Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study.
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ABSTRACT:
SUBMITTER: Chopra S
PROVIDER: S-EPMC8209146 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundEnlarged ventricles and reduced hippocampal volume are consistently found in patients with first-episode schizophrenia. Studies investigating brain structure in antipsychotic-naive patients have generally focused on the striatum. In this study, we examined whether ventricular enlargement and hippocampal and caudate volume reductions are morphological traits of antipsychotic-naive first-episode schizophrenia.MethodsWe obtained high-resolution 3-dimensional T1-weighted magnetic resonance imaging scans for 38 antipsychotic-naive first-episode schizophrenia patients and 43 matched healthy controls by use of a 3-T scanner. We warped the brain images to each other by use of a high-dimensional intersubject registration algorithm. We performed voxel-wise group comparisons with permutation tests. We performed small volume correction for the hippocampus, caudate and ventricles by use of a false discovery rate correction (p < 0.05) to control for multiple comparisons. We derived and analyzed estimates of brain structure volumes. We grouped patients as those with (n = 9) or without (n = 29) any lifetime substance abuse to examine the possible effects of substance abuse.ResultsWe found that hippocampal and caudate volumes were decreased in patients with first-episode schizophrenia. We found no ventricular enlargement, differences in global volume or significant associations between tissue volume and duration of untreated illness or psychopathology. The hippocampal volume reductions appeared to be influenced by a history of substance abuse. Exploratory analyses indicated reduced volume of the nucleus accumbens in patients with first-episode schizophrenia.LimitationsThis study was not a priori designed to test for differences between schizophrenia patients with or without lifetime substance abuse, and this subgroup was small.ConclusionReductions in hippocampal and caudate volume may constitute morphological traits in antipsychotic-naive first-episode schizophrenia patients. However, the clinical implications of these findings are unclear. Moreover, past substance abuse may accentuate hippocampal volume reduction. Magnetic resonance imaging studies addressing the potential effects of substance abuse in antipsychotic-naive first-episode schizophrenia patients are warranted.
| S-EPMC2834791 | biostudies-literature
Project description:ObjectiveGuidelines for antipsychotic use in first-episode psychosis (FEP) recommend that medication be chosen initially on the basis of side effect profile with doses at the lower end of the range. Our objective was to describe the pattern of antipsychotic use in FEP over a period of 21 years in the context of changing clinical guidelines and the development of specialist early intervention in psychosis (EIP) services.SettingA community-based mental health service in South County Dublin (population 187 000) and a large private hospital.ParticipantsParticipants included 465 patients with FEP (146 from an epidemiological study (1995-1999) and 319 from a specialist EIP service (2005-2016)). Treatment with antipsychotic medication did not exceed 30 days at study entry.Outcome measuresThis is a descriptive study of prescribing practices in the context of service development and changing guidelines.ResultsFirst-generation antipsychotics were prescribed for 65% of the early cohort compared with 4.3% of the EIP cohort. Olanzapine was initially prescribed for 79.7% of EIP patients. Initial doses of medication were frequently low (≤50% British National Formulary (BNF) maximum) in both cohorts (71% and 78.6%). The demographic and clinical factors investigated did not influence the initial choice of antipsychotic medication significantly. Univariate logistic regression analysis suggested inpatient treatment setting was associated with a higher initial dose (>50% BNF maximum) of antipsychotic medication. Increasing dose requirements over the first month of engagement with an EIP service was associated with poorer global functioning at baseline, greater positive symptoms at baseline and the inpatient treatment setting. However, these associations were not seen in the multivariable model.ConclusionsSecond-generation antipsychotic prescribing predominates, but guidelines are often overlooked when choosing olanzapine notwithstanding lower initial dosages. EIP services should include proactive support for optimising medicines in line with evidence-based guidelines.
