1. Antidepressant medications

a. Selective serotonin reuptake inhibitors

Many studies and meta-analyses have compared SSRIs among themselves as well as with other classes of antidepressants. Differences in efficacy and tolerability between SSRIs and TCAs, assessed through a meta-analysis of 102 studies (85), found no overall difference in efficacy between TCAs and SSRIs. However, TCAs appeared more efficacious in inpatients (p=0.012), and amitriptyline was more effective than SSRI comparators (p=0.012), although publication bias could not be excluded. By contrast, SSRIs as a class (p <0.01) and, more specifically, paroxetine (p=0.001), fluoxetine (p <0.01), sertraline (p <0.05), and citalopram (p <0.01) had a significantly lower rate of dropouts for side effects. Other meta-analyses have compared the SSRIs among themselves and with other newer antidepressant agents. Cipriani and colleagues (96) performed a multiple-treatments meta-analysis, which encompassed 117 randomized controlled trials and 25,928 subjects. Incorporating efficacy and treatment discontinuation, they found the greatest degree of overall acceptability with escitalopram and sertraline, with greatest efficacy for mirtazapine, escitalopram, venlafaxine, and sertraline as compared with duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine. Gartlehner and colleagues (95) also compared the benefits and side effects of second-generation antidepressants including SSRIs using 6 good- or fair-quality systematic reviews or meta-analyses and 155 good- or fair-quality double-blind, placebo-controlled, or head-to-head randomized controlled trials of at least 6 weeks' duration to assess efficacy and 35 observational studies with at least 100 participants and follow-up of at least 12 weeks to assess harms. Although the side effect profiles and onset of action differed among the antidepressants, no differences in efficacy or effectiveness were found.

A systematic review of 28 randomized studies (89) showed that, even in anxious depression, SSRIs (fluoxetine, paroxetine, citalopram, sertraline, and escitalopram) are comparable in efficacy to other antidepressant medications (bupropion, amitriptyline, mirtazapine, imipramine, nefazodone, and venlafaxine), both in depression and anxiety parameters. When compared with venlafaxine, fluoxetine was less effective both in depression and anxiety scores, while paroxetine was less effective in anxiety scores only. No differences were found between venlafaxine and the other SSRIs.

A Cochrane meta-analysis (84) that included 132 randomized studies (almost all double blind) did not find significant differences in fluoxetine efficacy versus TCAs. When fluoxetine was compared with newer antidepressants, venlafaxine was superior, and within the class of SSRIs, sertraline was significantly superior. However, fluoxetine was significantly better tolerated than TCAs as a class and, more specifically, was better tolerated than amitriptyline, clomipramine, desipramine, and imipramine; no differences were noted in comparison with all of the other medications. Similar meta-analyses compared sertraline (126) and escitalopram (992) to other antidepressive agents. Although differences were small, there was a trend for sertraline to be more acceptable and efficacious than comparator antidepressants, including TCAs, SSRIs, and several newer antidepressants (126). Escitalopram was found to be more efficacious than citalopram and fluoxetine in terms of response and remission of depressive symptoms and was associated with lower rates of treatment discontinuation than subjects receiving duloxetine (992).

Another meta-analysis of 21 studies (98) compared efficacy and tolerability of each SSRI (except escitalopram) against the SSRI class overall and showed no difference in efficacy among the drugs. Rates of dropout due to side effects were significantly lower in patients treated with sertraline (p <0.05) and significantly higher in patients treated with fluvoxamine (p <0.01), although the dropout rate in fluvoxamine-treated patients appeared to vary with medication dose. In this meta-analysis, side effects and discontinuation reactions were observed more often with paroxetine than with other SSRIs. Interaction with other drugs was higher with fluoxetine, fluvoxamine, and paroxetine than with sertraline and citalopram, although citalopram was overrepresented in deaths due to overdose.

A systematic review based on 18 randomized, double-blind trials (94), which compared escitalopram with either citalopram, venlafaxine, paroxetine, sertraline, or bupropion, found no differences in efficacy between escitalopram and the other medications (except for the comparison with citalopram, which showed a significant difference in two of four studies). Rates of study withdrawal due to side effects were lower with escitalopram than with venlafaxine (p <0.05) or paroxetine (p <0.05).

Another meta-analysis of 32 randomized clinical trials studied the efficacy and tolerability of antidepressants in people older than age 55 years (704). This study found that there was no difference in efficacy between TCAs and SSRIs, but SSRIs were better tolerated. Compared with patients who were taking TCAs, patients who were taking SSRIs were less likely to withdraw from the study overall or because of side effects, in particular. The qualitative analysis of side effects showed a small increase in gastrointestinal and neuropsychiatric side effects associated with TCAs.

Overall, the findings of multiple randomized trials and meta-analyses indicate comparable efficacies for SSRIs relative to TCAs, although some data suggest greater efficacy for TCAs in inpatient samples. Selective serotonin reuptake inhibitors also appear to have comparable efficacy to other non-TCA antidepressants, although venlafaxine shows superior efficacy in some studies, and comparisons of SSRIs and MAOIs have not been done. In terms of tolerability, SSRIs show consistently fewer dropouts in clinical trials than TCAs, and side effects are also reported less often with SSRIs. There also do not seem to be significant differences in efficacy among the SSRIs. Fluvoxamine appears to have more side effects and more problems with drug interactions than the other SSRIs; drug interactions are also more problematic with fluoxetine and paroxetine than with citalopram, escitalopram, or sertraline.

