Toxoplasmosis in a Cohort of Italian Patients With Bipolar and Psychotic Disorders: How Infection May Affect Clinical Features?

This study investigated the seroprevalence of Toxoplasma gondii in a cohort of 101 Italian inpatients affected by mood or schizophrenia-spectrum disorders and compared clinical features between seronegative and seropositive subjects. Patients diagnosed according to DSM-5 criteria underwent clinical assessments and blood collection to test parasite-specific IgG/IgM serum levels. Twenty-eight patients (27.7%) had IgG anti-T. gondii, and none had IgM antibodies. We found higher prevalence rate in patients aged 40 years or older, as compared with younger. No significant association was detected between T. gondii and a specific diagnostic category; however, bipolar disorder (BD)-II showed the highest positivity rate (40.9%). The seropositive status was significantly associated with a lower presence of psychotic symptoms, higher number of total episodes of predominant excitatory polarity, longer illness duration, and lower severity of current episode, particularly anxiety, depressive, and withdrawal/retardation symptoms. These preliminary results seem to point out an association between chronic toxoplasmosis and a specific subtype of BD.

Non-Functional Trace Amine-Associated Receptor 1 Variants in Patients With Mental Disorders.

Background: The G protein-coupled receptor (GPCR) trace amine-associated receptor 1 (TAAR1) is expressed across brain areas involved in emotions, reward and cognition, and modulates monoaminergic and glutamatergic neurotransmissions. TAAR1 is stimulated with nanomolar affinity by 3-iodothyronamine (T1AM), an endogenous messenger considered a novel branch of thyroid hormone signaling. The human gene for TAAR1 maps to locus 6q23, within a region associated with major mental disorders. Materials and Methods: We screened a cohort of patients with major mental disorders (n = 104) and a group of healthy controls (n = 130) for TAAR1 variants. HEK293 cells were transiently transfected with: i) wild-type TAAR1 and ii) mutated TAAR1, either in homozygous or heterozygous state. Cell surface expression and Gs/adenylyl cyclase activation upon administration of ß-phenylethylamine (PEA), T1AM, and RO5166017, were assessed. Results: We detected 13 missense variants in TAAR1 coding region, with a significant enrichment in patients as compared to healthy controls (11 vs. 1, 1 variant in both groups, p < 0.01). In silico analysis identified four dysfunctional variants, all in patients. Three of these-R23C, Y131C, and C263R-were functionally characterized. In cells co-transfected with wild-type and mutated TAAR1, we observed a significant reduction of cell surface expression. In heterozygosity, the three TAAR1 variants substantially dampened Gs signaling in response to PEA, and, more robustly, to T1AM. Co-stimulation with PEA and RO5166017 did not yield any improvement in Gs signaling. R23C, Y131C, and C263R are rare in the general population and map in functionally important highly conserved positions across TAAR1 orthologous and paralogous genes. Conclusions: Our findings suggest that disruptions of TAAR1 activity may be relevant to the pathophysiology of mental disorders, thereby providing a promising target for novel psychopharmacological interventions.

Systematic Review of Sleep Disturbances and Circadian Sleep Desynchronization in Autism Spectrum Disorder: Toward an Integrative Model of a Self-Reinforcing Loop.

