Enhanced cortisol suppression following administration of low-dose dexamethasone in first-episode psychosis patients

OBJECTIVE Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis and hyper-activity of this system have been described in patients with psychosis. Conversely, some psychiatric disorders such as post-traumatic stress disorder (PTSD) are characterised by HPA hypo-activity, which could be related to prior exposure to trauma. This study examined the cortisol response to the administration of low-dose dexamethasone in first-episode psychosis (FEP) patients and its relationship to childhood trauma. METHOD The low-dose (0.25 mg) Dexamethasone Suppression Test (DST) was performed in 21 neuroleptic-naive or minimally treated FEP patients and 20 healthy control participants. Childhood traumatic events were assessed in all participants using the Childhood Trauma Questionnaire (CTQ) and psychiatric symptoms were assessed in patients using standard rating scales. RESULTS FEP patients reported significantly higher rates of childhood trauma compared to controls (p = 0.001) and exhibited lower basal (a.m.) cortisol (p = 0.04) and an increased rate of cortisol hyper-suppression following dexamethasone administration compared to controls (33% (7/21) vs 5% (1/20), respectively; p = 0.04). There were no significant group differences in mean cortisol decline or percent cortisol suppression following the 0.25 mg DST. This study shows for the first time that a subset of patients experiencing their first episode of psychosis display enhanced cortisol suppression. CONCLUSIONS These findings suggest there may be distinct profiles of HPA axis dysfunction in psychosis which should be further explored.

Cortisol and dehydroepiandrosterone-sulphate levels correlate with symptom severity in first-episode psychosis

Dehydroepiandrosterone (DHEA) and its sulphate form (DHEA) are neuroactive steroids with antiglucocorticoid properties. An imbalance in the ratio of cortisol to DHEA(S) has been implicated in the pathophysiology of stress-related psychiatric disorders. This study prospectively investigated circulating cortisol, DHEAS and their ratio in first-episode psychosis (FEP) patients compared to healthy controls, and their relationship to perceived stress, psychotic, negative and mood symptoms. METHODS: Blood cortisol and DHEAS levels were obtained in 39 neuroleptic-naïve or minimally-treated FEP patients and 25 controls. Twenty-three patients and 15 controls received repeat assessments after 12 weeks. Perceived stress was assessed using the Perceived Stress Scale and symptoms were assessed in patients using standard rating scales. RESULTS: At baseline, no differences were observed in cortisol, DHEAS or the cortisol/DHEAS ratio between patients and controls. There were also no group differences in the change in these biological variables during the study period. Within FEP patients, decreases in cortisol and the cortisol/DHEAS ratio over time were directly related to the improvement in depression (r = 0.45; p = 0.031, r = 0.52; p = 0.01), negative (r = 0.51; p = 0.006, r = 0.55; p = 0.008) and psychotic symptoms (cortisol only, r = 0.53; p = 0.01). Perceived stress significantly correlated with DHEAS (r = 0.51; p = 0.019) and the cortisol/DHEAS ratio (r = -0.49; p = 0.024) in controls, but not patients, possibly reflecting an impaired hormonal response to stress in FEP patients. CONCLUSIONS: These findings further support the involvement of the stress system in the pathophysiology of psychotic disorders, with implications for treatment strategies that modulate these neurosteroids.

Relationship between vocational status and perceived stress and daily hassles in first-episode psychosis: An exploratory study

PURPOSE Vocational recovery is a primary treatment goal of young people with first-episode psychosis (FEP), yet treatment in this domain is often delayed due to concerns that it might be too stressful. This study aimed to examine whether a relationship exists between vocational status and level of perceived stress and daily hassles in FEP. METHODS Forty-seven FEP participants were recruited upon admission to the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne. Demographics, psychopathology, perceived stress (Perceived Stress Scale; PSS) and daily hassles (Hassles Scale; HS) were measured. RESULTS Regarding vocational status, 19 participants were unemployed, 13 were employed, 14 were students, and 1 reported 'home duties'. ANOVAs and post hoc tests comparing the first three groups on perceived stress and daily hassles revealed that the mean PSS Total and mean PSS Distress scores of the employed group were significantly lower than those of the unemployed and student groups. Regarding hassles scores, the employed group had a significantly lower mean Hassles Intensity score than the unemployed group. Results were largely unchanged when covariates were included. There were no significant differences between the three groups in levels of anxiety, negative or positive symptoms. The employed group reported lower depression than the student group, but this finding disappeared after controlling for gender. CONCLUSIONS These results provide preliminary evidence supporting the notion that working or studying is not associated with increased perceived stress or daily hassles in FEP. The findings require replication in larger samples and in different phases of psychosis.

