Updated November 2021
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If you’re struggling with depression or if you know someone who is: You’re not alone. There are resources and support networks, new therapies and emerging research, and a wide range of interventions, tools, and medical-care options. We’ll cover many of them in this article—as always, talk to your doctor about what’s best for you.
For Immediate Help
If you are in crisis, please contact the National Suicide Prevention Lifeline by calling 800.273.TALK (8255) or the Crisis Text Line by texting HOME to 741741 in the United States. If you’re outside the United States, please visit iasp.info.
The World Health Organization (WHO) estimates that 4.4 percent of the global population suffers from depression. Eight percent of American adults have depression, and women are twice as likely to be depressed as men (Brody, Pratt, & Hughes, 2018).
Depression is a wide-ranging disorder that can affect many aspects of your life beyond your mood. It can be associated with lower energy levels and substance use disorders. It can affect work performance and interpersonal relationships, and it can lead to physical manifestations of illness, such as heart problems. Depression can cause more impairment than other chronic diseases and can lead to suicide. Suicide was the tenth leading cause of death in the US in 2019, killing 47,000 people (Kessler, 2012; National Institutes of Mental Health, 2021; Wells et al., 1989).
It’s shocking that depression can be overlooked and even stigmatized in our society, contributing to a culture of shame. There is still more work to do, but we’re grateful that many gains have been made in recent years toward destigmatizing depression and starting important conversations about mental health.
Depression can take many forms, including major depression, seasonal affective disorder, situational depression, postpartum depression, and bipolar disorder. We will focus mainly on major depressive disorder (MDD), also called clinical depression or unipolar depression.
Symptoms of Depression
Depression can come and go in bouts or be more persistent, as is the case with major depression. Symptoms vary from person to person and may include changes in sleep, appetite, and energy; loss of interest in daily activities; and thoughts of suicide.
One of the leading depression theories since the 1990s has been that depression is biological: that it is caused in part by changes in the brain and chemical imbalances. This theory has been debated, and today much of the medical community believes that a wide range of factors—biological, emotional, physical, environmental, etc.—could be at the root of depression and that this could look different for different people. Research has looked at genetic susceptibility (depression runs in families) and the impact of trauma, stress, a lack of social connection, illnesses, and medical conditions.
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) defines psychological disorders such as depression with various diagnostic criteria. Major depressive disorder is defined by the DSM-5 as at least two weeks of depressed mood or lack of pleasure in everyday activities, in addition to several other symptoms which may include weight loss or appetite change, insomnia or hypersomnia, fatigue, feelings of worthlessness or guilt, lack of concentration, recurrent thoughts of death or suicide, and psychomotor agitation, which is when anxious restlessness is associated with making movements, such as tapping, that serve no purpose or are unintentional (American Psychiatric Association, 2013).
While the DSM has been used since the 1970s to aid with diagnosis, it lumps all depressed individuals into one category for treatment, which is not necessarily useful. Even the National Institute of Mental Health acknowledges that not all symptoms need to be present and that subsymptomal depression may also be distressing and require treatment. The bottom line: Seek help if you feel you may need it or want it, regardless of whether you meet the DSM-5 criteria for clinical depression (National Institute of Mental Health, 2018).
A healthy, well-rounded Mediterranean diet is ideal for mental and physical health. Moderating caffeine and alcohol intake is also key.
Food is important to nearly every aspect of our health and well-being. Researchers in Australia determined that a Mediterranean diet intervention consisting of nutritious food, cooking workshops, and social eating was a cost-effective treatment for depression compared to a social support group intervention (Segal et al., 2018). Additionally, a meta-analysis of twenty-one studies found that eating a Western diet (red and processed meats, refined grains, sweets, high-fat dairy products, and a low intake of fruits and vegetables) was associated with a greater risk of depression than a Mediterranean diet (fruit, vegetables, whole grains, fish, olive oil, and low-fat dairy) (Li et al., 2017). Researchers have questioned whether this is due to the more well-rounded diet or if the key here is increased omega-3 intake from fish. Alternatively, people eating the Mediterranean diet may also practice other protective behaviors.
Coffee lovers: Research has suggested that coffee, which is a major source of caffeine, may modulate neurotransmitters in the brain such as dopamine and serotonin, and consumption has been associated with decreased risk of depression and suicide (Wang, Shen, Wu, & Zhang, 2016). Scientists in Finland wanted to see how the amount of coffee people drink might affect risk of suicide, and they found that there is a J-shaped association with coffee drinking and risk of suicide. People who were moderate coffee drinkers (two or three cups per day) had the lowest risk of suicide, while the highest risk of suicide was among heavy coffee drinkers (eight or more cups per day) (Tanskanen et al., 2000). If you like coffee and tolerate it well, stick to a couple cups a day.
While a glass of wine suits some people, excess drinking can be particularly hard on people with depression. Several studies have shown that increased alcohol use (as well as misuse of drugs) has been linked to higher risk of depression and suicide (Hawton, Casañas i Comabella, Haw, & Saunders, 2013). According to the CDC (Centers for Disease Control and Prevention), moderate alcohol consumption is one drink per day for women and two drinks per day for men (CDC, 2018). If you drink more than that, consider whether it’s good for you and seek help if you need it. The NIH has a guide for seeking help and treatment for alcohol issues.
Nutrients and Supplements for Depression
Proper intake of omega-3 fatty acids, folate, vitamin B12, and vitamin D through diet or supplementation may be beneficial for people with depression.
Omega-3 polyunsaturated fatty acids include alpha-linolenic acid (which is found in flaxseed, chia seeds, and walnuts), eicosapentaenoic acid (EPA, which is found in seafood) and docosahexaenoic acid (DHA, which is also primarily found in seafood). There is a debate among researchers about whether omega-3 supplementation is beneficial for major depression and whether the type of omega-3 makes a difference. A 2012 meta-analysis by researchers at Yale found that omega-3 treatment for depression was not effective and that most of the published studies showing benefits were biased (Bloch & Hannestad, 2012). In contrast, a 2016 meta-analysis, which included many of the same studies as the 2012 meta-analysis, found a beneficial effect of omega-3s that was similar to the effect of antidepressants. The researchers also found that benefits were greater in participants also taking antidepressants and for higher doses of EPA (Mocking et al., 2016). Recent studies have failed to confirm evidence of benefits, so it seems the answer isn’t quite clear yet on whether omega-3s are beneficial for all people with depression (Suradom et al., 2021; Thesing et al., 2020). Many Americans probably do not get enough omega-3s from their diet alone, so it may be worth finding a good fish oil or algae supplement containing both EPA and DHA.
Folate and Vitamin B12
Vitamin B12 and folate work together in the body, and low levels of both have been associated with increased risk of depression and poor response to antidepressant medications.
Sometimes referred to as vitamin B9, folate can be found in foods such as spinach, black-eyed peas, asparagus, brussels sprouts, romaine lettuce, avocado, broccoli, and kidney beans. Your body needs folate to help transform protein into important chemical messengers called neurotransmitters—these include serotonin, dopamine, and norepinephrine. Vitamin B12, also called cobalamin, is found almost exclusively in animal-derived foods. Supplementation is required for a vegan diet and is recommended for a vegetarian diet.
