On Lexapro and Wellbutrin Getting Depressed Again
J Psychiatr Pract. Author manuscript; bachelor in PMC 2009 Nov 17.
Published in final edited form as:
PMCID: PMC2778329
NIHMSID: NIHMS119470
An Open Pilot Study of the Combination of Escitalopram and Bupropion-SR for Outpatients With Major Depressive Disorder
Andrew F. Leuchter
Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, U.s.A
Ira G. Lesser
Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, California, UsA
Madhukar H. Trivedi
Section of Psychiatry, University of Texas Southwestern Medical School Dallas, Texas, UsaA
A. John Blitz
Department of Psychiatry, Academy of Texas Southwestern Medical School Dallas, Texas, U.S.A
David Due west. Morris
Department of Psychiatry, Academy of Texas Southwestern Medical School Dallas, Texas, UsA
Diane Warden
Department of Psychiatry, University of Texas Southwestern Medical Schoolhouse Dallas, Texas, The statesA
Maurizio Fava
Department of Psychiatry, Massachusetts Full general Hospital Boston, Massachusetts, U.S.A
Stephen R. Wisniewski
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health Pittsburgh, Pennsylvania, U.Southward.A
James F. Luther
Department of Epidemiology, Academy of Pittsburgh Graduate Schoolhouse of Public Health Pittsburgh, Pennsylvania, United states of americaA
Bradley N. Gaynes
Department of Psychiatry, Academy of North Carolina at Chapel Hill Chapel Hill, North Carolina, U.Southward.A
Jonathan W. Stewart
Department of Psychiatry, Columbia University Medical Center New York, New York, U.S.A
Abstract
Objective
Monotherapy with a selective serotonin reuptake inhibitor (SSRI) is the most mutual initial treatment for major depressive disorder (MDD), just this monotherapy leads to remission in fewer than a third of patients. The combination of the SSRI escitalopram and bupropion-SR is commonly used for treating patients with MDD who have had an inadequate response to antidepressant monotherapy. This pilot study was conducted to evaluate this combination in the handling of MDD in patients with chronic or recurrent MDD to gauge prophylactic, tolerability, and remission rates.
Method
In this written report, 51 outpatients with chronic or recurrent non-psychotic MDD were treated with a combination of escitalopram and bupropion-SR for upwardly to 12 weeks. Participants were started on escitalopram at x mg/mean solar day, and bupropion-SR was then added at week i, starting at 150 mg/mean solar day. The maximum dose of escitalopram was 20 mg/solar day and the maximum dose of bupropion-SR was 400 mg/day.
Results
Rates of response (62%) and remission (fifty%) at study go out (based on participants for whom at least 1 post-baseline measure was nerveless) were significantly higher than is typical for SSRI monotherapy. The level of treatment emergent events was depression, and simply iii participants (six%) discontinued handling due to side effects. The mean maximum dose of escitalopram was 18 mg/day, which was achieved by week 6, and the hateful dose at study leave was also 18 mg/day. The hateful maximum dose of bupropion-SR was 329 mg/twenty-four hour period, which was achieved by week 8, and the hateful dose at written report exit was 327 mg/twenty-four hours.
Conclusions
These results advise that the combination of escitalopram and bupropion-SR is constructive and well tolerated. Further controlled trials comparing this combination with monotherapy are needed.
Keywords: major depressive disorder, bupropion, escitalopram, medication combinations, adverse events
INTRODUCTION
Selective serotonin reuptake inhibitors (SSRIs) are the medications nigh commonly used as first-line handling for major depressive disorder (MDD). SSRIs, which are typically well tolerated and safety, usually lead to improvement in depressive symptoms; still, full remission does not occur in most patients. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) report assessed response and remission rates in 2,876 patients with MDD following initial handling with a highly selective SSRI, citalopram. After up to xiv weeks of treatment with citalopram at doses up to threescore mg/day, only 28.6% of patients had remission of low based on scores on the 17-item Hamilton Rating Scale for Low (HRSD17)1 in the modified intent-to-treat sample (i.e., participants with at least one post-baseline visit).2 Patients in the STAR*D study who did non accomplish remission with citalopram handling could move on to ane of several alternative treatments, one of which was a combination of citalopram with bupropion-SR (Wellbutrin SR). Trivedi and colleagues 3 reported that 29.7% of the patients in the group who received adjunctive bupropion-SR in doses up to 400 mg/solar day for an additional 12 weeks (based on the total intent-to-treat sample) accomplished remission.
Because the swell bulk of patients with MDD do not remit with initial SSRI monotherapy, it is appropriate to evaluate alternative approaches to antidepressant therapy. The current exercise of offset using antidepressant monotherapy for eight--12 weeks does not pb to remission in most patients; in the STAR*D study, almost patients did not remit until their treatment either was inverse to a 2nd antidepressant or they received an antidepressant combination handling. The current prototype that specifies first using a full course of antidepressant monotherapy may, therefore, contribute to protracted handling from which many patients will fail to benefit, and there may exist meaning attrition.4 In order to shorten the time to remission, one possible selection is to use a combination of antidepressant medications early on in the form of the illness. Theoretically, apply of 2 medications with complementary mechanisms of activeness as an early on handling choice could lead to remission and a shorter course of illness for many patients.5 Before such a handling strategy could be considered for widespread apply, notwithstanding, it would be necessary to show that it was safe and well-tolerated for a range of subjects with MDD.
The combination of bupropion-SR and an SSRI is a handling strategy that is ordinarily used for treatment-resistant MDD.6 The ii medications have disparate (and possibly complementary) mechanisms of action.seven This combination is also popular considering open-label studies accept suggested that it is safe, effective, and may assist reverse some of the sexual dysfunction seen with SSRI monotherapy.8 All the same, systematic data are express regarding the safety, tolerability, and effectiveness of combinations of an SSRI plus bupropion-SR in the treatment of a range of patients with MDD. Given the depression remission rates accomplished using optimal dosing and duration of handling with single SSRIs, combining an SSRI and bupropion-SR early in the course of treatment may exist useful in achieving college rates of response and remission, specially for those with chronic or recurrent depression.
