Thomas D. Geracioti

Impaired Cholecystokinin Secretion in Bulimia Nervosa

Bulimia nervosa is a prevalent disorder of unknown cause, characterized by recurrent episodes of uncontrollable eating. In the light of recent evidence that the gastrointestinal hormone cholecystokinin induces satiety and reduces food intake in laboratory animals and humans, we investigated the hypothesis that abnormalities in cholecystokinin secretion and satiety may occur in patients with bulimia and contribute to their disturbed eating patterns. Blood levels of cholecystokinin and subjective satiety were measured in 14 women with bulimia and 10 normal women before and after a mixed-liquid meal. The total integrated plasma cholecystokinin response to eating was significantly impaired in patients with bulimia (P less than 0.05) as was postprandial satiety. Fasting cholecystokinin levels were similar in both populations (approximately 0.8 pmol per liter). After eating, however, mean (+/- SEM) peak plasma cholecystokinin levels increased to 4.1 +/- 0.9 pmol per liter in normal controls but to only 2.1 +/- 0.2 pmol per liter in patients with bulimia nervosa (P less than 0.05). After an open trial of tricyclic antidepressants in a subgroup of five patients with bulimia, the postprandial cholecystokinin response to eating increased significantly, to 6.6 +/- 1.2 pmol per liter (P less than 0.05), and there was an increase in the satiety response. We conclude that patients with bulimia do not have normal satiety and have impaired secretion of cholecystokinin in response to a meal. Preliminary evidence suggests that both these abnormalities may be improved by treatment with tricyclic antidepressants.

Corticotropin-releasing hormone in depression and post-traumatic stress disorder

Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a wide range of behaviors including arousal, motor function, feeding, and reproduction. Because depressed patients are often hypercortisolemic and intracerebroventricular administration of CRH to experimental animals produces a syndrome reminiscent of depression, dysregulation of this compound has been suggested to be involved in the pathogenesis of depressive and anxiety disorders. Studies of cerebrospinal fluid CRH levels and clinical neuroendocrine tests in patients with anxiety and affective disorders have supported this hypothesis. This review discusses these neuroendocrine findings in melancholic and atypical depression as well as post-traumatic stress disorder (PTSD). Overall, the data suggest that melancholic depression is characterized by hyperactive central CRH systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand, atypical depression is characterized by hypoactive central CRH systems and accompanying underactivity of the hypothalamic-pituitary-adrenal axis. Furthermore, the neuroendocrinology of PTSD appears to be unique, in that patients have hyperactive central CRH systems with underactivity of the pituitary-adrenal axis.

Elevated Cerebrospinal Fluid Substance P Concentrations in Posttraumatic Stress Disorder and Major Depression

OBJECTIVE The authors tested the hypothesis that concentrations of the pain-transmitting neuropeptide substance P are elevated in the CSF of patients with major depression or posttraumatic stress disorder (PTSD), which have overlapping symptoms. The authors also sought to determine if CNS substance P concentrations change on provocation of symptoms in PTSD patients. METHOD The authors measured CSF substance P concentrations in medication-free patients with either major depression or PTSD and in healthy comparison subjects. Next, using a within-subject, crossover design, the authors sampled CSF for 6 hours through an indwelling subarachnoid catheter in PTSD patients before, during, and after exposure to a 60-minute traumatic or neutral videotape stimulus. RESULTS Both depressed and PTSD patients had significantly elevated basal CSF substance P concentrations. In the challenge study, marked increases in CSF substance P concentrations were found only after precipitation of PTSD symptoms. CSF substance P concentrations increased by 169% and 90.6% of baseline levels at 10 and 70 minutes, respectively, after the start of the traumatic videotape but changed by only 1.1% and -8.1% of baseline levels 10 and 70 minutes after the start of the neutral videotape. CONCLUSIONS These results suggest that elevated CNS substance P concentrations are involved in both major depression and PTSD. The marked increase in CSF substance P concentrations during and after the symptom-provoking stimulus, but not after the neutral stimulus, implicates CNS release of substance P in the mechanism of acute PTSD symptoms. These data also reveal that CNS substance P responds acutely to psychological stress in humans.

Low Cerebrospinal Fluid Neuropeptide Y Concentrations in Posttraumatic Stress Disorder

BACKGROUND Neuropeptide Y (NPY), a peptide neurotransmitter that regulates stress and anxiety, has been proposed to be a stress resilience factor in humans. Posttraumatic stress disorder (PTSD) is a stress-related anxiety disorder. We hypothesized that central nervous system NPY is dysregulated in PTSD and sought to redress the absence of central NPY data in the disorder. METHODS We determined morning NPY concentrations in cerebrospinal fluid (CSF) from 10 male subjects with chronic combat-related PTSD and from 13 healthy men. Neuropeptide Y-like immunoreactivity was measured by enzyme immunoassay (EIA). RESULTS As compared with the normal comparison subjects, PTSD patients had significantly lower concentrations of CSF neuropeptide Y (mean CSF NPY was 360.0 +/- 17.7 pg/mL in control subjects but only 233.6 +/- 28.7 pg/mL in PTSD patients [p = .0008]). Adjustments for age and body mass index (BMI) still revealed a highly significant reduction in CSF NPY in the PTSD group (p = .003). CONCLUSIONS Men with combat-related PTSD have low CSF concentrations of the putative resiliency hormone NPY, possibly related to the disorder or to extreme stress exposure per se.

