Jeffrey A. Lieberman

The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study.A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments.Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects.The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

<h2>Summary</h2> The unpredictability and uncertainty of the COVID-19 pandemic; the associated lockdowns, physical distancing, and other containment strategies; and the resulting economic breakdown could increase the risk of mental health problems and exacerbate health inequalities. Preliminary findings suggest adverse mental health effects in previously healthy people and especially in people with pre-existing mental health disorders. Despite the heterogeneity of worldwide health systems, efforts have been made to adapt the delivery of mental health care to the demands of COVID-19. Mental health concerns have been addressed via the public mental health response and by adapting mental health services, mostly focusing on infection control, modifying access to diagnosis and treatment, ensuring continuity of care for mental health service users, and paying attention to new cases of mental ill health and populations at high risk of mental health problems. Sustainable adaptations of delivery systems for mental health care should be developed by experts, clinicians, and service users, and should be specifically designed to mitigate disparities in health-care provision. Thorough and continuous assessment of health and service-use outcomes in mental health clinical practice will be crucial for defining which practices should be further developed and which discontinued. For this Position Paper, an international group of clinicians, mental health experts, and users of mental health services has come together to reflect on the challenges for mental health that COVID-19 poses. The interconnectedness of the world made society vulnerable to this infection, but it also provides the infrastructure to address previous system failings by disseminating good practices that can result in sustained, efficient, and equitable delivery of mental health-care delivery. Thus, the COVID-19 pandemic could be an opportunity to improve mental health services.

Background:We examined relapse after response to a first episode of schizophrenia or schizoaffective disorder.Methods: Patients with first-episode schizophrenia were assessed on measures of psychopathologic variables, cognition, social functioning, and biological variables and treated according to a standardized algorithm.The sample for the relapse analyses consisted of 104 patients who responded to treatment of their index episode and were at risk for relapse.Results: Five years after initial recovery, the cumulative first relapse rate was 81.9% (95% confidence interval [CI], 70.6%-93.2%);the second relapse rate was 78.0% (95% CI, 46.5%-100.0%).By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2% (95% CI, 61.5%-100.0%).Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times (hazard ratio for an initial relapse, 4.89 [99% CI, 2.49-9.60];hazard ratio for a second relapse, 4.57 [99% CI, 1.49-14.02]).Subsequent analyses controlling for antipsychotic drug use showed that patients with poor premorbid adaptation to school and premorbid social withdrawal relapsed earlier.Sex, diagnosis, obstetric complications, duration of psychotic illness before treatment, baseline symptoms, neuroendocrine measures, methylphenidate hydrochloride challenge response, neuropsychologic and magnetic resonance imaging measures, time to response of the initial episode, adverse effects during treatment, and presence of residual symptoms after the initial episode were not significantly related to time to relapse. Conclusions:There is a high rate of relapse within 5 years of recovery from a first episode of schizophrenia and schizoaffective disorder.This risk is diminished by maintenance antipsychotic drug treatment.

OBJECTIVE: The duration of untreated psychosis may influence response to treatment, reflecting a potentially malleable progressive pathological process. The authors reviewed the literature on the association of duration of untreated psychosis with symptom severity at first treatment contact and with treatment outcomes and conducted a meta-analysis examining these relationships. METHOD: English-language articles on duration of untreated psychosis published in peer-reviewed journals through July 2004 were reviewed. Studies that quantitatively assessed the duration of untreated psychosis; identified study subjects who met the criteria for nonaffective psychotic disorders at or close to first treatment; employed cross-sectional analyses of duration of untreated psychosis and of baseline symptoms, neurocognition, brain morphology, or functional measures or prospectively analyzed symptom change, response, or relapse; assessed psychopathology with clinician-rated instruments; and reported subjects’ diagnoses (a total of 43 publications from 28 sites) were included in the meta-analysis. RESULTS: Shorter duration of untreated psychosis was associated with greater response to antipsychotic treatment, as measured by severity of global psychopathology, positive symptoms, negative symptoms, and functional outcomes. At the time of treatment initiation, duration of initially untreated psychosis was associated with the severity of negative symptoms but not with the severity of positive symptoms, general psychopathology, or neurocognitive function. CONCLUSIONS: Duration of untreated psychosis may be a potentially modifiable prognostic factor. Understanding the mechanism by which duration of untreated psychosis influences prognosis may lead to better understanding of the pathophysiology of schizophrenia and to improved treatment strategies.

Second-generation (atypical) antipsychotic drugs are widely used to treat psychosis, aggression, and agitation in patients with Alzheimer's disease, but their benefits are uncertain and concerns about safety have emerged. We assessed the effectiveness of atypical antipsychotic drugs in outpatients with Alzheimer's disease.In this 42-site, double-blind, placebo-controlled trial, 421 outpatients with Alzheimer's disease and psychosis, aggression, or agitation were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day), quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per day), or placebo. Doses were adjusted as needed, and patients were followed for up to 36 weeks. The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale at 12 weeks.There were no significant differences among treatments with regard to the time to the discontinuation of treatment for any reason: olanzapine (median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median, 7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the discontinuation of treatment due to a lack of efficacy favored olanzapine (22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1 weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of treatment due to adverse events or intolerability favored placebo. Overall, 24% of patients who received olanzapine, 16% of patients who received quetiapine, 18% of patients who received risperidone, and 5% of patients who received placebo discontinued their assigned treatment owing to intolerability (P=0.009). No significant differences were noted among the groups with regard to improvement on the CGIC scale. Improvement was observed in 32% of patients assigned to olanzapine, 26% of patients assigned to quetiapine, 29% of patients assigned to risperidone, and 21% of patients assigned to placebo (P=0.22).Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00015548 [ClinicalTrials.gov].).

One important risk factor for cardiovascular disease is the metabolic syndrome (MS), yet limited data exist on its prevalence in US patients with schizophrenia.Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assessment of MS prevalence was performed based on National Cholesterol Education Program (NCEP) criteria, and also using a fasting glucose threshold of 100 mg/dl (AHA). Subjects with sufficient anthropometric data, data on use of antihypertensives, hypoglycemic medications or insulin, and fasting glucose and lipid values >8 h from last meal were included in the analysis. Comparative analyses were performed using a randomly selected sample from NHANES III matched 1:1 on the basis of age, gender and race/ethnicity.Of 1460 CATIE baseline subjects, 689 met analysis criteria. MS prevalence was 40.9% and 42.7%, respectively using the NCEP and AHA derived criteria. In females it was 51.6% and 54.2% using the NCEP and AHA criteria, compared to 36.0% (p = .0002) and 36.6% (p = .0003), respectively for males. 73.4% of all females (including nonfasting subjects) met the waist circumference criterion compared to 36.6% of males. In a logistic regression model with age, race and ethnicity as covariates, CATIE males were 138% more likely to have MS than the NHANES matched sample, and CATIE females 251% more likely than their NHANES counterparts. Even when controlling for differences in body mass index, CATIE males were still 85% more likely to have MS than the NHANES male sample, and CATIE females 137% more likely to have MS than females in NHANES.The metabolic syndrome is highly prevalent in US schizophrenia patients and represents an enormous source of cardiovascular risk, especially for women. Clinical attention must be given to monitoring for this syndrome, and minimizing metabolic risks associated with antipsychotic treatment.

Neurocognitive impairment in schizophrenia is severe and is an important predictor of functional outcome. The relative effect of the second-generation (atypical) antipsychotic drugs and older agents on neurocognition has not been comprehensively determined.To compare the neurocognitive effects of several second-generation antipsychotics and a first-generation antipsychotic, perphenazine.Randomized, double-blind study of patients with schizophrenia assigned to receive treatment with olanzapine, perphenazine, quetiapine fumarate, or risperidone for up to 18 months as reported previously by Lieberman et al. Ziprasidone hydrochloride was included after its approval by the Food and Drug Administration.Fifty-seven sites participated, including academic sites and treatment mental health facilities representative of the community.From a cohort of 1460 patients in the treatment study, 817 completed neurocognitive testing immediately prior to randomization and then after 2 months of treatment.The primary outcome was change in a neurocognitive composite score after 2 months of treatment. Secondary outcomes included neurocognitive composite score change at 6 months and 18 months after continued treatment and changes in neurocognitive domains.At 2 months, treatment resulted in small neurocognitive improvements of z = 0.13 for olanzapine (P<.002), 0.25 for perphenazine (P<.001), 0.18 for quetiapine (P<.001), 0.26 for risperidone (P<.001), and 0.12 for ziprasidone (P<.06), with no significant differences between groups. Results at 6 months were similar. After 18 months of treatment, neurocognitive improvement was greater in the perphenazine group than in the olanzapine and risperidone groups. Neurocognitive improvement predicted longer time to treatment discontinuation, independently from symptom improvement, in patients treated with quetiapine or ziprasidone.After 2 months of antipsychotic treatment, all groups had a small but significant improvement in neurocognition. There were no differences between any pair of agents, including the typical drug perphenazine. These results differ from the majority of previous studies, and the possible reasons are discussed.

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

OBJECTIVE: Neuropsychological impairments are well documented in schizophrenia and are important targets of treatment. Information about the severity and pattern of deficits after treatment for the first psychotic episode and about relationships between these deficits and syndromal characteristics remains limited. METHOD: Comprehensive neuropsychological assessments including 41 individual tests were given to 94 patients with first-episode schizophrenia after initial stabilization of psychosis and to a comparison group of 36 healthy volunteers. Profiles of neuropsychological deficits and the relationship of deficits to sex and handedness were examined. Correlations of neuropsychological deficit with a broad range of historical and clinical characteristics, including outcome, were explored. RESULTS: Patients had a large generalized neuropsychological deficit (1.5 standard deviations compared to healthy volunteers). Patients also had, superimposed on the generalized deficit, subtle relative deficits (less than 0.5 standard deviation compared to their own average profile) in memory and executive functions. Learning/memory dysfunction best distinguished patients from healthy individuals; after accounting for this difference, only motor deficits further distinguished the groups. Patients with higher neuropsychological ability had only memory deficits, and patients with lower ability had both memory and executive deficits. No sex differences were observed beyond the normal advantage for men in motor speed. Dextral patients had less severe generalized deficit. Severity of residual symptoms was associated with greater generalized deficit. Executive and attentional deficits were most linked to global functional impairment and poor outcome. CONCLUSIONS: The results document a large generalized deficit, and more subtle differential deficits, in clinically stabilized first-episode patients. Learning/memory deficits were observed even in patients with less severe generalized deficit, but the pattern was unlike the amnestic syndrome and probably reflects different mechanisms. Executive and attentional deficits marked the more severely disabled patients, and may portend relatively poor outcome. Failure to develop typical patterns of cerebral dominance may increase the risk for greater generalized deficit.

Clozapine is an atypical antipsychotic agent that is more effective than standard neuroleptic drugs in the treatment of patients with refractory schizophrenia. Unlike classic neuroleptic agents, clozapine is not associated with the development of acute extrapyramidal symptoms or tardive dyskinesia. The main factor limiting its use is the risk of potentially fatal agranulocytosis, estimated to occur in 1 to 2 percent of treated patients. After clozapine was approved by the Food and Drug Administration, it became available for marketing in the United States in February 1990 only as part of a special surveillance system (the Clozaril Patient Management System, or CPMS), in which a weekly white-cell count was required for the patient to receive a supply of the drug.

Background Studies of people with schizophrenia assessed using magnetic resonance imaging (MRI) usually include patients with first-episode and chronic disease, yet brain abnormalities may be limited to those with chronic schizophrenia. Aims To determine whether patients with a first episode of schizophrenia have characteristic brain abnormalities. Method Systematic review and meta-analysis of 66 papers comparing brain volume in patients with a first psychotic episode with volume in healthy controls. Results Atotal of 52 cross-sectional studies included 1424 patients with a first psychotic episode; 16 longitudinal studies included 465 such patients. Meta-analysis suggests that whole brain and hippocampal volume are reduced (both P &lt; 0.0001) and that ventricular volume is increased ( P &lt; 0.0001) in these patients relative to healthy controls. Conclusions Average volumetric changes are close to the limit of detection by MRI methods. It remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.

