Search

Objective: Because previous preclinical and clinical studies have implicated the endogenous opioid system in major depression and in the neurochemical action of antidepressants, the authors examined how DNA variation in the [micro]-opioid receptor gene may influence population variation in response to citalopram treatment. Method: A total of 1,953 individuals from the Sequenced Treatment Alternatives to Relieve Depression ([STAR.sup.*]D) study were treated with citalopram and genotyped for 53 single nucleotide polymorphisms (SNPs) in a 100-kb region of the OPRM1 gene. The sample consisted of Non-Hispanic Caucasians, Hispanic Caucasians, and African Americans. Population stratification was corrected using 119 ancestry informative markers and principal components analysis. Markers were tested for association with phenotypes for general and specific citalopram response as well as remission. Results: Association between one SNP and specific citalopram response was observed. After Bonferroni correction, the strongest finding was the association between the rs540825 SNP and specific response. The rs540825 polymorphism is a nonsynonymous SNP in the final exon of the [micro]-opioid receptor-IX isoform of the OPRM1 gene, resulting in a histidine to glutamine change in the intracellular domain of the receptor. When Hispanic and Non-Hispanic Caucasians were analyzed separately, similar results in the population-corrected analyses were detected. Conclusions: These results suggest that rates of response to antidepressants and consequent remission from major depressive disorder are influenced by variation in the [micro]-opioid receptor gene as a result of either an effect on placebo response or true pharmacologic response.

Objective: Phase III clinical trials for depression enroll participants with major depressive disorder according to stringent inclusion and exclusion criteria. These patients may not be representative of typical depressed patients seeking treatment. This analysis used data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project--which used broad inclusion and minimal exclusion criteria--to evaluate whether phase III clinical trials recruit representative depressed outpatients. Method: Of 2,855 participants, 22.2% met typical entry criteria for phase III clinical trials (efficacy sample) and 77.8% did not (nonefficacy sample). These groups were compared regarding baseline sociodemographic and clinical features and the characteristics and outcomes of acute-phase treatment. Results: The efficacy sample had a shorter average duration of illness and lower rates of family history of substance abuse, prior suicide attempts, and anxious and atypical symptom features. Despite similar medication dosing and time at exit dose, the efficacy participants tolerated citalopram better. They also had higher rates of response (51.6% versus 39.1%) and remission (34.4% versus 24.7%). These differences persisted even after adjustments for baseline differences. Conclusions: Phase III trials do not recruit representative treatment-seeking depressed patients. Broader phase III inclusion criteria would increase the generalizability of results to practice, potentially reducing placebo response and remission rates (reducing the risk of failed trials) but at the risk of some increase in adverse events.

Objective: The authors compared the effectiveness of cognitive therapy and pharmacotherapy as second-step strategies for outpatients with major depressive disorder who had received inadequate benefit from an initial trial of citalopram. Cognitive therapy was compared with medication augmentation and switch strategies. Method: An equipoise-stratified randomization strategy was used to assign participants to either augmentation of citalopram with cognitive therapy (N=65) or medication (N=117; either sustained-release bupropion [N=56] or buspirone [N= 61]) or switch to cognitive therapy (N=36) or another antidepressant (N=86; sertraline [N=27], sustained-release bupropion [N=28], or extended-release venlafaxine [N=31]). Treatment outcomes and the frequency of adverse events were compared. Results: Less than one-third of participants consented to randomization strata that permitted comparison of cognitive therapy and pharmacotherapy. Among participants who were assigned to second-step treatment, those who received cognitive therapy (either alone or in combination with citalopram) had similar response and remission rates to those assigned to medication strategies. For those who continued on citalopram, medication augmentation resulted in significantly more rapid remission than augmentation with cognitive therapy. Among those who discontinued citalopram, there were no significant differences in outcome, although those who switched to a different antidepressant reported significantly more side effects than those who received cognitive therapy alone. Conclusions: After an unsatisfactory response to citalopram, patients who consented to random assignment to either cognitive therapy or alternative pharmacologic strategies had generally comparable outcomes. Pharmacologic augmentation was more rapidly effective than cognitive therapy augmentation of citalopram, whereas switching to cognitive therapy was better tolerated than switching to a different antidepressant.