The purpose of this study was to examine the safety, tolerability, and efficacy of the combination of the SSRI escitalopram (the s-isomer of citalopram) and bupropion-SR in an open up label trial involving outpatients with nonpsychotic chronic and/or recurrent MDD. Escitalopram was selected as the SSRI because information technology is ane of the most usually used medications for MDD, is well tolerated, and has a depression chance of drug-drug interactions.
MATERIALS AND METHODS
This pilot study was performed as office of the Low Trials Network, a national infrastructure for research in low funded past the National Institute of Mental Health (NIMH). The investigation was carried out in accordance with the latest version of the Declaration of Helsinki. The project was overseen past the network's National Coordinating Center at the University of Texas Southwestern Medical School and the Information Coordinating Heart at the University of Pittsburgh. A Information Safe and Monitoring Board oversaw prophylactic bug, the capability and integrity of information, and the study's capabilities to meet its objectives. The written report was conducted at four sites: the Department of Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine at the University of California Los Angeles (UCLA), the Department of Psychiatry at Harbor-UCLA Medical Center, the Clinical Research Establish at the Academy of Kansas School of Medicine, and the Department of Psychiatry at the Columbia University College of Physicians and Surgeons.
Participants
The written report enrolled outpatients, xviii--65 years of age, who met Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-Four)ix criteria for chronic and/or recurrent non-psychotic MDD every bit documented by a DSM-Four checklist and confirmed by the Mini-International Neuropsychiatric Interview Plus (MINI Plus).x Participants were recruited through their treating md or dispensary staff using confidential procedures approved past local Institutional Review Boards, or via flyers and/or posters in the customs. Participants had to exist fluent in English, since non-English-speaking personnel were non bachelor for the report. Participants also had to be able to sympathise the nature of the study and sign written informed consent. After consent was obtained, a physician determined eligibility for participation based on a diagnostic interview. To be enrolled in the written report, participants had to take a baseline score ≥ 14 on the 17-item Hamilton Rating Scale for Depression (HRSD17).ane In addition, to participate in the written report, patients were required to have clinician approval indicating that treatment with antidepressant medications in combination was appropriate and safe based on the patients' symptoms and medical condition, particularly for participants who were taking other not-excluded concomitant medications. Participants in the written report received $80 as bounty for their time.
Patients were excluded if they had a lifetime history of bipolar I or Two disorder or bipolar disorder not otherwise specified (NOS), schizophrenia, schizoaffective disorder, psychosis NOS, anorexia nervosa or bulimia nervosa, or a current primary diagnosis of obsessive-compulsive disorder. Patients were excluded if they had a clear-cut intolerance for either escitalopram or bupropion-SR or a lack of response to an adequate trial of the combination in the current episode of MDD (patients who had failed to respond to monotherapy with one of the drugs were eligible to participate). The study as well excluded patients who had received and did not respond to 7 or more sessions of electroconvulsive therapy during the current episode of MDD. Women who were sexually active and were not using adequate contraception, or who were pregnant or breast-feeding were also excluded from the study. Boosted exclusion criteria included any general medical condition or concomitant medication(south) that contraindicated use of the medication combination used in the study; the need for firsthand hospitalization for substance/alcohol detoxification or treatment, or firsthand hospitalization for a psychiatric disorder; or the use of exclusionary medications (antipsychotic or anticonvulsant medications, mood stabilizers, primal nervous system stimulants, or antidepressant medication used for the treatment of depression or other purposes such as smoking abeyance). Patients taking thyroid medication for hypothyroidism could exist included if they had been stable on the medication for 3 months, as could patients who were participating in a modality of psychotherapy that was not targeting depressive symptoms (e.g., supportive therapy, marital therapy). Patients who were receiving therapy that was depression-specific, such as cognitive therapy or interpersonal psychotherapy of depression, were excluded. Patients were also excluded if they had current booze dependence or abuse (i.due east., during the previous 6 months), pregnant liver affliction for which the use of the study medication was contraindicated, a known hypersensitivity to either study medication, uncontrolled narrow-angle glaucoma, or if they were taking monoamine oxidase inhibitors.
Measures
Participants were seen for eight clinic visits, including evaluation at baseline and at weeks i, 2, 4, vi, 8, ten, and 12. The baseline visit lasted nigh one hour and each follow-up visit lasted approximately 30 minutes. The Quick Inventory of Depressive Symptomatology--Self-Rated (QIDS-SR16)11 , 12 was collected at baseline and at each clinic visit every bit a chief outcome measure of remission and response and of severity of depression. Self-reports take frequently been used in effectiveness trials (east.one thousand., the Affect13 and PATHWAYSxiv studies). In improver, the QIDS-SR16 is highly reflective of results obtained with the HRSD17. Information technology reduces patient burden, provides a cost-efficient and reliable measure of outcome that abrogates the need for independent clinician ratings, is every bit sensitive to symptom change as clinician ratings,15 and has been proven to be equally reliable and valid as the Quick Inventory of Depressive Symptomatology--Clinician Rating (QIDS-C16).11 , 12 Severity of depressive symptoms was as well assessed at baseline and at each subsequent visit by clinicians using the QIDS-Cxvi. Clinicians also assessed side effects and possible adverse events during the course of handling using the cocky-study Frequency, Intensity, and Burden of Side Effects Rating (FIBSER),16 the 55-item, self-report Systematic Assessment for Handling Emergent Events--Systematic Inquiry (SAFTEE-SI),17 the 4-item, clinician-rated Barnes Akathisia Rating Scale (Bars),18 and the 5-item, clinician-rated Abnormal Involuntary Movement Calibration (AIMS).19 These measures provided consistent data regarding medication side effects and tolerability. Data on side effects and agin events were nerveless at each visit, along with measures of blood pressure, pulse, and weight. Written report physicians used the General Principles for Treatment Implementationxx and symptom severity and tolerability information to brand dose adjustments as needed. These measures and procedures (i.e., a measurement-based approach to care) were successfully used in the STAR*D written report and resulted in high-quality care with vigorous just tolerable dosing in both primary care and psychiatric settings.
