Long-term (3-year) neurocognitive effectiveness of antipsychotic medications in first-episode non-affective psychosis: a randomized comparison of haloperidol, olanzapine, and risperidone.

INTRODUCTION: The initially postulated superior neurocognitive effectiveness of second-generation antipsychotics is currently under debate. METHODS: A prospective, randomized, open-label study was carried out to compare the long-term neurocognitive effectiveness of haloperidol, olanzapine, and risperidone in the first episode of schizophrenia spectrum disorders. A final sample of 79 patients randomized to haloperidol (N = 28), olanzapine (N = 23), or risperidone (N = 28) who completed clinical and cognitive evaluations at baseline and 3-year follow-up was included in the final analysis. Forty-one healthy individuals were also included in the final analysis. The main outcome measure was cognitive changes at 3-year follow-up. Due to the fact that some of the patients had switched their initially prescribed antipsychotic medication during the course of the study (6 out of 28 in haloperidol group, 18 out of 23 in olanzapine group, and 24 out of 28 in risperidone group continued with the initial study drug at 3-year assessment), we have also conducted a per protocol analysis. RESULTS: Overall, cognitive changes were similar in the three treatment groups and controls, although a greater improvement in Rey Auditory Verbal Learning Test, Digit Symbol, and Iowa Gambling Test was found in the treatment groups. The better performance observed on Rey Auditory Verbal Learning Test and Digit Symbol in olanzapine treatment group was likely explained by the lower prevalence of use of antimuscarinic drugs. These results were essentially similar to those found in the intention-to-treat analysis. CONCLUSIONS: The major conclusion of this study is that haloperidol, olanzapine, and risperidone have not demonstrated substantial neurocognitive effectiveness, improving cognitive deficits present in the early phases of the illness. The study also underscores the importance of exploring new drugs for the treatment of cognitive impairments and associated functional disabilities in schizophrenia.

The relevance of cognitive, clinical and premorbid variables in predicting functional outcome for individuals with first-episode psychosis: a 3 year longitudinal study.

Real-world functional deficits are common and persistent in individuals with psychosis. Cognitive deficits have been shown to compromise functioning. We aimed to study the predictive values of premorbid, sociodemographic, and baseline clinical and neurocognitive factors on long-term functional outcome for individuals with first episode non-affective psychosis. We failed to demonstrate a significant relationship between cognitive deficits at baseline and functional disability at 3 year follow-up. Diagnosis of schizophrenia (OR=2.457, p=0.011), shorter education (OR=1.177, p=0.005) and poor premorbid social adjustment (OR=1.628, p=0.013) emerged as the strongest predictors for the 114 subjects (56%) that exhibited functional disability at 3-year follow-up. A considerable proportion of the variance in functioning (74% at 1 year and 77% at 3 year) remained unexplained by baseline variables. The set of variables that predicted functional outcome at medium- (1 year) and long-term (3 years) differed. In conclusion, the length of follow-up influenced the relationship between baseline variables and functional outcome. A substantial proportion of the variance in function was not explained by these variables and therefore the influence of other factors warrants further investigation. The data support the notion that premorbid social adjustment is an important aspect in functional outcome over the course of the illness.

Aripiprazole, ziprasidone, and quetiapine in the treatment of first-episode nonaffective psychosis: results of a 6-week, randomized, flexible-dose, open-label comparison.

