title: A multisite trial of mifepristone for the treatment of psychotic depression: a site-by-treatment interaction. A double-blind randomized study comparing imipramine with fluvoxamine in depressed inpatients The validity of major depression with psychotic features based on a community study. Rapid Reversal of Psychotic Depression Using Mifepristone Response of psychotic depression subtypes to pharmacotherapy. Factors associated with non-completion in a double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo for psychotic depression Effect of Antidepressant Medication Resistance on Short-term Response to Electroconvulsive Therapy Clinical and Biological Effects of Mifepristone Treatment for Psychotic Depression The pharmacological treatment of delusional depression. A placebo-controlled study of the antidepressant activity of moclobemide, a new MAO-A inhibitor. Efficacy and Safety of Mifepristone for the Treatment of Psychotic Depression Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol--a double-blind multicenter trial. Treatment of mood-congruent psychotic depression with imipramine. Citalopram versus nortriptyline in late‐life depression: a 12‐week randomized single‐blind study Resistance to antidepressant medications and short-term clinical response to ECT. Who benefits from electroconvulsive therapy? Combined results of the Leicester and Northwick Park trials. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. Treatment of unipolar psychotic depression: a randomized, double‐blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine Mifepristone versus Placebo in the Treatment of Psychosis in Patients with Psychotic Major Depression Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. A Double-Blind, Randomized Study of Olanzapine and Olanzapine/Fluoxetine Combination for Major Depression With Psychotic Features Limited efficacy of ketoconazole in treatment-refractory major depression. The Pharmacological Treatment of Delusional Depression: Part II Impact of prior pharmacotherapy on remission of psychotic depression in a randomized controlled trial. Persisting low use of antipsychotics in the treatment of major depressive disorder with psychotic features. A comparison of phenelzine and imipramine in depressed inpatients. Depressed in-patients respond differently to imipramine and mirtazapine. Faster onset of action of fluvoxamine in combination with pindolol in the treatment of delusional depression: a controlled study. Placebo response rates in psychotic and nonpsychotic depression. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: the study of pharmacotherapy of psychotic depression (STOP-PD).
abstract: Major Depression with Psychotic Features ( psychotic depression ) is a common , debilitating psychiatric disease . We hypothesized that mifepristone , a cortisol receptor ( GRII ) antagonist , would significantly reduce psychotic symptoms in psychotic depression . Two hundred fifty-eight patients with psychotic depression enrolled at 29 sites were r and omized to mifepristone or placebo for 7 days . The primary outcome was rapid and sustained response , defined as a 50 % or greater decrease in Brief Psychiatric Rating Scale - Positive Symptom Subscale scores at the end of treatment ( day7 ) and 49 days later ( day 56 ) . Cochran-Mantel-Haenszel compared proportions of responders to mifepristone versus placebo adjusting for site . Exploratory analyses compared response of patients with mifepristone plasma concentrations of > or = 1800 ng/ml to placebo . The primary endpoint was not statistically significant . However , the Breslow-Day test indicated a statistically significant site-by-treatment interaction . Mifepristone produced significantly higher response among the twenty sites who participated from the trial onset ( p<.05 ) , whereas no difference was observed at the nine sites added late in the trial . Patients with  mifepristone plasma levels > or = 1800 ng/ml were significantly more likely to respond than placebo patients ( Intent-to-Treat : OR=2.4 , p=.03 ; Initial 20 sites : OR=4.1 , p=.002 ) . The results of this trial are instructive in two respects . First , while statistical adjustments for [ corrected ] site are common in multisite clinical trials , this study reminds trialists to formally evaluate the interaction of site by treatment . Second , the association between increased  mifepristone plasma concentration levels and greater clinical response , detected despite the site-by-treatment interaction , suggests that higher plasma levels may be needed for maximizing the probability of a positive response 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 This article reports on the evidence for the validity of psychotic major depression as a distinct subtype based on cross-sectional and 1-year prospect i ve data from the Epidemiologic Catchment Area study . Consistent with findings from previous clinical studies , only about 14 % of major depressions were accompanied by psychotic features . Psychotic as compared with nonpsychotic depression had a more severe course , as reflected in increased risk of relapse , persistence over 1 year , suicide attempts , hospitalization , comorbidity , and financial dependency . These differences could not be explained by differences in demographic characteristics or by symptom severity , as assessed by symptom profile or number of symptoms . The boundary problem with schizophrenia and bipolar affective disorder that is seen in clinical studies was also found in this sample . To our knowledge , this is the first study to examine the validity of psychotic depression in a community sample ; the findings are consistent with those from clinical sample s. They support the clinical significance of psychotic depression and the continuation of its inclusion as a distinct subtype in DSM-IV The rationale for treating psychotic major depression