A Neuroanatomic and Pathophysiologic Framework for Novel Pharmacological Approaches to the Treatment of Post-traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a debilitating disorder inflicting high degrees of symptomatic and socioeconomic burdens. The development of PTSD results from a cascade of events with contributions from multiple processes and the underlying pathophysiology is complex, involving neurotransmitters, neurocircuitry, and neuroanatomical pathways. Presently, only two medications are US FDA-approved for the treatment of PTSD, both selective serotonin reuptake inhibitors (SSRIs). However, the complex underlying pathophysiology suggests a number of alternative pathways and mechanisms that may be targets for potential drug development. Indeed, investigations and drug development are proceeding in a number of these alternative, non-serotonergic pathways in an effort to improve the management of PTSD. In this manuscript, the authors introduce novel and emerging treatments for PTSD, including drugs in various stages of development and clinical testing (BI 1358894, BNC-210, PRAX-114, JZP-150, LU AG06466, NYV-783, PH-94B, SRX246, TNX-102), established agents and known compounds being investigated for their utility in PTSD (brexpiprazole, cannabidiol, doxasoin, ganaxolone, intranasal neuropeptide Y, intranasal oxytocin, tianeptine oxalate, verucerfont), and emerging psychedelic interventions (ketamine, MDMA-assisted psychotherapy, psilocybin-assisted psychotherapy), with an aim to examine and integrate these agents into the underlying pathophysiological frameworks of trauma-related disorders.

An accelerated course of TMS using intermittent theta burst for veterans with major depressive disorder: A case series.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a neuro-modulation technique for treatment-resistant major depressive disorder (MDD). Standard TMS protocols for MDD involve once-daily treatment for 6 to 9 weeks. We report a case series of an accelerated TMS protocol for outpatient MDD treatment. METHODS: From July 2020 through January 2021, patients deemed appropriate candidates for TMS treatment were offered an accelerated TMS protocol consisting of intermittent theta burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex, localized by the Beam F3 method, and consisting of 5 treatments daily for 5 days. Assessment scales were obtained as part of standard clinical care. RESULTS: A total of 19 veterans received the accelerated protocol and 17 completed treatment. Statistically significant mean reductions from baseline to end of treatment were observed across all assessment scales. Remission and response rates, as defined by changes in Montgomery-Åsberg Depression Rating Scale scores, were 47.1% and 64.7%, respectively. Treatments were well tolerated without unexpected or serious adverse events. CONCLUSIONS: This case series details the safety and efficacy of an accelerated iTBS TMS protocol consisting of 25 treatments over 5 days. Improved depressive symptoms were observed, with remission and response rates similar to standard TMS protocols of daily TMS for ≥6 weeks.

Atomoxetine in comorbid ADHD/PTSD: A randomized, placebo controlled, pilot, and feasibility study.

BACKGROUND: PTSD and ADHD often occur comorbidly. Research indicates that the cognitive deficits in PTSD may be related to the same disturbance of fronto-temporal systems as observed in ADHD, and ADHD has been shown to impact PTSD treatment outcomes. The presented study evaluated the safety and efficacy of atomoxetine in Veterans with comorbid ADHD/PTSD. METHODS: A double blind, randomized, placebo controlled, cross-over pilot and feasibility study was conducted. Atomoxetine was examined as an adjunctive treatment over this 10 weeks, two phase, crossover study which compared treatment with atomoxetine 80 mg daily to placebo daily. The primary outcome was improvement in ADHD symptoms as measured by the Conners' Adult ADHD Rating Scales-Self-Report: Short Version (CAARS-S:S), the Barkley Adult ADHD Rating Scale-IV (BAARS-IV), and the Adult ADHD Quality of Life-29 (AAQoL-29). Secondary outcomes included the Clinician Administered PTSD Scale (CAPS), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the response inhibition task Go/NoGo (GNG). RESULTS: Atomoxetine treated patients had greater reductions in ADHD symptoms as defined by total scores on the CAARS-S:S (F(1, 29) = 6.37, p = .017); both the BAARS-IV (F(1, 26) = 3.16, p = .087); and GNG overall errors test (F(1, 29) = 3.88, p = .06), reached a trend level of significance. No significant differences were noted in quality of life assessments, GNG latency periods, or CAPS scores. Atomoxetine was well-tolerated with no serious adverse events observed. CONCLUSIONS: In Veterans with ADHD comorbid with PTSD, atomoxetine demonstrated modest efficacy for ADHD symptoms; quality of life measures and PTSD symptoms were not affected.

Dopamine transporter (DAT1) gene in combat veterans with PTSD: A case-control study.

