Posttraumatic stress disorder in people with dementia: study protocol.

Background: Posttraumatic stress disorder (PTSD) is considered an independent risk factor for dementia. Despite the (clinical) evidence that PTSD is associated with neuropsychiatric symptoms in people with dementia, studies on its prevalence and clinical manifestation are limited, and their quality is affected by the lack of a structured method to diagnose PTSD in this population. The primary aim of the current study is to validate the 'TRAuma and DEmentia' interview as a diagnostic tool for PTSD in people with dementia and to test feasibility of EMDR treatment for people with PTSD and dementia.Methods: This prospective multi-centre study is divided into two parts. In study A, 90 participants with dementia will be included to test the criterion validity, inter-rater reliability and feasibility of the 'TRAuma and DEmentia' interview. In study B, 29 participants with dementia and PTSD will receive eye movement desensitisation and reprocessing therapy by a trained psychologist, and 29 participants with dementia and PTSD will be placed on the waiting list control group.Conclusion: This study aims to improve the diagnostic process of PTSD and to assess the effects of eye movement desensitisation and reprocessing treatment in people with dementia living in Dutch care facilities.Trial registration: NL70479.068.20 / METC 20-063 / OSF registration: https://doi.org/10.17605/OSF.IO/AKW4F.

This study protocol describes a two-part study on posttraumatic stress disorder in people with dementia in Dutch care facilities.The primary aim of the study is to validate the 'TRAuma and DEmentia' interview as a diagnostic tool for posttraumatic stress disorder in people with dementia.This study aims to test the feasibility of an evidence-based treatment for people with dementia and posttraumatic stress disorder in the form of eye movement desensitisation and reprocessing therapy.

Delayed affective recovery to daily-life stressors signals a risk for depression.

OBJECTIVE: The aim of this study is to investigate the time to affective recovery from daily-life stressors between healthy controls (HC) and two groups with an increased risk for developing depression: individuals with subclinical symptoms of depression (SSD), and individuals remitted from a depressive episode with residual symptoms of depression (RRS). METHOD: The experience sampling method (ESM) was used to measure affective recovery to daily-life stressors. Affective recovery was defined as the moment that negative affect (NA) returned to baseline level following the first stressful event of the day. We assessed two different operationalizations of the baseline: NA at the moment before the stressful event (t-1), and mean-person NA. The effect of stress intensity, and cumulative stress were also assessed. RESULTS: Survival analyses showed significantly longer recovery times for the at risk groups in comparison to healthy individuals, albeit no significant difference was found between the two at risk groups (i.e. SSD and RRS). There was also an effect of cumulative stress, but not stress intensity on time to recovery in that cumulative stress resulted in significantly longer recovery times for all three groups. LIMITATIONS: The present study is limited by the ESM sampling design, assessments take place post-stress and therefore do not capture peak stress. Additionally, we are only able to assess patterns at the group level. Finally, there is a significant age difference between groups. CONCLUSION: Individuals at risk for depression display a delayed recovery to daily-life stressors when compared to healthy controls, which is not explained by differences in stress intensity or cumulative stress. Understanding what is driving this delay may help combat the development of depression.

[Ethical issues for the further development of psychiatric deep brain stimulation]. / Ethische aandachtspunten bij de verdere ontwikkeling van psychiatrische diepe hersenstimulatie.

BACKGROUND: Except in the case of obsessive-compulsive disorder, deep brain stimulation (DBS) for psychiatric indications is an experimental treatment, reserved for the most severe and treatment resistant cases. AIM: To discuss ethical aspects for the further development of DBS in psychiatry. METHOD: Ethical reflection. RESULTS: The low number of patients and the experimental character of the treatment hamper the collection of scientific evidence and the safeguarding of patients being indicated for DBS. Apart from that, special care should be taken in assessing competency and the ability to provide informed consent. CONCLUSION: Interest in the subjective experiences of patients being treated with DBS, proactive ethical reflection and an increase in the scale of research efforts are essential for the acceptance and further development of DBS for psychiatric indications.

DNA methylation in the 5-HTT regulatory region is associated with CO2-induced fear in panic disorder patients.

