Diagnosis of amyotrophic lateral sclerosis (ALS) takes more than 1year from detection of first symptoms. The paper seeks to understand the ALS diagnostic process and adjustment from the perspective of informal caregivers.

The data stems from an interview study with 9 current and 13 bereaved informal caregivers of people with ALS in Switzerland. The interviews were analyzed using thematic analysis.

We identified 3 key themes pertaining to ALS diagnosis. In the first theme, we present the close involvement of informal caregivers in the “diagnosis journey.” Highlighted within this theme is the important role they play, which ultimately leads to diagnosis of ALS avoiding further delays. Second, we relay their perceptions on “diagnosis communication pitfalls” where they underlined empathy and planning from the part of medical professional, while communicating the terminal diagnosis of ALS. Participants’ reactions and adjustments post-ALS diagnosis are described in “the aftermath of diagnosis.” In this third theme, we highlight participants’ shock and their need to rethink overall life plans and roles in their family.

Diagnosis communication that is clear, empathetic, and adjusted to the needs of the patients as well as their caregivers is critical. More work is needed to improve diagnosis communication for ALS patients. Receiving the diagnosis of ALS leads to complete changes in life of caregivers. It is therefore necessary that medical professionals provide adequate support that allows them to plan for their future.

1. (I) Profound alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis regulation were repeatedly shown in depressed patients. The most sensitive challenge test of the HPA axis, the combined dexamethasone/CRH test (DEX/CRH test), shows an overstimulation of ACTH and cortisol in depressed patients. Under tricyclic antidepressant treatment, a normalization of the HPA axis overdrive was found to precede the clinical improvement.

2. (II) Lithium is a well established drug for the treatment of affective disorders. Yet, its exact mode of action and its effects on the HPA axis are still unknown.

Three 4-week studies with each 30 acutely depressed patients (unipolar, SCID I confirmed) were conducted. In study 1, patients refractory to a treatment trial with an antidepressant of at least four weeks were treated with lithium augmentation. In study 2 and 3, drug free patients were treated with lithium monotherapy or citalopram monotherapy respectively. Weekly HAM-D ratings were performed. In each study, the DEX/CRH test was conducted right before and four weeks after initiation of the pharmacotherapy.

All three pharmacological strategies showed good antidepressive efficacy. Both lithium monotherapy and lithium augmentation led to a (for most parameters significant) increase in the HPA axis activity. In contrast, citalopram monotherapy resulted in a decrease of the hormone response to the DEX/CRH test.

Low platelet MAO-B activity has been associated with various forms of impulsive behaviour and suicidality. The present study investigated the relationship between MAO-B activity in platelets and aspects of suicidality in depressed patients and controls.

In 87 patients with affective spectrum disorders (58% suffering from a Major Depressive Episode - MDE) the potential association between platelet MAO-B activity and suicidality was examined. 59 of the patients had committed suicide attempt recently (SA - “suicide attempters”), 28 patients were acutely depressed without having shown suicidal thoughts or suicidal behaviour in the past (NA - “non suicide attempters”).

SA and NA were comparable as to their diagnoses and general demographic and psychopathological parameters. MAO-B activity did not differ between SA and NA. No systematic correlations existed between MAO-B activity and any dimensions of suicidal behaviour or psychopathology. As a single finding only a weak positive association of higher MAO-B activity in SA with a fatal intention of the suicide attempt was observed.

Our findings do not support a consistent association of platelet MAO-B activity and suicidal behaviour in general, but specific facts of suicidality might be associated.

Neuroendocrine changes of the stress hormone system and REM sleep abnormalities are potential vulnerability markers for depression. Investigating underlying genetics provides new insights into the molecular pathways of these endophenotypes and into the pathophysiology of depression vulnerability. We selected a high-risk linkage and endophenotype approach, i.e., we investigated REM sleep abnormalities (REM density) and altered stress hormone regulation (dex/CRH test) in families with a high prevalence of major depression.