Differences among antipsychotics in effectiveness have turned out to be a topic of increasing research interest, although comparisons between the different second-generation antipsychotics are scarce. From October 2005 to March 2011, a prospective, randomized, open-label study comparing the effectiveness of aripiprazole, ziprasidone, and quetiapine in the short-term treatment of first-episode schizophrenia-spectrum disorders was undertaken. Two hundred two patients were randomly assigned to aripiprazole (n = 78), ziprasidone (n = 62), or quetiapine (n = 62) and followed up for 6 weeks. The primary effectiveness measure was all-cause of treatment discontinuation. In addition, an analysis based on per protocol populations was conducted in the analysis for clinical efficacy. The overall dropout rate at 6 weeks was small (6.4%). The treatment discontinuation rate differed significantly between treatment groups (aripiprazole, 15%; ziprasidone, 19%; and quetiapine, 35%; χ(2) = 8.529; P = 0.014). Insufficient efficacy in the group of quetiapine is the main reason for discontinuation rate differences (χ = 10.139; P = 0.006). The mean time to all-cause discontinuation was significantly different between the groups (log-rank, 12.783; P = 0.001). Quetiapine was associated with a greater depressive symptoms improvement than ziprasidone (P = 0.045). The rate of responders at 6 weeks differed between the groups (F = 6, 116; P = 0.047), with a higher rate of the responders with aripiprazole. The profile of adverse effects varies between the treatments. Patients on quetiapine were less likely to be prescribed concomitant medications. Treatment with quetiapine was associated with a higher risk of treatment discontinuation during treatment owing to insufficient efficacy. Differences in effectiveness between second-generation antipsychotics would determine their position in everyday clinical practice and could help physicians choose the more efficacious antipsychotics.

Predictors of neurocognitive impairment at 3 years after a first episode non-affective psychosis.

BACKGROUND: Neurocognitive impairment is a core component of schizophrenia. However, patients show great variability in the level and course of deficits. The goal of the present longitudinal study was to identify predictors of neurocognitive impairment in first episode psychosis patients. METHODS: Neurocognitive performance was analyzed in a cohort of 146 patients 3 years after a first episode non-affective psychosis. Subgroups, impaired vs. unimpaired, were compared on baseline clinical, neuropsychological, premorbid and sociodemographic characteristics. RESULTS: Fifty-nine percent of participants presented general neurocognitive impairment and regression analyses demonstrated that clinical and sociodemographic characteristics were not predictive variables. A model composed of premorbid IQ, verbal memory and motor dexterity correctly classified 79.6% of the individuals. CONCLUSIONS: The present study gives information on frequency and neurocognitive profile of subtypes of patients showing impairment. Our results suggest general neurocognitive impairment is a trait dimension of the disorder related to specific cognitive dysfunctions.

Alternativas comunitarias a la hospitalización de agudos para pacientes psiquiátricos graves / Community alternatives to acute inpatient care for severe psychiatric patients

Objetivos. La psiquiatría comunitaria ha descansado principalmente en la utilización de dispositivos intermedios de salud metal de media y larga estancia. Persiste sin embargo en el sistema de salud mental un gran desequilibrio entre las necesidades asistenciales de los pacientes y la provisión de servicios comunitarios para el tratamiento de la patología psiquiátrica aguda y grave. Teniendo ésto en consideración, el objetivo principal de éste artículo es revisar la evidencia científica actual acerca de la eficacia y la viabilidad de implementar nuevos modelos de atención psiquiátrica que permitan llenar el vacío existente en la provisión de cuidados a los pacientes agudos y graves en la comunidad y en el medio hospitalario. El articulo, finalmente, propone un modelo de atención combinada y equilibrada (balanced care approach)en el que se integren de manera eficaz dentro del sistema de salud mental los elementos clave de las nuevas alternativas que se han desarrollado para el tratamiento de la patología mental aguda y grave tanto en el nivel hospitalario como comunitario. Material y método. Se ha llevado a cabo una revisión de la literatura actual para identificar los elementos esenciales del tratamiento de la enfermedad psiquiátrica aguda y grave. Para ello se revisaron las bases de datos Medline (1966-2010), EMBASE (1980-2010) y PsycINFO (1985-2010)usando las palabras clave relacionadas con: Tratamiento Asertivo-comunitario; Tratamiento Domiciliario; Intervención en Crisis; "Hospital Psiquiátrico de Día, Agudo"; Desinstitucionalización; Modelos de Servicios de Salud Mental. Resultados. Han sido identificados tres modalidades de atención psiquiátrica intensiva para el tratamiento de la patología psiquiátrica aguda y grave: Atención Intensiva y Continuada de Día (Acute Continuous Day Care -ACDC-), o también denominado "Hospital de Día de Agudos"; Atención Asertivo Comunitaria (Assertive Outreach Care -AOC-) y; Tratamiento Agudo Domiciliario (Home Acute Care -HAC-)que también incorpora Programas de Resolución de Crisis. La viabilidad y utilidad de implementar estas distintas alternativas de atención psiquiátrica intensiva a la patología psiquiátrica aguda y grave, está avalada por la evidencia científica existente. Sin embargo, en la revisión realizada se detectó que, aun cuando dichas alternativas de atención intensiva pueden ser consideradas como complementarias y podían por lo tanto combinarse para alcanzar una mayor eficacia en la recuperación clínica y social de los pacientes, lo cierto es que se implementan de manera independiente. No se dispone por lo tanto de evidencia científica acerca de la eficacia y viabilidad de un programa integrado de asistencia que incorpore los elementos clave de cada una de ellas. Conclusiones. Con el fin de avanzar en el Modelo Comunitario de atención a la enfermedad mental sería preciso incorporar en el Sistema de Salud Mental un "Subsistema de Atención Aguda Intensiva e Integrada" en el que se combinaran de manera eficiente y equilibrada las estrategias de intervención señaladas (AU)