Some evidence suggests that supplementation with vitamin B12 and folate (or methylfolate, a specific form of folate) may be helpful, although this evidence is limited. A 2018 meta-analysis concluded that folate or methylfolate may be a good add-on to selective serotonin reuptake inhibitor (SSRI) antidepressant therapy. Whether these vitamins are beneficial across the board for depression treatment is not clear, but it’s worth making sure your multivitamin contains folate plus B12 (Huang et al., 2018; Morris, Fava, Jacques, Selhub, & Rosenberg, 2003; Papakostas et al., 2004; Roberts, Carter, & Young, 2018; Sangle et al., 2020; Trautmann et al., 2020).
Low levels of vitamin D (the “sunshine vitamin”) are associated with depression, and some studies have shown that supplements may be helpful (Anglin, Samaan, Walter, & McDonald, 2013). A 2014 meta-analysis of seven clinical trials found that vitamin D supplementation didn’t improve depressive symptoms, but when the researchers looked at just the two studies on clinically depressed patients, they found that vitamin D did improve depression (Shaffer et al., 2014). Another meta-analysis published in 2014 found that among people who were deficient in vitamin D, supplementation with at least 800 IU per day improved depression as much as antidepressants (Spedding, 2014).
While there is not general agreement among researchers about whether supplementation may be beneficial for depression, many people may not be getting enough vitamin D from their diet or the sun, so supplementation may be advised regardless. People who live far from the equator may be especially low in vitamin D and have increased risk of depression (see the light therapy section for more) (Melrose, 2015). If you always cover up with clothing or sunblock when are you are outside or if you have dark skin, you may be low in vitamin D.
S-adenosylmethionine (SAMe) is involved in the synthesis and metabolism of neurotransmitters and has been used in Europe to treat depression. In the US, it is available as a dietary supplement. A 2016 systematic review of eight clinical trials concluded that the quality of the research was too low to reach firm conclusions. However, preliminary results suggested that SAMe alone may be as effective as some antidepressant drugs, and that there may be a benefit to combining SAMe with antidepressants. There has been relatively little research into SAMe for depression, so hopefully more well-controlled trials will be carried out in the near future to determine if there is promise for its use in treating depression (Galizia et al., 2016; Sharma et al., 2017).
Tryptophan and 5-Hydroxytryptophan
You may have heard about these amino acids and their mood-lifting effects. Tryptophan is an amino acid found in all protein foods but most associated with Thanksgiving turkey. It is the primary building block for serotonin: With the help of vitamin B6, the body converts tryptophan to 5-hydroxytryptophan (5-HTP), which is then made into serotonin. Both tryptophan and 5-HTP are available as nonprescription dietary supplements. The results that support using these supplements are primarily from small, uncontrolled studies; however, tryptophan continues to be a popular supplement for many people (Lindseth, Helland, & Caspers, 2015; Shaw, Turner, & Mar, 2002).
Lifestyle Changes for Depression
Exercise, social support, and sleep are all necessary ingredients for good mental health. Managing stress, spending time in nature, and using social media consciously may also be helpful.
Exercising regularly is one of the best things you can do for your overall health. A meta-analysis of twenty-three clinical trials found that exercise itself is an effective treatment for depression—so for people who don’t want to (or can’t) try more-aggressive treatment options, exercising alone may be enough. The authors also found that exercise is an effective add-on treatment to antidepressant medications (Kvam, Kleppe, Nordhus, & Hovland, 2016).
Which types of exercise are best? Two separate studies, a meta-analysis and a systematic review, found that moderate-intensity aerobic exercise supervised by a trainer or group fitness leader was beneficial (Schuch et al., 2016; Stanton & Reaburn, 2014). Our recommendation: Find something you like that you can stick with.
Social support has been shown to be protective against depression. A meta-analysis of one hundred studies found that among children, parental support is most important, whereas spousal support is most important for adults, especially for men, followed by friendships (Gariépy, Honkaniemi, & Quesnel-Vallée, 2016). While pushing family and friends away can be common with depression, it’s important to keep your loved ones close or find emotional support from other avenues (a therapist, group activities, etc.).
Depression can affect your ability to get a good night’s rest, or, on the other hand, you may be sleeping all the time. A meta-analysis found that it’s important to be somewhere in the middle: Individuals with short sleep duration and those who got too much sleep had increased risk for depression compared to those who got a normal night’s rest. The researchers’ explanation was that light sleepers may be tired through the next day, while heavy sleepers may not get a good workout in the next day. One issue is that researchers define “short” versus “long” sleep duration differently—some say less than five hours is too little, and others say less than seven may be too little. Some say more than eight hours is too much, and others say more than nine hours is too much (Zhai, Zhang, & Zhang, 2015). It seems that moderate sleep is the best way to go.
The UN estimates that by 2050, 68 percent of the world will live in urbanized areas, with less access to green space and nature. It’s more important than ever to reconnect with nature in whatever way is available to you. Being immersed in nature—in a park, on a hike, staring out at the ocean from your beach chair—can make you feel small, in a good way. You might relax; your ego might drip away; you might notice that you’re a part of something much greater than yourself. At least, that’s what researchers studying the benefits of nature on mental health believe. In 1981, a University of Michigan architect found that at the State Prison of Southern Michigan, prisoners who occupied cells without access to windows with a view of nature had more frequent sick-call visits than those with nature views (Frumkin, 2001).
Since then, several preliminary studies have shown that more contact with nature improves individuals’ mental health and cognition (Berman et al., 2012; Gascon et al., 2015). A 2017 study of over 23,000 Korean citizens found that greater access to green space was associated with decreased depressive symptoms (Kim & Kim, 2017). While the research is still new and emerging, it’s enough for us to want to unplug and get outdoors.
A cruel irony of depression is that people often feel like they’re alone, when in reality depression is something that they share with millions of other people. We’re also in the age of social media, connected with more people than ever, yet many of us still feel disconnected. Technology gives us opportunities to connect with people online (and in potentially meaningful ways) but has resulted in less face-to-face time with others in which we could have meaningful conversations and interactions. Studies have shown that among both adolescents and adults, more frequent social media users had higher measures of depression, whereas frequent adolescent social media users also had worse anxiety, self-esteem, and sleep (Lin et al., 2016; Woods & Scott, 2016). It’s possible that people with depression may be using social media more often; it isn’t clear yet if social media can cause depression or mental health issues. If using social media causes you to feel lonely, upset, or sad, try to limit your use and take some time to disconnect from your phone.
