Predicting onset of early- and late-treatment resistance in first-episode schizophrenia patients using advanced shrinkage statistical methods in a small sample

Although approximately 1/3 of individuals with schizophrenia are Treatment Resistant (TR), identifying these subjects prospectively remains challenging. The Treatment Response and Resistance in Psychosis working group defines <20% improvement as an indicator of TR, though its utility in First Episode Schizophrenia (FES) remains unknown. In a prospective cohort of FES (n = 129) followed up for 5 years, we evaluated two improvement thresholds for ‘probable TR’; <20% and <50% based on positive, negative, and total symptoms. We ascertained (1) the ecological validity (i.e., the ability to identify an expected subgroup of 1/3rd of patients); (2) the predictive validity (i.e., ability to predict poor global functioning) and (3) the clinical utility (association with clozapine use at the 5th year). Using the criteria of a total symptom reduction of <50% or negative symptom reduction of <20% resulted in ‘probable TR’ rates of 37% and 33%, respectively. Using <20% positive or total symptoms criteria resulted in very low rates, indicating minimal utility in FES. <50% total symptom criterion best predicted the global functioning over 5 years. Clozapine use was only predicted by positive symptom criterion. Prospective characterization of TRS is possible at 6 months after FES through a time-based approach using a 50% threshold for symptom change in treatment-adherent patients.

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Effects of comorbid alcohol use disorder on the clinical outcomes of first-episode schizophrenia: a nationwide population-based study

Annals of General Psychiatry ◽

10.1186/s12991-021-00353-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Soojin Ahn ◽

Youngjae Choi ◽

Woohyeok Choi ◽

Young Tak Jo ◽

Harin Kim ◽

...

Keyword(s):

Alcohol Use ◽

Clinical Outcomes ◽

Alcohol Use Disorder ◽

Small Sample ◽

First Episode ◽

Control Group ◽

Diagnostic Code ◽

Psychiatric Admissions ◽

First Episode Schizophrenia ◽

The Impact

Abstract Background Alcohol use disorder (AUD) is a common psychiatric comorbidity in schizophrenia, associated with poor clinical outcomes and medication noncompliance. Most previous studies on the effect of alcohol use in patients with schizophrenia had limitations of small sample size or a cross-sectional design. Therefore, we used a nationwide population database to investigate the impact of AUD on clinical outcomes of schizophrenia. Methods Data from the Health Insurance Review Agency database in South Korea from January 1, 2007 to December 31, 2016 were used. Among 64,442 patients with first-episode schizophrenia, 1598 patients with comorbid AUD were selected based on the diagnostic code F10. We performed between- and within-group analyses to compare the rates of psychiatric admissions and emergency room (ER) visits, and medication possession ratio (MPR) between the patients with comorbid AUD and control patients matched for the onset age, sex, and observation period. Results The rates of psychiatric admissions and ER visits in both groups decreased after the time point of diagnosis of AUD; however, the decrease was significantly greater in the patients with comorbid AUD compared to the control patients. While the comorbid AUD group showed an increase in MPR after the diagnosis of AUD, MPR decreased in the control group. The rates of psychiatric admissions, ER visits, and MPR were worse in the comorbid AUD group both before and after the diagnosis of AUD. Conclusions The results emphasize an importance of psychiatric comorbidities, especially AUD, in first-episode schizophrenia and the necessity of further research for confirmative findings of the association of AUD with clinical outcomes of schizophrenia.

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ECT in schizophrenia: a review of the evidence

Acta Neuropsychiatrica ◽

10.1017/neu.2018.32 ◽

2018 ◽

Vol 31 (03) ◽

pp. 115-127 ◽

Cited By ~ 7

Author(s):

Sandeep Grover ◽

Swapnajeet Sahoo ◽

Anjumoni Rabha ◽

Raman Koirala

Keyword(s):

