Papers by Keith Nuechterlein
F1000Research, 2014
Objective To estimate the efficacy of exercise on depressive symptoms compared with non-active co... more Objective To estimate the efficacy of exercise on depressive symptoms compared with non-active control groups and to determine the moderating effects of exercise on depression and the presence of publication bias. Design Systematic review and meta-analysis with meta-regression. Data sources The Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, Embase, SPORTDiscus, PsycINFO, Scopus and Web of Science were searched without language restrictions from inception to 13 September2022 (PROSPERO registration no CRD42020210651). Eligibility criteria for selecting studies Randomised controlled trials including participants aged 18 years or older with a diagnosis of major depressive disorder or those with depressive symptoms determined by validated screening measures scoring above the threshold value, investigating the effects of an exercise intervention (aerobic and/or resistance exercise) compared with a non-exercising control group. Results Forty-one studies, comprising 2264 participants post intervention were included in the meta-analysis demonstrating large effects (standardised mean difference (SMD)=−0.946, 95% CI −1.18 to −0.71) favouring exercise interventions which corresponds to the number needed to treat (NNT)=2 (95% CI 1.68 to 2.59). Large effects were found in studies with individuals with major depressive disorder (SMD=−0.998, 95% CI −1.39 to −0.61, k=20), supervised exercise interventions (SMD=−1.026, 95% CI −1.28 to −0.77, k=40) and moderate effects when analyses were restricted to low risk of bias studies (SMD=−0.666, 95% CI −0.99 to −0.34, k=12, NNT=2.8 (95% CI 1.94 to 5.22)). Conclusion Exercise is efficacious in treating depression and depressive symptoms and should be offered as an evidence-based treatment option focusing on supervised and group exercise with moderate intensity and aerobic exercise regimes. The small sample sizes of many trials and high heterogeneity in methods should be considered when interpreting the results.
Schizophrenia bulletin, 2016
Cognitive training (CT) and aerobic exercise have separately shown promise for improving cognitiv... more Cognitive training (CT) and aerobic exercise have separately shown promise for improving cognitive deficits in schizophrenia. Aerobic exercise releases brain-derived neurotrophic factor, which promotes synaptic plasticity and neurogenesis. Thus, aerobic exercise provides a neurotrophic platform for neuroplasticity-based CT. The combination of aerobic exercise and CT may yield more robust effects than CT alone, particularly in the initial course of schizophrenia. In a pilot study, 7 patients with a recent onset of schizophrenia were assigned to Cognitive Training & Exercise (CT&E) and 9 to CT alone for a 10-week period. Posit Science programs were used for CT. Neurocognitive training focused on tuning neural circuits related to perceptual processing and verbal learning and memory. Social cognitive training used the same learning principles with social and affective stimuli. Both groups participated in these training sessions 2d/wk, 2h/d. The CT&E group also participated in an aerobic...
Schizophrenia Research, 2012
Reduced suppression of the auditory P50 event-related potential has long been associated with sch... more Reduced suppression of the auditory P50 event-related potential has long been associated with schizophrenia, but the mechanisms associated with the generation and suppression of the P50 are not well understood. Recent investigations have used spectral decomposition of the electroencephalograph (EEG) signal to gain additional insight into the ongoing electrophysiological activity that may be reflected by the P50 suppression deficit. The present investigation extended this line of study by examining how both a traditional measure of sensory gating and the ongoing EEG from which it is extracted might be modified by the presence of concurrent visual stimulation-perhaps better characterizing gating deficits as they occur in a realworld, complex sensory environment. The EEG was obtained from 18 patients with schizophrenia and 17 healthy control subjects during the P50 suppression paradigm and while identical auditory paired-stimuli were presented concurrently with affectively neutral pictures. Consistent with prior research, schizophrenia patients differed from healthy subjects in gating of power in the theta range; theta activity also was modulated by visual stimulation. In addition, schizophrenia patients showed intact gating but overall increased power in the gamma range, consistent with a model of NMDA receptor dysfunction in the disorder. These results are in line with a model of schizophrenia in which impairments in neural synchrony are related to sensory demands and the processing of multimodal information.
