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Neuromelanin-sensitive MRI (NM-MRI) purports to detect the content of neuromelanin (NM), a product of dopamine metabolism that accumulates with age in dopamine neurons of the substantia nigra (SN). Interindividual variability in dopamine function may result in varying levels of NM accumulation in the SN; however, the ability of NM-MRI to measure dopamine function in non-neurodegenerative conditions has not been established. Here, we validated that NM-MRI signal intensity in postmortem midbrain specimens correlated with regional NM concentration even in the absence of neurodegeneration, a prerequisite for its use as a proxy for dopamine function. We then validated a voxelwise NM-MRI approach with sufficient anatomical sensitivity to resolve SN subregions. Using this approach and a multimodal dataset of molecular PET and fMRI data, we further showed the NM-MRI signal was related to both dopamine release in the dorsal striatum and resting blood flow within the SN. These results suggest that NM-MRI signal in the SN is a proxy for function of dopamine neurons in the nigrostriatal pathway. As a proof of concept for its clinical utility, we show that the NM-MRI signal correlated to severity of psychosis in schizophrenia and individuals at risk for schizophrenia, consistent with the well-established dysfunction of the nigrostriatal pathway in psychosis. Our results indicate that noninvasive NM-MRI is a promising tool that could have diverse research and clinical applications to investigate in vivo the role of dopamine in neuropsychiatric illness.

This exploratory trial was conducted to test the effects of an alpha7 nicotinic receptor partial agonist, TC-5619, on cognitive dysfunction and negative symptoms in subjects with schizophrenia. In the United States and India, 185 outpatients (18-60 years; male 69%; 46% tobacco users) with schizophrenia treated with quetiapine or risperidone monotherapy were randomized to 12 weeks of placebo (n=91) or TC-5619 (n=94; orally once daily 1 mg day 1 to week 4, 5 mg week 4 to 8, and 25 mg week 8 to 12). The primary efficacy outcome measure was the Groton Maze Learning Task (GMLT; executive function) of the CogState Schizophrenia Battery (CSB). Secondary outcome measures included: CSB composite score; Scale for Assessment of Negative Symptoms (SANS); Clinical Global Impression-Global Improvement (CGI-I); CGI-severity (CGI-S); and Subject Global Impression-Cognition. GMLT statistically favored TC-5619 (P=0.036) in this exploratory trial. SANS also statistically favored TC-5619 (P=0.030). No other secondary outcome measure demonstrated a drug effect in the total population; there was a statistically significant drug effect on working memory in tobacco users. The results were typically stronger in favor of TC-5619 in tobacco users and occasionally better in the United States than in India. TC-5619 was generally well tolerated with no clinically noteworthy safety findings. These results support the potential benefits of TC-5619 and alpha7 nicotinic receptor partial agonists for cognitive dysfunction and negative symptoms in schizophrenia.

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.

Individuals at clinical high-risk (CHR) of developing psychosis, as well as patients with recent psychosis onset (RO), experience significant negative symptoms that detrimentally impact daily-life functioning and are associated with poor outcomes, even in those who do not convert to psychosis. Targeting negative symptoms may thus hold promise for the treatment of CHR and RO patients. Building from previous findings we examined whether the catechol-O-methyltransferase ( COMT ) Val 158 Met functional polymorphism and fasting peripheral proline concentration predicts the severity of negative symptoms experienced by adolescents and young adults at CHR or those with RO. As hypothesized, the interaction between fasting plasma proline and COMT predicted negative symptoms, as measured via the Scale for the Assessment of Negative Symptoms (SANS) total ( n  = 50, β  = 0.066, adjusted p  = 0.007) and global severity scores ( n  = 50, coefficient = 0.026, adjusted p  = 0.003): Higher proline was beneficial for Val/Val subjects, but detrimental to those with the Met allele. In a secondary analysis, the COMT x proline interaction also predicted symptoms measured via the Clinical Assessment Interview for Negative Symptoms (CAINS) total scores ( n  = 50, β-coefficient = 0.035, adjusted p  = 0.044), although this result did not reach the Benjamini-Hochberg’s threshold for significance. Further, there was a trend towards significance for an association with social and interpersonal function (Global Functioning-Social, coefficient = −0.005, adjusted p  = 0.055). Negative symptoms are intractable and largely unaddressed by current medications. This study further supports a relationship between peripheral proline and COMT influencing negative symptoms such as anhedonia, in young CHR individuals and those with RO. That higher proline has converse effects on symptoms by COMT may have implications for the development of therapeutics to intervene early and specifically target the interaction pathway.