Intervention
Participants were started on escitalopram x mg/day, and bupropion-SR 150 mg/day was added at calendar week i. Participants were eligible to receive an increased dose of escitalopram (an additional 10 mg/twenty-four hour period) starting at week four, or of bupropion-SR (up to an additional 300 mg/twenty-four hours at week iv or 400 mg/twenty-four hour period at weeks vi--10) if they did non respond to the medication combination (score on QIDS-Cxvi eleven , 12 ≥ ix) or had a partial response (QIDS-C16 = 6--8). Medications were maintained at the same dosage if participants achieved remission (QIDS-Cxvi ≤ 5). Dosage of the medications could exist decreased or the participant could exit the study if pregnant side effects could non be managed within the protocol.
Data Analysis
The goals of this study were to determine the proportion of participants who achieved remission and to evaluate the side furnishings experienced by the participants. Remission was divers as a QIDS-SRsixteen score ≤ 5 at the final dispensary visit. Response was defined equally an comeback of ≥ 50% on the QIDS-SR16 score relative to baseline. Intolerable side effects were defined as compunction due to side effects or an indication of at least astringent damage due to side effects as rated on the FIBSER. A 90% confidence interval was used to gauge the variability of each proportion.
Descriptive statistics are presented as means (standard deviations) for continuous variables and percentages for discrete variables. Kaplan-Meier methods were used to estimate the cumulative proportion with first remission, first response, and study discontinuation.
RESULTS
Of the 53 participants who were screened for the written report, 2 were adamant to exist ineligible, none refused to participate, and 51 were enrolled in the protocol. Sociodemographic and clinical characteristics of the sample are shown in Tabular array 1. Participants were predominantly female and Caucasian, with multiple past episodes of depression. The boilerplate elapsing of the electric current episode was more than than 5 years (hateful = 67 ± 103 months]. Approximately ii-thirds of participants met criteria for chronic low and three-quarters met criteria for recurrent depression. Of the 51 participants, 21 (41%) participants had had no prior antidepressant trials, 20 (39%) had had one failed prior antidepressant trial, and 10 (20%) had had two prior failed antidepressant trials. More than one-half had some caste of suicidal ideation. Farther details on comorbid diagnoses are presented in Table one.
Table 1
Sociodemographic and clinical characteristics
| Characteristic | Due north4 | Hateful±SD due north (%) |
|---|---|---|
| Age, yr | 51 | 45 ± 14 |
| Male gender | 51 | 14 (27) |
| Race | ||
| Caucasian | 51 | 46 (xc) |
| African-American | 51 | 2 (4) |
| Other | 51 | 3 (six) |
| Illness onset age, twelvemonth | 51 | 24 ± 14 |
| Number of lifetime episodes | 51 | 5 ± 5 |
| Current episode duration, months | 51 | 67 ± 103 |
| Received psychotropics, current episode | 51 | 18 (35) |
| Number of prior failed trials | ||
| 0 | 51 | 21 (41) |
| 1 | 51 | 20 (39) |
| two | 51 | 10 (xx) |
| MINIi diagnoses (current) | ||
| Major depressive episode | 51 | 51 (100) |
| Mood disorder related to GMC2 | 51 | 1 (two) |
| Substance-induced mood disorder | 51 | 0 (0) |
| Chronic depression | 51 | 33 (65) |
| Recurrent depression | 51 | 38 (75) |
| Melancholic depression | 51 | 21 (41) |
| Dysthymiaiii | 38 | 2 (v) |
| Suicide risk | 51 | 28 (55) |
| Agoraphobia | 51 | ii (iv) |
| Panic disorder without agoraphobia | 51 | 1 (2) |
| Panic disorder with agoraphobia | 51 | ane (ii) |
| Agoraphobia without panic history | 51 | 0 (0) |
| Agoraphobia with panic history | 51 | 1 (2) |
| Agoraphobia without history of limited symptom attacks | 51 | 0 (0) |
| Social phobia | 51 | 6 (12) |
| Specific phobia | 51 | four (viii) |
| Obsessive-compulsive disorder (OCD) | 51 | 3 (half dozen) |
| GMC-related OCD | 51 | 0 (0) |
| Substance-induced OCD | 51 | 0 (0) |
| Posttraumatic stress disorder | 51 | 1 (ii) |
| Alcohol dependence | 51 | 0 (0) |
| Alcohol abuse | 51 | 0 (0) |
| Substance dependence | 51 | 0 (0) |
| Substance corruption | 51 | 0 (0) |
| Generalized anxiety disorder | 51 | 17 (33) |
| Premenstrual dysphoric disorder | 36 | iv (11) |
The mean maximum dose of escitalopram was eighteen mg/solar day and of bupropion-SR was 329 mg/solar day; these doses were achieved by handling weeks 6 and 8, respectively (Table 2). The mean doses at week 12 were 16 mg/day of escitalopram and 328 mg/day of bupropion-SR. Of the 51 participants who entered the protocol, x discontinued before completion, 3 due to medication side effects and 7 due to reasons unrelated to medication (e.g., fourth dimension commitments). Two of the three participants who withdrew due to side effects discontinued during the first week of the protocol. The highest frequency, intensity, and brunt of side effects were reported between weeks 2 and 8 of treatment. One serious adverse issue was reported, a hospitalization for worsening depression and the evolution of suicidal ideation after medication was discontinued.
