Treatment resistance is a major challenge in psychiatric disorders. Early detection of potential future resistance would improve prognosis by reducing the delay to appropriate treatment adjustment and recovery. Here, we sought to determine whether neurodevelopmental markers can predict therapeutic response.

Healthy controls (N = 236), patients with schizophrenia (N = 280) or bipolar disorder (N = 78) with a known therapeutic outcome, were retrospectively included. Age, sex, education, early developmental abnormalities (obstetric complications, height, weight, and head circumference at birth, hyperactivity, dyslexia, epilepsy, enuresis, encopresis), neurological soft signs (NSS), and ages at first subjective impairment, clinical symptoms, treatment, and hospitalization, were recorded. A supervised algorithm leveraged NSS and age at first clinical signs to classify between resistance and response in schizophrenia.

Developmental abnormalities were more frequent in schizophrenia and bipolar disorder than in controls. NSS significantly differed between controls, responsive, and resistant participants with schizophrenia (5.5 ± 3.0, 7.0 ± 4.0, 15.0 ± 6.0 respectively, p = 3 × 10−10) and bipolar disorder (5.5 ± 3.0, 8.3 ± 3.0, 12.5 ± 6.0 respectively, p < 1 × 10−10). In schizophrenia, but not in bipolar disorder, age at first subjective impairment was three years lower, and age at first clinical signs two years lower, in resistant than responsive subjects (p = 2 × 10−4 and p = 9 × 10−3, respectively). Age at first clinical signs and NSS accurately predicted treatment response in schizophrenia (area-under-curve: 77 ± 8%, p = 1 × 10−14).

Neurodevelopmental features such as NSS and age of clinical onset provide a means to identify patients who may require rapid treatment adaptation.

The main aim of this study was to explore whether specific groups of patients with first episode non-affective psychosis could be identified on a psychopathological basis and, then, whether such identified groups could be validated by exploring their correlation with a variety of neurodevelopmental markers.

Eighty-seven patients with a first episode of non-affective psychotic disorder were consecutively recruited. We assessed psychopathology and neurological soft signs using the PANSS and the Neurological Evaluation Scale, respectively. We collected information on obstetric complications, premorbid adjustment and family history.

All PANSS symptoms were analysed using principal component analysis and four factors were obtained (negative, disorganization, positive and paranoid). Subsequently, the four factors were subjected to a cluster analysis where three groups emerged: “paranoid” (n = 40), “low score” (n = 29) and “negative” (n = 18) subtype. After adjusting by sex and age, we found that the “negative group” had poorer social premorbid adjustment, worse verbal fluency and higher prevalence of both obstetric complications and neurological soft signs, when compared with the “low score” group. Similarly, the “negative group” showed significantly poorer social premorbid adjustment and higher number of neurological soft signs than the “paranoid group”.

Our results support that, among non-affective first onset psychotic patients, those with predominant negative symptoms are more likely to correlate with higher presence of neurodevelopmental markers.

Motor abnormalities (MAs) are the primary manifestations of schizophrenia. However, the extent to which MAs are related to alterations of subcortical structures remains understudied.

We aimed to investigate the associations of MAs and basal ganglia abnormalities in first-episode psychosis (FEP) and healthy controls. Magnetic resonance imaging was performed on 48 right-handed FEP and 23 age-, gender-, handedness-, and educational attainment-matched controls, to obtain basal ganglia shape analysis, diffusion tensor imaging techniques (fractional anisotropy and mean diffusivity), and relaxometry (R2*) to estimate iron load. A comprehensive motor battery was applied including the assessment of parkinsonism, catatonic signs, and neurological soft signs (NSS). A fully automated model-based segmentation algorithm on 1.5T MRI anatomical images and accurate corregistration of diffusion and T2* volumes and R2* was used.

FEP patients showed significant local atrophic changes in left globus pallidus nucleus regarding controls. Hypertrophic changes in left-side caudate were associated with higher scores in sensory integration, and in right accumbens with tremor subscale. FEP patients showed lower fractional anisotropy measures than controls but no significant differences regarding mean diffusivity and iron load of basal ganglia. However, iron load in left basal ganglia and right accumbens correlated significantly with higher extrapyramidal and motor coordination signs in FEP patients.

