OBJECTIVES:To examine the literature for evidence of adverse events associated with the use of intranasal oxytocin in older adults (60+). METHODS:A systematic review was undertaken according to PRISMA guidelines. Peer-reviewed literature was searched for studies involving intranasal oxytocin use in older populations. The Joanna Briggs Institute's (JBI) critical appraisal tool was used to assess the quality of included studies. RESULTS:The search identified nine randomized controlled trials (RCTs) that investigated the effects of intranasal oxytocin on a total sample size of 331 older participants. Adverse effects associated with oxytocin administration were predominantly mild and varied inconsistently between studies. Compared to placebo intranasal oxytocin was not significantly associated with severe adverse outcomes in doses ranging from 24 to 72 IU after single dose and or repeated doses in the short-term. CONCLUSION:In a population of older adults, intranasal oxytocin is devoid of serious adverse events. Although this review offers valuable insights, it may not fully reflect the potential adverse events associated with the long-term administration of intranasal oxytocin such as would be expected in its clinical application if approved for the treatment of dementia.

BackgroundFunctional Neurological Disorder (FND) is associated with anxiety and depression, and perhaps with joint hypermobility, which is itself associated with anxiety and depression. We conducted a survey to explore the relationship between these.MethodsAn online survey of people with FND was conducted, with participants asked to nominate healthy controls from their social group to join. Participants were asked about their anxiety (measured with GAD7), depression (measured with PHQ9) and joint hypermobility (measured with 5PQ). A regression analysis was conducted using a general linear model.Results215 people with FND and 22 people without FND were included in the analysis. GAD7, PHQ9 and hypermobility scores were all higher in the group with FND, with 74% of people with FND meeting the common cut-off for a diagnosis of joint hypermobility syndrome, as compared with 45% of those without FND. Anxiety, depression and joint hypermobility scores all predicted FND status, with joint hypermobility the strongest. Hypermobility moderated the effect of anxiety, with the effect being stronger at lower levels of anxiety.ConclusionWhile anxiety, depression and hypermobility symptoms each appear to contribute to FND, the role of anxiety is moderated by hypermobility, particularly when anxiety is lower.

OBJECTIVES:This review examines the literature to determine whether physical design features of psychiatric facilities can help reduce aggressive behaviours in an adult patient population. METHODS:Using PRISMA's methodology, we conducted a narrative review of peer-reviewed primary studies on the physical design features and aggressive behaviours in psychiatric facilities. The Joanna Briggs Institute's (JBI) critical appraisal tool was used to assess the quality of included studies. RESULTS:A total of eight studies were identified. The findings revealed underlying themes in physical design efforts to reduce the incidences of aggressive behaviours, which included changes in structural design (e.g. single rooms; visiting/living/recreational areas; views of outdoors/nature; and uncrowded spaces) and changes in interior design (e.g. art and home-like/comforting environment). There were varying measures of patient aggression. CONCLUSIONS:There was mixed evidence that superficial or structural design changes to psychiatric wards reduced patient aggression. Some studies found reduced aggression; others found no changes, while one study found increased aggression following the implementation of physical design changes. The methodological limitations of the available studies made it difficult to draw causative links and further research on the topic is needed.

Aim Deep brain stimulation (DBS) is a safe and effective treatment option for people with refractory obsessive‐compulsive disorder (OCD). Yet our understanding of predictors of response and prognostic factors remains rudimentary, and long‐term comprehensive follow‐ups are lacking. We aim to investigate the efficacy of DBS therapy for OCD patients, and predictors of clinical response. Methods Eight OCD participants underwent DBS stimulation of the nucleus accumbens (NAc) in an open‐label longitudinal trial, duration of follow‐up varied between 9 months and 7 years. Post‐operative care involved comprehensive fine tuning of stimulation parameters and adjunct multidisciplinary therapy. Results Six participants achieved clinical response (35% improvement in obsessions and compulsions on the Yale Brown Obsessive Compulsive Scale (YBOCS)) within 6–9 weeks, response was maintained at last follow up. On average, the YBOCS improved by 45% at last follow up. Mixed linear modeling elucidated directionality of symptom changes: insight into symptoms strongly predicted ( P = 0.008) changes in symptom severity during DBS therapy, likely driven by initial changes in depression and anxiety. Precise localization of DBS leads demonstrated that responders most often had their leads (and active contacts) placed dorsal compared to non‐responders, relative to the Nac. Conclusion The clinical efficacy of DBS for OCD is demonstrated, and mediators of changes in symptoms are proposed. The symptom improvements within this cohort should be seen within the context of the adjunct psychological and biopsychosocial care that implemented a shared decision‐making approach, with flexible iterative DBS programming. Further research should explore the utility of insight as a clinical correlate of response. The trial was prospectively registered with the ANZCTR (ACTRN12612001142820).

