Effects of galantamine on social interaction impairments in cholecystokinin receptor-2 overexpression mice.

We examined whether galantamine (GAL), a cholinesterase inhibitor and allosteric potentiating ligand for α7 nicotinic acetylcholine receptor (nAChR), had an impact on emotional abnormalities in forebrain-specific cholecystokinin receptor-2 overexpressed transgenic mice. Treatment with GAL (1 mg/kg, s.c.) attenuated the decrease of social interaction time, but failed to attenuate anxiety-like behavior in the elevated plus-maze test. The effect of GAL was blocked by an α7 nAChR antagonist, methyllycaconitine (3 mg/kg, i.p.). These results suggest that GAL improved social interaction impairments via α7 nAChR and could be useful to treat sociability-related emotional abnormalities.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

New V1a receptor antagonist. Part 1. Synthesis and SAR development of urea derivatives.

Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Starting from a moderately potent HTS hit (7), we identified a molecule (49) having nanomolar binding strength and functional activity, which is in the same range as the potency of clinically tested V1a antagonists.

New V1a receptor antagonist. Part 2. Identification and optimization of triazolobenzazepines.

Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Continuing our previous work, we found an in vitro and in vivo orally active V1a selective antagonist molecule (40) among [1,2,4]triazolo[4,3-a][1]benzazepines.

[Treatment of refractory aggressiveness by amygdalotomy and posteromedial hypothalamotomy by radiofrequency]. / Tratamiento de la agresividad refractaria mediante amigdalotomia e hipotalamotomia posteromedial por radiofrecuencia.

INTRODUCTION: Since, under certain circumstances, defensive or attacking behaviours display a pattern of motor dominance, as observed in subjects who participate in contact or fighting sports, aggressive behaviour was considered to have a dominant motor pattern. With the aim of preventing the functional problems reported with bilateral lesion procedures involving both the central nucleus of the amygdala and the posteromedial hypothalamus, the decision was made to combine them; thus, an amygdalotomy of the central nucleus of the amygdala and a posteromedial hypothalamotomy were to be performed simultaneously and unilaterally, on the basis of the motor dominance of the patient determined by means of the Edinburgh test. PATIENTS AND METHODS: This study describes the surgical experience in a series of nine patients diagnosed with refractory neuroaggressive syndrome. As part of the study protocol, a magnetic resonance brain scan was performed to rule out the presence of neoplasms, vascular diseases, infections and degenerative disorders. The degree of aggressiveness was quantified using Yudofsky's Overt Aggression Scale. Additionally, manual dominance was determined by means of the Edinburgh test. RESULTS AND CONCLUSIONS: Good control of aggressiveness was seen immediately. In some cases it was necessary to reduce the antipsychotic or benzodiazepine medication, as it was seen to increase aggressiveness. Only one case required a second surgical intervention. Follow-up was achieved in 100% of the cases at 24 months and 78% at 36 months.

TITLE: Tratamiento de la agresividad refractaria mediante amigdalotomia e hipotalamotomia posteromedial por radiofrecuencia.Introduccion. Dado que, en algunas circunstancias, las conductas defensivas o de ataque muestran un patron de dominancia motora, tal como se observa en los sujetos dedicados a los deportes de contacto o de lucha, se considero que la conducta agresiva tiene un patron motor dominante. Con el fin de evitar los problemas funcionales descritos con los procedimientos de lesion bilateral tanto del nucleo central de la amigdala como del hipotalamo posteromedial, se decidio combinarlos; es decir, realizar amigdalotomia del nucleo central de la amigdala e hipotalamotomia posteromedial de manera unilateral y simultanea, basandose en la dominancia motora del paciente mediante la prueba de Edimburgo. Pacientes y metodos. Este estudio muestra la experiencia quirurgica en una serie de nueve pacientes con el diagnostico de sindrome neuroagresivo resistente al tratamiento farmacologico. Dentro del protocolo de estudio, se les realizo resonancia magnetica cerebral para descartar la presencia de neoplasias, enfermedades vasculares, infecciones y trastornos degenerativos. El grado de agresividad se cuantifico mediante la escala global de agresividad de Yudofsky. Adicionalmente, se determino la dominancia manual a traves de la prueba de Edimburgo. Resultados y conclusiones. El buen control de la agresividad se observo de modo inmediato. En algunos casos fue necesario reducir la medicacion de antipsicoticos o benzodiacepinas, ya que aumentaban la agresividad. Solo un caso requirio una segunda cirugia. Se logro seguimiento del 100% de los casos en 24 meses y del 78% en 36 meses.

