Interactive effects of polygenic risk and cognitive subtype on brain morphology in schizophrenia spectrum and bipolar disorders.

Grey matter volume (GMV) may be associated with polygenic risk for schizophrenia (PRS-SZ) and severe cognitive deficits in people with schizophrenia, schizoaffective disorder (collectively SSD), and bipolar disorder (BD). This study examined the interactive effects of PRS-SZ and cognitive subtypes of SSD and BD in relation to GMV. Two-step cluster analysis was performed on 146 clinical cases (69 SSD and 77 BD) assessed on eight cognitive domains (verbal and visual memory, executive function, processing speed, visual processing, language ability, working memory, and planning). Among them, 55 BD, 51 SSD, and 58 healthy controls (HC), contributed to focal analyses of the relationships between cognitive subtypes, PRS-SZ and their interaction on GMV. Two distinct cognitive subtypes were evident among the combined sample of cases: a 'cognitive deficit' group (CD; N = 31, 20SSD/11BD) showed severe impairment across all cognitive indices, and a 'cognitively spared' (CS; N = 75; 31SSD/44BD) group showed intermediate cognitive performance that was significantly worse than the HC group but better than the CD subgroup. A cognitive subgroup-by-PRS-SZ interaction was significantly associated with GMV in the left precentral gyrus. Moderation analyses revealed a significant negative relationship between PRS-SZ and GMV in the CD group only. At low and average (but not high) PRS-SZ, larger precentral GMV was evident in the CD group compared to both CS and HC groups, and in the CS group compared to HCs. This study provides evidence for a relationship between regional GMV changes and PRS-SZ in psychosis spectrum cases with cognitive deficits, but not in cases cognitively spared.

Treatments for objective and subjective cognitive functioning in young people with depression: Systematic review of current evidence.

AIM: Cognitive deficits are recognized features of depressive disorders in youth aged 12-25. These deficits are distressing, predict functional impairment and limit the effectiveness of psychological therapies. Cognitive enhancement using behavioural, biochemical or physical treatments may be useful in young people with depression, but studies have not been synthesized. The aim was to systematically review the evidence for treatments for objective and subjective cognitive functioning, and their acceptability and functional outcomes in people aged 12-25 with depression. METHOD: Three electronic databases were searched for articles using pre-specified criteria. Pharmacological treatments were not eligible. Risk of bias was rated using the Cochrane Collaboration's revised risk-of-bias tool. Dual full-text article screening, data extraction and quality ratings were completed. RESULTS: Twelve studies were included for review (median participant age: 20.39 years), five of which were randomized-controlled trials (RCTs). Sample sizes were generally small (median = 23; range: 9-46). Eight studies investigated behavioural treatments including aerobic exercise, cognitive training and education or strategy-based methods. Four studies examined repetitive transcranial magnetic brain stimulation (rTMS). Most behavioural treatments revealed preliminary evidence of improved cognitive function in youth depression. Consent rates were greatest for exercise- and education-based approaches, which may indicate higher acceptability levels. Findings from rTMS trials were mixed, with only half showing cognitive improvement. Functional outcomes were reported by three behavioural treatment trials and one rTMS trial, with functional improvement reported only in the former. Some concern of risk of bias was found in each RCT. CONCLUSION: Behavioural treatments, such as exercise, cognitive training and education/strategy-focused techniques, show encouraging results and appear to be acceptable methods of addressing cognitive deficits in youth depression based on participation rates. Brain stimulation and biochemical treatments (e.g., nutrient-based treatment) require further investigation.

Structural and functional neural correlates of schizotypy: A systematic review.

Schizotypy refers to a multidimensional construct that spans a range of cognitive, behavioral, and personality features, representing liability to psychosis on a continuum between health and illness. Schizotypy has been associated with functional and structural brain alterations as potential intermediate phenotypes on the developmental path to psychosis. We scanned the literature between February 2019 and August 1, 2020 using PubMed, Medline, APA PsycINFO, and ProQuest. We identified eligible articles conducted on participants assessed with psychometric schizotypy across the health-illness spectrum and reporting a direct statistic between schizotypy and a structural, task-related, or functional magnetic resonance imaging brain measure. Articles not peer-reviewed and not written in English were excluded. We systematically reviewed 84 studies that determined the changes in gray matter, brain activation, and connectivity associated with schizotypy in both healthy and clinical cohorts. Morphological and functional changes in the default and the frontoparietal networks, specifically frontal and temporal cortices, were most frequently associated with schizotypy. Yet, we were unable to identify consistent patterns of morphological or functional brain aberration associated with schizotypy, due to methodological differences between studies in the conceptualization and measurement of schizotypy. Efforts toward greater methodological concordance in future neuroimaging research of schizotypy are needed to improve the identification of brain-based endophenotypes for schizophrenia. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

EEG correlates of attentional control in anxiety disorders: A systematic review of error-related negativity and correct-response negativity findings.