According to Kuhn’s argument science progresses by ‘paradigm shifts’ (Kuhn, 1962), an expression now so accepted that it has become entrenched in the lexicon of multiple disciplines. Kuhn’s classic examples included the shift from the Ptolemaic geocentric view of the planetary system to the Copernican heliocentric notion. On the horizon for the treatment of schizophrenia are non-dopaminergic acting agents which, if primary pharmacological actions mean anything at all, sit uncomfortably within the prevailing dopamine paradigm of antipsychotic drug action. Does the advent of such agents herald a Kuhnian ‘revolution’ in the understanding of antipsychotic drug action with an attendant ‘paradigm shift’ from the dopamine hypothesis of schizophrenia? When introduced into clinical practice seven decades ago, chlorpromazine was rightly considered a breakthrough treatment for schizophrenia. It enabled many patients, who would otherwise have been confined long-term to mental hospitals, to be discharged to the community. While there were significant therapeutic benefits, these were offset by the associated neurological side effects (Stroup et al., 2000). The intervening years have resulted, arguably, in little in the way of improved efficacy with respect to the pharmacological treatment of the positive and negative symptoms, but current medications have a somewhat more benign neurological side effect profile (Stroup et al., 2000). Nevertheless, like the prototypical phenothiazine antipsychotic medications, current drugs are believed to derive their therapeutic benefits, at least in part, by antagonism/partial agonism at the dopamine D2 class of receptors (this includes D2-Short, D2-Long, D3 and D4 receptors) (Ginovart and Kapur, 2012). Recognition of the pharmacological actions of medications contributed significantly to an initial formulation of a dopamine hypothesis of schizophrenia. A more sophisticated iteration of the hypothesis focussed on the activity of dopamine within specific neuronal circuits. Overactivity of dopamine within the mesolimbic pathway is postulated to be responsible for positive symptoms of the disorder, while underactivity in meso-cortical pathways is posited to be responsible for negative and cognitive symptoms (Stahl, 2004). Within this framework of the modified hypothesis, alterations of the activity of other neurotransmitter systems (most notably a hypoactive glutamatergic system) have been accommodated. Although the hypothesis has been criticised as too reliant on the inference from drug effects to underlying disease process (Moncrieff, 2009), it nevertheless remains a plausible explanation of some symptoms of the disorder. The hypothesis has formed a useful drug discovery paradigm to the extent that all currently approved treatments can be considered to conform to a dopaminergic view of schizophrenia/antipsychotic drug action. Pre-clinical and early phase studies indicate that molecules without a primary dopamine D2-antagonist/partial agonist effect may be effective for the treatment of schizophrenia. At face value, the efficacy of such compounds questions the continuing utility of the dopamine hypothesis. A case in point is that of ulotaront (SEP-363856), which is in the preliminary stages of clinical evaluation. Ulotaront is a trace amine-associated receptor (TAAR-1) and 5HT1A agonist. In pre-clinical studies the molecule blocked phencyclidine (PCP)-induced hyperactivity, pre-pulse inhibition and PCP-induced deficits in social interaction and cognition, widely used mouse phenotypes for antipsychotic drug discovery (Dedic et al., 2019). A short-term (4-week) double-blind, placebo-controlled trial showed superiority for the active compound in treating relapse of schizophrenia (Koblan et al., 2020). In the open label continuation phase of this study ulotaront maintained efficacy over 6 months (Correll et al., 2021). Clearly, further clinical evaluations are necessary to robustly establish clinical efficacy. Nevertheless, taken together the two parts of this study offer preliminary validation of non-dopaminergic mechanisms as A challenge to the dopamine orthodoxy in schizophrenia?

