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Hyperprolactinemia is a known adverse drug reaction to antipsychotic treatment. Antipsychotic blood levels are influenced by cytochrome P450 enzymes, primarily CYP2D6. Variation in CYP450 genes may affect the risk of antipsychotic-induced hyperprolactinemia. We undertook a systematic review and meta-analysis to assess whether CYP2D6 functional genetic variants are associated with antipsychotic-induced hyperprolactinemia. The systematic review identified 16 relevant papers, seven of which were suitable for the meta-analysis (n = 303 participants including 134 extreme metabolisers). Participants were classified into four phenotype groups as poor, intermediate, extensive, and ultra-rapid metabolisers. A random effects meta-analysis was used and Cohen's d calculated as the effect size for each primary study. We found no significant differences in prolactin levels between CYP2D6 metabolic groups. Current evidence does not support using CYP2D6 genotyping to reduce risk of antipsychotic-induced hyperprolactinemia. However, statistical power is limited. Future studies with larger samples and including a range of prolactin-elevating drugs are needed. more...

Background:Concerns regarding potential neurological complications of COVID-19 are being increasingly reported, primarily in small series. Larger studies have been limited by both geography and specialty. Comprehensive characterisation of clinical syndromes is crucial to allow rational selection and evaluation of potential therapies. The aim of this study was to investigate the breadth of complications of COVID-19 across the UK that affected the brain.Methods:During the exponential phase of the pandemic, we developed an online network of secure rapid-response case report notification portals across the spectrum of major UK neuroscience bodies, comprising the Association of British Neurologists (ABN), the British Association of Stroke Physicians (BASP), and the Royal College of Psychiatrists (RCPsych), and representing neurology, stroke, psychiatry, and intensive care. Broad clinical syndromes associated with COVID-19 were classified as a cerebrovascular event (defined as an acute ischaemic, haemorrhagic, or thrombotic vascular event involving the brain parenchyma or subarachnoid space), altered mental status (defined as an acute alteration in personality, behaviour, cognition, or consciousness), peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction, or muscle), or other (with free text boxes for those not meeting these syndromic presentations). Physicians were encouraged to report cases prospectively and we permitted recent cases to be notified retrospectively when assigned a confirmed date of admission or initial clinical assessment, allowing identification of cases that occurred before notification portals were available. Data collected were compared with the geographical, demographic, and temporal presentation of overall cases of COVID-19 as reported by UK Government public health bodies.Findings:The ABN portal was launched on April 2, 2020, the BASP portal on April 3, 2020, and the RCPsych portal on April 21, 2020. Data lock for this report was on April 26, 2020. During this period, the platforms received notification of 153 unique cases that met the clinical case definitions by clinicians in the UK, with an exponential growth in reported cases that was similar to overall COVID-19 data from UK Government public health bodies. Median patient age was 71 years (range 23–94; IQR 58–79). Complete clinical datasets were available for 125 (82%) of 153 patients. 77 (62%) of 125 patients presented with a cerebrovascular event, of whom 57 (74%) had an ischaemic stroke, nine (12%) an intracerebral haemorrhage, and one (1%) CNS vasculitis. 39 (31%) of 125 patients presented with altered mental status, comprising nine (23%) patients with unspecified encephalopathy and seven (18%) patients with encephalitis. The remaining 23 (59%) patients with altered mental status fulfilled the clinical case definitions for psychiatric diagnoses as classified by the notifying psychiatrist or neuropsychiatrist, and 21 (92%) of these were new diagnoses. Ten (43%) of 23 patients with neuropsychiatric disorders had new-onset psychosis, six (26%) had a neurocognitive (dementia-like) syndrome, and four (17%) had an affective disorder. 18 (49%) of 37 patients with altered mental status were younger than 60 years and 19 (51%) were older than 60 years, whereas 13 (18%) of 74 patients with cerebrovascular events were younger than 60 years versus 61 (82%) patients older than 60 years. Interpretation:To our knowledge, this is the first nationwide, cross-specialty surveillance study of acute neurological and psychiatric complications of COVID-19. Altered mental status was the second most common presentation, comprising encephalopathy or encephalitis and primary psychiatric diagnoses, often occurring in younger patients. This study provides valuable and timely data that are urgently needed by clinicians, researchers, and funders to inform immediate steps in COVID-19 neuroscience research and health policy. Funding: None. more...