Objective: Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients' willingness to accept different second-step treatment approaches. Method: Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only. Results: Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy. Conclusions: Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment.

Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N= 3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of [less than or equal to] 5 on the Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-S[R.sub.16]) (equivalent to [less than or equal to] 7 on the 17-item Hamilton Rating Scale for Depression [HRS[D.sub.17]]) defined remission; a QIDS-S[R.sub.16] total score of [greater than or equal to] 11 (HRS[D.sub.17][greater than or equal to] 14) defined relapse. Results: The QIDS-S[R.sub.16] remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. Conclusions: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed. (Am J Psychiatry 2006; 163:1905-1917)

Objective: Loss of response to a previously effective antidepressant is a common clinical problem. Retrospective analyses have shown that the pattern of response during antidepressant treatment (late onset and persistent versus other patterns) can be used to predict relapse during continuation and maintenance treatment and possibly to identify placebo responses to treatment. This study was designed to test the predictive value of response pattern prospectively and to examine the data for other predictors of relapse. Method: Five hundred seventy persons with major depressive disorder were treated with fluoxetine for 12 weeks and their pattern of response was determined. Those who responded (N=292) underwent random assignment, under double-blind conditions, to continue taking fluoxetine or to switch to placebo for 52 weeks or until relapse. Survival analysis was used to examine the effect of covariates on relapse. Results: Although fluoxetine was significantly more effective than placebo during maintenance treatment, this chronically ill group had a high rate of relapse. Contrary to previous findings, a pattern of acute response was not predictive of relapse. Chronicity, symptom severity, a neurovegetative symptom pattern, and female gender were all associated with a significantly greater risk of relapse, with no difference observed between fluoxetine and placebo. Conclusions: The pattern of response to acute treatment appears to be inconsistently predictive of relapse. There is a high rate of relapse with both active medication and placebo in patients with chronic depression. Illness characteristics predict loss of response both to fluoxetine and to placebo. No variable examined was predictive of differential relapse rates between fluoxetine and placebo.

Objective: More than 40% of patients with major depressive disorder do not achieve remission even after two optimally delivered trials of antidepressant medications. This study compared the effectiveness of lithium versus triiodothyronine ([T.sub.3]) augmentation as a third-step treatment for patients with major depressive disorder. Method: A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or who were intolerant to an initial prospective treatment with citalopram and a second switch or augmentation trial were randomly assigned to augmentation with lithium (up to 900 rag/day; N=69) or with [T.sub.3] (up to 50 [micro]g/day: N-73) for up to 14 weeks. The primary outcome measure was whether participants achieved remission, which was defined as a score [less than or equal to] 7 on the 17-item Hamilton Depression Rating Scale. Results: After a mean of 9.6 weeks (SD= 5.2) of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with [T.sub.3] augmentation, although the difference between treatments was not statistically significant. Lithium was more frequently associated with side effects (p=0.045), and more participants in the lithium group left treatment because of side effects (23.2% versus 9.6%; p= 0.027). Conclusions: Remission rates with lithium and [T.sub.3] augmentation for participants who experienced unsatisfactory results with two prior medication treatments were modest and did not differ significantly. The lower side effect burden and ease of use of [T.sub.3] augmentation suggest that it has slight advantages over lithium augmentation for depressed patients who have experienced several failed medication trials.

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 prospective medication trials. Method: Adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or had withdrawn from treatment because of intolerance in three previous prospective medication trials were randomly 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 [less than or equal to] 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.

Objective: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients 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 prospective, 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 outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 m/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of [less than or equal to] 7 on the 17-item Hamilton Rating Scale for Depression. The 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-[SR.sub.16]), obtained at treatment visits, provided secondary outcomes of remission (score [less than or equal to] 5 at exit) and response ([greater that or equal to] 50% reduction in score from baseline). Results: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-[SR.sub.16] scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-[SR.sub.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 resulted in low remission rates (

