0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Metyrapone as Additive Treatment in Major Depression:  A Double-blind and Placebo-Controlled Trial FREE

Holger Jahn, MD; Mildred Schick, MD; Falk Kiefer, MD; Michael Kellner, MD; Alexander Yassouridis, PhD; Klaus Wiedemann, MD
[+] Author Affiliations

Author Affiliations: Department of Psychiatryand Psychotherapy, University Hospital Hamburg-Eppendorf, Hamburg (Drs Jahn,Schick, Kiefer, Kellner, and Wiedemann), and Department of Biostatistics atthe Max-Planck-Institute of Psychiatry, Munich (Dr Yassouridis), Germany.


Arch Gen Psychiatry. 2004;61(12):1235-1244. doi:10.1001/archpsyc.61.12.1235.
Text Size: A A A
Published online

Background  Inhibitors of steroid synthesis have been reported to exert antidepressive effects, according to preliminary findings.

Objective  To test whether the addition of metyrapone to standard antidepressants induces a more rapid, more efficacious, and sustained treatment response in patients with major depression.

Design  Double-blind, randomized, placebo-controlled trial.

Setting  Hospitalized care.

Patients  Sixty-three inpatients with a DSM-IV diagnosis of major depression and a baseline score 18 points or higher on the Hamilton Rating Scale for Depression.

Interventions  Random allocation to 2 treatment groups receiving either placebo or metyrapone (1 g/d) for the first 3 weeks during a 5-week treatment with standard serotonergic antidepressants (nefazodone or fluvoxamine).

Main Outcome Measures  Primary outcome criteria were the number of responders and the time to onset of action. Responder rates were considered twice after 3 and 5 weeks with a definition of treatment response as 30% and 50% reduction, respectively, of baseline Hamilton Rating Scale for Depression scores. Onset of action was defined as the time point at which at least a 20% reduction of baseline Hamilton Rating Scale for Depression scores occurred.

Results  Using intention-to-treat analysis, we found that a higher proportion of patients receiving metyrapone showed a positive treatment response at day 21 (23 of 33 patients) and at day 35 (19 of 33 patients) compared with placebo patients (day 21: 13 of 30 patients; Fisher exact P = .031; day 35: 10 of 30 patients; Fisher exact P = .047). The clinical course of patients treated with metyrapone showed an earlier onset of action (Kaplan-Meier analysis; log-rank test P<.006) beginning in the first week. The plasma concentrations of corticotropin and deoxycortisol were significantly higher during metyrapone treatment (multivariate analysis of covariance, P<.05), whereas cortisol remained largely unchanged. Metyrapone treatment was well tolerated without serious adverse effects.

Conclusions  Metyrapone is an effective adjunct in the treatment of major depression, accelerating the onset of antidepressant action. A better treatment outcome compared with standard treatment and a sustained antidepressive effect were observed.

Figures in this Article

Our understanding of the neuroendocrine pathophysiology of depressionhas made significant progress in recent years, which should help to developnew remedies. Alterations of the hypothalamic-pituitary-adrenal (HPA) axisare the most consistent pathological endocrine findings in depression.13 The key regulator ofHPA axis activity, corticotropin-releasing hormone (CRH), is increased indepression.46 Theeffects of CRH are modulated by neuropeptides79 andmonoaminergic transmitters.10,11 Theexaggerated HPA function in depression appears to be also the result of animpaired glucocorticoid receptor (GR)12,13 andmineralocorticoid receptor (MR)14,15 feedbackcontrol. Whether HPA-axis hyperactivity is initially caused by a CRH overdriveresulting in MR/GR dysfunction or vice versa by dysregulation at another levelis yet undecided.16,17

Hence, attempts have been made to treat depression by directly targetingHPA-axis activity. Currently, 3 major pathways are investigated: (1) administrationof CRH antagonists like R12191918; (2) administrationof GR antagonists like RU 486 or Org 345171921;and (3) treatment with steroid-synthesis inhibitors like ketoconazole, aminoglutethimide,or metyrapone.22

Preclinical studies nurture the hope for new therapeutic strategiesbased on steroid-synthesis inhibition,23 butclinical data about the antidepressive efficacy of these compounds are mainlyconfined to small open-label trials and case reports.2430 Firstreports date back to the 1970s when Jeffcoate et al31 treateddepressed Cushing patients with metyrapone. In 1991, Murphy32 reportedthe first case of a successfully treated depressed patient. One single-blindcrossover trial of metyrapone and 2 small double-blind studies on ketoconazolein the treatment of depression have been published.3335

Our aim was to conduct the first prospective, randomized, placebo-controlled,and double-blind clinical trial of metyrapone as additive treatment in depression.Metyrapone was preferred because this compound inhibits selectively the 11β-hydroxylaseand the 11β-hydroxysteroid-dehydrogenase type 1 (11β-HSD-1),36,37 thereby exerting direct effects withinthe central nervous system.38 The additiveapproach was applied because the intended inclusion of severely depressedpatients made a pure placebo group ethically challenging.39 Furthermore,the continuous use of an antidepressant allowed a standardized follow-up afterthe double-blind period.

The questions to be answered were whether metyrapone exerts potentiatingeffects during a standard antidepressant therapy and whether an earlier onsetof action and an improved overall and sustained treatment response can beachieved. Because GR/MR distribution40 as wellas 11β-HSD-1 activities41,42 aresubject to sexual dimorphism in humans, the sample was prospectively stratifiedfor sex and balanced for treatment with 2 selected serotonergic antidepressants.

SUBJECTS

A total of 352 inpatients referred within a 3-year period from May 1998to May 2001 to 2 specialized wards for affective disorders at the UniversityHospital Hamburg met DSM-IV43 diagnosticcriteria for major depressive disorder according to assessments by 3 experiencedpsychiatrists (H.J., M.S., and K.W.). These prospective participants werescreened for inclusion and exclusion criteria. A total of 63 inpatients gaveinformed consent and were included in the trial (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Flow chart of the study recruitingand randomization procedures.

Graphic Jump Location

Inclusion criteria were (1) a diagnosis of major depressive disorder,single or recurrent according to DSM-IV criteria(diagnoses 296.2 or 296.3); (2) a minimum baseline score of 18 points on theHamilton Rating Scale for Depression, 21-item version (HAMD-21)44;(3) age from 18 to 75 years; (4) a period of at least 5 days free from antidepressants,antipsychotics, mood stabilizers, and all other medications except mild antihypertensiveagents; and (5) a negative result on urinary drug screening. Criteria forexclusion were (1) a current DSM-IV diagnosis forother axis I psychiatric disorders; (2) serious medical conditions, especiallythose associated with adrenal insufficiency; and (3) pregnancy, nursing, orrefusal by women to use a reliable method of birth control.

Participants were randomly assigned to a study group if they satisfiedthese criteria. The study sample was stratified for sex and balanced for the2 serotonergic antidepressants used (nefazodone and fluvoxamine). The studywas approved by the local ethics committee. Written informed consent was obtainedfrom all subjects.

MEDICATION

The 63 participants who met the inclusion criteria were randomly assignedto the treatment groups. The pharmacological reason for the use of serotonergiccompounds is based on the presumed hippocampal effects of metyrapone on 5HT-1Areceptors. The clinical rationale for the use of these compounds is basedon activating properties of fluvoxamine and sedative effects of nefazodone,allowing inclusion of inhibited as well as agitated patients. The respectiveantidepressant was selected according to clinical symptomatology.

Following baseline assessments, subjects entered a 3-week, double-blindtreatment period with either metyrapone (250 mg given orally 4 times a day)or placebo (4 times a day) at 8 AM, 12 PM, 6 PM, and 10 PM, in addition to a standard antidepressanttreatment with nefazodone or fluvoxamine. The dose range for fluvoxamine was150 to 200 mg/d and for nefazodone 300 to 400 mg/d after 1 week of treatment.

The medication with metyrapone or placebo and each of the serotonergicantidepressants was started simultaneously on day 1 of the study. After day21, patients continued to take the antidepressant, but metyrapone or placebomedication was stopped. The study ended after 5 weeks.

Both serotonergic antidepressants were given as commercially availableoriginal medication. Metyrapone was capsuled, and identical placebo capsuleswere produced. Allocation codes were provided in sealed envelopes for eachpatient at the pharmacy of University Hospital Hamburg, where formulationand blinding were conducted. The randomization was organized by a computer-generatedlist using the PLAN procedure from the SAS/STAT software (SAS Institute Inc,Cary, NC). The concomitant use of lorazepam was allowed for a maximum of 8days from day 0 to day 7 of the 35-day treatment period.

