• A case report of clozapine augmentation with granulocyte colony stimulating factor (G-CSF)

      Broughton, Trevor; Millward, Tim; Geelan, Steve (2012)
      For some patients clozapine represents the only option for controlling the debilitating symptoms of schizophrenia. More tragic are those cases where previously successful treatment with clozapine is withdrawn as a result of blood dyscrasia. In this article, the authors describe such a case. In this instance it was possible to continue treatment with clozapine to good effect by using granulocyte colony stimulating factor (G-CSF) as an adjunct. This article further explores the decision-making process and the clinical evidence behind this approach. © 2012 Copyright Taylor and Francis Group, LLC.
    • A meta-psychiatric approach to the 'core' problem in schizophrenia

      Cheetham, Anna; D'Silva, Karen (2006)
      Background: The lateralisation and disconnection hypotheses attempt to understand schizophrenia from a third person perspective. We hypothesised that these two phenomena may also affect the international schizophrenia research community.
    • A meta-psychiatric approach to the core problem

      Cheetham, Anna; D'Silva, Karen (2006)
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    • A retrospective case comparison study of the relationship between an Integrated Care Pathway for people diagnosed with schizophrenia in acute mental health care and service users' length of stay, readmission rates and follow up within 7 days of discharge

      Attfield, Julie (2017)
      BACKGROUND: Integrated Care Pathways (ICPs) are used to deliver mental health services, yet evidence relating to outcomes is mixed. AIM: To compare service users' length of stay, readmission rates and follow up within 7 days of discharge in a mental health Trust using an ICP to direct the care of people diagnosed with schizophrenia with a Trust using a non-ICP method of care planning in England. METHOD: A cohort study with a random sample of 400 service users with outcomes analysed retrospectively. RESULTS: The ICP Trust had a 13.5 day shorter average length of stay, this difference was statistically significant. No statistically significant differences were observed in rates of readmission or follow up within 7 days of discharge. DISCUSSION AND IMPLICATIONS: Mental health nurses are central to the delivery of the psychosocial aspects of ICPs in particular and judging by the link between psychosocial interventions and quality of mental health care, it is possible that nurse-led psychosocial interventions contributed to the reduced length of stay. RELEVANCE STATEMENT: Mental health nurses play an important role in the development and delivery of ICPs. Using psychosocial interventions, mental health nurses might contribute to positive outcomes. This article is protected by copyright. All rights reserved.
    • A survey of eMedia-delivered interventions for schizophrenia used in randomized controlled trials

      Shokraneh, Farhad; Adams, Clive E. (2017)
      Background: Randomized trials evaluating electronic Media (eMedia) delivery of interventions are increasingly frequent in mental health. Although a number of reviews have reported efficacy of these interventions, none has reviewed the type of eMedia interventions and quality of their description. We therefore decided to conduct a survey of eMedia-delivered interventions for schizophrenia. Methods: We surveyed all relevant trials reliably identified in the Cochrane Schizophrenia Group’s comprehensive register of trials by authors working independently. Data were extracted regarding the size of the trial, interventions, outcomes and how well the intervention was described. Results: eMedia delivery of interventions is increasingly frequent in trials relevant to the care of people with schizophrenia. The trials varied considerably in sample sizes (mean =123, median =87, range =20-507), and interventions were diverse, rarely evaluating the same approaches and were poorly reported. This makes replication impossible. Outcomes in these studies are limited, have not been noted to be chosen by end users and seem unlikely to be easy to apply in routine care. No study reported on potential adverse effects or cost, end users satisfaction or ease of use. None of the papers mentioned the use of CONSORT eHealth guidelines. Conclusion: There is a need to improve reporting and testing of psychosocial interventions delivered by eMedia. New trials should comply with CONSORT eHealth guidance on design, conduct and reporting, and existing CONSORT should be updated regularly, as the field is constantly evolving. © 2017 Naeem et al.
    • A systematic review of the soteria paradigm for the treatment of people diagnosed with schizophrenia

