Low Norepinephrine and Depression: Is There A Link?

Norepinephrine also sometimes referred to as “noradrenaline” works as both a hormone and neurotransmitter. It helps promote vigilant concentration and is different from dopamine in the fact that dopamine has a greater influence on cognition. When you become stressed, norepinephrine is secreted by the sympathetic nervous system which leads to an increased amount of heart contractions.

It serves as a stress hormone and is associated with both the “fight-or-flight” response as well as epinephrine (adrenaline). In addition to increasing blood flow to your muscles, it also helps provide people with a boost of energy. Among individuals that believe their depression may be a result of “low arousal,” increasing norepinephrine may prove to be a solution.

Does having low norephinephrine cause depression?

If you happen to have low norepinephrine (or abnormal levels), it may contribute to feelings of depression. Most people aren’t aware that there are other neurotransmitters besides “serotonin” involved in depression. I already wrote about dopamine vs. serotonin for depression and concluded that dopamine isn’t looked at enough as a potential contributor. Most trials with drugs point to the fact that people tend to improve most with SSRI’s – drugs that target serotonin.

However just because most people respond well to SSRI’s does not necessarily mean that all people respond well to this class of drugs. Some people find that a drug like Adderall treats depression significantly better than SSRI’s. Everyone is in a different situation and it is important to recognize that if a certain neurotransmitter is targeted without success, it may be smart to try a different class of drugs.

Low levels of norepinephrine are linked to: lower arousal (e.g. sedation), lower alertness, and depression. Abnormally high levels of norepinephrine are linked to being over-aroused or “anxious.” Most people would not want to increase their norepinephrine if they have bad anxiety – as the level of this neurotransmitter is likely already too high. In cases of ADHD with comorbid depression, it is thought that norepinephrine may be a contributing factor.

Link between low norepinephrine and depression?

Some hypothesize that there may be a link to imbalances in norepinephrine levels and depression. This is because certain people respond well to drugs that work to prevent the reuptake of norepinephrine. Most antidepressants work on preventing the reuptake of serotonin. However a newer class of antidepressants called “SNRI” work on both serotonin as well as norephinephrine.

There are also other classes of drugs including: “NDRI’s” and “NRI’s” that have helped people overcome depressive symptoms. There is a lot of evidence supporting the idea that norepinephrine is involved in depression. When levels are low, a person can lack motivation, healthy cognition, and intellectual skills – all of which are vital for social success. Other evidence shows that when norepinephrine is reduced in rats, they become inactive, have poor appetites, and are model aspects of depression.

Although this evidence doesn’t necessarily mean that humans with norepinephrine would behave the same way as rats, it does suggest that it could contribute to depression. There is further thought that stress-induced changes to the immune system and endocrine system can be reversed by treating a person with a norepinephrine reuptake inhibitor.

It has also been discovered that when a person is treated with an SSRI like Paxil, adding a drug that inhibits reuptake of norepinephrine may result in more relief and efficacy of the SSRI. Although “low norepinephrine” may not necessarily cause depression, preventing reuptake of this neurotransmitter (i.e. increasing it) has been associated with relief.

Norepinephrine reuptake inhibitors: SNRI’s, NDRI’s, NRI’s, TCA’s

The good thing about drugs that work on norepinephrine is that they are typically not associated with major weight gain. Even in cases of SNRI’s in which serotonin is targeted, most people notice that their weight stays the same.

It is thought that the norepinephrine helps offset the serotonin to prevent major weight gain. Another benefit associated with this class of drugs is that they tend to increase energy levels. It is also thought that when drugs work to prevent the reuptake of norepinephrine, they may also indirectly have an impact on dopamine.

