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.

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.

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.

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.

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.

Classifying antipsychotic agents : need for new terminology.

Converging data from multiple lines of research provide growing understanding of the pharmacological basis of the efficacy and tolerability of antipsychotic agents. This review highlights some of the drawbacks of the current practice of classifying antipsychotic agents into first- and second-generation agents, and argues that much of what is known about an antipsychotic agent in terms of its efficacy and tolerability can be predicted from its binding affinity at different receptors. This makes a case for a new system of classification that reflects the receptor binding affinity profiles of individual antipsychotic agents. In its quest to make a compelling case, the review provides detailed explanations for the pharmacological basis of antipsychotic efficacy, antipsychotic-induced weight gain and diabetes mellitus, cognitive effects and other adverse effects.

Heart rate variability in depressed elderly.

OBJECTIVE: The present study examines a measure of cardiac autonomic function, the heart rate variability (HRV), in a group of depressed elderly. Cardiac autonomic abnormalities have been implicated as a potential mediator of cardiovascular events and sudden death in depression. Because aging is associated with decreased cardiac vagal activity, it is possible that autonomic abnormalities are even more pronounced in the older depressed patients. DESIGN: Cross-sectional comparison between those with or without depression. The groups were compared using the Wilcoxon matched-pair sign-rank test. SETTING: Advanced Center for Interventions and Services Research for Late-Life Mood Disorders at University of Pittsburgh Medical Center. PARTICIPANTS: Fifty-three patients with major depression (mean age: 73.3; SD: 7.4; range: 60-93) and an equal number of age and gender-matched subjects as a comparison group. INTERVENTION: None. MEASUREMENTS: Time domain and frequency domain measures of HRV. RESULTS: The groups did not differ in any of the time domain or frequency domain measures of HRV. As expected, subjects without depression displayed decreasing cardiac vagal function with aging (Spearman correlation coefficient r(s) = -0.33, p = 0.02). However, there was no significant change in vagal function with age in the depressed (r = 0.12, p= 0.38). Post-hoc analysis using Fisher's z(r) transformation revealed that the relationship between age and cardiac vagal function was significantly different between the groups (z = 2.32, p = 0.02). CONCLUSIONS: Our findings suggest that age has differential influence on vagal function in individuals with and without depression, a difference with implications for cardiovascular disease risk in depression. Prospective studies of cardiac vagal activity in depressed patients with or without preexisting cardiac disease in different age groups are needed to replicate and extend these findings.

Electroencephalographic sleep profiles in single-episode and recurrent unipolar forms of major depression: II. Comparison during remission.

BACKGROUND: Previous studies indicate that recurrent forms of depression are associated with greater biological disturbances as compared to single-episode cases. This study examines whether the observed differences in the sleep patterns during recurrent and single-episode depression persist into remission following nonpharmacologic treatment. METHODS: Two groups of patients (27 single episode [SE] and 53 recurrent unipolar [RU]) with major depression underwent sleep studies before and after nonpharmacologic treatment. Groups were equated for age, severity, and proportion of men and women. Groups were compared using multivariate analyses of covariance and/or analyses of covariance to examine six sets of sleep measures. RESULTS: The differences observed between the SE and RU groups during the index episode persisted into early remission. The findings of greater disturbances of sleep continuity, rapid eye movement sleep and diminished slow wave sleep in the RU group supports the hypothesis that recurrent depression is associated with a more severe neurophysiological substrate than clinically comparable SE cases. CONCLUSIONS: Although these observations are consistent with an illness progression model, the possibility that recurrent affective illness is associated with a more virulent, stable phenotype cannot be ruled out. Resolution of this issue requires longitudinal and family studies.

Maintenance treatment of insomnia: what can we learn from the depression literature?

Insomnia and depression are common problems with profound public health consequences. When left untreated, both conditions have high rates of persistence and recurrence. Maintenance treatment for depression is fairly well established, but there is no evidence-based consensus regarding the safety and efficacy of maintenance therapy for insomnia. Consequently, long-term treatment of insomnia is driven primarily by the individual choices of patients and their clinicians. This article compares and contrasts the current state of research in the maintenance therapy of depression and insomnia and highlights gaps in the insomnia literature.

Treatment of insomnia associated with clinical depression.

Sleep disturbances are almost always present in patients with depression. Though sleep disturbances generally abate with the resolution of depression, some patients continue to report poor sleep. Since a number of studies have demonstrated that insomnia increases the risk of new-onset depression and recurrence of depression, optimal management of insomnia associated with depression becomes an important clinical goal. Antidepressant agents have variable effects on sleep and in fact, some antidepressants seem to worsen sleep in patients with depression. This article reviews various treatment options in the management of patients presenting with insomnia and depression, including single agents, combination strategies and behavioral interventions.

Integrating psychotherapy and pharmacotherapy to improve outcomes among patients with mood disorders.

A number of studies have demonstrated comparable benefits of psychosocial interventions and pharmacologic treatments in subgroups of patients with mood disorders. The two treatment modalities are often combined in clinical practice. However, concerns about the costs of health care are paramount. For the optimum but judicious use of resources, it is valuable for mental health professionals to know the indications for and evidence pertaining to the efficacy of combined treatment. The authors demonstrate that a reexamination of existing research data in light of the recent advances in understanding of the design of clinical trials reveals a systematic underestimation of the benefits of combined treatment for certain subgroups of patients. Existing studies of combined treatments need to be reexamined in light of information about design sensitivity, ceiling effects, and nonspecific placebo effects. The authors summarize by arguing for a new generation of adequately powered investigations of efficacy, which they believe is necessary before the issue of cost-effectiveness can be properly addressed.