| S-EPMC7852941 | biostudies-literature
Project description:BACKGROUND:Long-term treatment with antipsychotic medications in early episode schizophrenia spectrum disorders is common, but both short and long-term effects on the illness are unclear. There have been numerous suggestions that people with early episodes of schizophrenia appear to respond differently than those with multiple prior episodes. The number of episodes may moderate response to drug treatment. OBJECTIVES:To assess the effects of antipsychotic medication treatment on people with early episode schizophrenia spectrum disorders. SEARCH STRATEGY:We searched the Cochrane Schizophrenia Group register (July 2007) as well as references of included studies. We contacted authors of studies for further data. SELECTION CRITERIA:Studies with a majority of first and second episode schizophrenia spectrum disorders comparing initial antipsychotic medication treatment with placebo, milieu, or psychosocial treatment. DATA COLLECTION AND ANALYSIS:Working independently, we critically appraised records from 681studies, of which five studies met inclusion criteria. John Rathbone from the Schizophrenia Group supported us with the data extraction. We calculated risk ratios (RR) and their 95% confidence intervals (CI) where possible. For continuous data, we calculated mean difference (MD). We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. MAIN RESULTS:Five studies with a combined N = 998 met inclusion criteria. Four studies (N = 724) provided leaving the study early data and results suggested that individuals treated with a typical antipsychotic medication are less likely to leave the study early than those treated with placebo (Chlorpromazine: 3 RCTs N = 353, RR 0.4 CI 0.3 to 0.5, NNT 3.2, Fluphenaxine: 1 RCT N = 240, RR 0.5 CI 0.3 to 0.8, NNT 5; Thioridazine: 1 RCT N = 236, RR 0.44 CI 0.3 to 0.7, NNT 4.3, Trifulperazine: 1 RCT N = 94, RR 0.96 CI 0.3 to 3.6). Two studies (Cole 1964; May 1976) contributed data to assessment of side effects and present a general pattern of more frequent side effects among individuals treated with typical antipsychotic medications compared to placebo. Rappaport 1978 suggested a higher rehospitalisation rate for those receiving chlorpromazine compared to placebo (N = 80, RR 2.29 CI 1.3 to 4.0, NNH 2.9). However, a higher attrition in the placebo group is likely to have introduced a survivor bias into this comparison, as this difference becomes non-significant in a sensitivity analysis on intent-to-treat participants (N = 127, RR 1.69 CI 0.9 to 3.0). One study (May 1976) contributes data to a comparison of trifluoperazine to psychotherapy on long-term health in favour of the trifluoperazine group (N = 92, MD 5.8 CI 1.6 to 0.0); however, data from this study are also likely to contain biases due to selection and attrition. One study (Mosher 1995) contributes data to a comparison of typical antipsychotic medication to psychosocial treatment on six-week outcome measures of global psychopathology (N = 89, MD 0.01 CI -0.6 to 0.6) and global improvement (N = 89, MD -0.03 CI -0.5 to 0.4), indicating no between-group differences. On the whole, there is very little useable data in the few studies meeting inclusion criteria. AUTHORS' CONCLUSIONS:With only a few studies meeting inclusion criteria, and with limited useable data in these studies, it is not possible to arrive at definitive conclusions. The preliminary pattern of evidence suggests that people with early episode schizophrenia treated with typical antipsychotic medications are less likely to leave the study early, but more likely to experience medication-related side effects. Data are too sparse to assess the effects of antipsychotic medication on outcomes in early episode schizophrenia.
| S-EPMC4105695 | biostudies-other
Project description:It is becoming increasingly clear that longer duration of untreated psychosis (DUP) is associated with adverse clinical outcomes in patients with psychosis spectrum disorders. Because this association is often cited when justifying early intervention efforts, it is imperative to better understand underlying biological mechanisms. We enrolled 66 antipsychotic-naïve first-episode psychosis (FEP) patients and 45 matched healthy controls in this trial. At baseline, we used a human connectome style diffusion-weighted imaging (DWI) sequence to quantify white matter integrity in both groups. Patients then received 16 weeks of treatment with risperidone, 51 FEP completed the trial. We compared whole-brain fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD), and radial diffusivity between groups. To test if structural white matter integrity mediates the relationship between longer DUP and poorer treatment response, we fit a mediator model and estimated indirect effects. We found decreased whole-brain FA and AD in medication-naive FEP compared with controls. In patients, lower FA was correlated with longer DUP (r = -0.32; p = 0.03) and poorer subsequent response to antipsychotic treatment (r = 0.40; p = 0.01). Importantly, we found a significant mediation effect for FA (indirect effect: -2.70; p = 0.03), indicating that DUP exerts its effects on treatment response through affecting white matter integrity. Our data provide empirical support to the idea the DUP may have fundamental pathogenic effects on the natural history of psychosis, suggest a biological mechanism underlying this phenomenon, and underscore the importance of early intervention efforts in this disabling neuropsychiatric syndrome.
