The FOsmetpantotenate Replacement Therapy (FORT) randomized, double-blind, Placebo-controlled pivotal trial: Study design and development methodology of a novel primary efficacy outcome in patients with pantothenate kinase-associated neurodegeneration.

BACKGROUND/AIMS: Pantothenate kinase-associated neurodegeneration is a rare neurodegenerative disease with a variable clinical phenotype. Fosmetpantotenate is in clinical development as a replacement therapy that targets the underlying cause of pantothenate kinase-associated neurodegeneration. The FOsmetpantotenate Replacement Therapy pivotal trial-an ongoing phase 3, randomized, double-blind, placebo-controlled, multicenter trial-examines the efficacy and safety of fosmetpantotenate in patients with pantothenate kinase-associated neurodegeneration aged 6-65 years. The FOsmetpantotenate Replacement Therapy trial required the development and validation of a novel patient-reported outcome measure specifically relevant to pantothenate kinase-associated neurodegeneration. The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale was developed to assess activities of daily living related to motor functioning in patients with pantothenate kinase-associated neurodegeneration to evaluate clinically meaningful change as the primary efficacy endpoint in clinical trials. This article describes the design of the FOsmetpantotenate Replacement Therapy pivotal trial and the development of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale. METHODS: A systematic, iterative process consistent with the US Food and Drug Administration guidance and advice from the Committee for Medicinal Products for Human Use at the European Medicines Agency was used to evaluate and adapt or remove scale items of an existing widely used instrument for movement disorders to be pantothenate kinase-associated neurodegeneration-specific, and to create new items. Modification of scale items was based on input from international experts, patient advocacy leaders, and primary caregivers. A clinimetric study of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale conducted in patients with pantothenate kinase-associated neurodegeneration or their caregivers (N = 40 at first assessment; N = 39 at second assessment) demonstrated high content and construct validity and excellent test-retest reliability over an approximately 2-week period. The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale was developed to be broadly useful within clinical and research settings in the examination of patient response to pantothenate kinase-associated neurodegeneration therapies. RESULTS: Approximately 82 patients will be enrolled in the ongoing FOsmetpantotenate Replacement Therapy pivotal trial. Change from baseline in Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living score over the 24-week double-blind period is the primary efficacy endpoint for the FOsmetpantotenate Replacement Therapy trial. Treatment effect will be evaluated using a mixed model for repeated measures analysis to assess data from all visits simultaneously. CONCLUSION: The development and implementation of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale in the FOsmetpantotenate Replacement Therapy trial illustrates the feasibility and potential patient benefit of putting into practice the current regulatory guidance on the use of patient-reported outcomes in clinical trials. These processes can be broadly applied to clinical trial methodology that requires newly created or revised patient-reported outcome measures to evaluate outcome change as a primary efficacy endpoint. The goal of such measures in patients with pantothenate kinase-associated neurodegeneration is to facilitate development of disease-modifying therapeutics in multiple drug development programs.

A Novel PDE10A Inhibitor for Tourette Syndrome and Other Movement Disorders.

BACKGROUND: Tourette syndrome is a neurodevelopmental movement disorder involving basal ganglia dysfunction. PDE10A inhibitors modulate signaling in the striatal basal ganglia nuclei and are thus of interest as potential therapeutics in treating Tourette syndrome and other movement disorders. METHODS: The preclinical pharmacology and toxicology, human safety and tolerability, and human PET striatal enzyme occupancy data for the PDE10A inhibitor EM-221 are presented. RESULTS: EM-221 inhibited PDE10A with an in vitro IC50 of 9 pM and was >100,000 selective vs. other PDEs and other CNS receptors and enzymes. In rats, at doses of 0.05-0.50 mg/kg, EM-221 reduced hyperlocomotion and the disruption of prepulse inhibition induced by MK-801, attenuated conditioned avoidance, and facilitated novel object recognition, consistent with PDE10A's inhibition. EM-221 displayed no genotoxicity and was well tolerated up to 300 mg/kg in rats and 100 mg/kg in dogs. In single- and multiple-day ascending dose studies in healthy human volunteers, EM-221 was well tolerated up to 10 mg, with a maximum tolerated dose of 15 mg. PET imaging indicated that a PDE10A enzyme occupancy of up to 92.8% was achieved with a ~24 h half-life. CONCLUSIONS: The preclinical and clinical data presented here support the study of EM-221 in phase 2 trials of Tourette syndrome and other movement disorders.