Stressful life events can increase your likelihood for recurring depression and physical illness (Burcusa & Iacono, 2007; Holmes & Rahe, 1967). It might be that stress accumulates over time, eventually triggering major issues. There is also evidence that stress reactivity (how you respond to everyday stressful events) impacts the development of depression (Booij, Snippe, Jeronimus, Wichers, & Wigman, 2018; Felsten, 2004). Learning to cope with stressful life events is important to both mental and physical well-being. Incorporating mindfulness, yoga, meditation, and social activities may help with stress. For more on this, see the alternate treatments section. You can also take the Stress Test, which was developed in the 1960s to measure social and life events that can have a meaningful impact on a person’s stress and well-being. The test asks you to recount the number of stressful life events you’ve had in the past year (Holmes & Rahe, 1967).
Conventional Treatment Options for Depression
The most common treatment options for depression are psychotherapy and antidepressants. There are many different styles of therapy and types of antidepressants, and they have varying potential benefits and potential side effects. Treatment is entirely individual, and it may take some time to find what works best.
Cognitive Behavioral Therapy (CBT)
Cognitive behavioral therapy (CBT) is among the most popular evidence-based treatments for depression. It’s usually delivered in hour-long one-on-one sessions with a patient and their therapist. The theory behind it is that psychological problems are rooted in unhelpful ways of thinking and behaving. With CBT, people learn new coping mechanisms and work on changing negative patterns going forward. Several studies have shown that CBT is as effective as antidepressants at treating depression and is even more effective as a combined therapy with antidepressants.
Internet-based CBT has also been shown to be helpful for treating depression, and it may be more effective when a therapist provides guidance as opposed to the CBT being self-guided. A recent review concluded that there was not yet enough evidence to indicate that smartphone-delivered CBT is efficacious for depression. However, some new research into smartphone-delivered CBT has shown favorable results when used together with medication, giving hope for more convenient alternatives to in-person therapy for those who are time-strapped (Cuijpers et al., 2013; Karyotaki et al., 2021; Mantani et al., 2017; Webb, Rosso, & Rauch, 2017).
What’s the Difference between Psychiatrists, Psychologists, and Therapists?
A psychiatrist has a medical degree and can prescribe medications. A psychologist has a doctorate in psychology and cannot prescribe medications. “Therapist” is an umbrella term for any health professional a person sees to talk through their issues—a therapist can have a background in psychology, social work, or other forms of counseling. Some individuals may see both a psychiatrist and therapist, while others may see just one or the other. It depends on whether the person is interested in taking antidepressants or other prescribed medications.
It’s important to find someone you feel you can talk to and that you jibe with. It may take some time to find a therapist you like, but it can be well worth it in the long run to find a good fit. See our article with psychotherapist Satya Doyle Byock, MA, LPC, on how to find a therapist who’s right for you.
Interpersonal Therapy (IPT)
Interpersonal therapy (IPT) is a type of talk therapy that is delivered in three phases across a twelve- to sixteen-week period. The first phase focuses on targeting the clinical diagnosis as well as any interpersonal context around it (for example, the patient’s parent may have recently passed away). The second phase focuses on working through interpersonal problems, such as properly mourning the death of a loved one or resolving a marital dispute. The last phase focuses on helping the patient feel more capable solving interpersonal problems and more empowered moving forward post-treatment (Markowitz & Weissman, 2004).
IPT has been shown in several studies to be effective at treating acute depression and may also help prevent new disorders and relapse (Cuijpers, Donker, Weissman, Ravitz, & Cristea, 2016).
Problem-Solving Therapy (PST)
Another common type of psychotherapy is called problem-solving therapy (PST), which focuses on training people in attitudes and skills to solve daily problems in two phases. In the first phase, which is called “problem orientation,” the therapist explores how the client views their problem and helps them identify and restructure the problem based on their strengths. The second phase focuses on the client’s problem-solving style, creating strategies to overcome problems (Gellis & Kenaley, 2008).
A recent meta-analysis found that PST may be an effective treatment for adult depression, with similar success as other types of psychotherapy (Cuijpers, de Wit, Kleiboer, Karyotaki, & Ebert, 2018).
There are many different types of medications that can be taken for depression, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective serotonin noradrenaline reuptake inhibitors (SSNRIs). Less commonly used medications include monoamine oxidase inhibitors (MAOIs), trazodone, and lithium.
A 2018 meta-analysis of 522 clinical trials of twenty-one different antidepressants found that, in adults with major depression, every antidepressant was more effective than a placebo. All twenty-one drugs led to improvements in symptoms that were greater than the improvement seen in those taking a placebo. Results varied among trials, but in general, the two drugs that were most acceptable to the patients—with the fewest side effects causing patients to drop out of the studies—were fluoxetine (an SSRI better known as Prozac) and agomelatine. Agomelatine is a newer drug that is related to melatonin, the hormone that regulates the sleep cycle (Cipriani et al., 2018).
Each antidepressant has its own considerations and potential side effects (such as sexual dysfunction, sleep disturbances, and weight gain), so your doctor or psychiatrist will generally prescribe a low dose at first, and it may take some tweaking to find the right medication and dose for you (Ferguson, 2001). Like most tools, antidepressants are not an immediate fix; they can take several weeks to kick in and are generally prescribed for nine months or longer to prevent relapse.
Please note: Use of antidepressants may increase suicidal thoughts in teenagers and young adults, so they should see a therapist for frequent checkups when beginning a new antidepressant or making any change, up or down, to the dosage (Turnipseed & Magid, 2008). One meta-analysis concluded that for children and teenagers fluoxetine was the only drug to offer benefits beyond those of a placebo pill. And when the authors considered the risk-benefit trade-off they concluded that in general antidepressants are not worth the risks for children and teenagers. Approval by regulatory agencies is lacking for the use of many antidepressants in children, yet they are frequently prescribed off-label (Cipriani et al., 2016; Meister et al., 2020).
A Conversation Around Antidepressants
Antidepressants seem to be the norm now for depression treatment. An analysis of NIH data by The New York Times found that the rate of antidepressant use in the US has tripled since 2000, and those who take antidepressants for two or more years has increased by 60 percent since 2010. One proposed cause of this increase in use may be that users simply don’t stop taking them. Stopping antidepressants too suddenly can cause severe symptoms and depressive relapse. If you are considering going off antidepressants—which is possible for some people—please talk to your doctor and taper off with the help of medical professionals. Severe problems are commonly associated with antidepressant withdrawal, including anxiety, sleep disturbances, sadness, fatigue, and brain zaps (some people feel as if their brain is being shocked)—which many patients are not warned about and researchers haven’t studied thoroughly enough (Cartwright, Gibson, Read, Cowan, & Dehar, 2016; Ostrow, Jessell, Hurd, Darrow, & Cohen, 2017).
Antidepressants work for some people, and many credible psychiatrists will explain that they have saved their patients’ lives. There is no shame—at all—in taking medication. It just might not be right for everyone (nothing is). Some researchers suggest that antidepressants benefit primarily severely depressed people and that antidepressants are only slightly better than a placebo for mild to moderate depression.