Eleven families were so far included, comprising 82 high risk family members. 32 of them were unaffected, 33 remitted, and 17 suffered from an affective disorder at the time of the investigation. Illumina Infinium Whole Genome genotyping with 100k bead chips was performed. Variance component (VC), and a quantitative trait linkage analysis (QTL) on polysomnographic (REM density) and neuroendocrine vulnerability markers (dex/CRH test) were applied.

Linkage analysis (VC, QTL) revealed suggestive linkage (LOD score > 2) for altered REM density at loci of the chromosomes 2, 4, 8 and X. The linkage results on chromosomes 2 and X correspond to previous findings. No results were obtained with a classical diagnosis based linkage approach.

The use of quantitative vulnerability markers in a high risk family study and a SNP based whole genome approach revealed a number of loci with suggestive linkage, that were not detectable with the classical linkage approach. Our findings suggest the suitability of investigating vulnerability marker in combination with a SNP based whole genome approach in complex disorders like depression.

In depression, changes in EEG sleep measures are well documented findings. However, the predictive value of these alterations for treatment and long-term course of depression still warrants clarification. Therefore, we examined whether the previous course of depression, treatment response during antidepressant therapy, and the long-term outcome in follow-up are associated with sleep regulation. Since the hypothalamic-pituitary-adrenocortical (HPA) system may play a crucial role in depression's neurobiology, we evaluated HPA system function as well.

15 patients (4 men, 11 women; age 43–59) with depression were enrolled in the study. HPA system assessment using the combined DEX/CRH test and sleep EEG studies were conducted at baseline, after a 6 week antidepressant treatment period (trimipramine), and at follow-up, i.e., after 2-10 years.

The previous clinical course, i.e., the number of episodes until baseline, correlated significantly with EEG sleep measures i.e. sleep continuity values, slow wave sleep (SWS) and REM latency.

During treatment sleep continuity values improved and the correlation with the previous long-term course disappeared. The correlation with SWS persisted. The only sleep EEG marker at baseline predictive for treatment response was REM latency.

In the prospective long-term outcome SWS and REM density variables were related to the occurrence of recurrences. These sleep EEG markers correlated closely with HPA system regulation.

The long-term outcome of depression is related to the sleep EEG pattern: SWS and REM density measures may reflect predictive markers for the long-term course. These markers are associated with HPA system regulation.

To determine predictors of transition from ultrahigh risk into psychosis.

The Dutch EDIE trial has included 201 people with an ultrahigh risk for psychosis. These were included with both a referral based strategy and a screening all help-seeking people strategy. The study had a 24 month inclusion period and an 18 mont follow-up period with each patient. The preliminary results are presented.

A loogistic regression was performed over 164 cases. 29 patients developed a psychosis.

Predictor variables were depression, social intercation anxiety, positive symptoms on the CAARMS, negative symptoms on the CAARMS, quality of life, social functioning, genetic risk, and the personal beliefs about illness.

The backward logistice regression (likelyhood ratio) discarded four variables. Predictors of psychosis were depression, positive symptoms, genetic liability and beliefs about illness at basline.

People with hihd scores on depression and positive symptoms are likely to develop a psychosis. Also those who have a psychotic parent and positive symptoms a more lekly to make a transition. Interestingly people that consider their condition as hopeless, feel entrapped by their condition, excluded by other pople and not in control of symptoms also have a heightened chance for developing psychosis in this sample.

Psychological stress is associated with accelerated cellular aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear.

We examined the effect of stress on a DNA methylation age predictor that was shown to correlate strongly with chronological age across human tissues (Horvath 2013). Genome-wide DNA methylation was measured in peripheral blood using the 450K Illumina array in three independent cohorts: the Grady Trauma Project/GTP (N=366); a panic disorder case/control sample recruited at the Max Planck Institute of Psychiatry/MPI-P (N=318); and the Conte Center for the Psychobiology of Early-Life Trauma/Conte (N=42). Age acceleration was calculated by subtracting chronological age from age predicted by DNA methylation. Psychiatric symptomatology and stressors were assessed using standard questionnaires.