Objective: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, but the rates, timing, and baseline predictors of remission in 'real world' patients are not established. The authors' primary objectives in this study were to evaluate the effectiveness of citalopram, an SSRI, using measurement-based care in actual practice, and to identify predictors of symptom remission in outpatients with major depressive disorder. Method: This clinical study included outpatients with major depressive disorder who were treated in 23 psychiatric and 18 primary care 'real world' settings. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks. The clinicians were assisted by a clinical research coordinator in the application of measurement-based care, which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures. Remission was defined as an exit score of [less than or equal to] 7 on the 17-item Hamilton Depression Rating Scale (HAM-D) (primary outcome) or a score of [less than or equal to] 5 on the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) (secondary outcome). Response was defined as a reduction of [greater than or equal to] 50% in baseline QIDS-SR score. Results: Nearly 80% of the 2,876 outpatients in the analyzed sample had chronic or recurrent major depression; most also had a number of comorbid general medical and psychiatric conditions. The mean exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47% (QIDS-SR). Patients in primary and psychiatric care settings did not differ in remission or response rates. A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment. Participants who were Caucasian, female, employed, or had higher levels of education or income had higher HAM-D remission rates; longer index episodes, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), more general medical disorders, and lower baseline function and quality of life were associated with lower HAM-D remission rates. Conclusions: The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials. The systematic use of easily implemented measurement-based care procedures may have assisted in achieving these results.

Objective: This study examined the utility of baseline psychomotor speed, measured with neuropsychological tests, to predict fluoxetine response in moderately depressed outpatients. The authors hypothesized that since psychomotor slowing in depressed patients has been linked to reduced dopaminergic neurotransmission, patients with slowing would be unresponsive to fluoxetine, a selective serotonin reuptake inhibitor. Method: After baseline neuropsychological testing, patients were treated openly with fluoxetine for 12 weeks. Thirty-seven patients completed the trial. Results: Compared to the 25 patients who responded, the 12 patients who did not respond to fluoxetine exhibited significantly poorer performance in verbal fluency on the Controlled Oral Word Association Test FAS and in color naming on the Stroop Color and Word Test. In addition, the nonresponders tended to perform worse than the responders on the Stroop Color and Word Test reading subtest and the WAIS-III digit symbol subtest. Differential treatment response was specific to psychomotor speed because responders and nonresponders did not perform differently on tasks of executive functioning, attention, visuospatial functioning, or verbal intelligence. Conclusions: Psychomotor slowing may identify a subgroup of depressed patients who have a dopaminergic deficit that is unresponsive to fluoxetine monotherapy and who should therefore receive an alternative treatment.

Objective: Subsyndromal major depressive disorder is common among HIV-positive adults. This study was designed to assess the efficacy of dehydroepiandrosterone (DHEA) as a potential treatment. Method: One hundred forty-five patients with subsyndromal depression or dysthymia were randomly assigned to receive either DHEA or placebo; 90% (69 of 77) of the DHEA patients and 94% (64 of 68) of the placebo patients completed the 8week trial. The primary measure of efficacy was a Clinical Global Impression improvement rating of 1 or 2 (much or very much improved) plus a final Hamilton Depression Rating Scale score [less than or equal to]8. Outcome was assessed by using intent-to-treat analysis, followed by completer analysis. Safety was assessed by queries about side effects at every study visit plus measures of CD4 cell count and HIV RNA viral load at baseline and week 8. DHEA dosing was flexible (100-400 mg/day). Results: On the basis of clinicians' ratings, DHEA was superior in the intent-to-treat analysis, where the response rate was 56% (43 of 77) for the DHEA group versus 31% (21 of 68) for the placebo group. In the completer analysis, the response rate was 62% (43 of 69) for the DHEA group, compared to 33% (21 of 64) for the placebo patients. The number needed to treat was 4 on the basis of intent-to-treat data and 3.4 on the basis of completer data. Few adverse events were reported in either treatment group, and no significant changes in CD4 cell count or HIV RNA viral load were observed in either group. Conclusions: Nonmajor but persistent depression is common in patients with HIV/AIDS, and DHEA appears to be a useful treatment that is superior to placebo in reducing depressive symptoms. The low attrition rate in this group of physically ill patients, together with requests for extended open-label treatment, reflect high acceptance of this readily available intervention.

