Depression Archives - Health Tips From The Professor

Do GLP-1 Drugs Increase Suicide Risk?

October 22, 2024 by Dr. Steve Chaney

The Pros and Cons Of GLP-1 Drugs

Author: Dr. Stephen Chaney

You’ve seen the ads. You just inject these “miracle” drugs into your thigh once a week, and your excess weight magically disappears. They look like the simple solution for weight loss everyone has been looking for.

More about that in a minute. Let’s first talk about what these drugs are how they work.

What GLP-1 Drugs Are: These drugs are commonly referred to as GLP-1 drugs. But their full name is GLP-1-like receptor agonists. That’s a mouthful, so let me break it down for you.

GLP-1 stands for glucagon-like peptide-1. Glucagon-like peptide-1 is produced by the stomach whenever we eat a meal. It is a hormone that binds to receptors in key organs and reduces appetite and lowers blood sugar (more about this in a minute).

GLP-1-like drugs are peptides designed to resemble the portion of the glucagon-like peptide that binds to GLP-1 receptor. The term agonist means that these drugs have the same effect as the naturally occurring GLP-1 peptide.

The difference is that the naturally occurring GLP-1 peptide hormone is rapidly degraded, so it stays in the bloodstream for a very short time after each meal. In contrast, the GLP-1-like receptor agonist drugs are designed to be much more stable, remaining in the bloodstream for a week or more. That’s why these drugs only need to be injected on a weekly basis.

How GLP-1 Drugs Work: GLP-1 drugs:

Bind to GLP-1 receptors on the pancreas and stimulate insulin release. This can help type 2 diabetics control their blood sugar levels.

Bind to GLP-1 receptors on the stomach and reduce the rate of gastric emptying. This prolongs the feeling of fullness after each meal.

Bind to GLP-1 receptors on the small intestine and reduce gut motility, which increases transit time through the small intestine. This also prolongs the feeling of fullness. But it can also lead to gastrointestinal side effects.

Bind to GLP-1 receptors on the brain and turn down your “appestat”. This reduces feelings of hunger between meals.

A Brief History Of GLP-1 Drugs

GLP-1 drugs have been around since 2005.But the newest and most successful class of GLP-1 drugs (e.g., Ozempic) was developed in 2017 by a Danish pharmaceutical company called Novo Nordisk to help type 2 diabetics control their blood sugar levels.

However, once it became apparent that patients on Ozempic achieved significant weight loss, doctors started prescribing it for weight loss even though it had only been approved for controlling blood sugar. This is a practice described as “off label” use. It became so popular for weight loss that diabetics started to have trouble getting their prescriptions filled.

Novo Nordisk ramped up their production of Ozempic and introduced a second, higher potency drug, Wegovy, that is marketed primarily for weight loss. And, of course, where there is money to be made other companies have introduced their own GLP-1-like receptor agonists for both controlling blood sugar and weight loss.

The popularity of these drugs can only be described as a tsunami. To help you put it into perspective:

Novo Nordisk’s market value is currently over $500 billion. That is larger than the GDP of Denmark where it is located.

One in eight adults in the United States are either taking or have taken a GLP-1 drug.

GLP-1 drugs have had 1.2 billion Tik Tok views since 2021.

The Pros And Cons Of GLP-1 Drugs

Let me be clear. These drugs work. For people with poorly controlled type 2 diabetes or severe obesity-related health issues, they can be a godsend. But like any “quick fix” weight loss drugs they are overprescribed.

The reality is that unless people on the drugs make healthy lifestyle changes, the weight comes back as soon as they quit using the drugs. So, for most people these drugs are not a short-term weight loss solution. They are a long-term necessity if they want to keep the weight off.

And whenever we are thinking about long-term drug use, we need to ask whether they are safe for long-term use.

That brings me to a story. When I was still teaching medical students, the co-director of the first-year course we ran was a medical geneticist. In his introductory lecture to the medical students he made the comment, “The only safe drug is a new drug”. After a dramatic pause he completed the statement with, “That’s because they haven’t discovered all the side effects yet.”

Let me elaborate. Before a drug can be approved by the FDA it must be proven safe and effective in a series of clinical trials. But those clinical trials have their drawbacks. They are relatively short and include a relatively small group of patients.

Sometimes it is only after a drug has been used by millions of patients for several years that we know of some of their most dangerous side-effects. For that reason, the FDA and regulatory agencies in other countries have a monitoring system for detecting “adverse drug reactions” (side-effects) after the drug has been approved.

Simply put, doctors report adverse drug reactions to a central agency. When enough adverse events of a particular type have been detected, clinical studies are initiated to determine how significant that side effect is.

Medical history is littered with drugs that passed the initial company-run clinical studies with flying colors and were introduced to the general public with great fanfare – only to be withdrawn a few years later once serious side-effects had been discovered. One might ask whether GLP-1 drugs may be in the same category.