Recovery of stress-impaired social behavior by an antagonist of the CRF binding protein, CRF6-33, in the bed nucleus of the stria terminalis of male rats.

Social stress is recognized to promote the development of neuropsychiatric and mood disorders. Corticotropin releasing factor (CRF) is an important neuropeptide activated by social stress, and it contributes to neural and behavioral adaptations, as indicated by impaired social interactions and anhedonic effects. Few studies have focused on the role of the CRF binding protein (CRFBP), a component of the CRF system, and its activity in the bed nucleus of stria terminalis (BNST), a limbic structure connecting amygdala and hypothalamus. In this study, animals' preference for sweet solutions was examined as an index of stress-induced anhedonic responses in Wistar rats subjected to four brief intermittent episodes of social defeat. Next, social approach was assessed after local infusions of the CRFBP antagonist, CRF fragment 6-33 (CRF6-33) into the BNST. The experience of brief episodes of social defeat impaired social approach behaviors in male rats. However, intra-BNST CRF6-33 infusions restored social approach in stressed animals to the levels of non-stressed rats. CRF6-33 acted selectively on social interaction and did not alter general exploration in nether stressed nor non-stressed rats. These findings suggest that BNST CRFBP is involved in the modulation of anxiety-like responses induced by social stress.

Targeting the Oxytocin System: New Pharmacotherapeutic Approaches.

Deficits in social behavioral domains, such as interpersonal communication, emotion recognition, and empathy, are a characteristic symptom in several neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD). The neuropeptide oxytocin (OT) has emerged as a key regulator of diverse social behaviors in vertebrates and, thus, has been identified as a potential therapeutic target for improving social dysfunction. In recent years, the field of OT research has seen an explosion of scientific inquiry, producing a more comprehensive picture of oxytocinergic signaling and the pathways that regulate its release and degradation in the brain. In this review, we provide an analysis of how this information is being exploited to accelerate the discovery of novel oxytocinergic therapeutics.

Taurine modulates acute ethanol-induced social behavioral deficits and fear responses in adult zebrafish.

Ethanol (EtOH) is a central nervous system (CNS) depressant drug that modifies various behavioral domains (i.e., sociability, aggressiveness, and memory) by promoting disinhibition of punished operant behavior and neurochemical changes. Taurine (TAU) is a ß-amino sulfonic acid with pleiotropic roles in the brain. Although exogenous TAU is found in energy drinks and often mixed with alcohol in beverages, the putative risks of mixing TAU and EtOH are poorly explored. Here, we investigated whether TAU modulates social and fear responses by assessing shoaling behavior, preference for conspecifics, and antipredatory behavior of adult zebrafish acutely exposed to EtOH. Zebrafish shoals (4 fish per shoal) were exposed to water (control), TAU (42, 150, and 400 mg/L), 0.25% (v/v) EtOH alone or in association with TAU for 1 h, and their behaviors were analyzed at different time intervals (0-5 min, 30-35 min, and 55-60 min). The effects of TAU and EtOH were further tested in a social preference test and during exposure to a predator. Both EtOH and TAU co-treated fish showed a higher shoal dispersion, while TAU 400/EtOH group shoal area had a similar profile when compared to control. However, in the social preference test, TAU 400/EtOH impaired the seeking for conspecifics. Regarding fear-like behaviors, TAU-cotreated fish showed a prominent reduction in risk assessments when compared to EtOH alone. Overall, we demonstrate that TAU modulates EtOH-induced changes in different behavioral domains, suggesting a complex relationship between social and fear-like responses.

Molecular Hydrogen Prevents Social Deficits and Depression-Like Behaviors Induced by Low-Intensity Blast in Mice.

