Social isolation and psychosis: an investigation of social interactions and paranoia in daily life.

Social isolation has been suggested to foster paranoia. Here we investigate whether social company (i.e., being alone vs. not) and its nature (i.e., stranger/distant vs. familiar other) affects paranoia differently depending on psychosis risk. Social interactions and paranoid thinking in daily life were investigated in 29 patients with clinically stable non-affective psychotic disorders, 20 first-degree relatives, and 26 controls (n = 75), using the experience sampling method (ESM). ESM was completed up to ten times daily for 1 week. Patients experienced marginally greater paranoia than relatives [b = 0.47, p = 0.08, 95% CI (- 0.06, 1.0)] and significantly greater paranoia than controls [b = 0.55, p = 0.03, 95% CI (0.5, 1.0)], but controls and relatives did not differ [b = 0.07, p = 0.78, 95% CI (- 0.47, 0.61)]. Patients were more often alone [68.5% vs. 44.8% and 56.2%, respectively, p = 0.057] and experienced greater paranoia when alone than when in company [b = 0.11, p = 0.016, 95% CI (0.02, 0.19)]. In relatives this was reversed [b = - 0.17, p < 0.001, 95% CI (- 0.28, - 0.07)] and in controls non-significant [b = - 0.02, p = 0.67, 95% CI (- 0.09, 0.06)]. The time-lagged association between being in social company and subsequent paranoia was non-significant and paranoia did not predict the likelihood of being in social company over time (both p's = 0.68). All groups experienced greater paranoia in company of strangers/distant others than familiar others [X2(2) = 4.56, p = 0.03] and being with familiar others was associated with lower paranoia over time [X2(2) = 4.9, p = 0.03]. Patients are frequently alone. Importantly, social company appears to limit their paranoia, particularly when being with familiar people. The findings stress the importance of interventions that foster social engagement and ties with family and friends.

A Novel Virtual Reality Assessment of Functional Cognition: Validation Study.

BACKGROUND: Cognitive deficits are present in several neuropsychiatric disorders, including Alzheimer disease, schizophrenia, and depression. Assessments used to measure cognition in these disorders are time-consuming, burdensome, and have low ecological validity. To address these limitations, we developed a novel virtual reality shopping task-VStore. OBJECTIVE: This study aims to establish the construct validity of VStore in relation to the established computerized cognitive battery, Cogstate, and explore its sensitivity to age-related cognitive decline. METHODS: A total of 142 healthy volunteers aged 20-79 years participated in the study. The main VStore outcomes included verbal recall of 12 grocery items, time to collect items, time to select items on a self-checkout machine, time to make the payment, time to order coffee, and total completion time. Construct validity was examined through a series of backward elimination regression models to establish which Cogstate tasks, measuring attention, processing speed, verbal and visual learning, working memory, executive function, and paired associate learning, in addition to age and technological familiarity, best predicted VStore performance. In addition, 2 ridge regression and 2 logistic regression models supplemented with receiver operating characteristic curves were built, with VStore outcomes in the first model and Cogstate outcomes in the second model entered as predictors of age and age cohorts, respectively. RESULTS: Overall VStore performance, as indexed by the total time spent completing the task, was best explained by Cogstate tasks measuring attention, working memory, paired associate learning, and age and technological familiarity, accounting for 47% of the variance. In addition, with λ=5.16, the ridge regression model selected 5 parameters for VStore when predicting age (mean squared error 185.80, SE 19.34), and with λ=9.49 for Cogstate, the model selected all 8 tasks (mean squared error 226.80, SE 23.48). Finally, VStore was found to be highly sensitive (87%) and specific (91.7%) to age cohorts, with 94.6% of the area under the receiver operating characteristic curve. CONCLUSIONS: Our findings suggest that VStore is a promising assessment that engages standard cognitive domains and is sensitive to age-related cognitive decline.

A systematic review of TMS and neurophysiological biometrics in patients with schizophrenia.

