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Background and AimsIn the United Kingdom, patients on clozapine whose hematological parameters fall below certain thresholds are placed on the Central Non-Rechallenge Database (CNRD), meaning that they cannot be prescribed clozapine again except under exceptional circumstances. This practice was discontinued in the United States in 2015 by expanding the hematological monitoring guidelines, allowing more patients to receive clozapine. Our objective was to investigate the implications this policy change would have on clozapine utilization in the United Kingdom.MethodsThis was an observational, retrospective analysis of patients registered on the CNRD in a large mental health trust. The first objective was to compare the number of patients placed on the CNRD under the United Kingdom and the US Food and Drug Administration (FDA) criteria. The second objective was to explore the hematological and clinical outcomes of CNRD patients. The third objective was to investigate the hematological outcomes of patients rechallenged on clozapine after nonrechallengeable status.ResultsOne hundred and fifteen patients were placed on CNRD from 2002 to 2019, of whom 7 (6%) met the equivalent criteria for clozapine discontinuation under the FDA guidelines. Clinical outcomes, as measured by the Clinical Global Impression-Severity scale, were worse 3 months after clozapine cessation than on clozapine (t = −7.4862; P < .001). Sixty-two (54%) patients placed on CNRD were rechallenged. Fifty-nine of those (95%) were successfully rechallenged; 3 patients were placed back on CNRD, only one of which would have had to stop clozapine again under FDA criteria.ConclusionImplementation of the updated FDA’s monitoring criteria in the United Kingdom would significantly reduce clozapine discontinuation due to hematological reasons. The evidence suggests an urgent need for revising the UK clozapine monitoring guidelines to improve outcomes in treatment-resistant schizophrenia.

Clozapine is the only antipsychotic that is effective in treatment-resistant schizophrenia. However, in certain clinical situations, such as the emergence of serious adverse effects, it is necessary to discontinue clozapine. Stopping clozapine treatment poses a particular challenge due to the risk of psychotic relapse, as well as the development of withdrawal symptoms. Despite these challenges for the clinician, there is currently no formal guidance on how to safely to discontinue clozapine. We assessed the feasibility of developing evidence-based recommendations for (1) minimizing the risk of withdrawal symptoms, (2) managing withdrawal phenomena, and (3) commencing alternatives treatment when clozapine is discontinued. We then evaluated the recommendations against the Appraisal of Guidelines for Research and Evaluation (AGREE) II criteria. We produced 19 recommendations. The majority of these recommendation were evidence-based, although the strength of some recommendations was limited by a reliance of studies of medium to low quality. We discuss next steps in the refinement and validation of an evidence-based guideline for stopping clozapine and identify key outstanding questions.

Treatment-resistant schizophrenia (TRS) affects around one-third of individuals with schizophrenia. Although a number of sociodemographic and clinical predictors of TRS have been identified, data on the genetic risk of TRS are sparse. We aimed to investigate the association between a polygenic risk score for schizophrenia and treatment resistance in patients with schizophrenia. We conducted a nationwide, population-based follow-up study among all Danish individuals born after 1981 and with an incident diagnosis of schizophrenia between 1999 and 2007. Based on genome-wide data polygenic risk scores for schizophrenia were calculated in 862 individuals with schizophrenia. TRS was defined as either clozapine initiation or at least 2 periods of different antipsychotic monotherapies and still being hospitalized. We estimated hazard rate ratios (HRs) for TRS in relation to the polygenic risk score while adjusting for population stratification, age, sex, geographical area at birth, clinical treatment setting, psychiatric comorbidity, and calendar year. Among the 862 individuals with schizophrenia, 181 (21.0%) met criteria for TRS during 4674 person-years of follow-up. We found no significant association between the polygenic risk score and TRS, adjusted HR = 1.13 (95% CI: 0.95–1.35). Based on these results, the use of the polygenic risk score for schizophrenia to identify individuals with TRS is at present inadequate to be of clinical utility at the individual patient level. Future research should include larger genetic samples in combination with non-genetic markers. Moreover, a TRS-specific developed polygenic risk score would be of great interest towards early prediction of TRS.

