Andor E. Simon

Defining subjects at risk for psychosis : A comparison of two approaches

The ability to detect individuals at high risk for developing schizophrenia before they express the disease will lead to targeted early intervention. It has been proposed that subjects at risk share a core deficit with people who already have schizophrenia. This includes cognitive impairment, affective symptoms, social isolation and decline in social functioning. In a sample of 104 help-seeking patients from a specialised outpatient clinic we investigated how well two different sets of criteria define the at-risk group and capture this core deficit. One set of criteria is the well-established ultra high-risk model of McGlashan et al. [McGlashan 2001 (SIPS) McGlashan, T. H., Miller, T. J., Woods, S. W., et al. (2001) Structured Interview for Prodromal Syndromes (Version 3.0, unpublished manuscript). New Haven, Connecticut: PRIME Research Clinic, Yale School of Medicine.]; the other criteria were those defined by Cornblatt et al. [Cornblatt, B., Lencz, T., Smith, C.W., Correll, C.U., Auther, A., Nakayama, E., 2003. The schizophrenia prodrome revisited: a neurodevelopmental perspective. Schizophr. Bull. 29, 633-651.]. There was considerable overlap in the two sets of criteria. However, when the basic symptoms of Klosterkötter [Klosterkötter, J., Hellmich, M., Steinmeyer, E.M., Schultze-Lutter, F., 2001a. Diagnosing schizophrenia in the initial prodromal phase. Arch. Gen. Psychiatry, 58, 158-164.] were included in the McGlashan et al. model, a more narrow and homogeneous group was defined.

Ultra high-risk state for psychosis and non-transition: a systematic review

BACKGROUND Most effort in ultra high-risk (UHR) research has been directed at defining the clinical and neurobiological characteristics of those UHR subjects who go on to develop psychosis. The characteristics and outcome of the remaining UHR subjects have remained relatively unexplored. METHOD We performed a systematic review of clinical UHR studies to investigate whether information was available on the characteristics and outcome of UHR subjects who did not convert to psychosis. RESULTS Of 2462 potentially relevant papers, 31 met inclusion criteria, i.e. 20 naturalistic and 11 intervention studies. On average 76% (range 46-92.6%) of the UHR patients made no transition to psychosis during follow-up (range 6 to 40 months). Nearly half of the studies provided no characteristics of those UHR subjects who did not develop psychosis. Six studies reported remission rates from initial UHR status (range 15.4% to 54.3%). Linear regression showed that more recent studies reported significantly lower transition rates as compared to earlier publications. An older mean age at baseline was associated with significant lower transition rates in publications with follow-ups exceeding 1 year. CONCLUSIONS Our review illustrates that the long-term outcome of UHR subjects that do not develop psychosis is to date under-investigated. The studies reporting remission rates suggest that UHR criteria capture a non-negligible proportion of subjects that do not convert to psychosis.

Heterogeneity of Psychosis Risk Within Individuals at Clinical High Risk: A Meta-analytical Stratification

IMPORTANCE Individuals can be classified as being at clinical high risk (CHR) for psychosis if they meet at least one of the ultra-high-risk (UHR) inclusion criteria (brief limited intermittent psychotic symptoms [BLIPS] and/or attenuated psychotic symptoms [APS] and/or genetic risk and deterioration syndrome [GRD]) and/or basic symptoms [BS]. The meta-analytical risk of psychosis of these different subgroups is still unknown. OBJECTIVE To compare the risk of psychosis in CHR individuals who met at least one of the major inclusion criteria and in individuals not at CHR for psychosis (CHR-). DATA SOURCES Electronic databases (Web of Science, MEDLINE, Scopus) were searched until June 18, 2015, along with investigation of citations of previous publications and a manual search of the reference lists of retrieved articles. STUDY SELECTION We included original follow-up studies of CHR individuals who reported the risk of psychosis classified according to the presence of any BLIPS, APS and GRD, APS alone, GRD alone, BS, and CHR-. DATA EXTRACTION AND SYNTHESIS Independent extraction by multiple observers and random-effects meta-analysis of proportions. Moderators were tested with meta-regression analyses (Bonferroni corrected). Heterogeneity was assessed with the I2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and the Egger test. MAIN OUTCOMES AND MEASURES The proportion of each subgroup with any psychotic disorder at 6, 12, 24, 36, and 48 or more months of follow-up. RESULTS Thirty-three independent studies comprising up to 4227 individuals were included. The meta-analytical proportion of individuals meeting each UHR subgroup at intake was: 0.85 APS (95%CI, 0.79-0.90), 0.1 BLIPS (95%CI, 0.06-0.14), and 0.05 GRD (95%CI, 0.03-0.07). There were no significant differences in psychosis risk at any time point between the APS and GRD and the APS-alone subgroups. There was a higher risk of psychosis in the any BLIPS greater than APS greater than GRD-alone subgroups at 24, 36, and 48 or more months of follow-up. There was no evidence that the GRD subgroup has a higher risk of psychosis than the CHR- subgroup. There were too few BS or BS and UHR studies to allow robust conclusions. CONCLUSIONS AND RELEVANCE There is meta-analytical evidence that BLIPS represents separate risk subgroup compared with the APS. The GRD subgroup is infrequent and not associated with an increased risk of psychosis. Future studies are advised to stratify their findings across these different subgroups. The CHR guidelines should be updated to reflect these differences.

