Structural modifications of the ACTH-(4-9) analog ORG 2766 yields peptides with high biological activity.

The behavioral effects of two peptides (HOE 427) and ORG 31433) related to the ACTH-(4-9) analog ORG 2766 were investigated in Wistar rats in a number of tests in which Org 2766 is active. Subcutaneous administration of HOE 427 in a dose of 0.5 ng/kg or ORG 31433 in doses of 0.5-5.0 ng/kg facilitated passive avoidance behavior whereas these peptides attenuated the avoidance response in doses of 25 ng/kg and 250 ng/kg respectively. ORG 31433 (0.1 - 1.0 microgram/kg) decreased motor activity of group housed rats tested under low light conditions. Furthermore subcutaneous (1.0- 10.0 ng/kg) or oral (10 microgram/kg) administration of ORG 31433 accelerated functional recovery from 6-hydroxydopamine (6-OHDA)-induced lesions in the nucleus accumbens which cause motor hypoactivity. The experiments show that as compared to ORG 2766 the peptides HOE 427 and ORG 31433 induce qualitatively similar responses but are approximately 10 to 100 times more potent. These data may imply that substitution of the C-terminal COOH group of ORG 2766 yields neuropeptides with increased potency.     

Analysis of the facilitatory effect of the ACTH-(4-9) analog ORG 2766 on active social contact in rats

Pairs of male rats were tested for active social interaction, either in a familiar test arena under low illumination or in an unfamiliar test arena under high illumination conditions. Rats tested in an unfamiliar environment and under high light, spent less time in active social contact than rats tested under familiar, low light conditions. This effect was most pronounced during the first half of the 10 minute test period. Intraperitoneal injections of ACTH-(1-24) and ACTH-(4-10) (50 micrograms/kg) administered 5 minutes before the test decreased, whereas the same dose of the synthetic ACTH-(4-9) analog ORG 2766 increased the time spent in active social contact, when rats were tested under unfamiliar, high light conditions. The effects of ACTH-(4-10) and ORG 2766 were present in the second and first half of the test period respectively. Dose response relationship studies with ORG 2766 showed that 0.5 micrograms/kg of this peptide facilitated social contact under both test conditions and the dose response relation followed an inverted U-shaped curve under the familiar low light condition, but not under the unfamiliar, high light condition. ACTH-(4-10) and ORG 2766 failed to influence active social contact, when administered 30 minutes before the test. The change in social contact by ACTH-(4-10) and ORG 2766 was not accompanied by an alteration in ambulation of the rats. It is concluded that ACTH-(4-10) and ORG 2766 decrease and increase respectively social interaction of pairs of rats. The expression of these effects however, depends on the test and treatment conditions and may be related to the action of brain-born ACTH-like peptides.     

The ACTH/MSH(4-9) analogue ORG 2766 stimulates microtubule formation in axons of central neurons of the snail Lymnaea stagnalis.

Central nervous systems of the pond snail Lymnaea stagnalis were incubated in vitro in different concentrations of ORG 2766 (10(-9)-2.5 x 10(-4) M) for 10 and 20 h. Quantitative ultrastructural study of cross sections of the cerebral commissure showed that the number of microtubules in large axons had increased after 10 h of incubation by approximately 50% (Experiment 1) and 30% (Experiment 2), respectively. No further increase was observed after 20 h of incubation. (The higher concentrations were studied.) Maximal stimulation was already found at a concentration of 10(-8) M. At a concentration of 10(-9) M control levels were observed. It is concluded that ORG 2766 stimulates microtubule formation already at very low concentrations. It is not clear whether the compound stimulates synthesis of tubulin, induces assembly of microtubules, or causes an increase in stability of microtubules. Nevertheless, ultrastructural data on the morphology of the glial cells indicate that these cells are activated by ORG 2766 treatment, which suggest that ORG 2766 has general trophic effects.     