Neuropeptide Y and posttraumatic stress disorder

Resiliency to the adverse effects of extraordinary emotional trauma on the brain varies within the human population. Accordingly, some people cope better than others with traumatic stress. Neuropeptide Y (NPY) is a 36-amino-acid peptide transmitter abundantly expressed in forebrain limbic and brain stem areas that regulate stress and emotional behaviors. Studies largely in rodents demonstrate a role for NPY in promoting coping with stress. Moreover, accruing data from the genetic to the physiological implicate NPY as a potential ‘resilience-to-stress’ factor in humans. Here, we consolidate findings from preclinical and clinical studies of NPY that are of relevance to stress-associated syndromes, most prototypically posttraumatic stress disorder (PTSD). Collectively, these data suggest that reduced central nervous system (CNS) NPY concentrations or function may be associated with PTSD. We also link specific symptoms of human PTSD with extant findings in the NPY field to reveal potential physiological contributions of the neuropeptide to the disorder. In pursuit of understanding the physiological basis and treatment of PTSD, the NPY system is an attractive target.

Cerebrospinal fluid and plasma β-endorphin in combat veterans with post-traumatic stress disorder

Abstract Opioid-mediated analgesia develops in experimental animals following traumatic stress and increased opioid-mediated analgesia has been observed in combat veterans with post-traumatic stress disorder (PTSD). These observations have led to the hypothesis that increased central nervous system (CNS) opioidergic activity exists in patients with PTSD. However, direct CNS data on opioid peptide concentrations and dynamics in patients with PTSD are lacking. We withdrew cerebrospinal fluid (CSF) via a flexible, indwelling subarachnoid catheter over a 6-h period and determined hourly CSF concentrations of immunoreactive β-endorphin (irβEND) in 10 well-characterized combat veterans with PTSD and nine matched normal volunteers. Blood was simultaneously withdrawn to obtain plasma for irβEND. PTSD symptom clusters, as measured by the CAPS, were correlated with neuroendocrine data. Mean CSF irβEND was significantly greater in patients with PTSD compared with normals and there was a negative correlation between the irβEND and PTSD intrusive and avoidant symptoms of PTSD. No intergroup difference between plasma ieβEND was found, nor was there a significant correlation between CSF and plasma irβEND. Immunoreactive β-lipotropin (irβLPH) and pro-opiomelanocortin (irPOMC), both precursors of βEND, were much more plentiful in human CSF than was β-endorphin itself, as has been previously reported. It remains to be determined whether the increased CNS opioid concentrations predate traumatic stress, thereby conferring a vulnerability to dissociative states and PTSD itself, or result from the trauma. The negative correlation between CSF irβEND and avoidant and intrusive symptoms suggests that CNS hypersecretion of opioids might constitute an adaptive response to traumatic experience. Poor correlation between CSF and plasma irβEND limits use of plasma measures to assess CNS opioid activity.

Effects of the vanilloid agonist olvanil and antagonist capsazepine on rat behaviors.

Vanilloid receptors (VR) are molecular integrators of painful chemical and physical stimuli. Olvanil is an agonist of the vanilloid receptor; capsazepine is a competitive VR antagonist. The authors were interested in investigated the effects of these compounds on anxiety-like behaviors in rats using the elevated plus maze. In addition, the authors examined the effects of olvanil on the Porsolt swim test. Doses of 0, 0.2, 1.0 and 5.0 mg/kg olvanil, respectively, yielded percent open arm entries at 5 min of 25+/-10.1, 19.3+/-7.1, 14.9+/-5.9 and 0+/-0. We demonstrated a drug effect by showing that the mean of the 0.2, 1 and 5 mg/kg doses was significantly lower than the 0 mg/kg dose at P<.05. In addition, the authors examined the effect of olvanil on the ability of rats to perform in the Porsolt swim test. Float time for rats was tested with 0.1 or 2 mg/kg olvanil and differences between the float times for the lower and higher doses were significant at P<.05. In addition, the effects of various doses of the vanilloid antagonist capsazepine was examined on elevated plus maze behavior. Doses of 0, 1, 5 and 10 mg/kg yielded percent time in the open arms at 5 min of 1.46+/-1.38, 15.05+/-10.42, 11.54+/-10.57, and 14.56+/-7.86. The mean of the 1, 5 and 10 mg/kg doses was significantly greater than the percent time in the open arms for the vehicle, consistent with a drug effect. The results suggest that the vanilloid agonists and antagonists may impact on behaviors involving anxiety and affect. However, it cannot be ruled that the findings could be due to nonspecific motor effect.