Table ii
Dosage, discontinuation, and adverse events by week
| Week 0 | Week 1 | Week 2 | Week iv | Week 6 | Calendar week viii | Week 10 | Week 12 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Characteristic | N | Mean±SD n (%Northward) | N | Mean± SD due north (%N) | N | Mean±SD due north (%N) | N | Mean±SD n (%N) | Due north | Mean±SD due north (%North) | North | Mean±SD north (%N) | N | Hateful±SD due north (%North) | N | Mean±SD n (%N) |
| Bupropion-SR, mg | 39 | 150±0 | 46 | 157±33 | 45 | 267±63 | 42 | 295±85 | 38 | 329±85 | 40 | 328±80 | 41 | 328±85 | ||
| Escitalopram, mg | fifty | 10±0 | twoscore | 10±1 | 46 | 10±two | 45 | 17±5 | 42 | eighteen±4 | 38 | xviii±iv | 40 | eighteen±four | 41 | xvi±5 |
| Side effects (FIBSER1) | ||||||||||||||||
| ≥ 50% of the time | xl | 9 (23) | 46 | 17 (37) | 45 | 17 (38) | 41 | 11 (27) | 38 | 14 (37) | 39 | 14 (36) | 41 | 10 (24) | ||
| ≥ Moderate intensity | 40 | 12 (30) | 46 | 17 (37) | 45 | xvi (36) | 41 | 16 (39) | 38 | 14 (37) | 39 | 13 (33) | 41 | eleven (27) | ||
| ≥ Moderate burden | xl | vii (18) | 46 | 8 (17) | 45 | 11 (24) | 41 | nine (22) | 38 | 8 (21) | 39 | 7 (eighteen) | 41 | 6 (xv) | ||
| Cumulative discontinuation | ||||||||||||||||
| Any reason | 51 | 5 (10) | 51 | 5 (10) | 51 | 5 (10) | 51 | 6 (12) | 51 | viii (sixteen) | 51 | 9 (18) | 51 | ten (20) | 51 | 10 (twenty) |
| Side effects | 51 | 2 (four) | 51 | 2 (4) | 51 | 2 (4) | 51 | 2 (four) | 51 | 3 (vi) | 51 | three (6) | 51 | 3 (6) | 51 | 3 (6) |
| Hypertension2 | 47 | 2 (four) | 38 | ane (3) | 45 | 3 (vii) | 45 | 3 (7) | 41 | 0 (0) | 38 | 2 (5) | 38 | 0 (0) | 39 | 0 (0) |
| ≥ 10% systolic increase | 38 | iv (11) | 44 | 3 (7) | 44 | 2 (5) | 41 | 5 (12) | 37 | 6 (16) | 37 | 2 (5) | 38 | 5 (13) | ||
| ≥ 10% diastolic increase | 38 | 6 (16) | 44 | eight (18) | 44 | 11 (25) | 41 | six (15) | 37 | 7 (nineteen) | 37 | 7 (19) | 38 | 8 (21) | ||
| Pulse | 47 | 76±ten | 38 | 76±10 | 45 | 77±11 | 44 | 76±10 | 41 | 76±ten | 38 | 77±10 | 37 | 77±13 | 39 | 77±eleven |
| ≥ 10% pulse increment | 38 | 9 (24) | 44 | 10 (23) | 43 | 12 (28) | 41 | 15 (37) | 37 | 11 (30) | 37 | 12 (32) | 38 | 14 (37) | ||
| Weight, lb | 48 | 190±61 | 38 | 188±61 | 43 | 190±62 | 43 | 192±62 | 41 | 191±64 | 36 | 192±67 | 37 | 192±64 | 38 | 188±67 |
| ≥ 7% weight increase | 37 | 0 (0) | 43 | 0 (0) | 43 | 0 (0) | 41 | 0 (0) | 35 | 0 (0) | 37 | 0 (0) | 38 | 1 (3) | ||
| AIMSthree full score ≥ 2 | 51 | 1 (2) | 39 | i (3) | 45 | ii (4) | 45 | 1 (ii) | 41 | one (2) | 38 | 0 (0) | 38 | 1 (three) | xl | 1 (three) |
| ≥ Moderate akathisiaiv | l | 1 (2) | 39 | 0 (0) | 45 | 0 (0) | 45 | one (2) | 41 | 0 (0) | 38 | 0 (0) | 38 | 0 (0) | forty | 0 (0) |
Of the 46 patients for whom information from at least one post-baseline visit were bachelor, 24 patients (52%) reported at to the lowest degree a moderate side-effect burden (divers by a FIBSER score > 2) at some point during the study, although simply 7 patients (fifteen%) reported this level of burden at their terminal visit (Table iii). A variety of specific somatic complaints were reported on the SAFTEE-SI prior to handling (Tabular array iv), the most prevalent being "problem sleeping," "weakness and fatigue," "irritable," "trouble concentrating," and "feeling drowsy or sleepy." The most commonly reported treatment-emergent side furnishings at any point during the course of treatment were "feelings of drowsiness or sleepiness," "delayed, absent orgasm," "loss of sexual interest," "aloofness," "nightmares," and "muscle twitching." (Table 4) Of those symptoms not present at baseline, those with the highest incidence at the terminal study visits were "delayed, absent orgasm," "sweating excessively," "sexual arousal issues," and "apathy." Very few subjects reported sexual difficulties at the cease of the study that were worse than at baseline: in that location was one report of "loss of sexual involvement" and one of "delayed, absent orgasm" that were worse than at report entry. Of the participants who presented with a specific somatic symptom, nearly reported an improvement in the severity of the symptom at study exit, except for those with "numbness or tingling" in whom the severity of the complaint improved in only half of the participants. Weight gain and akathisia were uncommon. The side-effect burden was lower among participants who remitted than in those who did non, but rates of hypertension, weight change, and akathisia were not different among remitters and nonremitters (Table v).
