Optimally combining transcranial magnetic stimulation with antidepressants in major depressive disorder: A systematic review and Meta-analysis.

There is a critical knowledge gap in optimally combining transcranial magnetic stimulation (TMS) and antidepressants to treat patients with major depressive disorder (MDD). TMS is effective in treating MDD in patients who have failed at least one antidepressant trial, with accelerated protocols showing faster remission in treatment-resistant depression (TRD). Although clinicians routinely augment antidepressants with TMS, there is a knowledge gap in stopping versus continuing antidepressants or the dosing strategies when starting or tapering TMS. These considerations are important when considering maintenance TMS (delivered alone or in combination with suitable antidepressants) to maintain remission in MDD after the index course of TMS. As the first step towards filling this knowledge gap, we reviewed randomized controlled trials (RCTs) and open-label trials from 2 databases (PubMed/Medline and EMBASE) that compared active TMS combined with a pre-specified antidepressant dosed in the same manner for adults with MDD versus sham TMS combined with the same antidepressant as in the active arm. All studies were published between January 1, 2000, and December 31, 2023. We excluded case reports, case series, and clinical studies that augmented TMS with antidepressants and vice versa. We found 10 RCTs (n = 654 participants) and performed a meta-analysis. This showed active TMS combined with pre-specified antidepressants had greater efficacy for MDD treatment than sham TMS combined with the same antidepressants as in the active arm (Hedge's g = 1; 95 % CI [0.27, 1.73]). The review and meta-analysis indicate greater short-term efficacy in combining antidepressants with TMS from the get-go in MDD. Given the increasing role of accelerated TMS protocols in expediting remission in MDD and the results of our meta-analysis, we advocate for RCTs examining the short-term and long-term effects of various antidepressant classes on these TMS protocols in MDD. This can also optimize and individualize maintenance TMS protocols to prevent relapse in MDD.

Intermittent theta burst stimulation and functional connectivity in people living with HIV/AIDS who smoke tobacco cigarettes: a preliminary pilot study.

Background: People living with HIV (PLWHA) smoke at three times the rate of the general population and respond poorly to cessation strategies. Previous studies examined repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (L. dlPFC) to reduce craving, but no studies have explored rTMS among PLWHA who smoke. The current pilot study compared the effects of active and sham intermittent theta-burst stimulation (iTBS) on resting state functional connectivity (rsFC), cigarette cue attentional bias, and cigarette craving in PLWHA who smoke. Methods: Eight PLWHA were recruited (single-blind, within-subject design) to receive one session of iTBS (n=8) over the L. dlPFC using neuronavigation and, four weeks later, sham iTBS (n=5). Cigarette craving and attentional bias assessments were completed before and after both iTBS and sham iTBS. rsFC was assessed before iTBS (baseline) and after iTBS and sham iTBS. Results: Compared to sham iTBS, iTBS enhanced rsFC between the L. dlPFC and bilateral medial prefrontal cortex and pons. iTBS also enhanced rsFC between the right insula and right occipital cortex compared to sham iTBS. iTBS also decreased cigarette craving and cigarette cue attentional bias. Conclusion: iTBS could potentially offer a therapeutic option for smoking cessation in PLWHA.

Treatment of Cognitive Deficits and Behavioral Symptoms Following COVID-19-Associated Autoimmune Encephalitis With Intravenous Immunoglobulin: A Case Report and Review of the Literature.

Coronavirus disease 2019 (COVID-19) is associated with long-term neuropsychiatric sequelae. We describe a 60-year-old male patient's history and symptom trajectory encompassing the development of behavioral symptoms and cognitive deficits following pneumonia and subsequent autoimmune encephalitis associated with COVID-19. We also describe changes in these facets with correlative changes in his immunological parameters after both acute intravenous immunoglobulin (IVIG) therapy and chronic periodic IVIG therapy every two weeks over the course of two years. ​​​​​​We review the literature on the treatment of long COVID-19 symptoms spanning cognitive and behavioral domains. In addition, we also elucidate current literature on the role of IVIG infusions for these symptoms using our patient's presentation and improvement in symptoms as an illustrative example.

Comparing cigarette-cue attentional bias between people with HIV/AIDS and people with opioid use disorder who smoke.