A particularly well-known researcher at Harvard, Irving Kirsch, PhD, has written about how the serotonin theory of depression is unfounded—because nobody really knows how SSRIs work or why—and has been perpetuated by pharmaceutical companies. It’s true that the “positive” studies on antidepressants are often sponsored by pharmaceutical companies and that studies that find antidepressant use to have insignificant results or no benefit may not be published at all. This is called publication bias (Fournier et al., 2010; Healy, 2015; Jakobsen et al., 2017; Khan & Brown, 2015; Kirsch et al., 2008; Kirsch, Moore, Scoboria, & Nicholls, 2002; Kirsch & Sapirstein, 1998).
As the larger debate continues over antidepressants, it’s important for individuals to be able to make informed decisions about what’s best for them with their doctors. The potential side effects and withdrawal symptoms can be taken into account along with the potential benefits. If you’ve tried other treatment options first (exercise, therapy, etc.) to no avail or are severely depressed and need more help, antidepressants may be the right choice for you. And again, if you’re reading this and you’re currently taking antidepressants, there is zero shame in doing so.
Brain Stimulation Therapy
You’ve probably seen horror movies about psych wards giving electric shocks to unwilling patients: Brain stimulation therapy is definitely not that. It’s done under general anesthesia. Electric currents are sent through the brain, which triggers a brief seizure that can change the brain chemistry and often reverse depressive symptoms.
There are various types of brain stimulation therapy, including electroconvulsive therapy (ECT), vagus nerve stimulation, repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy, and deep brain stimulation. These types of therapies are generally used when other treatments, like therapy and antidepressants, fail; this is called treatment-resistant depression.
Of all these therapies, ECT has been shown to be the most effective for depression, specifically showing benefits for people with severe treatment-resistant depression and older adults. These therapies do have side effects that warrant serious consideration, including memory issues in the months following treatment. However, memory generally returns after a while (Khalid, Atkins, Tredget, Champney-Smith, & Kirov, 2008; Weiner & Reti, 2017).
Alternate Treatment Options for Depression
Mind-body therapies, such as meditation and yoga, have been shown to be effective for depression treatment. Light therapy may be helpful, especially for those with seasonal affective disorder. St. John’s wort is an herbal supplement that has been well-researched for its antidepressant activity.
As nature ebbs and flows with the change of seasons, so can our moods if we don’t get enough sunshine. Seasonal affective disorder (SAD) is a type of depression with recurring seasonal patterns, typically appearing in the fall and winter and passing come summer. Women and those who live farther from the equator are more likely to be diagnosed with SAD (National Institute of Mental Health, 2016). Light therapy (a broad-spectrum bright white light box that mimics sunlight without as many harmful UV rays) is a low-cost treatment that has been shown to be as effective as CBT in treating SAD (Golden et al., 2005; Rohan et al., 2015). A meta-analysis found that light therapy may also be beneficial for nonseasonal depression, although evidence was limited (Perera et al., 2016).
Overall, the small cost seems well worth it if you live in a colder climate. Try exposing your face to a full-spectrum light for twenty to thirty minutes first thing in the morning for some added sunshine and increase the time gradually as desired. Find a light made specifically for SAD that has an intensity of 10,000 lux, and has good UV filtering. Looking directly into UV light causes damage to the eyes. The Mayo Clinic has detailed information on how to go about light therapy (Mayo Clinic, 2016).
While mindfulness is starting to become more mainstream, your doctor probably won’t prescribe ten minutes of sitting per day for depression. But this might help. Developed by Jon Kabat-Zinn, a professor at the University of Massachusetts Medical School and the author of numerous books on mindfulness, mindfulness-based stress reduction (MBSR), and its spin-off developed by psychologists, mindfulness-based cognitive therapy (MBCT), have been thoroughly studied since the late 1990s for their impact of various aspects of mental health and well-being.
Sara Lazar, a professor at Harvard who studies the neuroscience of yoga and meditation, has published several studies showing how mindful meditation can improve mental flexibility and reduce depressive symptoms and relapse in individuals with depression (Shapero et al., 2018). A 2014 meta-analysis found that both MBSR and MBCT were beneficial for individuals with depressive disorder, but MBCT may be more effective due to its emphasis on depression treatment (Strauss, Cavanagh, Oliver, & Pettman, 2014). A meta-analysis by researchers at Johns Hopkins found that eight weeks of a mindfulness meditation program can result in small improvements in anxiety, depression, pain, and stress. The researchers concluded that mindfulness meditation and antidepressants may be similarly effective (Goyal et al., 2014). Organizations such as Insight LA offer mindfulness workshops. You can also find a mindfulness-based therapist or practice on your own using online guided meditations or meditation apps.
The practice of yoga extends beyond the physical postures (asanas) through its emphasis on mindfulness, nonattachment, and equanimity, which may improve the negative mental aspects of depression. Yoga has been shown in meta-analyses and reviews to be an effective treatment alone and as an add-on for depression, with a similar effect to antidepressants (Cramer, Anheyer, Lauche, & Dobos, 2017; Gong, Ni, Shen, Wu, & Jiang, 2015; Nanthakumar, 2020). You can find a local studio or practice on your own; there are many free tutorials and videos online. For more on the benefits of yoga, particularly hot yoga, see the clinical trials section below.
A growing number of people are seeking out Eastern modalities to help treat depression. A meta-analysis of thirteen clinical trials found that acupuncture was an effective add-on to antidepressant treatment over a six-week period (Chan, Lo, Yang, Chen, & Lin, 2015). Another systematic review found that acupuncture helped improve depression-related insomnia, especially when acupuncture was given as an add-on to regular antidepressant medication (Dong et al., 2017). While more high-quality evidence is needed to examine acupuncture as a long-term treatment option for depression, there is promising short-term evidence for its benefits.
St. John’s wort
Currently sold as a dietary supplement in the US, St. John’s wort has been shown to be an effective short-term treatment for mild to moderate depression. A 2016 meta-analysis found that it is similarly effective to antidepressants with fewer side effects. Although commonly used in Europe by medical professionals for mild to moderate depression, it is not used as frequently in the US. It is not clear whether it is helpful for periods of time longer than twelve weeks or for severe depression.
Important warning: St. John’s wort interacts with and affects the levels of a number of drugs, and it should not be used in combination with prescription antidepressants. It may also decrease the effectiveness of certain medications, such as birth control, some HIV drugs, and others (Cui & Zheng, 2016; National Center for Complementary and Integrative Medicine, 2020).
Used in Greece, the Middle East, and traditional Chinese medicine, saffron is a both a spice and medicinal herb that has been shown to be quite effective at improving moderate depression, with several studies showing that its efficacy is similar to that of antidepressants (Lopresti & Drummond, 2014). A 2011 systematic review of saffron found that six studies showed beneficial effects when extracts of both the stigma and the petal of the saffron flower were consumed (Dwyer, Whitten, & Hawrelak, 2011). This is promising because the saffron stigma is much more expensive than the petal. Saffron extracts are sold as dietary supplements, and at least thirty milligrams of a saffron extract containing 2 percent safranal is considered an active daily dose (Hausenblas, Heekin, Mutchie, & Anton, 2015).
