Rapid antidepressant treatments can contribute to how the brain can reorganise its activity to defeat depression


Ketamine alleviates depressive symptoms within hours, with the most significant change typically seen a day after its administration.

However, the symptoms often reappear within a week. According to researchers at the University of Helsinki, neural connections strengthened by the quick treatment of depression are consolidated in the brain during the deep sleep periods of the following night.

To prevent the circle of negative thoughts regaining supremacy, depressed patients also need therapy.

Depression and long-term stress have been demonstrated to cause changes in the brain which offer a partial explanation for depressive moods, apathy, memory difficulties and other symptoms commonly associated with depression.

Unbroken circles of negative thoughts are also often a distinct aspect of the mental status of depressed patients. This is down to very active and selective brain function.

“In turn, this strengthens the neural connections associated with precisely this type of thinking. Less active connections and neural networks supporting normal brain function weaken due to a lack of use, which completes the circle of negativity.

The result is an imbalance of activity among neural networks, and clinical depression,” says Associate Professor Tomi Rantamäki from the Faculty of Pharmacy, University of Helsinki.

The vicious circle could be broken by guiding the brain back towards a more comprehensive mode of action. Such guidance can be boosted by means of psychotherapy, but the effects manifest slowly.

In recent years, rapid-acting modes of treatment for depression have been investigated, potentially offering entirely novel approaches.

The latest new product is a nasal spray that contains esketamine, which was just granted a marketing authorisation in Europe.

“What ketamine, psychiatric electroconvulsive therapy, nitrous oxide and certain other therapies already in use or currently being trialed have in common is the fact that they increase the activity of broad cortical areas and strengthen synaptic connections.

At their best, they force the broad neural networks of the cerebral cortex into an entirely new kind of interaction, which makes it possible to weaken the previous imbalance,” notes Samuel Kohtala, a postdoctoral researcher at the University of Helsinki.

However, such rapid relief is only temporary, unless the plasticity mechanisms endogenous to the nervous system are utilised.

“According to the synaptic homeostasis hypothesis, synapses strengthened during the day undergo a process of renormalisation in deep sleep, which is dominated by slow-wave activity.

The most potentiated synapses may retain their relative strength better than weaker synapses, which presents an opportunity for learning new information while purging the network of excessive noise.

We think that rapid antidepressant treatments share the ability to regulate both synaptic potentiation and the reciprocal homeostatic mechanisms, which weaken synaptic strength during sleep.

Either of these mechanisms can contribute to how the brain can reorganise its activity to defeat depression,” Kohtala says.

Based on the studies, molecular mechanisms implicated in neuronal plasticity are particularly activated during periods of slow-wave activity. Thus, slow-wave responses could be a useful measure for determining treatment efficacy and developing novel treatments.

The researchers point out that, boosted by similar mechanisms, brain function may again be derailed during subsequent sleep periods, unless the neural networks driving the depression are sufficiently controlled, for example, by means of psychotherapy.

“The main symptoms of depression can be artificially affected by destabilising the functioning of neural networks. A more permanent effect requires tackling the root causes of the problem as well,” Rantamäki emphasises.

Ketamine: Cellular and Molecular Mechanisms

Ketamine exerts its initial rapid antidepressant properties via the NMDA receptor blockade and a prolonged change in glutamatergic signaling downstream of the NMDA blockade, ultimately resulting in increased synaptic strength and plasticity.

Current research efforts have focused on uncovering the sequence of events that lead from blockade to rapid improvement in mood, cognition and behavior. Experiments investigating the role of glutamatergic transmission indicate that blockade of NMDA receptor-induced firing of gamma aminobutyric acid (GABA)ergic interneurons disinhibits glutamatergic pyramidal cells [15], thus increasing glutamate release and activation of AMPA receptors, and culminating in an activity-dependent release of BDNF [13, 16].

Ultimately changes in glutamatergic transmission activate the mammalian target of rapamycin (mTOR) signaling pathway and affect downstream structural changes in dendritic spines and local synaptic protein synthesis, including BDNF [17].

BDNF secretion, activation of the tropomyosin receptor-kinase B (TrkB) receptor, and downstream trafficking lead to further dendritic structural complexity, spine and BDNF synthesis, and synaptic plasticity.

The functional effects of BDNF trafficking are compromised by polymorphisms such as BDNF Val66Met [18, 19]. Ultimately changes in critical local neuronal circuits converge via enhanced synaptic plasticity and neuronal synchronization, especially in areas involved in mood and behavior, to produce rapid antidepressant effects [11, 13].

Notable in these observations is that manipulation of many steps in this signaling cascade either replicate or reverse the effects of ketamine in various rodent models of depression. For instance, the multi-day antidepressant effects of ketamine, as well as the synaptic spine production associated with its use, are blocked by rapamycin, which prevents activation of the mTOR pathway [13, 16].

