Excerpts from article:

“The observation that higher rates of schizophrenia and other nonaffective psychotic disorders are associated with city living is robustly replicated across epidemiologic studies conducted throughout Northern Europe and North America. The weight of this evidence, combined with exhaustive investigations of potential bias, suggest that methodological artifacts are unlikely to explain such associations. Instead, they imply a causal role for underlying environmental factors more common in urban settings. Evidence from northern Europe strongly links social factors, including deprivation, inequality, and social isolation, to raised rates of nonaffective psychotic disorders in urban settings, and while mechanisms through which such factors influence psychosis remain uncharacterized, they may include effects of social stress and possibly exposure to socially distributed biological factors, such as poor nutrition, infections, and/or pollutants.

The first idea is consistent with emerging neurobiological evidence, which has found that healthy volunteers who live or grew up in more urban environments show heightened activity in the amygdala and perigenual anterior cingulate cortex, respectively, after stress. These 2 interconnected brain regions are involved in threat perception and social evaluative stress processing, which may be more demanding in response to city life, and which are associated with psychotic disorder. Nonetheless, a definitive statement about causality (or refutation of it) awaits results of ongoing efforts to produce convergent evidence that elucidates the exact mechanisms through which some or all of these factors account for differential rates of psychotic disorder in some urban populations.

It does not follow, however, that city living should be associated with psychotic disorders in all contexts. Indeed, recent data from southern Europe suggest that the association may not pertain even across European countries, while findings from rural England suggest urbanicity per se need not be the primary social construct driving increased incidence rates in some environments.

New data from the World Health Survey (WHS) published by DeVylder et al further expand our purview and underscore how mistaken it could be to assume that city living has the same meaning across the globe. Across 42 low- and middle-income countries (LMICs), they found no consistent pattern of urban-rural differences in the prevalence of subclinical psychotic experiences (PEs). However, as we expand the epidemiological horizon, we cannot afford to uncritically accept evidence that emerges on urban-rural differences. Studying PEs does not yield direct evidence about variation in psychotic disorders, given that PEs are relatively common, yet to be conclusively associated with polygenic risk for schizophrenia, and associated with risks for several other psychiatric disorders and have low positive predictive value for psychotic disorders. We must be even more cautious about WHS findings on psychotic disorders, which were based on a single-question item asking whether a physician had ever diagnosed survey participants with a psychotic disorder. In LMICs, access to clinical care is often very limited, and the diagnosis, communication, and understanding of the term psychotic disorder is likely to vary widely. Finally, WHS data are measures of prevalence rather than incidence. With respect to psychotic disorders in LMICs, where rural-to-urban migration has strongly contributed to rapid urbanization, urban-rural differences in prevalence could be influenced by reverse causation, if people who developed such disorders were less likely to migrate than their peers or more likely return home after psychosis onset.

The attempt to use the WHS data to study urban-rural differences in psychosis underscores the need for a new, global vista, long overdue in epidemiologic studies of city living and psychosis. Although these findings do not invalidate Northern European findings on urban living and associated risk of psychotic disorders, they do challenge us to investigate whether such gradients exist elsewhere and understand why or why not this may be the case.

Moreover, global investigations of PEs are important in their own right, given that they predict several adverse psychopathologies. In this regard, it is unfortunate that DeVylder et al were unable to contextualize cultural variation between and within these vastly different countries to explore reasons for the apparent heterogeneity in urban-rural differences in PE prevalence, instead favoring a meta-analytic approach which led to pooled, null effects. A multitude of factors may account for why PEs were more apparent in urban Laos, Estonia, and Mali and rural Vietnam, Hungary, and South Africa, which, given the large WHS sample sizes, were unlikely to be chance findings. For example, the social construction of urban environments in each of these countries is likely to vary, following complex historical, sociocultural morphologies that alter both the patterns of exposure to putative social or biological risk factors in such environments, as well as the very meaning of urban or rural living. More fundamentally, we know little about possible cross-cultural variation in endorsement of PEs between or within LMICs, which could have contributed to differential urban-rural patterns in the WHS data.