Massage and Aromatherapy
While getting a massage is typically considered a luxury, research suggests that regular massage with aromatherapy may be beneficial for depression. A small study in China found benefits from both inhalation of a mixture of lavender, sweet orange, and bergamot essential oils, and massage with this mixture. After eight weeks of twice weekly treatments, a group of adults over sixty reported reduced symptoms of depression (Xiong et al., 2018). Other small studies have found that both aromatherapy massage and regular massage can reduce depression in patients with illnesses such as cancer and HIV (Chang, 2008; Poland et al., 2013). While large-scale studies are needed to confirm these findings, getting massages more regularly could be a great way to improve your mood, relax, or simply treat yourself.
Music as a healing modality dates back to ancient times (Apollo was the ancient god of both music and medicine). Music can affect your mood and energy levels, by lulling you to sleep or waking you up. Recently, there has been a surge of research into music therapy delivered one-on-one or in a group session with a therapist as an adjunct treatment for chronic pain, cancer, mental health disorders, and a variety of other conditions. A 2017 meta-analysis found that music therapy is beneficial for short-term treatment of depression and can be a good add-on to other treatment options (Aalbers et al., 2017).
A review of twenty-seven studies found music therapies to be particularly beneficial for people over sixty. When music is combined with meditation, it may further improve well-being. One study by researchers at UCSD found that Tibetan sound bowl meditation reduced participants’ tension, anger, fatigue, and depressed mood while increasing their sense of spiritual well-being (Goldsby et al., 2017).
New and Promising Research on Depression
In recent years, there has been an exciting resurgence in research on the therapeutic usage of psychedelics for mental health conditions such as depression. And new research has drawn a connection between our gut microbiome and mental health.
How Do You Evaluate Clinical Studies and Identify Promising Results?
The results of clinical studies are described throughout this article, and you may wonder which treatments are worth discussing with your doctor. When a particular benefit is described in only one or two studies, consider it of possible interest, or perhaps worth discussing, but definitely not conclusive. Repetition is how the scientific community polices itself and verifies that a particular treatment is of value. When benefits can be reproduced by multiple investigators, they are more likely to be real and meaningful. We’ve tried to focus on review articles and meta-analyses that take all the available results into account; these are more likely to give us a comprehensive evaluation of a particular subject. Of course, there can be flaws in research, and if by chance all of the clinical studies on a particular therapy are flawed—for example with insufficient randomization or lacking a control group—then reviews and meta-analyses based on these studies will be flawed. But in general, it’s a compelling sign when research results can be repeated.
Certain cultures have a long history of using hallucinogenic plants as part of their rituals and ceremonies. In the 1950s, the golden age of psychedelics began in the Western world with researchers and psychologists alike studying the drugs. Numerous studies around this time found benefits of these drugs and therapists began administering them to their patients, including several high-profile celebrities. As use began to increase outside of laboratories and sweep across college campuses, fears began to mount about the growing popularity of recreational drug use. In 1970, President Nixon signed the Controlled Substances Act which lumped marijuana, psilocybin, LSD, and MDMA together with heroin and other Schedule 1 drugs (illegal drugs that have high abuse potential, no medical use, and severe safety concerns). With that, the field of psychedelic research became illegal and was pushed underground, save for a few academic institutions that still had the green light to continue their studies.
Recently, there has been a resurgence of psychedelic research, with several FDA-funded studies looking at effects on depression, addiction, PTSD, and other mental health disorders—with very promising findings. Please be advised that while the research is exciting, these studies have been carried out by experienced therapists using carefully calibrated doses, and many of these drugs are still illegal in the United States. To read more about the science and shamanism of psychedelics, see our Q&A with Charles Grob, MD, leading researcher in the field of psychedelic-assisted therapy.
Magic mushrooms, which contain the psychedelic chemical psilocybin, have been used in Central American culture for hundreds of years. More recently psilocybin has been studied in the West for its ability to improve depression, addiction, and anxiety. Several recent studies have shown that psilocybin-assisted psychotherapy can drastically reduce depressive symptoms and possibly even treatment-resistant depression (when two or more treatment options do not work for someone) (Carhart-Harris et al., 2018; Griffiths et al., 2016; Ross et al., 2016).
One study at NYU found that a single low dose of psilocybin clinically reduced depression in 60 to 80 percent of patients—even six and half months later (Ross et al., 2016). A phase 2 clinical trial at Johns Hopkins University reported impressive success in reducing symptoms of major depression after two moderated psilocybin sessions plus a number of preparatory and follow-up sessions (Davis et al., 2021).
Historically used in Amazonian culture, ayahuasca is a vine that can be made into a brew, eliciting psychedelic effects when consumed. The Global Ayahuasca Project surveyed almost 12,000 ayahuasca users from 2017 to 2020 about their experiences. Of the people who reported depression prior to ayahuasca use, 78 percent said that its use either very much improved or completely resolved their depression. However, 2.7 percent said that it worsened their condition (Sarris et al., 2021).
Researchers in Brazil have looked into ayahuasca-assisted psychotherapy for treatment-resistant depression and have reported a rapid antidepressant effect. About half of the patients experienced vomiting in these studies. (Osório et al., 2015; Palhano-Fontes et al., 2019; Sanches et al., 2016). More well-controlled research is needed on the safety and feasibility of ayahuasca as a depression treatment.
Generally used for anesthesia, IV infusions of ketamine have also been shown to be extremely successful at improving symptoms in individuals with treatment-resistant depression (Kraus et al., 2017; Murrough et al., 2013). A 2014 meta-analysis of thirteen studies found that ketamine exhibits short-term antidepressant effects that last two to three days (Fond et al., 2014). Repeated infusions may be helpful for preventing relapse over the longer term (Shiroma et al., 2020).
Based on this research and its designation as a breakthrough therapy for depression, the FDA approved esketamine, a derivative of ketamine, as a nasal spray for treatment-resistant depression in early 2019. Because of safety concerns, it is available only in specially certified medical offices.
MDMA has gained a somewhat negative reputation because of its street forms, ecstasy and molly, which are used as party drugs in rave culture. But there has been interesting research showing that MDMA can be helpful in psychotherapy for people with PTSD and possibly other mental health disorders such as depression. The thought is that MDMA opens individuals up, which helps them form a closer relationship with their therapist and dive into discussions on difficult topics (Yazar‐Klosinski & Mithoefer, 2017). MDMA may also act on the same serotonin receptors as antidepressants, exhibiting a similar effect. However, animal studies have shown that large doses of MDMA can be neurotoxic (Patel & Titheradge, 2015).
The Multidisciplinary Association for Psychedelic Studies (MAPS) recently completed the first FDA-approved phase 3 clinical trial of MDMA-assisted psychotherapy for PTSD, with the goal of expanding research to other mental health conditions and having MDMA approved as a prescription drug. The protocol included up to three sessions with MDMA (or placebo) plus multiple therapy sessions for preparation and follow-up. MDMA treatment provided significant benefits for people suffering from PTSD, including improvement in symptoms of depression (Mitchell et al., 2021). There’s more about MDMA and MAPS in our Q&A with psychiatrist Emily Williams, MD, a MAPS-trained MDMA-assisted psychotherapist.
