Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management.

Populations with common physical diseases - such as cardiovascular diseases, cancer and neurodegenerative disorders - experience substantially higher rates of major depressive disorder (MDD) than the general population. On the other hand, people living with MDD have a greater risk for many physical diseases. This high level of comorbidity is associated with worse outcomes, reduced adherence to treatment, increased mortality, and greater health care utilization and costs. Comorbidity can also result in a range of clinical challenges, such as a more complicated therapeutic alliance, issues pertaining to adaptive health behaviors, drug-drug interactions and adverse events induced by medications used for physical and mental disorders. Potential explanations for the high prevalence of the above comorbidity involve shared genetic and biological pathways. These latter include inflammation, the gut microbiome, mitochondrial function and energy metabolism, hypothalamic-pituitary-adrenal axis dysregulation, and brain structure and function. Furthermore, MDD and physical diseases have in common several antecedents related to social factors (e.g., socioeconomic status), lifestyle variables (e.g., physical activity, diet, sleep), and stressful live events (e.g., childhood trauma). Pharmacotherapies and psychotherapies are effective treatments for comorbid MDD, and the introduction of lifestyle interventions as well as collaborative care models and digital technologies provide promising strategies for improving management. This paper aims to provide a detailed overview of the epidemiology of the comorbidity of MDD and specific physical diseases, including prevalence and bidirectional risk; of shared biological pathways potentially implicated in the pathogenesis of MDD and common physical diseases; of socio-environmental factors that serve as both shared risk and protective factors; and of management of MDD and physical diseases, including prevention and treatment. We conclude with future directions and emerging research related to optimal care of people with comorbid MDD and physical diseases.

Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia: A systematic review and network meta-analysis with normalized entropy assessment.

OBJECTIVE: To integrate all evidence derived from randomized controlled trials (RCTs) of both pharmacological and nonpharmacological augmentation interventions for clozapine-resistant schizophrenia (CRS). METHODS: Six major electronic databases were systematically searched for RCTs published until July 10, 2021. The primary outcome was change in overall symptoms, and the secondary outcomes were positive and negative symptoms and acceptability. We performed random-effects network meta-analysis. Normalized entropy was calculated to examine the uncertainty of treatment ranking. RESULTS: We identified 35 RCTs (1472 patients with 23 active augmentation treatments) with a mean daily clozapine dose of 440.80 (91.27) mg for 1168.22 (710.28) days. Network meta-analysis of overall symptoms (reported as standardized mean difference; 95 % confidence interval) with consistent results indicated that mirtazapine (-4.41; -5.61, -3.21), electroconvulsive therapy (ECT) (-4.32; -5.43, -3.21), and memantine (-2.02; -3.14, -0.91) were ranked as the best three treatments. For positive symptoms, ECT (-5.18; -5.86, -4.49) was ranked the best with less uncertainty. For negative symptoms, memantine (-3.38; -4.50, -2.26), duloxetine (-3.27; -4.25, -2.29), and mirtazapine (-1.73; -2.71, -0.74) were ranked the best three treatments with less uncertainty. All antipsychotics, N-methyl d-aspartate receptor agonists, and antiepileptics were not associated with more efficacy than placebo. Compared to placebo, only amisulpride had statistically significant lower discontinuation rate (risk ratio: 0.21; 95 % CI: 0.05, 0.93). CONCLUSION: Add-on mirtazapine, ECT, and memantine were the most efficacious augmentation options for CRS. Data on other important outcomes such as cognitive functioning or quality of life were rarely reported, making further large-scale, well-designed RCTs necessary. (PROSPERO number, CRD42021262197.).

Can magnetic resonance imaging enhance the assessment of potential new treatments for cognitive impairment in mood disorders? A systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force.

BACKGROUND: Developing treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions. METHODS: We included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist. RESULTS: We identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as 'fair'. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred. CONCLUSIONS: Modulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

Assessment of Noninvasive Brain Stimulation Interventions for Negative Symptoms of Schizophrenia: A Systematic Review and Network Meta-analysis.