Background Schizophrenia (Sz) and other psychoses are complex mental disorders, characterised by sensory, cognitive and emotional symptoms, but mainly distinguished by positive and negative symptoms. Cognitive impairment is a core feature of schizophrenia, with research into cognitive deficits indicating that cognitive impairment precedes clinical disease onset and is still evident after positive symptoms are no longer present. The current mainstream treatment for Sz are first and second-generation antipsychotics, such as chlorpromazine and aripiprazole respectively. However, about a third of patients treated with antipsychotic drugs have no change in their symptoms despite adequate trials of several antipsychotic drugs. Treatment-resistant schizophrenia (TRS) refers to individuals with a F20-F29 diagnosis who have had at least two courses of antipsychotic treatment with little to no symptomatic relief. Emerging evidence into the factors associated with antipsychotic treatment response has investigated genetic, demographic and clinical factors and their relation to treatment response, with emerging evidence from cognitive data inferring a domain specific deficit in TRS populations for verbal, general cognition (IQ) and executive function tasks. Methods Publications were selected from a systematic search from four databases: PsycINFO, Ovid MEDLINE(R), Scopus and Web of Science. Following inclusion/exclusion criteria, cognitive test outcomes were extracted for each responder group (TRS/NTRS; treatment responders), as well as variables such as age of psychotic illness onset, average chlorpromazine equivalents and duration of illness. Neuropsychological tasks and subtests identified across publications were then grouped into one of seven exclusive cognitive domains (e.g. executive function) prior to analysis based on recommendations from existing literature. Following this, a random-effects model was adopted to test the differences between responder groups in each cognitive domain across publications. Results From the 17 publications identified, sample sizes ranged from 817 to 36, with the majority of publications using a sample size of ~65 TRS/NTRS cases, and a total sample size of N = 1,943 across studies. The random-effects model indicates that cases reaching treatment resistance criteria demonstrated marked neuropsychological performance generally across all domains (d = 0.372, 95CIs 0.29; 0.46], p< .001), with this being most marked in tasks of verbal memory and learning (d = 0.49, 95CIs [0.28; 0.70], p Discussion In line with existing literature, treatment resistant schizophrenia appears to demonstrate domain specific marked performance on tasks relating to verbal memory, verbal intelligence, as well as tasks relating to executive function, attention and working memory in relation to responders. When considering the clinical importance of identification of treatment resistance in the early disease stages (i.e. at first episode) the use of domain specific cognitive testing could help improve prediction of future antipsychotic response/non-response.

Background Approximately one third of patients with schizophrenia display suboptimal response to two trials of non-clozapine antipsychotic medication and may be termed treatment resistant. Clozapine is the only licensed pharmacotherapy for treatment resistant schizophrenia, but response to clozapine is variable and can only be determined through a trial of treatment. Understanding demographic and clinical sources of varied response to clozapine may be useful in the optimisation of clinical treatment algorithms and stratification of patient groups for clinical trials of early use of clozapine. Methods We systematically reviewed literature to investigate clinical and demographic factors associated with variation in clozapine response. Articles were eligible for review if they reported differences in clozapine response as a function of baseline variables within patient samples of schizophrenia spectrum disorders. In a second step, a random-effects meta-analysis to study group mean differences in age, age of onset and duration of illness between clozapine responders and non-responders was performed. Results Thirty-one articles were eligible for qualitative review. The systematic review found that a poorer response to clozapine was associated with older age at clozapine initiation, younger age at illness onset and longer delay in clozapine initiation. A higher number of previous hospitalisations and antipsychotic trials prior to treatment with clozapine were also associated with poorer outcomes. Both systematic review and meta-analysis identified that longer durations of illness before clozapine initiation were associated with worse clinical outcomes. In a total sample of 313 participants (n = 158 responders), clozapine responders had a significantly shorter duration of illness than non-responders (g = - 0.31; 95% CI, 0.06 - 0.56; p = 0.02). Analysis was then limited to studies with a minimum follow-up period of 12 weeks to align with the recommended amount of time to monitor clozapine response. The difference in duration of illness between responder versus non-responder groups remained significant and overall effect size increased (g = - 0.42; 95% CI, 0.17 – 0.67; p < 0.001). Between study heterogeneity was low (Q = 3.59, I2 = 0%, P = 0.61). Discussion The results imply that delay in clozapine treatment is associated with worse response and support the view that initiation of clozapine earlier in illness may be beneficial. Although we cannot make causal assertions from the data presented, poor response to clozapine when prescribed after a longer delay is likely due to a combination of factors; including the effects of sustained active symptoms on neurobiological integrity, social functioning and self-care. Given evidence that early non-response to conventional antipsychotics predicts a later diagnosis of treatment resistance and poorer outcomes, identifying treatment resistance and prescribing clozapine earlier in the illness course would prevent unnecessary loss of time in the treatment of refractory psychosis. Current research into clinical variables associated with clozapine response is limited to few studies but future investigation into the predictive value of these variables is warranted. This is important given the relative ease and low-cost clinical information can be obtained from acutely unwell patient groups who may poorly tolerate more invasive research and clinical procedures.

