Jeffrey R. Strawn

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.

The co-occurrence of cigarette smoking and bipolar disorder: phenomenology and treatment considerations.

Heffner JL, Strawn JR, DelBello MP, Strakowski SM, Anthenelli RM. The co‐occurrence of cigarette smoking and bipolar disorder: phenomenology and treatment considerations. 
Bipolar Disord 2011: 13: 439–453.

Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder

BACKGROUND Although elevated concentrations of both corticotropin-releasing hormone (CRH) and norepinephrine are present in the cerebrospinal fluid (CSF) of patients with post-traumatic stress disorder (PTSD), the effects of exposure to traumatic stimuli on these stress-related hormones in CSF are unknown. METHODS A randomized, within-subject, controlled, cross-over design was used, in which patients with war-related PTSD underwent 6-h continuous lumbar CSF withdrawal on two occasions per patient (6-9 weeks apart). During one session the patients watched a 1-h film containing combat footage (traumatic film) and in the other a 1-h film on how to oil paint (neutral film). At 10-min intervals, we quantified CRH and norepinephrine in CSF, and ACTH and cortisol in plasma, before, during, and after symptom provocation. Subjective anxiety and mood were monitored using 100-mm visual analog scales. Blood pressure and heart rate were obtained every 10min from a left leg monitor. RESULTS Eight of 10 patients completed two CSF withdrawal procedures each. A major drop in mood and increases in anxiety and blood pressure occurred during the traumatic relative to the neutral videotape. CSF norepinephrine rose during the traumatic film relative to the neutral videotape; this rise directly correlated with magnitude of mood drop. In contrast, CSF CRH concentrations declined during the trauma-related audiovisual stimulus, both absolutely and relative to the neutral stimulus; the magnitude of CRH decline correlated with degree of subjective worsening of anxiety level and mood. Plasma cortisol concentrations were lower and ACTH levels similar during the stress compared with the neutral videotape. CONCLUSIONS CSF concentrations of the stress hormones norepinephrine and CRH differentially change after exposure to 1h of trauma-related audiovisual stimulation in chronic, combat-related PTSD. While the CSF norepinephrine increase was postulated, the decline in CSF CRH levels is surprising and could be due to audiovisual stress-induced increased uptake of CSF CRH into brain tissue, increased CRH utilization, increased CRH degradation, or to an acute stress-related inhibition or suppression of CRH secretion.

Assessment and treatment of anxiety disorders in children and adolescents.

Recent advances in the developmental epidemiology, neurobiology, and treatment of pediatric anxiety disorders have increased our understanding of these conditions and herald improved outcomes for affected children and adolescents. This article reviews the current epidemiology, longitudinal trajectory, and neurobiology of anxiety disorders in youth. Additionally, we summarize the current evidence for both psychotherapeutic and psychopharmacologic treatments of fear-based anxiety disorders (e.g., generalized, social, and separation anxiety disorders) in children and adolescents. Current data suggest that these disorders begin in childhood and adolescence, exhibit homotypic continuity, and increase the risk of secondary anxiety and mood disorders. Psychopharmacologic trials involving selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SSNRIs) are effective in pediatric patients with anxiety disorders and have generally demonstrated moderate effect sizes. Additionally, current data support cognitive behavioral therapy (CBT) for the treatment of these conditions in youth and suggest that the combination of psychotherapy + an SSRI may be associated with greater improvement than would be expected with either treatment as monotherapy.

Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat-related posttraumatic stress disorder

The hypothalamic neuropeptide, orexin-A has a number of regulatory effects in humans and pre-clinical evidence suggests a link to neuroendocrine systems known to be pathophysiologically related to posttraumatic stress disorder (PTSD). However, there are no reports of central nervous system (CNS) or peripheral orexin-A concentrations in patients with PTSD, or any anxiety disorder. Cerebrospinal fluid (CSF) and plasma levels of orexin-A were serially determined in patients with PTSD and healthy comparison subjects to characterize the relationships between orexin-A (in the CNS and peripheral circulation) and central indices of monoaminergic neurotransmission and to determine the degree to which CNS orexin-A concentrations reflect those in the circulating blood. CSF and plasma samples were obtained serially over a 6-h period in 10 male combat veterans with chronic PTSD and 10 healthy male subjects through an indwelling subarachnoid catheter. Orexin-A concentrations were determined in plasma and CSF and CSF levels of the serotonin metabolite, 5-hydroxyindolacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid (HVA), were determined over the sampling period. CSF and plasma orexin-A concentrations were significantly lower in the patients with PTSD as compared with healthy comparison subjects at all time points. In addition, CSF orexin-A concentrations strongly and negatively correlated with PTSD severity as measured by the Clinician-Administered PTSD Scale (CAPS) in patients with PTSD. Peripheral and CNS concentrations of orexin-A were correlated in the healthy comparison subjects and peripheral orexin-A also correlated with CNS serotonergic tone. These findings suggest low central and peripheral orexin-A activity in patients with chronic PTSD are related to symptom severity and raise the possibility that orexin-A is part of the pathophysiological mechanisms of combat-related PTSD.

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.

Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations.

Neuroleptic malignant syndrome (NMS) is a serious and potentially fatal adverse effect of antipsychotic drugs. The diagnosis of NMS commonly requires core symptoms of hyperthermia and muscle rigidity. Although diagnostic criteria for NMS have been established and are widely accepted and used, it should be recognized that atypical presentations pose a diagnostic dilemma, as hyperthermia and/or muscle rigidity may be absent or develop slowly over several days, leading to impairment or a significant delay in diagnosis and treatment. Evidence from case reports and retrospective evaluations supports a concept of atypical NMS, particularly with regard to treatment with atypical antipsychotics. However, it remains unclear whether these atypical presentations represent early or impending NMS. Furthermore, it is unclear whether dysfunction in other neurotransmitter systems, in addition to dopamine, may be involved in the pathogenesis of NMS induced by atypical antipsychotics. In patients receiving any antipsychotic, clinicians should carefully evaluate any features of NMS and should not prematurely exclude a diagnosis of NMS in cases where severe rigidity or hyperthermia is not initially apparent.

Psychopharmacologic Treatment of Children and Adolescents with Anxiety Disorders

Over the last decade, psychopharmacologic treatments for pediatric anxiety disorders have been developed and increasingly subjected to randomized, controlled trials. The authors summarize the data concerning the use of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), atypical anxiolytics, and benzodiazepines. The extant data suggest that SSRIs--both as monotherapy and when combined with psychotherapy--are effective in the treatment of pediatric anxiety disorders. In addition, some TCAs and SNRIs are effective. However, randomized controlled trials do not suggest efficacy for benzodiazepines or the atypical anxiolytic, buspirone, for children and adolescents with anxiety disorders.

Physiologic Changes Associated With Violence and Abuse Exposure An Examination of Related Medical Conditions

Although the extant evidence is replete with data supporting linkages between exposure to violence or abuse and the subsequent development of medical illnesses, the underlying mechanisms of these relationships are poorly defined and understood. Physiologic changes occurring in violence- or abuse-exposed individuals point to potentially common biological pathways connecting traumatic exposures with medical outcomes. Herein, the evidence describing the long-term physiologic changes in abuse- and violence-exposed populations and associated medical illnesses are reviewed. Current data support that (a) specific neurobiochemical changes are associated with exposure to violence and abuse; (b) several biological pathways have the potential to lead to the development of future illness; and (c) common physiologic mechanisms may moderate the severity, phenomenology, or clinical course of medical illnesses in individuals with histories of exposure to violence or abuse. Importantly, additional work is needed to advance our emerging understanding of the biological mechanisms connecting exposure to violence and abuse and negative health outcomes.