BACKGROUND: Transcranial magnetic stimulation can be combined with electromyography (TMS-EMG) and electroencephalography (TMS-EEG) to evaluate the excitatory and inhibitory functions of the cerebral cortex in a standardized manner. It has been postulated that schizophrenia is a disorder of functional neural connectivity underpinned by a relative imbalance of excitation and inhibition. The aim of this review was to provide a comprehensive overview of TMS-EMG and TMS-EEG research in schizophrenia, focused on excitation or inhibition, connectivity, motor cortical plasticity and the effect of antipsychotic medications, symptom severity and illness duration on TMS-EMG and TMS-EEG indices. METHODS: We searched PsycINFO, Embase and Medline, from database inception to April 2020, for studies that included TMS outcomes in patients with schizophrenia. We used the following combination of search terms: transcranial magnetic stimulation OR tms AND interneurons OR glutamic acid OR gamma aminobutyric acid OR neural inhibition OR pyramidal neurons OR excita* OR inhibit* OR GABA* OR glutam* OR E-I balance OR excitation-inhibition balance AND schizoaffective disorder* OR Schizophrenia OR schizophreni*. RESULTS: TMS-EMG and TMS-EEG measurements revealed deficits in excitation or inhibition, functional connectivity and motor cortical plasticity in patients with schizophrenia. Increased duration of the cortical silent period (a TMS-EMG marker of γ-aminobutyric acid B receptor activity) with clozapine was a relatively consistent finding. LIMITATIONS: Most of the studies used patients with chronic schizophrenia and medicated patients, employed cross-sectional group comparisons and had small sample sizes. CONCLUSION: TMS-EMG and TMS-EEG offer an opportunity to develop a novel and improved understanding of the physiologic processes that underlie schizophrenia and to assess the therapeutic effect of antipsychotic medications. In the future, these techniques may also help predict disease progression and further our understanding of the excitatory/inhibitory balance and its implications for mechanisms that underlie treatment-resistant schizophrenia.

Attachment styles moderate Theory of Mind differences between persons with schizophrenia, first-degree relatives and controls.

OBJECTIVES: Theory of Mind (ToM) plays a role in social functioning and is impaired in patients with schizophrenia and to a lesser degree in first-degree relatives, compared to healthy controls. This study investigates whether attachment styles moderate these observed group differences in ToM. METHODS: This cross-sectional study included a sample of 51 patients, 23 first-degree relatives, and 49 controls who completed assessments of anxious and avoidant attachment (Psychosis Attachment Measure), ToM (Reading the Mind in the Eyes Test), and estimated cognitive ability. Patients' symptoms were assessed with the Positive and Negative Syndrome Scale. RESULTS: Patients differed from controls and relatives in ToM performance but not in attachment avoidance or attachment anxiety. Attachment anxiety showed an interaction with group over ToM. The interaction was significant only between patients and controls but not between patients and relatives or relatives and controls. Post-hoc analysis showed that patients and controls showed differential ToM performance at average and high attachment anxiety. In patients, symptom levels did not moderate the association between attachment and ToM. CONCLUSIONS: Attachment anxiety is related to poorer levels of ToM in patients, suggesting this may have a contributory role in schizophrenia. The findings stress the need for longitudinal research into the directionality of the relationship between ToM and attachment anxiety. PRACTITIONER POINTS: Relationships with significant others might be a factor that influences the way in which social information is processed by persons with a diagnosis of a psychotic disorder. In patients, higher levels of attachment anxiety - that is, low self-worth, fear of abandonment and rejection, continuous vigilance of threat-related cues - were associated with a lower ability to understand the mental states of others. However, at lower levels of attachment anxiety, their ToM performance was comparable to that of relatives and controls. This effect was not influenced by symptom severity. Further research is required to confirm the potential influence of attachment insecurity on ToM ability as the latter is strongly related to patient's functional outcomes.

A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis.

