***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: An open field trial was conducted comparing desipramine and an active placebo in separate population s of chronic cocaine and phencyclidine ( PCP ) abusers , who discontinued their abuse . Subjects who received desipramine  showed a decrease in depressive symptoms after a 20 - 40 day period regardless of whether they abused PCP or cocaine BACKGROUND The N-methyl-d-aspartate receptor antagonist ketamine has rapid antidepressant effects in major depression . Psychotomimetic symptoms , dissociation and hemodynamic changes are known side effects of ketamine , but it is unclear if these side effects relate to its antidepressant efficacy . METHODS Data from 108 treatment-resistant in patients meeting criteria for major depressive disorder and bipolar disorder who received a single subanesthetic ketamine infusion were analyzed . Pearson correlations were performed to examine potential associations between rapid changes in dissociation and psychotomimesis with the Clinician-Administered Dissociative States Scale ( CADSS ) and Brief Psychiatric Rating Scale ( BPRS ) , respectively , manic symptoms with Young Mania Rating Scale ( YMRS ) , and vital sign changes , with percent change in the 17-item Hamilton Depression Rating scale ( HDRS ) at 40 and 230min and Days 1 and 7 . RESULTS Pearson correlations showed significant association between increased CADSS score at 40min and percent improvement with ketamine in HDRS at 230min ( r=-0.35 , p=0.007 ) and Day 7 ( r=-0.41 , p=0.01 ) . Changes in YMRS or BPRS Positive Symptom score at 40min were not significantly correlated with percent HDRS improvement at any time point with ketamine . Changes in systolic blood pressure , diastolic blood pressure , and pulse were also not significantly related to HDRS change . LIMITATIONS Secondary data analysis , combined diagnostic groups , potential unblinding . CONCLUSIONS Among the examined mediators of ketamine׳s antidepressant response , only dissociative side effects predicted a more robust and sustained antidepressant . Prospect i ve , mechanistic investigations are critically needed to underst and why intra-infusion dissociation correlates with a more robust antidepressant efficacy of ketamine BACKGROUND Although significant evidence suggests that diminished monoamine function is associated with clinical depression , catecholamine or indoleamine depletion alone has not been associated with significant mood changes in unmedicated depressed subjects or never-depressed control subjects . This study assesses the integrated role of these monoamine systems in depressed patients . METHODS Unmedicated depressed subjects underwent a 2-week , double-blind , r and om-ordered crossover study consisting of the following active and control conditions respectively : indoleamine ( via tryptophan depletion ) plus catecholamine ( via alpha-methyl-paratyrosine administration ) depletion and , separately , indoleamine plus sham ( via diphenhydramine administration ) catecholamine depletion .  Ten subjects completed both conditions ; two subjects were withdrawn after active testing and one after control testing . RESULTS Mean Hamilton Depression Rating Scale ( HDRS ) scores decreased progressively throughout the study days ( baseline 26.7 points + /- 1.7 SEM and termination 20.0 + /- 2.4 , active depletion ; baseline 26.1 points + /- 2.3 SEM and termination 23.2 + /- 2.6 , control testing ) but did not differ between groups . Only three patients demonstrated 20 % or greater increases from baseline HDRS at any point during the observation days . CONCLUSIONS Overall , results show that simultaneous disruptions of indoleamine and catecholamine function do not exacerbate symptoms in unmedicated depressed subjects , thus lending further support to the notion that monoamines regulate mood in actively depressed patients via indirect mechanisms A sample of  placebo-controlled tricyclic antidepressant studies was examined retrospectively to determine whether there was any difference in the relative efficacy of the tricyclic when it was compared against an inert placebo as against an active ( atropine ) placebo with anticholinergic side effects . Fewer studies showed a significant difference between atropine placebo and drug than between inert placebo and drug . The possibilities that atropine has a specific antidepressant effect , or that side effects amplify placebo responses are considered BACKGROUND Although hypotheses about the therapeutic mechanism of action of light therapy have focused on serotonergic mechanisms , the potential role , if any , of catecholaminergic pathways has not been fully explored . METHODS Sixteen patients with seasonal affective disorder who had responded to a st and ard regimen of daily 10000-lux light