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Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task.

Recent reports have demonstrated that disruption of CB(1) receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAH-compromised mice also exhibited a significant increase in acquisition rate. The CB(1) receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB(1) receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB(1) receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

Amidohydrolases↗

Risperidone augmentation in the treatment of severe adolescent OCD in SSRI-refractory cases: a case-series.

BACKGROUND AND METHODS: The adverse effects and potential clinical value of risperidone as augmentation to selective serotonin reuptake inhibitor (SSRI) treatment in treatment resistant severe adolescent OCD patients were examined in 17 adolescents (15-19 years old, 8 males and 9 females) in an open label trial of risperidone 1-2 mg daily. RESULTS: After 12 weeks of augmenting treatment, statistically significant improvements were reflected in OCD symptom ratings (mean total Y-BOCS/CY-BOCS scores after treatment with second SSRI 24.2 +/- 2.6 versus 19.9 +/- 2.9, p < 0.001) and global assessment scores (mean CGAS, 69.4 +/- 11.4 versus 74.7 +/- 9.6, p < 0.001). Four patients had moderate improvement of more than 25% reduction in Y-BOCS scores in OCD symptoms. Further 10 patients had a reduction of 10-25% in total score, indicating slight improvement. One patient (6%) dropped from clinical OCD to a subclinical level of OCD (Y-BOCS total score < 15). No patient was found to have worsened during augmentation treatment. Eight cases had weight gain and sedation was reported in four cases. CONCLUSION: These preliminary findings suggest that augmentation with risperidone in dosages up to 2 mg daily might be efficient in adolescents with treatment resistant OCD.

Adolescent↗

A meta-analytic review of Wisconsin Card Sorting Test and verbal fluency performance in obsessive-compulsive disorder.

INTRODUCTION: Abnormalities in associative frontostriatal circuits are often associated with obsessive-compulsive disorder (OCD), leading many researchers to predict that executive dysfunction should be particularly pronounced. However, deficits on putative tests of this construct have not consistently been identified. METHODS: The present study used quantitative techniques to integrate results from 32 studies that assessed OCD patients' performance on tests of phonemic fluency, semantic fluency, and/or the Wisconsin Card Sorting Test (WCST). RESULTS: As has been found for patients with focal frontal (but not focal nonfrontal) cortical lesions, relative to healthy controls OCD patients were comparably impaired on tests of phonemic and semantic fluency (rs = .33 and .37, respectively). However, in contrast to patients with focal frontal lobe injuries, fluency deficits did not qualify as differential deficits relative to psychomotor speed. Moreover, although a prominent view in the literature is that set-shifting is particularly compromised, the WCST was less sensitive to the presence of OCD than phonemic and semantic fluency, and also failed to qualify as a differential deficit. CONCLUSIONS: For patients with OCD, deficits on tests of verbal fluency and the WCST do not appear to reflect executive dysfunction, but are instead consistent with a more generalised cognitive impairment.

Cognition Disorders↗

Case study: obsessive-compulsive disorder after severe traumatic brain injury in an adolescent.

The neurological underpinnings of obsessive-compulsive disorder (OCD) are still largely undetermined. We report a prospective case study of a young subject who developed OCD and impulsive aggression after traumatic brain injury. The implications are that frontal and temporal lobe lesions may be sufficient to precipitate OCD in the absence of clear striatal injury and that compulsivity and impulsivity may represent different psychophysiological states.

Brain↗

Anxiety disorders and tic severity in juveniles with Tourette's disorder.

OBJECTIVE: It was hypothesized that comorbidity with anxiety disorders would predict tic severity in youths with Tourette's disorder (TD). METHOD: Subjects were 190 youths meeting DSM-III-R diagnostic criteria for TD who were consecutively referred to a pediatric psychopharmacology program between 1994 and 1997. Subjects were initially evaluated with a clinical interview and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic version. Statistical analysis used t tests, chi 2 tests, and logistic regression analysis. RESULTS: One hundred thirty-four subjects were classified as mild/moderate and 56 as severe TD cases. No meaningful differences were found in socioeconomic status, gender distribution, or age at onset of TD between the 2 groups. The 2 groups could not be differentiated by the presence of comorbid mood or disruptive behavior disorders including attention-deficit hyperactivity disorder. Although obsessive-compulsive disorder (OCD) was overrepresented among the severe TD cases, the difference failed to reach statistical significance. Excluding social and simple phobias, all other anxiety disorders were more clearly overrepresented among subjects with severe TD; separation anxiety disorder most robustly predicted tic severity, irrespective of the presence of OCD or other anxiety disorders. CONCLUSION: Findings suggest that non-OCD anxiety disorders in general and separation anxiety disorder in particular may be significantly associated with tic severity in referred TD patients.