A Scale to Assess Activities of Daily Living in Pantothenate Kinase-Associated Neurodegeneration.

OBJECTIVE: Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal-recessive, neurodegenerative disorder with a mixed-motor phenotype caused by a defective PanK2 enzyme, for which there are few adequate treatment options. Clinimetrically sound measures of patient-reported outcomes are necessary to facilitate therapeutic development for this debilitating disease. This study's objective was to develop such a scale and assess its clinimetric properties. METHODS: A conceptually driven, iterative, content development process incorporating input from experts, caregivers, and patients was used. Scale items were initially adapted from the Unified Parkinson's Disease Rating Scale (UPDRS) Part II resulting in the 12-item Pantothenate Kinase-Associated Neurodegeneration Activities of Daily Living (PKAN-ADL). The PKAN-ADL scale was administered to caregivers (n = 37) and patients (n = 2) twice over 2 weeks, along with selected Quality of Life in Neurological Disorders (Neuro-QoL) measures, selected attributes of the Health Utilities Index (HUI)-2/3, and the Stroke Aphasia Depression Questionnaire (SADQ-10) to assess construct validity. RESULTS: Internal consistency was 0.93, with excellent test-retest reliability (intraclass correlation coefficient = 0.99). Of the 12 items, 25% (n = 3) showed a ceiling effect >30% (range, 31-54) and 42% (n = 5) showed a floor effect >30% (range, 31-46), reflecting disease heterogeneity. Convergent validity was shown with Neuro-QoL measures (rs > 0.90) and HUI-2/3 attributes (rs ≥ 0.48); divergent validity was demonstrated with the SADQ-10 (r = 0.11). Participants reported a high level of comprehension (98%), and average item relevance ratings (0-10 scale) ranged from 7.0 to 9.9. CONCLUSION: The PKAN-ADL scale demonstrated acceptable content validity, with evidence of construct validity and excellent reliability. Overall results support the use of the PKAN-ADL scale in clinical trials.

Diagnostic and clinical experience of patients with pantothenate kinase-associated neurodegeneration.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder with brain iron accumulation (NBIA). OBJECTIVES: To assess PKAN diagnostic pathway, history, and burden across the spectrum of PKAN severity from patient and/or caregiver perspectives. METHODS: Caregivers of patients (n = 37) and patients themselves (n = 2) were interviewed in a validation study of the PKAN-Activities of Daily Living (ADL) scale. The current study used quartiles of the PKAN-ADL total score to divide patients by severity of impairment (Lowest, Second Lowest, Third Lowest, Highest). Diagnostic and treatment history, healthcare utilization, disease burden, and caregiver experience were compared between groups. RESULTS: The analyses included data from 39 patients. Mean age at PKAN symptom onset (P = 0.0007), initial MRI (P = 0.0150), and genetic testing (P = 0.0016) generally decreased across the PKAN severity spectrum. The mean duration of illness did not differ among PKAN severity groups (range, 9.7-15.2 years; P = 0.3029). First MRI led to diagnosis in 56.4% of patients (range, 30.0-90.0%). A mean (SD) of 13.0 (13.1) medical and 55.2 (78.5) therapy visits (eg, physical, speech) occurred in the past year. More patients in the higher PKAN severity groups experienced multiple current functional losses and/or earlier onset of problems (P-values < 0.0500). Over half (56.8%) of caregivers experienced a change in employment because of caregiving. The percentage of patients requiring full-time caregiving increased across the PKAN severity spectrum (range, 11.1-100%; P = 0.0021). CONCLUSIONS: PKAN diagnosis was often delayed, most probably due to low awareness. Considerable burden of functional impairment and high healthcare utilization were found across the PKAN severity spectrum.