Detonation of explosive devices creates blast waves, which can injure brains even in the absence of external injuries. Among these, blast-induced mild traumatic brain injury (bmTBI) is increasing in military populations, such as in the wars in Afghanistan, Iraq, and Syria. Although the clinical presentation of bmTBI is not precisely defined, it is frequently associated with psycho-neurological deficits and usually manifests in the form of poly-trauma including psychiatric morbidity and cognitive disruption. Although the underlying mechanisms of bmTBI are largely unknown, some studies suggested that bmTBI is associated with blood-brain barrier disruption, oxidative stress, and edema in the brain. The present study investigated the effects of novel antioxidant, molecular hydrogen gas, on bmTBI using a laboratory-scale shock tube model in mice. Hydrogen gas has a strong prospect for clinical use due to easy preparation, low-cost, and no side effects. The administration of hydrogen gas significantly attenuated the behavioral deficits observed in our bmTBI model, suggesting that hydrogen application might be a strong therapeutic method for treatment of bmTBI.

Oxytocin receptor gene variations and socio-emotional effects of MDMA: A pooled analysis of controlled studies in healthy subjects.

Methylenedioxymethamphetamine (MDMA) increases oxytocin, empathy, and prosociality. Oxytocin plays a critical role in emotion processing and social behavior and has been shown to mediate the prosocial effects of MDMA in animals. Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the oxytocin receptor (OXTR) may influence the emotional and social effects of MDMA in humans. The effects of common genetic variants of the OXTR (rs53576, rs1042778, and rs2254298 SNPs) on the emotional, empathogenic, and prosocial effects of MDMA were characterized in up to 132 healthy subjects in a pooled analysis of eight double-blind, placebo-controlled studies. In a subset of 53 subjects, MDMA produced significantly greater feelings of trust in rs1042778 TT genotypes compared with G allele carriers. The rs53576 and rs225498 SNPs did not moderate the subjective effects of MDMA in up to 132 subjects. None of the SNPs moderated MDMA-induced impairments in negative facial emotion recognition or enhancements in emotional empathy in the Multifaceted Empathy Test in 69 subjects. MDMA significantly increased plasma oxytocin concentrations. MDMA and oxytocin concentrations did not differ between OXTR gene variants. The present results provide preliminary evidence that OXTR gene variations may modulate aspects of the prosocial subjective effects of MDMA in humans. However, interpretation should be cautious due to the small sample size. Additionally, OXTR SNPs did not moderate the subjective overall effect of MDMA (any drug effect) or feelings of "closeness to others". TRIAL REGISTRATION: ClinicalTrials.gov: http://www.clinicaltrials.gov, No: NCT00886886, NCT00990067, NCT01136278, NCT01270672, NCT01386177, NCT01465685, NCT01771874, and NCT01951508.

Chronic nicotine improves cognitive and social impairment in mice overexpressing wild type α-synuclein.

In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.

Melanocortin 4 receptor stimulation improves social deficits in mice through oxytocin pathway.

Several studies on humans and mice support oxytocin's role in improving social behaviour, but its use in pharmacotherapy presents some important limiting factors. To date, it is emerging a pharmacological potential for melanocortin 4 receptor (MC4R) agonism in social deficits treatment. Recently, we demonstrated that the deletion of the NFKB1 gene, which encodes the p50 NF-κB subunit, causes impairment in social behaviours, with reductions in social interactions in mice. In this work, we tested the acute effects of THIQ, a selective melanocortin 4 receptor (MC4R) agonist. THIQ treatment increased social interactions both in wild type and p50-/- mice. In particular, after treatment with THIQ, p50-/- mice showed a prosocial behaviour analogous to that of basal WT mice. Moreover, intranasal treatment with an oxytocin antagonist blocked social interactions induced by THIQ, demonstrating that its prosocial effects are mediated by the oxytocin pathway. The data obtained reinforce using MC4R agonists to ameliorate social impairment in NDDs.

Neonatal erythropoietin mitigates impaired gait, social interaction and diffusion tensor imaging abnormalities in a rat model of prenatal brain injury.