Objective: To investigate whether diagnostic agreement and concordance between non-psychiatric (medical and surgical) doctors and consultation-liaison psychiatry changes within junior doctors' terms. Method: This was a retrospective cohort analysis of referrals from medical and surgical units to a consultation-liaison psychiatry service. Diagnostic agreement was calculated across all diagnoses and expressed as a percentage. Diagnostic concordance (expressed using Cohen's Kappa) was calculated for the two most common diagnoses of depression and delirium. Diagnostic agreement and concordance in the first two weeks (Timepoint A) were compared to those in the last two weeks (Timepoint B) of junior doctors' terms. Results: Around half the referrals (Timepoint A = 48.1%, Timepoint B = 54.0%) were excluded as no diagnosis was listed. Diagnostic agreement over all diagnoses was 31.7% (Timepoint A) and 29.9% (Timepoint B) and was not statistically different. Diagnostic concordance for depression increased from fair to moderate but was not statistically significant. Diagnostic concordance for delirium was substantial for both timepoints and were not statistically different. Conclusions: No statistically significant change in diagnostic accuracy over a junior doctors' term was found in this study.

Objective: There have been multiple reports of increased joint hypermobility (JH) in functional somatic syndromes (FSS). We sought to evaluate the evidence for an association. Methods: A systematic search of the databases Medline and PsycINFO was conducted to identify all controlled studies from inception to February 2020 measuring the association of an FSS and JH. Records were identified and screened, and full-text articles assessed for eligibility by two independent authors. Meta-analysis was performed using random-effects modelling with the DerSimonian and Laird method. Results: We found 220 studies initially, which yielded 11 studies for inclusion in the qualitative review and 10 in the quantitative analysis - 5 studies on fibromyalgia, 3 on chronic fatigue syndrome and 3 on functional gastrointestinal disorder. Nine of the 11 studies found increased rates of JH in FSS compared to controls, though most studies were fair to poor in quality. Meta-analysis showed a weighted summary effect odds ratio of 3.27 (95% CI: 1.83, 5.84; p < 0.001) of JH in FSS, suggesting greater odds of FSS in individuals with JH than in those without. Conclusions: There is some evidence for an association between FSS and JH, but this is limited by the generally poor quality of studies and the narrow range of FSS studied. Better research is needed to confirm these findings as well as evaluate causation using prospective cohort studies.

Introduction: Major depressive disorder (MDD) remains one of the most prevalent mental health conditions. It is a chronic, relapsing condition and despite multiple treatment options, many patients fail to achieve remission of symptoms. Inadequacy of treatment has stimulated the search for agents with significant therapeutic advantages. Areas covered: This review examines literature concerning the use of desvenlafaxine in the treatment of MDD published since a previous analysis in this journal in 2014. Published papers were identified via a PubMed and Web of Science search and excluded congress presentations. Results from clinical trials in MDD, systematic reviews, and post hoc analyses in patient subgroups, are reviewed. Expert opinion: Desvenlafaxine was an effective antidepressant with favorable safety and tolerability in adults. Efficacy was demonstrated in the subgroup of peri- and post-menopausal women with MDD but not in children and adolescents. There is a relatively low potential for drug-drug interactions due to its metabolic profile. Hepatic impairment does not significantly alter dose requirements, whereas severe renal disease requires some adjustments of dose. Desvenlafaxine maybe suitable in patients with comorbid physical illnesses. Desvenlafaxine can be a first line consideration for the treatment of cases of MDD uncomplicated by medical comorbidities.

Understanding the mechanism of psychogenic non-epileptic seizures (PNES) is challenging. A recent review grouped currently hypothesised psychological models into four: (1) traumatic dissociation, (2) hard-wired anxious-arousal responses, (3) conversion defences and (4) conditioned behaviours, but concluded that determining which of these was correct, if any, went far beyond the available evidence.1 Patients’ subjective reports may lend striking support to some models, but are necessarily post-hoc, and susceptible to iatrogenic suggestion.2 Neuroimaging, such as functional MRI, provides more objective evidence, but is typically restricted to the inter-ictal phase because of potential movement during the scan.3 Single photon emission computed tomography (SPECT) would have distinct advantages in imaging of the peri-ictal state as the tracer injection and uptake occur at the time of the seizure while the scanning can be completed later, after the seizure has finished, overcoming the motion issues. The ictal scan could then be compared with an inter-ictal SPECT to determine the ictal contribution to cerebral blood flow. This process is standard for epilepsy surgery workup, and we combined the databases from two epilepsy surgery centres to find opportunistic cases where the ictal scans of potential surgery cases proved to be of PNES—either because the initial epilepsy diagnosis was mistaken or because the scan captured a comorbid non-epileptic …