Background: A compelling number of studies, conducted in both children and adults, have reported an association between sleep disturbances/circadian sleep alterations and autism spectrum disorder (ASD); however, the data are sparse and the nature of this link is still unclear. The present review aimed to systematically collect the literature data relevant on sleep disturbances and circadian sleep dysrhythmicity related to ASD across all ages and to provide an integrative theoretical framework of their association. Methods: A systematic review of the MEDLINE, PubMed, and Cochrane databases was conducted from November 2018 to February 2019. The search strategies used were MeSH headings and keywords for "sleep-wake circadian rhythms" OR "circadian sleep disorders" OR "sleep-wake pattern" OR "sleep disorders" OR "melatonin" AND "autism spectrum disorder" OR "autism". Results: One hundred and three studies were identified, 15 regarded circadian sleep dysrhythmicity, 74 regarded sleep disturbances, and 17 regarded melatonin alterations in children and adults with ASD. Our findings suggested that autistic subjects frequently present sleep disturbances in particular short sleep duration, low sleep quality/efficiency, and circadian sleep desynchronization such as delayed phases and/or eveningness. Sleep disturbances and circadian sleep alterations have been related to the severity of autistic symptoms. Genetic studies have shown polymorphisms in circadian CLOCK genes and in genes involved in melatonin pathways in subjects with ASD. Conclusions: Sleep disturbances and circadian sleep alterations are frequent in subjects with autistic symptoms. These subjects have shown polymorphisms in clock genes expression and in genes involved in melatonin production. The impairment of circadian sleep regulation may increase the individual's vulnerability to develop symptoms of ASD by altering the sleep regulation in toto, which plays a key role in normal brain development. Even though controversies and "research gaps" are present in literature at this point, we may hypothesize a bidirectional relation between circadian sleep dysfunction and ASD. In particular, circadian sleep dysrhythmicity may predispose to develop ASD symptoms and vice versa within a self-reinforcing feedback loop. By targeting sleep disturbances and circadian sleep dysrhythmicity, we may improve treatment strategies for both children and adults with ASD.

Insomnia and depressive symptoms during the menopausal transition: theoretical and therapeutic implications of a self-reinforcing feedback loop.

Insomnia is a common and recurring condition during the menopausal transition that negatively affects both quality of life and health. Peri-menopausal insomnia has a multifactorial etiology; previous depression, hormonal changes and age/hormone-related irregularity in circadian rhythms can contribute to menopausal insomnia. Age-related poor health, pain and stress may favor the development of insomnia, while vasomotor symptoms, in particular hot flashes, may contribute to chronic forms of insomnia by activating a vicious cycle. Insomnia increases two- to threefold the risk of developing depressive symptoms during the peri-menopause. In fact, the menopausal transition is a window of vulnerability for the development of depressive symptoms, in which the risk of a major depressive disorder is 2-4 times greater than in the premenopausal period. Depression naturally has a negative impact on daily functioning, quality of life and health. Since the relationship between insomnia and depressive symptoms has been shown to be bidirectional, the aim of this review is to provide a brief overview of their association in the context of the menopausal transition. By exploring the potential pathways of their bidirectional relationship, this overview should be useful for preventive and therapeutic purposes. By treating insomnia we may be able to interrupt the self-reinforcing feedback loop with depressive symptoms, and thereby improve affective symptoms and women's wellbeing in this period of their life.

Lithium and valproate serum level fluctuations within the menstrual cycle: a systematic review.

Some women affected by mood disorders experience mood instability during the premenstrual phase. Assuming that fluctuations in drug serum levels may contribute to the worsening of mood symptoms, we carried out a systematic review of available studies that investigated changes in lithium and valproate levels in relation to menstrual phases. We selected five studies; four of which assessed menstrual fluctuations in lithium serum levels and one in valproate levels. Study samples included women in their fertile age affected by bipolar disorder, epilepsy as well as healthy ones. Preliminary results showed a close relationship between cyclic premenstrual exacerbation of affective symptoms and a significant decrease in lithium levels during the luteal phase, despite stable oral doses, in bipolar women. In healthy women, lithium levels were influenced by neither menstrual cycle phases nor oral contraceptives use. Valproate serum levels in epileptic women showed a small, nonsignificant decline during the mid-luteal phase. Pharmacokinetic sex differences in adsorption, volume distribution, hepatic metabolism, and renal excretion of mood stabilizers have been supposed to partly explain such menstrual serum level fluctuations. A better understanding in this field could help to counteract the distress related to premenstrual phase, improving therapeutic management of mood disorders in women.