IntroductionClozapine is among the most effective antipsychotics used for treatment resistant schizophrenia. Adverse reactions to clozapine include neutropenia. Case series report that clozapine-treated patients with COVID-19 have no documented neutropenia.ObjectivesWe sought to investigate the potential adverse effect of coronavirus disease (COVID-19) in patients taking clozapine.MethodsWe retrospectively inspected data of 13 consecutive patients on clozapine, admitted to Highgate Mental Health Centre -Camden & Islington NHS Foundation Trust between March and June 2020. Selection was based on their COVID-19 symptoms presentation and/or COVID-19 positive test. We used a linear regression model with COVID status as independent variable and absolute neutrophil count (ANC) as dependent variable to inform about a correlation between COVID-19 status and neutrophil count. STATA was used for statistics.ResultsWe collected data on thirteen patients of which nine were male. The median age was of 41.97 years; six subjects were Black, three were Asian and four were White Caucasian. Ten subjects tested positive to COVID-19 and 3 were suspected cases -these latter were excluded from stastical analysis. During COVID-19 infection, neutrophils count (ANC) dropped significantly to 4.215 from a baseline value of 5.337. The beta values of 0.83 shows that ANC declined significantly during COVID-19 infection (p =2 = 95%). In three of thirteen patients, ANC drop was significant and changed the patients’ monitoring status from green to amber and required frequent blood tests.ConclusionsClinicians should bear in mind that a significant drop in neutrophils count may occur in COVID-19 -infected patients taking clozapine.DisclosureNo significant relationships. more...

Self-prescribing of sexual hormones for gender affirmation is a potentially widespread and poorly studied phenomenon that many clinicians are unaware of. The uncontrolled use of hormones poses significant health hazards, which have not been previously reported in the literature. We have collected seven clinical cases in general adult psychiatry settings (both inpatient and outpatients), describing transgender and gender non-conforming individuals’ (TGNC) self-prescribing and self-administering hormones bought from the Internet without any medical consultation. Among these cases, two were taking androgens, and the rest were taking oestrogens. The main reason for self-administration of hormones seems to be the lack of access to specialised care due to discrimination and long waiting lists. We advocate for clinicians to be aware of the phenomenon and proactively help TGNC individuals by enquiring about self-prescribing of hormones, providing information and referring to the most appropriate treatment centre as well as encourage a public debate on the discrimination and the stigma that TGNC population suffer from. Overall, there is an urgent need for the implementation of different and innovative health care services for TGNC individuals as well as more targeted prevention strategies on such underreported and highly risky behaviours. Furthermore, it is necessary for every clinician involved in the care for TGNC people to be aware of their special needs and be able to be an allied and an advocate to help in reducing stigma and discrimination that affect the access to care for this often underserved population. more...

Objective The pharmacological self-management of novel psychoactive substance (NPS)-induced psychopathological consequences represents a fast growing phenomenon. This is facilitated by the frequent sharing of NPS intake experiences online and by the ease of access to a range of psychotropic medications from both the online and street market. Olanzapine is anecdotally reported by Web users to be the most frequent self-prescribed medication to cope with NPS-induced psychoses. Hence, we aimed here at better assessing olanzapine use/misuse for this purpose. Methods Exploratory qualitative searches of 163 discussion fora/specialized websites have been carried out in four languages (English, German, Spanish, and Italian) in the time frame November 2012–2013. Results Most NPS-users allegedly self administer with olanzapine to manage related psychotic crises/“bad trips”. This may be typically taken only for a few days, at a dosage range of 5–50 mg/day. Conclusions Only a few research studies have formally assessed the effectiveness of olanzapine and indeed of other second-generation antipsychotics to treat NPS-induced psychosis. Olanzapine was suggested here from a range of pro drug websites as being the “ideal” molecule to terminate “bad trips”. Health professionals should be informed about the risks related to olanzapine misuse. Copyright © 2015 John Wiley & Sons, Ltd. more...

Background: Novel Psychoactive Substances (NPS) are a heterogeneous class of synthetic molecules including synthetic cannabinoid receptor agonists (SCRAs). Psychosis is associated with SCRAs use. There is limited knowledge regarding the structured assessment and psychometric evaluation of clinical presentations, analytical toxicology and clinical management plans of patients presenting with psychosis and SCRAs misuse. Methods: We gathered information regarding the clinical presentations, toxicology and care plans of patients with psychosis and SCRAs misuse admitted to inpatients services. Clinical presentations were assessed using the PANSS scale. Vital signs data were collected using the National Early Warning Signs tool. Analytic chemistry data were collected using urine drug screening tests for traditional psychoactive substances and NPS. Results: We described the clinical presentation and management plan of four patients with psychosis and misuse of SCRAs. Conclusion: The formulation of an informed clinical management plan requires a structured assessment, identification of the index NPS, pharmacological interventions, increases in nursing observations, changes to leave status and monitoring of the vital signs. The objective from using these interventions is to maintain stable physical health whilst rapidly improving the altered mental state. more...

