S05
Biochemical and genetic markers in patients with alcohol dependence and affective disorders and their correlation with alcohol intake
- U. Preuss, F. Wurst
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- 23 March 2020, pp. S19-S20
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Rates of comorbid affective disorders in alcohol-dependent individuals are significant. Biomarkers of alcohol use may support the diagnosis of high and frequent alcohol use in these individuals. The aim of these analyses of the WHO-ISBRA Study on State and Trait Markers of Alcohol Use and Dependence is to compare biomarkers of alcohol use across individuals with and without comorbid alcohol dependence and affective disorders. Significantly, higher values of these biomarkers are hypothesized in individuals with comorbid disorders compared to alcohol dependence only. Assessment of Alcohol dependence and comorbid depression and bipolar disorders were conducted using an adapted version of the Alcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS). Altogether, n = 1863 individuals were included into the analyses, of whom n = 299 had a lifetime history of depression and n = 20 a bipolar disorder. Clinical characteristics like mean alcohol intake last month and biomarkers including ASAT, GGT, CDT, 5-HTOL/5-HIAA ratio and MAO-Activity were included into the analyses. Results indicate that AD only subjects had higher measures of all biomarkers compared to comorbid bipolar and depression subjects, while the latter had a higher alcohol intake during last month.
Since this is a cross-sectional study, conducted in emergency rooms of several countries, this allegedly divergent result in alcohol intake in comorbid subjects compared to higher biomarkers in AD only subjects may indicate that drinking is more frequent in alcohol-dependent individuals while bipolar and depressed subjects may have more episodic pattern of alcohol intake. The latter may lead to shorter periods of intake compared to the chronic and frequent use of this substance in alcohol-dependent individuals and higher biomarkers of alcohol use.
Disclosure of interestThe authors have not supplied their declaration of competing interest.
S06
Potential relationship between inflammatory markers, neuroimaging findings and treatment response in depression
- A. Szulc
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- 23 March 2020, p. S20
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Pharmacological therapy in mental disorders is usually effective in 60–70%, the treatment reaction is worsening with the disease progression, and proper medication and early treatment regimen choice is crucial. Research showed that specific brain changes (structural and functional) are present in depressed patients. These abnormalities are probably linked to neurodegeneration. There is also an evidence that inflammation contributes to the depression pathophysiology, and both these processes – neurodegeneration and inflammation are related.
Novel biological markers allow us to better understand the individual mechanisms of treatment response in depression. Recently, several biological measures have been proposed, amongst them – neuropsychological dysfunction, decreased GABA level in proton magnetic resonance spectroscopy (1H MRS), body weight, genetic factors and peripheral inflammatory markers. Latest research found that brain changes assessed with neuroimaging methods (including 1H MRS, e.g. glutamatergic system abnormalities), correlate with peripheral inflammatory markers. Furthermore, both these factors taken together may serve as one integrated treatment prediction marker in depressed patients.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S07
Developmental trajectories to bipolar disorder
- S. Frangou
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- 23 March 2020, p. S20
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Background
Childhood subclinical phenotypes have been informative for etiological research and as a target for preventative interventions. Using a prospective longitudinal general population cohort we investigated whether childhood manic symptoms predicted a diagnosis of bipolar disorder (BD) or other psychiatric disorders by early adulthood.
MethodsSubthreshold manic symptoms at age 11 years (n = 1907) and clinical outcomes by age 19 years (n = 1584) were ascertained in the TRacking Adolescents’ Individual Lives Survey (TRAILS), a prospective Dutch community cohort. We used latent class analysis to stratify TRAILS participants at age 11 years into distinct classes based on the pattern and severity of childhood manic symptoms. We then determined the association between class membership and clinical diagnoses by age 19 years.
ResultsAt age 11 years, we identified a normative class with negligible symptoms (n = 862), a mildly symptomatic (n = 846) and a highly symptomatic class (n = 199). The risk of BD was moderately increased in individuals in the mildly symptomatic class (OR = 2.65, 95% CI 1.41–5.01), and substantially increased in the highly symptomatic class (OR = 7.08, 95% CI = 3.32–15.11). Children in the highly symptomatic class were additionally characterized by lower IQ and socioeconomic status, greater family dysfunction and increased rates of parental psychiatric morbidity. Class membership did not show significant associations with depressive, anxiety and substance abuse disorders by age 19 years.
