Structural changes in the hippocampus and amygdala at first episode of psychosis

Hippocampus and amygdala changes have been implicated in the pathophysiology and symptomatology of both schizophrenia (SCZ) and bipolar disorder (BD). However relationships between illness course, neuropathological changes and variations in symptomatology remain unclear. This investigation examined the associations between hippocampus and amygdala volumes and symptom dimensions in schizophrenia and bipolar disorder patients after their first episode of psychosis. Symptom severity was associated with decreases in hippocampus/amygdala complex volume across groups. In keeping with previous work bilateral hippocampus and amygdala volume reductions were also identified in the SCZ patients while in BD patients only evidence of amygdala inflation reached significance. The study concludes that there appear to be important relationships between volume changes in the hippocampus and amygdala and dimensions and severity of symptomatology in psychosis. Structural alterations are apparent in both SCZ and BD after first episode of psychosis but present differently in each illness and are more severe in SCZ.     

Correlates of cognitive deficits in first episode schizophrenia

OBJECTIVE: The presence of cognitive dysfunction in schizophrenia has been well documented, but questions remain about whether there are relationships between this dysfunction and clinical symptomatology. If present, such relationships should be most clearly observable in patients with first episode schizophrenia; that is, before the effects of chronic illness, institutionalization, or treatment might confound them. METHOD: 307 schizophrenia subjects in their first episode of illness were recruited to participate in a clinical trial comparing the long-term efficacy of haloperidol and risperidone. The psychopathology, cognitive functioning, early treatment history, and duration of untreated psychosis of these subjects were assessed prior to their assignment to randomized, double-blind treatment. Approximately two-thirds of the subjects were receiving antipsychotic treatment at the time of assessment; however, the duration of treatment was limited to 12 weeks or less. RESULTS: The severity of negative symptoms at the time of assessment was associated with deficits in memory, verbal fluency, psychomotor speed and executive function. Positive symptoms were not associated with cognitive deficits. Also, the duration of untreated illness (DUI) prior to assessment was not significantly associated with cognitive impairment. CONCLUSIONS: The results of this study of first episode schizophrenia patients suggest that a relationship exists between negative symptoms and cognitive dysfunction. However, that relationship accounts for only a minor portion of the variance (i.e., 10-15%) in the severity of cognitive dysfunction after controlling for a number of potentially confounding factors. This finding provides support for the theory that the neurobiological processes that give rise to symptomatology and cognitive dysfunction in schizophrenia are partially overlapping.     

Lack of association between duration of untreated illness and severity of cognitive and structural brain deficits at the first episode of schizophrenia

OBJECTIVE: The purpose of the study was to determine whether the duration of illness before antipsychotic drug treatment for schizophrenia was associated with the severity of cognitive deficits and volumetric brain structure anomalies observed in some patients with a first episode of schizophrenia. METHOD: Duration of psychotic symptoms and of other symptoms marking a behavioral change was estimated from structured interviews with 50 patients who had a first episode of schizophrenia and their family members. Interviews were conducted within a month of the patients' hospitalization. Duration of untreated psychotic symptoms and of behavioral change was correlated with neuropsychological summary scores from a comprehensive cognitive battery and with measurements of lateral ventricular, temporal lobe, and cerebral hemispheric volumes. RESULTS: No significant correlations were observed between measures of untreated illness and the severity of either cognitive or structural brain deficits at baseline. CONCLUSIONS: The duration of untreated symptoms of schizophrenia, for which an association with an uncontrolled toxic brain process has been proposed, is unlikely to explain why first-episode patients with schizophrenia have widespread deficits in cognitive functioning and have detectable ventricular enlargement and some loss of cortical mass.     