Objectives. Community psychiatry has mainly relied upon intermediate long term care services while there is a large gap between patient’s needs and availability of acute care services. Taking this into consideration, the main aim of this paper is to review the evidence supporting the efficacy and feasibility of implementing the new models of care developed to fulfil the gap in the provision of community and hospital care for acute and severely ill patients. Finally the paper will propose a "care balanced approach" to integrate the key elements of the new alternatives of acute community and hospital care in the mental health system. Material and Method. A review of the current literature was used to identify the key components of acute care for psychiatric illness. For this purpose Medline (1966-2010), EMBASE (1980-2010), and PsycINFO (1985-2010) databases were reviewed using key terms relating to assertive outreach, home treatment/crisis resolution, psychiatric acute day care, deinstitutionalization, Mental Health Service Models. Results. Three main types of acute care have been identified: Acute Continuous Day Care (ACDC) -day hospitals-, Assertive Outreach Care (AOC) -Assertive Community and Assertive Outreach teams-, and Home Acute Care (HAC)-Crisis resolution, Home treatment teams-. The feasibility of these alternatives is supported by available evidence. Although these acute care alternatives may be complementary and could be combined for achieving a greater positive impact on the clinical and social recovery of the patients, there are usually implemented independently. Conclusions. An integrative acute care subsystem combining these three strategies in a balanced care system should be formally incorporated to the advanced community model in mental health care(AU)

Community alternatives to acute inpatient care for severe psychiatric patients.

OBJECTIVES: Community psychiatry has mainly relied upon intermediate long term care services while there is a large gap between patient's needs and availability of acute care services. Taking this into consideration, the main aim of this paper is to review the evidence supporting the efficacy and feasibility of implementing the new models of care developed to fulfil the gap in the provision of community and hospital care for acute and severely ill patients. Finally the paper will propose a "care balanced approach" to integrate the key elements of the new alternatives of acute community and hospital care in the mental health system. MATERIAL AND METHOD: A review of the current literature was used to identify the key components of acute care for psychiatric illness. For this purpose Medline (1966-2010), EMBASE (1980-2010), and PsycINFO (1985-2010) databases were reviewed using key terms relating to assertive outreach, home treatment/crisis resolution, psychiatric acute day care, deinstitutionalization, Mental Health Service Models. RESULTS: Three main types of acute care have been identified: Acute Continuous Day Care (ACDC) -day hospitals -, Assertive Outreach Care (AOC) -Assertive Community and Assertive Outreach teams-, and Home Acute Care (HAC) -Crisis resolution, Home treatment teams-. The feasibility of these alternatives is supported by available evidence. Although these acute care alternatives may be complementary and could be combined for achieving a greater positive impact on the clinical and social recovery of the patients, there are usually implemented independently. CONCLUSIONS: An integrative acute care subsystem combining these three strategies in a balanced care system should be formally incorporated to the advanced community model in mental health care.