Brain Connectivity Abnormalities Predating the Onset of Psychosis Correlation With the Effect of Medication

IMPORTANCE Brain imaging studies have identified robust changes in brain structure and function during the development of psychosis, but the contribution of abnormal brain connectivity to the onset of psychosis is unclear. Furthermore, antipsychotic treatment can modulate brain activity and functional connectivity during cognitive tasks. OBJECTIVES To investigate whether dysfunctional brain connectivity during working memory (WM) predates the onset of psychosis and whether connectivity parameters are related to antipsychotic treatment. DESIGN Dynamic causal modeling study of functional magnetic resonance imaging data. SETTING Participants were recruited from the specialized clinic for the early detection of psychosis at the Department of Psychiatry, University of Basel, Basel, Switzerland. PARTICIPANTS Seventeen participants with an at-risk mental state (mean [SD] age, 25.24 [6.3] years), 21 individuals with first-episode psychosis (mean [SD] age, 28.57 [7.2] years), and 20 healthy controls (mean [SD] age, 26.5 [4] years). MAIN OUTCOME AND MEASURE Functional magnetic resonance imaging data were recorded while participants performed an N-back WM task. Functional interactions among brain regions involved in WM, in particular between frontal and parietal brain regions, were characterized using dynamic causal modeling. Bayesian model selection was performed to evaluate the likelihood of alternative WM network architectures across groups, whereas bayesian model averaging was used to examine group differences in connection strengths. RESULTS We observed a progressive reduction in WM-induced modulation of connectivity from the middle frontal gyrus to the superior parietal lobule in the right hemisphere in healthy controls, at-risk mental state participants, and first-episode psychosis patients. Notably, the abnormal modulation of connectivity in first-episode psychosis patients was normalized by treatment with antipsychotics. CONCLUSIONS AND RELEVANCE Our findings suggest that the vulnerability to psychosis is associated with a progressive failure of functional integration of brain regions involved in WM processes, including visual encoding and rule updating, and that treatment with antipsychotics may have the potential to counteract this.

Moving beyond transition outcomes: Meta-analysis of remission rates in individuals at high clinical risk for psychosis

Recent evidence suggests that transition risks from initial clinical high risk (CHR) status to psychosis are decreasing. The role played by remission in this context is mostly unknown. The present study addresses this issue by means of a meta-analysis including eight relevant studies published up to January 2012 that reported remission rates from an initial CHR status. The primary effect size measure was the longitudinal proportion of remissions compared to non-remission in subjects with a baseline CHR state. Random effect models were employed to address the high heterogeneity across studies included. To assess the robustness of the results, we performed sensitivity analyses by sequentially removing each study and rerunning the analysis. Of 773 subjects who met initial CHR criteria, 73% did not convert to psychosis along a 2-year follow. Of these, about 46% fully remitted from the baseline attenuated psychotic symptoms, as evaluated on the psychometric measures usually employed by prodromal services. The corresponding clinical remission was estimated as high as 35% of the baseline CHR sample. The CHR state is associated with a significant proportion of remitting subjects that can be accounted by the effective treatments received, a lead time bias, a dilution effect, a comorbid effect of other psychiatric diagnoses.

