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Neurological soft signs in first-episode schizophrenia: State- and trait-related relationships to psychopathology, cognition and antipsychotic medication effects
Abstract
Background:
Neurological soft signs (NSS) are proposed to represent both state- and trait-related features of schizophrenia.
Method:
We assessed the course of NSS with the Neurological Evaluation Scale (NES) over 12months of standardised treatment in 126 patients with first-episode schizophrenia, schizophreniform or schizoaffective disorder, and evaluated their state- and trait-related associations with psychopathology, functionality, cognition and antipsychotic treatment. We considered change scores from baseline to be state-related and endpoint scores to be trait-related.
Results:
Significant effects for time were recorded for all NSS domains. For state-related change-scores greater improvements in sensory integration were predicted by more improvement in working memory (p=0.01); greater improvements in motor sequencing scores were predicted by more improvement in working memory (p=0.005) and functionality (p=0.005); and greater improvements in NES Total score were predicted by more improvement in disorganised symptoms (p=0.02). There were more substantial associations between trait-related endpoint scores than for state-related change scores. For endpoint scores lower composite cognitive score predicted poorer sensory integration (p=0.001); higher Parkinsonism score predicted poorer motor co-ordination (p=0.0001); lower composite cognitive score (p=0.001) and higher Parkinsonism score (p=0.005) predicted poorer motor sequencing; higher Parkinsonism score (p=0.0001) and disorganised symptoms (p=0.04), and lower composite cognitive score (p=0.0007) predicted higher NES total score.
Conclusions:
NSS improved with treatment, but were weakly associated with improvements in psychopathology. Studies investigating NSS as trait-markers should ensure that patients have been optimally treated at the time of testing, and should take possible effects of extrapyramidal symptoms into account.
... More importantly, direct relationships between spontaneous MAs and psychopathology have been established in CHR individuals and patients with schizophrenia. In antipsychotic-naïve patients with FEP, MAs have been related to positive and negative symptom severity and cognitive dysfunction (Cuesta et al., 2014;Emsley et al., 2017;Peralta et al., 2018;White et al., 2009). Also, in CHR individuals relationships with psychopathology have been found: NSS have been related to negative symptoms, and spontaneous involuntary movements in the upper body to positive, negative and total psychopathology symptoms (Mittal et al., , 2007b. ...
... The other 17 studies related MAs to symptom severity levels measured on clinical rating scales: ten of them found that patients with higher levels of MAs had higher scores on overall, positive and negative symptom severity at follow-up. These studies related lower levels of NSS at baseline (White et al., 2009), a reduction of NSS over time (Bachmann et al., 2005;Emsley et al., 2017;Mayoral et al., 2008Mayoral et al., , 2012Scheffer, 2004;Whitty et al., 2003Whitty et al., , 2006, and lower levels of parkinsonism, dyskinesia and/or catatonia (Peralta and Cuesta, 2011;Rasmussen et al., 2017) to better treatment outcome. Seven studies did not find significant longitudinal relationships between MAs and symptomatic outcome measures (Chan et al., 2015;Chen et al., 2005;Cortese et al., 2005;Emsley et al., 2005;Kopala et al., 1997;Oosthuizen et al., 2003;Peralta et al., 2018), but most studies did establish cross-sectional relationships between MAs and symptom severity: all but one of them (Oosthuizen et al., 2003) found significant cross-sectional relationships between NSS or dyskinesia and negative symptom severity. ...
... Of the nine studies that reported functional outcome measures, six reported a significant association between elevated baseline NSS scores (Chiliza et al., 2015;Cuesta et al., 2018;Ferruccio et al., 2021) or stable (versus decreasing) NSS scores over time (Bachmann et al., 2005;Emsley et al., 2017;Whitty et al., 2006) and/or the presence of other MAs to long-term (range: 1-10 years) poor social functioning at follow-up. One of them also found a significant relationship between elevated NSS scores at baseline and poorer quality of life at one-year follow-up in 126 patients with FEP (Chiliza et al., 2015). ...
Schizophrenia spectrum disorders have heterogeneous outcomes and currently no marker predicts the course of illness. Motor abnormalities (MAs) are inherent to psychosis, the risk of psychosis, symptom severity, and brain alterations. However, the prognostic value of MAs is still unresolved. Here, we provide a systematic review of longitudinal studies on the prognostic role of MAs spanning individuals at clinical high risk for psychosis (CHR), patients with first-episode psychosis (FEP), and chronic schizophrenia. We included 68 studies for a total of 23,630 subjects that assessed neurological soft signs (NSS), hypo- or hyperkinetic movement disorders and/or catatonia as a prognostic factor on clinical and functional outcomes. We found increased levels of MAs, in particular NSS, parkinsonism, and dyskinesia, were related to deteriorating symptomatic and poor functional outcome over time. Collectively, the findings emphasize the clinical, prognostic and scientific relevance of MA assessment and detection in individuals with or at risk of psychosis. In the future, instrumental measures of MA are expected to further augment detection, early intervention and treatment strategies in psychosis.
... The picture on FE patients is less clear. Whereas patients' NSS status improved in several studies (30,31,42,45,58), the patients' cohort fell into two subgroups in the majority of studies, mostly with one subgroup exhibiting an improving and another a stable NSS course over time. ...
... Researchers reported more extensively on negative symptoms compared to other symptoms present at the catamnestic examination. Many groups found a positive or increasing correlation over time between total NSS scores and negative symptoms (30,37,40,42,44,(48)(49)(50)(51)(52)(53)58), as well as correlations between motor signs and negative symptoms (39,47). One group described partial correlations of negative symptoms with primitive reflexes (34). ...
... Their group also reported paralleling trends of NSS and Winsconsin Card Sorting Test (WCST) perseverative errors in both patient groups as well as higher scores in logical memory, delayed logical memory, and WCST category, which authors relate to worse motor coordination and total NSS scores. In another study (42), working memory amelioration was predicted by sensory integration and motor coordination, whereas motor sequencing was predicted by working memory. Jahn et al. (43) even found correlations between NSS and all subscales of the modified WCST. ...
Background
Neurological soft signs (NSS) represent minor neurological signs, which indicate non-specific cerebral dysfunction. In schizophrenia, their presence has been documented extensively across all stages of the disease. Until recently, NSS were considered an endophenotype or a trait phenomenon. During the past years, however, researchers report fluctuations of the NSS scores.
Aims
To further clarify the question whether NSS exhibit state or trait components or both, studies that have investigated NSS longitudinally were reviewed.
Method
Studies which have assessed NSS longitudinally in adults suffering from schizophrenia, were searched for. The time frame was January 1966 to June 2017. Studies on teenagers were excluded because of interferences between brain maturation and pathology.
Results
Twenty-nine follow-up studies were identified. They included patients during different stages of their illness and mainly used established instruments for NSS assessment. Patients with a first episode or a remitting course predominantly show a decrease of NSS over time, whereas a worsening of NSS can be found in the chronically ill. It was shown that change of NSS total scores over time is predominantly caused by motor system subscales and to a lesser extent by sensory integration scales. With respect to medication, the majority of studies agree on a relationship between medication response and improvement of NSS while the type of antipsychotic does not seem to play a major role. Moreover, where information on side-effects is given, it does not favor a strong relationship with NSS. However, NSS seem to correlate with negative and cognitive symptoms.
Conclusion
Studies manifest a conformity regarding the presence of NSS in schizophrenia patients on the one hand. On the other hand, fluctuations of NSS scores have been widely described in subgroups. Taken together results strongly support a state-trait dichotomy of NSS. Thus, the usage of NSS as an endophenotype has to be called into question.
... Los niveles de los NSS disminuyen a lo largo del curso clínico de la esquizofrenia, siendo este efecto más pronunciado en pacientes con un curso de remisión frente a aquellos que no remiten (31,43). La mayor reducción de los NSS ocurre dentro de los primeros 6 meses, sin encontrarse mejorías significativas después (44).Mayoral et al., llevaron a cabo un estudio en niños y adolescentes con primer episodio psicótico, determinando que la gravedad de los NSS es mayor respecto a los controles sanos durante el primer episodio psicótico y luego de dos años (45). Con respecto a la progresión de los NSS en el seguimiento a los dos años, el grupo de control sano mostró una disminución en el dominio de integración sensorial y el valor total de la NES. ...
... En diferentes estudios se encontró que altos niveles de NSS se correlacionan con un deterioro de la función cognitiva (32,34,(51)(52)(53); es más, los NSS predecirían un daño en las conexiones de la red cerebral frontalsubcortical, la cual se postula que sería el substrato fisiopatológico fundamental de la disfunción cognitiva en diversos síndromes psiquiátricos (54). En un estudio reciente se encontró mayor asociación entre los NSS y el desempeño cognitivo en término de puntuaciones finales, lo que sugiere una asociación cercana entre los componentes de rasgo de los NSS y la función cognitiva (44). El déficit de la función ejecutiva en los pacientes con esquizofrenia no está asociado con un único proceso de daño neurológico durante la vida fetal, sino que correspondería a la vía final común de varios procesos (55). ...
... pacientes con características clínicas diferentes) (71). Por otro lado, existen estudios, como el de Emsley et al., en donde se confirmó, parcialmente, que los NSS mejoran con los antipsicóticos (44). ...
La esquizofrenia es un trastorno que incluye múltiples signos y síntomas en diferentes áreas (positiva, negativa, afectiva, motora, cognitiva, entre otras). De ellas, la dimensión motora ha adquirido notable importancia durante las últimas décadas. En tal contexto, los llamados signos neurológicos blandos (NSS) son de especial interés como posible expresión endofenotípica de la esquizofrenia, debido a su alta prevalencia en pacientes con este trastorno, y en sus familiares de primer grado. Estas alteraciones neurológicas están asociadas con síntomas negativos y de desorganización conductual, así como con deterioro neurocognitivo y pobre rendimiento funcional. Además, los NSS permitirían diferenciar distintos subgrupos de pacientes esquizofrénicos, con requerimientos específicos en cuanto a tratamiento, seguimiento, rehabilitación social y neurocognitiva. Asimismo, en estudios de neuroimágenes se han puesto en evidencia una gran variedad de alteraciones estructurales y funcionales, relacionadas con la heterogeneidad de los NSS. El presente artículo es una revisión actualizada de la literatura respecto al tema, intentando presentar una visión general de los estudios más representativos.
... In contrast, catatonia primarily manifests as psychomotor alterations, which are more closely associated with disruptions in the fronto-parietal (orbitoand prefrontal cortex) and limbic (e.g., amygdala and hypothalamus) regions 10,11 . From a clinical point of view, NSS encompass subtle deficits in motor coordination, sensory integration, and motor sequencing, reflecting early neurodevelopmental alterations [12][13][14][15][16][17] . TD, a condition characterized by involuntary repetitive movements, and parkinsonism, marked by psychomotor slowing, rigidity, and tremor, can result from prolonged antipsychotic use [18][19][20] or spontaneously 21 . ...
... Schizophrenia (2025)16 Published in partnership with the Schizophrenia International Research Society ...