Despite these limitations, these results press us to build theory and collect in-depth empirical data that reveal the variety of meanings of city living across contexts, and explain how and why observed associations between city living and psychotic disorders differ across these contexts. A recent study of men in Chengdu, China, underscores how profoundly the meaning of city living might differ by sociocultural and historical context, where rapid urbanization has been driven by rural-to-urban labor migration over a single generation. Here, rural-to-urban labor migrants were not found to be at increased risk of severe psychotic symptoms indicative of likely disorder, but men born in more urban areas were. Such data allow us to generate new theories in this context. Perhaps internal migrants are a selectively resilient group relative to men born in Chinese cities, those left behind, and those who returned to rural areas. Perhaps early-life exposure to adversities in urban environments holds greater causative relevance for psychotic disorders than adulthood exposure. Perhaps settlement patterns for labor migrants in Chengdu foster strong bonding social capital, irrespective of material conditions.

Overcoming some of the challenges above will require us to expand carefully conducted incidence studies of psychotic disorder in LMIC settings. This could provide a falsifiable methodology for testing different causative theories in samples across different settings, with different patterns of genetic, social, and biological exposures. Such studies will also be vital for global public mental health, given the seismic shifts in population dynamics anticipated over the next 30 years; by 2050, the United Nations anticipates that two-thirds of the world’s population will live in cities, with 90% of this growth occurring in Africa and Asia. The WHS findings stimulate us to expand our scope of enquiry, and as such, they are important for psychosis research.

As with all public health issues, however, the costs of misinterpreting their results may have negative unintended consequences. Just as we should not expect a universal association between city living and psychotic disorders, nor should we infer from pooled results on PEs across heterogeneous, uncharacterized settings that such associations do not exist. Rather, we should anticipate and seek to understand the causes of heterogeneous associations between city living and psychotic disorders as we develop a global purview of the epidemiology of psychotic disorders in a fast-changing world.”

Kirkbride JB, Keyes KM, Susser E: City Living and Psychotic Disorders – Implications of Global Heterogeneity for Theory Development. JAMA Psychiatry 75(12):1211-1212 (2018).


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Abstract:  “Most people with bipolar disorder spend a significant percentage of their lifetime experiencing either subsyndromal depressive symptoms or major depressive episodes, which contribute greatly to the high levels of disability and mortality associated with the disorder. Despite the importance of bipolar depression, there are only a small number of recognised treatment options available. Consecutive treatment failures can quickly exhaust these options leading to treatment-resistant bipolar depression (TRBD). Remarkably few studies have evaluated TRBD and those available lack a comprehensive definition of multi-therapy-resistant bipolar depression (MTRBD).Aims: To reach consensus regarding threshold definitions criteria for TRBD and MTRBD. ……..

TRBD criteria in bipolar depression was defined as failure to reach sustained symptomatic remission for 8 consecutive weeks after two different treatment trials, at adequate therapeutic doses, with at least two recommended monotherapy treatments or at least one monotherapy treatment and another combination treatment. MTRBD included the same initial definition as TRBD, with the addition of failure of at least one trial with an antidepressant, a psychological treatment and a course of electroconvulsive therapy.

The proposed TRBD and MTRBD criteria may provide an important signpost to help clinicians, researchers and stakeholders in judging how and when to consider new non-standard treatments. However, some challenging diagnostic and therapeutic issues were identified in the consensus process that need further evaluation and research.”


Hidalgo-Mazzei D, Berk M, Cipriani A, Cleare AJ, lorio AD, Dietch D, Geddes JR, Goodwin GM, Grunze H, Hayes JF, Jones I, Kasper S, Macritchie K, AcAllister-Williams RH, Morriss R, Nayrouz S, Pappa S, Soares JC, Smith DJ, Suppes T, Talbot P, Vieta E, Watson S, Yatham LN, Young AH, Stokes PRA: Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition. British J. Psychiatry, doi: 10.1192/bjp.2018.257. [Epub ahead of print, Dec. 6, 2018].



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Abstract: “The discovery of the mechanisms underlying light-gated ion channels called channel rhodospins and the subsequent development of optogenetics illustrates how breakthroughs in science and technology can span multiple levels of scientific inquiry. Our knowledge of how channelrhodopsins work emerged from research at the microscopic level that investigated the structure and function of algal proteins. Optogenetics, on the other hand, exploits the power of channelrhodospins and similar proteins to investigate phenomena at the supra-macroscopic level, notably the neural circuits involved in animal behavior that may be relevant for understanding neuropsychiatric disease. This article is being published to celebrate Peter Hegemann, Karl Deisseroth and Ed Boyden receiving a 2018 Canada Gairdner International Award “for the discovery of light-gated ion channel mechanisms, and for the discovery of optogenetics, a technology that has revolutionized neuroscience”.”