BACKGROUND: Clozapine is uniquely effective in treatment-resistant psychosis but remains underutilised, partly owing to psychotic symptoms leading to non-adherence to oral medication. An intramuscular formulation is available in the UK but outcomes remain unexplored. AIMS: This was a retrospective clinical effectiveness study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis over a 3-year period. METHOD: Successful initiation of oral clozapine after intramuscular prescription was the primary outcome. Secondary outcomes included all-cause clozapine discontinuation 2 years following initiation, and 1 year after discharge. Discontinuation rates were compared with a cohort prescribed only oral clozapine. Propensity scores were used to address confounding by indication. RESULTS: Among 39 patients prescribed intramuscular clozapine, 19 received at least one injection, whereas 20 accepted oral clozapine when given an enforced choice between the two. Thirty-six (92%) patients successfully initiated oral clozapine after intramuscular prescription; three never transitioned to oral. Eight discontinued oral clozapine during the 2-year follow-up, compared with 83 out of 162 in the comparator group (discontinuation rates of 24% and 50%, respectively). Discontinuation rates at 1-year post-discharge were 21%, compared with 44% in the comparison group. Intramuscular clozapine prescription was associated with a non-significantly lower hazard of discontinuation 2 years after initiation (hazard ratio 0.39, 95% CI 0.14-1.06) and 1 year after discharge (hazard ratio 0.37, 95% CI 0.11-1.24). The only reported adverse event specific to the intramuscular formulation was injection site pain and swelling. CONCLUSIONS: Intramuscular clozapine prescription allowed transition to oral maintenance in an initially non-adherent cohort. Discontinuation rates were similar to patients only prescribed oral clozapine and comparable to existing literature.

Understanding misidentification syndromes using the integrative memory model.

Misidentification syndromes occur commonly in neuropsychiatric practice and can be explained through aberrant integration of recollection and familiarity, in keeping with a dysfunction at the level of the attributional system in the new integrative memory model. We examine neuroimaging findings associated with Fregoli and Capgras syndromes and compare these with the proposed neural substrate of the integrative memory model supporting the core and attribution functions.

Differential neural reward mechanisms in treatment-responsive and treatment-resistant schizophrenia.

BACKGROUND: The significant proportion of schizophrenia patients refractory to treatment, primarily directed at the dopamine system, suggests that multiple mechanisms may underlie psychotic symptoms. Reinforcement learning tasks have been employed in schizophrenia to assess dopaminergic functioning and reward processing, but these have not directly compared groups of treatment-refractory and non-refractory patients. METHODS: In the current functional magnetic resonance imaging study, 21 patients with treatment-resistant schizophrenia (TRS), 21 patients with non-treatment-resistant schizophrenia (NTR), and 24 healthy controls (HC) performed a probabilistic reinforcement learning task, utilizing emotionally valenced face stimuli which elicit a social bias toward happy faces. Behavior was characterized with a reinforcement learning model. Trial-wise reward prediction error (RPE)-related neural activation and the differential impact of emotional bias on these reward signals were compared between groups. RESULTS: Patients showed impaired reinforcement learning relative to controls, while all groups demonstrated an emotional bias favoring happy faces. The pattern of RPE signaling was similar in the HC and TRS groups, whereas NTR patients showed significant attenuation of RPE-related activation in striatal, thalamic, precentral, parietal, and cerebellar regions. TRS patients, but not NTR patients, showed a positive relationship between emotional bias and RPE signal during negative feedback in bilateral thalamus and caudate. CONCLUSION: TRS can be dissociated from NTR on the basis of a different neural mechanism underlying reinforcement learning. The data support the hypothesis that a favorable response to antipsychotic treatment is contingent on dopaminergic dysfunction, characterized by aberrant RPE signaling, whereas treatment resistance may be characterized by an abnormality of a non-dopaminergic mechanism - a glutamatergic mechanism would be a possible candidate.

Stimulating thought: a functional MRI study of transcranial direct current stimulation in schizophrenia.

Individuals with schizophrenia typically suffer a range of cognitive deficits, including prominent deficits in working memory and executive function. These difficulties are strongly predictive of functional outcomes, but there is a paucity of effective therapeutic interventions targeting these deficits. Transcranial direct current stimulation is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive effects; however, there is limited understanding of its mechanism. This was a double-blind randomized sham controlled pilot study of transcranial direct current stimulation on a working memory (n-back) and executive function (Stroop) task in 28 individuals with schizophrenia using functional magnetic resonance imaging. Study participants received 30 min of real or sham transcranial direct current stimulation applied to the left frontal cortex. The 'real' and 'sham' groups did not differ in online working memory task performance, but the transcranial direct current stimulation group demonstrated significant improvement in performance at 24 h post-transcranial direct current stimulation. Transcranial direct current stimulation was associated with increased activation in the medial frontal cortex beneath the anode; showing a positive correlation with consolidated working memory performance 24 h post-stimulation. There was reduced activation in the left cerebellum in the transcranial direct current stimulation group, with no change in the middle frontal gyrus or parietal cortices. Improved performance on the executive function task was associated with reduced activity in the anterior cingulate cortex. Transcranial direct current stimulation modulated functional activation in local task-related regions, and in more distal nodes in the network. Transcranial direct current stimulation offers a potential novel approach to altering frontal cortical activity and exerting pro-cognitive effects in schizophrenia.

