This review (2015) discusses research developments regarding therapeutic compounds that exert their antidepressant efficacy via the glutamatergic, cholinergic, and opioid systems. The authors encourage innovative research strategies for improving the efficacy of treatments such as ketamine, whose effects are rapid but not long-lasting.
Abstract
“Review: Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments—especially for treatment-resistant depression (TRD)—are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research.”
Authors: G. I. Papakostas & D. F. Ionescu
Summary
INTRODUCTION
Depression is one of the most devastating medical disorders known to mankind. Many people with depression need treatment throughout their lifetime, but treatments do not work sufficiently for many.
The evolution of antidepressant therapy for TRD is undergoing a remarkable revolution. Researchers are now focusing on compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems, as well as device based and procedural therapies for patients with difficult-to-treat depression.
NOVEL THERAPEUTICS: REVIEW
Ketamine has been shown to have rapid, robust, and sustained antidepressant effects in well-characterized patients with TRD. Ketamine has been shown to have a high effect in reducing scores on the Montgomery Asberg Depression Rating Scale.
Ketamine has been shown to decrease depressive symptoms in patients with unipolar and bipolar anxious depression, as well as suicidal ideation and anhedonia. It has also been shown to decrease the symptoms of depression in patients with TRD.
Ketamine is classified as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, though its antidepressant mechanism of action remains largely unknown. It may act by stimulating translation pathways for proteins involved in neuronal plasticity, and by decreasing inflammation.
Lanicemine, a moderate-affinity low-trapping NMDA-receptor blocker, has been tested as an antidepressant in both preclinical and clinical settings. Its antidepressant action was rapid and short-lived, but its psychotomimetic and dissociative side effects did not differ compared with placebo.
Another larger study provides further evidence for lanicemine’s rapidly acting antidepressant properties and superior side effect profile. Lanicemine significantly decreased MADRS scores from baseline to week 3 in patients randomized to 100 mg, and this effect lasted for up to 5 weeks following the last infusion.
Memantine is a low-to-moderate affinity NMDA-receptor antagonist that has been approved for Alzheimer’s dementia, but has not shown significant antidepressant effects in depression trials.
Riluzole, an FDA-approved medication for amyotrophic lateral sclerosis, inhibits glutamate release via sodium channel inactivation, while blocking NMDA-receptor activation and enhancing AMPA expression. It has been hypothesized that riluzole could extend the antidepressant properties of a single ketamine infusion, while simultaneously avoiding ketamine’s unwanted side effects.
MK-0657, an antagonist at the NR2B subunit of the NMDA receptor, was studied in 21 medication-free patients with TRD. No significant mood improvements were seen on the MADRS, though rapid antidepressant effects were appreciated.
Nitrous oxide is similar to ketamine in that it is a non-competitive antagonist of the NMDA receptor. It was found to be effective in treating symptoms of depression in patients with TRD.
GLYX-13, a functional partial agonist at the NMDA-receptor glycine site, has been shown to produce antidepressant effects in rats, without the unwanted side effects that accompany ketamine. It has also been shown to improve depression scores in humans.
Avanir has started recruiting patients for Phase II testing of AVP-786, which is a novel combination of deuterium-modified dextromethorphan hydrobromide and low-dose quinidine sulfate.
Org 263576, an AMPA positive allostergic modulator (AMPA PAM) in development, improved clinically relevant cognitive measures of executive functioning and speed of processing in healthy volunteers and was associated with increases in growth hormone and decreases in cortisol at the end of treatment.
Metabotropic glutamate receptor modulators may be effective against depression. Basimglurant, an antagonism of the mGluR5 postsynaptic receptor, showed consistent antidepressant efficacy across primary and secondary end points in one 9-week double-blind, placebo control study in 333 patients with TRD.
Scopolamine, often used for motion sickness, has been found to rapidly decrease symptoms of depression and anxiety in both unipolar and bipolar patients, though those with treatment-naive depression showed greater improvements.
Mecamylamine and dexmecamylamine (TC-5214) are nicotinic-receptor antagonists that have been studied for the treatment of depression. Mecamylamine was superior to placebo in improving primary and secondary depression outcomes when augmented to citalopram treatment in incomplete responders with depression.
CP-601,927, a selective nicotinic acetylcholine receptor partial agonist, failed to show superior antidepressant efficacy to placebo as an augmentation agent to selective serotonin reuptake inhibitors in one Phase II randomized trial.
ALKS 5461, a compound that combines buprenorphine and samidorphan, is an attempt to create a functional kappa receptor antagonist, sans addiction potential. It has shown positive efficacy and safety data, with no abuse with withdrawal concerns.