Predicting relapse after a first episode of non-affective psychosis: a three-year follow-up study.

BACKGROUND: Preventing relapse during the first years of illness has a critical impact on lifelong outcomes in schizophrenia. A better understanding and improvement in factors which influence relapse should diminish the risk of relapse and consequently improve the outcome of the illness. OBJECTIVE: To identify factors associated with relapse after 3 years of a first episode in a sample of non-affective psychosis patients who are representative of clinical practice in an epidemiological catchment. METHOD: We analyzed socio-demographic and clinical data from a cohort of patients who were treated in a specialized early intervention service and who were at risk of relapse during a 3-year follow-up. Univariate analyses, logistic regression and survival analyses were performed. The analyzed variables included gender, age at onset, duration of untreated psychosis, clinical severity at baseline, insight at baseline, premorbid functioning, substance use, family history of psychosis and adherence to medication. RESULTS: Of the 140 patients considered to be at risk for relapse, 91 (65%) individuals relapsed at least once over the three-year period. The relapse rates at 1 year and 2 years were 20.7% and 40.7%, respectively. Adherence to medication was the only significant predictor of relapse after a three-year follow-up [hazard ratio (HR) 4.8, 95% confidence interval (CI) 2.9-7.7; p < 0.001]. Comparison of the mean time of relapse between adherent and non-adherent patients also revealed statistically significant differences (933 and 568 days, respectively). 50% of patients will relapse despite being categorized as treatment adherents. CONCLUSION: Non-adherence to medication is the biggest predictive factor of relapse after a first episode of psychosis.

Homocysteine and cognition in first-episode psychosis patients.

In the last years, there has been growing evidence linking elevated homocysteine levels with cognitive dysfunction in several neurological and neuropsychiatric diseases. The aim of the present study was to investigate the potential relationship between elevated homocysteine levels and cognitive deficits in first-episode psychosis patients. Plasma levels and cognitive performance of 139 patients and 99 healthy volunteers were compared. Patients were classified as elevated homocysteine (>90 percentile for controls) and normal and compared on 22 cognitive outcome measures grouped into cognitive domains known to be impaired in schizophrenia. Patients had a statistically significant increase in plasmatic homocysteine levels. In addition, they presented with significantly increased cognitive deficits. However, no relationship between homocysteine levels and cognitive impairment was detected. These results suggest the need for further studies to clarify the role of homocysteine in the etiology and prognosis of psychosis.

Using structural equations to test for a direct effect of some antipsychotics on triglyceride levels in drug-naïve first-episode psychosis patients.

Some antipsychotics probably increase the risk of metabolic syndrome. Antipsychotics may differentially influence some elements of metabolic syndrome (obesity, hyperlipidemia, hyperglycemia or hypertension) through various pharmacological mechanisms. In a published study of all first psychotic episodes in a Spanish hospital's catchment area population in Cantabria (Spain), patients were randomly assigned to receive haloperidol (3-9 mg/day), olanzapine (5-20mg/day) or risperidone (3-6 mg/day). In this article, a structural-equation modeling approach tested the mechanistic hypothesis that olanzapine directly (without the mediation of weight gain) increases triglyceride levels, whereas risperidone and haloperidol do not have these effects. A structural equation model was built using the 110 patients whose assigned antipsychotic was not changed during the first 3 months of treatment, and who provided both triglyceride and body mass index (BMI) measurements at baseline and at the end of the 3rd month of treatment. A second structural equation included 72 patients whose antipsychotic was not changed during the first year. After 3 months and controlling for confounders, olanzapine patients had triglyceride levels that were 29.2mg/dL higher [95% confidence interval, (10.9, 47.5)] than those of risperidone patients with comparable baseline triglyceride levels. After 12 months, they were 63.1mg/dL higher (18.6, 107.6) than those of patients with a comparable history of triglyceride values during the first 3 months. Haloperidol effects on triglyceride levels and BMI were no different from those of risperidone. In conclusion, olanzapine increased triglyceride levels without the mediation of weight gain during a one-year study in naïve patients.