The effect of atypical antipsychotics on pituitary gland volume in patients with first-episode psychosis: A longitudinal MRI study

BACKGROUND: Pituitary volume is currently measured as a marker of hypothalamic-pituitary-adrenal hyperactivity in patients with psychosis despite suggestions of susceptibility to antipsychotics. Qualifying and quantifying the effect of atypical antipsychotics on the volume of the pituitary gland will determine whether this measure is valid as a future estimate of HPA-axis activation in psychotic populations. AIMS: To determine the qualitative and quantitative effect of atypical antipsychotic medications on pituitary gland volume in a first-episode psychosis population. METHOD: Pituitary volume was measured from T1-weighted magnetic resonance images in a group of 43 first-episode psychosis patients, the majority of whom were neuroleptic-naive, at baseline and after 3months of treatment, to determine whether change in pituitary volume was correlated with cumulative dose of atypical antipsychotic medication. RESULTS: There was no significant baseline difference in pituitary volume between subjects and controls, or between neuroleptic-naive and neuroleptic-treated subjects. Over the follow-up period there was a negative correlation between percentage change in pituitary volume and cumulative 3-month dose of atypical antipsychotic (r=-0.37), i.e. volume increases were associated with lower doses and volume decreases with higher doses. CONCLUSIONS: Atypical antipsychotic medications may reduce pituitary gland volume in a dose-dependent manner suggesting that atypical antipsychotic medication may support affected individuals to cope with stress associated with emerging psychotic disorders.

Pituitary volume and early treatment response in drug-naïve first-episode psychosis patients

BACKGROUND: An early response to antipsychotic treatment in patients with psychosis has been associated with a better course and outcome. However, factors that predict treatment response are not well understood. The onset of schizophrenia and related disorders has been associated with increased levels of stress and hyper-activation of the hypothalamic-pituitary-adrenal (HPA) axis. This study examined whether pituitary volume at the onset of psychosis may be a potential predictor of early treatment response in first-episode psychosis (FEP) patients. METHODS: We investigated the relationship between baseline pituitary volume and symptomatic treatment response over 12 weeks using mixed model analysis in a sample of 42 drug-naïve or early treated FEP patients who participated in a controlled dose-finding study of quetiapine fumarate. Logistic regression was used to examine predictors of treatment response. Pituitary volume was measured from magnetic resonance imaging scans that were obtained upon entry into the trial. RESULTS: Larger pituitary volume was associated with less improvement in overall psychotic symptoms (Brief Psychiatric Rating Scale (BPRS) P=0.031) and positive symptoms (BPRS positive symptom subscale P=0.010). Regardless of gender, patients with a pituitary volume at the 25th percentile (413 mm(3)) were approximately three times more likely to respond to treatment by week 12 than those at the 75th percentile (635 mm(3)) (odds ratio=3.07, CI: 0.90-10.48). CONCLUSION: The association of baseline pituitary volumes with early treatment response highlights the importance of the HPA axis in emerging psychosis. Potential implications for treatment strategies in early psychosis are discussed.

Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis

Background We examined pituitary volume before the onset of psychosis in subjects who were at ultra-high risk (UHR) for developing psychosis. Methods Pituitary volume was measured on 1.5-mm, coronal, 1.5-T magnetic resonance images in 94 UHR subjects recruited from admissions to the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia and in 49 healthy control subjects. The UHR subjects were scanned at baseline and were followed clinically for a minimum of 1 year to detect transition to psychosis. Results Within the UHR group, a larger baseline pituitary volume was a significant predictor of future transition to psychosis. The UHR subjects who later went on to develop psychosis (UHR-P, n = 31) had a significantly larger (+12%; p = .001) baseline pituitary volume compared with UHR subjects who did not go on to develop psychosis (UHR-NP, n = 63). The survival analysis conducted by Cox regression showed that the risk of developing psychosis during the follow-up increased by 20% for every 10% increase in baseline pituitary volume (p = .002). Baseline pituitary volume of the UHR-NP subjects was smaller not only compared with UHR-P (as described above) but also compared with control subjects (−6%; p = .032). Conclusions The phase before the onset of psychosis is associated with a larger pituitary volume, suggesting activation of the HPA axis.

