' tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [18F]-FDOPA PET in a large sample of healthy volunteers (N = 94) and assessed the correlation with simple, short tests of working memory capacity, trait impulsivity, and sEBR. We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.