Children who are born preterm are at risk for encephalopathy of prematurity, a leading cause of cerebral palsy, cognitive delay and behavioral disorders. Current interventions are limited and none have been shown to reverse cognitive and behavioral impairments, a primary determinant of poor quality of life for these children. Moreover, the mechanisms of perinatal brain injury that result in functional deficits and imaging abnormalities in the mature brain are poorly defined, limiting the potential to target interventions to those who may benefit most. To determine whether impairments are reversible after a prenatal insult, we investigated a spectrum of functional deficits and diffusion tensor imaging (DTI) abnormalities in young adult animals. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) would induce multiple functional deficits concomitant with reduced microstructural white and gray matter integrity, and tested whether these abnormalities could be ameliorated using postnatal erythropoietin (EPO), an emerging neurorestorative intervention. On embryonic day 18 uterine arteries were transiently occluded for 60min via laparotomy. Shams underwent anesthesia and laparotomy for 60min. Pups were born and TSHI pups were randomized to receive EPO or vehicle via intraperitoneal injection on postnatal days 1 to 5. Gait, social interaction, olfaction and open field testing was performed from postnatal day 25-35 before brains underwent ex vivo DTI to measure fractional anisotropy, axial diffusivity and radial diffusivity. Prenatal TSHI injury causes hyperactivity, impaired gait and poor social interaction in young adult rats that mimic the spectrum of deficits observed in children born preterm. Collectively, these data show for the first time in a model of encephalopathy of prematurity that postnatal EPO treatment mitigates impairments in social interaction, in addition to gait deficits. EPO also normalizes TSHI-induced microstructural abnormalities in fractional anisotropy and radial diffusivity in multiple regions, consistent with improved structural integrity and recovery of myelination. Taken together, these results show behavioral and memory deficits from perinatal brain injury are reversible. Furthermore, resolution of DTI abnormalities may predict responsiveness to emerging interventions, and serve as a biomarker of CNS injury and recovery.

Repeated fluvoxamine treatment recovers early postnatal stress-induced hypersociability-like behavior in adult rats.

Childhood maltreatment is associated with impaired adult brain function, particularly in the hippocampus, and is not only a major risk factor for some psychiatric diseases but also affects early social development and social adaptation in later life. The aims of this study were to determine whether early postnatal stress affects social behavior and whether repeated fluvoxamine treatment reverses these changes. Rat pups were exposed to footshock stress during postnatal days 21-25 (at 3 weeks old: 3wFS). During the post-adolescent period (10-14 weeks postnatal), the social interaction test and Golgi-cox staining of dorsal hippocampal pyramidal neurons were performed. Following exposure to footshock stress, 3wFS rats showed an increase in social interaction time, which might be practically synonymous with hypersociability, and a decrease in spine density in the CA3 hippocampal subregion, but not in CA1. These behavioral and morphological changes were both recovered by repeated oral administration of fluvoxamine at a dose of 10 mg/kg/day for 14 days. These findings suggest that the vulnerability of the hippocampal CA3 region is closely related to social impairments induced by physical stress during the juvenile period and shed some light on therapeutic alternatives for early postnatal stress-induced emotional dysfunction.

Eszopiclone for persistent negative symptoms in schizophrenia - An unintended N-of-1 study.

Persistent negative and cognitive symptoms in patients with schizophrenia pose a significant challenge to clinicians. Being a heterogeneous cluster of symptoms with potentially distinct underlying pathogenesis, it is important to examine novel therapies based on emerging neurobiological evidence. Eszopiclone is known to enhance the deficient sleep spindles that are related to impairments in learning and memory in schizophrenia. In this report we highlight the potential utility of eszopiclone in treating persistent negative symptoms in a patient with chronic schizophrenia. The unintended N-of-1 design that spanned out over a period of 24weeks demonstrated improvements in negative symptoms while the patient was on eszopiclone and worsening of these symptoms while unintentionally being off eszopiclone treatment. These observations suggest a reasonable degree of specificity of our patient's response to eszopiclone, thus warranting future sleep-EEG guided systematic studies.

Sociability impairments in Genetic Absence Epilepsy Rats from Strasbourg: Reversal by the T-type calcium channel antagonist Z944.