with glucocorticoid receptor ( GR ) antagonists is review ed . Five patients with psychotic major depression were given 600 mg of mifepristone in a 4-day , double-blind , placebo-controlled crossover study . All the patients completed the protocol and adverse effects were not observed or reported . All of the five patients showed substantial improvements in their Hamilton Rating Scale for Depression scores while they were receiving mifepristone , and four of the five patients showed substantial improvement in their Brief Psychiatric Rating Scale scores . Little , if any , improvement was seen with placebo . These preliminary results suggest that short-term use of GR antagonists may be effective in the treatment of psychotic major depression and that additional study , perhaps using higher doses or more treatment days , seems warranted Patients with psychotic depression respond well when treated with a combination of an antidepressant and antipsychotic medication . We previously reported that they will respond in a similar fashion when treated with amoxapine monotherapy . There are few prospect i ve studies on the pharmacologic treatment response of psychotic depression subtypes . We treated 37 in patients , 21 with mood congruent ( MC ) psychotic depression and 16 with mood incongruent ( MI ) psychotic depression , in a r and omized double-blind fashion with either the combination of amitriptyline and perphenazine or with amoxapine for 4 weeks . Depression and psychosis ratings improved in a similar manner in both the MC or MI patients irrespective of medication treatment group . Global response rates were similar in the MI patients and MC patients . The data suggest that classifying psychotic depression into MC versus MI subtypes may have limited acute prognostic value in pharmacotherapy response rates High rates of attrition have been reported in r and omized controlled trials of patients with severe psychiatric illness , including psychotic depression ( MDpsy ) . The purpose of this study is to examine factors associated with overall attrition and with subtypes of attrition in the Study of the Pharmacotherapy of Psychotic Depression ( STOP-PD ) . Secondary analysis of data collected in a multi-site , r and omized , placebo-controlled trial . Clinical services of academic hospitals . Participants comprised 259 persons with MDpsy , aged 18 - 93 years . The intervention consisted of the r and om allocation to 12 weeks of treatment of either olanzapine plus sertraline or olanzapine plus placebo . Demographic and clinical variables associated with overall non-completion and sub-types of non-completion of r and omized treatment . One hundred and seventeen ( 45.2 % ) subjects did not complete 12 weeks of r and omized treatment . In a logistic regression analysis , inpatient entry status , olanzapine monotherapy , and higher cumulative medical burden were statistically significant independent predictors of overall non-completion . In a multinomial logistic regression model that examined predictors of subtypes of non-completion , subjects who entered the study as an inpatient were less likely to complete because of inadequate efficacy as determined by the investigator , and older subjects were less likely to complete because of poorer tolerability . Subjects who were assigned to olanzapine monotherapy , younger subjects , and subjects who entered the study as in patients were less likely to complete because of reasons other than efficacy or tolerability . Underst and ing factors that contribute to premature discontinuation in studies of MDpsy , and to the specific reasons for attrition , has the potential to improve the management of this disorder , as well as improve the design of future clinical trials of MDpsy Abstract : This prospect i ve study assessed the influence of resistance to antidepressant pharmacotherapy on the short-term response to subsequent electroconvulsive therapy ( ECT ) . Previous research has shown that patients with medication resistance were less likely to respond to ECT . This finding may be applicable to the population of depressed in patients in The Netherl and s , where ECT is often preceded by several medication trials . Eighty-five patients ( 61 female and 24 male patients ) with DSM-IV criteria for depressive disorder , both with and without mood congruent psychotic features , were included for analysis . Medication resistance was rated with the Antidepressant Treatment History Form . Medication resistance was predefined in accordance with the previous research in this field . When a reduction of at least 50 % on the 17-item version of the Hamilton Rating Scale for Depression ( HRSD ) between pre- and post-ECT is used as response criterion , medication-resistant patients were equally likely to respond to subsequent ECT ( 30/48 = 82.5 % ) than patients without medication resistance ( 30/37 = 81.1 % ) . Even when post-ECT HRSD score ≤7 was used ( full remission ) , there was no significant difference between medication-resistant patients ( 21/48 = 43.8 % ) and patients without medication resistance ( 15/37 = 40.5 % ) . When potential confounding variables were taken into account , these differences remain nonsignificant . In contrast to earlier research , medication resistance does not influence short-term response to subsequent ECT and it can still be of considerable efficacy Psychotic major depression ( PMD ) is found to be a relatively common psychiatric condition that affects up to nearly 20 % of patients with major depression . Previous studies by our group have shown rapid reversal of psychotic symptoms in some PMD patients treated with mifepristone , in addition to restoring a more normal afternoon cortisol release . The rationale for treating patients with PMD with a glucocorticosteroid receptor antagonist is further discussed . In total , 30 patients with PMD were treated with