Sensori- and psychomotor abnormalities are an inherent part of schizophrenia-spectrum disorders (SSD) pathophysiology and linked to psychopathological symptoms as well as cognitive and global functioning. However, how these different symptom clusters simultaneously interact with each other is still unclear. Here, we examined 192 SSD patients (37.75 ± 12.15 years, 73 females). First, we investigated the cross-sectional prevalence and overlap of individual sensori- and psychomotor abnormalities. Second, we applied network analysis methods to simultaneously model the associations between Neurological Soft Signs (NSS), level of akathisia, parkinsonism symptoms, tardive dyskinesia (TD) and catatonia signs as well as cognition, psychopathology, global functioning and daily antipsychotic dose. The largest centralities were exhibited by NSS (0.90), catatonia signs (0.82) and global functioning (0.79). NSS showed strong partial correlations with cognition and parkinsonism symptoms (edge weight, ew = 0.409 and ew = 0.318, respectively). Catatonia signs showed strong connections with global functioning (ew = 0.333). In contrast, TD, akathisia and daily antipsychotic dose were weakly connected with other variables (e.g., largest ew=0.176 between TD and akathisia). In conclusion, NSS and cognition, parkinsonism symptoms and NSS as well as catatonia signs and global functioning seem to be preferentially connected in SSD. The daily medication had little influence on sensori- and psychomotor abnormalities, indicating that they are features of core SSD pathophysiology. Future studies should incorporate these relationships to enhance the understanding of SSD.
... In the past, motor abnormalities were mainly attributed to side effects of antipsychotic medication 1,4,5 . However, spontaneous motor abnormalities appear at all stages of the illness and may interact differentially with antipsychotic medication [5][6][7] . In fact, 67% of antipsychotic-naïve patients 8 and 80% of chronic schizophrenia patients 9 exhibit at least one motor symptom. ...
... Negative symptom severity may also affect motor behaviour including gait parameters 7,22,[59][60][61][62] . Previous reports failed to demonstrate a consistent association between negative symptoms and gait parameters; however, negative symptoms were only assessed with PANSS negative instead of a dedicated scale 19,29,30 . ...
Schizophrenia is a severe mental disorder, in which 50% of the patients present with motor abnormalities such as psychomotor slowing. Slow spontaneous gait has been reported in schizophrenia. However, comprehensive objective instrumental assessments of multiple gait conditions are missing. Finally, the specific gait patterns of subjects with psychomotor slowing are still unknown. Therefore, this study aimed to objectively assess multiple gait parameters at different walking conditions in patients with schizophrenia with and without psychomotor slowing. Also, we hypothesised gait impairments to correlate with expert ratings of hypokinetic movement disorders and negative symptoms. We collected gait data (GAITRite®) in 70 patients with psychomotor slowing (SRRS (Salpetriere retardation rating scale) ≥15), 22 non-psychomotor slowed patients (SRRS < 15), and 42 healthy controls. Participants performed four walking conditions (self-selected speed, maximum speed, head reclined, and eyes closed) and six gait parameters were extracted (velocity, cadence, stride length, functional ambulation profile (FAP), and variance of stride length and time). Patients with psychomotor slowing presented slower velocity, lower cadence, and shorter stride length in all walking conditions compared to healthy controls, with the non-slowed patients in an intermediate position (all F > 16.18, all p < 0.001). Secondly, slower velocity was associated with more severe hypokinetic movement disorders and negative symptoms. In conclusion, gait impairments exist in a spectrum with healthy controls on one end and patients with psychomotor slowing on the other end. Patients with psychomotor slowing are specifically impaired when an adaptation of gait patterns is required, contributing to the deleterious effects of sedentary behaviours.
... To complicate things, a study on treatment naïve patients reported no significant relation between the NSS severity and treatment, duration of illness, remission status, positive symptoms, negative symptoms and disorganized symptoms [108]. However, sex, age and age at onset might play a significant role [109,110] A recent study on a sample of similar size with ours but in first-episode patients, NSS reported that NSS improved with treatment, but were weakly associated with improvements in psychopathology. The current study results are in sharp contrast with this study [110]. ...
... However, sex, age and age at onset might play a significant role [109,110] A recent study on a sample of similar size with ours but in first-episode patients, NSS reported that NSS improved with treatment, but were weakly associated with improvements in psychopathology. The current study results are in sharp contrast with this study [110]. ...
Objective: Neurological soft signs (NSS) are a group of minor non-localizable neurological abnormalities found more often in patients with schizophrenia. The aim of the current study was to investigate their temporal stability and relationship to the overall outcome over a 12-month period.
Material and methods: The study sample included 133 stabilized patients suffering from schizophrenia (77 males and 56 females; aged 33.55 ± 11.22 years old). The assessment included the application at baseline and after 12 months of the Neurological Evaluation Scale (NES), and a number of scales assessing the clinical symptoms and adverse effects. The statistical analysis included ANOVA, exploratory t-test and Pearson correlation coefficients with Bonferroni correction.
Results: In stabilized patients, NSS are stable over a 12-month period with only the subscale of NES-sensory integration manifesting a significant worsening, while, in contrast, most of the clinical variables improved significantly. There was no relationship of NES scores with the magnitude of improvement. The only significant negative correlation was between NES-motor coordination and Positive and Negative Syndrome Scale-GP change at 1 year.
Discussion: The results of the current study suggest that after stabilization of patients with schizophrenia, there are probably two separate components, a ‘trait’ which is stable over a 12-month period, and a ‘degenerative’ component with a tendency to worsen probably in parallel with the progression of the illness and in correlation with the worsening of negative symptoms. However, the statistical support of the ‘degenerative’ component is weak.
• Significant outcomes
• Neurological softs signs are stable over a 12-month period, with the exception of ‘sensory integration’ which manifests significant improvement irrespective of treatment response.
• They do not respond to treatment with antipsychotics.
• They do not constitute a prognostic factor to predict improvement over a period of 1 year. Neurological soft signs constitute a trait symptom of schizophrenia which is stable though time.
• Limitations
• All the subjects have been previously hospitalized which may represent a more severe form of schizophrenia.
• Also, all patients were under antipsychotic and some also under benzodiazepine medications.
• Patients with comorbid somatic disorders were excluded which may decrease generalizability of results.
... NSS, though non-specific, has been implicated to have an association with functional abnormalities in specific brain regions. 28 MPA scores were found to have a strong association with NSS scores, favours the neurodevelopmental basis of BD. 29 Previous studies have found higher MPAs in BD, 30 similar to our current findings and further supports this hypothesis. Impairments in various subscores of NSS suggest a more widespread neuroanatomical involvement in BD. ...
Background
Neurological soft signs (NSSs), minor physical anomalies (MPAs), and oculomotor abnormalities were plausible biomarkers in bipolar disorder (BD). However, specific impairments in these markers in patients after the first episode mania (FEM), in comparison with first-degree relatives (high risk [HR]) of BD and healthy subjects (health control [HC]) are sparse.
Aim of the study
This study aimed at examining NSSs, MPAs, and oculomotor abnormalities in remitted adult subjects following FEM and HR subjects in comparison with matched healthy controls. Investigated when taken together, could serve as composite endophenotype for BD.
Methods
NSSs, MPAs, and oculomotor abnormalities were evaluated in FEM ( n = 31), HR ( n = 31), and HC ( n = 30) subjects, matched for age (years) ( p = 0.44) and sex ( p = 0.70) using neurological evaluation scale, Waldrop's physical anomaly scale and eye tracking (SPEM) and antisaccades (AS) paradigms, respectively.
Results
Significant differences were found between groups on NSSs, MPAs, and oculomotor parameters. Abnormalities are higher in FEM subjects compared to HR and HC subjects. Using linear discriminant analysis, all 3 markers combined accurately classified 72% of the original 82 subjects (79·2% BD, 56·70% HR, and 82·1% HC subjects).
Conclusions
AS and SPEM could enhance the utility of NSSs, and MPAs as markers for BD. The presence of these abnormalities in FEM suggests their role in understanding the etiopathogenesis of BD in patients who are in the early course of illness. These have the potential to be composite endophenotypes and have further utility in early identification in BD.
... Although it has been established that NES scores improve with antipsychotic treatment (Emsley et al., 2017), with no association between antipsychotic dosage and NES total score (Bachmann et al., 2014;Fritze et al., 2020), our study showed a correlation between antipsychotic dosage and NES total score. These findings could be explained by the discrepancy between treatment dosages and treatment guidelines in the treatment of Lebanese schizophrenic patients found in a previous study (Dib et al., 2018). ...
Introduction: Evidence has shown that neurological soft signs are strongly associated with neurocognitive dysfunction. Therefore, the primary objective of this study was to assess the association between NSS and cognitive impairments in a sample of inpatients with schizophrenia. The secondary objective was to explore the association between NSS total scores and functioning. Methods: The study enrolled 95 inpatients diagnosed with schizophrenia disorders and 45 healthy controls. The neurological evaluation scale (NES) was used to assess neurological soft sign while the Brief Assessment of Cognition in Schizophrenia (BACS) was used to evaluate cognitive functioning in patients with schizophrenia. Results: Patients with schizophrenia had significantly higher mean scores on the NES total test and subtests than the control group. Higher cognition was significantly associated with lower NES total and subtest scores. Higher functional independence was significantly associated with a lower NES total score (Beta = −.25), lower motor coordination subtest score (Beta = −.04), and lower others subtest (Beta = −.12). When taking the functional independence scale as the dependent variable, a higher NES total score was significantly associated with lower functioning (Beta = −0.03). Conclusion: NSS were associated to neurocognitive impairments in almost every domain among patients with schizophrenia. Further prospective research is still needed to confirm this role.
... We hypothesize that the kinetic movement of fingers during keyboard/touchscreen typing embeds features related to subtle decline in motor sequencing and force steadiness 12 . These are referred to as Neurological Soft Signs (NSS), sub-clinical motor abnormalities that can serve as early "warning signs" of brain dysfunction, and additional clinical evaluation remains essential for precise diagnosis [13][14][15] . ...
