title: A double-blind randomized study comparing imipramine with fluvoxamine in depressed inpatients Nortriptyline in Geriatric Depression Resistant to Serotonin Reuptake Inhibitors: Case Series Bupropion in tricyclic antidepressant nonresponders with unipolar major depressive disorder. Medication augmentation after the failure of SSRIs for depression. [The concept of resistant depression and therapeutic strategies, particularly, with venlafaxine]. Strengthening clinical effectiveness trials: Equipoise-stratified randomization Citalopram treatment of fluoxetine nonresponders. Efficacy of venlafaxine in patients with major depressive disorder who have unsustained or no response to selective serotonin reuptake inhibitors: an open-label, uncontrolled study. Monoamine oxidase inhibitors in resistant major depression. A double-blind comparison of brofaromine and tranylcypromine in patients resistant to tricyclic antidepressants. Venlafaxine and paroxetine in treatment-resistant depression. Double-blind, randomised comparison. A double-blind, randomized study to provide safety information on switching fluoxetine-treated patients to paroxetine without an intervening washout period. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. The therapeutic efficacy of paroxetine: (a) an open study in patients with major depression not responding to antidepressants; (b) a double‐blind comDarison with amitriptyline in I depressed outpatients A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients Benefits from mianserin augmentation of fluoxetine in patients with major depression non‐responders to fluoxetine alone The 16-Item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression Response to an open trial of a second SSRI in major depression. Time to recovery, chronicity, and levels of psychopathology in major depression. A 5-year prospective follow-up of 431 subjects. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial Consensus guidelines in the treatment of major depressive disorder. Efficacy of venlafaxine and predictors of response in a prospective open-label study of patients with treatment-resistant major depression. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Treatment strategy in depression Switching versus augmentation: a prospective, naturalistic comparison in depressed, treatment-resistant patients. Are patients who are intolerant to one serotonin selective reuptake inhibitor intolerant to another? Citalopram treatment of paroxetine-intolerant depressed patients. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial. Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial. Lithium Augmentation of Nortriptyline for Subjects Resistant to Multiple Antidepressants Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline. Nortriptyline for treatment-resistant depression. Efficacy of bupropion in tricyclic-resistant or intolerant patients. Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetine treatment Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Treatment of imipramine-resistant recurrent depression, III: Efficacy of monoamine oxidase inhibitors. Fluvoxamine in the treatment of tricyclic-resistant depression. Nefazodone therapy in patients with treatment-resistant or treatment-intolerant depression and high psychiatric comorbidity. Efficacy of venlafaxine in major depression resistant to selective serotonin reuptake inhibitors Switching to Reboxetine: An Efficacy and Safety Study in Patients With Major Depressive Disorder Unresponsive to Fluoxetine Serotonin reuptake inhibition vs. norepinephrine reuptake inhibition: a double-blind differential-therapeutic study with fluvoxamine and oxaprotiline in endogenous and neurotic depressives. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Citalopram and bupropion-SR: combining versus switching in patients with treatment-resistant depression. A One-Year Comparison of Vagus Nerve Stimulation with Treatment as Usual for Treatment-Resistant Depression Fluoxetine in tricyclic refractory major depressive disorder. Citalopram treatment of fluoxetine-intolerant depressed patients. L-5HTP in depression resistant to re-uptake inhibitors. An open comparative study with tranylcypromine. Desipramine-yohimbine combination treatment of refractory depression. Implications for the beta-adrenergic receptor hypothesis of antidepressant action. Venlafaxine extended release versus conventional antidepressants in the remission of depressive disorders after previous antidepressant failure: ARGOS study. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Treatment strategy in depression Amisulpride versus fluoxetine in patients with dysthymia or major depression in partial remission: a double-blind, comparative study. Pharmacological choices after one antidepressant fails: a survey of UK psychiatrists. A double-blind crossover trial of imipramine and phenelzine for outpatients with treatment-refractory depression. Efficacy and safety of mirtazapine in major depressive disorder patients after SSRI treatment failure: an open-label trial. Switching to bupropion in fluoxetine-resistant major depressive disorder. Efficacy and tolerability of tranylcypromine versus phenelzine: a double-blind study in antidepressant-refractory depressed inpatients.
abstract: Objective To compare the efficacy of imipramine and fluvoxamine in in patients from two centers suffering from a depressive disorder according to DSM IV criteria . Methods The study included 141 patients with a depressive disorder according to DSM IV criteria . After a drug-free and placebo run-in period of 1 week , patients were r and omized to imipramine or fluvoxamine ; doses of both drugs were adjusted to a predefined target blood level . Efficacy was evaluated 4 weeks after attaining predefined adequate plasma level . Results The mean age of the study group ( 47 males , 94 females ) was 51.8 ( range 19–65 ) years . Of these 141 patients , 56 had episode duration longer than 1 year , 48 had mood congruent psychotic features , and 138 patients received medication . Seven patients did not complete the medication trial . The total number of patients using concurrent medication was 12/138 ( 8.6 % ) . On the primary outcome criteria patients on imipramine improved significantly better on the change of illness severity score of the CGI ( χ2 exact trend test=4.089 , df=1 , P=0.048 ) . There was no significant difference in 50 % or more reduction on the HRSD , the other primary outcome criterion . On the secondary outcome criteria the mean reduction of the HRSD scores was significantly larger in the imipramine group than in the fluvoxamine group ( mean difference=3.1 , st and ard error (SE)=1.4 , t=2.15 , df=136 , P=0.033 ) . There was no significant difference in the number of patients with an HRSD ≤7 at the final evaluation . Conclusions In depressed in patients imipramine is more efficacious than fluvoxamine . Both drugs were well tolerated by all patients Research on treatment-resistant depression in the elderly has been limited , and recommendations for clinical man agement have often been extrapolated from studies using nongeriatric patients . This report describes a series of 10 elderly patients with refractory depression who were treated with nortriptyline  after failing to respond to an ade quate trial of a serotonin reuptake inhibitor .  Seven ( 70 % ) of the patients responded to the addition or substitution of nortriptyline . All seven of the responders have remained on nortriptyline for maintenance therapy , none of whom have experienced recurrence of their depression after an average treatment duration of 1 year . Response to nor triptyline  occurred in about 4 weeks in most patients . The mean daily dose of nortriptyline  was 54 mg , and the mean plasma level was 97 ng/mL. Minor side effects occurred in three patients . No patients developed significant electrocardiogram changes .  Nortriptyline , possibly due to its different mechanism of action , may be effective as either an adjunctive or replacement antidepressant in some cases of geriatric depression that are resistant to sero tonin reuptake inhibitors . ( J Geriatr Psychiatry Neurol 2001 ; 14:28 - 32 ) Tricyclic antidepressant ( TCA ) medications are among the most widely used pharmacologic treatments for depression . However , a substantial number of patients fail to respond to these agents . Few st and ardized trials of pharmacologic treatments for TCA nonresponders are available . Bupropion has an apparently different mechanism of action than TCAs and represents a possible treatment for the TCA nonresponder . Based on positive results from pilot studies , a st and ardized study evaluating bupropion in TCA nonresponders was conducted . Forty-one depressed out patients who had failed to respond to adequate documented TCA treatment , defined by specific criteria of dosage , duration , and plasma concentrations , entered a 1-week single-blind placebo phase , followed by an open 8-week bupropion treatment phase utilizing doses of up to the maximum daily dose of 450 mg . Response was measured by change on the Hamilton Depression Rating Scale ( HAM-D ) , Clinical Global Impressions-Severity ( CGI-S ) and Improvement ( CGI-I ) Scales , and the Hamilton Anxiety Rating Scale ( HAM-A ) .  Bupropion treatment result ed in an improvement in depression on all outcome measures . Forty-nine percent were considered " responders , " in that they achieved > or = 50 % improvement on the 28-item HAM-D. Fifty-four percent were classified as responders based on a CGI-I rating of much or very much improved . Statistically significant improvement in depressive symptoms , measured by mean scores for the HAM-D , CGI-S , and HAM-A , was achieved at the end of the study ( as compared to baseline ) . Twelve patients ( 32 % ) had a HAM-D score of < or = 10 at termination . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Although clinicians frequently add a second medication to an initial , ineffective antidepressant drug , no r and omized controlled trial has compared the efficacy of this approach . METHODS We r and omly assigned 565 adult out patients who had nonpsychotic major depressive disorder without remission despite a mean of 11.9 weeks of citalopram therapy  ( mean final dose , 55 mg per day ) to receive sustained-release bupropion ( at a dose of up to 400 mg per day ) as augmentation and 286 to receive buspirone ( at a dose of up to 60 mg per day ) as augmentation . The primary outcome of remission of symptoms was defined as a score of 7 or less on the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) at the end of this study ; scores were obtained over the telephone by raters blinded to treatment assignment . The 16-item Quick Inventory of Depressive Symptomatology -- Self-Report ( QIDS-SR-16 ) was used to determine the secondary outcomes of remission ( defined as a score of less than 6 at the end of this study ) and response ( a reduction in baseline scores of 50 percent or more ) . RESULTS The sustained-release bupropion group and the buspirone group had similar rates of HRSD-17 remission ( 29.7 percent and 30.1 percent , respectively ) , QIDS-SR-16 remission ( 39.0 percent and 32.9 percent ) , and QIDS-SR-16 response ( 31.8 percent and 26.9 percent ) . Sustained-release bupropion , however , was associated with a greater reduction ( from baseline to the end of this study ) in QIDS-SR-16 scores than was buspirone ( 25.3 percent vs. 17.1 percent , P<0.04 ) , a lower QIDS-SR-16 score at the end of this study ( 8.0 vs. 9.1 , P<0.02 ) , and a lower dropout rate due to intolerance ( 12.5 percent vs. 20.6 percent , P<0.009 ) . CONCLUSIONS Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical setting s. Augmentation with sustained-release bupropion does have certain advantages , including a greater reduction in the number and severity of symptoms and fewer side effects and adverse events . ( Clinical Trials.gov number , NCT00021528 . ) About 30 % of depressed patients exhibit depression that is resistant to antidepressant treatment . This resistance may be primary or associated with a concomitant psychiatric or somatic disease . Venlafaxine has shown potent efficacy in certain severe depressions in in- patients and in patients presenting with resistant depression in an open-label study . It was considered of interest to compare , under double-blind , the efficacy of venlafaxine ( 200 to 300 mg/day ) and that of paroxetine ( 30 to 40 mg/day ) ( for 6 weeks ) in 123 patients presenting with major depression resistant to two correctly conducted antidepressant treatments in the course of an episode of depression of duration not exceeding 8 months . The patients were required not to present with organic disease , particularly endocrine disease . After 28 days of treatment , half of the patients receiving venlafaxine and one third of the patients receiving paroxetine showed a 50 % reduction in their total score on the Hamilton scale . In addition , the percentage of patients presenting with remission was significantly higher in the group receiving venlafaxine ( 42 % ) compared to that receiving paroxetine ( 20 % ) . These results require confirmation over the long term and in other forms of resistant depression As psychiatric practice patterns evolve to take advantage of the growing list of treatments with proven efficacy , research studies with broader aims will become increasingly important . R and omized trials may need to accommo date multiple treatment options . In completely r and omized design s , patients are assigned at r and om to one of the options , requiring that patients and clinicians find each of the options acceptable . In " clinician 's choice " design s , patients are r and omized to a small number of broad strategies and the choice of specific option within the broad strategy is left up to the clinician . The clinician 's choice design permits some scope to patient and clinician preferences , but sacrifices the ability to make r and omization-based comparisons of specific options . We describe a new approach , which we call the " equipoise stratified " design , that merges the advantages and avoids the disadvantages of the other two design s for clinical trials . The three design s are contrasted , using the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression trial as an example BACKGROUND We assessed the tolerability and utility of switching fluoxetine nonresponders to citalopram the day that fluoxetine therapy was stopped . METHOD Fifty-eight out patients with DSM-IV major depressive episode and prospect ively confirmed nonresponse to fluoxetine ( mean final dose = 31 mg/day ) were switched directly to citalopram ( 20 mg/day ) . Of the 58 patients , 44 ( 76 % ) had never been successfully treated with antidepressant medication . During a 12-week open-label treatment period , citalopram could be titrated up to a maximum dose of 60 mg/day . Response was evaluated using the Clinical Global Impressions ( CGI ) scale , the 24-item Hamilton Rating Scale for Depression , and several other measures . RESULTS Eighty-one percent ( N = 47 ) completed the trial , and citalopram ( mean dose = 38.8 mg/day ) was well tolerated . The intent-to-treat CGI response rate was 46 % ( 26/57 ) at week 6 and 63 % ( 36/57 ) at study endpoint ; the completer response rate was 76 % among the 47 patients who completed the 12-week trial . Improvement from baseline on all dependent measures was statistically significant after the first week of citalopram treatment . CONCLUSION Fluoxetine nonresponders can be quickly switched to citalopram , with good tolerability and reasonable chance of therapeutic benefit . Further work is necessary to assess the merits of this treatment strategy relative to other options BACKGROUND Approximately half of patients who are prescribed selective serotonin re-uptake inhibitors ( SSRIs ) either do not respond to treatment or do not experience a sustained response . OBJECTIVE The purpose of this study was to assess the efficacy of venlafaxine immediate-release ( IR ) and extended-release ( XR ) in out patients who either did not respond to SSRI treatment or did not maintain a sustained response . METHODS Out patients who met the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition ( DSM-IV ) criteria for major depressive disorder who were previously treated with an SSRI ( fluoxetine > or = 20 mg/d ; sertraline > or = 50 mg/d ; paroxetine > or = 20 mg/d ) for > or = 6 weeks , but demonstrated an inadequate or unsustained response , were switched  to venlafaxine ( IR or XR formulation , 50 - 400 mg/d , titrated from 37.5 mg/d ) for > or = 6 weeks . Response at 6 to 8 weeks was defined as total score < or = 10 on the modified 25-item Hamilton Depression ( HAM-D25 ) rating scale or total score > or = 5 on the 21-item Patient Global Improvement ( PGI-21 ) scale . Remission was defined as a HAM-D25 total score < or = 8 or PGI-21 score > or = 7 . Tests were administered by an unblinded , board-certified psychiatrist . RESULTS A total of 73 patients ( 54 women , 19 men ; mean age , 38.6 years ) were enrolled and treated with venlafaxine IR ( n = 63 ) or venlafaxine XR ( n = 10 ) ; 33 were SSRI nonresponders and 36 had an unsustained response to SSRI treatment . Four patients receiving venlafaxine IR discontinued due to drug-related adverse events ( agitation , sedation , or nausea ) . Data from these patients were excluded from the analysis . After 6 to 8 weeks of treatment , 94.2 % ( 65/69 ) of patients were considered responders ( HAM-D25 or PGI-21 criteria ) ; 91.3 % ( 63/69 ) of patients responded to treatment as assessed by both measures . Eighty-seven percent ( 60/69 ) and 85.5 % ( 59/69 ) of patients achieved remission based on HAM-D,5 and PGI-21 criteria , respectively . Response/remission rates were comparable among patients treated with SSRIs , regardless of whether patients had failed to respond to treatment with 1 or 2 SSRIs . CONCLUSION Venlafaxine IR/venlafaxine XR may be effective in out patients with major depressive disorder who do not respond or have an unsustained response to SSRIs . However , r and omized , controlled trials are needed before any conclusions can be drawn about the efficacy of this agent in this population In a double-blind study the selective monoamine oxidase-A inhibitor brofaromine was compared with the classical MAOI tranylcypromine in 39 patients with major depression resistant to treatment with tricyclic antidepressants .  Concerning efficacy no significant differences were found . Ten out of 22 patients responded to brofaromine and 5 out of 17 patients to tranylcypromine .  Adverse effects favoured brofaromine . Although orthostatic hypotension occurred in both groups , severe decrease in blood pressure and dizziness occurred significantly more with tranylcypromine . Both MAOIs caused a decrease in stage 4 and REM sleep and an increase in REM latency . In most patients receiving tranylcypromine  REM sleep was completely abolished BACKGROUND About one-third of patients fail to respond to initial antidepressant therapy , which suggests a need for more effective drugs . AIMS To compare the efficacy and safety of venlafaxine and paroxetine in 122 patients with non-chronic treatment-resistant depression . METHOD In- patients or out- patients satisfying DSM-III-R criteria for major depression in evolution for less than eight months , having a baseline HAM-D score > or = 18 and a HAM-D Item 3 score < 3 were eligible . Patients were required to have a history of resistance to two previous antidepressant treatments and a CGI improvement score of 3 at the beginning of treatment . Doses were adjusted to 200 - 300 mg/day for venlafaxine and 30 - 40 mg/day for paroxetine . RESULTS For the observed-case analysis , the response rate was 51.9 % for venlafaxine and 32.7 % for paroxetine ( P = 0.044 ) , and a remission was achieved in 42.3 % of venlafaxine-treated and 20.0 % of paroxetine-treated patients ( P = 0.01 ) . The incidence of adverse effects was comparable between treatment groups . CONCLUSIONS Venlafaxine showed some evidence of superiority to paroxetine in this difficult-to-treat patient population BACKGROUND The long elimination half-lives of fluoxetine and norfluoxetine , the active metabolite of fluoxetine , are of potential consequence when alternative antidepressant agents are introduced after the termination of fluoxetine therapy . It is not known whether paroxetine , an antidepressant agent in the same pharmacologic class as fluoxetine , can be substituted for fluoxetine without the need for an intervening washout period . The objective of this trial was to assess the tolerability of an immediate switch from fluoxetine to paroxetine therapy . METHOD Patients who were treated for moderate to moderately severe major depressive disorder ( DSM-III-R 296.2 or 296.3 ) with a stable dose of fluoxetine for a minimum of 6 weeks ' duration were r and omized in a double-blind fashion to one of two treatment groups . One group ( N = 123 ) was started on 20 mg of paroxetine daily the morning after their last dose of fluoxetine , and the other group ( N = 119 ) was started on 20 mg of paroxetine daily following a 2-week placebo-washout period . Patient visits were scheduled at weekly intervals for a total of 4 weeks . Adverse experience monitoring was conducted at each visit . RESULTS There was no difference in the proportion of patients who discontinued prematurely from the trial due to an adverse experience . Eight patients in the immediate-switch group and 6 patients in the placebo-washout group withdrew from the trial in response to an adverse experience ( p = .63 , chi-square ) . The overall profile of adverse experiences was similar in the two treatment groups over the 4-week period . The incidence of adverse experiences in the first 2 weeks following the initiation of paroxetine was generally lower in the group with the intervening 2-week placebo-washout period . CONCLUSION The immediate switch from fluoxetine to paroxetine was as well tolerated as the switch to paroxetine after a 2-week placebo-washout period BACKGROUND Patients with chronic forms of major depression are difficult to treat , and the relative efficacy of medications and psychotherapy is uncertain . METHODS We r and omly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with  nefazodone ( maximal dose , 600 mg per day ) , the cognitive behavioral- analysis system of psychotherapy ( 16 to 20 sessions ) , or both . At base line , all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression ( indicating clinical ly significant depression ) . Remission was defined as a score of 8 or less at weeks 10 and 12 . For patients who did not have remission , a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less . Raters were unaware of the patients ' treatment assignments . RESULTS Of the 681 patients , 662 attended at least one treatment session and were included in the analysis of response . The overall rate of response ( both remission and satisfactory response ) was 48 percent in both the nefazodone group and in the psychotherapy group , as compared with 73 percent in the combined-treatment group . ( P<0.001 for both comparisons ) . Among the 519 subjects who completed