Antidepressant, antipsychotic and psychological interventions in subjects at high clinical risk for psychosis: OASIS 6-year naturalistic study.

BACKGROUND: Recent randomized controlled trials suggest some efficacy for focused interventions in subjects at high risk (HR) for psychosis. However, treating HR subjects within the real-world setting of prodromal services is hindered by several practical problems that can significantly make an impact on the effect of focused interventions. METHOD: All subjects referred to Outreach and Support in South London (OASIS) and diagnosed with a HR state in the period 2001-2012 were included (n = 258). Exposure to focused interventions was correlated with sociodemographic and clinical characteristics at baseline. Their association with longitudinal clinical and functional outcomes was addressed at follow-up. RESULTS: In a mean follow-up time of 6 years (s.d. = 2.5 years) a transition risk of 18% was observed. Of the sample, 33% were treated with cognitive behavioural therapy (CBT) only; 17% of subjects received antipsychotics (APs) in addition to CBT sessions. Another 17% of subjects were prescribed with antidepressants (ADs) in addition to CBT. Of the sample, 20% were exposed to a combination of interventions. Focused interventions had a significant relationship with transition to psychosis. The CBT + AD intervention was associated with a reduced risk of transition to psychosis, as compared with the CBT + AP intervention (hazards ratio = 0.129, 95% confidence interval 0.030-0.565, p = 0.007). CONCLUSIONS: There were differential associations with transition outcome for AD v. AP interventions in addition to CBT in HR subjects. These effects were not secondary to baseline differences in symptom severity.

Using structural neuroanatomy to identify trauma survivors with and without post-traumatic stress disorder at the individual level.

BACKGROUND: At present there are no objective, biological markers that can be used to reliably identify individuals with post-traumatic stress disorder (PTSD). This study assessed the diagnostic potential of structural magnetic resonance imaging (sMRI) for identifying trauma-exposed individuals with and without PTSD. METHOD: sMRI scans were acquired from 50 survivors of the Sichuan earthquake of 2008 who had developed PTSD, 50 survivors who had not developed PTSD and 40 healthy controls who had not been exposed to the earthquake. Support vector machine (SVM), a multivariate pattern recognition technique, was used to develop an algorithm that distinguished between the three groups at an individual level. The accuracy of the algorithm and its statistical significance were estimated using leave-one-out cross-validation and permutation testing. RESULTS: When survivors with PTSD were compared against healthy controls, both grey and white matter allowed discrimination with an accuracy of 91% (p < 0.001). When survivors without PTSD were compared against healthy controls, the two groups could be discriminated with accuracies of 76% (p < 0.001) and 85% (p < 0.001) based on grey and white matter, respectively. Finally, when survivors with and without PTSD were compared directly, grey matter allowed discrimination with an accuracy of 67% (p < 0.001); in contrast the two groups could not be distinguished based on white matter. CONCLUSIONS: These results reveal patterns of neuroanatomical alterations that could be used to inform the identification of trauma survivors with and without PTSD at the individual level, and provide preliminary support to the development of SVM as a clinically useful diagnostic aid.

Are we really mapping psychosis risk? Neuroanatomical signature of affective disorders in subjects at ultra high risk.

BACKGROUND: The majority of people at ultra high risk (UHR) of psychosis also present with co-morbid affective disorders such as depression or anxiety. The neuroanatomical and clinical impact of UHR co-morbidity is unknown. METHOD: We investigated group differences in grey matter volume using baseline magnetic resonance images from 121 participants in four groups: UHR with depressive or anxiety co-morbidity; UHR alone; major depressive disorder; and healthy controls. The impact of grey matter volume on baseline and longitudinal clinical/functional data was assessed with regression analyses. RESULTS: The UHR-co-morbidity group had lower grey matter volume in the anterior cingulate cortex than the UHR-alone group, with an intermediate effect between controls and patients with major depressive disorder. In the UHR-co-morbidity group, baseline anterior cingulate volume was negatively correlated with baseline suicidality/self-harm and obsessive-compulsive disorder symptoms. CONCLUSIONS: Co-morbid depression and anxiety disorders contributed distinctive grey matter volume reductions of the anterior cingulate cortex in people at UHR of psychosis. These volumetric deficits were correlated with baseline measures of depression and anxiety, suggesting that co-morbid depressive and anxiety diagnoses should be carefully considered in future clinical and imaging studies of the psychosis high-risk state.

Reduced parahippocampal cortical thickness in subjects at ultra-high risk for psychosis.

BACKGROUND: Grey matter volume and cortical thickness represent two complementary aspects of brain structure. Several studies have described reductions in grey matter volume in people at ultra-high risk (UHR) of psychosis; however, little is known about cortical thickness in this group. The aim of the present study was to investigate cortical thickness alterations in UHR subjects and compare individuals who subsequently did and did not develop psychosis. METHOD: We examined magnetic resonance imaging data collected at four different scanning sites. The UHR subjects were followed up for at least 2 years. Subsequent to scanning, 50 UHR subjects developed psychosis and 117 did not. Cortical thickness was examined in regions previously identified as sites of neuroanatomical alterations in UHR subjects, using voxel-based cortical thickness. RESULTS: At baseline UHR subjects, compared with controls, showed reduced cortical thickness in the right parahippocampal gyrus (p < 0.05, familywise error corrected). There were no significant differences in cortical thickness between the UHR subjects who later developed psychosis and those who did not. CONCLUSIONS: These data suggest that UHR symptomatology is characterized by alterations in the thickness of the medial temporal cortex. We did not find evidence that the later progression to psychosis was linked to additional alterations in cortical thickness, although we cannot exclude the possibility that the study lacked sufficient power to detect such differences.

