Eric Y.H. Chen

Intervention in individuals at ultra high risk for psychosis : a review and future directions

OBJECTIVE Over the last 15 years, a focus on early intervention in psychotic disorders has emerged. Initially, the early psychosis movement focused on timely recognition and phase-specific treatment of first-episode psychosis. However, early psychosis researchers suspected that pushing the point of intervention even further back to the prodromal phase of psychotic disorders may result in even better outcomes. This article reviews intervention research in the ultra-high-risk phase of psychotic disorders. DATA SOURCES A literature search of intervention trials with ultra-high-risk cohorts published after 1980 was conducted on PubMed with the search terms prodrome and intervention. STUDY SELECTION All published intervention trials with ultra-high-risk cohorts. DATA SYNTHESIS The first generation of intervention trials indicated that both pharmacologic and psychological intervention strategies may be of value in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. CONCLUSIONS Further controlled intervention trials with larger sample sizes are required in order to confirm and extend these findings. We argue that the clinical staging model provides a framework for the rationale and design of such studies, with simpler, safer, and more benign interventions being better candidates for first-line treatment, while more complex and potentially harmful treatments should be reserved for those cases in which response has failed to occur. Recent evidence indicates that neuroprotective agents, such as essential fatty acids, may be a suitable form of intervention for the ultra-high-risk phase of psychotic disorders, with a positive risk-benefit balance. Ethical aspects have become more salient given the recently observed declining transition rate in ultra-high-risk samples. We outline the key questions for the next generation of ultra-high-risk intervention trials.

Cerebral grey, white matter and csf in never-medicated, first episode schizophrenia.

We report the first voxel-based morphometric (VBM) study to examine cerebral grey and white matter and cerebrospinal fluid (CSF) using computational morphometry in never-medicated, first-episode psychosis (FEP). Region-of-interest (ROI) analysis was also performed blind to group membership. 26 never-medicated individuals with FEP (23 with DSM-IV schizophrenia) and 38 healthy controls had MRI brain scans. Groups were balanced for age, sex, handedness, ethnicity, paternal socio-economic status, and height. Healthy controls were recruited from the local community by advertisement. Grey matter, white matter, and CSF: global brain volume ratios were significantly smaller in patients. Patients had significantly less grey matter volume in L and R caudate nuclei, cingulate gyri, parahippocampal gyri, superior temporal gyri, cerebellum and R thalamus, prefrontal cortex. They also had significantly less white matter volume in the R anterior limb of the internal capsule fronto-occipital fasciculus and L and R fornices, and significantly greater CSF volume especially in the R lateral ventricle. Excluding the 3 subjects with brief psychotic disorder did not alter our results. Our data suggest that fronto-temporal and subcortical-limbic circuits are morphologically abnormal in never-medicated, schizophrenia. ROI analysis comparing the schizophrenia group (n=23) with the healthy controls (n=38) confirmed caudate volumes were significantly smaller bilaterally by 11%, and lateral ventricular volume was significantly larger on the right by 26% in the patients. Caudate nuclei and lateral ventricular volume measurements were uncorrelated (Pearson correlation coefficient 0.30, p=0.10), ruling out the possibility of segmentation artefact. Ratio of lateral ventricle to caudate volume was bilaterally significantly increased (p<0.005, 2-tailed), which could represent an early biomarker in first-episode, never-medicated schizophrenia.

Schizophrenic Patients and Their Unaffected Siblings Share Increased Resting-State Connectivity in the Task-Negative Network but Not Its Anticorrelated Task-Positive Network

BACKGROUND Abnormal connectivity of the anticorrelated intrinsic networks, the task-negative network (TNN), and the task-positive network (TPN) is implicated in schizophrenia. Comparisons between schizophrenic patients and their unaffected siblings enable further understanding of illness susceptibility and pathophysiology. We examined the resting-state connectivity differences in the intrinsic networks between schizophrenic patients, their unaffected siblings, and healthy controls. METHODS Resting-state functional magnetic resonance images were obtained from 25 individuals in each subject group. The posterior cingulate cortex/precuneus and right dorsolateral prefrontal cortex were used as seed regions to identify the TNN and TPN through functional connectivity analysis. Interregional connectivity strengths were analyzed using overlapped intrinsic networks composed of regions common to all subject groups. RESULTS Schizophrenic patients and their unaffected siblings showed increased connectivity in the TNN between the bilateral inferior temporal gyri. By contrast, schizophrenic patients alone demonstrated increased connectivity between the posterior cingulate cortex/precuneus and left inferior temporal gyrus and between the ventral medial prefrontal cortex and right lateral parietal cortex in the TNN. Schizophrenic patients exhibited increased connectivity between the left dorsolateral prefrontal cortex and right inferior frontal gyrus in the TPN relative to their unaffected siblings, though this trend only approached statistical significance in comparison to healthy controls. CONCLUSION Resting-state hyperconnectivity of the intrinsic networks may disrupt network coordination and thereby contribute to the pathophysiology of schizophrenia. Similar, though milder, hyperconnectivity of the TNN in unaffected siblings of schizophrenic patients may contribute to the identification of schizophrenia endophenotypes and ultimately to the determination of schizophrenia risk genes.