either 600 mg/day mifepristone or placebo for 8 days in a r and omized double-blind manner . The Hamilton Depression Rating Scale ( HDRS ) and the Brief Psychiatric Rating Scale ( BPRS ) were administered at baseline and again after 8 days of treatment . Cortisol and ACTH were measured hourly from 1800 to 0900 at baseline and after 8 days of treatment . Significantly , more patients in the mifepristone group ( seven of 15 ) showed a 50 % or greater decline on the BPRS positive symptom subscale , an index of psychotic symptoms , as compared to the placebo group ( two of 15 ) . Patients who received mifepristone had lower HDRS and BPRS scores at study completion compared to those who received placebo , but these differences were not statistically significant . In addition , mifepristone significantly elevated cortisol and ACTH levels and steepened ascending slopes from 1800 to 0100 and from 0100 to 0900 as compared to placebo . Clinical and biological effects of mifepristone were comparable among males and females . Age was found to significantly and positively correlate with changes in cortisol and ACTH . These results suggest that short-term use of mifepristone may be effective in the treatment of PMD and may re-regulate the HPA axis . Additional blinded studies are warranted The authors investigated the pharmacological treatment of  delusional depression  by assigning patients on a r and om double-blind basis to amitriptyline alone , perphenazine alone , or a combination of the two . Fourteen ( 78 % ) of the 18 patients assigned to amitriptyline plus perphenazine were responders , compared with seven ( 41 % ) of 17 patients treated with amitriptyline alone and three ( 19 % ) of the 16 patients treated with perphenazine alone . The combination of amitriptyline and perphenazine was clearly superior ( p less than .01 ) Preliminary open trials performed by the authors and others with Moclobemide , a new MAO-A inhibitor , indicated that the drug has a satisfactory antidepressant activity . In the present double-blind study Moclobemide has been compared to placebo in a group of 34 unipolar psychotic or neurotic depressed patients . The mean daily dose of Moclobemide was 297 mg and treatment lasted from two to four weeks . Drug effectiveness was measured by improvements in the Hamilton Rating Scale for Depression ( HRSD ) , Clinical Global Impression ( CGI ) and 100 mm Visual Analogue Scale ( VAS ) . The results have shown that the active drug was markedly superior to placebo . The mean total score of HRSD was reduced from 41.7 to 16.5 in 18 pts . treated with Moclobemide and from 36.3 to 29.1 in 16 pts . who received placebo .  Self- assessment with VAS showed a mean reduction from 82.7 mm to 42.2 mm and from 84.3 to 70.6 mm respectively . Moderate to marked improvement was observed by the CGI in 15 cases treated with Moclobemide and mild to moderate in 5 cases who received placebo . The treatment was well tolerated Open-label studies and r and omized clinical trials have suggested that mifepristone may be effective for the treatment of major depression with psychotic features ( psychotic depression ) . A recent study reported a correlation between mifepristone plasma concentration and clinical response . The current study aim ed to evaluate the safety and efficacy of mifepristone and , secondarily , to test whether response was significantly greater among patients with mifepristone plasma concentrations above an a priori hypothesized threshold . A total of 433 patients who met criteria for psychotic depression were r and omly assigned to receive 7 days of either mifepristone ( 300 , 600 , or 1200 mg ) or placebo . Response was defined as a 50 % reduction in psychotic symptoms on both days 7 and 56 . Cochran-Mantel-Haenszel tests compared ( 1 ) the proportion of responders among patients assigned mifepristone versus placebo and ( 2 ) the proportion of responders among the subset of patients with plasma concentrations greater than 1660 ng/mL versus placebo . Mifepristone was well tolerated at all 3 doses . The proportion of responders r and omized to mifepristone did not statistically differ from placebo . Patients with trough mifepristone plasma concentrations greater than 1660 ng/mL were significantly more likely to have a rapid and sustained reduction in psychotic symptoms than those who received placebo . The study failed to demonstrate efficacy on its primary end point . However , the replication of a statistically significant linear association between  mifepristone plasma concentration and clinical response indicates that mifepristone at sufficient plasma levels may potentially be effective in rapidly and durably reducing the psychotic symptoms of patients with psychotic depression BACKGROUND Patients with delusional depression are difficult to treat . The atypical antidepressant trimipramine was effective in a previous 4-week open label pilot study in patients with this disorder . The major neurobiological effect of trimipramine is the inhibition of the hypothalamic-pituitary-adrenocortical ( HPA ) system . In delusional depression HPA overactivity is more distinct than in other subtypes of depression . HPA suppression is thought to contribute to the action of trimipramine . METHODS In a double-blind , r and omized , placebo controlled multicenter trial we compared the effects of trimipramine monotherapy versus a combination of amitriptyline and haloperidol . Dosage was increased stepwise from 100 mg up to 400 mg trimipramine and from 100 mg up to 200 mg amitriptyline combined with 2 mg up to 7.5 mg haloperidol . The average dose of trimipramine was higher than that of amitriptyline throughout the trial . During sixth week mean dosage ( + /-st and ard deviation ) were 356.1+/-61.2 mg trimipramine , 184.0+/-23.6 mg amitriptyline and 6.3+/-1.8 mg haloperidol . During six weeks psychometric assessment s were