Thomas G. Adams

PTSD: from neurobiology to pharmacological treatments

Posttraumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder characterized by symptoms of re-experience, avoidance, and hyperarousal that can arise immediately or many years after exposure to a traumatic event and injury. Although extensive research has been done over the past 30 years, the etiology of PTSD remains largely unknown. Several neurobiological systems have been implicated in the pathophysiology and vulnerability for developing PTSD; however, first-line pharmacotherapies are limited. Less than 30% achieve full remission, and even then, approved pharmacological treatments often take weeks for therapeutic effect. This article aims to review the pathophysiology of PTSD within multiple neurobiological systems and how these mechanisms are used as pharmacologic targets of treatment, as well as their potential for future targets of intervention. Highlights of the article We reviewed the neurobiological abnormalities in PTSD as they relate to well-established, preliminary, and future targets for pharmacological interventions. Abnormalities across different neurotransmitter systems have been implicated in the pathophysiology of PTSD but none of these systems function uniformly among all patients with PTSD First-line pharmacotherapy for PTSD provides a suboptimal response rates. Future pharmacological targets for PTSD include the cannabinoid and oxytocin systems, as well glutamatergic modulating agents. Drug development for PTSD should specifically address various dimensions of PTSD symptomatology.

Assessing sexually intrusive thoughts: Parsing unacceptable thoughts on the Dimensional Obsessive-Compulsive Scale

Sexual obsessions are a common symptom of obsessive-compulsive disorder (OCD), often classified in a broader symptom dimension that includes aggressive and religious obsessions, as well. Indeed, the Dimensional Obsessive-Compulsive Scale (DOCS) Unacceptable Thoughts Scale includes obsessional content relating to sexual, violent, and religious themes associated with rituals that are often covert. However, there is reason to suspect that sexual obsessions differ meaningfully from other types of unacceptable thoughts. We conducted two studies to evaluate the factor structure, initial psychometric characteristics, and associated clinical features of a new DOCS scale for sexually intrusive thoughts (SIT). In the first study, nonclinical participants (N=475) completed the standard DOCS with additional SIT questions and we conducted an exploratory factor analysis on all items and examined clinical and cognitive correlates of the different scales, as well as test-retest reliability. The SIT Scale was distinct from the Unacceptable Thoughts Scale and was predicted by different obsessional cognitions. It had good internal consistency and there was evidence for convergent and divergent validity. In the second study, we examined the relationships among the standard DOCS and SIT scales, as well as types of obsessional cognitions and symptom severity, in a clinical sample of individuals with OCD (N=54). There were indications of both convergence and divergence between the Unacceptable Thoughts and SIT scales, which were strongly correlated with each other. Together, the studies demonstrate the potential utility of assessing sexually intrusive thoughts separately from the broader category of unacceptable thoughts.

OCD is associated with an altered association between sensorimotor gating and cortical and subcortical 5-HT1b receptor binding

Obsessive-compulsive disorder (OCD) is characterized by impaired sensorimotor gating, as measured using prepulse inhibition (PPI). This effect may be related to abnormalities in the serotonin (5-HT) system. 5-HT1B agonists can impair PPI, produce OCD-like behaviors in animals, and exacerbate OCD symptoms in humans. We measured 5-HT1B receptor availability using (11)C-P943 positron emission tomography (PET) in unmedicated, non-depressed OCD patients (n=12) and matched healthy controls (HC; n=12). Usable PPI data were obtained from 20 of these subjects (10 from each group). There were no significant main effects of OCD diagnosis on 5-HT1B receptor availability ((11)C-P943 BPND); however, the relationship between PPI and (11)C-P943 BPND differed dramatically and significantly between groups. 5-HT1B receptor availability in the basal ganglia and thalamus correlated positively with PPI in controls; these correlations were lost or even reversed in the OCD group. In cortical regions there were no significant correlations with PPI in controls, but widespread positive correlations in OCD patients. Positive correlations between 5-HT1B receptor availability and PPI were consistent across diagnostic groups only in two structures, the orbitofrontal cortex and the amygdala. Differential associations of 5-HT1B receptor availability with PPI in patients suggest functionally important alterations in the serotonergic regulation of cortical/subcortical balance in OCD.