b. Serotonin norepinephrine reuptake inhibitors

The efficacy of venlafaxine, desvenlafaxine, and duloxetine, which are classified as SNRIs, and mirtazapine, which (although not an SNRI) also enhances both serotonin and norepinephrine neurotransmission, has been demonstrated in placebo-controlled studies of depressed patients (101, 102, 105, 113, 993, 994, 995). A number of studies have contrasted these "dual-action" antidepressants with the SSRIs. Although most individual studies have not found statistically significant differences (see, for example, references 226 and 421), meta-analyses of controlled studies of venlafaxine (101, 104, 996, 997), duloxetine (102), and mirtazapine (113) using SSRIs as comparators have generally documented small (i.e., 4%–10%) albeit reliable differences in the likelihood of response or remission favoring the dual-action drugs. Papakostas et al. (995) similarly found an average difference of 4% in response/remission rates in a meta-analysis of a broader grouping of antidepressant drugs that affect norepinephrine and serotonin. These average effects are generally below the magnitude of difference that is widely considered to be clinically significant. It is possible that a small average difference in an overall pool of patients may obscure larger and more meaningful differences among selected subgroups of depressed patients (e.g., more severely depressed patients [102], inpatients [561], or postmenopausal women [998]), but this suggestion has yet to be confirmed by analyses of larger data sets. At present, the efficacy of desvenlafaxine has only been established versus placebo (993, 994); there are not yet any published studies assessing its benefits relative to other antidepressants. Nevertheless, as the principal active metabolite of venlafaxine, it is likely to have a comparable efficacy profile.

Perahia et al. (999) conducted a randomized controlled trial of duloxetine versus paroxetine and placebo in an outpatient setting in patients who met the criteria for major depressive disorder. After 8 weeks, duloxetine at 80 mg/day (N=93) and at 120 mg/day (N=103) was found to be superior to placebo (N=99). However, paroxetine was not superior to placebo in this study. Perahia et al. also conducted a relapse prevention study (1000), in which patients were randomly assigned to receive duloxetine or placebo for 26 weeks after a 12-week open-label treatment phase. The 136 patients who received duloxetine had a relapse rate of 23%, compared with the 39% relapse rate among the 142 patients who received placebo (p0.005). A large cohort study by Raskin et al. (1001) followed 1,279 patients in 52 treatment centers taking 80–120 mg/day of duloxetine over 52 weeks. Patients were assessed by multiple instruments at 6, 28, and 52 weeks. At 6 weeks, 50.8% achieved a score of <8 on the HAM-D. The rate of response increased to 75.6% at week 28 and 81.7% at week 52, with no safety concerns identified in the course of the study.

Venlafaxine extended release (XR) has also been extensively studied. Rudolph and Feiger (1002) conducted an 8-week outpatient trial of venlafaxine XR compared with fluoxetine and placebo. In this trial, 100 patients received venlafaxine XR (75–225 mg/day), 193 received fluoxetine (20–60 mg/day), and 98 received placebo. Remission rates, determined by an HRSD score of <8, were 37% in the venlafaxine XR arm, 22% in the fluoxetine arm, and 18% in the placebo arm. Sauer et al. (1003) compared 76 patients who received venlafaxine XR (75–150 mg/day) with 75 patients who received amitriptyline (75–150 mg/day). Venlafaxine XR yielded response rates of 39.5%, compared with 41.7% for amitriptyline. Saiz-Ruiz et al. (1004) followed 59 patients receiving venlafaxine over 6 months. Seventy percent of these patients completed the study, and the response rate, determined by a 50% reduction in the HRSD score, was 81%. In another cohort study, Mitchell et al. (1005) found response rates at 8 weeks to be 52.6%, measured by the MADRS, among 312 patients with treatment-resistant illness taking venlafaxine in an open-label trial. Response rates at 10 months as measured by the MADRS increased to 73% in 149 patients who continued treatment in an extension phase of the study (1006).

Fewer studies have been conducted with desvenlafaxine; however, meta-analysis shows that it also is efficacious in the acute treatment of major depressive disorder (99). In the nine randomized, double-blind, placebo-controlled 8-week long trials with desvenlafaxine, there were 1,342 subjects in fixed dose study arms (50, 100, 200, or 400 mg/day), 463 subjects in flexible dose study arms (100–400 mg/day), and 1,108 subjects in placebo study arms. Desvenlafaxine showed greater efficacy than placebo in rates of response as well as remission, with no greater benefit (and greater discontinuation rates) at doses greater than 50 mg daily. Overall rates of treatment discontinuation due to adverse effects were 3% for placebo and 12% for desvenlafaxine (168). Treatment emergent adverse effects included transient nausea and erectile dysfunction in men. Mean blood pressure was statistically increased in the desvenlafaxine group, but this change was clinically significant in only 2% of desvenlafaxine subjects, compared with 1% of the placebo group.

c. Other antidepressant medications
+ 1. Bupropion

Meta-analyses of controlled trials have shown that bupropion is superior to placebo and is generally comparable in efficacy to both TCAs and SSRIs (105, 169, 1007). All three formulations of bupropion are superior to placebo (106), and early studies with the immediate-release formulation found it to be generally comparable in efficacy to the TCAs (105, 1008–1011). The newer sustained-release and extended-release formulations have been primarily compared with the SSRIs, and meta-analyses have established comparable efficacy (169, 1012).

Several studies have compared bupropion sustained release (SR) to SSRIs and placebo. A randomized controlled trial by Croft et al. (1013) compared bupropion SR to sertraline and placebo over 8 weeks of treatment and found both drugs to have efficacy superior to placebo. Bupropion SR had a lower rate of sexual dysfunction than sertraline. These findings were confirmed in a 16-week study that again compared bupropion SR with sertraline and placebo (1014). Another 8-week study found bupropion SR, but not sertraline, to be superior to placebo and again documented lower rates of sexual dysfunction with bupropion SR than sertraline (1015). Similar results were found when bupropion SR was compared with other SSRIs. One study comparing bupropion SR with paroxetine found equivalent efficacy (1016). In another trial, with approximately 150 patients in each arm, bupropion had similar efficacy to fluoxetine with a significantly lower burden of side effects (1017). Lower rates of sexual dysfunction have also been found with bupropion compared with sertraline (1013–1015) or paroxetine (1016). A survey of 6,297 patients in primary care settings found the incidence of sexual dysfunction with bupropion to be 22%–25%. This incidence was comparable to the incidence with nefazodone (28%) but lower than that with SSRIs and venlafaxine (36%–43%) (1018). Several small studies have examined whether bupropion might serve as a potential treatment for SSRI-induced sexual side effects, with varying results (132, 1019, 1020).