Background The mechanisms that underlie and may mediate the therapeutic response to clozapine in treatment resistant schizophrenia (TRS) are unclear. Basic science studies have indicated that clozapine may modulate brain glutamate, but this has not yet been investigated in man. The aim of this study was to determine whether clozapine alters brain glutamate levels in patients with TRS, and the associations with clinical outcome. Methods The study included patients with TRS who were about to start clozapine as part of their normal clinical care. Glutamate levels were measured in the anterior cingulate cortex (ACC) and right caudate nucleus using proton magnetic resonance spectroscopy (1H-MRS) before clozapine initiation (n=37) and again after 12-weeks of clozapine treatment (n=27). Symptoms were principally assessed using the PANSS. 1H-MRS scans were also acquired in a comparator group of healthy volunteers (n = 16). Results Over the 12 weeks of clozapine treatment there was a significant reduction in glutamate in the caudate (n = 22, F = 7.61 P < 0.05) but not in the ACC. The percentage reduction in caudate glutamate was positively associated with the percentage reduction in total PANSS score (n = 23, r = 0.42, P = 0.04). ACC Glx (glutamate plus glutamine) prior to clozapine initiation was higher in patients with TRS than in healthy volunteers (P=0.03). Discussion Improvements in symptoms following clozapine initiation in TRS may be related to reductions in glutamate in the caudate nucleus. In contrast, ACC glutamate levels appear to remain high during the first three months of clozapine treatment.

The debate endures as to whether schizophrenia and bipolar disorder are separate entities or different manifestations of a single underlying pathological process. Here, we argue that this sterile argument obscures the fact that the truth lies somewhere in between. Thus, recent studies support a model whereby, on a background of some shared genetic liability for both disorders, patients with schizophrenia have been subject to additional genetic and/or environmental factors that impair neurodevelopment; for example, copy number variants and obstetric complications are associated with schizophrenia but not with bipolar disorder. As a result, children destined to develop schizophrenia show an excess of neuromotor delays and cognitive difficulties while those who later develop bipolar disorder perform at least as well as the general population. In keeping with this model, cognitive impairments and brain structural abnormalities are present at first onset of schizophrenia but not in the early stages of bipolar disorder. However, with repeated episodes of illness, cognitive and brain structural abnormalities accumulate in both schizophrenia and bipolar disorder, thus clouding the picture.

Background Schizophrenia may be associated with elevations in glutamate levels in the anterior cingulate cortex (ACC), and this may be particularly apparent in patients who have not responded well to conventional antipsychotic treatment (Egerton et al., 2012; Mouchliantis et al., 2016). This suggests that compounds that can decrease ACC glutamate levels may have therapeutic potential for this group. N-acetylcysteine (NAC) is one such compound, currently under investigation as an adjunctive therapy for schizophrenia. The effects of NAC on brain glutamate levels and physiology in schizophrenia have not been previously evaluated. The primary aim of this study was to examine whether a single oral dose of NAC can alter brain glutamate levels in schizophrenia. The secondary aim was to characterise the effects of NAC on regional brain perfusion. Methods In a double-blind placebo-controlled crossover study, twenty patients with a diagnosis of schizophrenia underwent two 3 Tesla MRI scans, performed one week apart, and following administration of a single oral dose of 2400mg NAC or matching placebo. Proton magnetic resonance spectroscopy (1H-MRS) was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling (pCASL) was used to measure the effects of NAC on resting cerebral blood flow (CBF) in the same regions. 1H-MRS spectra were analysed using LCModel version 6.3-0I using a standard basis set. Individual CBF maps were pre-processed in the Automatic Software for ASL Processing (ASAP) toolbox running in SPM-8 in Matlab 6.5. The effects of NAC on 1H-MRS metabolite levels were determined using paired samples t-tests. Changes in rCBF were determined using within-subjects, second-level analysis implemented in SPM-8. Results In the ACC, Glx/Cr was significantly reduced in the NAC compared to placebo condition (t(17) = 2.40; P = .03, d = 0.64). There was no significant effect of condition on Glu/Cr in the ACC, or on Glx/Cr or Glu/Cr in the right caudate nucleus, or on any of the other metabolites quantifiable from the 1H-MRS spectra. There were no significant differences in CBF in the ACC (mean (SD) placebo = 47.22 (8.81); NAC = 46.83 (7.29); t(18) = .349, P = .73) or in the right caudate nucleus (mean (SD) placebo = 37.51 (7.48); NAC = 37.77 (6.71); t(18) -.310, P = .76) in the NAC compared to placebo condition. There was also no significant difference in global CBF between conditions (mean (SD) placebo = 39.64 (10.02); NAC = 40.03 (9.13); t(18) = -.398, P = .70). Discussion These results provide preliminary evidence that NAC may reduce ACC glutamate metabolites in schizophrenia. Future studies will need to determine the extent to which reductions in glutamate metabolites following a single dose of a glutamatergic compound are indicative of longer-term efficacy in improving symptoms.