When you look at the official Ozempic and Wegovy websites they say that the most common adverse reactions, reported in ≥5% of patients in their clinical trials, were nausea, vomiting, diarrhea, abdominal pain, and constipation. These side effects are fully predictable for drugs that inhibit gastric emptying and reduce gut motility. They are also easy to detect in short term clinical studies.

More recently, several reports have suggested that these drugs reduce muscle mass. This is not life-threatening, but it is concerning for older patients trying to maintain muscle mass and for anyone trying to lose weight.

That’s because your muscles are among the most metabolically active tissues in your body. When muscle mass decreases, basal metabolic rate (the rate at which you burn calories 24 hours per day) also decreases. With that in mind, you don’t need to be a genius to understand why loss of muscle mass is a concern for anyone trying to lose weight.

However, more troubling reports have recently surfaced about increases in suicidal behavior in people using GLP-1 drugs. During the company-run clinical trials only 0.27% of drug users reported an increase in suicidal thoughts or behavior, so the drug companies are saying, “Nothing to see here”. However, those clinical trials excluded patients with suicidal tendencies from their analysis, while no such exclusion is recommended for prescribing these drugs.

The authors of the study (G Schoretsanitis et al, JAMA Network Open, 7(8):e2423385, 2024) I will describe today decided to take a closer look at the association of suicidal behavior with GLP-1 drug use.

How Was This Study Done?

The authors obtained their data from the WHO Individual Case Safety Reports database. It is the largest database of its kind in the world, with over 28 million reports of suspected adverse drug reports from 140 member countries.

From this database they identified 107 reports of suicidal and/or self-injurious adverse drug reactions associated with the class of GLP-1 drugs that include Ozempic and Wegovy between July 2011 and August 2023. Key characteristics from these 107 reports were:

Median age = 48 years.
Percentage of female patients = 55%.
Length of GLP-1 use before symptoms were reported = 80 days.
Other medications used were primarily medications for diabetes (15.9%), depression (13.1%), and anxiety (4.7%).
The suicide was successful in 6.5% of the reports.
Suicidal thoughts and/or behaviors disappeared in 62% of the cases after discontinuing the drug.

The authors performed a statistical method known as a disproportionality analysis of suicidal thoughts and behaviors in this group of GLP-1 users. Simply put, they asked whether the frequency of suicidal thoughts or behaviors was disproportionally high for patients using GLP-1 drugs compared to all other drugs in the database for which suicidal tendencies have been reported.

In case you are thinking this is a strange comparison, let me explain why it was chosen.

The WHO Individual Case Safety Reports database (and similar databases maintained by the FDA and other national health organizations) only contains reports of adverse drug reactions. There is no way of comparing the number of adverse drug reactions with the number of people taking the drug. So, you cannot use the database to estimate the percentage of people using GLP-1 drugs who develop suicidal thoughts or behaviors.

Even if it were possible to estimate the percentage of GLP-1 users who develop suicidal tendencies, databases like this significantly undercount the percentage of adverse drug reactions. That’s because if the symptoms are mild, patients often do not report them to their doctors. And busy doctors don’t always report them to the FDA or WHO. It is primarily the cases that result in hospitalization that get reported.

Do GLP-1 Drugs Increase Suicide Risk?

For simplicity, I am restricting myself to the data in this paper related to the Ozempic and Wegovy class of GLP-1 drugs. The results with other classes of GLP-1 drugs were not as clear.

The authors reported:

The Ozemic/Wegovy class of GLP-1 drugs were associated with a disproportionately higher risk of suicidal thoughts and behaviors compared with other drugs in the WHO database.

The disproportionately higher risk remained significant when the authors looked at patients who were using the GLP-1 drugs with either antidepressants or anxiety medications.

- The authors interpreted this as suggesting that people with anxiety or depression may be at higher risk of suicidal thoughts and behaviors when taking this class of GLP-1 drugs.

The authors concluded, “This study using the WHO database found a signal of semaglutide [the class of GLP-1 drugs that includes Ozempic and Wegovy] associated suicidal ideation [suicidal thoughts and behaviors], which requires urgent clarification.”

What Does This Study Mean For You?

I don’t want to overemphasize the significance of this study.

It does not prove an association of this class of GLP-1 drugs with suicidal thoughts and behaviors.

It does not provide definitive information about other classes of GLP-1 drugs. There appeared to be an increased risk, but the data were not statistically significant.

However, it is the first study to show there might be an association with GLP-1 drugs and suicidal behavior.

- Suicide is not a trivial side-effect, which is why the authors said it “requires urgent clarification” by future clinical studies designed specifically to address this possibility. For example, the premarketing clinical trials by the drug companies excluded patients with depression, anxiety, or suicidal tendencies. Since these are likely to be the most vulnerable group, future clinical studies should perhaps focus on this group.