Trauma exposure and posttraumatic stress disorder among primary care patients with bipolar spectrum disorder.

OBJECTIVE: To examine relationships between exposure to trauma, bipolar spectrum disorder (BD) and posttraumatic stress disorder (PTSD) in a sample of primary care patients. METHODS: A systematic sample (n = 977) of adult primary care patients from an urban general medicine practice were interviewed with measures including the Mood Disorders Questionnaire, the PTSD Checklist-Civilian Version, and the Medical Outcomes Study 12-Item Short Form Health Survey. RESULTS: Compared with patients who screened negative for BD (n = 881), those who screened positive (n = 96) were 2.6 times [95% confidence interval (CI): 1.6-4.2] as likely to report physical or sexual assault, and 2.9 times (95% CI: 1.6-5.1) as likely to screen positive for current PTSD. Among those screening positive for BD, comorbid PTSD was associated with significantly worse social functioning. These results controlled for selected background characteristics, current major depressive episode, and current alcohol/drug use disorder. CONCLUSION: In an urban general medicine setting, trauma exposure was related to BD, and the frequency of PTSD among patients with BD appears to be common and clinically significant. These results suggest an unmet need for mental health care in this specific population and are especially important in view of available treatments for BD and PTSD.

Distorted maternal mental representations and atypical behavior in a clinical sample of violence-exposed mothers and their toddlers.

OBJECTIVE: To determine whether maternal violence-related posttraumatic stress disorder (PTSD), reflective functioning (RF), and/or quality of mental representations of her child predict maternal behavior within a referred sample of interpersonal violence-exposed mothers and their children (ages 8-50 months). METHOD: Forty-one dyads completed two videotaped visits including measures of maternal mental representations and behavior. RESULTS: Negative and distorted maternal mental representations predicted atypical behavior (Cohen's d>1.0). While maternal PTSD and RF impacted mental representations, no significant relationships were found between PTSD, RF, and overall atypical caregiving behavior. Severity of maternal PTSD was however positively correlated with the avoidant caregiving behavior subscale. CONCLUSIONS: Maternal mental representations of her child are useful risk-indicators that mark dysregulation of trauma-associated emotions in the caregiver.

The psychology of ongoing threat: relative risk appraisal, the September 11 attacks, and terrorism-related fears.

There are now replicated findings that posttraumatic stress disorder (PTSD) symptoms related to the September 11, 2001, attacks occurred in large numbers of persons who did not fit the traditional definition of exposure to a traumatic event. These data are not explained by traditional epidemiologic "bull's eye" disaster models, which assume the psychological effects are narrowly, geographically circumscribed, or by existing models of PTSD onset. In this article, the authors develop a researchable model to explain these and other terrorism-related phenomena by synthesizing research and concepts from the cognitive science, risk appraisal, traumatic stress, and anxiety disorders literatures. They propose the new term relative risk appraisal to capture the psychological function that is the missing link between the event and subjective response in these and other terrorism-related studies to date. Relative risk appraisal highlights the core notion from cognitive science that human perception is an active, multidimensional process, such that for unpredictable societal threats, proximity to the event is only one of several factors that influence behavioral responses. Addressing distortions in relative risk appraisal effectively could reduce individual and societal vulnerability to a wide range of adverse economic and ethnopolitical consequences to terrorist attacks. The authors present ways in which these concepts and related techniques can be helpful in treating persons with September 11- or terrorism-related distress or psychopathology.

Open-Label Fosmetpantotenate, a Phosphopantothenate Replacement Therapy in a Single Patient with Atypical PKAN.