Childhood absence epilepsy (CAE) is associated with interictal co-morbid symptoms including abnormalities in social behaviour. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) is a model of CAE that exhibits physiological and behavioural alterations characteristic of the human disorder. However, it is unknown if GAERS display the social deficits often observed in CAE. Sociability in rodents is thought to be mediated by neural circuits densely populated with T-type calcium channels and GAERS contain a missense mutation in the Cav3.2 T-type calcium channel gene. Thus, the objective of this study was to examine the effects of the clinical stage pan-T-type calcium channel blocker, Z944, on sociability behaviour in male and female GAERS and non-epileptic control (NEC) animals. Female GAERS showed reduced sociability in a three-chamber sociability task whereas male GAERS, male NECs, and female NECs all showed a preference for the chamber containing a stranger rat. In drug trials, pre-treatment with 5mg/kg of Z944 normalized sociability in female GAERS. In contrast, female NECs showed impaired sociability following Z944 treatment. Dose-dependent decreases in locomotor activity were noted following Z944 treatment in both strains. Treatment with 10mg/kg of Z944 altered exploration such that only 8 of the 16 rats tested explored both sides of the testing chamber. In those that explored the chamber, significant preference for the stranger rat was observed in GAERS but not NECs. Overall, the data suggest that T-type calcium channels are critical in regulating sociability in both GAERS and NEC animals. Future research should focus on T-type calcium channels in the treatment of sociability deficits observed in disorders such as CAE.

mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus.

Epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous sclerosis complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1 +/- and Tsc2 +/- mouse models by mammalian target of rapamycin (mTOR) inhibitors. However, at least 70 % of individuals with TSC also have epilepsy, known to complicate the severity and treatment responsiveness of the behavioural phenotype. No previous study has examined the impact of seizures on neurocognitive reversal by mTOR inhibitors. Adult Tsc2 +/- (Eker)-rats express social deficits similar to Tsc2 +/- mice, with additive social deficits from developmental status epilepticus (DSE). DSE was induced by intraperitoneal injection with kainic acid at post-natal days P7 and P14 (n = 12). The experimental group that modelled TSC pathology carried the Tsc2 +/- (Eker)-mutation and was challenged with DSE. The wild-type controls had not received DSE (n = 10). Four-month-old animals were analysed for social behaviour (T1), then treated three times during 1 week with 1 mg/kg everolimus and finally retested in the post-treatment behavioural analysis (T2). In the experimental group, both social interaction and social cognition were impaired at T1. After treatment at T2, behaviour in the experimental group was indistinguishable from controls. The mTOR inhibitor, everolimus, reversed social deficit behaviours in the Tsc2 haploinsufficiency plus DSE animal model to control levels.

A Prospective Open-Label Trial of Memantine Hydrochloride for the Treatment of Social Deficits in Intellectually Capable Adults With Autism Spectrum Disorder.

This prospective 12-week open-label trial evaluates the tolerability and efficacy of memantine hydrochloride for the treatment of core social and cognitive deficits in adults with high-functioning autism spectrum disorder (ASD). Measures for assessment of therapeutic response included the Social Responsiveness Scale-Adult Research Version (SRS-A), disorder-specific Clinical Global Impression scales, Behavior Rating Inventory of Executive Functioning-Adult Self-Report, Diagnostic Analysis of Nonverbal Accuracy Scale, and Cambridge Neuropsychological Test Automated Battery. Eighteen adults (mean age, 28 ± 9.5 years) with high-functioning ASD (SRS-A raw score, 99 ± 17) were treated with memantine (mean dose, 19.7 ± 1.2 mg/d; range, 15-20 mg), and 17 (94%) completed the trial. Treatment with memantine was associated with significant reduction on informant-rated (SRS-A, -28 ± 25; P < 0.001) and clinician-rated (Clinical Global Impression-Improvement subscale ≤2, 83%) measures of autism severity. In addition, memantine treatment was associated with significant improvement in ADHD and anxiety symptom severity. Significant improvement was noted in nonverbal communication on the Diagnostic Analysis of Nonverbal Accuracy Scale test and in executive function per self-report (Behavior Rating Inventory of Executive Functioning-Adult Self-Report Global Executive Composite, -6 ± 8.8; P < 0.015) and neuropsychological assessments (Cambridge Neuropsychological Test Automated Battery). Memantine treatment was generally well tolerated and was not associated with any serious adverse events. Treatment with memantine appears to be beneficial for the treatment of ASD and associated psychopathology and cognitive dysfunction in intellectually capable adults. Future placebo-controlled trials are warranted.