Different duration of at‐risk mental state associated with neurofunctional abnormalities. A multimodal imaging study

Objectives: Neurofunctional alterations are correlates of vulnerability to psychosis, as well as of the disorder itself. How these abnormalities relate to different probabilities for later transition to psychosis is unclear. We investigated vulnerability‐ versus disease‐related versus resilience biomarkers of psychosis during working memory (WM) processing in individuals with an at‐risk mental state (ARMS). Experimental design: Patients with “first‐episode psychosis” (FEP, n = 21), short‐term ARMS (ARMS‐ST, n = 17), long‐term ARMS (ARMS‐LT, n = 16), and healthy controls (HC, n = 20) were investigated with an n‐back WM task. We examined functional magnetic resonance imaging (fMRI) and structural magnetic resonance imaging (sMRI) data in conjunction using biological parametric mapping (BPM) toolbox. Principal observations: There were no differences in accuracy, but the FEP and the ARMS‐ST group had longer reaction times compared with the HC and the ARMS‐LT group. With the 2‐back > 0‐back contrast, we found reduced functional activation in ARMS‐ST and FEP compared with the HC group in parietal and middle frontal regions. Relative to ARMS‐LT individuals, FEP patients showed decreased activation in the bilateral inferior frontal gyrus and insula, and in the left prefrontal cortex. Compared with the ARMS‐LT, the ARMS‐ST subjects showed reduced activation in the right inferior frontal gyrus and insula. Reduced insular and prefrontal activation was associated with gray matter volume reduction in the same area in the ARMS‐LT group. Conclusions: These findings suggest that vulnerability to psychosis was associated with neurofunctional alterations in fronto‐temporo‐parietal networks in a WM task. Neurofunctional differences within the ARMS were related to different duration of the prodromal state and resilience factors. Hum Brain Mapp 33:2281–2294, 2012.

Help-seeking pathways in early psychosis

IntroductionUnderstanding the help-seeking pathways of patients with a putative risk of developing psychosis helps improving development of specialised care services. This study aimed at obtaining information about: type of health professionals contacted by patients at putative risk for psychosis on their help-seeking pathways; number of contacts; type of symptoms leading to contacts with health professionals; interval between initial contact and referral to a specialised outpatient service.MethodThe help-seeking pathways were assessed as part of a prospective study in 104 patients with suspected at-risk states for psychosis.ResultsThe mean number of contacts prior to referral was 2.38. Patients with psychotic symptoms more often contacted mental health professionals, whereas patients with insidious and more unspecific features more frequently contacted general practitioners (GPs).ConclusionsGPs have been found to under-identify the insidious features of emerging psychosis (Simon et al. (2005) Br J Psychiatry 187:274–281). The fact that they were most often contacted by patients with exactly these features calls for focussed and specialised help for primary care physicians. Thus, delays along the help-seeking pathways may be shortened. This may be of particular relevance for patients with the deficit syndrome of schizophrenia.

Cognitive functioning in at-risk mental states for psychosis and 2-year clinical outcome

BACKGROUND Cognitive impairment is prevalent in at-risk mental states (ARMS) for psychosis. METHOD We studied cognitive functioning at baseline in ARMS individuals and investigated its power to predict ARMS persistence and remission at 2-year follow-up. RESULTS 196 patients were recruited. At baseline the ARMS population included 26 subjects meeting basic symptom (BS) criteria and 73 subjects fulfilling ultra-high risk (UHR) criteria. Two control groups were defined: 48 patients in a first episode of psychosis (FE), and 49 help-seeking patient controls (PCO). In 144 patients follow-up data were obtained. The 2-year risk of conversion to psychosis was 20%. Remission from an initial UHR state occurred in two thirds of the follow-up sample. UHR patients that converted to psychosis or did not remit during the follow-up (UHR(n-rem)) showed similar impairment in global cognitive functioning at baseline as the FE group, whereas global cognitive functioning in UHR patients with subsequent remission (UHR(rem)) approximated performances of the BS and PCO groups. UHR(n-rem) and UHR(rem) patients differed significantly on immediate verbal memory, but showed similarly impaired executive functions. Normal immediate verbal memory uniquely predicted remission from an at-risk state with a positive predictive value of 82%. CONCLUSIONS Cognitive deficits are a characteristic feature of true ARMS patients. Verbal memory function appears critical in determining outcome.