Hearts and Minds: Real-Life Cardiotoxicity With Clozapine in Psychosis.

BACKGROUND: Schizophrenia has a 1% prevalence in the population; 30% of these patients are treatment refractory. Clozapine is the only drug licensed to treat treatment refractory psychosis, but concerns about potential adverse effects result in only a proportion of eligible patients being treated. Although a well-documented neutropenia risk is mitigated by routine blood testing, cardiac toxicity is a commonly cited reason to discontinue clozapine treatment. However, there is little data on the real-life cardiac outcomes in those receiving clozapine treatment. METHODS: Retrospective review of electrocardiogram, echocardiogram, and clinical outcomes in 39 inpatients with treatment-refractory schizophrenia, treated with clozapine and other antipsychotic medication, referred for cardiology opinion. RESULTS: Commonest reasons for referral were development of left ventricular (LV) impairment or sinus tachycardia with normal LV function. Patients were reviewed by a range of cardiologists, receiving varied interventions.Median LV ejection fraction in the clozapine group was normal (52%). Serial echocardiograms demonstrated that clozapine-treated patients with LV impairment had no change in LV ejection fraction over a 4-month follow-up. Left ventricular ejection fraction did not differ between patients treated with clozapine and other antipsychotics. However, over an 11-year follow-up period, 48% of patients had discontinued clozapine treatment. CONCLUSIONS: This naturalistic study demonstrates that clozapine is not associated with significant cardiac mortality or morbidity. There is a real need for multidisciplinary working between specialist cardiologists and psychiatrists caring for these complex patients to facilitate optimal long-term physical and mental health outcomes.

Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies.

BACKGROUND: Oxytocin (OXT) plays a prominent role in social cognition and may have clinical applications for disorders such as autism, schizophrenia and social anxiety. The neural basis of its mechanism of action remains unclear. METHODS: We conducted a systematic literature review of placebo-controlled imaging studies using OXT as a pharmacological manipulator of brain activity. RESULTS: We identified a total of 21 studies for inclusion in our review, and after applying additional selection criteria, 11 of them were included in our fMRI voxel-based meta-analysis. The results demonstrate consistent alterations in activation of brain regions, including the temporal lobes and insula, during the processing of social stimuli, with some variation dependent on sex and task. The meta-analysis revealed significant left insular hyperactivation after OXT administration, suggesting a potential modulation of neural circuits underlying emotional processing. LIMITATIONS: This quantitative review included only a limited number of studies, thus the conclusions of our analysis should be interpreted cautiously. This limited sample size precluded a more detailed exploration of potential confounding factors, such as sex or other demographic factors, that may have affected our meta-analysis. CONCLUSION: Oxytocin has a wide range of effects over neural activity in response to social and emotional processing, which is further modulated by sex and task specificity. The magnitude of this neural activation is largest in the temporal lobes, and a meta-analysis across all tasks and both sexes showed that the left insula demonstrated the most robust activation to OXT administration.

I spy with my little eye - the detection of intentional contingency in early psychosis.

INTRODUCTION: Paranoid delusions have been associated with a tendency to over-attribute intentionality and contingency to others' actions and incidental events in individuals with chronic psychosis. However, this hyper-associative perception bias has not been investigated in the early illness stages of psychosis, during which it may play a particularly crucial role in the formation of symptoms. METHOD: We used an experimental paradigm with 20 short film clips of simple animate and inanimate shapes that either moved in a contingent or non-contingent manner to investigate the perception of contingency in 38 adolescents with early psychosis and 93 healthy control adolescents. Participants rated the contingency between the shapes' movements on a scale from 0 to 10. The data were analysed with multilevel regression analyses to account for repeated measures within subjects. RESULTS: There were no significant differences between patients and controls; both perceived the contingency of the shapes' movements similarly across all conditions and patients' contingency perception was unrelated to their levels of paranoid delusions. CONCLUSION: Contingency perception was unimpaired in patients with early psychosis, suggesting that it might still be intact in the early illness stages. Future studies should set out to determine whether the early illness stages could offer a window for interventions that counteract the development of hyper-associative perceptions of contingency.

