Search

Early identification of symptoms that can predict treatment-resistant schizophrenia (TRS) could help clinicians to avoid delays in clozapine therapy. This study aims to investigate symptom patterns that could predict TRS using a discovery/replication study design. First, we followed a cohort of inpatients with schizophrenia (n = 164) in which the most discriminative items at baseline of the Positive and Negative Syndrome Scale (PANSS) were determined using logistic regression with TRS status as an outcome. Using Receiver Operating Characteristic (ROC) curves, we tested the prediction performance of multiple combinations of the identified items. The same items' combination was tested in an independent replication sample of (n = 207) outpatients with schizophrenia. In the discovery sample, the best combination to predict TRS at the discharge was the sum of three baseline PANSS items – conceptual disorganization (P2), difficulty in abstract thinking (N5), and unusual thought content (G9). The P2 + N5 + G9 model yielded an area under the curve (AUC) of 0.881, a sensitivity of 77.8%, and a specificity of 83.3%. In the outpatient sample, the model P2 + N5 + G9 predictive accuracy for TRS was only in the range of “acceptable” with an AUC of 0.756 and sensitivity of 72.3% and a specificity of 74.4%. Overall, the P2 + N5 + G9 model corresponds to the construct of formal thought disorder composed of disorganized thinking, concrete thinking, and bizarre-idiosyncratic thinking. Pronounced levels of these symptoms are easily identifiable in clinical practice and may be a feasible strategy in TRS. Replicating in first-episode cohorts is desirable to understand the likely clinical utility.

Contemporary theories propose that dysregulation of emotional perception is involved in the aetiology of psychosis. 298 healthy adolescents were assessed at age 14- and 19-years using fMRI while performing a facial emotion task. Psychotic-like experiences (PLEs) were assessed with the CAPE-42 questionnaire at age 19. The high PLEs group at age 19 years exhibited an enhanced response in right insular cortex and decreased response in right prefrontal, right parahippocampal and left striatal regions; also, a gradient of decreasing response to emotional faces with age, from 14 to 19 years, in the right parahippocampal region and left insular cortical area. The right insula demonstrated an increasing response to emotional faces with increasing age in the low PLEs group, and a decreasing response over time in the high PLEs group. The change in parahippocampal/amygdala and insula responses during the perception of emotional faces in adolescents with high PLEs between the ages of 14 and 19 suggests a potential ‘aberrant’ neurodevelopmental trajectory for critical limbic areas. Our findings emphasize the role of the frontal and limbic areas in the aetiology of psychotic symptoms, in subjects without the illness phenotype and the confounds introduced by antipsychotic medication.

Psychotic disorders can be exacerbated by the hormonal changes associated with childbirth, but the extent to which exacerbations occur with the menstrual cycle is unclear. We addressed this issue by conducting a systematic review. Embase, Medline, and PsychINFO databases were searched for studies that measured exacerbations of psychotic disorders in relation to the menstrual cycle. We extracted exacerbation measure, definition of menstrual cycle phase, and measurement of menstrual cycle phase. Standard incidence ratios were calculated for the perimenstrual phase based on the observed admissions during this phase divided by the expected number of admissions if the menstrual cycle had no effect. Random effects models were used to examine pooled rates of psychiatric admission in the perimenstrual phase. Nineteen studies, comprising 1193 participants were eligible for inclusion. Eleven studies examined psychiatric admission rates, 5 examined symptoms scores, 2 examined self-reported exacerbation, and 1 examined both admission rates and symptom scores. A random effects model demonstrated the rate of admissions during the perimenstrual phase was 1.48 times higher than expected (95% CI: 1.31–1.67), with no significant heterogeneity detected. Four of six symptom score studies reported perimenstrual worsening, but lack of consistency in timepoints precluded meta-analysis. Two studies examining self-reported menstrual exacerbations reported prevalences ranging from 20% to 32.4%. Psychiatric admission rates are significantly higher than expected during the perimenstrual phase. There is some evidence that a worsening of psychotic symptoms also occurs during this phase, but further research with more precise measurement of the menstrual cycle and symptomatology is required.