performed weekly . For HPA monitoring a dexamethasone/corticotropin-releasing hormone ( Dex/CRH ) test was performed before active medication and at the end of treatment . Additionally tolerability was monitored by ECG , EEG assessment of extrapyramidal symptoms and akathisia , clinical laboratory routine and recording of blood pressure and heart rate . Adverse events were documented . RESULTS 94 patients were enclosed into the study . The per protocol sample consisted of 33 patients of the trimipramine group and of 24 patients of the amitriptyline/haloperidol group . The decrease of the Hamilton depression ( HAMD ) score ( 24 items ) showed non-inferiority of trimipramine compared to amitriptyline/haloperidol . Twenty-eight patients ( 84.84 % ) in the trimipramine arm and 17 patients ( 70.83 % ) in the amitriptyline/haloperidol arm were responders ( HAMD < or=50 % ) . Remission ( HAMD<8 ) was found in 18 ( 54.55 % ) patients after trimipramine and in 11 ( 45.83 % ) patients after amitriptyline/haloperidol . No significant differences were found concerning response and remission . The cortisol and ACTH response in the Dex/CRH test decreased between days 1 and 42 in both groups . Serious side effects were not reported . CONCLUSION In all , trimipramine monotherapy appears to be an effective treatment in delusional depression BACKGROUND Most studies report a poor response of psychotic depressed patients to treatment with a tricyclic antidepressant alone compared to combined treatment with an antipsychotic preparation and compared to non-psychotic depressed patients . However , the issue of optimal treatment of psychotic depressed patients has not been resolved as yet . Previously , we reported a significant difference in response to mirtazapine compared to imipramine in a r and omised , double-blind , fixed-blood-level study with in- patients with major depression . In the current study we focus on the treatment response to imipramine in a group of patients with psychotic depression and compare this to patients who manifest no psychotic features . Our aim in presenting these findings was to contribute to the discussion on the optimal treatment of psychotic depressed patients . METHODS Fifty-two patients with a unipolar major depression ( DSM-IIIR ) , comprising 15 patients with mood-congruent psychotic features and 37 patients with no psychotic features , were commenced on treatment with imipramine after a drug-free and placebo-washout period of 7 days . The dose of imipramine was adjusted for all patients to a predetermined blood level . The Hamilton ( HRSD ) and Montgomery-Asberg ( MADRS ) Depression Rating Scales were used to evaluate treatment response . RESULTS Of the 45 patients who completed the study , nine of the 13 psychotic patients ( 69.2 % ) and 14 of the 32 non-psychotic patients ( 43.8 % ) responded to treatment . The patients with psychotic features demonstrated a lower mean final HRSD score , together with a greater fall in MADRS score over time , compared to the non-psychotic group . Both these findings remained statistically significant after controlling for a number of possible confounding factors . CONCLUSIONS These results demonstrate that , in this group of patients with mood-congruent psychotic depression , imipramine used on its own together with strict control of serum drug levels produced a high treatment response rate of 70 % . CLINICAL IMPLICATION S If replicated , these findings suggest that imipramine with control of blood levels of medication may be a useful first-line treatment for depressed patients with mood-congruent psychotic features . LIMITATIONS Our sample size was modest . This fact may caution against generalisation of the results Objective : The aim of this single‐blind study was to examine the efficacy and tolerability of citalopram compared to nortriptyline in moderate to severe major depressive patients aged 60 years or over OBJECTIVE Traditionally , it has been widely assumed that the likelihood of response to ECT is independent of the adequacy of previous treatment with antidepressant medications . However , recent research has raised the possibility that medication-resistant patients with depression have a poorer clinical ECT outcome than patients who have not failed previous adequate medication trials . METHOD Medication resistance of 100 patients with primary , unipolar , nonpsychotic major depression was evaluated during the index episode with the Antidepressant Treatment History Form . Patients were recruited and treated with ECT at three sites ; st and ardized ECT and clinical assessment procedures were used . Clinical outcome was assessed immediately and 1 week after completion of the ECT course . RESULTS Patients who previously had failed one or more adequate antidepressant medication trials were less likely to respond to subsequent ECT than patients not known to be medication resistant . This finding held within each study site , whether clinical response was assessed categorically or in terms of the magnitude of symptomatic improvement and after the authors accounted for other potential predictors of clinical outcome . Resistance to heterocyclic antidepressants predicted poorer outcome after ECT , while resistance to selective serotonin reuptake inhibitors and monoamine oxidase inhibitors did not show significant predictive relations . CONCLUSIONS While a substantial percentage of medication-resistant patients respond to ECT , clinical outcome in this group is inferior to that of patients without established medication resistance . The predictive power of medication resistance is generalizable across diverse clinical setting s , particularly for heterocyclic antidepressants , which perhaps suggests an overlap in the mechanisms of actions of ECT and this medication class This paper describes the results obtained by combining data from the Northwick Park and Leicester r and omised controlled trials of ECT .  