Summary: Sigma-1 receptors subdue systemic inflammation, which can be lethal, as in the case of septic shock. Mice lacking the endoplasmic reticulum sigma-1 receptor had exacerbated responses to LPS (lipopolysaccharides) or fecal slurry. The antidepressant fluvoxamine can bind sigma-1 and acts as a receptor agonist. Therapeutic treatment of mice in two inflammatory models revealed that fluvoxamine lowered inflammatory cytokine production and improved survival. The authors suggest that repurposing fluvoxamine to enhance sigma-1 receptor activity may be beneficial for treating sepsis.

Rosen DA, Seki SM, Fernández-Castañeda A, Beiter RM, Eccles JD, Woodfolk JA, Gaultier A: Modulation of the signa-1 receptor-IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 11, (478), Feb. 6, 2019; eaau5266; DOI: 10.1126/scitranslmed.aau5266.

https://www.ncbi.nlm.nih.gov/pubmed/30728287

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Abstract: “Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.”

Vadodaria KC, Ji Y, Skime M, Paquola A, Nelson T, Hall-Flavin D, Fredlender C, Heard KJ, Deng Y, Le AT, Dave S, Fung L, Li , Marchetto MC, Weinshilboum R, Gage FH: Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. Mol. Psychiatry [Epub ahead of print, Jan. 30, 2019; doi: 10.1038/s41380-019-0363-y].

https://www.ncbi.nlm.nih.gov/pubmed/30700803

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Summary: “UNICEF estimates that there are approximately 8 million children worldwide who live in institutions. Institutional rearing often involves severe psychosocial neglect associated with suboptimal brain and behavioral development. This study uses data from the only existing longitudinal RCT of foster care for institutionally reared children to examine trajectories of memory and executive functioning from childhood to adolescence. We show that institutional rearing is associated with persistent problems in certain functional domains, and developmental stagnancy in others, across this transitional period. There is suggestive evidence that children assigned to early foster care may demonstrate some catch-up over time. Brain activity in childhood is associated with long-term outcomes through age 16, together underscoring the impact of early neglect on children’s neurocognitive development.”

Wade M, Fox NA, Zeanah CH and Nelson III, CA: Long-term effects of institutional rearing, foster care, and brain activity on memory and executive functioning. Proc.Natl. Acad. Sci. USA 116 (5): 1808-1813 (2019).

https://www.ncbi.nlm.nih.gov/pubmed/30642973

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Abstract “Internet technology offers psychiatrists new opportunities for remote interaction with patients. It also raises issues regarding therapeutic effectiveness, safety, technical problems and possibilities for overcoming them, and matters related to specific mental health problems such as autism. The case presented concerns an adolescent male with severe social impairment and isolation as manifestations of Asperger’s syndrome.

The patient … accepted contact with psychiatric services through telepsychiatry, which enabled initial assessment and the development of a therapeutic relationship.

In due course the patient was able to attend the clinic in person. He became somewhat reconciled to his family. With appropriate adaptations he was able to resume his education and career.

Telepsychiatry shows promise in engaging with patients with autism spectrum disorders. As experience accrues, there is some evidence that it is safe and effective. Adaptations to traditional clinical psychotherapy may be required.”

Clarke CS: Telepsychiatry in Asperger’s syndrome. Ir. J. Psychol. Med. 35(4): 325-328 (2018).

https://www.ncbi.nlm.nih.gov/pubmed/30501669

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Abstract:  “The authors sought to describe the emergent course of bipolar disorder in offspring of affected parents subgrouped by parental response to lithium prophylaxis.

Parent bipolar disorder was confirmed by the best-estimate procedure and lithium response by research protocol. High-risk offspring (N=279) and control subjects (N=87) were blindly assessed, annually on average, with the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version or the Schedule for Affective Disorders and Schizophrenia-Lifetime version. DSM-IV diagnoses were confirmed using the best-estimate procedure in blind consensus reviews. Cumulative incidence and median age at onset were determined for lifetime syndrome- and symptom-level data. Mixed models assessed the association between parent and offspring course. A multistate model was used to estimate the clinical trajectory into bipolar disorder.

The cumulative incidence of bipolar disorder was 24.5%, and the median age at onset was 20.7 years (range, 12.4 to 30.3). The clinical course of the affected parent was associated with that of the affected child. Depressive episodes predominated during the early bipolar course, especially among offspring of lithium responders. Childhood sleep and anxiety disorders significantly predicted 1.6-fold and 1.8-fold increases in risk of mood disorder, respectively, and depressive and manic symptoms predicted 2.7-fold and 2.3-fold increases in risk, respectively. The best-fit model of emerging bipolar disorder was a progressive sequence from nonspecific childhood antecedents to adolescent depression to index manic or hypomanic episode. Subthreshold sleep symptoms were significantly associated with transition from well to non-mood disorder, and psychotic symptoms in mood episodes were significantly associated with transition from unipolar to bipolar disorder.

Bipolar disorder in individuals at familial risk typically unfolds in a progressive clinical sequence. Childhood sleep and anxiety disorders are important predictors, as are clinically significant mood symptoms and psychotic symptoms in depressive episodes.”

