A systematic review on mediators between adversity and psychosis: potential targets for treatment.

Various psychological and biological pathways have been proposed as mediators between childhood adversity (CA) and psychosis. A systematic review of the evidence in this domain is needed. Our aim is to systematically review the evidence on psychological and biological mediators between CA and psychosis across the psychosis spectrum. This review followed PRISMA guidelines. Articles published between 1979 and July 2019 were identified through a literature search in OVID (PsychINFO, Medline and Embase) and Cochrane Libraries. The evidence by each analysis and each study is presented by group of mediator categories found. The percentage of total effect mediated was calculated. Forty-eight studies were included, 21 in clinical samples and 27 in the general population (GP) with a total of 82 352 subjects from GP and 3189 from clinical studies. The quality of studies was judged as 'fair'. Our results showed (i) solid evidence of mediation between CA and psychosis by negative cognitive schemas about the self, the world and others (NS); by dissociation and other post-traumatic stress disorder symptoms; and through an affective pathway in GP but not in subjects with disorder; (iii) lack of studies exploring biological mediators. We found evidence suggesting that various overlapping and not competing pathways involving post-traumatic and mood symptoms, as well as negative cognitions contribute partially to the link between CA and psychosis. Experiences of CA, along with relevant mediators should be routinely assessed in patients with psychosis. Evidence testing efficacy of interventions targeting such mediators through cognitive behavioural approaches and/or pharmacological means is needed in future.

A Novel Earwax Method to Measure Acute and Chronic Glucose Levels.

Diabetes is the fourth cause of death globally. To date, there is not a practical, as well as an accurate sample for reflecting chronic glucose levels. We measured earwax glucose in 37 controls. Participants provided standard serum, glycated hemoglobin (HbA1c) and earwax samples at two time-points, one month apart. The specimens measured baseline fasting glucose, a follow-up postprandial glucose level and a between sample chronic glucose, calculated using the average level on the two occasions. The baseline earwax sample was obtained using a clinical method and the follow-up using a novel self-sampling earwax device. The earwax analytic time was significantly faster using the novel device, in comparison to the clinical use of the syringe. Earwax accurately reflected glucose at both assessments with stronger correlations than HbA1c. Follow-up postprandial concentrations were more significant than their respective fasting baseline concentrations, reflecting differences in fasting and postprandial glycemia and more efficient standardization at follow up. Earwax demonstrated to be more predictable than HbA1c in reflecting systemic fasting, postprandial and long-term glucose levels, and to be less influenced by confounders. Earwax glucose measurements were approximately 60% more predictable than HbA1c in reflecting glycemia over a month. The self-sampling device provided a sample that might accurately reflect chronic glycemia.

Measuring Earwax Cortisol Concentration using a non-stressful sampling method.

BACKGROUND: "Short-term" samples are not the most appropriate for reflecting chronic cortisol concentration. Although hair is used for reflecting the systemic level of this hormone, its use as a "long-term" measure appears clinically problematic. Local and systemic stress and non-stress related factors may release cortisol that is accumulated in hair. Non-stressful earwax sampling methods may provide a more accurate specimen to measure chronic cortisol concentration. METHODS: Earwax from both ears of 37 controls were extracted using a clinical procedure commonly associated with local pain. One month later, earwax from the left ear side was extracted using the same procedure, and earwax from the right ear side was more comfortably obtained, using a novel earwax self-sampling device. Participants also provided one centimetre of hair that represented the retrospective month of cortisol output, and one serum sample that reflected the effect of systemic stressors on cortisol levels. Earwax (ECC), Hair (HCC) and Serum (SCC) Cortisol Concentration were correlated and compared. Confounders' effect on cortisol levels were studied. RESULTS: The highest levels of cortisol concentration were found in serum, and the lowest in hair (p < 0.01). Left-ECC was larger than Right-ECC (p = 0.03). Right-ECC was the only sample unaffected by confounders (all p > 0.05). A Pearson correlation showed that Right-ECC and HCC samples were moderately correlated between them (r = 0.39; p = 0.03). CONCLUSIONS: The self-sampling device did not increase cortisol locally. It provided the cortisol level that was least likely to be affected by confounding factors over the previous month. ECC using the novel device might constitute another accurate, but more suitable and affordable specimen for measuring chronic cortisol concentration.