A polymorphism in the gene encoding the serotonin (5-HT) transporter (5-HTT) has been shown to moderate the response to CO2 inhalation, an experimental model for panic attacks (PAs). Recurrent, unpredictable PAs represent, together with anticipatory anxiety of recurring attacks, the core feature of panic disorder (PD) and significantly interfere with patients' daily life. In addition to genetic components, accumulating evidence suggests that epigenetic mechanisms, which regulate gene expression by modifying chromatin structure, also play a fundamental role in the etiology of mental disorders. However, in PD, epigenetic mechanisms have barely been examined to date. In the present study, we investigated the relationship between methylation at the regulatory region of the gene encoding the 5-HTT and the reactivity to a 35% CO2 inhalation in PD patients. We focused on four specific CpG sites and found a significant association between the methylation level of one of these CpG sites and the fear response. This suggests that the emotional response to CO2 inhalation might be moderated by an epigenetic mechanism, and underlines the implication of the 5-HT system in PAs. Future studies are needed to further investigate epigenetic alterations in PD and their functional consequences. These insights can increase our understanding of the underlying pathophysiology and support the development of new treatment strategies.

Human fear conditioning: From neuroscience to the clinic.

Both clinicians and neuroscientists have been long interested in the topic of fear conditioning, with recent advances in neuroscience, in particular, igniting a shared interest in further translation between these domains. Here, we review some historical aspects of this relationship and the progress that has been made in translating the neuroscientific study of fear conditioning to the conceptualization and treatment of mental disorders, especially anxiety-related disorders. We also address some conceptual and methodological challenges faced by this research, and offer some suggestions to support future progress in the field.

No differences in olanzapine- and risperidone-related weight gain between women and men: a meta-analysis of short- and middle-term treatment.

OBJECTIVE: A plethora of data deriving from single studies as well as meta-analyses demonstrates that weight gain is associated with the exposure to the majority of antipsychotics (AP). However, potential sex differences have widely evaded the attention of AP treatment trials. It is hypothesised that female patients gain more weight compared with male patients due to their enhanced susceptibility to adverse drug reactions. METHOD: A meta-analysis was conducted using clinical trials of AP that reported weight change separately for female and male patients. Duration of AP use was stratified in four categories: <6 weeks, 6-16 weeks, 16-38 weeks and >38 weeks. Forest plots were generated for men and women separately, stratified by AP as well as by duration of use. Sex differences were tested by performing meta-regression. RESULTS: Data of 26 studies were used in the present analysis because sufficient data were available only for olanzapine, risperidone and the no-medication group. Both female and male patients showed considerable weight gain after switch or initiate of olanzapine or risperidone, but meta-regression analyses did not show significant sex differences. CONCLUSION: The present meta-analysis revealed that sex differences in AP-related weight gain have been under investigated hampering the detection of sex-specific patterns. In chronic patients switching to olanzapine or risperidone receiving short-or middle-term treatment, AP were associated with weight gain in both sex subgroups and no significant differences were reported.

The long-term association of OCD and depression and its moderators: A four-year follow up study in a large clinical sample.

BACKGROUND: Depression is the most common comorbidity in obsessive-compulsive disorder (OCD). However, the mechanisms of depressive comorbidity in OCD are poorly understood. We assessed the directionality and moderators of the OCD-depression association over time in a large, prospective clinical sample of OCD patients. METHODS: Data were drawn from 382 OCD patients participating at the Netherlands Obsessive-Compulsive Disorder Association (NOCDA) study. Cross-lagged, structural equation modeling analyses were used to assess the temporal association between OCD and depressive symptoms. Assessments were conducted at baseline, two-year and four-year follow up. Cognitive and interpersonal moderators of the prospective association between OCD and depressive symptoms were tested. RESULTS: Cross-lagged analyses demonstrated that OCD predicts depressive symptoms at two-year follow up and not vice a versa. This relationship disappeared at four-year follow up. Secure attachment style moderated the prospective association between OCD and depression. CONCLUSIONS: Depressive comorbidity in OCD might constitute a functional consequence of the incapacitating OCD symptoms. Both OCD and depression symptoms demonstrated strong stability effects between two-year and four-year follow up, which may explain the lack of association between them in that period. Among OCD patients, secure attachment represents a buffer against future depressive symptoms.

Deep brain stimulation of the subthalamic nucleus in obsessive-compulsive disorder: Neuroanatomical and pathophysiological considerations.