BACKGROUND: Anxiety disorders are highly prevalent and cause substantial personal, social and economic burden. Altered attentional control has been shown to be present across anxiety disorders and is associated with specific changes in brain activity which can be recorded by electroencephalogram (EEG). These include changes in the EEG markers of error-related negativity (ERN) and correct-response negativity (CRN), both believed to reflect response monitoring and attentional control pathophysiology in anxiety. The aim of this review was to systematically assess the research on ERN and CRN in attentional control in individuals with clinical anxiety and healthy controls, across emotional and non-emotional attentional control. METHODS: A comprehensive literature search was conducted for studies published prior to October 22nd, 2020. Details of the protocol for this systematic review were registered on PROSPERO (CRD42019144885). RESULTS: 66 studies had their data extracted. All 66 studies measured ERN, with 85% finding significantly increased ERN amplitudes associated with clinical anxiety. Only 44 of the extracted studies analysed CRN and only ~20% of these found significant changes in CRN amplitude associated with individuals with clinical anxiety. LIMITATIONS: There were several anxiety disorders that had either limited literature (i.e. specific phobia, separation anxiety disorder or agoraphobia) or nil literature (i.e. selective mutism) available. No extracted studies included samples of older adults (i.e. aged 60+ years), and only six extracted studies included measures of emotional attentional control. CONCLUSIONS: Findings indicate the promising utility of ERN of attentional control as a robust, transdiagnostic trait marker of clinical anxiety.

The Heart-Brain Connection in Depression: Can it inform a personalised approach for repetitive transcranial magnetic stimulation (rTMS) treatment?

There is growing enthusiasm into the frontal-vagal network theory of major depressive disorder (MDD) and the potential role of a frontal-vagal network in the therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) treatment for MDD. A review of the autonomic nervous system (ANS) in MDD and its role in antidepressant treatment for MDD is timely. The literature supports the well-established notion of ANS dysfunction in MDD and the benign effect of selective serotonin reuptake inhibitors, but not tricyclic antidepressants, on perturbed ANS function in MDD. Notwithstanding, there is some evidence that ANS measures have the capacity to inform response to antidepressant medication treatment. While there is a paucity of studies on the effects of rTMS on the ANS, critically, there is preliminary support that rTMS may alleviate ANS dysfunction in MDD and that ANS measures are associated with rTMS treatment response. These observations are consistent with the frontal-vagal theory of depression and the emerging literature on the use of ANS measures for personalising and optimising rTMS treatment of MDD.

Investigating high- and low-frequency neuro-cardiac-guided TMS for probing the frontal vagal pathway.

BACKGROUND: Investigating approaches for determining a functionally meaningful dorsolateral prefrontal cortex (DLPFC) stimulation site is imperative for optimising repetitive transcranial magnetic stimulation (rTMS) response rates for treatment-resistant depression. One proposed approach is neuro-cardiac-guided rTMS (NCG-TMS) in which high frequency rTMS is applied to the DLPFC to determine the site of greatest heart rate deceleration. This site is thought to index a frontal-vagal autonomic pathway that intersects a key pathway believed to underlie rTMS response. OBJECTIVE: We aimed to independently replicate previous findings of high-frequency NCG-TMS and extend it to evaluate the use of low-frequency rTMS for NCG-TMS. METHODS: Twenty healthy participants (13 female; aged 38.6 ± 13.9) underwent NCG-TMS on frontal, fronto-central (active) and central (control) sites. For high-frequency NCG-TMS, three 5 s trains of 10 Hz were provided at each left hemisphere site. For low-frequency NCG-TMS, 60 s trains of 1 Hz were applied to left and right hemispheres and heart rate and heart rate variability outcome measures were analysed. RESULTS: For high-frequency NCG-TMS, heart rate deceleration was observed at the left frontal compared with the central site. For low-frequency NCG-TMS, accelerated heart rate was found at the right frontal compared with central sites. No other site differences were observed. CONCLUSION: Opposite patterns of heart rate activity were found for high- and low-frequency NCG-TMS. The high-frequency NCG-TMS data replicate previous findings and support further investigations on the clinical utility of NCG-TMS for optimising rTMS site localisation. Further work assessing the value of low-frequency NCG-TMS for rTMS site localisation is warranted.

