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The article presents a study which investigates whether patients' depressive symptom levels and dermatology-related quality of life changed compared with pre-pandemic rates and during different pandemic waves. It mentions that the captured 12-month suicidality among these patients during COVID-19 pandemic.

Psoriasis is a systemic, relapsing, inflammatory disease associated with serious comorbidities including mood problems and/or unhealthy lifestyle behaviours. Cutaneous and systemic abnormalities in innate and acquired immunity play a role in its pathogenesis. The exact pathogenetic mechanism remains elusive. Evidence is accumulating that TNF-alpha, IL-17 and IL- 23 signalling are highly relevant as targeting these pathways reduces disease activity. Evidence suggests a strong link between psoriasis and depression in adults. The International Psoriasis Council (IPC) held a roundtable event, "Psoriasis and Mental Health", in Barcelona, Spain which focused on the presence of depression and suicidality, plus the role of neuroinflammation in psoriasis, sleep disruption and the impact of depression on cardiovascular disease outcomes. We summarize here the expert presentations to provide additional insight into the understanding of psychiatric comorbidities of psoriasis and of the impact of chronic, systemic inflammation on neuro- and cardiovascular outcomes. the associations between psoriasis and other psychiatric comorbidities are still controversial and warrant further attention. [ABSTRACT FROM AUTHOR]

These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement. [ABSTRACT FROM AUTHOR]

Positron Emission Tomography (PET) imaging has become a prominent tool to capture the spatiotemporal distribution of neurotransmitters and receptors in the brain. The outcome of a PET study can, however, potentially be obscured by suboptimal and/or inconsistent choices made in complex processing pipelines required to reach a quantitative estimate of radioligand binding. Variations in subject selection, experimental design, data acquisition, preprocessing, and statistical analysis may lead to different outcomes and neurobiological interpretations. We here review the approaches used in 105 original research articles published by 21 different PET centres, using the tracer [11C]DASB for quantification of cerebral serotonin transporter binding, as an exemplary case. We highlight and quantify the impact of the remarkable variety of ways in which researchers are currently conducting their studies, while implicitly expecting generalizable results across research groups. Our review provides evidence that the foundation for a given choice of a preprocessing pipeline seems to be an overlooked aspect in modern PET neuroscience. Furthermore, we believe that a thorough testing of pipeline performance is necessary to produce reproducible research outcomes, avoiding biased results and allowing for better understanding of human brain function. [ABSTRACT FROM AUTHOR]

Deep brain stimulation is a potential option for patients with treatment-refractory depression. Deep brain stimulation benefits have been reported when targeting either the subgenual cingulate or ventral anterior capsule/nucleus accumbens. However, not all patients respond and optimum stimulation-site is uncertain. We compared deep brain stimulation of the subgenual cingulate and ventral anterior capsule/nucleus accumbens separately and combined in the same seven treatment-refractory depression patients, and investigated regional cerebral blood flow changes associated with acute and chronic deep brain stimulation. Deep brain stimulation-response was defined as reduction in Montgomery-Asberg Depression Rating Scale score from baseline of ≥50%, and remission as a Montgomery-Asberg Depression Rating Scale score ≤8. Changes in regional cerebral blood flow were assessed using [15O]water positron emission tomography. Remitters had higher relative regional cerebral blood flow in the prefrontal cortex at baseline and all subsequent time-points compared to non-remitters and non-responders, with prefrontal cortex regional cerebral blood flow generally increasing with chronic deep brain stimulation. These effects were consistent regardless of stimulation-site. Overall, no significant regional cerebral blood flow changes were apparent when deep brain stimulation was acutely interrupted. Deep brain stimulation improved treatment-refractory depression severity in the majority of patients, with consistent changes in local and distant brain regions regardless of target stimulation. Remission of depression was reached in patients with higher baseline prefrontal regional cerebral blood flow. Because of the small sample size these results are preliminary and further evaluation is necessary to determine whether prefrontal cortex regional cerebral blood flow could be a predictive biomarker of treatment response. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT2A receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT2A receptors. Positron emission tomography studies using the SERT ligand [11C]DASB and the 5-HT2A receptor ligand [11C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT2A receptor availability (binding potential, BPND) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BPND and higher 5-HT2A receptor BPND in cortical, but not subcortical regions. Decreased SERT BPND was regionally associated with upregulated 5-HT2A receptor BPND. In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Scanning properties and analytic methodology of the 5-HT2A receptor-selective positron emission tomography (PET) tracer 11C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects. Methods: 64 11C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18–55years). 12 subjects were scanned twice (duration 150min) to provide data on plasma analysis, model order estimation, and stability and test–retest characteristics of outcome measures. All other scans were 90min duration. 3 subjects completed scanning at baseline and following 5-HT2A receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT2A receptors. Results: Optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120min. Binding potential (BPP and BPND) test–retest variability was very good (7–11%) in neocortical regions other than orbitofrontal, and moderately good (14–20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT2A receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6μg to remain below 5% receptor occupancy. 11C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BPND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT2A receptors was 14.0±5.0% per decade, and higher in prefrontal regions. Conclusions: Our data confirm and extend support for 11C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT2A receptors in the human brain. [Copyright &y& Elsevier]