Obsessive-compulsive disorder (OCD) is among the most disabling chronic psychiatric disorders and has a significant negative impact on multiple domains of quality of life. For patients suffering from severe refractory OCD, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been applied. Reviewing the literature of the last years we believe that through its central position within the cortico-basal ganglia-thalamocortical circuits, the STN has a coordinating role in decision-making and action-selection mechanisms. Dysfunctional information-processing at the level of the STN is responsible for some of the core symptoms of OCD. Research confirms an electrophysiological dysfunction in the associative and limbic (non-motor) parts of the STN. Compared to Parkinson׳s disease patients, STN neurons in OCD exhibit a lower firing rate, less frequent but longer bursts, increased burst activity in the anterior ventromedial area, an asymmetrical left-sided burst distribution, and a predominant oscillatory activity in the δ-band. Moreover, there is direct evidence for the involvement of the STN in both checking behavior and OCD symptoms, which are both related to changes in electrophysiological activity in the non-motor STN. Through a combination of mechanisms, DBS of the STN seems to interrupt the disturbed information-processing, leading to a normalization of connectivity within the cortico-basal ganglia-thalamocortical circuits and consequently to a reduction in symptoms. In conclusion, based on the STN׳s strategic position within cortico-basal ganglia-thalamocortical circuits and its involvement in action-selection mechanisms that are responsible for some of the core symptoms of OCD, the STN is a mechanism-based target for DBS in OCD.

CO2 exposure as translational cross-species experimental model for panic.

The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral-emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.

The brain acid-base homeostasis and serotonin: A perspective on the use of carbon dioxide as human and rodent experimental model of panic.

Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed.

Age of onset in obsessive-compulsive disorder: admixture analysis with a large sample.

BACKGROUND: Research into age of onset in obsessive-compulsive disorder (OCD) has indicated significant differences between patients with early and late onset of the disorder. However, multiple criteria have been used arbitrarily for differentiating between early- and late-onset OCD, rendering inconsistent results that are difficult to interpret. METHOD: In the current study, admixture analysis was conducted in a sample of 377 OC patients to determine the number of underlying populations of age of onset and associated demographic and clinical characteristics. Various measures of anxiety, depression, co-morbidity, autism, OCD, tics and attention deficit hyperactivity disorder (ADHD) symptoms were administered. RESULTS: A bimodal age of onset was established and the best-fitting cut-off score between early and late age of onset was 20 years (early age of onset ≤19 years). Patients with early age of onset were more likely to be single. Early age of onset patients demonstrated higher levels of OCD severity and increased symptoms on all OCD dimensions along with increased ADHD symptoms and higher rates of bipolar disorder. CONCLUSIONS: It is suggested that 20 years is the recommended cut-off age for the determination of early versus late age of onset in OCD. Early age of onset is associated with a generally graver OCD clinical picture and increased ADHD symptoms and bipolar disorder rates, which may be related to greater functional implications of the disorder. We propose that age of onset could be an important marker for the subtyping of OCD.

Prenatal stress and subsequent exposure to chronic mild stress in rats; interdependent effects on emotional behavior and the serotonergic system.

Exposure to prenatal stress (PS) can predispose individuals to the development of psychopathology later in life. We examined the effects of unpredictable chronic mild stress (CMS) exposure during adolescence on a background of PS in male and female Sprague-Dawley rats. PS induced more anxiety-like behavior in the elevated zero maze in both sexes, an effect that was normalized by subsequent exposure to CMS. Moreover, PS was associated with increased depression-like behavior in the forced swim test in males only. Conversely, sucrose intake was increased in PS males, whilst being decreased in females when consecutively exposed to PS and CMS. Hypothalamo-pituitary-adrenal (HPA) axis reactivity was affected in males only, with higher stress-induced plasma corticosterone levels after PS. Markedly, CMS normalized the effects of PS on elevated zero maze behavior as well as basal and stress-induced plasma corticosterone secretion. At the neurochemical level, both PS and CMS induced various sex-specific alterations in serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) immunoreactivity in the dorsal raphe nucleus, hippocampus and prefrontal cortex with, in line with the behavioral observations, more profound effects in male offspring. In conclusion, these findings show that prenatal maternal stress in Sprague-Dawley rats induces various anxiety- and depression-related behavioral and neuroendocrine changes, as well as alterations in central 5-HT and TPH2 function, predominantly in male offspring. Moreover, CMS exposure partially normalized the effects of previous PS experience, suggesting that the outcome of developmental stress exposure largely depends on the environmental conditions later in life and vice versa.