PSYCHOPATHOLOGIC ASSESSMENTS

Following the assessment of inclusion and exclusion criteria on day0, data were collected, including information about the history of illnessand sociodemographic data concerning family and social, psychological, andmedical problems. The psychopathometric assessments were performed at days0, 3, 7, 14, 21, 28, and 35 between 10 AM and 1 PM.External ratings were the HAMD-21,44 the Montgomery-AsbergDepression Rating Scale (MADRS),45 and theClinical Global Impressions scale.46 Self-ratinginstruments were the Beck Depression Inventory (revised 21-item version)47 and the Zung Self-Rating Depression Scale (20-itemversion).48 Adverse effects were assessed bya German adaptation of the Udvalg for Kliniske Undersogelser (UKU) side effectscale.49 External rating instruments were appliedby 2 authors (H.J. and M.S.), who had training sessions to assure high qualityand interrater reliability.

BIOCHEMISTRY

Blood samples were drawn between 8:30 and 9:30 AM ondays 0, 1, 3, 7, 10, 14, 21, 28, and 35 for clinical chemistry, endocrineparameters (cortisol, 11-deoxycortisol, corticotropin [ACTH], and dehydroepiandrosterone[DHEA]), and drug monitoring of fluvoxamine and nefazodone during the steady-statephase (data given for day 14).

Endocrine parameters were determined by commercial radioimmunoassayswith coated tube techniques (cortisol, 11-deoxycortisol, DHEA; DRG-Instruments,Marburg, Germany) or immunoradiometrically (ACTH; Nichols Institute, San JuanCapistrano, Calif). The cross-reactivity of cortisol determinations with 11-deoxycortisolwas less than 0.1%.

Fluvoxamine and nefazodone were determined after automated extractionvia column switching by reverse-phase high-performance liquid chromatographyusing UV detection.50

During the trial, only 1 author (K.W.) had access to laboratory datato control for clinically relevant changes.

STATISTICS

The intention-to-treat sample of 63 patients was estimated to be sufficientto detect large effect sizes with a power of 85% at an α level of.05.For the statistical evaluation of outcome criteria, the intention-to-treatsample of 63 patients with the dropouts classified as nonresponders has beentaken into consideration, whereas for hormones, the statistical evaluationwas based on those 60 patients who actually received medication during thestudy. Missing values were substituted using a last observation carried forwardapproach.

A priori primary outcome criteria were (1) 2 psychometric criteria definedby the number of responders and the time to onset of action and (2) the courseof concentrations of ACTH, cortisol, 11-deoxycortisol, and DHEA. The numberof responders was considered twice after 3 and 5 weeks by defining the treatmentresponse as a 30% and 50% reduction, respectively, from baseline HAMD scores.Onset of action was determined by the survival analytical approach of Stassen,51 which defines the onset of action as the time pointat which at least a 20% reduction of baseline HAMD scores occurred. Otherpsychometric scores, demographic parameters, and adverse effects were consideredas secondary variables.

Differences in the responder rates between the treatment groups weretested by Fisher exact test. The other main criterion, the time to onset ofaction, was analyzed with a Kaplan-Meier survival analysis and embedded log-ranktest as described,51 considering dropouts ascensored cases.

Multivariate analyses of covariance (MANCOVA) with sex as a covariatewere further applied for testing the effects of treatment, antidepressantmedication, and time on secondary variables like HAMD and MADRS. Accordingto the underlying data structure, differences between metyrapone and placeboin demographic baseline variables or adverse effects were tested by MANCOVAor nonparametric tests (Fisher exact test or median test). Associations betweensome variables in the various experimental conditions were tested with thePearson correlation coefficients. To characterize the study sample on a descriptivelevel, rates of remission defined as a HAMD score of less than 8 at day 35were calculated, and a Quitkin pattern analysis based on the Clinical GlobalImpressions scale to define the time point, when at least a marked improvementwas detectable, was performed.51 Also, therelapse rates after week 3, defined as a persistent 20% increase in HAMD scores,and the treatment effect sizes were derived.

For the hormonal variables, sex was considered a covariate. Multivariateanalyses of covariance with a repeated-measures design were applied to testthe effects of treatment and antidepressant medication (between-subject factorswith 2 levels: metyrapone or placebo; nefazodone or fluvoxamine) and time(a within-subject factor with 9 levels) on ACTH, cortisol, deoxycortisol,and DHEA as dependent variables. A complementary statistical evaluation (posthoc analysis) by MANCOVA focused on possible differences in the endocrineparameters between responders and nonresponders at the end of the study (day35). Response, treatment, and time were considered as influential variablesand sex and baseline concentrations as covariates.

In cases of significant factor effects in the MANCOVA, univariate Ftests and tests with contrasts were conducted to identify those variablescontributing significantly to these effects and to locate the time pointsof significant differences. As a nominal level of significance, α = .05was accepted. All post hoc tests (univariate F tests and tests with contrasts)were performed at a reduced level of significance (Bonferroni correction)to keep the type I error less than or equal to 0.05. Measures are given inmean ± SEM unless otherwise stated.

STUDY SAMPLE

Eleven patients of the metyrapone group and 9 of the placebo group receiveda DSM-IV 296.2x diagnosis, and 22 of the metyrapone-treatedand 21 of the placebo-treated patients were classified as recurrently depressedpatients (DSM-IV 296.3x).Regarding diagnoses, historyof depression (duration of illness, age at time of onset, number of episodes,severity of current episode, and duration of current episode), and baselinepsychopathometric scores (HAMD, MADRS, Clinical Global Impressions-SeverityGrade scale, Beck Depression Inventory,and Zung Self-Rating Depression Scale),no significant differences between metyrapone and placebo were detected (Table 1 and Table2). Women had suffered more previous episodes than men.The medianfor previous episodes in women was 3 (minimum/maximum, 1/21), compared with2 in men (minimum/maximum, 1/8). Furthermore, the duration of the currentindex episode prior to study inclusion was longer in men (median, 4 months;minimum/maximum, 1/24 months) than in women (median, 2 months; minimum/maximum,0.5/19 months).

Of the 63 patients randomized, 56 patients completed the trial and 7patients dropped out. Three dropouts revoked their consent after inclusionand before the treatment was started, and 4 patients left during the studybecause of adverse effects. Four dropouts were assigned to the placebo group,3 to the metyrapone group, 4 to the fluvoxamine group, and 3 to the nefazodonegroup. Five of 7 dropouts were women.

With regard to premedication, 2 of 33 patients in the metyrapone groupreceived fluoxetine 4 weeks prior to the inclusion date. Both patients tookit for fewer than 10 days. In the placebo group, 1 of 30 patients had takenfluoxetine for a few days 2 weeks before inclusion. In the metyrapone group,1 patient received nefazodone prior to inclusion and was switched to fluvoxaminebecause of previous adverse effects; 1 patient received fluvoxamine for 3days, 11 days before inclusion in the trial. In the placebo group, 1 patientwas exposed to fluvoxamine for 1 day, a week before entering the hospital.Regarding data of all antidepressants taken within a 4-week period prior toinclusion as well as lifetime exposure to antidepressants, no differencesbetween the treatment groups were detectable. One patient in each group receiveda β-blocker in low dose.

PSYCHOPATHOLOGICAL OUTCOME

Considering the main outcome, the responder rates in the metyraponegroup at day 21 and day 35 were significantly greater than those in the placebogroup. Twenty-three of 33 patients in the metyrapone group vs 13 of 30 patientsin the placebo group showed a positive treatment response using the 30% reductioncriterion of the HAMD at day 21 (Fisher exact P = .031).At day 35, 19 responders in the metyrapone group vs 10 responders in the placebogroup yielded a significantly better response rate and better treatment outcomein the metyrapone group (50% reduction criterion; Fisher exact P = .047).The course of the HAMD scores is shown for bothtreatments in Figure 2, and the treatmentefficacy is similarly detectable with HAMD, MADRS, Beck Depression Inventory,and Zung Self-Rating Depression Scale with effect sizes ranging from 0.37to 0.73 (Table 2).

Place holder to copy figure label and caption
Figure 2.

Hamilton Rating Scale for Depression,21-item version (HAMD-21) scores for the metyrapone group (solid circles)and the placebo group (open circles) for days 0, 3, 7, 14, 21, 28, and 35on the intention-to-treat sample. Data are presented as mean ± SEM.Asterisks indicate time points with significant group differences. The y-axisis cut below a HAMD score of 10.

