Whole Health Library

Frank is a 64-year-old retired Vietnam Veteran who receives his care at a large urban Community-Based Outpatient Center (CBOC).  His primary care provider, whom he has been seeing for a couple of years now, is concerned that Frank is depressed.  He scored a “9” on the Patient Health Questionnaire (PHQ-9), indicating mild depression, but he has scored higher in the past.  Six months ago, he was given a suicide risk evaluation, and he was assessed as being a low overall risk.  He has had suicidal thoughts in the past.  Frank is reluctant to change medications again because he has already done so three times.  Frank’s clinician is wondering what other options to consider to help Frank and has connected Frank with some Whole Health colleagues at the local VA hospital, including a psychologist who also teaches meditation and a psychiatrist who is known to “think outside the pillbox.”

Frank has been receiving VA for care for several years.  His wife died 10 years ago, and Frank has been living alone since then.  He struggled with depression (and complicated grief) when his wife died, but with the support of family and a Veterans’ grief group, he got back on his feet and has been coping well for the past few years.  Recently, he has lost several of his friends, and he is beginning to feel the effects of aging.  Frank agrees with his provider about needing to do more about his depression.

One of Frank’s clinical team members suggested fill out a Personal Health Inventory (PHI) to help identify what really matters to him.  He scheduled a visit with a Whole Health Coach, and was introduced to Jerry, a Whole Health Partner who has dealt with depression himself.

On his PHI, Frank rates himself a 2 out of 5 for his overall physical well-being and a 1 out of 5 for overall mental and emotional well-being. When asked what matters most to him and why he wants to be healthy, Frank responded:

“My family is important to me. I feel great whenever I talk to my grandchildren or I’m spending time with them.”

Care team members have noted that whenever Frank talks about his grandkids, he lights up.  Frank acknowledges that when he is around them, he has more energy and feels happier than usual.

Frank rated himself on where he is, and where he would like to be for the various areas of self-care.  After reviewing these with his Whole Health Coach, Jerry, and exploring options, Frank decided to first focus on the areas of Moving the Body and Recharge.  His initial goals will be to walk at least 15 minutes every day and talk with his grandchildren, who live some distance away, at least 4 times a week.  He also agrees to try Mindfulness-Based Cognitive Therapy (MBCT).

For more information, follow the link to Frank’s PHI.

In 2023, 29% of adult Americans reported having ever been diagnosed with depression, a 10% increase from 2015.[1]  Nearly 37% of women and 34% of people aged 18-29 have current depression or are currently being treated for it.[1]  Nearly 8.3% of adults experience major depressive disorder, and 31% of them have treatment-resistant depression.[179,180] Depression is the most common mental illness[2] and the leading cause of disability worldwide.[3]  Worldwide, and estimated 20% of Veterans have depression.[181]  While studies note that approximately 15% of U.S. Veterans have been diagnosed with depression, it is likely underdiagnosed.[4,182]

Emotional health is an important aspect of mental health, not to mention an important aspect of Whole Health overall.  Humans experience multiple emotional states (over 27, according to one recent study, though estimates vary).[5]  People with depression might describe feeling sadness, guilt, remorse, or fear, but they may also report feeling a complete absence of emotion.  Depression is  complex, challenging-to-treat, and often terminal; having an array of potential options is essential.

Not surprisingly, depression is one of the chronic conditions for which Complementary and Integrative Health (CIH) therapies are most frequently used by the general population.[6]  This is true for Veterans as well.  The 2015 HAIG report, which surveyed 141 VA facilities, found that depression was one of the top five most common diagnoses for which Veterans are treated within VA using CIH.[7] 

Personalizing Care

Mindful Awareness has been described as a practice of learning to focus attention on moment-by-moment experience with an attitude of curiosity, openness, and acceptance.  Mindful awareness is a general approach to living, but it can be used to work with many specific issues or concerns, and depression is no exception.  A particularly helpful resource is the book, The Mindful Way Through Depression, by Mark Williams and colleagues.[25]  Mindfulness-based interventions, such as mindfulness-based stress reduction and mindfulness-based cognitive therapy (MBCT) outperform other treatments, such as health education, supportive psychotherapy, and relaxation training.[193]  They reduce rumination, and reduce anxiety, distress, and depression for people who have chronic diseases.[194,195]  Specific techniques that invoke mindful awareness are featured in the Power of the Mind section, later in this overview.

Few studies have focused specifically on using mindful-awareness training for bipolar disorder (BPD); a 2018 review found that mindful awareness may help to some degree with anxiety and depression-related symptoms, but not with manic symptoms.[26]  A 2022 meta-analysis showed benefits for mindfulness-based interventions on anxiety, but not depression or mania.[196]

Physical Activity

Exercise alone is comparable to medications or psychotherapy in terms of its benefits for depression. [27]  Combining exercise with various psychotherapeutic approaches appears to be even more effective than exercise alone.[28,29]  It seems to augment medication effects as well.[30]

A 2024 meta-analysis of 218 studies including 14,170 patients found that, compared to active controls, walking or jogging, yoga, strength training, mixed aerobic exercises, and tai chi or qigong all led to moderate reductions in depression.[197]  Level of intensity of any given type of exercise was proportional to its efficacy.  Aerobic and anaerobic activities are equally effective.[33]  Exercising on an ongoing basis does make a difference.  Consistency is key.[31,32]

Exercise has been helpful for depression in people whether or not they have comorbidities.[197]  For example, it has been found to be helpful for depression in frail elderly people (though benefits in non-frail elderly are less clear), people with COVID-19, those with Parkinson’s disease, chronic neck pain, and dementia.[198-202]  There is a nonlinear inverse relationship between levels of depression and cardiovascular health.[203]

In addition to decreasing symptoms, further benefits of exercise include reduced risk for relapse, improved self-esteem, and, of course, higher levels of physical fitness (with all the other additional health benefits that confers).[31,32]  Physical activity may produce immediate improvement in mood.[34]  Therefore, starting systematic exercise early on in a depressive episode may be especially beneficial during the period of waiting for medications or psychotherapy to take effect.

Physical activity reduces risk of suicidal ideation, according to a 2018 meta-analysis.[35] People who are active versus inactive in general have a lower risk (OR=0.87).  The same was true for those who met activity guidelines versus those who did not (OR=0.91).  A 2017 study found that five different genetic patterns known to be linked to an increased risk of depression and suicidal ideation were attenuated by regular exercise in military personnel.[36]

How does physical activity help?  Exercise has been shown to regulate neurotransmitters and promote nerve cell growth; exactly how it affects depression is unknown.[37,38]  It may be due to changes in nerve cell development in the brain.[39]  Reduction in nerve cell growth and toxicity in the hippocampus are thought to be mediated through proinflammatory chemicals, such as IL-6.  Increases in macrophage activity and in the production of proinflammatory cytokines have been consistently reported in depressed patients.[40]  It has been shown that exercise can alter cellular immunity and reduce markers of inflammation, thereby modifying the metabolism of key neurotransmitters.[39]

More information is available in the “Moving the Body” overview on the VA Whole Health website.

Yoga

As noted in the previous section, yoga decreases symptoms of depression.  Compiling study data related to yoga as a treatment for depression is challenging.  There are many different forms of yoga, and practices stem from many diverse traditions incorporating a wide variety of techniques.  A 2023 meta-analysis of 23 studies—with some methodological limitations noted—of 1,420 participants concluded yoga-based interventions “...may help to improve mental health in adults diagnosed with anxiety or depressive disorders...”[204]  A 2020 systematic review concluded, noting methodological challenges in studies, yoga seems to lead to some reductions in depression in children and adolescents.[205]

Potential reasons for yoga to have positive effects on depression include modulation of the HPA axis, regulation of neurotransmitters, decreases in rumination, promotion of more adaptive thinking, and behavioral activation.[204]  

For more information, follow the link to “An Introduction to Yoga for Whole Health.”

Tai chi

A 2024 systematic review and meta-analysis involving 20 studies of 1,798 older people found that Tai Chi has benefit for reducing depressive symptoms.[206]  Another meta-analysis conducted in 2023 found that four different Traditional Chinese Medicine exercise types were beneficial, with Tai Chi showing more benefit than others, which included Yi Jin Jing and Ba Duan Jin.[207]  Tai Chi seems to have a positive effect on depression for people with specific comorbidities, including multiple sclerosis, cancer, stroke, and heart failure.[208,209]

Limited evidence seems to suggest both short- and long-term tai chi practices (40-minute sessions, ranging from one to four sessions per week over a course of 6 to 48 weeks) reduce depression symptoms.[42]  No adverse events related to the use of tai chi for depression treatment have been reported. 

