This review (2017) examines treatment strategies for depression based on neuroplasticity induction via non-invasive brain stimulation and NMDA receptor and glutamatergic modulation via ketamine. The authors raise concerns over the long-term antidepressive efficacy and safety of ketamine and highlight other MDA receptor and glutamate modulators, such as sarcosine, which show antidepressive effects in small-scale studies.

Abstract

“Review: Major depressive disorder is a severe and complex mental disorder. Impaired neurotransmission and disrupted signalling pathways may influence neuroplasticity, which is involved in the brain dysfunction in depression. Traditional neurobiological theories of depression, such as monoamine hypothesis, cannot fully explain the whole picture of depressive disorders. In this review, we discussed new treatment directions of depression, including modulation of glutamatergic system and noninvasive brain stimulation. Dysfunction of glutamatergic neurotransmission plays an important role in the pathophysiology of depression. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has rapid and lasting antidepressive effects in previous studies. In addition to ketamine, other glutamatergic modulators, such as sarcosine, also show potential antidepressant effect in animal models or clinical trials. Noninvasive brain stimulation is another new treatment strategy beyond pharmacotherapy. Growing evidence has demonstrated that superficial brain stimulations, such as transcranial magnetic stimulation, transcranial direct current stimulation, cranial electrotherapy stimulation, and magnetic seizure therapy, can improve depressive symptoms. The antidepressive effect of these brain stimulations may be through modulating neuroplasticity. In conclusion, drugs that modulate neurotransmission via NMDA receptor and noninvasive brain stimulation may provide new directions of treatment for depression. Furthermore, exploring the underlying mechanisms will help in developing novel therapies for depression in the future.”

Authors: Yu-Jhen Huang, Hsien-Yuan Lane & Chieh-Hsin Lin

Summary

Introduction

Major depressive disorder is a severe major mental disorder that can lead to suicidal risk and functional impairment. Current treatment outcomes are suboptimal, with only 30% of patients achieving full remission after first-line antidepressant treatment.

In addition to neurotransmission theory, disrupted signalling pathway and neuroplasticity also play key roles in the pathophysiology of depression. Increased neural plasticity may be the new therapeutic target in the treatment of depression.

Modulating Glutamatergic System in the Treatment of Depression

Investigation of the relationship between glutamatergic system and depression begins with the NMDA receptor, which plays an important role in long-term potentiation, anxiety and depressive disorder.

Ketamine, an NMDA receptor antagonist, is effective for treating depression. A single subanesthetic dose of 0.5 mg/kg of ketamine over 40-minute IV infusion can improve depressive symptoms in patients with MDD and attenuate suicidal ideation.

Ketamine’s long-term antidepressant effect is still under investigation. Repeated infusions may be needed for maintaining the antidepressant effect of ketamine, but no protracted adverse effects have been found in these repeated dose studies.

Ketamine is a mixture of two isoforms, R () ketamine and S (+) ketamine. R () ketamine has more analgesic effect than S (+) ketamine, but S (+) ketamine has more psychotomimetic effect and is associated with more cerebral and systemic hemodynamic side effect compared with R () ketamine.

Ketamine activates the mTOR pathway by increasing presynaptic glutamate release, which in turn stimulates the Akt and ERK pathways. The mTOR pathway increases downstream synaptic protein synthesis by phosphorylating p70 S6 kinase and inhibiting 4E binding proteins (4E-BP).

Ketamine increases brain-derived neurotrophic factor (BDNF) activity by stimulating the AMPA receptor, which leads to activity-dependent release of BDNF and then inhibition of eEF2K, which relieves inhibition upon BDNF translation.

Ketamine can increase the number of mature mushroom-shaped spines and excitatory postsynaptic currents in prefrontal cortex by increasing P70S6K and 4E-BP1 phosphorylation, and increasing postsynaptic density proteins.

Ketamine may also act by inhibiting GSK-3, an important protein in brain function. Ketamine’s antidepressant effect was absent in mice with persistently active GSK-3.

Ketamine may be effective in treating depression through modulating cortical GABA levels. However, inconsistent results have been found regarding the relationship between GABA levels and ketamine’s antidepressant effect.

Ketamine may be used in the treatment of depression, but strong evidence is still lacking. Moreover, long-term administration may cause psychotomimetic effect, cognitive impairment, abuse, and dependence.