Bupropion has also been studied as a treatment for anxiety associated with major depressive disorder. In one large trial, patients were randomly assigned to receive bupropion SR (N=234), sertraline (N=225), or placebo (N=233). Patients treated with bupropion SR or sertraline experienced significantly greater relief from anxiety symptoms than those who received placebo. Compared with sertraline, bupropion appeared to be associated with similar relief of anxiety in patients with major depressive disorder (1021).

Bupropion has also been shown to reduce the risk of relapse following successful antidepressant treatment with bupropion. In a 44-week double-blind trial of bupropion responders (1022), patients were randomly assigned to continue taking bupropion or change to placebo. Continued treatment with bupropion after acute phase response reduced the risk of relapse, compared with placebo, with few differences in side effects reported between the two groups.

+ 2. Mirtazapine

The efficacy of mirtazapine has been established in placebo-controlled studies (1023, 1024), two individual studies versus venlafaxine (1025, 1026), and in meta-analyses of studies comparing it to TCAs (1027–1029) and SSRIs (1030). Quitkin et al. (1030) analyzed three studies comparing patients with major depressive disorder treated with mirtazapine (N=289) to patients treated with fluoxetine or paroxetine (N=285). Although mirtazapine and SSRIs had similar efficacy over 6–8 weeks, a greater proportion of patients had onset of therapeutic benefit at week 1 with mirtazapine as compared with an SSRI (13% versus 6%). In a meta-analysis by Watanabe et al. (1031), mirtazapine was superior to SSRIs in response and remission rates at 2 weeks (12 trials), although it was comparable to SSRIs at the end of treatment (6–12 weeks). In a subgroup analysis, mirtazapine produced greater response than paroxetine (three trials) and venlafaxine (two trials). At 2 weeks as well as at the end of 6–12 weeks' treatment (8 trials used to obtain outcomes), mirtazapine had comparable efficacy to TCAs. A meta-analysis of six studies (1027) found mirtazapine to have comparable efficacy to amitriptyline over 6–8 weeks, with both drugs showing superiority to placebo.

Several randomized controlled trials have compared mirtazapine to SSRIs. Benkert et al. (1032) randomly assigned patients with major depressive disorder to treatment with mirtazapine (N=127) or paroxetine (N=123) over 6 weeks, and Wade et al. (1033) randomly assigned 197 primary care patients with HAM-D scores of at least 18 to mirtazapine (N=99) or paroxetine (N=98) over 24 weeks of treatment. In both studies, the treatments had equal efficacy at study endpoint, but mirtazapine demonstrated a different profile of side effects. Another trial randomly assigned elderly depressed patients (at least age 65 years) to mirtazapine (N=126) or paroxetine (N=120) over 8 weeks (1034). Compared with paroxetine, mirtazapine showed a greater benefit at day 14, had less attrition for side effects, and was significantly more effective in improving sleep. It was also more effective in reducing HAM-D scores by the study endpoint, although response and remission rates were not significantly different. Two randomized trials, one 8 weeks long (N=299) (1035) and the other a 6-week study (N=132) in Chinese patients, have compared treatment with mirtazapine to fluoxetine and found no differences in overall efficacy, although the onset of improvement and side effect profiles differed as with paroxetine. A similar pattern of outcomes was also observed when mirtazapine was compared with citalopram (N=270) in an 8-week trial (1036) and when an oral disintegrating form of mirtazapine was compared with sertraline (N=345) in another 8-week trial (1037).

Mirtazapine has also been compared with venlafaxine (both immediate release [IR] and extended release [XR] forms) in randomized controlled trials. In an 8-week trial, Guelfi et al. (1025) followed patients with major depressive disorder (HAM-D scores of at least 25) receiving mirtazapine (N=78) and venlafaxine IR (N=79). Mirtazapine and venlafaxine did not differ significantly in depression outcomes, although sleep was better with mirtazapine, and significantly more patients taking venlafaxine IR (15%) dropped out due to side effects, compared with patients taking mirtazapine (5%). A similar 8-week trial (1026) found no significant differences in final outcome or tolerability between venlafaxine XR and mirtazapine, although mirtazapine showed greater benefit during the first 15 days of therapy.

Patients with major depressive disorder who were not responsive or who were intolerant of two prior treatments with antidepressants were randomly assigned to treatment with mirtazapine (N=114) or nortriptyline (N=121) for up to 12 weeks as part of the STAR*D trial (471). Remission rates were 12% for mirtazapine and 20% for nortriptyline. There were no significant differences in any outcome measure, and the medications were comparably tolerated. Neither mirtazapine nor nortriptyline was particularly effective as monotherapy for patients who had not benefited from two consecutive treatment trials.

Mirtazapine has been shown to decrease rates of relapse following acute phase treatment. Thase et al. (1038) compared 78 patients who received mirtazapine to 78 patients who received placebo over 9 months following an 8- to 12-week treatment with an antidepressant. Patients taking mirtazapine had about a 50% reduction in relapse rates. However, patients taking mirtazapine gained 1.4 kg more weight than those taking placebo across the 9 months of continuation phase therapy.