As I said at the beginning of this article, we often don’t know about the most serious side effects of new drugs until they have been on the market for a few years. And it is studies like this one that are often the first indication of serious side effects.

So, here are my recommendations for you:

We don’t yet know for sure whether suicidal tendencies are a side-effect of GLP-1 drugs, but you need to be aware that this is a possibility.

If you suffer from depression, anxiety, or suicidal thoughts GLP-1 drugs may not be the best choice for you. At the very least you should discuss the risks and benefits with your doctor before using them.

If you are using GLP-1 drugs and experience an increase in depression, anxiety, or suicidal tendencies you should discontinue the drug immediately and report your side effects with your doctor.

My most important recommendation is that unless you are dangerously obese, you should consider healthier, drug-free approaches to losing weight. Simple changes in diet and lifestyle can give you gradual weight loss. More importantly, diet and lifestyle change can lead to permanent weight loss. And you will experience side benefits rather than side effects

The Bottom Line

GLP-1 drugs have become immensely popular for weight loss. If you believe the ads, all you need to do is to inject yourself with the drug and those excess pounds will magically appear.

However, we often don’t know about the most serious side effects of new drugs until they have been on the market for a few years. And there have been reports of increased suicide risk associated with the use of GLP-1 drugs.

A recent study looked the increased risk of suicidal thoughts and behaviors associated with the use of GLP-1 drugs. If found:

GLP-1 drugs were associated with a disproportionately higher risk of suicidal thoughts and behaviors compared with other drugs.

The disproportionately higher risk remained significant when the authors looked at patients who were using the GLP-1 drugs along with either antidepressants or anxiety medications.

- The authors interpreted this as suggesting that people with anxiety or depression may be at higher risk of suicidal thoughts and behaviors when taking GLP-1 drugs.

For more details on this study and what it means for you read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.

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My posts and “Health Tips From the Professor” articles carefully avoid claims about any brand of supplement or manufacturer of supplements. However, I am often asked by representatives of supplement companies if they can share them with their customers.

My answer is, “Yes, as long as you share only the article without any additions or alterations. In particular, you should avoid adding any mention of your company or your company’s products. If you were to do that, you could be making what the FTC and FDA consider a “misleading health claim” that could result in legal action against you and the company you represent.

For more detail about FTC regulations for health claims, see this link.

https://www.ftc.gov/business-guidance/resources/health-products-compliance-guidance

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About The Author

Dr. Chaney won numerous teaching awards at UNC, including the Academy of Educators “Excellence in Teaching Lifetime Achievement Award”.

Dr Chaney also ran an active cancer research program at UNC and published over 100 scientific articles and reviews in peer-reviewed scientific journals. In addition, he authored two chapters on nutrition in one of the leading biochemistry text books for medical students.

Since retiring from the University of North Carolina, he has been writing a weekly health blog called “Health Tips From the Professor”. He has also written two best-selling books, “Slaying the Food Myths” and “Slaying the Supplement Myths”. And most recently he has created an online lifestyle change course, “Create Your Personal Health Zone”. For more information visit https://chaneyhealth.com.

For the past 45 years Dr. Chaney and his wife Suzanne have been helping people improve their health holistically through a combination of good diet, exercise, weight control and appropriate supplementation.

Which Nutrients Prevent Prenatal Depression?

May 14, 2024 by Dr. Steve Chaney

What Does This Study Mean For You?

Author: Dr. Stephen Chaney

Yes, you read the headline correctly. Everyone talks about postnatal depression. But prenatal depression is also a “thing”, especially during the third trimester.

Worldwide, 4-20% of women experience some degree of depression during the third trimester – with pregnant women in high-income countries at the lower end (4-10%) of depression risk.
In contrast, the incidence of postnatal depression is 10-15%.

It is probably no coincidence that the incidence of depression is greatest during the third trimester and during the postnatal period.

The third trimester is the most difficult part of pregnancy for many women.
When a woman brings her baby home from the hospital her orderly life becomes chaotic.

But what role does nutrition play?

While not definitive, many studies suggest that supplementation with B vitamins, especially folic acid, B6, and B12; omega-3 fatty acids; vitamin D; and iron reduce the risk of postnatal depression.
However, there is much less information on which nutrients reduce the risk of prenatal depression.

Based on studies suggesting both iron and vitamin D deficiencies may negatively impact mental health, the authors of this study (JL Evanchuk et al, The Journal Of Nutrition. 154, 174-184, 2024) set out to determine whether iron and/or vitamin D deficiencies increase the risk of prenatal depression during the first trimester.

How Was This Study Done?

The authors recruited 2189 newly pregnant mothers from Calgary and Edmonton in Ontario Canada between 2009 and 2012. Participants in the study visited clinics in the area upon entry into the study; midway through the first, second, and third trimesters; and at multiple timepoints up to 3 months during the postpartum period.

