Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016.

There are currently no validated pharmacotherapies for posttraumatic stress disorder (PTSD)-related insomnia. The purpose of the National Adaptive Trial for PTSD-Related Insomnia (NAP Study) is to efficiently compare to placebo the effects of three insomnia medications with different mechanisms of action that are already prescribed widely to veterans diagnosed with PTSD within U.S. Department of Veterans Affairs (VA) Medical Centers. This study plans to enroll 1224 patients from 34 VA Medical Centers into a 12- week prospective, randomized placebo-controlled clinical trial comparing trazodone, eszopiclone, and gabapentin. The primary outcome measure is insomnia, assessed with the Insomnia Severity Index. A novel aspect of this study is its adaptive design. At the recruitment midpoint, an interim analysis will be conducted to inform a decision to close recruitment to any "futile" arms (i.e. arms where further recruitment is very unlikely to yield a significant result) while maintaining the overall study recruitment target. This step could result in the enrichment of the remaining study arms, enhancing statistical power for the remaining comparisons to placebo. This study will also explore clinical, actigraphic, and biochemical predictors of treatment response that may guide future biomarker development. Lastly, due to the COVID-19 pandemic, this study will allow the consenting process and follow-up visits to be conducted via video or phone contact if in-person meetings are not possible. Overall, this study aims to identify at least one effective pharmacotherapy for PTSD-related insomnia, and, perhaps, to generate definitive negative data to reduce the use of ineffective insomnia medications. NATIONAL CLINICAL TRIAL (NCT) IDENTIFIED NUMBER: NCT03668041.

Investigating components of pranayama for effects on heart rate variability.

OBJECTIVE: Traditional Indian breath control practices of Pranayama have been shown to increase indices of heart rate variability (HRV) that are generally held to reflect parasympathetic nervous system (PNS) tone. To our knowledge, individual components of pranayama have not been separately evaluated for impact on HRV. The objective of this study was to isolate five components of a pranayama practice and evaluate their impact on HRV. METHODS: In a crossover clinical trial, 46 healthy adults were allocated to complete five activities in random order, over five separate visits: 1) sitting quietly; 2) self-paced deep breathing; 3) externally-paced deep breathing; 4) self-paced Sheetali/Sheetkari pranayama; and 5) externally paced Sheetali/Sheetkari pranayama RESULTS: Our final sample included 25 participants. There was a significant increase in a time-domain index of HRV, the root mean square successive differences between RR intervals (RMSSD), during the five interventions. The change in logRMSSD ranged from 0.2 to 0.5 (p < .01 in all conditions by paired t-test). Greater increases were evident during externally-paced breathing than during self-paced breathing (mean pre-during logRMSSD change of 0.50 vs. 0.36, p = .02) or sitting quietly (mean, 0.17 ms; p = .005 and 0.02 when comparing Activities 3 and 5 to Activity 1 by random intercept model with Tukey correction for multiple comparisons). Lastly, pre-during increase in RMSSD was greater for Sheetali/Sheetkari vs. deep breathing, when controlling for respiration rate, though not significantly different (p = .07 in random intercept model) CONCLUSIONS: RMSSD increased with paced breathing, deep breathing, and Sheetali/Sheetkari pranayama, reinforcing evidence of a physiologic mechanism of pranayama. TRIAL REGISTRATION: NCT03280589 https://www.clinicaltrials.gov/ct2/show/NCT03280589?term=sheetali&draw=2&rank=1.

A Prospective Longitudinal Investigation of Cortical Thickness and Gyrification in Schizophrenia.

BACKGROUND: Cortical thickness (CT) and gyrification are complementary indices that assess different aspects of gray matter structural integrity. Both neurodevelopment insults and acute tissue response to antipsychotic medication could underlie the known heterogeneity of treatment response and are well-suited for interrogation into the relationship between gray matter morphometry and clinical outcomes in schizophrenia (SZ). METHODS: Using a prospective design, we enrolled 34 unmedicated patients with SZ and 23 healthy controls. Patients were scanned at baseline and after a 6-week trial with risperidone. CT and local gyrification index (LGI) values were quantified from structural MRI scans using FreeSurfer 5.3. RESULTS: We found reduced CT and LGI in patients compared to controls. Vertex-wise analyses demonstrated that hypogyrification was most prominent in the inferior frontal cortex, temporal cortex, insula, pre/postcentral gyri, temporoparietal junction, and the supramarginal gyrus. Baseline CT was predictive of subsequent response to antipsychotic treatment, and increase in CT after 6 weeks was correlated with greater symptom reductions. CONCLUSIONS: In summary, we report evidence of reduced CT and LGI in unmedicated patients compared to controls, suggesting involvement of different aspects of gray matter morphometry in the pathophysiology of SZ. Importantly, we found that lower CT at baseline and greater increase of CT following 6 weeks of treatment with risperidone were associated with better clinical response. Our results suggest that cortical thinning may normalize as a result of a good response to antipsychotic medication, possibly by alleviating potential neurotoxic processes underlying gray matter deterioration.

A longitudinal magnetic resonance spectroscopy study investigating effects of risperidone in the anterior cingulate cortex and hippocampus in schizophrenia.