+ 3. Nefazodone and trazodone

The efficacy of nefazodone has been established in placebo-controlled trials, with efficacy comparable to both TCAs and SSRIs (105, 1039–1042); however, its recent use has been limited after case reports suggested a risk of rare but potentially fatal hepatotoxicity (180). While an early review of trazodone (114) concluded that trazodone is as effective as TCAs in the treatment of depression, other investigators have found trazodone to be less effective than other antidepressant medications (115, 1043–1045), a conclusion supported by the results of at least one meta-analysis (93). In a review of 18 studies from 1980 through 2003, Mendelson (173) found that trazodone, when compared with various control groups, did improve sleep. However, it was also associated with significant side effects, and tolerance may develop with prolonged use.

d. Tricyclic antidepressants

Since the first trial in which a tricyclic compound (imipramine) was shown to improve major depressive disorder symptoms (1046), hundreds of subsequent randomized controlled trials have demonstrated the efficacy of this antidepressant class as a treatment for major depressive disorder (105). Several reviews of this early literature suggested that approximately 50%–75% of patients with major depressive disorder treated with tricyclic and related antidepressant medications respond, compared with 25%–33% of patients who receive placebo (487, 1047–1049). The efficacy of individual agents and subclasses of tricyclics (e.g., secondary amines or tertiary amines) appears to be comparable, although amitriptyline may possess a slightly stronger effect across all studies (1050), and the tertiary amine tricyclics (amitriptyline, clomipramine, and imipramine) may have a stronger antidepressant effect than the secondary amine tricyclics and maprotiline in studies of hospitalized depressed patients (117).

The meta-analysis of Barbui et al. (1050) reviewed 181 randomized controlled trials of amitriptyline, generally of 6–8 weeks' duration, in inpatient and outpatient settings. Amitriptyline was found to be superior to SSRIs in studies of inpatients, but there was no difference in efficacy in outpatients. Selective serotonin reuptake inhibitors were better tolerated. Arroll et al. (1051) compared TCAs with SSRIs in a meta-analysis of 15 randomized controlled trials in primary care settings. Both TCAs and SSRIs were effective, but tolerability comparisons across studies favored SSRIs. Wohlfarth et al. (1052) reviewed 30 randomized controlled trials conducted between 1979 and 1991, with a combined sample size of 1,555 men and 2,331 women. Tricyclic antidepressants were more effective than placebo across age and gender groups.

Several trials have compared TCAs against interpersonal therapy and CBT and against the combination of TCAs and IPT or CBT. Reynolds et al. (1053) followed 80 patients who were at least age 50 years and had a bereavement-related depression in a 16-week factorial design trial in which patients received IPT or case management and nortriptyline or placebo. Nortriptyline (with or without IPT) was more effective than placebo (with or without IPT). Patients receiving combined nortriptyline and IPT had the highest study completion rate. Interpersonal psychotherapy alone (i.e., IPT plus placebo) was not found to be an effective treatment for bereavement-related major depressive disorder. However, in a continuation trial (N=107) over 24 months (315), combination therapy was found to be more effective than monotherapy in patients age 70 years or older. All patients had been first stabilized on combination nortriptyline and IPT before entering the continuation phase. In a 16-week randomized controlled trial among 102 elderly patients with major depressive disorder, Thompson et al. (1054) found that combined treatment with CBT and nortriptyline was superior to CBT alone, which was superior to nortriptyline alone. Combined treatment was particularly effective in patients with severe depression, as measured by HAM-D scores.

For patients with major depressive disorder who received ECT following a prior nonresponse to treatment with an antidepressant, van den Broek (1055) found that 12 patients randomly assigned to receive imipramine (200–300 ng/mL plasma level) had a greater improvement in all measures in preventing relapse than the 15 patients randomly assigned to receive placebo.

Results of some investigations have suggested that TCAs are particularly effective for patients with more severe symptoms of major depressive disorder (1056–1060), as well as for patients with melancholia (562, 1061–1063). Superior efficacy for TCAs, compared with SSRIs, has been documented in meta-analyses of inpatient studies (117).

e. Monoamine oxidase inhibitors

Monoamine oxidase inhibitors have also been shown in multiple trials to be effective treatments for major depressive disorder. Although some earlier comparisons employing lower doses of MAOIs found TCAs to be superior, MAOIs are now considered to have comparable efficacy to TCAs for most patients with major depressive disorder (119, 120, 1064–1067). Results of several investigations suggest that MAOIs may be particularly effective in treating subgroups of patients with major depressive disorder with atypical features such as reactive moods, reversed neurovegetative symptoms, and sensitivity to rejection (572, 1068, 1069). Monoamine oxidase inhibitors have also been shown to be effective treatments for some patients who have not responded to other antidepressant medications (1064, 1067, 1070, 1071).

In more recent controlled trials, 6 mg/24 hours of transdermal selegiline was compared with placebo in 177 adults with major depressive disorder in a 6-week trial (1072). The transdermal patch was found to be more effective than placebo and was well tolerated without the need for dietary restrictions. These findings were replicated in two subsequent studies by Amsterdam (124) (N=365; dose, 6 mg/24 hours; duration, 6 weeks) and Feiger et al. (125) (N=265; dose, 6–12 mg/24 hours; duration, 8 weeks).

Tranylcypromine in doses of 30–60 mg/day has been compared with the combination of venlafaxine IR (up to 300 mg/day) and mirtazapine (up to 60 mg/day) in 109 patients with treatment-resistant depression in a 12-week randomized trial (121). Neither the MAOI (7% remission rate) nor the combination strategy (14% remission rate) were particularly effective in this group of difficult-to-treat depressed patients, although efficacy was compromised by the use of low tranylcypromine doses. Monoamine oxidase inhibitor therapy was significantly less well tolerated and had a significantly higher dropout rate.

Limited evidence suggests that the nonselective MAOIs have comparable efficacy. Tranylcypromine and phenelzine were found to have similar response rates (44% and 47%, respectively) in a 5-week trial of 77 patients with severe major depressive disorder who had been nonresponsive to a TCA or SSRI medication (1073). Clinical experience suggests that some patients who fail to benefit from one of these MAOIs may benefit from a different one—after allowing a several-week period of washout.