More information is available on the VA Whole Health Tai Chi page. 

Light Therapy

Serotonin receptor binding potential (which is associated with depression) is negatively correlated with the duration of daily sunshine one receives.  Serotonin receptor binding lowers with increased sunlight during spring and rises when sunlight decreases in the fall.[43]  High serotonin receptor density is associated with low extracellular serotonin, and vice versa.[44]  Light therapy is commonly used as an effective treatment modality for patients with seasonal affective disorder, and it has been found useful as an adjunctive modality with pharmacotherapy in both unipolar and bipolar depression, though recent reviews have called for better-quality trials to confirm these findings.[45,210] 

American Psychiatric Association guidelines for the treatment of major depressive disorder, both seasonal and nonseasonal, consider bright light therapy a low-risk and low-cost option.[47]  A few meta-analyses, including Cochrane review, supported at least modest benefit of bright light therapy when compared with placebo for nonseasonal depression. [46,48] There are a few side effects associated with light therapy.  Headache, eye strain, nausea, agitation, and potential hypomania induction in some patients with bipolar disorder may occur.[49]

As a primary treatment, light therapy may be recommended as a one- to two-week time-limited trial in mild to moderate seasonal depression.[46]  Light therapy dosing recommendations range from 30 to 60 minutes of full-spectrum (10,000 Lux) light daily from special bulbs, or indirect daylight exposure in the early morning. One should not stare directly at a light source. Therapy is effective so long as light meets the eye at an angle of 30–60°.[50]

In animal studies, light therapy seems to enhance adenosine triphosphate production (ATP), improving blood flow, lowering inflammation, stimulating stem cells, and supporting various repair and healing processes.[211]  Brain-derived neurotrophic factor levels in humans correlate with responses to light therapy.[212]

Living Space and Mood

Positive psychology

In 1998, Seligman established positive psychology, which emphasizes using skills and positive attributes to promote cognitive, physical, and emotional well-being.  The focus is on positive qualities and not merely on weaknesses, illness, or what is wrong.[51]  

A recent review found that positive psychology interventions led to significant increases in happiness and life satisfaction, as well as decreased depressive symptoms.[52]  A systematic review of 3,400 studies found that use of positive psychology strategies (increasing positive emotions; developing personal strengths; and seeking direction, meaning, and engagement for the day-to-day life of patients) reduced signs and symptoms of depression and had the potential to prevent depressive episodes as well.[53]  Different interventions have been found to be helpful specifically for health care workers.[227]

Personal Development Toopls and Depression

As noted in the Personal Development overview, there are many skills and abilities one can use to facilitate better health in general.  This is also true specifically for mental health.  For example:

• Quality of Work Life. A European review concluded that the “fraction” of depression attributable to psychosocial work factors like job strain, job insecurity, bullying at work, and long hours, is at least 8%.[228]  Shift workers have a higher risk of depression, with a 2023 cohort study of over 175,000 workers noting that the hazard ration for depression with shift work was 1.22.[229]  When a person feels their work is boring, they have a higher risk of depression.[230]  Losing one’s job can also contribute to depression.[231]
• During the pandemic, depression and resilience were found to be inversely related.[232] A 2023 meta-analysis found a strong connection between depression, resilience, and childhood trauma.[233]  Activities or practices that can cultivate resilience may be protective against depression, and trauma-informed care may be helpful.[234] 
• Hope and Optimism. Dispositional optimism is associated with lower risk of depression, particularly in younger people.[235]  Optimism can be taught.[236]
• Self-Compassion. A meta-analysis of 56 trials found that self-compassion interventions had small to medium post immediate posttest effects on reducing depressive symptoms and small effects when assessed at follow up.[237]  More studies are needed, but cultivating self-compassion may be of benefit and little risk of harm for treatment of people with depression.[238]
• A 2018 systematic review and meta-analysis found that forgiveness interventions effectively reduce levels of depression and promote positive affect.[239]
• A 2023 meta-analysis concluded that people who experienced gratitude interventions had fewer symptoms of depression and better overall mental health.[240]
• Kindness and Compassion. Prosocial acts can lessen depression and bring positive feelings.[241]  Research does note that affective empathy (the sensations we get in response to others’ emotions) can be linked to a greater risk for depressive symptoms.[242]
• Laughter and Humor. Humor therapy was found to improve depression and anxiety symptoms in a 2023 review of 29 studies from studies conducted in multiple countries.[243]  A 2019 review concluded that laughter-inducing therapies seem to reduce depression but note that more research is needed.[244]
• Art therapy has positive effects on depression, anxiety, and psychological distress in people with cancer and a variety of other populations.[245-247]  Music therapy is also beneficial.[248]
• Work-Life Balance/Integration. Balance is associated with fewer depressive symptoms in college students.[249]  Women who return to work after family leave (not the same for men) experience more depressive symptoms.[250]
• Lifelong Learning. Some research indicates that “cultivating curiosity may help prevent the development of future anxiety and depressive symptoms.”[251,252] 
• Volunteering has been found to be associated with decreased levels of depression in elderly people.[253]  This seems to be true in a 2013 review for volunteers in general.[254]
• Healthy Finances. There is an association between depression and financial stress, according to a 2022 systematic review of 40 observational studies and a 2023 scoping review.[255,256]

General nutrition recommendations

Numerous clinical and observational studies have focused on whether or not there is an association between type of diet and depression onset. 

• A 2018 review concluded that “...the number of persons who would need to change their diet, from the lowest- to the highest-quality category in order to prevent one case of depression is approximately 47.”[54] The authors note that this is on par with the number needed to treat for many other interventions (including statin drugs to prevent vascular disease.)  They also note that more research is needed to confirm how diet and depression relate to one another. 
• A 2009 study including nearly 2,500 participants found that a diet high in processed foods was a risk factor for depression in the next five years, whereas a whole foods diet reduced risk.[55,257]
• A 2016 review concluded a reduced risk of depression was linked most strongly with increasing dietary intake of seafood, vegetables, fruits, and nuts.[56] A 2021 review found a stronger link for fruit intake than for vegetable intake, noting that a combination of both is likely best.[258]  Consuming raw fruits and vegetables also seems to lower risk of depression, though consuming them in processed forms may not.[62]
• A 2023 umbrella review of meta-analyses found that higher adherence to the Mediterranean Diet and lower Dietary Inflammatory Index scores were significantly associated with a lower depression risk; there were not enough studies for researchers to comment on the effects of a vegetarian diet or the Dietary Approaches to Stop Hypertension (DASH) diet.[259]
• Isolating information about specific chemical compounds is a major challenge, and it is perhaps most useful to focus on a healthy overall diet, rather than becoming overly focused on any one chemical compound. Some of the nutrients found to have a likely impact on the occurrence of depression in recent reviews include folic acid, vitamin B12, omega-3 fatty acids, zinc, selenium, vitamin B6, and magnesium.  Fiber Total dietary fiber intake also is associated with lower depression risk.[260]  Dietary antioxidants like green tea polyphenols are also associated with lower depression and depressive symptoms.[261]
• A 2010 meta-analysis noted that people with obesity are 55% more likely to develop depression, and depressed patients are more likely to become obese.[57]
• People with severe food insecurity are twice as likely to suffer from depression than people without food insecurity.[262]

A few studies support a causal relationship between daily excess sucrose and caffeine intake and depression.[58,59].  A small cohort trial found that eliminating refined sucrose and caffeine from the diets of people experiencing unexplained depression resulted in improvements by one week.  Symptoms recurred when patients were challenged with these substances again but not when they were given placebo.[60]  Research findings support a low-carbohydrate diet, ketogenic diet, and the avoidance of sugar sweetened beverages as means for maintaining positive emotional states and preventing relapses.[263]  Sugar-sweetened beverage consumption is associated with a 10.8 (CI 1.06-1.10) risk of depression.[264]  A 2012 Spanish study found that consuming fast food and commercial baked goods may have a detrimental effect on depression as well.[65]

Alcohol-related problems are more likely in depressed people.[63]  Alcohol temporarily increases serotonin, but ultimately it decreases neurotransmitter levels.[64]  Elimination of alcohol seems to reduce depressive symptoms.[11]

Anti-Inflamatory Diet

Studies have demonstrated that increased levels of pro-inflammatory compounds in the body contribute to the behavioral changes associated with depression.[265]  There are causal relationships between depression and inflammation, and inflammation is associated with abnormalities in neurotransmitter regulation.[266]  People with depression have higher levels of pro-inflammatory cytokines, including interleukins 1-beta, 6, and 18, as well as tumor necrosis factor-alpha.[267] 

Data from the Nurses’ Health Study indicates that a proinflammatory diet pattern increases depression risk.[65]  A 2022 systematic review concluded that “...both following a healthy diet, in particular incorporating vegetables and fruits, and avoiding a pro-inflammatory diet like junk foods, fast foods, and high meat intake may lower the risk of developing depressive symptoms or clinical depression.”  Several anti-inflammatory diets have been developed and may prove beneficial.[66]  The Mediterranean Diet is a popular example.[259]  For further details, review the “Whole Health Tool: The Anti-Inflammatory Diet” in the Passport to Whole Health.

