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How to Navigate SSRI Alternatives for Depression

Written by Dr. Michael Ruscio, DC on May 30, 2023

Written by Dr. Michael Ruscio, DC on May 30, 2023 — Reviewed by Hilary Watts

Diet, Lifestyle, Mindfulness, and Supplements Can Improve Your Symptoms of Depression

• Natural SSRI Alternatives|
• The Research Behind Natural Antidepressants|
• What Causes Depression?|
• SSRI Medications 101|
• The Takeaway|

Depression, a condition where you lose interest in daily activities for long periods of time, is a common type of mood disorder that can affect any person. When you experience the symptoms of depression, your prescribing physician may recommend a medication called a selective serotonin reuptake inhibitor, or SSRI for short. But pausing to take a look at SSRI alternatives before you reach for a prescription can be a serious game-changer for your mood. 

For years, we thought that certain serotonin-related genes and the lack of serotonin (a neurotransmitter) were the root causes of depression. A solid body of evidence, and now a large and compelling umbrella meta-analysis shows that rather than being related to our genetics, depressive symptoms may be the result of poor gut health, micronutrient deficiencies, inflammation, or another imbalance [1]. This is great news because all of these root causes can be addressed with natural therapies like probiotics, exercise, time in nature, sauna therapy, and more.

Don’t get me wrong, SSRI medications can work for some people. But for many, starting with natural SSRI alternatives and, if needed, later moving to prescription medications can help you avoid side effects. If you’re already taking an SSRI, you don’t have to stop it in order to incorporate natural therapies — it’s never too late to address the underlying cause of your symptoms. However, if you would like to stop your medication or add supplements like SAMe, St. John’s Wort, or tryptophan, you should always speak with your doctor first to avoid any interactions or withdrawal symptoms.

In this article, I’ll share the best natural SSRI alternatives, and what the research tells us about how they stack up to prescription medications. 

Natural SSRI Alternatives

Before we get into the specifics about the best natural SSRI alternatives, I want to give you an overview of the many available options. This chart details the various therapies in each category, and the research-based best-use recommendations:

As you can see, there are a number of natural SSRI alternative treatment options to choose from. And I use many of these in the clinic to help people heal their symptoms of depression. I want to emphasize that I’m not against SSRI medications, or any antidepressant for that matter. 

However, in most cases, I do recommend starting with some of these natural therapies, which help to resolve underlying issues that contribute to depressive symptoms. They also have little-to-no side effects, often don’t require you to rely on a lifelong pill, and can be extremely effective. 

If your symptoms are severe and/or persist after trying natural options, prescription medications are another tool in the toolkit. Now let’s take a look at the research on natural SSRI alternatives.  

Natural SSRI Alternatives: The Research

Since depression can be a symptom of a gut issue, inflammation, and/or a micronutrient deficiency, it’s important to target those underlying causes in order to experience complete healing. Here are some of the best natural SSRI alternatives and how they work.

SSRI Alternatives: Dietary Supplements

There are a variety of dietary supplements that have been found to improve depressive symptoms:

• Probiotics. Depression is common in people with gut health conditions, for example, people with IBS are three times more likely to have depression when compared to healthy people [13, 14]. Probiotics can help improve the balance of organisms in your gut, reduce overzealous immune system activity, and reduce the inflammation that may cause you to suffer from depressive symptoms [15, 16, 17]. In addition, a meta-analysis of 20 randomized controlled trials found probiotics possibly helped to improve depression by improving BDNF levels and reducing CRP levels [18].

• St. John’s Wort. This herbal supplement may act similarly to SSRIs by altering serotonin levels and has been found to be as effective for mild-to-moderate depression as SSRI medications [19]. It seems to be better tolerated than traditional SSRIs. But it may not be as effective for people with severe depression (major depressive disorder) [19, 20]. Always speak to a healthcare provider before adding this herbal supplement as serious side effects can result [2].

• Fish oil. Omega-3 polyunsaturated fatty acids may have anywhere from a small to a very large positive effect on depressive symptoms [3, 21]. Fish oil may reduce inflammation, and improve nerve formation, neuroplasticity, nerve communication, and the function of the hypothalamic-pituitary-adrenal (HPA) axis [4, 21]. This means less stress and inflammation, both of which can help depression.

• Saffron. This spice has been found to be as effective as an SSRI medication and a tricyclic antidepressant [22]. Saffron may act on the serotonergic system but also has antioxidant, anti-inflammatory, and neuroprotective qualities, and it may modulate the HPA axis [23].