Tabular array iii
Handling-emergent adverse events, remission, and responsei
| Baseline | E'er | Get out | ||||
|---|---|---|---|---|---|---|
| Characteristic | N | n (%Due north±.5CI2) | N | n (%N±.5CItwo) | Northward | n (%Northward±.5CI2) |
| ≥Moderate side effect brunt3 | 46 | 24 (52±14) | 46 | 7 (15±10) | ||
| Hypertension4 | 47 | two (iv±5) | 49 | 8 (16±10) | 49 | 0 (0±0) |
| ≥10% systolic increase | 45 | 12 (27±13) | 45 | vii (16±eleven) | ||
| ≥ten% diastolic increase | 45 | 17 (38±14) | 45 | 9 (20±12) | ||
| ≥7% weight increase | 45 | 1 (ii±3) | 45 | 1 (2±3) | ||
| AIMSv total score ≥2 | 51 | i (2±3) | 51 | five (ten±8) | 51 | 1 (2±iii) |
| ≥Moderate akathisiahalf-dozen | 50 | ane (ii±3) | 51 | 2 (4±5) | 51 | 0 (0±0) |
| Remission7 | 46 | xxx (65±14) | 46 | 23 (fifty±fourteen) | ||
| Response8 | 45 | 33 (73±13) | 45 | 28 (62±14) | ||
Table 4
Systematic assessment for handling emergent effects: percentage present and percent change1
| All participantsii | Furnishings not present at baseline | Results at study exit for effects present at baseline | ||||||
|---|---|---|---|---|---|---|---|---|
| Effect | Niii | Baseline | Post-baselineiv | Leaveiv | N | Worse | Aforementioned | Better |
| Problem sleeping | 45 | 33 (73) | 8 (18) | 1 (2) | 33 | i (3) | 8 (24) | 24 (73) |
| Nightmares | 45 | 15 (33) | 12 (27) | iii (7) | 15 | 0 (0) | 3 (20) | 12 (fourscore) |
| Feeling drowsy or sleepy | 45 | 23 (51) | 15 (33) | 3 (7) | 23 | i (4) | 3 (xiii) | 19 (83) |
| Feeling nervous or hyper | 45 | 19 (42) | 10 (22) | two (4) | 19 | 0 (0) | 3 (xvi) | 16 (84) |
| Weakness or fatigue | 45 | 26 (58) | x (22) | two (4) | 26 | 0 (0) | 4 (15) | 22 (85) |
| Irritable | 45 | 26 (58) | 5 (xi) | 0 (0) | 26 | 0 (0) | 5 (19) | 21 (81) |
| Poor memory | 45 | 16 (36) | 7 (16) | 0 (0) | 16 | 0 (0) | 5 (31) | eleven (69) |
| Trouble concentrating | 45 | 26 (58) | vii (sixteen) | 0 (0) | 26 | one (four) | eight (31) | 17 (65) |
| Feeling strange or unreal | 45 | 11 (24) | 2 (4) | 0 (0) | 11 | 0 (0) | i (nine) | 10 (91) |
| Hearing or seeing things | 45 | 0 (0) | 2 (4) | 0 (0) | 0 | 0 (0) | 0 (0) | 0 (0) |
| Abnormal sensations | 45 | 2 (iv) | half-dozen (13) | ane (2) | ii | 0 (0) | 0 (0) | ii (100) |
| Numbness or tingling | 45 | vi (13) | 3 (7) | 0 (0) | 6 | 0 (0) | 3 (50) | 3 (50) |
| Dizziness or faintness | 45 | 6 (13) | 6 (13) | 0 (0) | 6 | 0 (0) | 1 (17) | 5 (83) |
| Headache | 45 | 18 (twoscore) | 6 (13) | 0 (0) | 18 | 0 (0) | 5 (28) | 13 (72) |
| Blurred Vision | 45 | vii (xvi) | half-dozen (thirteen) | iii (seven) | 7 | 0 (0) | 1 (fourteen) | 6 (86) |
| Ringing in ears | 45 | 2 (four) | iv (9) | two (4) | 2 | 0 (0) | 0 (0) | 2 (100) |
| Stuffy olfactory organ | 45 | 7 (16) | vii (16) | 3 (7) | seven | 0 (0) | 1 (14) | half-dozen (86) |
| Dry out oral cavity | 45 | 11 (24) | 10 (22) | 2 (four) | 11 | 0 (0) | 3 (27) | 8 (73) |
| Increased salivation | 45 | iii (7) | 2 (4) | 0 (0) | 3 | 0 (0) | 0 (0) | 3 (100) |
| Muscle cramps, stiffness | 45 | 11 (24) | 8 (eighteen) | i (2) | eleven | 0 (0) | two (eighteen) | 9 (82) |
| Muscle twitching | 45 | 4 (9) | 12 (27) | iii (vii) | iv | 0 (0) | 0 (0) | 4 (100) |
| Trouble sitting still | 45 | 7 (16) | 7 (16) | ii (4) | 7 | 0 (0) | ii (29) | 5 (71) |
| Tremor, shakiness | 45 | 3 (vii) | viii (18) | 4 (9) | 3 | 0 (0) | 0 (0) | 3 (100) |
| Poor coordination | 45 | ii (4) | seven (16) | ane (2) | 2 | 0 (0) | 0 (0) | two (100) |
| Slurred spoken communication | 45 | two (4) | 0 (0) | 0 (0) | 2 | 0 (0) | 0 (0) | ii (100) |
| Heartbeat rapid, pounding | 45 | 8 (eighteen) | 2 (4) | 0 (0) | 8 | 0 (0) | 2 (25) | 6 (75) |
| Trouble communicable breath | 44 | 4 (ix) | v (11) | three (seven) | 4 | 0 (0) | 0 (0) | 4 (100) |
| Chest pain | 45 | 2 (4) | 2 (four) | 0 (0) | 2 | 0 (0) | 0 (0) | 2 (100) |
| Nausea, vomiting | 45 | 1 (2) | 7 (16) | 3 (7) | ane | 0 (0) | 0 (0) | i (100) |
| Abdominal discomfort | 45 | eleven (24) | 10 (22) | 0 (0) | 11 | 0 (0) | 0 (0) | eleven (100) |
