An automatic analysis framework for FDOPA PET neuroimaging.

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size.

Associations between psoriatic arthritis and mental health among patients with psoriasis: A replication and extension study using the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

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.

Brain structure and connectivity in psoriasis and associations with depression and inflammation; findings from the UK biobank.

Background: Psoriasis is a chronic systemic inflammatory skin disease, coexisting with depression in up to 25% of patients. Little is known about the drivers of comorbidity, including shared neurobiology and depression brain imaging patterns in patients. An immune-mediated crosstalk between the brain and skin has been hypothesized in psoriasis. With the aim of investigating brain structure and connectivity in psoriasis in relation to depression comorbidity, we conducted a brain imaging study including the largest psoriasis patient sample to date (to our knowledge) and the first to investigate the role of depression and systemic inflammation in brain measures. Effects of coexisting psoriatic arthritis (PsA), which represents joint involvement in psoriasis and a higher putative inflammatory state, were further explored. Methods: Brain magnetic resonance imaging (MRI) data of 1,048 UK Biobank participants were used (131 comorbid patients with psoriasis and depression, age-and sex-matched to: 131 non-depressed psoriasis patients; 393 depressed controls; and 393 non-depressed controls). Interaction effects of psoriasis and depression on volume, thickness and surface of a-priori defined regions of interest (ROIs), white matter tracts and 55x55 partial correlation resting-state connectivity matrices were investigated using general linear models. Linear regression was employed to test associations of brain measures with C-reactive protein (CRP) and neutrophil counts. Results: No differences in regional or global brain volumes or white matter integrity were found in patients with psoriasis compared to controls without psoriasis or PsA. Thickness in right precuneus was increased in psoriasis patients compared to controls, only when depression was present (ß = 0.26, 95% CI [Confidence Intervals] 0.08, 0.44; p = 0.02). In further analysis, psoriasis patients who had PsA exhibited fronto-occipital decoupling in resting-state connectivity compared to patients without joint involvement (ß = 0.39, 95% CI 0.13, 0.64; p = 0.005) and controls (ß = 0.49, 95% CI 0.25, 0.74; p < 0.001), which was unrelated to depression comorbidity. Precuneus thickness and fronto-occipital connectivity were not predicted by CRP or neutrophil counts. Precuneus thickening among depressed psoriasis patients showed a marginal correlation with recurrent lifetime suicidality. Conclusions: Our findings provide evidence for a combined effect of psoriasis and depression on the precuneus, which is not directly linked to systemic inflammation, and may relate to suicidality or altered somatosensory processing. The use of the UK Biobank may limit generalizability of results in populations with severe disease.

The effect of the Covid-19 pandemic on illness perceptions of psoriasis and the role of depression: Findings from a cross-sectional study.

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.

Depression and Suicidality in Patients With Psoriasis and the Role of Psoriatic Arthritis: A Cross-sectional Study in a Tertiary Setting.

BACKGROUND: Depression is overrepresented in psoriasis. However, it is not clear whether the presence of psoriatic arthritis (PsA) independently increases patients' depressive burden. Furthermore, current evidence regarding suicidality risk of psoriasis populations is conflicting, and the role of PsA in suicidality outcomes of psoriasis is unknown. OBJECTIVES: (i) To test whether PsA is associated with depression and lifetime suicidal ideation among patients with psoriasis; (ii) to capture different suicidal phenomena in these patients; and (iii) to investigate whether suicidality and depressive symptom severity are associated with clinical markers of psoriasis severity and chronicity. METHODS: A cross-sectional survey of tertiary patients (n = 219, aged 18-65 years) with dermatologist-confirmed chronic plaque psoriasis, of whom 84 had rheumatologist-confirmed PsA, was undertaken. The Hospital Anxiety and Depression Scale and Sheehan-Suicidality Tracking Scale were used to assess depression and lifetime suicidality, respectively. RESULTS: PsA presence was associated with depression in patients with psoriasis, independent of other physical comorbidities (adjusted odds ratio 2.92, 95% confidence interval 1.53-5.68). Furthermore, patients with PsA experienced significantly higher levels of anhedonia and anxiety, after controlling for psychiatric history. Of all participants, 48.8% reported lifetime suicidal ideation with or without intent, 21.3% reported suicidal planning, and 9.4% reported suicide attempts. Lifetime suicidality prevalence did not differ between patients with and without PsA. Depressive symptom severity and lifetime suicidality scores were not associated with objective measures of psoriasis severity or treatment group. CONCLUSIONS: These data suggest that joint involvement in psoriasis is associated with higher depressive burden. There is a need for routine depression screening among patients with psoriasis, particularly when PsA is present. Anhedonia appears to be a particularly relevant symptom in the depression phenotype of this population. We did not find a statistically significant association between PsA and suicidality. Nevertheless, suicidality rates in tertiary patients with psoriasis appear to be higher than those in the general population. Suicidality monitoring is recommended to help in reducing future psychiatric morbidity and mortality in patients with psoriasis.

Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA).

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.

Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [11C](R)-PK11195. The primary outcome was binding potential (BPND) in the anterior cingulate cortex (ACC). Secondary outcomes were BPND in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BPND was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F1,58 = 0.407, p = 0.526). Compared with controls, BPND was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BPND in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification.

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.

Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology.

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.

Psoriasis and Mental Health Workshop Report: Exploring the Links between Psychosocial Factors, Psoriasis, Neuroinflammation and Cardiovascular Disease Risk.