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. 11C-DASB PET scans were performed on the HRRT camera. Binding potentials (BPND) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30±10%), was similar across brain regions, but varied widely across subjects (15–46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at <25% occupancy and greatest suppression was associated with highest occupancy (25–46%). However, several subjects with occupancy (36–39%) in the higher range had no appetite suppression. SERT occupancy by clinical doses of sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET. [ABSTRACT FROM AUTHOR]

In healthy humans, there is an apparent dissociation between cognitive and affective consequences of reduced brain serotonin (5-HT), as rapid tryptophan depletion (RTD) causes alterations in a consistent constellation of cognitive processes in the general absence of mood deterioration. This study aimed to investigate possible neural mechanisms underlying this relative dissociation by measuring the effects of reduced 5-HT on regional cerebral blood flow (rCBF). A total of 16 healthy, euthymic male subjects (mean age 39±9 years) without a personal or family history of affective disorder had mood ratings and single photon emission computed tomography scans with the rCBF tracer 99mTc-HMPAO under reduced 5-HT (RTD) and control conditions. Across individuals, modest positive and negative changes in subjective happiness associated with RTD were significantly correlated with change of rCBF in a cluster comprising subgenual (affective) anterior cingulate cortex (ACC) and associated regions (Brodmann's area (BA) 25, posterior BA11 and 47, caudate nucleus and ventral striatum; SPM99 p<0.05, corrected). The covariation was such that increasing sadness was associated with increased rCBF and vice versa. Independent of mood change, RTD was associated with reduced rCBF in the dorsal (cognitive) ACC (BA32; SPM99 p<0.05, corrected). The subgenual prefrontal cortex and dorsal ACC are important components of the ventral and dorsal neural systems that regulate and integrate affective and cognitive functions. The results therefore suggest that the dissociation between affective and cognitive consequences of RTD may possibly be attributable to differential effects of reduced 5-HT on these neural systems.Neuropsychopharmacology (2006) 31, 1757–1767. doi:10.1038/sj.npp.1301022; published online 11 January 2006 [ABSTRACT FROM AUTHOR]

Rapid tryptophan (Trp) depletion (RTD) has been reported to cause deterioration in the quality of decision making and impaired reversal learning, while leaving attentional set shifting relatively unimpaired. These findings have been attributed to a more powerful neuromodulatory effect of reduced 5-HT on ventral prefrontal cortex (PFC) than on dorsolateral PFC. In view of the limited number of reports, the aim of this study was to independently replicate these findings using the same test paradigms. Healthy human subjects without a personal or family history of affective disorder were assessed using a computerized decision making/gambling task and the CANTAB ID/ED attentional set-shifting task under Trp-depleted (n=17; nine males and eight females) or control (n=15; seven males and eight females) conditions, in a double-blind, randomized, parallel-group design. There was no significant effect of RTD on set shifting, reversal learning, risk taking, impulsivity, or subjective mood. However, RTD significantly altered decision making such that depleted subjects chose the more likely of two possible outcomes significantly more often than controls. This is in direct contrast to the previous report that subjects chose the more likely outcome significantly less often following RTD. In the terminology of that report, our result may be interpreted as improvement in the quality of decision making following RTD. This contrast between studies highlights the variability in the cognitive effects of RTD between apparently similar groups of healthy subjects, and suggests the need for future RTD studies to control for a range of personality, family history, and genetic factors that may be associated with 5-HT function.Neuropsychopharmacology (2006) 31, 1519–1525. doi:10.1038/sj.npp.1300980; published online 23 November 2005 [ABSTRACT FROM AUTHOR]