Trust versus paranoia: abnormal response to social reward in psychotic illness.

Psychosis is characterized by an elementary lack of trust in others. Trust is an inherently rewarding aspect of successful social interactions and can be examined using neuroeconomic paradigms. This study was aimed at investigating the underlying neural basis of diminished trust in psychosis. Functional magnetic resonance imaging data were acquired from 20 patients with psychosis and 20 healthy control subjects during two multiple-round trust games; one with a cooperative and the other with a deceptive counterpart. An a priori region of interest analysis of the right caudate nucleus, right temporo-parietal junction and medial prefrontal cortex was performed focusing on the repayment phase of the games. For regions with group differences, correlations were calculated between the haemodynamic signal change, behavioural outcomes and patients' symptoms. Patients demonstrated reduced levels of baseline trust, indicated by smaller initial investments. For the caudate nucleus, there was a significant game × group interaction, with controls showing stronger activation for the cooperative game than patients, and no differences for the deceptive game. The temporo-parietal junction was significantly more activated in control subjects than in patients during cooperative and deceptive repayments. There were no significant group differences for the medial prefrontal cortex. Patients' reduced activation within the caudate nucleus correlated negatively with paranoia scores. The temporo-parietal junction signal was positively correlated with positive symptom scores during deceptive repayments. Reduced sensitivity to social reward may explain the basic loss of trust in psychosis, mediated by aberrant activation of the caudate nucleus and the temporo-parietal junction.

Uncertainty and confidence from the triple-network perspective: voxel-based meta-analyses.

Our subjective confidence about particular events is related to but independent from the objective certainty of the stimuli we encounter. Surprisingly, previous investigations of the neurophysiological correlates of confidence and uncertainty have largely been carried out separately. After systematically reviewing the blood oxygenation-level dependent functional magnetic resonance imaging (BOLD fMRI) literature, and splitting studies on the basis of their task requirements, a voxel-based meta-analysis was performed to identify: (i) those regions which are replicably modulated by the uncertainty of environmental conditions; (ii) those regions whose activity is robustly affected by our subjective confidence; and (iii) those regions differentially activated at these contrasting times. In further meta-analyses the consistency of activation between these judgement types was assessed. Increased activation was consistently observed in the salience (anterior cingulate cortex and insula) and central executive network (dorsolateral prefrontal and posterior parietal cortices) in conditions of increased uncertainty; by contrast, default mode network (midline cortical and medial temporal lobe) regions robustly exhibited a positive relationship with subjective confidence. Regions including right parahippocampal gyrus were positively modulated by magnitude across both certainty and confidence judgements. This region was also shown to be more significantly modulated by confidence magnitude as compared with degree of environmental certainty. The functional and methodological implications of these findings are discussed with a view to improving future investigation of the neural basis of metacognitive judgement.

Trust and social reciprocity in adolescence--a matter of perspective-taking.

Changes in social behaviour from childhood to adulthood have been suggested to be driven by an increased sensitivity to others' perspectives. Yet, the link between perspective-taking and social processes, such as trust and reciprocity, has rarely been investigated during adolescence. Using two trust games with a cooperative and an unfair counterpart and an online perspective-taking task with 50 adolescents, we show that those with a higher perspective-taking tendency demonstrate greater trust towards others and higher levels of trust during cooperative interactions. Both low and high perspective-takers adapted their levels of trust in response to unfair behaviour. However, high perspective-takers reduced their trust more drastically and showed more malevolent and less benevolent tit-for-tat when they were treated unfairly by their counterpart. The findings suggest that a higher perspective-taking tendency in adolescence is associated with specific mechanisms of trust and reciprocity, as opposed to undifferentiated increases in positive social behaviour towards others.

To trust or not to trust: the dynamics of social interaction in psychosis.