Duration of untreated psychosis is associated with orbital-frontal grey matter volume reductions in first episode psychosis

BackgroundDelay in treatment of psychosis is associated with poor clinical and social outcome and is measured as the duration of untreated psychosis (DUP) prior to treatment of the first episode. It has been suggested that this may be mediated through toxic effects of psychosis on the structure and function of the brain. Equivocal evidence exists regarding association between longer DUP and neuro-anatomical changes such as, reduced grey matter volume in specific regions in the brain and deficits in neurocognitive functions.ObjectiveTo examine if duration of untreated psychosis (DUP) preceding treatment of a first episode of psychosis is associated with structural brain abnormalities and deficits in neurocognitive functions.MethodWe investigated the relationship between DUP and grey matter volume using voxel-based morphometry techniques and with multiple domains of cognition. Eighty patients with a first episode of psychosis were separated into two equal sized groups based on a median split (18 weeks) of their DUP.ResultsCompared to the short-DUP group (mean DUP 7.9 weeks ± 5.6), the long-DUP group (mean 113.7 weeks ± 170.4) showed significant grey matter volume reductions in orbital–frontal regions (bilateral medial frontal gyrus and bilateral rectal gyrus, BA 11) and parietal regions (postcentral gyrus and superior parietal lobule) as well as a significant reduction in whole brain grey matter volume (p < 0.04). For schizophrenia spectrum cases only these findings were confined to left rectal gyrus. There were no differences in white matter or cerebral spinal fluid volumes or on cognitive functions. Results are controlled for antipsychotic medication exposure.LimitationsThe inherent difficulty in separating slow and insidious onset from long-DUP may limit the interpretation of our results and there may be an overlap between DUP and duration of illness (including the prodrome).ConclusionPatients with a longer delay in treatment of psychosis show a significant reduction in overall grey matter volume with specific reductions in the inferior-orbital region. These results provide some support to a possible neurotoxic effect of prolonged untreated psychosis.     

Cognitive deterioration and duration of untreated psychosis

Aim: To examine the relationship between cognitive deterioration and the duration of untreated psychosis (DUP) in a first‐episode psychosis sample. Method: We assessed a consecutive sample of first‐episode psychosis participants (N = 50) with measures of cognitive deterioration and DUP. Results: Using correlations and stepwise linear regressions, we found strong relationships between DUP and measures of cognitive deterioration. Conclusions: The length of DUP predicted cognitive deterioration. These results highlight a potential DUP grace period (>6 months) in which significant cognitive deterioration may be averted.     

Volume reduction of the left planum temporale gray matter associated with long duration of untreated psychosis in schizophrenia: a preliminary report

A longer duration of untreated psychosis (DUP) in schizophrenia is reported to lead to a poorer clinical outcome, possibly reflecting a neurodegenerative process after the onset of overt psychosis. However, the effect of DUP on brain morphology in schizophrenia is still poorly understood. In this study, we used magnetic resonance imaging to investigate the relation between DUP and volumetric measurements for the superior temporal sub-regions (Heschl's gyrus, planum temporale, and caudal superior temporal gyrus), the medial temporal lobe structures (hippocampus and amygdala), and the frontal lobe regions (prefrontal area and anterior cingulate gyrus) in a sample of 38 schizophrenia patients (20 males and 18 females) whose illness duration was less than five years. We found a significant negative correlation between DUP and the volume of gray matter in the left planum temporale even after controlling for age, age at illness onset, and duration and dosage of neuroleptic medication. There was no such correlation for the other brain regions including each sub-region of the prefrontal cortex (the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, ventral medial prefrontal cortex, orbitofrontal cortex, and straight gyrus). When subjects were divided into two groups around the median DUP, the long-DUP group had a significantly smaller planum temporale gray matter than the short-DUP group. These findings may reflect a progressive pathological process in the gray matter of the left planum temporale during the initial untreated phase of schizophrenia, whereas abnormalities in the medial temporal regions might be, as has been suggested from previous longitudinal findings, relatively static at least during the early course of the illness.     