Influence of personality disorder on the treatment of panic disorder--comparison study

Most clinicians tend to believe that the occurrence of the anxiety disorder in comorbidity with a personality disorder often leads to longer treatment, worsens the prognosis, and thus increasing treatment costs. The study is designed to compare the short-term effectiveness of combination of cognitive behavioral therapy and pharmacotherapy in patient suffering with panic disorder with and without personality disorder. METHOD: We compare the efficacy of 6th week therapeutic program and 6th week follow up in patients suffering with panic disorder and/or agoraphobia and comorbid personality disorder (29 patients) and panic disorder and/or agoraphobia without comorbid personality disorder (31 patients). Diagnosis was done according to the ICD-10 research diagnostic criteria confirmed with MINI and support with psychological methods: IPDE, MCMI-III and TCI. Patients were treated with CBT and psychopharmacs. They were regularly assessed in week 0, 2, 4, 6 and 12 by an independent reviewer on the CGI (Clinical Global Improvement) for severity and change, PDSS (Panic Disorder Severity Scale), HAMA (Hamilton Anxiety Rating Scale), SDS (Sheehan Disability Scale), HDRS (Hamilton Depression Rating Scale), and in self-assessments BAI (Beck Anxiety Inventory) and BDI (Beck Depression Inventory). RESULTS: A combination of CBT and pharmacotherapy proved to be the effective treatment of patients suffering with panic disorder and/or agoraphobia with or without comorbid personality disorder. The 12th week treatment efficacy in the patients with panic disorder without personality disorder had been showed significantly better compared with the group with panic disorder comorbid with personality disorder in CGI and specific inventory for panic disorder--PDSS. Also the scores in depression inventories HDRS and BDI showed significantly higher decrease during the treatment comparing with group without personality disorder. But the treatment effect between groups did not differ in objective anxiety scale HAMA, and subjective anxiety scale BAI.     

Cyclic AMP in female mouse brain is altered by the adrenocorticotropic hormone(4-9) analogue organon 2766

Cyclic AMP content was determined in 12 brain regions of young adult female mice at 30 min and at 24 h following an intraperitoneal injection of the tri-substituted adrenocorticotropic hormone(4-9) [ACTH(4-9)] analogue Organon 2766 [ORG 2766]. Animals were killed by focused 3.5 kW microwave radiation applied for 350 ms. Unlike previously reported responses in male mice, at 30 min post-injection there were no detectable differences in cyclic AMP content between the placebo and ORG 2766-treated animals. By contrast, 24 h after injection, the content of cyclic AMP was changed significantly in 8 of the 12 brain regions examined: medulla-pons, septal area, thalamus, hypothalamus, hippocampus, olfactory bulb, and parietal and occipital cortices. In most of the regions examined, differences consisted of 50% or greater reductions of tissue cyclic AMP content. The changes were unrelated to the estrus cycle of these animals.     

Cyclic AMP in Female Mouse Brain is Altered by the Adrenocorticotropic Hormone(4–9) Analogue Organon 2766

Abstract: Cyclic AMP content was determined in 12 brain regions of young adult female mice at 30 min and at 24 h following an intraperitoneal injection of the tri-substituted adrenocorticotropic hormone(4–9) [ACTH(4–9)] analogue Organon 2766 [ORG 2766]. Animals were killed by focused 3.5 kW microwave radiation applied for 350 ms. Unlike previously reported responses in male mice, at 30 min post-injection there were no detectable differences in cyclic AMP content between the placebo and ORG 2766-treated animals. By contrast, 24 h after injection, the content of cyclic AMP was changed significantly in 8 of the 12 brain regions examined: medulla-pons, septal area, thalamus, hypothalamus, hippocampus, olfactory bulb, and parietal and occipital cortices. In most of the regions examined, differences consisted of 50% or greater reductions of tissue cyclic AMP content. The changes were unrelated to the estrus cycle of these animals     

Melanocortins and fast axonal transport in intact and regenerating sciatic nerve

The effect of ACTH/MSH peptides on fast axonal transport along intact or regenerating sciatic nerve was examined following injection of tritiated leucine into the rat lumbar spinal cord. The rate of fast axonal transport was not significantly changed by treatment with ACTH/MSH(4-10), the ACTH(4-9) analog ORG 2766, hypophysectomy, or adrenalectomy. Fast axonal transport was unchanged in regenerating nerves and in regenerating, ACTH(4-10)-treated nerves. However, treatment with ORG 2766 in dosages of either 1 or 10 micrograms/kg/day IP for seven days significantly reduced (62% and 64%, respectively) the crest height of the fast axonal transport curve of intact sciatic nerve. The results suggest that the reported peptide-induced enhancement of nerve regeneration is not due to changes in the rate of fast axonal transport.     