Medication adherence of individuals with a first episode of psychosis

Objective To determine rates of adherence to antipsychotic medication in first episode patients and the correlates of adherence in this group. Method Subjects were the first 200 admissions to an Early Psychosis Program. Adherence was determined on a three-point scale. Symptoms, medication side-effects, quality of life, substance use and family involvement were examined longitudinally. Results In their first year in the program 39% were non-adherent, 20% inadequately adherent, and 41% adherent. Non-adherent patients demonstrated more positive symptoms, more relapses, more alcohol and cannabis use, reduced insight, and poorer quality of life. They were younger, had an earlier age of onset and less likely to have a family member involved in treatment. Conclusion Results for this group are similar to those reported in the literature. Correlates are often the consequence of non-adherence. Non-compliance has to be anticipated and relationships maintained with patients and families to intervene as soon as possible to minimize the consequence of non-compliance.

The first episode of psychosis: The experience of relatives

Objective The aim was to determine the extent of and the correlates of the distress and impact of care families of patients with first episode psychosis were experiencing when they first came for treatment. Method Subjects were 238 individuals who had presented with a first episode of psychosis and their family members. Family members were assessed with the Psychological General Well-Being Scale, and the Experience of Caregiving Inventory. Patient data included assessment of positive and negative symptoms, depression, quality of life, and substance use. Results Family members of these first-episode patients were experiencing distress and difficulties. It was the family's appraisal of the impact of the illness that was associated with their psychological well-being. Conclusion As the majority of these first episode families are keen to be involved early and have engaged in an intervention programme, the next step should be an evaluation of their involvement to determine if it is effective.

Can exploring natural recovery from substance misuse in psychosis assist with treatment? A review of current research

Substance misuse in people with psychosis presents significant problems, but trials of treatments to address it show little sustained advantage over control conditions. An examination of mechanisms underpinning unassisted improvements may assist in the refinement of co-morbidity treatments. This study reviewed existing research on natural recovery from substance misuse in people with psychosis. To address this issue, a systematic search identified only 7 articles that fulfilled the criteria. Their results suggest that people with psychosis report similar reasons to change as do non-psychotic groups, although they did not clarify whether the relative frequencies or priority orders were the same. Differences involved issues relating to the disorder and the functional problems faced by this group: receipt of treatment for mental health difficulties, worsening of mental health difficulties, and homelessness. The current research on reasons for change in people with psychosis is sparse and has significant limitations, and as yet it offers little inspiration for new treatments. A more fertile source may prove to be a detailed investigation of successful substance control strategies that are used in self-management by this group.

Natural recovery from cannabis use in people with psychosis: A qualitative study

- Objective There is rapidly growing evidence of natural recovery from cannabis use in people with psychosis, but little is known about how it occurs. This qualitative study explores what factors influence the decision to cease cannabis use, maintain cessation, and prevent relapse. - Methods Ten people with early psychosis and lifetime cannabis misuse, who had been abstinent for at least a month, were recruited from public adult mental health services. These six men and four women participated in a semi-structured qualitative interview assessing reasons for addressing cannabis use, effective change strategies, lapse contexts, and methods used to regain control. Interpretative phenomenological analysis was used to identify themes in their responses. - Results Participants had a mean age of 23 years (SD = 3.7), started using cannabis at age 13.7 (SD = 1.6), began daily use at 17 (SD = 3.1), and had abstained from cannabis for 7.9 months (SD = 5.4). Awareness of the negative impact of substance use across multiple domains and the presence of social support for cannabis cessation were seen as vital to sustained success, as was utilization of a combination of coping strategies. The ability to address pressure from substance-using peers was commonly mentioned. - Conclusions Maximally effective treatment may need to focus on eliciting a range of benefits of cessation and control strategies and on maximizing both support for change and resistance to peer pressure. Further research might focus on comparing perceived effective strategies between individuals who obtain sustained cessation versus those who relapse.