Graphic Jump Location

Concerning the time to onset of action, the Kaplan-Meier survival analysis(Figure 3) indicated a significantlyshorter time to improvement for the metyrapone group than for the placebogroup (log-rank test, P<.006). Fifty percent ofthe metyrapone-treated patients showed early improvement by a HAMD score reductionof at least 20% at day 7. In the placebo group, a 20% improvement was reachedby 50% of the patients only at day 14. At day 35, all patients from the metyraponegroup showed at least a 20% improvement, whereas in the placebo group, 5 of30 did not show any improvement. The lower panel of Figure 3 depicts the Quitkin pattern51 ofthe Clinical Global Impressions scale scores also indicating a faster onsetof action induced by metyrapone. About the same proportion of patients inboth groups showed no marked improvement on the Clinical Global Impressionsscale until the study’s end (metyrapone, 6/33; placebo, 10/30). Theremission rates at week 5, defined as a total HAMD score of less than 8 points,were 10/33 in the metyrapone group and 7/30 in the placebo group. The relapserate after day 21, defined as a persistent 20% increase in HAMD scores today 35, was very low and similar for the metyrapone group (3/33) and the placebogroup (3/30). Analyzing the influence of treatment, antidepressant medication,and time on the sum scores of the HAMD and MADRS, with sex and baseline scoresas covariates, we observed significant effects of treatment (F2,52 = 4.52;significance of F = 0.02) and time (F10,47 = 6.16;significance of F<0.001) on each of the considered scales (univariate Ftests, P<.05). Fluvoxamine and nefazodone didnot significantly differ in their antidepressant efficacy, neither alone norin interaction with the factors treatment and time. Tests with polynomialcontrasts revealed significantly stronger reductions of HAMD (F1,56 = 42.63;significance of F<0.001) and MADRS (F1,56 = 52.75;significance of F<0.001) scores by metyrapone compared with placebo ateach time point until day 35 (Figure 2).

Place holder to copy figure label and caption
Figure 3.

Onset of action analyses: Stassenanalysis with a Kaplan-Meier survival model (upper panel) and Quitkin patternanalysis (lower panel). For details, see the “Results” section.

Graphic Jump Location

The MADRS scores showed an earlier and more pronounced reduction thanthe HAMD scores in the metyrapone group, verifying the statement that theMADRS is sensitive to early antidepressant actions.41 Item-3(inner tension) and item-10 (suicidal ideation) showed especially fast reductionsfor patients treated with metyrapone.

ENDOCRINE MEASURES

The MANCOVA of the endocrine data showed significant main effects oftreatment (F4,52 = 8.05; significance of F = 0),time (F32,1642 = 9.18; significance of F = 0),and antidepressant medication (F4,52 = 3.61; significanceof F = 0.01), as well as a significant interaction effect of all3 factors (F32,1642 = 1.83; significance of F = 0.003)attributed to all hormones except DHEA (univariate F tests, P<.05). Subsequent univariate F tests showed that cortisol showedslightly higher concentrations in the fluvoxamine group after commencing treatment.Both antidepressants did not show different effects on ACTH, 11-deoxycortisol,and DHEA. By analyses of simple effects of antidepressant medication withinthe factors treatment and time, significant differences did not emerge atthe various time points of the study for any of the endocrine variables. Therefore,it is not necessary to differentiate between the antidepressants regardingthe endocrine variables. Also, sex as a covariate did not significantly influencethe investigated hormones.

By analysis of the simple effects of treatment and time, we found thatduring metyrapone treatment, ACTH, 11-deoxycortisol, and DHEA showed significantelevations of plasma concentrations compared with baseline (test with polynomialcontrasts; P values for a second-degree polynomial<.05) (Table 3). These elevationswere already significant at day 1 for 11-deoxycortisol, ACTH, and DHEA. Thesehormones were also significantly increased during the entire 3-week treatmentperiod compared with placebo (tests with contrasts, P<.05).For cortisol, there was a trend toward slightly higher cortisol concentrations(P values for a first-degree polynomial = .052).

Table Graphic Jump LocationTable 3. Endocrine Parameters for the Metyrapone and Placebo Groups*

After discontinuation of metyrapone, the concentrations of ACTH, 11-deoxycortisol,and DHEA decreased reasonably, and, apart from still-increased ACTH concentrationsat day 35 in the metyrapone group, no significant differences from placeboremained (test with contrasts, P<.05). Duringplacebo, analyses of time effects also showed slightly increased ACTH and11-deoxycortisol concentrations compared with baseline, which were similarfor fluvoxamine and nefazodone. Cortisol for the whole placebogroup and DHEA concentrations remained largely unchanged.

With metyrapone, a significant correlation between ACTH and 11-deoxycortisolplasma concentrations emerged (rbeta = 0.953; P<.001 at day 21), and a similar but less robust correlation wasfound between ACTH and DHEA (rbeta = 0.518; P<.01 at day 21). No significant correlations between these parametersappeared in the placebo group. Also, no significant correlation was detectedbetween ACTH and cortisol levels during metyrapone administration as evidenceof a sufficient enzyme block.

RESPONSE AND ENDOCRINE VARIABLES

Comparing responders and nonresponders in the metyrapone group, a positivetreatment response after 5 weeks appeared to be associated with greater elevationsof ACTH and 11-deoxycortisol plasma concentrations (Table 4) (Figure 4), althoughthis difference failed to reach statistical significance in a post hoc MANCOVA.

Place holder to copy figure label and caption
Figure 4.

Time course of corticotropin (ACTH)concentrations in relation to treatment and responder status at day 35. Dataare presented as mean ± SEM. Responders show higher ACTHconcentrations compared with nonresponders in the metyrapone group. For details,see the “Results” section.

Graphic Jump Location
Table Graphic Jump LocationTable 4. Endocrine Parameters for the Responder and Nonresponder Factionsof the Metyrapone and Placebo Groups*

There was no significant association between basal cortisol levels atday 0 and treatment outcome at day 21 or day 35, although baseline cortisolconcentrations were higher for the responders taking metyrapone. No differenceemerged in the response rate by splitting the patient sample at a cutoff ofgreater than 30 μg/dL of cortisol at baseline. Higher basal cortisol concentrationswere not associated with a more favorable outcome during metyrapone treatment.

SAFETY AND TOLERABILITY

The metyrapone treatment was well tolerated, and no serious adverseeffects occurred. Minor adverse effects had a low incidence (Table 5) and were predominantly reported by women (mean ± SEMadverse events reported: women, 3.32 ± 0.47; men, 2.55 ± 0.40).Only nausea and headaches were reported significantly more often during metyraponetreatment compared with placebo (Fisher exact P = .037and P = .048, respectively). Adverse effectswere mainly due to the serotonergic antidepressant treatment, especially inthe first 2 weeks. Patients receiving fluvoxamine reported more nausea andrestlessness, while patients taking nefazodone complained more frequentlyof a dry mouth. We did not observe any alterations in general clinical chemistryparameters.

Table Graphic Jump LocationTable 5. Frequencies of Adverse Effects
COMPLIANCE AND COMEDICATION

All patients taking metyrapone showed significant elevations of 11-deoxycortisol;therefore, full compliance can be assumed. At the end of the treatment course,both raters and patients guessed whether placebo or metyrapone had been taken.An association analysis (κ coefficient) showed no agreement betweenraters’ and patients’ guesses and the identity of the given medication.

Plasma concentrations of both antidepressants showed that all patientswere compliant with the respective treatment. Mean ± SEMplasma concentration at steady state for nefazodone was 691 ± 23ng/mL, for the metabolite meta-chlorophenylpiperazine (mCPP) 41 ± 1.6ng/mL, and for fluvoxamine 77 ± 3.4 ng/mL. No effect of metyraponeon these concentrations was detected, and no associations between plasma concentrationsof antidepressants and outcome parameters emerged.

Lorazepam was restricted to the first 8 days (day 0 to day 7) of thestudy, according to our protocol. Thirteen of 30 patients in the placebo group(mean ± SEM dose, 1.18 ± 0.24 mg/d of lorazepam)and 11 of 33 patients in the metyrapone group (mean ± SEMdose, 1.47 ± 0.28 mg/d of lorazepam) received lorazepam.No association between administration of lorazepam and treatment responseemerged.

Major results of this study were that the addition of metyrapone toa standard serotonergic antidepressant treatment led to a significantly betteroverall treatment outcome and a significantly more rapid onset of therapeuticaction. These beneficial effects outlasted the 21-day treatment period independentlyof the serotonergic antidepressant used, ie, nefazodone or fluvoxamine.

Our study is the first placebo-controlled, double-blind trial of metyraponeused as an augmentation agent in the treatment of patients with major depression.Our findings validate the results of an earlier open-label study27 andthe only other placebo-controlled, single-blind crossover study33 onmetyrapone. This latter study is not directly comparable to ours because 30mg/d of hydrocortisone, which itself has psychotropic effects, was co-administered.Antidepressant effects were also observed applying the cortisol-synthesisinhibitor ketoconazole in a controlled study with 20 depressed patients,34 where merely 3 hypercortisolemic patients improved.Malison et al35 found only limited efficacyin treatment-refractory major depression. In our substantially larger sample,metyrapone enhanced antidepressant efficacy independently of eucortisolemicor hypercortisolemic basal morning plasma cortisol concentrations.