Patients who suffered from depression in which retardation and delusions were features and who received real ECT  had a significantly improved outcome at the end of four weeks of treatment ( as measured by improvement in the HRSD ) in comparison with those who received simulated ECT . However , this treatment effect was not detectable at six-month follow-up . Patients who were neither retarded nor deluded did not benefit significantly from real as opposed to simulated ECT In a multicenter , double-blind , parallel group trial , the efficacy of risperidone ( RIS ) was compared with a combination of haloperidol and amitriptyline ( HAL/AMI ) over 6 weeks in patients with coexisting psychotic and depressive symptoms with either a schizoaffective disorder , depressive type , a major depression with psychotic features , or a nonresidual schizophrenia with major depressive symptoms according to DSM-III-R criteria . A total of 123 patients ( 62 RIS ; 61 HAL/AMI ) were included ; the mean daily dosage at endpoint was 6.9 mg RIS versus 9 mg HAL combined with 180 mg AMI .  Efficacy results for those 98 patients ( 47 RIS ; 51 HAL/AMI ) who completed at least 3 weeks of double-blind treatment revealed in both treatment groups large reductions in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale ( RIS 37 % ; HAL/AMI 51 % ) and the Bech-Rafaelsen Melancholia Scale total scores ( RIS 51 % ; HAL/AMI 70 % ) . The reductions in the Brief Psychiatric Rating Scale and the Bech-Rafaelsen Melancholia Scale scores in the total group were significantly larger in the HAL/AMI group than in the RIS group ( p < 0.01 ) , mostly because of significant differences in the subgroup of patients suffering from depression with psychotic features , whereas treatment differences in the other diagnostic subgroups were not significant . The incidence of extrapyramidal side effects as assessed by the Extrapyramidal Symptom Rating Scale was slightly higher under RIS ( 37 % ) than under HAL/AMI ( 31 % ) . Adverse events were reported by 66 % of RIS and 75 % of HAL/AMI patients . The results of this trial suggest that the therapeutic effect of HAL/AMI is superior to RIS in the total group of patients with combined psychotic and depressive symptoms . However , subgroup differences have to be considered OBJECTIVE To conduct the first r and omized study comparing the efficacy of an antidepressant alone versus an antidepressant plus a neuroleptic in the treatment of late-life psychotic depression . METHOD The efficacy of nortriptyline plus placebo versus nortriptyline plus perphenazine was compared in 36 patients aged 50 years or older presenting with a major depressive episode with psychotic features ( DSM-III-R criteria ) . Patients were started openly on nortriptyline treatment titrated to therapeutic levels . They were then r and omly assigned under double-blind conditions to addition of perphenazine or placebo . Outcomes were compared in the 2 treatment groups using measures including the Hamilton Rating Scale for Depression ( HAM-D ) and the Brief Psychiatric Rating Scale ( BPRS ) ; side effects were assessed with the Geriatric Movement Disorder Assessment . RESULTS Both treatments were well tolerated . Of the 36 r and omly assigned patients , 2 ( 1 in each group ) dropped out due to treatment-related adverse effects . Four additional patients dropped out for administrative reasons . Thirty patients received nortriptyline for at least 4 weeks combined with either perphenazine ( N = 14 ) or placebo ( N = 16 ) for at least 2 weeks ( median = 9 weeks ) . There was no significant difference between the completers in the 2 treatment groups when comparing their scores on the HAM-D , the BPRS , its psychoticism subscale , or any side effects measure . Rates of response ( defined as resolution of both depression and psychosis ) did not differ significantly in the 2 groups ( nortriptyline-plus-perphenazine group , 50 % vs. nortriptyline-plus-placebo group , 44 % ) . CONCLUSION When treating older patients with psychotic depression , the addition of a moderate dose of a traditional neuroleptic to a tricyclic antidepressant was well tolerated but did not improve efficacy . This finding supports existing data suggesting that the pathophysiology ( and thus the required treatment ) of psychotic depression may be different early and late in life Wijkstra J , Burger H , van den Broek WW , Birkenhäger TK , Janzing JGE , Boks MPM , Bruijn JA , van der Loos MLM , Breteler LMT , Ramaekers GMGI , Verkes RJ , Nolen WA . Treatment of  unipolar psychotic depression :  a r and omized , double‐blind study comparing imipramine , venlafaxine , and venlafaxine plus quetiapine BACKGROUND Abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression ( PMD ) . Recent studies have suggested that the antiglucocorticoid , mifepristone might have a role in the treatment of PMD . The current study tested the efficacy of mifepristone treatment of the psychotic symptoms of PMD . METHODS 221 patients , aged 19 to 75 years , who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics , participated in a double blind , r and omized , placebo controlled study . Patients were r and omly assigned to either 7 days of mifepristone ( n = 105 ) or placebo ( n = 116 ) followed by 21 days of usual treatment . RESULTS Patients treated with mifepristone were significantly more likely to achieve response , defined as a 30 % reduction in the Brief Psychiatric Rating Scale ( BPRS ) . In addition , mifepristone treated patients were significantly more likely to achieve a 50 % reduction in the BPRS Positive Symptom Scale ( PSS ) . No significant differences were observed on measures of depression . CONCLUSION A seven day course of mifepristone followed by usual treatment appears to be effective and well tolerated in the treatment of psychosis in