Effective Treatment ◽

Electroconvulsive Therapy ◽

Suicidal Behaviour ◽

Treatment Guidelines ◽

Meta Analysis ◽

Treatment Resistance ◽

First Episode ◽

Treatment Resistant ◽

Predictors Of Response ◽

First Episode Schizophrenia

AbstractElectroconvulsive therapy (ECT) was initially used for the treatment of schizophrenia, but over the years with the advent of antipsychotics, its use in schizophrenia has been limited. Treatment guidelines vary in their recommendations for the use of ECT in schizophrenia. The usual indications of its use among patients with schizophrenia include treatment resistance, to augment pharmacotherapy, to manage catatonia, suicidal behaviour, severe agitation and clozapine-resistant schizophrenia. Available literature, including meta-analysis and systematic reviews, suggest that ECT is a safe and effective treatment in patients with schizophrenia. However, despite the available evidence, it is highly underutilised and is often used as one of the last resort among patients with schizophrenia. This review focuses on the indications of use of ECT in schizophrenia, studies evaluating its effectiveness, efficacy in certain special situations like first episode schizophrenia, adolescents, catatonia etc., predictors of response to ECT in schizophrenia and influence of various ECT-related parameters on efficacy/effectiveness among patients with schizophrenia. From the review, it can be concluded that ECT is not only is beneficial as an augmenting strategy in treatment-resistant schizophrenia but also can be used effectively in patients with schizophrenia in various other situations.

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Seasonality of symptom onset in first-episode schizophrenia

Psychological Medicine ◽

10.1017/s0033291702006712 ◽

2002 ◽

Vol 33 (1) ◽

pp. 163-167 ◽

Cited By ~ 14

Author(s):

NICHOLAS OWENS ◽

PATRICK D. McGORRY

Keyword(s):

Statistical Methods ◽

Symptom Onset ◽

Seasonal Distribution ◽

First Episode ◽

Seasonal Patterns ◽

Schizophreniform Disorder ◽

Seasonal Trends ◽

Pooled Data ◽

First Episode Schizophrenia

Background. There have been numerous reports of seasonal trends in psychotic illnesses. In schizophrenia, seasonal trends in incidence have been shown to be especially apparent in first-episode cases. Most previous research has used date of admission as a proxy for date of incidence of disorder; we present results of an investigation into seasonal trends in dates of onset of symptoms in a group of 295 first-episode cases of schizophrenia and schizophreniform disorder.Method. Data were analysed using statistical methods appropriate for detecting seasonal trends in pooled data over 6 years.Results. Only male cases of schizophrenia and schizophreniform disorder showed a significant seasonal distribution to dates of onset of symptoms, with a peak in August (winter).Conclusion. True seasonal patterns are present in schizophrenia incidence, but their consistency with other published studies and wider significance, is difficult to ascertain because of different methods used in dating incidence of disorder.

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Insulin-signaling abnormalities in drug-naïve first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin

European Psychiatry ◽

10.1016/j.eurpsy.2019.08.012 ◽

2019 ◽

Vol 62 ◽

pp. 124-129 ◽

Cited By ~ 6

Author(s):

Dimitrios Kapogiannis ◽

Henrik Dobrowolny ◽

Joyce Tran ◽

Maja Mustapic ◽

Thomas Frodl ◽

...

Keyword(s):

Insulin Resistance ◽

Extracellular Vesicles ◽

Insulin Signaling ◽

Total Protein ◽

Small Sample ◽

First Episode ◽

Model Assessment ◽

Drug Naïve ◽

Threonine Kinases ◽

First Episode Schizophrenia

Abstract Background: Metabolic syndrome and impaired insulin sensitivity may occur as side effects of atypical antipsychotic drugs. However, studies of peripheral insulin resistance using the homeostatic model assessment of insulin resistance (HOMA-IR) or oral glucose tolerance tests (OGTT) suggest that abnormal glucose metabolism is already present in drug-naive first-episode schizophrenia (DNFES). We hypothesized impairments of neuronal insulin signaling in DNFES. Methods: To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood extracellular vesicles enriched for neuronal origin (nEVs). Phosphorylated insulin signal transduction serine-threonine kinases pS312-IRS-1, pY-IRS-1, pS473-AKT, pS9-GSK3β, pS2448-mTOR, pT389-p70S6K and respective total protein levels were determined in plasma nEVs from 48 DNFES patients and healthy matched controls after overnight fasting. Results: Upstream pS312-IRS-1 was reduced at trend level (p = 0.071; this condition may amplify IRS-1 signaling). Exploratory omnibus analysis of downstream serine-threonine kinases (AKT, GSK3β, mTOR, p70S6K) revealed lower phosphorylated/total protein ratios in DNFES vs. controls (p = 0.013), confirming decreased pathway activation. Post-hoc-tests indicated in particular a reduced phosphorylation ratio of mTOR (p = 0.027). Phosphorylation ratios of p70S6K (p = 0.029), GSK3β (p = 0.039), and at trend level AKT (p = 0.061), showed diagnosis-dependent statistical interactions with insulin blood levels. The phosphorylation ratio of AKT correlated inversely with PANSS-G and PANSS-total scores, and other ratios showed similar trends. Conclusion: These findings support the hypothesis of neuronal insulin resistance in DNFES, small sample sizes notwithstanding. The counterintuitive trend towards reduced pS312-IRS-1 in DNFES may result from adaptive feedback mechanisms. The observed changes in insulin signaling could be clinically meaningful as suggested by their association with higher PANSS scores.

