On the influence of serotonin- and sex steroid-related genetic variation on mood, anxiety, personality, autism and transsexualism

Background: The neurotransmitter serotonin has been related to mood and anxiety, and variation in genes that encode important members of the serotonergic system may hence affect mood- and anxiety-related traits. Sex steroids influence brain development, and variation in genes encoding androgen and estrogen receptors, or enzymes needed for sex steroid synthesis, may be of importance for both personality traits and risk for psychiatric disorders. The specific aims of this thesis were: (i) to investigate the possible influence of serotonin-related genetic variation on the neural correlates of anxiety, and on mood- and anxiety-related phenotypes, including premenstrual dysphoric disorder (PMDD), depression and anxiety-related personality traits, (ii) to investigate the possible influence of sex steroid-related genetic variation on personality, autism spectrum disorder and transsexualism, and (iii) to try to ameliorate the chance of detecting effects of combinations of genetic variations by restricting the statistical analysis to particular patterns. Results: (i) The serotonin transporter (5-HTT) linked polymorphic region (5-HTTLPR) and a polymorphism in an important enzyme for serotonin synthesis (tryptophan hydroxylase 2; TPH2) were associated with amygdala response during presentation of angry faces in subjects with social phobia and controls. (ii) The same polymorphisms were associated with response to placebo and also with placebo-induced changes in amygdala activity during public speaking in subjects with social phobia. (iii) In men, genetic variation in the neurotrophic factor BDNF, which is closely related to the serotonergic system, was associated with the amount of serotonin transporter in the brain. (iv) Polymorphisms in genes that encode proteins important for the development of the serotonergic system (GATA2), for serotonin synthesis (TPH2) and for serotonergic transmission (5-HT3B) were associated with PMDD. (v) The 5-HTTLPR was shown to influence reports of controllable stressful life events in combination with the BDNF Val66Met polymorphism or anxiety-related personality traits in non-depressed men. (vi) Variants that may increase the function of the androgen receptor were associated with extraversion and spiritual acceptance in men. (vii) A variant that is associated with increased androgen receptor function was more common in women with autism spectrum disorder than in controls. (viii) The same androgen receptor polymorphism was associated with transsexualism in combination with polymorphisms in the genes encoding the estrogen receptor β or the testosterone-converting aromatase enzyme. (ix) A method that restricts the search for genetic combinations to monotone effect patterns was shown to increase the probability of finding gene-gene effects. Conclusions: The results support the notion that variation in genes that encode serotonin-related and sex steroid-related proteins are of importance for the psychiatric traits studied in this thesis

Transsexualism and personality : methodological and clinical studies on gender identity disorders

Patients suffering from transsexualism (TS) who apply for sex reassignment surgery (SRS) go through a complex evaluation process before being accepted for treatment. In general, the results from SRS are satisfying. However, further knowledge is needed to clearly delineate transsexualism from other related gender identity disorders (GID) and to improve the selection of candidates for SRS. Personality has for a long time been considered as the key concept for that purpose but systematic studies using reliable instruments are lacking. The present study aims at improving the assessment procedure, validating the concept of transsexualism and studying the outcome of SRS and important prognostic factors. Two methodological studies deal with the development and validation of two self-report instruments based on DSM-III-R: SCID screen covering Axis II personality disorders/traits and Global Assessment of Functioning (GAF-scale, Axis V). SCID screen diagnoses of personality disorders (PD) were compared with diagnoses from independent structured interviews by means of the SCID-II. The overall kappa in identifying a PD was 0.78 varying from 0.34 to 0.81 for the specific PDs when cut-off was adjusted. When applied to a group of GID-patients SCID screen diagnoses agreed well with clinical diagnoses (kappa 0.77). Self-report of the GAF also proved to be a reliable (overall Pearson r=0.62) and useful method and the study lends further support to the validity of Axis V. In three papers a group of 19 transsexuals was studied by means of a) SCID screen to examine their personality in a dimensional and traditional categorical way, b) the GAF-scale to study psychosocial functioning, c) Structural Analysis of Social Behavior (SASB) to examine self-image and d) Defense Mechanism Test (DMT) to analyze psychological defense structures from a psychodynamic perspective. Patients with atypical gender identity disorders (GIDAANT) and patients with borderline personality disorders as well as healthy subjects were used as contrast groups. Among the transsexuals 10 out of 19 had an additional axis I disorder and 37% had at least one PD, predominantly within cluster B. When analyzed dimensionally according to SCID screen, frequent subthreshold personality pathology was found and biological women fulfilled more axis II criteria than men. TS had less axis I and II pathology compared with GIDAANT and psychiatric patients. According to SASB, TS had a positive self-image with both self-control and spontaneous self and predominating self-love. They appeared significantly more healthy on self-image measures than GIDAANT patients. The DMT revealed a different pattern; TS patients were more disturbed in several areas than patients with borderline personality disorder. TS showed no ”emotional investment” and poorer reality orientation in contrast to both healthy controls and the borderline group but shared a similar pregenital pathology with the borderline patients. Finally, five-year outcome was studied among the transsexuals from a multidimensional approach (e.g. work, interpersonal relations, partnership, subjective opinion) and related to index- measurements on DSM-III-R, SCID screen, GAF, SASB and DMT. Based on combined outcome variables, 68% of the subjects were judged to have improved and 16% had an unsatisfactory outcome. One single case regretted the sex change. SCID screen pathology and SASB disturbances emerged as significant predictors for negative outcome, as well as male biological sex and lack of partnership. It was concluded, that although outcome is in general very favorable, the instruments under investigation, in particular SCID screen and SASB, revealed valuable prognostic information and they are suggested to become part of the future routine assessment of candidates for SRS.Diss. (sammanfattning) Umeå : Umeå universitet, 1995, härtill 6 uppsatser.digitalisering@um