Low-frequency rTMS is better tolerated than high-frequency rTMS in healthy people: Empirical evidence from a single session study.

Low-frequency and high-frequency repetitive transcranial magnetic stimulation (rTMS) are similarly efficacious for treatment-resistant depression. Low-frequency is posited to be better tolerated than high-frequency rTMS, however, this is not supported by empirical evidence to date. This study aimed to quantify and compare the tolerability of low-versus high-frequency rTMS. Twenty healthy participants (mean age 38.6 ±â€¯13.9 years) underwent low- and high-frequency rTMS administered on left frontal, fronto-central and central sites at 100% resting motor threshold. For the low-frequency protocol, 60 s of 1 Hz stimulation was applied at each site and for the high-frequency protocol, 3 × 5 s trains of 10 Hz stimulation with a 30 s inter-train interval were applied at each site. Tolerance for each stimulation type was assessed immediately after stimulation through participant ratings of overall intensity of scalp sensations, pain, muscle twitching, discomfort and any other sensation. Low-frequency rTMS was significantly less intense than high-frequency rTMS in overall intensity, pain, muscle twitching (all p < .01) and discomfort (p < .001). Limitations of this study include the healthy participant sample and administration of a single session of rTMS. While further work is needed in clinical samples using typical rTMS treatment protocols, these data provide the first evidence that low-frequency is better tolerated than high-frequency. These findings may inform clinical practice of rTMS treatment for depression (and other illnesses) by supporting the application of low-frequency protocols.

Elucidating the glutamatergic processes underlying mismatch negativity deficits in early stage bipolar disorder and schizophrenia: A combined 1H-MRS and EEG study.

Impairments in mismatch negativity (MMN) in schizophrenia are well-established; these findings have been extended to show impairments at early illness stages and in bipolar disorder. A substantial literature supports MMN as an index of NMDA receptor output, however, few studies have conducted in vivo assessments to elucidate the neurochemical underpinnings of MMN. Sixty young (16-33 years) participants with bipolar disorder (n = 47) or schizophrenia (n = 13) underwent 1H-MRS and MMN assessment. Glutamate over creatine (Glu/Cr) levels in the anterior cingulate cortex (ACC) and hippocampus were determined and MMN was measured frontally and temporally. Correlational analyses assessed the relationship between MMN amplitudes and Glu/Cr. Any significant relationships were assessed for specificity with a follow up correlation analysis of MMN and n-acetyleaspartate (NAA/Cr). No associations between frontal or temporal MMN and ACC or hippocampal Glu/Cr were noted in the bipolar group. In the schizophrenia group, frontal and right temporal MMN amplitudes corresponded with increased ACC Glu/Cr at the trend-level. Right temporal MMN was similarly significantly associated with NAA/Cr. MMN was not associated with hippocampal Glu/Cr. This work provides in vivo evidence that glutamatergic processes may underlie MMN generation in early stage schizophrenia but not in early stage bipolar disorder suggesting differences in the MMN mechanism in these groups. The negative association between ACC Glu/Cr and MMN is consistent with findings of reduced MMN and increased in vivo glutamatergic neurometabolite levels in early stage schizophrenia. Furthermore, these results indicate that examining in vivo NAA/Cr may have provide additional insights into the MMN mechanism in schizophrenia.

Sleep-wake, cognitive and clinical correlates of treatment outcome with repetitive transcranial magnetic stimulation for young adults with depression.

The utility of key phenotypes of depression in predicting response to repetitive transcranial magnetic stimulation (rTMS), namely sleep-wake behaviour, cognition and illness chronicity, has been understudied and not been extended to young samples. This study aimed to determine whether sleep-wake disturbance, cognition or depression chronicity are associated with rTMS outcome in young depressed adults. Sixteen depressed young adults diagnosed with mood disorders (aged 18-29 years) completed this open-label study. Neuronavigationally targeted high-frequency rTMS was administered at 110% of motor threshold on the left dorsolateral prefrontal cortex for 20 sessions over 4 weeks. Clinical, sleep-wake and cognitive assessments were undertaken pre- and post-treatment. Repeated-measures and correlational analyses determined pre- and post-treatment changes and predictors of treatment outcome. rTMS significantly reduced depression and anxiety. Better cognitive flexibility, verbal learning, later age of onset and greater number of depressive episodes were associated with better treatment outcome. There were no other significant/trend-level associations. rTMS had no effect on sleep-wake or cognitive measures. We provide the first evidence for the utility of cognitive flexibility and verbal learning in predicting rTMS outcome in depressed young adults. This research provides preliminary support for rTMS as an early intervention for depression and supports the need for sham-controlled trials.

