Drugs, Guts, Brains, but Not Rock and Roll: The Need to Consider the Role of Gut Microbiota in Contemporary Mental Health and Wellness of Emerging Adults.

Emerging adulthood (ages 18-25) is a critical period for neurobiological development and the maturation of the hypothalamic-pituitary-adrenal axis. Recent findings also suggest that a natural perturbation of the gut microbiota (GM), combined with other factors, may create a unique vulnerability during this period of life. The GM of emerging adults is thought to be simpler, less diverse, and more unstable than either younger or older people. We postulate that this plasticity in the GM suggests a role in the rising mental health issues seen in westernized societies today via the gut-brain-microbiota axis. Studies have paid particular attention to the diversity of the microbiota, the specific function and abundance of bacteria, and the production of metabolites. In this narrative review, we focus specifically on diet, physical activity/exercise, substance use, and sleep in the context of the emerging adult. We propose that this is a crucial period for establishing a stable and more resilient microbiome for optimal health into adulthood. Recommendations will be made about future research into possible behavioral adjustments that may be beneficial to endorse during this critical period to reduce the probability of a "dysbiotic" GM and the emergence and severity of mental health concerns.

Access and Health System Impact of an Early Intervention Treatment Program for Emerging Adults with Mood and Anxiety Disorders.

OBJECTIVES: Early intervention programs are effective for improving outcomes in first-episode psychosis; however, less is known about their effectiveness for mood and anxiety disorders. We sought to evaluate the impact of an early intervention program for emerging adults with mood and anxiety disorders in the larger health system context, relative to standard care. METHODS: Using health administrative data, we constructed a retrospective cohort of cases of mood and anxiety disorders among emerging adults aged 16 to 25 years in the catchment of the First Episode Mood and Anxiety Program (FEMAP) in London, Ontario, between 2009 and 2014. This cohort was linked to primary data from FEMAP to identify service users. We used proportional hazards models to compare indicators of service use between FEMAP users and a propensity score-matched group of nonusers receiving care elsewhere in the health system. RESULTS: FEMAP users (n = 490) had more rapid access to a psychiatrist relative to nonusers (hazard ratio [HR], 2.82; 95% confidence interval, 2.45 to 3.26; median time, 16 vs. 71 days). In the year following admission, FEMAP users also had lower rates of emergency department use for mental health reasons (HR, 0.73; 95% CI, 0.53 to 0.99). We did not observe differences in psychiatric hospitalization rates. CONCLUSIONS: An early intervention model of care for mood and anxiety disorders is associated with better access to psychiatric care and lower use of the emergency department. Our findings suggest that early intervention services for mood and anxiety disorders may be beneficial from a health systems perspective, and further research on the effectiveness of this model of care is warranted.

Presenting concerns of emerging adults seeking treatment at an early intervention outpatient mood and anxiety program.

This study examined presenting concerns and characteristics of emerging adults (EAs) seeking treatment at an early intervention program for mood and anxiety disorders to better understand presenting concerns when treatment is needed. During an intake assessment conducted by a social worker or clinical psychologist, participants (N = 548; 62% female, 38% male) reported their top three current life concerns, which were analyzed qualitatively using thematic analysis. Participants completed a battery of questionnaires assessing demographic information, symptomatology, and daily functioning. Females presented with significantly higher levels of anxiety, and both females and younger individuals (age 16-18) presented with significantly higher levels of depression compared to males and older individuals (age 19-26), respectively. The two most commonly reported presenting concerns were problems in interpersonal relationships and academics, and females were more likely to report academic concerns than males. The majority of participants reported seeking help for a wide range of problems commonly faced by EAs (83.7%), and participants rarely expressed concerns about particular symptoms of mood and/or anxiety disorders (16.3%). EAs and those supporting EAs may benefit from learning when psychosocial concerns are indicative of mental health challenges warranting professional attention.

Youth Perspectives on the Mental Health Treatment Process: What Helps, What Hinders?