The unmet timely diagnosis requirements, that take place years after substantial neural loss and neuroperturbations in neuropsychiatric disorders, affirm the dire need for biomarkers with proven efficacy. In Parkinson’s disease (PD), Mild Cognitive impairment (MCI), Alzheimers disease (AD) and psychiatric disorders, it is difficult to detect early symptoms given their mild nature. We hypothesize that employing fine motor patterns, derived from natural interactions with keyboards, also knwon as keystroke dynamics, could translate classic finger dexterity tests from clinics to populations in-the-wild for timely diagnosis, yet, further evidence is required to prove this efficiency. We have searched PubMED, Medline, IEEEXplore, EBSCO and Web of Science for eligible diagnostic accuracy studies employing keystroke dynamics as an index test for the detection of neuropsychiatric disorders as the main target condition. We evaluated the diagnostic performance of keystroke dynamics across 41 studies published between 2014 and March 2022, comprising 3791 PD patients, 254 MCI patients, and 374 psychiatric disease patients. Of these, 25 studies were included in univariate random-effect meta-analysis models for diagnostic performance assessment. Pooled sensitivity and specificity are 0.86 (95% Confidence Interval (CI) 0.82–0.90, I ² = 79.49%) and 0.83 (CI 0.79–0.87, I ² = 83.45%) for PD, 0.83 (95% CI 0.65–1.00, I ² = 79.10%) and 0.87 (95% CI 0.80–0.93, I ² = 0%) for psychomotor impairment, and 0.85 (95% CI 0.74–0.96, I ² = 50.39%) and 0.82 (95% CI 0.70–0.94, I ² = 87.73%) for MCI and early AD, respectively. Our subgroup analyses conveyed the diagnosis efficiency of keystroke dynamics for naturalistic self-reported data, and the promising performance of multimodal analysis of naturalistic behavioral data and deep learning methods in detecting disease-induced phenotypes. The meta-regression models showed the increase in diagnostic accuracy and fine motor impairment severity index with age and disease duration for PD and MCI. The risk of bias, based on the QUADAS-2 tool, is deemed low to moderate and overall, we rated the quality of evidence to be moderate. We conveyed the feasibility of keystroke dynamics as digital biomarkers for fine motor decline in naturalistic environments. Future work to evaluate their performance for longitudinal disease monitoring and therapeutic implications is yet to be performed. We eventually propose a partnership strategy based on a “co-creation” approach that stems from mechanistic explanations of patients’ characteristics derived from data obtained in-clinics and under ecologically valid settings. The protocol of this systematic review and meta-analysis is registered in PROSPERO; identifier CRD42021278707. The presented work is supported by the KU-KAIST joint research center.
... First, antipsychotic medications could affect the extent to which soft signs are behaviorally expressed 56,57 . NSS severity may improve with treatment and over time 58 . On the other hand, a study in children and adolescents at ultra-high risk (UHR) for psychosis found that antipsychotic treatment does not affect severity of NSS 59 , and another found no relationship between current antipsychotic dosage and NSS severity 60 . ...
Neurological soft signs (NSS) are common in patients with schizophrenia. However, the neural substrates of NSS remain poorly understood. Using legacy PubMed, we performed a systematic review and included studies that assessed NSS and obtained neuroimaging data in patients with a schizophrenia spectrum disorder published up to June 2020. We systematically reviewed 35 relevant articles. Studies consistently implicate the basal ganglia and cerebellum as structural substrates of NSS and suggest that somatomotor and somatosensory regions as well as areas involved in visual processing and spatial orientation may underlie NSS in psychosis spectrum disorders. Additionally, dysfunction of frontoparietal and cerebellar networks has been implicated in the pathophysiology of NSS. The current literature outlines several structural and functional brain signatures that are relevant for NSS in schizophrenia spectrum disorder. The majority of studies assessed gray matter structure, but only a few studies leveraged other imaging methods such as diffusion weighted imaging, or molecular imaging. Due to this, it remains unclear if white matter integrity deficits or neurometabolic alterations contribute to NSS in the illness. While a substantial portion of the literature has been conducted in patients in the early illness stages, mitigating confounds of illness chronicity, few studies have been conducted in antipsychotic medication-naïve patients, which is a clear limitation. Furthermore, only little is known about the temporal evolution of NSS and associated brain signatures. Future studies addressing these pivotal gaps in our mechanistic understanding of NSS will be important.
... In the present study, we examined the associations of sex and gender with putative indicators of neurodevelopmental compromise in firstepisode schizophrenia spectrum disorders. The indicators that we considered were a family history of schizophrenia (Lobato et al., 2001), obstetric complications (Lewis and Murray, 1987), premorbid adjustment (Preston et al., 2002), neurological soft signs (Emsley et al., 2017;Whitty et al., 2003), and cognition (Bora, 2015;Melle, 2019;Tripathi et al., 2018). For gender role endorsement, we focused on masculinity scores, which are known to be lower in schizophrenia patients compared to controls, irrespective of their natal sex (Luckhoff et al., 2021;Sajatovic et al., 2005). ...
Background
It has been proposed that sex and gender differences described in schizophrenia can be explained from a neurodevelopmental perspective.
Aim
In this study, we examined the associations of biological sex and gender role endorsement with putative indicators of neurodevelopmental compromise.
Methods
We used the Bem Sex Role Inventory to calculate masculinity scores in 77 patients with a first episode of a schizophrenia spectrum disorder, and selected the following indicators of neurodevelopmental compromise: family history of schizophrenia, obstetric complications, premorbid functioning, neurological soft signs, and cognitive function. Secondary objectives included the moderating effects of age of onset of illness, substance use and negative symptoms on these associations.
Results
There were no significant sex differences across any of the indicators of neurodevelopmental compromise. However, lower masculinity scores correlated significantly with poorer premorbid adjustment, sensory integration deficits and worse overall cognitive performance. Stepwise linear regression identified poorer premorbid adjustment in early adolescence and lower verbal learning scores as independent predictors of lower masculinity scores. In contrast to sex, gender showed several associations with indicators of neurodevelopmental compromise.
Conclusions
Lower masculinity scores may represent part of a phenotype for a neurodevelopmental anomaly that places some individuals on a pathway to schizophrenia.
... The parent studies were both prospective longitudinal non-comparative studies where we followed up people with FES who were treated with the lowest effective dose of flupenthixol decanoate medication over 12-24 months. 26,27,28,29,30,31 Participants in the parent studies were recruited from community health clinics and from first admissions to Tygerberg and Stikland Hospitals in the broader Cape Town area. The inclusion criteria for both parent studies were as follows: men and women; aged 16-45 years; inpatients or outpatients; presenting with a first psychotic episode, confirmed by the Diagnostic and Statistical Manual of Mental Diseases, fourth edition, text revisions (DSM-IV TR) criteria for schizophrenia, schizophreniform or schizoaffective disorder. ...
Background:
Childhood trauma may contribute to poorer premorbid social and academic adjustment which may be a risk factor for schizophrenia.
Aim:
We explored the relationship between premorbid adjustment and childhood trauma, timing of childhood trauma's moderating role as well as the association of clinical and treatment-related confounders with premorbid adjustment.
Setting:
We conducted a secondary analysis in 111 patients with first-episode schizophrenia (FES) disorders that formed part of two parent studies, EONKCS study (n =73) and the Shared Roots study (n =38).
Methods:
Type of childhood trauma was assessed with the Childhood Trauma Questionnaire, short-form and premorbid adjustment using the Premorbid Adjustment Scale. Timing of childhood trauma was assessed using the Life Events Checklist and life events timeline. Linear regression analyses were used to assess the moderating effect of timing of childhood trauma. Clinical and treatment-related confounders were entered into sequential hierarchical regression models to identify independent predictors of premorbid adjustment across key life stages.
Results:
Childhood physical neglect was associated with poorer premorbid academic functioning during childhood and early adolescence, and poorer premorbid social functioning during early and late adolescence. By hierarchical regression modelling (r 2 = 0.13), higher physical neglect subscale scores (p = 0.011) independently predicted poorer premorbid social adjustment during early adolescence. Timing of childhood trauma did not moderate the relationship between childhood trauma and premorbid functioning.
Conclusion:
In patients with FES, childhood physical neglect may contribute to poorer premorbid social functioning during early adolescence. This may provide us with an opportunity to identify and treat at-risk individuals earlier.
... Researchers found that NSS are rather not related to medication (10,(15)(16)(17)(18)(19), since they are present in first-episode patients (10,(20)(21)(22)(23)(24)(25)(26)(27)(28) as well as in individuals at risk and in relatives (29)(30)(31)(32)(33). Moreover, NSS are associated with negative symptoms, formal thought disorders, and cognitive symptoms in general (4,17,26,(34)(35)(36)(37)(38)(39)(40)(41), as well as with fluctuations of psychopathology over time (20,25,26,42,43). ...
Neurological soft signs (NSS) represent minor neurological features and have been widely studied in psychiatric disease. The assessment is easily performed. Quantity and quality may provide useful information concerning the disease course. Mostly, NSS scores differ significantly between patients and controls. However, literature does not give reference values. In this pilot study, we recruited 120 healthy women and men to build a cross-sectional, census-based sample of healthy individuals, aged 20 to >70 years, subdivided in 10-year blocks for a close approach to the human lifeline. Testing for NSS and neurocognitive functioning was performed following the exclusion of mental and severe physical illness. NSS scores increased significantly between ages 50+ and 60+, which was primarily accountable to motor signs. Gender and cognitive functioning were not related to changes of scores. Although the number of individuals is small, study results may lay a foundation for further validation of NSS in healthy individuals.
... Even though these three physical findings of palmomental reflex (Gupta et al., 1995;Keshavan et al., 1979), glabellar tap (Stevens, 1978) and increased blink rate (Karson et al., 1990) have been independently shown to be increased in untreated schizophrenia compared to healthy subjects, these signs are certainly not specific to this disorder. The absence of these signs in the current examination may reflect the possible effects of treatment since neurological soft signs have been reported to disappear with treatment (Emsley et al., 2017). While using these or other 'soft' neurological signs as sole markers of diagnosis or treatment is not going to yield good prediction models, they may be of value in corroborating diagnostic decisions when used in concert with other clinical data. ...
... The presence of NSS, as pointed out by Faruk-Demirel, Demirel, Tayibb-Kadak, Emül & Duran (2016), constitutes a non-specific vulnerability factor associated with different psychological and psychiatric disorders such as schizophrenia ( Chan et al., 2016;Chrobak et al., 2016;Emsley et al., 2017;Mithun, Kamal, Aparajeeta & Subrata, 2016;Schulze, Papiol & Fatjo, 2016), obsessive-compulsive disorder (Chetail-Vijay & Shubhangi , 2016;Dhuri & Parkar, 2016;Peng et al., 2012) and attention deficit hyperactivity disorder (Abdel-Aziz, El Sheikh, Mohsen, Khalil & Hassan, 2016;Cardo, Casanovas, Banda & Servera, 2008;Jingbo-Gong, Jingtao-Xie, Yajie-Zhang, & Su-Hong-Wang, 2015). These disorders lead to considerable negative results in the psychosocial realm, even affecting mental processes such as social cognition (Pitizianti et al., 2017). ...
... Para autores como Faruk-Demirel, Demirel, Tayibb-Kadak, Emül y Duran (2016), los SNB son un factor de vulnerabilidad inespecífico asociado a distintos trastornos psicológicos y psiquiátricos, entre los que se encuentran, entre otros, la esquizofrenia (Chan et al., 2016;Chrobak et al., 2016;Emsley et al., 2017;Mithun, Kamal, Aparajeeta & Subrata, 2016;Papiol, Fatjo-Vilas & Shulze, 2016), el trastorno obsesivo compulsivo (Chetail-Vijay & Shubhangi, 2016;Dhuri & Parkar, 2016;Peng et al., 2012) y el trastorno por déficit de atención e hiperactividad (Abdel-Aziz, ...