Objective. Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder with variable onset, rate of progression, and phenotypic expression. Later-onset, more slowly progressive PKAN often presents with neuropsychiatric as well as motor manifestations that include speech difficulties, progressive dystonia, rigidity, and parkinsonism. PKAN is caused by biallelic PANK2 mutations, a gene that encodes pantothenate kinase 2, a regulatory enzyme in coenzyme A biosynthesis. Current therapeutic strategies rely on symptomatic relief. We describe the treatment of the first, later-onset PKAN patient with oral fosmetpantotenate (previously known as RE-024), a novel replacement therapy developed to bypass the enzymatic defect. Methods. This was an open-label, uncontrolled, 12-month treatment with fosmetpantotenate of a single patient with a later-onset, moderately severe, and slowly progressive form of PKAN. Results. The patient showed improvement in all clinical parameters including the Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia Scale, the EuroQol five-dimensional three-level (EQ-5D-3L) scale, timed 25-foot walk test, and electroglottographic speech analysis. Fosmetpantotenate was well-tolerated with only transient liver enzyme elevation which normalized after dose reduction and did not recur after subsequent dose increases. Conclusions. Fosmetpantotenate showed promising results in a single PKAN patient and should be further studied in controlled trials.

Posttraumatic stress disorder in primary care one year after the 9/11 attacks.

OBJECTIVE: To screen for posttraumatic stress disorder (PTSD) in primary care patients 7-16 months after 9/11 attacks and to examine its comorbidity, clinical presentation and relationships with mental health treatment and service utilization. METHOD: A systematic sample (n=930) of adult primary care patients who were seeking primary care at an urban general medicine clinic were interviewed using the PTSD Checklist: the Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire and the Medical Outcome Study 12-Item Short Form Health Survey (SF-12). Health care utilization data were obtained by a cross linkage to the administrative computerized database. RESULTS: Prevalence estimates of current 9/11-related probable PTSD ranged from 4.7% (based on a cutoff PCL-C score of 50 and over) to 10.2% (based on the DSM-IV criteria). A comorbid mental disorder was more common among patients with PTSD than patients without PTSD (80% vs. 30%). Patients with PTSD were more functionally impaired and reported increased use of mental health medication as compared to patients without PTSD (70% vs. 18%). Among patients with PTSD there was no increase in hospital and emergency room (ER) admissions or outpatient care during the first year after the attacks. CONCLUSIONS: In an urban general medicine setting, 1 year after 9/11, the frequency of probable PTSD appears to be common and clinically significant. These results suggest an unmet need for mental health care in this clinical population and are especially important in view of available treatments for PTSD.

A psychometric analysis of Project Liberty's adult enhanced services referral tool.

OBJECTIVES: Project Liberty was the first federally funded crisis counseling program to offer evidence-informed treatments to crisis counseling recipients in need of more intensive clinical intervention. The Adult Enhanced Services Referral Tool was developed as a screening instrument for making and monitoring referrals to enhanced services. This study aimed to examine how well the tool functioned for identifying persons who would perceive a need for professional treatment. METHODS: A one-page tool was created that assessed demographic characteristics, risk categories, and psychological reactions to the focal event, September 11, 2001. Psychosocial reactions were assessed by the 12-item SPRINT-E, which is an expanded version of the Short Post-Traumatic Stress Disorder Rating Interview (SPRINT). The SPRINT-E was embedded in the Adult Enhanced Services Referral Tool. Data were collected from 788 clients who received crisis counseling between June and October 2003. RESULTS: The SPRINT-E is a unidimensional measure of distress and dysfunction. Internal consistency was excellent for the total sample (alpha=.93) and subsamples. Among the 543 clients offered referral, 71 percent accepted. Among those offered referral, the number of intense reactions (score of 4, quite a bit, or 5, very much) was by far the strongest predictor of referral acceptance. CONCLUSIONS: The SPRINT-E was successfully integrated into the crisis counseling program and provided an apparently successful, empirical basis for referral from counseling to professional treatment. Results of the brief psychological assessment provided a stronger basis for referral to treatment than membership in a risk category (for example, family member of deceased) alone.