In this study we explored adolescent perceptions of what was most helpful and most challenging about mental health treatment for mood and/or anxiety disorders. Youth seeking treatment at the First Episode Mood and Anxiety Program were recruited to participate in a follow-up survey about their experiences of mental health care services. Responses to two open-ended questions were analyzed for emerging themes and differences between age groups and gender. Males were more likely to report therapy as being helpful than females, 16-18 year olds were more likely to report medication as a challenge to treatment and 19-26 year olds were more likely to report accessing services as a challenge to treatment. Understanding what helps and what hinders treatment-seeking youth can guide both clinical treatment and service delivery models for this population.

Early Intervention in Mood and Anxiety Disorders: The First Episode Mood and Anxiety Program (FEMAP).

The First Episode Mood and Anxiety Program (FEMAP) was developed for youth with mood and/or anxiety concerns in London, Ontario, to provide early intervention for these disorders, similar to the first-episode psychosis programs across Ontario and Canada. The logic and causal models of the pathway to and through FEMAP are described and inclusion/exclusion criteria are delineated. Results of the process evaluation of the model and preliminary data from a treatment-effectiveness evaluation and ongoing cost-comparison evaluation are provided. Several characteristic quotes from youth utilizing the service are included, as is an overview of utilization statistics. Challenges and lessons learned are conveyed.

"I just have to stick with it and it'll work": experiences of adolescents and young adults with mental health concerns.

Mental health issues are common among adolescents and young adults but service utilization in this group is low. This study aimed to better understand the experiences of older adolescents and young adults who were experiencing symptoms of depression or anxiety, including the factors that affected their decision to seek treatment and their feelings about their experience of mental health issues. We conducted semi-structured interviews with 37 older adolescents and young adults. Participants tended to have a sophisticated understanding of the causes of mental disorders, but to have been unsure about whether their own experiences of depression or anxiety were the result of a mental disorder, or just "normal" experiences. They reported concerns about taking medication and about keeping information about their condition private. They also felt that it was important to them to be active participants in their own care.

Health-related quality of life among adolescents and young adults with mood and anxiety concerns.

OBJECTIVES: To characterize health related quality of life (HRQOL) for Canadians aged 16 to 25 (adolescents and young adults, AYAs) seeking care for mood and anxiety concerns at the First Episode Mood and Anxiety Program, in London, Ontario and to identify factors associated with HRQOL in this population. METHODS: AYAs completed demographic, psychometric, and HRQOL questionnaires. We calculated 36-Item Short-Form Health Survey (SF-36) scores standardized to Canadian and US population norms. We computed Short Form 6 Dimension (SF-6D) utilities conducting multivariable linear regression analysis, adjusting for age, sex, ethnoracial minority status, parental marital/cohabitation status, parental education, the Anxiety Sensitivity Index (ASI-R), Montgomery-Åsberg Depression Rating Scale Self-Report (MADRS-S), Sheehan Disability Scale (SDS), and a modified Inventory of College Students' Recent Life Experiences (ICSRLE-M). RESULTS: Amongst 182 AYAs who completed questionnaires, mean physical component summary (PCS), mental component summary (MCS) and SF-6D utility scores were low, 43.8 (SD = 16.6), 19.0 (SD = 11.9) and .576 (SD = .074), respectively. Maternal post-secondary education, depression (MADRS-S) and functional impairment (SDS) were significantly associated with SF-6D utility. CONCLUSION: This cohort of mental healthcare-seeking AYAs had significantly impaired psychometric and utility-based measures of quality of life, underscoring the importance of timely access to healthcare services for this population.

Predispose, precipitate, perpetuate, and protect: how diet and the gut influence mental health in emerging adulthood.