Resilience in mental health: linking psychological and neurobiological perspectives.

OBJECTIVE: To review the literature on psychological and biological findings on resilience (i.e. the successful adaptation and swift recovery after experiencing life adversities) at the level of the individual, and to integrate findings from animal and human studies. METHOD: Electronic and manual literature search of MEDLINE, EMBASE and PSYCHINFO, using a range of search terms around biological and psychological factors influencing resilience as observed in human and experimental animal studies, complemented by review articles and cross-references. RESULTS: The term resilience is used in the literature for different phenomena ranging from prevention of mental health disturbance to successful adaptation and swift recovery after experiencing life adversities, and may also include post-traumatic psychological growth. Secure attachment, experiencing positive emotions and having a purpose in life are three important psychological building blocks of resilience. Overlap between psychological and biological findings on resilience in the literature is most apparent for the topic of stress sensitivity, although recent results suggest a crucial role for reward experience in resilience. CONCLUSION: Improving the understanding of the links between genetic endowment, environmental impact and gene-environment interactions with developmental psychology and biology is crucial for elucidating the neurobiological and psychological underpinnings of resilience.

[The characterisation of anxiety disorders: staging and profiling based on common sense]. / De karakterisering van angststoornissen: stageren en profileren met gezond verstand.

BACKGROUND: Clinicians need to be well informed about staging and profiling so that they can divide patients with anxiety disorders into groups according to the phase and severity of their illness. The group to which the patient is assigned determines the types of treatment he or she receives. AIM: To investigate ways in which clinicians can be helped to apply staging and profiling procedures to patients with anxiety disorders. METHOD: We searched the literature for articles about the staging and profiling of anxiety disorders. RESULTS: There seems to be practically no literature relating to the staging and profiling of anxiety disorders. However, in daily practice clinicians do attempt to classify their patients and use forms of staging when deciding on special types of treatment for their patients and when assessing the length of treatment required. The revised Dutch guidelines on anxiety disorders include a generalised form of staging, called 'stepped care’. These revisions have been made on the basis of consensus decisions reached by the guideline committee. CONCLUSION: The revised guidelines on anxiety disorders assist clinicians with the application of staging in their daily practice. However, because of the lack of scientific data, our article closes with the presentation of a research agenda.

The association between social phobia, social anxiety cognitions and paranoid symptoms.

OBJECTIVE: Previous research suggests high levels of comorbidity between social phobia and paranoid symptoms, although the nature of this association remains unclear. METHOD: Data were derived from the Early Developmental Stages of Psychopathology study, a 10-year longitudinal study in a representative German community sample of 3021 participants aged 14-24 years at baseline. The Munich-Composite International Diagnostic Interview was used to assess social phobia and paranoid symptoms, along with data on social phobia features. Cross-sectional and longitudinal analyses were conducted. Differential associations with environmental risk factors and temperamental traits were investigated. RESULTS: Lifetime social phobia and paranoid symptoms were associated with each other cross-sectionally (OR = 1.80, 95% CI = 1.31-2.47). Lifetime paranoid symptoms were associated specifically with social anxiety cognitions. Lifetime cognitions of negative evaluation predicted later onset of paranoid symptoms, whereas onset of social phobia was predicted by cognitions of loss of control and fear/avoidance of social situations. Lifetime social phobia and paranoid symptoms shared temperamental traits of behavioural inhibition, but differed in environmental risks. CONCLUSIONS: The present study showed that paranoid symptoms and social phobia share similarities in cognitive profile and inhibited temperament. Avoidance appears to be important in the development of social phobia, whereas cannabis use and traumatic experiences may drive paranoid thinking in vulnerable individuals.

Acids in the brain: a factor in panic?

Several methods to experimentally induce panic cause profound acid-base disturbances. Evidence suggests that CO(2) inhalations, lactate infusions and, to a certain extent, voluntary hyperventilation can conceivably lead to a common scenario of brain acidosis in the face of disparate intravascular pH alterations. The importance of this event is reflected in data that support a model in which experimental panic attacks, as proxy to those occurring spontaneously, constitute a response to acute brain acidosis. Given that central CO(2)/H(+) chemoreception is an important drive for ventilation, and many chemosensitive neurons are related to respiration and arousal, this model can explain much of the connection between panic and respiration. We propose that the shared characteristics of CO(2)/H(+) sensing neurons overlap to a point where threatening disturbances in brain pH homeostasis, such as those produced by CO(2) inhalations, elicit a primal emotion that can range from breathlessness to panic.

