Does glutamate hold the key to unlocking major depressive disorder?

Despite over 50 years of drug development in major depressive disorder (MDD), patients and their clinicians still face significant limitations regarding onset of efficacy, response rate and remission risk.  Until now, the monoaminergic system has been the main focus of drug development for MDD, but the glutamatergic system is showing significant potential as a novel therapeutic target, and was the focus of an engaging expert science exchange at ECNP2018.

Professor Eduard Vieta (University of Barcelona, Spain) introduced the potential of the glutamate system as the most exciting new development in psychiatry for decades, and of great relevance to clinicians. There has been significant progress in the development of a range of anti‑depressant drugs, but limited by the current catecholamine paradigm.

Why do we need new treatments?

Of importance to clinicians, is that first line agents are only successful in achieving remission in 36.8% of patients1, and usually take 2 to 4 weeks to show efficacy.  Success rate worsens by the more agents you have to try, with the STAR*D study showing remission rates dropped to 30.6%, 13.7% and 13.0% with second, third and fourth line agents, respectively1.

Glutamate is the major excitatory neurotransmitter, found extensively throughout the central nervous system (CNS)

The current unmet need in MDD treatment, Professor Vieta said, is for faster onset of improvement in symptoms, greater clinical efficacy, and better tolerability.  The first being crucial for continued patient adherence to treatment, as side effects often present before efficacy is achieved.  This leads to the paradox that patients can feel worse when they first start treatment than before.

The role of glutamate in MDD

Glutamate is the major excitatory neurotransmitter, found extensively throughout the central nervous system (CNS), with links to many other neurotransmitter pathways. Release at synapses leads to short term post-synaptic excitation and longer-term changes in synaptic strength and neuroplasticity, regulation of second messengers and gene expression.

Interest in the glutamatergic pathway is not new, with studies since the 1990s

Interest in the glutamatergic pathway is not new, with studies since the 1990s showing altered glutamate levels in depression, and the anti-depressant effects of blocking glutamate receptors, but needed to translate into viable therapeutic agents. Portella et al2 found significantly decreased ventromedial pre-frontal cortex glutamate levels in remitted-recurrent and chronic MDD compared to first episode and healthy controls, and a negative correlation with disease duration. Genes involved in glutamatergic synaptic neurotransmission are significantly associated with MDD3. Other studies have found contrasting results for cerebrospinal fluid glutamine, with levels increased in depression4 and reduced in refractory affective disorder5

Genes involved in glutamatergic synaptic neurotransmission are significantly associated with MDD

In MDD, alterations in glutamatergic neurotransmission and intracellular signalling result in decreased levels of brain-derived neurotrophic factor (BDNF) and other key neurotrophins, with neuronal atrophy and reduced synaptic plasticity.

The glutamatergic system explained

Professor Pierre Blier (University of Ottawa, Canada) explained how glutamate acts via two classes of receptor, ionotropic (ligand gated ion channels) and metabotropic (G‑protein coupled).  Ionotropic glutamate receptors are further subdivided into α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), NMDA, and Kainate receptors, with NMDA receptors requiring binding of a co-agonist glycine. They directly modulate cations (e.g. sodium) through the membrane and facilitate excitatory neurotransmission. Metabotropic glutamate receptors have three sub-groups, and indirectly modulate postsynaptic ion channels and regulate diverse cellular processes.

An interesting insight comes from autoimmune encephalitis, characterised by anti-N-methyl-d-aspartate (NMDA) receptor autoantibodies6. 4% of these patients have mostly affective psychiatric symptoms, described vividly in the book by Susannah Cahalan ‘Brain on Fire’.

The potential of glutamate modulators

The glutamatergic system is complex and ubiquitous throughout the brain, hence the fear that intervening with pharmaceutical agents will cause harm as well as good. Despite these concerns, emerging evidence shows that a number of different agents acting on the NMDA and AMPAR receptors, may have antidepressant properties, including antagonists, partial agonists, and allosteric modulators. The seemingly contradictory modes of action of some of the drugs are due to factors such as differences in location of receptor target and dose used. With further research, agents acting on these receptors may emerge which are both efficacious and safe for the treatment of depression.

Educational financial support for this session was provided by Allergan plc

  1. Rush et al. Am J Psychiatry 2006;163:1905-17
  2. Portella et al. J Psychiatric Res 2011;45(4):427-34
  3. Lee et al. Transl Psychiatry 2012;2:e184
  4. Levine et al. Biol Psychiatry 2000;47(4):586-93
  5. Frye et al. Biol Psychiatry 2007;61(10):1221
  6. Leon-Caballero Neurosci Biobehav Res 2015;55:403-12
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