Medicine often employs the 4Ps of predisposing, precipitating, perpetuating, and protective factors to identify salient influences on illness states, and to help guide patient care. Mental illness is a significant cause of morbidity and mortality worldwide. Mental health is a complex combination of biological, psychological, environmental, and social factors. There is growing interest in the gut-brain-microbiome (GBM) axis and its impact on mental health. We use the medical model of the 4Ps to explore factors involving the connection between nutrition and the GBM axis and their associated risks with mental health problems in emerging adults (EAs), a life stage when mental illness onset is the most common. We review the impact of current dietary trends on the GBM and on mental health, and the role that gut microbiome-based interventions can have in modulating the GBM axis of EAs. We discuss the implications of gut health on the GBM and areas for clinical intervention.

Cannabis use, addiction risk and functional impairment in youth seeking treatment for primary mood or anxiety concerns.

Cannabis use is common in youth and there is evidence that the co-occurrence of cannabis use (and other substance use) with mental illnesses predicts poorer outcomes, including suicide. The main purposes of this study were to: (i) identify rates of cannabis use and substance use disorder risk, and (ii) predictors for cannabis use among youth seeking help for mood and/or anxiety concerns in a sample population prescreened to exclude primary substance use disorders; and (iii) to determine if there was an association between cannabis use and functional impairment in this sample. We investigated substance use risk as well as hypothesized predictors of cannabis use and functional impairment including demographic characteristics, socioeconomic status, trait coping style, age of onset of several risk behaviors, current use of common addictive substances, level of functional impairment, and current psychiatric symptom severity. Results showed that approximately half of the participants were at moderate to high risk for a substance use disorder, and just over 4% appeared to have a primary substance use disorder. They also suggested an association between cannabis use and gender (male), age of first cannabis use, recent cigarette use, and functional impairment. Independently, functional impairment was predicted by inattentive coping style, depression severity, and total cannabis use score. These results confirm a high risk for addictive disorders and an association between cannabis use and functional impairment in this sample. These results support the need for substance use treatment programs to optimize care wherever youth with primary mood and/or anxiety concerns are seen.

Multi-study evaluation of neuroimaging-based prediction of medication class in mood disorders.

Clinicians often face a dilemma in diagnosing bipolar disorder patients with complex symptoms who spend more time in a depressive state than a manic state. The current gold standard for such diagnosis, the Diagnostic and Statistical Manual (DSM), is not objectively grounded in pathophysiology. In such complex cases, relying solely on the DSM may result in misdiagnosis as major depressive disorder (MDD). A biologically-based classification algorithm that can accurately predict treatment response may help patients suffering from mood disorders. Here we used an algorithm to do so using neuroimaging data. We used the neuromark framework to learn a kernel function for support vector machine (SVM) on multiple feature subspaces. The neuromark framework achieves up to 95.45% accuracy, 0.90 sensitivity, and 0.92 specificity in predicting antidepressant (AD) vs. mood stabilizer (MS) response in patients. We incorporated two additional datasets to evaluate the generalizability of our approach. The trained algorithm achieved up to 89% accuracy, 0.88 sensitivity, and 0.89 specificity in predicting the DSM-based diagnosis on these datasets. We also translated the model to distinguish responders to treatment from nonresponders with up to 70% accuracy. This approach reveals multiple salient biomarkers of medication-class of response within mood disorders.

Brain Environment Interactions: Stress, Posttraumatic Stress Disorder, and the Need for a Postmortem Brain Collection.

Stress, especially the extreme stress of traumatic events, can alter both neurobiology and behavior. Such extreme environmental situations provide a useful model for understanding environmental influences on human biology and behavior. This paper will review some of the evidence of brain alterations that occur with exposure to environmental stress. This will include recent studies using neuroimaging and will address the need for histological confirmation of imaging study results. We will review the current scientific approaches to understanding brain environment interactions, and then make the case for the collection and study of postmortem brain tissue for the advancement of our understanding of the effects of environment on the brain.Creating a brain tissue collection specifically for the investigation of the effects of extreme environmental stressors fills a gap in the current research; it will provide another of the important pieces to the puzzle that constitutes the scientific investigation of negative effects of environmental exposures. Such a resource will facilitate new discoveries related to the psychiatric illnesses of acute stress disorder and posttraumatic stress disorder, and can enable scientists to correlate structural and functional imaging findings with tissue abnormalities, which is essential to validate the results of recent imaging studies.