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Electrocardiographic signs of autonomic imbalance in medicated patients with first-episode schizophrenia spectrum disorders – relations to first treatment discontinuation and five-year remission status

European Psychiatry ◽

10.1016/j.eurpsy.2010.12.002 ◽

2012 ◽

Vol 27 (3) ◽

pp. 213-218 ◽

Cited By ~ 2

Author(s):

Robert Bodén ◽

Leif Lindström ◽

Pentti Rautaharju ◽

Johan Sundström

Keyword(s):

Heart Rate ◽

Small Sample ◽

First Episode ◽

Autonomic Balance ◽

Schizophrenia Spectrum Disorders ◽

Prognostic Information ◽

Remission Status ◽

Schizophrenia Spectrum ◽

Spectrum Disorders ◽

First Episode Schizophrenia

AbstractPurposeTo explore measures in electrocardiograms (ECG) influenced by autonomic balance in early schizophrenia spectrum disorders and to examine their relation to subsequent first antipsychotic pharmacotherapy discontinuation and five-year remission status.Subjects and methodsTwelve-lead ECGs were recorded at baseline in 58 patients with first-episode schizophrenia spectrum disorders and in 47 healthy controls of similar age. Selected ECG variables included heart rate and measures of repolarization. Pharmacotherapy data were extracted from medical records. At a five-year follow-up the patients were interviewed and assessed with the Positive and Negative Syndrome Scale.ResultsPatients had higher heart rate and a different ST-T pattern than the controls. High T-wave amplitudes in the leads aVF and V5 and ST-elevations in V5 were associated both with higher risk of an earlier discontinuation of first antipsychotic pharmacotherapy and with non-remission five years later.Discussion and conclusionIn this longitudinal cohort study, simple ECG measures influenced by autonomic balance in the early phase of schizophrenia spectrum disorders contained prognostic information. As this is the first report of this association and is based on a relatively small sample, the results should be interpreted with caution.

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Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses

Psychological Medicine ◽

10.1017/s0033291716002014 ◽

2016 ◽

Vol 46 (15) ◽

pp. 3231-3240 ◽

Cited By ~ 95

Author(s):

J. Lally ◽

O. Ajnakina ◽

M. Di Forti ◽

A. Trotta ◽

A. Demjaha ◽

...

Keyword(s):

Treatment Resistance ◽

First Episode ◽

Early Age ◽

Treatment Resistant ◽

Total Study Population ◽

Illness Onset ◽

Schizophrenia Spectrum ◽

First Episode Schizophrenia ◽

First Contact ◽

The Relationship

BackgroundClozapine remains the only evidence-based antipsychotic for treatment-resistant schizophrenia (TRS). The ability to predict which patients with their first onset of schizophrenia would subsequently meet criteria for treatment resistance (TR) could help to diminish the severe functional disability which may ensue if TR is not recognized and correctly treated.MethodThis is a 5-year longitudinal assessment of clinical outcomes in a cohort of 246 first-episode schizophrenia spectrum patients recruited as part of the NIHR Genetics and Psychosis (GAP) study conducted in South London from 2005 to 2010. We examined the relationship between baseline demographic and clinical measures and the emergence of TR. TR status was determined from a review of electronic case records. We assessed for associations with early-, and late-onset TR, and non-TR, and differences between those TR patients treated with clozapine and those who were not.ResultsSeventy per cent (n= 56) of TR patients, and 23% of the total study population (n= 246) were treatment resistant from illness onset. Those who met criteria for TR during the first 5 years of illness were more likely to have an early age of first contact for psychosis (<20 years) [odds ratio (OR) 2.49, 95% confidence interval (CI) 1.25–4.94] compared to those with non-TR. The relationship between an early age of first contact (<20 years) and TR was significant in patients of Black ethnicity (OR 3.71, 95% CI 1.44–9.56); and patients of male gender (OR 3.13 95% CI 1.35–7.23).ConclusionsFor the majority of the TR group, antipsychotic TR is present from illness onset, necessitating increased consideration for the earlier use of clozapine.