Traumatized mothers can change their minds about their toddlers: Understanding how a novel use of videofeedback supports positive change of maternal attributions.

This study explored the use of a brief experimental intervention that integrates principles of infant-parent psychotherapy, videofeedback, controlled exposure to child distress in the context of parental posttraumatic stress disorder (PTSD), and stimulation of parental reflective functioning (RF). The Clinician Assisted Videofeedback Exposure Session (CAVES) was applied to 32 interpersonal violence-exposed mothers of very young children (8-50 months) with respect to change of maternal perception of her child. While we found no significant reduction over two videotaped assessment visits with a mental health professional, we did find a significant reduction in the degree of negativity of maternal attributions towards her child following the videotaped visit focused on the CAVES (p<.01). Maternal RF, a mother's capacity to think about mental states in herself and her child, accounted for 11% of the variance in reduction of maternal negativity after accounting for baseline levels of negativity. Clinician-assisted videofeedback appears to support emotional self-regulation of mothers with violence-related PTSD. Focusing with a therapist on videofeedback of child separation distress exposes mothers to avoided mental states of helplessness and perceived loss of protection. Negative maternal attributions may mark violent trauma-associated emotion dysregulation and projected self-representations of the maltreated mother.

Is Exposure Necessary? A Randomized Clinical Trial of Interpersonal Psychotherapy for PTSD.

OBJECTIVE: Exposure to trauma reminders has been considered imperative in psychotherapy for posttraumatic stress disorder (PTSD). The authors tested interpersonal psychotherapy (IPT), which has demonstrated antidepressant efficacy and shown promise in pilot PTSD research as a non-exposure-based non-cognitive-behavioral PTSD treatment. METHOD: The authors conducted a randomized 14-week trial comparing IPT, prolonged exposure (an exposure-based exemplar), and relaxation therapy (an active control psychotherapy) in 110 unmedicated patients who had chronic PTSD and a score >50 on the Clinician-Administered PTSD Scale (CAPS). Randomization stratified for comorbid major depression. The authors hypothesized that IPT would be no more than minimally inferior (a difference <12.5 points in CAPS score) to prolonged exposure. RESULTS: All therapies had large within-group effect sizes (d values, 1.32-1.88). Rates of response, defined as an improvement of >30% in CAPS score, were 63% for IPT, 47% for prolonged exposure, and 38% for relaxation therapy (not significantly different between groups). CAPS outcomes for IPT and prolonged exposure differed by 5.5 points (not significant), and the null hypothesis of more than minimal IPT inferiority was rejected (p=0.035). Patients with comorbid major depression were nine times more likely than nondepressed patients to drop out of prolonged exposure therapy. IPT and prolonged exposure improved quality of life and social functioning more than relaxation therapy. CONCLUSIONS: This study demonstrated noninferiority of individual IPT for PTSD compared with the gold-standard treatment. IPT had (nonsignificantly) lower attrition and higher response rates than prolonged exposure. Contrary to widespread clinical belief, PTSD treatment may not require cognitive-behavioral exposure to trauma reminders. Moreover, patients with comorbid major depression may fare better with IPT than with prolonged exposure.

Science for the community: assessing mental health after 9/11.

Reactions to the September 11 attacks across the United States were pervasive, and persons throughout the country reported experiences akin to posttraumatic stress disorder (PTSD) in the first week following the attacks. In the New York area, 2 major surveys conducted 4 to 8 weeks after the attacks found that approximately 1 in 10 persons probably met full criteria for PTSD related to September 11. Although tobacco, alcohol, and marijuana use did increase, it was largely among persons already using these substances. The greatest increase, not surprisingly, occurred among persons with PTSD and major depressive disorder. Nationwide during the same time period, rates of PTSD related to September 11 were estimated at 2.7% to 4.3%, a striking finding in that the attacks were witnessed primarily on television outside the New York area. In all studies, having anxiety symptoms or meeting criteria for PTSD was strongly associated with number of hours of television watched on September 11 and in the days afterward. A number of explanations for this new finding are possible. These data can inform our understanding of trauma-related diagnoses, further the evolving diagnostic definitions of the Diagnostic and Statistical Manual of Mental Disorders, and contribute to etiologic models of PTSD. Future directions for postdisaster survey research are briefly discussed.

