Table 1.
Pharmacologic Treatments for Anxious Depression
| Study | Participants and Design | Definition of Anxious Depressiona | Primary Findings |
| SSRIs | |||
| Spalletta et al16 | Open-label, monotherapy with fluoxetine (n = 22), aged 18–75 y, 50 d, type 2 evidence | First-episode MDD (with or without comorbid dysthymia) plus a score ≥ 15 on the HARS | Both depression and anxiety symptoms significantly decreased starting within 10 d of treatment |
| Fava et al17 | Randomized; double-blind to fluoxetine (n = 35), sertraline (n = 43), or paroxetine (n = 30); 10–16 wk; type 2 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Patients had a similarly high response to all 3 medications (fluoxetine, 73%; sertraline, 86%; paroxetine, 77%; overall P = .405) and similar remission rates (fluoxetine, 53%; sertraline, 62%; paroxetine, 50%; overall P = .588); all 3 medications had favorable tolerability profiles |
| Feiger et al18 | Post hoc, pooled data from 5 studies, randomized, double-blind, controlled to sertraline (n = 334) or fluoxetine (n = 320), aged ≥ 18 y, ≥12 wk, type 1 evidence | DSM-III-R or DSM-IV MDD plus HDRS A/S score ≥ 7 at baseline | Anxious depression improved with both sertraline and fluoxetine, with ≥ 70% response rate; 47% remission rate for both treatment groups |
| Papakostas et al19 | Post hoc, pooled data from 5 studies, randomized, double-blind, placebo-controlled to SSRIs (escitalopram, citalopram, or sertraline; n = 445 with anxious depression; n = 584 with nonanxious depression) or placebo (n = 311 with anxious depression, n = 350 with nonanxious depression), aged 18–65 y, 8 wk, type 1 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | In those with severe depression (MADRS score ≥ 30), the presence of anxious depression served as a treatment moderator: “responsive” (severe/nonanxious) and “unresponsive” (severe/anxious) to SSRI over placebo |
| Farabaugh et al21 | Post hoc, open-label to fluoxetine (n = 510 overall, n = 156 with anxious depression), aged 18–65 y, 12 wk, type 2 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Anxious depression status at baseline did not predict remission |
| Papakostas et al22 | Post hoc, randomized, double-blind, placebo-controlled to fluoxetine-clonazepam (cotherapy) or fluoxetine-placebo (monotherapy) (n = 80 total, n = 46 with anxious depression), aged ≥ 18 y, 3 wk, type 1 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Anxious depression did not predict treatment response; however, the difference in remission rates between the cotherapy and monotherapy groups with anxious depression (32.2%) were numerically, but not statistically, higher than remission rates for nonanxious depression (9.7%) |
| Fava et al23 | Post hoc pooled data from 2 randomized, double-blind, placebo-controlled studies; compared cotherapy with eszopiclone and SSRI (fluoxetine or escitalopram, n = 178) to placebo and SSRI cotherapy (n = 169) in anxious depression; aged 21–64 y; 8 wk; type 1 evidence | Baseline HDRS score ≥ 14 plus HDRS A/S score ≥ 7 | Insomnia and response rates improved in the eszopiclone-SSRI group compared to placebo-SSRI; however, remission rates were not significantly different, and response rates were no longer significant once insomnia items were removed from the HDRS |
| SNRIs | |||
| Nasso et al24 | Open-label to duloxetine (n = 101 total, n = 55 with anxious depression), aged 18–65 y, 8 wk, type 2 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Patients with anxious depression had greater total HDRS score improvements at all time points, and the improvements increased proportionally over time (P = .04) compared to nonanxious patients with depression |
| Fava et al25 | Open-label to duloxetine (n = 249 total, n = 109 with anxious depression), aged ≥ 18 y, 12 wk, type 2 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Patients with anxious depression had significantly larger improvements later in the course of treatment on HDRS total score (wk 12, P < .05) and HDRS A/S (day 42 onward, P < .05); patients with anxious depression had significantly shorter median time to response compared to patients with nonanxious depression (28 and 46 d, respectively, P = .031) |
| Howland et al26 | Post hoc, open-label to duloxetine (n = 249), aged ≥ 18 y, 12 wk, type 2 evidence | None, examined relation of continuous HDRS A/S score on remission and response | Higher scores on the HDRS A/S were associated with lower rates of response and remission |
