The Autism-Psychosis Continuum Conundrum: Exploring the Role of the Endocannabinoid System.

Evidence indicates shared physiopathological mechanisms between autism and psychosis. In this regard, the endocannabinoid system has been suggested to modulate neural circuits during the early stage of neurodevelopment, with implications for both autism and psychosis. Nevertheless, such potential common markers of disease have been investigated in both autism and psychosis spectrum disorders, without considering the conundrum of differentiating the two groups of conditions in terms of diagnosis and treatment. Here, we systematically review all human and animal studies examining the endocannabinoid system and its biobehavioral correlates in the association between autism and psychosis. Studies indicate overlapping biobehavioral aberrancies between autism and schizophrenia, subject to correction by modulation of the endocannabinoid system. In addition, common cannabinoid-based pharmacological strategies have been identified, exerting epigenetic effects across genes controlling neural mechanisms shared between autism and schizophrenia. Interestingly, a developmental and transgenerational trajectory between autism and schizophrenia is supported by evidence that exogenous alteration of the endocannabinoid system promotes progression to inheritable psychosis phenotypes in the context of biobehavioral autism vulnerability. However, evidence for a diametral association between autism and psychosis is scant. Several clinical implications follow from evidence of a developmental continuum between autism and psychosis as a function of the endocannabinoid system dysregulation.

Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence.

Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading to the investigation of molecules targeting the immune-glutamatergic system in ASD treatment. Palmitoylethanolamide (PEA) is a naturally occurring saturated N-acylethanolamine that has proven to be effective in controlling inflammation, depression, epilepsy, and pain, possibly through a neuroprotective role against glutamate toxicity. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in ASD. Studies indicate altered serum/brain levels of PEA and other endocannabinoids (ECBs)/acylethanolamines (AEs) in ASD. Altered PEA signaling response to social exposure and altered expression/activity of enzymes responsible for the synthesis and catalysis of ECBs/AEs, as well as downregulation of the peroxisome proliferator activated receptor-α (PPAR-α) and cannabinoid receptor target GPR55 mRNA brain expression, have been reported. Stress and exposure to exogenous cannabinoids may modulate ECBs/AEs levels and expression of candidate genes for neuropsychiatric disorders, with implications for ASD. Limited research suggests that PEA supplementation reduces overall autism severity by improving language and social and nonsocial behaviors. Potential neurobiological underpinnings include modulation of immune response, neuroinflammation, neurotrophy, apoptosis, neurogenesis, neuroplasticity, neurodegeneration, mitochondrial function, and microbiota activity, possibly through peroxisome proliferator-activated receptor-α (PPAR-α) activation.

Longitudinal assessment of the effect of cannabis use on hospital readmission rates in early psychosis: A 6-year follow-up in an inpatient cohort.

Cannabis is the most commonly used illicit drug in psychosis patients and has been identified as a risk factor for relapse and subsequent hospital readmission, having substantial economic implications. To clarify the contribution of cannabis consumption to hospital readmission, a consecutive inpatient cohort of 161 early psychosis patients was included into the study. Data on cannabis use at admission and number of hospital readmissions and length of stay (LOS, number of inpatient days) in a 6-year follow-up was extracted from clinical notes. 62.4% of the patients had lifetime cannabis use. Their admission lasted on average 54.3 ±â€¯75 days and over the following 6 years patients had 2.2 ±â€¯2.8 hospital readmissions, for a total of 197.4 ±â€¯331.5 days. Cannabis use significantly predicted the number of hospital readmissions and LOS in the following 6 years, the latter remaining significant after adjusting for use of other substance. Cannabis-using patients of male gender and Black ethnicity had a longer LOS at follow-up compared to female patients and other ethnic groups, respectively. Having a history of cannabis use when admitted to an early intervention inpatient unit for psychosis is associated with a higher number of subsequent hospital readmissions and a longer LOS, especially in male and Black patients.

The effect of cross-sex hormonal treatment on gender dysphoria individuals' mental health: a systematic review.

Cross-sex hormonal treatment represents a main aspect of gender dysphoria health care pathway. However, it is still debated whether this intervention translates into a better mental well-being for the individual and which mechanisms may underlie this association. Although sex reassignment surgery has been the subject of extensive investigation, few studies have specifically focused on hormonal treatment in recent years. Here, we systematically review all studies examining the effect of cross-sex hormonal treatment on mental health and well-being in gender dysphoria. Research tends to support the evidence that hormone therapy reduces symptoms of anxiety and dissociation, lowering perceived and social distress and improving quality of life and self-esteem in both male-to-female and female-to-male individuals. Instead, compared to female-to-male individuals, hormone-treated male-to-female individuals seem to benefit more in terms of a reduction in their body uneasiness and personality-related psychopathology and an amelioration of their emotional functioning. Less consistent findings support an association between hormonal treatment and other mental health-related dimensions. In particular, depression, global psychopathology, and psychosocial functioning difficulties appear to reduce only in some studies, while others do not suggest any improvement in these domains. Results from longitudinal studies support more consistently the association between hormonal treatment and improved mental health. On the contrary, a number of cross-sectional studies do not support this evidence. This review provides possible biological explanation vs psychological explanation (direct effect vs indirect effect) for the hormonal treatment-induced better mental well-being. In conclusion, this review indicates that gender dysphoria-related mental distress may benefit from hormonal treatment intervention, suggesting a transient reaction to the nonsatisfaction connected to the incongruent body image rather than a stable psychiatric comorbidity. In this perspective, timely hormonal treatment intervention represents a crucial issue in gender dysphoria individuals' mental health-related outcome.