精神分裂症未治期及其影响因素研究

目的 了解精神分裂症患者首次正式开始治疗前的疾病未治疗期间(duration of untreated illness, DUI)和精神病未治疗期间(duration of untreated psychosis,DUP)及其影响因素.方法 应用诺丁汉起病症状量表(Nottingham onset schedule, NOS)调查上海市精神卫生中心的精神分裂症患者,共收集117例.同时,应用自编问卷对患者家属进行访谈,调查可能影响患者及时就诊的因素.结果 ① 精神分裂症患者DUI中位数是181天, DUP中位数是84天.② 首发非特异性精神症状以失眠和情绪障碍最为常见,出现频度超过50%;首发精神病性症状以幻听和被害妄想最为常见,出现频度达到47%.③ 影响患者就诊的主要因素是家属不认识精神病和患者不愿接受诊治.④ 以DUI中位数181天将患者区分为长DUI组和短DUI组,发现:长DUI组中回答家庭成员意见不一致是延误就诊因素的比例显著高于短DUI组(χ2=3.9,P<0.05).结论 精神分裂症患者从发病到开始治疗的疾病未治疗期间较长.影响DUI和DUP的因素是多方面的,值得进一步深入研究.     

Measurement and reporting of the duration of untreated psychosis

Aim: The aim of this study was to investigate the demographic, illness and methodological factors associated with mean and median duration of untreated psychosis (DUP). Methods: A systematic review and meta‐analysis of the published studies of DUP and an examination of available DUP distributions. Results: DUP was longer in samples with a higher proportion of patients with schizophrenia and was shorter in samples that included affective psychosis. Sex, age, and the methods of measuring the onset and end‐point of DUP and the type of service in which the studies were performed did not contribute to the heterogeneity of the mean or median DUP values. Mean DUP is significantly prolonged by a small number of patients, and the median DUP is a poor indicator of the rate at which patients present. Conclusions: The DUP of patients with affective and non‐affective psychosis should be examined separately in order to make measures of DUP more meaningful and comparable, and DUP should be reported using more comprehensive measures. We suggest a method of reporting DUP based on the rate of presentation of first‐episode psychosis patients rather than the length of DUP.     

Increased basal ganglia volumes in velo-cardio-facial syndrome (deletion 22q11.2).

BACKGROUND: This study evaluated differences in caudate volumes in subjects with velo-cardio-facial syndrome due to a 22q11.2 (22qDS) deletion. Because psychosis is observed in 30% of adult subjects with 22qDS, this neurogenetic disorder could represent a putative model for a genetically mediated subtype of schizophrenia.METHODS: Caudate volumes were measured on high-resolution magnetic resonance images in 30 children and adolescents with 22qDS and 30 gender- and age-matched normal comparison subjects.RESULTS: Caudate head volumes were increased in the 22qDS group independent of neuroleptic medications. Subjects with 22qDS also displayed an abnormal pattern of asymmetry in the anterior caudate, with left side greater than right.CONCLUSIONS: Alterations in the basal ganglia circuitry have been implicated in learning, cognitive, and behavioral problems in children and therefore could be involved in the expression of the neurobehavioral phenotype expressed by subjects with 22qDS. Abnormal caudate volume is a neurodevelopmental feature shared with schizophrenia, further establishing 22qDS as a potential neurodevelopmental model for this disorder.     

Basal ganglia volume in unmedicated patients with schizophrenia is associated with treatment response to antipsychotic medication

We investigated the relationship between basal ganglia volume and treatment response to the atypical antipsychotic medication risperidone in unmedicated patients with schizophrenia. Basal ganglia volumes included the bilateral caudate, putamen, and pallidum and were measured using the Freesurfer automated segmentation pipeline in 23 subjects. Also, baseline symptom severity, duration of illness, age, gender, time off medication, and exposure to previous antipsychotic were measured. Treatment response was significantly correlated with all three regions of the bilateral basal ganglia (caudate, putamen, and pallidum), baseline symptom severity, duration of illness, and age but not gender, time off antipsychotic medication, or exposure to previous antipsychotic medication. The caudate volume was the basal ganglia region that demonstrated the strongest correlation with treatment response and was significantly negatively correlated with patient age. Caudate volume was not significantly correlated with any other measure. We demonstrated a novel finding that the caudate volume explains a significant amount of the variance in treatment response over the course of 6 weeks of risperidone pharmacotherapy even when controlling for baseline symptom severity and duration of illness.     