Objective: The serotonin system is believed to play a role in modulating impulsivity and violence. Previous imaging studies have implicated the anterior regulate and orbitofrontal cortex in impulsive aggression. This study evaluated regional serotonin transporter distribution in the brain of individuals with impulsive aggression by using positron emission tomography (PET) with the serotonin transporter PET radiotracer [11C]McN 5652. Method: Ten individuals with impulsive aggression and 10 age- and sex-matched healthy comparison subjects underwent [11C]McN 5652 PET. All individuals were medication free at the time of scanning. Regional total distribution volumes were derived by using a one-tissue compartment kinetic model with arterial input function. Outcome measures of serotonin transporter availability included the binding potential and the specific-to-nonspecific partition coefficient (V3"). Results: Serotonin transporter availability was significantly reduced in the anterior cingulate cortex of individuals with impulsive aggression compared with healthy subjects, as noted by differences in both binding potential (mean=3.1 mug [SD=1.9] versus 5.0 ml/g [SD=2.0], respectively) and V3" (mean=0.1 5 [SD=0.09] versus 0.26 [SD=0.09]). In other regions examined, serotonin transporter density was nonsignificantly lower in individuals with impulsive aggression compared with healthy subjects. Conclusions: Pathological impulsive aggressivity might be associated with lower serotonergic innervation in the anterior cingulate cortex, a region that plays an important role in affective regulation. [ABSTRACT FROM AUTHOR]

Although abnormal serotonin (5-HT) function is implicated in a range of mental disorders, there is currently no method to directly assess 5-HT synaptic levels in the living human brain. The in vivo binding of some dopamine (DA) radioligands such as 11C-raclopride is affected by fluctuations in endogenous DA, thus providing an indirect measure of DA presynaptic activity. Attempts to identify a serotonergic radiotracer with similar properties have proved unsuccessful. Here, we investigated in humans the effects of reduced synaptic 5-HT on the in vivo binding of the 5-HT transporter (SERT) radioligand 11C-DASB, using Positron Emission Tomography (PET) and the rapid tryptophan depletion (RTD) technique. Eight (8) subjects (5M, 3F) were scanned with 11C-DASB under control and reduced endogenous 5-HT conditions, in a within-subject, double-blind, counterbalanced, crossover design. Regional distribution volumes (VT) were calculated using kinetic modeling and metabolite-corrected arterial input function. 11C-DASB specific binding was estimated as binding potential (BP) and specific to nonspecific equilibrium partition coefficient (V [ABSTRACT FROM AUTHOR]