| Nelson9 | Post hoc pooled data from 11 randomized, double-blind, placebo-controlled trials evaluating duloxetine in the treatment of MDD (n = 2,841 total; n = 1,326 with anxious depression in first analysis; n = 1,519 in second analysis); aged ≥ 18 y; 7- to 9-wk trials; type 1 evidence | First analysis: MDD plus HDRS A/S score ≥ 7 at baseline | First analysis: all depressed patients had higher response to duloxetine vs placebo, with overall response rate higher for anxious depressives; however, anxious depressives were less likely to remit due to greater initial depression severity27 |
| Second analysis: MDD plus scores greater than the median for the sum of HDRS psychic and somatic anxiety items | Second analysis: patients with anxious depression had significantly lower remission rates compared to nonanxious depressed patients (28% vs 35.2%, respectively, P < .001) but no difference in response rates | ||
| Akkaya et al28 | Randomized, open-label to venlafaxine extended release (n = 50, n = 22 with anxious depression) or reboxetine (n = 43, n = 34 with anxious depression), aged 18–65 y, 10 wk, type 2 evidence | MDD plus HARS score ≥ 22 at baseline | No significant differences were observed in response and remission rates from depression between treatment groups in those with anxious depression |
| SSRIs vs other medication classes | |||
| SSRIs vs bupropion | |||
| Papakostas et al29 | Post hoc, pooled analysis from 10 double-blind, randomized clinical trials comparing bupropion to SSRIs (n = 1,275), 6 to 16 wk, type 1 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Response rates were greater with SSRI treatment compared to bupropion on total HDRS (65.4% vs 59.4%, P = .03) and HARS (61.5% vs 54.5%, P = .03), but remission rates did not differ |
| SSRIs vs SNRIs | |||
| Davidson et al30 | Post hoc, randomized, double-blind, parallel-group to venlafaxine, fluoxetine, or placebo (n = 1,454 total; n = 587 with anxious depression); data pooled from 5 studies (3 were placebo-controlled); aged ≥ 18 y; 6 wk; type 1 evidence | MDD (DSM-III-R or DSM-IV) plus > 2 on the HDRS psychic anxiety item at baseline | Anxious depression remission rates were significantly greater than placebo in the venlafaxine group from wk 3 (17% vs 6%, P = .005) to wk 6 (34% vs 15%, P < .001); no significant improvement was found in the fluoxetine group; remission rates for venlafaxine were greater than those of the fluoxetine group at 3 wk (P = .017) and 6 wk (P = .019) |
| Sir et al31 | Post hoc, randomized, double-blind subgroup analysis of venlafaxine extended release (n = 54) vs sertraline (n = 66); aged ≥ 18 y; 8 wk; type 2 evidence | MDD plus HDRS A/S score ≥ 7 | Both treatments were effective, regardless of anxiety status, with no significant differences between groups |
| Papakostas and Larsen32 | Post hoc pooled analysis from 13 double-blind, randomized controlled trials comparing escitalopram with active competitor (citalopram, sertraline, paroxetine, venlafaxine, or duloxetine) or placebo (n = 3,919 total; n = 1,883 with anxious depression), 8 wk, type 1 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Anxious depressives had lower remission rates on MADRS (37.6% vs 44.1%, P < .0001) and HDRS (34.3% vs 45.3%, P < .0001); escitalopram was consistently more effective than placebo and equally as effective as the SNRIs or other SSRIs; no differences were found between subjects in response rates, adherence, tolerability, or side effect profile |
| SSRIs vs TCAs | |||
| Marchesi et al33 | Randomized, double-blind to fluoxetine (n = 75) or amitriptyline (n = 67) following a 1-wk single-blind placebo lead-in, 10 wk, type 1 evidence | DSM-III MDD plus a score > 5 on the HDRS items agitation, psychic anxiety, and somatic anxiety or with at least 1 of these items having a score > 3 | Both groups responded to treatment, although the amitriptyline group had a faster response at wk 3; no significant differences were found with as-needed benzodiazepine use or number/severity of side effects |
| Versiani et al34 | Randomized, double-blind to fluoxetine (n = 77) or amitriptyline (n = 80) following a 2-wk single-blind placebo lead-in, Latin American population, aged ≥ 18 y, 8 wk, type 1 evidence | MDD plus a total score ≥ 18 on the HARS | Patients responded to both treatments, although fluoxetine was significantly better tolerated than amitriptyline |