Taken together, iron load in left basal ganglia may have a role in the emergence of extrapyramidal signs and NSS of FEP patients and in consequence in the pathophysiology of psychosis.

Functional decline among patients with mental illness is not unique to individuals with psychotic disorders. Despite this, research on early predictors of functional outcome mainly focused on individuals thought to have an ‘at risk mental state’ (ARMS) for psychosis. There is evidence suggesting that certain early vulnerability markers, such as neurological soft signs (NSS), may explain variability in functional outcomes independent of the level of psychosis risk and the traditional diagnostic classification.

Structural equation modeling was applied to baseline data from a prospective longitudinal study of 138 young individuals in treatment with secondary services for non-psychotic disorders. We evaluated theoretically based models of pathways to functional outcome starting from NSS. The intervening variables were established according to previous evidence and drawn from two general categories: cognition (neuro- and social-) and negative symptoms (expressive and experiential).

A final trimmed model was a single path running from NSS to neurocognition to experiential negative symptoms to outcome. It could not be improved by adding or dropping connections that would change the single path to multiple paths. The indirect effect from NSS to outcome was significant. The validity of the model was independent of the ARMS status and the psychiatric diagnosis.

Our results provide evidence for a single pathway model in which the starting and intervening variables represent modifiable trans-diagnostic therapeutic targets to improve functional trajectories in young individuals with a recent-onset psychiatric diagnosis and different levels of psychosis risk.

Accuracy of risk algorithms for psychosis prediction in “at risk mental state” (ARMS) samples may differ according to the recruitment setting. Standardized criteria used to detect ARMS individuals may lack specificity if the recruitment setting is a secondary mental health service. The authors tested a modified strategy to predict psychosis conversion in this setting by using a systematic selection of trait-markers of the psychosis prodrome in a sample with a heterogeneous ARMS status.

138 non-psychotic outpatients (aged 17–31) were consecutively recruited in secondary mental health services and followed-up for up to 3 years (mean follow-up time, 2.2 years; SD = 0.9). Baseline ARMS status, clinical, demographic, cognitive, and neurological soft signs measures were collected. Cox regression was used to derive a risk index.

48% individuals met ARMS criteria (ARMS-Positive, ARMS+). Conversion rate to psychosis was 21% for the overall sample, 34% for ARMS+, and 9% for ARMS-Negative (ARMS−). The final predictor model with a positive predictive validity of 80% consisted of four variables: Disorder of Thought Content, visuospatial/constructional deficits, sensory-integration, and theory-of-mind abnormalities. Removing Disorder of Thought Content from the model only slightly modified the predictive accuracy (−6.2%), but increased the sensitivity (+9.5%).

These results suggest that in a secondary mental health setting the use of trait-markers of the psychosis prodrome may predict psychosis conversion with great accuracy despite the heterogeneity of the ARMS status. The use of the proposed predictive algorithm may enable a selective recruitment, potentially reducing duration of untreated psychosis and improving prognostic outcomes.

Neurological soft signs (NSS) have long been considered potential endophenotypes for schizophrenia. However, few studies have investigated the heritability and familiality of NSS. The present study examined the heritability and familiality of NSS in healthy twins and patient–relative pairs.

The abridged version of the Cambridge Neurological Inventory was administered to 267 pairs of monozygotic twins, 124 pairs of dizygotic twins, and 75 pairs of patients with schizophrenia and their non-psychotic first-degree relatives.

NSS were found to have moderate but significant heritability in the healthy twin sample. Moreover, patients with schizophrenia correlated closely with their first-degree relatives on NSS.

Taken together, the findings provide evidence on the heritability and familiality of NSS in the Han Chinese population.

Neurological soft signs (NSS) have been inconsistently reported in obsessive-compulsive disorder (OCD) but may make an impact on treatment response.

The current study examined the presence of NSS in two independent European samples of OCD patients (combined 85 patients and 88 matched healthy controls) using a standardized instrument and conducted a meta-analysis of all published studies identified in the literature with the aim to provide a more definitive answer to the question of whether OCD patients are characterized by increased NSS.