To treat or not to treat: puberty suppression in childhood-onset gender dysphoria.

Puberty suppression using gonadotropin-releasing-hormone analogues (GnRHa) has become increasingly accepted as an intervention during the early stages of puberty (Tanner stage 2-3) in individuals with clear signs of childhood-onset gender dysphoria. However, lowering the age threshold for using medical intervention for children with gender dysphoria is still a matter of contention, and is more controversial than treating the condition in adolescents and adults, as children with gender dysphoria are more likely to express an unstable pattern of gender variance. Furthermore, concerns have been expressed regarding the risks of puberty suppression, which are poorly understood, and the child's ability to make decisions and provide informed consent. However, even if the limited data available mean that it is not possible to make a conclusive treatment recommendation, some safety criteria for puberty suppression can be identified and applied.

Psychological Support, Puberty Suppression, and Psychosocial Functioning in Adolescents with Gender Dysphoria.

INTRODUCTION: Puberty suppression by gonadotropin-releasing hormone analogs (GnRHa) is prescribed to relieve the distress associated with pubertal development in adolescents with gender dysphoria (GD) and thereby to provide space for further exploration. However, there are limited longitudinal studies on puberty suppression outcome in GD. Also, studies on the effects of psychological support on its own on GD adolescents' well-being have not been reported. AIM: This study aimed to assess GD adolescents' global functioning after psychological support and puberty suppression. METHODS: Two hundred one GD adolescents were included in this study. In a longitudinal design we evaluated adolescents' global functioning every 6 months from the first visit. MAIN OUTCOME MEASURES: All adolescents completed the Utrecht Gender Dysphoria Scale (UGDS), a self-report measure of GD-related discomfort. We used the Children's Global Assessment Scale (CGAS) to assess the psychosocial functioning of adolescents. RESULTS: At baseline, GD adolescents showed poor functioning with a CGAS mean score of 57.7 ± 12.3. GD adolescents' global functioning improved significantly after 6 months of psychological support (CGAS mean score: 60.7 ± 12.5; P < 0.001). Moreover, GD adolescents receiving also puberty suppression had significantly better psychosocial functioning after 12 months of GnRHa (67.4 ± 13.9) compared with when they had received only psychological support (60.9 ± 12.2, P = 0.001). CONCLUSION: Psychological support and puberty suppression were both associated with an improved global psychosocial functioning in GD adolescents. Both these interventions may be considered effective in the clinical management of psychosocial functioning difficulties in GD adolescents.

Dissociative symptoms in individuals with gender dysphoria: is the elevated prevalence real?

This study evaluated dissociative symptomatology, childhood trauma and body uneasiness in 118 individuals with gender dysphoria, also evaluating dissociative symptoms in follow-up assessments after sex reassignment procedures were performed. We used both clinical interviews (Dissociative Disorders Interview Schedule) and self-reported scales (Dissociative Experiences Scale). A dissociative disorder of any kind seemed to be greatly prevalent (29.6%). Moreover, individuals with gender dysphoria had a high prevalence of lifetime major depressive episode (45.8%), suicide attempts (21.2%) and childhood trauma (45.8%), and all these conditions were more frequent in patients who fulfilled diagnostic criteria for any kind of dissociative disorder. Finally, when treated, patients reported lower dissociative symptoms. Results confirmed previous research about distress in gender dysphoria and improved mental health due to sex reassignment procedures. However, it resulted to be difficult to ascertain dissociation in the context of gender dysphoria, because of the similarities between the two conditions and the possible limited application of clinical instruments which do not provide an adequate differential diagnosis. Therefore, because the body uneasiness is common to dissociative experiences and gender dysphoria, the question is whether dissociation is to be seen not as an expression of pathological dissociative experiences but as a genuine feature of gender dysphoria.

Concomitant psychiatric problems and hormonal treatment induced metabolic syndrome in gender dysphoria individuals: a 2 year follow-up study.