Importance: Negative symptoms have a detrimental impact on functional outcomes and quality of life in people with schizophrenia, and few therapeutic options are considered effective for this symptomatic dimension. Studies have suggested that noninvasive brain stimulation (NIBS) interventions may be effective in treating negative symptoms. However, the comparative efficacy of different NIBS protocols for relieving negative symptoms remains unclear. Objective: To compare the efficacy and acceptability of different NIBS interventions for treating negative symptoms. Data Sources: The ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, ClinicalTrials.gov, and Web of Science electronic databases were systematically searched from inception through December 7, 2021. Study Selection: A frequentist model network meta-analysis was conducted to assess the pooled findings of trials that evaluated the efficacy of repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation, transcranial random noise stimulation, transcutaneous vagus nerve stimulation, and transcranial direct current stimulation on negative symptoms in schizophrenia. Randomized clinical trials (RCTs) examining NIBS interventions for participants with schizophrenia were included. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were independently extracted by multiple observers. The pair-wise meta-analytic procedures were conducted using a random-effects model. Main Outcomes and Measures: The coprimary outcomes were changes in the severity of negative symptoms and acceptability (ie, dropout rates owing to any reason). Secondary outcomes were changes in positive and depressive symptoms. Results: Forty-eight RCTs involving 2211 participants (mean [range] age, 38.7 [24.0-57.0] years; mean [range] proportion of female patients, 30.6% [0%-70.0%]) were included. Compared with sham control interventions, excitatory NIBS strategies (standardized mean difference [SMD]: high-definition transcranial random noise stimulation, -2.19 [95% CI, -3.36 to -1.02]; intermittent theta-burst stimulation, -1.32 [95% CI, -1.88 to -0.76]; anodal transcranial direct current stimulation, -1.28 [95% CI, -2.55 to -0.02]; high-frequency rTMS, -0.43 [95% CI, -0.68 to -0.18]; extreme high-frequency rTMS, -0.45 [95% CI, -0.79 to -0.12]) over the left dorsolateral prefrontal cortex with or without other inhibitory stimulation protocols in the contralateral regions of the brain were associated with significantly larger reductions in negative symptoms. Acceptability did not significantly differ between the groups. Conclusions and Relevance: In this network meta-analysis, excitatory NIBS protocols over the left dorsolateral prefrontal cortex were associated with significantly large improvements in the severity of negative symptoms. Because relatively few studies were available for inclusion, additional well-designed, large-scale RCTs are warranted.

Incidence, prevalence, and global burden of autism spectrum disorder from 1990 to 2019 across 204 countries.

Autism spectrum disorder (ASD) substantially contributes to the burden of mental disorders. Improved awareness and changes in diagnostic criteria of ASD may have influenced the diagnostic rates of ASD. However, while data on trends in diagnostic rates in some individual countries have been published, updated estimates of diagnostic rate trends and ASD-related disability at the global level are lacking. Here, we used the Global Burden of Diseases, Injuries, and Risk Factors Study data to address this gap, focusing on changes in prevalence, incidence, and disability-adjusted life years (DALYs) of ASD across the world. From 1990 to 2019, overall age-standardized estimates remained stable globally. Both prevalence and DALYs increased in countries with high socio-demographic index (SDI). However, the age-standardized incidence decreased in some low SDI countries, indicating a need to improve awareness. The male/female ratio decreased between 1990 and 2019, possibly accounted for by increasing clinical attention to ASD in females. Our results suggest that ASD detection in low SDI countries is suboptimal, and that ASD prevention/treatment in countries with high SDI should be improved, considering the increasing prevalence of the disorder. Additionally, growing attention is being paid to ASD diagnosis in females, who might have been left behind by ASD epidemiologic and clinical research previously. ASD burden estimates are underestimated as GBD does not account for mortality in ASD.

The prevalence, odds, predictors, and management of tobacco use disorder or nicotine dependence among people with severe mental illness: Systematic review and meta-analysis.

The prevalence, correlates, and management of tobacco use disorder (TUD) or nicotine dependence (ND) among people with severe mental illness (SMI), namely schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), remain unclear. Therefore, a systematic review and meta-analysis was conducted. Electronic databases were systematically searched from inception to July 12, 2020, for observational studies documenting the prevalence, odds, and correlates of TUD/ND among people with SMI; randomized controlled trials (RCTs) informing the management of TUD/ND in people with SMI were also included. Random-effects meta-analyses were conducted. Sources of heterogeneity were explored. Nineteen observational studies, including 7527 participants with SMI met inclusion criteria. TUD/ND co-occurred in 33.4-65% of people with SMI. Rates were higher among males. While bupropion and varenicline represent promising treatment opportunities for schizophrenia with TUD/ND, non-pharmacological interventions require further research, mainly for people with primary mood disorders. TUD/ND represent prevalent co-occurring conditions among people with SMI. Further well-designed RCTs are warranted to inform their management.

Socioeconomic inequality in the risk of intentional injuries among adolescents: a cross-sectional analysis of 89 countries.