The prevalence and correlates of childhood trauma in patients with early psychosis

Objective: To describe the prevalence and demographic, clinical and functional correlates of childhood trauma in patients attending early psychosis clinics. Method: Participants were recruited from outpatients attending four early psychosis services. Exposure to childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Psychopathology was measured using the Positive and Negative Syndrome Scale and the Depression, Anxiety and Stress Scale. Social and vocational functioning and substance use were also assessed. Results: Over three-quarters of the 100 patients reported exposure to any childhood trauma. Emotional, physical and sexual abuse were reported by 54%, 23% and 28% of patients, respectively, while 49% and 42% of patients reported emotional and physical neglect, respectively. Female participants were significantly more likely to be exposed to emotional and sexual abuse. Exposure to childhood trauma was correlated with positive psychotic symptoms and higher levels of depressive, anxiety and stress symptoms; however, it had no impact on social or vocational functioning or recent substance use. Conclusion: Exposure to childhood trauma was common in patients with early psychosis, and associated with increased symptomatology. Existing recommendations that standard clinical assessment of patients with early psychosis should include inquiry into exposure to childhood trauma are supported.

Antioxidant defense system and family environment in adolescents with family history of psychosis

[EN] Our objective was to determine antioxidant defence activity in healthy controls (HC) and healthy unaffected second-degree relatives of patients with early onset psychosis (HC-FHP),and to assess its relationship with familiar environment measured using the Family Environment Scale (FES). Methods: We included 82 HC and 14 HC-FHP aged between 9 and 17 years. Total antioxidant status,lipid peroxidation, antioxidant enzyme activities and glutathione levels were determined in blood samples. Results:There was a significant decrease in the total antioxidant level in the HC-FHP group compared with the HC group (OR = 2.94; p = 0.009), but no between-group differences in the Global Assessment of Functioning (GAF) scale scores. For the FES, the HC-FHP group had significantly higher scores in the cohesion (p = 0.007) and intellectual-cultural dimensions (p=0.025). After adjusting for these two FES dimensions, total antioxidant status remained significantly different between groups (OR = 10.86, p = 0.009).

Plasma brain-derived neurotrophic factor levels, learning capacity and cognition in patients with first episode psychosis

Background: Cognitive impairments are seen in first psychotic episode (FEP) patients. The neurobiological underpinnings that might underlie these changes remain unknown. The aim of this study is to investigate whether Brain Derived Neurotrophic Factor (BDNF) levels are associated with cognitive impairment in FEP patients compared with healthy controls. Methods: 45 FEP patients and 45 healthy controls matched by age, gender and educational level were selected from the Basque Country area of Spain. Plasma BDNF levels were assessed in healthy controls and in patients. A battery of cognitive tests was applied to both groups, with the patients being assessed at 6 months after the acute episode and only in those with a clinical response to treatment. Results: Plasma BDNF levels were altered in patients compared with the control group. In FEP patients, we observed a positive association between BDNF levels at six months and five cognitive domains (learning ability,immediate and delayed memory, abstract thinking and processing speed) which persisted after controlling for medications prescribed, drug use, intelligence quotient (IQ) and negative symptoms. In the healthy control group, BDNF levels were not associated with cognitive test scores. Conclusion: Our results suggest that BDNF is associated with the cognitive impairment seen after a FEP. Further investigations of the role of this neurotrophin in the symptoms associated with psychosis onset are warranted.

Cannabis use and involuntary admission may mediate long-term adherence in first-episode psychosis patients: a prospective longitudinal study

Background: This study aimed to examine factors associated with treatment adherence in first-episode psychosis (FEP) patients followed up over 8 years, especially involuntary first admission and stopping cannabis use. Methods: This prospective, longitudinal study of FEP patients collected data on symptoms, adherence, functioning,and substance use. Adherence to treatment was the main outcome variable and was categorized as ‘good’ or ‘bad’. Cannabis use during follow-up was stratified as continued use, stopped use, and never used. Bivariate and logistic regression models identified factors significantly associated with adherence and changes in adherence over the 8-year follow-up period. Results: Of the 98 FEP patients analyzed at baseline, 57.1% had involuntary first admission, 74.4% bad adherence,and 52% cannabis use. Good adherence at baseline was associated with Global Assessment of Functioning score (p = 0.019), Hamilton Depression Rating Scale score (p = 0.017) and voluntary admission (p < 0.001). Adherence patterns over 8 years included: 43.4% patients always bad, 26.1% always good, 25% improved from bad to good. Among the improved adherence group, 95.7% had involuntary first admission and 38.9% stopped cannabis use. In the subgroup of patients with bad adherence at baseline, involuntary first admission and quitting cannabis use during follow up were associated with improved adherence. Conclusions: The long-term association between treatment adherence and type of first admission and cannabis use in FEP patients suggest targets for intervention to improve clinical outcomes.