Journal of Abnormal Psychology, 2014
Individuals with schizophrenia face significant challenges in daily functioning, and while social... more Individuals with schizophrenia face significant challenges in daily functioning, and while social cognition predicts how well patients respond to these challenges, associated physiological mechanisms remain unspecified. The present study draws from polyvagal theory and tested the hypothesis that respiratory sinus arrhythmia (RSA), an established indicator of the capacity to selfregulate and adapt to environmental demands, combines with social cognition to predict functional outcome. Using data from 41 schizophrenia patients and 36 healthy comparison subjects, we replicated group differences in RSA and social cognition and also demonstrated that RSA and social cognition interact to predict how effectively patients manage work and independent living activities. Specifically, RSA did not enhance functional outcomes when social cognition was already strong, but higher levels of RSA enabled effective role functioning when social-cognitive performance was impaired. Jointly, RSA and social cognition accounted for 40% of the variance in outcome success, compared with 21% when evaluating social cognition alone. As polyvagal theory suggests, physiological flexibility and self-regulatory capacity may compensate for poorer social-cognitive skills among schizophrenia patients.
Schizophrenia Research, 2010
Do physiological changes occur shortly prior to psychotic relapse in schizophrenia outpatients? W... more Do physiological changes occur shortly prior to psychotic relapse in schizophrenia outpatients? We addressed this question in a group of schizophrenia outpatients by measuring changes in symptoms and changes in activation of the sympathetic nervous system, as indexed by changes in skin conductance level (SCL), on a biweekly basis for between one and two years. All six outpatients exhibited heightened SCL within two weeks prior to relapse or exacerbation, compared to SCL proceeding continued remission. These results shed light on the psychotic relapse process and are consistent with neural diathesis-stress models of schizophrenia.
Schizophrenia Research, 2007
It is unresolved whether avoidant personality disorder (APD) is an independent schizophrenia (Sz)... more It is unresolved whether avoidant personality disorder (APD) is an independent schizophrenia (Sz)-spectrum personality disorder (PD). Some studies find APD and social anxiety symptoms (Sxs) to be separable dimensions of psychopathology in relatives (Rels) of schizophrenics while other studies find avoidant Sxs to be correlated with schizotypal and paranoid Sxs. Rates of APD among first-degree Rels of Sz probands, attention-deficit/hyperactivity disorder (ADHD) probands, and community control (CC) probands were examined. Further analyses examined rates when controlling for the presence of schizotypal (SPD) and paranoid (PPD) personality disorders, differences in APD Sxs between relative groups, and whether APD in Rels of Szs reflects a near miss for another Sz-spectrum PD. Three hundred sixty-two first-degree Rels of Sz probands, 201 relatives of ADHD probands, and 245 Rels of CC probands were interviewed for the presence of DSM-III-R Axis I and II disorders. Diagnoses, integrating family history, interview information, and medical records, were determined. APD occurred more frequently in Rels of Sz probands compared to CC probands (p b 0.001) and also when controlling for SPD and PPD (p b 0.005). Two Sxs of APD were most characteristic of the Rels of Sz probands: "avoids social or occupational activities…" and "exaggerates the potential difficulties…" 65% of the Rels of Sz probands who had diagnoses of APD were more
Schizophrenia Research, 2008
The Psychosis Proneness Scales developed by the Chapmans and colleagues (Chapman et al., 1995) ar... more The Psychosis Proneness Scales developed by the Chapmans and colleagues (Chapman et al., 1995) are widely used to identify nonpatient individuals who are hypothesized to possess heightened vulnerability to schizophrenia and related psychopathology. Yet surprisingly little is known about whether schizophrenia patients themselves show abnormalities on these scales across different clinical states, as would be expected for vulnerability indicators. Scores on four of the Psychosis Proneness Scales were evaluated at three assessment points over a 15-month period in healthy controls (n = 54) and in recent-onset schizophrenia patients (n = 72) who experienced symptom fluctuations across assessments. Patients showed steady elevations on the Physical Anhedonia Scale across time and clinical state, consistent with a stable vulnerability indicator. Patients had higher scores on the Perceptual Aberration and Magical Ideation Scales than controls throughout the followup period but scores also changed across clinical states, consistent with a mediating vulnerability indicator. Patients had higher scores on the Impulsive Non-Conformity Scale than controls only during a psychotic state, reflecting an episode indicator. The longitudinal characteristics of these scales in people who are actually diagnosed with schizophrenia provide key evidence for the validity of three commonly used psychometric indicators of vulnerability to psychosis.