Los Signos Neurológicos Blandos (SNB) son indicativos de interrupciones generalizadas en las redes de trabajo neuronal de áreas cortico-subcorticales, cuya presencia conlleva a problemas en el desarrollo neurocognitivo del niño que representan repercusiones académicas negativas. En la presente investigación se evaluó y comparó la presencia de SNB con los procesos cognitivos de 144 participantes mexicanos de estrato socioeconómico medio-bajo con edades entre los 6 y 11 años sin antecedentes neurológicos o psiquiátricos por medio de los Cuestionarios de Madurez Neuropsicológica (CUMANIN) y Madurez Neuropsicológica Escolar (CUMANES). Los resultados indicaron diferencias significativas por sexo, ya que las niñas presentaron mejor desempeño en la articulación de palabras. En los grupos por edad, las diferencias significativas se encontraron en leximetría-comprensión, visopercepción y función ejecutiva-errores; y, en general, los participantes mostraron presencia de SNB de desarrollo, que incluyen afectaciones en: lenguaje (problemas articulatorios, alteraciones del lenguaje oral y escrito, dificultad para encontrar palabras), psicomotricidad, visopercepción y otras funciones cognitivas. Al final, se concluye que la identificación y diagnóstico temprano de los SNB permite disminuir el riesgo de fracaso escolar.
... Although NSS is prevalent in various kinds of psychiatric conditions, such as bipolar disorder, obsessive-compulsive disorder, its prevalence has been shown to be higher in schizophrenia than in other psychiatric disorders [3,4]. Neurocognitive deficits (ND), as core symptoms of schizophrenia, have been consistently reported in schizophrenia patients and their first-degree unaffected relatives (FDR) [5,6], though NSS or ND in the first-episode schizophrenia and unaffected relatives of schizophrenia had enjoyed much attention in the literatures [7,8]. However, few studies were committed to explore the relationship between NSS and cognitive deficits in remitted patients with schizophrenia (RP) and FDR. ...
Neurological soft signs (NSS) and neurocognitive deficits (ND) are highly prevalent in schizophrenia, and have been separately proposed as candidate endophenotypes of schizophrenia. However, few relevant studies focus on remitted patients with schizophrenia (RP) and integrate NSS and ND as a composite endophenotype. This study aimed to explore the NSS and ND and examine the comparative relationship between them in RP, their first-degree unaffected relatives (FDR), and healthy controls, furthermore, to seek potential endophenotypes subitems of NSS and ND and create a composite endophenotype. 86 RP, 86 FDR, and 86 healthy controls were included. NSS and ND were independently assessed with Cambridge Neurological Inventory and MATRICSTM Consensus Cognitive Battery. RP had more NSS and ND than FDR in all subitems except disinhibition, information processing speed, working memory, and visual memory. Similarly, FDR presented poorer performance than controls in all subscales except disinhibition, sensory integration, working memory, and visual memory. Six subitems of NSS and ND met the criteria of endophenotype and the three groups were most accurately classified (71.2%) with these subitems working as a composite endophenotype. Moreover, information processing speed, attention, and social cognition were associated with sensory integration in RP and FDR. These findings add evidences that certain subitems of NSS and ND might be the endophenotypes of schizophrenia and integrating these endophenotypes may prove useful in identifying schizophrenia and high-risk individuals. Furthermore, sensory integration and specific cognitive domains covary, hence suggesting an overlap of compromised underlying neural systems.
... Most importantly, spontaneous Parkinsonism in drug-naïve first-episode patients predict poor cognitive function at 6 months follow-up [50••]. A recent naturalistic longitudinal study in first-episode patients indicated that NSS decreased over 1 year, while Parkinsonism and hyperkinesias increased [51]. However, the temporal dynamics of NSS appeared unrelated to changes in psychopathology. ...
Purpose of review:
Motor abnormalities are an intrinsic feature of psychosis. Neurological soft signs, Parkinsonism, dyskinesia, and other motor phenomena are frequently observed in subjects at clinical or genetic risk for psychosis as well as first-episode patients, chronic patients. Here, we review the most recent literature on motor assessments and pathophysiology in psychosis.
Recent findings:
Instrumental measures of fine motor performance, balance, spontaneous motor activity, and gesture indicated motor abnormalities in subjects at risk and across stages of schizophrenia. Motor phenomena are associated with distinct symptom dimensions and may indicate poor outcomes. Neuroimaging studies demonstrated altered neural maturation within critical motor networks in subjects at risk. Furthermore, specific categories of motor dysfunction were associated with distinct structural and functional alterations in the motor system in schizophrenia. Motor abnormalities provide a unique window into the pathobiology of psychosis and have the potential to guide screening, staging, and outcome prediction.
Background:
Neurological soft signs (NSS), as subtle, nonlocalising neurological abnormalities, are considered as the potential markers of psychosis. However, comparative studies of antipsychotic-naïve patients with first-episode psychosis (FEP) and first degree relatives (FDRs) are uncommon. We compared the prevalence and pattern of NSS in FEPs, their healthy FDRs and a healthy non-relatives' control group (HC), highlighted the relationship between NSS and psychopathology and proposed cut-off scores for prevalence studies.
Materials and methods:
Two hundred and two participants per group were recruited. The FEPs were consecutive attendees; FDRs were accompanying caregivers; while the HC were from hospital staff. The Brief Psychiatric Rating Scale and the Neurological Evaluation Scale were used to assess psychopathology dimensions and NSS, respectively.
Results:
Using an item score of two ('substantial impairment'), the prevalence of at least one NSS was: 91.5% (95% confidence interval [CI]: 86.7%-94.9%), 16.8% (95% CI: 11.8%-22.7%) and 6.5% (95% CI: 3.5%-10.9%), respectively, for FEP, FDRs and HC. FEPs were impaired in a broad range of signs. The noteworthy relationships were as follows: (i) a significant correlation between the negative symptoms' dimension versus number of NSS (r = 0.4), and NSS total score (r = 0.3), (ii) the anxiety/depression dimension correlated negatively with number of NSS (r = -0.3) and (iii) NSS cut across psychosis categories. We propose a cut-off score of ≥ 4 for the number of signs signifying probable impairment.
Conclusion:
The findings indicate that, subject to further studies, NSS could be regarded as a broader phenotype of neurologic dysfunction associated with psychosis proness.
Background and hypothesis:
Two machine learning derived neuroanatomical signatures were recently described. Signature 1 is associated with widespread grey matter volume reductions and signature 2 with larger basal ganglia and internal capsule volumes. We hypothesized that they represent the neurodevelopmental and treatment-responsive components of schizophrenia respectively.
Study design:
We assessed the expression strength trajectories of these signatures and evaluated their relationships with indicators of neurodevelopmental compromise and with antipsychotic treatment effects in 83 previously minimally treated individuals with a first episode of a schizophrenia spectrum disorder who received standardized treatment and underwent comprehensive clinical, cognitive and neuroimaging assessments over 24 months. Ninety-six matched healthy case-controls were included.
Study results:
Linear mixed effect repeated measures models indicated that the patients had stronger expression of signature 1 than controls that remained stable over time and was not related to treatment. Stronger signature 1 expression showed trend associations with lower educational attainment, poorer sensory integration, and worse cognitive performance for working memory, verbal learning and reasoning and problem solving. The most striking finding was that signature 2 expression was similar for patients and controls at baseline but increased significantly with treatment in the patients. Greater increase in signature 2 expression was associated with larger reductions in PANSS total score and increases in BMI and not associated with neurodevelopmental indices.
Conclusions:
These findings provide supporting evidence for two distinct neuroanatomical signatures representing the neurodevelopmental and treatment-responsive components of schizophrenia.
The placebo effect across psychiatric disorders is still not well understood. In the present study, we conducted meta-analyses including meta-regression, and machine learning analyses to investigate whether the power of placebo effect depends on the types of psychiatric disorders. We included 108 clinical trials (32,035 participants) investigating pharmacological intervention effects on major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ). We developed measures based on clinical rating scales and Clinical Global Impression scores to compare placebo effects across these disorders. We performed meta-analysis including meta-regression using sample-size weighted bootstrapping techniques, and machine learning analysis to identify the disorder type included in a trial based on the placebo response. Consistently through multiple measures and analyses, we found differential placebo effects across the three disorders, and found lower placebo effect in SCZ compared to mood disorders. The differential placebo effects could also distinguish the condition involved in each trial between SCZ and mood disorders with machine learning. Our study indicates differential placebo effect across MDD, BD, and SCZ, which is important for future neurobiological studies of placebo effects across psychiatric disorders and may lead to potential therapeutic applications of placebo on disorders more responsive to placebo compared to other conditions.
Schizophrenia patients exhibit subtle and non-localizing neurological abnormalities, known as neurological soft signs (NSS). Life-span evidence suggests that NSS vary along the course of schizophrenia. An association between NSS and treatment response has been proposed, suggesting that NSS reflect the underlying neuropathology development in schizophrenia. However, few studies have investigated the relationship between NSS and treatment resistance in first-episode schizophrenia patients. We conducted a longitudinal study on 52 first-episode schizophrenia patients, who were assessed at baseline, the sixth month, and the fifth year using the abridged version of the Cambridge Neurological Inventory. The trajectories of NSS between 29 treatment-responsive patients (with full symptomatic remission) and 23 treatment-resistant patients (who received clozapine) were compared using mixed model ANOVA. We also controlled for the effect of age and estimated IQ, using a mixed ANCOVA model. Although the two schizophrenia groups had comparable NSS at the baseline, their trajectories of NSS differed significantly. Compared with their treatment-responsive counterparts, treatment-resistant schizophrenia patients had worsening of NSS over time. Our findings support the potential utility of NSS in identifying treatment resistance in first-episode schizophrenia. Progressive worsening of NSS in treatment-resistant schizophrenia patients may reflect the development of underlying neuropathology. Further studies using large samples of treatment-resistant schizophrenia patients are needed.
This study systematically compared duration of untreated illness (DUI) with duration of untreated psychosis (DUP) in prediction of impairment at first-episode psychosis and investigated the extent to which these relationships are influenced by premorbid features. The Cavan-Monaghan First Episode Psychosis Study ascertained cases of first-episode psychosis in rural Ireland via all routes to care with limited variations in socioeconomic milieu. Cases were evaluated for DUI and DUP and assessed clinically for psychopathology, neuropsychology, neurology, insight and quality of life, together with premorbid features. Analyses then determined prediction of clinical assessments by DUI versus DUP. The study population consisted of 163 cases of first episode psychosis, among which 74 had a schizophrenia spectrum disorder. Shorter DUI but not DUP predicted less severe positive and general symptoms, while shorter DUP and particularly DUI predicted less severe negative symptoms; neither shorter DUP nor shorter DUI predicted less severe cognitive impairment or fewer neurological soft signs; shorter DUP and DUI predicted increased quality of life; shorter DUI but not DUP predicted greater insight. Only prediction of quality of life was weakened by consideration of premorbid features. Results were generally similar across the two diagnostic groupings. The present findings systematically delineate associations with DUI versus DUP across domains of impairment in first episode psychosis. They suggest that DUI may reflect a more insidious process than DUP and that reduction in DUI may be associated with more consistent and broader diminutions in impairment than for DUP.
Purpose:
There is limited evidence on the use of antipsychotic medications to treat people with schizophrenia in Sub-Saharan Africa (SSA). This systematic literature review identified original research on use of antipsychotic drugs for primary psychotic disorders in SSA, assessed the methodological quality of studies, summarized intervention strategies, and examined patient-level outcomes.