Back to table of contents Previous article Next article No AccessDuration of psychosis and outcome in first-episode schizophreniaPublished Online:1 Apr 2006https://doi.org/10.1176/ajp.149.9.1183AboutSectionsView articleAbstractPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleAbstractOBJECTIVE: This study was undertaken to assess the potential effect of duration of untreated illness on outcome in a group of first-episode schizophrenic patients. METHOD: Seventy patients with schizophrenia diagnosed according to the Research Diagnostic Criteria entered the study and were followed for up to 3 years. All patients received standardized treatment and uniform assessments both during the acute phase of their illness and throughout the follow-up period. Outcome was measured in terms of time to remission of acute psychotic symptoms as well as degree of symptom remission. RESULTS: The mean duration of psychotic symptoms before initial treatment was 52 weeks, preceded by a substantial prepsychotic period. According to survival analysis, duration of illness before treatment was found to be significantly associated with time to remission as well as with level of remission. The effect of duration of illness on outcome remained significant when diagnosis and gender variables, themselves associated with outcome, were controlled in a regression analysis. Duration of illness was not correlated with age at onset, mode of onset, premorbid adjustment, or severity of illness at entry into the study. CONCLUSIONS: Duration of psychosis before treatment may be an important predictor of outcome in first-episode schizophrenia. Acute psychotic symptoms could reflect an active morbid process which, if not ameliorated by neuroleptic drug treatment, may result in lasting morbidity. Further implications of these findings are discussed. 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Gur, M.D., Ph.D.1 March 2006 | American Journal of Psychiatry, Vol. 163, No. 3Schizophrenia Research, Vol. 83, No. 2-3Schizophrenia Research, Vol. 86, No. 1-3Schizophrenia Research, Vol. 86, No. 1-3CNS Spectrums, Vol. 11, No. 5International Journal of Psychiatry in Clinical Practice, Vol. 10, No. 4Psychiatry and Clinical Neurosciences, Vol. 60, No. 2Acta Psychiatrica Scandinavica, Vol. 113, No. 4Perspectives In Psychiatric Care, Vol. 42, No. 2Status of First-Episode Psychosis Patients Presenting for Routine Care in a Defined Catchment Area1 January 2006 | The Canadian Journal of Psychiatry, Vol. 51, No. 1BMC Public Health, Vol. 6, No. 1Advances in Psychiatric Treatment, Vol. 12, No. 4British Journal of Psychiatry, Vol. 188, No. 3British Journal of Psychiatry, Vol. 189, No. 3Revista Brasileira de Psiquiatria, Vol. 28, No. 2Hallucinations in children and adolescentsCurrent Psychosis & Therapeutics Reports, Vol. 3, No. 4First-Episode Psychosis, Early Intervention, and Outcome: What Have We Learned?1 December 2005 | The Canadian Journal of Psychiatry, Vol. 50, No. 14Relationship Between Duration of Untreated Psychosis and Outcome in First-Episode Schizophrenia: A Critical Review and Meta-AnalysisDiana O. Perkins, M.D., M.P.H., Hongbin Gu, Ph.D., Kalina Boteva, M.D., and Jeffrey A. Lieberman, M.D.1 October 2005 | American Journal of Psychiatry, Vol. 162, No. 10Hippocampus Volume and Treatment Delays in First-Episode SchizophreniaBeng-Choon Ho, M.R.C.Psych., Daniel Alicata, M.D., Carmencita Mola, M.D., and Nancy C. Andreasen, M.D., Ph.D.1 August 2005 | American Journal of Psychiatry, Vol. 162, No. 8Recovery From Schizophrenia: A Concept in Search of ResearchRobert Paul Liberman, M.D., and Alex Kopelowicz, M.D.1 June 2005 | Psychiatric Services, Vol. 56, No. 6Intervención farmacológica en la fase prodrómica inicial de la psicosis12 May 2020 | European psychiatry (Ed. 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Schizophrenia is a brain disorder that is expressed in the form of abnormal mental functions and disturbed behavior. These manifestations characteristically appear in the late second and third decades of life as a heterogeneous constellation of three classes of clinical features. Positive symptoms include delusions (false beliefs), hallucinations (false perceptions), and thought disorganization. Negative symptoms refer to the loss of motivation and emotional vibrancy. Disturbances in basic cognitive functions, such as attention, executive functions, and specific forms of memory (particularly working memory), are also consistently observed in patients and are now thought to be central to the behavioral disturbances and functional disability of schizophrenia. In addition, many patients have concomitant mood symptoms including depression and anxiety that may contribute to the 10% lifetime incidence of suicide in schizophrenia.

OBJECTIVE: Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel’s recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings. METHOD: A consensus meeting including psychiatric and other medical experts assembled on October 17–18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached. RESULTS: Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations. CONCLUSIONS: The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants’ belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia.To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition.Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes.Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1).Patients with first-episode psychosis (DSM-IV) and healthy volunteers.Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d).Brain volume changes assessed by MRI.Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume.Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

Violent behavior is uncommon, yet problematic, among schizophrenia patients. The complex effects of clinical, interpersonal, and social-environmental risk factors for violence in this population are poorly understood.To examine the prevalence and correlates of violence among schizophrenia patients living in the community by developing multivariable statistical models to assess the net effects of psychotic symptoms and other risk factors for minor and serious violence.A total of 1410 schizophrenia patients were clinically assessed and interviewed about violent behavior in the past 6 months. Data comprise baseline assessments of patients enrolled in the National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness.Adult patients diagnosed as having schizophrenia were enrolled from 56 sites in the United States, including academic medical centers and community providers.Violence was classified at 2 severity levels: minor violence, corresponding to simple assault without injury or weapon use; and serious violence, corresponding to assault resulting in injury or involving use of a lethal weapon, threat with a lethal weapon in hand, or sexual assault. A composite measure of any violence was also analyzed.The 6-month prevalence of any violence was 19.1%, with 3.6% of participants reporting serious violent behavior. Distinct, but overlapping, sets of risk factors were associated with minor and serious violence. "Positive" psychotic symptoms, such as persecutory ideation, increased the risk of minor and serious violence, while "negative" psychotic symptoms, such as social withdrawal, lowered the risk of serious violence. Minor violence was associated with co-occurring substance abuse and interpersonal and social factors. Serious violence was associated with psychotic and depressive symptoms, childhood conduct problems, and victimization.Particular clusters of symptoms may increase or decrease violence risk in schizophrenia patients. Violence risk assessment and management in community-based treatment should focus on combinations of clinical and nonclinical risk factors.

Cognitive deficits are a fundamental feature of the psychopathology of schizophrenia. Yet the effect of treatment on this dimension of the illness has been unclear. Atypical antipsychotic medications have been reported to reduce the neurocognitive impairment associated with schizophrenia. However, studies of the pattern and degree of cognitive improvement with these compounds have been methodologically limited and have produced variable results, and few findings have been replicated. To clarify our understanding of the effects of atypical anti psychotic drugs on neurocognitive deficits in patients with schizophrenia, we have (1) reported on newly established standards for research design in studies of treatment effects on cognitive function in schizophrenia, (2) reviewed the literature on this topic and determined the extent to which 15 studies on the effect of atypical antipsychotics met these standards, (3) performed a meta-analysis of the 15 studies, which suggested general cognitive enhancement with atypical antipsychotics, and (4) described the pharmacological profile of these agents and considered the pharmacological basis for their effects on neurocognition. Finally, we suggest directions for the development of new therapeutic strategies.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation.Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]).Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation.For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine's serious side effects.

The authors conducted a review and meta-analysis of studies that compared the efficacy and tolerability of typical and second-generation antipsychotics for patients with treatment-resistant schizophrenia.A systematic search revealed 12 controlled studies (involving 1,916 independent patients), which were included in the review. For the seven studies that compared clozapine to a typical antipsychotic, a meta-analysis was performed to examine clozapine's effects on overall psychopathology, response rate, extrapyramidal symptoms, and tardive dyskinesia.The meta-analysis confirmed that treatment-resistant schizophrenic patients have more favorable outcomes when treated with clozapine rather than a typical antipsychotic, as reflected by Brief Psychiatric Rating Scale total score, categorical response rate, Scale for the Assessment of Negative Symptoms score, Simpson-Angus Rating Scale score, and compliance rate. Clozapine also conferred benefits on the sickest treatment-resistant schizophrenic patients. Patients treated with olanzapine also had more favorable outcomes with regard to categorical response and compliance rates.In the aggregate, the results of a meta-analysis indicated that clozapine exhibits superiority over typical antipsychotics in terms of both efficacy (as measured by improvement in overall psychopathology) and safety (in terms of reduced extrapyramidal side effects). However, the magnitude of the clozapine treatment effect was not consistently robust. Efficacy data for other second-generation antipsychotics in the treatment of patients with refractory schizophrenia were inconclusive. There is, therefore, a growing need to consider new and different treatment strategies, whether they be adjunctive or monotherapeutic, for schizophrenia that continues to be resistant or only partially responsive to treatment.

The National Institute of Mental Health initiated the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) program to evaluate the effectiveness of antipsychotic drugs in typical settings and populations so that the study results will be maximally useful in routine clinical situations. The CATIE schizophrenia trial blends features of efficacy studies and large, simple trials to create a pragmatic trial that will provide extensive information about antipsychotic drug effectiveness over at least 18 months. The protocol allows for subjects who receive a study drug that is not effective to receive subsequent treatments within the context of the study. Medication dosages are adjusted within a defined range according to clinical judgment. The primary outcome is all-cause treatment discontinuation because it represents an important clinical endpoint that reflects both clinician and patient judgments about efficacy and tolerability. Secondary outcomes include symptoms, side effects, neurocognitive functioning, and cost-effectiveness. Approximately 50 clinical sites across the United States are seeking to enroll a total of 1,500 persons with schizophrenia. Phase 1 is a double-blinded randomized clinical trial comparing treatment with the second generation antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone to perphenazine, a midpotency first generation antipsychotic. If the initially assigned medication is not effective, subjects may choose one of the following phase 2 trials: (1) randomization to open-label clozapine or a double-blinded second generation drug that was available but not assigned in phase 1; or (2) double-blinded randomization to ziprasidone or another second generation drug that was available but not assigned in phase 1. If the phase 2 study drug is discontinued, subjects may enter phase 3, in which clinicians help subjects select an open-label treatment based on individuals' experiences in phases 1 and 2.

Pathomorphology of the limbic system has been described in post-mortem studies of schizophrenia. To determine whether this could be detected in living patients and was not secondary to the treatment or the chronicity of the disease itself, we measured the volumes of the hippocampus-amygdala complex and adjoining temporal horns of 34 patients in their first episode of schizophrenia and 25 normal volunteers using T1 weighted contiguous coronal magnetic resonance images of 3.1 mm width. The results demonstrate abnormal medial temporal lobe morphology in a subgroup of patients at the onset of their illness. There were clear laterality effects and sex differences: hippocampal tissue was significantly smaller only in the left hemisphere of male patients, whereas enlargement of the whole temporal horn or its anterior portion was present on the left side in both sexes. Dysfunction of the limbic mesiotemporal structures might explain some of the clinical features of the disease.

Schizophrenia is commonly considered a neurodevelopmental disorder that is associated with significant morbidity; however, unlike other neurodevelopmental disorders, the symptoms of schizophrenia often do not manifest for decades. In most patients, the formal onset of schizophrenia is preceded by prodromal symptoms, including positive symptoms, mood symptoms, cognitive symptoms, and social withdrawal. The proximal events that trigger the formal onset of schizophrenia are not clear but may include developmental biological events and environmental interactions or stressors. Treatment with antipsychotic drugs clearly ameliorates psychotic symptoms, and maintenance therapy may prevent the occurrence of relapse. The use of atypical antipsychotic agents may additionally ameliorate the pathophysiology of schizophrenia and prevent disease progression. Moreover, if treated properly early in the course of illness, many patients can experience a significant remission of their symptoms and are capable of a high level of recovery following the initial episode. Because the clinical deterioration that occurs in schizophrenia may actually begin in the prepsychotic phase, early identification and intervention may favorably alter the course and outcome of schizophrenia.

These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry Guidelines for Biological Treatment of Schizophrenia published in 2005. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful and these guidelines are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A–F; Bandelow et al. 2008b, World J Biol Psychiatry 9:242). This first part of the updated guidelines covers the general descriptions of antipsychotics and their side effects, the biological treatment of acute schizophrenia and the management of treatment-resistant schizophrenia.

Background: Beginning with Kraepelin, schizophrenia has been viewed as a progressive disorder. Although numerous studies of the longitudinal course of schizophrenia have demonstrated the clinical deterioration that occurs predominantly in the early stages of the illness, the pathophysiology of this clinical phenomenon has not been established. This aspect of the illness may be of critical importance to understanding the pathogenesis of schizophrenia and determining preventive therapeutic strategies. Abnormalities in brain morphology have been consistently described in schizophrenia, but it is not known when in the natural history of the illness they arise and whether they are progressive. Previous studies of brain morphology have been inconclusive, in part because of the variability of methods for image acquisition and analysis, assessment of patients already at chronic stages of their illness with extensive prior treatment exposure, and inadequate periods of follow-up. Methods: To address these questions we examined 107 patients in their first episode of schizophrenia or schizoaffective disorder and 20 healthy volunteers using high resolution magnetic resonance imaging (MRI) and clinical assessments of psychopathology and treatment outcome for periods of up to 6 years. Fifty-one patients and 13 control subjects had MRIs after at least 12 months of follow-up. Results: Results confirm the findings of ventricular enlargement and anterior hippocampal volume reductions in first episode schizophrenia patients that have been previously reported. In addition, we found changes in selected structures over time in relation to treatment outcome, including increases in ventricular volume that were associated with poor outcome patients. Contrary to our hypothesis, there were no significant reductions in cortical and hippocampal volumes over time. Conclusions: The finding of progressive ventricular enlargement in patients with poor outcome schizophrenia is consistent with the hypothesis that persistent positive and negative symptoms result in progressive brain changes in the form of ventricular enlargement, possibly due to neurodegeneration rather than the confounding effects of treatment. Future studies of first episodes of schizophrenia should utilize higher resolution imaging techniques that compare clinically well characterized patients with and without poor outcome and recurrent symptoms to control subjects who are well matched to patients for age and gender. There is also a need to control for treatment effects of typical antipsychotic medication on brain structure.

