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.

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.

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.

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.

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.

See think act scale: Validation of the Dutch version of a measure of relational security in high secure forensic psychiatric care.

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.

Psychopathic tendency in violent offenders is associated with reduced aversive Pavlovian inhibition of behavior and associated striatal BOLD signal.

Background: Violent 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 methods: Here 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. Results: Psychopathic 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. Conclusion: These 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.

Striatal dopamine dissociates methylphenidate effects on value-based versus surprise-based reversal learning.

Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults (N = 100) were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D2/3-receptor antagonist sulpiride. Striatal dopamine synthesis capacity was indexed with [18F]DOPA positron emission tomography. Methylphenidate improved and sulpiride decreased overall accuracy and response speed. Both drugs boosted reward versus punishment learning signals to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate gates both attention and reward learning.

Effects of average reward rate on vigor as a function of individual variation in striatal dopamine.

RATIONALE: We constantly need to decide not only which actions to perform, but also how vigorously to perform them. In agreement with an earlier theoretical model, it has been shown that a significant portion of the variance in our action vigor can be explained by the average rate of rewards received for that action. Moreover, this invigorating effect of average reward rate was shown to vary with within-subject changes in dopamine, both in human individuals and experimental rodents. OBJECTIVES: Here, we assessed whether individual differences in the effect of average reward rate on vigor are related to individual variation in a stable measure of striatal dopamine function in healthy, unmedicated participants. METHODS: Forty-four participants performed a discrimination task to test the effect of average reward rate on response times to index vigor and completed an [18F]-DOPA PET scan to index striatal dopamine synthesis capacity. RESULTS: We did not find an interaction between dopamine synthesis capacity and average reward rate across the entire group. However, a post hoc analysis revealed that participants with higher striatal dopamine synthesis capacity, particularly in the nucleus accumbens, exhibited a stronger invigorating effect of average reward rate among the 30 slowest participants. CONCLUSIONS: Our findings provide converging evidence for a role of striatal dopamine in average reward rate signaling, thereby extending the current literature on the mechanistic link between average reward rate, vigor, and dopamine.

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.

Testing the Effects of a Virtual Reality Game for Aggressive Impulse Management: A Preliminary Randomized Controlled Trial among Forensic Psychiatric Outpatients.

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.

Association of the neutrophil to lymphocyte ratio and white blood cell count with response to pharmacotherapy in unipolar psychotic depression: An exploratory analysis.

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 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.

Threat-Avoidance Tendencies Moderate the Link Between Serotonin Transporter Genetic Variation and Reactive Aggression.

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.

The cognitive effects of a promised bonus do not depend on dopamine synthesis capacity.

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.

Psychomotor Retardation and the prognosis of antidepressant treatment in patients with unipolar Psychotic Depression.

BACKGROUND: Psychomotor Retardation is a key symptom of Major Depressive Disorder. According to the literature its presence may affect the prognosis of treatment. Aim of the present study is to investigate the prognostic role of Psychomotor Retardation in patients with unipolar Psychotic Depression who are under antidepressant treatment. METHODS: The Salpetriere Retardation Rating Scale was administered at baseline and after 6 weeks to 122 patients with unipolar Psychotic Depression who were randomly allocated to treatment with imipramine, venlafaxine or venlafaxine plus quetiapine. We studied the effects of Psychomotor Retardation on both depression and psychosis related outcome measures. RESULTS: 73% of the patients had Psychomotor Retardation at baseline against 35% after six weeks of treatment. The presence of Psychomotor Retardation predicted lower depression remission rates in addition to a higher persistence of delusions. After six weeks of treatment, venlafaxine was associated with higher levels of Psychomotor Retardation compared to imipramine and venlafaxine plus quetiapine. CONCLUSIONS: Our data confirm that Psychomotor Retardation is a severity marker of unipolar Psychotic Depression. It is highly prevalent and predicts lower effectivity of antidepressant psychopharmacological treatment.