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Abstract 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.

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.

IntroductionTerrorism 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.MethodsA 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.ResultsIn 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.DiscussionThe 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 registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=275354, identifier: CRD42021275354.

The mechanisms underpinning the variability in methylphenidate’s effects on cognition remain unclear. Here, the authors show that such effects reflect changes in striatal dopamine-related output gating of task-relevant cortical signals, and that these changes depend on baseline dopamine synthesis capacity.

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.

BackgroundViolent offenders with psychopathic tendencies are characterized by instrumental, i.e., planned, callous, and unemotional (aggressive) behavior and have been shown to exhibit abnormal aversive processing. However, the consequences of abnormal aversive processing for instrumental action and associated neural mechanisms are unclear.Materials and methodsHere we address this issue by using event-related functional magnetic resonance imaging (fMRI) in 15 violent offenders with high psychopathic tendencies and 18 matched controls during the performance of an aversive Pavlovian-to-instrumental transfer paradigm. This paradigm allowed us to assess the degree to which aversive Pavlovian cues affect instrumental action and associated neural signaling.ResultsPsychopathic tendency scores were associated with an attenuation of aversive Pavlovian inhibition of instrumental action. Moreover, exploratory analyses revealed an anomalous positive association between aversive inhibition of action and aversive inhibition of BOLD signal in the caudate nucleus of violent offenders with psychopathic tendencies. In addition, psychopathic tendency also correlated positively with amygdala reactivity during aversive versus neutral cues in Pavlovian training.ConclusionThese findings strengthen the hypothesis that psychopathic tendencies in violent offenders are related to abnormal impact of aversive processing on instrumental behavior. The neural effects raise the possibility that this reflects deficient transfer of aversive Pavlovian inhibitory biases onto neural systems that implement instrumental action, including the caudate nucleus.

Relational security is considered an essential form of security in forensic psychiatric care. Research on relational security is important, but is hampered by the lack of instruments to assess and monitor this concept in clinical practice. Within this current study the psychometric properties of the Dutch version of the See Think Act (STA) scale, an instrument designed to measure relational security as perceived by forensic staff members within secure settings, was studied. Results show that the internal consistency of the STA total scale was good. However, the internal consistency of the subscales was relatively low compared to other studies using the original English or the Chinese version of the STA scale. The factor structure found in the original English version of the scale was not confirmed within this sample. With regard to the validity of the instrument results were promising, finding relationships with aspects of ward climate and team reflexivity. Further research and development is needed regarding the STA scale, making it more suitable for monitoring and studying this clinically relevant concept in forensic care.

Abstract Reward motivation is known to enhance cognitive control. However, detrimental effects have also been observed, which have been attributed to overdosing of already high baseline dopamine levels by further dopamine increases elicited by reward cues. Aarts et al. (2014) indeed demonstrated, in 14 individuals, that reward effects depended on striatal dopamine synthesis capacity, measured with [18F]FMT-PET: promised reward improved Stroop control in low-dopamine individuals, while impairing it in high-dopamine individuals. Here, we aimed to assess this same effect in 44 new participants, who had previously undergone an [18F]DOPA-PET scan to quantify dopamine synthesis capacity. This sample performed the exact same rewarded Stroop paradigm as in the prior study. However, we did not find any correlation between reward effects on cognitive control and striatal dopamine synthesis capacity. Critical differences between the radiotracers [18F]DOPA and [18F]FMT are discussed, as the discrepancy between the current and our previous findings might reflect the use of the potentially less sensitive [18F]DOPA radiotracer in the current study.