SNRI’s

Cymbalta: This is an SNRI medication that is used as an antidepressant and to help individuals manage chronic pain.
Effexor: This is another popular SNRI medication that is considered very powerful in the treatment of major depression.
NRI’s

NRI’s

Strattera: This is a medication primarily used to treat ADHD. However if you believe that your depression is caused by low norepinephrine levels, this may work extremely well. Some people notice a very good antidepressant effect from this medication, despite the fact that prescribing it for depression is considered “off label.”

NDRI’s

Wellbutrin: This is an NDRI class drug that targets both norepinephrine and dopamine to a lesser degree. Many people have had success with this medication and it is widely regarded as one of the safest, most effective antidepressants on the market.

TCA’s

Tricyclic antidepressants tend to also have an effect on norepinephrine which may be why they can be extremely activating. At lower doses many of these medications increase histamine, which may result in feelings of drowsiness. However, at higher doses various TCA’s can be very stimulating. An example would be that of Nortriptyline – at low doses it can be used as a sleep aid. When you increase the dose of the drug, it can be very activating due to the noradrenergic response.

How do you know if you have low norepinephrine?

There is no real way to know whether you have low levels of norepinephrine other than to conduct some experimentation. If you happen to respond better to SNRI’s than treatment with SSRI’s, targeting norepinephrine could be a better treatment option. Additionally, you could try a medication like Wellbutrin (Bupropion) to see whether it helps alleviate your depressive symptoms.

If you respond to a norepinephrine reuptake inhibiting drug, it doesn’t necessarily mean you have “low norepinephrine,” rather it signifies that you respond better to drugs that target this particular neurotransmitter. Unless you have had your neurotransmitter levels checked, don’t assume that any are “low” rather think about the fact that you may respond better to certain ones being targeted.

My thoughts on norepinephrine and antidepressants

I haven’t had the greatest of experiences with SNRI’s or drugs that primarily target norepinephrine for my depression, but many people have. I have some degree of underlying anxiety and believe that increasing this neurotransmitter ultimately makes me feel more anxious than necessary. I have also found that when taking drugs affecting norepinephrine, I tend to have more energy – which is an upside.

I believe drugs that target norepinephrine can play a role in treating depression, but ultimately I don’t think that a single neurotransmitter is a “culprit” for a person’s depression. With that said, if you have tried many drugs that affect serotonin and haven’t had success, it may be time to switch up the treatment with a drug that targets norepinephrine and/or dopamine.

For individuals that know norepinephrine is the cause of depression, a drug like Strattera should theoretically work best – as it solely targets this neurotransmitter. Most people either respond very well to norepinephrine-based drugs or they don’t notice much of anything. Ideally if you have ADHD and comorbid depression and suspect norepinephrine may be the X-factor, trying a medication like Strattera would be the logical option.

References

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131098/
http://psycnet.apa.org/psycinfo/1978-28927-001
http://www.ncbi.nlm.nih.gov/pubmed/10703757
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2553257/
http://www.ncbi.nlm.nih.gov/pubmed/12359676

Reader discussion (7)

Previously published reader comments are preserved below. New comments are not currently being accepted.