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.

Cerebral serotonin transporter measurements with [11C]DASB: A review on acquisition and preprocessing across 21 PET centres.

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.

Medication nonadherence in bipolar disorder: a narrative review.

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.

Microglial activation, white matter tract damage, and disability in MS.

OBJECTIVE: To investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS. METHODS: Patients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [11C](R)-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison. RESULTS: [11C](R)-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls. CONCLUSIONS: PET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.

Acute and chronic changes in brain activity with deep brain stimulation for refractory depression.

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.

Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study.

BACKGROUND: Major depressive disorder is associated with raised peripheral inflammatory markers. Mounting evidence also suggests that inflammation is involved in suicidal behavior. However, the involvement of inflammation in the brains of individuals with depression, and its association with suicidal ideation, needs further clarification. Translocator protein (TSPO), which is upregulated in activated glia (predominantly microglia), can be measured as an indication of neuroinflammation in vivo using positron emission tomography and TSPO-specific radioligands. METHODS: We used [11C](R)-PK11195 positron emission tomography to compare TSPO availability in the anterior cingulate cortex (ACC), prefrontal cortex, and insula between 14 medication-free patients in a major depressive episode of at least moderate severity and 13 matched healthy control subjects. In a post hoc analysis, we also compared TSPO availability between patients with and without suicidal thoughts. RESULTS: Multivariate analysis of variance indicated significantly higher TSPO in patients compared with control subjects (p = .005). The elevation was of large effect size and significant in the ACC (p = .022, Cohen's d = 0.95), with smaller nonsignificant elevations in the prefrontal cortex (p = .342, Cohen's d = 0.38) and insula (p = .466, Cohen's d = 0.29). TSPO was not elevated in patients without suicidal thinking but was significantly increased in those with suicidal thoughts compared with those without, most robustly in the ACC (p = .008) and insula (p = .023). CONCLUSIONS: We confirm evidence for increased TSPO availability, suggestive of predominantly microglial activation, in the ACC during a moderate to severe major depressive episode. Our findings provide further incentive for evaluating anti-inflammatory therapies in major depressive disorder.

Deep brain stimulation of the periaqueductal gray releases endogenous opioids in humans.

Deep brain stimulation (DBS) of the periaqueductal gray (PAG) is used in the treatment of severe refractory neuropathic pain. We tested the hypothesis that DBS releases endogenous opioids to exert its analgesic effect using [11C]diprenorphine (DPN) positron emission tomography (PET). Patients with de-afferentation pain (phantom limb pain or Anaesthesia Dolorosa (n=5)) who obtained long-lasting analgesic benefit from DBS were recruited. [11C]DPN and [15O]water PET scanning was performed in consecutive sessions; first without, and then with PAG stimulation. The regional cerebral tracer distribution and kinetics were quantified for the whole brain and brainstem. Analysis was performed on a voxel-wise basis using statistical parametric mapping (SPM) and also within brainstem regions of interest and correlated to the DBS-induced improvement in pain score and mood. Brain-wide analysis identified a single cluster of reduced [11C]DPN binding (15.5% reduction) in the caudal, dorsal PAG following DBS from effective electrodes located in rostral dorsal/lateral PAG. There was no evidence for an accompanying focal change in blood flow within the PAG. No correlation was found between the change in PAG [11C]DPN binding and the analgesic effect or the effect on mood (POMSSV) of DBS. The analgesic effect of DBS in these subjects was not altered by systemic administration of the opioid antagonist naloxone (400ug). These findings indicate that DBS of the PAG does indeed release endogenous opioid peptides focally within the midbrain of these neuropathic pain patients but we are unable to further resolve the question of whether this release is responsible for the observed analgesic benefit.

Managing inadequate antidepressant response in depressive illness.

INTRODUCTION OR BACKGROUND: Depression frequently fails to respond to initial treatment. SOURCES OF DATA: Predominantly meta-analyses and RCTs but supplemented where necessary by additional data and the authors' clinical experience. AREAS OF AGREEMENT: A systematic assessment to identify remedial causes of poor response should be followed by planned sequential treatment trials. Joint decision making by the patient and clinician is essential. Strategies with the strongest support are antidepressant augmentation with lithium or second generation antipsychotics and adding cognitive behavioural treatment. Electroconvulsive therapy is highly effective in resistant depression but there is a high relapse rate when treatment ends. AREAS OF CONTROVERSY: Some pharmacological strategies have inconsistent data (e.g. antidepressant combinations, T3 augmentation) or limited preliminary data (e.g. ketamine, antidepressant augmentation with pramipexole). The efficacy of vagus nerve stimulation, deep brain stimulation and repetitive transcranial magnetic stimulation is unclear. GROWING POINTS: A greater understanding of the causes of depression may assist the development of more effective treatments. AREAS TIMELY FOR DEVELOPING RESEARCH: Role of glutamate antagonists and psychological treatments, other than cognitive behavioural therapy, as adjunctive treatments.

Pre- and postsynaptic serotonergic differences in males with extreme levels of impulsive aggression without callous unemotional traits: a positron emission tomography study using (11)C-DASB and (11)C-MDL100907.

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-HT(2A) receptor availability was measured in multiple brain regions using positron emission tomography with (11)C-DASB and (11)C-MDL100907, respectively, and compared between high-IA and low-IA groups. Correlations were measured between SERT and 5-HT(2A) 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-HT(2A) 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.