Effects of Baseline Problematic Alcohol and Drug Use on Internet-Based Cognitive Behavioral Therapy Outcomes for Depression,Panic Disorder and Social Anxiety Disorder

Purpose

Patients’ problematic substance use prevalence and effects were explored in relation to internet-based cognitive behavioral therapy (ICBT) outcomes for depression, panic disorder and social anxiety disorder.

Methods

At baseline and treatment conclusion, 1601 ICBT patients were assessed with self-rated measures for alcohol and drug use (AUDIT/DUDIT), depressive symptoms (MADRS-S), panic disorder symptoms (PDSS-SR) and social anxiety symptoms (LSAS-SR).

Results

Problematic substance use (AUDIT ≥8 for men, ≥6 for women; DUDIT ≥1) occurred among 32.4% of the patients; 24.1% only alcohol, 4.6% only drugs, and 3.7% combined alcohol and drug use. Hazardous alcohol use and probable alcohol dependence negatively affected panic disorder outcomes, and hazardous drug use led to worse social anxiety outcomes. Depression outcomes were not affected by substance use. Treatment adherence was negatively affected by problematic drug use among men and 25–34 year olds; combined substance use negatively affected adherence for women and 35–64 year olds.

Conclusion

Problematic substance use does not preclude ICBT treatment but can worsen outcomes, particularly problematic alcohol use for panic disorder patients and hazardous drug use for social anxiety patients. ICBT clinicians should exercise particular caution when treating men and younger patients with problematic drug use, and women or older patients with combined substance use.     

Can ACTH analogs support discriminative learning in rats?

Ten rats were trained to discriminate between the stimulus properties of subcutaneously (SC) administered MSH/ACTH4-10 and saline in a two-lever, food-motivated operant task. After 12 weeks of discriminative training with 100 micrograms/kg MSH/ACTH4-10, half the rats received 200 micrograms/kg MSH/ATCH4-10, whereas the other half were administered 400 micrograms/kg, for 6 additional weeks. Subsequently, all rats continued training on 50 micrograms/kg ORG 2766 (SC) and, after 12 weeks of training, were randomly assigned to receive either 100 or 200 micrograms/kg ORG 2766. The results of this extensive 36 week training schedule indicate that only 1 of the 10 rats learned to discriminate the interoceptive cues produced by the ACTH analogs. However, this rat's performance was so sustained and errorless that the possibility exists that it was relatively more sensitive to the effects of MSH/ACTH4-10 and its analogs and that these substances may support discriminative learning in the rat.     

Maternal panic disorder and congenital abnormalities: a population-based case-control study

BACKGROUND: Maternal panic disorder in pregnancy is the most common manifestation of anxiety disorders in Hungary. The association between panic disorder during pregnancy and structural birth defects, i.e., congenital abnormalities, was studied. METHODS: The prevalence of maternal panic disorder in cases with different congenital abnormalities was compared to that of matched controls in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities. RESULTS: Of 22,843 cases with congenital abnormalities, 210 (0.9%) had mothers with panic disorder during pregnancy compared to 187 (0.5%) of 38,151 controls (adjusted prevalence odds ratio [POR] 1.6; 95% CI, 1.3-2.0). Specific groups of congenital abnormalities were also assessed versus controls. Cases with isolated cleft lip with or without cleft palate (CL/P) (adjusted POR, 3.4; 95% CI, 1.3-9.0) and multiple congenital abnormalities (adjusted POR, 3.0; 95% CI, 1.2-7.2) were more likely to have had mothers with panic disorder during the study pregnancy. Notably, among mothers with panic disorders, the associations were found only in offspring of untreated mothers. CONCLUSIONS: A higher rate of isolated CL/P and multiple congenital abnormalities may be caused by the direct biological effect of panic disorder or by the interaction of maternal panic disorder and lifestyle factors. Antipanic drug treatment seems to have a protective effect for isolated CL/P and multiple congenital abnormalities. Birth Defects Research (Part A), 2006.     