As expected, the major findings were that metyrapone intervened withcortisol synthesis, inducing marked increases of plasma ACTH, the cortisolprecursor 11-deoxycortisol, and the neurosteroid DHEA. During metyrapone treatment,we did not observe significant decreases in basal morning plasma cortisolconcentrations, which is in line with the findings of Raven et al.37 These observations can be explained by the dosageregimen, administering metyrapone during daytime until the nadir of cortisolsecretion, when HPA-axis feedback mechanisms are especially responsive. Aconsiderable rebound of plasma cortisol concentrations occurs in the morninghours, driven by the elevated ACTH concentrations. During placebo, both antidepressants,which are known to interact with the Cytochrom P450 system, increased ACTHand 11-deoxycortisol concentrations compared with baseline, while cortisolfor the whole group and DHEA remained largely unchanged. However, no differentialinteraction of both antidepressants with metyrapone was detected.

No apparent correlation emerged between basal plasma cortisol concentrationsbefore starting metyrapone treatment and the overall outcome. The respondersin the metyrapone group had insignificantly higher cortisol concentrations,but morning cortisol concentrations show a large variability and are a weakmeasure of overall HPA-axis activity. Patients showing improvement with metyraponedeveloped larger increases of ACTH and 11-deoxycortisol compared with nonresponders,although this effect did not reach significance. One explanation would bethat patients taking metyrapone improved according to the extent of steroid-synthesisinhibition. However, leaner patients who received higher average doses ofmetyrapone per kg showed the same differences in treatment response, and nocorrelation with the body weight index emerged (data not shown). Hence, ourfindings in the responder faction may reflect a more sensitive hypothalamicor hippocampal feedback, leading to a reset of the circadian rhythm of theHPA axis or unmasking of central CRH overdrive.32

Metyrapone also significantly increased the plasma concentrations ofthe cortisol precursor 11-deoxycortisol, which itself has psychotropic effects,52 and of the neuroactive steroid DHEA, which exertsantiglucocorticoid, anxiolytic, and antidepressive actions.5356 Neuroactivesteroids act on γ-aminobutyric acid A and progesterone receptors inhumans.57 Metyrapone induces profound long-termchanges of synthesis and concentrations of such steroids, and a correlationbetween a reduction in MADRS scores and an increase of neuroactive urinaryand plasma steroids has been found.37 WhereasRaven et al37 did not find changes in the urinarysecretion of DHEA, we observed significant elevations of plasma DHEA.

Although the antidepressive and neuroendocrine effects of metyraponeare clearly demonstrated by our study, the mechanisms of actions are stillfar from elucidated. Besides the reset of HPA-axis activity and the enhancedrelease of neuroactive steroids, we surmise that alternative mechanisms cooperateto yield the therapeutic effects. Steroid actions and feedback regulationare determined by their tissue concentrations, which are largely regulatedby prereceptor metabolism. The enzyme 11β-HSD regulates the steroid accessto receptors, catalyzing the conversion of active 11-hydroxy-glucocorticoidslike cortisol into their inactive keto-forms. One form, the 11β-HSD-1,is widely expressed in the hypothalamus, hippocampus, cerebellum, and neocortex,36 maybe acting as a tissue-specific modulator of glucocorticoidaction.58 This enzyme’s reaction is bidirectional,and in intact neurones the reduced nicotinamide-adenine dinucleotide phosphate(NADPH)–dependent reduction of 11-deoxysteroids is the predominant reaction,regenerating active glucocorticoids in neuronal target cells.59

Whereas ketoconazole mainly blocks steroid synthesis at the adrenallevel, metyrapone crosses the blood-brain barrier60 andinhibits the conversion of the endogenous precursor 11-deoxycortisol to cortisolboth at the adrenals and in the brain, acting on the 11-beta-hydroxylase.In addition, metyrapone blocks the 11-oxoreductase activity of the 11β-HSD-138 either directly or indirectly by increased formationof endogenous inhibitors, eg, progesterone-derivates.61 Thus,metyrapone is able to decrease cortisol concentrations in the brain independentlyof circulating steroid levels. This potential to decouple central nervoustissues from peripheral steroid concentrations62 hasbeen demonstrated in humans,63 and behavioralconsequences of altered hippocampal 11β-HSD-1 activity were recentlyshown in an animal model.64

A specific site of action of metyrapone could be the hippocampus, where11β-hydroxylase and 11β-HSD-1 are colocalized with MR.36,65 Inhibitionof cortisol synthesis in this region would deplete MR from their ligands,and MR should subsequently be up-regulated. This regulatory sequel can bedemonstrated for many antidepressant drugs, which increase the binding capacityand gene expression of MR in the hippocampus in the rat.6668 Increasesof hippocampal MR levels precede the decrease in CRH messenger RNA in thehypothalamic paraventricular nucleus69 andthe readjustment of the HPA-axis activity.68,70 Complementarily,the MR antagonist spironolactone hampered antidepressive effects of amitriptylinein humans.15 Therefore, metyrapone might assista faster restoration of MR function, which accelerates the attainment of newallostatic equilibrium.16

The reduced occupation of GR and MR by cortisol in the hippocampus couldconsecutively accelerate the up-regulation of 5HT-1A receptors, which areessential for the action of serotonergic antidepressants.14 Areduced availability of cortisol in the central nervous system, especiallyduring the evening, could directly promote the reset in positive feedbackloops. Such cortisol-dependent circuits are demonstrated in several brainareas, like the amygdala and hypothalamus7173 andnotably the hippocampus.74

Furthermore, the neogenesis of neurones within the hippocampus may beinvolved in the etiology of depression.75 Preliminaryexperiments show that metyrapone increases the number of new cells in thegyrus dentatus of the hippocampal formation in mice,76 maybepartly mediated by neurosteroids like DHEA.77 Moreover,metyrapone induces c-fos expression in limbic regions.78 Again,a restoration of hippocampal feedback onto HPA-axis activity could be assisted.

Several mechanisms are potentially responsible for the antidepressantefficacy of metyrapone. Shortcomings of our study were that HPA-axis activitywas characterized merely by morning cortisol concentrations. Seemingly eucortisolemicpatients frequently show other signs of HPA dysregulation in depression.15 More sensitive tests, like the combined dexamethasonsuppression test (DST)/CRH challenge, would allow a more refined analysisof hidden perturbations. The wash-out phase was short because our severelyill patients needed acute treatment.

Although steroid-synthesis inhibitors are not quite ready for routineclinical application, the findings of this study clearly warrant further studiesaimed at identifying subgroups of depressed patients who will benefit mostfrom this approach and surrogate markers to find the optimal dose regimen.

Correspondence: Holger Jahn, MD, Departmentof Psychiatry and Psychotherapy, University Hospital Hamburg-Eppendorf, Martinistr.52, 20246 Hamburg, Germany (jahn@uke.uni-hamburg.de).

Submitted for Publication: March 28, 2003;final revision received January 6, 2004; accepted June 10, 2004.

Funding/Support: Dr Schick was supported bya fellowship of the Graduiertenkolleg 255 (Deutsche Forschungsgemeinschaft,Bonn, Germany).

Acknowledgment: We thank Sebastian Schultz,PhD, and Michael Baehr, PhD (Pharmacy of the University Hospital of Hamburg,Hamburg, Germany) for preparation, randomization, and coding of the studymedication and Christoph Hiemke, PhD (University of Mainz, Mainz, Germany)for measurements of the plasma concentrations of antidepressants. We are especiallygrateful to Bernhard Menke, PhD (Novartis, Nuremberg, Germany) for the generoussupply of metyrapone.