Comparison of short-term (saliva) and long-term (hair) cortisol levels in out-patients with melancholic and non-melancholic major depression.

BACKGROUND: Major depressive episodes (MDEs) show diverse cortisol level alterations. Heterogeneity in symptom profiles, symptom severity and cortisol specimens may explain these heterogeneous results. Less severely ill out-patients with a non-melancholic MDE (NM-MDE) may have a variation in the rhythm of cortisol secretion rather than in its concentration. METHOD: Cortisol measures were taken (a) over a short-term period (12 h) by measuring daily salivary output using the area under the curve with respect to the ground (AUCg) and (b) over a long-term period (3 months) in hair. Additionally, cortisol reactivity measures in saliva - the cortisol awakening response and the 30 min delta cortisol secretion after awakening (DELTA) - were investigated in 19 patients with a melancholic MDE (M-MDE) and 52 with a NM-MDE, and in 40 matched controls who were recruited from the UK and Chile. Depression severity scores were correlated with different cortisol measures. RESULTS: The NM-MDE group showed a decreased AUCg in comparison with controls (P = 0.02), but normal cortisol reactivity and long-term cortisol levels. The M-MDE group did not exhibit any significant cortisol alterations nor an association with depression severity scores. Higher Hamilton Rating Scale for Depression score was linked with decreased hair cortisol concentration (HCC, P = 0.05) and higher DELTA (P = 0.04) in NM-MDEs, whereas decreased HCC was the sole alteration associated with out-patients with severe M-MDEs. CONCLUSIONS: The contrasting short- and long-term cortisol output results are compatible with an alteration in the rhythm of cortisol secretion in NM-MDEs. This alteration may consist of large and/or intense episodes of hypercortisolaemia in moderate NM-MDEs and frequent, but brief and sharp early-morning DELTAs in its severe form. These changes may reflect the effects of environmental factors or episodes of nocturnal hypercortisolaemia that were not measured by the short-term samples used in this study.

Cortisol levels in chronic fatigue syndrome and atypical depression measured using hair and saliva specimens.

BACKGROUND: Several diagnostic criteria for major depressive disorder (MDE) overlap with those of Chronic Fatigue Syndrome (CFS). Furthermore, atypical MDE (A-MDE), a subtype of MDE characterised by profound fatigue and which has frequently been linked with CFS, exhibits similar low cortisol levels to CFS. However, this result has been only found in specimens designed for measuring acute cortisol levels. In this study, we measure cortisol levels in subjects with CFS and in subjects with A-MDE, without psychiatric comorbidity, using both hair and saliva specimens, to gain a measure of both short and long-term cortisol levels in these two conditions. METHODS: Hair cortisol concentration, representing the cortisol concentration of the previous three months, and salivary cortisol, measured at six time-points across one day and including the cortisol awakening response (CAR), post-awakening delta cortisol and the total daily output, were assessed in an age and gender matched group of 34 controls, 15 subjects with A-MDE and 17 with CFS. RESULTS: CFS (mean 92.2 nmol/l.h, s.d. 33.2 nmol/l.h) and A-MDE (mean 89.1 nmol/l.h, s.d. 22.6 nmol/l.h) subjects both showed lower cortisol total daily output in saliva (AUCg) in comparison to healthy controls (mean 125.5 nmol/l.h, s.d. 40.6 nmol/l.h). However, hair cortisol concentration was not lower than that of controls in either patient group. CFS and A-MDE did not differ from one another on any cortisol measures. CFS subjects reported fewer daily hassles and less severe psychic anxiety symptoms in comparison to A-MDE subjects (all p < 0.05). However, they did not differ in the severity of somatic anxiety symptoms. There was also no difference in the presence of overlapping symptoms such as fatigability and concentration/memory problems between A-MDE and CFS subjects. CONCLUSION: Low levels of cortisol found using short-term measures of daily output may be transient, since cortisol levels were normal when a long-term measure (hair) was studied. This might be explained by a potential cortisol rhythm alteration. Although these disorders have their distinctive depressive and somatic features, they may from part of a wider group of Somatic Symptom Disorders (SSD), given the findings of the same pattern of cortisol secretion in both disorders and increased frequency of overlapping clinical features.