Anxiety Disorders↗

Psychopathology and movement disorders: a new perspective on the Gilles de la Tourette syndrome.

Attention is drawn to associations between movement disorders and psychopathology. The historical background of this is briefly reviewed, and then some recent research findings with regards to the Gilles de la Tourette syndrome are presented. In particular, associations between aggressive and obsessive compulsive disorder and Gilles de la Tourette movements are reported. Further there are associations between a family history of tics and obsessive compulsive disorder in the subsequent generation. It is concluded that the Gilles de la Tourette syndrome should not be viewed as a tic disorder, but a far more complex condition in which the tics form but one aspect.

Humans↗

[Role of the neurohypophysis in psychological stress].

Effects of different psychological stimuli on oxytocin (OT) and vasopressin (AVP) secretion are reviewed in animals and in humans. The secretion of neuropituitary hormones is also discussed in various psychiatric diseases such an anorexia nervosa, bipolar disorder, schizophrenia and obsessive-compulsive disorder. AVP and OT are secreted into the hypophyseal portal circulation by neurons which project from the paraventricular nucleus to the external zone of the median eminence. AVP and OT-containing neurons in the suprachiasmatic and paraventricular nuclei project to limbic areas, including the hippocampus, the subiculum, the ventral nucleus of the amygdala and the nucleus of the diagonal band. Specific AVP receptors which are pharmacologically different from the pressor and antidiuretic AVP receptors have been found in the anterior pituitary. OT receptors have been identified in a variety of forebrain sites. The neurohypophyseal secretion is regulated by the cholinergic muscarinic, histaminergic and beta-adrenergic systems. Stress alters the secretion of one or more of the hypothalamic factors which interact at the pituitary to increase the secretion of ACTH. AVP and OT have been shown to modulate the effect of Corticotropin-Releasing Factor (CRF) on ACTH secretion and appear to play a key role in mediating the ACTH response to stress. Although AVP is a relatively weak secretagogue for ACTH, it markedly potentiates the activity of CRF both in vitro and in vivo. The role of OT is more complex. In vitro, OT stimulates ACTH release at high doses whereas in human it inhibits ACTH secretion at low doses. The type of stressor appear to determine the relative importance of these secretatogues in ACTH response. Several recent studies indicate that psychological stressors display a similar degree of variety of secretagogue release patterns as was found earlier for physical stressors. A bewildering array of technique produces a bewildering array of conclusions. In rats, OT may be an important secretagogue during a novel stimulus, whereas the role for AVP is less clear. Indeed two studies out of ten suggest a stimulating role for AVP. In response to frustration and submission, OT and AVP are secreted. Regarding social isolation, results are difficult to interpret and the role of AVP could be species-dependent. In contrast plasma OT levels do not change. After restraint, ACTH release is primarily mediated by the active increase of OT and AVP does not appear to play a role. When restraint is associated with moderate levels of physical components and during immobilisation, all two secretagogs are involved in the ACTH response. With fear, ACTH response appears to be driven by OT. In humans, one study indicates that high emotionality women increase plasma OT in response to uncontrollable noise. Various neuroendocrine dysregulations have been observed in psychiatric disease. Either an increase or a decrease of the hypothalamic-pituitary-adrenal (HPA) function have been described in several illnesses. Effects of OT appear to be reciprocal to the effects of AVP. OT has been called the "amnestic" neuropeptide due to its capacity to attenuate memory consolidation and retrieval. AVP exhibits a central activating action on mood, memory and selective attention. Underweight patients with anorexia nervosa have abnormally high levels of centrally directed AVP and reduced OT levels. These modifications could enhance the retention of cognitive distortions of aversive consequences of eating. Patients with bipolar disorder show a biphasic secretion of AVP. Depressive episodes are associated with decreased vasopressinergic activity whereas manic episodes involve an increased release. AVP might be responsible for an increased catecholamine activity. In addition, lithium could act as an antagonist to AVP. In schizophrenic patients, studies using the apomorphine stimulation suggest increased oxytoninergic and decreased vasopressinergic functions. These findings are consistent with the beneficial role of AVP on schizophrenic symptoms noted in several trials. The increased OT could be responsible for "positive" symptomatology such as delusions and hallucinations. Obsessive compulsive disorder (OCD) includes a range of cognitive and behavioral disturbances that could be influenced by OT. In animals, several studies have emphasized the role of AVP in promoting repetitive grooming behaviors and maintaining conditioned response to aversive stimuli. In OCD patients, one study have reported that AVP/OT ratio was negatively correlated with symptom severity. However, an independent report found similar AVP concentrations in OC patients without a personal or family history of tic disorder and in normal subjects. Whether these modifications are only a consequence of the central disturbances or whether those peptides could participate in the pathogenesis of these affections remains to be elucidated.

Adrenocorticotropic Hormone↗