[18F]fallypride is a new positron emission tomography (PET) dopamine D2 receptor radiotracer that provides visualization of D2 receptors in both striatal and extrastriatal areas. Here, the vulnerability of [18F]fallypride binding to endogenous dopamine (DA) levels was evaluated by examining the effect of amphetamine on [18F]fallypride binding in striatal and extrastriatal regions. Data were acquired in three male baboons at three different doses of i.v. amphetamine, using two different [18F]fallypride administration protocols (single bolus and bolus plus constant infusion). Scans were performed following a single bolus of [18F]fallypride under control conditions and following 1 mg/kg i.v. amphetamine and with an [18F]fallypride bolus plus constant infusion design under control, 0.5 mg/kg, and 0.3 mg/kg amphetamine i.v. conditions. Significant decreases in [18F]fallypride binding potential were seen in striatum (-49%, -18%, and -14%), thalamus (-25%, -23%, and -14%), and hippocampus (-36%, -24%, and -12%) following 1 mg/kg, 0.5 mg/kg, and 0.3 mg/kg doses of amphetamine, respectively. Additional analyses were performed suggesting that these results were not artifacts of nonreceptor-related effects such as regional flow changes or partial volume effects. In conclusion, [18F]fallypride binding is vulnerable to endogenous competition by DA in striatum as well as extrastriatal regions, suggesting that this ligand may be suitable for the study presynaptic DA function in striatal and extrastriatal areas. Synapse 54:46-63, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D2 receptor agonist and [11C]NPA is a suitable radiotracer to image D2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D2 receptor antagonist radiotracer [11C]raclopride. Three male baboons were studied with [11C]raclopride and [11C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg-1 i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V3″). [11C]Raclopride V3″ was reduced by 24 ± 10%, 32 ± 6%, and 44 ± 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg-1, respectively. [11C]NPA V3″ was reduced by 32 ± 2%, 45 ± 3%, and 53 ± 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg-1, respectively. Thus, endogenous DA was more effective at competing with [11C]NPA binding compared to [11C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease. Synapse 52:188-208, 2004. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: Impulsive aggression (IA) in adults is associated with brain serotonin (5-HT) system abnormalities and is more common following childhood adversity. Within aggressive behavior, IA and callous unemotional (CU) traits are core components of differentiable factors with opposing 5-HT abnormalities. We aimed to investigate 5-HT abnormalities in IA and potential correlations with severity of childhood adversity while controlling for confounding 5-HT effects of high CU traits and mental disorders. Methods: Healthy male subjects (mean age 34 ± 9 years) without high CU traits were recruited with IA ratings in the high (n = 14) and low (n = 13) population extremes. Serotonin transporter (SERT) and 5-HT2A receptor availability was measured in multiple brain regions using positron emission tomography with 11C-DASB and 11C-MDL100907, respectively, and compared between high-IA and low-IA groups. Correlations were measured between SERT and 5-HT2A receptor availability, impulsivity and aggression, and childhood adversity. Results: Compared with the low-IA group, SERT were significantly higher in brainstem regions in the high-IA group (by 29.0% ± 11.4%) and modestly lower across cortical regions (by 11.1% ± 6.0%), whereas 5-HT2A receptors were also modestly lower (by 8.6% ± 4.0%). Across all subjects, brainstem SERT were significantly positively correlated with impulsivity, aggression, and childhood trauma ratings. Within the high-IA group, higher brainstem SERT was most strongly predicted by severity of childhood trauma (r = .76 in midbrain). Conclusions: Pre-and postsynaptic 5-HT differences are present in men with high levels of IA and are strongly suggestive of a persisting effect of childhood adversity on serotonergic neurodevelopment and emotional-behavioral control. [ABSTRACT FROM AUTHOR]