DNA methylation age strongly correlated with chronological age in all samples (r=0.9, p=2.5x10^-133). Cumulative lifetime stress but not childhood or current stress predicted age acceleration in GTP (p=0.012) and MPI-P (p=0.021). Moreover, epigenetic age acceleration predicted depression (GTP: p=0.002; Conte: p=0.014) and panic disorder (p=0.007). In secondary analyses, we examined the effect of lifetime stress on individual CpGs of the DNA methylation age predictor. After correcting for multiple comparisons, we identified in both GTP and MPI-P a stress-regulated CpG near MCAM, a gene implicated in aging-related diseases, including cardiovascular disease and cancers.

Cumulative lifetime stress, but not childhood or current stress, and psychiatric phenotypes are associated with accelerated epigenetic aging. Our findings may explain the accelerated cellular aging and increased disease risk associated with chronic stress and psychiatric disorders.

Self-ratings of psychotic experiences might be biased by depressive symptoms.

Data from a large naturalistic multicentre trial on depressed inpatients (n = 488) who were assessed on a biweekly basis until discharge were analyzed. Self-rated psychotic symptoms as assessed with the 90-Item Symptom Checklist (SCL-90) were correlated with the SCL-90 total score, the SCL-90 depression score, the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale 21 item (HAMD-21) total score, the Montgomery Åsberg Depression Rating Scale (MADRS) total score and the clinician-rated paranoid-hallucinatory score of the Association for Methodology and Documentation in Psychiatry (AMDP) scale.

At discharge the SCL-90 psychosis score correlated highest with the SCL-90 depression score (0.78, P<0.001) and with the BDI total score (0.64, P<0.001). Moderate correlations were found for the MADRS (0.34, P<0.001), HAMD (0.37, P<0.001) and AMDP depression score (0.33, P<0.001). Only a weak correlation was found between the SCL-90 psychosis score and the AMDP paranoid-hallucinatory syndrome score (0.15, P<0.001). Linear regression showed that change in self-rated psychotic symptoms over the treatment course was best explained by a change in the SCL-90 depression score (P<0.001). The change in clinician-rated AMDP paranoid-hallucinatory score had lesser influence (P = 0.02).

In depressed patients self-rated psychotic symptoms correlate poorly with clinician-rated psychotic symptoms. Caution is warranted when interpreting results from epidemiological surveys using self-rated psychotic symptom questionnaires as indicators of psychotic symptoms. Depressive symptoms which are highly prevalent in the general population might influence such self-ratings.

Current ultra-high-risk (UHR) criteria appear insufficient to predict imminent onset of first-episode psychosis, as a meta-analysis showed that about 20% of patients have a psychotic outcome after 2 years. Therefore, we aimed to develop a stage-dependent predictive model in UHR individuals who were seeking help for co-morbid disorders.

Baseline data on symptomatology, and environmental and psychological factors of 185 UHR patients (aged 14–35 years) participating in the Dutch Early Detection and Intervention Evaluation study were analysed with Cox proportional hazard analyses.

At 18 months, the overall transition rate was 17.3%. The final predictor model included five variables: observed blunted affect [hazard ratio (HR) 3.39, 95% confidence interval (CI) 1.56–7.35, p < 0.001], subjective complaints of impaired motor function (HR 5.88, 95% CI 1.21–6.10, p = 0.02), beliefs about social marginalization (HR 2.76, 95% CI 1.14–6.72, p = 0.03), decline in social functioning (HR 1.10, 95% CI 1.01–1.17, p = 0.03), and distress associated with suspiciousness (HR 1.02, 95% CI 1.00–1.03, p = 0.01). The positive predictive value of the model was 80.0%. The resulting prognostic index stratified the general risk into three risk classes with significantly different survival curves. In the highest risk class, transition to psychosis emerged on average ⩾8 months earlier than in the lowest risk class.

Predicting a first-episode psychosis in help-seeking UHR patients was improved using a stage-dependent prognostic model including negative psychotic symptoms (observed flattened affect, subjective impaired motor functioning), impaired social functioning and distress associated with suspiciousness. Treatment intensity may be stratified and personalized using the risk stratification.

Previous research has established the relationship between cannabis use and psychotic disorders. Whether cannabis use is related to transition to psychosis in patients at ultra-high risk (UHR) for psychosis remains unclear. The present study aimed to review the existing evidence on the association between cannabis use and transition to psychosis in UHR samples.

