Novel inflammatory targets for immunotherapies in pediatric patients with trichotillomania.

Immune dysregulation may be important in the etiology of obsessive-compulsive and related disordersandbody-focusedrepetitivebehaviors, such as Trichotillomania (TTM). The role of inflammation and inflammatory markers in TTM has received relatively little attention. This study was aimed to determine the expression levels of inflammatory markers (i.e. IL-1ß, IL-1α, IL-4, IL-6, IL-17, TNF-α and TGF-ß) in peripheral blood mononuclear cells of children with TTM and healthy controls and to evaluate their association with clinical variables. Seventy-seven patients with TTM and 107 healthy controls were enrolled in the study. Peripheral blood was collected in standardized conditions. The mean age of patients and controls did not differ significantly (10.8 ± 4.4 and 12.0 ± 3.2 years; respectively). The majority of patients with TTM and controls were females (n = 55, 71.4 % and n = 55, 51.4 %; respectively); with a greater preponderance of females among TTM. Patients with TTM had significantly elevated expression levels of TNF-α, IL-6 and IL-17 compared to controls. However, the expression level of IL-4 was significantly reduced in TTM patients compared to controls. Accordingly, we found a pro-inflammatory state in TTM and those findings may suggest novel treatment options for TTM and further, cross-disciplinary studies focusing on neuro- inflammation in TTM conducted on larger samples are needed.

Salivary sex hormones in adolescent females with trichotillomania.

Trichotillomania is several times more common in women and has peak onset around puberty. The role of sex hormones, however, has received little research. 11 adolescent girls with trichotillomania, post-menarche and not taking birth control, were examined on a variety of clinical measures. Participants provided saliva samples for analysis of estradiol, progesterone, and testosterone levels. Lower progesterone was associated with more severe symptoms and lower levels of all hormones were associated with worse overall functioning. Adolescents with trichotillomania exhibit a range of hormone levels but that lower levels of certain hormones may have important clinical associations.

Preventing, treating, and predicting barbering: A fundamental role for biomarkers of oxidative stress in a mouse model of Trichotillomania.

Barbering, where a "barber" mouse plucks hair from its cagemates or itself, is both a spontaneously occurring abnormal behavior in mice and a well validated model of Trichotillomania (TTM). N-Acetylcysteine, (NAC) a cysteine derived food additive, is remarkably effective in treating TTM patients, but its mechanism of action is unknown. Reactive Oxygen Species (ROS), also known as free radicals, form as a natural byproduct of the normal metabolism of oxygen. Under normal circumstances, cells are able to defend themselves against ROS damage with antioxidant pathways. NAC is the precursor to the main antioxidant produced to defend the brain. Therefore, we hypothesized that barbering is a disease of oxidative stress, whereby ROS and/or a failure of antioxidant defenses leads to neuronal damage that induces barbering in susceptible animals. We tested this hypothesis in 32 female C57BL/6J mice by treating half with 1g/kg BW/day of NAC in their diet, and testing for protection against developing barbering behavior and curing of barbering behavior, and simultaneously testing for a panel of biomarkers of oxidative stress. NAC reduced the chance that mice would be barbers, and this effect did not differ between healthy (i.e. prevention) and affected animals (i.e. cure). Barbering animals had elevated urinary antioxidant capacity, indicative of oxidative stress, at all timepoints. Additionally, after treatment the risk of barbering increased with decreasing hydroxy-2'-deoxyguanosine (8-OHdG) levels, and with increasing glutathione (GSH) and oxidized glutathione (GSSG) levels, further indicating that barbering mice were under oxidative stress regardless of treatment with NAC. We did not find compelling evidence that urinary total antioxidant capacity, or urinary 8-OHdG, could predict response to NAC treatment. We conclude that NAC is effective in preventing and/or curing barbering at least in part by promoting GSH synthesis, thereby preventing oxidative damage.

Plasmacytoid dendritic cells in alopecia areata: missing link?

BACKGROUND: Type I interferon (IFN) signature has been implicated in alopecia areata (AA). However, type I IFN source has never been documented. Plasmacytoid dendritic cells (PDCs) are generally known to be the main source and most potent producers of local type I IFNs. Their role in AA pathogenesis has never been investigated. OBJECTIVE: Investigate PDC role in AA. METHODS: Nineteen AA cases were retrieved from our database and were immunohistochemically tested for PDC occurrence and activity using anti-BDCA-2 and anti-MxA antibodies respectively. Comparison to 10 trichotillomania and 7 androgenetic alopecia (AGA) cases was also done. RESULTS: Plasmacytoid dendritic cells were present in all AA cases in a peri-bulbar location and, as indirectly assessed by MxA expression, were in an active state producing type I IFNs. All trichotillomania cases showed the presence of PDCs, though significantly less abundant and in a different distribution (mainly superficial perivascular) than that in AA. PDC presence and MxA expression were absent in AGA. CONCLUSIONS: Plasmacytoid dendritic cells constitute a central component of the peribulbar infiltrate in AA suggesting a significant role in AA pathogenesis. Additionally, PDC distribution could help in microscopically differentiating AA from trichotillomania or AGA.