ConclusionsThe results provide support to developmental models of BD, and suggest that manic symptoms in childhood may be a marker for adult disorders and therefore potentially useful for early identification of at risk individuals.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S08
Protecting the cardiometabolic health of young people experiencing psychosis
- D. Shiers,
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- 23 March 2020, p. S20
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This presentation will highlight how the early phase of major mental illness may provide a critical window of opportunity in which to prevent future life-restricting and life-shortening physical comorbidities.
Despite many recent advances in our understanding of severe mental illnesses, those affected still lose 15–20 years of life on average compared to the general population. Most premature deaths arise from the same common disorders that affect the general population such as cardiovascular disease, infections and cancers. Of these cardiovascular diseases is now the single biggest cause, far greater than suicide. Shockingly the mortality gap is still widening as the reduction in CVD morbidity and mortality seen in the general population over the last three decades continues to elude people with severe mental illnesses, for whom the prevalence of CVD, obesity and diabetes are now of epidemic proportion.
And yet, much of this epidemic can be predicted. High rates of tobacco use, physical inactivity and poor nutrition point to underlying health inequalities. Furthermore, initiation of antipsychotic treatment is associated with aggressive weight gain and metabolic disturbance from the early phase of psychosis, and yet often these adverse effects remain unmonitored and untreated.
This presentation will argue that these potentially modifiable risk factors provide natural targets for prevention from the onset of psychosis and its treatment. Extending the early intervention paradigm to embrace a far more holistic body & mind approach is overdue.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S09
Implementing the clinical standards of the National Institute for Health and Care Excellence (NICE) bipolar clinical guideline
- M. Tremblay, S. Palin
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- 23 March 2020, pp. S20-S21
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In the UK, the National Institute for Health and Care Excellence (NICE) sets standards for interventions to drive improvement in the quality of services delivered. The actual update of clinical guidelines remains patchy and difficult to ascertain.
NICE most recent guideline on the management of bipolar disorder in adults will be reviewed. A concept tool to facilitate adherence to NICE clinical standards will be presented along with detailed outcomes of its pilot application in a naturalistic treatment setting, which drove the average concordance from 32% for a team providing treatment as usual, to 92% for a team supporting their practice with the tool. This presentation will also address additional impacts of its use including allowing drawing key clinical characteristics of an index population of individuals suffering from bipolar disorder, supporting education and auditing the actual service delivery.
The usefulness of the tool to shape clinical practice according to NICE evidence-based standards will be outlined. Its versatility and limitations will be debated. The discussion of the findings will include epidemiological considerations as well as implications for mental and physical well-being.
Disclosure of interestThe authors have not supplied their declaration of competing interest.
S10
Alcohol and aggression
- A. Heinz, U. Kluge, M. Schouler-Ocak, A. Beck
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- 23 March 2020, p. S21
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About half of all murders are committed in Western industrialized countries by subjects under the influence of alcohol. Chronic alcohol use also increases the rate of violent attacks. These findings appear to be due to an interaction between acute and chronic environmental effects (acute alcohol consumption and chronic social isolation stress) on the one hand and limbic processing of aversive stimuli modulated by neurotransmitter systems such as dopamine and serotonin on the other. Animal experiments showed that early social isolation stress can induce serotonin dysfunction and appears to predispose individuals towards increased threat perception. Studies in humans revealed that depending on serotonergic neurotransmission and serotonin transporter genotype, some individuals are prone to show elevated functional activation elicited by aversive and threatening cues. Previous experience with alcohol-related aggression seems to further predispose an individual towards a “fight vs. flight” reaction when confronted with perceived threat during alcohol intake. Together, these findings point to complex gene-environment interactions and a specific role of social isolation stress in the development of alcohol-related aggression.
Disclosure of interestThe authors have not supplied their declaration of competing interest.
S11
Multi-morbidity: Psychosis early childhood adversity and substance use within homeless people
- M. Krausz
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- 23 March 2020, p. S21
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Homelessness is the most visible indicator for social marginalization and vulnerability. It is a risk factor for subsequent health threats and especially individuals with a history of trauma, substance use and severe persistent mental illness are at high risk to loose their homes, jobs and social networks.