Insight dimensions in first-episode psychosis patients: clinical, cognitive, pre-morbid and socio-demographic correlates.

AIM: To investigate pre-morbid, socio-demographic, clinical and cognitive variables as predictors of insight in a large and representative sample of first-episode psychosis patients. METHODS: The abbreviated Scale to Assess Unawareness of Mental Disorder was used to assess insight dimensions. Patients with good and poor insight were independently compared on insight dimensions and logistic regression analyses were conducted to identify explanatory variables associated with each insight dimension. RESULTS: The patients with good and poor insight of having a mental disorder differed in duration of untreated psychosis, diagnosis and attention, but only attention appeared as a predictor. The insight of the need for medication groups showed differences in age of onset, depression, severity of disorganized symptoms and hospitalization rate.Nevertheless, age of onset and disorganized symptoms seem to be the predictors. Groups of insight of the social consequences differed in duration of untreated psychosis, the negative and disorganized symptoms severity, disability, education, diagnosis and hospitalization rate.However, exclusively, the severity of disorganized symptoms seems to predict insight of social consequences. CONCLUSION: When independently analysed, the three insight dimensions showed different rates of affectation and different predictors. These results suggest that there must be different mechanisms underlying the lack of insight. First-episode psychosis is a crucial period for treatment adherence formation, an issue strongly associated with good insight. Thus, a more accurate evaluation of the predictors of lack of insight into each dimension is warranted to achieve a better comprehension of the lack of insight in schizophrenia and in turn, to implement treatment programmes seeking to improve it.

Effectiveness of haloperidol, risperidone and olanzapine in the treatment of first-episode non-affective psychosis: results of a randomized, flexible-dose, open-label 1-year follow-up comparison.

The aim of this study was to investigate the long-term effectiveness and efficacy of haloperidol, risperidone and olanzapine in first-episode schizophrenia-spectrum disorders. This was a prospective, randomized, open-label study. Data for the present investigation were obtained from a large epidemiological and 3-year longitudinal intervention programme of first-episode psychosis conducted at the University Hospital Marques de Valdecilla, Santander, Spain. One hundred and seventy-four patients were randomly assigned to haloperidol (N = 56), olanzapine (N = 55), or risperidone (N = 63) and followed up for 1 year. The primary effectiveness measure was all causes of treatment discontinuation. Effectiveness analyses were based on intend-to-treat populations. In addition, an analysis based on per protocol populations was conducted in the analysis for clinical efficacy. The treatment discontinuation rate for any cause was higher with haloperidol than with risperidone and olanzapine (χ(2) = 8.517; p = 0.014). The difference in discontinuation rate between risperidone and olanzapine was not significant (χ(2) = 0.063; p = 0.802). There were no significant advantages of any of the three treatments in reducing the severity of psychopathology. Risperidone and olanzapine demonstrated higher effectiveness relative to haloperidol, but the three antipsychotics were equally effective in reducing the severity of psychopathology. Specific clinical programmes and the use of second-generation antipsychotics may enhance the effectiveness of antipsychotic treatments.

Relapse prevention and remission attainment in first-episode non-affective psychosis. A randomized, controlled 1-year follow-up comparison of haloperidol, risperidone and olanzapine.