the study , the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group , as compared with 85 percent in the combined-treatment group ( P<0.001 for both comparisons ) . The rates of withdrawal were similar in the three groups . Adverse events in the nefazodone group were consistent with the known side effects of the drug ( e.g. , headache , somnolence , dry mouth , nausea , and dizziness ) . CONCLUSIONS Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral- analysis system of psychotherapy , the combination of the two is significantly more efficacious than either treatment alone Open study Twenty-eight adult patients ( seven males and 21 females ) comparable in terms of age and weight , who had a Hamilton Depression Rating Scale ( HAMD ) score of 18 or more while receiving alternative antidepressants ( mainly amitriptyline : 15 patients ) entered the six-week study without a washout period . All patients received 30 mg paroxetine once daily in the morning , and HAMD scores were measured at the end of weeks 1 , 2 , 4 , and 6 of treatment . Tolerability was also assessed and blood and urine sample s monitored Antidepressant effects of mirtazapine and imipramine were compared in a r and omized , double blind , fixed blood-level study with in- patients in a single centre . Patients with a DSM-III-R diagnosis of major depression and a Hamilton ( 17-item ) score of ≥18 were selected . After a drug-free and a placebowashout period of 7 days in total , 107 patients still fulfilling the HRSD criterion of ≥18 , started on active treatment . The dose was adjusted to a predefined fixed blood level to avoid suboptimal dosing of imipramine . Concomitant psychotropic medication was administered only in a few cases because of intolerable anxiety or intolerable psychotic symptoms . Eight patients dropped out and two were excluded from analyses because of non-compliance ; 97 completed the study . According to the main response criterion ( 50 % or more reduction on the HRSD score ) 11/51 ( 21.6 % ) patients responded on mirtazapine and 23/46 ( 50 % ) on imipramine after 4 weeks ' treatment on the predefined blood level . Such a dramatic difference in efficacy between antidepressants has not often been reported before . The selection of ( severely ill ) in- patients , including those with suicidal or psychotic features , may have significance in this respect . Optimization of treatment with the reference drug imipramine through blood level control , exclusion of non-compliance for both drugs , exclusion of most concomitant medication and a low drop-out rate may also have contributed . It is concluded that imipramine is superior to mirtazapine in the patient population studied Objective : To assess , in depressed patients , the clinical benefit of mianserin augmentation of fluoxetine or the the benefit of switching treatment from fluoxetine to mianserin The 16-item Quick Inventory of Depressive Symptomatology ( QIDS ) , a new measure of depressive symptom severity derived from the 30-item Inventory of Depressive Symptomatology ( IDS ) , is available in both self-report ( QIDS-SR(16 ) ) and clinician-rated ( QIDS-C(16 ) ) formats . This report evaluates and compares the psychometric properties of the QIDS-SR(16 ) in relation to the IDS-SR(30 ) and the 24-item Hamilton Rating Scale for Depression ( HAM-D(24 ) ) in 596 adult out patients treated for chronic nonpsychotic , major depressive disorder .  Internal consistency was high for the QIDS-SR(16 ) ( Cronbach 's alpha = .86 ) , the IDS-SR(30 ) ( Cronbach 's alpha = .92 ) , and the HAM-D(24 ) ( Cronbach 's alpha = .88 ) .  QIDS-SR(16 ) total scores were highly correlated with IDS-SR(30 ) ( .96 ) and HAM-D(24 ) ( .86 ) total scores . Item-total correlations revealed that several similar items were highly correlated with both QIDS-SR(16 ) and  IDS-SR(30 ) total scores . Roughly 1.3 times the QIDS-SR(16 )  total score is predictive of the HAM-D(17 ) ( 17-item version of the HAM-D ) total score . The QIDS-SR(16 ) was as sensitive to symptom change as the IDS-SR(30 ) and HAM-D(24 ) , indicating high concurrent validity for all three scales . The QIDS-SR(16 ) has highly acceptable psychometric properties , which supports the usefulness of this brief rating of depressive symptom severity in both clinical and research setting BACKGROUND We evaluated the efficacy of a second serotonin selective reuptake inhibitor ( SSRI ) in patients who had failed to respond to the first SSRI used . METHOD Fifty-five patients with major depression who had failed one of the SSRIs for their current depressive episode were included . After failing a trial of one SSRI , they received a second SSRI in an open clinical trial . RESULTS On the basis of the Clinical Global Impression-Improvement scale , 28 of 55 patients had a marked or complete antidepressant response . CONCLUSION These data provide preliminary clinical evidence that substituting a second SRI may be a useful clinical alternative in depressed patients who fail to respond to an adequate trial of an SSRI The course of illness of 431 subjects with major depression participating in the National Institute of Mental Health Collaborative Depression Study was prospect ively observed for 5 years . Twelve percent of the subjects still had not recovered by 5 years . There were decreasing rates of recovery over time . For example , 50 % of the subjects recovered within the first 6 months , and then the rate of recovery declined markedly . Instantaneous probabilities of recovery reflect that the longer a patient was ill , the lower his or her chances were of recovering . For patients still depressed , the likelihood of recovery within the next month declined from 15 % during the first 3 months of follow-up to 1 % to 2 % per month during years 3 , 4 , and 5 of this follow-up . The severity of current psychopathology predicted the probability of subsequent recovery . Subjects with moderately severe depressive symptoms , minor depression , or dysthymia had an 18-fold greater likelihood of beginning recovery within the next week than did subjects who were at full criteria for major depressive disorder . Many subjects who did not recover continued in an episode that looked more like dysthymia than major depressive disorder BACKGROUND After unsuccessful treatment for depression with a selective serotonin-reuptake inhibitor ( SSRI ) , it is not known whether switching to one antidepressant is more effective than switching to another . METHODS We r and omly assigned 727 adult out patients with a nonpsychotic major depressive disorder who had no remission of symptoms or could not tolerate the SSRI citalopram  to receive one of the following drugs for up to 14 weeks : sustained-release bupropion ( 239 patients ) at a maximal daily dose of 400 mg , sertraline ( 238 patients ) at a maximal daily dose of 200 mg , or extended-release venlafaxine ( 250 patients ) at a maximal daily dose of 375 mg . The study was conducted in 18 primary and 23 psychiatric care setting s. The primary outcome was symptom remission , defined by a total score of 7 or less on the 17-item Hamilton Rating Scale for Depression ( HRSD-17 ) at the end of the study . Scores on the Quick Inventory of Depressive Symptomatology - Self Report ( QIDS-SR-16 ) , obtained at treatment visits , determined secondary outcomes , including remission ( a score of 5 or less at exit ) and response ( a reduction of 50 percent or more on baseline scores ) . RESULTS Remission rates as assessed by the HRSD-17 and the QIDS-SR-16 , respectively , were 21.3 percent and 25.5 percent for sustained-release bupropion , 17.6 percent and 26.6 percent for sertraline , and 24.8 percent and 25.0 percent for extended-release venlafaxine . QIDS-SR-16 response rates were 26.1 percent for sustained-release bupropion , 26.7 percent for sertraline , and 28.2 percent for extended-release venlafaxine . These treatments did not differ significantly with respect to outcomes , tolerability , or adverse events . CONCLUSIONS After unsuccessful treatment with an SSRI , approximately one in four patients had a remission of symptoms after switching to another antidepressant . Any one of the medications in the study provided a reasonable second-step choice for patients with depression . ( Clinical Trials.gov number , NCT00021528 . ) BACKGROUND Although various strategies have been proposed to treat antidepressant nonresponders , little controlled research has been published that examines prospect ively the use of switching to an alternate antidepressant . METHODS This was a multisite study in which out patients with chronic major depression ( with or without concurrent dysthymia ) , who failed to respond to 12 weeks of double-blind treatment with either sertraline hydrochloride ( n = 117 ) or imipramine hydrochloride ( n = 51 ) , were crossed over or switched to 12 additional weeks of double-blind treatment with the alternate medication . Outcome measures included the 24-item Hamilton Rating Scale for Depression and the Clinical Global Impressions -- Severity and Improvement scales . RESULTS The switch from sertraline to imipramine ( mean dosage , 221 mg/d ) and from imipramine to sertraline ( mean dosage , 163 mg/d ) result ed in clinical ly and statistically significant improvements . The switch to sertraline treatment was associated with fewer adverse effect complaints and significantly less attrition owing to adverse effects . Although sertraline treatment also result ed in significantly higher response rates in the intent-to-treat sample s ( 60 % in the sertraline group and 44 % in the imipramine group ) , neither the intent-to-treat remission rates nor the response and remission rates among study completers differed significantly . Moreover , after considering the effect of attrition , there were no significant treatment effects on the more comprehensive generalized estimating equation analyses of the continuous dependent measures . CONCLUSIONS More than 50 % of chronically depressed antidepressant nonresponders benefited from a switch from imipramine to sertraline , or vice versa , despite a high degree of chronicity . As in the initial trial , sertraline was generally better tolerated than imipramine . Switching to a st and ard antidepressant of a different class is a useful treatment strategy for antidepressant nonresponders and could be considered a st and ard of comparison for future studies of novel alternate strategies BACKGROUND Recent reports describe discontinuation-emergent adverse events upon cessation of selective serotonin reuptake inhibitors including dizziness , insomnia , nervousness , nausea , and agitation . We hypothesized that interruption of fluoxetine treatment would be associated with fewer discontinuation-emergent adverse events than interruption of sertraline or paroxetine treatment , based on fluoxetine 's longer half-life . METHODS In this 4-week study , 242 patients with remitted depression receiving maintenance therapy with open-label fluoxetine , sertraline , or paroxetine for 4 - 24 months had their maintenance therapy interrupted with double-blind placebo substitution for 5 - 8 days . The  Symptom Question naire ( SQ ) , the Discontinuation-Emergent Signs and Symptoms checklist , the 28-item Hamilton Depression Rating Scale , and the Montgomery-Asberg Depression Rating Scale  were used to assess somatic distress and stability of antidepressant response . RESULTS Two hundred twenty patients ( 91 % ) completed the study . Following interruption of therapy , fluoxetine-treated patients experienced fewer discontinuation-emergent events than either sertraline-treated or paroxetine-treated