Persons diagnosed with schizophrenia have higher morbidity and mortality rates from cardiovascular disease, yet often have limited access to appropriate primary care screening or treatment. Metabolic disorders such as diabetes, hyperlipidemia and hypertension are highly prevalent in populations with schizophrenia, exceeding 50% in some studies; however, there have been few published studies on treatment rates among schizophrenia patients screened for these disorders.Using the baseline data from subjects (N=1460) recruited into the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, we examined the point prevalence of diabetes, hyperlipidemia and hypertension treatment at the time of enrollment for the entire cohort and those with fasting laboratory values obtained 8 or more hours since last meal.Rates of non-treatment ranged from 30.2% for diabetes, to 62.4% for hypertension, and 88.0% for dyslipidemia. Nonwhite men were more likely to be treated for DM and dyslipidemia than nonwhite women.These data indicate the high likelihood that metabolic disorders are untreated in patients with schizophrenia, with particularly high rates of non-treatment for hypertension and dyslipidemia. Nonwhite women may be especially vulnerable to undertreatment of dyslipidemia and diabetes compared to nonwhite men. The findings here support the need for increased attention to basic monitoring and treatment of cardiovascular risk factors in this vulnerable and often underserved psychiatric population.

Newer antipsychotic drugs have shown promise in ameliorating neurocognitive deficits in patients with schizophrenia, but few studies have compared newer antipsychotic drugs with both clozapine and conventional agents, particularly in patients who have had suboptimal response to prior treatments.The authors examined the effects of clozapine, olanzapine, risperidone, and haloperidol on 16 measures of neurocognitive functioning in a double-blind, 14-week trial involving 101 patients. A global score was computed along with scores in four neurocognitive domains: memory, attention, motor function, and general executive and perceptual organization.Global neurocognitive function improved with olanzapine and risperidone treatment, and these improvements were superior to those seen with haloperidol. Patients treated with olanzapine exhibited improvement in the general and attention domains but not more than that observed with other treatments. Patients treated with risperidone exhibited improvement in memory that was superior to that of both clozapine and haloperidol. Clozapine yielded improvement in motor function but not more than in other groups. Average effect sizes for change were in the small to medium range. More than half of the patients treated with olanzapine and risperidone experienced "clinically significant" improvement (changes in score of at least one-half standard deviation relative to baseline). These findings did not appear to be mediated by changes in symptoms, side effects, or blood levels of medications.Patients with a history of suboptimal response to conventional treatments may show cognitive benefits from newer antipsychotic drugs, and there may be differences between atypical antipsychotic drugs in their patterns of cognitive effects.

Since the introduction of chlorpromazine and throughout the development of the new-generation antipsychotic drugs (APDs) beginning with clozapine, the D(2) receptor has been the target for the development of APDs. Pharmacologic actions to reduce neurotransmission through the D(2) receptor have been the only proven therapeutic mechanism for psychoses. A number of novel non-D(2) mechanisms of action of APDs have been explored over the past 40 years but none has definitively been proven effective. At the same time, the effectiveness of treatments and range of outcomes for patients are far from satisfactory. The relative success of antipsychotics in treating positive symptoms is limited by the fact that a substantial number of patients are refractory to current medications and by their lack of efficacy for negative and cognitive symptoms, which often determine the level of functional impairment. In addition, while the newer antipsychotics produce fewer motor side effects, safety and tolerability concerns about weight gain and endocrinopathies have emerged. Consequently, there is an urgent need for more effective and better-tolerated antipsychotic agents, and to identify new molecular targets and develop mechanistically novel compounds that can address the various symptom dimensions of schizophrenia. In recent years, a variety of new experimental pharmacological approaches have emerged, including compounds acting on targets other than the dopamine D(2) receptor. However, there is still an ongoing debate as to whether drugs selective for singe molecular targets (that is, 'magic bullets') or drugs selectively non-selective for several molecular targets (that is, 'magic shotguns', 'multifunctional drugs' or 'intramolecular polypharmacy') will lead to more effective new medications for schizophrenia. In this context, current and future drug development strategies can be seen to fall into three categories: (1) refinement of precedented mechanisms of action to provide drugs of comparable or superior efficacy and side-effect profiles to existing APDs; (2) development of novel (and presumably non-D(2)) mechanism APDs; (3) development of compounds to be used as adjuncts to APDs to augment efficacy by targeting specific symptom dimensions of schizophrenia and particularly those not responsive to traditional APD treatment. In addition, efforts are being made to determine if the products of susceptibility genes in schizophrenia, identified by genetic linkage and association studies, may be viable targets for drug development. Finally, a focus on early detection and early intervention aimed at halting or reversing progressive pathophysiological processes in schizophrenia has gained great influence. This has encouraged future drug development and therapeutic strategies that are neuroprotective. This article provides an update and critical review of the pharmacology and clinical profiles of current APDs and drugs acting on novel targets with potential to be therapeutic agents in the future.

Standardized mortality rates are elevated in schizophrenia compared to the general population. The incidence of coronary heart disease (CHD) and the relative contribution of CHD to increased mortality in schizophrenia patients are not clear, despite recent concerns about metabolic complications of certain atypical antipsychotics. Ten-year risk for CHD was calculated for 689 subjects who participated in the Clinical Trials of Antipsychotic Treatment Effectiveness (CATIE) Schizophrenia Trial at baseline using the Framingham CHD risk function and were compared with age-, race- and gender-matched controls from the National Health and Nutrition Examination Survey (NHANES) III. Ten-year CHD risk was significantly elevated in male (9.4% vs. 7.0%) and female (6.3% vs. 4.2%) schizophrenia patients compared to controls (p = 0.0001). Schizophrenia patients had significantly higher rates of smoking (68% vs. 35%), diabetes (13% vs. 3%), and hypertension (27% vs. 17%) and lower HDL cholesterol levels (43.7 vs. 49.3 mg/dl) compared to controls (p < 0.001). Only total cholesterol levels did not differ between groups. Ten-year CHD risk remained significantly elevated in schizophrenia patients after controlling for body mass index (p = 0.0001). These results are consistent with recent evidence of increased cardiac mortality in schizophrenia patients. While the impact of cigarette smoking is clear, the relative contributions to cardiac risk of specific antipsychotic agents, diet, exercise, and quality of medical care remain to be clarified.

The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question by using MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occurred during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using the glutamate-reducing drug LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIzZmY3YTNjMTdjNTc3ZDI3Y2RmYjBlNjI4ODc1Mzk3YyIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc4NjY5MzMyfQ.DbF6kkd98WcD_fKHU1CIbvnykf2xwCPSaqsu1VvpQptDIpXiGj8SU6Fx-8upvGZQ2xZD0FkTglryU1nRqXF2ZLuCnJXUZAoLzymROFvU509Nwv8uJ7JnZJoII3sGf06K2VRXZ88ShfwJVNzVQl2GR4I2APz3D8HdlSFETQ7YPkUw8jGx9HMXuTg9Zk_RNW3XuZ5ywNT97VYh3ItdNPd-65Tl7FOZc29ip4TWDm_COZwIGHLdUM9-NOfRpB7Qby8v5w5gGWIOlGdJxNohPg5aLzuK13jjEs9VtCnDBFM8DEvdzbJxc5XYQobVGASlx12x3heqDzBZD3cbymcbG_NOIQ(mp4, (49.54 MB) Download video

The history of psychiatric research is filled with widely accepted etiologic and pathophysiologic theories that eventually were proven wrong. The prevailing pathophysiologic theories of schizophrenia have emphasized the role of abnormal neurodevelopment in determining the onset and course of the illness. Relatively little attention has been paid to the role of neurodegenerative processes despite the clinical course of the illness and the fact that most patients experience varying degrees of behavioral and cognitive deterioration. This is partially due to the absence of clear histologic evidence of neurodegeneration, but may also be due to the narrow traditional conception of neurodegeneration that is generally employed. This article suggests that the rejection of a role for neurodegeneration in the pathophysiology of schizophrenia is unproven and may be premature. A wholly neurodevelopmental perspective of the illness imbues the illness with a pessimistic inevitability and therapeutic nihilism that may be unwarranted. This article reviews selectively a diverse body of evidence that is consistent with the hypothesis that schizophrenia involves a limited neurodegenerative process reflected by the psychotic symptoms and that is most active in the early stages of the illness. The evidence for this hypothesis comes from studies of premorbid status, illness course, symptomatology and treatment effects as well as neuroimaging and postmortem findings. Recent results from the latter interpreted in the context of molecular neurobiology suggest new pathophysiologic models.

OBJECTIVE: There is growing interest in identifying and surmounting barriers to employment for people with schizophrenia. The authors examined factors associated with participation in competitive employment or other vocational activities in a large group of patients with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a multisite clinical trial comparing the effects of first- and second-generation antipsychotics. METHOD: Baseline data on more than 1,400 patients with a diagnosis of schizophrenia were collected before their entry into the CATIE study. Multinomial logistic regression was used to examine the relationship between participation in either competitive employment or other vocational activities and sociodemographic characteristics, schizophrenia symptoms, neurocognitive functioning, intrapsychic functioning, availability of psychosocial rehabilitation services, and local unemployment rates. RESULTS: Altogether, 14.5% of the patients reported participating in competitive employment in the month before the baseline assessment, 12.6% reported other (noncompetitive) employment activity, and 72.9% reported no employment activity. Participation in either competitive or noncompetitive employment was associated with having less severe symptoms, better neurocognitive functioning, and higher scores on a measure of intrapsychic functioning that encompassed motivation, empathy, and other psychological characteristics. Competitive employment, in contrast to other employment or no employment, was negatively associated with receipt of disability payments as well as with being black. Greater access to rehabilitation services was associated with greater participation in both competitive and noncompetitive employment. CONCLUSIONS: Overall employment of persons with schizophrenia seems to be impeded by clinical problems, including symptoms of schizophrenia and poorer neurocognitive and intrapsychic functioning. However, participation in competitive employment may be specifically impeded by the potentially adverse incentives of disability payments and by race and may be promoted by the availability of rehabilitation services.

OBJECTIVE: The study of social cognition in schizophrenia has received growing attention in recent years. At the same time, a large body of work has explored the neural basis of social cognition in both nonclinical and clinical groups, other than those with schizophrenia. The gap between these two literatures is considerable and may slow progress in creating a comprehensive social cognitive model of schizophrenia. This article attempts to bridge this gap by discussing how the neural basis of social cognition may inform future clinical research in schizophrenia. METHOD: PsycINFO and MEDLINE were systematically searched for articles pertaining to the neural basis of social cognition and social cognition in schizophrenia. Relevant studies were obtained and synthesized into a comprehensive review and integrative formulation. RESULTS: Striking parallels between these two areas of research were found. CONCLUSIONS: These parallels might help to better elucidate the underlying mechanisms for social cognitive and social behavioral impairments in schizophrenia as well as provide potential targets for treatment and drug development.

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An 'all-comer' approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13-0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an 'all-comer' clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

OBJECTIVE: The association of hyperglycemia and hypercholesterolemia with use of atypical antipsychotics has been documented in case reports and uncontrolled studies. The authors’ goal was to assess the effects of clozapine, olanzapine, risperidone, and haloperidol on glucose and cholesterol levels in hospitalized patients with schizophrenia or schizoaffective disorder during a randomized double-blind 14-week trial. METHOD: One hundred fifty-seven patients with schizophrenia or schizoaffective disorder who were inpatients at four hospitals were originally included in the study. The 14-week trial consisted of an 8-week fixed-dose period and a 6-week variable-dose period. Planned assessments included fasting glucose and cholesterol, which were collected at baseline and at the end of the 8-week period and the following 6-week period. RESULTS: One hundred eight of the 157 patients provided blood samples at baseline and at least at one point after random assignment to clozapine, olanzapine, risperidone, or haloperidol during the treatment trial. Seven of these patients had diabetes; their glucose levels were >125 mg/dl at baseline. Data from 101 patients were used for statistical analyses. During the initial 8-week period there was an overall significant increase in mean glucose levels. There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine (N=27) and those given haloperidol (N=25). The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period (N=22). Fourteen of the 101 patients developed abnormal glucose levels (>125 mg/dl) during the trial (six with clozapine, four with olanzapine, three with risperidone, and one with haloperidol). Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine (N=27) and those given olanzapine (N=26); cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine (N=22). CONCLUSIONS: In this prospective randomized trial, clozapine, olanzapine, and haloperidol were associated with an increase of plasma glucose level, and clozapine and olanzapine were associated with an increase in cholesterol levels. The mean changes in glucose and cholesterol levels remained within clinically normal ranges, but approximately 14% of the patients developed abnormally high glucose levels during the course of their participation in the study.

To examine the course and potential predictors of treatment response in the early phase of schizophrenia.Prospective study of an inception cohort.Psychiatric division of an academic medical center with a suburban metropolitan catchment area.Seventy first-episode patients who had undergone four biologic assessment procedures (brain magnetic resonance imaging, behavioral response to methylphenidate hydrochloride, growth hormone levels, eye tracking) were treated with a standardized antipsychotic drug protocol until recovery. Response was measured in terms of psychopathology and degree of remission.Using survival analysis, the proportion of patients remitting by 1 year was estimated at 83%. Mean and median times to remission were 35.7 weeks and 11 weeks, respectively. No baseline demographic or psychopathologic measure significantly predicted time to or level of remission. However, males tended to be nonresponders to treatment and have diagnoses of schizophrenia rather than schizoaffective disorder. Brain pathomorphology and abnormal basal growth hormone significantly predicted time to remission.These results indicate that the antipsychotic treatment response of first-episode schizophrenics is better than chronic multiepisode patients and suggest that specific pathobiologic markers reflect pathophysiologic processes that mediate antipsychotic treatment response.