ObjectivesTo investigate changes in daily mental health (MH) service use and mortality in response to the introduction and the lifting of the COVID-19 ‘lockdown’ policy in Spring 2020.DesignA regression discontinuity in time (RDiT) analysis of daily service-level activity.Setting and participantsMental healthcare data were extracted from 10 UK providers.Outcome measuresDaily (weekly for one site) deaths from all causes, referrals and discharges, inpatient care (admissions, discharges, caseloads) and community services (face-to-face (f2f)/non-f2f contacts, caseloads): Adult, older adult and child/adolescent mental health; early intervention in psychosis; home treatment teams and liaison/Accident and Emergency (A&E). Data were extracted from 1 Jan 2019 to 31 May 2020 for all sites, supplemented to 31 July 2020 for four sites. Changes around the commencement and lifting of COVID-19 ‘lockdown’ policy (23 March and 10 May, respectively) were estimated using a RDiT design with a difference-in-difference approach generating incidence rate ratios (IRRs), meta-analysed across sites.ResultsPooled estimates for the lockdown transition showed increased daily deaths (IRR 2.31, 95% CI 1.86 to 2.87), reduced referrals (IRR 0.62, 95% CI 0.55 to 0.70) and reduced inpatient admissions (IRR 0.75, 95% CI 0.67 to 0.83) and caseloads (IRR 0.85, 95% CI 0.79 to 0.91) compared with the pre lockdown period. All community services saw shifts from f2f to non-f2f contacts, but varied in caseload changes. Lift of lockdown was associated with reduced deaths (IRR 0.42, 95% CI 0.27 to 0.66), increased referrals (IRR 1.36, 95% CI 1.15 to 1.60) and increased inpatient admissions (IRR 1.21, 95% CI 1.04 to 1.42) and caseloads (IRR 1.06, 95% CI 1.00 to 1.12) compared with the lockdown period. Site-wide activity, inpatient care and community services did not return to pre lockdown levels after lift of lockdown, while number of deaths did. Between-site heterogeneity most often indicated variation in size rather than direction of effect.ConclusionsMH service delivery underwent sizeable changes during the first national lockdown, with as-yet unknown and unevaluated consequences.

Approximately one third of psychosis patients fail to respond to conventional antipsychotic medication, which exerts its effect via striatal dopamine receptor antagonism. The present study aimed to investigate impaired cognitive control as a potential contributor to persistent positive symptoms in treatment resistant (TR) patients. 52 medicated First Episode Psychosis (FEP) patients (17 TR and 35 non-TR (NTR)) took part in a longitudinal study in which they performed a series of cognitive tasks and a clinical assessment at two timepoints, 12 months apart. Cognitive performance at baseline was compared to that of 39 healthy controls (HC). Across both timepoints, TR patients were significantly more impaired than NTR patients in a task of cognitive control, while performance on tasks of phonological and semantic fluency, working memory and general intelligence did not differ between patient groups. No significant associations were found between cognitive performance and psychotic symptomatology, and no significant performance changes were observed from the first to second timepoint in any of the cognitive tasks within patient groups. The results suggest that compared with NTR patients, TR patients have an exacerbated deficit specific to cognitive control, which is established early in psychotic illness and stabilises in the years following a first episode.

Background Schizophrenia is characterized by prominent cognitive deficits, impacting on memory and learning; these are strongly associated with the prefrontal cortex. Objective/hypothesis To combine two interventions, transcranial direct current stimulation (tDCS) over the prefrontal cortex and cognitive training, to examine change in cognitive performance in patients with schizophrenia. Methods A double blind, sham-controlled pilot study of 49 patients with schizophrenia, randomized into real or sham tDCS stimulation groups. Subjects participated in 4 days of cognitive training (days 1, 2, 14, 56) with tDCS applied at day-1 and day-14. The primary outcome measure was change in accuracy on working memory and implicit learning tasks from baseline. The secondary outcome measure was the generalization of learning to non-trained task, indexed by the CogState neuropsychological battery. Data analysis was conducted using multilevel modelling and multiple regressions. Results 24 participants were randomized to real tDCS and 25 to sham. The working memory task demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 (b = 0.68, CI 0.14–1.21; p = 0.044) and at day-56 (b = 0.71, 0.16–1.26; p = 0.044). There were no significant effects of tDCS on implicit learning. Trend evidence of generalization onto untrained tasks of attention and vigilance task (b = 0.40, 0.43–0.77; p = 0.058) was found. Conclusions This is the first study to show a significant longer-term effect of tDCS on working memory in schizophrenia. Given the current lack of effective therapies for cognitive deficits, tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia.