Consensus statement update on posttraumatic stress disorder from the international consensus group on depression and anxiety.

OBJECTIVE: To provide an update to the "Consensus Statement on Posttraumatic Stress Disorder From the International Consensus Group on Depression and Anxiety" that was published in a supplement to The Journal of Clinical Psychiatry (2000) by presenting important developments in the field, the latest recommendations for patient care, and suggestions for future research. PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R. T. Davidson, Yves Lecrubier, and David J. Nutt. Other faculty who were invited by the chair were Randall D. Marshall, Charles B. Nemeroff, Arieh Y. Shalev, and Rachel Yehuda. EVIDENCE: The consensus statement is based on the 7 review articles in this supplement and the related scientific literature. CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed topics to be represented by the 7 review articles in this supplement, and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all faculty. CONCLUSION: There have been advancements in the science and treatment of posttraumatic stress disorder. Attention to this disorder has increased with recent world events; however, continued efforts are needed to improve diagnosis, treatment, and prevention of posttraumatic stress disorder.

Psychobiology of the acute stress response and its relationship to the psychobiology of post-traumatic stress disorder.

The literature to date that examines the biology of the acute stress reactions suggests that relatively lower baseline cortisol is associated with the development of PTSD. This is particularly informative because of the ongoing controversy surrounding baseline cortisol in PTSD. Studies have found low baseline cortisol, normal range, and elevated baseline cortisol in chronic PTSD, and it has been unclear whether this reflects methodologic differences across studies or true heterogeneity within the disorder. Thus, the few studies to date support the finding of low-normal baseline cortisol in chronic PTSD and suggest that it is a pre-existing functional trait. Whether it plays an etiologic role or is an epiphenomenon of some other process is unclear. What does seem clear, however, is that this characteristic is relatively nonspecific to PTSD, given the fact that low cortisol has been observed in multiple subject populations, including normal individuals under chronic stress as well as chronic medical conditions (for review see [23]). For example, it is possible that reduced baseline cortisol reflects the net result of input to the hypothalamus from cortical and subcortical regions of the brain linked to increased vigilance, sensitization to trauma because of prior traumatic experiences, or genetic factors. For example, primate studies have demonstrated persistent alterations in HPA axis functioning in animals reared by mothers living in moderately stressful conditions [24]. The development of PTSD is associated with sensitization of the startle response. Because the neurobiology of startle is well characterized, this finding implicates a role for specific neurocircuitry in PTSD [25]. Non-habituation of the startle response in PTSD appears related to sensitization specifically to contextual cues (i.e., the environment) that signal the presence of potential threat of danger-related fears [26]. This may be the neurobiological correlate to the over-generalization seen in PTSD that distinguishes the disorder from a simple trauma-induced phobia. The bed nucleus of the stria terminalis (BNST) is specifically implicated from preclinical research in the mediation of context-dependent cues [1]. Treatments that result in down-regulation of the BNST are therefore of particular interest in therapeutic models of prevention after trauma. The fact that a number of vulnerability factors associated with increased risk for developing PTSD are also likely to be biologically based (e.g., a genetic component, prior psychiatric history, prior family of history of psychiatric disorder), provides further evidence in support of a role for psychobiological factors in producing PTSD. Nevertheless, the considerable overlap on these measures between those who will develop PTSD, and those who eventually recover spontaneously, belies any attempt to identify any single or pathognomonic biological marker for risk. For now, the standard of care in predicting level of symptomatology and prognosis in the acute setting continues to be based on careful, informed, serial assessments of symptoms and functioning. Because the capacity to learn from and adapt to adverse conditions are essential to the survival of any species, understanding the neurobiological pathways that mediate learning from traumatic experiences in an adaptive way is as important as understanding the etiology of PTSD and other trauma-related maladaptive consequences. Biological models that trace the causal cascade of post-traumatic events in the brain and neuroendocrine systems may offer a multiplicity of possibilities for intervention. It is well established that conditioned responses are robust and persistent. Moreover, the primary mechanism of habituation is overlearning rather than extinction. Interventions that promote overlearning may therefore prove to be the most powerful and efficient preventative treatments. The therapeutics literature supports this hypothesis, in that brief psychosocial interventions based on sophisticated cognitive-behavioral models have proven effective in reducing suffering, symptom severity, and chronicity in individuals presenting with acute PTSD symptoms [27-29]. No acutely administered pharmacologic treatment to date has been shown effective in accelerating the process of recovery or in preventing the development of chronic PTSD. However, pharmacologic interventions that would prevent sensitization of circuits related to context-dependent threat perception, dysregulation of affect, and/or dysregulation of normal circadian rhythms are of theoretical interest and deserve further study.