Monitoring the effects of COVID-19 in emerging adults with pre-existing mood and anxiety disorders.

AIM: The COVID-19 quarantine closed many mental health services. Emerging adults with pre-existing mood or anxiety disorders were of concern for worsening symptoms. We sought to demonstrate a method for monitoring mental health status of a group of patients with reduced access to their usual mental health services during quarantine. METHODS: A total of 326 patients enrolled in the First-Episode Mood and Anxiety Program in London, Ontario, Canada were invited to participate in online questionnaires regularly. Patients were flagged for high level of risk based on depression scores, suicidal ideation and worsening in anxiety, depression or quality of health. All patients were also asked if they wanted contact with a clinician. RESULTS: One hundred and fourteen (35%) patients completed at least one questionnaire. Thirty were flagged based on scores; 37 (32.5%) participating patients requested help. Participants who were flagged for concerning scores were younger, more likely to be on the wait list for treatment, to have been laid off from work and have more functional impairment. Participants requesting support had higher symptom scores for depression and lower scores on quality of health. CONCLUSIONS: The process utilized here identified patients at risk and in need of clinical support in the context of pandemic quarantine. It provided an accessible avenue for invited patients to communicate both symptom status and need for contact. Such a process can provide valuable monitoring during times when the usual communications between patients and health care providers is compromised and clinician time is limited. It is easily implemented.

Factors associated with initiation of community-based therapy for emerging adults with mood and anxiety disorders.

AIM: The First Episode Mood and Anxiety Program (FEMAP) is a community-based early intervention program that has been shown to improve health outcomes for emerging adults (EAs) with mood and anxiety disorders. However, not all EAs who are admitted to the program initiate treatment. Our aim was to identify factors that distinguish those who initiated treatment from those who did not. METHODS: FEMAP administered questionnaires to EAs upon first contact with the program, collecting information on a range of socioeconomic, patient and condition-related factors. We compared EAs who initiated treatment in the program (n = 318, 87.4%) to those who did not (n = 46, 12.6%). To examine factors associated with treatment initiation, we specified a parsimonious logistic regression model, using the method of purposeful selection to choose from a range of candidate variables. RESULTS: Anxiety Sensitivity Index - Revised (ASI-R), binge drinking and cannabis use were included in the final logistic regression model. Each one-point increment in the ASI-R score was associated with a 1% increase in the odds of treatment initiation (OR = 1.014; 95% CI [1.003, 1.026]). No other variable was significantly associated with treatment initiation. CONCLUSIONS: Our study provides insight on the differences between EAs with mood and anxiety disorders who initiated targeted treatment services and those who did not. Anxiety sensitivity was significantly associated with treatment initiation at FEMAP. Our findings suggest that it may be anxiety sensitivity, rather than depression or functional impairment per se that drive treatment initiation among EAs.

Emotion regulation in emerging adults with major depressive disorder and frequent cannabis use.

In people with mental health issues, approximately 20% have co-occurring substance use, often involving cannabis. Although emotion regulation can be affected both by major depressive disorder (MDD) and by cannabis use, the relationship among all three factors is unknown. In this study, we used fMRI to evaluate the effect that cannabis use and MDD have on brain activation during an emotion regulation task. Differences were assessed in 74 emerging adults aged 16-23 with and without MDD who either used or did not use cannabis. Severity of depressive symptoms, emotion regulation style, and age of cannabis use onset were also measured. Both MDD and cannabis use interacted with the emotion regulation task in the left temporal lobe, however the location of the interaction differed for each factor. Specifically, MDD showed an interaction with emotion regulation in the middle temporal gyrus, whereas cannabis use showed an interaction in the superior temporal gyrus. Emotion regulation style predicted activity in the right superior frontal gyrus, however, this did not interact with MDD or cannabis use. Severity of depressive symptoms interacted with the emotion regulation task in the left middle temporal gyrus. The results highlight the influence of cannabis use and MDD on emotion regulation processing, suggesting that both may have a broader impact on the brain than previously thought.