PMD . This study suggests that the antiglucocorticoid , mifepristone , might represent an alternative to traditional treatments of psychosis in psychotic depression BACKGROUND Previous studies have reported the efficacy of selective serotonin reuptake inhibitors as monotherapy in the treatment of delusional depression . The clinical efficacy of venlafaxine , a serotonin-norepinephrine reuptake blocker , has been demonstrated in the treatment of patients with moderate-to-severe depression , but , to date , no evidence is available about its use in depressed patients with psychotic features . METHOD Under double-blind conditions , 28 hospitalized patients who met DSM-IV criteria for major depression , severe with psychotic features , were r and omly assigned to receive fluvoxamine or venlafaxine , 300 mg/day , for 6 weeks . Severity was evaluated using the Hamilton Rating Scale for Depression ( HAM-D ) and the  Dimensions of Delusional Experience Rating Scale ( DDERS ) administered at baseline and every week thereafter . Side effects were also recorded . Clinical response was defined as a reduction of the scores in the 21-item HAM-D to 8 or below and in the DDERS to 0 . RESULTS At study completion , the response rates were 78.6 % ( N = 11 ) and 58.3 % ( N = 7 ) for fluvoxamine and venlafaxine , respectively . No significant difference was found between drugs ( Fisher exact test , p = .40 ) . Analysis of covariance on HAM-D scores did not reveal a significantly different decrease of depressive symptomatology between the 2 treatment groups ( p = .14 ) . Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded . The overall safety profile of both fluvoxamine and venlafaxine was favorable . CONCLUSION The results of this pilot double-blind trial show that fluvoxamine is useful in the treatment of delusional depression and suggest that venlafaxine may also be an effective compound in the treatment of this disorder . The latter finding , although promising , warrants further replication in a larger sample of patients OBJECTIVE In this study the authors evaluated the efficacy and the tolerability of sertraline and paroxetine in the treatment of delusional depression . METHOD Under double-blind conditions , 46 hospitalized patients who met the DSM-III-R criteria for major depression with psychotic features were treated with sertraline or paroxetine for 6 weeks . RESULTS The response rates were 75 % and 46 % for sertraline and paroxetine , respectively . The dropout rate was substantial ( 41 % ) in the paroxetine group and was attributable to side effects . CONCLUSIONS Selective serotonin reuptake inhibitors administered alone are useful in the treatment of delusional depression Abstract : The purpose of this study was to compare the efficacy and safety of olanzapine ( OLZ ) monotherapy and an olanzapine/fluoxetine combination ( OFC ) with placebo ( PLA ) for unipolar major depression with psychotic features . Under a single protocol , two 8-week , double-blind trials were conducted at 27 sites . Patients ( n = 124 trial 1 , n = 125 trial 2 ) were r and omized to 1 of 3 treatment groups : OLZ ( 5 to 20 mg/d ) , PLA , or OFC ( olanzapine 5 to 20 mg/d + fluoxetine 20 to 80 mg/d ) . The primary outcome measure was the 24-item Hamilton Depression Rating Scale total score . For trial 1 , endpoint improvement for the OLZ group ( −14.9 ) was not significantly different from the PLA or OFC groups . The OFC group had significantly greater endpoint improvement ( −20.9 ) than the PLA group ( −10.4 , P = 0.001 ) ; this significant difference was present within 7 days of therapy and maintained at every subsequent visit . The OFC group also had significantly higher response rate ( 63.6 % ) than the PLA ( 28.0 % , P = 0.004 ) or OLZ ( 34.9 % , P = 0.027 ) groups . For trial 2 , there were no significant differences among treatment groups on the 24-item Hamilton Depression Rating Scale total scores or response rates . The combination exhibited a comparable safety profile with OLZ monotherapy and no significant increases in extrapyramidal symptoms compared with placebo . Patients with major depression with psychotic features treated with OLZ monotherapy did not demonstrate significant depressive symptom improvement compared with placebo in either trial ; however , an olanzapine/fluoxetine combination was associated with significant improvement compared with placebo in one trial and was well tolerated The authors examined the efficacy of ketoconazole in 16 adults with treatment-refractory major depressive disorder . Subjects participated in a 6-week , double-blind , placebo-controlled trial . Assessment s of mood were made using the Hamilton Rating Scale for Depression ( HAM-D ) , the Beck Depression Inventory ( BDI ) , and the Clinical Global Impression Scale ( CGI ) . Results showed that none of eight patients r and omly assigned to receive placebo and two of eight patients r and omly assigned to receive ketoconazole met criteria for response . As a group , patients assigned to receive ketoconazole showed no significant reductions in HAM-D , BDI , or CGI scores during the 6-week trial compared with those receiving placebo . These findings suggest a limited efficacy for ketoconazole in patients with treatment-refractory major depression This study investigated the pharmacological treatment of delusional depressives by assigning patients on a r and om double-blind basis to amitriptyline ( AT ) alone , perphenazine ( PER ) alone , or AT + PER . As reported in an earlier paper , the combination of AT + PER was the superior treatment with a response rate of 78 % compared with 41 % for AT alone and 19 % for PER alone . This difference is both clinical ly and statistically significant ( p < 0.01 ) . In this second article , the authors report that the patients on AT + PER  had higher plasma levels of AT and its pharmacologically active metabolite