Monoaminergics Vortioxetine was approved by the FDA in 2013 for the treatment of MDD. It is thought to combine direct serotonin receptor modulation with serotonin transporter inhibition, and may interrupt negative feedback mechanisms that control neuronal activity in several brain areas implicated in the pathophysiology of MDD.
Lisdexamfetamine dimesylate (LDX) is an inactive prodrug that is metabolized to dextroamphetamine, thereby gaining approval for the treatment of attention-deficit hyperactivity disorder. However, a Phase II trial found no statistically significant advantage over placebo.
Edivoxetine, a highly selective norepinephrine reuptake inhibitor, was studied as adjunctive therapy in depressed patients partially responsive to SSRIs, but failed to show efficacy in subsequent Phase III trials.
Pramipexole is a dopamine agonist that is FDA approved for the treatment of Parkinson’s disease and Restless Leg Syndrome. It has been shown to have modest antidepressant augmentation benefits in a small 8-week trial, but is not statistically significant.
Neutraceuticals and exercise L-methylfolate and S-adenosyl-methionine (SAMe) are important in neurotransmitter synthesis and have been studied as augmentation agents to antidepressants. However, a second trial found statistically significant antidepressant efficacy for adjunctive L-methylfolate at 15 mg day 1 compared with placebo, with comparable safety profiles.
MSI Methylation Sciences are currently conducting a large Phase II trial to examine the efficacy and safety of SAMe augmentation compared with placebo in patients with an inadequate response to their current antidepressant therapy.
Exercise can improve mood and overall wellbeing, and may help with depression. In one study, patients who exercised more had a better remission rate than those who exercised less, and this effect was more pronounced in men and women without a family history of mental illness.
The hormone Erythropoietin (EPO) has several roles in the central nervous system, including neuroprotection, neurodevelopment, and cognitive functions. However, a double-blind, placebo-controlled parallel-group design trial found mixed results for EPO’s antidepressant usefulness.
A double-blind, randomized clinical trial using testosterone in men with depression failed to show any statistically significant augmentation effects.
Infliximab, a monoclonal antibody inhibitor of tumor necrosis factor-, may improve symptoms of depression in patients with elevated biomarkers of inflammation, but does not appear to have generalized efficacy in TRD.
A recent meta-analysis found an association between nonsteroidal anti-inflammatory drugs and improvements in depression, and that celecoxib was particularly effective in improving antidepressant effects, remission and response.
Device-based therapies are thought to be effective in treating depression and anxiety disorders. Transcranial magnetic stimulation (TMS) uses magnetic pulses to induce electrical currents within the brain, and has been found to be as effective as venlafaxine plus low-frequency rTMS and venlafaxine alone for treatment-resistant depression.
Deep TMS (dTMS) utilizes an H-shaped coil to modulate neuronal activity in deeper regions of the brain, and has been hypothesized as useful for treating depression. It is also effective in patients who failed to respond to ECT or who relapsed after previous dTMS. One randomized, double-blind, controlled multi-center trial evaluated the efficacy and safety of dTMS in 212 unmedicated TRD patients. The results showed that dTMS significantly increased response and remission rates compared with sham treatment.
DISCUSSION
Over the past 5 years, atypical antipsychotic agents have continued to expand their evidence base supporting their efficacy as adjunctive treatments in MDD. However, their relative safety and tolerability concerns and slow onset of action pose two main limitations.
Phase III programs involving other cathecholaminergic-selective agents (LDX, edivoxetine) as well as dexmecamylamine have failed, highlighting a continued unmet need. However, some success has been noted with respect to the development of rapidly acting agents (for example, glutamatergic modulators and scopolamine), though there are several limitations. There has been very little done with respect to switching strategies for MDD, and clinicians often prefer to use adjunctive therapies in partial responders versus switching. Furthermore, study inclusion and exclusion criteria should be tailored according to the efficacy and tolerability of the intervention.
The ongoing RAPID study is a large NIMH-funded multi-site initiative that will examine and develop rapidly acting novel therapeutics for patients with TRD. This study will include an assessment of the antidepressant efficacy and tolerability of low-field magnetic stimulation augmentation of antidepressants and LY2456302, a potent, centrally acting, selective kappa-opioid receptor antagonist.
As reviewed, new treatments for resistant depression have broken away from monoaminergic antidepressant ‘dogma’ and into a wider realm of possibilities. The brain’s intricate highway system of neurocircuitry and neurotransmission is intimately connected.
Ketamine’s rapidly acting antidepressant properties remind us of the importance of serendipity in antidepressant research, and how these breakthroughs can be combined with biomarkers’ breakthroughs, target-engagement research and neuroscience-driven discovery.