Psychotic illness is associated with cognitive control deficits and abnormal recruitment of neural circuits subserving cognitive control. It is unclear to what extent this dysfunction underlies the development and/or maintenance of positive and negative symptoms typically observed in schizophrenia. In this study we compared fMRI activation on a standard Stroop task and its relationship with positive and negative symptoms in early psychosis (EP, N = 88) and chronic schizophrenia (CHR-SZ, N = 38) patients. CHR-SZ patients showed reduced frontal, striatal, and parietal activation across incongruent and congruent trials compared to EP patients. Higher positive symptom severity was associated with reduced activation across both trial types in supplementary motor area (SMA), middle temporal gyrus and cerebellum in EP, but not CHR-SZ patients. Higher negative symptom severity was associated with reduced cerebellar activation in EP, but not in CHR-SZ patients. A negative correlation between negative symptoms and activation in SMA and precentral gyrus was observed in EP patients and in CHR-SZ patients. The results suggest that the neural substrate of positive symptoms changes with illness chronicity, and that cognitive control related neural circuits may be most relevant in the initial development phase of positive symptoms. These findings also highlight a changing role for the cerebellum in the development and later maintenance of both positive and negative symptoms.

Background Clozapine is the only medication approved for those patients with schizophrenia who do not achieve a clinical response to standard antipsychotic treatment, yet it is still underused. Furthermore, in the case of a partial or minimal response to clozapine treatment, there is no clarity on the next pharmacologic intervention. Methods The National Psychosis Service is a tertiary referral inpatient unit for individuals with refractory psychosis. Data from 2 pooled data sets (for a total of 325 medical records) were analyzed for treatment trajectories between admission and discharge (2001-2016). Effectiveness of pharmacologic treatment was determined using change in symptoms, assessed using the Operational Criteria (OPCRIT) system applied retrospectively to the medical records. Analysis was focused on identifying the optimal medication regimens impacting clinical status during the admission. Results Less than a quarter of the patients were on clozapine treatment at the time of admission; this rate increased to 63.4% at the time of discharge. Initiating clozapine during admission (n = 136) was associated with a 47.9% reduction of symptoms as reflected by their OPCRIT score. In cases in which clozapine monotherapy did not achieve sufficient improvement in symptoms, the most effective clozapine augmentation strategy was adding amisulpride (n = 22, 60.8% reduction of symptoms), followed by adding a mood stabilizer (n = 36, 53.7% reduction). A less favorable option was addition of quetiapine (n = 15, 26.7% reduction). Conclusions Many people with longer-term and complex refractory illness do respond to clozapine treatment with suitable augmentation strategies when necessary. Furthermore, it is possible to advance clozapine prescribing in these complex patients when they are supported by a skilled and dedicated multidisciplinary team. The optimal therapeutic approach relies on confirmation of diagnosis and compliance and optimization of clozapine dose using therapeutic drug monitoring, followed by augmentation of clozapine with amisulpride or mood stabilizers. There is some preliminary evidence suggesting that augmentation strategies may impact differentially depending on the symptom profile.