Omega-3 Fatty Acids are one element in an anti-inflammatory diet that may be of particular benefit.  Moderate fish and omega-3 fatty acid intake (but not higher levels of intake) were linked to lower odds of having depression.  The effective dose is 0.5-1 grams of omega-3’s daily.[268]

Keep in mind that increasingly research is finding a link between depression and chronic inflammation.  Behaviors that reduce inflammation, such as eating an anti-inflammatory diet, taking omega-3 fatty acids, minimizing blood sugar spikes due to simple carbohydrates, and managing stress are worth considering.

Probiotics

Sleep

70% of people with mental disorders report sleep difficulties.[274]  There is growing body of research indicating that sleep and depression have a powerful bidirectional influence on one another.[275]  A 2023 review concluded that sleep disturbance is “...a modifiable risk factor in the development and maintenance of depression.”[276]  Treating sleep disturbances may prevent future depressive episodes.[277]  Nondepressed people with insomnia (compared to people with no sleep difficulties) have double the risk of developing depression,[68] and treating insomnia and other sleep disturbances may be of benefit for people with treatment-resistant depression.[278]  Poor sleep is also associated with increased risk of suicidal ideation, suicide attempts, and deaths by suicide.[69,70,279]

Melatonin and serotonin are closely related.  Melatonin is stimulated by lower light levels, and serotonin by higher.  Improved melatonin levels may be helpful in depression.  A 2023 systematic review and meta-analysis found that melatonin supplementation (in doses <10 mg daily, particularly over 4 weeks in duration) improved depression.[280]  Recent studies have linked evening chronotype (i.e., being a night owl, going to bed late and getting up late) with risk of depression, as well as neuroinflammation and suicide risk.[281,282]  It is not clear if becoming a “morning person” can negate these risks. 

Cognitive Behavioral Therapy for Insomnia (CBT-I) leads to decreased severity of depression and  to a significantly greater remission rate in both depression and insomnia.[71,283]  Most mindfulness-based interventions also can be effective options for improving sleep difficulties for people with depression.[284]  For example, eight weeks of Mindfulness-Based Cognitive Therapy (MBCT) targeting insomnia also improved sleep, anxiety, and depressive symptoms in patients with anxiety.[72]

More information is available in the Recharge overview.

Social support is a key component of depression treatment.[73-75]  Higher social support has been linked to lower risk of suicide in OEF and OIF Veterans.[76]  Conversely, social isolation, loneliness, alienation and feelings of not belonging are linked to higher risk of suicidal outcomes.[285]  A review of 51 studies concluded that perceived emotional support and large, diverse social networks had significant protective effects against depression.[286]  Elderly people who experience social connected ness have less depression.[287]  A 2018 trial found that “loneliness was associated with higher levels of depression and suicidal ideation, as well as lower patient activation and help-seeking intentions.”[77]  Relationship strain has a significant impact on depressive symptoms and happiness and should be considered.[288]

Recent reviews, influenced by self-determination theory, suggest that how much a person perceives social contacts to fulfill or undermine their basic psychological needs determines both the positive or negative health mood effects of their relationships.[78]  Interpersonal influences have an effect on emotional regulation.  How a person responds may be linked to depression risk.[79]  Social support interventions should focus on both strengthening relationships that fulfill basic psychological needs and removing negative relationships that a person sees as undermining their well-being.

A 2022 review concluded that more research is needed to determine if social prescribing favorably affects mental health outcomes.[289]  Encouraging people to join social groups (e.g., arts-based groups, exercise groups) seems to be helpful for mild to moderate depression.[290]

It would seem that most ways of encouraging more social connection and/or building relationships could have potential benefit for people with depression; be sure to tailor the approach to each individual.  More information on relationships and health is available in the Family, Friends, and Coworkers overview on the VA Whole Health website.

Spirituality can play a significant role in influencing mood.  Depression strikes at one’s very sense of meaning and purpose, so exploring how a person can enhance that sense is fundamental. Miller and colleagues reported a 90% decreased risk in major depression, assessed prospectively, in adult offspring of depressed people who reported that religion or spirituality was highly important to them.[80]  A 2019 review of 152 studies found that 49% of them reported at least one significant association between religiosity and spirituality and improved depression course; 10% indicated an association with more depression or mixed results.[291]  Frequency of church attendance was not significantly related to depression risk.[80] Placing a high importance on religion or spirituality is associated with having a thicker cerebral cortex,[81] which may confer resilience to the development of depressive illness in individuals at high familial risk for major depression.  A 2023 review and meta-analysis focused on religiosity and spirituality in young people noted that the 74 studies reviewed were of low to moderate quality but did find that “...interventions that involved religious and spiritual practices for depression and anxiety in young people were mostly effective.”[292]

A 2023 meta-analysis exploring the relationship between purpose in life and depression found a mean weighted effect size of -0.49.[293]  A 2019 evaluation of data from the National Health and Resilience in Veterans Study concluded that a higher level of “global meaning” reported by Veterans was linked to a significantly lower likelihood of suicide in Veterans who experienced morally injurious experiences related to deployment.[82] 

Meaning therapy, described as “...an integrative and positive existential psychotherapy that focuses on personal meaning to empower clients with resources to overcome inevitable negative events and build a life worth living...”  was studied in cancer patients in a 2024 systematic review.[294]  The authors concluded it significantly improved depression, psychologic distress, and hopelessness; it also decreased the desire for a hastened death.

For more information, go to the Spirit & Soul overview.

Mindfulness-Based Therapies

Initial research on mindfulness looked at its influence on stress reduction.  Strong evidence supports the use of mindfulness approaches in this role.[83,84]  In general, mindfulness meditation affects the prefrontal cortex, reducing vulnerability to depression, and it decreases rumination and reactivity.[85]  A 2017 review article concluded that mindfulness-based interventions, in general, are “effective for reducing anxiety and depression symptom severity in a range of individuals...” and that they outperform health education, relaxation training, and supportive psychotherapies...” while being comparable with cognitive behavior therapy.[395]

A 2022 scoping review concluded that it reduces depression in people with chronic diseases in general.[296]  A 2020 RCT found it helps university students with depression as well.[297,298]  MBSR also seems to be beneficial for depression in people who also have insomnia, and a 2023 meta-analysis found that mindfulness seemed to act “as a buffer” against depression related to COVID-19.[299,300]  Mindfulness interventions of 4 to 8 weeks duration were found to reduce depression in nurses in a meta-analysis that included 807 nurses, with the longer interventions having a greater effect.[301]  56 physicians who completed a virtual mindfulness-based intervention had significant reductions in depression.[302]

A number of specific mindfulness-based interventions have demonstrated effectiveness for reduction in depression symptoms, including the following[86,87]:

Mindfulness-Based Stress Reduction (MBSR)

More information about MBSR courses can be found at UMass Center for Mindfulness.  MBSR is an 8-week course that takes participants through a variety of ways to be mindful, outside of the framework of any organized religions.  In Veterans, one trial found improvements in perceived stress, depressive symptoms, and quality of life after a six-week mindfulness course.[88]  Mindfulness-based stress reduction has been successfully used in the VA environment for depression and PTSD. [89]  It also improved quality of life.  