INTRODUCTION: In 2015, the elimination of hunger worldwide by 2030 was declared by the United Nations as a Sustainable Development Goal. However, food insecurity remains pervasive, contributing to socioeconomic health inequalities. The overall objective was to investigate the relationship between food insecurity and intentional injuries among adolescents. METHODS: Individual-level data from the Global School-based Student Health Survey from 89 countries were used (370 719 adolescents, aged 12-17 years). Multilevel logistic regressions were used to examine the sex-specific association between the level of food insecurity (none, medium and high) and intentional injuries (interpersonal violence and suicide attempts), accounting for the clustering of observations within surveys. Random-effects meta-analyses were used to analyse dose-response relationships. RESULTS: Medium and high food insecurity were associated with increased odds of reporting an injury from interpersonal violence among both sexes. A positive dose-response relationship was found, where each level increase in food insecurity was associated with a 30% increase in the odds of an injury due to interpersonal violence among boys (1.30; 95% CI 1.26 to 1.34) and a 50% increase among girls (1.53; 95% CI 1.46-1.62). The odds for suicide attempts increased by 30% for both sexes with each level increase in food insecurity (boys: 1.29; 95% CI 1.25-1.32; girls: 1.29; 95% CI 1.25-1.32). DISCUSSION: The findings indicate that socioeconomic inequalities exist in the risk of intentional injuries among adolescents. Although additional studies are needed to establish causality, the present study suggests that the amelioration of food insecurity could have implications beyond the prevention of its direct consequences.

Alcohol use disorders.

Alcohol use disorders consist of disorders characterised by compulsive heavy alcohol use and loss of control over alcohol intake. Alcohol use disorders are some of the most prevalent mental disorders globally, especially in high-income and upper-middle-income countries; and are associated with high mortality and burden of disease, mainly due to medical consequences, such as liver cirrhosis or injury. Despite their high prevalence, alcohol use disorders are undertreated partly because of the high stigma associated with them, but also because of insufficient systematic screening in primary health care, although effective and cost-effective psychosocial and pharmacological interventions do exist. Primary health care should be responsible for most treatment, with routine screening for alcohol use, and the provision of a staggered treatment response, from brief advice to pharmacological treatment. Clinical interventions for these disorders should be embedded in a supportive environment, which can be bolstered by the creation of alcohol control policies aimed at reducing the overall level of consumption.

Socioeconomic Deprivation, Adverse Childhood Experiences and Medical Disorders in Adulthood: Mechanisms and Associations.

Severe socioeconomic deprivation (SED) and adverse childhood experiences (ACE) are significantly associated with the development in adulthood of (i) enhanced inflammatory status and/or hypothalamic-pituitary-adrenal (HPA) axis dysfunction and (ii) neurological, neuroprogressive, inflammatory and autoimmune diseases. The mechanisms by which these associations take place are detailed. The two sets of consequences are themselves strongly associated, with the first set likely contributing to the second. Mechanisms enabling bidirectional communication between the immune system and the brain are described, including complex signalling pathways facilitated by factors at the level of immune cells. Also detailed are mechanisms underpinning the association between SED, ACE and the genesis of peripheral inflammation, including epigenetic changes to immune system-related gene expression. The duration and magnitude of inflammatory responses can be influenced by genetic factors, including single nucleotide polymorphisms, and by epigenetic factors, whereby pro-inflammatory cytokines, reactive oxygen species, reactive nitrogen species and nuclear factor-κB affect gene DNA methylation and histone acetylation and also induce several microRNAs including miR-155, miR-181b-1 and miR-146a. Adult HPA axis activity is regulated by (i) genetic factors, such as glucocorticoid receptor polymorphisms; (ii) epigenetic factors affecting glucocorticoid receptor function or expression, including the methylation status of alternative promoter regions of NR3C1 and the methylation of FKBP5 and HSD11ß2; (iii) chronic inflammation and chronic nitrosative and oxidative stress. Finally, it is shown how severe psychological stress adversely affects mitochondrial structure and functioning and is associated with changes in brain mitochondrial DNA copy number and transcription; mitochondria can act as couriers of childhood stress into adulthood.

Systematic assessment of environmental risk factors for bipolar disorder: an umbrella review of systematic reviews and meta-analyses.

