Rapid-acting antidepressants and the circadian clock

Abstract

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.

Fig. 1. Organization of the circadian clock.

A Representative schema depicting efferent and afferent signaling to the suprachiasmatic nucleus (SCN) (black arrows). These include limbic structures including the infralimbic cortex (LC), lateral septal nucleus (LSN), basal forebrain of the stria terminalis (BST), ventral subiculum (VS), paraventricular thalamic nuclei (PVT), nucleus accumbens (NAc), ventral tegmental area (VTA), medial preoptic nucleus (MPO), dorsal raphe nucleus (DRN), median raphe nucleus (MRN) and hypothalamic nuclei [i.e., dorsomedial hypothalamus (DMH), and the retino-hypothalamic tract (RHT)] [28, 30]. The lateral habenula (LHb) efferent and afferent connections are shown (red arrows), ventral lateral geniculate (Vlgn), intergeniculate leaflet (IGL), rostromedial tegmental nucleus (RMTg) [25, 28, 34, 116, 220]. B A predictive model in which ketamine and sleep deprivation elicit common transcriptional responses by blocking BMAL1/CLOCK function at specific times of the day (Zeitgebers-ZTs) associated with neuronal and behavioral responses [94, 95, 219]. Changes in the acrophase and/or amplitude of the CCGs participating at different regulatory levels could affect mood. The 7 clock-controlled genes represent potential components of rapid antidepressant actions of ketamine and sleep deprivation.

Fig. 2. Implication of the circadian clock in the regulation of neural signaling and behavior.

A Proposed mechanisms of action of ketamine and sleep deprivation on the glutamatergic synapse. (1) ketamine and sleep deprivation activate astrocytes, which induces the exocytosis of adenosine, stimulating the P2 × 7 (ATP-gated P2X receptor cation channel family) receptor and releasing glutamate (GLU) into the intraneuronal space. Adenosine also binds A1R in NSCs inducing its proliferation via MEK/ERK-AKT pathways [, –168]. Astrocytes might further receive humoral signals acting as zeitgebers from blood vessels thereby contributing to circadian neuronal activity [170, 221]. (2) Ketamine blocks NMDA receptors at the inhibitory GABAergic interneuron, leading to disinhibition of glutamatergic transmission [75]. (3) In turn, glutamate triggers the release of BDNF at postsynaptic neurons leading to stimulation of the TrkB-AKT-mTOR and subsequent synaptic protein synthesis [67, 78, 79]. Inhibition of GSK3β (which is controlled by the circadian clock) contributes to the activation of mTOR [, –225]. Dopamine also contributes to plasticity via the AKT-GSK3 pathway [226]. B Neuronal plasticity might be further enhanced by the inhibition (or phase-shift) of the BMAL1-CLOCK recruitment to Per2 Dusp1, Notch2, or Homer1 promoters [95]. Per2 functions as a scaffold to recruit TSC1, Raptor, and mTOR suppressing mTOR activity [227], Dusp1 negatively regulates the MAPK pathway by dephosphorylation of ERK1/2 [127]. The transcriptional reduction of Dusp1 might disinhibit ERK1/2 which in turn blocks the TSC2 complex resulting in the induction of mTOR-mediated protein synthesis. Also, ERK1/2 activates the CREB-mediated transcription of bdnf, which indirectly induces protein synthesis by blocking the TSC2 complex via AKT. The transcriptional reduction of Notch1 promotes the neurogenesis involved in neural stem cell (NSC) maintenance [159]. Homer1 transcription is further modulated by CREB and participates in the synaptic plasticity-induced by sleep deprivation and ketamine [60, 228]. These mechanisms would be operating in different brain areas related to mood reward, and cognitive demanding tasks such as memory, attention, and decision-making such as the mPFC, hippocampus, striatum, ACC, and other brain regions.