Background: Despite some evidence that psoriatic arthritis (PsA) may increase psychological burden in psoriasis, the mental health of this subpopulation is under-investigated., Objectives: To investigate whether PsA is associated with higher depression and anxiety in moderate-to-severe psoriasis; explore whether pain mediates these associations; and estimate the prevalence of undiagnosed and untreated depression., Methods: Baseline data from British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) participants completing the Hospital Anxiety and Depression Scale (HADS) were analysed., Results: 707 patients ( n  = 540 with psoriasis only; n  = 167 with PsA) were included. Depression prevalence was higher in patients with than without PsA, when a HADS-depression subscale cut-off ≥8 was used (33% vs. 23%, adjusted Odds Ratio [OR] (95% Confidence Intervals [CI]) = 1.64 (1.09-2.45)), but did not differ using the HADS cut-off ≥ 11. Anxiety prevalence was higher among PsA patients, regardless of HADS cut-off (cut-off ≥11: adjusted OR (95% CI) = 1.62 (1.07-2.45)). Pain fully mediated the effect of PsA on depression and anxiety in psoriasis. 53.6% of participants identified as depressed did not have a known psychiatric disorder; two thirds of depressed participants were not treated., Conclusions: PsA comorbidity in psoriasis is associated with higher anxiety; its association with depression appears to be robust when milder depressive syndromes are included, but less consistent for higher-threshold depression definitions. Depression remains unrecognized and untreated in over half of moderately-to-severe psoriasis patients. Routine depression and anxiety screening is recommended in psoriasis and PsA. PsA comorbidity may increase depression and anxiety in psoriasis through pain experience., Competing Interests: C. Elise Kleyn has received honoraria, consultant and/or research funding from Janssen, Eli Lilly, LEO, Novartis, Abbvie, UCB, Almirall, Pfizer, and L’Oréal. Hector Chinoy has received personal compensation for activities with Novartis, UCB, Lilly, Biogen, Orphazyme as a speaker, advisory board member or consultancy, grants via The University of Manchester from Novartis, UCB and MedImmune, and has received travel support from Abbvie and Janssen. Richard B. Warren has received research grants from AbbVie, Almirall, Amgen, Celgene, Janssen, Lilly, Leo, Medac, Novartis, Pfizer, and UCB and consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DiCE, GSK, Janssen, Lilly, Leo, Medac, Novartis, Pfizer, Sanofi, Sun Pharma, UCB, and UNION. Georgia Lada has received speaker honoraria from Janssen, Lilly, Leo, and Novartis. Peter S. Talbot has no conflicts of interest., (© 2022 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Illness perceptions in psoriasis have an impact on adherence and disability. Changes in dermatological healthcare provision during the Covid-19 pandemic and distress may have affected illness perceptions in psoriasis patients., Objectives: To test whether illness perceptions about psoriasis changed during the first year of the Covid-19 pandemic compared to pre-pandemic in a tertiary population with psoriasis and whether pandemic effects differed depending on depressive burden, given this population's high depression prevalence., Methods: In a cross-sectional survey of n  = 188 tertiary patients with dermatologist-confirmed psoriasis recruited before and during the pandemic, eight illness perceptions domains were assessed using the Brief-Illness Perceptions Questionnaire (BIPQ). Presence of depression was assessed with the Hospital Anxiety and Depression Scale (HADS)., Results: Beliefs about treatment control and patients' understanding of psoriasis were significantly worse in patients responding during the pandemic compared to before Covid-19. These differences were greater when depression was absent (treatment control: adjusted p  < 0.001; coherence: adjusted p  = 0.01). However, participants during the pandemic felt less emotionally affected (adjusted p  = 0.02) and concerned (adjusted p  = 0.007) about psoriasis, independently of depression., Conclusions: We found diverse pandemic effects on illness perception domains in psoriasis. Uncertainty and reduced healthcare access may drive poorer treatment and coherence beliefs during Covid-19. These beliefs can hinder patients' health-promoting behaviours and may explain the high pandemic non-adherence reported previously in psoriasis. Appropriate interventions are needed to establish positive long-term cognitions and improve psoriasis management, for example, using the PsoWell patient materials. Dermatology services should invest in engaging and educating patients regardless of concurrent psychological distress., Competing Interests: C. Elise Kleyn has received honoraria, consultant and/or research funding from Janssen, Eli Lilly, LEO, Novartis, Abbvie, UCB, Almirall, Pfizer, and L’Oréal. Hector Chinoy has received personal compensation for activities with Novartis, UCB, Lilly, Biogen, Orphazyme as a speaker, advisory board member or consultancy, grants via The University of Manchester from Novartis, UCB and MedImmune, and has received travel support from Abbvie and Janssen. Richard B. Warren has received research grants from AbbVie, Almirall, Amgen, Celgene, Janssen, Lilly, Leo, Medac, Novartis, Pfizer, and UCB and consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DiCE, GSK, Janssen, Lilly, Leo, Medac, Novartis, Pfizer, Sanofi, Sun Pharma, UCB, and UNION. GL has received speaker honoraria from Janssen, Lilly, Leo, and Novartis. Peter S. Talbot has no conflicts of interest., (© 2022 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min-1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Positron Emission Tomography (PET) imaging has become a prominent tool to capture the spatiotemporal distribution of neurotransmitters and receptors in the brain. The outcome of a PET study can, however, potentially be obscured by suboptimal and/or inconsistent choices made in complex processing pipelines required to reach a quantitative estimate of radioligand binding. Variations in subject selection, experimental design, data acquisition, preprocessing, and statistical analysis may lead to different outcomes and neurobiological interpretations. We here review the approaches used in 105 original research articles published by 21 different PET centres, using the tracer [ 11 C]DASB for quantification of cerebral serotonin transporter binding, as an exemplary case. We highlight and quantify the impact of the remarkable variety of ways in which researchers are currently conducting their studies, while implicitly expecting generalizable results across research groups. Our review provides evidence that the foundation for a given choice of a preprocessing pipeline seems to be an overlooked aspect in modern PET neuroscience. Furthermore, we believe that a thorough testing of pipeline performance is necessary to produce reproducible research outcomes, avoiding biased results and allowing for better understanding of human brain function.