Insular volume abnormalities associated with different transition probabilities to psychosis

Background Although individuals vulnerable to psychosis show brain volumetric abnormalities, structural alterations underlying different probabilities for later transition are unknown. The present study addresses this issue by means of voxel-based morphometry (VBM). Method We investigated grey matter volume (GMV) abnormalities by comparing four neuroleptic-free groups: individuals with first episode of psychosis (FEP) and with at-risk mental state (ARMS), with either long-term (ARMS-LT) or short-term ARMS (ARMS-ST), compared to the healthy control (HC) group. Using three-dimensional (3D) magnetic resonance imaging (MRI), we examined 16 FEP, 31 ARMS, clinically followed up for on average 3 months (ARMS-ST, n=18) and 4.5 years (ARMS-LT, n=13), and 19 HC. Results The ARMS-ST group showed less GMV in the right and left insula compared to the ARMS-LT (Cohens d 1.67) and FEP groups (Cohens d 1.81) respectively. These GMV differences were correlated positively with global functioning in the whole ARMS group. Insular alterations were associated with negative symptomatology in the whole ARMS group, and also with hallucinations in the ARMS-ST and ARMS-LT subgroups. We found a significant effect of previous antipsychotic medication use on GMV abnormalities in the FEP group. Conclusions GMV abnormalities in subjects at high clinical risk for psychosis are associated with negative and positive psychotic symptoms, and global functioning. Alterations in the right insula are associated with a higher risk for transition to psychosis, and thus may be related to different transition probabilities.

Subclinical hallucinations in adolescent outpatients: An outcome study

OBJECTIVE We assessed the continued prevalence at one year and association with clinical variables of subclinical hallucinations ascertained at baseline in a cohort of adolescent outpatients referred to a specialized early psychosis service. We further assessed the prevalence of psychiatric disorders in adolescents presenting subclinical hallucinations. METHOD 84 adolescent patients were sampled from a longitudinal, prospective study that assesses the course of clinical and neuropsychological measures in patients identified as at high clinical risk for psychosis. Subclinical hallucinations were measured using the Scale of Prodromal Symptoms (SOPS) with its companion interview manual (Structured Interview for Prodromal Symptoms, SIPS) [Miller, T.J., McGlashan, T.H., Woods, S.W., Stein, K., Driesen, N., Corcoran, C.M., Hoffman, R., Davidson, L., 1999. Symptom assessment in schizophrenic prodromal states. Psychiatr. Q. 70, 273-287; McGlashan, T.H., Miller, T.J., Woods, S.W., Rosen, J.L., Hoffman, R.E., Davidson, L., 2001. Structured Interview for Prodromal Syndromes (Version 3.0, unpublished manuscript). PRIME Research Clinic, Yale School of Medicine New Haven, Connecticut. ], and the Schizophrenia Proneness Instrument -Adult Version (SPI-A) [Schultze-Lutter, F., Addington, J., Ruhrmann, S., Klosterkötter, J., 2007. Schizophrenia Proneness Instrument (SPI-A). Giovanni Fioriti, Rome, Italy]. At one-year follow-up, only patients reporting subclinical hallucinations at initial assessment were studied. RESULTS Full remission of subclinical hallucinations occurred in over half and at least partial remission in two thirds of these patients at one-year follow-up. Mood disorders were present in 62.5% of adolescents with subclinical hallucinations at initial assessment. SOPS measures for depression, deficient attention and for unusual/delusional thought were significantly associated with subclinical hallucinations at baseline. However, sustained experience of subclinical hallucinations at one-year follow-up was only predicted by the global level of functioning at baseline, while cannabis abuse, psychiatric and psychopharmacological treatment were not predictors. CONCLUSIONS Subclinical hallucinations occur across a wide range of mental states in adolescents and show high rates of remission. Our results warrant that the clinical meaning of such phenomena needs to be carefully weighed against the specific developmental phenomena in this particular age range.