Stress-related sleep reactivity is associated with insomnia, psychopathology and suicidality in pregnant women: preliminary results.

INTRODUCTION: Depression and anxiety symptoms are commonly experienced by women during pregnancy and may have negative consequences on mothers and newborns. Deterioration of sleep quality throughout pregnancy increases insomnia, which may lead to adverse outcomes including increased psychopathology in the perinatal period. Thus, identifying women at high risk of developing insomnia may have important clinical implications on maternal-fetal outcomes. Stress-related sleep reactivity is a well-established risk factor for future insomnia, depression, and anxiety in general adult samples. However, little is known of sleep reactivity and its relations to sleep and mood pathology in pregnancy. Therefore, we explored sleep reactivity in pregnant women and its relations to prenatal symptoms of insomnia, depression, anxiety, and suicidality. METHOD: Sixty-two pregnant women (mean age 33.6 ± 3 years, 20.6 ± 0.6 weeks of pregnancy) were evaluated during their routine visit at the Gynecological Unit of the University of Pisa, Italy, using the Insomnia Severity Index (ISI) for insomnia symptoms, the Ford Insomnia Response to Stress Test for sleep reactivity (FIRST), Edinburgh Postnatal Depression Scale (EPDS) for depressive symptoms, and the Zung Self Rating Anxiety Scale (SAS) for anxiety symptoms. Item #10 of the EPDS was used to assess for suicidality. Differences in means between women with high vs low stress-related sleep reactivity were calculated using t-test or Mann-Whitney U/Wilcoxon test. Linear/multiple regression analyses have been performed to study associations between variables. RESULTS: Pregnant women with high stress-related sleep reactivity, relative to those with low reactivity, reported greater symptoms of insomnia (t = 6.5, 0.004) as well as higher rates of depression (62.0% vs 6.1%, p < 0.001), anxiety (55.1% vs 15.1%, p = 0.030), and suicidality (17.2% vs 3.0%, p = 0.025). Multivariate models revealed sleep reactivity to correlate independently with symptoms of insomnia, depression, and anxiety, when controlling for comorbid symptoms. CONCLUSIONS: In mid-pregnancy, women with high sleep reactivity report elevated symptoms of insomnia, depression, and anxiety, and are more likely to endorse suicidal ideation. As a prognostic marker of future insomnia and psychiatric illness, early detection of high prenatal sleep reactivity holds potential to prevent the development of sleep and mood pathology during pregnancy, thereby potentially improving maternal and child outcomes.

Chronobiological dis-rhythmicity is related to emotion dysregulation and suicidality in depressive bipolar II disorder with mixed features.

In Bipolar Disorder, chronobiological rhythm alterations play a key role by negatively influencing its entire trajectory. Our aim was to assess their potential association with emotion dysregulation and suicidality in subjects with Bipolar Disorder. Eighty-five patients with Bipolar Disorder - II depressive episode with mixed features were recruited and 35 as healthy controls. Subjects were evaluated with SCID-DSM-5, the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), the DERS: Difficulties in Emotion Regulation Scale, the Beck Depression Inventory-II (BDI-II), the Young Mania Rating Scale (YMRS) and the Scale for Suicide Ideation (SSI). When compared to healthy controls, subjects with bipolar disorder showed significantly higher scores in the BRIAN, the DERS, the BDI-II, the YMRS and the SSI total scores. Chronobiological dis-rhythmicity was significantly related to the severity of depressive symptoms, emotion dysregulation, and suicidality in bipolar individuals. In particular, the dis-rythmicity of the sleep/wake pattern showed a significant correlation with manic symptoms, the dis-rythmicity of daily activities with depressive symptoms and emotion dysregulation and that of social life with suicidality. Emotion dysregulation played as a mediator for the association between chronobiological dis-rhythmicity and depressive symptoms (mediated effect = 3.25, p = 0.001) and for social life dis-rhythmicity and suicidality (mediated effect = 2.52, p = 0.011) as well. Therefore, our findings showed that chronobiological dis-rhythmicity in bipolar individuals was related to the severity of mood swings, emotion dysregulation and suicidality. The assessment of potential alteration in chronobiological rhythms should be investigated in the clinical setting in subjects with bipolar disorder to identify those who may benefit from early chronobiological intervention.

