The Relationship Between Hormones, Neurotransmitters and Depression - What Can We Do?

Believe it or not, experiencing depressed moods every so often is normal. There should be a natural ebb and flow to one's moods - that's just the way humans are wired. You cannot be "up" all the time because then you would not understand the importance of experiencing "lows". Experiencing a depressed mood is normal as it is a response to the events or times in our lives when we experience a loss or respond to a stressor.


I was asked to answer the following questions by a friend:

  1. When or how would I know if depression is caused by a hormonal or chemical imbalance?

  2. Is my depression the manifestation of my lifestyle? And if I changed my lifestyle should it help or treat my depression?


I thought, "You know, I am interested in this too since I struggle with depression and it "runs in my family". However, this article is strictly for educational purposes only and covers only what a few research articles say about these topics. You should consult with a trusted healthcare professional or therapist about specific problems you are dealing with.


Anywho, I don't like to keep you waiting for the answers, so let's dig in!


Curiously, depression's etiology is not yet fully understood. However, depression is thought to be multi-factorial perhaps caused by one or several of the following: negative thoughts, poor nutrition, genetics, stressful life event(s), substance or alcohol abuse, lack of physical activity, and neurochemical dysregulation. I am going to focus on the three factors that are bolded for the purposes of this article.


There are several hypotheses that try to explain the etiology of depression:


<> The monoamine hypothesis

<> Stress-related changes in the hypothalamic-pituitary-adrenal axis

<> Stress-related changes in the hypothalamic-pituitary-gonadal axis

<> Inflammation

<> Genetics

<> Structural and functional brain changes


Again, for the purposes of this article, we are going to focus on the bolded points.


First, let's review a well-known mechanism thought to play a major part in the pathogenesis of depression: an alteration in monoamine neurotransmission (mono- means "one", -amine relates to an "amine group" in chemistry). The monoamines include dopamine, serotonin, and norepinephrine. You are probably familiar with pharmaceuticals that treat depression by affecting one of the monoamines, such as selective serotonin reuptake inhibitors or SSRIs for short which primarily targets serotonin.

 

A quick lesson: think of these neurotransmitters (dopamine, serotonin, and norepinephrine) as keys. On each neural cell (neuron) is a lock. To get the cell to respond in a certain way (for example, to make you feel relaxed and in a good mood) the key, serotonin, has to connect with the right lock, aka its corresponding receptor. So, serotonin has a particular shape that connects perfectly with a receptor that corresponds perfectly with serotonin - we will call the receptor that binds with serotonin a serotonin receptor.

 

What does alteration in monoamine neurotransmission mean?

It can mean that the number of receptors is altered in some way that affects normal neurotransmitter functioning, that the amount of neurotransmitters produced is reduced, or that the transport and transmission of neurotransmitters are altered in some way as to cause problems. For example, serotonin metabolite levels have been reported to be decreased in patients diagnosed with depression, therefore serotonin is thought to be implicated in depression (source).


Let's continue our discussion about the neurotransmitters norepinephrine and dopamine.


Norepinephrine:

Norepinephrine is interesting because it is affected by stress, specifically chronic stress. In brief, stress causes the hypothalamus to release more corticotropin-releasing factor (or hormone) (CRF) which subsequently causes the increased release of ACTH from the pituitary gland. The extra ACTH leaving the pituitary gland stimulates the adrenal gland to increase the synthesis of cortisol and norepinephrine. Increased levels of these two hormones increase your sympathetic response (think: the FIGHT in fight or flight), and in turn, release inflammatory cytokines (think: loose bullets traveling through your body causing harm) that may affect your neurological response to stress. The increases in inflammatory cytokines may affect your vulnerability to experience symptoms of depression.

Dopamine:

Dopamine is a neurotransmitter that is involved in the motivation and reward pathways in the brain. In clinical depression, patients often feel little desire or motivation to do things that they used to love. They also usually find very little pleasure in anything they do. These symptoms of depression are thought to be the result of your reward system malfunctioning. Additionally, the fact that pharmaceutical drugs, such as bupropion, increase dopamine levels and have positive effects on mood makes using these drugs an attractive treatment option for depression.

Now that we have a better understanding of which neurotransmitters are thought to have an impact on the depressed brain let's take a closer look at how sex hormones (specifically, the ebb and flow of estrogen) may affect depression.

 

Sex Hormones and Depression: Estrogen

You guys, our bodies are simply amazing. I learned a lot doing the research for this article and I hope you find it amazing as well.


I'll start with the main point:

Estrogen (specifically, estradiol) is known to have a variety of effects in the brain including mood regulation, regulation of the stress response and regulation of emotional perception.


What does this mean?

Periods of low estrogen (usually days 1 - 10 of your menstrual cycle and the few days leading up to the start of your cycle) may increase your chances of experiencing depression symptoms (Newhouse and Albert, 2015).



 

Question 1:

When or how would I know if depression is caused by a hormonal or chemical imbalance?


Answer: The truth is that depression could manifest from a variety of different factors as you have read here. Early adverse events, childhood trauma, stressful events, poor nutrition, lack of exercise, genetics, abuse of illegal substances or alcohol, negative moods/outlook of life, lack of social support, and/or neurochemical dysregulation could all be playing a part in the pathogenesis of depression. Therefore, it is extremely difficult to pinpoint an exact cause of depression.