Background: Special populations like people living with HIV/AIDS (PLWHA) and people with opioid use disorder (OUD) smoke tobacco cigarettes at rates three to four times greater than the general population. Patients with tobacco use disorder exhibit attentional bias (AB) for cigarette cues. Eye tracking can quantify this bias by measuring fixation time (FT) on cigarette and matched neutral cues, to calculate an AB score. Although previous studies have measured this bias in people who smoke without any other comorbid conditions, no study, to our knowledge, has measured or compared this bias in special populations. Methods: We performed exploratory analyses on eye tracking data collected in two separate randomized clinical trials (RCTs) (NCT05049460, NCT05295953). We compared FT and cigarette-cue AB score (measured by subtracting FT on neutral cues from FT on cigarette cues) between PLWHA and people with OUD who smoke, using a visual probe task and Tobii Pro Fusion eye tracker. We used two cigarette cue types, one encompassing people smoking cigarettes and the other consisting of cigarette paraphernalia. We used two cue presentation times, 1000 and 2000 milliseconds (ms). Results: Cues of people smoking cigarettes elicited greater AB than cues of cigarette paraphernalia across both subject groups when cues were presented for 2000 ms, but not 1000 ms. PLWHA who smoke exhibited greater AB for cues of people smoking cigarettes than cigarette paraphernalia when presented for 2000 ms compared to people with OUD who smoke. Conclusion: We use cigarette-cue AB to quantify craving and cigarette consumption in two populations smoking at elevated rates. The addition of social cues potentiates cigarette cue AB, based on cue type and stimulus presentation time. Understanding the neurobiology of this relationship can help design novel smoking cessation treatments that target AB and prevent relapse in these populations with suboptimal response to smoking cessation treatments. Trial registration: Clinical trials that provided the data for post hoc analyses are NCT05049460 and NCT05295953.

Network Centrality and Modularity of Structural Covariance Networks in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study.

Introduction: Cortical thickness (CT) and surface area (SA) are established biomarkers of brain pathology in posttraumatic stress disorder (PTSD). Structural covariance networks (SCNs) are represented as graphs with brain regions as nodes and correlations between nodes as edges. Methods: We built SCNs for PTSD and control groups using 148 CT and SA measures that were harmonized for site in n = 3439 subjects from Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA)-Psychiatric Genomics Consortium (PGC) PTSD. We compared centrality between PTSD and controls as well as interactions of diagnostic group with age, sex, and comorbid major depressive disorder (MDD) status. We investigated associations between network modularity and diagnostic grouping. Results: Nodes with higher CT-based centrality in PTSD compared with controls included the left inferior frontal sulcus, left fusiform gyrus, left superior temporal gyrus, and right inferior temporal gyrus. Children (<10 years) and adolescents (10-21) with PTSD showed greater centrality in frontotemporal areas compared with young (22-39) and middle-aged adults (40-59) with PTSD, who showed higher centrality in occipital areas. The PTSD diagnostic group interactions with sex and comorbid MDD showed altered centrality in occipital regions, along with greater visual network (VN) modularity in PTSD subjects compared with controls. Conclusion: Structural covariance in PTSD is associated with centrality differences in occipital areas and VN modularity differences in a large well-powered sample. In the context of extensive structural covariance remodeling taking place before and during adolescence, the present findings suggest a process of cortical remodeling that commences with trauma and/or the onset of PTSD but may also predate these events. Impact statement Centrality is a graph theory measure that offers insights into a node's relationship with all other nodes in the brain. Centrality pinpoints the drivers of brain communication within networks and nodes and may be a promising target for treatments such as neuromodulation. Modularity can pinpoint modules that exist within larger networks and quantify the connections between these modules. Centrality and modularity complement functional and structural connectivity measurements within specific brain networks.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Emotion Processing Deficit in Euthymic Bipolar Disorder: A Potential Endophenotype.