In addition to the usual pregnancy wellness tests, participants filled out a 24-hour dietary recall and a Supplemental Intake Questionnaire to determine intakes of iron and vitamin D.

Note: The participants were all advised to take some form of prenatal supplement during the study. That’s because prenatal supplements are considered “the standard of care” for pregnant woman, so it would be considered unethical not to include a prenatal supplement in this study.

At the mid-point of the second trimester blood samples were drawn and analyzed for biomarkers of iron and vitamin D insufficiency. For iron the biomarkers were serum ferritin, soluble transferrin receptor, and hepcidin. For vitamin D, the biomarkers were 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and 3-epi-25-hydroxyvitamin D.

Iron deficiency was defined as serum ferritin levels <15 µg/L. Vitamin D insufficiency was defined as 25-hydroxyvitamin D levels < 75nmol/L. The other biomarkers were used to confirm these diagnoses.

Maternal depression was measured midway through the third trimester and ~3 months postpartum using 10-item questionnaire called the Edinburg Postnatal Depression Scale (EPDS). The EPDS ranks depression on a scale of 0 to 30, with a score of ≥13 considered an indication of likely depression.

The characteristics of the women enrolled in this study were:

Average age = 31.5
Average prepregnancy BMI = 23 (healthy weight).
Married or cohabitating with a partner = 97%.
Highly educated (college or postgraduate degree) = 68%.
Income above $70,000/year = 78%.
First child = 54%.
White = 80%.

Based on the Edinburg Depression Scale, probably depression for the 1822 women who completed the study was 5.6% during the third trimester and 4.4% 3 months postpartum.

Note: The low incidence of depression seen in this study was probably due to:

The women in this study were of high socioeconomic status and were receiving excellent healthcare.

The women in this study were taking prenatal supplements that provided both iron and vitamin D.

Which Nutrients Prevent Prenatal Depression?

As I mentioned when describing how the study was designed, all participants in this study were advised to take a prenatal supplement. Consequently:

94% of the women in this study were taking a supplement containing iron with an average supplemental iron intake of 26 mg/day.

- Note: The RDA for iron during pregnancy is 30 mg/day and most prenatal supplements provide 27 mg/day.

68% of the women in this study were taking a supplement containing vitamin D, with an average supplemental vitamin D intake of 330 IU/day.

- Note: The RDA for vitamin D during pregnancy is 600 IU/day, but most prenatal supplements provide far less than that.

When the investigators looked at iron and vitamin D status during the second trimester:

63.3% of the women had adequate levels of both iron and vitamin D.

14.8% of the women were low in vitamin D but had adequate iron levels.

18.4% of the women were low in iron but had adequate levels of vitamin D.

3.5% of the women were low in both iron and vitamin D.

RDAs are supposed to be enough to meet the nutrient requirements of 97-98% of healthy individuals, so it is perhaps surprising to see so many women with insufficient levels of iron (21.9%) and/or vitamin D (18.3%) in this study. This could be due to:

Insufficient intake.

- This is a likely explanation for vitamin D because the supplements women were using in this study provided around half the recommended RDA for vitamin D and the women lived at a northern latitude where sun exposure makes a small contribution to vitamin D levels.

- However, this is a less likely explanation for insufficient iron levels because the supplements provided 87% of the RDA for iron.

Inadequate RDAs. Studies like this one provide a rigorous test for the adequacy of existing RDAs. This study suggests the existing RDA for iron is adequate to meet the needs of ~80% of pregnant women, which is reassuring. However, it may need to be increased to reach the goal of meeting the iron requirements for 97-98% of pregnant women.

But the important question is whether the iron and vitamin D insufficiencies seen in this study mattered. The data suggested that they did.

For pregnant women with low iron, but adequate vitamin D levels in the second trimester, there was a small, but significant, increased risk of experiencing depression symptoms in the third trimester.

For pregnant women with low iron and vitamin D levels in the second trimester, the risk of experiencing depression symptoms in the third trimester increased by 2.2 points in the 30-point Edinburg Depression Scale.

- This is equivalent to a 7.4% increased risk of depression from deficiencies of iron and vitamin D alone – and these are only 2 of at least 8 nutrients thought to be associated with maternal depression.

The authors concluded, “Maternal iron and vitamin D biomarkers, measured during midpregnancy, were independently associated with third trimester maternal depression symptoms…This investigation is one of the first to report on the combined adequacy of maternal iron and vitamin D status during pregnancy and its impact on maternal depression.

The novelty of this work reinforces the need to ask similar questions [with other nutrients and] in other pregnant populations. Future investigations should report on the status of multiple nutrients and explore their independent and combined impact on health outcomes of pregnant individuals and their children.”

What Does This Study Mean For You?

Depression during pregnancy is bad for you. And because your fetus can sense your mood, it is bad for your baby. So, what should you do?