Objective: Behavioral, electrophysiological, and imaging studies have found evidence that anxiety disorders are associated with left hemisphere dysfunction or higher than normal activation of right hemisphere regions. Few studies, however, have examined hemispheric asymmetries of function in social phobia, and the influence of comorbidity with depressive disorders is unknown. The present study used dichotic listening tests to assess lateralized cognitive processing in patients with social phobia, depression, or comorbid social phobia and depression. Method: The study used a two-by-two factorial design in which one factor was social phobia (present versus absent) and the second factor was depressive disorder (present versus absent). A total of 125 un-medicated patients with social phobia, depressive disorder, or comorbid social phobia and depressive disorder and 44 healthy comparison subjects were tested on dichotic fused-words, consonant-vowel syllable, and complex tone tests. Results: Patients with social phobia with or without a comorbid depressive disorder had a smaller left hemisphere advantage for processing words and syllables, compared with subjects without social phobia, whereas no difference between groups was found in the right hemisphere advantage for processing complex tones. Depressed women had a larger left hemisphere advantage for processing words, compared with nondepressed women, but this difference was not seen among men. Conclusions: The results support the hypothesis that social phobia is associated with dysfunction of left hemisphere regions mediating verbal processing. Given the importance of verbal processes in social interactions, this dysfunction may contribute to the stress and difficulty experienced by patients with social phobia in social situations.

Objective: Although the newer antidepressants are widely used, little is known about how long it takes to see their full effect. The authors sought to determine how many weeks a fluoxetine trial with no improvement should continue before treatment is changed. Method: The data involved 840 patients in a 12-week open trial of fluoxetine, 20 mg/day, followed by a blinded, placebo-controlled discontinuation study. Outcomes at 4, 6, 8, 10, and 12 weeks were classified as nonresponse, partial response, response, and remission and were based on Hamilton Depression Rating Scale scores. The rate of remission at week 12 was calculated for each group of patients without remission at the earlier time points. The time to relapse during weeks 13-26 of the discontinuation study was examined in patients taking placebo and fluoxetine in relation to status at week 6. Results: Patients unimproved at week 6 had a remission rate at week 12 of 31%-41%. For patients with remission at week 12, level of improvement at week 6 did not affect prognosis in weeks 13-26. Of the unimproved patients at week 8, 23% had remissions by week 12. The week 12 remission rate for unimproved patients at week 4 was clearly high enough to justify continued treatment; the rate for unimproved patients at week 10 was too low. Conclusions: These data suggest that nonresponse to fluoxetine should not be declared until 8 weeks of treatment have elapsed. Practitioners should discuss trial length with patients at the beginning of treatment.

Objective: The study examined a large data set to determine whether patients' sex affected the outcome of antidepressant treatment. Method: Data for 1,746 patients aged 18-65 years who had been treated with tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), fluoxetine, or placebo were examined in a retrospective analysis to determine whether men and women differed in their responses to antidepressants. To examine the effect of menopausal status in the absence of data on individual patients' menopausal status, results for female patients younger or older than age 50, 52, 54, and 56 were compared. Results: Men and women both younger and older than age 50 had equivalent response rates to tricyclics and fluoxetine. Women had a statistically superior response to MAOIs. Placebo response was equivalent across all groups. Conclusions: Neither sex nor menopausal status may be relevant in antidepressant treatment of adult depressed patients up to 65 years of age. Although women had a statistically superior response to MAOIs, this difference may not be clinically relevant.

Objective: The atypical subtype of depression appears to be both well validated and common. Although monoamine oxidase inhibitors are effective in treating atypical depression, their side effects and prescription-associated dietary restrictions reduce their suitability as a first-line treatment. The objective of this study was to estimate the efficacy of the selective serotonin reuptake inhibitor (SSRI) fluoxetine in the treatment of major depression with atypical features. Method: One hundred fifty-four subjects with DSM-IV major depression who met the Columbia criteria for atypical depression were randomly assigned to receive fluoxetine, imipramine, or placebo for a 10-week clinical trial. Imipramine was included because its known efficacy for treatment of atypical depression helped to calibrate the appropriateness of the study group. Results: In both intention-to-treat and completer groups, the effectiveness of both fluoxetine and imipramine was significantly better than that of placebo. The two medications did not differ from each other in effectiveness. Significantly more patients dropped out of treatment with imipramine than with fluoxetine. Before treatment, patients on average rated themselves as very impaired on psychological dimensions of general health and moderately impaired on physical dimensions, compared with population norms. The self-ratings of patients who responded to treatment essentially normalized on these measures. Conclusions: Despite earlier data that SSRIs might be the treatment of choice, fluoxetine appeared to be no better than imipramine in the treatment of atypical depression, although fluoxetine was better tolerated than imipramine.