Desynchrony of fear in phobic exposure.

Intuitively, phobic exposure would seem to be a very stressful experience. However, it is not clear whether the characteristic feature of a classic stress response, activation of the hypothalamic-pituitary-adrenal (HPA) axis, is present in phobic fear. Some instances of phobic fear have been found to be accompanied by robust increases in cortisol, whereas in other instances a dissociation between subjective-behavioural arousal and the HPA-axis has been found. The latter is referred to as desynchrony of fear. The aim of the current study was to test the hypothesis that phobic fear is similar to normal fear and, as such, is accompanied by a robust increase in cortisol values. In all, 16 spider phobic subjects and 16 healthy controls participated in the study. During and following a standardised stepwise exposure paradigm, saliva samples were collected for cortisol determination. In contrast to the controls, the spider phobics reacted with a strong fear reaction to the spiders. However, cortisol levels remained unaffected. The phobic response did not resemble the classic 'fight or flight' response. Some suggest that the HPA-axis response has become extinguished in modern man. Yet, it is possible that phobic fear is not a derivative of an ancient fear but rather a separate entity that relies on other neuroendocrinological systems.

The effects of opioid receptor blockade on experimental panic provocation with CO2.

Several reports have linked, among other aspects, the role of an opioid system in respiratory physiology with underlying mechanisms of panic attacks. The involvement of the opioid system in experimental panic is to be further probed. This study aimed to determine whether opioid blockade would increase panic-related symptomatology on provocation with 35% CO2 inhaled by healthy volunteers. Participants in a double-blind, randomised crossover design orally received either 50 mg of naltrexone or placebo. Most subjects undertook a double inhalation of 35% CO2 one hour after pre-medication, and a separate group did so after five hours. The reactivity to CO2 and the symptoms elicited by naltrexone alone were measured. Among other findings, naltrexone pre-medication alone elicited significant increments in panic-related symptoms. Responses to CO2 were not significantly different between conditions in either group. These preliminary findings suggest that exposure to opioid blockade alone can potentially elicit symptoms that resemble panic, however, without modifying the response to experimental panic provocation with 35% CO2.

The influence of ethanol infusion on the effects of 35% CO2 challenge. A study in panic disorder patients and healthy volunteers.

UNLABELLED: Alcohol and panic disorders co-occur at a rate that exceeds chance significantly. Early experimental work suggests that alcoholic subjects, compared to non-alcoholics, are less sensitive to sodium lactate and that alcohol intake reduces the response to a 35% CO(2) challenge in Panic Disorder patients. The present study documents the direct pharmacological effect of ethanol infusion on CO(2) induced panic. METHODS: According to a placebo-controlled, double-blind, randomized, cross-over design 10 drug free panic disorder patients and 16 healthy volunteers underwent a 35% CO(2) challenge after intravenous infusion of a moderate dose of ethanol on one test day and of placebo on another test day. RESULTS: Compared to the placebo condition, the effect of the CO(2) challenge was significantly smaller after ethanol infusion (P = 0.041). DISCUSSION: A moderate dose of ethanol decreased the response to a 35% CO(2) without inducing pre challenge sedation. CONCLUSION: The results comfort earlier findings of a direct pharmacological effect of ethanol on panic.

Anxiety sensitivity in children of panic disorder patients.

Anxiety sensitivity (AS), which refers to the tendency to interpret anxiety-related bodily sensations as having potentially harmful somatic, psychological or social consequences, has been proposed as a vulnerability factor for the development of panic disorder (PD). The current study examined the anxiety sensitivity levels in children of parents with panic disorder. Children of panic disorder patients (n = 68) and children of healthy parents (n = 68) filled out the Childhood Anxiety Sensitivity Index, while parents completed the Anxiety Sensitivity Index. Children of parents with panic disorder did not display higher levels of anxiety sensitivity than children of healthy parents. Furthermore, no association between anxiety sensitivity levels of parents with panic disorder and their children was found. Anxiety sensitivity is not clearly manifest in children of parents with panic disorder and might be a developing vulnerability factor that may increase towards late adolescence or early adulthood.