| Uher et al35 | Post hoc, open-label, partially randomized to escitalopram or nortriptyline to examine if depression subtypes predict response (n = 811 total, n = 451 with anxious depression), 12 wk, type 2 evidence | ICD-10/DSM-IV MDD plus ≥ 7 on the HDRS A/S | Compared to nonanxious depressive subjects, those with anxious depression did not differ on recurrence, episode duration, antidepressant treatment history, attrition, dose of either antidepressant (P < .05), or outcome of treatment on any of the 3 depression rating scales (overall: MADRS, P = .12; HDRS, P = .43; BDI, P = .95); however, when the analysis was restricted to randomly allocated individuals only, anxious depression was associated with worse outcome overall (MADRS, P = .0041; HDRS, P = .0184; BDI, P = .0043) and with escitalopram (MADRS, P = .0088; BDI, P = .0148) |
| Tollefson et al8 | Post hoc meta-analysis of 19 randomized, double-blind clinical trials comparing fluoxetine vs placebo and fluoxetine vs TCAs; n = 3,183 total depression (n = 631 with anxious depression in the fluoxetine vs placebo analysis and n = 511 with anxious depression in the fluoxetine vs TCA analysis); 6 to 7 wk; type 1 evidence | MDD (Research Domain Criteria or DSM), and 1 study used bipolar depression; plus HDRS A/S score ≥ 7 at baseline | Anxious depression did not significantly predict treatment outcome; both groups, regardless of anxiety status, responded positively to fluoxetine and TCAs |
| Lenze et al36 | Post hoc, double-blind; examined response, dropouts, side effects between anxious depression (n = 42) and nonanxious depression (n = 74) with nortriptyline or paroxetine; elderly subjects only (≥ 60 y); 12 wk; type 2 evidence | MDD plus a score ≥ 5 on the sum of the psychic anxiety and somatic anxiety items on the HDRS | No significant overall differences were seen in response between anxious and nonanxious subjects with depression (P = .12); however, those with anxious depression were prescribed more benzodiazepines (P = .002) |
| Antipsychotics | |||
| Trivedi et al37 | Post hoc pooled data from 2 randomized, double-blind, placebo-controlled trials evaluating aripiprazole augmentation to standard antidepressant therapy in subjects with previous treatment failures; 384 patients with anxious depression (aripiprazole: n = 183, placebo: n = 201) were compared to 259 patients with nonanxious depression (aripiprazole: n = 138, placebo: n = 121); aged 18–65 y; 14-wk studies; type 1 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Adjunctive aripiprazole is effective for the treatment of depression, regardless of anxiety status |
| Thase et al38 | Post hoc; 2 studies used for pooled analysis; randomized, double-blind, placebo-controlled to once-daily quetiapine extended release (150 mg–300 mg) monotherapy (n = 968 total, n = 788 with anxious depression); aged 18–65 y; 8 wk; type 1 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Patients with anxious depression were as responsive to quetiapine extended release as those with nonanxious depression; however, those with anxious depression had significantly more adverse events than those with nonanxious depression (89.7% vs 78.8%, respectively) |
| Comparisons across multiple medication classes | |||
| Fava et al1 | STAR*D level 1: post hoc, open-label to citalopram (n = 2,876 total; n = 1,530 with anxious depression), aged 18–75 y, 12–14 wk, type 2 evidence | MDD plus HDRS A/S score ≥ 7 at baseline | Level 1: remission was less likely and took longer in anxious depression; experienced significantly greater side effect frequency, intensity, and burden and had more serious adverse events |
| Farabaugh et al39 | Level 2: post hoc, open-label, randomized to switch to bupropion sustained release, sertraline, venlafaxine extended release, or cognitive therapy or to augment citalopram with bupropion, buspirone, or cognitive therapy; aged 18–75 y; n = 1,282 total | Level 2: Patients with anxious depression had worse outcomes with psychopharmacologic and cognitive therapy switching and augmentation options | |
| Wu et al40 | Post hoc, randomized, double-blind, fixed-dose trials of 8 possible antidepressant and augmentation strategies: paroxetine monotherapy (20 mg/d), 2 monotherapy switch options (venlafaxine extended release 225 mg/d or mirtazapine 45 mg/d), or augmentation strategies to paroxetine with risperidone (2 mg/d), sodium valproate (600 mg/d), buspirone (30 mg/d), trazodone (100 mg/d), or thyroid hormone (80 mg/d); Chinese population (n = 375, n = 262 with anxious depression); aged 18–65 y; 8 wk; type 2 evidence | MDD plus HDRS A/S score ≥ 7 | Compared to patients with nonanxious depression, those with anxious depression had lower remission rates on HDRS scores (52.3% vs 33.2%, P = .001), self-rating depression scale (48.7% vs 36.6%, P = .029), and CGI improvement (46.9% vs 38.9%, P = .038) and had more residual depressive and anxiety/somatization symptoms at endpoint (P = .000) |
