Measuring Neurotransmitter

[jay]

Dr. Mariano:

You speak frequently about importance of Neurotransmitters. How does one properly acess these levels, however?

I ask this because my family physician recently informed me that it is impossible.

He states taht one cannot prove that your brain neurons are operating at high norepinephrine levels during neuronal firing events , for example. He claims that neither a urine test nor a blood test corresponds to the levels in the brain and therefore their is no way to access the levels. he stated that is why when patients come to thier doctor and suffer from depression, the only way to tell whether it is an issue with brain chemistry is to simlpe try different types of depression medicine and if the patient responds positively then we know that was the issue. Any comments, please?

[DrMariano2]

@jay 908 wrote:

Dr. Mariano:

You speak frequently about importance of Neurotransmitters. How does one properly acess these levels, however?

I ask this because my family physician recently informed me that it is impossible.

He states taht one cannot prove that your brain neurons are operating at high norepinephrine levels during neuronal firing events , for example. He claims that neither a urine test nor a blood test corresponds to the levels in the brain and therefore their is no way to access the levels. he stated that is why when patients come to thier doctor and suffer from depression, the only way to tell whether it is an issue with brain chemistry is to simlpe try different types of depression medicine and if the patient responds positively then we know that was the issue. Any comments, please?

In treating depression using only antidepressants, there are actually few choices available. Antidepressants either raise serotonin, raise norepinephrine, or raise both. This is their primary mechanism of action. This is fairly limited since often norepinephrine is already excessive. They also insignificantly raise dopamine. They may block histamine or acetylcholine.

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The bigger picture is that depression is that it is a multisystemic illness. I consider these systems one system – as part of the mind. But from a conventional perspective, it is a multisystemic problem involving the nervous system, endocrine system and immune system, plus cellular metabolism and nutrition. This is why an antidepressant often doesn’t work well – it is only part of the solution.

These days, I just don’t go through trial and error by giving a person an antidepressant if they have depression. I want to determine first the causes of depression from a physiologic perspective. I want to determine the pathophysiology of depression. Much of the pathophysiology of depression and other mood disorders is already in the psychiatric textbooks. But often this section is ignored completely during assessment and treatment, much to the disservice of the patient.

Once I decide to give an antidepressant, generally, I have to determine if that person may benefit from increasing serotonin or norepinephrine or both, as part of their overall treatment. I generally don’t give a medication that raises norepinephrine if a patient already has enough or has excessive amounts. Why would I? I would also be careful about raising serotonin if the patient isn’t making enough dopamine – since restlessness or agitation or even suicide may be an outcome. The effects on histamine, acetylcholine and other neurotransmitters and hormones would also have to be considered. Treating a person with an antidepressant is actually a complicated process. But once pathophysiology is determined, the choice often is fairly clear and trial and error is minimized.

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One just has to know anatomy and physiology to realize it is possible to monitor at least some of the neurotransmitters.

Norepinephrine is the easiest neurotransmitter to measure and correspond to nervous system levels. It is the primary stress signal. It primarily is produced in the brain by neurons in the locus ceruleus. These neurons go upwards connecting to structures including the cortex, and connect downwards to the neurons which start the sympathetic nervous system chain. The sympathetic nervous system then go down in two chains parallel to the spine down the trunk. They branch off to the rest of the body. The sympathetic nervous system chain has collections of neurons called ganglia. The adrenal medulla is one such ganglion. When measuring norepinephrine in plasma, one can measure stress signaling all the way to the locus ceruleus – so long as the adrenal medulla (where most of the norepinephrine in plasma is produced) is attached to the rest of the sympathetic nervous system (in some conditions, such as diabetes, they can be disconnected).

Serotonin can also be also be measured – as a serum serotonin level or urine 5-HIAA, serotonin’s metabolite. 90% of serotonin is produced by neurons of the enteric nervous system – the part of the nervous system that is in the stomach. However, there is good correlation between this part of the nervous system and the central nervous system.

The key to interpretation is this: norepinephrine and serotonin are control signals. It is not the individual firing events that is important but the overall tone of these firing events – i.e. the frequency and amplitude together. It is like listening to a musical note rather than listening to a single sine curve of a sound wave.

This concept of “tone” is also similar to what one measures when monitoring hormones. Hormones may be given off in a pulsatile manner. But it is the overall “tone” that is important. This is why one tries to measure the most stable version of some hormones or do 24-hour measurements. DHEA, for example, varies in amplitude several times a second. Its level is not as useful since it is the overall “tone” that is important. DHEA-s, which gives more stable levels, gives us a better idea of what DHEA is doing as a hormone / signal.

Other neurotransmitters are more difficult to monitor at this time since finding a correlate to central nervous system function is difficult. Sometimes they may be inferred from the results of other lab tests. For example, if iron (ferritin) and Vitamin D are low, there is a good chance dopamine is low. If Vitamin D is low, there is a good chance serotonin is low. If prolactin is high, dopamine is low. etc. Otherwise, one would have to rely on clues from the history and physical exam and correlate those findings with what we theoretically know about nervous system function.

The easiest proof that the level of serotonin and norepinephrine corresponds to brain levels is to just correlate it with behavior. For example, if norepinephrine is high, I can generally say a person is going to be stressed, irritable or anxious, has a high likelihood of having insomnia, may have hypertension, et., etc. If serotonin is low, then the person would have more difficulty modulating stress, would have more difficulty ignoring stress, stresses would hit that person harder.

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One of the fun things I do is to calibrate lab test scales to behavior. This way, I can obtain labs and determine then determine what general tone of behavior a person may have based on the lab test. I often can get this right – an indication of how useful lab tests are.

Another one of the fun things to do is to do it the other way – to estimate neurotransmitter, hormone, and nutrient levels from the history and/or physical, then later confirm it with the lab test. Often, I can get it right from these angles also.

[jay]

Doctor, thank you, again for the detailed answer. One other question, if I may.

You stated:

that Antidepressants either raise serotonin, raise norepinephrine, or raise both.For example, if norepinephrine is high, I can generally say a person is going to be stressed, irritable or anxious, has a high likelihood of having insomnia, may have hypertension, et., etc.

Why would doctors give a medication like Lexapro, which I am told significantly improves the symptoms of anxiety if norepinephrine increases anxiety?

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[DrMariano2]

@jay 958 wrote:

You stated:

that Antidepressants either raise serotonin, raise norepinephrine, or raise both.For example, if norepinephrine is high, I can generally say a person is going to be stressed, irritable or anxious, has a high likelihood of having insomnia, may have hypertension, et., etc.

Why would doctors give a medication like Lexapro, which I am told significantly improves the symptoms of anxiety if norepinephrine increases anxiety?

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Sorry. I should have been more specific and clear:

I referred to the various mechanisms of action that different antidepressants have.

Antidepressants, such as Lexapro, Paxil, and Prozac, primarily raise serotonin.

Antidepressants, such as Wellbutrin, primarily raise norepinephrine.

Antidepressants, such as Effexor or Cymbalta or Imipramine, raise both serotonin and norepinephrine. They are called “dual-acting” or “SNRIs” – serotonin-norepinephrine reuptake inhibitors.

Increasing serotonin can help reduce norepinephrine signaling, which then reduces anxiety.

The dose needs to be just enough but not too much for if serotonin is raised excessively, then dopamine signaling is reduced. Serotonin may reduce norepinephrine, but reducing dopamine may raise norepinephrine. At a certain serotonin level, this balance favors increasing norepinephrine, and anxiety worsens rather than improves. The lower dopamine signal also may cause motor restlessness. This coupled with anxiety results in agitation and sometimes suicide attempts.

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