Development and Validation of a Nonremission Risk Prediction Model in First-Episode Psychosis: An Analysis of 2 Longitudinal Studies.

Psychosis is a major mental illness with first onset in young adults. The prognosis is poor in around half of the people affected, and difficult to predict. The few tools available to predict prognosis have major weaknesses which limit their use in clinical practice. We aimed to develop and validate a risk prediction model of symptom nonremission in first-episode psychosis. Our development cohort consisted of 1027 patients with first-episode psychosis recruited between 2005 and 2010 from 14 early intervention services across the National Health Service in England. Our validation cohort consisted of 399 patients with first-episode psychosis recruited between 2006 and 2009 from a further 11 English early intervention services. The one-year nonremission rate was 52% and 54% in the development and validation cohorts, respectively. Multivariable logistic regression was used to develop a risk prediction model for nonremission, which was externally validated. The prediction model showed good discrimination C-statistic of 0.73 (0.71, 0.75) and adequate calibration with intercept alpha of 0.12 (0.02, 0.22) and slope beta of 0.98 (0.85, 1.11). Our model improved the net-benefit by 15% at a risk threshold of 50% compared to the strategy of treating all, equivalent to 15 more detected nonremitted first-episode psychosis individuals per 100 without incorrectly classifying remitted cases. Once prospectively validated, our first episode psychosis prediction model could help identify patients at increased risk of nonremission at initial clinical contact.

Effect of delaying treatment of first-episode psychosis on symptoms and social outcomes: a longitudinal analysis and modelling study.

BACKGROUND: Delayed treatment for first episodes of psychosis predicts worse outcomes. We hypothesised that delaying treatment makes all symptoms more refractory, with harm worsening first quickly, then more slowly. We also hypothesised that although delay impairs treatment response, worse symptoms hasten treatment, which at presentation mitigates the detrimental effect of treatment delay on symptoms. METHODS: In this longitudinal analysis and modelling study, we included two longitudinal cohorts of patients with first-episode psychosis presenting to English early intervention services from defined catchments: NEDEN (recruiting 1003 patients aged 14-35 years from 14 services between Aug 1, 2005, and April 1, 2009) and Outlook (recruiting 399 patients aged 16-35 years from 11 services between April 1, 2006, and Feb 28, 2009). Patients were assessed at baseline, 6 months, and 12 months with the Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale for Schizophrenia, Mania Rating Scale, Insight Scale, and Social and Occupational Functioning Assessment Scale. Regression was used to compare different models of the relationship between duration of untreated psychosis (DUP) and total symptoms at 6 months. Growth curve models of symptom subscales tested predictions arising from our hypotheses. FINDINGS: We included 948 patients from the NEDEN study and 332 patients from the Outlook study who completed baseline assessments and were prescribed dopamine antagonist antipsychotics. For both cohorts, the best-fitting models were logarithmic, describing a curvilinear relationship of DUP to symptom severity: longer DUP predicted reduced treatment response, but response worsened more slowly as DUP lengthened. Increasing DUP by ten times predicted reduced improvement in total symptoms (ie, PANSS total) by 7·339 (95% CI 5·762 to 8·916; p<0·0001) in NEDEN data and 3·846 (1·689 to 6·003; p=0·0005) in Outlook data. This was true of treatment response for all symptom types. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN (coefficients 0·099 [95% CI 0·033 to 0·164]; p=0·0028 in NEDEN and 0·007 [-0·081 to 0·095]; p=0·88 in Outlook). INTERPRETATION: Long DUP was associated with reduced treatment response across subscales, consistent with a harmful process upstream of individual symptoms' mechanisms; response appeared to worsen quickly at first, then more slowly. These associations underscore the importance of rapid access to a comprehensive range of treatments, especially in the first weeks after psychosis onset. FUNDING: UK Department of Health, National Institute of Health Research, and Medical Research Council.

Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study.