nortriptyline ( NT ) than the patients on  AT alone . Although the response rate had a direct relationship to AT + NT plasma levels , an analysis of variance showed that the group of patients treated with AT + PER still had a significantly higher response rate , even after controlling for the plasma levels of AT + NT ( p < 0.05 ) . There was also a correlation between PER plasma levels and clinical response Having failed to respond to an adequate antidepressant treatment course predicts poorer treatment outcomes in patients with major depression . However , little is known about the impact of prior treatment on the outcome of  major depression with psychotic features ( MDpsy ) . We examined the effect of prior treatment history on the outcome of pharmacotherapy  of MDpsy in patients who participated in the STOPD-PD study , a r and omized , double-blind , clinical trial comparing a combination of olanzapine plus sertraline vs. olanzapine plus placebo . The strength of treatment courses received prior to r and omization was classified using a vali date d method . A hierarchy of outcomes was hypothesized based on treatments received prior to r and omization and r and omized treatment . A high remission rate was observed in subjects with a history of no prior treatment or inadequate treatment who were treated with a combination of olanzapine and sertraline .  A low remission rate was observed in subjects who had previously failed to respond to an antidepressant alone and who were treated with olanzapine monotherapy . A low remission rate was also observed in subjects who had previously failed to respond to a combination of an antipsychotic and an antidepressant . Similar to patients with major depression , these results emphasize the impact of prior pharmacotherapy on treatment outcomes in patients with MDpsy OBJECTIVE Practice guidelines recommend the use of a combination of an antidepressant and an antipsychotic for the pharmacologic treatment of major depressive disorder with psychotic features ( MD-Psy ) . We assessed the extent to which the  pharmacotherapy  received by patients with MD-Psy under usual care conforms to these recommendations . METHOD We assessed the  pharmacotherapy  received under usual care conditions by 100 patients with MD-Psy prior to enrollment in STOP-PD ( Study of the Pharmacotherapy of Psychotic Depression ) , a 12-week r and omized , controlled trial comparing olanzapine plus sertraline to olanzapine plus placebo . Our assessment took place from January 2003 to May 2004 . The strength of antidepressant trials was rated using the Antidepressant Treatment History Form ( ATHF ) . The strength of antipsychotic trials or combinations of antidepressants and antipsychotics was rated using a modified version of the ATHF . We also determined whether the strength of antipsychotic or combination trials was associated with age , the duration of the current depressive episode , medical burden , cognitive status , or the severity of depressive or psychotic symptoms . RESULTS Most patients with MD-Psy were treated with antidepressants ( N = 82 , 82 % ) or antipsychotics ( N = 65 , 65 % ) . About half of the patients ( N = 48 , 48 % ) received therapeutic doses of an antidepressant ; 10 % ( N = 10 ) received an intermediate dose of an antipsychotic , and 6 % ( N = 6 ) received a high dose . Overall , only 5 % ( N = 5 ) received a combination of an adequate dose of an antidepressant and a high dose of an  antipsychotic .  The strength of both antipsychotic trials ( p = .021 ) and combination trials ( p = .039 ) was significantly associated only with a longer duration of the current depressive episode . CONCLUSIONS These findings show a persisting low use of  antipsychotics  in the treatment of MD-Psy . Given the high morbidity rates associated with MD-Psy , it is important to continue to educate clinicians regarding its identification and treatment . CLINICAL TRIALS REGISTRATION Clinical Trials.gov identifier NCT00056472 Phenelzine and imipramine were compared double-blind , in 43 depressed in patients . A placebo week preceded drug treatment ; this allowed early identification of placebo responders who did not therefore enter the study . After three weeks treatment , the two drugs were equally effective on Hamilton , Beck and SCL-90 measures of depression and anxiety . On the the SCL-90 scales of hostility and paranoia  imipramine was more effective ; in some patients phenelzine was associated with increased hostility . Measurement of MAO inhibition and plasma tricyclic levels indicated that adequate doses were generally used - ( mean 81 mg/day phenelzine and 144 mg/day imipramine ) Tricyclic antidepressants and more recent antidepressants are generally considered to have equivalent efficacy in the treatment of depression . After a previous report of a marked difference in the response to mirtazapine compared to imipramine , we report here an analysis of different symptom clusters . One hundred seven consecutive in- patients with major depression ( Diagnostic and Statistical Manual III-R , DSM-III-R ) and a Hamilton Rating Scale for Depression ( HRS-D ) score of 18 points or more were r and omly assigned to double-blind treatment . Two and four weeks after predefined blood levels had been obtained , the severity of depression was assessed using the HRS-D. The mean dosages used were 235 mg/day of imipramine and 77 mg/day of mirtazapine , the latter being in excess of the 15 - 45 mg/day range currently advised . Total HRS-D scores and seven symptom clusters were analyzed in the 85 patients ( 79 % ) who were not receiving any co-medication .  