MRI volumetric and 31P MRS metabolic correlates of caudate nucleus in antipsychotic-naïve schizophrenia

Objective: To examine the volumetric and metabolic correlates of caudate nucleus in antipsychotic‐naïve schizophrenia patients in comparison with healthy controls. Method: Twelve antipsychotic‐naïve schizophrenia patients and 13 healthy controls underwent ³¹P magnetic resonance spectroscopy of basal ganglia. Magnetic resonance imaging volume of caudate nuclei was measured using scion image software. Results: Patients had significantly smaller caudate volume than healthy controls. Phosphocreatine (PCr)/total phosphorous and PCr/total adenosine tri‐phosphate ratios of both caudate nuclei were significantly lower in patients than controls. Significant negative correlation was found between the left caudate volume and left PCr/total phosphorus ratio in the patients. Age at onset of psychosis had i) significant negative correlation with right and left caudate volumes and ii) significant positive correlation with left PCr/total phosphorus ratio. Conclusion: The metabolic and volumetric abnormalities of caudate nucleus in antipsychotic‐naïve schizophrenia patients support neurodevelopmental etiopathogenesis.     

Durée de psychose non traitée : état des lieux et analyse critique

IntroductionPrognosis of schizophrenia has not significantly improved despite extensive research. There is often a relatively long delay between onset of symptoms and treatment initiation. Lately, duration of untreated psychosis (DUP), the time between the onset of psychosis and initiation of treatment, has been one of the most studied variables in patients presenting for a first psychotic episode in order to evaluate the impact of early intervention on the prognosis of schizophrenia. In the literature, a variety of criteria have been used to define both transition to psychosis and initiation of treatment. Furthermore, the dating of both of these variables is usually retrospective, further complicating the measurement of DUP.MethodsWe conducted a comprehensive review about DUP using Pubmed and Google Scholar databases up to January 2015 using the following keywords “schizophrenia”, “duration of untreated psychosis”, “duration of untreated illness” and “early intervention”. Papers were included if they were published in French or English.ResultsThe mean DUP was found to be 2 years but it can vary according to multiple factors such as denial of illness by the patient and family, withdrawal and isolation from friends and relatives, diagnostic errors, paranoid views of the mental health treatment systems, or negative symptoms. Long DUP may also be a correlate of poor premorbid functioning or of an insidiously unfolding psychosis. Considerable discrepancies exist in the way that DUP is estimated in different studies. Although the clinical interview remains the most common way of measuring DUP, so far there is no evidence for favoring one method over another. Regardless of measurement method, a longer DUP is found to be associated with poorer outcome in schizophrenia in both the short and long-term across a number of domains: symptoms severity, remission rates, the risk of relapse, global functioning and quality of life. Its role in functional outcome appears to be mediated largely by negative symptoms, for which there is still no effective treatment. A recent meta-analysis has shown that shorter DUP is associated with less severe negative symptoms at short and long-term follow-up, especially when DUP is shorter than 9 months. The mechanism of the relationship between DUP and outcome is still undefined. A hypothesis is that the shorter the DUP, the more likely the intervention is being applied during the period in which neurobiological deficit processes in schizophrenia are most active.DiscussionA study of the duration of untreated illness (DUI), which is defined as the DUP and the prodromal phase, seems necessary because results of studies evaluating the effect of early detection and intervention in individuals with clinical high risk for psychosis are promising. A number of interventions such as omega 3 fatty acids and integrated psychosocial interventions seem to delay transition in the at-risk population. However, replication studies are lacking, and a great proportion of at high-risk individuals will spontaneously remit or develop diseases other than chronic psychosis, making us question the advantages and disadvantages of a treatment. Taking into consideration the high prevalence of comorbidities in individuals referred for clinical high-risk state and their effect on the individual's functioning, future interventions in the field need to address not only the preventative efficacy on psychosis transition but also their effectiveness in improving the functioning of this population and their effect on the outcome of schizophrenia when transition to psychosis has occurred.ConclusionDespite the huge advances in the field of schizophrenia, many questions remain unanswered and huge efforts are still necessary to understand the pathophysiology of this illness in order to improve its outcome.     