[Social Anxiety Disorder and Depression].

Social anxiety disorder (SAD ; also known as social phobia) is a prevalent disorder with an onset mostly in childhood or adolescence. Furthermore, SAD was found to be a predictor of the subsequent development of depressive disorder. There is a possibility that early interven- tion for SAD may prevent the subsequent development of depressive disorder. SSRI treatment may benefit patients with primary SAD and comorbid depressive disorder. Moreover, it is important to pay attention to depressive symptoms showing atypical features or bipolarity. Clearly, much more work is needed to establish the treatment of patients with SAD who fail to respond to SSRI.

[Oxytocin in the treatment of the social deficits associated to autism spectrum disorders]. / La oxitocina en el tratamiento de los déficits sociales asociados a los trastornos del espectro autista.

INTRODUCTION: The recent involvement of oxytocin in social behavior of animals and humans has motivated the study of its effects on the social behavior of individuals with autism spectrum disorders (ASD). AIMS: To review the current state of oxytocin studies concerning its therapeutic potential in treating social deficits of the ASD population, and to establish likely future directions to be taken by the studies in this field. DEVELOPMENT: Some studies have linked oxytocin to the pathophysiology of autistic disorders. Most studies that have administered oxytocin (mainly with intranasal administration of 24 IU) to ASD subjects have shown significant improvements in their social performance with acceptable safety parameters. However, there is controversial data as the outcome measures are widely dispersed, the samples are reduced and heterogeneous, and the treatment durations are different. The limitations related to the lack of understanding of the oxytocin's action mechanisms and the symptomatic heterogeneity of ASD are hampering progress towards the establishment of oxytocin as a treatment of ASD patients. Recent studies suggest the investigation of the combination of the oxytocin treatment with social skills training, and the enhancement of endogenous secretion of oxytocin. CONCLUSION: The effects of oxytocin are promising regarding the treatment of social deficits in ASD individuals. Future studies should aim to facilitate understanding of the oxytocin's ways of action and to establish the optimal treatment regime.

TITLE: La oxitocina en el tratamiento de los deficits sociales asociados a los trastornos del espectro autista.Introduccion. La implicacion de la oxitocina en la conducta social de animales y humanos ha llevado a estudiar los efectos de su administracion en el comportamiento y cognicion social de pacientes con trastornos del espectro autista (TEA). Objetivos. Revisar la investigacion sobre el potencial terapeutico de la oxitocina en el tratamiento de los deficits sociales de la poblacion con TEA y discutir las probables direcciones futuras de los estudios en este campo. Desarrollo. Diversos trabajos han relacionado la oxitocina con la fisiopatologia de los TEA. La mayoria de los estudios que han administrado oxitocina, generalmente por via intranasal (24 UI), ha observado mejoras significativas en el rendimiento social, sin detectar efectos secundarios destacables. No obstante, existen datos contradictorios debido a la heterogeneidad de las variables analizadas por los diferentes estudios, al uso de muestras heterogeneas y pequeñas o a la diferente duracion de los tratamientos. Las limitaciones relacionadas con la falta de comprension de los mecanismos de accion de la oxitocina y la diversidad sintomatologica de los TEA dificultan el establecimiento de este peptido como tratamiento de los pacientes autistas. Estudios recientes destacan la conveniencia de explorar el efecto de la combinacion del tratamiento de oxitocina con programas conductuales de intervencion en habilidades sociales, asi como la potenciacion de la secrecion endogena de oxitocina. Conclusiones. Los efectos de la administracion de oxitocina resultan prometedores en relacion con el tratamiento de los deficits sociales en individuos con TEA. Estudios futuros deberian facilitar la comprension de las vias de accion de la oxitocina y el establecimiento de pautas optimas de tratamiento.