Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies.

Psychological pain is a relatively understudied and potentially important construct in the evaluation of suicidal risk. Psychological pain also referred to as 'mental pain' or 'psychache' can be defined as an adverse emotional reaction to a severe trauma (e.g., the loss of a child) or may be associated with an illness such as depression. When psychological pain levels reach intolerable levels, some individuals may view suicide as the only and final means of escape. To better understand psychological pain, we previously developed and validated a brief self-rating 10-item scale, Mee-Bunney Psychological Pain Assessment Scale [MBP] in depressed patients and non-psychiatric controls. Our results showed a significant increase in psychological pain in the depressed patients compared to controls. We also observed a significant linear correlation between psychological pain and suicidality in the depressed patient cohort. The current investigation extends our study of psychological pain to a diagnostically heterogeneous population of 57 US Veterans enrolled in a suicide prevention program. In addition to the MBP, we administered the Columbia Suicide Severity Rating Scale (C-SSRS), Beck Depression Inventory (BDI-II), Beck Hopelessness Scale (BHS), and the Barratt Impulsiveness Scale (BIS-11). Suicidal patients scoring above a predetermined threshold for high psychological pain also had significantly elevated scores on all the other assessments. Among all of the evaluations, psychological pain accounted for the most shared variance for suicidality (C-SSRS). Stepwise regression analyses showed that impulsiveness (BIS) and psychological pain (MBP) contributed more to suicidality than any of the other combined assessments. We followed patients for 15 months and identified a subgroup (24/57) with serious suicide events. Within this subgroup, 29% (7/24) had a serious suicidal event (determined by the lethality subscale of the C-SSRS), including one completed suicide. Our results build upon our earlier findings and recent literature supporting psychological pain as a potentially important construct. Systematically evaluating psychological pain along with additional measures of suicidality could improve risk assessment and more effectively guide clinical resource allocation toward prevention.

A growing number of epidemiological and experimental studies has established that circadian disruption is strongly associated with psychiatric disorders, including major depressive disorder (MDD). This association is becoming increasingly relevant considering that modern lifestyles, social zeitgebers (time cues) and genetic variants contribute to disrupting circadian rhythms that may lead to psychiatric disorders. Circadian abnormalities associated with MDD include dysregulated rhythms of sleep, temperature, hormonal secretions, and mood which are modulated by the molecular clock. Rapid-acting antidepressants such as subanesthetic ketamine and sleep deprivation therapy can improve symptoms within 24 h in a subset of depressed patients, in striking contrast to conventional treatments, which generally require weeks for a full clinical response. Importantly, animal data show that sleep deprivation and ketamine have overlapping effects on clock gene expression. Furthermore, emerging data implicate the circadian system as a critical component involved in rapid antidepressant responses via several intracellular signaling pathways such as GSK3β, mTOR, MAPK, and NOTCH to initiate synaptic plasticity. Future research on the relationship between depression and the circadian clock may contribute to the development of novel therapeutic strategies for depression-like symptoms. In this review we summarize recent evidence describing: (1) how the circadian clock is implicated in depression, (2) how clock genes may contribute to fast-acting antidepressants, and (3) the mechanistic links between the clock genes driving circadian rhythms and neuroplasticity.

Substance Use Disorder (SUD) is a major public health concern affecting an estimated 22.5 million individuals in the United States. The primary aim of this study was to characterize psychological pain in a cohort of patients participating in outpatient treatment for SUD. A secondary aim was to determine the relationships between pre-treatment assessments of psychological pain, depression, anxiety and hopelessness with treatment retention time and completion rates. Data was analyzed from 289 patients enrolled in an outpatient community drug treatment clinic in Southern California, U.S. A previously determined threshold score on the Mee-Bunney Psychological Pain Assessment Scale (MBP) was utilized to group patients into high and low-moderate scoring subgroups. The higher pain group scored higher on measures of anxiety, hopelessness and depression compared to those in the low-moderate pain group. Additionally, patients scoring in the higher psychological pain group exhibited reduced retention times in treatment and more than two-fold increased odds of dropout relative to patients with lower pre-treatment levels of psychological pain. Among all assessments, the correlation between psychological pain and treatment retention time was strongest. To our knowledge, this is the first study to demonstrate that psychological pain is an important construct which correlates with relevant clinical outcomes in SUD. Furthermore, pre-treatment screening for psychological pain may help target higher-risk patients for clinical interventions aimed at improving treatment retention and completion rates.

Background

Conventional antidepressants usually require several weeks to achieve a full clinical response in patients with major depressive disorder, an illness associated with dysregulated circadian rhythms and a high incidence of suicidality. Two rapid-acting antidepressant strategies, low-dose ketamine (KT) and sleep deprivation (SD) therapies, dramatically reduce depressive symptoms within 24 hours in a subset of major depressive disorder patients. However, it is unknown whether they exert their actions through shared regulatory mechanisms. To address this question, we performed comparative transcriptomics analyses to identify candidate genes and relevant pathways common to KT and SD.

Methods

We used the forced swim test, a standardized behavioral approach to measure antidepressant-like activity of KT and SD. We investigated gene expression changes using high-density microarrays and pathway analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment Analysis) in KT- and SD-treated mice compared with saline-treated control male mice.

Results

We show that KT and SD elicit common transcriptional responses implicating distinct elements of the circadian clock and processes involved in neuronal plasticity. There is an overlap of 64 genes whose expression is common in KT and SD. Specifically, there is downregulation of clock genes including Ciart, Per2, Npas4, Dbp, and Rorb in both KT- and SD-treated mice.

Conclusions

We demonstrate a potential involvement of the circadian clock in rapid antidepressant responses. These findings could open new research avenues to help design chronopharmacological strategies to treat major depressive disorder.

The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.