James BDecember 29, 2014
The role of Norepinephrine in is a curious one. In head-to-head clinical trials, the SNRIs have not proved any more efficacious than the SSRIs. Furthermore, NARIs (norepinephrine/noradrenaline reuptake inhibitors) such as Reboxetine have shown little positive data that they have worked, and in Reboxetine's case specifically, have actually been harmful. Many of the negative result trials for Rebox were originally unpublished. After this data was later made available, a few meta-analysis studies demonstrated that Reboxetine often times did not outperform placebo or compare to a gold-standard treatment (e.g., SSRI). In some trials, Reboxetine performed worse than placebo, so this is why it was concluded that it can sometimes "do more harm than good." This is the reason that Pfizer finally gave up on the US approval process of Reboxetine several years ago. http://www.bmj.com/content/341/bmj.c4737.full http://www.ncbi.nlm.nih.gov/pmc/articles/PMC161714/ Personally speaking, Reboxetine worsened my depression. But on the flip side, I've found that the SNRI Cymbalta has probably been the most advantageous antidepressant I've tried in recent years, so there is most likely some antidepressant component to the norepinephrine profile of it. A couple studies of genetic correlation with early onset depression sufferers (Levinson et al. 2003, Hahn et al, 2008) found that the NET -182 T/C SNP may contribute to this risk. So this might provide further evidence that norepinephrine might be an intimately involved in some cases.
mikeMay 15, 2015
Reboxetine is a much better med for ADD with anxiety than it is for depression. It's very similar to Strattera.
SilkeFebruary 11, 2016
I am curious where I can find what the normal levels of noradrenaline are and the level of noradrenalin in the body when its preparing for fight and flight? Any ideas what the levels are in the body? An internet source about the levels in a human body would be greatly appreciated ?. Thanks.
cierraApril 5, 2016
Hi, I'd like to say that this article was a very big help with some of my research in ADD and Depression. My boyfriend has been struggling for a long time, fighting both. Just recently he was checked out of a mental hospital, and the new meds that were supposed to help, are not. It breaks my heart knowing that so many people struggle with these disorders. Every case is personal, and I'd like to find a cure. I'm young, but I'm very passionate on this subject. I'd love to hear from the author of this article for more information. :) Thank you.
Anand MadhuApril 14, 2016
When the author postulates a link between low Norepi levels and Depression, he is right. I've researched and written on this matter. Find my thesis here: https://www.academia.edu/17243562/Theoretical_investigations_into_the_nature_of_the_human_brain Abstract: Psychological neural circuits are comprised of Dopaminic and Norepic work stations, that can be compared to logic gates; while the Norepic workstation can be called the biological “And” Gate, the Dopaminergic work station can be called a simple “booster gate”, for which no standard comparisons exist. These are the two elegantly-designed biological gates which control much of our "quantum psychological" (infinitesimal boosts in signalling) operations. The most important finding is the cause of Alzheimer’s disease. If more Dopaminergic work stations are present in a given individual; if his neurostructural ideology is more Dopaminergic/Dopaminic (in parallel, he will suffer a Norepinephrine deficiency, which is better known as "Dopamine beta hydroxylase deficiency" – such a neurostructural ideology translates, as shown in this paper, into a higher electric signal density, i.e., overly strong (cumulatively) flows of current in certain neural regions, which leads to neuronal collapses due to unidentified reasons that may be any of the following (or their combinations): chemical stress, mechanical stress (e.g.: fatigue), and/or overheating. This, then, is the cause of dementia. Neuronal collapses brought about by dangerous current surges is nothing but dementia. Neuroinflammation, often wrongly regarded as the culprit behind AD, seems to be merely a repair reaction. The pathogenic detail is not just that there is too less Norepi in the brain – "The loss of noradrenergic [Norepic] neurons is a striking feature of dementia (AD)" – but also that there is too much Dopaminergic logic gate control, in particular identifiable types of brains, whose owners may contract dementia if the gross mental metabolic rate is not controlled.
KevinJune 28, 2016
I have ADHD/had initially tried Wellbutrin and Nuvigil: both actually made me drowsy (very); then Concerta (did little/nothing); and finally Adderall (works). Was recently given Sertraline: It seems to counter some of the Adderall effects (increased fatigue/appetite). I've asked my psychiatrist and pharmacist: both say the Sertraline shouldn't affect the Adderall; though I've read some SSRIs can affect Dopamine (Sertraline wasn't necessarily mentioned; but if one, why not another?). I'm (of course) not asking for professional advice; just an opinion/direction that I can research/discuss with my doctor (stubborn).
DougJanuary 5, 2018
I have treatment resistant depression and went through many antidepressants, ketamine and TMS before I finally found an treatment that gave me a decent amount of relief: the tricyclic NRI desipramine. Adderall also makes me feel much better, and it raises dopamine and norepinephrine in the brain.