Holsboer  FDoerr  HGGerken  AMuller  OASippell  WG Cortisol, 11-deoxycortisol and ACTH concentrations after dexamethasonein depressed patients and healthy volunteers. Psychiatry Res 1984;1115- 23
PubMed Link to Article
Holsboer  FGerken  AStalla  GKMuller  OA Blunted aldosterone and ACTH release after human CRH administrationin depressed patients. Am J Psychiatry 1987;144229- 231
PubMed
Carroll  BJCurtis  GCMendels  J Neuroendocrine regulation in depression, II: discrimination of depressedfrom nondepressed patients. Arch Gen Psychiatry 1976;331051- 1058
PubMed Link to Article
Nemeroff  CBWiderlov  EBissette  GWalleus  HKarlsson  IEklund  KKilts  CDLoosen  PTVale  W Elevated concentrations of CSF corticotropin-releasing factor-likeimmunoreactivity in depressed patients. Science 1984;2261342- 1344
PubMed Link to Article
Arborelius  LOwens  MJPlotsky  PMNemeroff  CB The role of corticotropin-releasing factor in depression and anxietydisorders. J Endocrinol 1999;1601- 12
PubMed Link to Article
Winokur  GBlack  DWNasrallah  A DST nonsuppressor status: relationship to specific aspects of the depressivesyndrome. Biol Psychiatry 1987;22360- 368
PubMed Link to Article
Raadsheer  FCHoogendijk  WJGStam  FCTilders  FJHSwaab  DF Increased numbers of corticotropin-releasing hormone expressing neuronesin the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994;60436- 444
PubMed Link to Article
Dinan  TGLavelle  EScott  LVNewell-Price  JMedbak  SGrossmann  AB Desmopressin normalizes the blunted adrenocorticotropin response tocorticotropin-releasing hormone in melancholic depression: evidence of enhancedvasopressinergic responsivity. J Clin Endocrinol Metab 1999;842238- 2240
PubMed Link to Article
Wiedemann  KJahn  HKellner  M Effects of natriuretic peptides upon hypothalamo-pituitary-adrenocorticalsystem activity and anxiety behavior. Exp Clin Endocrinol Diabetes 2000;1085- 13
PubMed
Calogero  AEGalluci  WTChrousos  GPGold  PW Catecholamine effects upon rat hypothalamic corticotropin-releasinghormone secretion in vitro. J Clin Invest 1988;82839- 846
PubMed Link to Article
Wong  MLKling  MAMunson  PJListwak  SLicinio  JProlo  PKarp  BMcCutcheon  IEGeracioti  TD  JrDeBellis  MDRice  KCGoldstein  DSVeldhuis  JDChrousos  GPOldfield  EHMcCann  SMGold  PW Pronounced and sustained central hypernoradrenergic function in majordepression with melancholic features: relation to hypercortisolism and corticotropin-releasinghormone. Proc Natl Acad Sci U S A 2000;97325- 330
PubMed Link to Article
Modell  SYassouridis  AHuber  JHolsboer  F Corticosteroid receptor function is decreased in depressed patients. Neuroendocrinology 1997;65216- 222
PubMed Link to Article
Posener  JADeBattista  CWilliams  GHSchatzberg  AF Cortisol feedback during the HPA quiescent period in patients withmajor depression. Am J Psychiatry 2001;1582083- 2085
PubMed Link to Article
Lopez  JFChalmers  DTLittle  KYWatson  SJ Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptorin rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 1998;43547- 573
PubMed Link to Article
Holsboer  F Stress, hypercortisolism and corticosteroid receptors in depression:implications for therapy. J Affect Disord 2001;6277- 91
PubMed Link to Article
De Kloet  ERVreugdenhil  EOitzl  MSJoels  M Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19269- 301
PubMed
Holsboer  FBarden  N Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 1996;17187- 205
PubMed Link to Article
Zobel  AWNickel  TKünzel  HEAckl  NSonntag  AIsing  MHolsboer  F Effects of the high-affinity corticotropin-releasing hormone receptorI antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res 2000;34171- 181
PubMed Link to Article
van der Lely  AJFocken  Kvan der Mast  RCLamberts  SW Rapid reversal of acute psychosis in the Cushing syndrome with thecortisol-receptor antagonist mifepristone (RU486). Ann Intern Med 1991;114143- 144
PubMed Link to Article
Murphy  BEFilipini  DGhadirian  AM Possible use of glucocorticoid receptor antagonists in the treatmentof major depression: preliminary results using RU 486. J Psychiatry Neurosci 1993;18209- 213
PubMed
Belanoff  JKFlores  BHKalezhan  MSund  BSchatzberg  AF Rapid reversal of psychotic depression using mifepristone. J Clin Psychopharmacol 2001;21516- 521
PubMed Link to Article
Wolkowitz  OMReus  VI Treatment of depression with antiglucocorticoid drugs. Psychosom Med 1999;61698- 711
PubMed Link to Article
Healy  DGHarkin  ACryan  JFKelly  JPLeonard  BE Metyrapone displays antidepressant-like properties in preclinical paradigms. Psychopharmacology (Berl) 1999;145303- 308
PubMed Link to Article
Iizuka  HKishimoto  ANakamura  JMizukawa  R Clinical effects of cortisol synthesis inhibition on treatment-resistantdepression. Nihon Shinkei Seishin Yakurigaku Zasshi 1996;1633- 36
PubMed
Ravaris  CLSateia  MJBeroza  KWNoordsy  DLBrinck-Johnsen  T Effect of ketoconazole on a hypophysectomized, hypercortisolemic, psychoticallydepressed woman. Arch Gen Psychiatry 1988;45966- 967
PubMed Link to Article
Wolkowitz  OMReus  VIManfredi  FIngbar  JBrizendine  LWeingartner  H Ketoconazole administration in hypercortisolemic depression. Am J Psychiatry 1993;150810- 812
PubMed
Ghadirian  AMEngelsmann  FDhar  VFilipini  DKeller  RChouinard  GMurphy  BE The psychotropic effects of inhibitors of steroid biosynthesis in depressedpatients refractory to treatment. Biol Psychiatry 1995;37369- 375
PubMed Link to Article
Anand  AMalison  RMcDougle  CJPrice  LH Antiglucocorticoid treatment of refractory depression with ketoconazole:a case report. Biol Psychiatry 1995;37338- 340
PubMed Link to Article
Thakore  JHDinan  TG Cortisol synthesis inhibition: a new treatment strategy for the clinicaland endocrine manifestations of depression. Biol Psychiatry 1995;37364- 368
PubMed Link to Article
Amsterdam  JDMosley  PDRosenzweig  M Assessment of adrenocortical activity in refractory depression: steroidsuppression with ketoconazole. Nolan  WZohar  JRoose  SAmsterdam  JedsRefractory Depression Chichester, England John Wiley & Sons199- 210
Jeffcoate  WJSilverstone  JTEdwards  CRBesser  GM Psychiatric manifestations of Cushing’s syndrome: response tolowering of plasma cortisol. Q J Med 1979;48465- 472
PubMed
Murphy  BE Treatment of major depression with steroid suppressive drugs. J Steroid Biochem Mol Biol 1991;39239- 244
PubMed Link to Article
O’Dwyer  AMLightman  SLMarks  MNCheckley  SA Treatment of major depression with metyrapone and hydrocortisone. J Affect Disord 1995;33123- 128
PubMed Link to Article
Wolkowitz  OMReus  VIChan  TManfredi  FRaum  WJohnson  RCanick  J Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biol Psychiatry 1999;451070- 1074
PubMed Link to Article
Malison  RTAnand  APelton  GHKirwin  PCarpenter  LMcDougle  CJHeninger  GRPrice  LH Limited efficacy of ketoconazole in treatment-refractory major depression. J Clin Psychopharmacol 1999;19466- 470
PubMed Link to Article
Seckl  JR 11 β-Hydroxysteroid dehydrogenase in the brain: a novel regulatorof glucocorticoid action? Front Neuroendocrinol 1997;1849- 99
PubMed Link to Article
Raven  PWO’Dwyer  AMTaylor  NFCheckley  SA The relationship between the effects of metyrapone treatment on depressedmood and urinary steroid profiles. Psychoneuroendocrinology 1996;21277- 286
PubMed Link to Article
Raven  PWCheckley  SATaylor  NF Extra-adrenal effects of metyrapone include inhibition of the 11-oxoreductaseactivity of 11 beta-hydroxysteroid dehydrogenase: a model for 11-HSD I deficiency. Clin Endocrinol (Oxf) 1995;43637- 644
PubMed Link to Article
Charney  DSNemeroff  CBLewis  LLaden  SKGorman  JMLaska  EMBorenstein  MBowden  CLCaplan  AEmslie  GJEvans  DLGeller  BGrabowski  LEHerson  JKalin  NHKeck  PE  JrKirsch  IKrishnan  KRKupfer  DJMakuch  RWMiller  FGPardes  HPost  RReynolds  MMRoberts  LRosenbaum  JFRosenstein  DLRubinow  DRRush  AJRyan  NDSachs  GSSchatzberg  AFSolomon  SConsensus Development Panel, National depressive and manic-depressive association consensus statementon the use of placebo in clinical trials of mood disorders. Arch Gen Psychiatry 2002;59262- 270
PubMed Link to Article
Watzka  MBidlingmaier  FBeyenburg  SHenke  RTClusmann  HElger  CESchramm  JKlingmuller  DStoffel-Wagner  B Corticosteroid receptor mRNA expression in the brains of patients withepilepsy. Steroids 2000;65895- 901
PubMed Link to Article
Raven  PWTaylor  NF Steroid metabolism in healthy men and women. J Endocrinol 1995;147 ((suppl 2)) 100