| S-EPMC7658031 | biostudies-literature
Project description:BackgroundDiffusion tensor imaging suggests that white matter alterations are already evident in first episode psychosis patients (FEP) and may become more prominent as the duration of untreated psychosis (DUP) increases. But because the tensor model lacks specificity, it remains unclear how to interpret findings on a biological level. Here, we used a biophysical diffusion model, Neurite Orientation Dispersion and Density Imaging (NODDI), to map microarchitecture in FEP, and to investigate associations between DUP and microarchitectural integrity.MethodsWe scanned 78 antipsychotic medication-naïve FEP and 64 healthy controls using a multi-shell diffusion weighted sequence and used the NODDI toolbox to compute neurite density (ND), orientation dispersion index (ODI) and extracellular free water (FW) maps. AFNI's 3dttest++ was used to compare diffusion maps between groups and to perform regression analyses with DUP.ResultsWe found that ND was decreased in commissural and association fibers but increased in projection fibers in FEP. ODI was largely increased regardless of fiber type, and FW showed a mix of increase in decrease across fiber tracts. We also demonstrated associations between DUP and microarchitecture for all NODDI indices.ConclusionsWe demonstrated that complex microarchitecture abnormalities are already evident in antipsychotic-naïve FEP. ND alterations are differentially expressed depending on fiber type, while decreased fiber complexity appears to be a uniform marker of white matter deficit in the illness. Importantly, we identified an empirical link between longer DUP and greater white matter pathology across NODDI indices, underscoring the critical importance of early intervention in this devastating illness.
| S-EPMC10038586 | biostudies-literature
Project description:Neuroimaging studies investigating patients with schizophrenia often report appreciable volumetric reductions and cortical thinning, yet the cause of these deficits is unknown. The association between subcortical and cortical structural alterations, and glutamatergic neurometabolites is of particular interest due to glutamate's capacity for neurotoxicity; elevated levels may be related to neuroanatomical compromise through an excitotoxic process. To this end, we explored the relationships between glutamatergic neurometabolites and structural measures in antipsychotic-naive patients experiencing their first non-affective episode of psychosis (FEP). Sixty antipsychotic-naive patients with FEP and 60 age- and sex-matched healthy controls underwent a magnetic resonance imaging session, which included a T1-weighted volumetric image and proton magnetic resonance spectroscopy in the precommissural dorsal caudate. Group differences in precommissural caudate volume (PCV) and cortical thickness (CT), and the relationships between glutamatergic neurometabolites (ie, glutamate+glutamine (Glx) and glutamate) and these structural measures, were examined. PCV was decreased in the FEP group (p<0.001), yet did not differ when controlling for total brain volume. Cortical thinning existed in the FEP group within frontal, parietal, temporal, occipital, and limbic regions at a 5% false discovery rate. Glx levels were negatively associated with PCV only in the FEP group (p=0.018). The observed relationship between Glx and PCV in the FEP group is supportive of a focal excitotoxic mechanism whereby increased levels of glutamatergic markers are related to local structural losses. This process may be related to the prominent structural deficits that exist in patients with schizophrenia.
| S-EPMC4987861 | biostudies-other
Project description:IntroductionThyroid hormones play an essential role in hippocampal development, a key structure in psychosis. However, the role of these hormones in first-episode psychosis (FEP) has received limited attention. It has been hypothesized that thyroid hormones could cause morphological modifications in the hippocampal structure through the upregulation of brain-derived neurotrophic factor (BDNF). In this study, we primarily aimed to determine the relationship between thyroid-stimulating hormone (TSH) levels, peripheral BDNF levels, and hippocampal volume in antipsychotic-naïve FEP patients. We also aimed to determine whether TSH levels were associated with clinical symptomatology.Materials and methodsA total of 50 antipsychotic-naïve FEP patients were included in the study. At baseline, we collected fasting blood samples and registered sociodemographic and clinical variables (substance use, DUP, PANSS, GAF, and CDSS). Structural T1 MRI was performed at baseline to quantify brain volumes. No control group was used for this study.ResultsOf the 50 patients, more than one-third (36%) presented alterations in TSH levels, mainly elevated levels (32% of patients). The TSH levels were inversely correlated with both peripheral BDNF and hippocampal volume. On the multivariate analysis, the model that best predicted the relative hippocampal volume was a single variable model (TSH levels). No significant association was observed between TSH levels and clinical symptomatology.DiscussionThese results suggest that thyroid hormones could have a neuroprotective effect on the hippocampus in FEP patients, possibly through their effect by increasing BDNF concentrations, which could attenuate brain injury and neuroinflammation. Nevertheless, thyroid hormones could also affect hippocampal volume through other pathways.