OBJECTIVES: The pathophysiology of bipolar disorder is likely to involve both genetic and environmental risk factors. In our study, we aimed to perform a systematic search of environmental risk factors for BD. In addition, we assessed possible hints of bias in this literature, and identified risk factors supported by high epidemiological credibility. METHODS: We searched the Pubmed/MEDLINE, EMBASE and PsycInfo databases up to 7 October 2016 to identify systematic reviews and meta-analyses of observational studies that assessed associations between putative environmental risk factors and BD. For each meta-analysis, we estimated its summary effect size by means of both random- and fixed-effects models, 95% confidence intervals (CIs), the 95% prediction interval, and heterogeneity. Evidence of small-study effects and excess of significance bias was also assessed. RESULTS: Sixteen publications met the inclusion criteria (seven meta-analyses and nine qualitative systematic reviews). Fifty-one unique environmental risk factors for BD were evaluated. Six meta-analyses investigated associations with a risk factor for BD. Only irritable bowel syndrome (IBS) emerged as a risk factor for BD supported by convincing evidence (k=6; odds ratio [OR]=2.48; 95% CI=2.35-2.61; P<.001), and childhood adversity was supported by highly suggestive evidence. Asthma and obesity were risk factors for BD supported by suggestive evidence, and seropositivity to Toxoplasma gondii and a history of head injury were supported by weak evidence. CONCLUSIONS: Notwithstanding that several environmental risk factors for BD were identified, few meta-analyses of observational studies were available. Therefore, further well-designed and adequately powered studies are necessary to map the environmental risk factors for BD.

The relationship of the perceived impact of the current Greek recession with increased suicide risk is moderated by mental illness in patients with long-term conditions.

OBJECTIVE: Adverse life events may contribute to the emergence of suicidality. We aimed to test the relationship between the impact of the Greek recession and suicidal risk in people with long-term conditions (LTCs) and to determine whether this relationship is moderated by the presence of a mental disorder. METHODS: Suicidal risk (RASS) and crisis parameters were assessed in a cross-sectional survey including 376 patients with LTCs (type-II diabetes mellitus, rheumatological disorders and chronic obstructive pulmonary disease) attending the Emergency Department or specialty clinics. A diagnosis of mental disorder was confirmed by the Mini International Neuropsychiatric Interview (MINI) interview. Hierarchical regression models were used to quantify moderator effects. RESULTS: Suicidal risk was significantly associated with the perceived impact of the recession (p=0.028). However, moderation analysis showed that this relationship was significant only in those diagnosed with either major depressive disorder or generalized anxiety disorder. CONCLUSIONS: These findings suggest that the perceived impact of the current Greek recession is not correlated with suicidal risk per se, but the recession may act as precipitator in combination with other risk factors, such as the presence of a mental illness, thus supporting the importance of early diagnosis and treatment of mental disorders in vulnerable groups.

Physical multimorbidity and psychosis: comprehensive cross sectional analysis including 242,952 people across 48 low- and middle-income countries.

BACKGROUND: In people with psychosis, physical comorbidities, including cardiovascular and metabolic diseases, are highly prevalent and leading contributors to the premature mortality encountered. However, little is known about physical health multimorbidity in this population or in people with subclinical psychosis and in low- and middle-income countries (LMICs). This study explores physical health multimorbidity patterns among people with psychosis or subclinical psychosis. METHODS: Overall, data from 242,952 individuals from 48 LMICs, recruited via the World Health Survey, were included in this cross-sectional study. Participants were subdivided into those (1) with a lifetime diagnosis of psychosis ("psychosis"); (2) with more than one psychotic symptom in the past 12 months, but no lifetime diagnosis of psychosis ("subclinical psychosis"); and (3) without psychotic symptoms in the past 12 months or a lifetime diagnosis of psychosis ("controls"). Nine operationalized somatic disorders were examined: arthritis, angina pectoris, asthma, diabetes, chronic back pain, visual impairment, hearing problems, edentulism, and tuberculosis. The association between psychosis and multimorbidity was assessed by multivariable logistic regression analysis. RESULTS: The prevalence of multimorbidity (i.e., two or more physical health conditions) was: controls = 11.4% (95% CI, 11.0-11.8%); subclinical psychosis = 21.8% (95% CI, 20.6-23.0%), and psychosis = 36.0% (95% CI, 32.1-40.2%) (P < 0.0001). After adjustment for age, sex, education, country-wise wealth, and country, subclinical psychosis and psychosis were associated with 2.20 (95% CI, 2.02-2.39) and 4.05 (95% CI, 3.25-5.04) times higher odds for multimorbidity. Moreover, multimorbidity was increased in subclinical and established psychosis in all age ranges (18-44, 45-64, ≥ 65 years). However, multimorbidity was most evident in younger age groups, with people aged 18-44 years with psychosis at greatest odds of physical health multimorbidity (OR = 4.68; 95% CI, 3.46-6.32). CONCLUSIONS: This large multinational study demonstrates that physical health multimorbidity is increased across the psychosis-spectrum. Most notably, the association between multimorbidity and psychosis was stronger among younger adults, thus adding further impetus to the calls for the early intervention efforts to prevent the burden of physical health comorbidity at later stages. Urgent public health interventions are necessary not only for those with a psychosis diagnosis, but also for subclinical psychosis to address this considerable public health problem.