Weaver  JUTaylor  NFMonson  JPWood  PJKelly  WF Sexual dimorphism in 11 beta hydroxysteroid dehydrogenase activityand its relation to fat distribution and insulin sensitivity: a study in hypopituitarysubjects. Clin Endocrinol (Oxf) 1998;4913- 20
PubMed Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition.  Washington, DC American Psychiatric Association1994;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Montgomery  SAAsberg  MA New depression rating scale designed to be sensitive to change. Br J Psychiatry 1979;134382- 389
PubMed Link to Article
National Institute of Mental Health, CGI: Clinical Global Impressions. Guy  WBonato  RRedsManual for the ECDEUAssessment Battery Rev ed. Chevy Chase, Md National Institute ofMental Health1970;12-1- 12-6
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 567
PubMed Link to Article
Zung  WW Self-rating depression scale. Arch Gen Psychiatry 1965;1263- 70
PubMed Link to Article
Lingjaerde  OAhlfors  UGBech  PDencker  SJElgen  K The UKU side effect rating scale: a new comprehensive rating scalefor psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treatedpatients. Acta Psychiatr Scand 1987;334 ((suppl 74)) 1- 100
Link to Article
Hartter  SWetzel  HHiemke  C Automated determination of fluvoxamine in plasma by column-switchinghigh-performance liquid chromatography. Clin Chem 1992;382082- 2086
PubMed
Montgomery  SABech  PBlier  PMoller  HJNierenberg  AAPinder  RMQuitkin  FMReimitz  PERosenbaum  JFRush  AJStassen  HHThase  ME Selecting methodologies for the evaluation of differences in time toresponse between antidepressants. J Clin Psychiatry 2002;63694- 699
PubMed Link to Article
Heuser  G Induction of anesthesia, seizures and sleep by steroid hormones. Anesthesiology 1967;28173- 183
PubMed Link to Article
Majewska  MDDemirgören  SSpivak  CELondon  ED The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonistof the GABA A receptor. Brain Res 1990;526143- 146
PubMed Link to Article
Wolkowitz  OMReus  VIKeebler  ANelson  NFriedland  MBrizendine  LRoberts  E Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 1999;156646- 649
PubMed
Rupprecht  RHolsboer  F Neuroactive steroids: mechanisms of action and neuropsychopharmacologicalperspectives. Trends Neurosci 1999;22410- 416
PubMed Link to Article
Rupprecht  Rdi Michele  FHermann  BStrohle  ALancel  MRomeo  EHolsboer  F Neuroactive steroids: molecular mechanisms of action and implicationsfor neuropsychopharmacology. Brain Res Brain Res Rev 2001;3759- 67
PubMed Link to Article
Rupprecht  RStrohle  AHermann  Bdi Michele  FSpalletta  GPasini  AHolsboer  FRomeo  E Neuroactive steroid concentrations following metyrapone administrationin depressed patients and healthy volunteers. Biol Psychiatry 1998;44912- 914
PubMed Link to Article
Seckl  JRWalker  BR Minireview: 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specificamplifier of glucocorticoid action. Endocrinology 2001;1421371- 1376
PubMed
Yau  JLSeckl  JR 11-beta-hydroxysteroid dehydrogenase type 1 in the brain: thickeningthe glucocorticoid soup. Mol Psychiatry 2001;6611- 614
PubMed Link to Article
Stith  RDPerson  RJDana  RC Metyrapone inhibition of 3H-hydrocortisone uptake and binding in variousbrain regions of the pig. Neuroendocrinology 1976;22183- 192
PubMed Link to Article
Gomez-Sanchez  EPCox  DFoecking  MGanjam  VGomez-Sanchez  CE 11beta-hydroxysteroid dehydrogenases of the choriocarcinoma cell lineJEG-3 and their inhibition by glycyrrhetinic acid and other natural substances. Steroids 1996;61110- 115
PubMed Link to Article
Masuzaki  HPaterson  JShinyama  HMorton  NMMullins  JJSeckl  JRFlier  JS A transgenic model of visceral obesity and the metabolic syndrome. Science 2001;2942166- 2170
PubMed Link to Article
Rask  EOlsson  TSoderberg  SAndrew  RLivingstone  DEJohnson  OWalker  BR Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Meta 2001;861418- 1421
Link to Article
Yau  JLNoble  JKenyon  CJHibberd  CKotelevtsev  YMullins  JJSeckl  JR Lack of tissue glucocorticoid reactivation in 11-beta-hydroxysteroiddehydrogenase type 1 knockout mice ameliorates age-related learning impairments. Proc Natl Acad Sci U S A 2001;984716- 4721
PubMed Link to Article
MacKenzie  SMClark  CJFraser  RGomez-Sanchez  CEConnell  JMDavies  E Expression of 11beta-hydroxylase and aldosterone synthase genes inthe rat brain. J Mol Endocrinol 2000;24321- 328
PubMed Link to Article
Seckl  JRFink  G Antidepressants increase glucocorticoid and mineralocorticoid receptormRNA expression in rat hippocampus in vivo. Neuroendocrinology 1992;55621- 626
PubMed Link to Article
Reul  JMStec  ISMSöder  MHolsboer  F Chronic treatment of rats with the antidepressant amitriptyline attenuatesthe activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology 1993;133312- 320
PubMed
Gesing  ABilang-Bleuel  ADroste  SLinthorst  ACEHolsboer  FReul  JMHM Psychological stress increases hippocampal mineralocorticoid receptorlevels: involvement of corticotropin-releasing hormone. J Neurosci 2001;214822- 4829
PubMed
Brady  LSWhitfield  HJ  JrFox  RJGold  PWHerkenham  M Long-term antidepressant administration alters corticotropin-releasinghormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expressionin rat brain: therapeutic implications. J Clin Invest 1991;87831- 837
PubMed Link to Article
Reul  JMGesing  ADroste  SStec  ISMWeber  ABachmann  CBilang-Bleuel  AHolsboer  FLinthorst  ACE The brain mineralocorticoid receptor: greedy for ligand, mysteriousin function. Eur J Pharmacol 2000;405235- 249
PubMed Link to Article
Lupien  SJGillin  CJHauger  RL Working memory is more sensitive than declarative memory to the acuteeffects of corticosteroids: a dose response study in humans. Behav Neurosci 1999;113420- 430
PubMed Link to Article
Makino  SGold  PWSchulkin  J Effects of corticosterone on CRH mRNA and content in the bed nucleusof the stria terminalis: comparison with the effects in the central nucleusof the amygdala and the paraventricular nucleus of the hypothalamus. Brain Res 1994;657141- 149
PubMed Link to Article
Makino  SGold  PWSchulkin  J Corticosterone effects on corticotropin-releasing hormone mRNA in thecentral nucleus of the amygdala and the parvocellular region of the paraventricularnucleus of the hypothalamus. Brain Res 1994;640105- 112
PubMed Link to Article
Joels  MDe Kloet  ER Control of neuronal excitability by corticosteroid hormones. Trends Neurosci 1992;1525- 30
PubMed Link to Article
Jacobs  BLvan Praag  HGage  FH Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000;5262- 269
PubMed Link to Article
Schick  MKiefer  FKämpf  PArlt  JWiedemann  KJahn  H Cell-turnover in the gyrus dentatus in mice is enhanced by metyraponetreatment. Pharmacopsychiatry 2001;34198
Karishma  KKHerbert  J Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampusof the rat, promotes survival of newly formed neurons and prevents corticosterone-inducedsuppression. Eur J Neurosci 2002;16445- 453
PubMed Link to Article
Rotllant  DOns  SCarrasco  JArmario  A Evidence that metyrapone can act as a stressor: effect on pituitaryadrenal hormone, plasma glucose and brain c-fos induction. Eur J Neurosci 2002;16693- 700
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Flow chart of the study recruitingand randomization procedures.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Hamilton Rating Scale for Depression,21-item version (HAMD-21) scores for the metyrapone group (solid circles)and the placebo group (open circles) for days 0, 3, 7, 14, 21, 28, and 35on the intention-to-treat sample. Data are presented as mean ± SEM.Asterisks indicate time points with significant group differences. The y-axisis cut below a HAMD score of 10.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Onset of action analyses: Stassenanalysis with a Kaplan-Meier survival model (upper panel) and Quitkin patternanalysis (lower panel). For details, see the “Results” section.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Time course of corticotropin (ACTH)concentrations in relation to treatment and responder status at day 35. Dataare presented as mean ± SEM. Responders show higher ACTHconcentrations compared with nonresponders in the metyrapone group. For details,see the “Results” section.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 3. Endocrine Parameters for the Metyrapone and Placebo Groups*
Table Graphic Jump LocationTable 4. Endocrine Parameters for the Responder and Nonresponder Factionsof the Metyrapone and Placebo Groups*
Table Graphic Jump LocationTable 5. Frequencies of Adverse Effects

References

Holsboer  FDoerr  HGGerken  AMuller  OASippell  WG Cortisol, 11-deoxycortisol and ACTH concentrations after dexamethasonein depressed patients and healthy volunteers. Psychiatry Res 1984;1115- 23
PubMed Link to Article
Holsboer  FGerken  AStalla  GKMuller  OA Blunted aldosterone and ACTH release after human CRH administrationin depressed patients. Am J Psychiatry 1987;144229- 231
PubMed
Carroll  BJCurtis  GCMendels  J Neuroendocrine regulation in depression, II: discrimination of depressedfrom nondepressed patients. Arch Gen Psychiatry 1976;331051- 1058
PubMed Link to Article
Nemeroff  CBWiderlov  EBissette  GWalleus  HKarlsson  IEklund  KKilts  CDLoosen  PTVale  W Elevated concentrations of CSF corticotropin-releasing factor-likeimmunoreactivity in depressed patients. Science 1984;2261342- 1344
PubMed Link to Article
Arborelius  LOwens  MJPlotsky  PMNemeroff  CB The role of corticotropin-releasing factor in depression and anxietydisorders. J Endocrinol 1999;1601- 12
PubMed Link to Article
Winokur  GBlack  DWNasrallah  A DST nonsuppressor status: relationship to specific aspects of the depressivesyndrome. Biol Psychiatry 1987;22360- 368
PubMed Link to Article
Raadsheer  FCHoogendijk  WJGStam  FCTilders  FJHSwaab  DF Increased numbers of corticotropin-releasing hormone expressing neuronesin the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994;60436- 444
PubMed Link to Article
Dinan  TGLavelle  EScott  LVNewell-Price  JMedbak  SGrossmann  AB Desmopressin normalizes the blunted adrenocorticotropin response tocorticotropin-releasing hormone in melancholic depression: evidence of enhancedvasopressinergic responsivity. J Clin Endocrinol Metab 1999;842238- 2240
PubMed Link to Article
Wiedemann  KJahn  HKellner  M Effects of natriuretic peptides upon hypothalamo-pituitary-adrenocorticalsystem activity and anxiety behavior. Exp Clin Endocrinol Diabetes 2000;1085- 13
PubMed
Calogero  AEGalluci  WTChrousos  GPGold  PW Catecholamine effects upon rat hypothalamic corticotropin-releasinghormone secretion in vitro. J Clin Invest 1988;82839- 846
PubMed Link to Article
Wong  MLKling  MAMunson  PJListwak  SLicinio  JProlo  PKarp  BMcCutcheon  IEGeracioti  TD  JrDeBellis  MDRice  KCGoldstein  DSVeldhuis  JDChrousos  GPOldfield  EHMcCann  SMGold  PW Pronounced and sustained central hypernoradrenergic function in majordepression with melancholic features: relation to hypercortisolism and corticotropin-releasinghormone. Proc Natl Acad Sci U S A 2000;97325- 330
PubMed Link to Article
Modell  SYassouridis  AHuber  JHolsboer  F Corticosteroid receptor function is decreased in depressed patients. Neuroendocrinology 1997;65216- 222
PubMed Link to Article
Posener  JADeBattista  CWilliams  GHSchatzberg  AF Cortisol feedback during the HPA quiescent period in patients withmajor depression. Am J Psychiatry 2001;1582083- 2085
PubMed Link to Article
Lopez  JFChalmers  DTLittle  KYWatson  SJ Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptorin rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 1998;43547- 573
PubMed Link to Article
Holsboer  F Stress, hypercortisolism and corticosteroid receptors in depression:implications for therapy. J Affect Disord 2001;6277- 91
PubMed Link to Article
De Kloet  ERVreugdenhil  EOitzl  MSJoels  M Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998;19269- 301
PubMed
Holsboer  FBarden  N Antidepressants and hypothalamic-pituitary-adrenocortical regulation. Endocr Rev 1996;17187- 205
PubMed Link to Article
Zobel  AWNickel  TKünzel  HEAckl  NSonntag  AIsing  MHolsboer  F Effects of the high-affinity corticotropin-releasing hormone receptorI antagonist R121919 in major depression: the first 20 patients treated. J Psychiatr Res 2000;34171- 181
PubMed Link to Article
van der Lely  AJFocken  Kvan der Mast  RCLamberts  SW Rapid reversal of acute psychosis in the Cushing syndrome with thecortisol-receptor antagonist mifepristone (RU486). Ann Intern Med 1991;114143- 144
PubMed Link to Article
Murphy  BEFilipini  DGhadirian  AM Possible use of glucocorticoid receptor antagonists in the treatmentof major depression: preliminary results using RU 486. J Psychiatry Neurosci 1993;18209- 213
PubMed
Belanoff  JKFlores  BHKalezhan  MSund  BSchatzberg  AF Rapid reversal of psychotic depression using mifepristone. J Clin Psychopharmacol 2001;21516- 521
PubMed Link to Article
Wolkowitz  OMReus  VI Treatment of depression with antiglucocorticoid drugs. Psychosom Med 1999;61698- 711
PubMed Link to Article
Healy  DGHarkin  ACryan  JFKelly  JPLeonard  BE Metyrapone displays antidepressant-like properties in preclinical paradigms. Psychopharmacology (Berl) 1999;145303- 308
PubMed Link to Article
Iizuka  HKishimoto  ANakamura  JMizukawa  R Clinical effects of cortisol synthesis inhibition on treatment-resistantdepression. Nihon Shinkei Seishin Yakurigaku Zasshi 1996;1633- 36
PubMed
Ravaris  CLSateia  MJBeroza  KWNoordsy  DLBrinck-Johnsen  T Effect of ketoconazole on a hypophysectomized, hypercortisolemic, psychoticallydepressed woman. Arch Gen Psychiatry 1988;45966- 967
PubMed Link to Article
Wolkowitz  OMReus  VIManfredi  FIngbar  JBrizendine  LWeingartner  H Ketoconazole administration in hypercortisolemic depression. Am J Psychiatry 1993;150810- 812
PubMed
Ghadirian  AMEngelsmann  FDhar  VFilipini  DKeller  RChouinard  GMurphy  BE The psychotropic effects of inhibitors of steroid biosynthesis in depressedpatients refractory to treatment. Biol Psychiatry 1995;37369- 375
PubMed Link to Article
Anand  AMalison  RMcDougle  CJPrice  LH Antiglucocorticoid treatment of refractory depression with ketoconazole:a case report. Biol Psychiatry 1995;37338- 340
PubMed Link to Article
Thakore  JHDinan  TG Cortisol synthesis inhibition: a new treatment strategy for the clinicaland endocrine manifestations of depression. Biol Psychiatry 1995;37364- 368
PubMed Link to Article
Amsterdam  JDMosley  PDRosenzweig  M Assessment of adrenocortical activity in refractory depression: steroidsuppression with ketoconazole. Nolan  WZohar  JRoose  SAmsterdam  JedsRefractory Depression Chichester, England John Wiley & Sons199- 210
Jeffcoate  WJSilverstone  JTEdwards  CRBesser  GM Psychiatric manifestations of Cushing’s syndrome: response tolowering of plasma cortisol. Q J Med 1979;48465- 472
PubMed
Murphy  BE Treatment of major depression with steroid suppressive drugs. J Steroid Biochem Mol Biol 1991;39239- 244
PubMed Link to Article
O’Dwyer  AMLightman  SLMarks  MNCheckley  SA Treatment of major depression with metyrapone and hydrocortisone. J Affect Disord 1995;33123- 128
PubMed Link to Article
Wolkowitz  OMReus  VIChan  TManfredi  FRaum  WJohnson  RCanick  J Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biol Psychiatry 1999;451070- 1074
PubMed Link to Article
Malison  RTAnand  APelton  GHKirwin  PCarpenter  LMcDougle  CJHeninger  GRPrice  LH Limited efficacy of ketoconazole in treatment-refractory major depression. J Clin Psychopharmacol 1999;19466- 470
PubMed Link to Article
Seckl  JR 11 β-Hydroxysteroid dehydrogenase in the brain: a novel regulatorof glucocorticoid action? Front Neuroendocrinol 1997;1849- 99
PubMed Link to Article
Raven  PWO’Dwyer  AMTaylor  NFCheckley  SA The relationship between the effects of metyrapone treatment on depressedmood and urinary steroid profiles. Psychoneuroendocrinology 1996;21277- 286
PubMed Link to Article
Raven  PWCheckley  SATaylor  NF Extra-adrenal effects of metyrapone include inhibition of the 11-oxoreductaseactivity of 11 beta-hydroxysteroid dehydrogenase: a model for 11-HSD I deficiency. Clin Endocrinol (Oxf) 1995;43637- 644
PubMed Link to Article
Charney  DSNemeroff  CBLewis  LLaden  SKGorman  JMLaska  EMBorenstein  MBowden  CLCaplan  AEmslie  GJEvans  DLGeller  BGrabowski  LEHerson  JKalin  NHKeck  PE  JrKirsch  IKrishnan  KRKupfer  DJMakuch  RWMiller  FGPardes  HPost  RReynolds  MMRoberts  LRosenbaum  JFRosenstein  DLRubinow  DRRush  AJRyan  NDSachs  GSSchatzberg  AFSolomon  SConsensus Development Panel, National depressive and manic-depressive association consensus statementon the use of placebo in clinical trials of mood disorders. Arch Gen Psychiatry 2002;59262- 270