Psychotic illness is a disorder of social interaction unique to humans. However, up to now research has failed to pin down the exact determinants of the complex and interactive processes associated with the development of trust and reciprocity in psychosis. Utilizing a novel multi-round version of an interactive trust game experiment, we show that patients with psychosis and healthy relatives with a heightened risk for the illness exhibit lower baseline levels of trust compared with healthy controls. This effect partly overlapped with a reduced general intelligence. Furthermore, patients were unable to modify their trusting behaviour neither in response to information about the general trustworthiness of their interaction partner, nor in response to their partners' specific direct behavioural feedback. Relatives, in contrast, modified their trusting behaviour towards similar levels as healthy subjects in response to both. The results show that behavioural flexibility in response to socially relevant information is a critical determinant of success in the instantiation and maintenance of social relationships. A lack thereof may drive social dysfunction and the progression from subclinical symptoms to a full-blown psychosis. This offers a testable mechanistic hypothesis for progression from prodrome to psychotic illness, and may provide a therapeutic avenue to grapple the psychotic symptoms of social dysfunction.

Theory of mind, insecure attachment and paranoia in adolescents with early psychosis and healthy controls.

OBJECTIVE: Impaired Theory of Mind (ToM) is found in adults with schizophrenia and is associated with paranoid symptoms. Insecure attachment is proposed to underlie impaired ToM as well as paranoia. Insight into associations between insecure attachment and impaired ToM skills may help clinicians and patients to understand interpersonal difficulties and use this knowledge to improve recovery. This study used a visual perspective-taking task to investigate whether cognitive ToM is already impaired in adolescents with early psychosis as compared to controls. Also investigated was whether perspective-taking and paranoia are associated with insecure (adult) attachment. METHODS: Thirty-two adolescent patients with early psychosis and 78 healthy controls participated in this cross-sectional study design and completed the level 1 perspective-taking task, psychopathology assessments (CAPE, PANSS), paranoid thoughts (GPTS), attachment style (PAM) and the WASI vocabulary. RESULTS: Patients did not significantly differ in level-1 perspective-taking behaviour compared to healthy controls. No significant associations were found between perspective-taking, paranoia and attachment. Insecure attachment was significantly related to paranoid thoughts, after controlling for illness-related symptoms. CONCLUSION: No impairment of level-1 perspective-taking was found in adolescent patients with early psychosis compared to healthy controls. Results indicate that level-1 perspective-taking is not impaired during the early stages of psychotic illness. The association between paranoia and attachment support previous findings and provide further insight into the nature of psychotic symptoms. Understanding the role of attachment in paranoia may help patients and their care workers to gain insight into the reasons for the development or persistence of symptoms. Future research should compare early psychosis samples with more chronic samples to explore whether perspective-taking deteriorates during the course of the illness.

Neuroimaging glutamatergic mechanisms differentiating antipsychotic treatment-response.

Glutamatergic dysfunction is associated with failure to respond to antipsychotic medication in individuals with schizophrenia. Our objective was to combine neurochemical and functional brain imaging methods to investigate glutamatergic dysfunction and reward processing in such individuals compared with those with treatment responsive schizophrenia, and healthy controls. 60 participants played a trust task, while undergoing functional magnetic resonance imaging: 21 classified as having treatment-resistant schizophrenia, 21 patients with treatment-responsive schizophrenia, and 18 healthy controls. Proton magnetic resonance spectroscopy was also acquired to measure glutamate in the anterior cingulate cortex. Compared to controls, treatment responsive and treatment-resistant participants showed reduced investments during the trust task. For treatment-resistant individuals, glutamate levels in the anterior cingulate cortex were associated with signal decreases in the right dorsolateral prefrontal cortex when compared to those treatment-responsive, and with bilateral dorsolateral prefrontal cortex and left parietal association cortex when compared to controls. Treatment-responsive participants showed significant signal decreases in the anterior caudate compared to the other two groups. Our results provide evidence that glutamatergic differences differentiate treatment resistant and responsive schizophrenia. The differentiation of cortical and sub-cortical reward learning substrates has potential diagnostic value. Future novel interventions might therapeutically target neurotransmitters affecting the cortical substrates of the reward network.

New approaches to antipsychotic medication adherence - safety, tolerability and acceptability.