Illness perceptions of people with long-term conditions are associated with frequent use of the emergency department independent of mental illness and somatic symptom burden.

OBJECTIVE: To determine whether illness perceptions of patients with long-term conditions (LTCs) are associated with urgent healthcare use and whether this association is independent from mental illness and somatic symptom burden. METHODS: Illness perceptions (B-IPQ) and somatic symptom severity (PHQ-15) were assessed in 304 patients with diabetes, rheumatological disorders and COPD attending an Accident and Emergency Department (AED) in Greece over a one year period. The presence of mental illness was determined by the Mini International Neuropsychiatric Interview. A Generalized Linear Model (Negative Binomial) regression was used to determine the associations of illness perceptions with AED use after adjusting for mental illness, somatic symptom severity, disease parameters and demographics. RESULTS: Eighty-six patients (28.3%) reported at least one visit to the AED during the previous year and 75 (24.7%) twice or more. 124 patients (40.8%) had some form of mental disorder with 85 (28.0%) meeting criteria for major depressive disorder. The degree to which the patients had an understanding of their illness (illness comprehensibility) (p<0.01) along with younger age (p<0.05), additional comorbidities (p<0.05) and greater somatic symptom burden (p<0.001) was strongly associated with AED use; AED visits were expected to be reduced by 9.1% for each unit increase in illness comprehensibility. CONCLUSIONS: The way people perceive their illness influences urgent healthcare seeking behavior independent of somatic symptom burden. This finding indicates that information provision may prove effective in reducing urgent healthcare use and encourage the design of psycho-educational interventions targeting disease-related cognitions in an attempt to prevent unnecessary healthcare utilization.

Health-related quality of life in patients with ankylosing spondylitis: a comprehensive review.

Ankylosing spondylitis (AS) is a complex systemic rheumatological disease which often causes severe disability and impaired quality of life (QoL). We searched the PubMed/MEDLINE electronic database for available literature on QoL and its predictors in patients with AS. Recent evidence indicates that AS patients have poorer QoL compared to the general population, but similar to that of patients with other rheumatological disorders. Disease activity is one of the most powerful predictors of QoL, however latest advances in pharmacological treatment (namely, anti-TNF-α) along with physical exercise can minimize the effects of AS on QoL. Psychological distress symptoms contribute to impaired QoL both directly and indirectly by influencing disease activity. The impact of other psychosocial variables, however, is less studied and more prospective investigations are necessary, which could eventually lead to the development of psychosocial interventions that are personalized to this patient population.

Illness perceptions and psychological distress associated with physical health-related quality of life in primary Sjögren's syndrome compared to systemic lupus erythematosus and rheumatoid arthritis.

Notwithstanding that psychological distress and illness perceptions are important in determining outcomes in rheumatic diseases, few studies investigated these variables in primary Sjögren's syndrome (pSS). We aimed to compare illness perceptions and psychological distress in patients with pSS, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and to test whether their associations with health-related quality of life (HRQoL) are similar in these groups of patients. In 57 patients with pSS, 75 with SLE and 199 with RA, we administered the Patient Health Questionnaire (PHQ-9), the Symptom Check-List and the Brief-Illness Perception Questionnaire to assess psychological variables and the World Health Organization Quality of Life Instrument, Short-Form to assess HRQoL. Hierarchical regression models determined the associations of psychological variables with HRQoL after adjusting for demographic variables and clinical parameters. The prevalence of clinically significant depressive symptoms (PHQ-9 ≥ 10) was 24.6 % in pSS, 29.3 % in SLE and 25.1 % in RA. Patients with pSS showed little understanding of their disease (comprehensibility) and attributed more symptoms to their illness (identity) compared with the other groups of patients. Illness perceptions and depressive symptoms were independently associated with physical HRQoL in a similar pattern in all three groups. In pSS, however, the patients' worries about the consequences of their illness was a stronger correlate of physical HRQoL than pain. These findings indicate that psychological factors are important correlates of HRQoL in these disease groups and encourage the design of psycho-educational therapies targeting disease-related cognitions in pSS in an attempt to improve patient's physical HRQoL.