In this issue of Molecular Psychiatry, we have multiple articles that present exciting advances. Mitochondrial dysfunction is a topic that we are highlighting, and it is addressed by three articles that cover the full spectrum of research translation [1], from animal work, to genetics, and therapeutics. Manuel Gardea-Resendez et al. – see also commentary by Scaini & Quevedo – report that, in patients with bipolar disorder, antidepressants that increase mitochondrial energetics appear to elevate the risk of treatment-emergent mania (TEM) [2, 3]. They showed that adjusting for age, sex and BD subtype, TEM+ was more frequent with antidepressants that increased (24.7%), versus decreased (13.5%) mitochondrial energetics (OR = 2.21; p = 0.000009). Ene et al. showed that transplantation of allogenic healthy mitochondria into the medial prefrontal cortex of adolescent rats was beneficial in a rat model of schizophrenia, while detrimental in healthy control rats [4]. Specifically, disparate initial changes in mitochondrial function and inflammatory response were associated with opposite long-lasting changes in proteome, neurotransmitter turnover, neuronal sprouting and behavior in adulthood. A similar inverse shift in mitochondrial function was also observed in human lymphoblastoid cells derived from patients with schizophrenia and healthy subjects due to the interference of the transplanted mitochondria with their intrinsic mitochondrial state. Additionally, in this issue, Crawford et al provided evidence that Golgi apparatus, endoplasmic reticulum and mitochondrial function may be implicated in Alzheimer’s disease after studying differential gene-expression and associated disrupted biological pathway analyses in postmortem brain samples of subjects with Alzheimer’s disease polygenic risk scores vs. case/controls (cerebellum/temporal cortex) [5]. These articles advance our knowledge of the potential roles for mitochondrial dysfunction is various psychiatric disorders.

Starting from Selye’s remarkable and pioneering work, stress has been identified as a key risk factor for psychiatric disorders [6,7,8]. The neurobiology of stress is addressed in this issue by three remarkable papers. The patterns of spontaneous activity of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus following exposure to chronic unpredictable stress (CUS) were studied by Fang et al. [9]. They showed that CUS exposure increased spontaneous firing of POMC neurons in both male and female mice, attributable to reduced GABA-mediated synaptic inhibition and increased intrinsic neuronal excitability. Collectively, their results indicate that chronic stress induces both synaptic and intrinsic plasticity of POMC neurons, leading to neuronal hyperactivity. They suggest that POMC neuron dysfunction drives chronic stress-related behavioral deficits. It is well known that maternal prenatal stress causes dysfunction of the HPA axis feedback mechanism in their offspring in adulthood. In this issue, Liu et al report that telomerase reverse transcriptase (TERT) gene knockout causes hyperactivity of the HPA axis without hippocampal glucocorticoid receptor (GR) deficiency [10]. Their study also suggests that the prenatal high level of glucocorticoid exposure-induced hypomethylation at Chr13:73764526 in the first exon of mouse Tert gene accounted for TERT deficiency in the dentate gyrus (DG) and hypothalamic–pituitary–adrenal (HPA)axis abnormality in the adult offspring. This conceptually novel work reveals a novel GR-independent mechanism underlying prenatal stress-associated HPA axis impairment, providing a new angle for understanding the mechanisms for maintaining HPA axis homeostasis. Studying young people who participated in the Philadelphia Neurodevelopmental Cohort (PNC), Wong et al provided direct evidence for a global acceleration of brain development associated with traumatic exposures in youths [11]. With a normative model established with quantile regression, they demonstrated that high traumatic stress load was positively associated with poorer cognitive functioning and more psychopathology mediated by accelerated gray matter maturation. Furthermore, in their sample, stressor reactivity score (SRS), representing a normative functional response after controlling for traumatic stress load, was positively associated with accelerated gray matter maturation, particularly in the visual, somatomotor, limbic, and default mode networks and subcortical regions.