You can consult with your doctor about which antidepressants are safe to take during pregnancy. But the truth is there are no good choices. There are some antidepressants that are off limits. There are other antidepressants that appear to have little short-term risks, but we have no idea if there are long-term risks for your child.

So, what about natural approaches? Let’s start with nutrition.

The biggest takeaway from this study is that prenatal supplements may not be sufficient to prevent nutritional deficiencies that may cause prenatal depression for pregnant women.

This does not mean that every pregnant woman suffering prenatal depression should increase their iron and vitamin D levels.

However, if you are experiencing prenatal depression, you might want to ask your doctor about checking your iron and vitamin D status to determine if extra iron and/or vitamin D would be beneficial.

And to put this study into its proper perspective we need to remember that iron and vitamin D deficiencies are only two of many nutrients that may increase the risk of prenatal depression.

For example, in addition to iron and vitamin D, prenatal depression is associated with deficiencies of:

B vitamins, especially folate, B6 and B12. Most prenatal supplements provide the recommended RDA of folate for pregnant women, but not all contain RDA amounts of B6 and B12.

Calcium and magnesium. Very few prenatal supplements provide the recommended RDA for calcium and magnesium.

Omega-3s, especially DHA. Very few prenatal supplements provide DHA, and the few that do usually provide inadequate amounts of DHA.

So, when you are having your nutrition conversation with your doctor, you might not want to limit your conversation to iron and vitamin D.

Alternately, as I suggested last week’s issue of “Health Tips From the Professor”, you might wish to add a multivitamin supplement and an omega-3 supplement providing at least 300 mg of DHA plus EPA. This simple step would be sufficient to assure you have adequate levels of nutrients thought to be important for reducing the risk of prenatal depression.

And, of course, there are other lifestyle factors, as well. For example:

Diets high in highly processed foods are known to increase the risk of depression. And whole food, primarily plant-based diets decrease the risk of depression.

Overweight and obesity increase the risk of depression.

Regular exercise decreases the risk of depression.

The Bottom Line

A recent study looked at whether taking a prenatal supplement was sufficient to eliminate deficiencies of iron and vitamin D during pregnancy and whether deficiencies of these two nutrients during the second trimester of pregnancy increased the risk of depression during the third trimester.

When the investigators looked at iron and vitamin D status during the second trimester:

14.8% of the women were low in vitamin D but had adequate iron levels.

18.4% of the women were low in iron but had adequate levels of vitamin D.

3.5% of the women were low in both iron and vitamin D.

But the important question is whether the iron and vitamin D insufficiencies seen in this study mattered. The data suggested that they did.

For pregnant women with low iron, but adequate vitamin D levels in the second trimester, there was a small, but significant, increased risk of experiencing depression symptoms in the third trimester.

For pregnant women with low iron and vitamin D levels in the second trimester, the risk of experiencing depression symptoms in the third trimester increased by 2.2 points in the 30-point Edinburg Depression Scale.

This is equivalent to a 7.4% increased risk of depression from deficiencies of iron and vitamin D alone.

When you consider that iron and vitamin D are just two of 8 or more nutrients thought to be important for preventing depression during pregnancy, the question becomes what you can do to decrease your risk of developing depression during pregnancy and after the birth of your child.

For more details about the study and what it means for you, read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.

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For more detail about FTC regulations for health claims, see this link.

https://www.ftc.gov/business-guidance/resources/health-products-compliance-guidance

___________________________________________________________________________

About The Author

Dr. Chaney has a BS in Chemistry from Duke University and a PhD in Biochemistry from UCLA. He is Professor Emeritus from the University of North Carolina where he taught biochemistry and nutrition to medical and dental students for 40 years. Dr. Chaney won numerous teaching awards at UNC, including the Academy of Educators “Excellence in Teaching Lifetime Achievement Award”. Dr Chaney also ran an active cancer research program at UNC and published over 100 scientific articles and reviews in peer-reviewed scientific journals. In addition, he authored two chapters on nutrition in one of the leading biochemistry text books for medical students.

Does Vitamin D Prevent Depression?

October 13, 2020 by Dr. Steve Chaney

Why You Can’t Believe Everything You Read

The days are getting shorter and Seasonal Depression, often called the “winter blues”, will soon be upon us. Most of the research on Seasonal Depression has centered on the effect of sunlight on our hormones.

However, sunlight is also responsible for the synthesis of vitamin D in our skin cells. So, some experts have hypothesized that low levels of 25-hydroxyvitamin D, the active form of vitamin D, in our blood also play a role in the winter blues.

If so, that could have important implications for managing depression, especially in older adults. Depression is estimated to affect around 6.5 million of the 49 million adults over the age of 65 in our country. Treatment costs for older adults in this country are estimated at $9 billion/year.

If something as simple and inexpensive as a vitamin D supplement could reduce the risk of depression, it would be a huge boon to our health care system.