Methods:
PubMed, PsychInfo, Cochrane Collaboration, African Journals Online, and CINAHL databases were searched for studies in SSA that focused on antipsychotic treatment for primary psychotic disorders and that investigated at least one patient-level outcome. Articles in English and published before April 2019 were included. Epidemiological studies, drug discontinuation studies, studies with drugs other than antipsychotics, and multicenter studies that did not specify SSA results were excluded. An adapted standardized instrument assessed methodological quality.
Results:
Twenty-six articles were reviewed. Three levels of evidence were found: single-group reports, quasi-experimental studies, and randomized controlled trials. Study outcomes included change in psychiatric symptoms, adverse effects, remission rates, or change in functional status. Nine studies reported improvements in psychiatric symptoms with antipsychotic medication. Seven studies investigating adverse effects of antipsychotics found that they were associated with an increase in metabolic syndrome. Two studies reported that remission was achieved in most subjects, and one study reported improvements in functional status.
Conclusions:
Despite adverse effects, treatment with antipsychotic medications may be beneficial for individuals with primary psychotic disorders in SSA. Apart from South Africa, there is a scarcity of research on antipsychotics from countries in SSA, and there are numerous important gaps in the literature.
Minor neurological signs are subtle deficits in sensory integration, motor coordination, and sequencing of complex motor acts present in excess in the early stages of psychosis. Still, it remains unclear whether at least some of these signs represent trait or state markers for psychosis and whether they are markers of long-term disease outcome of clinical utility. We examined the relationship between neurological function at illness onset assessed with the Neurological Evaluation Scale and subsequent illness course in 233 patients from AESOP-10 (Aetiology and Ethnicity in Schizophrenia and Other Psychoses), a 10-year follow-up study of a population-based cohort of individuals recruited at the time of their first episode of psychosis in the United Kingdom. In 56 of these patients, we also explored changes in neurological function over time. We included a group of 172 individuals without psychosis as controls. After 10 years, 147 (63%) patients had developed a non-remitting course of illness, and 86 (37%) a remitting course. Already at first presentation, patients who developed a non-remitting course had significantly more primary, motor coordination, and total signs than both remitting patients and healthy controls. While Motor Coordination signs did not change over time, rates of Primary, Sensory Integration, and Total signs increased, independently of illness course type. These findings suggest that motor coordination problems could be a useful early, quick, and easily detectable marker of subsequent clinical outcome. With other motor abnormalities, a measure of motor incoordination could contribute to the identification of the most vulnerable individuals, who could benefit from targeted and more assertive treatment approaches.
Neurological soft signs (NSS) have garnered increasing attention in psychiatric research on motor abnormalities in schizophrenia spectrum disorders (SSD). However, it remains unclear whether the assessment of NSS severity could have been confounded by current antipsychotic dosage. In this study, we recruited 105 patients with SSD that underwent a comprehensive motor assessment evaluating NSS and extrapyramidal motor symptoms (EPMS) by means of standardized instruments. Current antipsychotic dosage equivalence estimates were determined by the classical mean dose method (doses equivalent to 1 mg/d olanzapine). We used multiple regression analyses to describe the relationship between NSS, EPMS and antipsychotic medication. In line with our expectations, current antipsychotic dosage had no significant effects on NSS total score (p = 0.27), abnormal involuntary movements (p = 0.17), akathisia (p = 0.32) and parkinsonism (p = 0.26). Further, NSS total score had a significant effect on akathisia (p = 0.003) and parkinsonism (p = 0.0001, Bonferroni corr.), but only marginal effect on abnormal involuntary movements (p = 0.08). Our results support the notion that NSS are not significantly modulated by current antipsychotic dosage in SSD. The associations between NSS, akathisia and parkinsonism, as revealed by this study, support the genuine rather than medication-dependent origin of particular motor abnormalities in SSD.
Treatment resistant schizophrenia (TRS) is defined by poor or non-response to conventional antipsychotic agents. Functional capacity is defined as the baseline potential of a patient to function in the community, irrespective of actual achievements gained, and has never been studied in TRS. Here, we screened 182 patients with psychotic symptoms and separated them in TRS (n = 28) and non-TRS (n = 32) ones, to evaluate whether they exhibited differential extents and predictive clinical variables of functional capacity. Functional capacity was measured by the UCSD Performance-Based Skills Assessment (UPSA). Psychotic symptoms by PANSS, social functioning by PSP and SLOF, clinical severity of the illness, cognitive functioning, and neurological soft signs (NSS) were assessed. TRS patients had non-significant lower UPSA scores compared to non-TRS (t-test: p > 0.05). In TRS, UPSA score correlated with multiple clinical variables. The highest effect sizes were observed for PANSS negative score (r = -0.67, p < 0.005); SLOF Area1 score (r = 0.66, p < 0.005); NSS severity (r = -0.61, p < 0.005). Multivariate analysis showed that main predictors of UPSA score in TRS patients were PANSS negative score, education years, NSS, Problem Solving performances, and PSP score (F = 11.12, R2 = 0.75, p < 0.0005). These variables were not predictive of UPSA score in non-TRS patients. Hierarchical analysis found that variance in UPSA score mainly depended on negative symptoms, NSS, and problem solving (F = 15.21, R2 = 0.65, p < 0.0005). Path analysis individuated two separate paths to UPSA score. These results delineate a limited and independent group of candidate predictors to be putatively accounted for therapeutic interventions to improve functional capacity, and possibly social functioning, in TRS patients.
This prospective study examined the course of neurological soft signs (NSS) in patients with first episode schizophrenia and its relationship with negative symptoms and cognitive functions. One hundred and forty-five patients with first-episode schizophrenia were recruited, 29 were classified as having prominent negative symptoms. NSS and neuropsychological measures were administered to all patients and 62 healthy controls at baseline. Patients were then followed-up prospectively at six month intervals for up to a year. Patients with prominent negative symptoms exhibited significantly more motor coordination signs and total NSS than patients without prominent negative symptoms. Patients with prominent negative symptoms performed worse than patients without negative symptoms in working memory functions but not other fronto-parietal or fronto-temporal functions. Linear growth model for binary data showed that the prominent negative symptoms were stable over time. Despite general improvement in NSS and neuropsychological functions, the prominent negative symptoms group still exhibited poorer motor coordination and higher levels of NSS, as well as poorer working memory than patients without prominent negative symptoms. Two distinct subtypes of first-episode patients could be distinguished by NSS and prominent negative symptoms.
Neurological soft signs (NSS) comprise subtle deficits in sensory integration, motor coordination, and sequencing of complex motor acts, which are typically observed in the majority of schizophrenia patients, including chronic cases and neuroleptic-naïve first-episode patients. However, recent studies clearly demonstrate that NSS are not a static feature of schizophrenia but vary in the clinical course of the disorder. This effect was investigated in a meta-analysis based on 17 longitudinal studies published between 1992 and 2012. Studies included between 10 and 93 patients with schizophrenia spectrum disorders (total number 787) with follow-up periods between 2 and 208 weeks. Beside the Neurological Examination Scale, the Cambridge Neurological Inventory and the Heidelberg NSS Scale were used to assess NSS. All but three studies found NSS to decrease in parallel with remission of psychopathological symptoms. This effect was more pronounced in patients with a remitting compared to a non-remitting, chronic course (Cohen’s d 0.81 vs. 0.15) and was significantly correlated with length of the follow-up period (r = −0.64) but not with age (r = 0.28). NSS scores did not decrease to the level typically observed in healthy controls. From a clinical perspective, NSS may therefore be used to identify subjects at risk to develop schizophrenia and to monitor disease progression.
Background:
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.
Method:
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).
Results:
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.
Conclusions:
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.
Neurological soft signs (NSS) are hypothesized as candidate endophenotypes for schizophrenia, but their prevalence and relations with clinical and demographic data are unknown. The authors undertook a quantification (meta-analysis) of the published literature on NSS in patients with schizophrenia and healthy controls. A systematic search was conducted for published articles reporting NSS and related data using standard measures in schizophrenia and healthy comparison groups.
A systematic search was conducted for published articles reporting data on the prevalence of NSS in schizophrenia using standard clinical rating scales and healthy comparison groups. Meta-analyses were performed using the Comprehensive Meta-analysis software package. Effect sizes (Cohen d) indexing the difference between schizophrenic patients and the healthy controls were calculated on the basis of reported statistics. Potential moderator variables evaluated included age of patient samples, level of education, sample sex proportions, medication doses, and negative and positive symptoms.
A total of 33 articles met inclusion criteria for the meta-analysis. A large and reliable group difference (Cohen d) indicated that, on average, a majority of patients (73%) perform outside the range of healthy subjects on aggregate NSS measures. Cognitive performance and positive and negative symptoms share 2%-10% of their variance with NSS.
NSS occur in a majority of the schizophrenia patient population and are largely distinct from symptomatic and cognitive features of the illness.
The atypical antipsychotic olanzapine has extensively been compared with haloperidol, whereas studies vs. other (conventional) neuroleptics are scarce. This exploratory double-blind 4-week study was designed to compare the efficacy and the safety of olanzapine (OLA) and flupenthixol (FLU) which have recently been considered as a "partially atypical" antipsychotics.
Twenty-eight inpatients with schizophrenia (DSM-IV) were randomly assigned for treatment with OLA (N = 15, 5-20 mg/d) or FLU (N = 13, 5-20 mg/d). The Brief Psychiatric Rating Scale (BPRS) and the Negative Symptoms Rating Scale (NSRS), plus the Patient Global Impression (PGI) and Clinical Global Impression (CGI) scales, were used to assess the efficacy of both compounds; safety was determined by using the Simpson Angus Scale (SAS) and the Abnormal Involuntary Movement Scale (AIMS) and by assessing treatment-emergent adverse events. Non-parametric statistics were applied.
BPRS and NSRS scores improved in both groups (exploratory tests; all p < or = 0.02). Similar results were observed for CGI-Severity, CGI- and PGI-Improvement. There were no significant group differences. Responder rates (at least 40 % decrease in BPRS total) were 9/13 OLA patients (69 %) and 9/12 FLU patients (75 %). EPS events were reported only in the FLU group (p < 0.01); FLU patients needed significantly more anticholinergic medication. Weight gain was higher in OLA patients (p < 0.01). Overall, fewer patients with adverse events were observed in the OLA group (p = 0.04). No significant changes were noted on SAS and AIMS scores.
Findings from this study suggest that overall and negative symptomatology improved in both treatment groups, while the safety and tolerability profiles differed for both substances.