2. Electroconvulsive therapy

The efficacy of ECT has been demonstrated in multiple clinical trials, including trials of real versus sham ECT. In a meta-analysis of the efficacy of ECT in the treatment of depressive disorders, the six trials (256 patients) that included sham ECT controls yielded a standard effect size of 0.91 favoring real ECT, consistent with a strong effect of active ECT (235). In the one sham ECT study that used unilateral ECT, no difference was found, but the treatment was not delivered sufficiently above the seizure threshold to be effective (236). In comparison with pharmacotherapy, meta-analyses similarly show an advantage for ECT with a standard effect size of 0.80 across 18 trials (1,144 participants) (235). Comparisons of ECT against specific antidepressant classes show ECT to be superior to SSRIs, TCAs, and MAOIs (236, 425). In terms of technical aspects of ECT administration, meta-analyses show a more substantial effect of bilateral ECT than unilateral ECT (236), with a standard effect size of 0.32 for 22 trials and 1,408 participants (235). However, many of the included studies did not adjust the stimulus doses of ECT to account for differences in seizure threshold across patients, which may have increased the apparent benefit of bilateral ECT. When stimulus dosing was assessed, higher stimulus doses relative to the patient's seizure threshold were associated with greater benefit than stimulus doses closer to the seizure threshold (standard effect size = 0.73 for seven trials and 342 participants) (235). The efficacy of ECT given twice weekly did not differ from that of ECT given 3 times/week (236).

Much information about ECT response and specific factors that predict response has come from the Consortium for Research in ECT (CORE) study, a large trial funded by the National Institute of Mental Health (NIMH) in which continuation pharmacotherapy was compared with continuation ECT. In the acute phase of that trial in which 253 patients were treated with bitemporal ECT 3 times/week, 79% of the sample had an acute sustained response, with remission occurring in 75% of patients after ECT (mean number of treatments = 8 ± 3). Response to ECT occurred rapidly, with over one-half of patients showing response by the end of the first week of treatment (240). Suicidal ideation also resolved rapidly during the course of ECT, with substantial resolution in 38% by the end of the first week, 61% by the end of the second week, and 80% by the end of the treatment course (243). Individuals who were older (715) or who exhibited psychosis (241) or atypical features (578) had a greater likelihood of achieving remission, although the presence of melancholic features was not associated with a greater likelihood of response (499). Also, unlike prior studies that had shown reduced rates of remission with ECT in patients with treatment-resistant depression (1074, 1075), the CORE study found that neither resistance to antidepressants as a whole nor resistance to any specific class of antidepressants was associated with an altered response to ECT (426).

In contrast to the high rates of ECT response found in the CORE study and in meta-analyses of clinical efficacy trials, ECT appears to have a lower rate of response when delivered in community settings. Prudic et al. (237) examined clinical outcomes following ECT and over 6 months of follow-up in 347 patients who received ECT at one of seven hospitals in the New York metropolitan area. Remission occurred in only about one-third to one-half of the sample, and two-thirds of those with remission experienced a relapse during the follow-up period. Having residual symptoms, psychotic features, or a co-occurring personality disorder conferred a heightened risk of relapse.

Other studies have delineated technical factors relating to the efficacy of ECT, including stimulus intensities and electrode placements. Sackeim et al. (253) randomly assigned 96 depressed patients to treatment with a bitemporal or right unilateral electrode placement at a low dose or high dose relative to the patient's seizure threshold. Patients treated with bilateral ECT had comparable response rates regardless of stimulus dose (65% for low dose versus 63% for high dose), whereas patients receiving low-dose right unilateral ECT had only a 17% response, and those receiving high-dose right unilateral ECT had an intermediate response (43%). In a subsequent randomized double-blind study of 80 depressed patients, an even higher dose of right unilateral ECT was used (500% above the seizure threshold). At this stimulus dose, right unilateral ECT showed comparable efficacy to bilateral ECT (65%) and superior efficacy to right unilateral ECT given at 50% or 150% above seizure threshold, for which the response rates were 35% and 30%, respectively. That high-dose right unilateral ECT has comparable benefits to bilateral ECT has also been shown in two randomized studies by McCall et al., one of which included 77 patients and used right unilateral ECT at eight times the seizure threshold (1076) and one of which included 72 patients and used a high fixed dose of 403 millicoulombs for right unilateral ECT (1077).

Several smaller studies have examined bifrontal electrode placement in comparison with bitemporal or right unilateral electrode placements. Bailine et al. (1078), who studied 48 patients with scores of 17 or higher on the 17-item version of the Hamilton Rating Scale for Depression (HAM-D-17) who were randomly assigned equally to receive bifrontal or bitemporal ECT (mean number of treatments = 6 ± 2.5), reported no difference in remission rates between the two groups. Ranjkesh et al. (1079) found no difference in HAM-D scores among patients receiving at least eight sessions of bifrontal (moderate dose, N=15), bitemporal (low dose, N=15), or right unilateral (high dose, N=15) electrode placement in an Iranian inpatient sample of patients with an initial score of 16 or higher on the 24-item Hamilton Rating Scale for Depression (HAM-D-24). Similarly, Eschweiler et al. (1080) compared the effects of six right unilateral ECT treatments (250% stimulus intensity of titrated threshold) and six bifrontal ECT treatments (150% of threshold) over a 3-week period in a randomized double-blind trial of 92 patients and found no difference in response rates between the two electrode placements.

In addition to efficacy and ECT technique, the cognitive effects of ECT have been a focus of considerable study, typically as a part of studies examining various electrode placements. In terms of the time to recover reorientation after ECT, Sackeim et al. (253) found that patients receiving bilateral ECT took substantially longer to regain their orientation than patients receiving right unilateral ECT, and the time to regain orientation increased with the stimulus dose. In addition, the time to regain orientation immediately after ECT, as well as the patient's baseline cognitive status, predicted the patient's cognitive status after the ECT course and at 2-month follow-up assessment (251). Regardless of the stimulus dose of right unilateral ECT that was used, bilateral ECT was associated with more prominent effects on cognition at follow-up assessments (253, 1081). Relative to bilateral ECT (at one and one-half times the seizure threshold), high-dose right unilateral ECT (at eight times the seizure threshold) produced comparable effects on memory, and neither electrode placement produced prolonged anterograde amnesia (1076). Lisanby et al. (248) studied 55 patients with major depression in a randomized double-blind trial of bitemporal and right unilateral ECT at low and high stimulus doses and compared the patients' function on a Personal and Impersonal Memory Test with that of a parallel group of normal control subjects. Bitemporal ECT was found to cause more prominent impairments that were most notable for impersonal events and that were independent of stimulus dose or clinical outcome. Studies of other electrode placements have shown either no difference (1080) or beneficial effects (1078, 1079) of bifrontal electrode placement relative to bitemporal electrode placement. Another factor that may relate to memory dysfunction is the number of ECT treatments administered per week, with two studies showing less prominent amnesia with twice-weekly ECT rather than ECT given 3 times/week (1082).

The cognitive effects observed in naturalistic community settings also appear to differ from those observed in research trials (252). The seven hospitals in the community study showed considerable variation from one another immediately after ECT and at the 6-month follow-up assessment. These differences seemed primarily related to differences in ECT technique across sites, with use of sine wave stimulation and bilateral ECT being associated with greater and more persistent cognitive effects on several cognitive measures, compared with brief pulse and right unilateral ECT. Given the lower efficacy rates for ECT that were also seen in the community sample, residual or recurrent depressive symptoms may also have contributed to the poorer cognitive outcomes. These findings suggest a need to optimize efficacy as well as minimize cognitive effects in clinical practice.


3. Transcranial magnetic stimulation

A substantial number of studies of TMS have been conducted, but most have had small sample sizes, and the studies overall have yielded heterogeneous results. Further complicating the interpretation of the TMS literature is the variability in stimulation intensities (relative to the motor threshold), stimulus parameters (e.g., pulses/second, pulses/session), anatomical localization of stimulation, and number of TMS sessions in the treatment course. A recent meta-analysis of 24 studies (with a total of 1,092 subjects) found that individuals with treatment-resistant depression were more likely to respond to TMS than to sham treatment (25% with TMS versus 17% with sham; NNT=6) (270). However, for active treatment and for sham treatment, remission occurred in fewer than 10% of subjects (270). Another meta-analysis that included 33 studies also found active TMS to be more effective than sham treatment in patients with major depression but also noted substantial variability across studies (271). Studies with stimulation intensities below 90% of motor threshold appeared to show less benefit (271). Based on a meta-analysis that included six independent trials of left dorsolateral prefrontal cortex TMS in a total of 195 patients, older individuals and those with treatment-resistant depressive episodes may also be less likely to respond (1083). Another meta-analysis of these six clinical trials found TMS to be no different from sham treatment overall in the treatment of major depression; however, the power within these studies to detect a difference was generally low (273). Schutter (272) also examined studies of TMS over the left dorsolateral prefrontal cortex and found an overall weighted mean effect size of 0.39 for TMS based on findings from 30 studies and 1,164 patients. This meta-analysis did not find any differences in the response of individuals with medication-resistant major depression as compared with those without documented medication resistance, nor did it find any evidence of study heterogeneity or publication bias. Multiple earlier meta-analyses also demonstrated benefits of TMS (1084–1087), but include an overlapping set of studies with those assessed in more recent meta-analyses. If anything, however, earlier studies demonstrated less efficacy for TMS than more recent studies (272, 1088). The duration of TMS effects has not been well studied, but one meta-analysis of 14 studies showed a robust response to TMS compared with sham TMS after 2 weeks of treatment (standardized mean difference = –0.35; 95% confidence interval = –0.66 to –0.04), but no statistically significant benefit of active TMS at 2-week follow-up (1089).

The largest published trial of TMS was a randomized, double-blind, multisite study of patients who had not responded to one to four prior trials of antidepressant therapy and were free of other medications at the time of the study (268). Subjects received sham TMS (N=146) or active TMS delivered to the left dorsolateral prefrontal cortex, 5 times/week for 4–6 weeks with 10 pulses/second and 3,000 pulses/session at 120% of motor threshold. At weeks 4 and 6 of the study there was a trend for greater improvement in MADRS scores in the active TMS group, but this result did not reach statistical significance. Rates of remission also did not differ between the two groups, although secondary outcome measures, including the HAM-D and response rates, did indicate a beneficial effect of TMS. In an open-label extension study of this trial (1090), 85 subjects who had received sham TMS showed significant reductions in MADRS scores after changing to active TMS; 42.4% of these patients met response criteria, and 20% had remission of their depressive symptoms by 6 weeks. Of subjects who had received active TMS and continued to receive an additional 6 weeks of treatment (N=73), 26% showed a response to TMS, and 11% achieved symptom remission. Subsequent analysis of the data from these trials (274) showed that lesser degrees of treatment resistance were associated with better response to TMS. The lack of a co-occurring anxiety disorder also appeared to be associated with a better response to TMS in the open-label extension phase of the trial.

In another large multisite trial conducted in Europe, 127 subjects with treatment-resistant depression who were being treated with antidepressant medication (venlafaxine or mirtazapine) were randomly assigned to receive active (N=62) or sham (N=65) TMS delivered to the left dorsolateral prefrontal cortex, 5 times/week with 10 pulses/second and 2,000 pulses/session at 110% of motor threshold for 3 weeks. The two groups did not differ in their degree of improvement on the MADRS, HAM-D, or BDI scales, and a similar proportion of individuals in each group (31%) were classified as having responded to treatment (269).

Other smaller studies have compared TMS with ECT, with variable results. One of these studies showed ECT to be substantially more effective than TMS acutely in terms of HRSD scores and the proportion of responders at the end of the study, and, on the majority of outcome measures, ECT retained this benefit over TMS after 6 months of follow-up (275). In the other studies that compared TMS with ECT, rates of remission and response were comparable for the two treatments, although the response and remission rates for ECT in these studies were somewhat lower than typically reported in clinical ECT trials, and rates of response to TMS were higher than those reported in sham controlled trials of TMS (276–278, 1091). An additional randomized single-blind trial compared the responses of individuals who received 2 weeks of thrice-weekly unilateral ECT with the responses of individuals who received one unilateral ECT session and four TMS sessions each week (1092) and found no statistically significant differences in efficacy or side effects between the two approaches. The cognitive effects of TMS and ECT have been assessed in one open study (279), in which subjects treated with TMS reported memory to be unchanged or improved approximately 9 days after the treatment course as compared with unilateral ECT, which was associated with a greater degree of subjective, retrograde, and anterograde memory difficulties shortly after the end of the treatment course. A subsequent randomized single-blind trial (276) showed no significant difference between individuals who received TMS and those who received unilateral ECT when neuropsychological performance was tested at 2 and at 4 weeks of treatment. However, there was a trend for worsened performance in those receiving ECT versus a trend for improved performance in those receiving TMS.

Analysis of aggregate safety data from more than 10,000 treatment sessions with 325 patients treated at 23 clinical sites in the United States, Australia, and Canada showed that TMS was well tolerated, with less than 5% of subjects leaving the study due to adverse effects and no seizures or deaths observed (280). The most common adverse effects were transient headaches or scalp discomfort. Overall, side effects of treatment were mild to moderate in intensity and dissipated over the initial week of treatment.


4. Vagus nerve stimulation

The FDA approved VNS for treatment-resistant depression based on efficacy data from two different samples, for which acute and longer term data are available. The first sample consisted of 60 outpatients with chronic or recurrent major depressive disorder, bipolar I disorder, or bipolar II disorder who had not responded to at least two medication trials from different antidepressant classes. This cohort was first followed in an open-label fashion with 10 weeks of active stimulation after a 2-week period to permit recovery from surgery (281). On the primary outcome measure, the 28-item Hamilton Rating Scale for Depression (HAM-D-28), 30.5% of the sample showed a response (defined as at least a 50% reduction from the baseline HAM-D-28 score) and 15.3% of the sample had a full remission of symptoms (defined as HAM-D-28 of less than 11). Response was less likely to occur in patients who had received a greater number of unsuccessful antidepressant trials or who had received ECT prior to VNS. This cohort was then followed for up to 2 years naturalistically, with changes to psychotropic medications and VNS stimulus parameters permitted (479). In a last-observation-carried-forward analysis, response rates were 44% and 42% after 1 and 2 years, respectively, with remission rates of 27% and 22% at 1 and 2 years, respectively (479).

A subsequent VNS trial was a multisite randomized trial with 235 participants that included an acute sham-controlled phase (282) and a longer term naturalistic follow-up phase (477) and comparison with a relatively similar treatment-as-usual sample. In the acute phase, nonpsychotic outpatients with treatment-resistant major depressive disorder (N=210) or patients with depressed phase bipolar disorder (N=25) received 10 weeks of active or sham treatment after 2 weeks of recovery from implantation surgery. In terms of response (i.e., at least 50% reduction in HAM-D-24 score), there was no significant difference with VNS treatment (15.2% response vs. 10% for sham). These findings may be confounded by the frequent occurrence of hoarseness or voice alteration with stimulation (281), which may have affected the blinding of the study subjects or investigators. During the longer term naturalistic follow-up phase, in which changes in medication were permitted, the active VNS group received 9 additional months of VNS, and the sham group received 12 months of VNS (282). A repeated-measures linear regression analysis of the primary outcome measure showed significant reductions in HAM-D-24 scores, with response and remission rates of 27.2% and 15.8%, respectively, at the study endpoint (282). A similar but nonrandomized treatment-as-usual group (N=124) showed a response rate of 13%, suggesting a benefit of VNS (476).

To determine whether the benefits of VNS were durable, data from the studies described earlier in this section were combined, and the persistence of the antidepressive response was determined (478). Of individuals who had shown an early response (by 3 months of VNS), 66.7% and 64.6% of the overall group had maintained that response at 1 and 2 years, respectively. Of those who had shown a late response (by 12 months of VNS), 68.5% had maintained that response at 2 years, suggesting persistent benefits of VNS.

An additional uncontrolled multisite European trial showed somewhat lower rates of sustained response (44%) at 1 year of VNS treatment, although overall response and remission rates at 1 year were 53% and 33%, respectively (481). Other smaller, open-label trials have been recently reviewed and also show reductions in depressive symptoms when VNS is used in combination with other antidepressive treatments for individuals with treatment-resistant depression (480).

Across all studies, VNS was generally viewed as tolerable (480). Rates of study dropout were low (about 1%) during the initial 3 months of treatment (282), with about 80% of subjects continuing with VNS at the end of 2 years (479). Voice alteration or hoarseness occurred in about two-thirds of subjects in conjunction with stimulation (281). Coughing occurred in about one-quarter of individuals (281), and dyspnea and neck pain were also commonly reported (481).


5. Complementary and alternative treatments

a. St. John's wort

Despite a large number of trials examining St. John's wort (usually in the form of Hypericum perforatum extract), there is no consensus on its efficacy in major depressive disorder. A 2005 Cochrane meta-analysis (1093) provided a summary of treatment studies utilizing St. John's wort for the treatment of major depressive disorder. The published studies demonstrate heterogeneity in methods used and great inconsistency in study outcomes. A number of double-blind studies have demonstrated its superiority over placebo, although some have not (370, 371). In addition, St. John's wort may have better tolerability than TCAs and SSRIs, and several randomized studies have shown noninferiority relative to approved antidepressant medications, although the distinctive taste of St. John's wort extract may have caused some unblinding during the studies.