Background: Emotion processing deficits have been described in patients with bipolar disorder (BD) and are considered one of the core cognitive abnormalities in BD with endophenotype potential. However, the literature on specific impairments in emotion processing cognitive strategies (directive/cortical/higher versus intuitive/limbic/lower) in euthymic adult BD patients and healthy first-degree relatives/high-risk (HR) subjects in comparison with healthy controls (HCs) is sparse. Methods: We examined facial emotion recognition deficits (FERD) in BD (N = 30), HR (N = 21), and HC (N = 30) matched for age (years), years of education, and sex using computer-administered face emotions-Matching And Labeling Task (eMALT). Results: The three groups were significantly different based on labeling accuracy scores for fear and anger (FA) (P < 0.001) and sad and disgust (SD) (P < 0.001). On post-hoc analysis, HR subjects exhibited a significant deficit in the labeling accuracy of FA facial emotions (P < 0.001) compared to HC. The BD group was found to have significant differences in all FA (P = 0.004) and SD (P = 0.003) emotion matching as well as FA (P = 0.001) and SD (P < 0.001) emotion labeling accuracy scores. Conclusions: BD in remission exhibits FERD in general, whereas specific labeling deficits of fear and anger emotions, indicating impaired directive higher order aspect of emotion processing, were demonstrated in HR subjects. This appears to be a potential endophenotype. These deficits could underlie the pathogenesis in BD, with possible frontolimbic circuitry impairment. They may have potential implications in functional recovery and prognosis of BD.

The role of trauma, social support, and demography on veteran resilience.

Background: Historically, resilience has often been conceptualized as the sustained lack of symptoms following trauma exposure. In line with a novel conceptualization of resilience as being dynamic over lifespan, determined by interacting biological and environmental factors, we examined the VA Mid-Atlantic Post Deployment Mental Health Repository (PDMH) comprised of 3876 US Military Veterans with and without PTSD diagnoses. Methods: We performed regression modelling to study the relationship between resilience (measured with Connor Davidson Resilience Scale; CD-RISC), posttraumatic stress disorder (PTSD) severity (Davidson Trauma Scale; DTS), social support (Medical Outcome Study Social Support Survey; MOSSS), combat exposure (Combat Exposure Scale; CES), childhood trauma (Trauma Life Events Questionnaire; TLEQ), and demographic factors. CD-RISC was positively correlated with years of education and negatively correlated with DTS, CES and TLEQ scores. Results: We found an interaction between CD-RISC and CES in predicting PTSD severity (Davidson Trauma Scale). Specifically, high resilience predicted lower PTSD symptom severity than low resilience, this relationship was amplified with increasing levels of combat exposure. Structural equation modelling (SEM) identified an optimal latent variable that represents resilience and relationships between latent variables for resilience, trauma, and illness. We derived a resilience latent variable composed of age, education level, MOSSS and race. Conclusions: Our results support a conceptualization of resilience as a multifactorial determinant that coexists with PTSD, a state rather than trait variable, and can be quantified by biological and behavioural metrics. HIGHLIGHTS: • Historically, resilience has often been conceptualized as the sustained lack of symptoms following trauma exposure.• We examined the VA Mid-Atlantic Post Deployment Mental Health Repository (PDMH) comprised of 3876 US Military Veterans.• We found an interaction effect between CD-RISC and CES in predicting PTSD severity (Davidson Trauma Scale).

Antecedentes: Históricamente, la resiliencia a menudo se ha conceptualizado como la ausencia sostenida de síntomas después de la exposición al trauma. En línea con una novedosa conceptualización de la resiliencia como un fenómeno dinámico a lo largo de la vida, determinada por la interacción de factores biológicos y ambientales, examinamos el Repositorio de salud mental post-despliegue VA Mid-Atlantic (PDMH por sus siglas en ingles) compuesto por 3.876 veteranos militares de EE.UU. con y sin diagnósticos de TEPT.Métodos: Realizamos modelos de regresión para estudiar la relación entre resiliencia (medida con la Escala de resiliencia de Connor Davidson; CD-RISC por sus siglas en ingles), gravedad del trastorno de estrés postraumático (TEPT) (con Escala de Trauma de Davidson; DTS por sus siglas en ingles), apoyo social (Encuesta de Estudio de Resultados Médicos - Apoyo Social; MOSSS por sus siglas en ingles), exposición al combate (Escala de exposición al combate; CES por sus siglas en ingles), trauma infantil (Cuestionario de Eventos de vida traumáticos; TLEQ por sus siglas en ingles), y factores demográficos. CD-RISC se correlacionó positivamente con años de educación y se correlacionó negativamente con los puntajes de DTS, CES y TLEQ.Resultados: Encontramos una interacción entre CD-RISC y CES en la predicción de la gravedad del TEPT (Escala de trauma de Davidson). Específicamente, una alta resiliencia predijo menor gravedad de los síntomas de TEPT que una baja resiliencia, esta relación fue amplificada con niveles crecientes de exposición al combate. El modelo de ecuaciones estructurales (SEM por sus siglas en ingles) identificó una variable latente óptima que representa la resiliencia y las relaciones entre las variables latentes de resiliencia, trauma y enfermedad. Derivamos una variable latente de resiliencia compuesta por edad, nivel educativo, MOSSS y raza.Conclusiones: Nuestros resultados apoyan una conceptualización de la resiliencia como un determinante multifactorial que coexiste con el TEPT, una variable de estado más que de rasgo, y puede ser cuantificada con mediciones biológicas y conductuales.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium.

