Understanding the ‘Neurochemical Alphabet’ to Inform Treatment

In his recent NEI Congress session, Vladimir Maletic, MD, MS, University of South Carolina, Greenville, examined the neurobiologic underpinning of major psychiatric conditions such as major depressive disorder, bipolar disorder, and anxiety. Tune in to learn how the "neurochemical alphabet" should change clinicians' approach to treating patients the next day, how to optimize the balance between different neurotransmitters, and other important takeaways.

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Read the Transcript: 

Psychiatry and Behavioral Health Learning Network: How can health care professionals apply the understanding from your session at NEI into their clinical practice to optimize their treatment plans for patients with conditions such as mood disorders or anxiety?

Dr Vladimir Maletic: I think this is an important question and that is in the crux of all these presentations. So we're learning more about the neurobiologic underpinning of these major psychiatric conditions. Ultimately, how will that change our approach to treating our patients the next day? And there are some relatively important takeaways. Here would be one of those.

For many decades, we have conceived of, for example, major depressive disorder ultimately being a deficit disorder. There is not enough serotonin or epinephrine and dopamine. And therefore by boosting neuro transmission mediated by these modulating transmitters, we will correct the deficit. We now know that that is really not the case. Not only is there much greater complexity to mood disorders, so it's not about norepinephrine, serotonin, and dopamine, although they may play a role. We also have to keep in mind GABA and glutamate transmission. We also have to keep in mind changes in neuroplasticity and neurotrophic factors.

It is good to start thinking about intracellular signaling cascades because most likely very soon we'll have therapeutic agents that will have intracellular sites of action and directly influence these intracellular signaling cascades. And we also know that in segment of our patient suffering from mood disorders, there is a disordered inflammatory signaling in the brain that may contribute to some symptoms. So if we take on this perspective, again, getting to the bottom line, what is different? Well, if we're not correcting the deficit, more is not better.

Increasing neurotransmitter 1 or 2 in parallel, without the ceiling, without the upper limit, we know now is actually not in our patient's best interest. When we look at all the monoamines, and this theory now seems to apply to GABA and glutamate, neither too little nor too much is to our patient's benefit, we actually need to be somewhere in the middle of this inverted U, in the middle of this rainbow.
And what's more, we need to balance the relationship between serotonin, norepinephrine, and dopamine. Let me just give you a few very simple examples.

Let us say our patient has major depressive disorder, and they have low norepinephrine. Well at least theoretically, that should translate into being tired, into difficulty sustaining attention, the mind tends to wander, one gets distracted very easily, one feels a little bit sleepy. So if we increase norepinephrine to the optimum, now they will be alert, aware, oriented, fully focused—good top-down regulation of emotion. 

But if we exceed norepinephrine and herein is the danger of pushing up and up and up. A patient is in a, hypothetically in a state of hyper-arousal, which may be associated with more anxiety, apprehension, worries, maybe even panic attacks, sleep disturbance, irritability, agitation, hostility. And they may actually have lower energy, which is paradoxical. They may have more difficulty with their focus.

Both having too much and too little sometimes will have similar manifestations. And when we look at these major brain networks, which presumably underpin some of the symptoms of psychiatric disorders, we know that norepinephrine and dopamine, for example in salience network, somatomotor network, central executive network, have opposing function generalized to what serotonin does. And therefore it's not only a matter of optimizing one neurotransmitter, it's a matter of optimizing the balance between different neurotransmitters. And also the ultimate understanding is that when we modulate serotonin, norepinephrine, and dopamine, we are ultimately a regulating GABA glutamate balance. So these are some of the things that may have practical translation and also if we understand receptors and what the consequence of modulating certain receptor types when it comes to monoamines, but also GABA and glutamate. So if we understand that neurochemical alphabet, it may inform some of our treatment decisions so we can better help our patients. 

Vladimir Maletic, MD, MS, is a clinical professor of psychiatry and behavioral science at the University of South Carolina School of Medicine in Greenville, and a consulting associate in the Division of Child and Adolescent Psychiatry, Department of Psychiatry, at Duke University in Durham, North Carolina. Dr Maletic is a member of several professional organizations, including the Southern Psychiatric Association and The American College of Psychiatrists. In 2013-2014 he served as a program chair for the US Psychiatric and Mental Health Congress. His special areas of interest include the neurobiology of mood disorders, schizophrenia, pain, and the regulation of sleep and wakefulness. Dr Maletic is board-certified in psychiatry and neurology.