Duffy A, Goodday S, Keown-Stoneman C and Grof P: The Emergent Course of Bipolar Disorder: Observations Over Two Decades From the Canadian High-Risk Offspring Cohort. Amer. J. Psychiatry [Epub ahead of print, Dec. 11, 2018; doi: 10.1176/appi.ajp.2018.18040461.].

https://www.ncbi.nlm.nih.gov/pubmed/30525908

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Many studies have investigated impairments in cognitive domains in adults with autism spectrum disorder. Yet, to date, a comprehensive overview on the patterns of cognitive functioning is lacking. The present report summarizes the literature on nonsocial and social cognitive functioning in adults with autism spectrum disorder, allowing for comparison of the severity of deficits between different domains.

Results of this systematic review and meta-analysis suggest that adults with autism spectrum disorder show impairments in both social and nonsocial cognitive domains. Specifically, large impairments were found in theory of mind and emotion perception and processing, followed by medium impairments in processing speed and verbal learning and memory. The least altered cognitive domains were attention and vigilance. These findings contribute to the understanding of the patterns of cognitive functioning in these individuals and may assist in the identification of targets for cognitive interventions.

Velikonja T, Fett AK, Velthorst E: Patterns of Nonsocial and Social Cognitive Functioning in Adults With Autism Spectrum Disorder: A Systematic Review and Meta-analysis. JAMA Psychiatry [Epub ahead of print, Jan. 2, 2019; doi: 10.1001/jamapsychiatry.2018.3645.]

https://www.ncbi.nlm.nih.gov/pubmed/30601878

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Limits to human neurogenesis – really?

Lucassen PJ, Toni N, Kempermann G, Frisen J, Gage FH, Swaab DF: Limits to human neurogenesis – really? Molecular Psychiatry [Epub ahead of print, January 7, 2019; doi: 10.1038/s41380-018-0337-5.].

https://www.ncbi.nlm.nih.gov/pubmed/30617274

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Abstract: “Genetic discoveries about human brain development and neuropsychiatric syndromes have changed the landscape of psychiatric research. The genotyping of hundreds of thousands of individuals has identified many hundreds of genomic regions that are associated with psychiatric diagnoses, and progress is being made in uncovering the specific genes that underlie these statistical associations, although most are still undetermined. While there are great expectations that such genetic discoveries will lead to novel treatments based on fundamental mechanisms of illness, there are important caveats. Individual risk-associated common variants explain only a tiny fraction of individual liability. The degree to which common risk variants represent “core” pathogenic insights is controversial. Individuals with rare and more penetrant risk variants are often intellectually disabled, which raises epistemological questions about classification. In clinical research, the application of polygenic risk scores—the cumulative sum of associated alleles in an individual genome—to prediction models of environmental influences and outcome is gaining enthusiasm because these scores explain more liability, but predictions are small and not yet actionable for individuals. Psychiatry is intertwined with genomic medicine, and our understanding of what we call schizophrenia and the possibilities of improving the lives of affected individuals have never seemed more promising. Yet the research challenges are daunting; psychiatric syndromes ultimately reflect how the brain mishandles environmental information, which at the systems level is far “downstream” of the effect of genes in cells.”

Weinberger DR: Thinking About Schizophrenia in an Era of Genomic Medicine. Amer. J. Psychiatry [Epub ahead of print, Jan.1,2019].

https://doi.org/10.1176/appi.ajp.2018.18111275

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Mitochondrial dysfunction has been implicated in a number of brain disorders. Traditionally, mitochondria and mitochondrial DNA (mtDNA) have been thought to be exclusively maternally inherited in humans. In this report, Luo and colleagues identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominant-like inheritance. The authors suggest that, while the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring.

Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may lead to development of new therapeutic treatments for pathogenic mtDNA transmission.

Luo S, Valencia CA, Zhang J, Lee NC, Slone J, Gui B, Wang X, Li Z, Dell S, Brown J, Chen SM, Chien YH, Hwu WL, Fan PC, Wong LJ, Atwal PS and Huang T: Biparental Inheritance of Mitochondrial DNA in Humans. Proc. Natl. Acad. Sci. USA 115(51): 13039-13044 (2018).

https://www.ncbi.nlm.nih.gov/pubmed/30478036

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Administration of the antidepressant fluoxetine to zebrafish, a common laboratory model, reduced levels of the stress hormone cortisol as well as exploratory behavior, effects that persisted across generations, according to a study by Vera-Chang and colleagues. They state that this may be a cause for concern given the high prescription rates of fluoxetine to pregnant women and the potential long-term negative impacts on humans exposed to these therapeutic drugs.

Vera-Chang MN, St-Jacques AD, Gagné R, Martyniuk CJ, Yauk CL, Moon TW and Trudeau VL: Transgenerational hypocortisolism and behavioral disruption are induced by the antidepressant fluoxetine in male zebrafish Danio rerio. Proc. Natl. Acad. Sci. USA 115(52):E12435-E12442 (2018).

 https://www.ncbi.nlm.nih.gov/pubmed/30530669

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