SSRI Alternatives: Lifestyle

The truth is, how we live and think, and what we’re exposed to have the power to turn our genes on and off. So, by making some consistent lifestyle choices, we really have a lot of control over depressive symptoms. Here are some of the best lifestyle measures that serve as SSRI alternatives:

• Sun exposure. Vitamin D deficiency is common in people with depression. Daily sun exposure has been found to increase vitamin D levels and improve depressive symptoms in vitamin D-deficient people [24, 25].

• Walking in nature. Spending less time outdoors in nature is associated with higher depression scores [26]. And while that may be partially due to isolation in those with depression, research has found highly-quality evidence that walking or running in nature can improve depressive symptoms to a small or moderate degree [27, 28].

• Exercise. Exercise may exert antidepressant effects by improving circulating levels of brain-derived neurotrophic factor (BDNF), kynurenine, and IL-6 (an inflammatory marker) [29]. One meta-analysis that compared exercise to antidepressant medications found exercise had a moderate benefit, whereas antidepressants only had a small benefit [30]. If you’re new to exercise, simply start with walking and build yourself up to include moderate-intensity cardiovascular and strength training several times per week.

• Sauna. One systematic review of 7 trials found sauna use has a moderate to large positive effect on depression [9]. And just one infrared sauna session may reduce depression symptoms for 6 weeks [31]. Sauna may improve mood by signaling serotonin-specific neurons in the brain stem [9]. 

SSRI Alternatives: Mindfulness Exercises

Chronic emotional stress can lead to inflammation and set you up for poor gut health, both of which may cause symptoms of depression [32]. Mindfulness-based exercises have been found to improve depression:

• Meditation. Two meta-analyses and one randomized controlled trial have found mindfulness-based cognitive therapy (MBCT) to be as effective as antidepressants in the treatment of recurrent major depression [33]. And MBCT has been recommended as a go-to treatment for maintaining mental health after recovering from depression [33]. MBCT seems to improve the symptoms of major depression by improving mindfulness, reducing rumination and worry, and increasing compassion and self-awareness [34].

• Yoga. Two meta-analyses have found various types of yoga to lead to mild to moderate improvements in depression [11, 35]. Yoga may improve the symptoms of depression by increasing mindfulness, decreasing rumination, improving vagal control and heart rate variability, increasing BDNF, and decreasing cortisol [36].

SSRI Alternatives: Nutrition

Changing your diet is one of the most impactful strategies you can use to help lower inflammation in the body, which helps improve depressive symptoms. Several observational studies have linked an anti-inflammatory diet, like the Mediterranean diet, to lower rates of depression [12]. And, one randomized controlled trial found that people who learned how to cook a Mediterranean-style diet had bigger drops in their depression scores after three months on the diet than people who didn’t change what they ate [37]. 

Anti-inflammatory diets work by eliminating foods that cause inflammation, and bringing in foods, like nuts, vegetables, legumes, and omega-3 fatty acids, that can quiet the inflammatory process [37, 38, 39, 40]. While most of the research on diet and depression looks at the Mediterranean diet, any anti-inflammatory diet (like Paleo) will probably be effective. 

The Paleo diet focuses on whole foods and eliminates foods, like processed foods, artificial sweeteners, grains, beans, legumes, dairy products, and certain vegetable oils, that may provoke an immune system response and inflammation [41, 42].

Now that you know some natural SSRI alternatives, let’s review what causes depression and why serotonin may not be the ultimate target for people with depression. 

What Causes Depression?

While the development of depression is unique to each person, inflammation may be one root cause. Several observational studies have found higher levels of inflammation in people who are depressed [38, 39], and who have suicidal thoughts or who’ve tried to commit suicide [40]. 

Depression seems to rarely occur on its own, rather it’s been found to co-occur with just about every psychiatric and physical condition you can think of [43]. Several literature reviews have linked depression with chronic inflammatory illnesses like inflammatory bowel disease (IBD), cancer, and heart disease [44, 45]. 

One study showed that when depressed participants were given an SSRI antidepressant called fluoxetine (Prozac), their levels of inflammatory markers decreased [46]. This suggests that when medication does make an impact, it may partially be due to its ability to target inflammation, not just serotonin levels. 