Objective: Demonstration of antidepressant efficacy beyond 6 months has infrequently been addressed, and no long-term efficacy data exist for patients with chronic atypical depression. Method: Sixty patients with atypical depression (according to Columbia University criteria) of at least 2 years' duration and who had improved with imipramine or phenelzine were stabilized for 6 months and then randomly continued the same medication or placebo for 6 months. Results: Several baseline differences suggested that patients who entered the discontinuation trial on a regimen of phenelzine were more chronically depressed than the imipramine-treated patients. Survival analysis showed a marked advantage for phenelzine relative to placebo. In addition, patients switched to placebo from phenelzine experienced a recurrence of depressive symptoms significantly more often than patients switched to placebo from imipramine. Patients maintained with imipramine did not have lower relapse rates than those switched from imipramine to placebo. Recurrence rates were 23 % for patients maintained on a regimen of phenelzine, 41% for those maintained on a regimen of imipramine, 47% for those switched from imipramine to placebo, and 87% for placebo-treated patients originally treated with phenelzine. Conclusions: Patients with chronic atypical depression are at high risk of recurrence if phenelzine is withdrawn 6 months after initial improvement. Similar findings were not demonstrated for imipramine; this replicates acute trials demonstrating imipramine's relative ineffectiveness in patients with atypical depression. Differences in recurrence rates after the switch to placebo from phenelzine and imipramine could be due to the two drugs' different mechanisms of action or to baseline differences in the two populations.

Objective: The authors' goal was to analyze the acute phase of antidepressant drug treatment to identify placebo responses. Method: Patients rated as improved after 6 weeks of double-blind treatment with imipramine or phenelzine were followed for an additional 6 weeks of double-blind treatment. Initial responses were classified according to the speed of improvement (abrupt or gradual), the persistence or nonpersistence of improvement, and the timing of improvement (early or late onset). Results: It was predicted that patients with nonpersistent, abrupt responses to the drugs were actually experiencing a placebo response and would have the worst prognosis. In fact, this group accounted for a disproportionate number of the relapses. Nonpersistent responders to a drug had a 23.7% relapse rate, but persistent responders had only a 9.0% relapse rate, a significant difference. Conclusions: The authors conclude that a significant proportion of relapses within the first 6 weeks of treatment with an active drug are not related to loss of a true drug effect. Rather, some are related to loss of nonspecific placebo effects, and abrupt nonpersistent responses during drug treatment are most likely the result of placebo effects.

Objective: This study sought to determine what proportion of relapses during continuation therapy with antidepressants can be attributed to loss of nonspecific placebo effects while the patients are taking the drugs. Method: Depressed patients were studied over a 12-week period. One hundred sixty-four patients were randomly assigned to placebo, 174 to imipramine, and 169 to phenelzine. At 6 weeks 35 were judged to be responders to placebo, 70 to imipramine, and 96 to phenelzine. These patients continued their double-blind treatment for weeks 7-12. Results: Thirty-one percent of the patients who were taking placebo, approximately 12% who were taking imipramine, and approximately 9% who were taking phenelzine relapsed in the 7- to 12-week phase. Two different methods of estimating relapses suggested that during the first 3 months of treatment, a large percentage of the relapses of patients taking drugs was attributable to the loss of nonspecific placebo effects rather than true drug effects. Conclusions: A considerable proportion of relapses in the first 3 months of treatment with antidepressants appears to be due to loss of placebo effects. These clinically relevant data may be used to encourage patients who relapse during this period, and who erroneously conclude that antidepressant effects are temporary, to try another medication.