| S-EPMC10734033 | biostudies-literature
Project description:IntroductionOnly a few studies have comprehensively characterized default mode network (DMN) pathology on a structural and functional level, and definite conclusions cannot be drawn due to antipsychotic medication exposure and illness chronicity. The objective of this study was to characterize DMN pathology in medication-naïve first episode psychosis (FEP) patients, and determine if DMN structural and functional connectivity (FC) have potential utility as a predictor for subsequent antipsychotic treatment response.MethodsDiffusion imaging and resting state FC data from 42 controls and 52 FEP were analyzed. Patients then received 16 weeks of antipsychotic treatment. Using region of interest analyses, we quantified FC of the DMN and structural integrity of the white matter tracts supporting DMN function. We then did linear regressions between DMN structural and FC indices and antipsychotic treatment response.ResultsWe detected reduced DMN fractional anisotropy and axial diffusivity in FEP compared to controls. No DMN FC abnormalities nor correlations between DMN structural and FC were found. Finally, DMN fractional anisotropy and radial diffusivity were associated with response to treatment.ConclusionOur study highlights the critical role of the DMN in the pathophysiology suggesting that axonal damage may already be present in FEP patients. We also demonstrated that DMN pathology is clinically relevant, as greater structural DMN alterations were associated with a less favorable clinical response to antipsychotic medications.
| S-EPMC8364918 | biostudies-literature
Project description:BackgroundDespite a large body of schizophrenia research, we still have no reliable predictors to guide treatment from illness onset. The present study aimed to identify baseline clinical or neurobiological factors - including peripheral brain-derived neurotrophic factor (BDNF) levels and amygdala or hippocampal relative volumes - that could predict negative symptomatology and persistent negative symptoms in first-episode psychosis after 1 year of follow-up.MethodsWe recruited 50 drug-naive patients with first-episode psychosis and 50 age- and sex-matched healthy controls to study brain volumes. We performed univariate and multiple and logistic regression analyses to determine the association between baseline clinical and neurobiological variables, score on the PANSS negative subscale and persistent negative symptoms after 1 year of follow-up.ResultsLow baseline serum BDNF levels (p = 0.011), decreased left amygdala relative volume (p = 0.001) and more severe negative symptomatology (p = 0.021) predicted the severity of negative symptoms at 1 year, as measured by the PANSS negative subscale. Low baseline serum BDNF levels (p = 0.012) and decreased left amygdala relative volume (p = 0.010) predicted persistent negative symptoms at 1 year.LimitationsWe were unable to assess negative symptoms and their dimensions with next-generation scales, which were not available when the study was initiated.ConclusionThis study shows that a set of variables at baseline, including low BDNF levels, smaller left amygdala relative volume and score on the PANSS negative subscale are significant predictors of outcomes in first-episode psychosis. These findings might offer an initial step for tailoring treatments in first-episode psychosis.
| S-EPMC8789336 | biostudies-literature
Project description:BackgroundThe neurodevelopmental model of psychosis was established over 30 years ago; however, the developmental influence on psychotic symptom expression - how age affects clinical presentation in first-episode psychosis - has not been thoroughly investigated.MethodsUsing generalized additive modeling, which allows for linear and non-linear functional forms of age-related change, we leveraged symptom data from a large sample of antipsychotic-naïve individuals with first-episode psychosis (N = 340, 12-40 years, 1-12 visits), collected at the University of Pittsburgh from 1990 to 2017. We examined relationships between age and severity of perceptual and non-perceptual positive symptoms and negative symptoms. We tested for age-associated effects on change in positive or negative symptom severity following baseline assessment and explored the time-varying relationship between perceptual and non-perceptual positive symptoms across adolescent development.ResultsPerceptual positive symptom severity significantly decreased with increasing age (F = 7.0, p = 0.0007; q = 0.003) while non-perceptual positive symptom severity increased with age (F = 4.1, p = 0.01, q = 0.02). Anhedonia severity increased with increasing age (F = 6.7, p = 0.00035; q = 0.0003), while flat affect decreased in severity with increased age (F = 9.8, p = 0.002; q = 0.006). Findings remained significant when parental SES, IQ, and illness duration were included as covariates. There were no developmental effects on change in positive or negative symptom severity (all p > 0.25). Beginning at age 18, there was a statistically significant association between severity of non-perceptual and perceptual symptoms. This relationship increased in strength throughout adulthood.ConclusionsThese findings suggest that as maturation proceeds, perceptual symptoms attenuate while non-perceptual symptoms are enhanced. Findings underscore how pathological brain-behavior relationships vary as a function of development.
| S-EPMC8021611 | biostudies-literature