Josselyn SA:The past, present and future of light-gated ion channels and optogenetics. Elife.  2018 Oct 22;7. pii: e42367. doi: 10.7554/eLife.42367.



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Obsessive-compulsive disorder (OCD) is associated with increased mortality, but the causes of this increase are poorly understood. This study by Isomura and colleagues examined whether OCD is associated with increased risk of metabolic and cardiovascular complications.

Subjects diagnosed with OCD (n = 25,415) were identified and studied from a cohort of 12,497,002 individuals living in Sweden between 1973 and 2013. Results showed that OCD was associated with higher risk of metabolic/cardiovascular complications compared with the general population and their unaffected siblings. In the sibling comparison analysis, OCD patients had higher risks of obesity, type 2 diabetes mellitus, and circulatory system diseases. Compared with patients who were not taking serotonin reuptake inhibitors, patients taking higher doses of serotonin reuptake inhibitors and who had a longer duration of treatment had significantly lower risks of metabolic and cardiovascular complications, regardless of whether they were also taking antipsychotics. The authors concluded that OCD is associated with an increased risk of metabolic and cardiovascular complications. They also recommended monitoring of metabolic and cardiovascular health in patients with OCD early in the course of the disorder.

Isomura K, Brander G, Chang Z, Kuja-Halkola R, Rück C, Hellner C, Lichtenstein P, Larsson H, Mataix-Cols D, Fernández de la Cruz L: Metabolic and Cardiovascular Complications in Obsessive-Compulsive Disorder: A Total population, Sibling Comparison Study With Long-Term Follow-up. Biological Psychiatry 84(5): 324-331 (2018).


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Abstract:Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS (genome-wide association study) of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.”

 Demontis D, Walters RK, Martin J, Mattheisen M, Als TD, Agerbo E, Baldursson G, Belliveau R, Bybjerg-Grauholm J, Bækvad-Hansen M, Cerrato F, et al.: Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics [Epub ahead of print, Nov. 26, 2018; doi: 10.1038/s41588-018-0269-7.  ]


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Dysregulation of the dopamine system is a well-established component of schizophrenia pathophysiology, with regional differences in dopamine targets thought to shape disease symptoms. Increased presynaptic striatal dopamine synthesis and release are among the most consistent findings in patients. These alterations seem to occur early in the disease and are also observed in prodromal subjects that are at clinically high risk for developing schizophrenia. This article is a commentary on the study by Schifani and colleagues (Brain 141(7):2213-2224, 2018) which found the first direct evidence for disrupted prefronto-cortical dopamine stress regulation in schizophrenia.

Gomes FV and Grace AA: Cortical dopamine dysregulation in schizophrenia and its link to stress. Brain 141(7): 1897-1899 (2018).


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Abstract: “Heart valve disease (HVD) is a complex entity made by different pathological processes that ultimately lead to the abnormal structure and disorganization of extracellular matrix proteins resulting to dysfunction of the leaflets. At its final evolutionary step, treatments are limited to the percutaneous or surgical valve replacement, whatever the original cause of the degeneration. Understanding early molecular mechanisms that regulate valve interstitial cells remodeling and disease progression is challenging and could pave the way for future drugs aiming to prevent and/or reverse the process. Some valve degenerative processes such as the carcinoid heart disease, drug-induced valvulopathy and degenerative mitral valve disease in small-breed dogs are clearly linked to serotonin. The carcinoid heart is typically characterized by a right-sided valve dysfunction, observed in patients with carcinoid tumors developed from serotonin-producing gut enterochromaffin cells. Fenfluramine or ergot derivatives were linked to mitral and aortic valve dysfunction and share in common the pharmacological property of being 5-HT2B receptor agonists. Finally, some small-breed dogs, such as the Cavalier King Charles Spaniel are highly prone to degenerative mitral valve disease with a prevalence of 40% at 4 years-old, 70% at 7 years-old and 100% in 10-year-old animals. This degeneration has been linked to high serum serotonin, 5-HT2B receptor overexpression and SERT downregulation. Through the comprehension of serotonergic mechanisms involved into these specific situations, new therapeutic approaches could be extended to HVD in general.” Evidence also exists for pergolide and cabergoline being associated with a higher risk of cardiac valve regurgitation and pramipexole and cabergoline being associated with a higher risk of heart failure in patients with Parkinson’s disease. “This review summarizes clinical and molecular mechanisms linking the serotonergic system and heart valve disease, opening the way for future pharmacological research in the field.”