The Neuroanatomical Basis of Panic Disorder and Social Phobia in Schizophrenia: A Voxel Based Morphometric Study

ObjectiveIt is known that there is a high prevalence of certain anxiety disorders among schizophrenic patients, especially panic disorder and social phobia. However, the neural underpinnings of the comorbidity of such anxiety disorders and schizophrenia remain unclear. Our study aims to determine the neuroanatomical basis of the co-occurrence of schizophrenia with panic disorder and social phobia.MethodsVoxel-based morphometry was used in order to examine brain structure and to measure between-group differences, comparing magnetic resonance images of 20 anxious patients, 20 schizophrenic patients, 20 schizophrenic patients with comorbid anxiety, and 20 healthy control subjects.ResultsCompared to the schizophrenic patients, we observed smaller grey-matter volume (GMV) decreases in the dorsolateral prefrontal cortex and precentral gyrus in the schizophrenic-anxiety group. Additionally, the schizophrenic group showed significantly reduced GMV in the dorsolateral prefrontal cortex, precentral gyrus, orbitofrontal cortex, temporal gyrus and angular/inferior parietal gyrus when compared to the control group.ConclusionsOur findings suggest that the comorbidity of schizophrenia with panic disorder and social phobia might be characterized by specific neuroanatomical and clinical alterations that may be related to maladaptive emotion regulation related to anxiety. Even thought our findings need to be replicated, our study suggests that the identification of neural abnormalities involved in anxiety, schizophrenia and schizophrenia-anxiety may lead to an improved diagnosis and management of these conditions.     

Disgust implicated in obsessive-compulsive disorder.

Psychiatric classificatory systems consider obsessions and compulsions as forms of anxiety disorder. However, the neurology of diseases associated with obsessive-compulsive symptoms suggests the involvement of fronto-striatal regions likely to be involved in the mediation of the emotion of disgust, suggesting that dysfunctions of disgust should be considered alongside anxiety in the pathogenesis of obsessive-compulsive behaviours. We therefore tested recognition of facial expressions of basic emotions (including disgust) by groups of participants with obsessive-compulsive disorder (OCD) and with Gilles de la Tourette''s syndrome (GTS) with an without co-present obsessive-compulsive behaviours (GTS with OCB; GTS without OCB). A group of people suffering from panic disorder and generalized anxiety were also included in the study. Both groups with obsessive-compulsive symptoms (OCD; GTS with OCB) showed impaired recognition of facial expressions of disgust. Such problems were not evident in participants with panic disorder and generalized anxiety, or for participants with GTS without obsessions or compulsions, indicating that the deficit is closely related to the presence of obsessive-compulsive symptoms. Participants with OCD were able to assign words to emotion categories without difficulty, showing that their problem with disgust is linked to a failure to recognize this emotion in others and not a comprehension or response criterion effect. Impaired recognition of disgust is consistent with the neurology of OCD and with the idea that abnormal experience of disgust may be involved in the genesis of obsessions and compulsions.     

Differential responses to anxiogenic drugs in a mouse model of panic disorder as revealed by Fos immunocytochemistry in specific areas of the fear circuitry

Summary. Sensitivity to pharmacological challenges has been reported in patients with panic disorder. We have previously validated transgenic mice overexpressing the neurotrophin-3 (NT-3) receptor, TrkC (TgNTRK3), as an engineered murine model of panic disorder. We could determine that TgNTRK3 mice presented increased cellularity in brain regions, such as the locus ceruleus, that are important neural substrates for the expression of anxiety in severe anxiety states. Here, we investigated the sensitivity to induce anxiety and panic-related symptoms by sodium lactate and the effects of various drugs (the α2-adrenoceptor antagonist, yohimbine and the adenosine antagonist, caffeine), in TgNTRK3 mice. We found enhanced panicogenic sensitivity to sodium lactate and an increased intensity and a differential pattern of Fos expression after the administration of yohimbine or caffeine in TgNTRK3. Our findings validate the relevance of the NT-3/TrkC system to pathological anxiety and raise the possibility that a specific set of fear-related pathways involved in the processing of anxiety-related information may be differentially activated in panic disorder.     