BACKGROUND: No established treatment algorithm exists for patients with schizophrenia. Whether switching antipsychotics or early use of clozapine improves outcome in (first-episode) schizophrenia is unknown. METHODS: This three-phase study was done in 27 centres, consisting of general hospitals and psychiatric specialty clinics, in 14 European countries and Israel. Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1). Patients who did not meet symptomatic remission criteria at 4 weeks were randomly assigned to continue amisulpride or switch to olanzapine (≤20 mg/day) during a 6-week double-blind phase, with patients and staff masked to treatment allocation (phase 2). Randomisation was done online by a randomisation website; the application implemented stratification by site and sex, and applied the minimisation method for randomisation. Patients who were not in remission at 10 weeks were given clozapine (≤900 mg/day) for an additional 12 weeks in an open-label design (phase 3). The primary outcome was the number of patients who achieved symptomatic remission at the final visits of phases 1, 2, and 3, measured by intention-to-treat analysis. Data were analysed with a generalised linear mixed model, with a logistic link and binomial error distribution. This trial is registered with ClinicalTrials.gov, number NCT01248195, and closed to accrual. FINDINGS: Between May 26, 2011, and May 15, 2016, we recruited 481 participants who signed informed consent. Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1. 93 patients who were not in remission continued to the 6-week double-blind switching trial, with 72 (77%) patients completing the trial (39 on olanzapine and 33 on amisulpride); 15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87). Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission. The number of serious adverse events did not differ between the treatment arms in phase 2: one patient on olanzapine was admitted to hospital because of an epileptic seizure, and one patient on amisulpride was admitted to hospital twice because of exacerbations of psychotic symptoms. Over the course of the trial, two serious suicide attempts were reported. INTERPRETATION: For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation. FUNDING: European Commission Seventh Framework Program.

Correction: Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome.

[This corrects the article DOI: 10.1371/journal.pone.0144623.].

Correction: Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome.

[This corrects the article DOI: 10.1371/journal.pone.0144623.].

How age and gender predict illness course in a first-episode nonaffective psychosis cohort.

OBJECTIVE: Male gender and young age at onset of schizophrenia are traditionally associated with poor treatment outcome and often used to determine prognosis. However, many studies use nonincident samples and fail to adjust for symptom severity at onset. We hypothesized that age and gender would influence severity of presentation but would not predict outcome after adjustment for symptoms at presentation. METHOD: 628 people with first-episode ICD-9 and DSM-IV nonaffective psychosis from 2 historical cohorts recruited from sequential presentations in Canada and the United Kingdom (1996-1998) were assessed prospectively at presentation and over 12-18 months using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Models of the age-at-onset distributions with 2 underlying modes at similar ages in women (ages 23 years and 47 years) and men (ages 22 years and 46 years) had relatively good fits compared to single-mode models (χ(2)1 better by 9.2 for females, 8.0 for males, both P < .05). At presentation, scores for negative symptoms were 1.84 points worse for males (95% CI, 1.05 to 2.58; P < .001) in a mixed effects model. Younger age also predicted higher negative scores at presentation (partial correlation r = -0.18, P < .01; P < .001 in the mixed effects model). Findings were similar for cognitive-disorganized symptoms. However, after controlling for baseline symptoms, age at onset and gender did not significantly predict subsequent symptom course in the mixed effects models. CONCLUSIONS: Gender and age at onset are independently associated with symptoms at presentation but not with medium-term course of schizophrenia. This finding reinforces the importance of early identification and prevention of severe negative symptoms at first episode, whatever an individual's age and gender.

Therapist Effects and the Impact of Early Therapeutic Alliance on Symptomatic Outcome in Chronic Fatigue Syndrome.