Duration of untreated psychosis,ethnicity, educational level,and gender in a multiethnic South‐East Asian country: report from Malaysia schizophrenia registry

Introduction: Duration of untreated psychosis (DUP) determines the outcome of schizophrenia. Previously, there was no information about the DUP among patients in Malaysia with schizophrenia. The aim of the present study was to investigate the association between DUP and patients' demographic, social cultural background and clinical features. Method: This is a cross‐sectional study on patients who presented with first episode schizophrenia. Data from 74 primary care centers and hospitals between 1 January 2003 and 31 December 2007 were included in the analysis. All patients with first‐episode schizophrenia were enrolled in the study. Results: The mean DUP was 37.6 months. The indigenous community appeared to have the shortest DUP compared to the Malay, Chinese and Indian communities. Female, people with lower educational level, and comorbidity with medical illness during contact had longer DUP. Discussion: DUP in this multiethnicity country was found to be significantly short among the indigenous people, which may sugest that traditional values and strong family and community ties shorten the DUP. Educational level may need to be further investigated, because as upgrading the general educational level could lead to shorter DUP among the patients as well.     

Longitudinal assessment of psychopathological domains over late-stage schizophrenia in relation to duration of initially untreated psychosis: 3-year prospective study in a long-term inpatient population

There remains uncertainty regarding any progressive nature of psychopathology and cognitive dysfunction in late-stage schizophrenia, and whether duration of initially untreated psychosis (DUP) might be associated with such 'progression'. This study examines longitudinally, over 3 years, the psychopathology and neuropsychology in 82 inpatients with DSM-IV schizophrenia, many of whom were admitted in the pre-neuroleptic era. Increase in executive dysfunction exceeded that in general cognitive impairment. Positive but not negative symptom severity decreased modestly; the primary predictor of negative symptom severity was DUP. On index assessment, psychopathology evidenced a three-factor structure; at follow-up, psychomotor poverty evidenced greater prominence and cohesion, and was on both occasions predicted primarily by DUP, while reality distortion was altered and disorganisation disassembled into alternative elements. It would appear that as years of chronic, refractory illness accrue, psychomotor poverty becomes more sharply delineated and dominant within the overall structure of psychopathology, and its prominence is predicted enduringly by DUP.     

Long-term effects of a community intervention for early identification of first-episode psychosis

Objective: To assess whether an Early Case Identification Program (ECIP) for first‐episode psychosis (FEP), which showed no significant short‐term effects, has a delayed impact on duration of untreated psychosis (DUP). Method: Using a historical control design, FEP patients were assessed on clinical variables over three consecutive phases, 2 years prior, 2 years during and 3 years after implementation of the ECIP. Additional analyses were conducted on non‐affective and schizophrenia spectrum psychoses cases only. Results: There was no overall significant difference in DUP across the three phases. For cases treated within the first year of illness a nonsignificant reduction in DUP to less than 2 months observed during the active phase was sustained post‐ECIP. Conclusion: In some jurisdictions community‐wide early case detection may fail to have an immediate or delayed effect on DUP, especially for cases who normally present for treatment with DUP >1 year.     

Lack of an inverse relationship between duration of untreated psychosis and cognitive function in first episode schizophrenia

This study assessed the relationship between duration of untreated psychosis (DUP) and cognitive measures in order to assess if longer DUP was associated with worse performance. One hundred two patients with first episode schizophrenia or schizoaffective disorder were assessed on cognitive measures of speed of processing, episodic memory, executive function, and visual spatial processing at baseline (when patients were drug naive and after 16 weeks of olanzapine or risperidone treatment), so that a change score could be derived. DUP was defined by the emergence of psychiatric symptoms and the emergence of psychotic symptoms. Data were analyzed correlationally, parametrically (after the group was divided into long and short DUP by median split), and by regression. We found that DUP for psychotic symptoms in this group of patients was long, with a median of 46 weeks. Neither correlational, parametric analyses in which DUP served as a class variable, nor multiple regression indicated that longer DUP was associated with worse cognition at baseline or smaller magnitude of improvement in cognition. Our results suggest that while early intervention may be critical for symptom amelioration by shortening DUP, early intervention for treatment of psychiatric symptoms may have little or no impact on cognitive function. Furthermore, assuming that cognition is a core symptom of schizophrenia, the notion that ongoing psychosis is somehow toxic for a variety of information processing domains appears questionable.     