Clinical, neurocognitive and demographic factors associated with functional impairment in the Australian Brain and Mind Youth Cohort Study (2008-2016).

OBJECTIVES: We sought to determine the unique and shared contributions of clinical, neurocognitive and demographic factors to functional impairment in a large, transdiagnostic, clinical cohort of adolescents and young adults. DESIGN: Cross-sectional baseline data from a prospective, cohort study. SETTING: Help-seeking youth referred from outpatient services were recruited to the Brain and Mind Youth Cohort (2008-2016) in Sydney, Australia. PARTICIPANTS: In total, 1003 outpatients were recruited, aged between 12 and 36 years (mean= 20.4 years, 54% female), with baseline diagnoses of affective, psychotic, developmental or behavioural disorders. INTERVENTIONS: Treatment as usual. PRIMARY OUTCOME MEASURES: Social and occupational functioning was used to index level of functional impairment. Structural equation modelling was used to examine associations between neurocognition, core clinical symptoms and alcohol and substance use, and clinician-rated and researcher-rated functional impairment. Moderator analyses were conducted to determine the potential influence of demographic and clinical factors (eg, medication exposure). RESULTS: Independent of diagnosis, we found that neurocognitive impairments, and depressive, anxiety and negative symptoms, were significantly associated with functioning. The association of neurocognition with social and occupational functioning remained significant even when constraining for age (15-25-year-olds only) or diagnosis (affective disorders only) in the final model. CONCLUSIONS: This study demonstrated that, in a clinically representative sample of youth, the key determinants of functioning may not be disorder specific. Further, evidence of neurocognitive dysfunction suggests that interventions that target cognition and functioning should not necessarily be reserved just for older adults with established illness.

An update on adjunctive treatment options for bipolar disorder.

OBJECTIVES: Bipolar disorder is a complex illness often requiring combinations of therapies to successfully treat symptoms. In recent years, there have been significant advancements in a number of therapies for bipolar disorder. It is therefore timely to provide an overview of current adjunctive therapeutic options to help treating clinicians to inform their patients and work towards optimal outcomes. METHODS: Publications were identified from PubMed searches on bipolar disorder and pharmacotherapy, nutraceuticals, hormone therapy, psychoeducation, interpersonal and social rhythm therapy, cognitive remediation, mindfulness, e-Health and brain stimulation techniques. Relevant articles in these areas were selected for further review. This paper provides a narrative review of adjunctive treatment options and is not a systematic review of the literature. RESULTS: A number of pharmacotherapeutic, psychological and neuromodulation treatment options are available. These have varying efficacy but all have shown benefit to people with bipolar disorder. Due to the complex nature of treating the disorder, combination treatments are often required. Adjunctive treatments to traditional pharmacological and psychological therapies are proving useful in closing the gap between initial symptom remission and full functional recovery. CONCLUSIONS: Given that response to monotherapy is often inadequate, combination regimens for bipolar disorder are typical. Correspondingly, psychiatric research is working towards a better understanding of the disorder's underlying biology. Therefore, treatment options are changing and adjunctive therapies are being increasingly recognized as providing significant tools to improve patient outcomes. Towards this end, this paper provides an overview of novel treatments that may improve clinical outcomes for people with bipolar disorder.

Mismatch negativity in bipolar disorder: A neurophysiological biomarker of intermediate effect?