Objective: When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation. Method: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]). Results: Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation. Conclusions: For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine’s serious side effects.

Objective: Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder. Method: This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5–20 mg/day), risperidone (0.5–6 mg/day), or molindone (10–140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and ≥20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment. Results: In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. Conclusions: Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders.

Although there has been recent interest in the study of childhood and adolescent brain development, very little is known about normal brain development in the first few months of life. In older children, there are regional differences in cortical gray matter development, whereas cortical gray and white matter growth after birth has not been studied to a great extent. The adult human brain is also characterized by cerebral asymmetries and sexual dimorphisms, although very little is known about how these asymmetries and dimorphisms develop. We used magnetic resonance imaging and an automatic segmentation methodology to study brain structure in 74 neonates in the first few weeks after birth. We found robust cortical gray matter growth compared with white matter growth, with occipital regions growing much faster than prefrontal regions. Sexual dimorphism is present at birth, with males having larger total brain cortical gray and white matter volumes than females. In contrast to adults and older children, the left hemisphere is larger than the right hemisphere, and the normal pattern of fronto-occipital asymmetry described in older children and adults is not present. Regional differences in cortical gray matter growth are likely related to differential maturation of sensory and motor systems compared with prefrontal executive function after birth. These findings also indicate that whereas some adult patterns of sexual dimorphism and cerebral asymmetries are present at birth, others develop after birth.

Prenatal exposure to infection appears to increase the risk of schizophrenia and other neurodevelopmental disorders. We have hypothesized that cytokines, generated in response to maternal infection, play a key mechanistic role in this association. E16 timed pregnancy rats were injected i.p. with Escherichia coli lipopolysaccharide (LPS) to model prenatal exposure to infection. Placenta, amniotic fluid and fetal brains were collected 2 and 8h after LPS exposure. There was a significant treatment effect of low-dose (0.5mg/kg) LPS on placenta cytokine levels, with significant increases of interleukin (IL)-1beta (P<0.0001), IL-6 (P<0.0001), and tumor necrosis factor-alpha (TNF-alpha) (P=0.0001) over the 2 and 8h time course. In amniotic fluid, there was a significant effect of treatment on IL-6 levels (P=0.0006). Two hours after maternal administration of high-dose (2.5mg/kg) LPS, there were significant elevations of placenta IL-6 (P<0.0001), TNF-alpha (P<0.0001), a significant increase of TNF-alpha in amniotic fluid (P=0.008), and a small but significant decrease in TNF-alpha (P=0.035) in fetal brain. Maternal exposure to infection alters pro-inflammatory cytokine levels in the fetal environment, which may have a significant impact on the developing brain.

The authors compared the efficacy and safety of three atypical antipsychotics (clozapine, olanzapine, and risperidone) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder.In a double-blind trial, 157 inpatients with a history of suboptimal treatment response were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol for 14 weeks (an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period).Clozapine, risperidone, and olanzapine (but not haloperidol) resulted in statistically significant improvements in total score on the Positive and Negative Syndrome Scale. Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol. The atypical drugs, particularly olanzapine and clozapine, were associated with weight gain.The effects of atypical antipsychotics in this population were statistically significant but clinically modest. The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective. Clozapine was the most effective treatment for negative symptoms. However, the differences among treatments were small.

Abstract This study images dopamine release in response to a neurochemically specific challenge with the psychostimulant drug methylphenidate. Changes in synaptic dopamine induced by methylphenidate were evaluated with positron emission tomography and [ 11 C]raclopride, a D 2 receptor radioligand that is sensitive to endogenous dopamine. Methylphenidate significantly decreased striatal [ 11 C]raclopride binding. The decrease was variable and was negatively correlated with age. Mood and anxiety at baseline, were also correlated with methylphenidate‐induced DA changes. This strategy provides a tool to investigate the responsiveness of the dopamine system in the normal and diseased human brain and to investigate the neurochemical correlates of behavior. © 1994 Wiley‐Liss, Inc.

Few long-term studies have compared the efficacy and safety of typical and atypical antipsychotic medications directly in patients with a first episode of psychosis who met the criteria for schizophrenia or a related psychotic disorder. This study compared the acute and long-term effectiveness of haloperidol with that of olanzapine in patients with first-episode psychosis in a large, controlled clinical trial.Patients with first-episode psychosis (N=263) were randomly assigned under double-blind conditions to receive haloperidol or olanzapine and were followed for up to 104 weeks. Domains measured included psychopathology, psychosocial variables, neurocognitive functioning, and brain morphology and metabolism. This report presents data from clinical measures of treatment response and safety data from the 12-week acute treatment phase.Haloperidol and olanzapine were associated with substantial and comparable baseline-to-endpoint reductions in symptom severity, which did not differ significantly in last-observation-carried-forward analyses. However, in a mixed-model analysis, olanzapine-treated subjects had significantly greater decreases in symptom severity as measured by the Positive and Negative Syndrome Scale total score and negative and general scales and by the Montgomery-Asberg Depression Rating Scale but not as measured by the Positive and Negative Syndrome Scale positive scale and by the Clinical Global Impression severity rating. Olanzapine-treated patients experienced a lower rate of treatment-emergent parkinsonism and akathisia but had significantly more weight gain, compared with the haloperidol-treated patients. Overall, significantly more olanzapine-treated subjects than haloperidol-treated subjects completed the 12-week acute phase of the study (67% versus 54%).As expected on the basis of previous studies, both olanzapine and haloperidol were effective in the acute reduction of psychopathological symptoms in this group of patients with first-episode psychosis. However, olanzapine had several relative advantages in therapeutic response. Although the nature of adverse events differed between the two agents, retention in the study was greater with olanzapine. Retention in treatment is important in this patient population, given their risk of relapse. Longer-term results are needed to determine whether treatment with atypical antipsychotics results in superior outcomes for a first episode of schizophrenia.

Abstract These updated guidelines are based on a first edition of the World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia published in 2006. For this 2012 revision, all available publications pertaining to the biological treatment of schizophrenia were reviewed systematically to allow for an evidence-based update. These guidelines provide evidence-based practice recommendations that are clinically and scientifically meaningful. They are intended to be used by all physicians diagnosing and treating people suffering from schizophrenia. Based on the first version of these guidelines, a systematic review of the MEDLINE/PUBMED database and the Cochrane Library, in addition to data extraction from national treatment guidelines, has been performed for this update. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into six levels of evidence (A-F) and five levels of recommendation (1-5) ( Bandelow et al. 2008a ,b, World J Biol Psychiatry 9:242, see Table 1 ). This second part of the updated guidelines covers long-term treatment as well as the management of relevant side effects. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication and other pharmacological treatment options) of adults suffering from schizophrenia.

This study addressed the unique clinical properties attributed to the atypical antipsychotic clozapine, including its efficacy in patients with treatment-refractory psychosis and against negative symptoms, its lack of acute extrapyramidal side effects, and the longer time course of its therapeutic effects.The clinical responses of 84 schizophrenic inpatients (66 with treatment-refractory illness and 18 who were intolerant of antipsychotic treatment) were examined. After all previous antipsychotic medications had been withdrawn, the patients were treated with clozapine according to a standardized titration and dosage schedule. Patients who tolerated and responded to treatment were discharged and maintained on a regimen of clozapine for up to 52 weeks. Patients were evaluated for behavioral response and side effects after weeks 3, 6, 12, 26, 39, and 52 of treatment.Fifty percent of the patients with treatment-refractory illness and 76% of the treatment-intolerant patients responded to clozapine in up to 52 weeks. The optimal period for a trial of clozapine appeared to be 12-24 weeks. Clozapine exhibited therapeutic effects on negative symptoms, but these were not clearly independent of its effects on positive symptoms and extrapyramidal side effects. Several variables, including early age at onset of illness and female gender, were found to be predictors of poor response to treatment. Predictors of good response included the presence of extrapyramidal side effects during previous treatment with classic neuroleptics and a diagnosis of paranoid schizophrenia.These findings have important implications for the use of clozapine and our understanding of the pathophysiology of treatment-resistant schizophrenia.

This study examined the treatment response of patients with first-episode schizophrenia and schizoaffective disorder and potential predictors of response.First-episode patients were assessed on measures of psychopathology, cognition, social functioning, and biological parameters and treated according to a standardized algorithm.One hundred eighteen patients (52% male, mean age 25.2 years) entered the study. The cumulative percentage of patients responding by 1 year was 87%; the median time to response was 9 weeks. The following variables were significantly associated with less likelihood of response to treatment: male sex, obstetric complications, more severe hallucinations and delusions, poorer attention at baseline, and the development of parkinsonism during antipsychotic treatment. Variables not significantly related to treatment response were diagnosis (schizophrenia versus schizoaffective disorder), premorbid functioning, duration of psychotic symptoms prior to study entry, baseline disorganization, negative and depressive symptoms, baseline motor function, akathisia and dystonia during treatment, growth hormone and homovanillic acid measures, psychotic symptom activation to methylphenidate, and magnetic resonance measures.Patients with first-episode schizophrenia and schizoaffective disorder have high rates of response to antipsychotic treatment; there are specific clinical and pathobiologic predictors of response.

Little is known for certain about the genetics of schizophrenia. The advent of genomewide association has been widely anticipated as a promising means to identify reproducible DNA sequence variation associated with this important and debilitating disorder. A total of 738 cases with DSM-IV schizophrenia (all participants in the CATIE study) and 733 group-matched controls were genotyped for 492 900 single-nucleotide polymorphisms (SNPs) using the Affymetrix 500K two-chip genotyping platform plus a custom 164K fill-in chip. Following multiple quality control steps for both subjects and SNPs, logistic regression analyses were used to assess the evidence for association of all SNPs with schizophrenia. We identified a number of promising SNPs for follow-up studies, although no SNP or multimarker combination of SNPs achieved genomewide statistical significance. Although a few signals coincided with genomic regions previously implicated in schizophrenia, chance could not be excluded. These data do not provide evidence for the involvement of any genomic region with schizophrenia detectable with moderate sample size. However, a planned genomewide association study for response phenotypes and inclusion of individual phenotype and genotype data from this study in meta-analyses hold promise for eventual identification of susceptibility and protective variants.

Volumes of the mesiotemporal structures (hippocampus-amygdala complex) were measured in 19 men who were chronic multiepisode schizophrenics and 18 age-matched healthy controls using T1-weighted contiguous coronal magnetic resonance images of 3.1-mm width. Using the level of the mammillary bodies as an anatomical landmark, the whole hippocampus-amygdala complex was divided into an anterior section (mainly containing amygdaloid tissue) and a posterior section (mainly containing the hippocampal formation). Total mesiotemporal tissue volume was reduced significantly in the patient group compared to controls (-11%), with significant reductions in both left (-20%) and right (-15%) hippocampal sections. Reduced limbic tissue volume was associated with increased severity of psychopathology. Severity of positive psychotic symptoms (Brief Psychiatric Rating Scale [BPRS] psychosis factor) was correlated significantly with right and left total mesiotemporal volumes (Spearman rho's = -0.61 p < 0.01). Negative symptom scores (BPRS anergia factor, Scale for Assessment of Negative Symptoms [SANS] global items) were not significantly correlated with any mesiotemporal tissue volumes. The data corroborate and extend previous findings of temporolimbic structure volume reduction in schizophrenia, and suggest that the positive psychotic symptoms of schizophrenia are associated with anatomic anomalies in mesiotemporal structure.

The purported advantages of second-generation or "atypical" antipsychotics relative to first-generation antipsychotics have not been examined in patients with a first episode of schizophrenia. This flexible-dose study examined efficacy and safety in a randomized, double-blind, 52-week trial, comparing chlorpromazine (CPZ) and clozapine (CLZ) in treatment naive patients experiencing their first episode of schizophrenia. In all, 160 inpatients with first-episode schizophrenia or schizophreniform disorder were randomized to CPZ or CLZ and followed them for 52 weeks or until dropout. The primary efficacy measure was time to first remission and proportion of time remaining in remission. The analysis was supplemented by comparisons on a profile of clinical symptoms and side effects. Of these first-episode patients, 80% achieved remission within 1 year (79% CPZ, 81% CLZ). The Kaplan-Meier estimated median time to first remission was 8 weeks for CLZ vs 12 weeks for CPZ (chi(2)(1)=5.56, p=0.02). Both the rate of first achieving remission and the odds for being in remission during the trial were almost doubled for the CLZ group in comparison with the CPZ group. At 12 weeks, CLZ was superior on many rating scale measures of symptom severity while CPZ was not superior on any. These symptom differences remained significant when controlling for EPS differences. By 52 weeks many of the symptom differences between groups were no longer significantly different. Generally, CLZ produced fewer side effects than CPZ, particularly extrapyramidal side effects. There was no significant difference between treatments in weight change or glucose metabolism. For each prior year of untreated psychosis, there was a 15% decrease in the odds of achieving remission (OR=0.85; CI 0.75-0.95). A high proportion of first-episode patients remitted within 1 year. We detected no difference in the proportion of first-episode patients receiving CLZ or CPZ that achieved remission. However, first-episode patients receiving CLZ remitted significantly faster and remained in remission longer than subjects receiving CPZ. While the CLZ group showed significantly less symptomatology on some measures and fewer side effects at 12 weeks, the two treatment groups seemed to converge by 1 year. Longer duration of untreated psychosis was associated with lower odds of achieving remission.