In addition, the effects of chronic unpredictable stress (decreased spine density, depressive-like behavior) are known to be reversed with ketamine [20]; rapamycin similarly blocks ketamine’s effects.

An alternative interpretation is that the blockade of spontaneous (rather than evoked) glutamatergic activation of NMDA receptor blockade is critical to ketamine’s mechanism of action [21], resulting in the inability to activate eukaryotic elongation factor 2 (eEF2) kinase, blunting of eFF2 phosphorylation, and BDNF derepression [22]. Further research is needed to discriminate between these mechanisms. Finally, inhibition of rapid (30 min) BDNF synthesis by anisomycin after ketamine treatment prevented the long-term behavioral effects of ketamine measured with the forced swim test [21].

Sleep and Plasticity

Demonstrating increased synaptic plasticity in humans following ketamine administration is a challenging undertaking, especially in a clinical population of patients with severe treatment-resistant depression.

However, work from the Tononi laboratory at the University of Wisconsin suggests that some electrophysiological measures—such as sleep EEG and evoked potentials—are reliable indicators of increased synaptic plasticity in humans. In fact, high-density EEG studies have shown that manipulations leading to synaptic potentiation in local cortical circuits [rotation learning, high-frequency transcranial magnetic stimulation (TMS)] lead to a local increases in SWA during subsequent sleep [23]; in contrast, manipulations leading to synaptic depression (arm immobilization) lead to a local reduction in SWA [24].

Large-scale computer simulations, validated by experimental studies in both rats and animals, have demonstrated that sleep SWA directly reflects synaptic strength due to changes in neural synchronization and recruitment [25, 26]. Moreover, these studies have shown that the slopes of sleep slow waves represent a highly sensitive marker of synaptic strength in underlying circuits [27].

Several studies that directly examined the effect of BDNF on EEG sleep slow waves have also noted a close relationship between SWA and BDNF [9, 28]. Interestingly, these studies found that SWA is increased by intrahemispheric infusion of BDNF, diminished by BDNF antagonism [9], and increased by behavioral interventions that increase central levels of BDNF [28] as well as the plasticity-related genes Arc, Homer, and NGFI-A [28].

Acoustic suppression of SWA activity and its capacity to diminish perceptual learning [29] further supports the possibility that decreased levels of slow wave sleep per se may contribute to cognitive and memory deficits in some depressed patients.

Recent clinical studies have established another link between BDNF, sleep slow wave activity, and mood by showing that human carriers of the BDNF Met allele of the Val66Met polymorphism have reduced production of sleep slow waves [30]. Another study found that individuals with this polymorphism were less likely to respond to ketamine than the Val/Val allele [31].

Sleep Deprivation (And Other Sleep Interventions) as Rapidly Acting Interventions and Extenders of Remission

The robust and rapid antidepressant efficacy of SD therapy underlies its continued clinical and research use for over 5 decades [32, 33]. SD leads to increased slow wave sleep during recovery sleep, suggesting that the deficient production of sleep slow waves in many patients with depression may be part of a pathology that can be briefly reversed by the homeostatic processes activated by SD [34].

More recently, the synaptic homeostasis hypothesis [35], which extends the two-process model of sleep regulation described above [36], has provided a conceptual and cellular framework to understand the possible molecular underpinnings of SD therapy. Specifically, SD is associated with increased neurotrophic factors such as BDNF and VEGF [37, 38] as well as with synaptic plasticity and rapid remission of depression; notably, many of the same effects are observed with ketamine treatment. However, it is currently not known whether response to SD therapy predicts response to ketamine, which would provide support for a common mechanism underlying rapid antidepressant effects.

Interestingly, while SD therapy and ketamine treatment both exert rapid antidepressant effects, these interventions differ with regard to course of remission and relapse. One distinction concerns the depressogenic role of sleep in relapse, a core problem with SD therapy.

After the rapid response to SD therapy, sleep per se contributes to relapse, an effect often seen following the first night of recovery sleep, or possibly sooner following a daytime nap. In contrast, the rapid antidepressant effects of ketamine are not rapidly or robustly reversed by sleep. However, careful evaluation of this point is needed since a differential response to recovery sleep would suggest that SD and ketamine differ with respect to synaptic downscaling, the process associated with restorative function of sleep, sleep homeostasis [35], and the course of remission.

Relatedly, time to relapse can be rapid (<1 day) after SD therapy, but often extends past 4 to 7 days in those patients who respond to a single infusion of ketamine. Several adjunct interventions [lithium, selective serotonin reuptake inhibitors (SSRIs), phototherapy, chronotherapy] have been shown to prolong response to SD therapy [39–41].