The effectiveness of antipsychotics in preventing relapses and attaining symptomatic remission is a relevant topic of psychopharmacological research. The purpose of the present study was to compare the relapse and symptomatic remission rates during the first year of treatment between low doses of haloperidol and SGAs (olanzapine and risperidone) in drug-naïve first-episode non-affective psychosis individuals. This is a prospective, randomized, open-label study conducted from February 2001 to February 2006. Data for the present investigation were obtained from a large epidemiologic and 3-year longitudinal intervention program of first-episode psychosis (DSM-IV criteria) conducted at the University Hospital Marques de Valdecilla, Santander, Spain. One hundred and seventy four patients were randomly assigned to haloperidol (N = 56), olanzapine (N = 55), or risperidone (N = 63) and followed up for 1 year. Primary effectiveness measures were the time up to relapse and rates of relapse and symptomatic remission. There were no significant differences in the relapse rate between treatments (11.1% haloperidol; 18.5% olanzapine, and 13.8% risperidone) (χ(2) = 1.230; p = 0.541) or in the time up to relapse (Log Rank χ(2) = 0.308; p = 0.857). The rates of relapse for adherent (11.2%) and non-adherent (26.9%) patients were significantly different (χ(2) = 4.215; df = 1; p = 0.040). The remission rate did not differ significantly between treatment groups (χ(2) = 2.760; p = 0.252) and adherence to medication did not seem to significantly influence remission rates. We conclude that haloperidol, olanzapine and risperidone show a similar effectiveness in relapse prevention or in remission attainment during the first year of treatment.

Possible effects of some antipsychotic drugs on C-reactive protein in a drug-naïve psychotic sample.

Antipsychotic effects on C-reactive protein (CRP) have received little attention. This randomized open-label study investigated the possible effects of antipsychotics on CRP levels after 3 and 12 months of treatment in a Spanish drug-naïve sample taking haloperidol (N=36 after 3 months), olanzapine (N=36 after 3 months) or risperidone (N=39 after 3 months). After 3 months and adjusting for differences in baseline CRP levels, baseline smoking and high baseline triglyceride levels, patients on haloperidol treatment had CRP levels that were 92.7% higher than those of patients on risperidone treatment (p=0.009). After 12 months, only smoking was associated with increased CRP levels. Future studies need to verify that different antipsychotics may have differential effects on CRP levels, particularly after 3 months of treatment.

White matter integrity and cognitive impairment in first-episode psychosis.

OBJECTIVE: Impaired cognitive function has been identified as a core feature of schizophrenia. However, a significant proportion of patients do not show any cognitive deficits. The aim of this study was to assess if there were differences in white matter integrity between patients with and without cognitive impairment. METHOD: A diffusion tensor imaging study and neurocognitive assessment were conducted in 49 patients with first-episode psychosis and 41 healthy comparison subjects. Subjects were assessed using the Continuous Performance Test, the Grooved Pegboard Test, the Rey Auditory Verbal Learning Test, and the Trail Making Test Part B. For each test, the patient sample was subdivided according to performance, with those scoring more than one standard deviation below the normative mean categorized as impaired. For each cognitive domain, white matter fractional anisotropy in deficit and nondeficit subgroups was compared using a voxel-based analysis. A nonparametric statistical method, controlling for multiple comparisons, was applied. RESULTS: Impairment on the Trail Making Test Part B was associated with reduced fractional anisotropy in the right/left anterior thalamic radiation and inferior fronto-occipital fasciculus, forceps minor, and left superior and inferior longitudinal fasciculi. Patients exhibiting Grooved Pegboard Test impairment showed reduced fractional anisotropy in the forceps minor, inferior fronto-occipital fasciculus, anterior thalamic radiation, and corticospinal and corticopontine tracts. Impaired performance on the Rey Auditory Verbal Learning Test and Continuous Performance Test was not associated with significant differences in fractional anisotropy. CONCLUSION: Deficits in executive and motor functioning in patients with first-episode psychosis are associated with reductions in white matter integrity in the major fasciculi that connect the frontal and temporal cortices as well as in pathways connecting cortical and subcortical regions. Their presence at the onset of illness, in minimally medicated patients, indicates that these findings are not attributable to effects of chronic illness or its treatment.

White matter defects in first episode psychosis patients: a voxelwise analysis of diffusion tensor imaging.