The event-related potential, mismatch negativity (MMN), has been touted as a robust and specific neurophysiological biomarker of schizophrenia. Earlier studies often included bipolar disorder (BD) as a clinical comparator and reported that MMN was significantly impaired only in schizophrenia. However, with the increasing number of MMN studies of BD (with larger sample sizes), the literature is now providing somewhat consistent evidence of this biomarker also being perturbed in BD, albeit to a lesser degree than that observed in schizophrenia. Indeed, two meta-analyses have now shown that the effect sizes in BD samples suggest a moderate impairment in MMN, compared to the large effect sizes shown in schizophrenia. Pharmacologically, MMN is an extremely useful non-invasive probe of glutamatergic (more specifically, N-methyl-d-aspartate [NMDA] receptor) disturbances and this system has been implicated in the pathophysiology of both schizophrenia and BD. Therefore, it may be best to conceptualize/utilize MMN as an index of a psychopathology that is shared across psychotic and related disorders, rather than being a diagnosis-specific biomarker. More research is needed, particularly longitudinal designs including studies that assess MMN over an individual's life course and then examine NMDA receptor expression/binding post-mortem. At this point and despite a disproportionate amount of research, the current evidence suggests that with respect to BD, MMN is a neurophysiological biomarker of intermediate effect. With replication and validation of this effect, MMN may prove to be an important indicator of a common psychopathology shared by a significant proportion of individuals with schizophrenia and bipolar spectrum illnesses.

In vivo imaging of oxidative stress and fronto-limbic white matter integrity in young adults with mood disorders.

Fronto-limbic connectivity is compromised in mood disorders, as reflected by impairments in white matter (WM) integrity revealed by diffusion tensor imaging. Although the underlying mechanisms remain unclear, disruption to normal myelination due to oxidative stress is thought to play a key role. We aimed to determine whether fronto-limbic WM integrity is compromised, and associated with in vivo antioxidant levels (indexed by glutathione; GSH), in young adults with unipolar depression (DEP) and bipolar (BD) disorders. Ninety-four patients with DEP, 76 with BD and 59 healthy controls (18-30 years) underwent diffusion tensor and proton magnetic resonance spectroscopy imaging. Fractional anisotropy (FA) was calculated from the cingulum bundle (cingulate, hippocampus), fornix, stria terminalis (ST) and uncinate fasciculus tracts. GSH concentration was measured in anterior cingulate cortex (ACC) and hippocampus (HIPP). Compared to controls, DEP showed significantly reduced FA in ST, whereas BD did not significantly differ in FA across the five tracts. There were significant positive correlations between ST-FA and HIPP-GSH across groups. Regression analysis revealed that having DEP or BD and reduced HIPP-GSH were significantly associated with reduced ST-FA. Similarly, decreased ST-FA was associated with poorer neuropsychological performance in conjunction with having DEP. Our findings suggest a structural disconnectivity specific to the limbic region of young adults with DEP. Decreased WM integrity was associated with depleted levels of hippocampal GSH suggesting that this particular disruption may be linked to oxidative stress at early stages of illness. Young adults with BD do not have the same degree of impairment.

Lower In vivo Myo-Inositol in the Anterior Cingulate Cortex Correlates with Delayed Melatonin Rhythms in Young Persons with Depression.

Myo-inositol, a second messenger glucose isomer and glial marker, is potentiated by melatonin. In addition to common abnormalities in melatonin regulation, depressive disorders have been associated with reduced myo-inositol in frontal structures. This study examined associations between myo-inositol in the anterior cingulate cortex and the timing of evening melatonin release. Forty young persons with unipolar depression were recruited from specialized mental health services (20.3 ± 3.8 years old). Healthy controls were recruited from the community (21.7 ± 2.6 years old). The timing of dim light melatonin onset (DLMO) was estimated using salivary melatonin sampling. Myo-inositol concentrations (MI/CrPCr ratio) in the anterior cingulate cortex were obtained using proton magnetic resonance spectroscopy. After controlling for age, sex, and CrPCr concentration the depression group had significantly lower MI/CrPCr ratios than healthy controls [F(4, 75) = 11.4, p = 0.001]. In the depression group, later DLMO correlated with lower MI/CrPCr ratio (r = -0.48, p = 0.014). These findings suggest that neurochemical changes in the frontal cortex are associated with circadian disruptions in young persons with depression.

The N-methyl-D-aspartate receptor as a neurobiological intersection between bipolar disorder and alcohol use: a longitudinal mismatch negativity study.