A 2023 review and meta-analysis of 16 studies of 2,072 cancer patients, MBSR improved depression ratings relative to controls.[303]  A 2024 Chinese RCT concluded that an online MBSR course reduced depression and improved quality of life in caregivers of people with severe mental disorders.[304]  A 2022 trial involving 98 people with migraine did not find a benefit to taking an MBSR course, and a 2021 pilot RCT found that the full 8-week MBSR course seemed to help depression in health care professionals, but an abbreviated version of the class did not lead to significant changes.[305]

Mindfulness-Based Cognitive Therapy (MBCT)

Developed by Segal, Williams, and Teasdale, MBCT adapts the principles of the MBSR eight-week training course specifically to patients with bouts of recurrent depression.[90]  It is strongly recommended as an adjunctive treatment for unipolar (nonbipolar) depression and has strong evidence supporting its use.[91].  It significantly reduces risk of remission of depressive episodes, as well as overall symptom levels.[85]  In a 2023 review and meta-analysis, it was found to reduce depression and suicidal ideation in 13 studies that included 1,150 participants.[306,307]  In a 5-week abbreviated course in 54 people, MBCT was found to have large treatment effects for decreasing mood symptoms.[308]  A study of 1,282 cancer survivors found benefit for anxiety but not depression with an online MBCT course.[309]  MBCT was found to decrease insomnia in people with recurrent depression in one trial.[310]

Compassion Training

Loving-kindness meditations, which involve sending kindness to oneself and others, usually in a specific order, have a favorable impact on positive affect and psychological symptoms.[311]   The function of a part of the brain known as the amygdala is impaired in a number of mental disorders, including depression.[92]  Functional MRI studies of the effect of mindfulness on the amygdala found that after an eight-week course of cognitively-based compassion training, there was an increase in right amygdala response to negative images.  This change in the amygdala was significantly correlated with a decrease in depression scores.[93]  A study of 80 Chinese college students found that even a short video app with a guided loving-kindness meditation improved positive psychological capital and decreased suicidal ideation.[312]  A study that combined loving-kindness meditation and MBCT found that they had benefits for depression, rumination, quality of life, and other attributes in depressed people.[313]  Multiple examples of various loving-kindness and compassion meditations are available online, including through the VA Whole Health videos page.

Other Mindful Interventions

A 2024 review of 36 trials concluded that the effects of using mobile apps, many of which employed mindfulness training (and/or cognitive behavioral therapy) were unclear.[314]

Hypnotherapy

Hypnotherapy has been around for more than a century, and its role in treating depression has been investigated for over 20 years.[94]  A 2024 scoping review that chose 14 of 232 studies found that most of the studies meeting inclusion criteria suggested that hypnotherapy was effective in reducing depression symptoms, and it was noted that ins some studies, for some measures, hypnosis had superior effects to antidepressant treatment.  It will be helpful for more trials that tease out differences in efficacy between specific types of hypnotherapy.[95]

In the general population, hypnotherapy appears to have many benefits, with few adverse effects.[315]  Its success depends largely on the engagement of the patient.  Therapists must have skill in determining who is or is not an appropriate hypnotherapy candidate, as some people with past traumatic experiences may have them activated through entering a trance state.  One study found self-hypnosis to be a preferred mode of treatment of depression in a primary care setting and comparable to medications and CBT, in a partially randomized preference study design.[96]

Cognitive hypnotherapy (CH).  Alladin and collaborators combined hypnotherapy and CBT to create cognitive hypnotherapy, which became the focus of an evidence-based handbook they developed.[97]  CH is thought to achieve benefits through six means: 1) altering depressive mood, 2) establishing positive expectancy, 3) countering depressive rumination, 4) developing antidepressive neuropathways, 5) accessing and restricting unconscious cognitive distortions, and 6) behavioral activation.   It has been advocated as a potential intervention for depression in people receiving palliative care.[316]

Guided Imagery

Research related to Guided Imagery for depression is limited.  It is known that people with depression have more intrusive imagery and less ability to generate positive imagery, but more research is needed regarding how treatment can use imagery to help with depression.  A 2024 RCT found that imagery-based interventions have research support for their use by people with depression.[317]  A 2021 review did conclude that “...harnessing emotional mental imagery in psychological interventions could be a promising approach to reducing anxiety and depression...” in young people.[318]  One trial found that guided imagery reduced depression in people with fibromyalgia.[319] 

Relaxation

A 2008 Cochrane review concluded that in general, “Relaxation techniques were more effective at reducing self-rated depressive symptoms than no or minimal treatment, but not as effective as psychological treatment.”[98]  A 2024 systematic review of 46 publications form 16 countries concluded that progressive muscle relaxation is effective for reducing depression.[320]  A 2020 review reached the same conclusions, noting that relaxation techniques are safe, easily taught, and cost-effective.[321]  Another 2020 review found the benefits of relaxation therapy for depression comparable to psychotherapy.[322]  A review specific to women with breast cancer found that muscle relaxation training significantly reduced depression and anxiety.[323]

Creative Arts Therapy

Art Therapy.  A 2024 systematic review and meta-analysis found that visual art therapy has a statistically significant effect on reducing depression symptoms.[324]  Similar large-scale studies focused on people with cancer and older adults drew similar conclusions.[325]  A 2021 review highlighted that art therapy is useful in diagnosis, in addition to helping people to share more fully with others.[326]

Music Therapy.  A 2024 systematic review, while noting that studies with better methodology are still needed, noted that music therapy and music interventions are effective for an array of neuropsychiatric symptoms, including depression.[327]  A 2017 Cochrane review concluded that Music Therapy (MT) has short-term benefits for depression and works better when combined with medications than when medications are given alone.[99]  Several trials have been published, mostly in older patients, which suggest potential antidepressive effects when Music Therapy  was added to usual care.  A dose effect was seen; benefits were more pronounced with longer durations of treatment.[100]  MT relieves depression and anxiety for people with breast cancer, according to a 2023 systematic review.[328]  The same was found for older adults in a 2023 systematic review and meta-analysis.[329]  A 2008 Cochrane Review on MT for depression concluded MT  is well tolerated by people with depression and appears to be associated mostly with improvements in mood. [101]  Risks are minimal.  A 2022 systematic review and meta-analysis concluded that a music intervention by a music therapist is most effective, but even listening to a person’s preferred music for >1 hour per week has significant benefits.[330]

Dance Therapy.  A 2024 review concluded that dance movement therapy and dance movement interventions both had significant positive effects on depression in people with cancer.[331]  A 2023 systematic review found benefits for adults in general, noting that multiple styles – Dance Movement therapy, quadrille, Nogma, waltz, rumba, tango, and others – all reduced symptoms.[332]

Psychotherapy

Psychotherapeutic approaches could be featured in the previous section on mind-body approaches as well but are more mainstream than many of the approaches covered in that section.  The American Psychiatric Association (APA) considers psychotherapy to be a first-line therapeutic option for patients with mild to moderate major depressive disorder.  It can be used alone or, in cases of severe major depressive disorder, as combination therapy with other modalities.  A 2018 Cochrane review concluded, “Moderate-quality evidence shows that psychotherapy added to usual care (with antidepressants) is beneficial for depressive symptoms and for response and remission rates over the short term for patients with treatment-resistant depression. Medium- and long-term effects seem similarly beneficial....”[102]  Recent research has found/reinforced that therapies are effective in the elderly, in perinatal depression, and in people with general medical disorders; they are preferred by patients to medications and have longer-lasting effects.[335]  Psychotherapy has benefit in treatment-resistant depression as well.[336]

Using psychotherapy in combination with medications appears to have superior efficacy to use of medications alone in all levels of depression severity. A 2021 review and meta-analysis concluded that the optimal way to combine the two for major depressive disorder may be to integrate psychotherapy after “acute-phase medication therapy.”[337]  In terms of age groups, psychotherapy seems to be most beneficial in young adults, followed by those who are middle aged and older.

Factors to consider in choosing any of the psychotherapy modalities include the following:

• Availability of trained clinicians
• Patient preference
• Psychosocial context
• Prior beneficial response to psychotherapy
• The presence or absence of significant psychosocial stressors or interpersonal difficulties
• Intrapsychic conflict
• Presence of Axis II disorders (e.g., personality disorders)
• Stage, chronicity, and severity of major depressive episodes

The APA has a number of patient-friendly, informative videos and documents on psychotherapy.

Several psychotherapies practiced within the VA are described below, with a discussion of the state of the evidence supporting (or not supporting) their use.  The list is by no means comprehensive, and some approaches are much more widely available than others.  Recent studies have indicated that digital psychotherapy is also a viable option for treatment of depression, with cognitive behavioral therapy (CBT) having some of the most favorable research findings.  Phone-administered psychotherapy also has benefit.[339]

Clinicians are encouraged to know the various forms of psychotherapy available to people with depression so they can be effective matchmakers between a given individual and a given therapy (or therapist).  The “fit” between Veteran and therapist may be as important as the therapy itself.

Cognitive Behavioral Therapy (CBT)

CBT is the most-studied psychotherapy used for depression.[103]  The clinician guides the patient in identifying and replacing negative patterns of thinking with more positive and realistic approaches.  CBT includes education about the relationship between thoughts, behaviors, and emotions.  Patients are taught behaviors that serve as more productive responses to challenging circumstances or feelings.  CBT is considered a short-term therapy; the length is usually 10-20 sessions.  For more information, go to the National Alliance on Mental Illness (NAMI) website.