The association between psychosocial stress, interpersonal sensitivity, social withdrawal and psychosis relapse: a systematic review.

Psychosis is associated with a high risk of relapse, with 67% of clients relapsing within one year following a first episode. In light of the high personal, social, and healthcare costs of the illness, it is paramount to understand the risk factors associated with psychosis relapse. The current systematic review aims to critically review the role of psychosocial stress in psychosis relapse in individuals with an established psychotic disorder. This review systematically searched Ovid (PsycINFO, EMBASE, MEDLINE) literature databases from inception until 28th February 2022. Sixteen studies were eligible for inclusion. Most studies found that individuals with psychosis demonstrate high levels of psychosocial stress and are more likely to be socially withdrawn compared to healthy controls or other clinical presentations. Most studies reported a statistically significant association between psychosocial stress and psychosis relapse, as well as between social withdrawal and psychosis relapse. However, no studies examined the association between high levels of interpersonal sensitivity and psychosis relapse. Individuals with psychosis tend to experience high levels of psychosocial stress and social withdrawal, and these appear to increase the risk of psychosis relapse. Due to high levels of heterogeneity within the literature, we could only conduct a narrative synthesis of the findings. Future studies would benefit from employing a meta-analytic approach.

Psychosocial stress, interpersonal sensitivity, and social withdrawal in clinical high risk for psychosis: a systematic review.

Stress has repeatedly been implicated in the onset and exacerbation of positive symptoms of psychosis. Increasing interest is growing for the role of psychosocial stress in the development of psychosis symptoms in individuals at Clinical High Risk (CHR) for psychosis. A systematic review was therefore conducted to summarize the existing evidence base regarding psychosocial stress, interpersonal sensitivity, and social withdrawal in individuals at CHR for psychosis. An electronic search of Ovid (PsychINFO, EMBASE, MEDLINE, and GLOBAL HEALTH) was conducted until February 2022. Studies that examined psychosocial stress in CHR were included. Twenty-nine studies were eligible for inclusion. Psychosocial stress, interpersonal sensitivity, and social withdrawal were higher in CHR individuals compared to healthy controls and there was some evidence of their association with positive symptoms of psychosis. Two types of psychosocial stressors were found to occur more frequently with CHR status, namely daily stressors, and early and recent trauma, while significant life events did not appear to be significant. Greater exposure to psychosocial stress, emotional abuse, and perceived discrimination significantly increased risk of transition to psychosis in CHR. No studies examined the role of interpersonal sensitivity on transition to psychosis in CHR. This systematic review provides evidence for the association of trauma, daily stressors, social withdrawal, and interpersonal sensitivity with CHR status. Further studies investigating the impact of psychosocial stress on psychosis symptom expression in individuals at CHR and its effects on transition to psychosis are therefore warranted.

Pleiotropic cell-division defects and apoptosis induced by interference with survivin function.

Here we investigate the role of the control of apoptosis in normal cell division. We show that interference with the expression or function of the apoptosis inhibitor survivin causes caspase-dependent cell death in the G2/M phase of the cell cycle, and a cell-division defect characterized by centrosome dysregulation, multipolar mitotic spindles and multinucleated, polyploid cells. Use of a dominant-negative survivin mutant or antisense survivin complementary DNA disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21Waf1/Cip1 within centrosomes, and results in caspase-dependent cleavage of p21. Polyploidy induced by survivin antagonists is accentuated in p21-deficient cells, and corrected by exogenous expression of p21. These findings show that control of apoptosis and preservation of p21 integrity within centrosomes by survivin are required for normal mitotic progression.

Dysbindin modulates brain function during visual processing in children.

Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain function is poorly understood. It has been proposed that DTNBP1 may be associated with differences in visual processing. To test this, we examined the impact on visual processing in 61 healthy children aged 10-12 years of a genetic variant in DTNBP1 (rs2619538) that was common to all schizophrenia associated haplotypes in an earlier UK-Irish study. We tested the hypothesis that carriers of the risk allele would show altered occipital cortical function relative to noncarriers. Functional Magnetic Resonance Imaging (fMRI) was used to measure brain responses during a visual matching task. The data were analysed using statistical parametric mapping and statistical inferences were made at p<0.05 (corrected for multiple comparisons). Relative to noncarriers, carriers of the risk allele had greater activation in the lingual, fusiform gyrus and inferior occipital gyri. In these regions DTNBP1 genotype accounted for 19%, 20% and 14% of the inter-individual variance, respectively. Our results suggest that that genetic variation in DTNBP1 is associated with differences in the function of brain areas that mediate visual processing, and that these effects are evident in young children. These findings are consistent with the notion that the DTNBP1 gene influences brain development and can thereby modulate vulnerability to schizophrenia.

Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53.

The inhibitor of apoptosis protein survivin has been implicated in both cell cycle control and apoptosis resistance. To discriminate between these different roles, we used transgenic expression of survivin in the skin as a model for cell proliferation, differentiation, and apoptosis. Transgenic mice expressing survivin under the control of a keratin-14 promoter developed normally, without histologic abnormalities of the skin or hair, epidermal hyperplasia, or developmental abnormalities of basal or suprabasal epidermis. Keratinocyte proliferation assessed under basal conditions, or after ultraviolet-B (UVB) irradiation, or phorbol ester stimulation was unchanged in survivin transgenic mice. In contrast, survivin expression inhibited UVB-induced apoptosis in vitro and in vivo (i.e., sunburn cell formation), whereas it did not affect Fas-induced cell death. When crossed with p53 knockout mice, transgenic expression of survivin in a p53(+/-) background substituted for the loss of a second p53 allele and further inhibited UVB-induced apoptosis. These data provide the first in vivo evidence that survivin inhibits apoptosis and suggest that this pathway may oppose the elimination of cancerous cells by p53.

HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis.

The onset of psychosis is thought to involve interactions between environmental stressors and the brain, with cortisol as a putative mediator. We examined the relationship between the cortisol stress response and brain structure in subjects at ultra-high risk (UHR) for psychosis. Waking salivary cortisol was measured in 22 individuals at UHR for psychosis and 17 healthy controls. Grey matter volume was assessed using magnetic resonance imaging at 3 T. The relationship between the stress response and grey matter volume was investigated using voxel-based analyses. Our predictions of the topography of cortisol action as a structural brain modulator were informed by measures of brain glucocorticoid and mineralcorticoid receptor distribution obtained from the multimodal neuroanatomical and genetic Allen Brain Atlas. Across all subjects, reduced responsivity of the hypothalamus-pituitary-adrenal (HPA) axis was correlated with smaller grey matter volumes in the frontal, parietal and temporal cortex and in the hippocampus. This relationship was particularly marked in the UHR subjects in the right prefrontal, left parahippocampal/fusiform and parietal cortices. The subgroup that subsequently developed psychosis showed a significant blunting of HPA stress response, observed at trend level also in the whole UHR sample. Altered responses to stress in people at high risk of psychosis are related to reductions in grey matter volume in areas implicated in the vulnerability to psychotic disorders. These areas may represent the neural components of a stress vulnerability model.

Towards a Standard Psychometric Diagnostic Interview for Subjects at Ultra High Risk of Psychosis: CAARMS versus SIPS.

Background. Several psychometric instruments are available for the diagnostic interview of subjects at ultra high risk (UHR) of psychosis. Their diagnostic comparability is unknown. Methods. All referrals to the OASIS (London) or CAMEO (Cambridgeshire) UHR services from May 13 to Dec 14 were interviewed for a UHR state using both the CAARMS 12/2006 and the SIPS 5.0. Percent overall agreement, kappa, the McNemar-Bowker χ (2) test, equipercentile methods, and residual analyses were used to investigate diagnostic outcomes and symptoms severity or frequency. A conversion algorithm (CONVERT) was validated in an independent UHR sample from the Seoul Youth Clinic (Seoul). Results. There was overall substantial CAARMS-versus-SIPS agreement in the identification of UHR subjects (n = 212, percent overall agreement = 86%; kappa = 0.781, 95% CI from 0.684 to 0.878; McNemar-Bowker test = 0.069), with the exception of the brief limited intermittent psychotic symptoms (BLIPS) subgroup. Equipercentile-linking table linked symptoms severity and frequency across the CAARMS and SIPS. The conversion algorithm was validated in 93 UHR subjects, showing excellent diagnostic accuracy (CAARMS to SIPS: ROC area 0.929; SIPS to CAARMS: ROC area 0.903). Conclusions. This study provides initial comparability data between CAARMS and SIPS and will inform ongoing multicentre studies and clinical guidelines for the UHR psychometric diagnostic interview.

Control of apoptosis and mitotic spindle checkpoint by survivin.

Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry and controlling ploidy (chromosome number), the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein, survivin, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.

Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin.

The interface between apoptosis (programmed cell death) and the cell cycle is essential to preserve homeostasis and genomic integrity. Here, we show that survivin, an inhibitor of apoptosis over-expressed in cancer, physically associates with the cyclin-dependent kinase p34(cdc2) on the mitotic apparatus, and is phosphorylated on Thr(34) by p34(cdc2)-cyclin B1, in vitro and in vivo. Loss of phosphorylation on Thr(34) resulted in dissociation of a survivin-caspase-9 complex on the mitotic apparatus, and caspase-9-dependent apoptosis of cells traversing mitosis. These data identify survivin as a mitotic substrate of p34(cdc2)-cyclin B1 and suggest that survivin phosphorylation on Thr(34) may be required to preserve cell viability at cell division. Manipulation of this pathway may facilitate the elimination of cancer cells at mitosis.