Introduction: Agomelatine is an antidepressant with unique pharmacological actions; it is both a melatonin agonist and selective serotonin antagonist. Both actions combined are necessary for antidepressant efficacy. Effects on melatonin receptors enable resynchronisation of disrupted circadian rhythms with beneficial effects on sleep patterns. Areas covered: The issue of use of an antidepressant for depression co-morbid with somatic disorders is covered by the authors. A review of the literature from 2000 to August 2018 was undertaken using Scopus and Web of Science with the key words: agomelatine, depression, medical illness. Depression in Parkinson's disease, cardiovascular illness and type II diabetes is reviewed with evidence of efficacy. Bipolar depression and seasonal affective disorder may also react favourably. Agomelatine may have specific efficacy on symptoms of anhedonia. Expert opinion: Despite approval in some major jurisdictions, the drug has failed to gain registration in the United States. A defining issue may be questions about longer term efficacy: unequivocal effectiveness in placebo-controlled relapse prevention studies has not always been demonstrated. Continuation studies suggest maintenance of clinical responsiveness. A major disadvantage of the drug is its' potential hepatotoxicity and the need for repeated clinical laboratory tests.

Introduction: Schizophrenia is increasingly conceived as a disorder of brain network connectivity and organization. However, reports of network abnormalities during the early illness stage of psychosis are mixed. This study adopted a data-driven whole-brain approach to investigate functional connectivity and network architecture in a first-episode psychosis cohort relative to healthy controls and whether functional network properties changed abnormally over a 12-month period in first-episode psychosis. Methods: Resting-state functional connectivity was performed at two time points. At baseline, 29 first-episode psychosis individuals and 30 healthy controls were assessed, and at 12months, 14 first-episode psychosis individuals and 20 healthy controls completed follow-up. Whole-brain resting-state functional connectivity networks were mapped for each individual and analyzed using graph theory to investigate whether network abnormalities associated with first-episode psychosis were evident and whether functional network properties changed abnormally over 12months relative to controls. Results: This study found no evidence of abnormal resting-state functional connectivity or topology in first-episode psychosis individuals relative to healthy controls at baseline or at 12-months follow-up. Furthermore, longitudinal changes in network properties over a 12-month period did not significantly differ between first-episode psychosis individuals and healthy control. Network measures did not significantly correlate with symptomatology, duration of illness or antipsychotic medication. Conclusions: This is the first study to show unaffected resting-state functional connectivity and topology in the early psychosis stage of illness. In light of previous literature, this suggests that a subgroup of first-episode psychosis individuals who have a neurotypical resting-state functional connectivity and topology may exist. Our preliminary longitudinal analyses indicate that there also does not appear to be deterioration in these network properties over a 12-month period. Future research in a larger sample is necessary to confirm our longitudinal findings.

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.

Background White matter disruptions in schizophrenia have been widely reported, but it remains unclear whether these abnormalities differ between illness stages. We mapped the connectome in patients with recently diagnosed and chronic schizophrenia and investigated the extent and overlap of white matter connectivity disruptions between these illness stages. Methods Diffusion-weighted magnetic resonance images were acquired in recent-onset ( n = 19) and chronic patients ( n = 45) with schizophrenia, as well as age-matched controls ( n = 87). Whole-brain fiber tracking was performed to quantify the strength of white matter connections. Connections were tested for significant streamline count reductions in recent-onset and chronic groups, relative to separate age-matched controls. Permutation tests were used to assess whether disrupted connections significantly overlapped between chronic and recent-onset patients. Linear regression was performed to test whether connectivity was strongest in controls, weakest in chronic patients, and midway between these extremities in recent-onset patients (controls > recent-onset > chronic). Results Compared with controls, chronic patients displayed a widespread network of connectivity disruptions ( p < 0.01). In contrast, connectivity reductions were circumscribed to the anterior fibers of the corpus callosum in recent-onset patients ( p < 0.01). A significant proportion of disrupted connections in recent-onset patients (86%) coincided with disrupted connections in chronic patients ( p < 0.01). Linear regression revealed that chronic patients displayed reduced connectivity relative to controls, while recent-onset patients showed an intermediate reduction compared with chronic patients ( p < 0.01). Conclusions Connectome pathology in recent-onset patients with schizophrenia is confined to select tracts within a more extensive network of white matter connectivity disruptions found in chronic illness. These findings may suggest a trajectory of progressive deterioration of connectivity in schizophrenia.