CBT is effective for treating depression, and this was again affirmed by a 2022 systematic review and meta-analysis of 28 trials with nearly 4,000 participants.[340]  A 2019 meta-analysis confirmed that CBT works well for “primary care depression and anxiety.”  CBT decreases the risk of relapse if continued when a person is doing well,[104] and it works well for treatment resistant depression in tandem with medications.[341]  CBT can be as effective as medications in the acute treatment of depressed outpatients.[105]  CBT is equally efficacious in older adults compared to younger adults.[342]  A 2020 systematic review and meta-analysis found that computerized cognitive behavioral therapy (cCBT) is effective for reducing symptoms of anxiety and depression in adolescents and young adults.[343]  Internet-based CBT (iCBT) also proved beneficial; guided iCBT was more effective than unguided, and benefits were greater in people with depression that was moderate or severe. 

Interpersonal Therapy (IPT)

Developed in the 1970s, IPT is based on the idea that many psychological symptoms arise through interpersonal distress.[344]  Treatment usually is offered for 12-16 weeks and focuses on exploring relationships and how they influence—and are influenced by—one’s behavior and mood. 

A 2023 meta-analysis concluded that IPT has significant effects on reducing depression and helping with social functioning; benefits for overall function were less clear.[345]  A study of Veterans indicated that dynamic interpersonal therapy significantly decreases depression and anxiety.[346]  IPT can be as effective as medications in the acute treatment of depressed outpatients.[105]  The degree to which patient and therapist can resolve the interpersonal crisis on which IPT focuses (e.g. a role transition) appears to correlate with symptomatic improvement.[106] 

For more information, go to the International Society for Interpersonal Psychotherapy website.

Psychodynamic Therapy

Psychodynamic Therapy (PT) is defined differently in various studies.  It is also known as insight-oriented therapy.  It focuses on gaining insight into unconscious processes and how they manifest in the way a person behaves.[107]  Recent meta-analyses suggest that both short-term and long-term psychodynamic psychotherapy are effective for depressed patients[108,109] and that adding it to antidepressants increases treatment efficacy.[347]  PT seems to be comparable in effect to CBT.[348]

For more information, go to the Good Therapy website.

Problem-Solving Therapy

Problem-Solving Therapy (PST) is a brief intervention, done in four to eight sessions.  A therapist reviews the problems someone is experiencing and then focuses on solving one or more of those problems to demonstrate more effective problem-solving techniques.  PST has shown modest improvement in study participants with mild depressive symptoms; most studies have been done with geriatric populations.  Twelve sessions of problem-solving therapy were superior to supportive psychotherapy for this population with major depressive disorder and executive dysfunction.[110]  A 2021 systematic review and meta-analysis concluded that PST is effective for treating major depression in older adults.[349]

For more information, refer to the University of Auckland Problem Solving Therapy website.

Marital Therapy

Marital therapy (MT), or couple’s therapy, involves working with both a depressed person and their significant other.  MT showed comparable efficacy to individual psychotherapy for the treatment of depression in a 2006 meta-analysis.[111]  Several reviews have found that MT is effective for treating depressive symptoms and reducing risk for relapse.[112,113]  Some individual studies have suggested that the efficacy of MT may depend on whether or not marital problems are present.[114] Lower dropout rate and greater improvement in subjective symptoms of depression, at no greater cost, were found for a couples therapy group in comparison to medications alone.[115]  

Patients with major depressive disorder admitted to inpatient units were more likely to improve if family therapy was part of their treatment.  They had significant reductions in interviewer-rated depression and suicidal ideation.[116]

Acceptance and Commitment Therapy

Acceptance and Commitment Therapy (ACT) is another approach that incorporates mindful awareness to prevent depression relapse.  It is classed in this document as a “conventional therapy” because it is rapidly gaining popularity in VA facilities. ACT invokes mindfulness techniques, acceptance, and commitment/behavior-change strategies to enhance a person’s psychological flexibility.  A person learns to focus effectively on the present moment to address any given situation that arises.  People are encouraged to “make healthy contact” with thoughts, memories, feelings, and sensations they have avoided in the past.

Research has shown that ACT has powerful positive effects on depression, as well as many other illnesses.[117], likely through increases in psychological flexibility.[350]  Group-based ACT has shown benefit as well, according to a 2020 systematic review.[351]  A 2024 review and meta-analysis found that ACT was effective for depression and anxiety in people with fibromyalgia.[352] 

To learn more, go to the Association for Contextual Behavioral Science (ACBS) website

PHARMACEUTICALS

According to current APA guidelines, medication is recommended as one of the initial treatment choices for depression in adults.[353]  Effectiveness of antidepressant medications is generally comparable between classes and within classes of medications.  Therefore, there are several elements to take into consideration in choosing the initial medication.  These include medication response in prior episodes, expected side effects, safety, or tolerability of these side effects for the individual patient, what has worked for biological relatives with depression, pharmacological properties of the medication, cost, and patient preference.  Many studies demonstrate efficacy for various pharmacological and psychological therapies as first-line treatments; however, the degree to which they are effective is, in many studies, disappointing.  This is especially true in the treatment of depression in its mild to moderate forms.[22]  Specific guidance for pharmacotherapy for depression is beyond the scope of this document, but numerous large-scale reviews can be helpful.[118,354,355]

One study of note found that pharmaceutical treatments prevent the progression of microglial (nervous system immune cell) activation that otherwise will progress in people with depression.[119]  SSRIs seem to induce a “juvenile-like neuroplasticity” in the adult brain.[120]

OTHER CONVENTIONAL APPROACHES

Electroconvulsive Therapy (ECT)

Electroconvulsive Therapy (ECT) has the highest response and remission rates of any form of treatment for depression, leading to improvement for up to 70%–90% of those treated.[121]  ECT should be contemplated in patients with treatment-resistant depression.[356]  It may be first-line treatment in patients with severe major depression when a fast antidepressant response is desired and when any of the following elements are present: suicide risk, catatonia, psychotic features, severe illness, or food refusal with nutritional compromise.[122][357]  ECT is an important option for preventing depression relapses.[358]

Transcranial magnetic stimulation (TMS)

Transcranial Magnetic Stimulation (TMS) aims to produce electrical stimulation of superficial cortical neurons at left dorsolateral prefrontal cortex using a magnetic coil that generates rapidly alternating magnetic fields.  These fields are similar in strength to those used for MRIs.[123]  TMS has been approved by the FDA to treat depression in patients who have not had an acceptable response to at least one antidepressant trial in the current episode of illness.  A 2020 systematic review of 8 studies found that 39.5-50% of participants had a response to treatment and 16.6-76.9% achieved remission form major depressive disorder.  Comorbid disorders also responded quite favorably.[359]  A 2023 umbrella meta-analysis found that rTMS had an odds ratio for a response of 3.27 when compared to a sham procedure.[360]  A 2022 meta-analysis found repetitive TMS (rTMS) to be effective and safe method for treating older patients with depression.[361]  Efficacy is either less than or similar to that of ECT.[124]  TMS is well tolerated; the most common side effects are transient scalp discomfort and headaches.[125]

Vagus nerve stimulation (VNS)

Vagus Nerve Stimulation (VNS), which is FDA-approved as a depression treatment, involves implanting a device that sends electrical pulses to the brain.[362]  It stimulates brain activity in the amygdala and dorsolateral prefrontal cortex, which can lessen depression severity.[363]  It has been found useful in chronic depression, but not in the acute phase.[126]   VNS can safely be combined with ECT for patients with acute relapse. The cost is very high, tens of thousands of dollars for a day of surgery plus adjustments.[127,364]

A 2015 review noted that 10%-30% of people with depression and 20%-50% of those with bipolar disorder used CIH.[141] It is important to ask patients about use, and it is important, regardless of your standpoint regarding the use of complementary approaches, to be able to discuss them with people in your care. In 2016, the Canadian Network for Mood and Anxiety Therapies (CANMAT) created guidelines regarding CIH for depression, noting, ”For major depressive disorder (MDD) of mild to moderate severity, exercise, Light Therapy, St. John’s wort, omega-3 fatty acids, SAM-e, and yoga are recommended as first- or second-line treatments. Adjunctive exercise and adjunctive St. John’s wort are second-line recommendations for moderate to severe MDD.[142]

Nonbotanical supplements

Omega-3s, folate, magnesium, and zinc are on the VA formulary.  The others listed below are not; Veterans typically must pay for them out of pocket.

