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.

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.

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.

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.

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.

['Hyperventilation syndrome': often an easy to treat panic disorder]. / 'Hyperventilatiesyndroom': veelal goed behandelbare paniekstoornis.

Three patients, 2 men aged 35 and 26 years and 1 woman aged 41 years, had acutely occurring attacks, accompanied by diverse somatic complaints, and were diagnosed with hyperventilation syndrome. They recovered only when the complaints were recognised and treated as a panic disorder. Hyperventilation and the decrease of CO2 in the blood do not explain the symptoms and complaints in patients with panic disorder, a psychiatric disorder with a good prognosis. Treatment consists of cognitive behavioural therapy or a selective serotonin re-uptake inhibitor in the case of panic disorder and of a combination of those two treatments in the case of panic disorder with agoraphobia. Breathing exercises can form part of the behavioural therapy but not because the disorder is due to faulty breathing habits.

Neuroimmunological parameters in panic disorder.

BACKGROUND: The interaction between immune cells, neurotransmitters and the neuroendocrinological systems plays a role in affective disorders, especially depression. Although panic disorder (PD) shares a lot of features with depression, it is clearly a distinct disorder. Reports on immunological parameters in PD don't provide a clear picture of the immunological status of PD patients. This can partly be attributed to methodological differences between studies and small patient groups. OBJECTIVE: The present study aims to assemble all studies on immunological parameters in PD in order to combine all available data to gain a broader perspective on this matter. METHOD: PubMed was searched for studies describing immunological parameters in PD patients without comorbid disorders or medication use. All studies had to include a healthy control group and the outcome measures had to be shared by at least one other study. RESULTS: Fourteen articles were found. Although the T-lymphocytic branch and the innate immune system were normal, the B-lymphocytic branch showed some differences between PD patients and healthy controls. B-cell counts were increased in PD patients, which was underlined by increased human leucocyte antigen (HLA)-DR counts and increased immunoglobulin A levels. However, B-cell activity following mitogen stimulation was normal. CONCLUSIONS: PD patients show increased B-cell numbers. The finding that B-cell activity is not increased can possibly be attributed to functional exhaustion of these cells. The meaning of this finding remains unclear, although it may be potentially important in affective disorders as the same has been found in depression.

Symptom profiles of natural and laboratory panic attacks.

BACKGROUND: Little accurate information is available about the symptomatology of real-life panic attacks and about how well they are reproduced by an experimental model such as the 35% CO2 challenge. METHOD: Real-life panic symptoms were assessed in a group of 67 panic disorder patients, using daily life monitoring. Panic symptoms elicited by a 35% CO2 challenge were assessed in 61 panic disorder patients, and their frequency was compared with the real-life symptoms. RESULTS: The most frequent real-life symptoms were palpitations, dizziness and trembling. The 35% CO2 challenge reproduced well the majority of real-life symptoms. CONCLUSION: The findings suggest that the 35% CO2 challenge is a marker for spontaneous panic attacks, which are considered the core of panic disorder.