patients ( p < .001 ) . The mean SQ somatic symptom scale score in fluoxetine-treated patients was significantly lower than that in sertraline-treated and paroxetine-treated patients ( p < .001 ) . Fluoxetine-treated patients also experienced less reemergence of depressive symptoms than sertraline-treated or paroxetine-treated patients ( p < .001 ) . CONCLUSIONS Abrupt interruption of antidepressant therapy for 5 - 8 days was associated with the emergence of new somatic and psychological symptoms in patients treated with paroxetine and to a lesser degree sertraline , with few symptoms seen with fluoxetine The number of available antidepressant medications has increased dramatically in the last 10 years . Furthermore , no single medication is a panacea for all depressed patients -a fact underscored by r and omized , controlled trial evidence showing that when one medication fails , an alternative may succeed . Thus , a key issue in the treatment of depression is how to optimally orchestrate available medication options to maximally benefit the greatest number of patients most rapidly . One approach is the use of consensus guidelines or medication algorithms . This paper discusses the rationale for and critical issues in the development of medication algorithms , and the timely use of symptom measures to ensure proper implementation . Once developed , guidelines must be appropriately implemented by clinicians , adhered to by patients , and supported by administrators . These three stakeholder groups often need education , incentives , and ongoing support to implement such guidelines . Whether guidelines actually improve outcome is largely uninvestigated , although a recent study of depressed patients in primary care found that using guidelines did improve outcome but at an increased treatment cost . The clinical and economic impact of guideline -driven treatment for the severe and persistently depressed deserves study The aim of this study was to replicate the findings of a 1994 study , in which a 30 % response rate to venlafaxine was found in patients with treatment-refractory depression , as well as to examine for any predictors of such an outcome . The study was an 8-week , open-label , prospect i ve investigation of venlafaxine in doses up to 300 mg in 312 patients fulfilling criteria for either " absolute " or " relative " treatment resistance . By week 8 , 52.6 % of the patients had responded , which was defined as a 50 % reduction in scores on the Montgomery-Asberg Depression Rating Scale ; 49 % of those defined with " absolute resistance " demonstrated such an outcome . Forty-five percent of the patients with absolute resistance who had failed to respond to at least one tricyclic antidepressant responded to venlafaxine .  Response rates were higher in those with an absence ( 57.5 % ) compared with the presence ( 31.0 % ) of any comorbid psychiatric disorder ( p < 0.001 ) , " marked " ( 60.3 % ) compared with " mild or moderate " ( 51.6 % ) or " severe " ( 43.4 % ) baseline ratings on the patient-rated Clinical Global Impressions Scale ( p < 0.05 ) , and " relative " ( 61 % ) compared with " absolute " resistance ( 49 % ) ( p = 0.06 ) . Furthermore , improvement in scores of 20 % or 30 % at weeks 1 or 2 was associated with higher rates of final response ( p < 0.0005 ) . After logistic regression , both comorbid psychiatric illness ( p < 0.001 ) and early improvement ( p < 0.0001 ) remained significant and independent predictors of final response OBJECTIVE Few controlled studies have addressed the issue of which antidepressant medications should be recommended for out patients who have not responded to multiple treatment trials . This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant ( nortriptyline ) following two prospect i ve , consecutive , unsuccessful medication treatments for nonpsychotic major depressive disorder . METHOD Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks ( first step ) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone ( second step ) , adult out patients ( N=235 ) with nonpsychotic major depressive disorder were r and omly assigned to 14 weeks of treatment with mirtazapine ( up to 60 mg/day ) ( N=114 ) or nortriptyline ( up to 200 mg/day ) ( N=121 ) . The primary outcome , symptom remission , was defined a priori as a total exit score of < /=7 on the 17-item Hamilton Rating Scale for Depression . The 16-item Quick Inventory of Depressive Symptomatology-Self-Report ( QIDS-SR(16 ) ) , obtained at treatment visits , provided secondary outcomes of remission ( score < /=5 at exit ) and response ( > /=50 % reduction in score from baseline ) . RESULTS For mirtazapine , remission rates were 12.3 % and 8.0 % per the Hamilton and QIDS-SR(16 ) scores , respectively . For nortriptyline , remission rates were 19.8 % and 12.4 % , respectively . QIDS-SR(16 ) response rates were 13.4 % for mirtazapine and 16.5 % for nortriptyline . Neither response nor remission rates statistically differed by treatment , nor did these two treatments differ in tolerability or adverse events . CONCLUSIONS Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials result ed in low remission rates ( < 20 % ) among patients with major depressive disorder Antidepressants are ineffective in about 30 % of the patients with major depression . Besides electroconvulsive therapy ( ECT ) and lithium , MAO inhibitors have been suggested as an alternative in such patients . In 2 controlled , partial crossover studies involving 47 patients with major depression who had already been treated unsuccessfully with at least 2 cyclic antidepressants , the effect of the MAO inhibitor tranylcypromine was studied . The first study was an open comparison with L‐5‐hydroxytryptophan ( L‐5HTP ) , the second study a double‐blind comparison with nomifensine . Neither the patients treated with L‐5HTP nor the patients treated with nomifensine , except one , improved . In contrast , tranylcypromine was effective in 50 % of the patients . The depressions of the responders to tranylcypromine appeared to be more endogenous ( according Newcastle Scale II ) and of shorter duration than those of the non‐responders . It is concluded that MAO inhibitors such as tranylcypromine are an effective alternative to ECT and lithium in patients with major depression who have failed to respond to cyclic antidepressants OBJECTIVE ( 1 ) To directly compare the effectiveness of switching antidepressants with augmenting them in depressed patients who do not respond to an initial adequate trial and ( 2 ) to determine whether there is a decreased likelihood of response to a second switch or augmentation trial in those patients who did not respond to the first intervention for treatment-resistant depression . METHOD In a naturalistic , open-label design , all depressed out patients ( DSM-IV criteria ) who were treatment resistant were prospect ively assessed . Short- and long-term outcomes of switching versus augmentation were compared using the Clinical Global Impressions scale . RESULTS In the acute phase , 37 ( 50.0 % ) of 74 subjects responded to 1 of the 2 interventions for treatment-resistant depression . Forty-five percent ( N = 17 ) and 56 % ( N = 20 ) of the patients who had their antidepressant switched or augmented , respectively , responded to that intervention . Nearly three fourths ( 71.4 % ) of the acute responders maintained their response through 6 months of follow-up . In 18 patients who did not respond to the first switch or augmentation , 9 ( 50.0 % ) responded to a second trial . CONCLUSION Switching antidepressants was somewhat less effective than augmentation , although this difference was not statistically significant . For patients who do not respond to an augmentation or switch , our results suggest that a second trial for treatment-resistant depression may be as effective as the first BACKGROUND The question was asked whether patients who discontinue one serotonin selective reuptake inhibitor ( SSRI ) because of side effects can be treated successfully with another SSRI . METHOD 113 patients with major depression who had discontinued fluoxetine because of side effects were enrolled in an open , multicenter , 8-week study design ed to evaluate the tolerability and efficacy of sertraline . After a washout period of at least 3 weeks following fluoxetine discontinuation and an additional 1-week , single-blind , placebo washout period , patients began treatment with 50 mg of sertraline once daily . Doses were titrated upward as necessary to a maximum daily dose of 200 mg . Depressive symptoms and adverse events were evaluated weekly . RESULTS Based on the Clinical Global Impressions Scale , 79 ( 71.8 % ) of 110 patients evaluated for efficacy were " much " or " very much " improved relative to baseline . Only 11 ( 9.8 % ) of 112 patients discontinued sertraline because of adverse reactions . CONCLUSION These results suggest that patients who discontinue one SSRI because of side effects can be treated successfully with another We assessed the tolerability and antidepressant response to citalopram in a group of patients who could not tolerate a recent trial of paroxetine therapy . Sixty-one out patients with major depressive disorder and a confirmed history of intolerance to paroxetine ( mean final dose : 26.7 mg/day ) were switched after at least a 1 week washout to citalopram therapy ( 20 mg/day ) . During the 6-week , open label treatment protocol , citalopram could be titrated up to a maximum dose of 40 mg/day . Response was evaluated using the Clinical Global Impressions CGI scale , the 24-item Hamilton Rating Scale for Depression , and several other measures of symptoms and quality of life . Fifty-three patients ( 87 % ) completed 6 weeks of citalopram therapy ( mean intent-to-treat dose : 23.9 mg/day ) . The specific side effects that were reported to be intolerable during the earlier paroxetine trial typically recurred only less than 30 % of the time during citalopram therapy ; only 6 patients ( 10 % ) dropped out because of adverse events . The intent-to-treat CGI response rate was 56 % at study endpoint ; 62 % of the completers responded . Significant improvement from pretreatment was observed on various symptom measures after two weeks of citalopram therapy . Citalopram therapy was well tolerated , and more than one half of the patients who began treatment improved significantly . Although further work is necessary to assess the relative merits of this within-class switching strategy ( as compared to other options ) , these data provide further evidence that the various selective serotonin reuptake inhibitors do not have interchangeable tolerability profiles CONTEXT Selective serotonin reuptake inhibitors ( SSRIs ) are the most commonly prescribed class of antidepressant , yet it is not known whether one SSRI is more effective than another . OBJECTIVE To compare the effectiveness of 3 SSRIs ( paroxetine , fluoxetine , and sertraline ) in depressed primary care patients . DESIGN Open-label , r and omized , intention-to-treat trial , with patient enrollment occurring in April-November 1999 . SETTING Thirty-seven clinics in 2 US primary care research networks . PATIENTS A total of 573 depressed adult patients for whom their primary care physician thought that antidepressant therapy was warranted and who completed a baseline interview . INTERVENTIONS Patients were r and omly assigned to receive paroxetine ( n = 189 ) , fluoxetine ( n = 193 ) , or sertraline ( n = 191 ) for 9 months . Primary care physicians were allowed to switch patients to a different SSRI or non-SSRI antidepressant if they did not adequately respond to or tolerate the initial SSRI . MAIN OUTCOME MEASURES The primary outcome measure was change in the Medical Outcomes Study 36-Item Short-Form Health Survey ( SF-36 ) Mental Component Summary score ( range , 0 - 100 ) , compared across treatment groups at 1 , 3 , 6 , and 9 months . Secondary outcomes included other depression and psychological measures , multiple measures of social and work functioning , and other domains of health-related quality of life , such as physical functioning , concentration and memory , vitality , bodily pain , sleep , and sexual functioning . RESULTS Follow-up interviews were successfully completed in 94 % of patients at 1 month , 87 % at 3 months , 84 % at 6 months , and 79 % at 9 months . Responses to the 3 SSRIs were comparable on all measures and at all time points . The mean change in the SF-36 Mental Component Summary score at 9 months was + 15.8 in the paroxetine group , + 15.1 in the fluoxetine group , and + 17.4 in the sertraline group . The drugs were also associated with similar incidences of adverse effects and discontinuation rates . CONCLUSIONS The SSRI antidepressants paroxetine , fluoxetine , and sertraline were similar in effectiveness for depressive symptoms as well as multiple domains of health-related quality of life over the entire 9 months of this trial This was an 8-week , multicenter , open-label study of the efficacy and tolerability of venlafaxine in patients with treatment-resistant depression conducted in Canada . In patients or out patients aged 18 to 70 years with major depression were eligible if they had a 21-item Hamilton Rating Scale for Depression ( HAM-D-21 ) score of 2 > or = 18 and a documented history of unsatisfactory improvement after a minimum of 8 weeks of treatment with an adequate dose of an antidepressant . Treatment with venlafaxine was started at 37.5 mg twice daily , and the dose could be titrated upward to a maximum of 375 mg/day during the first 4 weeks on the basis of the investigator 's assessment of clinical response and tolerability . Of the 159 patients enrolled , 152 were evaluable for efficacy . The mean daily venlafaxine dose was 260 mg/day . The mean HAM-D-21 score decreased by 52 % , and the mean Montgomery-Asberg Depression Rating Scale score decreased by 50 % from baseline to day 56 . A response ( 50 % improvement from baseline ) was achieved by 58 % of patients on the HAM-D-21 , and a remission ( > or = 75 % improvement in the HAM-D-21 ) was observed in 28 % at day 56 . By day 56 , 88 % of patients had improved from baseline on the Clinical Global Impression Improvement scale . Only 8 % of the patients discontinued for adverse events . The most common adverse events were headache , insomnia , nausea , constipation , diaphoresis , and xerostomia . In conclusion , these results suggest that venlafaxine is effective and well tolerated for the management of patients with treatment-resistant major depression Lithium augmentation , the most studied augmentation strategy for depression , has not been evaluated in patients with a history of non-response to multiple antidepressants . The objective of this study was to assess the efficacy of lithium augmentation for patients with a history of treatment resistant depression who also failed a prospect i ve trial of nortriptyline .  We enrolled 92 subjects with treatment resistant depression . Treatment resistance was defined by at least one , but no more than five , adequate trials of antidepressants during the current episode . Subjects were treated with nortriptyline ( NT ) for 6 weeks . Those subjects who tolerated NT for 6 weeks and whose depression did not respond ( n=35 ) were r and omized to receive either lithium ( n=18 ) or placebo ( N=17 ) augmentation of nortriptyline for an additional 6 weeks . Response was defined as an equal to or greater than 50 % decrease in HAM-D-17 scores . After 6 weeks of double-blind augmentation , 12.5 % of subjects responded to lithium and 20.0 % to placebo . Our results revealed no significant difference between lithium and placebo augmentation . While lithium augmentation seems to be useful in depression refractory to a single medication in some studies , our data suggest limited usefulness of this option for patients refractory to multiple treatments . More definitive data await the outcome of the NIMH Sequential Treatment Alternatives to Relieve Depression ( STAR*D ) study BACKGROUND This study was conducted to determine if patients with major depressive disorder who had previously failed treatment with one serotonin selective reuptake inhibitor ( SSRI ) would respond to a different SSRI . METHOD Adult out patients ( N = 106 ) with DSM-III-R major depressive disorder and a history of either intolerance ( N = 34 ) or nonresponse ( N = 72 ) to treatment with sertraline  were treated with fluoxetine ( mean dose = 37.2 mg/day ) in a st and ardized , open-label , 6-week clinical trial . Outcome was assessed at each visit using the Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI-Improvement and CGI-Severity ) scales , and the Patient 's Global Improvement ( PGI ) scale . RESULTS Ninety-one patients ( 86 % ) completed the study . Sixty-seven patients ( 63 % ) responded to fluoxetine ( i.e. , experienced > or = 50 % reduction in HAM-D28 total score at endpoint versus baseline ) . In addition , clinical ly and statistically significant improvements were noted on all measures of depressive symptoms and global functioning . There was a nonsignificant trend for patients with a history of less vigorous sertraline trials to respond more favorably to fluoxetine . Fluoxetine therapy was generally well tolerated , and there were only slight differences in adverse events reported by patients who had been intolerant to sertraline versus those who were nonresponders . CONCLUSION These findings indicate that fluoxetine and sertraline , two widely used SSRIs , are not interchangeable . Patients who either have had trouble tolerating or have not responded to sertraline may do well on fluoxetine treatment BACKGROUND Up to 30 % of patients with major depression fail to respond to an antidepressant trial , with most taking a selective serotonin reuptake inhibitor ( SSRI ) as initial treatment . While the tricyclic antidepressants might be effective for SSRI nonresponders , they have been relegated to third- and fourth-line treatment . This study assesses the efficacy of nortriptyline for patients with treatment-resistant major depression . METHOD 92 patients with treatment-resistant DSM-III-R major depression , with resistance defined by at least 1 , but no more than 5 , well-documented adequate trials of antidepressants during the current episode , were treated openly with nortriptyline for 6 weeks . Patients were titrated up to full target doses of nortriptyline within 1 week , with target blood levels of 100 ng/mL. Response was defined as a 50 % or greater decrease of baseline 17-item Hamilton Rating Scale for Depression score . We performed an intent-to-treat analysis with the last observation carried forward . RESULTS Approximately 40 % of patients were responders ( N = 39 ) and 12 % were remitters ( N = 11 ) after 6 weeks of nortriptyline . Over a third of patients were unable to complete the trial . CONCLUSION Nortriptyline was effective for over a third of patients with treatment-resistant depression , and nortriptyline should be considered as potential treatment if patients fail to respond to other antidepressants Available evidence is review ed concerning the antidepressant efficacy of bupropion in patients who had failed to respond to or been unable to tolerate tricyclic antidepressants ( TCAs ) during prior episodes of depression . In patients classified as TCA nonresponders were r and omly assigned to double-blind treatment with bupropion ( N = 19 ) or placebo ( N = 11 ) . Patients receiving bupropion showed an excellent antidepressant response , whereas those receiving placebo showed minimal improvement ( p less than .001 ) . In patients who were classified as TCA responders responded well to double-blind treatment with bupropion , but also had a substantial , although significantly smaller ( p less than .05 ) , response to placebo . Out patients ( N = 33 ) with a history of nonresponse or nonresponse plus intolerance to TCAs showed marked improvement during open treatment with bupropion . The results from both double-blind and open treatment with bupropion demonstrate that this drug offers a promising alternative therapy for patients with a history of poor response to TCAs Abrupt interruption or cessation of selective serotonin reuptake inhibitor ( SSRI ) treatment may result in discontinuation or treatment interruption symptoms . Recent reports suggested these symptoms occur more frequently with shorter half-life SSRIs . Previous studies indicated a 5–8-day treatment interruption result ed in fewer discontinuation-emergent adverse events in  fluoxetine-treated patients than in paroxetine-treated patients . This study examines the effects of shorter treatment interruption ( 3–5 days ) , as would occur if patients miss just a few doses of medication . Patients successfully treated for depression with fluoxetine or paroxetine  underwent treatment interruption in a double-blind fashion . Treatment interruption-emergent symptoms were assessed using the Discontinuation-Emergent Signs and Symptoms checklist . Other assessment s included the Montgomery – Åsberg Depression Rating Scale , Clinical Global Impressions-Severity scale and a social functioning question naire . Of 150 patients enrolled , 141 completed the study . Following treatment interruption , fluoxetine-treated patients experienced fewer treatment interruption-emergent events than did paroxetine-treated patients . The paroxetine treatment group also experienced significant increases in depressive symptoms , clinical global severity scores and difficulty in social functioning ; the fluoxetine treatment group did not . These results are consistent with reports suggesting abrupt interruption of treatment with paroxetine is more often associated with somatic and psychological symptoms than is abrupt interruption of fluoxetine . Patients treated with fluoxetine appeared to be protected by its longer half-life CONTEXT The Texas Medication Algorithm Project is an evaluation of an algorithm-based disease management program for the treatment of the self-declared persistently and seriously mentally ill in the public mental health sector . OBJECTIVE To present clinical outcomes for patients with major depressive disorder ( MDD ) during 12-month algorithm-guided treatment ( ALGO ) compared with treatment as usual ( TAU ) . DESIGN Effectiveness , intent-to-treat , prospect i ve trial comparing patient outcomes in clinics offering ALGO with matched clinics offering TAU . SETTING Four ALGO clinics , 6 TAU clinics , and 4 clinics that offer TAU to patients with MDD but provide ALGO for schizophrenia or bipolar disorder . Patients Male and female out patients with a clinical diagnosis of MDD ( psychotic or nonpsychotic ) were divided into  ALGO and TAU groups . The ALGO group included patients who required an antidepressant medication change or were starting antidepressant therapy .  The TAU group initially met the same criteria , but because medication changes were made less frequently in the TAU group , patients were also recruited if their Brief Psychiatric Rating Scale total score was higher than the median for that clinic 's routine quarterly evaluation of each patient . MAIN OUTCOME MEASURES Primary outcomes included ( 1 ) symptoms measured by the 30-item Inventory of Depressive Symptomatology-Clinician-Rated scale ( IDS-C(30 ) ) and ( 2 ) function measured by the Mental Health Summary score of the Medical Outcomes Study 12-item Short-Form Health Survey ( SF-12 ) obtained every 3 months . A secondary outcome was the 30-item Inventory of Depressive Symptomatology-Self-Report scale ( IDS-SR(30 ) ) . RESULTS All patients improved during the study ( P<.001 ) , but ALGO patients had significantly greater symptom reduction on both the IDS-C(30 ) and IDS-SR(30 ) compared with TAU . ALGO was also associated with significantly greater improvement in the SF-12 mental health score ( P = .046 ) than TAU . CONCLUSION The ALGO intervention package during 1 year was superior to TAU for patients with MDD based on clinician-rated and self-reported symptoms and overall mental functioning BACKGROUND The effectiveness of monoamine oxidase inhibitors ( MAOIs ) in tricyclic resistant depression has received surprisingly little systematic study . METHOD Patients who failed to respond to sustained , adequate treatment with the tricyclic imipramine ( mean maximum dosage = 260 mg/day ) and interpersonal psychotherapy were withdrawn from imipramine and treated in a st and ardized , but open-label 6-week trial with either phenelzine ( N = 4 ; 60 mg/day ) or tranylcypromine ( N = 36 ; mean = 38.5 mg/day ) and continued interpersonal psychotherapy . RESULTS Forty of 42 patients ( 95 % ) completed the trial , of whom 23 ( 58 % ) responded to treatment . Highly significant improvement was documented on measures of depression , reversed neurovegetative symptoms , and somatic symptoms . Response was significantly correlated with severity of depression ( pre-MAOI score on the Hamilton Rating Scale for Depression ) , severity of a composite score of anergic and reversed neurovegetative features , and low levels of improvement during initial imipramine/interpersonal psychotherapy . Of patients who met criteria for proposed subforms of anergic or atypical depression , 67 % ( 18/27 ) responded ( p less than .05 ) ; 77 % ( 17/22 ) of patients who scored above the mean on the composite measure of anergic and reversed neurovegetative features responded ( p less than .01 ) . CONCLUSION These findings provide strong evidence of the utility of MAOIs in tricyclic-resistant depression , especially in patients with features such as fatigue , volitional inhibition , motoric retardation , hypersomnia , and /or weight gain Following an initial double-blind , r and omized , parallel treatment group comparison of fluvoxamine , desipramine , and placebo in 89 out patients with major depression at two centers , double-blind crossover to fluvoxamine was offered to 13 of 22 desipramine-treated completers of the initial phase who were considered failures on desipramine .  Twelve elected to cross over to blinded fluvoxamine , and eleven continued on fluvoxamine for at least eight weeks . Nine of these eleven improved , and overall there was a statistically significant decrease in average Hamilton Depression Scores , from 24 to 13 , for these fluvoxamine-treated desipramine-resistant patients Given the potentially severe functional impairment , morbidity , and high costs associated with refractory depression , it is important to explore all treatment options that may benefit patients with this disorder . This is a retrospective , uncontrolled analysis of our experience with nefazodone therapy in treatment-resistant and treatment-intolerant depression . Potential c and i date s for nefazodone therapy were referred by their treating psychiatrist . Documentation of failure to respond to previous antidepressant therapy , a diagnosis of clinical depression according to criteria in the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , and completion of a Beck Depression Inventory ( BDI ) were required before initiation of nefazodone . A follow-up BDI was obtained after > or = 4 weeks of nefazodone therapy . A Clinical Global Inventory ( CGI ) score was obtained retrospectively based on documentation of target symptoms in the clinical record of the last clinic visit . The study group consisted of 20 patients with treatment-resistant or treatment-intolerant major depression who received nefazodone therapy . The mean ( + /- SD ) age of the group was 48.1+/-9.4 years . The mean number of previously failed antidepressant trials was 1.9+/-0.6 . Psychiatric comorbidity in this group was substantial , with posttraumatic stress disorder ( PTSD ) found in 11 ( 55 % ) patients , substance abuse in 3 ( 15 % ) patients , and personality disorder found in 2 ( 10 % ) patients . After treatment with nefazodone , 11 of 20 patients ( 55 % ) were rated on the CGI as much or very much improved . In addition , 9 patients ( 45 % ) had > 20 % improvement on BDI , 3 patients ( 15 % ) had 10 % to 20 % improvement , and 6 patients ( 30 % ) had < 10 % change . Two patients ( 10 % ) discontinued nefazodone therapy due to adverse effects . Analysis of our experience with nefazodone therapy in a population with treatment-resistant depression and a high degree of psychiatric comorbidity suggests that approximately 50 % of patients may have substantial response to treatment , with a smaller proportion having a more modest clinical response . While receiving nefazodone therapy , most patients continued to take concurrently prescribed psychotropic medications , primarily anxiolytics or other antidepressants . Of interest was the positive drug response among a subgroup of individuals with depression and chronic , severe PTSD . Larger , controlled studies are needed to determine whether these preliminary observations are confirmed INTRODUCTION Some studies suggest that venlafaxine , due to its pharmacodynamic characteristics , could be an effective drug in depression , resistant to other antidepressive agents . This investigation explores the efficacy and tolerability of venlafaxine in major depression , resistant to a selective serotonin reuptake inhibitor ( SSRI ) . METHODS A multicenter naturalistic study was performed during 6 months and included those patients diagnosed of major depression according to the criteria of DSM-IV who had a minimum score of 18 on the Hamilton Depression Rating Scale ( HAM-D ) and who had not responded to previous treatment with a SSRI at therapeutic doses for a minimum of 4 weeks . The assessment of efficacy was performed with the HAM-D scale , the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the Hamilton Anxiety Rating Scale ( HAM-A ) and the Global Clinical Impression ( GCI ) . Tolerability was evaluated by recording the adverse reactions and with the GCI score on overall drug tolerability . RESULTS A total of 69 patients , of which 59 were evaluable for efficacy ( they had fulfilled at least 4 weeks of treatment ) , were included . About 81 % of all of them obtained a reduction of at least 50 % in the HAM-D , 74 % were considered as " quite improved " or " very improved " in the GCI and 69 % met both criteria . The mean dose of venlafaxine used was 170.4 ( S.D.=43.8 ) mg . Of the 21 patients who did not complete the 6 months of treatment , 3 were due to lack of efficacy , 6 due to adverse effects and 12 for other reasons . About 89.2 % of side effects were considered as mild or moderate . CONCLUSION The results of our study support the efficacy and tolerability of venlafaxine in patients suffering from depression who have not responded to SSRI treatment The aim of the present study was to evaluate the efficacy and safety of an immediate switch to reboxetine , a selective noradrenaline reuptake inhibitor ( selective NRI ) , in patients with depression unresponsive to the selective serotonin reuptake inhibitor ( SSRI ) fluoxetine . The study included 128 adult out patients with DSM-IV major depressive disorder ( MDD ) who had not responded to at least 6 to 12 weeks of fluoxetine treatment , with at least 3 weeks of treatment on a minimum dose of 40 mg/d . Patients were switched , without a washout period , to reboxetine 4 mg twice daily , with the possibility of increasing the dose to 10 mg/d ( given in divided doses ) after 4 weeks of treatment . Efficacy was assessed using the 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) and the Clinical Global Impression Improvement ( CGI-I ) and Severity ( CGI-S ) scales . Safety was evaluated by recording spontaneously reported adverse events . A statistically significant ( P < 0.001 ) improvement in the mean total HAM-D-17 score was seen from baseline by week 1 of treatment with reboxetine , and the improvement continue to week 8 . CGI-I and CGI-S scores were similarly improved . The switch to reboxetine was well tolerated ; the most common treatment-emergent adverse events were insomnia , headache , dry mouth , diaphoresis , and constipation , all of which were mild to moderate in severity and decreased in frequency as the study progressed . Immediate switching to reboxetine appears to be a safe and effective treatment for patients with depression who have failed to respond to an adequate dose of fluoxetine The antidepressive properties of the specific serotonin reuptake inhibitor fluvoxamine and the specific norepinephrine reuptake inhibitor oxaprotiline were investigated in a sequential design with the aim of evaluating the hypothesis that two distinct biochemical subtypes of depression exist . Responders were treated for 7 weeks with the compound to which they had responded . After 1 placebo week , the nonresponders were switched to the alternative compound . An evaluation of the data obtained during the 3-week treatment periods from 24 patients ( 37 trials ) with major depression revealed a highly significant reduction of Hamilton Scores with both compounds , oxaprotiline and fluvoxamine . If the patients with major depression are subdivided into two groups , endogenous depressives and neurotic depressives , there is no significant difference between the therapeutic improvements ( both compounds ) achieved in the two groups . The data shows that only about 20 % of the nonresponders on one compound responded to the alternative drug , whereas 90 % of responders ( within 3 weeks ) were still responders after 7 weeks . The data are at variance with the concept of two distinct biochemical subtypes of depression ( serotonergic vs. norepinephrinergic ) .  Dexamethasone suppression tests , performed in 23 patients , gave no prognostic hint as to whether the patients reacted well to drug therapy or not STAR*D is a multisite , prospect i ve , r and omized , multistep clinical trial of out patients with nonpsychotic major depressive disorder . The study compares various treatment options for those who do not attain a satisfactory response with citalopram , a selective serotonin reuptake inhibitor antidepressant . The study enrolls 4000 adults ( ages 18 - 75 ) from both primary and specialty care practice s who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode . After receiving citalopram ( level 1 ) , participants without sufficient symptomatic benefit are eligible for r and omization to level 2 treatments , which entail four switch options ( sertraline , bupropion , venlafaxine , cognitive therapy ) and three citalopram augment options ( bupropion , buspirone , cognitive therapy ) . Those who receive cognitive therapy ( switch or augment options ) at level 2 without sufficient improvement are eligible for r and omization to one of two level 2A switch options ( venlafaxine or bupropion ) . Level 2 and 2A participants are eligible for r and om assignment to two switch options ( mirtazapine or nortriptyline ) and to two augment options ( lithium or thyroid hormone ) added to the primary antidepressant ( citalopram , bupropion , sertraline , or venlafaxine ) ( level 3 ) . Those without sufficient improvement at level 3 are eligible for level 4 r and om assignment to one of two switch options ( tranylcypromine or the combination of mirtazapine and venlafaxine ) . The primary outcome is the clinician-rated , 17-item Hamilton Rating Scale for Depression , administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments . Secondary outcomes include self-reported depressive symptoms , physical and mental function , side-effect burden , client satisfaction , and health care utilization and cost . Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessment OBJECTIVE There are limited data comparing medication strategies in patients with treatment-resistant depression . In this study , we compared the effects of combining citalopram and bupropion-SR versus switching to the other monotherapy in treatment-resistant depression . METHOD This was a naturalistic , open-label cohort study . Patients with DSM-IV major depressive disorder who had not responded to at least 1 previous antidepressant and at least 6 weeks of treatment with citalopram or bupropion-SR were treated in a st and ard clinical protocol . In alternate months , eligible consecutive patients were treated by adding citalopram or bupropion-SR , or by switching to the other medication . Patients were assessed at baseline and after 6 weeks of treatment with the 29-item version of the  Structured Interview Guide for the Hamilton Depression Rating Scale , Seasonal Affective Disorders Version ( SIGH-SAD ) . RESULTS A total of 61 patients completed the study : 32 in the combination condition and 29 in the monotherapy switch condition . The combination condition was superior to the monotherapy switch in the SIGH-SAD change score ( -14.8 vs. -10.1 , respectively , p < .04 ) and the proportion of patients in clinical remission ( 28 % vs. 7 % , p < .05 ) . There were no differences in the proportion of patients who had side effects or in the severity of the side effects experienced . CONCLUSION The results of this cohort study suggest that combining citalopram and bupropion-SR is more effective than switching to a monotherapy . Combination treatment was well tolerated with no greater side effect burden than monotherapy . Limitations of this study include the nonr and omized design , open-label treatment , and small sample size BACKGROUND Previous reports have described the effects of vagus nerve stimulation plus treatment as usual ( VNS+TAU ) during open trials of patients with treatment-resistant depression ( TRD ) . To better underst and these effects on long-term outcome , we compared 12-month VNS+TAU outcomes with those of a comparable TRD group . METHODS Admission criteria were similar for those receiving VNS+TAU ( n = 205 ) or only TAU ( n = 124 ) . In the primary analysis , repeated- measures linear regression was used to compare the VNS+TAU group ( monthly data ) with the TAU group ( quarterly data ) according to scores of the 30-item Inventory of Depressive Symptomatology-Self-Report ( IDS-SR(30 ) ) . RESULTS The two groups had similar baseline demographic data , psychiatric and treatment histories , and degrees of treatment resistance , except that more  TAU participants had at least 10 prior major depressive episodes , and the VNS+TAU group had more electroconvulsive therapy before study entry . Vagus nerve stimulation plus treatment as usual was associated with greater improvement per month in IDS-SR(30 ) than TAU across 12 months ( p < .001 ) . Response rates according to the 24-item Hamilton Rating Scale for Depression ( last observation carried forward ) at 12 months were 27 % for VNS+TAU and 13 % for TAU ( p < .011 ) . Both groups received similar TAU ( drugs and electroconvulsive therapy ) during follow-up . CONCLUSIONS This comparison of two similar but nonr and omized TRD groups showed that VNS+TAU was associated with a greater antidepressant benefit over 12 months Data regarding open-label treatment with fluoxetine following failure to respond to tricyclic antidepressants ( TCAs ) or intolerance of TCA side effects , suggest a response rate between 51.4 % and 62.1 % , depending on the definition of TCA refractoriness employed . Double-blind study of this issue would extend these findings . Fluoxetine is well tolerated in patients unable to tolerate TCAs .  Within this population , more than 80 % of patients unable to tolerate TCAs found fluoxetine acceptable . Fluoxetine , as an alternative to polypharmaceutical augmentation , may represent a logical choice as the next step in therapy for a patient who has initially been treated with a TCA and has proven refractory or intolerant BACKGROUND We assessed the tolerability of and response to  citalopram in depressed patients who had discontinued fluoxetine treatment due to adverse events . METHOD Fifty-five out patients with DSM-IV major depressive disorder and a confirmed history of intolerance to fluoxetine ( mean final dose = 24.6 mg/day ) were switched to citalopram ( 20 mg/day ) after a 2- to 4-week single-blind placebo washout period . During a 6-week , open-label treatment protocol , citalopram could be titrated up to 40 mg/day . Safety and tolerability , including reemergence of symptoms that previously had been associated with fluoxetine , were assessed by recording all spontaneously reported or observed adverse events . Efficacy was evaluated using the Hamilton Rating Scale for Depression ( HAM-D ) , the Clinical Global Impressions ( CGI ) scale , and several other measures . Response was defined as a CGI-Improvement score at endpoint of 1 or 2 ( i.e. , very much or much improved ) . RESULTS Ninety-five percent of patients ( N = 52 ) completed the citalopram trial . The only adverse events reported by more than 5 patients ( > or= 10 % ) were pharyngitis ( 15 % ) and constipation ( 11 % ) , and none of the 3 early terminations were attributed to adverse events . The rate of recurrence of the fluoxetine-associated  adverse events was low , with headache ( 3 [ 27 % ] of 11 cases ) , nausea ( 2 [ 22 % ] of 9 cases ) , and decreased libido ( 5 [ 18 % ] of 28 cases ) being the most common . Significant improvement from baseline HAM-D ( p < .001 ) was observed by the first week of citalopram therapy and continued until study end . The intent-to-treat CGI response rate was 65 % ( 36 of 55 patients ) at study endpoint ; 69 % ( 36 of 52 patients ) of the completers responded . CONCLUSION These data suggest that fluoxetine-intolerant patients can be treated effectively with citalopram L-5HTP and tranylcypromine were compared in an open , but controlled and cross-over study , in patients suffering from major depression ; all were non-responders to several reuptake inhibitors , including oxaprotiline and fluvoxamine .  After four unsuccessful sleep-deprivations , L-5HTP or tranylcypromine were given during four weeks in a crossover design . Of 17 patients given L-5HTP during both treatment periods , none responded , whereas of 26 patients treated with  tranylcypromine  , 15 responded . Thus , L-5HTP is not a therapeutically effective alternative in depressed patients who have not responded to reuptake inhibitors Pre clinical investigations have shown that combined administration of the alpha 2-adrenergic receptor antagonist yohimbine hydrochloride and the tricyclic antidepressant desipramine hydrochloride produces a reduction in brain beta-adrenergic receptor function within four days . Since the ability of antidepressant treatments to reduce beta-adrenergic receptor function has been hypothesized to mediate antidepressant efficacy , it was predicted that combined desipramine-yohimbine treatment would be a more rapid-acting and potent antidepressant regimen than desipramine alone . In the present investigation , the effects of desipramine ( N = 11 ) and desipramine-yohimbine ( N = 10 ) treatment on depressive symptoms , norepinephrine turnover , and blood pressure were determined in patients with major depression who had a history of nonresponse to st and ard antidepressant treatments . Neither desipramine nor desipramine-yohimbine proved to be an effective treatment , although concomitant yohimbine administration did attenuate the ability of desipramine to decrease plasma free and 24-hour urinary 3-methoxy-4-hydroxyphenyl-ethyleneglycol levels and blood pressure . Fifteen of the 21 patients eventually had a good response to pharmacologic treatments , particularly a desipramine-lithium carbonate or lithium carbonate-tranylcypromine sulfate combination treatment ( 11 of 14 responded ) . This study provides evidence against the beta-adrenergic receptor hypothesis of antidepressant action Serotonin-norepinephrine reuptake inhibitors ( SNRIs ) may be used as an alternative treatment for depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant . This r and omized , open-label , multicenter study compared the effectiveness of the SNRI venlafaxine extended release ( VXR ) with that of conventional antidepressants ( CA ) in patients who were referred to an outpatient psychiatric specialty care setting for treatment after failure to tolerate or respond to at least 4 weeks of treatment with a CA in a primary care setting . Patients with a Hamilton Depression Rating Scale ( HAM-D17 ) score > or = 17 were r and omly assigned to treatment with an alternative CA or VXR .  Remission was defined as a score < or = 7 on the HAM-D17 . Efficacy analyses were carried out on 3,097 patients from the intent-to-treat ( ITT ) population ( 1,632 VXR ; 1,465 CA ) . The antidepressants prescribed most frequently in the CA group were paroxetine ( 21.3 % ) , citalopram ( 20.1 % ) , sertraline ( 19.1 % ) , fluoxetine ( 17.0 % ) , and mirtazapine ( 7.9 % ) . After 24 weeks of treatment , the VXR group demonstrated a significantly higher remission rate than did the CA group ( 59.3 % VXR ; 51.5 % CA ; P<.0001 ; odds ratio : 1.37 ; 95 % CI : 1.19 - 1.58 ; P<.01 ) . Despite the limitations of the open design , the results of this study suggest that venlafaxine extended release may be more effective than the conventional antidepressants used in this study when treating depressed patients who do not tolerate or respond adequately to treatment with a conventional antidepressant OBJECTIVE The purpose of this study was to compare the effectiveness and tolerability of tranylcypromine and combination treatment with extended-release venlafaxine and mirtazapine in patients with treatment-resistant major depression whose current depressive episode had not responded adequately to treatment in three prior prospect i ve medication trials . METHOD Adult out patients with nonpsychotic major depressive disorder who had not achieved remission or had withdrawn from treatment because of intolerance in three previous prospect i ve medication trials were r and omly assigned to receive open-label treatment with either tranylcypromine ( N=58 ) or extended-release venlafaxine plus mirtazapine ( N=51 ) . The primary outcome measure was whether patients achieved remission , which was defined as a score < or = 7 at exit on the 17-item Hamilton Depression Rating Scale ( HAM-D ) . The HAM-D was administered by telephone by raters to whom treatment was masked . RESULTS Remission rates were not significantly different between the two treatment groups ( 6.9 % for the tranylcypromine group and 13.7 % for the venlafaxine plus mirtazapine group ) . The mean daily dose at exit for tranylcypromine was 36.9 mg ( SD=18.5 ) ; for venlafaxine , 210.3 mg ( SD=95.2 ) ; and for mirtazapine , 35.7 mg ( SD=17.6 ) . Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance . CONCLUSIONS Remission rates were modest for both the tranylcypromine group and the extended-release venlafaxine plus mirtazapine group , and the rates were not statistically different between groups . The lower side effect burden , lack of dietary restrictions , and ease of use of venlafaxine and mirtazapine suggest that this combination may be preferred over tranylcypromine for patients with highly treatment-resistant depression who have not benefited adequately from several prior treatments Antidepressants are ineffective in about 30 % of patients with major depression . Some authors then advise treatment of non‐responders with ( non‐tricyclic ) more selective reuptake inhibitors . In a double‐blind , partial crossover study , 71 patients were selected for treatment during 4 weeks with oxaprotiline and /or fluvoxamine , two non‐tricyclic antidepressants that are selective reuptake inhibitors of noradrenaline and serotonin respectively . All patients had failed to respond to earlier treatment with cyclic antidepressants during the current episode . Only 13 % of the patients responded , with 27 % of them responding to oxaprotiline and none to fluvoxamine . Moreover , a low response of 27 % was also obtained in the crossover phase , which included all non‐responders to the first treatment , oxaprotiline being effective in 39 % and fluvoxamine in 10 % of the patients . The results indicate that selective reuptake inhibitors are not an effective alternative for non‐responders to other cyclic antidepressants and that non‐responders to “ nor‐adrenergic ” antidepressants do not appear to have much chance of responding to “ serotonergic ” antidepressants and vice versa In a multicentre , double blind , parallel group study 281 patients with DSM III-R diagnosis of dysthymia or a single episode of major depression in partial remission were r and omised to 3 months of treatment with amisulpride  50 mg/day or fluoxetine  20 mg/day . The baseline Montgomery and Asberg Depression Rating Scale ( MADRS ) total score was reduced by at least 50 % in 74.1 % of patients ( 103/139 ) with amisulpride and 67.4 % ( 87/129 ) with fluoxetine ( P = 0.230 ) . No significant differences between treatment groups were found in the reductions in mean total score with the MADRS , Widlöcher psychomotor retardation scale , Sheehan disability scale , and CGI . Anxiety measured by HAM-A total mean score decreased significantly more with amisulpride ( 63 % ) than with fluoxetine ( 54 % ; P = 0.021 ) . There were 13 dropouts due to adverse events with amisulpride and ten with fluoxetine . The number of patients reporting at least one adverse event was similar in the two groups ( amisulpride 47.5 % ; fluoxetine 40.9 % ) . As expected , in the amisulpride group endocrine-like adverse events in female patients were the most common , while nausea , dyspepsia , anorexia and insomnia occurred more frequently with fluoxetine BACKGROUND At least 30 % of depressed patients fail to respond to adequate first-line anti-depressant medication . Several pharmacological strategies have been suggested to treat such refractory depression . There has been no survey of United Kingdom psychiatrists ' treatment preferences for refractory depression . This study was carried out to determine both experience and preference of various strategies for management of refractory depression . METHOD A total of 300 fellows , members and inceptors of the Royal College of Psychiatrists were r and omly selected and approached by postal question naire . They were asked to comment on management of a detailed clinical vignette of a case of depression with initial treatment failure . RESULTS The response rate was 63 % ( n = 175 ) . The most popular treatment choices were increasing dosage of tricyclic medication and change of medication of SSRI . The most rarely selected were augmentation with triiodothyronine ( T3 ) and augmentation with tryptophan or MAOIs .  Treatment choice was significantly influenced by previous experience . A large number ( 39 % ) of psychiatrists were not confident in treating refractory depression . CONCLUSION Surprisingly few psychiatrists chose to use the best proven pharmacological treatments such as augmentation with lithium or T3 . In view of this and the considerable proportion of psychiatrists lacking confidence in the management of refractory depression , this topic deserves priority as a topic for continuing professional development ( CPD ) courses OBJECTIVE Data from controlled studies concerning the response rates of patients to a second antidepressant medication after they have been unresponsive to a systematic trial of another antidepressant are extremely useful to clinicians for rational prescription of pharmacotherapy . Such information allows making an accurate prognosis , sustaining realistic hope in the patient , and achieving the best possible therapeutic outcome . This study was design ed to add to the scanty literature available on this subject . METHOD Eighty-nine mood-reactive , nonmelancholic , mainly chronically depressed out patients at a university research clinic who were unresponsive to vigorous double-blind trials of imipramine or phenelzine  were crossed over to treatment with the other drug under double-blind conditions . RESULTS Of 46 patients previously unresponsive to imipramine who completed phenelzine treatment , 31 ( 67 % ) responded to phenelzine . Of 22 patients previously unresponsive to phenelzine who completed imipramine treatment , nine ( 41 % ) responded to imipramine . The difference in response rates was statistically significant . Even after they had shown no response to 7 weeks of placebo and 6 weeks of imipramine treatment , 10 ( 83 % ) of 12 patients who then completed treatment with phenelzine responded . CONCLUSIONS These data suggest that among chronically ill , mood-reactive depressed patients with many symptoms of atypical depression , phenelzine is strikingly effective in those who have been nonresponders to imipramine and should be tried in such patients OBJECTIVE To evaluate the efficacy and safety of mirtazapine in depressed out patients who have shown nonresponse or intolerance to selective serotonin reuptake inhibitor ( SSRI ) therapy . METHOD In this open-label , 8-week study , the efficacy and safety of mirtazapine among 103 out patients with DSM-IV major depressive disorder who had failed previous therapy with an SSRI ( fluoxetine , paroxetine , or sertraline )  were evaluated . The primary efficacy measure was the 17-item Hamilton Rating Scale for Depression ( HAM-D-17 ) , and safety assessment s included reported adverse events , routine laboratory assessment s , physical examinations , and assessment s of vital signs . A 4-day washout period followed by mirtazapine treatment was compared with an immediate switch from the SSRI to mirtazapine . RESULTS Based on mean HAM-D-17 scores at endpoint and response rates of 48 % based on the criterion of > or = 50 % reduction in HAM-D-17 score , mirtazapine was found to be an effective treatment for a substantial proportion of patients for whom an SSRI was ineffective and /or poorly tolerated . Mirtazapine was well tolerated , with sedation and appetite increase/weight gain the most commonly reported adverse events . In addition , no difference in efficacy , safety , or tolerability was observed for patients undergoing an immediate switch from an SSRI ( after having been tapered to the minimal effective dose ) to mirtazapine , compared with those undergoing the imposition of a 4-day drug-free washout . CONCLUSION These results suggest that an immediate switch to mirtazapine may be a valid therapeutic option among patients who can not tolerate or do not respond to SSRIs Up to 50 % of patients with major depressive disorder ( MDD ) fail to respond to an antidepressant trial , with most taking a selective serotonin reuptake inhibitor ( SSRI ) as an initial treatment . Switching to bupropion , for depressed patients not responding to SSRIs , is a popular strategy among clinicians . This study assesses the efficacy of bupropion SR in the management of MDD resistant to a prospect i ve trial of fluoxetine . Twenty-nine patients with MDD refractory to an 8- to 12-week open-trial of fluoxetine  were enrolled in an 8-week open-trial of bupropion SR . Both a completer analysis ( n = 20 ) and a modified intent-to-treat analysis ( n = 26 ) were performed to evaluate  bupropion SR response rates . Using a completer analysis , seven patients ( 35.0 % ) were classified as responders , five ( 25.0 % ) partial responders , and eight ( 40.0 % ) nonresponders . A modified intent to treat analysis result ed in nine ( 34.6 % ) patients classified as responders , eight ( 30.8 % ) partial responders , and nine ( 34.6 % ) nonresponders . The overall proportion of remitters was 6/20 ( 30.0 % ) using a completer analysis and 6/26 ( 23.1 % ) using an MITT analysis . Approximately 60 % of patients with MDD resistant to a prospect i ve trial of fluoxetine experienced a full or partial response to bupropion SR . Bupropion SR should be considered as a potential treatment for patients who remain depressed despite treatment with BACKGROUND The aim of this study was to examine whether phenelzine is a suitable alternative to tranylcypromine in antidepressant-resistant depression . METHOD A total of 77 severely depressed in- patients , meeting the DSM-IV criteria for major depressive disorder , who failed to respond to fixed plasma level treatment with either tricyclic antidepressants or fluvoxamine were withdrawn from psychotropic medication  and included in a double-blind flexible-dose 5-week comparison of tranylcypromine and phenelzine . RESULTS Of the 77 patients , 67 ( 87 % ) completed the trial , of whom 35 ( 52 % ) responded . No significant differences in response between both drugs were observed . Seventeen ( 44 % ) of 39 patients responded to tranylcypromine and 18 ( 47 % ) of 38 to phenelzine ( > or = 50 % reduction in Hamilton Rating Scale for Depression [ HAM-D ] score ) . The mean reduction in HAM-D score was 10.4 + /- 8.3 for the tranylcypromine sample versus 8.3 + /- 8.4 for the phenelzine-treated patients . Only a few patients ( 10 % ) used concomitant psychotropic medication . A substantial number of patients experienced severe side effects , mainly dizziness , agitation , and insomnia ; the incidence was the same in both sample s ( 21 % ) . CONCLUSION No difference in efficacy was observed between both monoamine oxidase inhibitors in a sample of patients with severe antidepressant-refractory depression . Phenelzine appears to be a suitable alternative to tranylcypromine
target: The number of previous treatments with antidepressants was negatively correlated with treatment outcome .
  After a first SSRI , any switch within or between classes of antidepressants appears legitimate ( second SSRI , novel dual-acting antidepressants , selective norepinephrine or nor-adrenergic/dopaminergic agents , or tricyclic anti-depressant or mianserin ) .
  No unequivocal evidence is available to prove an advantage of a between-class switch .
background: OBJECTIVE Selective serotonin reuptake inhibitors ( SSRIs ) are frequently used as a first antidepressant for major depressive disorder but have response rates of 50 % to 60 % in daily practice .
  For patients with insufficient response to SSRIs , switching is often applied .
  This article aims to systematic ally review the evidence for switching pharmacotherapy after a first SSRI .