Schizophrenia Research, 2010
Objective-Cortical thickness reductions in prefrontal and temporal cortices have been repeatedly ... more Objective-Cortical thickness reductions in prefrontal and temporal cortices have been repeatedly observed in patients with schizophrenia. However, it remains unclear whether regional variations in cortical thickness may be attributable to disease-related or genetic-liability factors. Method-The structural magnetic resonance imaging data of 48 adult-onset schizophrenia patients, 66 first-degree non-psychotic relatives of schizophrenia patients, 27 community comparison (CC) probands and 77 CC relatives were examined using cortical pattern matching methods to map and compare highly localized changes in cortical gray matter thickness between groups defined by biological risk for schizophrenia. Results-Schizophrenia patients showed marked cortical thinning primarily in frontal and temporal cortices when compared to unrelated CC probands. Results were similar, though less pronounced when patients were compared with their non-psychotic relatives. Cortical thickness reductions observed in unaffected relatives compared to age-similar CC relatives suggestive of schizophreniarelated genetic liability were marginal, surviving correction for the left parahippocampal gyrus and inferior occipital cortex only. Conclusions-Observations of pronounced fronto/temporal cortical thinning in schizophrenia patients replicate prior findings. The lack of marked cortical thickness alterations in non-psychotic relatives of patients, suggests that disease processes are primary contributors toward cortical thickness reductions in the disorder. However, genetic factors may have a larger influence on abnormalities in the medial temporal lobe.
Schizophrenia Research, 2011
Context-Imaging and post-mortem studies provide converging evidence that subjects with schizophre... more Context-Imaging and post-mortem studies provide converging evidence that subjects with schizophrenia (SZ) have a dysregulated trajectory of frontal lobe myelination. Prior MRI studies suggested that early in treatment of SZ, antipsychotic medications initially increase frontal lobe white matter (WM) volume, which subsequently declines prematurely in chronic stages of the
Schizophrenia Research, 2010
Whether avoidant personality disorder symptoms are related to neurocognitive impairments that agg... more Whether avoidant personality disorder symptoms are related to neurocognitive impairments that aggregate in relatives of schizophrenics is unknown. We report the relationship between avoidant personality disorder symptoms and neurocognitive performance in the first-degree relatives of probands with schizophrenia. 367 first-degree relatives of probands with schizophrenia and 245 relatives of community controls were interviewed for the presence of avoidant personality symptoms and symptoms of paranoid and schizotypal personality disorders and administered neurocognitive measures. Relationships between neurocognitive measures and avoidant symptoms were analyzed using linear mixed models. Avoidant dimensional scores predicted performance on the span of apprehension (SPAN), 3-7 Continuous Performance Test (3-7 CPT), and Trail Making Test (TMT-B) in schizophrenia relatives. These relationships remained significant on the SPAN even after adjustment for paranoid or schizotypal dimensional scores and on the TMT-B after adjustment for paranoid dimensional scores. Moreover, in a second set of analyses comparing schizophrenia relatives to controls there were significant or trending differences in the degree of the relationship between avoidant symptoms and each of these neurocognitive measures even after adjustments for paranoid and schizotypal dimensional scores. The substantial correlation between avoidant and schizotypal symptoms suggests that these personality disorders are not independent. Avoidant and in some cases schizotypal dimensional scores are significant predictors of variability in these neurocognitive measures. In all analyses, higher levels of avoidant symptoms were associated with worse performance on the neurocognitive measures in relatives of schizophrenia probands. These results support the hypothesis that avoidant personality disorder may be a schizophrenia spectrum phenotype.
Schizophrenia Research, 2008
Visual masking deficit in schizophrenia has been suggested to be a potential vulnerability marker... more Visual masking deficit in schizophrenia has been suggested to be a potential vulnerability marker for schizophrenia. An important characteristic of a vulnerability marker is stability over time, but relatively little is known about the longitudinal course of masking performance of schizophrenia patients. In this study, we examined the stability of visual masking performance in recent-onset schizophrenia patients over an 18-month period. We administered both forward and backward masking trials with multiple stimulus onset asynchronies for four masking conditions at three time points (baseline, 6-month, and 18-month). Recent-onset schizophrenia patients showed stable masking performance for both forward and backward conditions over a period of 18 months. Furthermore, the stable performance was observed across all four masking conditions. The findings of this study provide further support for the view that visual masking deficits reflect a possible vulnerability marker for schizophrenia.
Schizophrenia Research, 2009
Context-Imaging and post-mortem studies provide converging evidence that patients with schizophre... more Context-Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination. The hypothesis that typical and atypical medications may differentially impact brain myelination in adults with schizophrenia was previously assessed with inversion recovery (IR) images. Increased white matter (WM) volume suggestive of increased myelination was detected in the patient group treated with an atypical antipsychotic compared to a typical one. Objective-In a follow-up reanalysis of MRI images from the original study, we used a novel method to assess whether the difference in WM volumes could be caused by a differential effect of medications on the intracortical myelination process. Design, setting, and participants-Two different male cohorts of healthy controls ranging in age from 18-35 years were compared to cohorts of subjects with schizophrenia who were treated with either oral risperidone (Ris) or fluphenazine decanoate (Fd). Main outcome measure-A novel MRI method that combines the distinct tissue contrasts provided by IR and proton density (PD) images was used to estimate intracortical myelin (ICM) volume.