Magnetic Resonance Spectroscopy is a popular approach to probe brain chemistry in schizophrenia (SZ), but no consensus exists as to the extent of alterations. This may be attributable to differential effects of populations studied, brain regions examined, or antipsychotic medication effects. Here, we measured neurometabolites in the anterior cingulate cortex (ACC) and hippocampus, two structurally dissimilar brain regions implicated in the SZ pathophysiology. We enrolled 61 SZ with the goal to scan them before and after six weeks of treatment with risperidone. We also scanned 31 matched healthy controls twice, six weeks apart. Using mixed effect repeated measures linear models to examine the effect of group and time on metabolite levels in each voxel, we report an increase in hippocampal glutamate + glutamine (Glx) in SZ compared to controls (p = 0.043), but no effect of antipsychotic medication (p = 0.330). In the ACC, we did not find metabolite alterations or antipsychotic medication related changes after six weeks of treatment with risperidone. The coefficients for the discriminant function (differentiating SZ from HC) in the ACC were greatest for NAA (-0.83), and in the hippocampus for Glx (0.76), the same metabolites were associated with greater treatment response in patients at trend level. Taken together, our data extends the existing literature by demonstrating regionally distinct metabolite alterations in the same patient group and suggests that antipsychotic medications may have limited effects on metabolite levels in these regions.

Sleep correlates of cognition in early course psychotic disorders.

BACKGROUND: Slow waves and sleep spindles, the main oscillations during non-rapid eye movement sleep, have been thought to be related to cognitive processes, and are impaired in psychotic disorders. Cognitive impairments, seen early in the course of psychotic disorders, may be related to alterations in these oscillations, but few studies have examined this relationship. METHOD: Twenty seven untreated patients with a recently diagnosed psychotic disorder had polysomnographic sleep studies and neuro-cognitive testing. RESULTS: Reduced power in the sigma range, which reflects spindle density, was associated with impaired attention, and reasoning, but not intelligence quotient (IQ). Slow wave sleep measures were not significantly associated with any cognitive measures. CONCLUSIONS: Impairments in sleep spindles may be associated with cognitive deficits in the early course of psychotic disorders. These observations may help clarify neuro-biologic mechanisms of cognitive deficits in psychotic disorders such as schizophrenia.

Decreased BDNF in patients with antipsychotic naïve first episode schizophrenia.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls. METHOD: Fasting serum BDNF levels were measured in 41 patients with treatment naive first episode psychosis (24 with schizophrenia, schizoaffective disorder or schizophreniform disorder, and 17 with non-schizophrenia psychotic disorders) and 41 age-matched healthy controls. RESULTS: A three group analyses of covariance (ANCOVA) showed a diagnosis effect (p=.038) in which patients with schizophrenia had lesser serum BDNF levels than patient with non-schizophrenia psychosis, who in turn had lesser BDNF levels than matched healthy controls. Planned two-group ANCOVAs suggested that patients with schizophrenia had lower serum BDNF level than matched controls (p=.016), whereas patients with non-schizophrenia psychosis did not differ from controls. There were no age effects on BDNF, but there was a trend (p=.08) for a gender by group interaction with greater reductions in female patients with schizophrenia. The BDNF levels did not correlate with magnitude of smoking, body mass index, severity of positive and negative symptoms or overall functioning. CONCLUSIONS: Serum BDNF may be reduced at the onset of psychosis but its role in the pathogenesis of schizophrenia remains unclear. Elucidating the role of BDNF in schizophrenia and related psychotic disorders may provide an important therapeutic target. Further studies are also needed to examine if patients with schizophrenia have more pronounced reductions in BDNF than those with affective psychosis.

Beat-to-beat heart rate and QT interval variability in first episode neuroleptic-naive psychosis.

INTRODUCTION: Though increased risk of sudden death in patients with schizophrenia is well-documented, the mechanisms remain unclear. Recent studies report two known risk factors for sudden cardiac death and other arrhythmias in schizophrenia, i.e., decreased RR interval variability (RRV) and increased QT interval variability (QTV). However, these studies did not control for the effects of medication. Herein, we report the results of our study comparing RRV and QTV in first episode neuroleptic-naive psychosis patients with healthy matched controls. METHODS: 24 patients with first episode neuroleptic naïve psychosis were matched with 26 healthy controls on age and gender. After an overnight fast, all participants underwent an electrocardiogram recording in the morning. RESULTS: In comparison with matched controls, patients with first episode neuroleptic-naïve psychosis had significantly increased QTV corrected for RRV, and decreased RRV. CONCLUSIONS: The observed alterations in RRV and QTV may reflect impaired cardiac autonomic function that could underlie risk for abnormal ventricular repolarization and thereby increase the risk of sudden death and other arrhythmias. Our data suggest that RRV and QTV alterations may be independent of medication effects in first episode psychosis patients.

Insomnia in patients with depression: some pathophysiological and treatment considerations.

The almost ubiquitous sleep disturbances in patients with depression commonly, but not always, subside with the remission of depression. Evidence linking insomnia with the risk of relapses in recurrent depression, as well as suicide, makes optimization of the treatment of insomnia associated with depression a priority. However, most antidepressant agents do not adequately address the sleep complaints in depression: their effects on sleep range from sizeable improvement to equally significant worsening. One approach to the management of insomnia associated with depression is to choose a sedating antidepressant agent such as trazodone, mirtazapine or agomelatine. A second approach is to start with a non-sedating antidepressant (e.g. the selective serotonin reuptake inhibitors, bupropion, venlafaxine or duloxetine); those with a persistent or treatment-emergent insomnia can be switched to a more sedating antidepressant, or offered a hypnotic or cognitive-behavioural therapy as adjunctive treatment. The review discusses the advantages and disadvantages of all treatment options, pharmacological and otherwise.