OBJECTIVE: Disruptions in white matter structure have consistently been shown in schizophrenia--but mainly in patients in whom the illness is well-established. In order to determine whether white matter abnormalities are present at illness onset, and to minimise the potentially confounding effects of chronic illness and treatment, we used diffusion tensor imaging to study a large cohort of first episode psychotic patients who were medication-naive. METHODS: Sixty two first episode patients and 54 controls matched on age, sex, years of education and laterality index underwent diffusion tensor imaging. Data were acquired on a GE Signa NVi 1.5 Tesla System. Fractional anisotropy maps were generated on a voxel-by-voxel basis. An optimized voxel-based morphometry technique was conducted with two-stage registration approach. Group differences were examined using a non-parametric statistical method. RESULTS: The voxelwise analysis revealed four clusters where fractional anisotropy values were significantly lower in patients than controls. These were localised bilaterally to regions of white matter corresponding to superior and inferior longitudinal fasciculus, forceps major, anterior and superior thalamic radiation and corpus callosum. CONCLUSIONS: Reductions in white matter integrity are present early in the course of the schizophrenia and localised in fascicule that connect brain regions implicated in the disorder.

Additive effect of NRG1 and DISC1 genes on lateral ventricle enlargement in first episode schizophrenia.

Neuregulin 1 (NRG1) and Disrupted-in-schizophrenia (DISC1) genes, which are candidate genes for schizophrenia, are implicated in brain development. We have previously reported an association between the T allele of the rs6994992 SNP within NRG1 gene and lateral ventricle (LV) enlargement in first-episode schizophrenia patients. Moreover, transgenic mice with mutant DISC1 have also been reported as showing LV enlargement. In this study, we examined the possible interactive effects of NRG1 and DISC1 on brain volumes in a sample of first-episode schizophrenia patients. Ninety-one patients experiencing their first episode of schizophrenia underwent genotyping of three SNPs within DISC1 and structural brain MRI. These results were combined with our previously reported genotypes on three SNPs within NRG1. The T/T genotype of rs2793092 SNP in DISC1 was significantly associated with increased LV volume. However, taking into account the rs6994992 SNP in the NRG1 gene, which was also associated with LV volume in a previous study, the DISC1 SNP only predicted LV enlargement among those patients carrying the T allele in the NRG1 SNP. Those patients with the "at risk" allelic combinations in both genes had LV volumes which were 48% greater than those with none of the allelic combinations. Our findings suggest that NRG1 and DISC1 genes may be associated with brain abnormalities in schizophrenia through their influence on related pathways of brain development.

Neurocognitive effectiveness of haloperidol, risperidone, and olanzapine in first-episode psychosis: a randomized, controlled 1-year follow-up comparison.

OBJECTIVE: To investigate the neurocognitive effectiveness of haloperidol, risperidone, and olanzapine in first-episode schizophrenia-spectrum disorders. METHOD: This prospective, randomized, open-label study was conducted from February 2001 to February 2005. Data for the present investigation were obtained from a large epidemiologic and 3-year longitudinal intervention program of first-episode psychosis (DSM-IV criteria) conducted at the outpatient clinic and the inpatient unit at the University Hospital Marques de Valdecilla, Santander, Spain. One hundred four patients randomly assigned to haloperidol (N = 35), olanzapine (N = 30), or risperidone (N = 39) who completed clinical and cognitive evaluations at baseline, 6 months, and 1 year were included in the final analysis. Thirty-seven healthy individuals were also longitudinally assessed. A neuropsychological battery that comprised 9 cognitive domains was used. The contribution of clinical changes, concomitant medications, and the severity of motor side effects to cognitive changes was controlled. The main outcome measure was cognitive changes at 1-year follow-up. RESULTS: The 3 treatment groups showed a significant improvement in cognitive scores after 1 year. The differential cognitive effectiveness between antipsychotics was insignificant. The magnitude of cognitive changes was similar in the 3 treatment groups and controls, although a greater improvement on the Finger Tapping Test, Trail Making Test B, and Rey Complex Figure Test was found in the treatment groups. Clinical changes, use of concomitant medications, and the emergence of motor side effects did not significantly account for cognitive changes over time. CONCLUSION: Haloperidol, olanzapine, and risperidone were equally effective in treating cognitive deficits of psychosis. The effect of practice clearly contributes to cognitive score improvements after treatment with antipsychotics. Our results provide important information regarding the practical utility of antipsychotic treatments to improve cognition and could have implications for developing novel approaches for cognitive pharmacotherapy in schizophrenia.

Glucose and lipid disturbances after 1 year of antipsychotic treatment in a drug-naïve population.

OBJECTIVE: This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first episode drug-naïve subjects after the first year of treatment. METHODS: A randomized, open-label, prospective clinical trial was conducted. Participants were 164 consecutive subjects included in a first episode program and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone. The main outcome measures were changes at 1 year in fasting glucose parameters (glucose, insulin levels and insulin resistance index) and changes in fasting lipid parameters (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol). RESULTS: 144 of the total sample were evaluated at 1 year. There was a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol and triglycerides. No pathological values in fasting glucose plasma levels were found at baseline and there were no changes after 1 year. Weight gain was positively correlated with changes in insulin levels, insulin resistance index and triglyceride levels. We did not detect statistically significant differences between treatments in any of the parameters evaluated. CONCLUSIONS: Fasting glycaemia and insulin concentrations at baseline do not support the hypothesis that schizophrenia is associated with an underlying abnormality in glucose metabolism. The changes in insulin and lipid parameters at 1 year seem to be related to the magnitude of weight gain. There were no significant differences between haloperidol, olanzapine and risperidone concerning metabolic adverse effects after the first year of treatment.

Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine.

BACKGROUND: The effect of antipsychotic drugs on brain morphology is under debate. Here we investigate the effects of risperidone, olanzapine and low doses of haloperidol on cortical and subcortical morphometry in first episode drug naïve patients with non-affective psychosis. METHODS: Morphological variables were measured in three treatment groups (haloperidol=18; risperidone=16; olanzapine=18) and in healthy subjects (N=38) at baseline and after one year. The relationship between brain morphometric changes and changes in clinical scores was also assessed. RESULTS: At one year, the three antipsychotics had had an equal effect on the gray matter cortical structure, overall and lobes (all p's>0.121.). A significant time-by-group interaction was found in lateral ventricle volume (F2,47=5.65; p=0.006). Post-hoc comparisons revealed a significant increase in lateral ventricles in patients treated with risperidone (p=0.009). Patients exposed to atypicals (olanzapine and risperidone) exhibited a decrease in caudate nucleus volume (p=0.001). In general, brain changes did not account in any significant manner for clinical changes over time in any treatment group. CONCLUSIONS: We conclude that low doses of haloperidol, risperidone and olanzapine seem to have an equal effect on the gray matter cortical structure after 1 year of treatment. In contrast to typical antipsychotics, atypicals have differential effects on lateral ventricle and caudate nucleus volumes.

1-year follow-up study of cognitive function in first-episode non-affective psychosis.

The longitudinal course of primary cognitive dysfunction seen in schizophrenia has yet to be fully clarified. Whereas some studies in chronic patients have revealed a progressive decline in cognitive abilities, those studies with first-episode patients have indicated that initial cognitive deficits might remain stable over time. The aim of this study was to examine the longitudinal course of cognitive functioning in patients with a first episode of schizophrenia. 112 patients with a first episode of schizophrenia-spectrum disorders and 22 healthy controls completed clinical and cognitive evaluations at baseline and again after 1 year. An extensive neuropsychological battery that comprised seven cognitive domains was used. Patients and controls improved their cognitive performance in virtually all the cognitive domains after one year. However, patients continued to show marked cognitive deficits after one year, unlike healthy volunteers. The longitudinal cognitive changes were similar in patients and controls in all domains except Verbal Memory (F = 11.67; df = 1; P = 0.001). The increase in cognitive scores found during early phases of the illness seems to be associated to practice-related changes and would not reflect a real cognitive enhancement but rather stability of deficit. Patients' deficits remained stable over time in all cognitive domains except Verbal Memory, in which less performance improvement was found. Further investigations are warranted to discern the variability in patterns of specific cognitive deficits over time.