The Default Mode Network
Why might some psychedelics have antidepressant effects? There are several proposed explanations, including this one: Users almost universally report a partial or complete loss of ego or sense of self. Some researchers have found that psychedelics reduce blood flow to the default mode network (DMN), which connects different areas of your brain and creates your ego (Carhart-Harris et al., 2012; Lebedev et al., 2015). The theory is that the DMN in depressed individuals may be overactive, which leads to overthinking (rumination) and negative mental patterns, and that decreased DMN functioning may reduce depressive symptoms (Carhart-Harris et al., 2017). These changes in the DMN following psychedelic experiences may be similar to those that occur during meditation (Brewer et al., 2011). More exciting research in this field is underway to elucidate exactly how psychedelics are seemingly able to jolt the mind of out its old patterns and form new, more positive ways of thinking.
With all the focus on the brain’s function in depression, you may not know that most of your serotonin (the chemical that is thought to be imbalanced in people with depression) is created in your digestive tract (Yano et al., 2015). Recent research has found that your gut microbiome plays a critical role in regulating serotonin production, so interventions to promote a healthy gut, such as probiotics, prebiotics, and a healthy diet, may be useful (Cenit, Sanz, & Codoñer-Franch, 2017; Liang, Wu, & Jin, 2018; Yano et al., 2015). A 2019 meta-analysis and a 2020 review found that probiotics had small but significant effects on improving depression as well as anxiety (Liu et al., 2019; Noonan et al., 2020). A particularly interesting study took fecal samples from depressed patients and transferred them to rats, which resulted in depressive symptoms in the animals as well (Kelly et al., 2016). More findings from this field could lead to better, individualized depression treatments targeting the gut-brain connection. Multiple clinical trials are recruiting participants internationally to assess the effects of probiotics in depression, including one at King’s College, London, which will use the multi-strain product Bio-Kult.
Medication Side Effects
A recent study in The Journal of the American Medical Association found that use of prescription medications was common among Americans, and that people who used multiple medications that have depression listed as a potential side effect had a higher likelihood of being depressed. The list of medications that include depression as a side effect is long. It includes antihypertensive drugs, birth control, and antacids, as well as commonly used analgesics, such as ibuprofen (Qato, Ozenberger, & Olfson, 2018). Talk to your doctor if you are consistently taking one of these drugs, especially if you’re on other medications with depression as a side effect.
Clinical Trials for Depression
Clinical trials are research studies intended to evaluate a medical, surgical, or behavioral intervention. They are done so that researchers can study a particular treatment that may not have a lot of data on its safety or effectiveness yet. If you’re considering signing up for a clinical trial, it’s important to note that if you’re placed in the placebo group, you won’t have access to the treatment being studied. It’s also good to understand the phase of the clinical trial: Phase 1 is the first time most drugs will be used in humans, so it’s about finding a safe dose. If the drug makes it through the initial trial, it can be used in a larger phase 2 trial to see whether it works well. Then it may be compared to a known effective treatment in a phase 3 trial. If the drug is approved by the FDA, it will go on to a phase 4 trial. Phase 3 and phase 4 trials are the most likely to involve the most effective and safest up-and-coming treatments. In general, clinical trials may yield valuable information; they may provide benefits for some subjects but have undesirable outcomes for others. Speak with your doctor about any clinical trial you are considering.
Where Do You Find Studies That Are Recruiting Subjects?
You can find clinical studies that are recruiting subjects on clinicaltrials.gov, which is a website run by the US National Library of Medicine. The database consists of all privately and publicly funded studies that are happening around the globe. You can search by a disease or a specific drug or treatment you’re interested in, and you can filter by country where the study is taking place.
Do you feel great after a hot yoga class? Research suggests this may be more than a post-workout glow. A few studies have shown that whole-body hyperthermia (extreme heat with temperatures of one hundred degrees Fahrenheit or higher) can reduce depressive symptoms in individuals with major depressive disorder (Janssen et al., 2016). To confirm these effects, there are a couple clinical trials assessing hyperthermia as a viable depression treatment at Massachusetts General Hospital. David Mischoulon, MD, PhD, is recruiting subjects for a phase 2 clinical trial of 60- to 120-minute whole-body hyperthermia sessions. Recruitment has been completed for a clinical trial of 90 minutes of hot yoga to improve depression.
Multiple clinical trials on ketamine treatment for depression are ongoing. In a phase 1/phase 2 trial at the University of Pittsburgh, Rebecca Price, PhD, is studying ketamine infusions in adults with depression. In a phase 3 clinical trial at Yale, Psychiatrist Michael Bloch, MD, is studying ketamine infusions in adolescents ages thirteen to seventeen who have severe depression.
There are a number of clinical studies assessing possible benefits of psilocybin for depression. A phase 2 trial at multiple locations in the US will compare psilocybin to a placebo control for treatment of major depressive disorder. The study will use a set and setting protocol that includes trained facilitators carrying out sessions for preparation, treatment, and post-dose integration. The primary investigator is Charles Raison, MD, of the Usona Institute.
Scott Aaronson, MD, is recruiting participants with moderate to severe depression that has been resistant to treatment. This trial is open-label with no placebo control, meaning that subjects know that they will be getting psilocybin treatment. This will take place at the Stanford Exploratory Therapeutics Laboratory and the VA Palo Alto Healthcare System/Stanford Medicine in Palo Alto, and the Sheppard Pratt Health System in Baltimore.
Stephen Dahmer, MD, at Vireo Health, is directing an anonymous survey asking about the use of entheogens, which are substances generally derived from plants that are ingested in order to alter one’s consciousness for therapeutic or spiritual purposes. These include ayahuasca, psilocybin mushrooms, and ibogaine. The survey aims to document the experiences of people who, at some time in the past five years, participated in entheogen therapy or treatment.
Deep Brain Stimulation
A number of clinical trials are recruiting people with treatment-resistant depression in order to test a kind of electrical therapy called deep brain stimulation. Katherine Scangos, MD, PhD, is the lead investigator for a trial at the University of California San Francisco that will test a personalized approach to brain stimulation. A device called the NeuroPace Responsive Neurostimulation (RNS) System will be implanted in the brain, and it will determine what type of brain activity is associated with depression. Small electrical impulses will be used to alter that brain activity and investigators will measure whether these changes help reduce depression symptoms. Success with this approach was recently reported in their first recruit (Scangos et al., 2021).
Inhaling nitrous oxide for one hour was shown to reduce symptoms of depression for the next two weeks in a small controlled clinical study (Nagele et al., 2021). Nitrous oxide acts similarly to ketamine in blocking signaling via what are called NMDA receptors. The regimen and dose will be fine-tuned in a trial currently recruiting at the Alfred Hospital in Melbourne, Australia, and soon at the University of Chicago.
Help in Crisis
If you are in crisis, please contact the National Suicide Prevention Lifeline by calling 800.273.TALK (8255) or the Crisis Text Line by texting HOME to 741741 in the United States. If you’re outside the United States, please visit iasp.info.