A prospective 3-year longitudinal study of cognitive predictors of relapse in first-episode schizophrenic patients

BACKGROUND Cognitive predictors of relapse have been extensively explored only in few long term longitudinal studies of first-episode schizophrenia. METHOD This study prospectively followed 93 patients with first-episode schizophrenia, schizophreniform disorder, and schizoaffective disorder for 3 years after their first-episode illness. Cognitive domains including verbal intelligence, verbal and visual memory, verbal fluency, and Wisconsin Card Sorting Test performance were investigated as potential predictors of relapse. RESULTS We found that by the first year 21% patients had relapsed, by the second year 33% had relapsed, and by the third year 40% had relapsed. There was a significant difference in the relapse rate between patients with good adherence and patients with poor adherence to medication regimes. A multiple logistic regression analysis revealed that after controlling for medication adherence, perseverative error in the Wisconsin Card Sorting Test was the only cognitive function that significantly predict relapse with an odds ratio of 2.4. CONCLUSIONS Cognitive flexibility in set shifting is related to tendency towards relapse in first-episode schizophrenic patients. Other cognitive factors appear not to be related to relapse. Possible mechanisms included the link between prefrontal dysfunction and sub-cortical dopamine system stability, as well as the effects of executive dysfunction on insight impairment and adherence behavior.

Persistent negative symptoms in first-episode schizophrenia: A prospective three-year follow-up study

BACKGROUND Negative symptoms are a core feature of schizophrenia. The evolution and trajectory of primary negative symptoms were under-studied. We aimed at evaluating the prevalence and stability of primary negative symptoms, and factors associated with persistent primary negative symptoms in a first-episode sample. METHOD Ninety-three Hong Kong Chinese aged 18 to 55 years presenting with first-episode schizophrenia-spectrum disorder were studied. Data on premorbid adjustment, socio-demographics, and baseline clinical and cognitive profiles were obtained. Psychopathological and vocational reassessments were conducted at 12, 24 and 36 months. Primary negative symptoms were defined as the presence of clinically significant negative symptoms excluding depression and extra-pyramidal signs. RESULTS At baseline, 25.8% of subjects exhibited primary negative symptoms. A quarter of patients had their initial primary negative symptoms status retained 12 months after treatment initiation. In both Year 2 and Year 3 of study period, around 70% of subjects had their primary negative symptoms status maintained for 12 months. At the end of three-year follow-up, 23.7% were categorized as having persistent primary negative symptoms. Male sex, unemployment at intake, prolonged duration of untreated psychosis, poorer premorbid academic and social functioning, poorer insight and worse vocational outcome were found to be associated with persistent primary negative symptoms. CONCLUSION Clinical status of primary negative symptoms in first-episode schizophrenia-spectrum disorder was unstable in the initial year of treatment. Baseline symptom assessment may not reliably predict development of persistent primary negative symptoms. Studying negative symptoms should take into account the longitudinal perspective, especially in the early course of psychotic disorders.

Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial

Objective To study rates of relapse in remitted patients with first episode psychosis who either continued or discontinued antipsychotic drugs after at least one year of maintenance treatment. Design 12 month randomised, double blind, placebo controlled trial. Setting Early psychosis outpatient clinics in Hong Kong. Participants 178 patients with first episode psychosis who had received at least one year of antipsychotic drug treatment between September 2003 and July 2006 and had no positive symptoms of psychosis. Interventions Patients received either maintenance treatment with quetiapine (400 mg/day) or placebo and were followed up for the next 12 months or until a relapse occurred. Main outcome measure Relapse assessed monthly and defined as re-emergence of psychotic symptoms (delusions, conceptual disorganisation, hallucinations, suspiciousness, and unusual thought content) according to predefined thresholds. Results 178 patients were randomised (89 to quetiapine and 89 to placebo). The Kaplan-Meier estimate of the risk of relapse at 12 months was 41% (95% confidence interval 29% to 53%) for the quetiapine group and 79% (68% to 90%) for the placebo group (P<0.001). Although quetiapine was generally well tolerated, the rate of discontinuation due to adverse or serious adverse events was greater in the quetiapine group (18%; 16/89) than in the placebo group (8%; 7/89) (relative risk 2.29, 95% confidence interval 0.99 to 5.28; χ2=3.20, df=1; P=0.07). Conclusion In a group of asymptomatic patients with first episode psychosis and at least one year of previous antipsychotic drug treatment, maintenance treatment with quetiapine compared with placebo resulted in a substantially lower rate of relapse during the following year. Trial registration Clinical trials NCT00334035.