Imipramine was more effective against the clusters related to core symptoms of depression : " depression and guilt " , " retardation " , and " melancholia " , respectively . Mirtazapine showed a biphasic response with regard to the clusters " sleep " and " anxiety/agitation " , respectively , which consisted of a marked response after two weeks of predefined blood level , but with a waning of this effect at four weeks . Imipramine produced a more gradual response on these clusters , which was more pronounced at four weeks than with mirtazapine . Two aspects of the present study could be related to this finding : blood level control result ed in optimal treatment with imipramine but not mirtazapine , and - most importantly - the patients were not receiving any anxiolytic or hypnotic co-medication . These findings suggest that mirtazapine may have anxiolytic and sedative properties and fewer antidepressant properties than imipramine in severely depressed in- patients This double-blind , controlled study was undertaken to investigate whether the addition of pindolol could improve the therapeutic response to fluvoxamine of depressed patients with psychotic features . After a 1-week placebo run-in period , 72 patients received fluvoxamine  300 mg/day in combination with placebo or pindolol 7.5 mg/day . At study completion , 28 ( 80 % ) of 35 patients treated with fluvoxamine plus placebo and 29 ( 80.5 % ) of 36 patients treated with fluvoxamine plus pindolol were categorized as responders ( reduction of their score on the 21-item Hamilton Rating Scale for Depression to 8 or less and on the Dimension for the Delusional Experience Rating Scale to 0 ) . In the third and fourth weeks , the response rates were significantly superior in the fluvoxamine plus pindolol group ( p = 0.0001 , p = 0.023 , respectively ) . Treatment response seemed to be unrelated to the demographic and the clinical characteristics recorded . No significant difference was found comparing plasma levels of fluvoxamine between groups , thus excluding a pharmacokinetic interaction . Other than mild nausea and sedation in a few patients , treatments were well tolerated . No medically significant adverse events occurred . Depressed patients with psychotic features who were administered pindolol experienced a more rapid improvement during fluvoxamine treatment . Thus , the combination of fluvoxamine with pindolol may be a useful pharmacologic strategy in the treatment of this disorder . A rapid clinical response in such patients is of relevance in clinical practice as well as in economic fields , given the direct and indirect costs of depression The authors reanalyzed data from two earlier studies that used double-blind placebo-controlled formats to study the efficacy of amitriptyline . Using a 14-day drug-free ' wash-out ' period , they found that the  placebo response rates were 0 % for psychotic depressives and 13.3 % for nonpsychotic depressives .  Amitriptyline  was significantly superior to placebo for both psychotic ( P less than or equal to 0.05 ) and nonpsychotic ( P less than or equal to 0.05 ) depressed patients CONTEXT Evidence for the efficacy of combination pharmacotherapy has been limited and without positive trials in geriatric patients with major depression ( MD ) with psychotic features . OBJECTIVES To compare remission rates of MD with psychotic features in those treated with a combination of atypical antipsychotic medication plus a serotonin reuptake inhibitor with those treated with antipsychotic monotherapy ; and to compare response by age . DESIGN Twelve-week , double-blind , r and omized , controlled trial . SETTING Clinical services of 4 academic sites . Patients Two hundred fifty-nine subjects with MD with psychotic features r and omized by age ( < 60 or > or = 60 years ) ( mean [ st and ard deviation ( SD ) ] , 41.3 [ 10.8 ] years in 117 younger adults vs 71.7 [ 7.8 ] years in 142 geriatric participants ) . Intervention Target doses of 15 to 20 mg of olanzapine per day plus masked sertraline or placebo at 150 to 200 mg per day . Main Outcome Measure Remission rates of MD with psychotic features . RESULTS Treatment with olanzapine/sertraline was associated with higher remission rates during the trial than olanzapine/placebo ( odds ratio [ OR ] , 1.28 ; 95 % confidence interval [ CI ] , 1.12 - 1.47 ; P < .001 ) ; 41.9 % of subjects who underwent combination therapy were in remission at their last assessment compared with 23.9 % of subjects treated with monotherapy ( chi(2)(1 ) = 9.53 , P = .002 ) . Combination therapy was comparably superior in both younger ( OR , 1.25 ; 95 % CI , 1.05 - 1.50 ; P = .02 ) and older ( OR , 1.34 ; 95 % CI , 1.09 - 1.66 ; P = .01 ) adults . Overall , tolerability was comparable across age groups . Both age groups had significant increases in cholesterol and triglyceride concentrations , but statistically significant increases in glucose occurred only in younger adults . Younger adults gained significantly more weight than older subjects ( mean [ SD ] , 6.5 [ 6.6 ] kg vs 3.3 [ 4.9 ] kg , P = .001 ) . CONCLUSIONS Combination pharmacotherapy is efficacious for the treatment of MD with psychotic features . Future research must determine the benefits vs risks of continuing atypical antipsychotic medications beyond 12 weeks . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00056472
target: Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo .
  Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone
background: BACKGROUND Evidence is limited regarding the most effective pharmacological treatment for psychotic depression :  combination of an antidepressant plus an antipsychotic , monotherapy with an antidepressant or monotherapy with an antipsychotic .
  This is an up date of a review first published in 2005 and last up date d in 2009 .
  OBJECTIVES 1 .
  To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression :  antidepressant monotherapy , antipsychotic monotherapy and the combination of an antidepressant plus an antipsychotic , compared with each other and /or with placebo.2 .
  To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment .