INTRODUCTION — Unipolar depression is highly prevalent, disabling, and recurrent. Community surveys in 14 countries have estimated that the lifetime prevalence of unipolar depressive disorders is 12 percent [1], and the World Health Organization ranks unipolar major depression as the 11th greatest cause of disability and mortality in the world, among 291 diseases and causes of injury [2]. Following recovery from one major depressive episode, the estimated rate of recurrence over two years is greater than 40 percent; after two episodes, the risk of recurrence within five years is approximately 75 percent [3].
In addition, initial treatment of unipolar major depression is often unsuccessful. The prospective, observational Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study initially treated 2876 outpatients with full doses of citalopram for up to 14 weeks, and found that remission occurred in only 33 percent [4].
As a result, many treatments, including complementary and alternative therapies, have been investigated for the initial treatment of depression, but have not been widely adopted due to limited evidence of their efficacy, safety, and tolerability. This topic reviews the evidence for these nonstandard treatments.
The general principles and prognosis for the initial treatment of depression are discussed separately, as are the choice of therapy for the initial treatment of depression and the evidence of efficacy of standard therapies, and the evidence for standard therapies that are used for initially treating depression in primary care patients and in patients with general medical illnesses. Continuation and maintenance treatment of major depression, the treatment of resistant depression and refractory depression, and the clinical manifestations and diagnosis of depression are also discussed separately.
●(See "Unipolar depression in adults and initial treatment: General principles and prognosis".)
●(See "Unipolar major depression in adults: Choosing initial treatment".)
●(See "Unipolar depression in adults: Continuation and maintenance treatment".)
●(See "Unipolar depression in adults: Choosing treatment for resistant depression".)
●(See "Unipolar depression in adults: Management of highly resistant (refractory) depression".)
●(See "Unipolar depression in adults: Clinical features".)
●(See "Unipolar depression in adults: Assessment and diagnosis".)
INVESTIGATIONAL MEDICATIONS — The drugs in the following subsections have been studied for the initial treatment of unipolar major depression, but are typically not used due to limited evidence of their efficacy, safety, and tolerability. As an example, the benefit of some medications (eg, lamotrigine) is no better than placebo. For other drugs, the evidence of efficacy is inconsistent, such that some studies indicate the treatment is helpful and other studies do not. Several of the drugs (eg, creatine and sarcosine) have been investigated in small samples or only one trial and the results need to be replicated before we can suggest using them routinely. Some studies were problematic in that they analyzed study completers (per protocol analysis), which can potentially bias the results, rather than analyzing all patients who were randomized (intent to treat analysis). In addition, some of the drugs are used in conjunction with another drug (eg, antidepressant) to accelerate response to initial treatment, and adherence to treatment may be worse with medication combinations than monotherapy [5]. Another problem is the lack of longer (eg, ≥8 weeks) trials to evaluate the benefits and risks; continuation and maintenance treatment generally consists of the regimen used for initial treatment.
Lamotrigine — Lamotrigine is not useful for unipolar major depression. Three randomized trials (total n >900 patients) that compared lamotrigine (≤200 mg per day) with placebo for up to eight weeks found no benefit for active treatment [6].
Lithium — We do not suggest lithium monotherapy for the initial treatment of unipolar major depression because there is far less evidence than there is for antidepressants. The role of lithium in treating unipolar depression is discussed separately. (See "Unipolar depression in adults: Treatment with lithium" and "Unipolar depression in adults: Choosing treatment for resistant depression", section on 'Minimal response to initial treatment'.)
Pindolol — Although the combination of pindolol plus an antidepressant has demonstrated efficacy as initial treatment for major depression, the benefits appear to wane or disappear:
●A meta-analysis of 12 randomized trials (n = 889 patients with unipolar major depression) compared pindolol plus selective serotonin reuptake inhibitors (SSRIs) with placebo plus SSRIs and found that response (reduction of baseline symptoms ≥50 percent) was more likely with pindolol than placebo within two weeks of starting treatment (relative risk 1.7, 95% CI 1.2-2.4; heterogeneity across studies was moderate). Within six weeks of starting treatment, response was still more likely with pindolol than placebo, but the advantage seemed to diminish (relative risk 1.11, 95% CI 1.02-1.20; heterogeneity across studies was minimal) [7].
●A meta-analysis of 11 trials (largely overlapping with the other meta-analysis) compared pindolol plus SSRIs with placebo plus SSRIs in 889 patients with unipolar or bipolar depression [8]. Response occurred in more patients treated with pindolol than placebo within two weeks of starting treatment (odds ratio 2.4, 95% CI 1.7-3.3). However, within six weeks of starting treatment, the benefits for pindolol and placebo were comparable (odds ratio 1.3, 95% CI 0.9-1.8). In addition, in some studies it was not clear whether pindolol/placebo was administered for the initial treatment of depression or treatment-resistant depression.
Both meta-analyses found that time to response was faster with pindolol than placebo [7,8].
Quetiapine — Quetiapine has demonstrated efficacy both as monotherapy and as an add-on treatment for unipolar depression [9], but ongoing concerns remain about safety issues and side effects, especially with long-term treatment. (See "Unipolar depression in adults: Treatment with second-generation antipsychotics", section on 'Quetiapine'.)
Scopolamine — Studies of intravenous scopolamine monotherapy suggest that the drug has antidepressant effects, and augmentation with scopolamine may help initial treatment of depression [10,11]. A six-week randomized trial compared oral scopolamine (0.5 mg per twice per day) plus citalopram (40 mg per day) with placebo plus citalopram in 40 patients with major depression [12]. Exclusion criteria included cognitive impairment, narrow-angle glaucoma, and prostatic hypertrophy; all patients received an eye examination and all males age >40 years underwent a digital rectal examination prior to enrollment. Remission occurred in more patients treated with scopolamine than placebo (65 versus 20 percent). However, scopolamine caused higher rates of blurred vision, dizziness, and dry mouth.
Statins — Combining statins with antidepressants can be efficacious for initial treatment of unipolar major depression [13]. A meta-analysis of three randomized trials (n = 165 patients) lasting 6 to 12 weeks compared statins plus antidepressants with placebo plus antidepressants; the statins were atorvastatin, lovastatin, or simvastatin, and the antidepressants were citalopram or fluoxetine [14]. Improvement was significantly greater with statins than placebo, and the clinical effect was moderate to large. In addition, the safety profile of statins and placebo was comparable. In a subsequent meta-analysis of the same three trials, the clinical benefit of antidepressants plus statins was large, compared with antidepressants plus placebo [15].
The efficacy of statins for treatment-refractory depression is discussed separately. (See "Unipolar depression in adults: Management of highly resistant (refractory) depression", section on 'Treatments with potential benefit'.)
Information about the administration and potential adverse effects of statins is discussed separately. (See "Statins: Actions, side effects, and administration".)
Stimulants — Central nervous system stimulants (eg, dextroamphetamine, methylamphetamine, methylphenidate, and pemoline) are rarely if ever used for the initial treatment of depression. Evidence that these drugs are beneficial is insufficient (eg, studies were characterized by small numbers of patients and short duration of treatment) and concerns exist about the potential for abuse and dependence with these medications.
Although a systematic review concluded that there was some evidence of efficacy for initially treating depressed patients with stimulants, we consider the data inadequate. The review included a meta-analysis of three randomized trials that compared monotherapy with either a stimulant (dextroamphetamine, methylphenidate, or pemoline) or placebo in 62 depressed patients, and found a significant, clinically large effect favoring stimulants for symptom improvement [16]. However, the small number of patients undermines our confidence in the results, and the duration of the trials was short (two to four weeks). Generalizability was also limited; in one trial, all patients were infected with human immunodeficiency virus (HIV) and in a second trial, all patients had suffered a traumatic brain injury. In addition, the systematic review included a second meta-analysis of a different set of three randomized trials (130 patients), and found that response (eg, reduction of baseline symptoms ≥50 percent) was comparable for stimulants and placebo (odds ratio 1.0, 95% CI 0.5-2.1). Subsequent to the systematic review, a 16-week randomized trial in 143 patients with geriatric depression demonstrated that citalopram (20 to 60 mg/day) plus methylphenidate (5 to 40 mg/day) was superior to monotherapy with either citalopram or methylphenidate [17]. (See "Diagnosis and management of late-life unipolar depression", section on 'Methylphenidate'.)
The efficacy of stimulants for treatment-resistant depression is discussed elsewhere, and the side effects and abuse potential of stimulants are discussed separately in the context of adult attention deficit hyperactivity disorder. (See "Unipolar major depression in adults: Augmentation of antidepressants with stimulants and stimulant-like drugs", section on 'Stimulants'.)
Testosterone for males — For depressed men who do not have hypogonadism, it appears that exogenous testosterone is not beneficial [18]. A meta-analysis of two randomized trials (n = 103 depressed, eugonadal men) compared intramuscular testosterone with placebo and found that active treatment was not beneficial [19].
In a subsequent meta-analysis of 27 randomized trials that compared testosterone with placebo in 1890 males with depression, improvement was greater with testosterone [20]. Nevertheless, some experts concluded that the results did not support using testosterone to treat unipolar depression, based upon the following issues [18]:
●The clinical benefit of testosterone in the meta-analysis was small and may not have been clinically meaningful.
●Risk of bias in the underlying trials was high or not clear.
●The heterogenous patient population included men with a variety of general medical conditions, and some of the men were hypogonadal.
●Many of the patients entered the trials without depressive disorders such as unipolar major depression or persistent depressive disorder (dysthymia).
●The long-term safety of testosterone is unknown.
In males with hypogonadism, it is not known whether testosterone improves unipolar major depression [18]. (See "Testosterone treatment of male hypogonadism", section on 'Other possible effects'.)
The efficacy of add-on testosterone for females with treatment-resistant depression is discussed separately. (See "Unipolar depression in adults: Management of highly resistant (refractory) depression", section on 'Treatments with little to no benefit'.)
Triiodothyronine — Adding triiodothyronine (T3) to antidepressants for the initial treatment of unipolar major depression may accelerate response, but it is not clear that doing so increases the probability of response, due to mixed results across studies. The efficacy and administration of T3 for the initial treatment of depression (as well as for treatment-resistant depression) is discussed separately. (See "Unipolar depression in adults: Augmentation of antidepressants with thyroid hormone".)
Zuranolone — Zuranolone (formerly called Sage-217) may be efficacious for depression and appears to have a relatively rapid onset of action. As an example, a two-week randomized trial compared zuranolone (30 mg/day) with placebo in patients with unipolar major depression (n = 89); 25 percent of the patients were using an antidepressant at baseline [21]. Remission occurred in more patients who received active drug than placebo (64 versus 26 percent). During posttreatment follow-up lasting for four weeks, the benefit of zuranolone persisted for another two weeks. There were no serious adverse effects. Adverse effects that occurred in at least 5 percent of the patients treated with zuranolone and twice as often with zuranolone than placebo included dizziness, nausea, and somnolence. In the United States, zuranolone is available to patients with depression only through a research protocol.
COMPLEMENTARY AND ALTERNATIVE THERAPIES — Complementary and alternative therapies include “natural treatments” and practices such as acupuncture, dietary supplements, herbal medicines, massage, meditation, and yoga, which serve as adjuncts or alternatives to standard (conventional) interventions [22]. The term integrative medicine refers to health care that utilizes both standard as well as complementary therapies [23]. Additional information about complementary and alternative medicine is available through the United States National Center for Complementary and Integrative Health, which is part of the National Institutes of Health.
The use of complementary and alternative medicine to treat depression is common [24]. A nationally representative survey in the United States found that among individuals with self-reported depression, approximately 50 percent used a complementary and alternative therapy in the past year [25]. Among individuals treated by a conventional clinician, two-thirds also used a complementary and alternative therapy.
Bright light therapy — Bright light therapy, also called phototherapy, is a standard initial treatment for mild to moderate unipolar major depression with a seasonal pattern. (See "Seasonal affective disorder: Treatment", section on 'Bright light therapy'.)
However, bright light therapy is generally not used as initial treatment of nonseasonal unipolar major depression, despite inclusion in some practice guidelines based upon positive results from randomized trials [26,27]. Results from some of the trials are difficult to interpret due to methodologic problems, such as small sample sizes, inclusion of patients with bipolar disorder, inadequate blinding and control conditions, inconsistencies in the timing and dose of therapy, and analyzing completers rather than by intent to treat.
In several randomized trials, bright light therapy was administered at a dose of 5000 to 10,000 lux for 30 to 60 minutes/day in the morning, for five or eight weeks [28-31]. One meta-analysis suggested that bright light therapy may be more likely to be efficacious if it is given for at least two weeks [29].
Evidence supporting the use of bright light therapy for nonseasonal depression includes a systematic review that performed a pooled analysis of 13 randomized trials, comparing the intervention with control conditions (eg, red or dim light) in 565 patients [31]. Response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received bright light therapy than controls (59 versus 38 percent). Other meta-analyses from the same review suggested that bright light therapy was efficacious for mild to moderate depression (eg, no suicidal behavior), but not severe depression, and that bright light therapy was efficacious when it was administered in the morning rather than other times of day.
Randomized trials also indicate that for patients with nonseasonal depression, bright light therapy may be efficacious either as monotherapy or in conjunction with antidepressant medication:
●Monotherapy – Randomized trials have found that the clinical benefit of bright light monotherapy is moderate to large:
•A meta-analysis of three trials, each lasting seven days, compared bright light therapy with a red light placebo control in 127 patients [32]. Improvement was greater with bright light therapy, and the clinical benefit was moderate.
•A meta-analysis of seven trials, lasting one to eight weeks, compared bright light therapy with a control condition (eg, dim light) in 296 patients [29]. Improvement was greater with bright light therapy, and the clinical benefit was moderate to large.
•A meta-analysis of 10 trials compared bright light therapy with a control condition (eg, red or dim light) in 341 patients [31]. Improvement was greater with bright light therapy, and the clinical benefit was moderate to large. However, heterogeneity across studies was also moderate to large.
●Bright light therapy plus antidepressant medication (eg, a selective serotonin reuptake inhibitor [SSRI]) – Randomized trials suggest that bright light therapy plus an antidepressant is more efficacious than antidepressant monotherapy, and that the clinical effect that is moderate [33]:
•A meta-analysis of four randomized trials compared bright light therapy plus an antidepressant with placebo light therapy plus an antidepressant in 212 patients with nonseasonal depression [28]. Most patients treated with bright light therapy received 10,000 lux for 30 or 60 minutes/day for five or eight weeks; the antidepressant was typically an SSRI. Improvement was superior in patients treated with bright light therapy, and the clinical benefit was moderate. Heterogeneity across studies was small to moderate.
•A meta-analysis of 10 randomized trials compared bright light therapy plus an antidepressant with a control condition plus an antidepressant in 458 patients with nonseasonal depression [30]. Patients were treated with bright light therapy at a dose 5000 to 10,000 lux for 30 to 120 minutes/day, and most patients were treated for five or eight weeks. The control condition typically included dim red light or an ion generator. Improvement was superior in patients treated with bright light therapy, and the clinical benefit was moderate.
In addition, adding an antidepressant to bright light therapy may be no better than bright light monotherapy. A meta-analysis of two randomized trials in 81 patients with nonseasonal depression compared bright light therapy plus an antidepressant with bright light therapy plus pill placebo and found that the benefit was comparable [28]. However, heterogeneity across studies was large.
Additional information about bright light therapy, including administration, safety, and side effects, is discussed separately in the context of seasonal affective disorder. (See "Seasonal affective disorder: Treatment", section on 'Bright light therapy'.)
Carnitine — Carnitine is a dietary supplement that is derived from amino acids and may be useful for initial treatment of unipolar depression:
●A meta-analysis of nine randomized trials compared carnitine with placebo in 467 patients with depressive syndromes that were the primary indication or a secondary indication in patients with fibromyalgia, migraine, or minimal hepatic encephalopathy [34]. Carnitine (most often 3 g/day) and placebo were prescribed as monotherapy in all patients, except for 40 who received the study drugs as add-on treatment with an antidepressant; the median length of follow-up across the nine trials was eight weeks. Improvement of depression was greater with carnitine than placebo and the clinical effect was large. In addition, the risk of adverse effects in the two groups was comparable. However, inconsistency across studies was large and there was evidence of publication bias.
●A second meta-analysis from the same systematic review included three trials lasting 7 or 12 weeks that compared carnitine (1 to 2 g/day) with an antidepressant in 324 patients with persistent depressive disorder (dysthymia) or depression secondary to fibromyalgia [34]. Improvement in the two groups was comparable, and adverse effects were less likely to occur with carnitine than an antidepressant (odds ratio 0.2, 95% CI 0.1-0.4).
The largest trial compared carnitine (1 g/day) with amisulpride (50 mg/day) in 193 patients with dysthymia for 12 weeks; the number of patients who were much or very much improved with carnitine and amisulpride was similar (65 and 64 percent) [35]. In addition, withdrawal due to adverse events occurred in fewer patients who received carnitine (3 versus 21 percent).
Additional information about carnitine is available from the United States National Institutes of Health: Office of Dietary Supplements.
Chronotherapy — Chronotherapy combines at least two of the following: sleep deprivation, bright light therapy, and sleep phase advance (going to bed and waking up earlier than usual). Each component is administered for different lengths of time. In one randomized trial, sleep phase advance was replaced with stabilizing sleep time by educating patients about sleep hygiene and encouraging a stable diurnal rhythm [36]. In addition, bright light therapy itself may induce sleep phase advance [33]. It is hypothesized that chronotherapy resets and stabilizes circadian rhythms by synchronizing internal circadian rhythms to the environmental light/dark cycle [37].
Based upon randomized trials, chronotherapy may perhaps be useful for short-term treatment of depression. A meta-analysis of four trials compared chronotherapy with control conditions in 202 patients with depressive syndromes (approximately 25 percent had bipolar disorder); all patients received pharmacotherapy [37]. Chronotherapy included sleep deprivation plus bright light therapy, and one trial also included sleep phase advance. Control conditions included exercise, dim light, or usual care. Improvement of depressive symptoms on day 5 to 7 was greater with chronotherapy than control conditions, and the clinical effect was moderate to large.
Additional information about bright light therapy and sleep deprivation is discussed elsewhere in this topic. (See 'Bright light therapy' above and 'Sleep deprivation' below.)
Creatine — Combining creatine with an antidepressant may be useful in the short-term treatment of unipolar major depression. An eight-week randomized trial compared creatine monohydrate (5 g per day) plus escitalopram (10 to 20 mg per day) with placebo plus escitalopram in 52 women with unipolar major depression (mostly first episode) [38]. Exclusion criteria included comorbid renal disease and serum creatinine levels that exceeded the normal range (>1.1 mg/dL). Remission occurred in more patients who received creatine than placebo (52 versus 26 percent). Adverse events were comparable for the two groups, and serum creatinine and blood urea nitrogen levels were within normal limits during the trial.
Glycyrrhizic acid — Glycyrrhizic acid is an herbal extract that may accelerate response to initial treatment of depression. A four-week randomized trial compared glycyrrhizic acid (150 mg three times daily) plus escitalopram (5 to 20 mg/day) with placebo plus escitalopram in patients with unipolar major depression (n = 56) [39]. Response, defined as reduction of baseline symptoms ≥50 percent, occurred in more patients who received adjunctive glycyrrhizic acid than placebo (67 versus 38 percent). In addition, the rate of adverse events in the two groups was comparable.
Music therapy — Music therapy includes regular meetings with a therapist who uses music to help patients process and express their experiences and feelings [40]. The intervention can be administered in an individual or group format, and consists of active methods (compositional, improvisational, or recreative) in which patients make music, and receptive methods in which patients listen to music.
The evidence suggests that music therapy may benefit patients with unipolar depression. A meta-analysis of three open-label randomized trials and one prospective controlled observational study compared music therapy plus usual care (eg, antidepressants and psychotherapy) with usual care alone in a total of 219 patients with unipolar depression [40]. Active treatment included 12 to 48 sessions administered over six weeks to three months. Improvement was greater in patients who received music therapy, and the clinical benefit was large.
Omega-3 fatty acids — Among patients who present for initial treatment of unipolar major depression, omega-3 fatty acids (n-3 polyunsaturated fatty acids) are generally not suitable as monotherapy [41]. Rather, they can be used to accelerate response to antidepressants; this approach is consistent with one treatment guideline that suggests prescribing omega-3 fatty acids at the beginning of treatment with antidepressants [42]. However, the benefit of omega-3 fatty acids for acceleration is not clear, due to conflicting results from different meta-analyses of randomized trials [43-51]. Heterogeneity across studies is typically substantial and publication bias may account for the benefits observed in some meta-analyses.
As an example, a meta-analysis of 25 randomized trials (n = 1373 patients with unipolar major depression) compared omega-3 fatty acids with placebo, either as monotherapy or combined with an antidepressant, and found a small but statistically significant advantage for active drug [52]. However, the investigators concluded that the effect was probably not clinically meaningful and represented a difference of only approximately two points on the 17-item Hamilton Rating Scale for Depression, which ranges from 0 to 52 (table 1). In addition, heterogeneity across studies was substantial, and publication bias probably skewed the analysis towards finding a beneficial effect for omega-3 fatty acids.
Four possible sources of variability in study outcomes are:
●Severity of illness – Benefits of omega-3 fatty acids seem to occur in patients with moderate major depression rather than milder illness. Omega-3 fatty acids have not been systematically studied in severe depression (eg, psychotic, suicidal, or hospitalized patients).
●Comorbidity – In addition, the benefit of omega-3 fatty acids may be limited to patients without general medical comorbidity. As an example, a meta-analysis of 10 randomized trials compared an antidepressant plus omega-3 fatty acids with an antidepressant plus placebo in 402 patients with unipolar major depression; improvement was greater with omega-3 fatty acids and the clinical benefit was moderate [50]. However, in the subgroup with comorbid coronary heart disease, diabetes, or neurologic disease, improvement of depression was comparable with omega-3 fatty acids and placebo. By contrast, improvement in patients without comorbidities was greater with omega-3 fatty acids than placebo, and the benefit was moderate to large.
●Eicosapentaenoic acid – It has been hypothesized that eicosapentaenoic acid is the key component in omega-3 fatty acid preparations, such that better outcomes for depression accrue to patients who are treated with larger amounts (eg, 1 to 2 grams per day) and proportions of eicosapentaenoic acid than docosahexaenoic acid (eg, >2:1) [42]. Evidence supporting this hypothesis includes the following:
•A meta-analysis of 16 randomized trials (n >6000 depressed patients) that found a significant, clinically small to moderate effect favoring eicosapentaenoic acid-predominant formulations of omega-3 fatty acids over placebo (heterogeneity across studies was moderate to large) [53]. By contrast, a meta-analysis of 12 randomized trials (n >3000) compared docosahexaenoic acid-predominant formulations with placebo and found that the benefits were comparable.
•In addition, a meta-analysis of 18 randomized trials compared eicosapentaenoic acid-predominant formulations of omega-3 fatty acids with placebo in 969 patients who were diagnosed with depressive syndromes, and found a significant, clinically moderate to large effect favoring active treatment over placebo (heterogeneity across studies was moderate to large) [53]. By contrast, no benefit was seen in meta-analyses of six trials that compared docosahexaenoic acid-predominant formulations with placebo in 501 patients.
●Inflammation – Response to eicosapentaenoic acid for depression may be greater in patients with high levels of inflammatory biomarkers (eg, interleukin-6 or C-reactive protein) than patients with low levels [42]. An eight-week trial randomly assigned patients with unipolar major depression (n = 155) to eicosapentaenoic acid, docosahexaenoic acid, or placebo, and found that improvement for the three groups was comparable [54]. However, in the subgroup of patients with high levels of inflammatory markers, improvement was greater with eicosapentaenoic acid than either docosahexaenoic acid or placebo. Additional information about inflammation and depression is discussed separately. (See "Unipolar depression in adults: Epidemiology".)
Use of omega-3 fatty acids as add-on therapy for treatment-resistant depression is discussed separately. (See "Unipolar depression in adults: Management of highly resistant (refractory) depression", section on 'Treatments with potential benefit'.)
Additional information about omega-3 fatty acids is discussed separately. (See "Fish oil: Physiologic effects and administration".)
The United States National Center for Complementary and Integrative Health and the National Library of Medicine also discuss the use of omega-fatty acids, including its use for depression.
Rhodiola — The herb Rhodiola rosea may perhaps help accelerate response to initial treatment of relatively mild depressive syndromes. In a 12-week trial, 98 patients with mild to moderate unipolar major depression were each treated with sertraline (dose not specified) and randomly assigned to adjunctive Rhodiola 0.3 g/day, Rhodiola 0.6 g/day, or placebo [55]. Improvement of depression was greater with each dose of adjunctive Rhodiola than placebo, and each dose of Rhodiola was well tolerated.
General information about Rhodiola is available from the United States National Center for Complementary and Integrative Health.
St. John’s wort — For patients who present with unipolar major depression, we suggest that clinicians not prescribe St. John’s wort (extracts of the plant Hypericum perforatum). Preparations of the drug vary in potency and are not standardized, the proper dose of St. John’s wort is not clear, and it is not clear if the drug is appropriate for patients with severe depression [56-58]. In addition, the maximum duration of treatment in randomized trials is 12 weeks and the persistence of the drug’s effects are thus not known. Avoiding St. John’s wort for the initial treatment of major depression is consistent with practice guidelines from the American Psychiatric Association, Royal Australian and New Zealand College of Psychiatrists, and the United Kingdom National Institute of Health and Clinical Excellence [26,56-58]. However, other treatment guidelines endorse St. John’s wort [27,59].
Randomized trials indicate that St. John’s wort can be efficacious and is relatively well tolerated:
●A systematic review of randomized trials concluded that the efficacy of St. John’s wort was superior to placebo and comparable to standard antidepressants, and that tolerability was superior with St. John’s wort compared with standard antidepressants; however, interpretation of the results is difficult because country of origin was associated with the benefits of St. John’s wort [60].
●A meta-analysis of 27 randomized trials compared St. John’s wort with SSRIs in patients diagnosed with depressive syndromes (n = 3126), and found that improvement, response, and remission were each comparable for the two groups, whereas adverse effects were less likely to occur with St. John’s wort (relative risk 0.77, 95% CI 0.70-0.84) [61]. A subsequent meta-analysis (27 trials, 3808 patients) found similar results [62].
St. John’s wort can interact with other medications; as an example, St. John’s wort appears to induce metabolism of other drugs (eg, anticoagulants, anticonvulsants, antiretrovirals, immunosuppressants, and oral contraceptives) via CYP3A4 hepatic enzymes. Also, concurrent use of St. John’s wort with SSRIs can cause the serotonin syndrome [26]. Specific interactions of St. John’s wort with other medications may be determined using the Lexicomp drug interactions tool (Lexi-Interact Online) included in UpToDate. Additional information about St. John’s Wort is discussed separately. (See "Clinical use of St. John's wort".)
The National Center for Complementary and Integrative Health website also discusses St. John’s Wort, including its use for depression.
S-adenosyl methionine — S-adenosyl methionine (SAMe) is a metabolite of folate that facilitates the synthesis of neurotransmitters (including dopamine, norepinephrine, and serotonin) and is available in the United States over-the-counter as a dietary supplement [63]. It is not clear whether SAMe is beneficial for initial treatment of unipolar major depression as monotherapy because of methodologic problems in studies that have evaluated the drug. As an example, a 12-week trial in 2014 randomly assigned 189 patients with unipolar major depression to SAMe (1600 to 3200 mg/day), escitalopram (10 to 20 mg/day), or placebo [64]. Response (reduction of baseline symptoms ≥50 percent) to SAMe, escitalopram, and placebo was comparable (36, 34, and 30 percent of patients). These results are difficulty to interpret because they rendered the study a failed trial, given that escitalopram is a well-established antidepressant based its efficacy in multiple trials. One possible explanation for the results may be that the placebo response rate was abnormally high [65].
Other evidence that suggests that SAMe is efficacious for depression is also questionable due to methodologic problems, including a 2003 meta-analysis of 12 randomized, placebo controlled trials in 434 patients with depressive syndromes [66]. Although the results suggested that improvement was superior with SAMe, 11 of these relatively old studies, dating back to 1982, had methodologic problems such that they were not included in a 2016 systematic review of SAMe for depression [63]. In another meta-analysis, which compared SAMe with imipramine (four trials, n = 619 patients) and found that the benefit was comparable, the trials lacked a placebo arm, making it difficult to interpret the results [63].
In yet other trials, promising results were not statistically significant. As an example, an eight-week randomized trial compared SAMe (800 mg/day) with placebo as monotherapy in 49 patients with unipolar major depression [67]. Improvement was numerically greater with SAMe and the clinical effect was moderate to large; nevertheless, the two groups did not differ statistically, perhaps due to the relatively small sample size.
Information about the use of SAMe as add-on therapy for treatment-resistant depression is discussed elsewhere. (See "Unipolar depression in adults: Management of highly resistant (refractory) depression".)
General information about SAMe is available from the United States National Institutes of Health: Office of Dietary Supplements and the .
Sarcosine — Sarcosine (also known as N-methylglycine) is derived from the amino acid glycine and may possibly be useful for major depression [68]. A six-week randomized trial compared sarcosine (mean dose 900 mg per day) with citalopram (mean dose 27 mg per day) in 40 patients with unipolar major depression [69]. Remission occurred in more patients who received sarcosine than citalopram (65 versus 5 percent), and the most common side effects of sarcosine were nausea and sedation. Problems with the study include the low dose of citalopram, the high rate of attrition, and a remission rate with citalopram that was lower than is typically observed [70].
Sleep deprivation — Sleep deprivation therapy, also known as wake therapy, involves depriving patients their normal sleep, either for the entire night (called total sleep deprivation) or the second half of the night (partial sleep deprivation) [33,37,71]. With total sleep deprivation, patients remain awake for approximately 36 hours; with partial sleep deprivation, patients sleep for three to four hours and remain awake for approximately 20 to 21 hours. Another variation of sleep deprivation therapy is to administer one night of sleep deprivation, followed by a night of recovery sleep the next day, and to administer this cycle for a total of three times in one week. Studies of sleep deprivation have often occurred in inpatient settings.
Improvement of depressive syndromes with sleep deprivation may occur in as little time as 24 hours, in contrast to antidepressant medications, which may take at least four to eight weeks [37,71]. However, sleep deprivation is feasible for only a brief time and relapse typically occurs after patients resume sleeping fully at night. Thus, sleep deprivation is not sustainable as a stand-alone therapy; rather, it may be useful as part of chronotherapy or to accelerate response in patients receiving pharmacotherapy [33,59]. (See 'Chronotherapy' above.)
The evidence suggests that for patients with depression, sleep deprivation is beneficial in 40 to 50 percent. As an example, a meta-analysis included six small randomized trials in which sleep deprivation was prescribed to 141 patients with depressive syndromes [71]. Most patients received total sleep deprivation as well as pharmacotherapy, but none of the patients were treated with bright light therapy, sleep phase advancement, electroconvulsive therapy, or transcranial magnetic stimulation. Response (eg, reduction of baseline depression scores ≥50 percent) occurred in 45 percent of patients. However, heterogeneity across studies was large, and other analyses were not performed to determine whether response occurred in more patients treated with sleep deprivation than controls.