The Canadian At Home/Chez Soi study aimed to better understand the entanglement of homelessness and mental illness and possible strategies to provide care to the most vulnerable. In 5 Canadian centers, over 2000 patients were included and randomized to different intervention arms based on a housing first approach.
Early trauma and foster care were as rampant as poly substance use, which explains a significant increase in mortality too.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S12
Are attention-deficit/hyperactivity disorder symptoms associated with a more severe course of substance use? A longitudinal study with young Swiss men
- F. Moggi
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- Published online by Cambridge University Press:
- 23 March 2020, p. S21
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Introduction
Adults with attention-deficit/hyperactivity disorder (ADHD) symptoms show higher prevalence rates for substance use disorders (SUD).
ObjectivesFew longitudinal studies have been conducted to observe the course of substance use among adults with ADHD.
AimsThis study examined the predictive value of ADHD symptoms during the course of substance use in a population sample.
MethodsIn two waves data from a representative sample of 5103 Swiss men in their early 20s were collected (baseline and 15-month follow-up) in the longitudinal “Cohort Study on Substance Use Risk Factors” (C-SURF). ADHD symptoms and substance use were assessed using the adult ADHD Self-Report Scale (ASRS-v1.1) and self-administered SUD questionnaires, respectively. Individuals who screened positive for ADHD (ADHD+) were compared to those who screened negative (ADHD−).
ResultsAt baseline, the 215 individuals in the ADHD+ group (4.2%) showed considerably higher prevalence and frequency of substance use and prevalence of alcohol, tobacco, and cannabis use disorders relative to the ADHD− group. While alcohol, tobacco, cannabis, and heroin use remained stable from baseline to follow-up, the ADHD+ group was more likely to begin using illicit drugs (i.e. amphetamines, speed, ecstasy, hallucinogens, and cocaine) and initiate nonmedical use of prescription drugs (i.e. stimulants/amphetamines, hypnotics, and tranquilizers) relative to the ADHD− group.
ConclusionsYoung men with ADHD symptoms displayed more severe substance use patterns and were at a high risk of initiating drug use within 15 months. The identification of ADHD symptoms during early adulthood may be relevant in early interventions to lower the risk of drug use.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S13
Autism and substance use comorbidity: Screening, identification and treatment
- P.J.M. van Wijngaarden-Cremers
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- Published online by Cambridge University Press:
- 23 March 2020, pp. S21-S22
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Objective
Autism spectrum disorders (ASD) are well-known for high prevalences of comorbid conditions especially anxiety, obsessions, depression, challenging behaviours.
In this presentation, we will consider the evidence for comorbidity between ASD and addiction [substance use disorders (SUD)] and explore the possible underlying explanations.
MethodsA literature study on similarities between addiction and ASD (at a phenotypical and neurobiological level) as well as a case note review on a year cohort of 120 consecutive admissions in an adult addiction psychiatry unit and 120 admissions in an adult ASD unit.
ResultsIn our addiction psychiatry cohort, 8 (men) on 118 patients were diagnosed with autism spectrum disorder. This is much higher than in the general population (1%). In the ASD cohort, the results are measured at the moment and the results will be presented in the presentation.
Autism spectrum disorders and addiction can both be perceived as developmental disorders in which a genetic predisposition and vulnerability interact with environmental factors. They can be induced by early stress thus affecting the proper functioning of the cortico-striatal dopaminergic regulation systems (and also the HPA axis). In “pure” ADHD this is attributed to a deregulation in the cognitive loops and the “impulsivity” endophenotype. Whereas in cases of ASD without an ADHD component the limbic and sensimotore cortico-striatal regulations loops are also involved.
ConclusionsThere are clear indications that a possible comorbidity of substance abuse disorder should be considered in cases of individuals with autism spectrum disorders. This finding is important for clinicians to take into account in assessing patients with addiction problems and ASD.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S14
Ethical challenges in the use of coercion
- M. Kastrup
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- 23 March 2020, p. S22
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The use of coercive measures remains one of the great challenges in psychiatry.
Increased focus on patient rights and autonomy, concern from user and relatives organizations as well as from human rights organizations all have contributed to that the use of all kinds of coercion is high on the agenda. And yet, we are still faced with that a number of psychiatric patients will experience that coercive measures are used as part of their treatment.