NeuroMark: An automated and adaptive ICA based pipeline to identify reproducible fMRI markers of brain disorders.

Many mental illnesses share overlapping or similar clinical symptoms, confounding the diagnosis. It is important to systematically characterize the degree to which unique and similar changing patterns are reflective of brain disorders. Increasing sharing initiatives on neuroimaging data have provided unprecedented opportunities to study brain disorders. However, it is still an open question on replicating and translating findings across studies. Standardized approaches for capturing reproducible and comparable imaging markers are greatly needed. Here, we propose a pipeline based on the priori-driven independent component analysis, NeuroMark, which is capable of estimating brain functional network measures from functional magnetic resonance imaging (fMRI) data that can be used to link brain network abnormalities among different datasets, studies, and disorders. NeuroMark automatically estimates features adaptable to each individual subject and comparable across datasets/studies/disorders by taking advantage of the reliable brain network templates extracted from 1828 healthy controls as guidance. Four studies including 2442 subjects were conducted spanning six brain disorders (schizophrenia, autism spectrum disorder, mild cognitive impairment, Alzheimer's disease, bipolar disorder, and major depressive disorder) to evaluate validity of the proposed pipeline from different perspectives (replication of brain abnormalities, cross-study comparison, identification of subtle brain changes, and multi-disorder classification using identified biomarkers). Our results highlight that NeuroMark effectively identified replicated brain network abnormalities of schizophrenia across different datasets; revealed interesting neural clues on the overlap and specificity between autism and schizophrenia; demonstrated brain functional impairments present to varying degrees in mild cognitive impairments and Alzheimer's disease; and captured biomarkers that achieved good performance in classifying bipolar disorder and major depressive disorder.

Alterations in default network connectivity in posttraumatic stress disorder related to early-life trauma.

BACKGROUND: The "default network" consists of a number of brain regions that exhibit correlated low-frequency activity at rest and that have been suggested to be involved in the processing of self-relevant stimuli. Activity in many of these areas has also been shown to be altered in individuals with posttraumatic stress disorder (PTSD). We hypothesized that the posterior cingulate cortex (PCC)/precuneus, part of the default network, would exhibit altered connectivity at rest with other areas of the default network and regions associated with PTSD. METHODS: Seventeen medicated and unmedicated female patients with chronic posttraumatic stress disorder (PTSD) related to early-life trauma and 15 healthy female controls underwent a 5.5-minute functional magnetic resonance imaging scan with their eyes closed. We assessed areas of the brain whose activity positively and negatively correlated with that of the PCC/precuneus in both groups. RESULTS: At rest, spontaneous low-frequency activity in the PCC/precuneus was more strongly correlated with activity in other areas of the default network in healthy controls than in patients with PTSD. Direct comparison of the 2 groups showed that PCC/ precuneus connectivity was also greater in healthy controls than in patients with PTSD in a number of areas previously associated with PTSD, including the right amygdala and the hippocampus/parahippocampal gyrus. LIMITATIONS: Because our PTSD sample comprised only women with chronic early-life trauma exposure, our results may not be generalizeable to male patients, to a population with single trauma exposure or to those who were adults when the trauma occurred. In addition, our sample included patients taking medication and it is not yet clear how altered connectivity is affected by medication. CONCLUSION: Spontaneous activity in the default network during rest, as measured using PCC correlations, is altered in patients with PTSD. The potential effects of psychotropic medications on default network connectivity in the present sample remain unknown. In this patient population, the observed alterations may be associated with the disturbances in self-referential processing often observed in patients with chronic PTSD related to early-life trauma.

