Summary Background Early immunotherapy administration improves outcomes in patients with N-methyl-D-aspartate receptor (NMDAR)-antibody encephalitis. As most patients with NMDAR-antibody encephalitis present to psychiatrists, the psychopathology of NMDAR-antibody encephalitis needs to be clearly defined to encourage accurate clinical identification and prompt treatment. Methods For this systematic review, we searched PubMed for all studies published in English between Jan 1, 2005, and Oct 7, 2017, to identify individually reported adult patients (≥18 years) who satisfied consensus criteria for definite NMDAR-antibody encephalitis. After generating a list of 50 fine-grained, lower-level features, we extracted psychopathological data in addition to demographic and aetiological data. The lower-level features were later ordered within higher-level categories. As a means of quality control, we filtered the data according to proxy markers of psychiatric involvement in their description. Subsequently, we compared lower-level features from individual patient data with operationalised psychiatric syndromes using a constrained combination approach and principal component analysis, and did a network analysis to explore the inter-relationships between multiple lower-level features. The review protocol was prospectively registered with PROSPERO, number CRD42017068981. Findings Of 1096 records identified in PubMed, 333 satisfied inclusion criteria and described 1100 patients in total with NMDAR-antibody encephalitis. The psychopathology of 505 (46%) patients with reported psychiatric symptoms was described in more detailed terms than only psychiatric or behavioural. 464 (91%) of the 505 patients were from papers in which patient data were reported individually. The remainder of the analyses focused exclusively on these 464 patients. Median age was 27 years (IQR 22–34), 368 (79%) of 464 patients were female and in 147 (32%), NMDAR-antibody encephalitis was associated with ovarian teratoma. The five higher-level categories into which the 464 patients most frequently grouped were behaviour (316 [68%]), psychosis (310 [67%]), mood (219 [47%]), catatonia (137 [30%]), and sleep disturbance (97 [21%]). The overall pattern of lower-level features was statistically stable across subgroups classified by age, sex, pregnancy association, presence of ovarian teratoma, prior herpes simplex virus encephalitis, and isolated psychiatric presentations (two-way ANOVA p=0·6–0·9). Constrained combination and principal component analyses found that mixtures of mood and psychosis syndromes fit each patient better than any single diagnosis alone, particularly for the patients in the psychiatric-described subgroup (mean ΔAkaike information criterion −0·04 in non-psychiatric-described subgroup vs 0·61 in psychiatric-described subgroup). The overlapping nature of the higher-level features was also enriched upon analysis of the psychiatric-d...
The idea that a longer duration of untreated psychosis (DUP) leads to poorer outcomes has contributed to extensive changes in mental health services worldwide and has attracted considerable research interest over the past 30 years. However, the strength of the evidence underlying this notion is unclear. To address this issue, we conducted an umbrella review of available meta‐analyses and performed a random‐effects meta‐analysis of primary studies. MEDLINE, Web of Science, PsycINFO and EMBASE were searched from inception to September 3, 2020 to identify relevant meta‐analyses of studies including patients with schizophrenia spectrum disorders, first‐episode psychosis, or affective and non‐affective psychosis. Thirteen meta‐analyses were included, corresponding to 129 individual studies with a total sample size of 25,657 patients. We detected potential violations of statistical assumptions in some of these meta‐analyses. We therefore conducted a new random‐effects meta‐analysis of primary studies. The association between DUP and each outcome was graded according to a standardized classification into convincing, highly suggestive, suggestive, weak, or non‐significant. At first presentation, there was suggestive evidence for a relationship between longer DUP and more severe negative symptoms (beta=–0.07, p=3.6×10–5) and higher chance of previous self‐harm (odds ratio, OR=1.89, p=1.1×10–5). At follow‐up, there was highly suggestive evidence for a relationship between longer DUP and more severe positive symptoms (beta=–0.16, p=4.5×10–8), more severe negative symptoms (beta=–0.11, p=3.5×10–10) and lower chance of remission (OR=2.16, p=3.0×10–10), and suggestive evidence for a relationship between longer DUP and poorer overall functioning (beta=–0.11, p=2.2×10–6) and more severe global psychopathology (beta=–0.16, p=4.7×10–6). Results were unchanged when analysis was restricted to prospective studies. These effect sizes are clinically meaningful, with a DUP of four weeks predicting >20% more severe symptoms at follow‐up relative to a DUP of one week. We conclude that DUP is an important prognostic factor at first presentation and predicts clinically relevant outcomes over the course of illness. We discuss conceptual issues in DUP research and methodological limitations of current evidence, and provide recommendations for future research.
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