The EPA Ethical Committee carried out a survey comprising the European associations of psychiatry in which a questionnaire was circulated regarding what the different associations found were the major ethical challenges in their respective countries.
Among the issues that have given rise to particular concern are the use of physical restraints including why some countries avoid physical restraints while other – e.g. Denmark – use it extensively. Why do we find such large differences? Is this due to different approaches to coercion, different traditions? Shortage of resources?
Another concern is that certain groups seem more likely to be subject to coercion compared to others. Thus, it has been demonstrated that patients belonging to ethnic minority groups are more likely to experience this.
The paper will focus on ethical problems and issues of concern related to the use of coercion. The focus will be on facets of international relevance with the aim to remain critical towards the use and when needed to strengthen the quality of coercive treatment care. URL: http://www.mariannekastrup.dk
Disclosure of interestThe author has not supplied his declaration of competing interest.
S15
Does the use of coercion improve the outcome of patients with severe mental disorders?
- M. Luciano
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- Published online by Cambridge University Press:
- 23 March 2020, p. S22
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Coercive measures have always been part of the psychiatric armamentarium; however, the clinical and ethical dilemma between the use of a “therapeutic” coercion and the loss of patients’ dignity is one of the most controversial issues in mental health practice. According to International guidelines, coercive measures should be adopted only when all the other less restrictive approaches failed and should be considered as the “last restrictive alternative”. Although coercive measures are frequently used to manage patients’ aggressive behaviors and self-harm, refusal of medication and impulsivity, their effect on patients’ outcome is not clear. In fact, the use of coercive measures can reduce patients’ aggressiveness and improve psychiatric symptoms, but can also have a negative impact in terms of therapeutic relationship, engagement with mental health services and self-stigma, arising negative feelings on patients and on mental health professionals. International attempts have been made to improve and harmonize the use of involuntary treatments. Recommendations of good clinical practice on the use of coercive involountary treatments and forced medications have been proposed by the EUNOMIA consortium, and the effect of coercion on the outcome of patients with severe mental disorders have been described. Results of this study will be reported as well as lessons learnt from other international experiences.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S16
Psychological pain and interpersonal theory of suicide
- A. Apter
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- Published online by Cambridge University Press:
- 23 March 2020, p. S22
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Psychological pain is an important variable in the understanding of suicidal individual.
This presentation describes the how psychological pain interacts with problems in communication to set up risk for serious suicidal behavior and describes some empirical studies supporting a model for using this concept in suicide prevention strategies.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S17
Pain perception in self-injurious behaviours
- C. Schmahl
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- 23 March 2020, pp. S22-S23
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Borderline personality disorder (BPD) is characterized by affective dysregulation and non-suicidal self-injurious behaviour (NSSI), which is closely linked with reduced pain perception. Several experimental studies revealed reduced pain sensitivity in BPD as well as significant correlations between pain perception, aversive inner tension and dissociation. Psychophysiological experiments revealed no deficit in the sensory-discriminative pain component in BPD. However, neurofunctional investigations point at alterations of the affective-motivational and the cognitive pain component in BPD. Preliminary evidence suggests that disturbed pain processing normalizes when patients stop NSSI after successful psychotherapeutic treatment. We could demonstrate that pain leads to a decrease in affective arousal and amygdala activity in patients with BPD and to an increase in amygdala-prefrontal connectivity. We are currently investigating the role of seeing blood and the importance of self-infliction of pain in the context of NSSI.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S18
Neural pathways of the association between pain and suicide
- K. van Heeringen
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- Published online by Cambridge University Press:
- 23 March 2020, p. S23
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Physical pain and psychological pain are risk factors for suicidal behaviour, and understanding of the neural pathways linking pain and suicide may contribute to suicide prevention. Neuroimaging studies have shown changes in association with physical and psychological pain and with suicidal behaviour. Psychological stressors such as social exclusion may trigger emotional pain that is associated with functional changes in the prefontal cortex, cingulate cortex, thalamus, and parahippocampal gyrus. This functional network shows considerable overlap with brain areas involved in physical pain and suicidal behaviour. Changes in the brain motivation-valuation circuitry may predict pain persistence and thus contribute to the development of suicidal thoughts and behaviours.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S19
Hikikomori and modern-type depression in Japan
- T. Kato
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- 23 March 2020, p. S23
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Maladaptive social interaction and its related-psychopathology have been highlighted in psychiatry especially among younger generations. “Hikikomori” defined as a syndrome with six months or longer of severe social withdrawal was initially reported in Japan, and the prevalence rate has been reported as 1.2% in Japanese population. The majority of hikikomori patients are adolescents and young adults who become recluses in their parents’ homes for months or years. They withdraw from contact with family, rarely have friends, and do not attend school or hold a job. An international vignette-used questionnaire survey indicates the spread of hikikomori in many other countries (Kato et al. Lancet, 2011; Kato et al. Soc Psychiatry Psychiatr Epidemiol, 2012). In addition, our international clinical studies have revealed the prevalence of hikikomori outside Japan (Teo et al., 2015). On the other hand, a novel form of maladaptive psychopathology, called modern-type depression has emerged in Japan (Kato et al. J Affect Disord, 2011; Kato et al. Psychiatry Clin Neurosci, 2016).
In this presentation, I will introduce “Hikikomori” and “modern-type depression” in Japan, and also propose novel diagnostic/therapeutic approach against them.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S20
International research on social withdrawal
- A.R. Teo
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- 23 March 2020, p. S23
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Introduction
Since the 1990s the term “Hikikomori” has emerged as a way to describe a modern form of severe social withdrawal first described in Japan. Recently, there have been increasing reports of Hikikomori around the globe.
ObjectivesTo describe operationalized research criteria for Hikikomori, as well as epidemiologic, diagnostic, and psychosocial features of the Hikikomori in international settings.
MethodsParticipants were recruited from sites in India, Japan, Korea, and the US. Hikikomori was defined as a six-month or longer period of spending almost all time at home and avoiding social situations and social relationships, associated with significant distress/impairment. Lifetime history of psychiatric diagnosis was determined by the Structured Clinical Interview for the DSM-IV Axis-I and Axis-II Disorders. Additional measures included the Internet Addiction Test, UCLA Loneliness Scale, Lubben Social Network Scale (LSNS-6), and Sheehan Disability Scale (SDS).
ResultsThirty-six participants meeting diagnostic criteria for Hikikomori were identified, with cases detected in all four countries. Avoidant personality disorder (41%), major depressive disorder (32%), paranoid personality disorder (32%), social anxiety disorder (27%), posttraumatic stress disorder (27%), and depressive personality disorder (27%) were the most common diagnoses. Sixty-eight percent had at least two psychiatric diagnoses. Individuals with Hikikomori had high levels of loneliness (UCLA Loneliness Scale M = 55.4, SD = 10.5), limited social networks (LSNS-6 M = 9.7, SD = 5.5), and moderate functional impairment (SDS M = 16.5, SD = 7.9).
ConclusionsHikikomori exists cross-nationally and can be assessed with a standardized assessment tool. Individuals with Hikikomori have substantial psychosocial impairment and disability, and a history of multiple psychiatric disorders is common.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S21
Transcultural issues in diagnostic process
- M. Kastrup,
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- 23 March 2020, pp. S23-S24
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Diagnostic systems and methods must respond to patients’ diversity in expressions of mental distress, social and cultural context and the meanings given to illness. Due to increasing migration and globalisation the challenge of considering diagnosis in the context of culture has become increasingly significant in Europe. And globalization has further led to changes in value systems and our awareness of patients with ethnic minority background.
Over recent decades, there has been an increasing development of psychiatric diagnosing with nosological categorisation combined with multi-axial schemas. Diagnosis, besides identifying a disorder and distinguishing one disorder from another disorder - differential diagnosis, has also an aim to include an overall understanding of the patient's situation.
We witness an upsurge in the attention paid to the cultural limitations to psychiatric diagnostic practice and treatment modalities. Guidelines for the psychiatric profession are in critical focus from a transcultural perspective. Some claim their universality independent of cultural context; others find cultural adaptation useful and necessary.
Do the diagnoses and clinical and ethical guidelines give meaning in the cultural setting? Are they compatible with the cultural values of the therapist and those of the patient and the family? Several sources claim the biomedical paradigm for being Western with insufficient consideration of the socio-political context.
The cultural formulation developed as part of DSM-IV and now DSM-5 is one model to support a systematic review of culture and context in psychiatric diagnosing.
The paper will discuss the advantages and shortcomings of current diagnostic categories and guidelines vis-à-vis the universe of traumatized refugees with other ethnic backgrounds.
URL: http://www.mariannekastrup.dk/
Disclosure of interestThe author has not supplied his declaration of competing interest.
S22
Interview and therapeutic rapport in diagnostic process
- L. Küey
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- 23 March 2020, p. S24
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Diagnostic assessment in psychiatry, as a formulation and as a joint re-construction process between the clinician and the patient, is essential in clinical care. Clinical interview is the crucial tool of the clinician in this process. Accordingly, a two-fold task is faced. On one hand, the clinician is in need of making a comprehensive diagnostic assessment to construct a valid and working formulation of the patient's situation and a treatment plan.
On the other hand, the bases for a psychotherapeutic alliance and rapport should be established. A comprehensive diagnostic assessment aims to bridge the current scientific evidence and knowledge with the uniqueness of the specific person who presents for care. The clinician facing the complexities of the human existence in health and ill mental health constructs working hypotheses in the context of the interview, to understand and formulate the psychopathological state. Clinical interview serving as a practical channel in constructing these hypotheses, also serves as the main tool in establishing a therapeutic alliance. The theory and practice of different schools of psychotherapies offer considerable contributions to the clinician in managing these tasks.
Understanding the meaning of the human suffering through empathy in a judgment free milieu is essential in the establishment of rapport, compliance and a better clinical outcome. This presentation will discuss the complexity of diagnostic process in psychiatry and emphasize the contributions of psychotherapeutic theory and skills and humanistic approaches in this process. Brief clinical vignettes from the authors’ clinical practice will be used to broaden the scope of discussion.
Disclosure of interestThe author has not supplied his declaration of competing interest.
S23
The role of IgG hypersensitivity and changes in gut microbiota in the pathogenesis and therapy of depressive disorders
- H. Karakula-Juchnowicz, P. Szachta, D. Juchnowicz, S. Grochowski, M. Gałęcka
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- 23 March 2020, pp. S24-S25
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Depression is a complex, heterogeneous psychiatric disorder with multifactorial aetiology. Substantial evidence indicates that depressive episodes are associated not only with changes in neurotransmission in the central nervous system (CNS), but also may lead to structural changes in the brain through neuroendocrine, inflammatory, and immunological mechanisms. Among the factors deserving special attention connected with developing systematic inflammation are altered intestinal permeability, IgG food intolerance, and changes in gut microbiota.
We present a possible scenario of the development of depression, linking elevated zonulin production, loosening of the tight junction barrier, an increase in permeability of the gut wall, and the passage of macromolecules, normally staying the gut, into the bloodstream, with the immuno-inflammatory cascade and induction of IgG-dependent food sensitivity. Alterations in bidirectional signaling between the gastrointestinal tract and the brain, so called “microbiota–gut–brain axis”, may be normalized by dietary immunomodulating factors, including prebiotics and probiotics. In the case of increased IgG concentrations, the implementation of an elimination–rotation diet may prove to be an effective method of reducing inflammation and, in this way, alleviating depressive symptoms.
Given complexity and variety of mood disorders, it is necessary to develop improved integration models. Preliminary study results raise hope that the new methods mentioned above, i.e. psychobiotics, prebiotics, an elimination-rotation diet, may be an important addition to the psychiatrist's armamentarium as therapeutic agents improving the efficacy of the treatment for affective disorders [1–3].
Disclosure of interestThe authors have not supplied their declaration of competing interest.
S24
Can the pathophysiology of autism be explained by the nature of the discovered urine peptides and dietary antigens?
- K.L. Reichelt
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- Published online by Cambridge University Press:
- 23 March 2020, p. S25
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Purpose
A: 1. To develop the urine analysis for exorphins for routine use in blood and cerebrospinal fluid (CSF).
2. Disorders where patient related validation must be carried out: schizophrenia, depression (uni- and bipolar) and autism.
MethodA: HPLC-MS/MS (fragmentation mass spectrometry) technology.