No evidence for DUP25 in patients with panic disorder using a quantitative real-time PCR approach

A duplication of chromosome 15q24-q26 (DUP25) has been reported to be associated with anxiety disorders. We tested for the presence of DUP25 in a sample of 50 patients with panic disorder and 50 controls using a quantitative real-time PCR approach. Contrary to the original finding, our results were compatible with the absence of DUP25, and no significant difference could be detected between patients and controls (P=1.0). Thus, our study does not support the hypothesis of an involvement of DUP25 in panic disorder.     

Predictors and Moderators of Internet- and Group-Based Cognitive Behaviour Therapy for Panic Disorder

Internet-based cognitive behaviour therapy (ICBT) can be equally effective as traditional face-to-face cognitive behaviour therapy (CBT) for treating panic disorder (PD). However, little is known about the predictors and moderators of outcome of ICBT when delivered in psychiatric outpatient settings. This study investigated a selection of outcome predictors and moderators of ICBT for panic disorder based on data from a randomised controlled trial where therapist-guided ICBT was compared with group CBT (GCBT) for panic disorder. Participants (N = 104) received 10 weeks of ICBT or GCBT and were assessed before and after treatment, and after six months. Multiple regression analyses were used to test for significant predictors of treatment outcome. Predictors of positive treatment response for both modalities were having low levels of symptom severity and work impairment. In addition, anxiety sensitivity was found to have a small negative relationship with treatment outcome, suggesting that anxiety sensitivity may slightly enhance treatment response. Treatment modality had a moderating effect on the relationship between domestic impairment and outcome and on the relationship between initial age of onset of panic symptoms and treatment outcome, favouring ICBT for patients having had an early onset of PD symptoms and for patients having a high domestic functional impairment. These results suggest that both ICBT and GCBT are effective treatment modalities for PD and that it is possible to predict a significant proportion of the long-term outcome variance based on clinical variables.     

Subtypes of Ataques de Nervios: The Influence of Coexisting Psychiatric Diagnosis

The current study assesses the relationship between presenting symptomatology of the self-labeled Hispanic popular diagnosis of ataques de nervios and the specific co-morbid psychiatric diagnoses. Hispanic subjects seeking treatment at an anxiety disorders clinic (n = 156) were assessed with a specially designed self-report instrument for both traditional ataque de nervios and panic symptoms, and with structured or semi-structured psychiatric interviews for Axis-I disorders. This report focuses on 102 subjects with ataque de nervios who also met criteria for panic disorder, other anxiety disorders, or an affective disorder. Distinct ataque symptom patterns correlated with co-existing panic disorder, affective disorders, or other anxiety disorders. Individuals with both ataque and panic disorder reported the most asphyxia, fear of dying, and increased fear during their ataques. People with ataques who also met criteria for affective disorder reported the most anger, screaming, becoming aggressive, and breaking things during ataques. Ataque positive subjects with other anxiety disorders were less salient for both panic-like and emotional-anger symptoms. The findings suggest that (a) ataque de nervios is a popular label referring to several distinct patterns of loss of emotional control, (b) the type of loss of emotional control is influenced by the associated psychiatric disorder, and (c) ataque symptom patterns may be a useful clinical marker for detecting psychiatric disorders. Further study is needed to examine the relationship between ataque de nervios and psychiatric disorders, as well as the relationship to cultural, demographic, environmental, and personality factors.     

Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta‐analysis

We conducted a meta‐analysis of randomized trials in which the effects of treatment with antidepressant medication were compared to the effects of combined pharmacotherapy and psychotherapy in adults with a diagnosed depressive or anxiety disorder. A total of 52 studies (with 3,623 patients) met inclusion criteria, 32 on depressive disorders and 21 on anxiety disorders (one on both depressive and anxiety disorders). The overall difference between pharmacotherapy and combined treatment was Hedges' g = 0.43 (95% CI: 0.31‐0.56), indicating a moderately large effect and clinically meaningful difference in favor of combined treatment, which corresponds to a number needed to treat (NNT) of 4.20. There was sufficient evidence that combined treatment is superior for major depression, panic disorder, and obsessive‐compulsive disorder (OCD). The effects of combined treatment compared with placebo only were about twice as large as those of pharmacotherapy compared with placebo only, underscoring the clinical advantage of combined treatment. The results also suggest that the effects of pharmacotherapy and those of psychotherapy are largely independent from each other, with both contributing about equally to the effects of combined treatment. We conclude that combined treatment appears to be more effective than treatment with antidepressant medication alone in major depression, panic disorder, and OCD. These effects remain strong and significant up to two years after treatment. Monotherapy with psychotropic medication may not constitute optimal care for common mental disorders.     