• The National Alliance on Mental Illness (NAMI) provides educational programs, resources, presentations, awareness events, and support for mental health.
• The National Institute of Mental Health provides information on how to find a provider or treatment.
• The Child Mind Institute has resources for parents and information about children’s mental health detection, care, and treatment.
• Active Minds is a nonprofit aimed at starting conversations about mental health and promoting advocacy and action.
• Healthy Minds is a PBS series by Dr. Jeffrey Borenstein that explains psychiatric conditions, speaks with patients and experts, and shares new information on research and treatment.
• Wherever You Go, There You Are: Mindfulness Meditation in Everyday Life by Jon Kabat-Zinn
• Peace Is Every Step by Thich Nhat Hanh
• Lost Connections by Johann Hari
• How to Change Your Mind by Michael Pollan
• MindShift is a free app from the nonprofit Anxiety Canada that offers evidence-based mental health tools, tips, and a journal to record thoughts.
• IntelliCare is a hub of several apps, developed by Northwestern University and funded by the National Institutes of Health, that use evidence-based methods to target mental health issues.
• TalkSpace connects users with licensed therapists over messenger.
• Waking Up provides thorough lessons on mindfulness theory and an introductory meditation course guided by neuroscientist and philosopher Sam Harris.
Related Reading and Listening on goop
Episodes of The goop Podcast
Afonso, R. F., Balardin, J. B., Lazar, S., Sato, J. R., Igarashi, N., Santaella, D. F., … Kozasa, E. H. (2017). Greater Cortical Thickness in Elderly Female Yoga Practitioners—A Cross-Sectional Study. Frontiers in Aging Neuroscience, 9.
Anglin, R. E. S., Samaan, Z., Walter, S. D., & McDonald, S. D. (2013). Vitamin D deficiency and depression in adults: systematic review and meta-analysis. British Journal of Psychiatry, 202(02), 100–107.
Berman, M. G., Kross, E., Krpan, K. M., Askren, M. K., Burson, A., Deldin, P. J., … Jonides, J. (2012). Interacting with Nature Improves Cognition and Affect for Individuals with Depression. Journal of Affective Disorders, 140(3), 300–305.
Booij, S. H., Snippe, E., Jeronimus, B. F., Wichers, M., & Wigman, J. T. W. (2018). Affective reactivity to daily life stress: Relationship to positive psychotic and depressive symptoms in a general population sample. Journal of Affective Disorders, 225, 474–481.
Brewer, J. A., Worhunsky, P. D., Gray, J. R., Tang, Y.-Y., Weber, J., & Kober, H. (2011). Meditation experience is associated with differences in default mode network activity and connectivity. Proceedings of the National Academy of Sciences, 108(50), 20254–20259.
Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. E., … Nutt, D. J. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 235(2), 399–408.
Carhart-Harris, Robin L., Erritzoe, D., Williams, T., Stone, J. M., Reed, L. J., Colasanti, A., … Nutt, D. J. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences, 109(6), 2138–2143.
Carhart-Harris, Robin L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., … Nutt, D. J. (2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports, 7(1), 13187.
Cartwright, C., Gibson, K., Read, J., Cowan, O., & Dehar, T. (2016). Long-term antidepressant use: patient perspectives of benefits and adverse effects. Patient Preference and Adherence, 10, 1401–1407.
Chan, Y.-Y., Lo, W.-Y., Yang, S.-N., Chen, Y.-H., & Lin, J.-G. (2015). The benefit of combined acupuncture and antidepressant medication for depression: A systematic review and meta-analysis. Journal of Affective Disorders, 176, 106–117.
Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., … Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. The Lancet, 391(10128), 1357–1366.
Cipriani, A., Zhou, X., Giovane, C. D., Hetrick, S. E., Qin, B., Whittington, C., … Xie, P. (2016). Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. The Lancet, 388(10047), 881–890.
Cui, Y., & Zheng, Y. (2016). A meta-analysis on the efficacy and safety of St John’s wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults. Neuropsychiatric Disease and Treatment, 12, 1715–1723.
Cuijpers, P., Berking, M., Andersson, G., Quigley, L., Kleiboer, A., & Dobson, K. S. (2013). A Meta-Analysis of Cognitive-Behavioural Therapy for Adult Depression, Alone and in Comparison with other Treatments. The Canadian Journal of Psychiatry, 58(7), 376–385.
Cuijpers, P., Donker, T., Weissman, M. M., Ravitz, P., & Cristea, I. A. (2016). Interpersonal Psychotherapy for Mental Health Problems: A Comprehensive Meta-Analysis. American Journal of Psychiatry, 173(7), 680–687.
Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2021). Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 78(5), 481–489.
Dong, B., Chen, Z., Yin, X., Li, D., Ma, J., Yin, P., Cao, Y., Lao, L., & Xu, S. (2017). The Efficacy of Acupuncture for Treating Depression-Related Insomnia Compared with a Control Group: A Systematic Review and Meta-Analysis. BioMed Research International, 2017, Article ID 9614810.
Fond, G., Loundou, A., Rabu, C., Macgregor, A., Lançon, C., Brittner, M., … Boyer, L. (2014). Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology, 231(18), 3663–3676.
Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant Drug effects and Depression Severity: A Patient-Level Meta-Analysis. JAMA : The Journal of the American Medical Association, 303(1), 47–53.
Gariépy, G., Honkaniemi, H., & Quesnel-Vallée, A. (2016). Social support and protection from depression: systematic review of current findings in Western countries. British Journal of Psychiatry, 209(04), 284–293.
Gascon, M., Triguero-Mas, M., Martínez, D., Dadvand, P., Forns, J., Plasència, A., & Nieuwenhuijsen, M. J. (2015). Mental Health Benefits of Long-Term Exposure to Residential Green and Blue Spaces: A Systematic Review. International Journal of Environmental Research and Public Health, 12(4), 4354–4379.
Golden, R. N., Gaynes, B. N., Ekstrom, R. D., Hamer, R. M., Jacobsen, F. M., Suppes, T., … Nemeroff, C. B. (2005). The Efficacy of Light Therapy in the Treatment of Mood Disorders: A Review and Meta-Analysis of the Evidence. American Journal of Psychiatry, 162(4), 656–662.
Goldsby, T. L., Goldsby, M. E., McWalters, M., & Mills, P. J. (2017). Effects of Singing Bowl Sound Meditation on Mood, Tension, and Well-being: An Observational Study. Journal of Evidence-Based Complementary & Alternative Medicine, 22(3), 401–406.
Goyal, M., Singh, S., Sibinga, E. M. S., Gould, N. F., Rowland-Seymour, A., Sharma, R., … Haythornthwaite, J. A. (2014). Meditation Programs for Psychological Stress and Well-being: A Systematic Review and Meta-analysis. JAMA Internal Medicine, 174(3), 357–368.
Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., … Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology, 30(12), 1181–1197.
Hardy, M. L., Coulter, I., Morton, S. C., Favreau, J., Venuturupalli, S., Chiappelli, F., … Shekelle, P. (2003). S-adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease. Evidence Report/Technology Assessment (Summary), (64), 1–3.