Importance Psychoticlike experiences (PLEs) are subclinical manifestations of psychotic symptoms and may reflect an increased vulnerability to psychotic disorders. Contemporary models of psychosis propose that dysfunctional reward processing is involved in the cause of these clinical illnesses. Objective To examine the neuroimaging profile of healthy adolescents at 14 and 19 years old points with PLEs, using a reward task. Design, Setting, and Participants A community-based cohort study, using both a cross-sectional and longitudinal design, was conducted in academic centers in London, Nottingham, United Kingdom, and Dublin, Ireland; Paris, France; and Berlin, Hamburg, Mannheim, and Dresden, Germany. A group of 1434 healthy adolescent volunteers was evaluated, and 2 subgroups were assessed at ages 14 and 19 years. Those who scored as either high or low PLE (based on the upper and lower deciles) on the Community Assessment of Psychic Experiences Questionnaire (CAPE-42) at age 19 years were included in the analysis. The study was conducted from January 1, 2016, to January 1, 2017. Main Outcomes and Measures Participants were assessed at age 14 and 19 year points using functional magnetic resonance imaging while performing a monetary incentive delay reward task. A first-level model focused on 2 predefined contrasts of anticipation and feedback of a win. The second-level analysis examined activation within the reward network using an a priori–defined region of interest approach. The main effects of group, time, and their interaction on brain activation were examined. Results Of the 1434 adolescents, 2 groups (n = 149 each) (high PLEs, n = 149, 50 [33.6%] male; low PLEs, n = 149, 84 [56.4%] male) were compared at ages 14 and 19 years. Two regions within the left and right middle frontal gyri showed a main effect of time on brain activation ( F 1, 93 = 5.559; P = .02; F 1, 93 = 5.009; P = .03, respectively); there was no main effect of group. One region within the right middle frontal gyrus demonstrated a significant time × group interaction ( F 1, 93 = 7.448; P = .01). Conclusion and Relevance The findings are consistent with evidence implicating alterations in prefrontal and striatal function during reward processing in the etiology of psychosis. Given the nature of this nonclinical sample this may reflect a combination of aberrant salience yielding abnormal experiences and a compensatory cognitive control mechanism necessary to contextualize them.

Clinical trials in psychiatry inherit methods for design and statistical analysis from evidence-based medicine. However, trials in other clinical disciplines benefit from a more specific relationship between instruments that measure disease state (e.g. biomarkers, clinical signs), the underlying pathology and diagnosis such that primary outcomes can be readily defined. Trials in psychiatry use diagnosis (i.e. a categorical label for a syndrome) as a proxy for the underlying disorder, and outcomes are defined, for example, as a percentage change in a univariatetotal scoreon some clinical instrument. We label this approach to defining outcomesweak aggregationof disease state. Univariate measures are necessary, because statistical methodology is both tractable and well-developed for scalar outcomes, but we show that weak aggregate approaches do not capture disease state sufficiently, potentially leading to loss of information about response to intervention. We demonstrate how multivariate disease state can be captured using geometric concepts of spaces defined over routine clinical instruments, and show how clinically meaningful disease states (e.g. representing different profiles of symptoms, recovery or remission) can be defined as prototypes (geometric locations) in these spaces. Then, we show how to derive univariate (scalar) measures, which capture patient's relationships to these prototypes and argue these representstrong aggregatesof disease state that may be a better basis for outcome measures. We demonstrate our proposal using a large publically available dataset. We conclude by discussing the impact of strong aggregates for analyses in traditional and novel trial designs.

The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition in the later stages of drug development. However, there is little agreement regarding the pattern of distribution of schizotypal features in the general population, creating uncertainty regarding the optimal control group that should be included in prospective trials. We aimed to address this question by comparing the performance of groups derived from the general population with low, average and high schizotypy scores over a range of cognitive and oculomotor tasks. We found that tasks dependent on frontal inhibitory mechanisms (N-Back working memory and anti-saccade oculomotor tasks), as well as a smooth-pursuit oculomotor task were sensitive to differences in the schizotypy phenotype. In these tasks the cognitive performance of ‘low schizotypes’ was significantly different from ‘high schizotypes’ with ‘average schizotypes’ having an intermediate performance. These results indicate that for evaluating putative cognition enhancers for treating schizophrenia in early-drug development studies the maximum schizotypy effect would be achieved using a design that compares low and high schizotypes.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterised by a persistent, pervasive pattern of inattention, impulsivity and hyperactivity. Stimulant medication such as methylphenidate has an established evidence base in the treatment of children and adolescents with ADHD. However, it is also associated with a risk of side effects which may include decreased appetite, increased blood pressure and possible reduced growth. Monitoring physical health in children and adolescents prescribed medication for ADHD is a key clinical responsibility and includes a number of parameters as outlined in the National Institute for Health and Care Excellence Guidelines. Ascertaining the centiles of physical observations is essential to put these into developmental context and accurately inform treatment decisions. This quality improvement project aimed to improve physical health monitoring in children and adolescents prescribed stimulant medication for ADHD within a large specialist urban inner-city Child and Adolescent Mental Health Service (CAMHS) in South London and Maudsley NHS Foundation Trust. Baseline data were obtained to establish the quality of physical monitoring including blood pressure, height, weight and centiles. Targeted interventions included the development of a novel web-based application designed to calculate and record centiles. We report an improvement in total proportion compliance with physical health monitoring from 24% to 75%. The frequency of recording baseline blood pressure centiles increased from 0% to 62%; recording baseline height centiles increased from 37% to 81% and recording baseline weight centiles increased from 37% to 81%. Improvement in the delivery of high-quality care was achieved and sustained through close collaboration with clinicians involved in the treatment pathway in order to elicit and respond effectively to feedback for improvement and codevelop interventions which were highly effective within the clinical system. We believe this model to be replicable in other CAMHS services and ADHD clinics to improve the delivery of high-quality clinical care.