Folate

People with depression have lower folate levels and lower dietary intake of folate than the general population.[131]  In fact, depression is a common symptom of folate deficiency, and people with low folate do not respond as well to SSRI medications.[369,370]  Folate is involved in serotonin metabolism,[132] with a role in methylation reactions that form the rate-limiting step in the production of neurotransmitters like serotonin.[133]  It is also involved biochemical pathways tied to glutamate excitation, microbiome function and immune system function in general.[371]  A 2023 narrative review concluded that in general, while findings have been mixed, research generally supports the use of folate for depression.[371]  A 2021 systematic review and meta-analysis found that folate supplementation is helpful as an adjunctive therapy in people taking SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs), and it may be most beneficial in combination with other therapies.[372]  L-methyl folate may be a more active and bioavailable form because it crosses the blood-brain barrier.  As a water-soluble set of compounds, folate tends to be very safe.

Magnesium

Magnesium’s first use dates back 100 years ago, when magnesium sulfate injected hypodermically was found to be helpful in patients with agitated depression.[134]  A 2023 systematic review and meta-analysis of a group of 325 participants concluded that magnesium supplementation led to significant declines in depression scores.[373]  2018 meta-analysis did not find a link between serum magnesium levels and depression.[135]  Magnesium’s exact mechanisms of action are unclear but may be related to the glutamatergic mechanism, since magnesium acts as physiological NMDA receptor antagonist.[136]  Oral magnesium supplementation may prevent depression and might be used as an adjunctive therapy, but further research is needed.[137]  Magnesium glycinate is a common form of magnesium used for supplementation, with fewer gastrointestinal effects.

Omega-3 fatty acids

People with depression have been found to have a deficiency of omega-3 fatty acids or an imbalance in the ratio of omega-6 and omega-3 fatty acids.[138]  Synaptic membrane fluidity is significantly determined by cholesterol and dietary polyunsaturated fat levels, and this significantly affects neurotransmitter synthesis and function.[139]  

A 2017 network meta-analysis found that omega-3 therapy was not as effective as SSRI therapy, but that when the two were combined, the effect was better than either intervention alone.[141]  A 2019 meta-analysis concluded that omega-3  supplements with 60% or greater eicosapentaenoic acid EPA, at doses of 1 gram EPA or less daily, had antidepressant effects.[374]  A 2024 systematic review and dose-response meta-analysis of 67 trials found that in people with and without depression, there was moderate-certainty evidence that depressive symptoms improved relative to omega-3 dose; in people with existing depression, the greatest improvement was seen at 1.5 grams per day.[375]  The analysis showed that “...omega-3 fatty acid supplementation significantly increased depression remission by 10 more per 100 in patients with depression...” noting that evidence was “low-certainty.”

Two other meta-analysis concluded that omega-3 supplementation demonstrated significant clinical benefit, noting that eicosopentaenoic acid (EPA) content was particularly important.[142,143]  In rat models, diets rich in omega-3 led to increased hippocampal neurogenesis.[140]  An elevated ratio of omega-6 to omega-3 fatty acids predicted depression development following interferon-alpha treatment.[144]  A low omega-3 index in late pregnancy was associated with a higher depression score three months postpartum.[145] 

Probiotics

Taking probiotics daily may modulate immune function and mood. For mood benefits, Bifidobacterium infantis has been found especially useful.[67,146]  A 2022 review concluded that “...microbes from the genus Lactobacillus and Bifidobacterium in the probiotic group with a minimum dose of 10⁸ colony forming units in various dose forms effectively treated depression.”[376]  A 2022 review noted that using probiotics synergistically with S-adenosylmethionine may be of benefit.[377]

In general, one billion (10⁹) colony forming units (CFUs) is a good starting point for dosing, and taking a variety of different species may be best.  It is recommended that probiotics be taken for at least two weeks and up to two months.  For more information, go to “Promoting a Healthy Microbiome with Food and Probiotics”.

S-Adenosyl methionine (SAMe)

Pronounced “Sammy,” S-adenosyl methionine is an amino acid derivative that is found in virtually all body tissues and fluids.  It plays a role in over 100 biochemical reactions, most of which involve the transfer of methyl groups.  SAMe is important for the synthesis and metabolism of proteins, nucleic acids, neurotransmitters, hormones, and many other compounds.  Severely depressed patients often have low levels of SAMe in the spinal fluid, and SAMe supplementation can normalize them.[147]  Deficiencies of B12 and folate are linked to low levels of SAMe in the nervous system.  SAMe’s mechanism of action is unclear, but higher SAMe levels have been linked to increased serotonin turnover and elevated dopamine and norepinephrine levels.  SAMe is often used for treatment of both depression and pain.  Some people refer to it as the supplement equivalent of duloxetine (Cymbalta). 

A 2016 Cochrane review that included eight trials noted a paucity of high-quality evidence but noted that SAMe often shows similar effects to SSRIs.[148]  A large 2024 systematic review and meta-analysis of 23 trials with 2,183 participants concluded that “Moderate-certainty evidence suggests that SAMe monotherapy may offer a moderate therapeutic benefit in alleviating depressive symptoms.  Considering its favorable acceptability provide, SAME monotherapy should be considered...”[378]  Another 2024 meta-analysis concluded it may provide relief of symptoms similar to imipramine or escitalopram, though study numbers are limited, and doses used in studies are quite variable.[379]

SAMe is thought to have a more rapid onset than many antidepressants, so some clinicians may use it as a stopgap while waiting for drug therapies to take effect.[149]  It can significantly improve remission rates in depressed patients who do not respond to medications.[150] SAMe tends to be quite safe.[150]  Side effects can occur with high doses, such as nausea, vomiting, diarrhea, constipation, nervousness, dry mouth, and headache, but these tend to be minimal in comparison with side effects from antidepressants.  Mania and hypomania are rarely reported.  Dosing ranges from 400 mg to 1,600 mg daily divided into two doses.  SAMe’s biggest drawback is that it can be quite expensive to purchase over the counter. 

Tryptophan and 5-hydroxytryptophan (5-HTP)

5-Hydoxytryptophan (5-HTP) is a compound formed as the amino acid tryptophan is converted into the neurotransmitter serotonin.  A 2010 Cochrane review found that in two of 108 trials, tryptophan and 5-HTP were better than placebo at alleviating depression.[149]  A variety of trials carried out since the 1970s indicate it is as effective as antidepressant medications, but study quality is limited.[380]  A 2020 meta-analysis concluded that 5-HTP led to a remission rate of 0.65 but noted that current studies are relatively weak.[381]

Standard dosing is 50-200 mg three times a day, and it is best to start with 50 mg doses and titrate up over a few weeks.  For a brief period, there was concern about a possible association between 5-HTP and the potentially fatal eosinophilia-myalgia syndrome, but this has been attributed to contamination of a specific batch of supplements made by one company, and overall, 5-HTP seems to be relatively safe.[382]  Tryptophan intake in the diet is inversely associated with depression risk.[151]  Most Americans get more than enough in their diets.

Vitamin D

Vitamin D Vitamin D deficiency is linked to an increase in depression risk in epidemiological studies.[383,384]  Vitamin D receptors are found in multiple brain structures, and it affects neurotransmitter release, neuroprotection, and neurotrophic factors.[385]  However, the actual benefit of supplementing vitamin D for depression is controversial, because reviews have produced conflicting results.[386]  One 2014 meta-analysis, which accounted for whether or not supplementation actually improved serum levels of 25-hydroxy vitamin D, did conclude that supplementation was as effective as antidepressant medications.[387]  A 2023 systematic review noted, given study bias, variation in dosing in studies, and variation in measurement tools, it was not possible for the review to be a “strong confirmation” that vitamin D supplementation is effective in the treatment of depression.[388]  In contrast, a 2023 umbrella meta-analysis of 10 previous meta-analyses revealed “...significant reduction in depression symptoms comparing participants on vitamin D supplements to those on placebo” with a standardized mean difference of -0.40.[389] 

Zinc and other minerals

Research suggests potential benefits of zinc supplementation for depression, either as a stand-alone therapy or as an adjunct to drug therapy.  A 2018 review suggested that levels of zinc, iron, copper, and selenium intake are inversely related to depression risk.[151]  A 2021 systematic review and meta-analysis concluded that zinc supplementation can reduce depressive symptoms in people already taking antidepressant drugs.[390]  Like folate, zinc may be most effective as an adjuvant therapy.  Zinc-sensing cell receptors may be partly linked to zinc’s efficacy.[152]

Botanicals [173]

Research on botanical remedies for depression has rapidly increased, particularly since 2015.  Surveys indicate that 44%-54% of depressed patients have used herbal remedies in the past 12 months.[154]  Most research focuses on the use of botanicals for mild to moderate depression.  Botanicals differ from medications, most notably because they are polyvalent.  That is, they contain multiple chemicals that may contribute to therapeutic benefit that may work in synergy to bring about a therapeutic effect.  This may lead to a lower rate of side effects but also to difficulties with standardization.  Since depressive disorders tend to be associated with comorbid anxiety and other psychiatric disorders, the use of polypharmacy in psychiatry is increasing; antipsychotics are often used along with antidepressants, for example.  Using multiple plant-based compounds (either from one remedy or a combination) may have similar benefits, but it lends complexity a far as knowing what compounds are beneficial. 