| Constipation | 45 | 2 (4) | 11 (24) | 3 (7) | ii | 0 (0) | 0 (0) | two (100) |
| Diarrhea | 45 | 2 (4) | five (11) | 2 (iv) | 2 | 0 (0) | 0 (0) | 2 (100) |
| Difficulty urinating | 45 | 0 (0) | 2 (four) | 0 (0) | 0 | 0 (0) | 0 (0) | 0 (0) |
| Frequent demand to urinate | 45 | 6 (xiii) | 7 (xvi) | 2 (4) | 6 | 0 (0) | 0 (0) | 6 (100) |
| Menstrual irregularities | 40 | 3 (8) | 3 (8) | 0 (0) | iii | 0 (0) | 0 (0) | 3 (100) |
| Loss of sexual involvement | 45 | 21 (47) | 12 (27) | ii (four) | 21 | i (5) | 6 (29) | 14 (67) |
| Sexual arousal issues | 43 | 15 (35) | 11 (26) | 4 (nine) | xv | 0 (0) | 3 (xx) | 12 (80) |
| Delayed, absent orgasm | 43 | 11 (26) | 13 (thirty) | vi (xiv) | xi | 1 (9) | ii (18) | 8 (73) |
| Sweating excessively | 45 | 8 (18) | 10 (22) | 4 (9) | 8 | 1 (13) | one (13) | half-dozen (75) |
| Fluid retention, swelling | 45 | 5 (11) | 2 (four) | 0 (0) | 5 | 0 (0) | 1 (xx) | 4 (80) |
| Ambition decreased | 45 | five (11) | 9 (twenty) | 3 (vii) | v | 0 (0) | 1 (twenty) | 4 (eighty) |
| Ambition increased | 45 | 14 (31) | five (11) | 0 (0) | 14 | 0 (0) | 0 (0) | 14 (100) |
| Weight gain | 45 | 11 (24) | half-dozen (13) | 0 (0) | eleven | 0 (0) | 0 (0) | 11 (100) |
| Weight loss | 45 | iii (vii) | iii (7) | one (2) | 3 | 0 (0) | 0 (0) | 3 (100) |
| Skin rash, allergy | 45 | 5 (xi) | 3 (7) | 0 (0) | 5 | 0 (0) | 0 (0) | 5 (100) |
| Diminished mental vigil | 44 | xv (34) | two (5) | 0 (0) | xv | ane (7) | v (33) | 9 (threescore) |
| Difficulty finding words | 45 | xiii (29) | 4 (nine) | 1 (2) | 13 | 2 (15) | 1 (8) | 10 (77) |
| Apathy | 45 | 13 (29) | 12 (27) | 4 (9) | 13 | i (8) | 1 (8) | eleven (85) |
| Dizziness | 45 | 7 (16) | four (9) | 3 (7) | vii | 0 (0) | 2 (29) | 5 (71) |
| Bruising | 44 | 2 (v) | 2 (5) | 1 (ii) | ii | 0 (0) | 0 (0) | 2 (100) |
| Hair thinning/loss | 45 | 3 (7) | two (4) | one (ii) | 3 | 0 (0) | ane (33) | 2 (67) |
| Hot flashes | 45 | 8 (18) | vi (13) | two (4) | 8 | ane (xiii) | 0 (0) | 7 (88) |
| Clenching of teeth | 45 | thirteen (29) | ane (two) | 0 (0) | 13 | 0 (0) | 3 (23) | ten (77) |
| Strange taste in mouth | 45 | 3 (seven) | 11 (24) | 3 (7) | 3 | 0 (0) | 0 (0) | 3 (100) |
| Unable to sit notwithstanding | 45 | v (11) | half dozen (xiii) | 2 (4) | 5 | 0 (0) | 1 (20) | 4 (80) |
| Bothered by side furnishings | 45 | 25 (56) | ten (22) | 3 (7) | 25 | 0 (0) | five (twenty) | 20 (80) |
Table v
Adverse events by remission at exitone
| Remission2 | ||||
|---|---|---|---|---|
| Feature | Total (N=46)3 | Yep (North=23) | No (N=23) | p |
| Side furnishings (FIBSER4) | ||||
| ≥50% of the fourth dimension | 12 (26.1) | three (13.0) | 9 (39.1) | 0.0439 |
| ≥Moderate intensity | 13 (28.3) | 4 (17.four) | 9 (39.i) | 0.1016 |
| ≥Moderate burden | eight (17.iv) | i (four.3) | 7 (30.4) | 0.0196 |
| Hypertensionv | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
| ≥10% systolic increase | seven (15.9) | iv (17.4) | iii (fourteen.iii) | 0.7785 |
| ≥ten% diastolic increase | 9 (20.5) | 5 (21.7) | 4 (19.0) | 0.8250 |
| Pulse | 77.0±10.4 | 76.three±9.0 | 77.eight±11.9 | 0.8194 |
| ≥ten% pulse increment | 15 (34.1) | vii (30.four) | 8 (38.1) | 0.5923 |
| Weight, per centum modify | -ane.four±seven.two | -2.6±9.0 | -0.2±four.5 | 0.2086 |
| ≥7% weight increment | ane (two.3) | 1 (four.3) | 0 (0.0) | 0.3338 |
| AIMS6 total score ≥ii | 1 (2.2) | 0 (0.0) | 1 (4.3) | 0.3120 |
| Moderate akathisia7 | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
Of the 49 patients for whom post-baseline data on blood pressure were available, 8 patients (sixteen%) had clinical hypertension defined equally systolic blood pressure > 140 and diastolic blood pressure > xc at some point during the study, but none of the patients had hypertension at the terminal visit (Table 3). However, up to 38% (17/45) of participants reported at least a 10% increment in systolic and/or diastolic blood pressure at some indicate during the study.