Schizophrenia Research, 2005
While research strongly supports the notion that stressful life events may trigger the exacerbati... more While research strongly supports the notion that stressful life events may trigger the exacerbation of psychotic symptoms in schizophrenia, the mechanisms through which affected individuals respond to life events during the early course of this disorder have received limited attention. This 12-month longitudinal study compared the frequencies, qualitative characteristics, and subjective appraisals of life events in recent-onset schizophrenia patients (n=78) and a nonpatient comparison sample (n=63). Negative and positive life events were assessed using a semi-structured interview every 4 weeks among patients and approximately every 4 months among controls, and participants appraised each event they experienced in terms of emotional impact, controllability, and effectiveness in handling the event. Schizophrenia patients reported significantly lower rates of life events than their nonpsychiatric counterparts across nearly every type of negative and positive event examined. In the context of generally lower event frequencies, patients appraised the negative and positive events they did experience as less controllable and more poorly handled than controls, and also appraised positive events as less desirable. Results are discussed in terms of their implications for understanding susceptibility to stress during the early course of schizophrenia.
Schizophrenia Bulletin, 2011
While the role of neurocognitive impairment in predicting functional outcome in chronic schizophr... more While the role of neurocognitive impairment in predicting functional outcome in chronic schizophrenia is now widely accepted, the results that have examined this relationship in the early phase of psychosis are surprisingly rather mixed. The predictive role of cognitive impairment early in the illness is of particular interest because interventions during this initial period may help to prevent the development of chronic disability. In a University of California, Los Angeles (UCLA) longitudinal study, we assessed schizophrenia patients with a recent first episode of psychosis using a neurocognitive battery at an initial clinically stabilized outpatient point and then followed them during continuous treatment over the next 9 months. Three orthogonal cognitive factors were derived through principal components analysis: working memory, attention and early perceptual processing, and verbal memory and processing speed. All patients were provided a combination of maintenance antipsychotic medication, case management, group skills training, and family education in a UCLA research clinic. A modified version of the Social Adjustment Scale was used to assess work outcome. Multiple regression analyses indicate that the combination of the 3 neurocognitive factors predicts 52% of the variance in return to work or school by 9 months after outpatient clinical stabilization. These data strongly support the critical role of neurocognitive factors in recovery of work functioning after an onset of schizophrenia. Cognitive remediation and other interventions targeting these early cognitive deficits are of major importance to attempts to prevent chronic disability.
Schizophrenia Bulletin, 2011
This study evaluated the longitudinal stability and functional correlates of social cognition dur... more This study evaluated the longitudinal stability and functional correlates of social cognition during the early course of schizophrenia. Fifty-five first-episode schizophrenia patients completed baseline and 12-month follow-up assessments of 3 key domains of social cognition (emotional processing, theory of mind, and social/ relationship perception), as well as clinical ratings of real-world functioning and symptoms. Scores on all 3 social cognitive tests demonstrated good longitudinal stability with test-retest correlations exceeding .70. Higher baseline and 12-month social cognition scores were both robustly associated with significantly better work functioning, independent living, and social functioning at the 12-month follow-up assessment. Furthermore, crosslagged panel analyses were consistent with a causal model in which baseline social cognition drove later functional outcome in the domain of work, above and beyond the contribution of symptoms. Social cognitive impairments are relatively stable, functionally relevant features of early schizophrenia. These results extend findings from a companion study, which showed stable impairments across patients in prodromal, first-episode, and chronic phases of illness on the same measures. Social cognitive impairments may serve as useful vulnerability indicators and early clinical intervention targets.
Schizophrenia Bulletin, 2011
Social cognitive impairments are consistently reported in schizophrenia and are associated with f... more Social cognitive impairments are consistently reported in schizophrenia and are associated with functional outcome. We currently know very little about whether these impairments are stable over the course of illness. In the current study, 3 different aspects of social cognition were assessed (emotion processing, Theory of Mind [ToM], and social relationship perception) at 3 distinct developmental phases of illness: prodromal, first episode, and chronic. In this cross-sectional study, participants included 50 individuals with the prodromal risk syndrome for psychosis and 34 demographically comparable controls, 81 first-episode schizophrenia patients and 46 demographically comparable controls, and 53 chronic schizophrenia patients and 47 demographically comparable controls. Outcome measures included total and subtest scores on 3 specialized measures of social cognition: (1) emotion processing assessed with the Mayer-Salovey-Caruso Emotional Intelligence Test, (2) ToM assessed with The Awareness of Social Inference Test, and (3) social relationship perception assessed the Relationships Across Domains Test. Social cognitive performance was impaired across all domains of social cognition and in all clinical samples. Group differences in performance were comparable across phase of illness, with no evidence of progression or improvement. Age had no significant effect on performance for either the clinical or the comparison groups. The findings suggest that social cognition in these 3 domains fits a stable pattern that has outcome and treatment implications. An accompanying article prospectively examines the longitudinal stability of social cognition and prediction of functional outcome in the first-episode sample.