Insomnia symptoms predict emotional dysregulation, impulsivity and suicidality in depressive bipolar II patients with mixed features.

INTRODUCTION: Insomnia symptoms are very common in Bipolar Disorder. Our aim was to assess the potential association between insomnia, emotion dysregulation and suicidality in subjects with Bipolar Disorder. METHODS: Seventy-seven subjects with Bipolar Disorder type II with a depressive episode with mixed features were recruited. Patients were assessed with SCID-DSM-5, the Insomnia Severity Index (ISI), the Difficulties in Emotion Regulation Scale (DERS), the Scale for Suicide Ideation (SSI) while evaluating manic and depressive symptoms. RESULTS: Subjects with insomnia symptoms compared to those without showed higher scores in the DERS scale and subscales, including impulsivity, and in the SSI scale. Insomnia symptoms significantly predicted the severity of depressive symptoms, emotion dysregulation, and suicidality in subjects with bipolar disorder. In particular, insomnia was related to difficulties in some areas of emotion regulation including impulsivity. Emotion dysregulation significantly mediated the association between insomnia and depressive symptoms (Z = 2.9, p = 0.004). Furthermore, emotional impulsivity mediated the association between insomnia symptoms and suicidality (Z = 2.2, p = 0.03). CONCLUSION: In our study, subjects with bipolar disorder suffering from insomnia experienced a greater severity of depressive symptoms and suicidality compared to subjects without insomnia. Insomnia was associated with emotion dysregulation, impulsivity and suicidality. Further research is necessary to investigate if these latter features may benefit from early insomnia treatment in subjects with bipolar disorder.

Lack of Resilience Is Related to Stress-Related Sleep Reactivity, Hyperarousal, and Emotion Dysregulation in Insomnia Disorder.

STUDY OBJECTIVES: According to the diathesis-stress model of insomnia, insomnia may develop in vulnerable individuals in response to stress. Resilience is a psychobiological factor that determines an individual's capacity to adapt successfully to stressful events and low resilience increases vulnerability for development of mental disorders. The aim was to explore resilience in subjects with insomnia and its relationship with the factors that contribute to its development and perpetuation. METHODS: The study consisted of 58 subjects with Insomnia Disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and 38 good sleepers. Resilience Scale for Adults (RSA), Ford Insomnia Response to Stress Test (FIRST), Pre-sleep Arousal Scale (PSAS), and Difficulties in Emotion Regulation Scale (DERS) were administered while taking into account psychiatric symptoms. Differences in means between groups were assessed using t test or Mann-Whitney U/Wilcoxon test. Linear/multivariable regression analyses and mediation analyses were performed. RESULTS: Subjects with insomnia (24 females, mean age 49 ± 2.1 years) had lower RSA and higher FIRST, DERS, and PSAS scores than good sleepers (22 females, mean age 47.2 ± 1.2 years). After controlling for anxiety/depressive symptoms, low resilience correlated with high stress-related sleep reactivity (P = .004), pre-sleep cognitive hyperarousal (P = .01) and emotion dysregulation (P = .01). Emotion dysregulation mediated the relationship between low resilience and cognitive hyperarousal (Z = 2.06, P = .03). CONCLUSIONS: Subjects with insomnia showed low resilience, which was related to high stress-related sleep reactivity, emotional dysregulation, and hyperarousal. If resilience helps to minimize the extent of pathogenesis in the developmental process, an early identification of vulnerable candidates should be useful for preventing insomnia development and maintenance. COMMENTARY: A commentary on this article appears in this issue on page 709.