UNLABELLED: Few studies have examined therapist effects and therapeutic alliance (TA) in treatments for chronic fatigue syndrome (CFS). Therapist effects are the differences in outcomes achieved by different therapists. TA is the quality of the bond and level of agreement regarding the goals and tasks of therapy. Prior research suffers the methodological problem that the allocation of therapist was not randomized, meaning therapist effects may be confounded with selection effects. We used data from a randomized controlled treatment trial of 296 people with CFS. The trial compared pragmatic rehabilitation (PR), a nurse led, home based self-help treatment, a counselling-based treatment called supportive listening (SL), with general practitioner treatment as usual. Therapist allocation was randomized. Primary outcome measures, fatigue and physical functioning were assessed blind to treatment allocation. TA was measured in the PR and SL arms. Regression models allowing for interactions were used to examine relationships between (i) therapist and therapeutic alliance, and (ii) therapist and average treatment effect (the difference in mean outcomes between different treatment conditions). We found no therapist effects. We found no relationship between TA and the average treatment effect of a therapist. One therapist formed stronger alliances when delivering PR compared to when delivering SL (effect size 0.76, SE 0.33, 95% CI 0.11 to 1.41). In these therapies for CFS, TA does not influence symptomatic outcome. The lack of significant therapist effects on outcome may result from the trial's rigorous quality control, or random therapist allocation, eliminating selection effects. Further research is needed. TRIAL REGISTRATION: ISRCTN74156610.

Mental health research priorities for Europe.

Mental and brain disorders represent the greatest health burden to Europe-not only for directly affected individuals, but also for their caregivers and the wider society. They incur substantial economic costs through direct (and indirect) health-care and welfare spending, and via productivity losses, all of which substantially affect European development. Funding for research to mitigate these effects lags far behind the cost of mental and brain disorders to society. Here, we describe a comprehensive, coordinated mental health research agenda for Europe and worldwide. This agenda was based on systematic reviews of published work and consensus decision making by multidisciplinary scientific experts and affected stakeholders (more than 1000 in total): individuals with mental health problems and their families, health-care workers, policy makers, and funders. We generated six priorities that will, over the next 5-10 years, help to close the biggest gaps in mental health research in Europe, and in turn overcome the substantial challenges caused by mental disorders.

Patients' subjective rating of mental health improvement in a randomised controlled trial.

We used UK CUtLASS RCT data to establish that patients' rating of mental health improvement (baseline to week 12) correlated significantly with percentage symptom improvement (PANSS). In a regression analysis predictors of the patient's week 12 mental health rating were percentage change in positive symptoms (PANSS), DAI score and the patient's rating of side effects. Patients in an RCT were able to subjectively rate their mental health status, validated by objective improvement on the PANSS.

Modafinil combined with cognitive training: pharmacological augmentation of cognitive training in schizophrenia.

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.

Modeling determinants of medication attitudes and poor adherence in early nonaffective psychosis: implications for intervention.

We aimed to design a multimodal intervention to improve adherence following first episode psychosis, consistent with current evidence. Existing literature identified medication attitudes, insight, and characteristics of support as important determinants of adherence to medication: we examined medication attitudes, self-esteem, and insight in an early psychosis cohort better to understand their relationships. Existing longitudinal data from 309 patients with early Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, nonaffective psychosis (83% first episode) were analyzed to test the hypothesis that medication attitudes, while meaningfully different from "insight," correlated with insight and self-esteem, and change in each influenced the others. Rosenberg Self-Esteem Scale, Birchwood Insight Scale, and Positive and Negative Syndrome Scale insight were assessed at presentation, after 6 weeks and 3 and 18 months. Drug Attitudes Inventory (DAI) and treatment satisfaction were rated from 6 weeks onward. Structural equation models of their relationships were compared. Insight measures' and DAI's predictive validity were compared against relapse, readmission, and remission. Analysis found five latent constructs best fitted the data: medication attitudes, self-esteem, accepting need for treatment, self-rated insight, and objective insight. All were related and each affected the others as it changed, except self-esteem and medication attitudes. Low self-reported insight at presentation predicted readmission. Good 6-week insight (unlike drug attitudes) predicted remission. Literature review and data modeling indicated that a multimodal intervention using motivational interviewing, online psychoeducation, and SMS text medication reminders to enhance adherence without damaging self-concept was feasible and appropriate.