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 designed to add to the scanty literature available on this subject. Method: Eighty-nine mood-reactive, nonmelancholic, mainly chronically depressed outpatients 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. (Am J Psychiatry 1993; 150:118-123)

Objective: The authors' goal was to explore the efficacy of antidepressant medications in outpatients with mild depression. Method: Four hundred one outpatients were diagnosed as depressed by DSM-III criteria. Atypical Depression Diagnostic Scale criteria were also applied to these patients; these criteria require reactivity of mood plus two of four associated features, including hypersomnia, hyperphagia, leaden paralysis, and pathological sensitivity to rejection. All patients were then randomly treated for 6 weeks with up to 300 mg/day of imipramine, up to 90 mg/day of phenelzine, or placebo. Outcome at 6 weeks was determined by clinical global improvement ratings. The outcomes of patients with entry Hamilton Rating Scale for Depression scores in the low (scores of 12 or lower), medium (scores of 13-15), and high (scores above 16) range were compared. Results: The majority (N=332, 83%) of the 401 depressed patients had definite or probable atypical depression. Among the 140 patients who bad low pretreatment Hamilton scale scores, 19 (33%) of S7 given placebo, 25 (60%) of 42 given imipramine, and 34 (83 %) of 41 given phenelzine responded. Each of the antidepressants was superior to placebo. Similar findings applied to the patients with medium and high Hamilton scale scores, except that the rates of placebo response were lower (29% and 10%, respectively). Conclusions: These data support the use of antidepressant medication for some mildly depressed patients, at least if they have atypical depression. Too few patients were included who did not have atypical depression to draw conclusions about such patients. (Am J Psychiatry 1992; 149:615-619)

In order to study different patterns of response to placebo among individuals diagnosed with depressive disorder, 144 clinic patients between the ages of 18 and 65 years were randomly assigned one of four treatment trials. The trials were carried out over a six-week period in a double-blind condition, so that until the end of the study, neither the patients nor the experimenters knew which participants were receiving antidepressants or identical looking placebos. Changes over time were measured by a gradient clinical improvement scale. Patients were monitored weekly, and categorized as having an abrupt or gradual onset of improvement. Fifty percent of the 144 patients receiving placebo were rated as demonstrating some improvement. Twenty-three percent improved abruptly and 27 percent improved gradually. Thirty-three percent of all improvements persisted over the six-week study period. The patients who improved gradually tended to show improvement that persisted over time and remained relatively constant throughout the study. Abrupt improvements proved to be very transient. Placebo-related rapid improvement may be related to the anticipation of help and optimism. Abrupt improvement does not resemble a true response to antidepressants, which generally require at least a two-week delay before actual improvement can be seen. Although the gradual improvements in this study more closely resembled a true drug response, the ability to distinguish spontaneous remission from true placebo effects will require further evaluation. (Consumer Summary produced by Reliance Medical Information, Inc.)

In a previous study, depressed patients who improved after treatment with placebo demonstrated two distinct types of improvement. Those who improved abruptly demonstrated only transient improvement. Improvements that occurred gradually tended to persist over time. In an attempt to compare abrupt versus gradual placebo-related improvement to improvement related to treatment with antidepressant medication, 263 patients who were diagnosed with either moderate or severe depression were studied. The patients ranged in age from 18 to 65 years and participated in a series of four drug-trials, each lasting for a period of six-weeks. The 180 moderately depressed patients and the 83 severely depressed patients were randomly assigned to receive appropriate classes of antidepressant medications. Of the moderately depressed patients, 22 percent improved abruptly, while 49 percent improved gradually. Among the more severely depressed patients, 28 percent improved abruptly while 48 percent demonstrated gradual improvement. These findings were consistent with the earlier study of abrupt versus gradual improvement among placebo-treated patients, in which the percentages of rapid versus gradual improvement were virtually identical. Abrupt improvements among the antidepressant-treated patients proved to be transient. However, gradual improvements in both placebo- and drug-treated patients were persistent and similar in nature. Results indicate that similar processes operate in abrupt and gradual improvements among placebo- and drug-treated depressed patients, although the mechanisms underlying this phenomenon are not yet understood. (Consumer Summary produced by Reliance Medical Information, Inc.)