A 2018 review featuring 110 herbal remedies found that only 1%-2% of studies were clinical.  Most herbals, like antidepressants, affected monoamine neurotransmitters (e.g., serotonin, norepinephrine, and dopamine).[155] A 2019 review concluded that using a shotgun approach to taking supplements (simultaneously taking a large array of them with hopes of combined benefit) is not effective.[166]

St. John’s wort (Hypericum perforatum)

St. John’s wort (SJW) is one of the main supplements used for treating depression.  In Germany, since 1984, t has been a licensed prescription medication, prescribed more than all other antidepressant medications in the country combined.[386]  St. John’s wort is not just an herbal SSRI; it seems to affect multiple different biochemical pathways.  It seems to have multiple mechanisms of action affecting serotonin, norepinephrine, dopamine, and GABA, monoamine oxidase and L-glutamate; it also affects interleukin-6, an inflammatory modulator, and cortisol.[391,392] 

A 2022 review of data from 27 papers concluded that “...SJW has shown to be comparable, if not more efficacious, than most standard treatment options for depression.”[393]  Favorable outcomes in studies include reduction in Hamilton Rating Scale for Depression (HAMD) scores,[154] lower relapse rate (18%), and longer time to relapse compared to placebo groups after 26 weeks of treatment.[161]  A 2017 network meta-analysis found that St. John’s wort was similar to SSRIs in terms of response rates, remission rates, and degree of change on the HAM-D scale.[141]  It was found to have superior effects relative to exercise or omega-3s.  Of note, it also had fewer adverse effects than SSRIs (relative risk 1.19).  Another 2017 meta-analysis concluded that St. John’s wort was comparable with SSRIs for people with mild to moderate depression.[162] 

If anyone ever asks what botanical has the most herb-medication interactions, it is St. John’s wort.  It alters the cytochrome P-450 3A4 detoxification pathway.  Caution should be used with taking SJW with antiretrovirals, warfarin, cyclosporine, or oral contraceptives, and several other medications.  Because it is known to be a mild MAO-I, similar dietary and medication interaction precautions should be taken as with an MAO-I drug.  While it is less likely to cause side effects than pharmacological antidepressants, SJW can cause GI symptoms, allergic reactions, constipation, dry mouth, fatigue, and sexual side effects.[386]

SJW typically dosed at 300 mg three times a day (sometimes 450mg twice daily) standardized to a minimum of 2-5% hyperforin and not less than 6% flavonoids for depression.[386]  SJW may take 2 months to reach full effects.  Some integrative clinicians will use SAMe for more immediate improvements while waking for SJW to be effective.

Roseroot (Rhodiola rosea)

Rhodiola, also called roseroot or stonecrop, grows at high-altitude in colder regions.  It has adaptogenic properties and effects on MAOs A and B.  It also enhances blood-brain barrier permeability and affects neuroplasticity.[394]  Roseroot significantly improved HAMD scores as well as insomnia, somatization, and emotional instability subscale outcome measures at doses of 340 mg daily of standardized extracts.[157]  A review of two RCTs and multiple open-label studies found a possible antidepressant effect.[158]  More research is needed, but it seems to have minimal adverse effects.[395]

Saffron (Crocus sativus)

Saffron is a spice that comes from the flower Crocus sativus; it is made from the long crimson styles that protrude from the center of the blossoms.  It has many active constituents that are antioxidant, mitochondrial function-improving, anti-inflammatory, and antidepressant in nature.[396]  A 2024 systematic review and meta-analysis found that saffron had an effect size of -4.26 relative to placebo in improving depression; it was non-inferior to antidepressants and was effective for multiple other psychological disorders as well.[397]  A 2019 meta-analysis concluded that saffron is superior to placebo and comparable with antidepressant medications, in treating mild to moderate depression.[398]  A 2018 review concluded that saffron has similar anti-depressant effects to SSRIs but with fewer side effects.[159]  Saffron demonstrated significant improvement for depression over placebo on Hamilton Depression Rating (HAMD)scores.[160]  Equivalent therapeutic response was demonstrated for saffron, imipramine 100 mg daily, and fluoxetine at 20 mg bid on the HAMD.  

Saffron, like many foodstuffs, has “Generally Recognized as Safe” status.  Petals and stamens are used in doses of 30 mg daily.

eamples of other herbals with potential benefits

• Bupleurum, used widely in Eastern Asia for centuries, has a number of antidepressant compounds which act through multiple neurotransmitter mechanisms and signaling pathways.[399]  More clinic research is needed.
• Bacopa monnieri is often used for overall brain health.  It shows some promise for depression.  Trial numbers are limited but effects on mood, anhedonia, memory, sleep and other mental functions have been noted.[400,401]
• Ginkgo biloba is useful in treating older patients (ages 51-78) with depression related to organic brain dysfunction, especially when they have proved unresponsive to standard drug treatment.[156]  Dosing used in depression studies was 40 mg to 80 mg three times daily of a 50:1 extract standardized to contain 24% ginkgo-flavone glycosides.  Due to potential anticoagulation effects, ginkgo should not be used by anyone during the periods before or after surgery or labor and delivery, and it should be used with caution in people with bleeding problems.  It may interact with blood thinners, calcium channel blockers, aminoglycoside antibiotics, anticonvulsants, and neuroleptics.
• Curcuma longa, or turmeric, is bright orange spice used in many Asian foods, contains curcumin and other anti-inflammatories that seem to have multiple benefits for inflammation.  A 2017 meta-analysis conclude that “Curcumin appears to be safe, well-tolerated, and efficacious among depressed patients.”  More robust randomized controlled trials with larger sample sizes and follow-up studies carried out over a longer duration should be planned to ascertain its benefits.”[163]

Other Biomolecular Therapies

Chinese Herbal Medicine (CHM)

A systematic review looking at studies that used a variety of different Chinese formulations for depression concluded that CHM was superior to placebo and as effective as antidepressants in terms of effects on HAMD scores; there were fewer adverse events as well.[164]

Psychedelics 

The potential of psychedelics to treat depression and other mental health disorders is the subject of a great deal of current research.  Psychedelics seem to affect inflammation, and it is theorized they may also reset brain networks by destabilizing and “resetting” them.[165] 

A 2024 systematic review and meta-analysis including 436 people found that psilocybin has significant favorable effects on depression scores.[401]  A 2023 systematic review and meta-analysis found that psilocybin, when given to people with life-threatening illness or major depressive disorder, found that “risk ratios for response and remission were large and significant in favor of psilocybin...” for bringing about response and remission.[402]  Ketamine, a dissociative anesthetic that induces intense psychedelic experiences, has also shown promise in early research for its ability to quickly alleviate symptoms of depression.[403]  Ayahuasca, evaluated in 2024 in a systematic literature review, also shows promise, but better-quality studies are needed.[404]

Low-Dose Naltrexone

There is a link between inflammation, oxidative stress, and mitochondrial dysfunction to depression, and working to reduce inflammation in the nervous system (mediated in part by microglia cells) may be beneficial.[405]  Low-dose naltrexone, which is typically administered at doses of 1.5-6 mg daily, is quite safe, and while it shows promise for treating depression, more research is needed.[406]

Chinese Herbal Medicine (CHM)

A systematic review looking at studies that used a variety of different Chinese formulations for depression concluded that CHM was superior to placebo and as effective as antidepressants in terms of effects on HAMD scores; there were fewer adverse events as well.[186]

Psychedelics

The potential of psychedelics to treat depression and other mental health disorders is the subject of a great deal of current research. They seem to affect inflammation, and it is theorized they may also reset a number of brain networks by destabilizing and “resetting” them.[187]

Aromatherapy

Aromatherapy effected mood in several small studies. A small nonrandomized pilot trial found that adjunctive aromatherapy allowed for reductions in dose of antidepres­sants compared with usual therapy. [189] Short-term, but not persistent, mood bene­fits were found for aromatherapy with citrus oil combined with massage in patients with cancer who were suffering from depression.[190] It was not clear in the latter study how much each element, that is massage or oils, contributed to the positive effect.