Neuroinflammation is addressed here by five papers. Enrico et al. used a machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup [12]. Sæther and colleagues studied patients with severe mental illnesses (SMI), such as schizophrenia (SZ) and bipolar (BD) spectrum disorders, investigating covariance patterns between inflammatory/immune-related markers and cognitive domains and further elucidate heterogeneity in a large SMI and healthy control (HC) cohort (SZ = 343, BD = 289, HC = 770) [13]. They applied canonical correlation analysis (CCA) to identify modes of maximum covariation between a comprehensive selection of cognitive domains and inflammatory/immune markers. The application of hierarchical clustering on covariance patterns identified by the CCA revealed a high cognition-low immune dysregulation subgroup with predominantly HC (24% SZ, 45% BD, 74% HC) and a low cognition—high immune dysregulation subgroup predominantly consisting of SMI patients (76% SZ, 55% BD, 26% HC). These subgroups should be further characterized both in terms of phenotypes and genetics.

Since our inception we have published 476 articles on Alzheimer’s disease (AD), including in October 2021 an entire Special Issue dedicated to advances in AD [7, 14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]. Three new and intriguing papers in this issue discuss neuroinflammation in Alzheimer’s disease (AD).

The relationship between AD and inflammation is complex and multipronged [65]. Very briefly, it is known that neurodegenerative processes, including, but not limited to, AD, precipitate an inflammatory response in the brain [66]. There is a widely accepted paradigm that the aging process is itself accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses—this was first called “inflamm-aging” (or inflammaging) by Franceshci et al. [67, 68]. In turn, central nervous system (CNS) inflammation drives the progression from the presence of amyloid plaque and tau tangles to the onset of dementia and Alzheimer’s disease [69, 70]. This has potential translational therapeutic implications. The inflammasome is a cytoplasmatic multi-protein complex that activates caspase-1 [71]. The inflammasome contributes to inflammaging, with observed caspase 1 activation in aging [72]. Flores et al have shown that pre-symptomatic caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging [73, 74]. There is also the added impact of infection-sepsis cognitive impairment [75].

Genome-wide association studies have reported genetic loci associated with the inflammatory pathway involved in AD [76]. In this issue, Sherva et al. identified significant risk loci in African ancestry GWAS of dementia in a large military cohort [77]. This is to date the largest GWAS of AD and dementia in individuals of African descent. Among the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. The authors suggest, among other things, that as GOPC suppresses complement attacks and inflammation and is cleaved by the γ-secretase complex in response to microbial infection, impairment of these activities in AD could reduce microglial phagocytic capacity and amyloid-β clearance. It is important to study various ethnic groups as genetic allele frequencies vary across populations [78]. Other factors also come into play in the inflammation-AD interface. Obesity, a public global health challenge, promotes a state of systemic inflammation, hyperleptinemia, and leptin resistance that has been identified as a risk factor for AD [79,80,81,82]. The microbiome, which regulates the inflammasome, has been increasingly linked to AD [8, 83, 84]. Using positron emission tomography (PET), Leng et al. showed that neuroinflammation is independently associated with brain network dysfunction in AD [85].

The work of Varma et al. is of exceptional translational relevance—that team provided multiple lines of evidence showing that hydroxychloroquine lowers AD and related dementias risk and rescues molecular phenotypes related to AD [86]. Hydroxychloroquine is a disease modifying antirheumatic drug (DMARD) that modulates immunity and which is widely used in the treatment of rheumatic diseases. Future studies should determine whether hydroxychloroquine could be part of therapeutic strategies to prevent or treat AD and related dementias. The complex but translationally important interface of multiple risk factors, neuroinflammation/inflammaging, Alzherimer’s disease, caspase1, and hydroxychloroquine is depicted in Fig. 1.

Fig. 1: Interrelationship of neuroinflammation/inflammaging, Alzheimer’s disease, caspase 1, and hydroxychloroquine.
figure 1

This diagram depicts the interrelationships of neuroinflammation/inflammaging, Alzheimer’s disease, caspase 1, and hydroxychloroquine treatment in the context of multiple risk factors.

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The continuum of infection-inflammation neurodegeneration is not restricted to AD. Ahn et al. showed that Helicobacter hepaticus augmentation triggers dopaminergic degeneration and motor disorders in mice with Parkinson’s disease [87].

In future issues, Molecular Psychiatry will continue to publish outstanding articles that advance our field.