Faculty Bibliography

Posttraumatic stress disorder (PTSD) is common in the general population, yet there are limitations to the effectiveness, tolerability, and acceptability of available first-line interventions. We review the extant knowledge on the effects of marijuana and other cannabinoids on PTSD. Potential therapeutic effects of these agents may largely derive from actions on the endocannabinoid system and we review major animal and human findings in this area. Preclinical and clinical studies generally support the biological plausibility for cannabinoids' potential therapeutic effects, but underscore heterogeneity in outcomes depending on dose, chemotype, and individual variation. Treatment outcome studies of whole plant marijuana and related cannabinoids on PTSD are limited and not methodologically rigorous, precluding conclusions about their potential therapeutic effects. Reported benefits for nightmares and sleep (particularly with synthetic cannabinoid nabilone) substantiate larger controlled trials to determine effectiveness and tolerability. Of concern, marijuana use has been linked to adverse psychiatric outcomes, including conditions commonly comorbid with PTSD such as depression, anxiety, psychosis, and substance misuse. Available evidence is stronger for marijuana's harmful effects on the development of psychosis and substance misuse than for the development of depression and anxiety. Marijuana use is also associated with worse treatment outcomes in naturalistic studies, and with maladaptive coping styles that may maintain PTSD symptoms. Known risks of marijuana thus currently outweigh unknown benefits for PTSD. Although controlled research on marijuana and other cannabinoids' effects on PTSD remains limited, rapid shifts in the legal landscape may now enable such studies, potentially opening new avenues in PTSD treatment research.

BACKGROUND: Research has demonstrated a strong link between trauma, posttraumatic stress disorder PTSD and substance use disorders (SUDs) in general and cannabis use disorders in particular. Yet, few studies have examined the impact of cannabis use on treatment outcomes for individuals with co-occurring PTSD and SUDs. METHODS: Participants were 136 individuals who received cognitive-behavioral therapies for co-occurring PTSD and SUD. Multivariate regressions were utilized to examine the associations between baseline cannabis use and end-of-treatment outcomes. Multilevel linear growth models were fit to the data to examine the cross-lagged associations between weekly cannabis use and weekly PTSD symptom severity and primary substance use during treatment. RESULTS: There were no significant positive nor negative associations between baseline cannabis use and end-of-treatment PTSD symptom severity and days of primary substance use. Cross-lagged models revealed that as cannabis use increased, subsequent primary substance use decreased and vice versa. Moreover, results revealed a crossover lagged effect, whereby higher cannabis use was associated with greater PTSD symptom severity early in treatment, but lower weekly PTSD symptom severity later in treatment. CONCLUSION: Cannabis use was not associated with adverse outcomes in end-of-treatment PTSD and primary substance use, suggesting independent pathways of change. The theoretical and clinical implications of the reciprocal associations between weekly cannabis use and subsequent PTSD and primary substance use symptoms during treatment are discussed.

1-octanol is a therapeutic candidate for disorders involving the abnormal activation of the T-type calcium current since it blocks this current specifically. Such disorders include essential tremor and a group of neurological and psychiatric disorders resulting from thalamocortical dysrhythmia (TCD). For example, clinically, the observable phenotype in essential tremor is the tremor itself. The differential diagnostic of TCD is not based only on clinical signs and symptoms. Rather, TCD incorporates an electromagnetic biomarker, the presence of abnormal thalamocortical low frequency brain oscillations. The effect of 1-octanol on brain activity has not been tested. As a preliminary step to such a TCD study, we examined the short-term effects of a single dose of 1-octanol on resting brain activity in 32 healthy adults using magnetoencephalograpy. Visual inspection of baseline power spectra revealed that the subjects fell into those with strong low frequency activity (set 2, n = 11) and those without such activity, but dominated by an alpha peak (set 1, n = 22). Cross-validated linear discriminant analysis, using mean spectral density (MSD) in nine frequency bands as predictors, found overall that 82.5% of the subjects were classified as determined by visual inspection. The effect of 1-octanol on the MSD in narrow frequency bands differed between the two subject groups. In set 1 subjects the MSD increased in the 4.5-6.5Hz and 6.5-8.5 Hz bands. This was consistent with a widening of the alpha peak toward lower frequencies. In the set two subjects the MSD decrease in the 2.5-4.5 Hz and 4.5-6.5 Hz bands. This decreased power is consistent with the blocking effect of 1-octanol on T-type calcium channels. The subjects reported no adverse effects of the 1-octanol. Since stronger low frequency activity is characteristic of patients with TCD, 1-octanol and other T-type calcium channel blockers are good candidates for treatment of this group of disorders following a placebo-controlled study.

Charles Marmar will present data from a prospective longitudinal cohort study of active-duty military. The total sample size of this ongoing study is n = 1800 and currently there are pre-and post deployment data available for over 600 individuals. Outcome trajectories were modeled and four primary outcome groups were identified. Pre-deployment inflammatory markers predicted progressive symptomatology following deployment

The intensive care unit (ICU) has been portrayed as psychologically stressful, with a growing body of research substantiating elevated rates of depression, posttraumatic stress disorder (PTSD), and other psychological disruptions in populations of critical care survivors. To explain these psychopathology elevations, some have proposed a direct effect of ICU admission upon the later development of psychopathology, whereas others highlight the complex interaction between the trauma of a life-threatening illness or injury and the stressful life-saving interventions often administered in the ICU. However, the conclusion that the ICU is an independent causal factor in trauma-related psychological outcomes may be premature. Current ICU research suffers from important methodological problems including lack of true prospective data, failure to employ appropriate comparison groups, sampling bias, measurement issues, and problems with statistical methodology. In addition, the ICU literature has yet to investigate important risk and resilience factors that have been empirically validated in the broader stress-response literature. The authors propose the application of these important constructs to the unique setting of the ICU. This review focuses on multiple aspects of the important but complex research question of whether the ICU confers risk for psychological distress above and beyond the traumatic impact of the serious health events that necessitate ICU treatment. (PsycINFO Database Record

A large number of studies have identified trajectories of adjustment following acute and aversive life events. In these studies, a stable trajectory of positive health or resilience is almost always the modal outcome (Bonanno, 2004; Bonanno et al., 2011). Infurna and Luthar (2016, this issue) reported that they replicated findings from two early studies in which trajectories of subjective well-being were identified before and after divorce, widowhood, and unemployment (Galatzer-Levy, Bonanno, & Mancini, 2010; Mancini, Bonanno, & Clark, 2011) and then reanalyzed these data in such a way to conclude a decrease in the prevalence of resilience. In this commentary, we discuss three serious flaws in Infurna and Luthar's claims. First, they did not actually replicate our original analyses. They used different data, time points, and parameters. Second, the model specifications in their reanalyses were not optimal because they increased variance, reduced variability in response to the stressor, and had lower entropy, indicating that their models more poorly captured unique patterns of response. Third, their reanalyses were theoretically uninformative as they minimized both group differences and overall responses to the stressor event and thus failed to identify widely acknowledged populations, such as chronic stress reactivity.

Major depressive disorder (MDD) contributes to a significant worldwide disease burden, expected to be second only to heart disease by 2050. However, accurate diagnosis has been a historical weakness in clinical psychiatry. As a result, there is a demand for diagnostic modalities with greater objectivity that could improve on current psychiatric practice that relies mainly on self-reporting of symptoms and clinical interviews. Over the past two decades, literature on a growing number of putative biomarkers for MDD increasingly suggests that MDD patients have significantly different biological profiles compared to healthy controls. However, difficulty in elucidating their exact relationships within depression pathology renders individual markers inconsistent diagnostic tools. Consequently, further biomarker research could potentially improve our understanding of MDD pathophysiology as well as aid in interpreting response to treatment, narrow differential diagnoses, and help refine current MDD criteria. Representative of this, multiplex assays using multiple sources of biomarkers are reported to be more accurate options in comparison to individual markers that exhibit lower specificity and sensitivity, and are more prone to confounding factors. In the future, more sophisticated multiplex assays may hold promise for use in screening and diagnosing depression and determining clinical severity as an advance over relying solely on current subjective diagnostic criteria. A pervasive limitation in existing research is heterogeneity inherent in MDD studies, which impacts the validity of biomarker data. Additionally, small sample sizes of most studies limit statistical power. Yet, as the RDoC project evolves to decrease these limitations, and stronger studies with more generalizable data are developed, significant advances in the next decade are expected to yield important information in the development of MDD biomarkers for use in clinical settings.