Association studies suggest that may be a possibility. For example, one recent meta-analysis of 6 clinical studies (H Li et al, The American Journal of Geriatric Psychiatry, 27: P1192-1202, 2019) reported that every 10 ng/mL increase in 25-hydroxyvitamin D was associated with a 12% decrease in the risk of depression in older adults.

However, association studies do not prove cause and effect.

Unfortunately, randomized, placebo controlled clinical trials have given mixed results. A few studies suggested that vitamin D might reduce depression risk, but most of the studies found no effect of vitamin D on depression risk. However, most of the published studies have been poorly designed They were too small, too short, or did not use validated methods for measuring depression.

This was the genesis of the current study (OI Okerke et al., JAMA, 324: 471-480, 2020). It was designed to be a definitive study that would avoid the defects of previous studies.

The study concluded that vitamin D supplementation does not decrease the risk of depression in older adults, and those were the headlines you have probably seen. But is that conclusion true? Let’s take a peek behind the curtain and analyze the study.

How Was The Study Done?

This study was an offshoot of the VITAL (VITamin D and OmegaA-3 TriaL) clinical study, so let me start by describing the characteristics of that study.

The VITAL study (JE Manson et al, New England Journal of Medicine, DOI: 10.1056/NEJMoa1811403) enrolled 25,871 healthy adults (average age = 67) in the United States. The study participants were 50% female, 50% male, and 20% African American. None of the participants had preexisting cancer or heart disease.

Study participants were given questionnaires on enrollment to assess clinical and lifestyle factors including dietary intake. Blood samples were taken from about 65% of the participants to determine 25-hydroxyvitamin D levels (a measure of vitamin D status) at baseline and at the end of the first year to assess the effectiveness of vitamin D supplementation. The participants were given either 2,000 IU of vitamin D/day or a placebo and followed for an average of 5.3 years.

This study consisted of 18,353 participants from the VITAL study. Ninety percent of the participants had no previous history of depression. Ten percent had previously been diagnosed or treated for depression but had been depression-free for over 2 years.

The participants filled out annual questionnaires to quantify the onset of depression by three criteria:

A diagnosis of depression by a physician.

Treatment for depression (medications, counseling, or both).

A questionnaire designed to evaluate symptoms of depression. The authors of the study referred to this as an assessment of their mood.

During the 5.3 year follow up period 3.6% of the participants reported the onset of diagnosed depression or a mood consistent with depression. This is consistent with previous studies showing that 1-5% of healthy, non-institutionalized older adults suffer from depression.

Does Vitamin D Prevent Depression?

The results of the study were clear.

Treatment with 2,000 IU of vitamin D3 compared to placebo for 5.3 years did not have a statistically significant effect on:

The incidence or recurrence of depression diagnosis, or…

Treatment for depression, or…

Clinically relevant depressive symptoms.

The authors concluded, “These findings do not support the use of vitamin D3 in adults to prevent depression.”

Why You Can’t Believe Everything You Read

It would be tempting to say, “Case closed. We now know for certain that vitamin D has no effect on depression.”

After all, this was an excellent study. It was large (18,353 participants), lasted a long time (5.3 years), and used well established measures of depression. What’s not to like?

Unfortunately, even well-designed studies can give misleading results. Let’s take a peek behind the curtain and see where this study went astray.

There were two glaring deficiencies in this study.

#1: Most of the participants had adequate vitamin D status at the beginning of the study. The average 25-hydroxyvitamin D level of participants at the beginning of the study was 31 ng/mL (78 nmol/L). The NIH considers 20-50 ng/mL (50-125 nmol/L) to be an adequate level of 25-hydroxyvitamin D for most physiological functions. This means that study participants started in the middle of the adequate range with respect to vitamin D status.

This was not a failure of study design. In fact, the authors of the study are to be commended for measuring the vitamin D status of participants at the beginning of the study. Many previous studies have neglected to do that.

The problem is that vitamin D has become extremely popular. Many Americans are already taking multivitamins or vitamin D supplements. To recruit enough people for the study the authors were forced to allow participants to enter the study even if they were taking vitamin D supplements, as long as the amount did not exceed 800 IU/day.

In short, most of the participants in this study were already supplementing with up to 800 IU/day of vitamin D. If so, they were allowed to continue taking their vitamin D supplements. The 2,000 IU of vitamin D was added to what they were already taking.

The question then becomes, if people are already taking RDA levels of supplemental vitamin D and their blood levels of 25-hydroxyvitamin D are already in the adequate range, do we really expect additional supplemental vitamin D to have a beneficial effect?

The author’s answer to that question was, “The mean baseline 25-hydroxyvitamin D level was 30.8 ng/mL; this value is already at a threshold for extraskeletal health benefits [health benefits other than bone health], and so the ability to observe effects of vitamin D3 supplementation may have been attenuated. [To determine whether vitamin D supplementation reduces the risk of depression] large-scale studies would be required to address the effects of high-dose, long-term vitamin D3 supplementation among those with nutrient deficiency.”