Ketamine has a risk of psychotomimetic effects, so other NMDA receptor antagonists are developed as potential antidepressants. AZD6765 (lanicemine) may have an antidepressant effect with a better safety profile, but it failed to show its efficacy in treatment-resistant MDD in phase II clinical trials.

Several selective NMDA receptor subtype 2B (NR2B) antagonists are being investigated as potential antidepressants, including knockdown of NR2B in the bed nucleus of the stria terminalis and genetic deletion of NR2B from principal cortical neurons.

CP-101, 606 (traxoprodil) is a selective NR2B antagonist that has potential antidepressant effects. Unfortunately, further development was stopped because of QTc prolongation.

MK-0657 is the first oral form selective NR2B antagonist developed as an antidepressant. It is being studied for treatment-resistant depression.

Ro25-6891 is another NR2B antagonist showing potential antidepressant effect in some preclinical studies. It can activate mTOR signalling.

D-Cycloserine is an NMDA partial agonist that can restore impaired long-term potentiation in neural cell adhesion molecule-deficient mice model and facilitate NMDA receptor-mediated synaptic potentials in rat hippocampal slices.

GLYX-13 is another NMDA glycine-site functional partial agonist, which has a potential antidepressant effect. It may also rely on AMPA/kainate receptor activation, and is currently under phase II trial.

Sarcosine is a natural compound with activity of NMDA partial agonist. It can improve depressive symptoms in both rodent models and patients with MDD.

Riluzole, a glutamate release inhibitor, increases glutamate reuptake, blocks NMDA receptor activity, and increases AMPA receptor trafficking, and has multiple effects in glutamatergic system. It has been shown to improve depressive symptoms in patients with depression.

Metabotropic glutamate receptor antagonists, such as LY341495 and MGS0039, may be another target for treating depression. These antagonists have antidepressant-like effects in the animal model of depression and may sustain antidepressant effects for 3-7 days after a single-dose injection.

Basimglurant, a selective mGlu5 negative allosteric modulator, shows potential antidepressant activity and excellent drug-like properties. Although it did not have significant difference to placebo in the major outcome, it did show significant improvements in secondary outcomes.

Brain Stimulation in the Treatment of Depression

Brain stimulation is another method to treat depressive disorders. It can improve neurocircuitry activity and neuroplasticity, and can improve connectivity in the prefrontal cortex.

Brain stimulation therapy may exert its antidepressant effect by modulating neuroplasticity. Electroconvulsive therapy (ECT) can stimulate neurogenesis in the frontal brain area and modulate white matter microstructure in pathways connecting frontal and limbic areas in patients with MDD.

ECT influences glutamatergic system and may have synergic effect in antidepressant effect. Ketamine and ECT may have better antidepressant effect.

Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for patients with MDD who are resistant to antidepressant treatment. It uses an electromagnetic coil on the scalp to create an alternating magnetic field.

TMS may work on depression by stimulating neurogenesis, modulating brain activity and neurotransmitters, and altering the imbalance between cortical excitability and regulation of serotonin and dopamine.

Current paradigm of TMS is based on previous studies, but the most effective protocol is still under investigation. Theta burst stimulation (TBS) and low-field synchronized transcranial magnetic stimulation (sTMS) are new protocols that aim to reduce administration duration and improve treatment efficacy.

Transcranial direct current stimulation (tDCS) is another method of noninvasive brain stimulation for the treatment of depressive disorders. It has been shown to be similarly effective to escitalopram in treating depression, but the results of following studies investigating treatment efficacy were disappointing.

Cranial electrotherapy stimulation (CES) applies pulsed, low amplitude electrical currents to the brain via scalp electrodes and has been approved for the treatment of anxiety, depression, and insomnia. Its effect on depression is still unknown.

Magnetic seizure therapy (MST) is a new variant of TMS, which uses high-intensity rTMS to evoke seizures like ECT but with better control. It has a treatment effect on depression, but the mechanism is still unclear.

Conclusion

MDD is a complex mental disorder that has no effective clinical treatment strategy. Ketamine is a promising new treatment, but more studies are needed to validate its efficacy and safety.

The underlying neurobiological mechanisms of depression treatments are based on the theory of neuroplasticity impairment. This indicates a novel direction in the future development of antidepressive treatment.