Of the 51 participants, more than l% (27 patients) responded to combination drug treatment by week 8, 65% (33/51) responded by week 12, and 62% (28/45) had responded at study exit. Of the 51 participants, 59% (30 patients) had remitted by the end of week 12 and 50% (23/46) had remitted at study leave (Table half-dozen). Of the 17 patients who had had no prior failed treatment trials and completed the written report, 64% (11 patients) were in remission at leave, compared with 58% (11/19) of those who had had 1 failed trial, and x% (1/9) of those who had had two prior failed handling trials (p = 0.017), showing an inverse relationship between the remission rate and the number of prior unsuccessful treatment trials. The times to first remission, first response, and discontinuation are presented in Figure i. For those participants who achieved remission, the percentage achieving first remission by week are shown in Figure two. About 40% of those who ultimately remitted did and then after vi weeks.
Cumulative probability of discontinuation, remission, and response by calendar week
Pct distribution of calendar week of first remission (QIDS-SR16 ≤5) for participants in remission at go out
Tabular array six
Outcomes by week
| Calendar week 0 | Week 1 | Calendar week two | Week 4 | Week 6 | Week 8 | Week x | Week 12 | Exit | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Characteristic | Due north | Mean±SD n (%N) | Northward | Mean±SD north (%N) | North | Mean±SD n (%N) | N | Mean±SD n (%Due north) | Due north | Mean±SD n (%N) | N | Mean±SD n (%N) | Due north | Mean±SD north (%N) | North | Mean±SD n (%Due north) | Northward | Mean±SD n (%N) |
| QIDS-C16 i | 50 | 15±three | 40 | 12±4 | 46 | 11±4 | 45 | ten±four | 42 | viii±4 | 38 | 8±4 | 40 | 7±4 | 41 | vii±5 | 51 | vii±v |
| QIDS-SR16 2 | 49 | fourteen±4 | 39 | 11±5 | 45 | x±4 | 45 | 9±5 | 41 | 8±5 | 38 | 8±5 | 38 | seven±v | 40 | vii±five | 50 | 7±5 |
| Cumulative remission3 | 51 | half-dozen (12) | 51 | viii (16) | 51 | 16 (31) | 51 | 21 (41) | 51 | 22 (43) | 51 | 25 (49) | 51 | 30 (59) | 46 | 23 (50) | ||
| Cumulative responsefour | 51 | vi (12) | 51 | 10 (twenty) | 51 | eighteen (35) | 51 | 25 (49) | 51 | 27 (53) | 51 | 31 (61) | 51 | 33 (65) | 45 | 28 (62) | ||
Give-and-take
The results of this study betoken that the combination of escitalopram and bupropion-SR is safe, well tolerated, and effective. The 12-week response and remission rates found for the combination were meaningfully college than those that take been reported with SSRI monotherapy in nearly studies, 3 , 21 and higher than those reported previously for combination therapy post-obit unsuccessful monotherapy.three Although the high remission rate reported in this written report is encouraging, and could advise that the combination of escitalopram and bupropion-SR is preferable to initial antidepressant monotherapy, this conclusion is not fully supported by the data presented hither. There was no comparison of the medication combination with monotherapy using the individual agents within the same study. Such a comparison would be necessary in order to demonstrate superiority of the combination. Furthermore, the medications were administered in an open up-label manner. Open up-label designs accept been reported to increase placebo response rates and, in the absenteeism of a placebo control group, information technology is difficult to assess the specific effectiveness of the medications.
A primary goal of this report was to establish whether this medication combination would exist prophylactic and well-tolerated in well characterized patients typical of those seen in "real earth" settings. A bulk of patients in this written report suffered from chronic and recurrent MDD and had failed to benefit from previous antidepressant medication treatment. For approximately 40% of subjects, the medication combination was the initial treatment in the electric current episode. In this wide range of subjects, few participants discontinued handling due to emergent adverse events, and the rates of the most common treatment-emergent events (sexual dysfunction, sweating, aloofness) were relatively low. Although this written report did not compare SSRI monotherapy with combined therapy, the rate of handling-emergent sexual dysfunction with the escitalopram bupropion combination therapy was lower in this report than has been noted in many previous reports of SSRI monotherapy.22 The SAFTEE-SI information betoken that very few of the adverse events reported were actually worse at the terminate of treatment than at the beginning (i.due east., apparent agin events may not have been treatment-related). Although some participants experienced increases in claret force per unit area, no cases of sustained hypertension were noted at report exit. Information technology is possible that using the combination of escitalopram and bupropion-SR as an initial therapy for the treatment of chronic and recurrent depression offers advantages over initial monotherapy.
Considering of the low remission rates seen with antidepressant monotherapy, and the favorable outcomes, safety, and tolerability of the escitalopram and bupropion-SR combination reported here and elsewhere, clinicians may want to consider using this medication combination before in the form of antidepressant treatment. This approach is supported by previous prospective studies and retrospective reports regarding the effectiveness of the combination of bupropion-SR and an SSRI. DeBattista et al.23 performed a prospective open-label 6-week study with 28 patients who were either partial- or not-responders to SSRI treatment. Bupropion-SR was added to these patients' preexisting medication regimen (primarily fluoxetine, sertraline, or paroxetine) in doses of 150--300 mg/day (hateful dose 275 mg/day). The medication combination was well tolerated, with only i participant discontinuing due to a treatment-emergent agin event, and 54% of participants responded by week six. In a 2nd open-label study, Lam et al.24 treated 61 patients with treatment-resistant depression who had non achieved remission with either bupropion-SR or citalopram alone by initiating 6 weeks of treatment using ane of 2 methods: switching to the other medication (northward = 29) or combining the two medications (n = 32). The mean dose of bupropion-SR used in the combination was 248 mg/day. In this report, the combined medication therapy was superior to either monotherapy to which patients were switched in terms of final depression rating scores and remission rates (28% for the combination versus 7% for monotherapy), although there was no statistically significant difference in response rates between monotherapy and combination therapy. The adverse events with combined therapy were not significantly different from those with monotherapy and no participants discontinued treatment due to side effects. Finally, Ramasubbu25 treated 6 patients who were partially responsive to a combination of an SSRI and lithium by calculation either desipramine or bupropion-SR. He reported that both medications yielded expert symptomatic improvement and that the addition of bupropion-SR was better tolerated.