My more direct answer would be, “This study provides no useful information on whether vitamin D3 supplementation reduces the risk of depression. What is needed are studies that start with a population that is deficient in vitamin D.”

An accurate conclusion from this study would have been, “If you are already taking vitamin D supplements and/or have an adequate vitamin D status, supplementation with an extra 2,000 IU of vitamin D3 provides no additional benefit with respect to the risk of developing depression.” But that is not what the headlines said.

#2: The study did not record the reason for the onset of depression. That is important because the top 3 causes of depression in adults 65 and older are:

Loss of a spouse or partner.

Chronic health issues.

Restricted blood flow to the brain.

It is unlikely that vitamin D supplementation would have much of an effect on these issues.

In contrast, seasonal depression, which is more likely to be affected by vitamin D supplementation, was not measured in this study.

The Bottom Line

You may have seen recent headlines saying that vitamin D supplementation has no effect on the risk of developing depression.

The study behind these headlines was a very well-designed study. It was large (18,353 participants), lasted a long time (5.3 years), and used well established measures of depression.

It would be tempting to say, “Case closed. We now know for certain that vitamin D supplementation has no effect on depression.”

Unfortunately, even well-designed studies can give misleading results. This one had a major flaw that made the data almost useless.

The problem is that most Americans are already taking multivitamins or vitamin D supplements. To recruit enough people for the study the authors were forced to allow participants to enter the study even if they were taking vitamin D supplements, as long as the amount did not exceed 800 IU/day.

That meant that most participants already had adequate blood levels of 25-hydroxyvitamin D at the beginning of the study.

Rather than saying that this study definitively shows that vitamin D supplementation has no effect on the risk of developing depression, I feel it would be more accurate to say, “This study provides no useful information on whether vitamin D3 supplementation reduces the risk of depression. What is needed are studies that start with a population that is deficient in vitamin D.”

For more details, read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure, or prevent any disease.

What Supplements Help Mental Health?

January 14, 2020 by Dr. Steve Chaney

Do Omega-3s Reduce Depression?

Author: Dr. Stephen Chaney

We are in the midst of a mental health crisis. According to the latest statistics:

· 19% of adults in the United States have some form of mental illness.

· 16.5% of youth ages 6-17 have some form of mental illness.

· The 5 most commonly diagnosed forms of mental illness are anxiety, depression, post-traumatic stress disorder, bipolar disease, and ADHD.

Even worse, mental illness appears to be increasing at an alarming rate among young people. For example:

· Between 2005 and 2017 depression increased 52% among adolescents.

· Between 2002 and 2017 depression increased 63% in young adults.

· Between 1999 and 2014 suicides have increased 24% in young adults. In the past few years suicides have been increasing by 2% a year in this group.

Much has been written about the cause of this alarming increase in mental illness. The short answer is that we don’t really know. But the most pressing question is what do we do about it?

The medical profession relies on powerful drugs to treat the symptoms of mental illness. These drugs don’t cure the illness. They simply keep the symptoms under control. Plus, if you have ever listened closely to the advertisements for these drugs on TV, you realize that they all have serious side effects that adversely affect your quality of life.

My “favorite” example is drugs for anxiety and depression. You are told that one of the side effects is “suicidal thoughts”. That means that the very drug someone could be prescribed to prevent suicides might actually increase their risk of suicide. Why would anyone take such a drug?

If drugs are so dangerous, what about supplements? Do they provide a safe, natural alternative for reducing the symptoms of mental illness? Some supplement companies claim their products cure mental illness. Are their claims true or are they just trying to empty your wallet?

How is a consumer to know which of these supplement claims are true and which are bogus? Fortunately, an international team of scientists has scoured the literature to find out which supplements have been proven to reduce mental health symptoms.

How Was The Study Done?

This was a massive study (J. Firth et al, World Psychiatry, 18: 308-324, 2019. It was a meta-review of 33 meta-analyses of randomized, placebo-controlled trials with a total of 10,951 subjects. The clinical trials included in this analysis analyzed the effect of 12 nutrients, either alone or in combination with standard drug treatment, on symptoms associated with 10 common mental disorders.

To help you understand the power of this meta-review, let me start by defining the term “meta-analysis”. A meta-analysis combines the data from multiple clinical studies to increase the statistical power of the data. Meta-analyses are considered to be the gold standard of evidence-based evidence.

However, not all meta-analyses are equally strong. They suffer from the “Garbage-In, Garbage-Out” phenomenon. Simply put, they are only as strong as the weakest clinical studies included in their analysis.

That is the strength of this meta-review. It did not simply combine the data from all 33 meta-analyses. It used stringent criteria to evaluate the quality of each meta-analysis and weighted the data appropriately.