OBJECTIVE: Few studies have characterized the epidemiology of first-episode psychoses in rural or urban settings since the introduction of early intervention psychosis services. To address this, the authors conducted a naturalistic cohort study in England, where such services are well established. METHOD: All new first-episode psychosis cases, 16-35 years old, presenting to early intervention psychosis services in the East of England were identified during 2 million person-years follow-up. Presence of ICD-10 F10-33 psychotic disorder was confirmed using OPCRIT [operational criteria for psychotic illness]. Incidence rate ratios were estimated following multivariable Poisson regression, adjusting for age, sex, ethnicity, socioeconomic status, neighborhood-level deprivation, and population density. RESULTS: Of 1,005 referrals, 687 participants (68.4%) fulfilled epidemiological and diagnostic criteria for first-episode psychosis (34.0 new cases per 100,000 person-years; 95% CI=31.5-36.6). Median age at referral was similar for men (22.5 years; interquartile range: 19.5-26.7) and women (23.4 years; interquartile range: 19.5-29.1); incidence rates were highest for men and women before 20 years of age. Rates increased for ethnic minority groups (incidence rate ratio: 1.4; 95% CI=1.1-1.6), as well as with lower socioeconomic status (incidence rate ratio: 1.3; 95% CI=1.2-1.4) and in more urban (incidence rate ratio: 1.4;95%CI=1.0-1.8) and deprived (incidence rate ratio: 2.1; 95% CI=1.3-3.3) neighborhoods, after adjustment for confounders. CONCLUSIONS: Pronounced variation in psychosis incidence, peaking before 20 years old, exists in populations served by early intervention psychosis services. Excess rates were restricted to urban and deprived communities, suggesting that a threshold of socioenvironmental adversity may be necessary to increase incidence. This robust epidemiology can inform service development in various settings about likely population-level need. more...

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the go/no-go task (GNGT). A double-blind, placebo-controlled, crossover-design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug dependent group under placebo. GSK598809 normalised ventral striatal reward response and enhanced response in the DRD3 rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition, nor were there any behavioural drug effects on response inhibition.CONCLUSION: GSK598809 modulated the neural network underlying reward anticipation but not response inhibition suggesting DRD3 antagonists may restore reward deficits in addiction.Neuropsychopharmacology accepted article preview online, 02 January 2017. doi:10.1038/npp.2016.289. more...

Drug and alcohol dependence are global problems with substantial societal costs. There are few treatments for relapse prevention and therefore a pressing need for further study of brain mechanisms underpinning relapse circuitry. The Imperial College Cambridge Manchester (ICCAM) platform study is an experimental medicine approach to this problem: using functional magnetic resonance imaging (fMRI) techniques and selective pharmacological tools, it aims to explore the neuropharmacology of putative relapse pathways in cocaine, alcohol, opiate dependent, and healthy individuals to inform future drug development. Addiction studies typically involve small samples because of recruitment difficulties and attrition. We established the platform in three centres to assess the feasibility of a multisite approach to address these issues. Pharmacological modulation of reward, impulsivity and emotional reactivity were investigated in a monetary incentive delay task, an inhibitory control task, and an evocative images task, using selective antagonists for µ-opioid, dopamine D3 receptor (DRD3) and neurokinin 1 (NK1) receptors (naltrexone, GSK598809, vofopitant/aprepitant), in a placebo-controlled, randomised, crossover design. In two years, 609 scans were performed, with 155 individuals scanned at baseline. Attrition was low and the majority of individuals were sufficiently motivated to complete all five sessions ( n=87). We describe herein the study design, main aims, recruitment numbers, sample characteristics, and explain the test hypotheses and anticipated study outputs. more...