| Logistic regression showed that the presence of anxious depression predicted worse outcome (RR = 2.004, P = .008), and those with anxious depression had more mild to moderate adverse events than those with nonanxious depression (42.3% vs 23.2%, P = .000) | |||
| Wiethoff et al41 | Post hoc, randomized, multicenter, multiphase study of 2 treatment algorithms (standardized stepwise treatment and computer/expert) vs treatment as usual; n = 429 total, n = 210 with anxious depression; aged 18–70 y; naturalistic study; type 2 evidence | ICD-10– and DSM-IV–confirmed MDD plus HDRS A/S ≥ 7 | Patients with anxious depression were significantly less likely to achieve remission after initial monotherapy (P = .018), had longer length of treatment until discharge (P = .016), and lower probability of staying remitted after discharge (P = .050); no differences were found in overall dropout frequency (P = .069), side effect reporting (P = .067), or as-needed tranquilizer use (P = .270) |
| Chan et al42 | Post hoc, randomized, single-blind to escitalopram/placebo (n = 224), bupropion/escitalopram (n = 221), or venlafaxine/mirtazapine (n = 220); the first medication given in each group was open-label, the second medication was single-blinded to the participant only; 7 mo; type 1 evidence | Recurrent MDD plus HDRS A/S score ≥ 7 at baseline | At wk 12, patients with anxious depression had a greater side effect burden (P = .0049) and were prescribed higher doses of venlafaxine (P = .0485) and mirtazapine (P = .0444); this continued at wk 28 (P = .0009), but doses no longer differed between groups; no differences were found between the 2 groups for response to any of the 3 treatments |
| Delini-Stula et al43 | Post hoc meta-analysis of 40 studies (38 double-blind, 2 single-blind) (n = 2,416 total) comparing moclobemide, imipramine, maprotiline, amitriptyline, mianserin, and placebo; varying lengths of studies; type 1 evidence | Defined 2 ways with 2 sets of analyses: (1) MDD or dysthymia plus > 2 on HDRS item 9 (agitation) (n = 190) (2) > 1.83 on HDRS A/S (n = 654) | Comparable efficacy of sedative and nonsedative antidepressants for treating anxious depression; benzodiazepine comedication had no added benefit; those with previous treatment failures were less likely to respond |
| Flint and Rifat44,45 | Post hoc, open-label study compared elderly subjects only (≥ 60 y) with anxious depression (n = 53)+ and nonanxious depression (n = 46)+ through a sequential administration trial with 3 treatment phases based on response; type 2 evidence | MDD plus HAD-A score ≥ 11 | Those with anxious depression were less likely to respond to nortriptyline monotherapy (P = .03) or nortriptyline ± lithium augmentation (P = .05); no differences in response were found with second-line therapy with phenelzine; those with anxious depression had higher attrition rates (P = .04) |
| Phase 1: Nortriptyline (6 wk), then nortriptyline + lithium (additional 2 wk) | After 2 years, no statistically significant differences were found between the 2 groups in the combined rates of relapse and recurrence (P = .21); however, those with continued significant anxiety scores at the point of response from the index depressive episode were found to have shorter time to relapse/recurrence | ||
| Phase 2: If nonresponsive to phase 1, then phenelzine (6 wk), then phenelzine + lithium (additional 2 wk) (n = 18 with anxious depression, n = 8 with nonanxious depression) | |||
| Phase 3: Electroconvulsive therapy (up to 12 treatments) or fluoxetine ± lithium (6 wk) |
a
MDD diagnosed by DSM-IV criteria unless otherwise stated; n = patients with anxious depression unless otherwise noted.
Abbreviations: A/S = HDRS anxiety/somatization factor score, BDI = Beck Depression Inventory, HAD-A = anxiety subscale of the Hospital Anxiety and Depression Scale, HARS = Hamilton Anxiety Rating Scale, HDRS = Hamilton Depression Rating Scale, MADRS = Montgomery-Asberg Depression Rating Scale, MDD = major depressive disorder, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, TCAs = tricyclic antidepressants.
Symbol: +n is the initial number of subjects who started.