Background: Low-grade inflammation occurs in a subgroup of patients with Major Depressive Disorder (MDD) and may be associated with response to antidepressant medications. The Neutrophil to Lymphocyte Ratio (NLR) and total White Blood cell Count (WBC) are markers of systemic inflammation which have not been investigated as predictors for outcome to pharmacotherapy in unipolar depression yet. Moreover, the association between inflammation and treatment response has not been studied in unipolar Psychotic Depression (PD). We conducted an exploratory analysis to examine the prognostic significance of NLR and WBC in pharmacotherapy of PD. Methods: Baseline NLR and WBC were examined in their association with response to seven weeks of treatment with antidepressants (venlafaxine or imipramine) and the combination of an antidepressant with an antipsychotic (venlafaxine plus quetiapine) in 87 patients with PD. Logistic regression models were adjusted for age, gender, Body Mass Index (BMI), depression severity, duration of the current episode and number of previous depressive episodes. Secondary outcomes were remission of depression and disappearance of psychotic symptoms. Results: Higher NLR was associated with increased response to pharmacotherapy (Exp(B) 1.66, 95 ​% CI 1.03–2.66, p ​= ​0.036), but not with remission of depression or disappearance of psychotic symptoms. WBC was not associated with any of the outcome measures. Conclusion: NLR may be a novel, inexpensive and widely available biomarker associated with response to pharmacotherapy in PD. The association between white blood cell measures and treatment outcome should be further investigated for different types of antidepressants in PD and in non-psychotic MDD.

The short (S) allele of the serotonin transporter-linked promoter region (5-HTTLPR) polymorphism has been linked to reactive aggression in men, but this association is less consistent in females. Reactive aggression has been particularly described as a result of fear-driven defense to threat, but how this interaction between defensive behavior and aggression is expressed in S-allele carriers remains unknown. In order to explore this interplay between 5-HTTLPR genotype, defensive behavior and reactive aggression, we combined genotyping with objective measures of action tendencies toward angry faces in an approach-avoidance task (AAT) and reactive aggression in the Taylor aggression paradigm (TAP) in healthy females, N = 95. This study shows that female S-allele carriers in general display increased implicit reactive aggression (administering aversive white noise) toward opponents. Furthermore, we found that threat-avoidance tendencies moderate the association between 5-HTTLPR genotype and aggression displayed on the TAP. Together, these findings indicate a positive correlation between avoidance of angry faces in the AAT and reactive aggression in the TAP exclusively present in S-allele carriers.

Prior laboratory experiments among healthy samples found that training avoidance movements to angry faces may lower anger and aggression, especially people high in trait anger. To enrich this training and make it more suitable for clinical applications, the present researchers developed it into a Virtual Reality Game for Aggressive Impulse Management (VR-GAIME). The current study examined the effects of this training in a randomized controlled trial among forensic psychiatric outpatients with aggression regulation problems (N = 30). In addition to the aggression replacement training, patients played either the VR-GAIME or a control game. Aggressive behavior was measured pre-, half-way, and post-treatment via self-report and clinicians ratings. No difference was found between the VR-GAIME and the control game. However, the participants reported gaining more insight into their own behavior and that of others. Future VR intervention tools in clinical settings may capitalize more on their benefits for self-reflection within interpersonal settings.

Recent studies have shown that while psychopathy and non-psychopathic antisociality overlap, they differ in the extent to which cognitive impairments are present. Specifically, psychopathy has been related to abnormal allocation of attention, a function that is traditionally believed to be indexed by event-related potentials (ERPs) of the P3-family. Previous research examining psychophysiological correlates of attention in psychopathic individuals has mainly focused on the parietally distributed P3b component to rare targets. In contrast, very little is known about the frontocentral P3a to infrequent novel events in psychopathy. Thus, findings on the P3 components in psychopathy are inconclusive, while results in non-psychopathic antisocial populations are clearer and point toward an inverse relationship between antisociality and P3 amplitudes. The present study adds to extant literature on the P3a and P3b in psychopathy by investigating component amplitudes in psychopathic offenders (N = 20), matched non-psychopathic offenders (N = 23) and healthy controls (N = 16). Also, it was assessed how well each offender group was able to differentially process rare novel and target events. The offender groups showed general amplitude reductions compared to healthy controls, but did not differ mutually on overall P3a/P3b amplitudes. However, the psychopathic group still exhibited normal neurophysiological differentiation when allocating attention to rare novel and target events, unlike the non-psychopathic sample. The results highlight differences between psychopathic and non-psychopathic offenders regarding the integrity of the neurocognitive processes driving attentional allocation, as well as the usefulness of alternative psychophysiological measures in differentiating psychopathy from general antisociality.