While repeated ketamine infusions extend the antidepressant response [42–44], concurrent treatment with riluzole, a presynaptic inhibitor of glutamate release and enhancer of AMPA trafficking and glial glutamate reuptake, does not alter the course of remission [45, 46]. Another study noted that treatment with the mood stabilizers lithium or valproate did not alter the relapse rate in individuals with bipolar depression treated with ketamine [10], but it remains unknown whether they may extend the interval to relapse.

The contribution of sleep in affecting the response to ketamine has not been directly evaluated. Microsleep episodes [47] as well as nighttime sleep restriction [48] have been shown to blunt and extend response to SD therapy [47] respectively, but similar research with ketamine has not been conducted. Taken together with the fact that altered glutamate transmission contributes to the rapid antidepressant mechanism of both SD therapy [40, 49, 50] and ketamine [13, 16••, 21••], suggests that sleep restriction and careful management of sleep after ketamine may prolong remission by affecting glutamatergic transmission.

Effects of Ketamine on Sleep and Slow Waves in Treatment-Resistant MDD

Earlier studies indicated that the NMDA antagonists ketamine [51] and MK-801 [52] increased SWA. Given the rapid anti-depressant effects associated with SD, as well as its ability to increase neurotrophins and SWA, we hypothesized that similar changes might also be associated with rapid mood change after ketamine infusion. To test the hypothesis that ketamine increased synaptic strength in conjunction with its rapid effects on mood, sleep slow waves (a putative central marker of plasticity) and BDNF (a peripheral marker of plasticity) were measured [53].

Montgomery-Åsberg Depression Rating Scale (MADRS) scores rapidly decrease and remain low for several days following ketamine treatment in patients with treatment-resistant MDD. In our recent clinical investigation of ketamine and sleep, plasma BDNF levels, SWA, and high amplitude waves increased after ketamine [53]. SWA and amplitude effects were increased during early sleep (first nREM period).

These slow wave effects were limited to the first night after ketamine infusion. Importantly, the first-night EEG slow wave changes were accompanied by an increase in slow wave slope, consistent with increased synaptic strength [27].

Further, in those patients who responded to ketamine (defined as a greater than 50 % reduction in MADRS score 230 min after infusion), changes in BDNF levels were proportional to changes in EEG slow wave parameters, suggesting that enhanced synaptic plasticity is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists.

Ketamine’s effects on sleep EEG were specific to low frequencies corresponding to the SWA range. Further, ketamine did not increase SWA in waking epochs prior to sleep onset, indicating that the change was sleep-specific. Negligible effects of the ketamine infusion on sleep EEG were measured in bands corresponding to sleep spindles, and alpha or theta frequencies [53].

In addition to significant ketamine-induced increases in levels of BDNF, SWA, high amplitude waves, and slope, the observed correlations between BDNF levels and slow wave parameters indicate a strong relationship between these measures.

Specifically, the positive correlations between changes in logBDNF and changes in relative SWA, as well as between changes in logBDNF and the incidence of high amplitude sleep slow waves, are consistent with the association between these markers of synaptic plasticity [9, 28]. Interestingly, most patients classified as ketamine responders had low levels of SWA and BDNF at baseline, followed by large increases in both of these measures after ketamine infusion [53].

Indeed, the low baseline production of SWA during the first nREM period predicted later response to ketamine in responders [54], suggesting that lower brain plasticity is a marker of ketamine response, which is reversed by ketamine in responders [53, 55].

Significant day-to-day changes in sleep variables appear to provide markers of an underlying sequence of signaling cascades associated with immediate (day one) and continued (day 2) mood response [53] involving synaptic plasticity and BDNF. Of special interest is the observation that ketamine-induced increases in sleep slow waves were confined to the first night after treatment but were then decreased toward baseline levels on night two (Fig. 1).

The timing of a day 1 increase in slow waves, followed by a decline toward baseline levels on day 2, is consistent with preclinical findings of Autry et al. [21] of an acute day 1 (30 min) increase in BDNF levels, followed by a day 2 decrease, and may be particularly important given the previously described association between BDNF and slow wave production [9, 28]. Thus, the decline of sleep slow waves on day 2 would be consistent with a decline in BDNF levels. However, because BDNF was not measured in the clinical study, this point requires further investigation.

It is also important to note that there was an increase in total sleep and a decrease in waking during both the first and second nights following ketamine infusion, indicating that persisting changes related to sleep consolidation may contribute to continued antidepressant mood effects. Overall, the increase in sleep slow waves appears to be a marker of the acute increase in BDNF and rapid antidepressant effects, whereas improved sleep quality is associated with extended mood response. Studies are ongoing to identify additional mediators of the extended mood response.


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