Aromatherapy

Aromatherapy, the use of aromatic compounds to bring about a particular healing response, has been used for millennia.  A 2017 systematic review concluded that aromatherapy has potential to be used effectively to treat depressive symptoms.  Aromatherapy massage seems to have even stronger effects that inhalation aromatherapy.[407] A 2022 meta-analysis focused on 1,039 patients with cancer found benefit as well, as did a large 2019 review conducted in the VA.[408,409]  In contrast, a 2022 review did not find a beneficial effect for depression.[410]

Essential oils tend to be quite safe to use; some people report allergic symptoms or irritation of the airways, and some people have difficulty tolerating strong odors; essential oils should not be used on mucus membranes, the eyes, damaged skin, or other tender areas.  Examples of oils commonly used for depression lavender and chamomile essential oils, as well as bergamot, sweet orange, sage, and ylang ylang.[411,412] 

BODY-BASED THERAPIES: Massage

Massage therapy, defined as intentional and systematic hand motion practiced on soft tissues of the body, has been found to decrease stress and muscle tension, increase pain threshold, and stimulate positive emotions.[168]  Classical European “Swedish” massage has been the most researched for depression.  The rationale for investigating the role of massage in depression stems from findings that massage leads to changes in electroencephalogram (EEG) patterns.  A symmetrical or left frontal pattern is found, which is associated with positive affect.  Massage also stimulates facial expressions and increases vagal activity, which has been shown to reduce depressed affect.[169]  A multicenter RCT found aromatherapy massage to be associated with clinically important benefit for depression symptoms for up to two weeks in patients with cancer.[167] 

A 2010 meta-analysis including 17 studies containing 786 persons concluded that massage therapy is significantly associated with alleviation of depressive symptoms.[170]  Given this information, massage should be seen as an effective ancillary treatment that likely promotes remission maintenance.  There is no evidence to support its being used alone as a first-line therapy. 

For more general information, refer to the Massage Therapy Whole Health Tool featured in the Passport to Whole Health, Chapter 16.”

Chinese Medicine and Acupuncture

In Chinese medicine (CM), one of the proposed etiologies of mental disorders is internal damage caused by the deregulation of the seven emotions: anger, worry, contemplation (thinking), sorrow (grief), fear, and shock.[171]  A systematic review and meta-analysis of 18 trials with 1,448 total participants found that applying  traditional CM to depression was beneficial; reviewers noted, however, that study quality was low overall.[413]

In acupuncture, points are stimulated by needles, electricity-augmented needles, and lasers.  There are also needleless approaches, including acupressure, where points are massaged but no needles are used.  Many mechanisms of action have been proposed for acupuncture.  It is thought to influence mood through the modulation of the neuroendocrine and immune systems, regulating levels of 5-HT, norepinephrine, dopamine, endorphins, and/or glucocorticoids and stimulating responses in the hypothalamus and hippocampus.[172]  Animal studies indicate that it may affect neuroplasticity in the hippocampus and other areas and decrease brain inflammation.[414]  Functional MRI studies demonstrate that acupuncture affects many parts of the brain, including the frontal and temporal lobes, the cingulate gyrus, the amygdala, and the hippocampus.[415] 

A 2018 Cochrane review concluded that acupuncture “...may result in a moderate reduction in the severity of depression when compared with treatment as usual or no treatment.  Use of acupuncture may lead to a small reduction in the severity of depression when compared with control acupuncture.  Effects of acupuncture versus medication and psychological therapy are uncertain, owing to the very low quality of evidence.”[173] 

Some additional findings related to acupuncture and depression include the following:

• A 2023 systematic review and meta-analysis, based on 19 trials involving 1,686 people concluded that moderate level evidence suggest that acupressure exhibits “...a significant beneficial effect on reducing the severity of depression compared with sham acupressure...”[416]
• A 2019 systematic review and meta-analysis concluded, based on 29 studies of 2,268 people, that acupuncture showed clinically significant reductions depression severity when compared with usual care and as an adjunct to medications, noting that trials were at a high risk of bias.
• A 2013 trial found that acupuncture in combination with the drug paroxetine led to a higher treatment response rate but no changes in remission rate.[174]
• A 2023 meta-analysis found that acupuncture is effective for post-stroke depression.[417]
• A 2021 meta-analysis found favorable results for the treatment of depression related to chronic pain.[418]
• A 2011 “systematic review of systematic reviews” looked at eight reviews that included 71 primary studies. Five of the reviews arrived at positive conclusions and three did not.[177]  The positive studies were all done in China.  The reviewers concluded that the effectiveness of acupuncture as a treatment for depression remains unproven.  
• A meta-analysis of eight RCTs by Wang and colleagues done in 2008 concluded that acupuncture can significantly reduce the severity of depression.[175]
• One study found that a combination of acupuncture plus low-dose fluoxetine was as effective for depression as the recommended dose of fluoxetine, with the lower dose being beneficial for people with intolerable side effects.[176]

In summary, acupuncture seems to have a favorable overall body of evidence of supporting clinical use as monotherapy, as augmentation for treatment of symptoms of depression, and for treatment of side effects of medication.  Not having a well-trained acupuncturist available might perhaps be the main obstacle to recommending this intervention.  Most acupuncturists will note that multiple sessions are needed to treat chronic conditions.  For example, a patient may be seen for 30-60 minutes a week for 8 weeks or more.  Adverse events of acupuncture are rare and include soreness, pain, bruising, and mild bleeding at the needle site.[171]  

Homeopathy

Evidence for the effectiveness of homeopathy in depression is limited, due to a lack of clinical trials of high quality or insufficient numbers of participants.[178]  Over 50 single case reports/studies mostly serve to indicate the range of remedies employed in patients whose symptoms include depression.  Homeopathic medicines rarely provoke adverse effects and when this occurs, they are relatively rare, mild, and transient.  More research is needed.

Based on the research summarized above, a Personalized Health Plan (PHP) was created for Frank.  The plan provided below is somewhat detailed, but of course the length of a PHP will vary for each individual, according to what is practical for them and for their care team.  Even once small change can constitute a PHP.  A more detailed plan could look like the one outlined in this section. 

Frank has seen his Integrative Health coach four times now and is feeling much happier. He learned the skill of paying attention and noticing the early signs and signals of feeling down.  That give him an opportunity to take action before he becomes sad and depressed. His family loved the idea of helping him connect more to the grandchildren.  They set up a Zoom account for him and scheduled a time every day (alternating between the families) for him to Zoom or talk on the phone with his grandkids.  He also learned how to get on the older kids’ Facebook pages.  He loves this.

Keeping a food diary helped him see that he often used food to feel better, particularly sweets.  If it was after 5 pm he might have an alcoholic beverage or two.  He noticed that eating sweets or drinking alcohol made him feel better at first and then worse.  And feeling worse would then result in him eating or drinking even more.  He decided that when he found himself having those cravings, he would get up and walk around the block.  When he returned, if he still wanted the food or drink, he could have it, but more than half of the time he found he no longer wanted it.  This fit nicely with the MOVE program, and he found the support through that program very helpful.  He was surprised to find that his sleep had improved as well and found even more benefit with the relaxation techniques he learned to use prior to sleep and any time he awakes.  Frank decided to become a VA volunteer and will start in two months when he feels more comfortable with his new routines.  He is also connecting with people from his local VFW.  Frank’s most recent PHQ-9 score was a “5,” which is on the borderline between minimal and mild depression and an improvement since the last score.

Patient Education Programs

Behavioral Health Lab
Translating Initiatives for Depression into Effective Solutions (TIDES)
VISN 2 Center for Integrated Healthcare
University of Massachusetts Center for Integrated Primary Care
VA-DoD Guidelines for the Management of Major Depressive Disorder (2016)
VA Primary Care-Mental Health Integration Initiative

Also, refer to VA national rollouts for Interpersonal Psychotherapy (IPT), CBT for Depression, and Problem Solving Therapy (PST).

“Depression” was written by Mario Salguero, MD, PhD and updated by J. Adam Rindfleisch, MPhil, MD (2014, updated 2024).

This Whole Health overview was made possible through a collaborative effort between the University of Wisconsin Integrative Health Program, VA Office of Patient Centered Care and Cultural Transformation, and Pacific Institute for Research and Evaluation.