BACKGROUND: Comorbid risky alcohol use in bipolar disorder (BD) is recognized for its high prevalence and clinical relevance, though understanding of its neurobiological underpinning is limited. The N-methyl-D-aspartate (NMDA) receptor has recognized alterations in BD and is a major site of ethanol's effects in the brain. The present study aimed to examine the NMDA receptor system in adolescents and young adults with BD by evaluating the longitudinal changes in a robust marker of NMDA function, mismatch negativity (MMN), in relation to changes in alcohol use patterns. METHODS: Forty-six BD patients (aged 16-30) were recruited at baseline and 59% (n = 27) returned for follow-up 17.9 +/- 7.3 months later. At both time-points a two-tone, passive, duration-deviant MMN paradigm was conducted and alcohol measures were collected. Pearson's correlations were performed between changes in MMN amplitudes and changes in alcohol use. Multiple regression was used to assess whether MMN amplitudes at baseline could predict alcohol use at follow-up. RESULTS: Reduction in risky drinking patterns was associated with increased temporal MMN and decreased fronto-central MMN. Larger temporal MMN at baseline was a significant predictor of greater alcohol use at follow-up. CONCLUSIONS: Results suggest risky alcohol use in BD may further compound pre-existing NMDA receptor abnormalities and, importantly, reducing alcohol use early in stages of illness is associated with changes in MMN. This highlights the importance of monitoring alcohol use from first presentation. In addition, preliminary results present an exciting potential for utility of MMN as a neurobiological marker used to determine risk for alcohol misuse in BD.

Emotional processing, p50 sensory gating, and social functioning in bipolar disorder.

Emotional processing has been reported to effect sensory gating as measured by the event-related potential known as P50. Because both P50 and emotional processing are dysfunctional in bipolar disorder (BD), we sought to investigate the impact that concurrent emotional processing has on sensory gating in this psychiatric population. P50 was recorded using a paired-click paradigm. Peak-to-peak amplitudes for stimulus 1 (S1) and stimulus 2 (S2) were acquired during the presentation of disgust and neutral faces to young adults with BD (n = 19) and controls (n = 20). Social functioning and quality-of-life self-reported measures were also obtained. The BD group had significantly larger P50 amplitudes elicited by the S2-disgust response compared with controls, but no significant difference in overall P50 sensory gating was found between the groups. There were also no differences between groups in S1-disgust or in either of the neutral P50 amplitudes. The BD group showed significant associations between sensory gating to disgust and measures of social functioning. Importantly, BD showed impaired filtering of auditory information when paired with an emotionally salient image. Thus, it appears that patients with the greatest impairment in sensory gating also have the most difficulty engaging in social situations.

Risky alcohol use predicts temporal mismatch negativity impairments in young people with bipolar disorder.

Alcohol misuse in bipolar disorder (BD) has a negative impact on illness progression. The NMDA/glutamatergic system is implicated in BD pathophysiology and is critically involved in the effects of alcohol on the brain. Mismatch negativity (MMN) is purported to reflect NMDA receptor output, providing a measure for investigating this association. Forty-two patients and 34 controls (16-30 years) were split into low and high-risk drinkers (based on the Alcohol Use Disorders Identification Test) and underwent a two-tone passive auditory oddball, duration deviant MMN paradigm. Multiple regression models revealed risky drinking and BD diagnosis were predictors of impaired temporal MMN. Potentially reflecting an additive effect of alcohol on a perturbed NMDA/glutamatergic system in BD, these findings highlight alcohol as both a modifiable risk factor of neurobiological impairments and as a potential confounder in MMN studies. Given the increasing use of glutamatergic agents for BD treatment, this finding is important clinically.

Longitudinal associations between mismatch negativity and disability in early schizophrenia- and affective-spectrum disorders.