In the research domain framework (RDoC), dysfunctional reward expectation has been proposed to be a cross-diagnostic domain in psychiatry, which may contribute to symptoms common to various neuropsychiatric conditions, such as anhedonia or apathy/avolition. We used a modified version of the Monetary Incentive Delay (MID) paradigm to obtain functional MRI images from 22 patients with schizophrenia, 24 with depression and 21 controls. Anhedonia and other symptoms of depression, and overall positive and negative symptomatology were also measured. We hypothesized that the two clinical groups would have a reduced activity in the ventral striatum when anticipating reward (compared to anticipation of a neutral outcome) and that striatal activation would correlate with clinical measures of motivational problems and anhedonia. Results were consistent with the first hypothesis: two clusters in both the left and right ventral striatum were found to differ between the groups in reward anticipation. Post-hoc analysis showed that this was due to higher activation in the controls compared to the schizophrenia and the depression groups in the right ventral striatum, with activation differences between depression and controls also seen in the left ventral striatum. No differences were found between the two patient groups, and there were no areas of abnormal cortical activation in either group that survived correction for multiple comparisons. Reduced ventral striatal activity was related to greater anhedonia and overall depressive symptoms in the schizophrenia group, but not in the participants with depression. Findings are discussed in relation to previous literature but overall are supporting evidence of reward system dysfunction across the neuropsychiatric continuum, even if the specific clinical relevance is still not fully understood. We also discuss how the RDoC approach may help to solve some of the replication problems in psychiatric fMRI research. more...

The pharmacological self-management of novel psychoactive substance (NPS)-induced psychopathological consequences represents a fast growing phenomenon. This is facilitated by the frequent sharing of NPS intake experiences online and by the ease of access to a range of psychotropic medications from both the online and street market. Olanzapine is anecdotally reported by Web users to be the most frequent self-prescribed medication to cope with NPS-induced psychoses. Hence, we aimed here at better assessing olanzapine use/misuse for this purpose.Exploratory qualitative searches of 163 discussion fora/specialized websites have been carried out in four languages (English, German, Spanish, and Italian) in the time frame November 2012-2013.Most NPS-users allegedly self administer with olanzapine to manage related psychotic crises/"bad trips". This may be typically taken only for a few days, at a dosage range of 5-50 mg/day.Only a few research studies have formally assessed the effectiveness of olanzapine and indeed of other second-generation antipsychotics to treat NPS-induced psychosis. Olanzapine was suggested here from a range of pro drug websites as being the "ideal" molecule to terminate "bad trips". Health professionals should be informed about the risks related to olanzapine misuse. more...

Negative symptoms occur in several major mental health disorders with undetermined mechanisms and unsatisfactory treatments; identification of their neural correlates might unveil the underlying pathophysiological basis and pinpoint the therapeutic targets. In this study, participants with major depressive disorder (n = 24), schizophrenia (n = 22), and healthy controls (n = 20) were assessed with 10 frequently used negative symptom scales followed by principal component analysis (PCA) of the scores. A linear model with the prominent components identified by PCA was then regressed on gray and white-matter volumes estimated from T1-weighted magnetic resonance imaging. In depressed patients, negative symptoms such as blunted affect, alogia, withdrawal, and cognitive impairment, assessed mostly via clinician-rated scales were inversely associated with gray matter volume in the bilateral cerebellum. In patients with schizophrenia, anhedonia, and avolition evaluated via self-rated scales inversely related to white-matter volume in the left anterior limb of internal capsule/anterior thalamic radiation and positively in the left superior longitudinal fasiculus. The pathophysiological mechanisms underlying negative symptoms might differ between depression and schizophrenia. These results also point to future negative symptom scale development primarily focused on detecting and monitoring the corresponding changes to brain structure or function. more...

The year 2013 marks the 75th anniversary of the invention of ECT. This paper provides a translation of the 1938 publication by Cerletti and Bini, with an introduction. The authors thought that it would be helpful, in the debate about ECT, to make accessible to people unfamiliar with Italian the first public account of ECT made by Cerletti and Bini in front of the Royal Medical Academy of Rome in May 1938. The introduction and translated paper refer to the methodical approach to the development of ECT, based on the scientific opinions and technological processes of the time, as well as the drive to provide treatment which is both cheaper and more acceptable to patients. The introduction also comments on changing attitudes to what remains an efficacious treatment. ECT has been wrongly represented as an obsolete, unscientific treatment more akin to a torture than to a therapy: some explanations for this are suggested. more...