A pilot study of noradrenergic and HPA axis functioning in PTSD vs. panic disorder.

The biological literature in the anxiety disorders has focused on comparisons between patient groups and normal volunteers, with relatively little comparative study of the anxiety disorders. We therefore conducted this pilot study to compare a group of patients with post-traumatic stress disorder (PTSD) (n = 7) to a contiguously studied panic disorder group (n = 17) and healthy control subjects (n = 16) on baseline levels of cortisol and 3-methoxy-4-hydroxyphenylglycol (MHPG), and response to clonidine challenge. Despite the small sample size, highly significant differences were found on the following measures: PTSD patients had lower cortisol, lower MHPG, reduced MHPG volatility to clonidine challenge, and marginally reduced cortisol volatility compared to patients with panic disorder. These biological findings support existing clinical, epidemiologic, family study, and clinical trial findings that distinguish these two disorders as distinct syndromes.

If we had known then what we know now: a review of local and national surveys following September 11, 2001.

There is little research on the consequences of large-scale violent disasters in a community despite their unfortunate prevalence over many decades. The primary source of epidemiological data for the greater New York community in dealing with the September 11, 2001, attacks was the Oklahoma City bombing. In the latter event, 45%; of directly exposed adults met criteria for a major psychiatric disorder 6 months later, including 34%; with posttraumatic stress disorder (PTSD). The first survey after the World Trade Center and Pentagon attacks, conducted within one week, revealed a remarkable degree of symptomatology across the nation in both adults and children. Forty-four percent of adults reported at least 1 of 5 PTSD screening symptoms in the 3-5 days after the attacks; 35% of parents reported children who had at least one symptom, and 47% of children worried about their own or someone else's safety. Coping behaviors were consistent with a community mental health model and included turning to open discussion (98%), religion (90%), and community activities (60%) in order to cope with their reactions. Rates of disorder were also high in a survey conducted 5-8 weeks later in Manhattan below 110th Street, with 38% saying they directly witnessed the World Trade Center attack. The current prevalence of new-onset PTSD was 7.5%, and of new-onset major depressive disorder, 9.7%. This translates into 67,000 persons with PTSD and 87,000 persons with major depression. This survey also found a significant increase in tobacco, alcohol, and marijuana use, but primarily among adults already using these substances. All surveys found strong associations between media exposure and symptomatology. The greatest need at this point in the literature is therapeutics research after such traumatic events.

Trauma-focused psychotherapy after a trial of medication for chronic PTSD: pilot observations.