Deep brain stimulation for obsessive-compulsive disorder : knowledge and concerns among psychiatrists, psychotherapists and patients

Background: Deep brain stimulation (DBS) is under investigation for severe obsessive-compulsive disorder (OCD) resistant to other therapies. The number of implants worldwide is slowly increasing. Therefore, it is of importance to explore knowledge and concerns of this novel treatment among patients and their psychiatric healthcare contacts. This information is relevant for scientific professionals working with clinical studies for DBS for this indication. Especially, for future study designs and the creation of information targeting healthcare professionals and patients. The aim of this study was to explore the knowledge and concerns toward DBS among patients with OCD, psychiatrists, and cognitive behavioral therapists. Methods: The study was conducted through web-based surveys for the aimed target groups -psychiatrist, patients, and cognitive behavioral therapists. The surveys contained questions regarding previous knowledge of DBS, source of knowledge, attitudes, and concerns towards the therapy. Results: The main source of information was from scientific sources among psychiatrists and psychotherapists. The patient's main source of information was the media. Common concerns among the groups included complications from surgery, anesthesia, stimulation side effects, and the novelty of the treatment. Specific concerns for the groups included; personality changes mentioned by patients and psychotherapists, and ethical concerns among psychiatrists. Conclusion: There are challenges for DBS in OCD as identified by the participants of this study; source and quality of information, efficacy, potential adverse effects, and eligibility. In all of which the current evidence base still is limited. A broad research agenda is needed for studies going forward

Deep Brain Stimulation in the Bed Nucleus of Stria Terminalis in Obsessive-Compulsive Disorder : 1-Year Follow-up

Background: Deep brain stimulation (DBS) is under investigation as a treatment for therapy-refractory obsessive-compulsive disorder (OCD). As a crucial part of the anxiety circuit, the bed nucleus of stria terminalis (BNST) has been proposed as a target for DBS in OCD. Here, we investigate clinical outcomes and safety of DBS in the BNST in a series of 11 participants with severe therapy-refractory OCD. Methods: Eleven consecutive participants diagnosed with refractory OCD were treated with BNST DBS and completed follow-up. The primary outcome was a change in scores of the Yale Brown Obsessive Compulsive Scale (YBOCS) at 1 year after surgery. Secondary outcomes included changes in scores of the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Global Assessment of Functioning. Results: At baseline, the mean ± SD YBOCS score was 33 ± 3.0, MADRS score was 29 ± 4.5, and GAF score was 49 ± 5.4. One year after DBS, mean ± SD YBOCS score was 20 ± 4.8 (38% improvement (range 10%−60%) P < 0.01), MADRS score was 21 ± 5.8 (27% improvement, range 4%−74%, P < 0.01), and Global Assessment of Functioning score was 55 ± 6.5 (12% improvement, range 4%−29%, P < 0.05). Of the 11 participants, 6 were considered responders (decrease in YBOCS ≥35%) and 4 partial responders (decrease in YBOCS 25%−34%). Surgical adverse events included 1 case of skin infection leading to reimplantation. The most common transient stimulation-related side effects were anxiety and insomnia. Conclusions: BNST DBS is a promising therapy in severe therapy-refractory OCD. Our results are in line with previous publications regarding effect and safety profile. Nevertheless, DBS for OCD remains an investigational therapy and should therefore be performed in multidisciplinary clinical studies

Distribution of electric field in patients with obsessive compulsive disorder treated with deep brain stimulation of the bed nucleus of stria terminalis