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Pharmacological agents to treat severe neuropsychiatric symptoms in major neurocognitive disorders.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are challenging to recognize and treat effectively. Despite very effective nonpharmacologic strategies, there are cases where severe BPSD may require biological intervention. The purpose of this review was to clarify safe and evidence-based use of pharmacological agents based on available clinical trial evidence. METHODS: A structured search strategy was used in PubMed, Embase, and PsycInfo to obtain the most relevant data regarding treatment of BPSD in patients with any-cause dementia. RESULTS: We screened 1,442 English-language abstracts. Following initial screening, we had 184 unique references to review. A secondary search of these and review articles gave a total of 117 to tabulate and discuss. We categorized the results based on the following classifications: antidepressants, first-generation antipsychotics, second-generation antipsychotics, anticonvulsants/mood stabilizers, sedatives, stimulants, steroid therapies, other medications, other medication strategies, and medication withdrawal. CONCLUSIONS: The judicious use of pharmacotherapy does seem to be appropriate in select cases where behavioral and psychological interventions have been partially effective or where symptoms confer imminent risk of harm.

Pharmacogenomic Testing in Psychiatry: Ready for Primetime?

Pharmacogenomic testing in clinical psychiatry has grown at an accelerated pace in the last few years and is poised to grow even further. Despite robust evidence lacking regarding efficacy in clinical use, there continues to be growing interest to use it to make treatment decisions. We intend this article to be a primer for a clinician wishing to understand the biological bases, evidence for benefits, and pitfalls in clinical decision-making. Using clinical vignettes, we elucidate these headings in addition to providing a perspective on current relevance, what can be communicated to patients, and future research directions. Overall, the evidence for pharmacogenomic testing in psychiatry demonstrates strong analytical validity, modest clinical validity, and virtually no evidence to support clinical use. There is definitely a need for more double-blinded randomized controlled trials to assess the use of pharmacogenomic testing in clinical decision-making and care, and until this is done, they could perhaps have an adjunct role in clinical decision-making but minimal use in leading the initial treatment plan.

Resilience as a translational endpoint in the treatment of PTSD.

Resilience is a neurobiological entity that shapes an individual's response to trauma. Resilience has been implicated as the principal mediator in the development of mental illness following exposure to trauma. Although animal models have traditionally defined resilience as molecular and behavioral changes in stress responsive circuits following trauma, this concept needs to be further clarified for both research and clinical use. Here, we analyze the construct of resilience from a translational perspective and review optimal measurement methods and models. We also seek to distinguish between resilience, stress vulnerability, and posttraumatic growth. We propose that resilience can be quantified as a multifactorial determinant of physiological parameters, epigenetic modulators, and neurobiological candidate markers. This multifactorial definition can determine PTSD risk before and after trauma exposure. From this perspective, we propose the use of an 'R Factor' analogous to Spearman's g factor for intelligence to denote these multifactorial determinants. In addition, we also propose a novel concept called 'resilience reserve', analogous to Stern's cognitive reserve, to summarize the sum total of physiological processes that protect and compensate for the effect of trauma. We propose the development and application of challenge tasks to measure 'resilience reserve' and guide the assessment and monitoring of 'R Factor' as a biomarker for PTSD.

Translational bioinformatics in mental health: open access data sources and computational biomarker discovery.