BACKGROUND: To date, all clinical trials using a single therapeutic modality (psychotherapy or pharmacotherapy) have found that even the best validated treatments for adults with chronic Posttraumatic Stress Disorder (PTSD) leave a substantial proportion of patients with disabling residual symptoms. METHOD: We reviewed the treatment course of three research patients with PTSD who received trauma-focused psychotherapy after experiencing a partial response to medication. Structured diagnostic interviews, validated symptom measures, and standardized treatment approaches were used to assess treatment response. RESULTS: All patients partially benefited from medication treatment, and the degree of benefit varied substantially. Also, all patients experienced an additional reduction in PTSD symptoms after a time-limited course of prolonged exposure therapy (PE). This finding differs from anecdotal observations among U.S. War veterans and has never been documented systematically among civilian adults with chronic PTSD. CONCLUSION: Maximizing treatment outcome in adults with chronic PTSD may require additional psychotherapy after a partial medication response, and further study is warranted.

Psychobiological dysregulation in violence-exposed mothers: salivary cortisol of mothers with very young children pre- and post-separation stress.

UNLABELLED: To understand the determinants of frightening/frightened and other atypical maternal behavior, the authors studied a sample of 41 inner-city mothers of very young children (ages 8-50 months), the mothers of whom had lifetime histories of interpersonal violent trauma (i.e., physical or sexual abuse, and domestic violence) and related posttraumatic stress. METHOD: The authors measured (1) maternal salivary cortisol levels before and 30 minutes after a videotaped play paradigm with their children, involving two separations and reunions; and (2) cortisol reactivity 30 minutes after separation stress. Data were analyzed using Pearson bivariate correlations, ANOVA, and multiple linear regressions. RESULTS: Salivary cortisol "baseline" values were significantly negatively correlated with childhood interpersonal violent trauma severity (i.e., trauma severity prior to age 16). However, cortisol reactivity was not significantly correlated with interpersonal violent trauma severity at this level of analysis. Although baseline salivary cortisol values were not significantly correlated with current overall psychiatric or depressive symptoms, they were negatively correlated with severity of current posttraumatic stress symptoms (PTSS) and with dissociative symptoms. Neither dimensions of negativity nor distortion of maternal attributions showed any significant association with prestress or poststress salivary cortisol levels. Salivary cortisol baseline was negatively correlated with atypical maternal behavior via measurement of the level of disrupted communication, at a trend-level of significance. CONCLUSIONS: Violent trauma-associated dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may be a marker for increased risk for intergenerational transmission via parenting behavior with young children. Low salivary cortisol prior to separation stress and blunted cortisol reactivity to separation may also be markers for posttraumatic stress.

Biopharmaceutical characterization, metabolism, and brain penetration of the triple reuptake inhibitor amitifadine.

Amitifadine (EB-1010, formerly DOV 21,947) is a serotonin-preferring triple reuptake inhibitor that is a drug candidate for major depressive disorder. We investigated several relevant biopharmaceutic and drug-like characteristics of amitifadine using in vitro methodology and additionally determined the in vivo brain to plasma ratio of the drug in rats. Amitifadine was highly plasma protein bound with over 99% of drug bound to human plasma proteins. Using Caco-2 cell lines, amitifadine was bidirectionally highly permeable and showed no evidence of active secretion. Amitifadine was metabolized slowly by human hepatocytes and the major metabolite was the lactam EB-10101. In vitro studies using human liver microsomes demonstrated that EB-10101 was formed by monoamine oxidase A (MAO-A) and a NADPHdependent enzyme, possibly a cytochrome P450 (CYP) isoform. Amitifadine was a moderate inhibitor of the human isoforms of the major drug metabolizing enzymes CYP2D6, CYP3A4, CYP2C9, and CYP2C19 (IC50 = 9 - 100 µM), but was a potent inhibitor of human CYP2B6 (IC50 = 1.8 µM). The brain to plasma ratio for amitifadine varied from 3.7 - 6.5 at various time points, indicating preferential partitioning into rat brain versus plasma. The low affinity for the major drug metabolizing CYP enzymes and metabolism by multiple pathways may reduce pharmacokinetic drug-drug interactions and effects of enzyme polymorphisms. Overall, these studies suggest that amitifadine has drug-like characteristics favorable for drug development.