<h3>Importance</h3> Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cortex (PFC) in schizophrenia. Despite the prevalence of the concept of prefrontal cortical hypodopaminergia in schizophrenia, in vivo imaging of dopamine release in the PFC has not been possible until now, when the validity of using the positron emission tomographic D2/3 radiotracer carbon 11–labeled FLB457 in combination with the amphetamine paradigm was clearly established. <h3>Objectives</h3> To (1) test amphetamine-induced dopamine release in the dorsolateral PFC (DLPFC) in drug-free or drug-naive patients with schizophrenia (SCZ) and healthy control (HC) individuals matched for age, sex, race/ethnicity, and familial socioeconomic status;(2) test blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging activation during a working memory task in the same participants; and (3) examine the relationship between positron emission tomographic and functional magnetic resonance imaging outcome measures. <h3>Design, Setting and Participants</h3> Positron emission tomographic imaging with carbon 11–labeled FLB457 before and following 0.5 mg/kg of amphetamine by mouth. Blood oxygenation level–dependent functional magnetic resonance imaging during the self-ordered working memory task. Twenty patients with schizophrenia recruited from the inpatient and outpatient research facilities at New York State Psychiatric Institute and 21 healthy control individuals participated, and data were acquired between June 16, 2011, and February 25, 2014. <h3>Main Outcomes and Measure</h3> The percentage change in binding potential (∆BP_ND) in the DLPFC following amphetamine, BOLD activation during the self-ordered working memory task compared with the control task, and the correlation between these 2 outcome measures. <h3>Results</h3> We observed significant differences in the effect of amphetamine on DLPFC BP_ND(mean [SD], ∆BP_NDin HC: −7.5% [11%]; SCZ: +1.8% [11%];<i>P</i> = .01); a generalized blunting in dopamine release in SCZ involving most extrastriatal regions and the midbrain; and a significant association between ∆BP_NDand BOLD activation in the DLPFC in the overall sample including patients with SCZ and HC individuals. <h3>Conclusions and Relevance</h3> To our knowledge, these results provide the first in vivo evidence for a deficit in the capacity for dopamine release in the DLPFC in SCZ and suggest a more widespread deficit extending to many cortical and extrastriatal regions including the midbrain. This contrasts with the well-replicated excess in dopamine release in the associative striatum in SCZ and suggests a differential regulation of striatal dopamine release in associative striatum vs extrastriatal regions. Furthermore, dopamine release in the DLPFC relates to working memory–related activation of this region, suggesting that blunted release may affect frontal cortical function.

An increasing body of evidence suggests that, in comparison to the general population, patients with severe mental illnesses such as schizophrenia or bipolar disorder have worse physical health and a far shorter life expectancy in developed countries, due primarily to premature cardiovascular disease.This article is based on presentations and discussion on somatic comorbidity in psychiatric illnesses by a group of 37 international experts during 2 meetings held in 2006.At the preparatory meeting in Paris, France, the group determined key topics for presentations and group discussions. During the meeting in Vienna, Austria, on day 1, each set of presentations was followed by discussions in small groups with the meeting participants. On day 2, conclusions reached by each discussion group were presented and used as a platform for a consensus view adopted by the meeting participants. The presentations and discussions were collated into a draft that was revised and approved by each of the bylined authors.General health care needs are commonly neglected in patients with severe mental illness, with suboptimal integration of general somatic and psychiatric care services, current lack of consensus as to which health care professionals should be responsible for the prevention and management of comorbid somatic illnesses in patients with severe mental disorders, and, at least in some countries, a paucity of funding for general somatic care for patients with severe mental disorders, especially those in long-term psychiatric treatment.The somatic health of patients with severe medical illnesses is too often neglected, thus contributing to an egregious health disparity. The reintegration of psychiatry and medicine, with an ultimate goal of providing optimal services to this vulnerable patient population, represents the most important challenge for psychiatry today, requiring urgent and comprehensive action from the profession toward achieving an optimal solution.

This 52-week randomized, double-blind, flexible-dose, multicenter study evaluated the overall effectiveness (as measured by treatment discontinuation rates) of olanzapine, quetiapine, and risperidone in patients early in the course of psychotic illness.Patients were randomly assigned to treatment with olanzapine (2.5-20 mg/day), quetiapine (100-800 mg/day), or risperidone (0.5-4 mg/day) administered in twice-daily doses. Statistical analyses tested for noninferiority in all-cause treatment discontinuation rates up to 52 weeks (primary outcome measure) based on a prespecified noninferiority margin of 20%.A total of 400 patients were randomly assigned to treatment with olanzapine (N=133), quetiapine (N=134), or risperidone (N=133). The mean modal prescribed daily doses were 11.7 mg for olanzapine, 506 mg for quetiapine, and 2.4 mg for risperidone. At week 52, all-cause treatment discontinuation rates were 68.4%, 70.9%, and 71.4% for olanzapine, quetiapine, and risperidone, respectively. Reductions in total score on the Positive and Negative Syndrome Scale (PANSS) were similar for the three treatment groups, but reductions in PANSS positive subscale scores were greater in the olanzapine group (at 12 weeks and at 52 weeks or withdrawal from study) and the risperidone group (at 12 weeks). The most common elicited adverse events for olanzapine were drowsiness (53%), weight gain (51%), and insomnia (38%); for quetiapine, drowsiness (58%), increased sleep hours (42%), and weight gain (40%); and for risperidone, drowsiness (50%), menstrual irregularities in women (47%), and weight gain (41%).Olanzapine, quetiapine, and risperidone demonstrated comparable effectiveness in early-psychosis patients, as indicated by similar rates of all-cause treatment discontinuation.

The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimer's disease and psychosis or agitated behavior.The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Alzheimer's disease effectiveness study included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinician's discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals.In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo.In this descriptive analysis of outpatients with Alzheimer's disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life.

The metabolic syndrome (MS) is associated with increased risk for diabetes mellitus and coronary heart disease, and is highly prevalent among schizophrenia patients. Given concerns over antipsychotic metabolic effects, this analysis explored MS status and outcomes in phase 1 of the CATIE Schizophrenia Trial. The change in proportion of subjects with MS and individual criteria was compared between antipsychotic treatment groups, along with mean changes for individual criteria. Primary analyses examined subjects with fasting laboratory assessments at baseline and 3 months. Other analyses examined 3-month changes in MS status, waist circumference (WC), HDL cholesterol and blood pressure in all subjects, metabolic changes at the end of phase 1 participation (EOP), and repeated measures changes in HDL, blood pressure (BP) and WC over phase 1. At 3 months, there were no significant between-drug differences for the change in proportion of subjects meeting MS status or individual MS criteria in the smaller fasting cohort (n = 281) or for those meeting criteria for parameters not dependent on fasting status (BP, HDL, WC) among all subjects (n = 660). Among all subjects whose MS status could be determined at 3 months (n = 660), MS prevalence increased for olanzapine (from 34.8% to 43.9%), but decreased for ziprasidone (from 37.7% to 29.9%) (p = .001). Although effect sizes varied across subgroups, at 3 months olanzapine and quetiapine had the largest mean increase in waist circumference (0.7 in. for both) followed by risperidone (0.4 in.), compared to no change for ziprasidone (0.0 in.) and a decrease in waist circumference for perphenazine (− 0.4 in.). Olanzapine also demonstrated significantly different changes in fasting triglycerides at 3 months (+ 21.5 mg/dl) compared to ziprasidone (− 32.1 mg/dl). EOP exposure data was obtained, on average, nine months from baseline for all metabolic variables. Results from EOP and repeated measures analyses were consistent with those at 3 months for mean changes in WC and fasting triglycerides, but between group differences emerged for HDL and SBP. This large non-industry sponsored study confirms the differential metabolic effects between antipsychotics. Clinicians are advised to monitor all metabolic parameters, including WC, HDL and serum triglycerides, during antipsychotic treatment.

Abstract Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia—from the premorbid through the prodromal stages to syndromal psychosis—and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.

<h3>Importance</h3> Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects. <h3>Objective</h3> To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia. <h3>Design, Setting, and Participants</h3> This randomized, double-blind, placebo-controlled, phase 3 clinical trial was conducted from November 13, 2014, to July 20, 2015, with data analyses performed from August 13 to September 15, 2015. Patients with schizophrenia who were aged 18 to 60 years and were experiencing an acute exacerbation of psychosis were enrolled from 12 clinical sites in the United States. <h3>Interventions</h3> Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks. <h3>Main Outcomes and Measures</h3> The prespecified primary efficacy end point was mean change from baseline to day 28 in the Positive and Negative Syndrome Scale (PANSS) total score vs placebo. The key secondary efficacy measure was the Clinical Global Impression–Severity of Illness (CGI-S) score. The PANSS subscale scores, social function, safety, and tolerability were also assessed. <h3>Results</h3> The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]). In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], −4.2; 95% CI, −7.8 to −0.6;<i>P</i> = .02; effect size [ES], −0.3) and the CGI-S (LSMD, −0.3; 95% CI, −0.5 to −0.1;<i>P</i> = .003; ES, −0.4). For 28 mg of lumateperone, the LSMD from baseline to day 28 was −2.6 (95% CI, −6.2 to 1.1;<i>P</i> = .16; ES, −0.2) on the PANSS total score and −0.2 (95% CI, −0.5 to 0.0;<i>P</i> = .02; ES, −0.3) on the CGI-S. Both lumateperone doses were well tolerated without clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors vs placebo. <h3>Conclusions and Relevance</h3> Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile. <h3>Trial Registration</h3> ClinicalTrials.gov identifier:NCT02282761

An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues. ITI-007 is a new molecular entity with a pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins.A phase II randomized, double-blind, placebo-controlled, and active-controlled trial was conducted at eight sites in the United States with randomization of 335 acutely psychotic adults with schizophrenia. ITI-007 (60 mg and 120 mg), placebo, and risperidone, included for assay sensitivity, were evaluated as monotherapy for 4 weeks. The primary outcome measure was the Positive and Negative Syndrome Scale total score, with secondary analyses conducted on symptom subscales.ITI-007 60 mg (p = .017, effect size = .4) and risperidone (p = .013, effect size = .4) demonstrated antipsychotic efficacy superiority over placebo on the primary end point. The results of secondary analyses reflected improvements in negative and depressive symptoms by ITI-007 60 mg. ITI-007 120 mg did not separate from placebo. However, both doses of ITI-007 were well tolerated in this patient population, as evidenced by low discontinuation and adverse event rates, and were associated with a benign metabolic profile as evidenced by significantly lower levels of prolactin, fasting glucose, total cholesterol, and triglycerides than risperidone.The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial. Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have expanded therapeutic efficacy in comparison with current antipsychotic drugs.

Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D(2)-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy ((1)H MRS) and positron emission tomography (PET)/single-photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed (1)H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ.

Objective This review of the scientific literature examines the potential adult sequelae of exposure to cannabis and related synthetic cannabinoids in adolescence. We examine the four neuropsychiatric outcomes that are likely most vulnerable to alteration by early cannabinoid use, as identified within both the clinical and preclinical research: cognition, emotional functioning, risk for psychosis, and addiction. Method A literature search was conducted through PubMed, PsychInfo, and Google Scholar with no publication date restrictions. The search terms used were “adolescent” and “adult,” and either “cannabis,” “marijuana,” “delta-9-tetra-hydrocannabinol,” or “cannabinoid,” which was then crossed with one or more of the following terms: “deficit,” “impairment,” “alteration,” “long-term,” “persistent,” “development,” “maturation,” and “pubescent.” Results The majority of the clinical and preclinical data point to a strong correlation between adolescent cannabinoid exposure and persistent, adverse neuropsychiatric outcomes in adulthood. Although the literature supports the hypothesis that adolescent cannabis use is connected to impaired cognition and mental health in adults, it does not conclusively demonstrate that cannabis consumption alone is sufficient to cause these deficits in humans. The animal literature, however, clearly indicates that adolescent-onset exposure to cannabinoids can catalyze molecular processes that lead to persistent functional deficits in adulthood, deficits that are not found to follow adult-onset exposure and that model some of the adverse outcomes reported in humans among adult populations of early-onset cannabis users. Conclusion Based on the data in the current literature, a strong association is found between early, frequent, and heavy adolescent cannabis exposure and poor cognitive and psychiatric outcomes in adulthood, yet definite conclusions cannot yet be made as to whether cannabis use alone has a negative impact on the human adolescent brain. Future research will require animal models and longitudinal studies to be carefully designed with a focus on integrating assessments of molecular, structural, and behavioral outcomes in order to elucidate the full range of potential adverse and long-term consequences of cannabinoid exposure in adolescence. This review of the scientific literature examines the potential adult sequelae of exposure to cannabis and related synthetic cannabinoids in adolescence. We examine the four neuropsychiatric outcomes that are likely most vulnerable to alteration by early cannabinoid use, as identified within both the clinical and preclinical research: cognition, emotional functioning, risk for psychosis, and addiction. A literature search was conducted through PubMed, PsychInfo, and Google Scholar with no publication date restrictions. The search terms used were “adolescent” and “adult,” and either “cannabis,” “marijuana,” “delta-9-tetra-hydrocannabinol,” or “cannabinoid,” which was then crossed with one or more of the following terms: “deficit,” “impairment,” “alteration,” “long-term,” “persistent,” “development,” “maturation,” and “pubescent.” The majority of the clinical and preclinical data point to a strong correlation between adolescent cannabinoid exposure and persistent, adverse neuropsychiatric outcomes in adulthood. Although the literature supports the hypothesis that adolescent cannabis use is connected to impaired cognition and mental health in adults, it does not conclusively demonstrate that cannabis consumption alone is sufficient to cause these deficits in humans. The animal literature, however, clearly indicates that adolescent-onset exposure to cannabinoids can catalyze molecular processes that lead to persistent functional deficits in adulthood, deficits that are not found to follow adult-onset exposure and that model some of the adverse outcomes reported in humans among adult populations of early-onset cannabis users. Based on the data in the current literature, a strong association is found between early, frequent, and heavy adolescent cannabis exposure and poor cognitive and psychiatric outcomes in adulthood, yet definite conclusions cannot yet be made as to whether cannabis use alone has a negative impact on the human adolescent brain. Future research will require animal models and longitudinal studies to be carefully designed with a focus on integrating assessments of molecular, structural, and behavioral outcomes in order to elucidate the full range of potential adverse and long-term consequences of cannabinoid exposure in adolescence.