BACKGROUND: Impaired mismatch negativity (MMN) is a robust finding in schizophrenia and, more recently, similar impairments have been reported in other psychotic- and affective-disorders (including at early stages of illness). Although cross-sectional studies have been numerous, there are few longitudinal studies that have explored the predictive value of this event-related potential in relation to clinical/functional outcomes. This study assessed changes in MMN (and the concomitant P3a) amplitude over time and aimed to determine the longitudinal relationship between MMN/P3a and functional outcomes in patients recruited during the early stage of a schizophrenia- or affective-spectrum disorder. METHODS: Sixty young patients with schizophrenia- and affective-spectrum disorders and 30 healthy controls underwent clinical, neuropsychological and neurophysiological assessment at baseline. Thirty-one patients returned for clinical and neuropsychological follow-up 12-30months later, with 28 of these patients also repeating neurophysiological assessment. On both occasions, MMN/P3a was elicited using a two-tone passive auditory paradigm with duration deviants. RESULTS: Compared with controls, patients showed significantly impaired temporal MMN amplitudes and trend-level deficits in central MMN/P3a amplitudes at baseline. There were no significant differences for MMN measures between the diagnostic groups, whilst the schizophrenia-spectrum group showed reduced P3a amplitudes compared to those with affective-spectrum disorders. For those patients who returned for follow-up, reduced temporal MMN amplitude at baseline was significantly associated with greater levels of occupational disability, and showed trend-level associations with general and social disability at follow-up. Paired t-tests revealed that MMN amplitudes recorded at the central-midline site were significantly reduced in patients over time. Interestingly, those patients who did not return for follow-up showed reduced frontal MMN and fronto-central P3a amplitudes compared to their peers who did return for repeat assessment. CONCLUSIONS: This study provides some evidence of the predictive utility of MMN at the early stages of schizophrenia- and affective-spectrum disorders and demonstrated that MMN impairments in such patients may worsen over time. Specifically, we found that young patients with the most impaired MMN amplitudes at baseline showed the most severe levels of disability at follow-up. Furthermore, in the subset of patients with repeat neurophysiological testing, central MMN was further impaired suggestive of neurodegenerative effects. MMN may serve as a neurophysiological biomarker to more accurately predict functional outcomes and prognosis, particularly at the early stages of illness.

Neuropsychological and socio-occupational functioning in young psychiatric outpatients: a longitudinal investigation.

BACKGROUND: Clinical symptoms and neuropsychological deficits are longitudinally associated with functional outcome in chronic psychiatric cohorts. The current study extended these findings to young and early-course psychiatric outpatients, with the aim of identifying cognitive markers that predict later socio-occupational functioning. METHODS: At baseline, 183 young psychiatric outpatients were assessed. Ninety-three returned for follow-up (M = 21.6 years old; SD = 4.5) with an average re-assessment interval of 21.6 months (SD = 7.0), and primary diagnoses of major depressive disorder (n = 34), bipolar disorder (n = 29), or psychosis (n = 30). The primary outcome measure was cross-validated with various other functional measures and structural equation modelling was used to map out the interrelationships between predictors and later functional outcome. RESULTS: Good socio-occupational functioning at follow-up was associated with better quality of life, less disability, current employment and being in a romantic relationship. The final structural equation model explained 47.5% of the variability in functional outcome at follow-up, with baseline neuropsychological functioning (a composite of memory, working memory and attentional switching) the best independent predictor of later functional outcome. Notably, depressive and negative symptoms were only associated with functioning cross-sectionally. Diagnosis at follow-up was not associated with functional outcome. CONCLUSIONS: Neuropsychological functioning was the single best predictor of later socio-occupational outcome among young psychiatric outpatients. Therefore, framing psychiatric disorders along a neuropsychological continuum is likely to be more useful in predicting functional trajectory than traditional symptom-based classification systems. The current findings also have implications for early intervention utilising cognitive remediation approaches.

Applying clinical staging to young people who present for mental health care.

AIM: The study aims to apply clinical staging to young people who present for mental health care; to describe the demographic features, patterns of psychological symptoms, disability correlates and clinical stages of those young people; and to report longitudinal estimates of progression from less to more severe stages. METHODS: The study uses cross-sectional and longitudinal assessments of young people managed in specialized youth clinics. On the basis of clinical records, subjects were assigned to a specific clinical 'stage' (i.e. 'help-seeking', 'attenuated syndrome', 'discrete disorder' or 'persistent or recurrent illness'). RESULTS: Young people (n = 209, mean age = 19.9 years (range = 12-30 years), 48% female) were selected from a broader cohort of n = 1483 subjects. Ten percent were assigned to the earliest 'help-seeking' stage, 54% to the 'attenuated syndrome' stage, 25% to the 'discrete disorder' stage and 11% to the later 'persistent or recurrent illness' stage. The interrater reliability of independent ratings at baseline was acceptable (κ = 0.71). Subjects assigned to the 'attenuated syndrome' stage reported symptom and disability scores that were similar to those assigned to later stages. Longitudinally (median = 48 weeks), transition to later clinical stages were 11% of the 'help-seeking', 19% of the 'attenuated syndrome' and 33% of the 'discrete disorder' groups. CONCLUSION: Among young people presenting for mental health care, most are clinically staged as having 'attenuated syndromes'. Despite access to specialized treatment, a significant number progress to more severe or persistent disorders.