OBJECTIVE: Several studies indicate increased prevalence of metabolic syndrome (MetS) among patients with psychiatric disorders as well as among individuals with gender dysphoria (GD) treated by cross-sex hormonal treatment. However, the MetS prevalence among hormone treated GD individuals suffering from psychiatric problems has not been detected. METHODS: From a sample of 146 GD patients we selected 122 metabolically healthy individuals in order to investigate the prevalence of MetS after the beginning of the cross-sex hormonal treatment in a 2 year follow-up assessment. Furthermore, we assessed differences in MetS prevalence between hormone treated GD patients with and without concomitant psychiatric problems. RESULTS: When treated with hormone therapy, GD patients reported changes in several parameters which are clustered in MetS, with statistically significant differences compared to baseline. Glyco-insulinemic alterations were more pronounced in male to female patients (MtFs). However, weight gain, waist circumference increases, blood pressure increases, and lipid alterations were similar in MtFs and female to male patients (FtMs). 14.8% of the sample at year 1 and 17.2% at year 2 developed MetS. Among patients with concomitant psychiatric problems, 50% at year 1 and 55% at year 2 developed MetS against 8% at year 1 and 10% at year 2 of patients without concomitant psychiatric problems. CONCLUSION: This study indicates that sex hormones induce MetS in a relatively low proportion of healthy GD individuals and especially during the first year of hormonal treatment. Most importantly, concomitant psychiatric problems are associated with considerably greater MetS prevalence in hormone treated GD individuals.

Transsexual patients' psychiatric comorbidity and positive effect of cross-sex hormonal treatment on mental health: results from a longitudinal study.

The aim of the present study was to evaluate the presence of psychiatric diseases/symptoms in transsexual patients and to compare psychiatric distress related to the hormonal intervention in a one year follow-up assessment. We investigated 118 patients before starting the hormonal therapy and after about 12 months. We used the SCID-I to determine major mental disorders and functional impairment. We used the Zung Self-Rating Anxiety Scale (SAS) and the Zung Self-Rating Depression Scale (SDS) for evaluating self-reported anxiety and depression. We used the Symptom Checklist 90-R (SCL-90-R) for assessing self-reported global psychological symptoms. Seventeen patients (14%) had a DSM-IV-TR axis I psychiatric comorbidity. At enrollment the mean SAS score was above the normal range. The mean SDS and SCL-90-R scores were on the normal range except for SCL-90-R anxiety subscale. When treated, patients reported lower SAS, SDS and SCL-90-R scores, with statistically significant differences. Psychiatric distress and functional impairment were present in a significantly higher percentage of patients before starting the hormonal treatment than after 12 months (50% vs. 17% for anxiety; 42% vs. 23% for depression; 24% vs. 11% for psychological symptoms; 23% vs. 10% for functional impairment). The results revealed that the majority of transsexual patients have no psychiatric comorbidity, suggesting that transsexualism is not necessarily associated with severe comorbid psychiatric findings. The condition, however, seemed to be associated with subthreshold anxiety/depression, psychological symptoms and functional impairment. Moreover, treated patients reported less psychiatric distress. Therefore, hormonal treatment seemed to have a positive effect on transsexual patients' mental health.

Hormonal treatment reduces psychobiological distress in gender identity disorder, independently of the attachment style.

INTRODUCTION: Gender identity disorder may be a stressful situation. Hormonal treatment seemed to improve the general health as it reduces psychological and social distress. The attachment style seemed to regulate distress in insecure individuals as they are more exposed to hypothalamic-pituitary-adrenal system dysregulation and subjective stress. AIM: The objectives of the study were to evaluate the presence of psychobiological distress and insecure attachment in transsexuals and to study their stress levels with reference to the hormonal treatment and the attachment pattern. METHODS: We investigated 70 transsexual patients. We measured the cortisol levels and the perceived stress before starting the hormonal therapy and after about 12 months. We studied the representation of attachment in transsexuals by a backward investigation in the relations between them and their caregivers. MAIN OUTCOME MEASURES: We used blood samples for assessing cortisol awakening response (CAR); we used the Perceived Stress Scale for evaluating self-reported perceived stress and the Adult Attachment Interview to determine attachment styles. RESULTS: At enrollment, transsexuals reported elevated CAR; their values were out of normal. They expressed higher perceived stress and more attachment insecurity, with respect to normative sample data. When treated with hormone therapy, transsexuals reported significantly lower CAR (P < 0.001), falling within the normal range for cortisol levels. Treated transsexuals showed also lower perceived stress (P < 0.001), with levels similar to normative samples. The insecure attachment styles were associated with higher CAR and perceived stress in untreated transsexuals (P < 0.01). Treated transsexuals did not expressed significant differences in CAR and perceived stress by attachment. CONCLUSION: Our results suggested that untreated patients suffer from a higher degree of stress and that attachment insecurity negatively impacts the stress management. Initiating the hormonal treatment seemed to have a positive effect in reducing stress levels, whatever the attachment style may be.