In a retrospective study of 27 patients who received combination treatment with bupropion-SR and an SSRI (primarily fluoxetine or sertraline),26 combination therapy was associated with greater symptomatic improvement than monotherapy, yet rates of agin events were similar in those receiving combination therapy compared with those receiving monotherapy. Spier27 reported on 15 patients who had accomplished an inadequate handling response with monotherapy and who were and so treated with bupropion-SR in improver to either an SSRI or venlafaxine. He plant that combination therapy was well tolerated, and that lxxx% of the patients responded. Finally, in a posthoc analysis of data from 53 geriatric patients who had not responded to paroxetine plus interpersonal psychotherapy, Whyte et al.28 compared a number of different switching strategies: switching to venlafaxine-XR monotherapy versus switching to a multifariousness of different combination strategies involving bupropion-SR, nortriptyline, or lithium. They reported that all of the medication combinations produced response rates comparable to the monotherapy strategy, and that all of the combinations were associated with college rates of treatment-emergent adverse events that led to discontinuation than was monotherapy. The lower reported efficacy and higher reported rates of discontinuation due to side effects may reflect the fact that the participants were geriatric patients, and this may limit generalizability of the findings.
The results of this pilot written report must exist interpreted with caution as there were several study limitations. This was an open up-label medication study and such studies ordinarily yield college rates of clinical improvement than do blinded studies. Furthermore, because this report had no monotherapy or placebo comparing groups, it is impossible to know how participants might have fared on monotherapy under similar clinical weather condition. Participants in the written report did receive more individualized attention (due east.yard., more than frequent visits, more diligent management) than is typical in routine clinical practice, which may have contributed to higher than usual remission and response rates. Finally, although nosotros did document symptom improvement with this medication combination, we did non document improvement in overall functional status.
Despite these limitations, the results presented hither are encouraging and indicate that pharmacotherapy with the combination of escitalopram and bupropion-SR merits consideration equally an early treatment option in MDD. However, this study does not assistance identify which patients are likely to benefit more from combination handling than monotherapy. Most clinicians utilise combination handling after an initial SSRI fails to benefit a patient. The present results betoken that, on the basis of safety and tolerability concerns, there is footling reason to reserve this medication combination for the later stages of treatment. This study included both patients who had received unsuccessful handling during the current episode and patients for whom this was the initial treatment. Patients in full general reported treatment-emergent adverse events that were limited in frequency and severity, and seldom led to discontinuation. Future controlled studies should compare monotherapy with this combination treatment in patients with a range of severity of depression to aid elucidate a possible role for this combination as an initial treatment for MDD.
Acknowledgments
This project has been funded with Federal funds from the National Institute of Mental Wellness, National Institutes of Health, nether Contract N01MH90003 to UT Southwestern Medical Middle at Dallas (P.I.: A.J. Rush). The content of this publication does not necessarily reverberate the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Regime. We appreciate the support of Forest Pharmaceuticals, Inc., and GlaxoSmithKline in providing medications at no cost for this trial. Nosotros also acknowledge the editorial support of Jon Kilner, K.Southward., M.A. (Pittsburgh, PA), and the secretarial back up of Fast Give-and-take Data Processing, Inc. (Dallas, TX).
The Data Safety Monitoring Board members for this study included: Jan Fawcett, G.D., Professor of Psychiatry, University of New Mexico School of Medicine; Andrew C. Leon, Ph.D., Professor of Biostatistics in Psychiatry, Weill Medical Higher of Cornell Academy; Richard I. Shader, Thousand.D., Professor, Tufts Academy School of Medicine; Craig Nelson, M.D., Professor in Residence, Academy of California San Francisco Department of Psychiatry; Pedro Fifty. Delgado, M.D., Dielmann Professor and Chairman, Section of Psychiatry, The University of Texas Wellness Sciences Center at San Antonio; Scott Kim, G.D., Ph.D., Professor of the Bioethics Plan; Academy of Michigan Health.
Contributor Data
Andrew F. Leuchter, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California, UsaA.
Ira Thousand. Lesser, Department of Psychiatry, Harbor-UCLA Medical Heart, Torrance, California, U.S.A.
Madhukar H. Trivedi, Section of Psychiatry, University of Texas Southwestern Medical School Dallas, Texas, U.S.A.
A. John Rush, Department of Psychiatry, University of Texas Southwestern Medical School Dallas, Texas, The statesA.
David West. Morris, Department of Psychiatry, University of Texas Southwestern Medical School Dallas, Texas, U.Due south.A.
Diane Warden, Section of Psychiatry, University of Texas Southwestern Medical School Dallas, Texas, United statesA.
Maurizio Fava, Department of Psychiatry, Massachusetts General Hospital Boston, Massachusetts, U.s.A.
Stephen R. Wisniewski, Section of Epidemiology, Academy of Pittsburgh Graduate School of Public Health Pittsburgh, Pennsylvania, UsaA.
James F. Luther, Section of Epidemiology, University of Pittsburgh Graduate Schoolhouse of Public Health Pittsburgh, Pennsylvania, U.s.A.
Bradley Due north. Gaynes, Department of Psychiatry, Academy of Due north Carolina at Chapel Loma Chapel Colina, North Carolina, UsaA.
Jonathan W. Stewart, Department of Psychiatry, Columbia University Medical Centre New York, New York, U.s.A.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778329/