With both a specific HPLC retention time and MS/MS (fragmentation) this method is close to an absolute technique for peptide recognition.
B: ELISA against specific proteins (gliadin, gluten and casein and transglutaminase 6) (Table 1 og 2).
BackgroundA: schizophrenia: increased opioid peptide levels have been found in Schizophrenia using HPLC, immune assay and behavioral tests. [1–6] as part of a general peptide increase in urine. Since peptides are signaling compounds inhibition of peptidases during transport and work up of samples is critical to prevent break down, which is as expected fast at room temperature.
Strongly supporting is view is the data on postpartum psychoses (a very symptom rich psychosis) where also amino acid sequence of human casomorphin found increased, has been done [7–8]. The opioids can explain most of the symptoms of the psychotic schizophrenic state [6]. It is of paramount importance then to measure these peptides in carefully diagnosed patients on and without medication, in urine, blood and spinal fluid.
As can be seen in Table 1, it is important to measure IgA and IgG antibodies against the precursor proteins for the exorphins, which are found increased by several groups, and also have direct effects on the nervous system [9].
B. In depression increase levels of peptides has been found [18,28,29] and also opioid levels measured as opium receptor binding peptides [28]. In schizoaffective psychosis MS/MS exact detection of exorphins have been published [6]. Also in this syndrome it is critical to be able to measure the exorphins in blood and CSF, especially since the peptidases involved in break down of exorphins are decreased in depressions [30,31]. Inflammatory interleukins are also increased in depressions both uni- and bipolar [32] indicative of inflammatory processes probably in the gut. Inflammatory interleukins increase the permeability of epithelial membranes [33].
C. Autism. Considerable work has been done using HPLC with UV detection and co-chromatography [12,34–40]. However, with HPLC–MS/MS we can ensure that we are measuring only the exorphins and not chromatographically similar peaks that hide inside the main peak [41–43]. We therefore need to validate the new method in autism for both urine, blood and CSF (CSF collected only when spinal tap has to be done in any case).
Inhibition of break down in urine, blood and cerebrospinal fluid (CSF)After extensive testing we have been left with three inhibitors. Citric acid 0.2 M; acetic acid 0.2 M and aprotenine [44,45].
These body fluids will be provided by Prof Dr E. Severance and Prof Dr R. Yolken (Johns Hopkins Univ.) and Prof Dr. Cunningham (Uppsala Univ. Sweden). Lab 1 provides monovettes with citric acid as peptidase inhibitor for urine collection. Blood will be collected in EDTA – aprotenin vacuum test tubes (Vacutainer) as will be CSF.
HPLC and MS/MS detection.
The amount of urine analyzed on the HPLC after work up = 250 nanomles creatinine. To pick out generally active peptides in any one disorder, five and five autistic children or schizophrenic derived and depressive derived urines are mixed, creatinine re-determined and rerun. Peaks that are common to all patients increase or remain the same, while individual peaks of material on the HPLC runs are diluted out.
The complete procedure is published in detail [48]. If we use reporter ions we do not have to match all the peaks as shown in attached figures. On Fig. 1, synthetic bovine β-casomorphine 1-4 (Y-P-F-P) is compared to biologically isolated compound from a batch of five autistic children. On Fig. 2, the faster routine analysis using reporter ions is shown for bovine β-casomorhne 1-4. Top trace is synthetic casomorphin 1-4 and bottom trace is biologically isolated compound. The complete analysis for a series of opioids is published [48].
Program is then in sequence:
– A: further validation of method for urine in the different disorders;
– B: validation of method for blood in the same disorders;
– C: validation of method for CSF (spinal fluid) in schizophrenics and depressive patients.
NB.
To avoid overlooking new compounds a complete HPLC run with UV 215 nm (peptide bonds); 280 nm (aromatic groups) and 325 nm (Indolyl-acryloid) shall be run for urines. If sufficient serum is available and spinal fluid these will also be run on HPLC in addition to MS/MS detection.
Antibody assays will be done at Johns Hopkins using ELISA, Transglutaminase 6 antibodies at Lab 1 also using ELISA assay.
Figures and references not available in the abstract.
Disclosure of interestThe authors have not supplied their declaration of competing interest.