A number of effective maintenance medication options exist for bipolar disorder (BD) and these are regarded as the foundation of long-term treatment in BD. However, nonadherence to medication is common in BD. For example, a large data base study in the United States of America (USA) showed that approximately half of patients with BD were nonadherent with lithium and maintenance medications over a 12 month period. Such nonadherence carries a high risk of relapse due to the recurrent nature of the illness and the fact that abrupt cessation of treatment, particularly lithium, may cause rebound depression and mania. Indeed, medication nonadherence in BD is associated with significantly increased risks of relapse, recurrence, hospitalization and suicide attempts and a decreased likelihood of achieving remission and recovery, as well as with higher overall treatment costs. Factors associated with nonadherence include adverse effects of medication, complex medication regimens, negative patient attitudes to medication, poor insight, rapid-cycling BD, comorbid substance misuse and a poor therapeutic alliance. Clinicians should routinely enquire about nonadherence in a nonjudgmental fashion. Potential steps to improve adherence include simple pragmatic strategies related to prescribing including shared decision-making, psychoeducation with a clear focus on adherence, reminders (traditional and digital), potentially using a depot rather than an oral antipsychotic, managing comorbid substance misuse and improving therapeutic alliance. Financial incentives have been shown to improve adherence to depot antipsychotics, but this approach raises ethical issues and its long-term effectiveness is unknown. Often a combination of approaches will be required. The strategies that are adopted need to be patient specific, reflecting that nonadherence has no single cause, and chosen by the patient and clinician working together., Competing Interests: Conflict of interest statement: In the last 3 years PMH has received honoraria for lecturing or consultancy work from Allergan, Galen, Janssen, Lundbeck, NewBridge Pharmaceuticals, Otsuka, Sunovion and Teva plus conference support from Janssen, Lundbeck and Sunovion. In the last 3 years PST has received honoraria for attending Advisory Board meetings from Galen Limited; Sunovion Pharmaceuticals Europe Ltd; myTomorrows; LivaNova Ltd. In the last 3 years RHMW has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion.

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15 mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. (11)C-DASB PET scans were performed on the HRRT camera. Binding potentials (BP(ND)) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30+/-10%), was similar across brain regions, but varied widely across subjects (15-46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at <25% occupancy and greatest suppression was associated with highest occupancy (25-46%). However, several subjects with occupancy (36-39%) in the higher range had no appetite suppression. SERT occupancy by clinical doses of sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET.

Unlabelled: Brain kappa-opioid receptors (ORs) may be involved in several pathologic conditions, such as addiction, psychosis, and seizures. (+/-)-4-Methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine (GR89696) is a potent and selective kappa-OR agonist. The (-)-isomer, GR103545, is the active enantiomer of GR89696. The aim of this study was to characterize the potential of 11C-GR103545 to image kappa-OR in vivo with PET., Methods: Brain uptake of 11C-GR103545 was studied in baboons under control conditions and after blockade by naloxone (1 mg/kg intravenously). Uptake of the racemic 11C-GR89696 and of the inactive enantiomer (+)-11C-GR89696 was also evaluated. Regional total distribution volumes were derived using the arterial input function and a 2-tissue-compartment model., Results: 11C-GR103545 showed excellent brain penetration and uptake kinetics, with significant washout observed within the time frame of the PET experiment. Naloxone pretreatment did not affect cerebellar total distribution volume and reduced total distribution volume in other regions to a level comparable to that in the cerebellum. The regional pattern of 11C-GR103545 binding potential was consistent with the distribution of kappa-OR in primate brain, with highest levels observed in anterior cortical regions (prefrontal cortex and cingulate cortex) and striatum. In most regions, the specific-to-nonspecific equilibrium partition coefficient (V3'') ranged from 1 to 2, predicting reliable quantification. 11C-GR103545 V3'' values were approximately double the 11C-GR89696 V3'' values, whereas (+)-11C-GR89696 V3'' values were negligible, demonstrating the enantiomeric selectivity of the binding and the advantage of using the pure active enantiomer for PET studies., Conclusion: 11C-GR103545 is a promising PET radiotracer for imaging the kappa-OR.