Hypoxic postconditioning corrects behavioral abnormalities in a model of post-traumatic stress disorder in rats

Protective effects of the novel technique of hypoxic postconditioning with a hypobaric hypoxia paradigm were studied in "stress-restress" model ofposttraumatic stress disorder in rats. It was shown that repeated (3 times) exposure of rats that survived after severe traumatic stress to mild hypobaric hypoxia (postconditioning mode) efficiently abolished the development of stress-induced anxiety state. Postconditioning had a clear anxiolytic effect both when it was delivered after traumatic stress and after restress, but the intensity of this effect depended on the period ofpathogenesis of the posttraumatic stress disorder, when postconditioning was given. The results indicate that suggested postconditioning model with repetitive mild hypobaric hypoxia exerts potent anxiolytic and stress-protective action.     

Recent trends in the incidence of anxiety diagnoses and symptoms in primary care

Background

Anxiety is common, with significant morbidity, but little is known about presentations and recording of anxiety diagnoses and symptoms in primary care. This study aimed to determine trends in incidence and socio-demographic variation in General Practitioner (GP) recorded diagnoses of anxiety, mixed anxiety/depression, panic and anxiety symptoms.

Methodology/Principal Findings

Annual incidence rates of anxiety diagnoses and symptoms were calculated from 361 UK general practices contributing to The Health Improvement Network (THIN) database between 1998 and 2008, adjusted for year of diagnosis, gender, age, and deprivation. Incidence of GP recorded anxiety diagnosis fell from 7.9 to 4.9/1000PYAR from 1998 to 2008, while incidence of anxiety symptoms rose from 3.9 to 5.8/1000PYAR. Incidence of mixed anxiety/depression fell from 4.0 to 2.2/1000PYAR, and incidence of panic disorder fell from 0.9/1000PYAR in 1998 to 0.5/1000PYAR in 2008. All these entries were approximately twice as common in women and more common in deprived areas. GP-recorded anxiety diagnoses, symptoms and mixed anxiety/depression were commonest aged 45–64 years, whilst panic disorder/attacks were more common in those 16–44 years. GPs predominately use broad non-specific codes to record anxiety problems in the UK.

Conclusions/Significance

GP recording of anxiety diagnoses has fallen whilst recording of anxiety symptoms has increased over time. The incidence of GP recorded diagnoses of anxiety diagnoses was lower than in screened populations in primary care. The reasons for this apparent under-recording and whether it represents under-detection in those being seen, a reluctance to report anxiety to their GP, or a reluctance amongst GPs to label people with anxiety requires investigation.     

Role of corticotropin releasing factor in anxiety disorders: a translational research perspective

Anxiety disorders are a group of mental disorders that include generalized anxiety disorder (GAD), panic disorder, phobic disorders (e.g., specific phobias, agoraphobia, social phobia) and posttraumatic stress disorder (PTSD). Anxiety disorders are among the most common of all mental disorders and, when coupled with an awareness of the disability and reduced quality of life they convey, they must be recognized as a serious public health problem. Over 20 years of preclinical studies point to a role for the CRF system in anxiety and stress responses. Clinical studies have supported a model of CRF dysfunction in depression and more recently a potential contribution to specific anxiety disorders (i.e., panic disorder and PTSD). Much work remains in both the clinical and preclinical fields to inform models of CRF function and its contribution to anxiety. First, we will review the current findings of CRF and HPA axis abnormalities in anxiety disorders. Second, we will discuss startle reflex measures as a tool for translational research to determine the role of the CRF system in development and maintenance of clinical anxiety.