The prevalence of treatment-resistant schizophrenia points to a discrete illness subtype, but to date its pathophysiologic characteristics are undetermined. Information transfer from ventral to dorsal striatum depends on both striato-cortico-striatal and striato-nigro-striatal subcircuits, yet although the functional integrity of the former appears to track improvement of positive symptoms of schizophrenia, the latter have received little experimental attention in relation to the illness. Here, in a sample of individuals with schizophrenia stratified by treatment resistance and matched controls, functional pathways involving four foci along the striatal axis were assessed to test the hypothesis that treatment-resistant and non-refractory patients would exhibit contrasting patterns of resting striatal connectivity. Compared with non-refractory patients, treatment-resistant individuals exhibited reduced connectivity between ventral striatum and substantia nigra. Furthermore, disturbance to corticostriatal connectivity was more pervasive in treatment-resistant individuals. The occurrence of a more distributed pattern of abnormality may contribute to the failure of medication to treat symptoms in these individuals. This work strongly supports the notion of pathophysiologic divergence between individuals with schizophrenia classified by treatment-resistance criteria.

One criticism was that the 12-month follow-up failed to capture a true clinical picture, and that more time was necessary to demonstrate their worth. The team that carried out this original work have now published 3-year data on 330 individuals detained under section of the Mental Health Act,1 randomised on discharge to CTO or voluntary status via Section 17 leave. No improvements in readmission rates, time to first readmission, or duration of readmissions were found for those placed on CTOs. The findings are even more powerful than the original results; CTOs now exist in various forms in over 75 jurisdictions, but no solid scientific evidence has yet been produced to support them. If there are subpopulations for whom (or specific circumstances in which) they work, such characteristics have yet to be delineated. A ‘least restrictive’ principle underpins the Mental Health Act, and a strong rebuttal is needed to justify ongoing CTO use – so-called ‘revolving-door patients' should not be replaced by revolving-door policy.

Tapping into your New Year resolutions, we present some cautionary data to consider.Recent research on novel addiction types suggests that, in addition to hunger, the urge to eat is considerably influenced by environmental cues. Obese individuals have been shown to be more sensitive to these, with subsequent stronger craving and larger portion sizes. Neurobiologically, this has been linked with pathological alterations to cue-triggered motivational responses in the nucleus accumbens (NAc) parallel to those seen in drug addiction. Oginsky et al investigated the effects of a junk-food diet on obesity-susceptible and obesity-resistant rats. Glutamatergic calcium-permeable AMPA receptor (CP-AMPAR) functioning in the NAc showed more rapid and long-lasting (for weeks after cessation of junk-food consumption) increases in the obesity-sensitive group. CP-AMPARs mediate cue-triggered food seeking, and their changes in the brain occurred before weight gain. The data support the concept that ‘junk food addiction’ induced by the consumption of fatty and high-sugar foods may be contributing to the obesity epidemic.