Posttraumatic Stress Disorder: An Integrated Overview of the Neurobiological Rationale for Pharmacology

Thirty years of research on the biology of posttraumatic stress disorder now provides a foundation for hypotheses related to the mechanisms underlying the pharmacotherapy of this disorder. Only two medications, sertraline and paroxetine, are approved by the U.S. Food and Drug Administration for the treatment of PTSD. While these medications are somewhat effective, other treatment mechanisms must be explored to address the unmet need for effective treatment. This article provides a concise summary of advances in our understanding of the neurobiology of PTSD that suggest novel approaches to pharmacotherapy.

The effects of inattentiveness and hyperactivity on posttraumatic stress symptoms: does a diagnosis of posttraumatic stress disorder matter?

Objective: To address the nature of associations between ADHD symptoms and posttraumatic stress disorder (PTSD) psychopathology in adult military veterans. Method: Ninety-five combat veterans, with PTSD (n = 63) and without PTSD (n = 32), were recruited for this study. PTSD was assessed with the Clinician-Administered PTSD Scale (CAPS) and ADHD was assessed with Connors’ Adult ADHD Rating Scale−Self-Report: Short Version (CAARS-S:S). Results: PTSD participants endorsed greater hyperactivity or restlessness, inattention or memory problems, and impulsivity or emotional lability scores than participants without PTSD. Among PTSD participants, inattention or memory problems and impulsivity or emotional lability were significant predictors of total PTSD symptoms, but only inattention or memory problems significantly predicted PTSD symptoms when other ADHD symptom clusters were considered simultaneously. Conclusion: Our data suggest that inattention may serve as a risk factor for posttraumatic stress symptoms following combat exposure.

Exposure to emotionally arousing, contamination-relevant pictorial stimuli interferes with response inhibition: Implication for obsessive–compulsive disorder

Multiple emotional processes are implicated in the pathogenesis of obsessions and compulsions and individuals diagnosed with obsessive-compulsive disorder (OCD) have reliably shown deficits in response inhibition. Little research has tested how emotional processes might interact with cognitive control in the context of OCD. High contamination obsessive-compulsive (OC) and low contamination-OC participants completed an emotional go/no-go task to measure the interfering effects contamination-threat images relative to neutral images on action restraint (errors of commission). Results revealed that high contamination-OC participants committed marginally more commission errors (11.04%) than low contamination-OC participants (10.30%) on neutral no-go trials, but this effect was not significant (p > .05). All participants committed significantly more errors of commission on contamination-threat trails relative to neutral no-go trials, p < .01, but the interfering effects of contamination-threat images was significantly larger (p = .05) for high-contamination-OC participants. Errors of commission almost doubled for high contamination-OC participants on contamination-threat no-go trials (20.78%), compared to a more modest increase for low contamination-OC participants (14.80%). These findings suggest that individuals with elevated symptoms of OCD may have significantly more difficulty inhibiting their actions when processing disorder relevant or emotionally arousing information. This observation has implications for the pathogenesis of obsessions and compulsions.

The Role of Stress in the Pathogenesis and Maintenance of Obsessive-Compulsive Disorder:

Individuals with obsessive-compulsive disorder often identify psychosocial stress as a factor that exacerbates their symptoms, and many trace the onset of symptoms to a stressful period of life or a discrete traumatic incident. However, the pathophysiological relationship between stress and obsessive-compulsive disorder remains poorly characterized: it is unclear whether trauma or stress is an independent cause of obsessive-compulsive disorder symptoms, a triggering factor that interacts with a preexisting diathesis, or simply a nonspecific factor that can exacerbate obsessive-compulsive disorder along with other aspects of psychiatric symptomatology. Nonetheless, preclinical research has demonstrated that stress has conspicuous effects on corticostriatal and limbic circuitry. Specifically, stress can lead to neuronal atrophy in frontal cortices (particularly the medial prefrontal cortex), the dorsomedial striatum (caudate), and the hippocampus. Stress can also result in neuronal hypertrophy in the dorsolateral striatum (putamen) and amygdala. These neurobiological effects mirror reported neural abnormalities in obsessive-compulsive disorder and may contribute to an imbalance between goal-directed and habitual behavior, an imbalance that is implicated in the pathogenesis and expression of obsessive-compulsive disorder symptomatology. The modulation of corticostriatal and limbic circuits by stress and the resultant imbalance between habit and goal-directed learning and behavior offers a framework for investigating how stress may exacerbate or trigger obsessive-compulsive disorder symptomatology.