Hausenblas, H. A., Heekin, K., Mutchie, H. L., & Anton, S. (2015). A systematic review of randomized controlled trials examining the effectiveness of saffron (Crocus sativus L.) on psychological and behavioral outcomes. Journal of Integrative Medicine, 13(4), 231–240.
Hrynyschyn, R., & Dockweiler, C. (2021). Effectiveness of Smartphone-Based Cognitive Behavioral Therapy Among Patients With Major Depression: Systematic Review of Health Implications. JMIR MHealth and UHealth, 9(2), e24703.
Huang, X., Fan, Y., Han, X., Huang, Z., Yu, M., Zhang, Y., … Xia, Y. (2018). Association between Serum Vitamin Levels and Depression in U.S. Adults 20 Years or Older Based on National Health and Nutrition Examination Survey 2005–2006. International Journal of Environmental Research and Public Health, 15(6), 1215.
Jakobsen, J. C., Katakam, K. K., Schou, A., Hellmuth, S. G., Stallknecht, S. E., Leth-Møller, K., … Gluud, C. (2017). Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis. BMC Psychiatry, 17.
Janssen, C. W., Lowry, C. A., Mehl, M. R., Allen, J. J. B., Kelly, K. L., Gartner, D. E., … Raison, C. L. (2016). Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry, 73(8), 789–795.
Karyotaki, E., Efthimiou, O., Miguel, C., Bermpohl, F. M. G., Furukawa, T. A., Cuijpers, P., Riper, H., Patel, V., Mira, A., Gemmil, A. W., Yeung, A. S., Lange, A., Williams, A. D., Mackinnon, A., Geraedts, A., Van Straten, A., Meyer, B., Björkelund, C., Knaevelsrud, C., … Forsell, Y. (2021). Internet-Based Cognitive Behavioral Therapy for Depression: A Systematic Review and Individual Patient Data Network Meta-analysis. JAMA Psychiatry, 78(4), 361–371.
Kelly, J. R., Borre, Y., O’ Brien, C., Patterson, E., El Aidy, S., Deane, J., … Dinan, T. G. (2016). Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. Journal of Psychiatric Research, 82, 109–118.
Khalid, N., Atkins, M., Tredget, J., Champney-Smith, K., & Kirov, G. (2008). The Effectiveness of Electroconvulsive Therapy in Treatment-Resistant Depression: A Naturalistic Study. J ECT, 24(2), 5. Khan, A., & Brown, W. A. (2015). Antidepressants versus placebo in major depression: an overview. World Psychiatry, 14(3), 294–300.
Kirsch, I., Deacon, B. J., Huedo-Medina, T. B., Scoboria, A., Moore, T. J., & Johnson, B. T. (2008). Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Medicine, 5(2).
Kirsch, I., Moore, T. J., Scoboria, A., & Nicholls, S. S. (2002). The emperor’s new drugs: An analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment, 5(1).
Kraus, C., Rabl, U., Vanicek, T., Carlberg, L., Popovic, A., Spies, M., … Kasper, S. (2017). Administration of ketamine for unipolar and bipolar depression. International Journal of Psychiatry in Clinical Practice, 21(1), 2–12.
Lavretsky, H., Altstein, L., Olmstead, R. E., Ercoli, L., Riparetti-Brown, M., St. Cyr, N., & Irwin, M. R. (2011). Complementary Use of Tai Chi Chih Augments Escitalopram Treatment of Geriatric Depression: A Randomized Controlled Trial. The American Journal of Geriatric Psychiatry, 19(10), 839–850.
Lebedev, A. V., Lövdén, M., Rosenthal, G., Feilding, A., Nutt, D. J., & Carhart‐Harris, R. L. (2015). Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin. Human Brain Mapping, 36(8), 3137–3153.
Lin, L. yi, Sidani, J. E., Shensa, A., Radovic, A., Miller, E., Colditz, J. B., … Primack, B. A. (2016). Association Between Social Media Use and Depression Among U.S. Young Adults. Depression and Anxiety, 33(4), 323–331.
Liu, R., Walsh, R., & Sheehan, A. (2019). Prebiotics and probiotics for depression and anxiety: A systematic review and meta-analysis of controlled clinical trials. Neuroscience & Biobehavioral Reviews, 102, 13-23.
Lopresti, A. L., & Drummond, P. D. (2014). Saffron (Crocus sativus) for depression: a systematic review of clinical studies and examination of underlying antidepressant mechanisms of action. Human Psychopharmacology, 29(6), 517–527.
Mantani, A., Kato, T., Horikoshi, M., Imai, H., Hiroe, T., Chino, B., … Kawanishi, N. (2017). Smartphone Cognitive Behavioral Therapy as an Adjunct to Pharmacotherapy for Refractory Depression: Randomized Controlled Trial. Journal of Medical Internet Research, 19(11).
Martiny, K., Refsgaard, E., Lund, V., Lunde, M., Sørensen, L., Thougaard, B., … Bech, P. (2012). A 9-week randomized trial comparing a chronotherapeutic intervention (wake and light therapy) to exercise in major depressive disorder patients treated with duloxetine. The Journal of Clinical Psychiatry, 73(9), 1234–1242.
Meister, R., Abbas, M., Antel, J., Peters, T., Pan, Y., Bingel, U., Nestoriuc, Y., & Hebebrand, J. (2020). Placebo response rates and potential modifiers in double-blind randomized controlled trials of second and newer generation antidepressants for major depressive disorder in children and adolescents: A systematic review and meta-regression analysis. European Child & Adolescent Psychiatry, 29(3), 253–273.
Mitchell, J. M., Bogenschutz, M., Lilienstein, A., Harrison, C., Kleiman, S., Parker-Guilbert, K., Ot’alora G., M., Garas, W., Paleos, C., Gorman, I., Nicholas, C., Mithoefer, M., Carlin, S., Poulter, B., Mithoefer, A., Quevedo, S., Wells, G., Klaire, S. S., van der Kolk, B., … Doblin, R. (2021). MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 27(6), 1025–1033.
Mocking, R. J. T., Harmsen, I., Assies, J., Koeter, M. W. J., Ruhé, H. G., & Schene, A. H. (2016). Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Translational Psychiatry, 6(3), e756.
Murrough, J. W., Iosifescu, D. V., Chang, L. C., Al Jurdi, R. K., Green, C. M., Perez, A. M., … Mathew, S. J. (2013). Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial. The American Journal of Psychiatry, 170(10), 1134–1142.
Nagele, P., Palanca, B. J., Gott, B., Brown, F., Barnes, L., Nguyen, T., Xiong, W., Salloum, N. C., Espejo, G. D., Lessov-Schlaggar, C. N., Jain, N., Cheng, W. W. L., Komen, H., Yee, B., Bolzenius, J. D., Janski, A., Gibbons, R., Zorumski, C. F., & Conway, C. R. (2021). A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression. Science Translational Medicine, 13(597), eabe1376.
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