Psychosis is a syndrome embedded in several disorders, including schizophrenia and bipolar disorder with psychotic features. Dopamine and glutamate are implicated in the pathophysiology of psychotic symptoms. Psychosocial treatments supplement pharmacologic therapy.

The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor–blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown.

Concerns have been raised that treatment with antipsychotic medication might adversely affect long-term outcomes for people with schizophrenia. The evidence cited for these concerns includes the association of antipsychotic treatment with brain volume reduction and with dopamine receptor sensitization, which might make patients vulnerable to relapse and illness progression. An international group of experts was convened to examine findings from clinical and basic research relevant to these concerns. Little evidence was found to support a negative long-term effect of initial or maintenance antipsychotic treatment on outcomes, compared with withholding treatment. Randomized controlled trials strongly support the efficacy of antipsychotics for the acute treatment of psychosis and prevention of relapse; correlational evidence suggests that early intervention and reduced duration of untreated psychosis might improve longer-term outcomes. Strategies for treatment discontinuation or alternative nonpharmacologic treatment approaches may benefit a subgroup of patients but may be associated with incremental risk of relapse and require further study, including the development of biomarkers that will enable a precision medicine approach to individualized treatment.

To account for the complex genetics, the developmental biology, and the late adolescent/early adulthood onset of schizophrenia, the "two-hit" hypothesis has gained increasing attention. In this model, genetic or environmental factors disrupt early central nervous system (CNS) development. These early disruptions produce long-term vulnerability to a "second hit" that then leads to the onset of schizophrenia symptoms. The cell-cell signaling pathways involved in nonaxial induction, morphogenesis, and differentiation in the brain, as well as in the limbs and face, could be targets for a "first hit" during early development. These same pathways, redeployed for neuronal maintenance rather than morphogenesis, may be targets for a "second hit" in the adolescent or adult brain. Furthermore, dysregulation of cell-cell signaling by a "first hit" may prime the CNS for a pathologic response to a "second hit" via the same signaling pathway. Thus, parallel disruption of cell-cell signaling in both the developing and the mature CNS provides a plausible way of integrating genetic, developmental, and environmental factors that contribute to vulnerability and pathogenesis in schizophrenia.

Neurocognitive deficits are recognized as a cardinal feature of schizophrenia, but the determinants of these deficits remain unknown. Recent reports have suggested that a functional polymorphism, Val(158)Met in exon III of the catechol-O-methyltransferase gene, shares approximately 4% variance with performance on the Wisconsin Card Sorting Test. These findings led to suggestions that the catechol-O-methyltransferase polymorphism may exert its effects by modulating prefrontal dopamine function, but few other neurocognitive measures have been examined, leaving open questions about phenotypic specificity.We examined the effects of the catechol-O-methyltransferase Val(158)Met polymorphism in 58 individuals with chronic schizophrenia who completed a battery of 15 neurocognitive tests, which were reduced to four reliable neurocognitive domain scores. We examined the effects of genotype on these four domains and on global neurocognitive ability.The Met allele was associated with better performance in the Processing Speed and Attention domain, but not with other domain scores measuring executive and visuoperceptual functions, declarative verbal learning and memory, simple motor ability, or global neurocognitive function. Genotype shared approximately 11% of variance with Processing Speed and Attention scores, and approximately 2% of variance with Wisconsin Card Sorting Test scores.The findings provide independent support for the hypothesis that the catechol-O-methyltransferase Val(158)Met polymorphism influences neurocognitive function in schizophrenia, and suggest that the functional effects may be expressed on measures of Processing Speed and Attention. This information may prompt reconsideration of the "prefrontal dopamine" hypothesis and invites examination of a broader range of effects in efforts to refine the neurocognitive phenotype that is most relevant to variation in catechol-O-methyltransferase expression.

OBJECTIVE: The effect of antipsychotic medication on neurocognitive function remains controversial, especially since most previous work has compared the effects of novel antipsychotic medications with those of high doses of conventional medications. This study compares the neurocognitive effects of olanzapine and low doses of haloperidol in patients with first-episode psychosis. METHOD: Patients with a first episode of schizophrenia, schizoaffective disorder, or schizophreniform disorder (N=167) were randomly assigned to double-blind treatment with olanzapine (mean modal dose= 9.63 mg/day) or haloperidol (mean modal dose=4.60 mg/day) for the 12-week acute phase of a 2-year study. The patients were assessed with a battery of neurocognitive tests at baseline and 12 weeks after beginning treatment. RESULTS: An unweighted neurocognitive composite score, composed of measures of verbal fluency, motor functions, working memory, verbal memory, and vigilance, improved significantly with both haloperidol and olanzapine treatment (effect sizes of 0.20 and 0.36, respectively, no significant difference between groups). A weighted composite score developed from a principal-component analysis of the same measures improved to a significantly greater degree with olanzapine, compared with haloperidol. Anticholinergic use, extrapyramidal symptoms, and estimated IQ had little effect on the statistical differentiation of the medications, although duration of illness had a modest effect. The correlations of cognitive improvement with changes in clinical characteristics and with side effects of treatment were significant for patients who received haloperidol but not for patients who received olanzapine. CONCLUSIONS: Olanzapine has a beneficial effect on neurocognitive function in patients with a first episode of psychosis. However, in a comparison of the effects of olanzapine and low doses of haloperidol, the difference in benefit is small.

<h3>Background:</h3> Previous studies have examined dose reduction and family treatment in schizophrenia, but none has examined their interaction. This study assessed the impact of dose reduction of antipsychotic medication and family treatment on relapse and rehospitalization during maintenance treatment. <h3>Methods:</h3> Subjects were 313 male and female outpatients at 5 centers with a<i>DSM-III-R</i>diagnosis of schizophrenia or schizoaffective disorder. In a 3X2 design, subjects were randomized to 1 of 3 medication strategies using fluphenazine decanoate under double-blind conditions: continuous moderate dose (standard) (12.5-50 mg every 2 weeks); continuous low dose (2.5-10 mg every 2 weeks); or targeted, early intervention (fluphenazine only when symptomatic). Subjects also were randomized to 1 of 2 family treatment strategies (supportive or applied). Supportive family management involved monthly group meetings. The more intensive applied family management involved monthly group meetings and home visits where communication and problem-solving skills were taught. Patients and families were treated and assessed for 2 years. <h3>Results:</h3> Both continuous low-dose and targeted treatment increased use of rescue medication and relapse; only targeted treatment increased rehospitalization. This pattern was consistent across both family treatments; there were no differences between family treatments. <h3>Conclusions:</h3> These findings reaffirm the value of antipsychotic medication in preventing relapse and rehospitalization. The absence of family treatment differences may be because both conditions engaged families.

This pilot study was undertaken to estimate the acute antipsychotic effect size and side effect propensity of risperidone and olanzapine in the pediatric population, in comparison to haloperidol, a conventional antipsychotic with established efficacy. Risperidone and olanzapine are widely used as first-line treatments to ameliorate psychotic symptoms in youth, but their abilities to specifically treat children and adolescents presenting due to psychotic symptoms have not been rigorously studied. Subjects, selected because of prominent positive psychotic symptoms, were randomly assigned to double-blind, parallel treatment with risperidone, olanzapine, or haloperidol for 8 weeks. The primary outcome was reduction in the Brief Psychiatric Rating Scale for Children total score from baseline to termination. An exploratory, descriptive analysis was done to compare the three treatments. A total of 50 patients, 8-19 years, participated. All treatments reduced symptoms significantly with p-values (corrected for multiple comparisons) of 0.0018 for each of the atypical agents and 0.012 for haloperidol. In all, 88% of subjects treated with olanzapine, 74% treated with risperidone, and 53% treated with haloperidol met response criteria. The primary side effects observed in all patients were mild to moderate sedation, extrapyramidal symptoms, and weight gain. Risperidone and olanzapine acutely reduced psychotic symptoms in this pediatric sample. Exploratory comparisons indicate the magnitude of the antipsychotic response with these atypical agents is comparable to that observed with haloperidol. However, youth treated with risperidone and olanzapine experienced weight gain and extrapyramidal effects that appear more prevalent and severe than reported in adults.

This article presents a new interview-based research instrument for assessing schizotypal symptoms and signs. The Structured Interview for Schizotypy (SIS), which was developed from experience gained in a large, controlled family study of schizophrenia in the west of Ireland and has been field-tested in three other locations, differs from previously available interviews in that it includes: (1) built-in contextual assessments of the pathological nature of certain symptoms (e.g., suspiciousness or ideas of reference); (2) multiple independently scored items, most with closed response options, per symptom scale; (3) extensive assessment of schizotypal signs; (4) symptom probes designed to make responding positively appear nondeviant; and (5) coverage of potentially relevant symptoms and signs not required in current criteria for schizotypal personality disorder. Schizotypal symptoms can be assessed with high reliability by the SIS. When sufficient variability is present, schizotypal signs are also reliably assessed by the SIS, although the reliability is generally lower than that found for symptoms. In three independent pilot studies, schizotypal symptoms and signs assessed by the SIS appear to discriminate significantly the relatives of schizophrenic patients from relatives of controls.

The developmental processes leading to neuropsychological deficits in schizophrenia are poorly understood. Both early developmental defects and subsequent deterioration may occur. Intelligence test profiles are often used to estimate premorbid ability and deterioration from prior levels of functioning. These characteristics were assessed in samples of first-episode (n = 51) and chronic (n = 50) schizophrenic patients. Although the groups showed few differences on tests to estimate premorbid intellectual ability, the chronic group performed worse on measures considered sensitive to deterioration. Dextral (right-handed) patients tended to have better performance; this effect was marked in the first-episode sample, especially on verbal tests. Male patients showed more evidence of deterioration than female patients. Subgroups differing in the time course of premorbid social dysfunction also differed in intelligence test profiles, suggesting that estimates of social and cognitive deterioration may have concurrent validity. The results support the hypothesis that patients differ in the course of cognitive decline and suggest that deterioration of function may follow the onset of overt psychosis in some patients. Prospective longitudinal studies of first-episode schizophrenic patients could directly test this hypothesis.

This article reviews eight published studies that describe clozapine's effects on TD and examines the outcome of 30 patients with TD treated with clozapine for up to 36 months. These data indicate that TD response to clozapine is variable but that approximately 43% of cases, particularly those with dystonic features, improved after clozapine treatment. Methodological limitations of the studies described, however, preclude definitive conclusions, which must await appropriately controlled trials.

Stimulant drugs such as cocaine and amphetamine are among the most commonly abused substances by schizophrenic patients. This may be due in part to aspects of the illness and treatment side effects that impel patients to use dopamine agonist drugs. Dopaminergic neural systems have been shown to mediate both stimulant drug effects and schizophrenia. Because of the hypothesized overlap in the pathophysiology of schizophrenia and the neurobiological effects of chronic stimulant use, the potential for serious complication of the primary disease by substance abuse exists. This article reviews the neurobiological mechanisms of behavioral sensitization and neurotoxicity associated with chronic stimulant administration in the context of pathophysiological theories of schizophrenia. Discussion focuses on the potential impact of stimulant use on the disease process as well as the manifest phenomenology and course of schizophrenia.

Enhancing medication adherence early in the course of schizophrenia and schizoaffective disorder may substantially improve long-term course. Although extensively studied in multi-episode patients, little data exist on medication adherence by first-episode patients.Medication adherence was assessed during the first year of treatment and following recovery from the first relapse in patients treated by a standardized medication algorithm.During the first year of treatment, patients with poorer premorbid cognitive functioning were more likely to stop antipsychotics (t=-2.54, df=75, p=0.01). Parkinsonian side effects increased the likelihood (hazard ratio=41.22; 95% CI=2.30, 737.89; p=0.01), and better executive function decreased the likelihood (hazard ratio=0.40; 95% CI=0.18, 0.88; p=0.02) that patients discontinued maintenance medication after a first relapse.Interventions to ameliorate cognitive deficits and Parkinsonian side effects may enhance treatment adherence.