Background Little is known about patients with a first episode of psychosis (FEP) who had first presented to prodromal services with an “at risk mental state” (ARMS) before making the transition to psychosis. We set out to identify the proportion of patients with a FEP who had first presented to prodromal services in the ARMS state, and to compare these FEP patients with FEP patients who did not have prior contact with prodromal services. Methods In this study information on 338 patients aged ≤37 years who presented to mental health services between 2010 and 2012 with a FEP was examined. The data on pathways to care, clinical and socio-demographic characteristics were extracted from the Biomedical Research Council Case Register for the South London and Maudsley NHS Trust. Results Over 2 years, 14 (4.1% of n = 338) young adults presented with FEP and had been seen previously by the prodromal services. These ARMS patients were more likely to enter their pathway to psychiatric care via referral from General Practice, be born in the UK and to have had an insidious mode of illness onset than FEP patients without prior contact with the prodromal services. Conclusions In the current pathways to care configuration, prodromal services are likely to prevent only a few at-risk individuals from transitioning to psychosis even if effective preventative treatments become available.

Background The extent to which poor academic achievement is associated with later schizophrenia is unclear. The aim of the present study was to update our prior meta-analyses which examined academic achievement in youth aged 16 years or younger who later developed schizophrenia or schizophrenia spectrum disorders (SSD) and those who did not (Dickson et al, 2012, Psychological Medicine, 42, 743–755). We also conducted a new meta-analysis on published studies that reported on general academic achievement in youth at-risk for schizophrenia/SSD aged 16 years or younger compared to typically developing youth Methods In addition to the five studies included in our earlier meta-analyses, a further three prospective investigations of birth or genetic high-risk cohorts were identified that reported results using objective measures of general academic achievement and of mathematics achievement for individuals who did and did not develop schizophrenia/SSD in adulthood. For our new meta-analysis we identified a total of seven studies that met the following inclusion criteria: (1) written in English; (2) objective measure of general academic achievement consisting of scores on least two core academic subjects (i.e., literacy and mathematics) at age 16 years or younger; (3) results provided for youth at high risk for developing schizophrenia/SSD in adulthood by virtue of having at least one first-degree relative with the disorder or reporting psychotic like-experiences (PLEs); and (4) sufficient data to calculate effect sizes. Results Meta-analyses showed that by age 16 years, individuals who later developed schizophrenia/SSD presented with significantly poorer general academic achievement (d=-0.26) and mathematics achievement (d=-0.21). Findings also indicated that during adolescence, youth with a family history of schizophrenia/SSD and youth reporting PLES were characterised by significantly lower general academic achievement than healthy peers (d=-0.39; d=-0.53, respectively). Discussion These results show that poor academic achievement precedes illness onset, and may represent an easily identifiable non-specific marker of biological, psychological and social risk processes underpinning the development of schizophrenia/SSD.

Overall Abstract: The superiority of clozapine for treatment refractory schizophrenia was, until very recently, seen as one of the few unshakeable truths in psychiatry. But the pre-eminence of clozapine has recently been called into question by meta-analyses. What are we to make of the fact that meta-analyses of clinical trials, supposedly the pinnacle of evidence based medicine, fail to show an effect which seems clearly evident to most clinicians, and on which many of our guidelines are based? Have we believed in a fairytale for the past three decades? Or do biases in RCTs and methodological limitations of meta-analyses explain the results? These questions will be discussed by Dan Siskind. Another way to address the question of efficacy is to examine the pharmaco-epidemiological evidence using population-based registers. Jari Tiihonen will present data from his seminal studies of mortality and readmission rates under clozapine treatment versus other antipsychotics, as well as other data. These data seem to show powerful positive effects of clozapine at the population level. Furthermore, more recent evidence suggests a role for clozapine in reducing rates of violent offending, with new data presented for the first time by Vishal Bhavsar. Finally, despite clinical guidelines recommending the use of clozapine, the actual rates of clozapine use are much lower than expected, with large regional and international variations. There is evidence that the burden of blood monitoring deters physicians from prescribing clozapine. Yvonne van der Zalm will present new data from a cluster randomised trial testing the efficacy and safety of an intervention to increase rates of clozapine prescribing by employing nurse practitioners trained in the initiation and monitoring of clozapine. John Kane, author of the first, seminal RCT of clozapine in 1988, will lead the discussion.

