Rocío Pérez-Iglesias

Antipsychotic-Induced Weight Gain in Chronic and First-Episode Psychotic Disorders : A Systematic Critical Reappraisal

Antipsychotic-induced weight gain is an important issue in the treatment of psychotic illnesses, and affects 80% of individuals being treated with antipsychotic drugs. However, the true dimension of weight gain and many accepted ‘facts’ in this area remain unclear as most research has been conducted in short-term trials and has included individuals receiving prolonged antipsychotic treatment.This review aims to systematically and critically review the evidence on weight gain induced by the two leading second-generation antipsychotics (olanzapine and risperidone) and the most widely researched first-generation antipsychotic (haloperidol) in patients with chronic and first-episode psychotic disorders.Weight gain was 3- to 4-fold greater in studies that included young patients with limited previous exposure to antipsychotic agents in both short-term studies (7.1–9.2 kg for olanzapine, 4.0–5.6 kg for risperidone and 2.6–3.8 kg for haloperidol vs 1.8–5.4 kg, 1.0–2.3 kg and 0.01–1.4 kg, respectively, in studies that included patients with chronic psychotic disorders) and long-term trials (10.2–15.4 kg for olanzapine, 6.6–8.9 kg for risperidone and 4.0–9.7 kg for haloperidol vs 2.0–6.2 kg, 0.4–3.9 kg and −0.7 to 0.4 kg, respectively). The same disparity was observed regarding the proportion of patients increasing their baseline weight by ≥7% (the cut-off for clinically significant weight gain).Recent studies carried out in young patients with first-episode psychosis (FEP), along with methodological artefacts in studies of chronic populations, suggest that the magnitude of weight gain reported by much of the literature could in fact be an underestimation of the true magnitude of this adverse effect. Although antipsychotics present idiosyncratic patterns of weight gain, they may also generate similar absolute gains.

Alterations in White Matter Evident Before the Onset of Psychosis

Background Psychotic disorders are associated with widespread reductions in white matter (WM) integrity. However, the stage at which these abnormalities first appear and whether they are correlates of psychotic illness, as opposed to an increased vulnerability to psychosis, is unclear. We addressed these issues by using diffusion tensor imaging (DTI) to study subjects at ultra high risk (UHR) of psychosis before and after the onset of illness. Methods Thirty-two individuals at UHR for psychosis, 32 controls, and 15 patients with first-episode schizophrenia were studied using DTI. The UHR subjects and controls were re-scanned after 28 months. During this period, 8 UHR subjects had developed schizophrenia. Between-group differences in fractional anisotropy (FA) and diffusivity were evaluated cross sectionally and longitudinally using a nonparametric voxel-based analysis. Results At baseline, WM DTI properties were significantly different between the 3 groups (P < .001). Relative to controls, first-episode patients showed widespread reductions in FA and increases in diffusivity. DTI indices in the UHR group were intermediate relative to those in the other 2 groups. Longitudinal analysis revealed a significant group by time interaction in the left frontal WM (P < .001). In this region, there was a progressive reduction in FA in UHR subjects who developed psychosis that was not evident in UHR subjects who did not make a transition. Conclusions People at UHR for psychosis show alterations in WM qualitatively similar to, but less severe than, those in patients with schizophrenia. The onset of schizophrenia may be associated with a progressive reduction in the integrity of the frontal WM.

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.

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.

Cognitive dysfunction in first-episode psychosis: the processing speed hypothesis

BACKGROUND Speed of processing is a cognitive process underlying cognitive dysfunction in people with chronic schizophrenia. AIMS To investigate the contribution of speed of processing to the cognitive deficits observed in a representative large sample with first-episode schizophrenia. METHOD People with a diagnosis of first-episode schizophrenia-spectrum disorders (n=26) and healthy controls (n=28) were compared on several cognitive measures before and after controlling for speed of processing. RESULTS Before controlling for speed of processing, patients and controls differed significantly on all cognitive measures. All significant differences in cognitive functioning disappeared when the result of the Digital Symbol Substitution Test was included as an additional covariate. CONCLUSIONS Speed of information processing may be considered a core cognitive deficit in schizophrenia and might be mediating a broader diversity of cognitive disturbances.

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.

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.