Retrosplenial cortex connectivity in schizophrenia.

In this paper, we build on our previous analysis [Bluhm, R.L., Miller, J., Lanius, R.A., Osuch, E.A., Boksman, K., Neufeld, R.W.J., et al., 2007 Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophrenia Bulletin 33, 1004-1012] of resting state connectivity in schizophrenia by examining alterations in connectivity of the retrosplenial cortex. We have previously demonstrated altered connectivity of the posterior cingulate/precuneus, particularly with other regions of the "default network" (which includes the medial prefrontal cortex and bilateral lateral parietal cortex). It was hypothesized that the retrosplenial cortex would show aberrant patterns of connectivity with regions of the default network and regions associated with memory. Patients with schizophrenia (N=17) and healthy controls (N=17) underwent a 5.5-min resting functional magnetic resonance imaging scan. Lower correlations were observed in patients with schizophrenia than in healthy controls between the retrosplenial cortex and both the temporal lobe and regions of the default network. In patients with schizophrenia, activity in the retrosplenial cortex correlated negatively with activity in bilateral anterior cingulate gyrus/medial prefrontal cortex (BA 32/10), despite the fact that these regions, as part of the default network, were expected to show positive correlations in activity. Connectivity of the retrosplenial cortex was greater in patients with more positive symptoms with areas previously associated with hallucinations, particularly the left superior temporal gyrus. These results suggest that spontaneous activity in the retrosplenial cortex during rest is altered in patients with schizophrenia. These alterations may help to explain alterations in self-oriented processing in this patient population.

Repetitive TMS combined with exposure therapy for PTSD: a preliminary study.

Treatment for anxiety and post-traumatic stress disorder (PTSD) includes exposure therapy and medications, but some patients are refractory. Few studies of repetitive transcranial magnetic stimulation (rTMS) for anxiety or PTSD exist. In this preliminary report, rTMS was combined with exposure therapy for PTSD. Nine subjects with chronic, treatment-refractory PTSD were studied in a placebo-controlled, crossover design of imaginal exposure therapy with rTMS (1Hz) versus sham. PTSD symptoms, serum and 24h urine were obtained and analyzed. Effect sizes for PTSD symptoms were determined using Cohen's d. Active rTMS showed a larger effect size of improvement for hyperarousal symptoms compared to sham; 24-h urinary norepinephrine and serum T4 increased; serum prolactin decreased. Active rTMS with exposure may have symptomatic and physiological effects. Larger studies are needed to confirm these preliminary findings and verify whether rTMS plus exposure therapy has a role in the treatment of PTSD.

Resting state default-mode network connectivity in early depression using a seed region-of-interest analysis: decreased connectivity with caudate nucleus.

AIM: Reports on resting brain activity in healthy controls have described a default-mode network (DMN) and important differences in DMN connectivity have emerged for several psychiatric conditions. No study to date, however, has investigated resting-state DMN in relatively early depression before years of medication treatment. The objective of the present study was, therefore, to investigate the DMN in patients seeking help from specialized mental health services for the first time for symptoms of depression. METHODS: Fourteen depressed subjects and 15 matched controls were scanned using 4-T functional magnetic resonance imaging while resting with eyes closed. All but one subject was medication free. A precuneus/posterior cingulate cortex (P/PCC) seed-region connectivity analysis was used to identify the DMN and compare study groups in regions of relevance to depression. RESULTS: The P/PCC analysis identified the DMN well in both study groups, consistent with prior literature. Direct comparison showed significantly reduced correlation between the P/PCC and the bilateral caudate in depression compared with controls and no areas of increased connectivity in the depressed group. CONCLUSIONS: The present study is the first to investigate resting-state DMN in the early stages of treatment-seeking for depression. Depressed subjects had decreased connectivity between the P/PCC and the bilateral caudate, regions known to be involved in motivation and reward processing. Deficits in DMN connectivity with the caudate may be an early manifestation of major depressive disorder.