Both empirical studies found elevated NSS scores in patients compared with matched controls. The results of the meta-analysis, which included 15 studies (combined 498 patients and 520 controls) showed large effect sizes (Hedges' g=1.27, 95% confidence interval 0.80–1.75), indicating that OCD patients have significantly higher rates of NSS than matched controls on both sides of the body and in multiple domains (motor coordination, sensory integration and primitive reflexes). The results were robust and remained largely unchanged in our reliability analyses, which controlled for possible outliers. Meta-regression was employed to examine the role of potential variables of interest including sociodemographic variables, symptom severity, medication effects and the use of different instruments, but none of these variables was clearly associated with NSS.

As a group, OCD patients are characterized by increased rates of NSS, compared with healthy controls. However, their origins and potential clinical importance remain to be clarified. Future directions for research are discussed.

There is a lack of consistent evidence regarding associations of neurological soft signs (NSS) with illness-related variables in schizophrenia. This study examined NSS in first-episode psychotic patients with respect to their factor structure and associations with risk factors, pre-morbid characteristics, psychopathology and spontaneous extrapyramidal syndromes.

First-episode, drug-naive patients with schizophrenia-spectrum disorders (n=177) were assessed for NSS using the Neurological Evaluation Scale, and its 26 constituting items were factor analysed. The identified neurological dimensions were then entered into hierarchical regression models as outcome dependent variables of a set of predictors including risk factors (familial loading for schizophrenia, obstetric complications), pre-morbid characteristics (neurodevelopmental delay, symptoms of attention deficit–hyperactivity disorder, pre-morbid functioning), psychopathological domains (reality distortion, disorganization, negative symptoms, mania, depression, catatonia) and spontaneous extrapyramidal syndromes (parkinsonism, dyskinesia, akathisia).

Five neurological domains were identified: sequencing, release signs, sensory integration, abnormal movements and coordination. Multivariate analyses showed independent associations (p<0.01) of sequencing with familial liability to schizophrenia, deterioration of pre-morbid adjustment and parkinsonism; release signs with obstetric complications, catatonic symptoms and parkinsonism; sensory integration with familial liability to schizophrenia; abnormal movements with familial liability to schizophrenia, obstetric complications, parkinsonism and dyskinesia; and coordination with neurodevelopmental delay. The empirically derived factors explained additional variance over and above that explained by subscale scores across the examined variables.

Familial liability to schizophrenia, obstetric complications, neurodevelopmental delay, deterioration in pre-morbid functioning and observable motor disorders appear to contribute independently to domains of neurological dysfunction. The findings support a neurodevelopmental model of NSS in schizophrenia.

Although minor motor and sensory deficits, or neurological soft signs (NSS), are a well-established finding in schizophrenia, the cerebral changes underlying these signs are only partly understood. We therefore investigated the cerebral correlates of NSS by using magnetic resonance imaging (MRI) in patients with schizophrenia and healthy controls.

Forty-two patients, all receiving atypical neuroleptics, with first-episode schizophrenia or schizophreniform disorder and 22 healthy controls matched for age and gender were included. NSS were examined on the Heidelberg Scale after remission of the acute symptoms before discharge and correlated to density values by using optimized voxel-based morphometry (VBM).

NSS scores were significantly higher in patients than healthy controls. Within the patient group NSS were significantly associated with reduced grey or white-matter densities in the pre- and post-central gyrus, pre-motor area, middle and inferior frontal gyri, cerebellum, caudate nucleus and thalamus. These associations did not apply for the control group, in whom only the associations between NSS and reduced frontal gyri densities could be confirmed.

The pattern of cerebral changes associated with NSS clearly supports the model of ‘cognitive dysmetria’ with a disrupted cortico-cerebellar-thalamic-cortical circuit in schizophrenia. The variety of sites may correspond with the clinical diversity of NSS, which comprises both motor and sensory signs, and with the putative heterogeneity of the pathogenetic changes involved. That the respective associations did not apply for the healthy control group indicates that NSS in patients and controls refer to different pathogenetic factors.