Objectives: Mass murder is associated with a lifetime history of substance use. We aimed to examine cannabis involvement among those who committed mass shootings in the United States from 1900 to 2019. Methods: We identified mass shooting events in the United States from 1900 to 2019 using publicly available English-language media reports and court/police records. People who perpetrated mass murders using methods other than firearms (eg, knives, automobiles) were used as a comparison group. Events were dichotomised into either prior to 1996 or from 1996 onward (first legalisation for medical use by California). Post-1960 data were used for additional analyses of a more modern era. Results: The proportion of those who committed mass shootings who had used, possessed, and/or distributed cannabis was significantly higher for events that occurred from 1996 onward, compared with prior to 1996 (11.2% vs 4.9%, p equivalent 0.002). The proportion of those committed mass murders by other methods who had used, possessed, and/or distributed cannabis did not significantly differ for events that occurred from 1996 onward, compared with prior to 1996 (4.8% vs 5.7%, p equivalent 0.76). When 58 mass shooting events and 31 mass murder events by other methods perpetrated before 1960 were excluded, results were similar when 1996 was used as a cutoff for the respective events (p equivalent 0.02 and p equivalent 0.40). Among those who committed mass shootings, those with cannabis involvement (n equivalent 74) were younger than those without (n equivalent 754) [28.7 vs 33.5 years, p < 0.001] and were of younger age group than older age group (11.9% vs 5.8%, p equivalent 0.002). Conclusion: Cannabis use May be harmful in subgroups of individuals (eg, those who committed mass shootings) who are vulnerable to cannabis use. This should be considered by policymakers, individuals with commercial interests, the public, and mental health and medical professionals when they debate related public health issues.

Duration of untreated psychosis (DUP) is defined as the time from the onset of psychotic symptoms until the first treatment. Studies have shown that longer DUP is associated with poorer response rates to antipsychotic medications and impaired cognition, yet the neurobiologic correlates of DUP are poorly understood. Moreover, it has been hypothesized that untreated psychosis may be neurotoxic. Here, we conducted a comprehensive review of studies that have examined the neurobiology of DUP. Specifically, we included studies that evaluated DUP using a range of neurobiologic and imaging techniques and identified 83 articles that met inclusion and exclusion criteria. Overall, 27 out of the total 83 studies (32.5%) reported a significant neurobiological correlate with DUP. These results provide evidence against the notion of psychosis as structurally or functionally neurotoxic on a global scale and suggest that specific regions of the brain, such as temporal regions, may be more vulnerable to the effects of DUP. It is also possible that current methodologies lack the resolution needed to more accurately examine the effects of DUP on the brain, such as effects on synaptic density. Newer methodologies, such as MR scanners with stronger magnets, PET imaging with newer ligands capable of measuring subcellular structures (e.g., the PET ligand [ 11 C]UCB-J) may be better able to capture these limited neuropathologic processes. Lastly, to ensure robust and replicable results, future studies of DUP should be adequately powered and specifically designed to test for the effects of DUP on localized brain structure and function with careful attention paid to potential confounds and methodological issues.