Among the larger and most rigorous recently published placebo-controlled trials, the studies by Shelton et al. (371) (N=200) and Davidson et al. (370) (N=340) did not demonstrate a difference between St. John's wort and placebo on primary outcome measures, but Lecrubier et al. (1094) found a significant difference between St. John's wort and placebo in mild to moderate depression (N=375). In addition, a recent review of 14 short-term, double-blind trials conducted in outpatients with mild to moderate symptoms of major depressive disorder demonstrated that St. John's wort in doses of 300 mg/day and 1,800 mg/day had efficacy superior to placebo and was generally comparable to low-dose TCA treatment (e.g., 30–150 mg/day of amitriptyline) (105). Side effects were observed in a lower proportion of individuals taking St. John's wort than among those taking a TCA (25% vs. 40%) (105).

b. S-adenosyl methionine

A number of studies have found SAMe to be efficacious in oral doses that range from 800 mg/day to 1,600 mg/day. In a double-blind trial, 15 inpatients with major depressive disorder received oral SAMe or placebo for 21 days (1095). Six of nine patients receiving SAMe demonstrated response as defined by a reduction of 50% or more in HAM-D scores, and depression ratings compared with placebo were significantly lower in the SAMe group than in the placebo group at days 14 and 21. Side effects were mild and transient. In a meta-analysis of studies comparing effects of SAMe with those of TCAs, SAMe was found to have better tolerability and greater efficacy in the treatment of depression, although the doses of TCAs were subtherapeutic in some studies (381). Data from two multicenter studies also demonstrated that parenteral and oral formulations of SAMe were comparable in efficacy to the TCA imipramine (1096), although side effects were significantly more frequent in the imipramine-treated group. In one of the larger controlled trials, which included 293 participants, Pancheri et al. (382) found SAMe (administered intramuscularly at a dose of 400 mg/day) and imipramine (administered by mouth at a dose of 150 mg/day) to be similarly efficacious in a 4-week trial. Other studies have focused on specific subgroups of patients, such as HIV-positive patients and postmenopausal women (1097, 1098).

c. Omega-3 fatty acids

Two large meta-analyses found benefits of omega-3 fatty acids overall in mood disorder trials (384, 385) but also highlighted the heterogeneity of study designs and results. The one monotherapy study of DHA for major depressive disorder in adults did not demonstrate benefit of DHA over placebo (1099), although small trials in major depressive disorder in children and in pregnant women did demonstrate a benefit of monotherapy with omega-3 fatty acids (EPA and DHA) (1100, 1101).

d. Folate

In a study by Coppen and Bailey (389) that included 127 subjects, 94% of women who received fluoxetine and 500 mcg/day of folate responded to treatment, compared with 61% of those who received fluoxetine and placebo (p <0.005). Patients who received folate were also less likely to report side effects (p <0.05).

e. Light therapy

In a meta-analysis, Golden et al. (395) found clinically significant benefit of bright light therapy in seasonal major depressive disorder (eight studies), with a large effect size (0.84), and in nonseasonal major depressive disorder in three studies with a medium effect size (0.53). However, the authors, who were participants of an APA work group on the topic of light therapy, determined that many of the studies of light therapy for mood disorders had methodological flaws, including small sample sizes, with only 13% of the studies they assessed meeting the inclusion criteria for their meta-analysis. Bright light therapy in nonseasonal major depressive disorder was not found to be significantly more efficacious than placebo in trials when used adjunctively in addition to antidepressants. As determined by the APA work group, an adequate placebo condition requires a maximum dose of 300 lux (versus at least 3,000 lux-hours for an active treatment condition for bright light treatment). Randomized, placebo-controlled studies have ranged from 7–42 days in treatment duration, with provision of between 2,500–10,000 lux illuminance of white light, with delivery time between 0.5–6 hours/day. Some published studies were found to have bright light exposure at levels too high to constitute a scientifically valid control condition, and the difficulty in creating a reasonable control condition for bright light therapy may have contributed to the limited evidence base to date. Control groups have included lower doses of white light, red light, active light avoidance, negative air ionizer, and no treatment. Despite heterogeneity of designs and results, evidence supports the efficacy of bright light as a monotherapy for acute major depressive disorder. Individualization of a regimen may be required in terms of lux, length of exposure, and time of day of delivery. In addition, patients should be monitored for emergence of mania during treatment (1102).

f. Acupuncture

Assessment of the evidence base for acupuncture is complicated by the fact that many reports are in Asian languages and therefore often overlooked by English language literature searches. Results from studies in acupuncture are difficult to interpret, because the description of the methods is often limited and there is variability in diagnosis and in interventions (403). Wang et al. (407) published a recent meta-analysis of eight trials of acupuncture and depression chosen from more than 200 studies on the basis of having a randomized design, specific diagnostic criteria for depression, and specific acupuncture interventions (manual, electro-acupuncture, or laser). The depression criteria included DSM, International Classification of Diseases, and Chinese Classification of Mental Disorders criteria. The meta-analysis did not demonstrate a benefit of acupuncture over control conditions on either response rates or remission but was based on a small number of trials with variable methodological quality. Consequently, additional systematic study is required to assess the role of acupuncture for major depressive disorder.

There have been few randomized, double-blind, placebo-controlled studies to inform the use of acupuncture for depression. In one published study, Allen et al. (405) compared 38 women, ages 18–45 years, who were assigned to three different groups: an acupuncture regimen specifically chosen to address their depression, sham acupuncture, or a waiting-list control condition. The active acupuncture group experienced a significantly greater remission rate. However, Allen et al. (406) failed to replicate these results in a larger randomized trial, in which 151 patients with major depressive disorder received acupuncture specific for depression, sham acupuncture, or a waiting-list condition. After 8 weeks, there was no evidence of benefit for the acupuncture intervention specific for depression, compared with sham acupuncture or the waiting-list condition. Response rates were 22% for the depression-specific acupuncture treatment and 39% for the sham acupuncture treatment.

In another randomized study, Luo et al. (404) compared effects of electro-acupuncture combined with placebo medication to the effects of amitriptyline in 241 inpatients. Electro-acupuncture appeared equivalent to amitriptyline at a dose of 150–175 mg/day in treating depression, with greater improvement for symptoms of anxiety, cognitive problems, and somatization; it also resulted in a lower side effect burden than amitriptyline. However, no group received the placebo medication alone, and no sham treatment was used to elucidate nonspecific benefits of acupuncture treatment.


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