Mental illness is increasingly recognized as both a significant cost to society and a significant area of opportunity for biological breakthrough. As -omics and imaging technologies enable researchers to probe molecular and physiological underpinnings of multiple diseases, opportunities arise to explore the biological basis for behavioral health and disease. From individual investigators to large international consortia, researchers have generated rich data sets in the area of mental health, including genomic, transcriptomic, metabolomic, proteomic, clinical and imaging resources. General data repositories such as the Gene Expression Omnibus (GEO) and Database of Genotypes and Phenotypes (dbGaP) and mental health (MH)-specific initiatives, such as the Psychiatric Genomics Consortium, MH Research Network and PsychENCODE represent a wealth of information yet to be gleaned. At the same time, novel approaches to integrate and analyze data sets are enabling important discoveries in the area of mental and behavioral health. This review will discuss and catalog into an organizing framework the increasingly diverse set of MH data resources available, using schizophrenia as a focus area, and will describe novel and integrative approaches to molecular biomarker discovery that make use of mental health data.

Maintenance ECT in schizophrenia: A systematic review.

Relapse after discontinuation of ECT is significant in patients with schizophrenia. The purpose of this systematic review was to examine use of M-ECT in schizophrenia to guide clinical decision making for relapse prevention in schizophrenia. We reviewed studies examining the role of continuation (C-ECT) and maintenance electroconvulsive therapy (M-ECT) in schizophrenia. Following PRISMA guidelines, we included randomized controlled trials, open label trials, retrospective chart reviews, case reports, and case series in this review. We evaluated adjunctive pharmacological regimens; ECT treatment parameters, including frequency, duration of continued treatment, electrode placement; clinical outcomes including cognitive side effects and relapse rates from included studies. Our findings suggest M-ECT could provide an effective form of relapse prevention in these patients and persistent cognitive side effects are minimal.

Strategies for dementia prevention: latest evidence and implications.

Dementia is a common and debilitating syndrome with enormous impact on individuals and societies. Preventing disease onset or progression would translate to public health and societal benefits. In this review, we discuss the latest evidence on interventions that may show promise for the prevention of cognitive decline. We appraise existing evidence primarily drawn from randomized controlled trials, systematic reviews, and meta-analyses, but also highlight observational studies in humans and relevant work in model organisms. Overall, there is currently limited evidence to support a cause-effect relationship between any preventive strategy and the development or progression of dementia. However, studies to date suggest that a multifactorial intervention comprising regular exercise and healthy diet, along with the amelioration of vascular risk factors, psychosocial stress, and major depressive episodes may be most promising for the prevention of cognitive decline. We discuss the challenges, future directions, and implications of this line of research.

A positron emission tomography study of the serotonergic system in relation to anxiety in depression.

Symptoms of anxiety are highly comorbid with major depressive disorder (MDD) and are known to alter the course of the disease. To help elucidate the biological underpinnings of these prevalent disorders, we previously examined the relationship between components of anxiety (somatic, psychic and motoric) and serotonin 1A receptor (5-HT1A) binding in MDD and found that higher psychic and lower somatic anxiety was associated with greater 5-HT1A binding. In this work, we sought to examine the correlation between these anxiety symptom dimensions and 5-HTT binding. Positron emission tomography with [11C]-3-amino-4-(3-dimethylamino-methylphenylsulfanyl)-benzonitrile ([11C]DASB) and a metabolite-corrected arterial input function were used to estimate regional 5-HTT binding in 55 subjects with MDD and anxiety symptoms. Somatic anxiety was negatively correlated with 5-HTT binding in the thalamus (ß=-.33, p=.025), amygdala (ß=-.31, p=.007) and midbrain (ß=-.72, p<.001). Psychic anxiety was positively correlated with 5-HTT binding in midbrain only (ß=.46, p=.0025). To relate to our previous study, correlation between 5-HT1A and 5-HTT binding was examined, and none was found. We also examined how much of the variance in anxiety symptom dimensions could be explained by both 5-HTT and 5-HT1A binding. The developed model was able to explain 68% (p<.001), 38% (p=.012) and 32% (p=.038) of the total variance in somatic, psychic, and motoric anxiety, respectively. Results indicate the tight coupling between the serotonergic system and anxiety components, which may be confounded when using aggregate anxiety measures. Uncovering serotonin's role in anxiety and depression in this way may give way to a new generation of therapeutics and treatment strategies.