This may also be why natural SSRI alternatives that are anti-inflammatory in nature like an elimination diet, exercise, and probiotics may be so beneficial for depressive symptoms. Interestingly, in patients who take antidepressant medications and still struggle with treatment-resistant depression, the levels of inflammatory markers are higher [47]

In addition, depression is commonly found in people with poor gut health [48] and nutrient deficiencies [49]. And people with depression may be more likely to suffer from gut dysbiosis (an imbalance of microbes) than people without depression [50]. This is why therapies like diet and probiotics, that target gut inflammation and dysbiosis may pack a stronger punch than SSRIs alone.

So, while the exact cause of depression isn’t fully understood, research seems to suggest that it’s often the symptom of some other underlying issue like poor gut health, a micronutrient deficiency, or inflammation — not just a serotonin imbalance. When these root causes are addressed with diet and lifestyle, depressive symptoms can be significantly improved. But what about SSRI medications? Let’s take a look at the research. 

SSRI Medications 101

Researchers have long believed that certain serotonin-related genes were harbingers of depression. So, SSRIs were created to target the serotonergic system to improve depressive symptoms. Here’s how we think they work [2]:

• After serotonin is released from a neuron to pass along messages to neighboring cells, the original neuron reabsorbs much of the serotonin to prevent “information overload”.
• Serotonin theory suggests that lower amounts of free serotonin outside the neuron can contribute to depression.
• SSRIs counteract this by preventing the neuron from reabsorbing the serotonin, so there’s more free serotonin that can go from neuron to neuron delivering chemical messages.

The FDA has approved the following SSRI medications for the treatment of depression:

• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Paroxetine (Paxil, Pexeva)
• Sertraline (Zoloft)

A large umbrella meta-analysis found no convincing evidence that depression is related to serotonin-related biochemistry or genes [1]. This news suggests we have way more power than we thought when it comes to relieving our own depressive symptoms. I want to make it clear though, that this new research doesn’t mean SSRIs aren’t effective or needed by some people. 

Several research trials of SSRI medications indicate they can effectively improve depressive symptoms [51], but we have to accept that not everyone benefits from them: 

• One meta-analysis found cancer patients who were given SSRIs didn’t experience improvement in their depressive symptoms above those given a placebo [52].
• Patients given SSRI medications often stop taking them either due to side effects (like dry mouth, sedation, and erectile dysfunction) or lack of symptom improvement [52]. 

In addition, trials of SSRI medications may suffer from unblinding bias, which means patients given a drug with obvious side effects (like an SSRI) may know they weren’t given a placebo, so they may overstate the effects of the drug, making the trial results unreliable [53]. 

If you’re currently taking an SSRI medication or other type of antidepressant like Wellbutrin (bupropion), venlafaxine, a monoamine oxidase inhibitor (MAOI), Effexor, Cymbalta (duloxetine), or mirtazapine and you feel it’s beneficial, then that’s great. But if you’d like to try natural therapies and heal your underlying imbalances, you don’t have to stop taking your antidepressants first. However, before you try supplements like St. John’s Wort, SAMe, or tryptophan, it’s important to speak with your doctor as they may interact with your medication. 

You might find natural therapies improve your symptoms dramatically, and it may be tempting to stop taking your SSRI medication. But suddenly stopping an SSRI can create withdrawal symptoms, so it’s always important to wean from these medications slowly and with guidance from your provider. 

Natural SSRI Alternatives Can Improve Depressive Symptoms

Depression is a commonly diagnosed mood condition that can affect anyone at any time. Until now, researchers believed low serotonin levels were the underlying cause of depressive symptoms, but a large umbrella meta-analysis has found no association between serotonin genetics and depression. Rather than being a result of low serotonin, depression seems to be the symptom of an underlying gut health issue, inflammation, a micronutrient deficiency, or other imbalance. 

Standard treatment for depression often includes an SSRI or other antidepressant medication. While these medications may be effective for some people, they aren’t always helpful, and they can have side effects. Natural SSRI alternatives (like probiotics, fish oil, exercise, sun exposure, time in nature, meditation, and an anti-inflammatory diet) work by addressing the underlying causes of depression.

If you’re struggling with the symptoms of depression, my book Healthy Gut, Healthy You is a great step-by-step gut healing guide that targets the root causes of depression. If you’d like a more personalized plan, contact us at the Ruscio Institute for Functional Health. And please remember to always speak with your healthcare provider before stopping or changing any antidepressant medication.

The Ruscio Institute has developed a range of high-quality formulations to help our patients and audience. If you’re interested in learning more about these products, please click here. Note that there are many other options available, and we encourage you to research which products may be right for you.