PubMed Link to Article
Watzka  MBidlingmaier  FBeyenburg  SHenke  RTClusmann  HElger  CESchramm  JKlingmuller  DStoffel-Wagner  B Corticosteroid receptor mRNA expression in the brains of patients withepilepsy. Steroids 2000;65895- 901
PubMed Link to Article
Raven  PWTaylor  NF Steroid metabolism in healthy men and women. J Endocrinol 1995;147 ((suppl 2)) 100
Weaver  JUTaylor  NFMonson  JPWood  PJKelly  WF Sexual dimorphism in 11 beta hydroxysteroid dehydrogenase activityand its relation to fat distribution and insulin sensitivity: a study in hypopituitarysubjects. Clin Endocrinol (Oxf) 1998;4913- 20
PubMed Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders,Fourth Edition.  Washington, DC American Psychiatric Association1994;
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;2356- 62
PubMed Link to Article
Montgomery  SAAsberg  MA New depression rating scale designed to be sensitive to change. Br J Psychiatry 1979;134382- 389
PubMed Link to Article
National Institute of Mental Health, CGI: Clinical Global Impressions. Guy  WBonato  RRedsManual for the ECDEUAssessment Battery Rev ed. Chevy Chase, Md National Institute ofMental Health1970;12-1- 12-6
Beck  ATWard  CHMendelson  MMock  JErbaugh  J An inventory for measuring depression. Arch Gen Psychiatry 1961;4561- 567
PubMed Link to Article
Zung  WW Self-rating depression scale. Arch Gen Psychiatry 1965;1263- 70
PubMed Link to Article
Lingjaerde  OAhlfors  UGBech  PDencker  SJElgen  K The UKU side effect rating scale: a new comprehensive rating scalefor psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treatedpatients. Acta Psychiatr Scand 1987;334 ((suppl 74)) 1- 100
Link to Article
Hartter  SWetzel  HHiemke  C Automated determination of fluvoxamine in plasma by column-switchinghigh-performance liquid chromatography. Clin Chem 1992;382082- 2086
PubMed
Montgomery  SABech  PBlier  PMoller  HJNierenberg  AAPinder  RMQuitkin  FMReimitz  PERosenbaum  JFRush  AJStassen  HHThase  ME Selecting methodologies for the evaluation of differences in time toresponse between antidepressants. J Clin Psychiatry 2002;63694- 699
PubMed Link to Article
Heuser  G Induction of anesthesia, seizures and sleep by steroid hormones. Anesthesiology 1967;28173- 183
PubMed Link to Article
Majewska  MDDemirgören  SSpivak  CELondon  ED The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonistof the GABA A receptor. Brain Res 1990;526143- 146
PubMed Link to Article
Wolkowitz  OMReus  VIKeebler  ANelson  NFriedland  MBrizendine  LRoberts  E Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry 1999;156646- 649
PubMed
Rupprecht  RHolsboer  F Neuroactive steroids: mechanisms of action and neuropsychopharmacologicalperspectives. Trends Neurosci 1999;22410- 416
PubMed Link to Article
Rupprecht  Rdi Michele  FHermann  BStrohle  ALancel  MRomeo  EHolsboer  F Neuroactive steroids: molecular mechanisms of action and implicationsfor neuropsychopharmacology. Brain Res Brain Res Rev 2001;3759- 67
PubMed Link to Article
Rupprecht  RStrohle  AHermann  Bdi Michele  FSpalletta  GPasini  AHolsboer  FRomeo  E Neuroactive steroid concentrations following metyrapone administrationin depressed patients and healthy volunteers. Biol Psychiatry 1998;44912- 914
PubMed Link to Article
Seckl  JRWalker  BR Minireview: 11beta-hydroxysteroid dehydrogenase type 1: a tissue-specificamplifier of glucocorticoid action. Endocrinology 2001;1421371- 1376
PubMed
Yau  JLSeckl  JR 11-beta-hydroxysteroid dehydrogenase type 1 in the brain: thickeningthe glucocorticoid soup. Mol Psychiatry 2001;6611- 614
PubMed Link to Article
Stith  RDPerson  RJDana  RC Metyrapone inhibition of 3H-hydrocortisone uptake and binding in variousbrain regions of the pig. Neuroendocrinology 1976;22183- 192
PubMed Link to Article
Gomez-Sanchez  EPCox  DFoecking  MGanjam  VGomez-Sanchez  CE 11beta-hydroxysteroid dehydrogenases of the choriocarcinoma cell lineJEG-3 and their inhibition by glycyrrhetinic acid and other natural substances. Steroids 1996;61110- 115
PubMed Link to Article
Masuzaki  HPaterson  JShinyama  HMorton  NMMullins  JJSeckl  JRFlier  JS A transgenic model of visceral obesity and the metabolic syndrome. Science 2001;2942166- 2170
PubMed Link to Article
Rask  EOlsson  TSoderberg  SAndrew  RLivingstone  DEJohnson  OWalker  BR Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Meta 2001;861418- 1421
Link to Article
Yau  JLNoble  JKenyon  CJHibberd  CKotelevtsev  YMullins  JJSeckl  JR Lack of tissue glucocorticoid reactivation in 11-beta-hydroxysteroiddehydrogenase type 1 knockout mice ameliorates age-related learning impairments. Proc Natl Acad Sci U S A 2001;984716- 4721
PubMed Link to Article
MacKenzie  SMClark  CJFraser  RGomez-Sanchez  CEConnell  JMDavies  E Expression of 11beta-hydroxylase and aldosterone synthase genes inthe rat brain. J Mol Endocrinol 2000;24321- 328
PubMed Link to Article
Seckl  JRFink  G Antidepressants increase glucocorticoid and mineralocorticoid receptormRNA expression in rat hippocampus in vivo. Neuroendocrinology 1992;55621- 626
PubMed Link to Article
Reul  JMStec  ISMSöder  MHolsboer  F Chronic treatment of rats with the antidepressant amitriptyline attenuatesthe activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology 1993;133312- 320
PubMed
Gesing  ABilang-Bleuel  ADroste  SLinthorst  ACEHolsboer  FReul  JMHM Psychological stress increases hippocampal mineralocorticoid receptorlevels: involvement of corticotropin-releasing hormone. J Neurosci 2001;214822- 4829
PubMed
Brady  LSWhitfield  HJ  JrFox  RJGold  PWHerkenham  M Long-term antidepressant administration alters corticotropin-releasinghormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expressionin rat brain: therapeutic implications. J Clin Invest 1991;87831- 837
PubMed Link to Article
Reul  JMGesing  ADroste  SStec  ISMWeber  ABachmann  CBilang-Bleuel  AHolsboer  FLinthorst  ACE The brain mineralocorticoid receptor: greedy for ligand, mysteriousin function. Eur J Pharmacol 2000;405235- 249
PubMed Link to Article
Lupien  SJGillin  CJHauger  RL Working memory is more sensitive than declarative memory to the acuteeffects of corticosteroids: a dose response study in humans. Behav Neurosci 1999;113420- 430
PubMed Link to Article
Makino  SGold  PWSchulkin  J Effects of corticosterone on CRH mRNA and content in the bed nucleusof the stria terminalis: comparison with the effects in the central nucleusof the amygdala and the paraventricular nucleus of the hypothalamus. Brain Res 1994;657141- 149
PubMed Link to Article
Makino  SGold  PWSchulkin  J Corticosterone effects on corticotropin-releasing hormone mRNA in thecentral nucleus of the amygdala and the parvocellular region of the paraventricularnucleus of the hypothalamus. Brain Res 1994;640105- 112
PubMed Link to Article
Joels  MDe Kloet  ER Control of neuronal excitability by corticosteroid hormones. Trends Neurosci 1992;1525- 30
PubMed Link to Article
Jacobs  BLvan Praag  HGage  FH Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000;5262- 269
PubMed Link to Article
Schick  MKiefer  FKämpf  PArlt  JWiedemann  KJahn  H Cell-turnover in the gyrus dentatus in mice is enhanced by metyraponetreatment. Pharmacopsychiatry 2001;34198
Karishma  KKHerbert  J Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampusof the rat, promotes survival of newly formed neurons and prevents corticosterone-inducedsuppression. Eur J Neurosci 2002;16445- 453
PubMed Link to Article
Rotllant  DOns  SCarrasco  JArmario  A Evidence that metyrapone can act as a stressor: effect on pituitaryadrenal hormone, plasma glucose and brain c-fos induction. Eur J Neurosci 2002;16693- 700
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 75

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles