José María Pelayo-Terán

Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a randomized clinical trial in a drug-naïve population

BACKGROUND There is little information about weight gain induced by antipsychotics at long-term. OBJECTIVE To quantify the weight gain induced by first (haloperidol) and second generation antipsychotics (olanzapine and risperidone) in a cohort of drug-naïve subjects after 1 year of treatment. METHODS This is a prospective, randomized clinical trial, including a representative sample of first episode psychotic incident cases from a population area of 555.000 people. The main outcome measures were changes in body weight and body mass index at 3 months and at 12 months. Both a per protocol analysis and an intention to treat analysis were conducted. RESULTS A total of 164 drug-naïve patients were included. At 12 months 144 patients were evaluated. Of them, 66% completed the protocol and 34% needed treatment switch. We found statistically significant differences in weight gain at 3 months: 3.8 kg (+/-4.1) for haloperidol, 5.9 kg (+/-5.1) for risperidone and 8.4 kg (+/-5.0) for olanzapine (F=7.045; p=0.002). After 1 year the difference in weight gain had disappeared: 9.7 kg (+/-5.7) for haloperidol, 8.9 kg (+/-8.8) for risperidone and 10.9 kg (+/-7.2) for olanzapine (F=0.817; p=0.445). CONCLUSIONS Drug-naïve patients experience an extraordinary weight gain after 1 year of treatment with haloperidol, olanzapine or risperidone. The main difference among these treatments is the pattern of weight gain but not the final amount of weight gain.

Epidemiological factors associated with treated incidence of first‐episode non‐affective psychosis in Cantabria: insights from the Clinical Programme on Early Phases of Psychosis

Aim: The aim of the study was to analyse the treated incidence of schizophrenia in Cantabria (Northern Spain) and the sociodemographic risk factors associated with the illness onset.

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

Reduced thalamic volume in first-episode non-affective psychosis: Correlations with clinical variables, symptomatology and cognitive functioning

Structural studies have inconsistently shown the presence of thalamic volume differences in patients with schizophrenia. However, only a few studies have examined the relation between thalamic structure and clinical and cognitive variables in early phases of the illness. Thalamic volumes in right-handed minimally treated first episode patients with non-affective psychosis (N=61) relative to those of right-handed healthy comparison subjects (N=40) were measured. Thalamic volumes in the right and left hemispheres and total thalamic volume were automatically segmented and analyzed using BRAINS2. Analysis of covariance was used to control for intracranial volume. Clinical symptoms were assessed by total scores of BPRS, SAPS and SANS. The relationship between three cognitive dimensions (verbal learning and memory, speed processing/executive functioning and sustained attention/vigilance), and thalamic volume was evaluated. The impact of the duration of untreated illness, untreated psychosis and prodrome period in thalamic morphometry was also explored. Right, left, and total thalamic volumes of the patients with non-affective psychosis were significantly smaller than those of the healthy subjects. Larger thalamic volumes were associated with an earlier age of onset, a poorer cognitive functioning and a more severe negative symptomatology. Thalamic volumetric differences between patients with non-affective psychosis and healthy controls are already present at early phases of the illness. However, further investigations are warranted to fully clarify the relationship between those structural anomalies and clinical and cognitive outcomes.

Caudate nucleus volume and its clinical and cognitive correlations in first episode schizophrenia

OBJECTIVE Striatal dysfunction has been traditionally implicated in the pathophysiology of schizophrenia. The purpose of this study is to examine the relationship between caudate nucleus volumes and clinical and cognitive features of schizophrenic patients in an early phase of their illness. METHODS Caudate nucleus volumes in previously untreated first episode patients with non-affective psychosis (N=76) and healthy comparison subjects (N=45) were measured. Caudate nucleus volume in the right and left hemispheres were automatically segmented and analyzed using BRAINS2. Analysis of covariance was used to control for intracranial volume. Severity of clinical symptoms was assessed using SAPS and SANS total scores. The relationship between cognitive dimensions, and caudate nucleus volume was evaluated. Finally, we examined the correlation between caudate volumes and the duration of untreated illness (DUI), duration of untreated psychosis (DUP) and duration of prodrome period (DPP). RESULTS Right, left, and total caudate nucleus volumes did not differ significantly between patients and controls. Those patients with a longer DUP have smaller caudate nucleus. In addition, caudate nucleus volume was positively correlated with the severity of psychotic symptomatology. No significant associations were found between caudate nucleus volume and cognitive functioning. CONCLUSION This group of first episode schizophrenia patients did not exhibit significant volumetric anomalies of the caudate nucleus. Despite this lack of volumetric abnormalities, a delay in receiving antipsychotic treatment and the severity of initial positive symptomatology were significantly associated with reduced caudate volume.

Effect of antipsychotics on peptides involved in energy balance in drug-naive, psychotic patients after 1 year of treatment

Weight gain has become one of the most common and concerning side effects of antipsychotic treatment. The mechanisms whereby antipsychotics induce weight gain are not known. It has been suggested that peptides related to food intake and energy balance could play a role in weight gain secondary to antipsychotic therapy. To better understand the pathophysiology of antipsychotic-induced weight gain, we studied the effects of 3 antipsychotic drugs (haloperidol, olanzapine, and risperidone) on peptides involved in energy balance (insulin, ghrelin, leptin, adiponectin, visfatin, and resistin) in a population of drug-naive patients with first episode of psychosis. A significant increase in weight (10.16 kg [SD, 8.30 kg]; P < 0.001), body mass index (3.56 kg/m2 [SD, 2.89 kg/m2]; P < 0.001), and fasting insulin (3.93 &mgr;U/mL [SD, 3.93 &mgr;U/mL]; P = 0.028), leptin (6.76 ng/mL [SD, 7.21 ng/mL]; P < 0.001), and ghrelin (15.47 fmol/mL [SD, 47.90 fmol/mL]; P = 0.009) plasma levels were observed. The increments in insulin and leptin concentrations were highly correlated with the increment in weight and body mass index and seem to be a consequence of the higher fat stores. The unexpected increase in ghrelin levels might be related with the causal mechanism of weight gain induced by antipsychotics. Finally, the 3 antipsychotics had similar effects in all parameters evaluated.

Neuropsychological functioning and brain structure in schizophrenia

Cognitive deficits are core features of schizophrenia that are already evident at early phases of the illness. The study of specific relationships between cognition and brain structure might provide valuable clues about neural basis of schizophrenia and its phenomenology. The aim of this article was to review the most consistent findings of the studies exploring the relationships between cognitive deficits and brain anomalies in schizophrenia. Besides several important methodological shortcomings to bear in mind before drawing any consistent conclusion from the revised literature, we have attempted to systematically summarize these findings. Thus, this review has revealed that whole brain volume tends to positively correlate with a range of cognitive domains in healthy volunteers and female patients. An association between prefrontal morphological characteristics and general inability to control behaviour seems to be present in schizophrenia patients. Parahippocampal volume is related to semantic cognitive functions. Thalamic anomalies have been associated with executive deficits specifically in patients. Available evidence on the relationship between cognitive functions and cerebellar structure is still contradictory. Nonetheless, a larger cerebellum appears to be associated with higher IQ in controls and in female patients. Enlarged ventricles, including lateral and third ventricles, are associated with deficits in attention, executive and premorbid cognitive functioning in patients. Several of these reported findings seem to be counterintuitive according to neural basis of cognitive functioning drawn from animal, lesion, and functional imaging investigations. Therefore, there is still a great need for more methodologically stringent investigations that would help in the advance of our understanding of the cognition/brain structure relationships in schizophrenia.

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 ps>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.

Cannabis abuse is associated with decision-making impairment among first-episode patients with schizophrenia-spectrum psychosis

BACKGROUND Cannabis use appears to be a risk factor for schizophrenia. Moreover, cannabis abusers show impaired decision-making capacities, linked to the orbitofrontal cortex (OFC). Although there is substantial evidence that first-episode schizophrenia patients show impairments in cognitive tasks associated with the dorsolateral prefrontal cortex (DLPFC), it is not clear whether decision making is impaired at schizophrenia onset. In this study, we examined the association between antecedents of cannabis abuse and cognitive impairment in cognitive tasks associated with the DLPFC and the OFC in a sample of first-episode patients with schizophrenia-spectrum disorders. METHOD One hundred and thirty-two patients experiencing their first episode of a schizophrenia-spectrum psychosis were assessed with a cognitive battery including DLPFC-related tasks [backward digits, verbal fluency (FAS) and the Trail Making Test (TMT)] and an OFC-related task [the Iowa Gambling Task (GT)]. Performance on these tasks was compared between patients who had and had not abused cannabis before their psychosis onset. RESULTS No differences were observed between the two groups on the performance of any of the DLPFC-related tasks. However, patients who had abused cannabis before their psychosis onset showed a poorer total performance on the gambling task and a lower improvement on the performance of the task compared to no-abusers. CONCLUSIONS Pre-psychotic cannabis abuse is associated with decision-making impairment, but not working memory and executive function impairment, among first-episode patients with a schizophrenia-spectrum psychosis. Further studies are needed to examine the direction of causality of this impairment; that is, does the impairment make the patients abuse cannabis, or does cannabis abuse cause the impairment?

Interleukin-12 plasma levels in drug-naïve patients with a first episode of psychosis: effects of antipsychotic drugs.

An overactivation of the Th1 activity in schizophrenia had been described. Interleukin-12 (IL-12), a proinflammatory cytokine, plays a key role in the regulation of the Th1 response. The aims of this study were to investigate the effect of first and second generation antipsychotic drugs on IL-12 production during the acute phase of the illness and its association with clinical features. Participants comprised 56 drug-naïve first episode psychotic patients and 28 healthy volunteers. Patients were initially randomly assigned to risperidone (n=16), olanzapine (n=20) or haloperidol (n=20); subject were maintained on the same medication throughout the study. Clinical assessments were conducted at baseline and at 6 weeks. IL-12 plasma levels were assessed at baseline and after 6 weeks of antipsychotic treatment. IL-12 haplotypes were also analysed. Patients showed higher IL-12 plasma levels at baseline compared with controls, and had a significant increase in IL-12 plasma level after 6 weeks of antipsychotic treatment. No significant differences in IL-12 level increase were found among the three antipsychotic treatments. IL-12 plasma levels at week 6 were not significantly associated with the severity of psychopathology at week 6. Thus, patients with a first episode of psychosis have inflammatory-like immunological function during early phases of the illness that it is independent of the antipsychotic treatment used.