Cortisol levels in unmedicated patients with unipolar and bipolar major depression using hair and saliva specimens.

BACKGROUND: Differentiating between unipolar and bipolar depression can be clinically challenging, especially at first presentation. Patterns of cortisol secretion could aid diagnostic discrimination in affective disorders although there has been little comparative research to date. In this study, we investigated acute (saliva) and chronic (hair) cortisol levels concurrently in unmedicated unipolar and bipolar disorders by using conventional diagnostic criteria and self-report measures. METHODS: Patients with unipolar and bipolar major depression and healthy controls were recruited and assessed. Cortisol levels were extracted from saliva and hair specimens. Depressive features were investigated according to diagnostic groups and with a continuous self-report measure of bipolarity using the Hypomania Checklist (HCL-33). RESULTS: Whilst a trend towards a reduction in the total daily salivary cortisol output-area under the curve with respect to the ground (AUCg)-was detected in depressive disorders across diagnosis, the self-administrated bipolarity index suggested that an increase in bipolarity symptoms predicted lower cortisol levels using AUCg. Chronic cortisol measurement did not discriminate unipolar from bipolar depression. CONCLUSION: Results suggested that whilst a low total daily salivary cortisol output (AUCg) might be associated with depressive symptoms, a self-reported measure of bipolarity predicts lower daily cortisol output.

Psychological trauma occurring during adolescence is associated with an increased risk of greater waist circumference in Early Psychosis patients treated with psychotropic medication.

BACKGROUND: It has been suggested that exposure to Childhood Trauma [CT] may play a role in the risk of obesity in Early Psychosis [EP] patients; however, whether this is independently of age at exposure to CT and the medication profile has yet to be investigated. METHODS: 113 EP-patients aged 18-35 were recruited from the Treatment and Early Intervention in Psychosis Program [TIPP-Lausanne]. Body Mass Index [BMI], Weight Gain [WG] and Waist Circumference [WC] were measured prospectively at baseline and after 1, 2, 3, 6 and 12 months of weight gain inducing psychotropic treatment. Patients were classified as Early-Trauma and Late-Trauma if the exposure had occurred before age 12 or between ages 12 and 16 respectively. Generalized Linear Mixed-Models were adjusted for age, sex, socioeconomic status, baseline BMI, medication and for diagnosis of depression. RESULTS: Late-Trauma patients, when compared to Non-Trauma patients showed greater WCs during the follow-up [p = 0.013]. No differences were found in any of the other follow-up measures. CONCLUSIONS: Exposition to CT during adolescence in EP-patients treated with psychotropic medication is associated with greater WC during the early phase of the disease. Further investigation exploring mechanisms underlying the interactions between peripubertal stress, corticoids responsiveness and a subsequent increase of abdominal adiposity is warranted.

Glutamatergic hypofunction in medication-free major depression: Secondary effects of affective diagnosis and relationship to peripheral glutaminase.