What Does Recovery From Schizophrenia Mean? Perceptions of Long-Term Patients

Background: The study investigated the meaning of recovery to eight people with chronic schizophrenia. Method: A qualitative methodology was used based on a 3-hour focus group. The material was transcribed and analysed into 18 subcategories and 4 categories; namely recovery as a multi-dimensional construct, the relationship of medication to recovery, a sense of hopelessness and helplessness about recovery, factors that promoted recovery. Discussion: Respondents believed that full recovery could not be said to have been achieved until they stopped medication and had a steady job. The support and care of family and friends were also vital, although sometimes problematic. Independent living has a different meaning in Chinese culture. Conclusions: Further research directions are suggested as well as ways to change attitudes to the inclusion of medication in recovery.

A 3-year prospective study of neurological soft signs in first-episode schizophrenia

Neurological soft signs are biological traits that underlie schizophrenia and are found to occur at higher levels in at-risk individuals. The expression of neurological soft signs may be modifiable during the onset of the first psychotic episode and the subsequent evolution of the illness and its treatment. This study investigates neurological soft signs in 138 patients with first-episode schizophrenia and tracks the expression of motor soft signs in the following 3 years. For the 93 patients who have completed the 3-year follow-up, we find that neurological soft signs are stable in the 3 years that follow the first psychotic episode, and that neurological soft signs are already elevated at the presentation of first-episode psychosis in medication-naive subjects. The level of neurological soft signs at clinical stabilization is lower for patients with a shorter duration of untreated psychosis. Although the quantity of neurological soft signs does not significantly change in the 3 years that follow the first episode, the relationship between neurological soft signs and negative symptoms does not become apparent until 1 year after the initial episode. A higher level of neurological soft signs is related to a lower educational level and an older age at onset, but the level of neurological soft signs does not predict the outcome in terms of relapse or occupational functioning.

The impact of family experience on the duration of untreated psychosis (DUP) in Hong Kong

BackgroundPrevious family experience of psychotic illness may play an important role in whether and when a patient seeks help in first-episode psychosis. This study investigated the relationship between family experience of psychosis and the duration of untreated psychosis in a prospective sample of first-episode psychosis patients in Hong Kong. We also studied the effects of pre-morbid adjustment, educational level, living alone, and mode of onset as potential determinants of the duration of untreated psychosis (DUP).MethodsA total of 131 first-episode psychosis patients in Hong Kong were recruited in a study of the DUP and related factors. The Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS) was used to measure the DUP and to provide a structured assessment of family history, educational level, household arrangement, and mode of onset.ResultsPrevious family experience of psychiatric illness (the presence of another family member who has been receiving psychiatric treatment) and an acute mode of onset were significant predictors of a shorter DUP. Educational level had a modest effect on its own, but was not significant in the binary logistic regression model. Living alone had a moderate effect size, but was non-significant, possibly because of the small proportion of single-person households in the sample. The symptom profile, pre-morbid adjustment, and other demographic factors were not significantly related to the DUP.ConclusionIn addition to the mode of onset, previous family experience plays an important role in the presentation of early psychosis. Educational efforts that target the family should be an important part of any strategy for the early detection of psychosis.

Neurocognitive deficits in first-episode schizophrenic patients and their first-degree relatives

Some neuropsychological abilities, particularly those affecting memory, attention and executive function, are impaired amongst both schizophrenic patients and their unaffected relatives, implying that these deficits are at least partly genetic in origin. However neuropsychological performance can be altered by medication, and has rarely been examined in first onset, drug naive patients. The objective of this study was to determine whether selected neurocognitive abilities are impaired in first‐onset schizophrenic patients and their relatives compared to controls. We examined attention and speed of information processing, memory and learning, verbal function, visuoconstructive abilities and executive function in 207 first‐episode schizophrenic patients (163 of whom were drug naïve), 322 of their first‐degree relatives and 133 unrelated normal controls. The data were subjected to multilevel modeling to compare neurocognitive performance between schizophrenic probands, relatives and controls while taking into account potential correlations among members of the same family; age, gender, and years of education were included as covariates. Of the three groups, schizophrenic patients performed poorest at all neuropsychological tests, suggestive of a broad range of neurocognitive deficits. Their first‐degree relatives showed a narrower pattern of poor performance at Digit Symbol, Digit Span, Trail Making, Verbal Fluency test, Tower of Hanoi, and WCST‐M tests. Our findings show that selected neurocognitive deficits especially attention and executive function are impaired in the families of schizophrenic patients. These patterns of neurocognitive deficits may represent “endophenotypes” denoting varying degrees of vulnerability to schizophrenia and may be of value in future molecular genetic studies.