Nordsletten and colleagues1 report on the first study looking at assortative mating and psychiatric disorders in a representative population sample (of over 700 000). Compared with the general population, the odds of having a partner who also suffers from a mental health problem – both within and across disorders – were significantly elevated: cross-assortative mating was approximately 0.15 for bipolar disorder, 0.36 for substance misuse, and over 0.40 for attention-deficit hyperactivity disorder, autism spectrum disorder (ASD) and schizophrenia. Overall, having one of these disorders was associated with an approximately two- to threefold increase in the odds of having a mate with the same or an alternative mental health condition. Interestingly and importantly, such cross-assortative mating was not found for a range of physical health conditions, including diabetes, rheumatoid arthritis and multiple sclerosis.

Recent work suggests that the amphetamine sensitization model of schizophrenia can safely be induced in healthy volunteers and is associated both with behavioral and dopaminergic hypersensitivity to amphetamine. However, the effects of a sensitization on brain function remain unclear.To assess the impact of a sensitizing dosage regimen of dextroamphetamine on human cortical functioning and cognition.Randomized, double-blind, parallel-groups design using pharmacological functional magnetic resonance imaging.The neuroimaging research unit at the Institute of Psychiatry, King's College London, London, England.Healthy male volunteers (n = 22).Dextroamphetamine (20 mg) or placebo administration at 4 testing sessions, using a dosage regimen shown to induce sensitization (ie, 3 doses administered with a 48-hour interdose interval and a final dose after a 2-week washout period).Sensitization was characterized by enhanced subjective response to the drug, changes in behavioral performance (reaction time and accuracy), and functional magnetic resonance imaging measurements of brain activity during an N-back working memory task.Sensitization was associated with more rapid responding during the performance of an intermediate-load working memory challenge. During a high-load cognitive challenge, sensitization did not produce performance deficits, but functional magnetic resonance imaging showed hyperactivity of the dorsolateral prefrontal cortex and aberrant recruitment of the superior temporal gyrus, caudate nucleus, and thalamus. Furthermore, the change in striatal activity was negatively correlated with the enhanced subjective effects of the drug, whereas prefrontal hyperactivity was positively correlated with sensitized measures of alertness.These transient load-dependent abnormalities of frontal and temporal activity induced by amphetamine sensitization support neuroimaging findings in schizophrenic patients, implying that amphetamine sensitization may help to bridge pathophysiological theories of schizophrenia that focus on pharmacological (dopaminergic) and cognitive mechanisms, respectively.

Background: Stratified or personalised medicine targets treatments for groups of individuals with a disorder based on individual heterogeneity and shared factors that influence the likelihood of response. Psychiatry has traditionally defined diagnoses by constellations of co-occurring signs and symptoms that are assigned a categorical label (e.g. schizophrenia). Trial methodology in psychiatry has evaluated interventions targeted at these categorical entities, with diagnoses being equated to disorders. Recent insights into both the nosology and neurobiology of psychiatric disorder reveal that traditional categorical diagnoses cannot be equated with disorders. We argue that current quantitative methodology (1) inherits these categorical assumptions, (2) allows only for the discovery of average treatment response, (3) relies on composite outcome measures and (4) sacrifices valuable predictive information for stratified and personalised treatment in psychiatry. Methods and findings: To achieve a truly 'stratified psychiatry' we propose and then operationalise two necessary steps: first, a formal multi-dimensional representation of disorder definition and clinical state, and second, the similar redefinition of outcomes as multidimensional constructs that can expose within- and between-patient differences in response. We use the categorical diagnosis of schizophrenia-conceptualised as a label for heterogeneous disorders-as a means of introducing operational definitions of stratified psychiatry using principles from multivariate analysis. We demonstrate this framework by application to the Clinical Antipsychotic Trials of Intervention Effectiveness dataset, showing heterogeneity in both patient clinical states and their trajectories after treatment that are lost in the traditional categorical approach with composite outcomes. We then systematically review a decade of registered clinical trials for cognitive deficits in schizophrenia highlighting existing assumptions of categorical diagnoses and aggregate outcomes while identifying a small number of trials that could be reanalysed using our proposal. Conclusion: We describe quantitative methods for the development of a multi-dimensional model of clinical state, disorders and trajectories which practically realises stratified psychiatry. We highlight the potential for recovering existing trial data, the implications for stratified psychiatry in trial design and clinical treatment and finally, describe different kinds of probabilistic reasoning tools necessary to implement stratification.