Reader Blake Stacey asked me to comment on this article about the development of new antidepressants. It is a very interesting development in the pursuit of more effective and selective antidepressants and reveals a great deal about the state of this neuroscience.

For background, current pharmacotherapy for many neurological disorders, including mood disorders like depression, focus on altering the activity of neurotransmitters – the chemical signals by which neurons communicate with each other. Some of the more important neurotransmitters include dopamine, serotonin, norepinephrine, GABA, and glutamate. As we would expect from a messy evolved system, these neurotransmitters are used in various parts of the brain for different purposes. There is a great deal of overlap – the same neurotransmitter may be used by several different subsystems in the brain.

Neurotransmitters carry their signal by binding to a receptor. So neuron 1 will secrete dopamine, for example, which will then cross the synapse to neuron 2 where it will bind to dopamine receptors which in turn then trigger neuron 2 to fire at some frequency. To make things more complex there are several types of dopamine (and other) receptors. These receptor subtypes may have different effects in the same synapse, or may exist in different concentrations in different parts of the brain.

Pharmacological agents exploit this complex system in numerous ways. They can block the production of a neurotransmitter, its release into the synapse, its inactivation in the synapse, or it may block or activate one or more receptor subtypes. The goal of drug development is to find agents that have a precise beneficial effect with minimal side effects. These efforts are frustrated by the fact that the same neurotransmitter is used in different subsystems – so while enhancing dopamine in the basal ganglia may improve a movement disorder it may cause psychotic side effects in the frontal lobes. Newer agents minimize side effects by specifically targeting receptor subtypes – but these are not cleanly divided in the different parts of the brain so while side effects are decreased, they are not eliminated.

In the past 50 years the treatment of depression has focused on enhancing the activity of dopamine, norepinephrine and serotonin. These drugs work, but only in about 50-60% of patients. The newer agents have usually tolerable side effects, but side effects (such as a decreased libido) are still a limiting factor in some patients and a great annoyance in others. There is definitely room for new approaches to depression and improved agents with more specificity and fewer side effects.

Recent research has focused on a new neurotransmitter – glutamate. Glutamate is a very complex neurotransmitter, partly because it is so widely expressed in the brain. It is the brain’s major activating neurotransmitter –it increases the firing of the neuron it binds to. It is also toxic to neurons if the concentration gets too high. Glutamate inhibitors are already widely used in the treatment of epilepsy, bipolar disorder, migraines, neuropathic pain, and in the treatment of certain neurodegenerative disorders, like ALS (motor neuron disease).

Glutamate is also a complex neurotransmitter with multiple receptor types that have different functions, and that is at the center of this new research. Two receptor types for glutamate are NMDA and AMPA. Both have been targets for neuroprotective and other agents.

The new research is looking at a drug long used as an anesthetic, with abuse potential as a hallucinogen – ketamine. Ketamime has been shown in several studies to rapidly treat depression. These studies have all been small, open label, and short term. So long term, larger, and placebo controlled trials are needed, but the drug at the very least shows significant promise.

Ketamine is also an NMDA blocker. The thinking is that by blocking NMDA there is more glutamate around to bind to AMPA, so the net effect of ketamine is also to increase AMPA receptor activity. This hypothesis was put to the test by Dr. Zarate of the NIMH and they found that the antidepressant effect of ketamine is reduced if AMPA receptors are also blocked, suggesting AMPA activity is necessary for the effect.

Now that this new approach has shown some preliminary promise, it is likely that pharmaceutical companies will look at existing drugs to study their anti-depressant effects, and also to develop new or modified agents for more activity and specificity. For example, it makes sense that if indirectly increasing AMPA by blocking NMDA treats depression, then direct AMPA agonists (activators) should have some anti-depressant effect also. Also, while ketamine seems to be effective in depression, it also causes hallucinations as a side effect, so pharmaceutical companies will want to find a related agent that minimizes or avoids this side effect (if possible).

As the basic science progresses we may also discover more subtypes of receptors (there are already subtypes known, and much is known about the proteins on these receptors and how they are modified by drugs and how this modification affects their activity). This may lead to even more specific and effective drugs.

But ultimately we will likely get to the limits of what pharmacological manipulation can do. As I said, we are dealing with a messy evolved system. This opens the door for exploitation, but also sets limits on specificity. For example, if every specific function in the brain were mediated by a distinct neurotransmitter-receptor system, without cross affinity (meaning that one neurotransmitter has some binding activity at another neurotransmitter’s receptors), then there would be no limit to our ability to manipulate specific functions without affecting others (producing desired effects without side effects). But alas this is not the case.

Therefore, eventually new approaches will be necessary to improve treatment. It is always difficult to speculate about what form future technology will take, because it is hard to predict which strategies will pan out and which ones will meet obstacles. But some new approaches the future may take include implantable computer chips that interface with the brain and modify or take over specific functions, genetic therapy to alter the activity of brain cells, and stem cell treatment to modify brain pathways and enhance cell populations. Even farther in the future we may imagine nano-machines to alter cell structure and function directly at the subcellular level. Probably, by the middle or end of this century, there will be other technologies not yet imagined.

For now the state of the art is making better drugs, and altering glutamate function for depression seems like a promising avenue. We’ll see.