therapy  were enrolled in a double-blind , placebo-controlled , r and omized crossover study . We compared the effects of tryptophan depletion with catecholamine depletion and sham depletion . Ingestion of a tryptophan-free amino acid beverage plus amino acid capsules was used to deplete tryptophan . Administration of the tyrosine hydroxylase inhibitor alpha-methyl-paratyrosine was used to deplete catecholamines . Diphenhydramine hydrochloride was used as an active placebo during sham depletion . The effects of these interventions were evaluated with measures of depression , plasma tryptophan levels , and plasma catecholamine metabolites . RESULTS Tryptophan depletion significantly decreased plasma total and free tryptophan levels . Catecholamine depletion significantly decreased plasma 3-methoxy-4-hydroxyphenylethyleneglycol and homovanillic acid levels . Both tryptophan depletion and catecholamine depletion , compared with sham depletion , induced a robust increase ( P<.001 , repeated- measures analysis of variance ) in depressive symptoms as measured with the Hamilton Depression Rating Scale , Seasonal Affective Disorder Version . CONCLUSIONS The beneficial effects of light therapy in the treatment of seasonal affective disorder are reversed by both tryptophan depletion and catecholamine depletion . These findings confirm previous work showing that serotonin plays an important role in the mechanism of action of light therapy and provide new evidence that brain catecholaminergic systems may also be involved OBJECTIVE Ketamine , a glutamate N-methyl-d-aspartate ( NMDA ) receptor antagonist , has shown rapid antidepressant effects , but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion . The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression . METHOD This was a two-site , parallel-arm , r and omized controlled trial of a single infusion of ketamine compared to an active placebo control condition , the anesthetic midazolam .  Patients with treatment-resistant major depression experiencing a major depressive episode were r and omly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio ( N=73 ) . The primary outcome was change in depression severity 24 hours after drug administration , as assessed by the Montgomery-Åsberg Depression Rating Scale ( MADRS ) . RESULTS The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment . After adjustment for baseline scores and site , the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points ( 95 % confidence interval [ CI ] , 3.20 to 12.71 ) . The likelihood of response at 24 hours was greater with ketamine than with midazolam ( odds ratio , 2.18 ; 95 % CI , 1.21 to 4.14 ) , with response rates of 64 % and 28 % , respectively . CONCLUSIONS Ketamine demonstrated rapid antidepressant effects in an optimized study design , further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression . More information on response durability and safety is required before implementation in clinical practice The mechanism of action of electroconvulsive therapy ( ECT ) in treating major depression is unknown . We studied two c and i date mechanisms through inhibiting simultaneously the synthesis of noradrenaline and serotonin in patients immediately after successful treatment with ECT  using a r and omised , placebo-controlled , double-blind crossover design . There were no significant changes in depression scores under any experimental conditions , or between the amine-depleted and placebo groups despite reductions of 61 % in serum homovanillic acid , 47 % in 3-methoxy-4-hydroxyenylethyleneglycol , and 89 % in serum tryptophan . Catecholamine and serotonin availability may not be necessary for maintaining the initial antidepressant response to ECT Psychopharmacological studies usually attempt to eliminate " nonspecific " influences on outcome by double-blind design s. In a r and omized , double-blind comparison of alprazolam , imipramine , and placebo , the great majority of panic disorder patients ( N = 59 ) and their physicians were able to rate accurately whether active drug or placebo had been given . Moreover , physicians could distinguish between the two types of active drugs . Inasmuch as correct rating was possible halfway through treatment , concerns about the internal validity of the double-blind strategy arise TOC summary The 50 % likelihood of receiving a drug or placebo in clinical trials modifies the outcome , an effect strongly modulated if minor onset sensations are associated with drug intake . ABSTRACT The knowledge of having only a 50 % chance of receiving an active drug can result in reduced efficacy in blinded r and omized clinical trials ( RCTs ) compared to clinical practice ( reduced external validity ) . Moreover , minor onset sensations associated with the drug ( but