The dopamine transporter (DAT1) gene has been postulated to be involved in PTSD; however, existing studies have shown inconsistencies when examining genotypic and allelic associations. The primary objective of this study was to examine whether DAT1-40bp-VNTR (DAT1) 9R polymorphism might increase the risk of PTSD development in combat veterans, utilizing a case-control gene association study with both control and PTSD cases having previous exposure to combat traumas. Participants with PTSD (N = 365) and combat-exposed controls without PTSD (N = 298) were included in analysis. After controlling for race, sex and age, when dichotomized, absence of DAT1 10R/10R genotypes was associated with PTSD diagnosis compared to no PTSD diagnosis; these results were not statistically significant when trichotomized 10R/10R, 10R/X, 9R/9R. Similarly, odds ratio for absence of 10R/10R genotype showed a statistically significant increase in the risk of developing PTSD. DAT1 genotype was also associated with statistically significant mean total CAPS scores, both when dichotomized and trichotomized. In conclusion, our results indicate that the absence of 10R/10R is associated with an increased risk of PTSD and higher CAPS total scores.

Clozapine utilization at the United States Veterans Health Administration: a descriptive report of prescribing patterns and patient characteristics among Operation Enduring Freedom/Operation Iraqi Freedom Veterans.

To identify the clozapine utilization rate at Veterans Health Administration, as well as patient characteristics, and correlates of use to garner a better understanding of the Veterans Health Administration-treated clozapine population. A longitudinal retrospective cohort analysis was conducted on all Operation Enduring Freedom/Operation Iraqi Freedom Veterans treated with clozapine prescriptions through Veterans Health Administration from 2006 to 2016. Descriptive and inferential analyses were conducted. The sample of 1.3 million veterans had 15 416 with schizophrenia-spectrum disorders, however; only 197 filled outpatient clozapine prescriptions through Veterans Health Administration, a clozapine utilization rate of 1.28%. Median days on clozapine were 305. Median number of antipsychotic medications was 12, with a median rank of clozapine being the eighth antipsychotic trialed. 59.90% of individuals had at least one period of maintenance clozapine treatment. The median number of psychiatric hospitalizations was four, and Clozapine rank was strongly associated with number of hospitalizations. There were no associations between acute versus maintenance clozapine use and either hospitalizations or mortality. Clozapine utilization was very low relative to recommended prescribing rates. Delayed initiation of clozapine was noted and was associated with increased number of hospitalizations. Lack of observed differences in mortality may be explained by low number of mortalities.

Ziprasidone Augmentation of SSRI Antidepressants in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Pilot Study of Augmentation Therapy.

BACKGROUND: Posttraumatic stress disorder (PTSD) is often a chronic, disabling illness for which antidepressant medications (ie, SSRI) are considered the primary psychopharmacological treatment. However, many patients remain refractory to antidepressants alone or in combination with psychotherapy. Safe and effective treatments for individuals with refractory PTSD are needed. This study aimed to examine ziprasidone augmentation of SSRI treatment of PTSD. METHODS: This was a 2-phase study. In phase 1, subjects were treated with paroxetine or sertraline for 8 weeks. Individuals refractory to the SSRI treatment then entered into phase II of the study and were randomized, in a double-blind fashion, to 8 weeks of treatment with either ziprasidone or placebo. The primary outcome measure was change in Clinician Administered PTSD Scale total scores with the intent-to-treat sample. Secondary outcome measures included Positive and Negative Syndrome Scale scores, measures of depression and anxiety, and safety measures. RESULTS: No significant differences were observed on the Clinician Administered PTSD Scale, Positive and Negative Syndrome Scale, or other outcome measures between ziprasidone and placebo groups. No significant differences were observed for safety measures including metabolic profiles, extrapyramidal symptoms/movement disorder rating scales, nor study dropout. CONCLUSIONS: Although no significant differences were noted in efficacy or safety measures between ziprasidone and placebo in this pilot study, the small sample size prevents definitive conclusions.

Serotonin Toxicity and Urinary Analgesics: A Case Report and Systematic Literature Review of Methylene Blue-Induced Serotonin Syndrome.

BACKGROUND: Serotonin syndrome (SS) is a potentially serious side effect of serotonergic drugs. Cases of SS have been reported from the administration of methylene blue (MB), an agent with monoamine oxidase inhibiting properties. To date, the reported cases of MB-induced SS have all been with MB given parenterally. We report a case induced by the initiation of a MB-containing oral agent. METHODS: A case of SS felt to be induced by the initiation of an MB-containing orally-administered urinary analgesic, started in a patient concurrently treated with multiple serotonergic drugs, is presented. A systematic literature review of MB-induced SS follows. The review consisted of searches in MEDLINE databases using the key terms "methylene blue" and "serotonin syndrome". The authors read all abstracts, and articles related to MB and serotonin toxicity; non-associated articles were discarded. Results are summarized. RESULTS: 23 manuscripts were identified, resulting in 50 unique cases of MB-induced SS. The majority of cases were related to peri-operative use of MB in parathyroidectomies or for the treatment of vasoplegic shock. All cases were associated with MB given parenterally. Concurrent treatment with serotonergic antidepressants was described in all 50 cases. Symptoms of SS ranged from mild to severe. One fatality was reported. CONCLUSIONS: Methylene blue can induce SS, felt to be secondary to MAOI properties. Although previous reports have exclusively been associated with MB given via parental administration, our case suggests that SS can be induced by oral administration of MB-containing agents.

Predictors of Lifetime Suicide Attempts in Individuals With Attenuated Psychosis Syndrome.

BACKGROUND: A strong association has been shown to exist between schizophrenia and suicide; however, research examining suicidality in the prodromal phase of psychotic disorders is limited. This study aimed to meet this need by examining potential risk factors for lifetime suicide attempts in a population of individuals with attenuated psychosis syndrome (APS), as defined in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders as a condition for further study. METHODS: A retrospective chart review was conducted to identify individuals with APS during a 5-year period across a large medical university's inpatient and outpatient settings. Sociodemographic and clinical factors were examined in relation to suicide attempts to identify risk factors for suicide attempts. χ analyses were used to analyze dichotomous variables, and t test analyses were used to compare means of continuous predictors among those with versus without suicide attempts. Final analyses consisted of fitting multivariate logistic regression models to control for sociodemographic factors. RESULTS: In total, 26.3% of the APS population had at least 1 lifetime suicide attempt. Six covariates were found to be statistically significant predictors of suicide attempts: Axis II disorders (P=0.006); history of trauma as a whole (P=0.022); the subcategory of sexual trauma (P=0.005); tobacco use (P=0.039); family history of nonpsychotic Axis I disorders (P=0.042); and number of hospitalizations (P=0.001). CONCLUSIONS: Suicidality is a prominent feature of APS, and a number of risk factors increase the likelihood of suicide attempts in this population.

Pyrotherapy for the Treatment of Psychosis in the 21st Century: A Case Report and Literature Review.

The concept that fevers can improve the condition of patients with certain medical and psychiatric diseases dates back to Hippocrates. Over the centuries, it has been observed that fevers and infectious agents have been beneficial for a broad spectrum of diseases, including neurologic conditions such as epilepsy and psychiatric illnesses including melancholy and psychosis. Interest in the concept of fever as a treatment for disease, termed pyrotherapy or pyretotherapy, peaked in the late 1800s and early 1900s thanks to the Nobel Prize winning work of Julius Wagner-Jauregg for his studies with malaria therapy for general paralysis of the insane, now more commonly referred to as neurosyphilis. The use of inoculations of infectious agents for their fever-inducing effects in the treatment of neurosyphilis quickly spread throughout the world, and, by the 1920s, it was considered by many to be the treatment of choice for neurosyphilis as well as other psychotic disorders. However, with the discovery of penicillin for the treatment of syphilis, which coincided with the advent of convulsion-oriented practices including electroconvulsive therapy and insulin coma for the treatment of psychotic disorders, pyrotherapy soon lost favor among psychiatrists and, since the 1950s, it has largely been overlooked by the scientific community. In this article, the authors provide a brief literature review of the history of pyrotherapy and present a case report of a woman with schizoaffective disorder and severe psychotic symptoms who experienced a remarkable resolution of psychotic symptoms following an episode of bacteremia with high fever.

Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: an open label pilot study.

Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N = 10, Mean age = 44 ± 16.4 SD, 6F) with unipolar depression. In addition to standard of care, they received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation (33-36 h), followed by a three-night sleep phase advance along with four 30-min sessions of bright light therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded at baseline prior to total sleep deprivation, and at protocol completion on day five. Both HAM17, and CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean of 24.7 ± 4.2 SD at baseline to a mean of 9.4 ± 7.3 SD on day five (p = .002) with six of the ten individuals meeting criteria for remission. CSSRS scores dropped from a mean of 19.5 ± 8.5 SD at baseline to a mean of 7.2 ± 5.5 SD on day five (p = .01). The results of this small pilot trial demonstrate that adjunctive Triple Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a small number of participants, an open label design, and the lack of a comparison group. Randomized controlled studies are needed.