A search of PsychInfo, Embase and Medline was conducted from 1996 to August 2015. The search yielded 5559 potentially relevant articles that were selected on title and abstract. Subsequently 36 articles were screened on full text for eligibility. Two random-effects meta-analyses were performed. First, we compared transition rates to psychosis of UHR individuals with lifetime cannabis use with non-cannabis-using UHR individuals. Second, we compared transition rates of UHR individuals with a current DSM-IV cannabis abuse or dependence diagnosis with lifetime users and non-using UHR individuals.

We found seven prospective studies reporting on lifetime cannabis use in UHR subjects (n = 1171). Of these studies, five also examined current cannabis abuse or dependence. Lifetime cannabis use was not significantly associated with transition to psychosis [odds ratio (OR) 1.14, 95% confidence interval (CI) 0.856–1.524, p = 0.37]. A second meta-analysis yielded an OR of 1.75 (95% CI 1.135–2.710, p = 0.01), indicating a significant association between current cannabis abuse or dependence and transition to psychosis.

Our results show that cannabis use was only predictive of transition to psychosis in those who met criteria for cannabis abuse or dependence, tentatively suggesting a dose–response relationship between current cannabis use and transition to psychosis.

To report the occurrence of a concurrent oropharyngeal papilloma and branchial cleft cyst linked by p16INK4A and human papillomavirus immunohistochemistry.

A 42-year-old woman presented with a 1-month history of a left lateral neck mass. Contrast enhanced computed tomography showed a hypodense lesion 20 mm in diameter anteromedial to the left sternocleidomastoid muscle. Ultrasound-guided fine needle aspiration suggested a branchial cleft cyst. Panendoscopy was performed at the time of neck mass removal, and a papillomatous lesion was removed from the left hypopharynx. Histopathological analysis showed the neck lesion to be a branchial cyst containing lymphoid tissue, and the oral lesion to be a squamous papilloma. Immunohistochemical analysis showed both the branchial cleft cyst and papilloma to be positive for p16INK4A expression and human papillomavirus DNA.

Histological and immunohistochemical analyses support the cystic transformation of lymph nodes, or the ‘Inclusion Theory’, as the aetiology of branchial apparatus anomalies, and raise the possibility that human papillomavirus infection may play a much larger role in disease of the head and neck than previously supposed.

Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).

For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.

Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.

AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

Although there is evidence for the effectiveness of interventions for psychosis among ultra-high-risk (UHR) groups, health economic evaluations are lacking. This study aimed to determine the cost effectiveness and cost–utility of cognitive–behavioural therapy (CBT) to prevent first-episode psychosis.

The Dutch Early Detection and Intervention Evaluation study was a randomized controlled trial of 196 UHR patients with an 18-month follow-up. All participants were treated with routine care (RC) for non-psychotic disorders. The experimental group (n = 95) received add-on CBT to prevent first-episode psychosis. We report the intervention, medical and travel costs, as well as costs arising from loss of productivity. Treatment response was defined as psychosis-free survival and quality-adjusted life years (QALYs) gained.

In the cost-effectiveness analysis, the proportion of averted psychoses was significantly higher in the CBT condition (89.5% v. 76.2%). CBT showed a 63.7% probability of being more cost effective, because it was less costly than RC by US$844 (£551) per prevented psychosis. In the cost–utility analysis, QALY health gains were slightly higher for CBT than for RC (0.60 v. 0.57) and the CBT intervention had a 52.3% probability of being the superior treatment because, for equal or better QALY gains, the costs of CBT were lower than those of RC.

Add-on preventive CBT for UHR resulted in a significant reduction in the incidence of first psychosis. QALY gains show little difference between the two conditions. The CBT intervention proved to be cost saving.

The gene product of the ABCB1 gene, the P-glycoprotein, functions as a custodian molecule in the blood–brain barrier and regulates the access of most antidepressants into the brain. Previous studies showed that ABCB1 polymorphisms predicted the response to antidepressants that are substrates of the P-gp, while the response to nonsubstrates was not influenced by ABCB1 polymorphisms. The aim of the present study was to evaluate the clinical application of ABCB1 genotyping in antidepressant pharmacotherapy.