      Ferriter, Michael; Huband, Nick (2008)
      Background: The "Soteria paradigm" attempts to support people diagnosed with schizophrenia spectrum disorders using a minimal medication approach. Interest in this approach is growing in the United Kingdom, several European countries, North America, and Australasia. Aims: To summarize the findings from all controlled trials that have assessed the efficacy of the Soteria paradigm for the treatment of people diagnosed with schizophrenia spectrum disorders. Methods: A systematic search strategy was used to identify controlled studies (randomized, pseudorandomized, and nonrandomized) employing the Soteria paradigm to treat adults and adolescents meeting the criteria for schizophrenia spectrum disorders according to International Classification of Diseases and Diagnostic and Statistical Manual for Mental Disorders criteria. Results: We identified 3 controlled trials involving a total of 223 participants diagnosed with first- or second-episode schizophrenia spectrum disorders. There were few major significant differences between the experimental and control groups in any of the trials across a range of outcome measures at 2-year follow-up, though there were some benefits in specific areas. Conclusions: The studies included in this review suggest that the Soteria paradigm yields equal, and in certain specific areas, better results in the treatment of people diagnosed with first- or second-episode schizophrenia spectrum disorders (achieving this with considerably lower use of medication) when compared with conventional, medication-based approaches. Further research is urgently required to evaluate this approach more rigorously because it may offer an alternative treatment for people diagnosed with schizophrenia spectrum disorders. © The Author 2007. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
    • Abnormal salience signaling in schizophrenia: The role of integrative beta oscillations

      Liddle, Elizabeth B.; Palaniyappan, Lena; Liddle, Peter F. (2016)
      Aberrant salience attribution and cerebral dysconnectivity both have strong evidential support as core dysfunctions in schizophrenia. Aberrant salience arising from an excess of dopamine activity has been implicated in delusions and hallucinations, exaggerating the significance of everyday occurrences and thus leading to perceptual distortions and delusional causal inferences. Meanwhile, abnormalities in key nodes of a salience brain network have been implicated in other characteristic symptoms, including the disorganization and impoverishment of mental activity. A substantial body of literature reports disruption to brain network connectivity in schizophrenia. Electrical oscillations likely play a key role in the coordination of brain activity at spatially remote sites, and evidence implicates beta band oscillations in long-range integrative processes. We used magnetoencephalography and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigate beta oscillations in nodes of a network implicated in salience detection and previously shown to be structurally and functionally abnormal in schizophrenia. Healthy participants, as expected, produced an enhanced beta synchronization to behaviorally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronization in response to irrelevant than to relevant stimuli. These findings not only support both the aberrant salience and disconnectivity hypotheses, but indicate a common mechanism that allows us to integrate them into a single framework for understanding schizophrenia in terms of disrupted recruitment of contextually appropriate brain networks.Copyright © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
    • Abnormal visuomotor processing in schizophrenia

      Palaniyappan, Lena; Kumar, Jyothika; Skelton, Michael; Christodoulou, Nikos G.; Katshu, Mohammad Z.; Liddle, Elizabeth B.; Liddle, Peter F. (2016)
      Subtle disturbances of visual and motor function are known features of schizophrenia and can greatly impact quality of life; however, few studies investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event-related beta desynchronisation (ERBD)), then increase above baseline for a short time after the movement (post-movement beta rebound (PMBR)); whilst in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a self-paced visuomotor paradigm and magnetoencephalography (MEG) to contrast these responses in patients with schizophrenia and control volunteers. We found significant reductions in the peak-to-peak change in amplitude from ERBD to PMBR in schizophrenia compared with controls. This effect was strongest in patients who made fewer movements, whereas beta was not modulated by movement in controls. There was no significant difference in the amplitude of visual gamma between patients and controls. These data demonstrate that clear abnormalities in basic sensorimotor processing in schizophrenia can be observed using a very simple MEG paradigm.
    • Abnormalities in structural covariance of cortical gyrification in schizophrenia

      Palaniyappan, Lena; Park, Bert G.; Liddle, Peter F. (2015)
      The highly convoluted shape of the adult human brain results from several well-coordinated maturational events that start from embryonic development and extend through the adult life span. Disturbances in these maturational events can result in various neurological and psychiatric disorders, resulting in abnormal patterns of morphological relationship among cortical structures (structural covariance). Structural covariance can be studied using graph theory-based approaches that evaluate topological properties of brain networks. Covariance-based graph metrics allow cross-sectional study of coordinated maturational relationship among brain regions. Disrupted gyrification of focal brain regions is a consistent feature of schizophrenia. However, it is unclear if these localized disturbances result from a failure of coordinated development of brain regions in schizophrenia. We studied the structural covariance of gyrification in a sample of 41 patients with schizophrenia and 40 healthy controls by constructing gyrification-based networks using a 3-dimensional index. We found that several key regions including anterior insula and dorsolateral prefrontal cortex show increased segregation in schizophrenia, alongside reduced segregation in somato-sensory and occipital regions. Patients also showed a lack of prominence of the distributed covariance (hubness) of cingulate cortex. The abnormal segregated folding pattern in the right peri-sylvian regions (insula and fronto-temporal cortex) was associated with greater severity of illness. The study of structural covariance in cortical folding supports the presence of subtle deviation in the coordinated development of cortical convolutions in schizophrenia. The heterogeneity in the severity of schizophrenia could be explained in part by aberrant trajectories of neurodevelopment.
    • Acetylsalicylic acid (aspirin) for schizophrenia