BACKGROUND: There is uncertainty as to whether alterations in glutamatergic function in affective disorders differ between unipolar and bipolar disorders and between depressive and euthymic states. Additionally, there are currently no available blood-based markers of central glutamatergic function to support clinical diagnosis and aid brain based investigations. METHODS: In this study, we measured levels of glutamate in the dorsal anterior cingulate cortex in-vivo using 1H-Magnetic Resonance Spectroscopy in medication free unipolar and bipolar patients (n = 29, 20 unipolar and 9 bipolar) experiencing a major depressive episode, in comparison with a group of matched healthy controls (n = 20). We also analysed peripheral glutaminase measured in serum to examine the relationship between central and peripheral measures. RESULTS: Anterior cingulate glutamate levels were reduced in both unipolar and bipolar depression groups relative to healthy controls, although this only reached significance in the unipolar group. Peripheral glutaminase levels did not differentiate bipolar from unipolar depression and a positive correlation with central glutamate levels did not reach statistical significance. LIMITATIONS: The sample of bipolar disorder patients was relatively small due to the difficulties involved in finding medication-free patients experiencing a depressive episode. CONCLUSIONS: These results suggest that glutamatergic hypofunction might represent a state marker for a depressive episode irrespective of diagnosis. Peripheral glutaminase did not index central glutamate levels in this study, which could potentially reflect a small magnitude of the effect requiring larger samples for detection.

Elevated fingernail cortisol levels in major depressive episodes.

BACKGROUND: The extent to which cortisol levels are elevated in major depressive episodes (MDE), and hence could act as a biomarker of illness, remains unclear. Although patient characteristics may explain some of this variation - for example elevated cortisol being more often found in patients with severe, psychotic or melancholic depression - problems with the methods used to measure cortisol may also have contributed to the inconsistent findings. Fingernails are a novel sample that can be used to assess aggregate cortisol concentrations over a 15-day period, and may provide a more accurate reflection of longer term cortisol level changes in MDE and help clarify this issue. This methodology has not yet been utilised in MDE. METHODS: Cortisol levels reflecting a period of 15days were measured using fingernails in a group of 26 subjects experiencing a major depressive episode (MDE) and in an age and gender matched group of 45 healthy controls. RESULTS: Depressed subjects showed significantly higher mean cortisol levels measured in fingernails when compared with control subjects. Higher levels of cortisol were associated with higher depression severity scores, a diagnosis of non-reactive depression, and more prominent melancholic symptoms. Conversely, fatigue was negatively correlated with cortisol levels. CONCLUSION: There is elevated cortisol in MDE when assessed using an aggregate measure over two weeks.Alterations in fingernail cortisol correlate with key clinical symptoms and subtypes of depression.

Cortisol levels in fingernails, neurocognitive performance and clinical variables in euthymic bipolar I disorder.

OBJECTIVES: Neurocognitive impairment has been found in bipolar patients. Hypercortisolemia is one possible cause but there has been no agreement on this. Previous sampling methods assessed only acute cortisol levels, whereas the association between cortisol and psychopathology might be better understood by investigating chronic levels. Fingernails are a novel method for measuring chronic cortisol concentration (CCC). Here, we measured CCC in euthymic bipolar disorder I (BD-I) patients and healthy controls using fingernails to investigate whether differences in CCC influenced neurocognitive performance. We also investigated whether differences in clinical illness variables influenced CCC in euthymic BD-I patients. METHODS: A previous study demonstrated neurocognitive impairment in euthymic BD-I patients. The current study included a portion of this sample: 40 BD-I versus 42 matched controls who provided fingernail samples. RESULTS: There was no statistically significant difference in CCC between controls and BD-I (P = .09). Logistic regression analyses revealed that euthymic bipolar I subjects with more than five years of current euthymia had decreased odds of having higher fingernail cortisol concentration (>71.2 pg/mg) compared to those with less than 1.5 years (P = .04). There was no association between CCC and cognitive impairment in all domains before and after adjustment for age and sex. CONCLUSIONS: The current evidence suggests CCC is not a trait biomarker in euthymic BD-I (BD-I). Longer periods of stability in affective disorders are associated with lower CCC. Fingernail cortisol does not seem to be implicated in neurocognitive impairment and BD-I. Future studies may investigate CCC in different illness phases of BD-I.