Data came from 58 depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project, whose ABCB1 gene test results were implemented into the clinical decision making process. Hamilton Depression Rating Scale (HAM-D) scores, remission rates, and duration of hospital stay were documented with dose and kind of antidepressant treatment.

Patients who received ABCB1 genotyping had higher remission rates [χ2(1) = 6.596, p = 0.005, 1-sided] and lower Hamilton sores [t(111) = 2.091, p = 0.0195, 1-sided] at the time of discharge from hospital as compared to patients without ABCB1 testing. Among major allele homozygotes for ABCB1 single nucleotide polymorphisms (SNPs) rs2032583 and rs2235015 (TT/GG genotype), an increase in dose was associated with a shorter duration of hospital stay [rho(28) = –0.441, p = 0.009, 1-sided], whereas other treatment strategies (eg, switching to a nonsubstrate) showed no significant associations with better treatment outcome.

The implementation of ABCB1 genotyping as a diagnostic tool influenced clinical decisions and led to an improvement of treatment outcome. Patients carrying the TT/GG genotype seemed to benefit from an increase in P-gp substrate dose.

Results suggest that antidepressant treatment of depression can be optimized by the clinical application of ABCB1 genotyping.

Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies.

We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings.

A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This ‘heritability’ was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10−8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R2 = 0.08 in SLEs (p = 0.03).

These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.

Traditionally, a 1-cm surgical resection margin is used for early oral tongue tumours.

All tumour stage one (n = 65) and stage two (n = 13) oral tongue cancers treated between January 1999 and January 2009 were followed for a median of 38 months (minimum 12 months). The sites of close and involved margins were histologically reviewed.

Involved and close margins occurred in 14 and 55 per cent of cases, respectively. The number of involved vs clear or close margins was equivalent in tumour stage one (90 vs 82 per cent), node-negative (100 vs 84 per cent) and perineural or lymphovascular invasion (20 vs 21 per cent) cases. Close or involved margins were similarly likely to be posterior (59 per cent) as anterior (41 per cent, p = 0.22), lateral (57 per cent) as medial (43 per cent, p = 0.34), and mucosal (59 per cent) as deep (41 per cent, p = 0.22). Local recurrence occurred in 28 per cent of cases at a median of 12 months, and was more likely in cases with involved (50 per cent) than clear or close margins (25 per cent, p = 0.10). Disease-free survival was worse in involved margins cases (p = 0.002).

Involved margins are common in early tongue tumours, and are associated with increased local recurrence and worse survival. Close or involved margins occur in all directions and all tumour types. A wider margin may be justified.

Depression frequently co-occurs with somatization, and somatic complaints have been reported as a vulnerability marker for affective disorders observable before disease onset. Somatization is thought to result from an increased attention to somatic sensations, which should be reflected in long-latency somatosensory evoked electroencephalogram (EEG) potentials (SSEPs) at the physiological level. Previous studies revealed that SSEPs are altered in depressed patients and suggested late SSEP components as vulnerability markers for affective disorders. Neurotransmitters such as serotonin, γ-aminobutyric acid (GABA) and the neuropeptide substance P may play an important role for both affective disorders and somatosensory processing.

We investigated the associations between SSEPs and polymorphisms within candidate genes of the serotonergic, GABAergic as well as the substance P system in subjects at high risk for affective disorders. The sample was composed of high-risk families participating in the Munich Vulnerability Study and genetic association analyses were calculated using qfam (family-based association tests for quantitative traits) implemented in PLINK 1.05.

We observed significant associations (false discovery rate <0.05) withstanding correction for multiple testing between late SSEP components (response strength 170–370 ms after stimulation) and four single nucleotide polymorphisms within the GABA transaminase (ABAT) gene region coding for a protein responsible for GABA degradation. No effects were found with the classical disease trait approach, suggesting SSEP marker specificity of the observed associations.

Our findings point to a possible role of ABAT gene-regulated GABA catabolism for an altered processing of somatosensory stimuli as a potential vulnerability marker for affective disorders.