The proteins cathepsin D, encoded by CTSD gene, and α2-macroglobulin, encoded by A2M gene, are involved in the biochemical pathway leading to deposition of β-amyloid. In these proteins two amino acid polymorphisms (CTSD-Ala/Val C→T and A2M-Ile/Val A→G) have been associated with an increased risk for Alzheimer's disease (AD), but conflicting results have been reported. We studied the association and the mutual interactions of the CTSD-C/T and A2M-A/G polymorphisms with sporadic AD in 100 patients with late-onset AD and 136 healthy elderly subjects as controls. The CTSD-T allele and the CTSD-C/T genotype are significantly more frequent in AD than in controls. The odds ratio (OR) for CTSD-T subjects is 1.93 [95% confidence interval (CI) = 1.01–3.72], and 2.07 (95% CI = 1.01–4.21) after adjustment for age, sex and APOE e4+ status, while no significant association was found for the A2M-A/G polymorphism. The coexistence of the CTSD-T with the A2M-G allele synergistically increased the OR for AD to 2.69 (95% CI = 1.13–6.34) [2.82 (95% CI = 1.12–7.17) after adjustment], and to 3.29 (95% CI = 1.33–8.16) if estimated for the allelic combination. Our data suggest that the CTSD-T allele of the CTSD-C/T polymorphism is associated with an increased relative risk for late-onset AD and, more interestingly, the combination of CTSD-T with the A2M-G allele seems to increase this risk. more...

Mild cognitive impairment (MCI) represents a heterogeneous group of cognitive disturbances at high risk of dementia. The amnestic subtype (aMCI) might be a prodromal state of Alzheimer's disease (AD). The aim of this study is the identification, by proton magnetic resonance spectroscopy (1H MRS), of modifications in brain metabolites able to detect subjects with aMCI at risk of conversion towards AD. Twenty-five subjects with aMCI and 29 normal elderly were enrolled; they underwent a comprehensive clinical and instrumental assessment, a cerebral 1H MRS scan to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (mI) and creatine (Cr) in the paratrigonal white matter, bilaterally. After 1 year, 5 MCI subjects became demented (progressive MCI, pMCI). Their baseline levels of metabolites were compared with those evaluated in stable MCI (sMCI) and in controls. We observed a significant difference of the NAA/Cr ratio between pMCI (1.48+/-0.08) and sMCI (1.65+/-0.12) and between pMCI and controls (1.63+/-0.16) in the left hemisphere, suggesting that this metabolic alteration can be detected before the clinical appearance of dementia. more...

In order to assess peripheral levels and activities of a broad spectrum of non-enzymatic and enzymatic antioxidants in elderly subjects with mild cognitive impairment (MCI) and Alzheimer’s disease (AD), plasma levels of water-soluble (Vitamin C and uric acid) and of lipophilic (Vitamin A, Vitamin E and carotenoids including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) antioxidant micronutrients as well as activities of plasma and red blood cell (RBC) superoxide dismutase (SOD) and of plasma glutathione peroxidase (GPx) were measured in 25 patients with MCI, 63 AD patients and 53 controls. Peripheral levels and activities of antioxidants were similarly lower in MCI and AD patients as compared to controls. As MCI may represent a prodromal stage of AD, and oxidative damage appears to occur as one of the earliest pathophysiological events in AD, an increased intake of antioxidants in patients with MCI could be helpful in lowering the risk of conversion to dementia. more...

OBJECTIVES: Hypertension is a risk factor for dementia and is associated with some of the brain changes that are found in Alzheimer's disease and other neurodegenerative diseases, such as atrophy and neurofibrillary tangles. We evaluated the cerebral white matter biochemical pattern in healthy older subjects, older patients with chronic hypertension, and patients with Alzheimer's disease (AD) using proton magnetic resonance spectroscopy (1H-MRS). DESIGN: Cross-sectional study. SETTING: University-affiliated outpatient clinic. PARTICIPANTS: Ten healthy older subjects, 10 cognitively intact older patients with chronic hypertension, and 10 older patients with early AD. MEASUREMENTS: All subjects underwent clinical examination, neuropsychological assessment, and 1H-MRS to measure N-acetylaspartate (NAA), myoinositol, choline, and creatine resonance signals in an 8-cm3 voxel located in the paratrigonal white matter region bilaterally. NAA/creatine, myoinositol/creatine, and choline/creatine ratios were measured, and the mean values were compared using one-way analysis of variance with Tukey test for post hoc analysis. RESULTS: A significantly higher mean myoinositol/creatine (ratio ± standard deviation) was found in hypertensive patients (0.67 ± 0.05) and in AD patients (0.68 ± 0.08) than in controls (0.56 ± 0.04) (P < .001). Conversely neither NAA/creatine ratio nor choline/creatine ratio differed among the three groups. CONCLUSIONS: In this study, cognitively intact chronic hypertensive older patients had a higher white matter myoinositol/creatine ratio compared with healthy older subjects, suggesting that myoinositol may be a sensitive marker of the effects of chronic hypertension on the brain. Moreover, the similar increase of myoinositol/creatine ratio in patients with hypertension and in those with early AD provides further evidence of common brain changes with these conditions. more...