Ayme-Dietrich E, Lawson R, Da-Silva S, Mazzucotelli JP, Monassier L: Serotonin contribution to cardiac valve degeneration: new insights for novel therapies? Pharmacol. Res.  [Epub ahead of print, Sept. 9, 2018;  pii: S1043-6618(18)30587-5. doi: 10.1016/j.phrs.2018.09.009].


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Abstract: “Strong evidence has emerged recently for the concept that herpes simplex virus type 1 (HSV1) is a major risk for Alzheimer’s disease. This concept proposes that latent HSV1 in brain of carriers of the type 4 allele of the apolipoprotein E gene (APOE-ε4) is reactivated intermittently by events such as immunosuppression, peripheral infection, and inflammation, the consequent damage accumulating, and culminating eventually in the development of Alzheimer’s. Population data to investigate this epidemiologically, e.g., to find if subjects treated with antivirals might be protected from developing dementia—are available in Taiwan, from the National Health Insurance Research Database, in which 99.9% of the population has been enrolled. This is being extensively mined for information on microbial infections and disease. Three publications have now appeared describing data on the development of senile dementia, and the treatment of those with marked overt signs of disease caused by varicella zoster virus (VZV), or by HSV. The striking results show that the risk of senile dementia is much greater in those who are HSV-seropositive than in seronegative subjects, and that antiviral treatment causes a dramatic decrease in number of subjects who later develop senile dementia. It should be stressed that these results apply only to those with severe cases of HSV1 or VZV infection, but when considered with the over 150 publications that strongly support an HSV1 role in Alzheimer’s, they greatly justify usage of antiherpes antivirals to treat Alzheimer’s. ….. Three indirectly relevant studies deal respectively with schizophrenia, relating to antiviral treatment to target HSV1, with the likelihood that HSV1 is a cause of fibromyalgia, and with fibromyalgia being associated with later development of senile dementia. Studies on the link between epilepsy, Alzheimer’s and herpes simplex encephalitis (HSE) are described also, as are the possible roles of APOE-ε4, HHV6 and HSV1 in epilepsy.”

Itzhaki RF: Corroboration of a Major Role for Herpes Simplex Virus Type 1 in Alzheimer’s Disease. Frontiers in Aging Neurosci., 19 October 2018 | https://doi.org/10.3389/fnagi.2018.00324


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Summary:  Light exerts a range of powerful biological effects beyond image vision, including effects on mood and learning. While the source of photic information affecting mood and cognitive functions is well established, via intrinsically photosensitive retinal ganglion cells (ipRGCs), the central mediators are unknown. Here, Fernandez and colleagues show that ipRGCs projections to the suprachiasmatic nucleus mediate the effects of light on learning, independently of the suprachiasmatic nucleus pacemaker function. However, mood regulation by light requires a suprachiasmatic nucleus-independent pathway linking ipRGCs to a previously unrecognized thalamic region, termed perihabenular nucleus. The perihabenular nucleus is integrated in a distinct circuitry with mood-regulating centers and is both necessary and sufficient for driving the effects of light on affective behavior. “Together, these results provide new insights into the neural basis required for light to influence mood and learning.”

Fernandez DC, Fogerson PM, Lazzerini Ospri L, Thomsen MB et al: Light Affects Mood and Learning through Distinct Retina-Brain Pathways. Cell 175(1): 71-84 (2018).


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“…Immune cells normally pounce on intruding bacteria and viruses. But in multiple sclerosis (MS), immune cells target the nervous system instead. Now, researchers may have pinpointed a long-sought molecule called a self-antigen that provokes these attacks, pointing a way toward potential new treatments.”


Specifically, guanosine diphosphate (GDP)-l-fucose synthase has been found to be an autoantigen that is recognized by cerebrospinal fluid-infiltrating CD4+ T cells from HLA-DRB3*-positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. “These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.”

Planas R, Santos R, Tomas-Ojer P, Cruciani C, Lutterotti A, Faigle W, Schaeren-Wiemers N, Espejo C, Eixarch H, Pinilla C, Martin R and Sospedra M: GDP-l-fucose synthase is a CD4+ T cell-specific autoantigen in DRB3*02:02 patients with multiple sclerosis. Science Transl. Med. 10(462). pii: eaat4301. doi: 10.1126/scitranslmed.aat4301; Oct. 10, 2018.


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