For women, an easy way to track if your depression corresponds with hormonal changes is to be aware of and write down any changes in your mood before and after the onset of menses. Tip: Day 1 of your period is when you first start bleeding. Most women's cycles are between 1 - 32 days. Clinically, organic acid tests can be run by your healthcare provider to test levels of cortisol, estrogen, and testosterone (among other sex hormones). The levels of these hormones will be key to understanding if your hormones are in balance or out of balance and thus, possibly predisposing you to the risk of depression.


As discussed above serotonin, dopamine, and norepinephrine are the three neurotransmitters that could potentially have an impact on the etiology of depression. Scientists believe that depression may be caused by some malfunction in these neurotransmitters (such as too little neurotransmitters) which has been shown to be helped by pharmaceuticals such as bupropion and Lexapro (among others). To my knowledge, the only sure-fire way to know if your depression is caused by a chemical (neurotransmitter) shortage is to start medication and evaluate with your healthcare provider if the medication is helping your depression symptoms. It has been suggested that approximately 60% of patients taking a second-generation antidepressant (such as an SSRI or SNRI) respond to treatment. (Rakel, Integrative Medicine, 2018) These findings only strengthen the hypothesis that depression stems from a multitude of possible risk factors and each patient should be evaluated individually on a case-by-case basis for proper treatment recommendations.


Question 2:

Is my depression the manifestation of my lifestyle? And if I changed my lifestyle should it help or treat my depression?


Answer: It is possible. You may be at a higher risk of suffering from depression symptoms if you abuse alcohol and other substances (illegal or legal), lack a strong social group (such as a fitness community, church, or other non-religious groups), do not engage in physical activity, or have poor nutrition.


Research on lifestyle modifications to help manage or treat depression has been positive.


Supplementing Probiotics:

A recent meta-analysis (2016) evaluated 5 randomized control trials of the effect that supplementing probiotics had on symptoms of depression. In the group of patients that were depressed, supplementing with probiotics accounted for a 0.73 reduction in the depression score. The probiotics used in the study intervention included

L. acidophilus, L. casei, and Bifidobacterium bifidum; one capsule/day for 8 weeks. (Huang et al., 2016).


Level of evidence: weak but promising


Physical activity:

The effect of exercise on depression symptoms has time and time again shown beneficial results. In fact, over 1,000 trials have been conducted to assess the relationship between exercise and depression. The benefits of exercise include increased self-esteem, a better level of fitness and a reduced risk of relapse of depression (Rakel, 2018).


Stopping smoking/drinking:

Short term drinking increases the amount of serotonin available in the brain; however, chronic use of alcohol actually decreases levels of serotonin over time. Discontinued use of alcohol is highly recommended.


If consuming alcohol is a part of your lifestyle, consider adopting a Mediterranean style eating plan that includes consuming moderate amounts of alcohol (for women one standard drink is 5 oz of wine) (Bayes et al., 2019)


Using Supplements to Help Manage Depression - What's the Evidence?


Omega-3 Fatty Acids:

Consuming appropriate amounts of both DHA and EPA is hypothesized to be rather important for proper structural and functional properties of neurological cellular membranes and has been shown in some studies to alleviate depression scores. More evidence is needed to make a definitive recommendation.


Vitamin D:

Most Americans reported consuming less than the RDA for vitamin D (NHANES data, 2015-2016). More studies are needed but some have found a beneficial effect in reducing depression scores. Generally, 2000-4000 IU/day of vitamin D is suggested.


S-Adenosylmethionine (SAMe):

SAMe is required for the proper synthesis of several neurotransmitters including serotonin and dopamine. SAMe synthesis has been shown to be impaired in depression and supplementation with SAMe has been shown to increase levels of these monoamines in the brain.


CAUTION: SAMe is NOT recommended for bi-polar disorder patients.


Recommended dose: 200 mg once or twice daily for two weeks. Each couple of weeks increase the dose by 200 mg until you reach a maximum dose of 1600 mg/daily. Please talk with a healthcare provider when starting any new supplementation regimen. CAUTION: high doses of SAMe may cause gas, vomiting, nausea, and diarrhea.

 

Bottom Line:

If you are struggling with symptoms of depression and they are severe, please talk with a healthcare provider or licensed therapist immediately to get help. General recommendations of adopting a healthy eating plan such as the Mediterranean Diet, starting a safe and effective exercise regimen, avoiding depressants such as smoking and alcohol are suggested. For women, tracking symptoms as it relates to your cycle will be prudent to establishing when symptoms are most noticeable or most severe. A general recommendation to start supplementing with Omega-3 fatty acids, vitamin D, and SAMe may be beneficial but you should seek professional recommendations from your healthcare provider or certified/licensed nutritionist for specific recommendations and dosing regimens.

 

I hope you found this article informational. If you have any direct questions, please comment or text me.


Part 2 of this article will explain and highlight recommendations for women to balance out your monthly cycle. Stay tuned!


In the meantime, check out additional articles on my website.


References:

Rakel, D. (2018). Integrative Medicine. 4th ed. Depression Chapter. Pages 36-45.


Albert, K. and Newhouse, P. (2019). Estrogen, Stress, and Depression: Cognitive and Biological Interactions. The Annual Review of Clinical Psychology. 15: 399-423.


Newhouse, P. and Albert, K. (2015). Estrogen, Stress, and Depression: A Neurocognitive Model. JAMA Psychiatry. 72(7): 727-729.


Bayes, J., Schloss, J., and Sibbritt, D. (2019). Effects of Polyphenols in a Mediterranean Diet on Symptoms of Depression: A Systematic Literature Review. Advances in Nutrition.


Huang, R., Wang, K., and Hu, J. (2017). S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. Journal of Clinical Psychiatry. 8: 483-

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