Validity of subjective versus objective quality of life assessment in people with schizophrenia.

BACKGROUND: Quality of life (QoL) is considered an important outcome in health research. It can be rated by the patient, or by an external assessor. We wished to identify the predictors of any discrepancies between these two approaches in people with schizophrenia. METHODS: Patients with DSM schizophrenia and related disorders (N = 80) completed both patient-rated (Lancashire Quality of Life Profile; LQOLP) and assessor-rated (Heinrich's Quality of Life Scale; QLS) measures of QoL. RESULTS: Patient-rated (LQOLP) and assessor-rated (QLS) measures showed a modest correlation (r = 0.38). In a regression analysis, independent predictors of subjectively-rated QoL being higher than objectively-assessed QoL in the same patient, were low insight score (BIS), negative symptoms (PANSS), absence of depression (CDSS), and less positive attitude toward prescribed treatment (DAI). CONCLUSIONS: In people with schizophrenia, scores on objectively- and subjectively-rated measures of quality of life can differ markedly. When comparing subjective to objective assessments, patients with depressive symptoms will value their QoL lower, and those with low insight will value their QoL higher. This has important implications for the utility and interpretation of QoL measures in schizophrenia.

Towards Horizon 2020: challenges and advances for clinical mental health research - outcome of an expert survey.

BACKGROUND: The size and increasing burden of disease due to mental disorders in Europe poses substantial challenges to its population and to the health policy of the European Union. This warrants a specific research agenda concerning clinical mental health research as one of the cornerstones of sustainable mental health research and health policy in Europe. The aim of this research was to identify the top priorities needed to address the main challenges in clinical research for mental disorders. METHODS: The research was conducted as an expert survey and expert panel discussion during a scientific workshop. RESULTS: Eighty-nine experts in clinical research and representing most European countries participated in this survey. Identified top priorities were the need for new intervention studies, understanding the diagnostic and therapeutic implications of mechanisms of disease, and research in the field of somatic-psychiatric comorbidity. The "subjectivity gap" between basic neuroscience research and clinical reality for patients with mental disorders is considered the main challenge in psychiatric research, suggesting that a shift in research paradigms is required. CONCLUSION: Innovations in clinical mental health research should bridge the gap between mechanisms underlying novel therapeutic interventions and the patient experience of mental disorder and, if present, somatic comorbidity. Clinical mental health research is relatively underfunded and should receive specific attention in Horizon 2020 funding programs.

MRI diffusion tractography study in individuals with schizotypal features: a pilot study.

Diffusion tensor imaging (DTI) studies have identified changes in white matter tracts in schizophrenia patients and those at high risk of transition. Schizotypal samples represent a group on the schizophrenia continuum that share some aetiological risk factors but without the confounds of illness. The aim of the current study was to compare tract microstructural coherence as measured by fractional anisotropy (FA) between 12 psychometrically defined schizotypes and controls. We investigated bilaterally the uncinate and arcuate fasciculi (UF and AF) via a probabilistic tractography algorithm (PICo), with FA values compared between groups. Partial correlations were also examined between measures of subclinical hallucinatory/delusional experiences and FA values. Participants with schizotypal features were found to have increased FA values in the left hemisphere UF only. In the whole sample there was a positive correlation between FA values and measures of hallucinatory experience in the right AF. These findings suggest subtle changes in microstructural coherence are found in individuals with schizotypal features, but are not similar to changes predominantly observed in clinical samples. Correlations between mild hallucinatory experience and FA values could indicate increasing tract coherence could be associated with symptom formation.

The temporal association between self-injurious thoughts and psychotic symptoms: a mobile phone assessment study.