Background: Deep brain stimulation (DBS) is being investigated as a treatment for therapy-refractory obsessive-compulsive disorder (OCD). Many different brain targets are being trialled. Several of these targets such as the ventral striatum (including the nucleus accumbens (NAc)), the ventral capsule, the inferior thalamic peduncle and the bed nucleus of stria terminalis (BNST)) belong to the same network, are anatomically very close to one another, or even overlap. Data is still missing on how various stimulation parameters in a given target will affect surrounding anatomical areas and impact the clinical outcome of DBS. Methods: In a pilot study of eleven participants with DBS of the BNST, we investigate through patient-specific simulation of electric field, which anatomical areas are affected by the electric field, and if this can be related to the clinical results. Our study, combined individual patient’s stimulation parameters at 12 and 24-months follow-up with image data from the preoperative MRI and postoperative CT. These data were used to calculate the distribution of electric field and create individual anatomical models of the field of stimulation. Results: The individual electric stimulation fields by stimulation in the BNST were similar at both the 12 and 24-months follow up, involving mainly anterior limb of the internal capsule (ALIC), genu of the internal capsule (IC), BNST, fornix, anteromedial globus pallidus externa (GPe) and the anterior commissure. A statistical significant correlation (p &lt; 0.05) between clinical effect measured by the Yale-Brown Obsessive Compulsive Scale and stimulation was found at the 12-month follow up in the ventral ALIC and anteromedial GPe. Conclusions: Many of the targets under investigation for OCD are in anatomical proximity. As seen in our study, off-target effects are overlapping. Therefore, DBS in the region of ALIC, NAc and BNST may perhaps be considered to be stimulation of the same target.Originally included in thesis in manuscript form with title: "Distribution of electric field in patients with obsessive-compulsive disorder treated with deep brain stimulation of the bed nucleus of stria terminalis".This article is part of the Topical Collection on Functional Neurosurgery - Other</p

Moderation and mediation of the effect of attention training in social anxiety disorder

While attention modification programs (AMP) have shown promise as laboratory-based treatments for social anxiety disorder, trials of internet-delivered AMP have not yielded significant differences between active and control conditions. To address these inconsistencies, we examined the moderational and mediational role of attention bias in the efficacy of attention training. We compared data reported by Carlbring et al. (2012) to an identical AMP condition, with the exception that participants were instructed to activate social anxiety fears prior to each attention training session (AMP + FACT; n = 39). We also compared all attention training groups to an internet-delivered cognitive-behavioral therapy (iCBT) condition (n = 40). Participants in the AMP + FACT group experienced greater reductions in social anxiety symptoms than both active (n = 40) and control (n = 39) groups reported by Carlbring et al., and did not differ in symptom reductions from the iCBT group. Higher attention bias predicted greater symptom reductions for participants who completed AMP, but not for the control group. Moreover, change in attention bias mediated the relationship between AMP group (active condition reported by Carlbring et al. versus AMP + FACT) and change in social anxiety symptoms. These results suggest the importance of interpreting findings related to symptom change in attention training studies in the context of bias effects. Trial registration: ISRCTN01715124

Exploring gender dysphoria and related outcomes in a prospective cohort study : protocol for the Swedish Gender Dysphoria Study (SKDS)

INTRODUCTION: There has been a drastic increase in the reported number of people seeking help for gender dysphoria in many countries over the last two decades. Yet, our knowledge of gender dysphoria and related outcomes is restricted due to the lack of high-quality studies employing comprehensive approaches. This longitudinal study aims to enhance our knowledge of gender dysphoria; different aspects will be scrutinised, focusing primarily on the psychosocial and mental health outcomes, prognostic markers and, secondarily, on the underlying mechanisms for its origin. METHODS AND ANALYSIS: The Swedish Gender Dysphoria Study is an ongoing multicentre longitudinal cohort study with 501 registered participants with gender dysphoria who are 15 years old or older. Participants at different phases of their clinical evaluation process can enter the study, and the expected follow-up duration is three years. The study also includes a comparison group of 458 age- and county-matched individuals without gender dysphoria. Data on the core outcomes of the study, which are gender incongruence and experienced gender dysphoria, body satisfaction and satisfaction with gender-affirming treatments, as well as other relevant outcomes, including mental health, social functioning and life satisfaction, are collected via web surveys. Two different research visits, before and after starting on gender-affirming hormonal treatment (if applicable), are planned to collect respective biological and cognitive measures. Data analysis will be performed using appropriate biostatistical methods. A power analysis showed that the current sample size is big enough to analyse continuous and categorical outcomes, and participant recruitment will continue until December 2022. ETHICS AND DISSEMINATION: The ethical permission for this study was obtained from the Local Ethical Review Board in Uppsala, Sweden. Results of the study will be presented at national and international conferences and published in peer-reviewed journals. Dissemination will also be implemented through the Swedish Gender Dysphoria Study network in Sweden