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Treatment Resistance: A Time-Based Approach For Early Identification in First Episode Samples

10.31234/osf.io/cgqpa ◽

2018 ◽

Author(s):

Kara Dempster ◽

Ross Norman ◽

Lena Palaniyappan

Keyword(s):

Early Intervention ◽

Treatment Response ◽

Intervention Program ◽

Negative Symptoms ◽

Treatment Resistance ◽

First Episode ◽

Symptom Improvement ◽

Treatment Resistant ◽

Early Intervention Program ◽

First Episode Schizophrenia

Background: Although approximately 1/3 of individuals with schizophrenia are Treatment Resistant (TR), identifying these subjects prospectively for early intervention remains challenging. The Treatment Response and Resistance in Psychosis (TRIPP; Howes et al, 2017) working group recently published consensus guidelines defining lack of response as a <20% improvement in symptoms. However, it is unclear whether these criteria are sensitive in First Episode Schizophrenia (FES). Method: Patients experiencing a first episode of psychosis referred to the Prevention and Early Intervention Program for Psychosis (PEPP) in London, Canada were followed-up with longitudinal symptom assessments. We evaluated two improvement thresholds for ‘probable TR’ classifications; <20% (as per TRIPP) and <50% to identify subjects satisfying ‘probable TR’ based on positive, negative, and total symptom domains.Results: Using the criterion of <50% total, or <20% negative symptom improvement,resulted in ‘probable TR’ rates of 37% and 33% respectively, with notable overlap between the 2criteria (77% satisfying both). Using a 20% cut-off for positive and total symptomsresulted in very low rates of ‘probable TR’. Logistic regression analyses demonstrated that poorpremorbid functioning, longer duration of untreated illness, and limited treatment response atmonths one and two were significantly associated with probable TR (<50% totalsymptom improvement).Conclusions: Our results suggest that probable TR may be identified at 6 months after FESusing a time-based approach only by including negative symptoms (either alone, with a 20%improvement threshold, or in addition to positive symptoms, with a total 50%threshold) in the definition.

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P.523 Neuromelanin MRI as biomarker for treatment resistance in first episode schizophrenia patients

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2020.09.382 ◽

2020 ◽

Vol 40 ◽

pp. S294-S295

Author(s):

M. Van Der Pluijm ◽

L. Meershoek ◽

L. De Haan ◽

J. Booij ◽

E. Van de Giessen

Keyword(s):

Treatment Resistance ◽

First Episode ◽

First Episode Schizophrenia

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Relationships between abnormal neural activities and cognitive impairments in patients with drug-naive first-episode schizophrenia

10.21203/rs.3.rs-15802/v2 ◽

2020 ◽

Author(s):

Wei Yan ◽

Rongrong Zhang ◽

Min Zhou ◽

Shuiping Lu ◽

Wenmei Li ◽

...

Keyword(s):

Cognitive Deficits ◽

Clinical Symptoms ◽

Cognitive Impairments ◽

Clinical Manifestations ◽

Small Sample ◽

First Episode ◽

Adult Intelligence Scale ◽

Drug Naïve ◽

The Right ◽

First Episode Schizophrenia

Abstract Background Prior resting state functional magnetic resonance imaging studies via the regional homogeneity (ReHo) method have demonstrated inconsistent and conflicting results because of several confounding factors, such as small sample size, medicinal influence, and illness duration. Relationships between ReHo measures and cognitive impairments in patients with drug-naive first-episode schizophrenia (dn-FES) are rarely reported. This study was conducted to explore the correlations between ReHo measures, cognitive deficits, and clinical symptoms in patients with dn-FES. Methods A total of 69 patients with dn-FES and 74 healthy controls were recruited. MATRICS Consensus Cognitive Battery (MCCB), Wechsler Adult Intelligence Scale (WAIS), and Positive and Negative Syndrome Scale (PANSS) were used to assess cognitive function, intelligence quotient (IQ), and clinical symptoms, respectively. The correlations between ReHo map and cognitive deficits, the severity of symptoms were examined using strict correlation analyses within brain areas. Results The ReHo values in the right middle frontal gyrus (MFG) and the superior frontal gyrus (SFG) increased in the dn-FES group, whereas the ReHo values in the right cuneus decreased. Correlation analysis showed that the ReHo values in the right MFG were positively correlated with attention/vigilance impairments, social cognition deficits, the severity of clinical manifestations. Conclusions These findings suggested that abnormal spontaneous activities in the right MFG reflect the illness severity and cognitive deficits, which serves as a basis for establishing the objective diagnostic markers and might be a clinical intervention target for patients with schizophrenia.

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