The Extrapyramidal Symptom Rating Scale (ESRS) was developed to assess four types of drug-induced movement disorders (DIMD): Parkinsonism, akathisia, dystonia, and tardive dyskinesia (TD). Comprehensive ESRS definitions and basic instructions are given. Factor analysis provided six ESRS factors: 1) hypokinetic Parkinsonism; 2) orofacial dyskinesia; 3) trunk/limb dyskinesia; 4) akathisia; 5) tremor; and 6) tardive dystonia. Two pivotal studies found high inter-rater reliability correlations in both antipsychotic-induced movement disorders and idiopathic Parkinson disease. For inter-rater reliability and certification of raters, >or=80% of item ratings of the complete scale should be +/-1 point of expert ratings and >or=70% of ratings on individual items of each ESRS subscale should be +/-1 point of expert ratings. During a cross-scale comparison, AIMS and ESRS were found to have a 96% (359/374) agreement between TD-defined cases by DSM-IV TD criteria. Two recent international studies using the ESRS included over 3000 patients worldwide and showed an incidence of TD ranging from 10.2% (2000) to 12% (1998). ESRS specificity was investigated through two different approaches, path analyses and ANCOVA PANSS factors changes, which found that ESRS measurement of drug-induced EPS is valid and discriminative from psychiatric symptoms.
Patients with schizophrenia are characterized by neurological abnormalities, which can be assessed by bedside clinical examination. These abnormalities have been argued to represent core features of the illness. We review studies published since our last review in 1988 that address the validity of neurological signs as a trait feature of schizophrenia.
We conducted a literature search in the following computer databases: MEDLINE, PSYCHLIT, EMBASE, and COCHRANE. The search was limited to articles published from January 1988 to May 2005.
Neurological signs occur in the majority of patients with schizophrenia. Their occurrence is independent of demographic and most medication variables. Neurological signs are strongly associated with negative symptoms and cognitive impairments. There is also evidence to suggest that their occurrence is under genetic control.
There is compelling evidence to suggest the hypothesis that neurological signs represent a trait feature of schizophrenia.
Neurological soft signs are frequently found in schizophrenia. They are indicators of both genetic liability and psychopathological symptoms. To further differentiate "trait" and "state" relations the authors compared the 1-year course of neurological soft signs in schizophrenia patients and comparison subjects.
Thirty-nine patients with first-episode schizophrenia spectrum disorders were examined after remission of acute symptoms and 14 months later. Established instruments assessed diagnoses, psychopathological symptoms, predictors of outcome, handedness, and neurological soft signs. Twenty-two age- and gender-matched comparison subjects were also examined twice.
Neurological soft sign scores in patients were significantly elevated relative to comparison subjects at both measurement points. Whereas neurological soft signs remained stable in comparison subjects (time 1: mean=4.8, SD=3.3; time 2: mean=4.6, SD=3.9), they significantly decreased in patients (time 1: mean=15.7, SD=7.1; time 2: mean=10.1, SD=7.9). This effect was more pronounced in patients with a favorable versus a chronic course and was mainly accounted for by motor signs. Predictors of follow-up neurological soft sign scores were neurological soft sign levels at remission and compliance with treatment.
Although neurological soft signs are intrinsic to schizophrenia, their level varies with the clinical course. Thus, neurological soft signs may correspond to both genetic liability and the activity of the disease process and may be considered as potential predictors of outcome.
Neurological soft signs (NSSs) bear the promise for early detection of schizophrenia spectrum disorders. Nonetheless, the sensitivity and specificity of NSSs in the psychosis continuum remains a topic of controversy. It is also unknown how NSSs reveal neurodevelopmental abnormality in schizophrenia. We investigated the effect sizes of NSSs in differentiating individuals with schizophrenia spectrum disorders from individuals with other psychiatric conditions and from covariate-matched healthy subjects. We also investigated the partitioned age-related variations of NSSs in both schizophrenia and healthy individuals. NSSs were assessed by the abridged version of the Cambridge Neurological Inventory (CNI) in 3105 participants, consisting of healthy individuals (n =1577), unaffected first-degree relatives of schizophrenia patients (n = 155), individuals with schizotypal personality disorder (n = 256), schizophrenia patients (n = 738), and other psychiatric patients (n = 379). Exact matching and propensity score matching procedures were performed to control for covariates. Multiple regression was used to partition age-related variations. Individuals along the schizophrenia continuum showed elevated levels of NSSs, with moderate effect sizes, in contrast to other psychiatric patients who had minimal NSSs, as well as matched healthy controls. Furthermore, the age-and-NSS relationship in schizophrenia patients was represented by a flat but overall elevated pattern, in contrast to a U-shaped pattern in healthy individuals. In sum, NSSs capture a moderate portion of psychosis proneness with reasonable specificity. Lifespan profiling reveals an abnormal developmental trajectory of NSSs in schizophrenia patients, which supports the endophenotype hypothesis of NSSs by associating it with the neurodevelopmental model of schizophrenia.
We describe the profile of NSS across the one-year course of schizophrenia in 84 Nigerian first-episode patients. They were assessed at baseline and 3 monthly for 12 months using the Neurological Evaluation Scale and the Positive and Negative Syndrome Scale (PANSS), and treated with flupenthixol decanoate. The pattern of NSS total and sub-category scores obtained from repeated measurements were investigated for responders (≥50% reduction of baseline PANSS scores) and non-responders using the method of repeated measures analysis of variance. Trait-like features of NSS categories were quantified using intraclass correlation coefficients (ICCs). NSS were present in 96.4% of the patients at baseline (mean 21.5 ± 11.1). The motor-sequencing sub-category was found unrelated to changes in schizophrenia psychopathology with treatment (positive, r = 0.19, p = 0.136., negative, r = 0.12, p = 0.350; disorganization, r = 0.16, p = 0.245; overall, r = 0.20, p = 0.112). Regardless of decrements in psychopathology, motor-sequencing scores remained relatively unchanged across the course of the disease (main effects: ‘responders’ F = 2.44, p = 0.930, ‘poor responders’ F = 0.27, p = 0.764, entire sample F = 1.87, p = 0.160). ICC was “substantial” at 0.8 (95% C.I = 0.6–0.9). Only the motor-sequencing NSS appear to be trait marker of schizophrenia in this sample. Other NSS seem to reflect symptomatic states of the disorder.
Neurological soft signs and neurocognitive impairments are commonly observed in first episode psychosis but the correlation of these factors remains controversial. Here, we evaluated 30 patients with remitted first episode psychosis and 30 healthy controls for the presence and severity of neurological soft signs (using the Neurological Evaluation Scale - NES) and for neurocognitive impairments (using seven subtests of the Cambridge Neuropsychological Test Automated Battery - CANTAB). NES score was higher in patients compared to controls. Neurocognitive impairment was evident in patients in the following domains: working memory, spatial recognition memory, attention set shifting, planning and inhibition. The NES revealed significant correlations with spatial working memory performance and Intra-Extra Dimensional Set Shifting (as a component of executive function). These correlations were observed both in patients and in controls. Planning and inhibition showed correlation with the total NES score and the sequencing of complex motor acts in both groups. In addition, spatial span and spatial recognition memory showed significant correlation with total NES score and the sequencing of complex motor acts in controls. The correlation between sequencing of complex motor acts and specific domains of neurocognitive tasks suggests that similar neuroanatomical substrates might be implicated in these processes.
To assess the feasibility and effectiveness of depot antipsychotic (flupenthixol decanoate) combined with an assertive monitoring programme (AMP) in first-episode schizophrenia.
This was a prospective, non-comparative, longitudinal study conducted over 12 months assessing patient acceptance, adherence, outcome in domains of psychopathology, functionality and quality of life, and tolerability.
Of 207 participants, 149 (72%) completed 12 months of treatment. Acceptance of and adherence to depot was good. Treatment response was achieved by 170 (82%) participants and remission by 124 (60%). Thirty-three (19%) responders relapsed and 10 (5%) participants met a priori criteria for treatment resistance. Treatment was generally well tolerated.
Combination of depot antipsychotic with an AMP may be an effective and safe intervention in early phases of schizophrenia, and may be particularly suitable for resource-constrained settings.
Background:
Animal and postmortem studies indicate that neuroleptic therapy may induce D2 dopamine receptor up-regulation in the basal ganglia.
Methods:
To address this phenomenon in a clinical study, we investigated the D2 dopamine receptor binding in 15 DSM-III-R schizophrenics in the drug-naive state and 3 days after completion of a standardized neuroleptic therapy (benperidol 12-16 mg/day, for 25 days) using single photon emission computed tomography (SPECT). SPECT scans were obtained 2 hours after intravenous injection of 185 MBq 123I-iodobenzamide. For analysis, basal ganglia to frontal cortex (BG/FC) ratios were calculated and the patient sample was subgrouped into patients with a favorable versus a poor treatment response.
Results:
Neuroleptic treatment led to decreased BG/FC ratios in patients with a favorable response, but increased ratios in the poor responders (df = 1, F = 4.1, p = .06). Changes of BG/FC ratios were significantly correlated with extrapyramidal side effects but not with neurological soft signs.
Conclusions:
Our findings suggest that neuroleptic therapy may induce D2 dopamine receptor up-regulation in a subgroup of patients characterized by poor treatment response and pronounced extrapyramidal side effects.
The minor neurological and cognitive deficits consistently reported in psychoses may reflect the same underlying brain dysfunction. Still, even in healthy individuals minor neurological abnormalities are associated with worse cognitive function. Therefore, establishing which neurological and cognitive deficits are specific to psychosis is essential to inform the pathophysiology of this disorder. We evaluated a large epidemiological sample of patients with first episode psychosis (n=242) and a population-based sample of healthy individuals (n=155), as part of the AESOP study. We examined neurological soft signs using the Neurological Evaluation Scale (Buchanan and Heinrichs, 1989), and generalized and specific cognitive deficits (memory; verbal abilities; attention, concentration and mental speed; executive functions and working memory; language; visual constructual/perceptual abilities). In patients, more neurological signs across all subscales were associated with worse general cognitive function, while in controls this was only present for sensory integration and sequencing signs. Furthermore, in patients, but not in healthy individuals, more sensory integrative signs were associated with deficits in specific cognitive domains, such as memory, verbal abilities, language, visual/perceptual, executive function (p ranging <0.001-0.002); sequencing signs with language, executive function, and attention (p<0.001-0.004); and motor signs with poorer verbal abilities (p=0.001). These findings indicate the presence of specific associations between neurological and cognitive deficits in psychosis that are distinct from those of healthy individuals.
Despite the rather large literature concerning emotional intelligence, the vast majority of studies concerning development and validation of emotional intelligence scales have been done in the Western countries. Hence, a major limitation in this literature is its decidedly Western focus. The aim of this research was to assess the psychometric properties of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) in a cross-cultural comparative context involving the collectivist Pakistani (Eastern culture) and the individualist French (Western culture) students. With the exception of significant mean differences on the MSCEIT scores between two cultures, the results concerning the validity of the MSCEIT generalized nicely across both cultures. The results from multisample analysis revealed that the MSCEIT has the property of factorial invariance across both cultures, including invariance of factor loadings, unique variances, and factor variance. For both Pakistani and French students, the MSCEIT scores were distinguishable from the Big Five personality dimensions, self-report emotional intelligence measures, and cognitive intelligence. Furthermore, in both cultures, the MSCEIT scores failed to demonstrate incremental validity against well-being measures, after controlling for cognitive intelligence and the Big Five personality dimensions. Finally, within each sample, females significantly scored higher than males on the MSCEIT total scores.