      Roberts, Tracey; Shokraneh, Farhad (2016)
      This is the protocol for a review and there is no abstract. The objectives are as follows: To investigate the effects of acetylsalicylic acid (aspirin), either as adjunct or stand alone treatment, for schizophrenia. Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
    • Acupuncture for schizophrenia

      Adams, Clive E. (2014)
      Background Acupuncture, with many categories such as traditional acupuncture, electroacupuncture, laser acupuncture, and acupoint injection, has been shown to be relatively safe with few adverse effects. It is accessible and inexpensive, at least in China, and is likely to be widely used there for psychotic symptoms. Objectives To review the effects of acupuncture, alone or in combination treatments compared with placebo (or no treatment) or any other treatments for people with schizophrenia or related psychoses. Search Methods We searched the Cochrane Schizophrenia Group Trials Register (February 2012) and inspected references of all identified studies. We contacted relevant authors for additional information. Selection Criteria We included all relevant randomized controlled trials involving people with schizophrenia-like illnesses, comparing acupuncture added to standard dose antipsychotics with standard dose antipsychotics alone, acupuncture added to low dose antipsychotics with standard dose antipsychotics, acupuncture with antipsychotics, acupuncture added to traditional chinese medicine (TCM) drug with TCM drug, acupuncture with TCM drug, electric acupuncture convulsive therapy with electroconvulsive therapy.
    • Acupuncture for schizophrenia

      Xia, Jun; Adams, Clive E. (2014)
      Background: Acupuncture, with many categories such as traditional acupuncture, electroacupuncture, laser acupuncture, and acupoint injection, has been shown to be relatively safe with few adverse effects. It is accessible and inexpensive, at least in China, and is likely to be widely used there for psychotic symptoms. Objectives: To review the effects of acupuncture, alone or in combination treatments compared with placebo (or no treatment) or any other treatments for people with schizophrenia or related psychoses. Search methods: We searched Cochrane Schizophrenia Group’s Trials Register (February 2012), which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO and clinical trials registries. We also inspected references of identified studies and contacted relevant authors for additional information. Selection criteria: We included all relevant randomised controlled trials involving people with schizophrenia-like illnesses, comparing acupuncture added to standard dose antipsychotics with standard dose antipsychotics alone, acupuncture added to low dose antipsychotics with standard dose antipsychotics, acupuncture with antipsychotics, acupuncture added to Traditional Chinese Medicine (TCM) drug with TCM drug, acupuncture with TCM drug, electric acupuncture convulsive therapy with electroconvulsive therapy. Data collection and analysis: We reliably extracted data from all included studies, discussed any disagreement, documented decisions and contacted authors of studies when necessary. We analysed binary outcomes using a standard estimation of risk ratio (RR) and its 95% confidence interval (CI). For continuous data, we calculated mean differences with 95% CI. For homogeneous data we used fixed-effect model. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. Main results: After an update search in 2012 the review now includes 30 studies testing different forms of acupuncture across six different comparisons. All studies were at moderate risk of bias. When acupuncture plus standard antipsychotic treatment was compared with standard antipsychotic treatment alone, people were at less risk of being 'not improved' (n = 244, 3 RCTs, medium-term RR 0.40 CI 0.28 to 0.57, very low quality evidence). Mental state findings were mostly consistent with this finding as was time in hospital (n = 120, 1 RCT, days MD -16.00 CI -19.54 to -12.46, moderate quality evidence). If anything, adverse effects were less for the acupuncture group (e.g. central nervous system, insomnia, short-term, n = 202, 3 RCTs, RR 0.30 CI 0.11 to 0.83, low quality evidence). When acupuncture was added to low dose antipsychotics and this was compared with standard dose antipsychotic drugs, relapse was less in the experimental group (n = 170, 1 RCT, long-term RR 0.57 CI 0.37 to 0.89, very low quality evidence) but there was no difference for the outcome of 'not improved'. Again, mental state findings were mostly consistent with the latter. Incidences of extrapyramidal symptoms - akathisia, were less for those in the acupuncture added to low dose antipsychotics group (n = 180, 1 RCT, short-term RR 0.03 CI 0.00 to 0.49, low quality evidence) - as dry mouth, blurred vision and tachycardia. When acupuncture was compared with antipsychotic drugs of known efficacy in standard doses, there were equivocal data for outcomes such as 'not improved' using different global state criteria. Traditional acupuncture added to TCM drug had benefit over use of TCM drug alone (n = 360, 2 RCTs, RR no clinically important change 0.11 CI 0.02 to 0.59, low quality evidence), but when traditional acupuncture was compared with TCM drug directly there was no significant difference in the short-term. However, we found that participants given electroacupuncture were significantly less likely to experience a worsening in global state (n = 88, 1 RCT, short-term RR 0.52 CI 0.34 to 0.80, low quality evidence). In the one study that compared electric acupuncture convulsive therapy with electroconvulsive therapy there were significantly different rates of spinal fracture between the groups (n = 68, 1 RCT, short-term RR 0.33 CI 0.14 to 0.81, low quality evidence). Attrition in all studies was minimal. No studies reported death, engagement with services, satisfaction with treatment, quality of life, or economic outcomes. Authors' conclusions: Limited evidence suggests that acupuncture may have some antipsychotic effects as measured on global and mental state with few adverse effects. Better designed large studies are needed to fully and fairly test the effects of acupuncture for people with schizophrenia.
    • Acute interventions for aggression and agitation in psychosis: Study protocol for a systematic review network meta-analysis