Study design: Longitudinal cohort design. Objectives: First, to explore the longitudinal outcomes for people who received early intervention vocational rehabilitation (EIVR); second, to examine the nature and extent of relationships between contextual factors and employment outcomes over time. Setting: Both inpatient and community-based clients of a Spinal Community Integration Service (SCIS). Methods: People of workforce age undergoing inpatient rehabilitation for traumatic spinal cord injury were invited to participate in EIVR as part of SCIS. Data were collected at the following three time points: discharge and at 1 year and 2+ years post discharge. Measures included the spinal cord independence measure, hospital anxiety and depression scale, impact on participation and autonomy scale, numerical pain-rating scale and personal wellbeing index. A range of chi square, correlation and regression tests were undertaken to look for relationships between employment outcomes and demographic, emotional and physical characteristics. Results: Ninety-seven participants were recruited and 60 were available at the final time point where 33% (95% confidence interval (CI): 24–42%) had achieved an employment outcome. Greater social participation was strongly correlated with wellbeing ( ρ =0.692), and reduced anxiety ( ρ =−0.522), depression ( ρ =−0.643) and pain ( ρ =−0.427) at the final time point. In a generalised linear mixed effect model, education status, relationship status and subjective wellbeing increased significantly the odds of being employed at the final time point. Tertiary education prior to injury was associated with eight times increased odds of being in employment at the final time point; being in a relationship at the time of injury was associated with increased odds of being in employment of more than 3.5; subjective wellbeing, while being the least powerful predictor was still associated with increased odds (1.8 times) of being employed at the final time point. Conclusions: EIVR shows promise in delivering similar return-to-work rates as those traditionally reported, but sooner. The dynamics around relationships, subjective wellbeing, social participation and employment outcomes require further exploration.

OBJECTIVES:To assess the efficacy of cognitive existential couple therapy (CECT) for relationship function, coping, cancer distress and mental health in men with localised prostate cancer and in their partners.PATIENTS SUBJECTS AND METHODS:A randomised controlled trial was conducted with 62 couples randomly assigned to the six-session CECT programme or care as usual. The couple's relationship function (primary outcome), and coping, cancer distress and mental health (secondary outcomes) were evaluated at T0 (baseline), T1 (after treatment) and T2 (9 months from T0). A repeated-measures analysis of covariance model, which incorporated T0 measurements as a covariate, was used to compare treatment groups at T1 and T2.RESULTS:After CECT, patients reported significantly greater use of adaptive coping (P = 0.03) and problem-focused coping (P = 0.01). These gains were maintained at follow-up, while relationship cohesion had improved (P = 0.03), as had relationship function for younger patients (P = 0.01). Younger partners reported less cancer-specific distress (P = 0.008), avoidance (P = 0.04), intrusive thought (P = 0.006), and hyperarousal (P = 0.01). Gains were maintained at follow-up, while relationship cohesion (P = 0.007), conflict resolution (P = 0.01) and relational function (P = 0.009) all improved.CONCLUSION:CECT resulted in improved coping for patients and lower cancer-distress for partners. Maintained over time this manifests as improved relationship function. CECT was acceptable to couples, alleviated long-term relationship decline, and is therefore suitable as a preventative mental health intervention for couples facing prostate cancer. Given resourcing demands, we recommend dissemination of CECT be targeted at younger couples, as CECT was more acceptable to the younger group, and they derived greater benefit from it.