INTRODUCTION: Antipsychotic pharmacotherapy is considered a first-line treatment in schizophrenia-related disorders and is associated with favorable prognosis and lower mortality rates. However, low adherence rates present a major clinical challenge. In this paper, we will review contemporary approaches to improve adherence to antipsychotic treatment, considering their mechanism of action, safety, tolerability and acceptability. AREAS COVERED: Novel pharmacological delivery methods included different routes of administration of registered medications (such as intramuscular clozapine preparation and transdermal asenapine), modifications of existing compounds (such as 3-monthly injectable formulation of paliperidone palmitate), and increased interest in oral long-acting medication formulations (such as with penfluridol). In addition, we reviewed innovative technology to monitor adherence, based on the use of electronic digital medicine systems and ingestible sensors. EXPERT OPINION: All of these diverse approaches were clinically relevant in enhancing treatment adherence and found to be safe and tolerable. The place of each approach is predicated on a personalized approach in each patient, and future research could usefully use large comparative studies to establish robust treatment guidelines. The implementation of new and varied approaches to antipsychotic treatment adherence is welcomed and have the potential to make a significant impact on morbidity in this often difficult-to-treat population.

Stimulating learning: A functional MRI and behavioral investigation of the effects of transcranial direct current stimulation on stochastic learning in schizophrenia.

Transcranial direct current stimulation (tDCS) of the medial prefrontal cortex (mPFC) is under clinical investigation as a treatment for cognitive deficits. We investigate the effects of tDCS over the mPFC on performance SSLT in individuals with schizophrenia, and the underlying neurophysiological effect in regions associated with learning values and stimulus-outcome relationships. In this parallel-design double-blind pilot study, 49 individuals with schizophrenia, of whom 28 completed a fMRI, were randomized into active or sham tDCS stimulation groups. Subjects participated in 4 days of SSLT training (days 1, 2, 14, 56) with tDCS applied at day-1, and during a concurrent MRI scan at day-14. The SSLT demonstrated a significant mean difference in performance in the tDCS treatment group: at day-2 and at day-56. Active tDCS was associated with increased insular activity, and reduced amygdala activation. tDCS may offer an important novel approach to modulating brain networks to ameliorate cognitive deficits in schizophrenia, with this study being the first to show a longer-term effect on SSLT.

Alpha3/alpha2 power ratios relate to performance on a virtual reality shopping task in ageing adults.

Background: Aspects of cognitive function decline with age. This phenomenon is referred to as age-related cognitive decline (ARCD). Improving the understanding of these changes that occur as part of the ageing process can serve to enhance the detection of the more incapacitating neurodegenerative disorders such as Alzheimer's disease (AD). In this study, we employ novel methods to assess ARCD by exploring the utility of the alpha3/alpha2 electroencephalogram (EEG) power ratio - a marker of AD, and a novel virtual reality (VR) functional cognition task - VStore, in discriminating between young and ageing healthy adults. Materials and methods: Twenty young individuals aged 20-30, and 20 older adults aged 60-70 took part in the study. Participants underwent resting-state EEG and completed VStore and the Cogstate Computerised Cognitive Battery. The difference in alpha3/alpha2 power ratios between the age groups was tested using t-test. In addition, the discriminatory accuracy of VStore and Cogstate were compared using logistic regression and overlying receiver operating characteristic (ROC) curves. Youden's J statistic was used to establish the optimal threshold for sensitivity and specificity and model performance was evaluated with the DeLong's test. Finally, alpha3/alpha2 power ratios were correlated with VStote and Cogstate performance. Results: The difference in alpha3/alpha2 power ratios between age cohorts was not statistically significant. On the other hand, VStore discriminated between age groups with high sensitivity (94%) and specificity (95%) The Cogstate Pre-clinical Alzheimer's Battery achieved a sensitivity of 89% and specificity of 60%, and Cogstate Composite Score achieved a sensitivity of 83% and specificity of 85%. The differences between the discriminatory accuracy of VStore and Cogstate models were statistically significant. Finally, high alpha3/alpha2 power ratios correlated strongly with VStore (r = 0.73), the Cogstate Pre-clinical Alzheimer's Battery (r = -0.67), and Cogstate Composite Score (r = -0.76). Conclusion: While we did not find evidence that the alpha3/alpha2 power ratio is elevated in healthy ageing individuals compared to young individuals, we demonstrated that VStore can classify age cohorts with high accuracy, supporting its utility in the assessment of ARCD. In addition, we found preliminary evidence that elevated alpha3/alpha2 power ratio may be linked to lower cognitive performance.