Duration of untreated psychosis and neuropsychological function in first episode psychosis

PURPOSE: We investigated whether duration of untreated psychosis (DUP) prior to first presentation was associated with cognitive function in first episode psychosis (FEP) subjects. We predicted that longer DUP would be associated with greater neurocognitive impairment. METHOD: 180 subjects with schizophrenia (and 93 subjects with Other Psychoses) performed a neurocognitive battery assessing IQ, verbal learning, working memory, visual learning and speed of processing. DUP was defined as the number of days between first onset of psychotic symptoms and first contact with psychiatric services. RESULTS: Longer DUP was associated with impaired performance in verbal IQ (p=0.04), verbal learning (p=0.02), and verbal working memory (p=0.04) in FEP subjects with schizophrenia. These associations remained significant for verbal IQ when scores were corrected for age, gender, educational level and ethnicity. CONCLUSIONS: Longer DUP is associated with poorer neurocognitive ability in schizophrenia subjects at time of first presentation. Since this was a cross-sectional study we can not tell whether longer DUP was a cause or a consequence of the poorer performance.     

Premorbid adjustment, symptom development and quality of life in first episode psychosis: a systematic review and critical reappraisal

Objective: To systematically review the relationship of premorbid adjustment to symptomatology in first episode psychosis (FEP), taking into account the influence of duration of untreated psychosis (DUP). Method: Electronic databases were searched to identify relevant studies. Results: A variety of approaches to the reporting of premorbid adjustment were identified. There was no significant association between premorbid adjustment and DUP, supporting the proposition that they are independent constructs. The effect of premorbid adjustment upon positive symptomatology was negligible. Premorbid adjustment had a modest effect upon negative symptoms and quality of life, increasing over duration of follow‐up. Conclusion: Premorbid adjustment remains a valid construct in the study of FEP. Both premorbid adjustment and DUP confer independent effects on aspects of symptomatology in FEP. Results for premorbid adjustment are similar to previous findings in more chronic samples. The potential for conceptualizing premorbid functioning by developmental, academic/social and typological approaches is currently underexploited.     

Family strengths: a potential determinant of the duration of untreated psychosis among hospitalized African-American first-episode patients

Aim: Evidence suggests that treatment delay, represented by the duration of untreated illness (DUI) and the duration of untreated psychosis (DUP), may be a potentially powerful determinant of the early course of primary psychotic disorders. Yet, research on the predictors of treatment delay has only just begun. To date, there are virtually no empirical data on the relationship between family functioning and treatment delay in the context of first‐episode psychosis. In this study, it was hypothesized that family strengths would be inversely correlated with DUI and DUP; and families of patients with a short DUI/DUP would have greater family strengths than those of patients with a long DUI/DUP. Methods: Family strengths (including pride and accord dimensions), DUI and DUP were assessed in 34 African Americans hospitalized for first‐episode psychosis and their respective 34 family members most involved in initiating care. Results: The total score of the Family Strengths scale and the accord subscale score were significantly inversely correlated with both DUI and DUP, although the correlation between the pride subscale score and DUI/DUP was not as strong and failed to reach statistical significance. Similarly, the family members of patients with a short DUI/DUP had higher family strength scores than those of patients with a long DUI/DUP. Conclusions: Given the dearth of research on the functioning of families beginning to initiate care for individuals with first‐episode psychosis, it is imperative to further clarify the role family characteristics may play in understanding treatment delay (DUI/DUP) and in the development of preventive interventions to facilitate early intervention for at‐risk populations.     

Caudate volume changes in first episode psychosis parallel the effects of normal aging: a 5-year follow-up study

We investigated whether the caudate nuclei volume (CNV) of 15 first episode psychosis patients increased after 5 years of treatment with either atypical antipsychotics or low doses of typical antipsychotics. Caudate volumes were measured from magnetic resonance imaging (MRI) scans in 15 patients and 10 healthy controls. Both groups demonstrated a significant 9% decline in caudate volume. We were unable to replicate previous reports of caudate enlargement in patients receiving antipsychotic treatment.