      Shokraneh, Farhad (2019)
      INTRODUCTION: Individuals with psychosis may access emergency services due to aggression and agitation. When the de-escalation technique fails to achieve tranquillisation, several pharmacological options are available. However, evidence on which intervention to prefer in terms of efficacy and tolerability to achieve resolution of the acute episode (ie, rapid tranquillisation) of aggression and agitation is currently fragmentary. METHODS AND ANALYSIS: We will include all randomised controlled trials comparing drugs or drug combinations or placebo for aggression or agitation episodes in adult individuals with psychosis. We will include individuals with psychosis (eg, schizophrenia and related disorders, bipolar disorder with psychotic symptoms, psychotic depression) but not substance or medication-induced psychosis or psychosis due to another medical condition. Our primary outcomes are the change in aggression or agitation scores within few hours since the administration of the intervention (efficacy outcome) and the proportion of participants who dropped out due to adverse effects (tolerability outcome). We will retrieve relevant studies from the register of studies of the Cochrane Schizophrenia Group. Also, we will run additional searches on CENTRAL, Embase and PubMed to retrieve potentially eligible studies focusing on other psychiatric diagnoses than those in the schizophrenia spectrum. We will conduct a random-effects network meta-analysis (NMA) for primary and secondary outcomes. In case of rare events of dichotomous outcomes, a common-effect Mantel-Haenszel NMA will be used instead. We will use the surface under the cumulative ranking curve and the mean ranks to rank all available treatments. Local and global methods of evaluation of inconsistency will be employed. Quality of evidence contributing to network estimates of the main outcomes will also be assessed with Confidence in Network Meta-Analysis. ETHICS AND DISSEMINATION: This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019137945.
    • Acute psychotic presentation in syphilis-the great imitator is back

      Katshu, Mohammad Z. (2021)
      In the late 19th and the early 20th century, general paresis of the insane, as it was known historically, or neurosyphilis was a common cause of new-onset psychosis. Symptomatic neurosyphilis was reported in 10-20% patients with syphilis (Singh & Romanowski 1999). The widespread use of penicillin resulted in a marked reduction in syphilis (Kim 1965). Towards the end of the 20th century, syphilis was considered a rare disease and its relevance in clinical training and practice in general, and in neuropsychiatric settings in particular, diminished (Ropper 2019). Unfortunately, there has been a global resurgence of syphilis over the past decade. In England, between 2010 and 2019, the number of newly diagnosed syphilis patients increased from 2646 to 7982 (Mitchell et al. 2020). A similar increase from 45844 to 115045 was observed in the USA between 2010 and 2018 (Centers for Disease Control and Prevention 2019). Despite these increasing numbers, the clinical interest in syphilis, known for its protean manifestations earning the name of the 'great imitator', remains low.
    • Acute transient psychotic disorder precipitated by Brexit vote

      Katshu, Mohammad Z. (2019)
      A man in his 40s was brought to the accident and emergency department in an acute psychotic state, 3 weeks after the European Union referendum results in the UK were declared. His mental health had deteriorated rapidly following the announcement of the results, with significant concerns about Brexit. He presented as agitated, confused and thought disordered. He had auditory hallucinations, and paranoid, referential, misidentification and bizarre delusions. He recovered completely within 2 weeks after a brief admission and treatment with olanzapine. He had experienced a similar episode of much less severity 13 years previously after major work related stress which resolved completely within a few days. He was experiencing stress related to work and family prior to the current episode which could potentially have been a contributory factor. Political events can act as major psychological stressors and have a significant impact on the mental health of people, especially those with a predisposition to develop mental illness.
    • Additional interventions to enhance the effectiveness of individual placement and support: A rapid evidence assessment