Background Approximately one-third of schizophrenia patients will not respond adequately to conventional antipsychotic treatment; termed treatment-resistant schizophrenia (TRS). The only antipsychotic recommended for this group is clozapine, which may have unique efficacy in improving residual symptoms. The biological mechanisms underlying its efficacy are poorly understood. Previous studies have examined the effects of clozapine on regional cerebral blood flow (rCBF) using radiotracer approaches in relatively small samples of patients, showing, in particular, frontal and limbic perfusion changes1,2,3. In this study, we evaluate the effects of clozapine on rCBF, measured with a non-invasive MRI technique - pulsed continuous arterial spin labelling (pCASL) - which does not require radiotracer injection, as part of an ongoing study to identify neuroimaging predictors and mediators of clozapine response. Methods Participants ≥18 years of age with TRS were recruited at the Institute of Psychiatry, Psychology & Neuroscience, Kings College London (UK). TRS status was ascertained by the documented failure to respond to at least two different antipsychotic trials of adequate length. Participants were either clozapine-naïve or had not taken clozapine for at least three months prior to the baseline MRI scan. After baseline MRI, clozapine was administered as part of routine clinical care for 12 weeks, after which a second MRI scan was performed. Symptomatic response was defined as a reduction of 20% of the Positive and Negative Syndrome Scale (PANSS)4 score and non-response was defined as 2.74. Results This is an interim analysis of 24 patients who completed both scans. Contrasts were examined at a whole brain, assumption-free voxel-wise analysis, restricted to grey matter and co-varied for global perfusion. Clozapine administration significantly decreased perfusion in the medial frontal gyrus. There was also a significant response x time interaction, centred in the left posterior cerebellum and extending to the bilateral visual cortex and right precuneus. Discussion These interim results indicate that pCASL may be able to identify brain regions in which activity is modulated by clozapine administration as well as areas that may mediate symptomatic improvement. A key question for future analyses will be the degree to which rCBF may predict symptomatic response to clozapine, as the ability to predict a good likelihood of response could enable earlier clozapine initiation. References 1. Lahti AC et al. Biol Psychiatry 2003; 53: 601–8. 2. Potkin SG et al. Mol Psychiatry 2003; 8: 109–13. 3. Molina V et al. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 948–54. 4. Kay SR et al. Psychiatry Res 1988; 23: 99–110. 5. Mato Abad VM et al. Magn Reson Imaging 2016; 34: 334–44.

UNLABELLED: Cannabis use is associated with an earlier age of onset of psychosis (AOP). However, the reasons for this remain debated. METHODS: We applied a Cox proportional hazards model to 410 first-episode psychosis patients to investigate the association between gender, patterns of cannabis use, and AOP. RESULTS: Patients with a history of cannabis use presented with their first episode of psychosis at a younger age (mean years = 28.2, SD = 8.0; median years = 27.1) than those who never used cannabis (mean years = 31.4, SD = 9.9; median years = 30.0; hazard ratio [HR] = 1.42; 95% CI: 1.16-1.74; P < .001). This association remained significant after controlling for gender (HR = 1.39; 95% CI: 1.11-1.68; P < .001). Those who had started cannabis at age 15 or younger had an earlier onset of psychosis (mean years = 27.0, SD = 6.2; median years = 26.9) than those who had started after 15 years (mean years = 29.1, SD = 8.5; median years = 27.8; HR = 1.40; 95% CI: 1.06-1.84; P = .050). Importantly, subjects who had been using high-potency cannabis (skunk-type) every day had the earliest onset (mean years = 25.2, SD = 6.3; median years = 24.6) compared to never users among all the groups tested (HR = 1.99; 95% CI: 1.50- 2.65; P < .0001); these daily users of high-potency cannabis had an onset an average of 6 years earlier than that of non-cannabis users. CONCLUSIONS: Daily use, especially of high-potency cannabis, drives the earlier onset of psychosis in cannabis users.

Background: Longitudinal studies are essential for understanding the trajectory and prognosis of patients diagnosed with schizophrenia, in particular those who are treatment resistant as this outcome is difficult to predict. However, follow-up is challenging within this patient population due to high relapse rates, difficulties recontacting participants due to regular change of address, and patients’ symptoms leading to their refusal to take part.