Neurological soft signs (NSS) are intrinsic features of psychosis that appear years before beginning a drug treatment. However, whether NSS respond to antipsychotics and whether these changes are clinically reliable and significant remains to be seen.
We sought to determine the effect of antipsychotics on NSS in a first-episode psychosis (FEP) sample who had never exposed to antipsychotics.
We included 100 antipsychotic-naïve patients with FEP in this study. 77 patients completed the study assessments at baseline, 1 month and 6 months. The Neurological Evaluation Scale (NES) evaluated NSS. Patients were alternatively selected to receive risperidone or olanzapine treatments and continued participation in their mental health setting during follow-up with one of four treatment groups: risperidone, olanzapine, mixed antipsychotics or no medication. We also included a control group of 28 healthy volunteers.
Treatment groups showed a statistically significant improvement on total NES scores and most NES subscales except for 'frontal signs', regardless of antipsychotic allocation. NSS changes were reliable; however, there was great variation in the total NES scores between treatment groups, ranging from 4% to 24%. Clinically meaningful changes (CMCs) on total NES scores ranged from 25% to 50%. Six patients (7.8%) demonstrated a reliable change (RC) and CMC on total NES scores.
NSS improved significantly over follow up regardless of the treatment regimen assigned to antipsychotic-naïve patients with a FEP. However, only 6 (7.8%) achieved a reliable and clinically meaningful improvement. The pattern of response of NSS to antipsychotic drugs evidenced both state and trait characteristics.
The aim of the study was to assess the dynamics of neurological soft signs (NSS) over four years from the clinical onset of schizophrenia, depending on the clinical course of the disease, and to evaluate the relationship of NSS to symptomatic dimensions in patients with first-episode schizophrenia. Sixty-eight patients with first-episode schizophrenia were included in the trial. The clinical status was assessed using Positive and Negative Syndrome Scale (PANSS) at the same time as the neurological examination, at admission to the hospital for first-episode schizophrenia and at a check-up examination four years later. The assessment of NSS using the Neurological Evaluation Scale (NES) coincided with the assessment of the clinical condition of the patients. According to the Andreasen remission criterion of schizophrenia, after four years we found that 57% of patients' were remitters and 43% were non-remitters. During the monitoring period, in remitters total NES score and sensory integration/sequencing of motor acts items of the NES decreased. In non-remitters, increase in the total NES score and the 'others' item of the NES was observed. A connection between the dynamics of NSS and the clinical course of schizophrenia, over the period of four years, and a relationship between NSS and negative schizophrenia symptoms was found.
In recent decades, the assessment of neurological soft signs (NSS) in patients with psychosis has become a subject of special interest. The study of the progression of NSS during adolescence will provide valuable information about the role of NSS as endophenotypes or biomarkers and about brain development at a stage in which brain maturation has not yet been completed.
Neurological soft signs were assessed in a sample of 110 first episodes of early-onset psychosis (EOP) and 98 healthy children and adolescents at two different times in a 2-year follow-up period.
Patients with EOP showed more NSS than controls both at baseline (p < .001) and the 2-year follow-up (p < .001). No differences were found in the number of signs among the different diagnostic subgroups (schizophrenia, bipolar disorder, and other psychoses). When we examined the changes in NSS over the follow-up, the reduction of NSS in the patients was greater than the controls for 'Motor coordination' (p = .032), 'Others' (p < .001), and 'Total score' (p < .001) of the NES.
Despite the greater reduction of NSS in patients than in controls along the follow-up, patients still have more neurological signs than healthy controls; therefore, these signs may be considered a trait marker. NSS do not seem to be specific to schizophrenia as they are present in different EOPs.
Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled trials to compare the effects of these two types of drugs in patients with schizophrenia.
We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation.
We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride -0.31 [95% CI -0.44 to -0.19, p<0.0001], clozapine -0.52 [-0.75 to -0.29, p<0.0001], olanzapine -0.28 [-0.38 to -0.18, p<0.0001], and risperidone -0.13 [-0.22 to -0.05, p=0.002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication.
Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost.
Neurological soft signs were assessed in 24 first episodes of early onset psychosis and 30 healthy adolescents over a 2-year period. Patients presented more neurological soft signs than controls and showed a significant decrease in some Neurological Evaluation Scale scores over the followup period. This decrease in the patient group was influenced by changes in symptomatology.
It remains unclear if the excess of neurological soft signs, or of certain types of neurological soft signs, is common to all psychoses, and whether this excess is simply an epiphenomenon of the lower general cognitive ability present in psychosis.
To investigate whether an excess of neurological soft signs is independent of diagnosis (schizophrenia v. affective psychosis) and cognitive ability (IQ).
Evaluation of types of neurological soft signs in a prospective cohort of all individuals presenting with psychoses over 2 years (n=310), and in a control group from the general population (n=239).
Primary (P<0.001), motor coordination (P<0.001), and motor sequencing (P<0.001) sign scores were significantly higher in people with any psychosis than in the control group. However, only primary and motor coordination scores remained higher when individuals with psychosis and controls were matched for premorbid and current IQ.
Higher rates of primary and motor coordination signs are not associated with lower cognitive ability, and are specific to the presence of psychosis.
The significance of neurological signs in schizophrenia is poorly understood. In part, this may reflect the marked variability in the methods of ascertainment in previous studies. The Neurological Evaluation Scale (NES) is designed to standardize the assessment of neurological impairment in schizophrenia. The battery consists of 26 items. Data on the interrater reliability for total score, functional areas of interest, and individual items are presented. Preliminary validity data demonstrate the ability of the battery to discriminate patients with schizophrenia from nonpsychiatric controls.
The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized
measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale
(PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS
was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative
symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring
positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the
four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely
correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually
exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with
antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both
typological and dimensional assessment.
The goal of this study was to assess neurological soft signs and developmental reflexes in schizophrenic patients who had never received neuroleptic medication and those who were receiving neuroleptic medication.
Neurological soft signs and developmental reflexes were examined in 26 schizophrenic patients who had never received a neuroleptic, 126 schizophrenic patients who were currently receiving neuroleptics, and 117 normal subjects.
Soft signs were present in 23% of the neuroleptic-naive and 46% of the medicated schizophrenic patients. Developmental reflexes were present in 19% of the neuroleptic-naive and 12% of the medicated patients. Both soft signs and developmental reflexes were absent in the normal subjects. There were significant differences between patients and normal subjects in neurological soft signs and developmental reflexes. The possibly confounding variables of age, age at onset, duration of illness, number of hospitalizations, Abnormal Involuntary Movement Scale (AIMS) scores, and Simpson-Angus Scale extrapyramidal symptom scores were assessed by using logistic regression in the patients who were receiving neuroleptics. AIMS scores and Simpson-Angus Scale scores correlated with soft signs in these patients.
The presence of neurological soft signs in schizophrenic patients who had never received neuroleptics indicates that these signs are present independent of medication effects, but it is possible that neuroleptics contribute to the prevalence of these abnormalities, as demonstrated by the patients who were receiving neuroleptics.
Since existing depression scales were designed for assessment of depression in non-psychotic populations, such scales have items which do not distinguish depressed from non-depressed psychotic subjects. The authors describe a new scale, the Calgary Depression Scale, which was designed for the assessment of depression in schizophrenia. The scale was derived from two existing scales by factor analysis and reliability analysis. It has been further tested in two new samples. In the first it has been shown to be reliable, congruent with a self-report scale and valid. In the second sample it has been shown that there is no overlap with negative or extrapyramidal symptoms.
Neurological soft signs (NSS) have been shown to be more prevalent in chronically ill and in acute or never-mediated patients with schizophrenia. If neurological soft signs are trait-like, then NSS scores should be relatively stable over time and should not be related to changes in patients' psychopathology or medication. Chronically hospitalized patients with schizophrenia were rated two or more times over a 5-year period with standard NSS and psychopathology scales. Total NSS scores were highly correlated over time, and changes in NSS scores at two time points were not significantly related to changes in psychopathology scores. Total NSS scores did not change significantly in a subsample rated when they were first treated with a traditional neuroleptic and later with an atypical neuroleptic. The findings suggest total NSS scores may have some characteristics of a trait-like feature in chronically hospitalized patients with schizophrenia.
The aim of this study was to examine the temporal stability of neurological abnormalities in first-episode schizophrenic patients, and to clarify the relationships between such abnormalities and psychopathology.
A total of 18 schizophrenic patients, 11 non-schizophrenic patients and 10 healthy volunteers were examined neurologically at first admission and 5 years later.
A significant increase in the number of neurological abnormalities was seen in schizophrenic patients with genetic predisposition and in patients with a non-remitting course of disease. Birth complications had an impact on the occurrence of neurological abnormalities at first admission.
The association between a deteriorating course of disease and neurological impairment supports the theory that any possible impairment of the brain in schizophrenia is aggravated during the first 5 years of disease.
The major purposes of this study were 1) to examine whether neurological signs predict cognitive performance in both schizophrenic patients and healthy subjects and 2) to determine the ability of neurological signs and neuropsychological tests to discriminate schizophrenic patients from healthy subjects.
Eighty-five patients with a DSM-III-R diagnosis of schizophrenia and 36 normal comparison subjects were included in the study. All subjects were administered a comprehensive neuropsychological test battery, and neurological signs were assessed with the Neurological Evaluation Scale. Stepwise regression analyses were used to predict neuropsychological test performance from the subscale scores on the Neurological Evaluation Scale. Forward stepwise linear discriminant function analyses were used to examine the discriminative ability of neurological subscale scores, neuropsychological test scores, and the two combined.
Scores on the Neurological Evaluation Scale predicted the neuropsychological test performance of both patients and comparison subjects. The sensory integration subscale score was the most frequent predictor of neuropsychological test performance. In contrast, the "others" subscale, which includes frontal release signs, abnormalities in eye movements, and short-term memory, was the most highly discriminating subscale, correctly classifying 78.5% of the total study group. The best predictors from the neuropsychological battery (category fluency and Trail Making Test, part A, time test) correctly classified 81.8%. When both sets of variables were used, the Neurological Evaluation Scale "others" subscale entered the discriminant function first.
Neurological signs are reliably related to measures of neuropsychological performance and also reliably discriminate between patients and healthy subjects. However, some neurological signs may be more sensitive to the presence of schizophrenia, while others may be more predictive of neuropsychological performance.
The heterogeneity and uncertain significance of neurologic exam abnormalities in schizophrenia prompted us to evaluate their factor structure. We administered a modified version of the Neurological Evaluation Scale (NES) to 103 unmedicated patients with schizophrenia. Data were distilled by combining right- and left-side scores, and by eliminating superfluous, rarely abnormal and unreliable items from the analysis. Exploratory principal components analysis yielded four factors: repetitive motor tasks (fist-ring, fist-edge-palm, alternating fist-palm, dysdiadochokinesis); cognitive-perceptual tasks (memory, audiovisual integration, right-left orientation, face-hand test, rhythm tapping reproduction); balancing tasks (Romberg, tandem gait); and the palmomental reflex. Evaluation of the relationship between these factors and clinical and demographic variables revealed a robust correlation between the cognitive-perceptual factor and full-scale IQ score. This analysis is a step toward developing empirical subscales of a modified NES, which may provide insights into the nature of neurologic impairment in schizophrenia and may prove clinically useful.