The placebo effect refers to a phenomenon that may be observed in patients who are given an inactive substance rather than a drug, yet experience improvements in symptoms anyway. Many factors are thought to contribute to a placebo response, such as the degree of suggestibility of the patient, the reinforcing behavior of the clinical staff, and the patient's outlook and expectations of treatment. The relationship between the placebo response and pill-taking was assessed among 50 patients diagnosed with mild but chronic depression being treated on an outpatient basis. The subjects were selected from those who showed improvement of symptoms after a 10-day placebo trial; the content of the pill was not divulged to the participants until the study was completed. These 50 subjects were then randomly assigned to continue the placebo protocol or to discontinue all medication for a six-week period. The patients were seen on a bi-weekly basis for this six-week period and all cases of relapse were noted. Demographic characteristics of the subjects were also noted; self-reported ratings, as well as clinical assessments of depression were performed. At the end of the six-week period, half of the patients in each group had relapsed. A total of 58 percent of all patients relapsed after three months. Except for marital status, none of the demographic variables correlated with outcome; married patients tended to maintain the placebo response more frequently than unmarried patients. It is concluded that once a placebo effect is obtained there is no apparent relationship between the maintenance of the effect and the continuance of pill-taking. (Consumer Summary produced by Reliance Medical Information, Inc.)

Forty-one patients who had failed to respond to 8 weeks of treatment with 20 mg of fluoxetine were randomly assigned to one of three treatments for 4 weeks: 40-60 mg/day of fluoxetine, 20 mg/day of fluoxetine plus 25-50 mg/day of desipramine, and 20 mg/day of fluoxetine plus 300-600 mg/day of lithium. Patients treated with high-dose fluoxetine (N = 15) did significantly better than patients treated with fluoxetine plus lithium (N = 14) and those treated with fluoxetine plus desipramine (N = 12). High-dose fluoxetine was the most effective treatment among partial responders to previous treatment, but high-dose fluoxetine and fluoxetine plus lithium were the most effective treatments among nonresponders.

The authors investigated the relationship between Cloninger's personality dimensions and DSM-III-R personality traits by comparison of scores on the Tridimensional Personality Questionnaire with axis II traits found in structured interviews with 99 patients. Consistent with theoretical predictions, axis II pathology was significantly related to personality dimensions after the effects of axis I disorders were controlled for.

Of 60 depressed alcoholics who completed an open trial of imipramine, 27 (45%) responded with improvement in both mood and drinking behavior, and eight (13%) responded after further dosage increases or treatment with disulfiram. In a subsequent 6-month, randomized discontinuation trial, four of 13 subjects (31%) relapsed during imipramine treatment and seven of 10 (70%) relapsed while taking placebo. This suggests a potential treatment approach for a high-risk subgroup of alcoholics.

It has been hypothesized that lithium, a drug commonly used to treat bipolar spectrum disorders (manic depression), possesses properties that are antagonistic to the pharmacological effects of cocaine. Previous studies have nonetheless failed to find any differences in response to lithium or placebos in treating cocaine abusers, and lithium has been proved to be inferior to treatment with desipramine. To further investigate this, an open trial examining 10 consecutive patients diagnosed with bipolar disorder who also sought treatment for cocaine dependence was performed. Each patient met the Diagnostic and Statistical Manual of Mental Disorders, third edition, revised (DSM-III-R), criteria for bipolar disorder, and the onset of the disorder preceded drug dependency. The subjects consisted of two women and eight men, and the bipolar disorders were characterized by hypomania, cyclothymia, major depression, which five of the 10 showed signs of. Seven patients had a history of alcohol or other drug dependence, and five had at least one first-degree relative with alcoholism. Lithium treatments were scheduled to last 12 weeks, but six subjects dropped out before completion; eight patients were treated for six or more weeks. A slight, but statistically insignificant, reduction in cocaine use was observed in the patients. The mood of five patients improved over this period, but only one patient had a reduction of cocaine euphoria while on lithium. A reduction of cocaine craving occurred in five of the subjects. In general, the results showed little efficacy of lithium as a cocaine abuse treatment in these bipolar patients. Some of the factors which may help explain these findings are discussed. For example, the high incidence of alcoholism and family history of alcoholism suggests the possibility of misdiagnosis of the affective disorder. (Consumer Summary produced by Reliance Medical Information, Inc.)