not with an inert placebo ) can further challenge the attribution of group differences to drug‐specific efficacy ( internal validity ) . We used a r and omized experimental study with inert placebos ( inert substance ) vs active placebos ( inducing minor sensations ) , and different instructions about group allocation ( probability of receiving drug : 0 % , 50 % , 100 % ) . One hundred forty‐four healthy volunteers were informed that a new application method for a well‐known painkiller would be tested . Pain thresholds were assessed before and after receiving nasal spray . Half of the nasal sprays were inert placebos ( sesame oil ) , while the other half were active placebos inducing prickling nasal sensations ( sesame oil with 0.014 % capsaicin ) . The major outcome was pain threshold after placebo application . A substantial expectation effect was found for the inert placebo condition , with participants who believed they had received an active drug reporting the highest pain thresholds . Active placebos show substantial differences to passive placebos in the 50 % chance group . Therefore , patient expectations are significantly different in placebo‐controlled clinical trials ( 50 % chance ) vs clinical practice ( 100 % chance ) . Moreover , minor drug onset sensations can challenge internal validity . Effect sizes for these mechanisms are medium , and can substantially compete with specific drug effects . For clinical trials , new study design s are needed that better control for these effects As part of a study of drug treatment of aggressive behavior to be reported separately , we have evaluated the double‐blind procedure in a recently completed comparison of the efficacy of lithium carbonate versus placebo in modifying aggressive behavior in nonpsychotic incarcerated delinquents . We conclude that the side effects of lithium carbonate are sufficient to reveal the medication to most subjects receiving it . Thus , while the study staff could not identify lithium‐receivers at better than chance levels , and while subjects who received placebo could not identify their medication at better than chance levels , subjects who received lithium could accurately identify it . On a weekly symptom check list there was no difference between lithium and placebo groups on average lithium target symptoms reported during 4‐week pre‐ and postmedication control periods ; however , lithium‐receivers reported significantly more target symptoms every week medication was administered . Of 16 subjects who quit the study , 14 had received lithium and nearly all of those who gave reasons for quitting specified side effects  , most often nausea . The method ological problems of using lithium in a double‐blind design might be overcome by employing a “ discontinuation ” design , or , speculatively , a double‐blind , cross‐over design utilizing an “ active placebo ” Objective : Although antidepressants are widely prescribed as analgesics in chronic back pain , their clinical pharmacology is not well established . Norepinephrine transporter blockade seems to be essential for analgesia , but optimal concentrations are unknown . Fixed-dose studies of serotonin reuptake inhibitors are generally negative , but such studies can not be interpreted clearly because efficacy might be detected if concentration-response relationships were known . We evaluated ( 1 ) the feasibility of conducting a controlled-concentration study of a norepinephrine ( desipramine ) and a serotonin reuptake ( fluoxetine ) inhibitor and ( 2 ) the relationship between achieved concentrations and analgesic response . Methods : This single-center , 12-week , double-blind , prospect i ve , controlled-concentration study r and omized 121 chronic back pain patients without major depression to active placebo ( benztropine mesylate )  or  to predetermined low , medium , or high concentrations of desipramine ( targets were 50 , 110 , and 
    Output:
    
The use of active placebos was clustered in specific research setting s and did not appear to reflect consistently the side effect profile of the experimental intervention , for example , selective serotonin reuptake inhibitors were compared with active placebos in pain trials but not in depression trials .
The main argument for active placebo was to reduce risk of unblinding ; the main argument against was the risk of unintended therapeutic effect .
Pharmacological active placebo control interventions are rarely used in r and omized clinical trials , but they constitute a method ological tool which merits serious consideration .
We suggest that active placebos are used more often in trials of drugs with noticeable side effects , especially in situations where the expected therapeutic effects are modest and the risk of bias due to unblinding is high