The relationship between psychotic symptoms and self-injurious thoughts (SITs) remains unclear. The short-term temporal associations between psychotic symptoms and SITs were explored. A sample of 36 people with a diagnosis of a psychotic disorder or at-risk mental state completed mobile phone-based measures at multiple times each day for 1 week. Clustered regression with time-lagged variables supported a relationship between paranoia and subsequent SITs. Hallucinations did not predict these thoughts when controlling for paranoia. The role of specific psychotic symptoms in triggering SITs is highlighted and the importance of considering these factors in risk management is discussed.

ROAMER: roadmap for mental health research in Europe.

Despite the high impact of mental disorders in society, European mental health research is at a critical situation with a relatively low level of funding, and few advances been achieved during the last decade. The development of coordinated research policies and integrated research networks in mental health is lagging behind other disciplines in Europe, resulting in lower degree of cooperation and scientific impact. To reduce more efficiently the burden of mental disorders in Europe, a concerted new research agenda is necessary. The ROAMER (Roadmap for Mental Health Research in Europe) project, funded under the European Commission's Seventh Framework Programme, aims to develop a comprehensive and integrated mental health research agenda within the perspective of the European Union (EU) Horizon 2020 programme, with a translational goal, covering basic, clinical and public health research. ROAMER covers six major domains: infrastructures and capacity building, biomedicine, psychological research and treatments, social and economic issues, public health and well-being. Within each of them, state-of-the-art and strength, weakness and gap analyses were conducted before building consensus on future research priorities. The process is inclusive and participatory, incorporating a wide diversity of European expert researchers as well as the views of service users, carers, professionals and policy and funding institutions.

Effect of prior treatment with antipsychotic long-acting injection on randomised clinical trial treatment outcomes.

BACKGROUND: It is uncertain whether antipsychotic long-acting injection (LAI) medication in schizophrenia is associated with better clinical outcomes than oral preparations. AIMS: To examine the impact of prior treatment delivery route on treatment outcomes and whether any differences are moderated by adherence. METHOD: Analysis of data from two pragmatic 1-year clinical trials in which patients with schizophrenia were randomised to either an oral first-generation antipsychotic (FGA), or a non-clozapine second-generation antipsychotic (SGA, CUtLASS 1 study), or a non-clozapine SGA or clozapine (CUtLASS 2 study). RESULTS: Across both trials, 43% (n = 155) of participants were prescribed an FGA-LAI before randomisation. At 1-year follow-up they showed less improvement in quality of life, symptoms and global functioning than those randomised from oral medication. This difference was confined to patients rated as less than consistently adherent pre-randomisation. The relatively poor improvement in the patients prescribed an LAI pre-randomisation was ameliorated if they had been randomised to clozapine rather than another SGA. There was no advantage to being randomly assigned from an LAI at baseline to a non-clozapine oral SGA rather than an oral FGA. CONCLUSIONS: A switch at randomisation from an LAI to an oral antipsychotic was associated with poorer clinical and functional outcomes at 1-year follow-up compared with switching from one oral antipsychotic to another. This effect appears to be moderated by adherence, and may not extend to switching to clozapine. This has implications for clinical trial design: the drug from which a participant is randomised may have a greater effect than the drug to which they are randomised.

Treating impaired cognition in schizophrenia: the case for combining cognitive-enhancing drugs with cognitive remediation.

Cognitive impairment is a well-documented feature of schizophrenia and represents a major impediment to the functional recovery of patients. The therapeutic strategies to improve cognition in schizophrenia have either used medications (collectively referred to as 'cognitive-enhancing drugs' in this article) or non-pharmacological training approaches ('cognitive remediation'). Cognitive-enhancing drugs have not as yet been successful and cognitive remediation has shown modest success. Therefore, we may need to explore new therapeutic paradigms to improve cognition in schizophrenia. The optimal approach may require a combination of cognitive-enhancing drugs with cognitive remediation. We review the available data from animal and human studies that provide the conceptual basis, proof-of-concept and illustrations of success of such combination strategies in experimental and clinical paradigms in other conditions. We address the major design issues relevant to the choice of the cognitive-enhancing drugs and cognitive remediation, as well as the timing and the duration of the intervention as will be relevant for schizophrenia. Finally, we address the practical realities of the development and testing of such combined approaches in the real-world clinical situation and conclude that while scientifically attractive, there are several practical difficulties to be overcome for this approach to be clinically feasible.

Integrating mobile-phone based assessment for psychosis into people's everyday lives and clinical care: a qualitative study.

BACKGROUND: Over the past decade policy makers have emphasised the importance of healthcare technology in the management of long-term conditions. Mobile-phone based assessment may be one method of facilitating clinically- and cost-effective intervention, and increasing the autonomy and independence of service users. Recently, text-message and smartphone interfaces have been developed for the real-time assessment of symptoms in individuals with schizophrenia. Little is currently understood about patients' perceptions of these systems, and how they might be implemented into their everyday routine and clinical care. METHOD: 24 community based individuals with non-affective psychosis completed a randomised repeated-measure cross-over design study, where they filled in self-report questions about their symptoms via text-messages on their own phone, or via a purpose designed software application for Android smartphones, for six days. Qualitative interviews were conducted in order to explore participants' perceptions and experiences of the devices, and thematic analysis was used to analyse the data. RESULTS: Three themes emerged from the data: i) the appeal of usability and familiarity, ii) acceptability, validity and integration into domestic routines, and iii) perceived impact on clinical care. Although participants generally found the technology non-stigmatising and well integrated into their everyday activities, the repetitiveness of the questions was identified as a likely barrier to long-term adoption. Potential benefits to the quality of care received were seen in terms of assisting clinicians, faster and more efficient data exchange, and aiding patient-clinician communication. However, patients often failed to see the relevance of the systems to their personal situations, and emphasised the threat to the person centred element of their care. CONCLUSIONS: The feedback presented in this paper suggests that patients are conscious of the benefits that mobile-phone based assessment could bring to clinical care, and that the technology can be successfully integrated into everyday routine. However, it also suggests that it is important to demonstrate to patients the personal, as well as theoretical, benefits of the technology. In the future it will be important to establish whether clinical practitioners are able to use this technology as part of a personalised mental health regime.

Non-neurological and metabolic side effects in the Cost Utility of the Latest Antipsychotics in Schizophrenia Randomised Controlled Trial (CUtLASS-1).

The impact of non-neurological and metabolic side effects (NNSEs) on the prescription of antipsychotics in real clinical practice remains unclear. We conducted an intention-to-treat, secondary analysis of data from a randomised, controlled trial (CUtLASS-1; n=227) to examine NNSEs emergent at 12 weeks and 52 weeks. A clinically significant difference was defined as double or half the symptoms in groups prescribed first- versus second-generation antipsychotics, represented by odds ratios greater than 2.0 (indicating advantage for first-generation drugs) or less than 0.5 (indicating advantage for the newer drugs). There were no differences between the treatment groups at baseline. At both 12 and 52 weeks follow-up, patients on second-generation drugs were more likely than their first-generation counterparts to experience cardiovascular problems and anticholinergic side effects, as well as increased sexual side effects in men. Objective weight gain was equivalent between the two groups at 12 weeks, but by one year fewer patients in the second-generation arm experienced weight gain and there was no significant difference with regard to percent change in BMI. These results suggest that there may be clinically significant increases in anticholinergic, cardiovascular, and sexual side effects for patients on second-generation drugs. The expected increased weight gain in the second-generation arm did not occur. This study provides evidence that clinicians should take a more nuanced approach toward expert antipsychotic prescription, rather than viewing the drugs as distinct classes.