Psychopharmacologic Treatment of Posttraumatic Stress Disorder in Children and Adolescents: A Review

OBJECTIVE Despite the high prevalence and significant morbidity associated with posttraumatic stress disorder (PTSD) in children and adolescents, there are limited and conflicting data to guide psychopharmacologic interventions. With these considerations in mind, we sought to summarize the current evidence for psychopharmacologic interventions in youth with PTSD. DATA SOURCES/STUDY SELECTION We conducted a literature review of the National Library of Medicine to identify publications of pharmacologic treatments for youth with PTSD or posttraumatic stress symptoms. The search was limited to articles written in English and published between 1966 and 2009. In addition, we manually searched each citation for additional references and the following journals: Journal of the American Academy of Child and Adolescent Psychiatry and the Journal of Child and Adolescent Psychopharmacology. DATA EXTRACTION All articles were manually reviewed and evaluated. Thereafter, each agent or class of medication was categorized by level of evidence. DATA SYNTHESIS Three double-blind, randomized controlled trials of selective serotonin reuptake inhibitors (SSRIs) and 1 double-blind randomized controlled trial of imipramine in children and adolescents with PTSD or acute stress disorder were identified. Additionally, several open-label studies and case series involving other classes of medications (eg, antiadrenergics, other antidepressants, and second-generation antipsychotics) were reviewed. CONCLUSIONS The extant data do not support the use of SSRIs as first-line treatments for PTSD in children and adolescents. There is limited evidence that the brief use of antiadrenergic agents, second-generation antipsychotics, and several mood stabilizers may attenuate some PTSD symptoms in youth. However, controlled trials of these agents in children and adolescents with PTSD are needed.

Cerebrospinal fluid neuropeptide Y in combat veterans with and without posttraumatic stress disorder

Accruing evidence indicates that neuropeptide Y (NPY), a peptide neurotransmitter, is a resilience-to-stress factor in humans. We previously reported reduced cerebrospinal fluid (CSF) NPY concentrations in combat-related posttraumatic stress disorder (PTSD) subjects as compared with healthy, non-combat-exposed volunteers. Here we report CSF NPY in combat-exposed veterans with and without PTSD. We quantified NPY concentrations in morning CSF from 11 male subjects with PTSD from combat in Iraq and/or Afghanistan and from 14 combat-exposed subjects without PTSD. NPY-like immunoreactivity (NPY-LI) was measured by EIA. The relationship between CSF NPY and clinical symptoms, as measured by the Clinician-Administered PTSD Scale (CAPS) and Beck Depression Inventory (BDI), was assessed, as was the relationship between combat exposure scale (CES) scores and CSF NPY. As compared with the combat-exposed comparison subjects without PTSD, individuals with PTSD had significantly lower concentrations of CSF NPY [mean CSF NPY was 258. 6 ± 21.64 pg/mL in the combat trauma-no PTSD group but only 180.5 ± 12.62 pg/mL in PTSD patients (p=0.008)]. After adjusting for CES and BDI scores the two groups were still significantly different with respect to NPY. Importantly, CSF NPY was negatively correlated with composite CAPS score and intrusive (re-experiencing) subscale scores, but did not significantly correlate with CES or BDI scores. Our current findings further suggest that NPY may regulate the manifestation of PTSD symptomatology, and extend previous observations of low CSF NPY concentrations in the disorder. Central nervous system NPY may be a clinically important pharmacotherapeutic target, and/or diagnostic measure, for PTSD.

The dopamine D3 receptor antagonist nafadotride inhibits development of locomotor sensitization to amphetamine

Behavioral sensitization is a well-studied model of behavioral plasticity mediated at least in part by dopaminergic systems believed to play an important role in several psychiatric conditions. In the rodent, locomotion is regulated by the opposing balance of D3 and D2 receptors, with D2 activation increasing and D3 stimulation inhibiting locomotion. However, receptor occupancy of D3 dopamine receptors is far greater than D2 or D1 occupancy at typical post-stimulant dopamine concentrations. We therefore hypothesized that tolerance of D3 receptor inhibition of locomotion contributes to the development of sensitization. To test this hypothesis, we examined the effect of the D3 receptor antagonist nafadotride on sensitization. As predicted, nafadotride inhibits augmentation of the locomotion response to repetitive amphetamine. This finding is consistent with the proposed model of adaptive down-regulation of D3 dopamine receptor function contributing to the development of behavioral sensitization.