Although it is well recognized that individuals with schizophrenia display evidence of subtle neurological impairment, its aetiopathological and clinical significance continues to be unclear.
Patients presenting with a first episode of schizophrenia or schizophreniform psychosis (DSM-IV criteria) were examined using two previously validated neurological examinations. The majority (N = 35) were examined prior to their 'first ever' dose of neuroleptic while the remaining patients (N = 21) had been medicated for less than one month. The manner in which neurological functioning is influenced by symptomatology and handedness was ascertained.
The majority of patients who were examined neuroleptic-naive displayed evidence of neurodysfunction. A combination of relative hand preference and symptomatology explained a significant proportion of the variance in neurological functioning. Mixed handedness among adults at the time of first presentation with schizophrenia was associated with more severe neurological impairment and a history of poorer scholastic attainment and pre-morbid social adjustment.
Neurological soft signs are an intrinsic part of schizophrenia rather than a direct consequence of treatment. Early developmental processes are associated with the level of subsequent neurological impairment in first episode schizophrenia. However, symptomatology appears to have an influence on the apparent severity of neurological impairment.
Neurological signs are found to be increased in schizophrenia in cross-sectional studies. Whether they progress with time is an important issue in addressing the course of the illness.
The current study investigated different groups of neurological signs in 43 stable chronic schizophrenic patients over a 3-year period using an operationalized instrument.
While symptoms and medication have remained largely unchanged in the 3-year period, significant increase in soft neurological signs (SNS) ('motor coordination', 'sensory integration' and 'disinhibition') has been observed. This contrasted with the stability of 'pyramidal', 'extrapyramidal', 'dyskinesia' and 'catatonia' signs. The increase in SNS appears not to be related to age, illness duration, symptoms or medication.
This finding suggests that SNS represent a marker sensitive to a possible late deterioration process in the course of a schizophrenic illness.
To determine rates of adherence to antipsychotic medication in first episode patients and the correlates of adherence in this group.
Subjects were the first 200 admissions to an Early Psychosis Program. Adherence was determined on a three-point scale. Symptoms, medication side-effects, quality of life, substance use and family involvement were examined longitudinally.
In their first year in the program 39% were non-adherent, 20% inadequately adherent, and 41% adherent. Non-adherent patients demonstrated more positive symptoms, more relapses, more alcohol and cannabis use, reduced insight, and poorer quality of life. They were younger, had an earlier age of onset and less likely to have a family member involved in treatment.
Results for this group are similar to those reported in the literature. Correlates are often the consequence of non-adherence. Non-compliance has to be anticipated and relationships maintained with patients and families to intervene as soon as possible to minimize the consequence of non-compliance.
Neurological soft signs (NSS) are minor neurological signs indicating non-specific cerebral dysfunction. Their presence has been documented extensively in schizophrenia but not during the first psychotic episode.
To review studies that have specifically investigated NSS at the time of the first psychotic episode.
A review of studies investigating neurological function in first-episode psychosis, using a clinical examination.
Patients with first-episode psychosis show an excess of NSS, particularly in the areas of motor coordination and sequencing, sensory integration and in developmental reflexes. Furthermore, NSS may be associated with a specific laterality pattern.
More studies on first-onset schizophrenia are needed, evaluating both sensory and motor neurological domains (scoring separately for the two sides of the body), integrating this knowledge with neuroimaging findings and clarifying the role of NSS as markers of cognitive dysfunction.
The Positive and Negative Syndrome Scale (PANSS) is a widely used instrument for measuring severe psychopathology in adult patients with schizophrenia. Data, primarily on chronic patients, have been used to define factors for the PANSS. The present study examines the PANSS factor structure in a large sample of subjects with recent-onset schizophrenia, schizophreniform disorder and schizoaffective disorder who had been exposed to very limited antipsychotic medication. Equamax factor analysis was conducted on PANSS baseline assessments from a multicenter, 11 country drug trial that enrolled 535 patients. The forced five-factor solution essentially corresponds to the factors most frequently described previously, namely negative, positive, disorganized (or cognitive), excited and anxiety/depression. In the exploratory analysis, a seven-factor solution was obtained, with depression and anxiety symptoms separating and a motor component emerging. The results of this study partially support the use of a five-factor model for the PANSS, but suggest that scales for catatonia, depressive and anxiety syndromes should be included in future studies.
Neurological soft signs and neuropsychological (NP) impairments are prevalent in schizophrenic patients. However, the relationship of these deficits is rarely studied, and it remains controversial in what way soft signs influence NP performance. The Neurological Evaluation Scale (NES) and a comprehensive neuropsychological test battery were used to assess soft signs and cognitive functions in 61 first-episode schizophrenic patients. The NP test battery included tests such as the California Verbal Learning Test, the Continuous Performance Test, the Span of Apprehension Test, the Stroop Color-Word Test, the Trail-Making Test and the Wisconsin Card Sorting Test. The NP tests were also administered to 87 healthy controls. The first-episode schizophrenic patients were split along the median of their NES total score (SS- vs. SS+). The level of NP performance and the differences in relative performance (shape of the NP profile) on NP functions between the two groups were assessed. The two groups (SS- vs. SS+) did not differ in any demographic or clinical variable. However, they differed in the level of their NP performance (profile mean) but did not show differential deficits in NP performance (profile shape). Neurologic soft signs influence NP performance and are correlated to a generalized NP deficit rather than to any specific NP functions.
Although patients with schizophrenia have increased rates of neurological soft signs, few studies have examined prospectively their trait or state characteristics in relation to psychopathology.
In a prospective study of 97 patients with first-episode schizophrenia (DSM-IV criteria) we assessed neurological soft signs and psychopathology at presentation and at 6 month follow-up for 73 cases. To establish whether soft signs were associated with variations in clinical state, neurological soft signs were measured using two validated examinations (Neurological Evaluation Scale and Condensed Neurological Examination); psychopathology was assessed using the Positive and Negative Syndrome Scale.
There was significant improvement in overall neurological function, primarily in motor-related and cortical signs, which were associated with improvement in psychopathology. Conversely, 'harder' signs were unrelated to improvement in psychopathology.
Neurological soft signs in schizophrenia are heterogenous. Motor and cortical signs evidence state-like characteristics and vary with clinical course, while 'harder' signs evidence more static, trait-like characteristics in accordance with a neurodevelopmental basis.
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.
Neurological abnormalities in subjects with schizophrenia have been regarded as diagnostically non-specific and non-localising. This study assessed the temporal stability of neurological abnormalities in subjects with first-episode schizophrenia over the course of 12 months. We also examined their relationships with psychiatric symptoms, medication effects and treatment outcome.
The sample comprised 66 largely medication-naive subjects who were treated according to a fixed protocol. We performed a factor analysis of the Neurological Evaluation Scale (NES) items, and relationships between the NES factors and various clinical and outcome measures were explored.
Five NES factors were identified, explaining 68.4% of the variance. While the NES total scores did not change significantly over time, poor performance on motor sequencing tests was related to longer duration of untreated psychosis, and showed a tendency to improve as psychiatric symptoms resolved. The most interesting finding was that high scores on the motor sequencing factor predicted the emergence of persistent dyskinesia at 24 months (ANCOVAR F(1, 20) = 19.287, p = 0.0002).
Two NES factors (motor sequencing and attention) are reasonably replicable across samples, and have potential relevance for the further exploration of the pathogenesis of schizophrenia, as well as possible clinical applications.
We examined the 2-year stability of neurological soft signs (NSS) in 29 patients after a first episode of psychosis. The numbers of NSS at inclusion and at 2 years follow-up were similar, but there was a significant increase in the numbers of NSS in the sub-group of patients whose dosage of antipsychotic medication had increased over time.
Motoric neurological soft signs (NSS) were investigated by means of the Brief Motor Scale (BMS) in 82 inpatients with DSM-III-R schizophrenic psychoses. To address potential fluctuations of psychopathological symptoms and extrapyramidal side effects, patients were examined in the subacute state, twice at an interval of 14 days on the average. NSS were significantly correlated with severity of illness, lower social functioning, and negative symptoms. Modest, but significant correlations were found between NSS and extrapyramidal side effects as assessed on the Simpson-Angus Scale. Neither the neuroleptic dose prescribed to the patient, nor scores for tardive dyskinesia and akathisia were significantly correlated with NSS. Moreover, NSS scores did not significantly differ between patients receiving clozapine and conventional neuroleptics. Patients in whom psychopathological symptoms remained stable or improved over the clinical course showed a significant reduction of NSS scores. This finding did not apply to those patients in whom psychopathological symptoms deteriorated. Our findings demonstrate that NSS in schizophrenic psychoses are relatively independent of neuroleptic side effects, but they are associated with the severity and persistence of psychopathological symptoms and with poor social functioning.
To examine the relationship between the severity of neurological soft signs at onset and at the 1-year follow-up of patients with schizophrenia, and to investigate temporal stability of neurological soft signs within 1year from the onset of the first episode schizophrenia.
The study included 92 first-episode male schizophrenic patients. Neurological soft signs were assessed on the Neurological Evaluation Scale (NES) during index hospitalization and at a 1-year follow-up. The patients were divided into remitters and non-remitters according to their psychiatric status assessed at the 1-year follow-up, using the Positive and Negative Syndrome Scale (PANSS).
A trend for a lower score for the NES item "others" in late remitters versus non-remitters at baseline was found during index hospitalization. At the 1-year follow-up, the overall severity of the neurological soft signs was statistically significantly higher in non-remitters than in remitters. Within 1year after index hospitalization, a significant reduction of neurological soft signs, with the exception of sensory integration, occurred in remitters. Within 1year after index hospitalization, the non-remitters reported a significant reduction of the overall NES score.
These findings in a population of patients with first episode schizophrenia are in accord with the findings of previous studies which found an association between neurological soft signs, treatment response and outcome. This association may characterize a subgroup of patients with a poor course of illness and outcome. Neurological soft signs might be regarded as one of the indicators of treatment outcome in patients suffering from their first episode of schizophrenia.
Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia.
We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636.
The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%.
This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.
The crucial role of neurological indicators in schizophrenia has been recognized as among the "target features" that encompass the idea that genetic and non-genetic processes lead to neurointegrative defects later manifested in neurocognitive systems. In addition, aberrant neurological indicators have also been suggested as potential endophenotypes in schizophrenia. In the current paper, we review evidence for the utility of quantifiable neurological soft signs as potential endophenotypes for schizophrenia spectrum disorders. We start by defining endophenotypes and justifying their utility. We highlight the key criteria that must be met for an endophenotype to be useful and assess the extent to which the manifestations of neurological soft signs meet these criteria. Finally, we recommend areas in which additional research should be done to further elucidate the potential use of neurological soft signs for schizophrenia research.
MATRICS Consensus Battery Manual
- K H Nuechterlein
- M F Green
Nuechterlein, K.H., Green, M.F., 2006. MATRICS Consensus Battery Manual. MATRICS Assessment Inc., Los Angeles.