      Boycott, Naomi; Schneider, Justine; McMurran, Mary (2012)
      Topic. Additional interventions used to enhance the effectiveness of individual placement and support (IPS). Aim. To establish whether additional interventions improve the vocational outcomes of IPS alone for people with severe mental illness. Method. A rapid evidence assessment of the literature was conducted for studies where behavioural or psychological interventions have been used to supplement standard IPS. Published and unpublished empirical studies of IPS with additional interventions were considered for inclusion. Conclusions. Six published studies were found which compared IPS alone to IPS plus a supplementary intervention. Of these, three used skills training and three used cognitive remediation. The contribution of each discrete intervention is difficult to establish. Some evidence suggests that work-related social skills and cognitive training are effective adjuncts, but this is an area where large RCTs are required to yield conclusive evidence.
    • Aggressive incidents in first-episode psychosis

      Milton, John (2001)
      Background: Recent research has reported increased risk of aggressive incidents by individuals with psychotic illness. Aims: To examine acts of aggression in first-episode psychosis. Method: Subjects with a first-episode psychosis were ascertained from a defined catchment area (Nottingham, UK) and reassessed at 3 years (n=166) using clinical interview, informants, health care and forensic records. Results: Of the subjects, 9.6% demonstrated at least one act of serious aggression (defined as weapon use, sexual assault or victim injury) during at least one psychotic episode and 23.5% demonstrated lesser acts of aggression (defined as all other acts of aggression). For all aggressive subjects (33.1%), unemployment (OR=3.6, 95% CI 1.6-8.0), comorbid substance misuse (OR=3.1, CI 1.1-8.8) and symptoms of overactivity at service contact (OR=6.9, CI 2.7-17.8) had independent effects on risk of aggression. Conclusions: We confirmed some previously reported demographic and clinical associations with aggression in first-episode psychosis but no relationship with specific psychotic symptoms or diagnostic groups was observed. Declaration of interest: Support was received from the National Health Service Executive (Trent Research & Development).
    • Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness

      Bagalkote, Hemant (2017)
      BACKGROUNDWhen treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice.OBJECTIVESThe main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia.DESIGNThe study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks.SETTINGSThe study was set in NHS multidisciplinary teams in adult psychiatry.PARTICIPANTSEligible participants were people aged 18-65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy.INTERVENTIONSInterventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks.MAIN OUTCOME MEASURESThe primary outcome measure was the proportion of 'responders', using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale.RESULTSA total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term.LIMITATIONSThe trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants.CONCLUSIONSThe risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride-clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride-clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings.TRIAL REGISTRATIONEudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876.FUNDINGThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 49. See the NIHR Journals Library website for further project information.
    • Amisulpride augmentation of clozapine for treatment-refractory schizophrenia: a double-blind, placebo-controlled trial

      Bagalkote, Hemant (2018)
      Background: A second antipsychotic is commonly added to clozapine to treat refractory schizophrenia, notwithstanding the limited evidence to support such practice. Methods: The efficacy and adverse effects of this pharmacological strategy were examined in a double-blind, placebo-controlled, 12-week randomized trial of clozapine augmentation with amisulpride, involving 68 adults with treatment-resistant schizophrenia and persistent symptoms despite a predefined trial of clozapine. Results: There were no statistically significant differences between the amisulpride and placebo groups on the primary outcome measure (clinical response defined as a 20% reduction in total Positive and Negative Syndrome Scale score) or other mental state measures. However, the trial under recruited and was therefore underpowered to detect differences in the primary outcome, meaning that acceptance of the null hypothesis carries an increased risk of type II error. The findings suggested that amisulpride-treated participants were more likely to fulfil the clinical response criterion, odds ratio 1.17 (95% confidence interval 0.40-3.42) and have a greater reduction in negative symptoms, but these numerical differences were not statistically significant and only evident at 12 weeks. A significantly higher proportion of participants in the amisulpride group had at least one adverse event compared with the control group (p = 0.014), and these were more likely to be cardiac symptoms. Conclusions: Treatment for more than 6 weeks may be required for an adequate trial of clozapine augmentation with amisulpride. The greater side-effect burden associated with this treatment strategy highlights the need for safety and tolerability monitoring, including vigilance for indicators of cardiac abnormalities, when it is used in either a clinical or research setting.