Brain activation during implicit sequence learning in individuals with trichotillomania.

Trichotillomania (TTM) may be related to obsessive-compulsive disorder (OCD) and other neuropsychiatric conditions characterized by cortico-striatal dysfunction. Functional imaging studies of OCD using an implicit learning task have found abnormalities in striatal and hippocampal activation. The current study investigated whether similar abnormalities occur in TTM. Functional MRI and the serial reaction time (SRT) task were used to assess striatal and hippocampal activation during implicit sequence learning in TTM and healthy control (HC) subjects. The results for 20 age- and education-matched participants (10 TTM, 10 HC) are reported. In comparison with HC participants, those with TTM exhibited no significant differences in implicit learning, or in activation within the striatum, hippocampus, or other brain regions. The current findings do not provide evidence for cortico-striatal dysfunction in TTM. Future studies directly comparing OCD and TTM subjects are warranted to confirm the specificity of abnormal striatal and hippocampal findings during implicit sequence learning in OCD.

Genetic correlates in trichotillomania--A case-control association study in the South African Caucasian population.

BACKGROUND: Trichotillomania (TTM), a prevalent and disabling psychiatric disorder characterized by repetitive hair-pulling, is presently classified as an impulse control disorder (ICD). Some have argued, however, that TTM is an obsessive-compulsive spectrum disorder (OCSD). There is some evidence that both disorders (OCD and TTM) are mediated by serotonergic (5-HT) and dopaminergic pathways. METHODS: The aim of the present investigation was to assess the role of candidate genes encoding components within the 5-HT and dopaminergic neurotransmitter pathways in mediating TTM. South African Caucasian TTM subjects (n=39), OCD (n=250) and control subjects (n=152) were genotyped for variants in 5-HT and dopaminergic candidate genes. RESULTS: Both genotypic and allelic distributions of the 5-HT receptor 2A (5-HT2A) T102C variant were found to be significantly different between the TTM and control subjects (p=0.028 and p=0.024, respectively), and a trend towards significance was noted between the TTM and OCD subjects (p=0.084 and p=0.080 for genotype and allele analyses, respectively), with the T102T-genotype found to confer susceptibility to the development of TTM. CONCLUSION: This investigation provides preliminary evidence for the involvement of 5-HT2A in the molecular aetiology of TTM and supports the need for further replication in a larger dataset. The present data are consistent with previous findings that 5-HT2A plays a role in mediating impulse dyscontrol.

Conceptual issues in trichotillomania, a prototypical impulse control disorder.

Impulse control disorders (ICDs) are characterized by irresistible urges to perform acts that result in a reduction of tension and possibly gratification, but also have negative consequences. Trichotillomania, an ICD, is characterized by a recurrent failure to resist impulses to pull out one's hair, resulting in noticeable hair loss. Limited information is available about structural and neurochemical differences in individuals with trichotillomania. Cognitive behavioral techniques are promising treatments for trichotillomania. Pharmacologic treatments have focussed on clomipramine and venlafaxine as potentially effective for the short term control of symptoms in trichotillomania. Selective serotonin reuptake inhibitors, though promising in open trials, seem to be largely ineffective in reducing hair pulling in controlled studies. Durability of pharmacologic benefit for the symptoms of trichotillomania, both in a small trial and in clinical experience, appears to be poor.

Regional cerebral glucose metabolism of women with trichotillomania.

Positron emission tomography and 18-F-fluorodeoxyglucose were used to study resting cerebral glucose metabolism in 10 adult women with trichotillomania and 20 age-matched female controls. As a group, the patients with trichotillomania showed significantly increased global (mean gray matter) and normalized right and left cerebellar and right superior parietal glucose metabolic rates. Contrary to expectation, this pattern differed from that seen in our previous investigation of obsessive-compulsive disorder. Clomipramine hydrochloride-induced improvement was negatively correlated with anterior cingulate and orbital frontal metabolism, of particular interest because similar results had been obtained for obsessive-compulsive disorder.