Schizophrenia Bulletin, 2002
Studies have reported that certain measures of intrafamilial transactions are associated with an ... more Studies have reported that certain measures of intrafamilial transactions are associated with an increased risk both for the initial onset of schizophrenia and for its recurrence following the initial episode of disorder. Two of the most studied of these are communication deviance (CD), a measure of subclinical thought disorder expressed in speech, and expressed emotion (EE), defined as notable attitudes of criticism and/or emotional overinvolvement manifested in a semistructured interview. A previous study (Goldstein et al. 1992) examined whether these two measures were associated with the presence of a diagnosable psychiatric disorder in the biological parents of recent-onset schizophrenia patients. In general, they were not. The present study went one step further. It examined whether these same measures were correlated with family history of schizophrenia or affective disorder in the biological parents and siblings of these same parents. High EE was not associated with a greater family history of schizophrenia spectrum disorders among the parent's parents and siblings but was unexpectedly found to be inversely associated with familial affective disorders. In contrast, CD was associated with a family history of schizophrenia spectrum disorders among the parent's parents and siblings. The findings are consistent with the possibility that CD may be an indicator of a genetic vulnerability factor for schizophrenia.
Psychophysiology, 2005
The ability of electrodermal variables to predict negative symptoms and functional outcome over a... more The ability of electrodermal variables to predict negative symptoms and functional outcome over a 1-year period in schizophrenia was investigated in 78 young, recent-onset outpatients. Patients were stabilized on standardized medication and largely free of psychotic symptoms. Higher levels of both tonic (skin conductance level, nonspecific skin conductance response rate) and phasic (number of skin conductance orienting responses) activity were associated with more negative symptoms and with a combination of poorer social and occupational outcome at 1-year follow-up. This pattern was seen in both male and female patients, and in older and younger patients. Results are interpreted as suggesting that high levels of arousal and overreactivity to the environment may interfere with efficient cognitive processing in schizophrenia, contributing to poor outcome, and that negative symptoms might partially serve as a means of coping with overarousal.
Psychophysiology, 2002
Test-retest stability of electrodermal~EDA! variables indexing both general autonomic arousal~e.g... more Test-retest stability of electrodermal~EDA! variables indexing both general autonomic arousal~e.g., skin conductance level, number of nonspecific skin conductance responses! and attention to external stimuli~e.g., number of skin conductance orienting responses, electrodermal responder0nonresponder status! was assessed in 71 young, recent-onset schizophrenia patients and 36 demographically matched normal subjects. Significant stability over a 1-year period was found for both patients and normal subjects for most EDA variables and for responder0nonresponder status, with test-retest correlations generally being higher for normal subjects. The lower reliability for patients was not attributable to symptomatic fluctuations during the follow-up period and may reflect poorer arousal regulation among the patients. Among measures of responding to nontask stimuli, a simple count of the number of orienting responses occurring was more stable than was a traditional trials-to-habituation measure.
Psychophysiology, 2010
Although malfunctioning of inhibitory processes is proposed as a pathophysiological mechanism in ... more Although malfunctioning of inhibitory processes is proposed as a pathophysiological mechanism in schizophrenia and has been studied extensively with the P50 gating paradigm, the brain regions involved in generating and suppressing the P50 remain unclear. The current investigation used EEG source analysis and the standard S1-S2 paradigm to clarify the neural structures associated with P50 gating in16 schizophrenia patients and 14 healthy subjects. Based on prior research, the superior temporal gyrus, hippocampus, dorsolateral prefrontal cortex, thalamus, and their dipole moments were evaluated. In modeling the P50, a neural network involving all four brain regions provided the best goodness-of-fit across both groups. In healthy subjects, the P50 ratio score correlated positively with the hippocampal dipole moment ratio whereas a significant association with the DLPFC dipole moment ratio was observed in schizophrenia patients. In each instance, the neural structure was found to account for unique variance in explaining the P50 ratio, along with some suggestion of DLPFC involvement in healthy subjects.
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Papers by Keith Nuechterlein