Clozapine (CLOZ) is an atypical antipsychotic drug being used with increasing frequency throughout the world and has recently been commercially marketed in the United States. Its unique properties make it a promising but challenging drug to use in the treatment of schizophrenia. In order to use CLOZ most effectively and efficiently, clinicians must be aware of its potential benefits and risks. This report is a review and critical evaluation of current knowledge regarding the clinical efficacy and side effects of CLOZ. Although CLOZ has proven to be effective in some treatment-refractory schizophrenic patients and to produce relatively few extrapyramidal side effects compared to classical neuroleptic drugs, several issues require further investigation including what defines neuroleptic intolerance, the optimal dose range, and the appropriate duration of a CLOZ treatment trial. Similarly, studies are needed to determine what role CLOZ should have in the treatment of patients with predominantly negative symptoms and those patients who are only partially responsive to standard neuroleptics. In addition, important questions remain as to what other conditions might be indications for CLOZ, for example, schizoaffective disorder, affective psychoses, and idiopathic Parkinson's disease.

The cortical neuropathology of schizophrenia includes neuronal atrophy, decreased neuropil, and alterations in neuronal density. Taken together with evidence of decreased synaptic markers and dendritic spines, the data suggest that synaptic circuitry is altered. Recent neuroimaging studies also indicate that a progressive loss of cortical gray matter occurs early in the course of schizophrenia. Although the mechanisms underlying these deficits are largely unknown, recent postmortem data implicate a role for altered neuronal apoptosis. Apoptosis, a form of programmed cell death, is regulated by a complex cascade of pro- and anti-apoptotic proteins. Apoptotic activation can lead to rapid neuronal death. However, emerging data also indicate that sub-lethal apoptotic activity can lead to a limited form of apoptosis in terminal neurites and individual synapses to cause synaptic elimination without cell death. For example, in Alzheimer's disease, a localized apoptotic mechanism is thought to contribute to early neurite and synapse loss leading to the initial cognitive decline. Recent studies indicate that apoptotic regulatory proteins and DNA fragmentation patterns are altered in several cortical regions in schizophrenia. This paper will review converging lines of data that implicate synaptic deficits in the pathophysiology of schizophrenia and propose an underlying role for apoptotic dysregulation.

A systematic review of the literature identified 64 published English-language papers that used proton (1H) magnetic resonance spectroscopy to measure N-acetylaspartate (NAA) concurrently in healthy controls and in patients with a diagnosis of schizophrenia (SZ). A total of 1209 controls and 1256 patients have been evaluated, with 88% of studies carried out at 1.5 T field strength, and 77% of studies focused on patients with chronic SZ. There is consistent evidence that NAA is reduced in a broad range of tissues in the SZ brain. Broad consensus (> or =10 studies) is emerging that NAA levels are reduced > or =5% in hippocampus and in both cortical gray matter (GM) and white matter (WM) of the frontal lobe. There is no evidence to support a hypothesis that relative NAA levels are reduced to a different degree in frontal lobe GM and WM, nor is there robust evidence of a difference in NAA levels between patients with first-episode and chronic SZ. Study reliability may be a problem, as most studies appear to be underpowered. With simple assumptions about the inherent difference in NAA levels between patients and controls, it can be calculated that a minimum sample size of approximately 39 patients and 39 controls is required for acceptable statistical power. Only three of 64 studies included enough subjects to have 80% power to detect a 10% NAA reduction in patients, and no studies were adequately powered to detect a 5% NAA reduction with 80% power.

Statistical shape analysis has become of increasing interest to the neuroimaging community due to its potential to precisely locate morphological changes and thus potentially discriminate between healthy and pathological structures. This paper describes a combined boundary and medial shape analysis based on two different shape descriptions applied to a study of the hippocampus shape abnormalities in schizophrenia. The first shape description is the sampled boundary implied by the spherical harmonic SPHARM description. The second one is the medial shape description called M-rep. Both descriptions are sampled descriptions with inherent point correspondence. Their shape analysis is based on computing differences from an average template structure analyzed using standard group mean difference tests. The results of the global and local shape analysis in the presented hippocampus study exhibit the same patterns for the boundary and the medial analysis. The results strongly suggest that the normalized hippocampal shape of the schizophrenic group is different from the control group, most significantly as a deformation difference in the tail region.

Back to table of contents Previous article Next article No AccessAbsence of regional hemispheric volume asymmetries in first-episode schizophreniaPublished Online:1 Apr 2006https://doi.org/10.1176/ajp.151.10.1437AboutSectionsView articleAbstractPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleAbstractOBJECTIVE: The goal of this study was to determine whether patients experiencing their first episode of schizophrenia differ from healthy subjects in regional cerebral hemispheric volumes or asymmetries. METHOD: Regional volumes corresponding to prefrontal, premotor, sensorimotor, occipitoparietal, and temporal lobes in each hemisphere were measured on contiguous coronal magnetic resonance images in 70 patients experiencing their first episode of schizophrenia and in 51 healthy comparison subjects. RESULTS: Patients did not differ from the comparison subjects in regional or total hemispheric volumes, but they had abnormal hemispheric asymmetries. Subjects in the comparison group had significant lateral asymmetries in each region: their occipitoparietal and sensorimotor regions were larger on the left, and their premotor, prefrontal, and temporal regions were larger on the right. Patients lacked lateral asymmetries and showed significantly less asymmetry than healthy subjects in occipitoparietal, premotor, and prefrontal regions. Absence of the normal asymmetry was more common among patients initially diagnosed with the undifferentiated than with the paranoid subtype of schizophrenia and was associated with more severe negative symptoms among men. Asymmetries were related to sex and handedness regardless of diagnosis; specifically, dextral men showed more asymmetry than nondextral men or dextral women. CONCLUSIONS: The absence of normal hemispheric asymmetries suggests an anomaly in the development of laterally specialized cerebral systems in schizophrenia, and this may be associated with an initial presentation of nonparanoid psychosis. Access content To read the fulltext, please use one of the options below to sign in or purchase access. Personal login Institutional Login Sign in via OpenAthens Purchase Save for later Item saved, go to cart PPV Articles - American Journal of Psychiatry $35.00 Add to cart PPV Articles - American Journal of Psychiatry Checkout Please login/register if you wish to pair your device and check access availability. Not a subscriber? Subscribe Now / Learn More PsychiatryOnline subscription options offer access to the DSM-5 library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development. 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This article reviews research on psychosocial treatment for first-episode psychosis.PsycINFO and MEDLINE were systematically searched for studies that evaluated psychosocial interventions for first-episode psychosis.Comprehensive (i.e., multielement) treatment approaches show promise in reducing symptoms and hospital readmissions, as well as improving functional outcomes, although few rigorously controlled trials have been conducted. Individual cognitive behavior therapy has shown modest efficacy in reducing symptoms, assisting individuals in adjusting to their illness, and improving subjective quality of life, but it has shown minimal efficacy in reducing relapse. Some controlled research supports the benefits of family interventions, while less controlled research has evaluated group interventions.Adjunctive psychosocial interventions early in psychosis may be beneficial across a variety of domains and can assist with symptomatic and functional recovery. More randomized, controlled trials are needed to evaluate the effectiveness of these interventions, particularly for multielement, group, and family treatments.

Using a pharmacogenetic approach in 185 schizophrenics who have been prospectively assessed for clozapine response, we have examined the hypothesis that polymorphisms in the 5-HT2A (HTR2A), and 5-HT2C (HTR2C) genes are involved in its variable response. A-1438 A-->G polymorphism in the putative promoter and a silent T-->C 102 substitution in HTR2A were in almost complete linkage disequilibrium, and neither was associated with response (T-->C. 102 allele: chi 2 = 0.02; 1 df, p = .90; genotype: chi 2 = 0.02, 2 df, p = .99). A his452tyr HTR2A polymorphism was found to be associated with clozapine response (his452tyr allele: chi 2 = 6.43, 1 df, p = .01 [p = .04, Bonferroni corrected]; genotype: chi 2 = 6.54, 2 df, p = .04 [p = .16, Bonferroni corrected]). No HTR2A haplotype was associated with response. Interethnic differences were observed in the frequencies of the cys23ser HTR2C polymorphism. This polymorphism was not significantly associated with response in either of the ethnic groups (Caucasian and African American genotype: chi 2 = 3.46, 2 df, p = .18; chi 2 = .31, 2 df, p = .86, respectively). Although replication is required, the overall results suggest that the his452tyr HTR2A polymorphism may be involved in clozapine response.

Second-generation antipsychotics have largely replaced first-generation antipsychotics for the treatment of schizophrenia, but a large-scale cost/effectiveness analysis has not been attempted.Patients with schizophrenia (N=1,493) were assigned to treatment with a first-generation antipsychotic (perphenazine) or one of four second-generation drugs (olanzapine, quetia-pine, risperidone, or ziprasidone) and followed for up to 18 months. Patients with tardive dyskinesia were prohibited from assignment to perphenazine. Patients could be reassigned at any time to another second-generation drug, including clozapine, but not to perphenazine. The cost analysis included medications plus health services use. Quality-adjusted life year (QALY) ratings were assessed on the basis of Positive and Negative Syndrome Scale (PANSS) subscale scores and side effects. An intention-to-treat analysis included all available observations, classified by initial drug assignment, and costs of reassignment of most patients to another second-generation drug. The analysis was repeated considering only treatment on initially assigned medications.Although QALY ratings, PANSS scores, and other quality of life measures indicated modest improvement over 18 months, there were no significant differences between perphenazine and any second-generation medication. Average total monthly health care costs were 300 dollars-600 dollars (20%-30%) lower for perphenazine than for second-generation antipsychotics because of lower drug cost. Differences in costs remained when maximally discounted drug prices were used for all patients and when only observations during treatment with the first medication were included.Treatment with perphenazine was less costly than treatment with second-generation antipsychotics with no significant differences in measures of effectiveness. However, the trial was limited by a high dropout rate, and longer-term neurological and metabolic side effects require further study.

These guide lines for the biological treatment of schizophrenia were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBO). The goal during the development of these guidelines was to review systematically all available evidence pertaining to the treatment of schizophrenia, and to reach a consensus on a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by all physicians seeing and treating people with schizophrenia. The data used for developing these guidelines have been extracted primarily from various national treatment guidelines and panels for schizophrenia, as well as from meta-analyses, reviews and randomised clinical trials on the efficacy of pharmacological and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into four levels of evidence (A-D). This first part of the guidelines covers disease definition, classification, epidemiology and course of schizophrenia, as well as the management of the acute phase treatment. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication, other pharmacological treatment options, electroconvulsive therapy, adjunctive and novel therapeutic strategies) of adults suffering from schizophrenia.

There are claims that second-generation antipsychotics produce fewer extrapyramidal side-effects (EPS) compared with first-generation drugs.To compare the incidence of treatment-emergent EPS between second-generation antipsychotics and perphenazine in people with schizophrenia.Incidence analyses integrated data from standardised rating scales and documented use of concomitant medication or treatment discontinuation for EPS events. Mixed model analyses of change in rating scales from baseline were also conducted.There were no significant differences in incidence or change in rating scales for parkinsonism, dystonia, akathisia or tardive dyskinesia when comparing second-generation antipsychotics with perphenazine or comparing between second-generation antipsychotics. Secondary analyses revealed greater rates of concomitant antiparkinsonism medication among individuals on risperidone and lower rates among individuals on quetiapine, and lower rates of discontinuation because of parkinsonism among people on quetiapine and ziprasidone. There was a trend for a greater likelihood of concomitant medication for akathisia among individuals on risperidone and perphenazine.The incidence of treatment-emergent EPS and change in EPS ratings indicated that there are no significant differences between second-generation antipsychotics and perphenazine or between second-generation antipsychotics in people with schizophrenia.

Objective: This study examined the relative effects of the second-generation antipsychotic drugs and an older representative agent on psychosocial functioning in patients with chronic schizophrenia. Method: Consenting patients were enrolled in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. In phase 1, patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months. Clozapine was included for patients who chose this pathway after discontinuing phase 1 due to inefficacy; all other patients received another second-generation antipsychotic. Psychosocial functioning was assessed using the Quality of Life Scale. Results: Psychosocial functioning modestly improved for the one-third of phase 1 patients who reached the primary Quality of Life Scale analysis endpoint of 12 months (average effect size 0.19 SD units). Although for several of the drugs individually there were significant changes from baseline, overall there were no significant differences between the different agents. Results were similar at 6 and 18 months. There were no significant differences among the treatment groups in the amount of change in the Quality of Life Scale total score or subscale scores at 6, 12, or 18 months. Patients treated with clozapine in the efficacy pathway made comparable gains. Early treatment discontinuations, especially among patients most impaired at baseline, limited the ability to achieve more substantial functional gains. Conclusions: All antipsychotic treatment groups in all phases made modest improvements in psychosocial functioning. There were no differences among them after 6, 12, or 18 months. More substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions.

Background: We evaluated the cross-sectional and longitudinal association of measures of both insight and attitudes toward medication to outcomes that included psychopathology and community functioning. Methods: Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) was a large 18-month follow-up study pharmacotherapy of people with schizophrenia. Insight was measured using the Insight and Treatment Attitudes Questionnaire and attitudes toward medication by the Drug Attitude Inventory. Widely known scales were used to assess symptoms of schizophrenia and depression and community functioning. Medication adherence was globally assessed by the treating psychiatrist using several sources of information. Bivariate correlations and mixed model regression analyses were used to test the relationship of insight and medication attitudes to outcomes at baseline and during the follow-up period. Regression models were used to evaluate the relationship between change in insight and medication attitudes and changes outcomes. Results: There was a significant relationship at baseline between insight and drug attitudes and symptoms of schizophrenia and depression, as well as with community functioning. Higher levels of insight at baseline were significantly associated with lower levels of schizophrenia symptoms at follow-up while more positive medication attitudes were significantly associated with both lower symptom levels and better community functioning. Change in insight scores over time was associated with declining schizophrenia symptoms but increasing levels of depression. Change toward more positive medication attitudes was associated, independently of changes in insight, with significant decreases in psychopathology, improvement in community functioning, and greater medication compliance. Conclusion: Greater patient understanding of their illness and more positive attitudes toward medication may improve outcomes. Educational interventions that affect these attitudes may be an important part of psychosocial rehabilitation and/or recovery-oriented services.

Previous analysis of data from CATIE showed that patients randomly assigned to switch to a new medication were more likely to discontinue study drug than those who stayed on the medication they had been taking prior to randomization. This study addresses additional outcomes measures evaluating symptoms, neurocognition, quality of life, neurological side effects, weight, and health costs. First, considering patients randomized to olanzapine or risperidone, outcomes among patients who had been on the drug to which they were randomized prior to CATIE (N=129 "stayers") were compared to outcomes of those who switched to either of these two drugs (N=269 "switchers"). A second set of analyses considered patients on baseline monotherapy with olanzapine (N=297); risperidone (N=252) or quetiapine (n=87) and compared those randomly assigned to stay on each of these medications with those assigned to switch to any of the other five phase 1 medications in CATIE. In mixed models of each outcome the independent variable of primary interest represented stay vs. switch, with multivariate adjustment for potential confounding factors.With one exception, there were no significant differences between stayers and switchers on any outcome measure in either set of analyses. The exception was that, in the second set of analyses, patients who stayed on olanzapine showed greater weight gain than those who switched from olanzapine to other drugs.Switching to a new medication yielded no advantage over staying on the previous medication. Staying on olanzapine was associated with greater weight gain.

Background: In the treatment of schizophrenia, changing antipsychotics is common when one treatment is suboptimally effective, but the relative effectiveness of drugs used in this strategy is unknown. This randomized, double-blind study compared olanzapine, quetiapine, risperidone, and ziprasidone in patients who had just discontinued a different atypical antipsychotic. Method: Subjects with schizophrenia (N=444) who had discontinued the atypical antipsychotic randomly assigned during phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) investigation were randomly reassigned to double-blind treatment with a different antipsychotic (olanzapine, 7.5–30 mg/day [N=66]; quetiapine, 200–800 mg/day [N=63]; risperidone, 1.5–6.0 mg/day [N=69]; or ziprasidone, 40–160 mg/day [N=135]). The primary aim was to determine if there were differences between these four treatments in effectiveness measured by time until discontinuation for any reason. Results: The time to treatment discontinuation was longer for patients treated with risperidone (median: 7.0 months) and olanzapine (6.3 months) than with quetiapine (4.0 months) and ziprasidone (2.8 months). Among patients who discontinued their previous antipsychotic because of inefficacy (N=184), olanzapine was more effective than quetiapine and ziprasidone, and risperidone was more effective than quetiapine. There were no significant differences between antipsychotics among those who discontinued their previous treatment because of intolerability (N=168). Conclusions: Among this group of patients with chronic schizophrenia who had just discontinued treatment with an atypical antipsychotic, risperidone and olanzapine were more effective than quetiapine and ziprasidone as reflected by longer time until discontinuation for any reason.

These guidelines for the biological treatment of schizophrenia were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal during the development of these guidelines was to review systematically all available evidence pertaining to the treatment of schizophrenia, and to reach a consensus on a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by all physicians seeing and treating people with schizophrenia. The data used for developing these guidelines have been extracted primarily from various national treatment guidelines and panels for schizophrenia, as well as from meta-analyses, reviews and randomised clinical trials on the efficacy of pharmacological and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and then categorised into four levels of evidence (A–D). This second part of the guidelines covers the long-term treatment as well as the management of relevant side effects. These guidelines are primarily concerned with the biological treatment (including antipsychotic medication, other pharmacological treatment options, electroconvulsive therapy, adjunctive and novel therapeutic strategies) of adults suffering from schizophrenia.

Previous studies of postnatal synaptic development in human frontal cortex have shown that synaptic density rises after birth, reaches a plateau in childhood and then decreases to adult levels by late adolescence. A similar pattern has been seen in nonhuman primate cortex. These earlier studies in human cortex are limited, however, by significant age gaps in study subjects at critical inflection points of the developmental curve. Additionally, it is unclear if synaptic development occurs in different patterns in different cortical layers in prefrontal cortex (PFC). The purpose of this study was to examine synaptic density in human PFC across development by measuring two synaptic marker proteins: synaptophysin (presynaptic), and postsynaptic density protein 95 (PSD-95; postsynaptic). Western blotting was used to assess the relative levels of synaptophysin and PSD-95 in dorsolateral PFC of 42 subjects, distributed in age from 18 weeks gestation to 25 years. In addition, synaptophysin immunoreactivity was examined in each layer of areas 9 and 46 of PFC in 24 subjects, ranging in age from 0.1-25 years. Synaptophysin levels slowly increased from birth until age 5 and then increased more rapidly to peak in late childhood around age 10. Synaptophysin subsequently decreased until the adult level was reached by mid-adolescence, around age 16. PSD-95 levels increased postnatally to reach a stable plateau by early childhood with a slight reduction in late adolescence and early adulthood. The pattern of synaptophysin immunoreactivity seen with immunohistochemistry was similar to the Western experiments but the changes across age were more subtle, with little change by layer within and across age. The developmental patterns exhibited by these synaptic marker proteins expand upon previous studies of developmental synaptic changes in human frontal cortex; synaptic density increases steadily from birth to late childhood, then decreases in early adolescence to reach adult levels by late adolescence.

Brain mechanisms underlying deficits in precision of transient memory storage in schizophrenia were investigated using a combined behavioral and event-related potential approach. Performance was measured simultaneously in 2 tasks: an AX-type visual continuous performance test (AX-CPT), which required subjects to press a button whenever they saw a letter A followed by a letter X, and a mismatch negativity paradigm. The AX-CPT is designed to assess prefrontal function, whereas mismatch negativity assesses functioning of the auditory sensory memory system.Subjects were 17 patients with chronic schizophrenia, 13 with recent-onset schizophrenia, and 20 normal comparison subjects. Potentials were recorded from 36 scalp locations in response to cue stimuli in the CPT and to duration- and pitch-deviant stimuli in the mismatch negativity paradigm. Behavioral measures including responses to incorrect cue-target sequences that should have been ignored ("false alarms") were analyzed as a function of cue-target interval.Chronic and recent-onset schizophrenic patients showed significantly decreased mismatch negativity amplitude but normal latency and topography. In the CPT, patients showed significantly higher rates of false alarms following incorrect cues ("BX" errors) and decreased rates of correct detections. Impaired performance correlated with decreased frontocentral event-related potential activation to incorrect cues that was manifest within several hundred milliseconds of cue presentation. All groups performed worse with increasing cue-target intervals. Patients were no more affected by increased cue-target interval than were controls.Schizophrenic patients are significantly impaired in their ability to form and utilize transient memory traces to guide behavior. These deficits are associated with failures of cortical activation occurring within several hundred milliseconds of stimulus presentation. A similar pattern of deficit is observed across sensory and cognitive systems. Arch Gen Psychiatry. 2000;57:1131-1137.

• In vivo brain imaging and postmortem investigations have demonstrated structural anomalies in the brains of schizophrenic patients. However, previous studies have not established clear relationships between the characteristic symptoms of the disorder and neuropathologic changes in specific brain regions. We have obtained high-resolution magnetic resonance brain images of first-episode schizophrenic and normal control subjects and, with a computerized mensuration system, determined the volumes of the different components of the entire ventricular system. Volumes of ventricular segments were significantly larger in patients than controls (differences ranged from 17% to 40%). Temporal horn enlargement consistently demonstrated significant correlations with a broad range of schizophrenic symptoms. Our data indicate that anomalies of limbic structures in the medial temporal lobe surrounding the temporal horn play a crucial pathophysiologic role in schizophrenia.

Schizophrenia is associated with cognitive deficits that are an intrinsic component of the disorder. Clozapine is an atypical antipsychotic that is superior to typical agents in the treatment of positive symptoms. The degree to which clozapine ameliorates cognitive deficits, however, is still controversial. Mismatch negativity (MMN), N200 (N2), and P300 (P3) are cognitive event-related potentials (ERPs) that index preattentive (MMN) and attention-dependent information processing (N2, P3) and provide a measure of cognitive deficits associated with schizophrenia. In schizophrenic patients deficient generation of MMN, N2, and P3 has been observed, suggesting impairments of discrete stages of information processing.This study investigates the effects of clozapine treatment on MMN, N2, and P3 generation. Patients were recruited from a haloperidol-controlled, double-blind treatment study of clozapine in chronic schizophrenia. ERPs were obtained at the beginning of the study and after 9 weeks (4 patients) and 16 weeks (13 patients) of treatment.Clozapine treatment was associated with a significant increase of P3 amplitude, which was not observed in the haloperidol group; however, clozapine treatment did not affect deficits in MMN and N2.These findings suggest that clozapine--in contrast to conventional antipsychotics--improves electrophysiological measures of attention-dependent information processing, but does not ameliorate preattentive deficits.

Objective:The purposes of this study were to investigate the rate (incidence) of tardive dyskinesia in elderly patients beginning treatment with antipsychotic medication and to identify risk factors for development of tardive dyskinesia in this age group. Method:A group of 261 neuroleptic-naive patients aged 55 or above were identified at the time they were starting antipsychotic drug treatment. This group is the complete study group; a preliminary report based on the first 160 patients was published previously. Patients were evaluated at baseline and followed up at 3-month intervals for periods ranging from 3 to 393 weeks. Assessments included abnormal involuntary movements, extrapyramidal signs, psychiatric symptoms, and medical and drug treatment histories.Results:The cumulative rates of tardive dyskinesia were 25%, 34%, and 53% after 1, 2, and 3 years of cumulative antipsychotic treatment. A greater risk of tardive dyskinesia was associated with history of ECT treatment, higher mean daily and cumulative antipsychotic doses, and presence of extrapyramidal signs early in treatment. Differences in tardive dyskinesia rates between diagnostic groups found in univariate analyses were attenuated when the authors controlled for these variables.Conclusions:Tardive dyskinesia rates for patients beginning treatment with conventional antipsychotics in their fifth decade or later are three to five times what has been found for younger patients, despite treatment with lower doses. Alternative treatments need to be investigated. Am J Psychiatry 1998; 155: 1521-1528

Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D(2) receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.

Persons with schizophrenia die earlier than the general population, in large part due to cardiovascular disease. The study objective was to examine effects of different antipsychotic treatments on estimates of 10-year coronary heart disease (CHD) risk calculated by the Framingham Heart Study formula.Change in 10-year risk for CHD was compared between treatment groups in 1125 patients followed for 18 months or until treatment discontinuation in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial.The covariate-adjusted mean change in 10-year CHD risk differed significantly between treatments. Olanzapine was associated with a 0.5% (SE 0.3) increase and quetiapine, a 0.3% (SE 0.3) increase; whereas risk decreased in patients treated with perphenazine, -0.5% (SE 0.3), risperidone, -0.6% (SE 0.3), and ziprasidone -0.6% (SE 0.4). The difference in 10-year CHD risk between olanzapine and risperidone was statistically significant (p=0.004). Differences in estimated 10-year CHD risk between drugs were most marked in the tertile of subjects with a baseline CHD risk of at least 10%. Among individual CHD risk factors used in the Framingham formula, only total and HDL cholesterol levels differed between treatments.These results indicate that the impact on 10-year CHD risk differs significantly between antipsychotic agents, with olanzapine producing the largest elevation in CHD risk of the agents studied in CATIE.

The authors sought to compare the effects of olanzapine, quetiapine, and risperidone on neurocognitive function in patients with early psychosis.In a 52-week double-blind, multicenter study, 400 patients early in the course of psychotic illness (<5 years) were randomly assigned to treatment with olanzapine (2.5-20 mg/day), quetiapine (100-800 mg/day), or risperidone (0.5-4 mg/day). The mean modal daily dose was 11.7 mg (SD=5.3) for olanzapine, 506 mg (SD=215) for quetiapine, and 2.4 mg (SD=1.0) for risperidone. A total of 224 patients completed neurocognitive assessments at baseline and at 12 weeks, and 81 patients also completed them at 52 weeks. Neurocognitive composite scores were calculated from the neurocognitive battery used in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and from the Brief Assessment of Cognition in Schizophrenia.At week 12, there was significant improvement in neurocognition for each treatment (p<0.01), but no significant overall difference between treatments. Composite z score improvements on the CATIE neurocognitive battery were 0.17 for olanzapine, 0.33 for quetiapine, and 0.32 for risperidone. Composite z score improvements on the Brief Assessment of Cognition in Schizophrenia were 0.19 for olanzapine, 0.34 for quetiapine, and 0.22 for risperidone. Statistically significant relationships between improvements in neurocognition and functional outcome were observed at weeks 12 and 52.Olanzapine, quetiapine, and risperidone all produced significant improvements in neurocognition in early-psychosis patients. Although cognitive improvements were modest, their clinical importance was suggested by relationships with improvements in functional outcome.