What Supplements Help Mental Health?

The strongest evidence was for omega-3 supplements. In the worlds of the authors:

· “Across 13 independent randomized control clinical trials in 1,233 people with major depression, omega-3 supplements reduced depressive symptoms significantly.”

o The average dose of omega-3s in these studies was 1,422 mg/day of EPA.

o The effect was strongest for omega-3 supplements containing more EPA than DHA and for studies lasting longer than 12 weeks.

o There was no evidence of publication bias in these studies. This is a very important consideration. Publication bias means that only studies with a positive effect were published while studies showing no effect were withheld from publication. That makes the effect look much more positive than it really is. The fact there was no evidence of publication bias strengthens this conclusion.

o Omega-3 supplements were more effective when used in combination with antidepressant drugs, but there was some evidence of publication bias in those studies.

· “Across 16 randomized control clinical trials reporting on ADHD symptom domains, significant benefits were observed for both hyperactivity/impulsivity and inattention.”

· Omega-3s had no significant effect on schizophrenia or bipolar disorder other than a mild reduction in depressive symptoms.

There was strong, but not definitive, evidence for folic acid and methylfolate supplements for depression.

· When used in conjunction with antidepressants both folic acid and methylfolate supplements “…were associated with significantly greater reductions in depressive symptoms compared to placebo, although there was large heterogeneity between trials.”

· The largest effects were observed with high dose methylfolate. In the words of the authors: “Two randomized control clinical trials examining a high dose (15 mg/day) of methylfolate administered in combination with antidepressants found moderate-to-large benefits for depressive symptoms.” However, to put this into perspective:

o 15 mg/day is 3,750% of the RDA. This is a pharmacological dose and should only be administered under the care of a physician.

o A smaller dose of 7.5 mg/day is ineffective.

o No comparison was made with folic acid at this dose, so we do not know whether folic acid would be equally effective.

· The authors concluded that there is emerging evidence for positive effects of vitamin D (>1,500 IU/day) for major depressive disorders and N-acetylcysteine (2-3 gm/day) in combination with drugs for mood disorders and schizophrenia. The term “emerging evidence” means there have been several recent studies reporting positive results, but more research is needed.

· The authors did not find evidence supporting the use of other vitamin and mineral supplements (E, C, zinc, magnesium, and inositol) for treating mental health disorders.

· The authors did not find enough high-quality studies to support claims about the effects of prebiotics or probiotics on mental health disorders.

Do Omega-3s Reduce Depression?

The evidence supporting the effectiveness of omega-3s in reducing symptoms of depression is strong. In the words of the authors: “The nutritional intervention with the strongest evidentiary support is omega-3, in particular EPA. Multiple meta-analyses have demonstrated that it has significant effects in people with depression, including high-quality meta-analyses with good confidence in findings…”

However, before you throw away your antidepressants and replace them with an omega-3 supplement, let me put this study into perspective for you.

· Depression can be a serious disease. If you just feel a little blue from time to time, try increasing your omega-3 intake. However, if you have major depression, don’t make changes to your treatment plan without consulting your physician.

· The best results were obtained when omega-3s were used in combination with antidepressants. This should be your starting point.

· Ideally, adding omega-3s to your treatment plan will allow your doctor to reduce or eliminate the drugs you are taking. That would have the benefit of reducing side effects associated with the drugs. However, I would like to re-emphasize this is a decision to take in consultation with your doctor. [My only caveat is if your doctor is unwilling to even consider natural approaches like omega-3 supplementation, it might be time to find a new doctor.]

· Finally, omega-3 supplementation is only one aspect of a holistic approach to good mental health. A healthy diet, exercise, supplementation, and stress reduction techniques all work together to keep your mind in tip-top shape.

The Bottom Line

There are lots of supplements on the market promising to cure depression and other serious mental health issues. Are they effective or are the claims bogus? Fortunately, a recent meta-review of 33 meta-analyses of high-quality clinical trials has answered that question. Here is their conclusion:

· The evidence is strongest for omega-3s and depression.

o The average dose of omega-3s in these studies was 1,422 mg/day of EPA.

o The effect was strongest for omega-3 supplements containing more EPA than DHA and for studies lasting longer than 12 weeks.

· There is fairly strong evidence for folate/folic acid supplements and depression, although there was large heterogeneity between trials.

· There is emerging evidence for vitamin D (>1,500 IU/day) and depression and N-acetylcysteine (2-3 gm/day) for depression and schizophrenia.

· Evidence for other supplements is currently inconclusive.

However, before you throw away your antidepressants and replace them with an omega-3 supplement, let me put this study into perspective for you.

· The best results were obtained when omega-3s were used in combination with antidepressants. That should be your starting point.

For more details, read the article above.

These statements have not been evaluated by the Food and Drug Administration. This information is not intended to diagnose, treat, cure or prevent any disease.