Vitamins — Multiple randomized trials indicate that vitamins do not increase the benefits of antidepressants for the initial treatment of major depression:
●A 52-week trial compared citalopram (20 to 40 mg/day) plus vitamin B12 (0.5 mg/day), folic acid (2 mg/day), and vitamin B6 (25 mg/day) with citalopram plus placebo in 146 patients with unipolar major depression [72]. The completer (per-protocol) analysis found that remission after 12 weeks was comparable for vitamins and placebo (78 and 79 percent).
●A 12-week trial compared fluoxetine (20 mg/day) plus thiamine (vitamin B1, 300 mg/day) with fluoxetine plus placebo in 51 inpatients with unipolar major depression [73]. Although improvement at week 6 was greater with thiamine than placebo, at week 12 improvement was comparable for the two groups.
Additional information about vitamins is discussed separately. (See "Overview of water-soluble vitamins".)
The National Center for Complementary and Integrative Health website also discusses the use of vitamins.
Whole body hyperthermia — Multiple randomized trials suggest that whole body heating may possibly ameliorate depression [74]:
●A randomized trial compared a single session of whole body hyperthermia with a sham condition in 29 patients with unipolar major depression who were subsequently followed for up to six weeks [75]. Neither antidepressants nor psychotherapy were allowed during the trial, and all patients were medically healthy. Whole body hyperthermia was induced with infrared lights and heating coils that raised the core body temperature to 38.5°C (101.3°F); the mean length of time required to do so was 107 minutes. Improvement was greater with whole body hyperthermia than the sham condition within one week and the benefit of active treatment persisted for six weeks. Adverse effects for the two groups were comparable. However, whole body hyperthermia is rarely available.
●In an open-label, eight-week randomized trial, 36 patients with unipolar depressive syndromes were randomly assigned to hyperthermic baths or a sham control condition two times per week for two weeks [76]. Patients receiving antidepressants at baseline continued pharmacotherapy during the trial. During treatment with hyperthermic baths, patients immersed their entire bodies, except the head, in a 40°C (104°F) pool for 20 to 30 minutes. Patients were then wrapped in warm blankets with hot water bottles filled with boiling water for at least 30 minutes. The control condition consisted of exposure to green light (<400 lux) for less than 40 minutes. At week 2, after four interventions, improvement of depression was greater with active treatment. However, at week 8, improvement was comparable in the two groups.
Zinc — The combination of an antidepressant plus the essential mineral zinc may possibly be useful for the initial treatment of unipolar depression [51]. A meta-analysis of three small randomized trials, lasting 6 to 12 weeks, compared an antidepressant plus zinc (25 mg/day) with an antidepressant plus placebo in 104 patients with unipolar major depression [50]. Among the 104 patients, 20 percent had treatment-resistant depression. Attrition was high in each study, and each trial used a completer (per protocol) analysis rather than an intent to treat analysis. Improvement was greater in patients who received zinc than placebo, and the clinical benefit was moderate to large.
Additional information about zinc is discussed separately. (See "Overview of dietary trace elements", section on 'Zinc'.)
Further information about zinc is reviewed on the United States National Institutes of Health: Office of Dietary Supplements website.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Depressive disorders".)
SUMMARY
●Many drugs that have been investigated for the initial treatment of unipolar major depression are typically not used due to limited evidence of their efficacy, safety, and tolerability. In addition, many of the drugs were used in conjunction with an antidepressant, and adherence to treatment may be worse with medication combinations than monotherapy. These nonstandard drugs include lamotrigine, lithium monotherapy, pindolol, quetiapine, scopolamine, statins, stimulants, testosterone for males, triiodothyronine, and zuranolone. (See 'Investigational medications' above.)
●Nonstandard treatments also include complementary and alternative therapies; one of the most widely studied of these is bright light therapy (for the initial treatment of nonseasonal depression). Other such therapies that have been examined in randomized trials include carnitine, chronotherapy, creatine, glycyrrhizic acid, music therapy, omega-3 fatty acids, Rhodiola, St. John’s wort, S-adenosyl methionine, sarcosine, sleep deprivation, vitamins, whole body hyperthermia, and zinc.
ACKNOWLEDGMENTS
The UpToDate editorial staff acknowledges Paul Ciechanowski, MD, who contributed to an earlier version of this topic review.
The UpToDate editorial staff also acknowledges Wayne Katon, MD (deceased), who contributed to an earlier version of this topic review.