Evidence from preclinical, epidemiological, and human studies indicates that inflammation, and in particular elevated interleukin-6 (IL-6) activity, may be related to clinical manifestations and pathophysiology of schizophrenia. Furthermore, studies in preclinical models suggest that decreasing IL-6 activity may mitigate or reverse some of these deficits. The purpose of this trial was to test whether an IL-6 receptor antibody, tocilizumab, would improve residual positive and negative symptoms and cognitive deficits in schizophrenia. We randomized 36 clinically stable, moderately symptomatic (i.e., Positive and Negative Syndrome Scale (PANSS) >60) individuals with schizophrenia to 3 monthly infusions of 8 mg/kg tocilizumab or placebo (normal saline). The primary outcome was effect at week 12 on the PANSS Total Score. Effects on the MATRICS, other PANSS subscales, Clinical Global Impression, and Global Assessment of Functioning were secondary outcomes. There were no observed treatment effects on any behavioral outcome measure. Baseline C-reactive protein (CRP) or cytokine levels did not predict treatment outcome, nor were there correlations between changes in these inflammatory markers and the measured outcomes. As expected, IL-6 and IL-8 increased, while CRP decreased, in the tocilizumab group compared with the placebo group. This study did not reveal any evidence that an IL-6 receptor antibody affects behavioral outcomes in schizophrenia. One potential explanation is the lack of capacity of this agent to penetrate the central nervous system. Additional trials of medications aimed at targeting cytokine overactivity that act directly on brain function and/or treatment in early-stage psychosis populations are needed.

The objective of this study (NCT01854944) was to assess D2/D3, 5-HT1A, 5-HT2A and serotonin transporter (SERT) occupancies of brexpiprazole in adult subjects with schizophrenia in order to identify the in vivo pharmacologic profile that may be relevant to the antipsychotic, antidepressant, and side effect profiles of the drug. Subjects were grouped into three independent cohorts of four subjects each. All subjects underwent positron emission tomography (PET) scans with two different radiotracers at baseline prior to brexpiprazole administration, and again on Day 10 after daily doses of either 4 mg (Cohorts 1 and 2), or 1 mg (Cohort 3). Cohort 1 received scans with [11C]-(+)-PHNO to measure D2 and D3 receptor occupancy and [11C]CUMI101 to measure 5-HT1A occupancy; Cohort 2 received [11C]MDL100907 for 5-HT2A occupancy and [11C]DASB for SERT occupancy; Cohort 3 underwent scanning with [11C]-(+)-PHNO and [11C]MDL100907. Five female and seven male subjects, aged 42 ± 8 years (range, 28–55 years), participated in this study. Dose dependency was observed at D2 receptors, with occupancies reaching 64 ± 8% (mean +/− SD) following 1 mg/day and 80 ± 12% following 4 mg/day. D3 receptor availability increased following 1 mg brexpiprazole treatment and did not change with 4 mg. Robust and dose-related occupancy was also observed at 5-HT2A receptors. Negligible occupancy (<5%) was observed at 5-HT1A and SERT at 4 mg/day. In summary, brexpiprazole demonstrated in vivo binding to D2 receptors and 5-HT2A receptors at steady state after 10 days of daily administration in a dose dependent manner, while binding to D3, 5-HT1A receptors and SERT was not detectable with the radiotracers used for these targets. This pharmacologic profile is consistent with the observed antipsychotic and antidepressant effects.

Mass shootings account for a small fraction of annual worldwide murders, yet disproportionately affect society and influence policy. Evidence suggesting a link between mass shootings and severe mental illness (i.e. involving psychosis) is often misrepresented, generating stigma. Thus, the actual prevalence constitutes a key public health concern. We examined global personal-cause mass murders from 1900 to 2019, amassed by review of 14 785 murders publicly described in English in print or online, and collected information regarding perpetrator, demographics, legal history, drug use and alcohol misuse, and history of symptoms of psychiatric or neurologic illness using standardized methods. We distinguished whether firearms were or were not used, and, if so, the type (non-automatic v. semi- or fully-automatic). We identified 1315 mass murders, 65% of which involved firearms. Lifetime psychotic symptoms were noted among 11% of perpetrators, consistent with previous reports, including 18% of mass murderers who did not use firearms and 8% of those who did (χ2 = 28.0, p < 0.01). US-based mass shooters were more likely to have legal histories, use recreational drugs or misuse alcohol, or have histories of non-psychotic psychiatric or neurologic symptoms. US-based mass shooters with symptoms of any psychiatric or neurologic illness more frequently used semi-or fully-automatic firearms. These results suggest that policies aimed at preventing mass shootings by focusing on serious mental illness, characterized by psychotic symptoms, may have limited impact. Policies such as those targeting firearm access, recreational drug use and alcohol misuse, legal history, and non-psychotic psychopathology might yield more substantial results.