PTSD is distressful and debilitating, following a non-remitting course in about 10% to 20% of trauma survivors. Numerous risk indicators of PTSD have been identified, but individual level prediction remains elusive. As an effort to bridge the gap between scientific discovery and practical application, we designed and implemented a clinical decision support pipeline to provide clinically relevant recommendation for trauma survivors. To meet the specific challenge of early prediction, this work uses data obtained within ten days of a traumatic event. The pipeline creates personalized predictive model for each individual, and computes quality metrics for each predictive model. Clinical recommendations are made based on both the prediction of the model and its quality, thus avoiding making potentially detrimental recommendations based on insufficient information or suboptimal model. The current pipeline outperforms the acute stress disorder, a commonly used clinical risk factor for PTSD development, both in terms of sensitivity and specificity.

Psychophysiological measures of fear expression provide observable intermediate phenotypes of fear-related symptoms. Research Domain Criteria (RDoC) advocate using neurobiological intermediate phenotypes that provide dimensional correlates of psychopathology. Negative Valence Systems in the RDoC matrix include the construct of acute threat, which can be measured on a physiological level using potentiation of the acoustic startle reflex assessed via electromyography recordings of the orbicularis oculi muscle. Impairments in extinction of fear-potentiated startle due to high levels of fear (termed fear load) during the early phases of extinction have been observed in posttraumatic stress disorder (PTSD). The goals of the current work were to examine dimensional associations between fear-related symptoms of PTSD and fear load variables to test their validity as an intermediate phenotype. We examined extinction of fear-potentiated startle in a cohort (n=269) of individuals with a broad range of civilian trauma exposure (range 0-13 traumatic events per person, mean=3.5). Based on previously reported findings, we hypothesized that fear load would be significantly associated with intrusion and fear memories of an index traumatic event. The results indicated that early extinction was correlated with intrusive thoughts (p=0.0007) and intense physiological reactions to trauma reminders (p=0.036). Degree of adult or childhood trauma exposure, and depression severity were not associated with fear load. After controlling for age, sex, race, income, level of prior trauma, and level of fear conditioning, fear load during extinction was still significantly predictive of intrusive thoughts (p=0.004). The significance of these findings is that they support dimensional associations with symptom severity rather than diagnostic category and, as such, fear load may emerge as a transdiagnostic intermediate phenotype expressed across fear-related disorders (e.g., specific phobia, social phobia).

Our understanding of how individuals react to the loss of a close loved one comes largely from studies of spousal bereavement. The extent to which findings are relevant to other bereavements is uncertain. A major methodological limitation of current studies has been a reliance on retrospective reporting of functioning and use of samples of individuals who have self-selected for participant in grief research. To address these limitations, in the current study we applied Latent Growth Mixture Modelling (LGMM) in a prospective population-based sample to identify trajectories of depression following spousal and child bereavement in later life. The sample consisted of 2512 individual bereaved adults who were assessed once before and three times after their loss. Four discrete trajectories were identified: Resilience (little or no depression; 68.2%), Chronic Grief (an onset of depression following loss; 13.2%), Depressed-Improved (high pre-loss depression that decreased following loss; 11.2%), and Pre-existing Chronic Depression (high depression at all assessments; 7.4%). These trajectories were present for both child and spousal loss. There was some evidence that child loss in later life was associated more strongly with the Chronic Grief trajectory and less strongly with the Resilience trajectory. However these differences disappeared when covariates were included in the model. Limitations of the analyses are discussed. These findings increase our understanding of the variety of outcomes following bereavement and underscore the importance of using prospective designs to map heterogeneity of response outcomes.