Although abnormal serotonin (5-HT) function is implicated in a range of mental disorders, there is currently no method to directly assess 5-HT synaptic levels in the living human brain. The in vivo binding of some dopamine (DA) radioligands such as (11)C-raclopride is affected by fluctuations in endogenous DA, thus providing an indirect measure of DA presynaptic activity. Attempts to identify a serotonergic radiotracer with similar properties have proved unsuccessful. Here, we investigated in humans the effects of reduced synaptic 5-HT on the in vivo binding of the 5-HT transporter (SERT) radioligand (11)C-DASB, using Positron Emission Tomography (PET) and the rapid tryptophan depletion (RTD) technique. Eight (8) subjects (5M, 3F) were scanned with (11)C-DASB under control and reduced endogenous 5-HT conditions, in a within-subject, double-blind, counterbalanced, crossover design. Regional distribution volumes (V(T)) were calculated using kinetic modeling and metabolite-corrected arterial input function. (11)C-DASB specific binding was estimated as binding potential (BP) and specific to nonspecific equilibrium partition coefficient (V(")(3)), using the cerebellum as reference region. RTD caused small but significant mean reductions in (11)C-DASB V(T) (-6.1%) and BP (-4.5%) across brain regions, probably explained by a concomitant reduction in (11)C-DASB plasma free fraction (f(1)) of similar magnitude. No significant change in (11)C-DASB V(")(3) was observed between control and reduced 5-HT conditions. Nor was there a significant relationship between the magnitude of tryptophan depletion and change in BP and V(")(3) across individual subjects. These results suggest that (11)C-DASB in vivo binding is not affected by reductions in endogenous 5-HT.

[(18)F]fallypride is a new positron emission tomography (PET) dopamine D(2) receptor radiotracer that provides visualization of D(2) receptors in both striatal and extrastriatal areas. Here, the vulnerability of [(18)F]fallypride binding to endogenous dopamine (DA) levels was evaluated by examining the effect of amphetamine on [(18)F]fallypride binding in striatal and extrastriatal regions. Data were acquired in three male baboons at three different doses of i.v. amphetamine, using two different [(18)F]fallypride administration protocols (single bolus and bolus plus constant infusion). Scans were performed following a single bolus of [(18)F]fallypride under control conditions and following 1 mg/kg i.v. amphetamine and with an [(18)F]fallypride bolus plus constant infusion design under control, 0.5 mg/kg, and 0.3 mg/kg amphetamine i.v. conditions. Significant decreases in [(18)F]fallypride binding potential were seen in striatum (-49%, -18%, and -14%), thalamus (-25%, -23%, and -14%), and hippocampus (-36%, -24%, and -12%) following 1 mg/kg, 0.5 mg/kg, and 0.3 mg/kg doses of amphetamine, respectively. Additional analyses were performed suggesting that these results were not artifacts of nonreceptor-related effects such as regional flow changes or partial volume effects. In conclusion, [(18)F]fallypride binding is vulnerable to endogenous competition by DA in striatum as well as extrastriatal regions, suggesting that this ligand may be suitable for the study presynaptic DA function in striatal and extrastriatal areas.

(-)-N-Propyl-norapomorphine (NPA) is a full dopamine (DA) D2 receptor agonist and [11C]NPA is a suitable radiotracer to image D2 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study the vulnerability of the in vivo binding of [11C]NPA to acute fluctuation in synaptic DA was assessed with PET in baboons and compared to that of the reference D2 receptor antagonist radiotracer [11C]raclopride. Three male baboons were studied with [11C]raclopride and [11C]NPA under baseline conditions and following administration of the potent DA releaser amphetamine (0.3, 0.5, and 1.0 mg kg(-1) i.v.). Kinetic modeling with an arterial input function was used to derive the striatal specific-to-nonspecific equilibrium partition coefficient (V3"). [11C]Raclopride V3" was reduced by 24 +/- 10%, 32 +/- 6%, and 44 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. [11C]NPA V3" was reduced by 32 +/- 2%, 45 +/- 3%, and 53 +/- 9% following amphetamine doses of 0.3, 0.5, and 1.0 mg kg(-1), respectively. Thus, endogenous DA was more effective at competing with [11C]NPA binding compared to [11C]raclopride binding, a finding consistent with the pharmacology of these tracers (agonist vs. antagonist). These results also suggest that 71% of D2 receptors are configured in a state of high affinity for agonists in vivo. In conclusion, [11C]NPA might provide a superior radiotracer to probe presynaptic DA function with PET in health and disease., (Copyright 2004 Wiley-Liss, Inc.)