Identifying Genetic Loci in Depression: TOX2 and FHIT
Identifying risk loci in major depressive disorder (MDD) via genome-wide association studies (GWASs) has proven difficult. An alternative genome-wide method, termed haplotype-block-based regional heritability mapping, targets the combined effects from multiple single nucleotide polymorphisms within haplotype blocks. Using this approach in a Scottish cohort, Zeng et al. (pages 312--321) identified a 24-kb region within TOX2 that is associated with MDD. Subsequent association tests traced this signal to MDD-associated single nucleotide polymorphisms with potentially functional effects, and the results were partially replicated in independent samples. These results suggest that TOX2 should be explored further in future studies.
Evidence suggests that depression can be conceptualized along a continuum ranging from mild symptoms to severe MDD, but GWASs to date have focused on a single phenotype. Direk et al. (pages 322--329) pooled published GWAS analyses of MDD and depressive symptoms to identify genetic variants underlying the entire depression continuum. They found one genome-wide significant locus (rs9825823) for the broad depression phenotype, which is located in an intron of FHIT, a protein-coding gene that is expressed in multiple brain regions and, among other things, plays a role in oxidative stress.
Neuroimaging Meta-analyses in Depression
Numerous studies have investigated structural and functional brain alterations in MDD. Here, Kambeitz et al. (pages 330--338) coupled a meta-analytic approach with machine learning to address whether patients with MDD could be differentiated from healthy control subjects using magnetic resonance imaging (MRI) data. Using data from 33 studies, they report an average of 77% classification accuracy. Classifications derived from resting-state functional MRI and diffusion tensor imaging data yielded higher accuracy than structural MRI and task-based functional MRI data. Thus, neuroimaging-based classification represents a promising approach, but accuracy must be improved before such models can be used clinically.
Evidence suggests a possible link between late-life depression (LLD) and brain volume loss, particularly within the hippocampus. Geerlings and Gerritsen (pages 339--350) performed a meta-analysis from 35 studies and found smaller hippocampal volume in patients with LLD, relative to control subjects. Effect sizes were larger for case-control studies, studies with lower quality, and studies with small sample sizes. These data indicate that while LLD may generally be associated with lower hippocampal volume, methodological issues and clinical factors influence this relationship.
Circadian Signatures of Rapid Antidepressant Effects
Sleep deprivation and ketamine are efficient and fast-acting antidepressant treatments, but whether there is a common mechanism underlying their therapeutic actions is unclear. Orozco-Solis et al. (pages 351--360) examined the effects on behavior and gene expression changes in the anterior cingulate cortex (ACC) of mice treated with sleep deprivation and ketamine. Their findings reveal that both treatments elicit common transcriptional responses related to neuronal plasticity and the circadian clock. They also identified 64 overlapping genes, which include several downregulated core clock genes. These data implicate involvement of the circadian clock in rapid antidepressant responses.
Ketamine’s rapid antidepressant effects may be expressed in changes in patterns of daily activity. Duncan et al. (pages 361--369) investigated this hypothesis in treatment-resistant patients with MDD or bipolar disorder using wrist activity monitors to measure circadian activity patterns. They discovered that ketamine, relative to placebo, had a mood-independent effect on the pattern of daily activity, and that clinical response is related to circadian differences at baseline. Responders showed advanced timing at baseline and day 1 after ketamine treatment and increased activity on day 3. These data link the antidepressant effects of ketamine to circadian rhythms in daily activity.
MAPK Phosphatase-1 in Depression
Both chronic stress and chronic pain are associated with the development of depression. The ACC is critically involved in the processing of stress and pain and is altered in depression. Here, Barthas et al. (pages 370--379) report an overexpression of the mitogen-activated protein kinase phosphatase-1 (MKP-1) in the ACC of mice displaying anxiodepressive-like behavior after chronic pain, chronic stress, or repeated ACC optogenetic stimulation. This upregulation was associated with the presence of chromatin marks and increased expression or activity of transcription factors. Ablation or blockade of MKP-1 inhibited depressive-like behaviors, suggesting that MKP-1 may serve as a novel target for the treatment of depression.
