Although atypical antipsychotics are on the rise, traditional treatment of psychotic (or delusional) depression mostly includes the addition of classical antipsychotics to antidepressants. As there are only few data supporting this approach compared with antidepressant monotherapy, and almost no data comparing it with antidepressants of the latest generation, we conducted a retrospective chart analysis and a prospective, randomized open study on the efficacy and tolerability of nefazodone monotherapy versus combined treatment with amitriptyline and haloperidol in psychotic depression. The results suggest that the addition of classical antipsychotics should be reserved for those with very severe psychotic symptoms, but may not be needed in milder forms. Copyright (c) 2003 S. Karger AG, Basel

Born, Christoph

Grunze, Heinz

Marcuse, Alain

Schaerer, Lars O.

Walden, Jörg

English

Heinz Grunze

Alain Marcuse

Lars O. Schärer

Christoph Born

Jörg Walden

Crossref

Nefazodone in Psychotic Unipolar and Bipolar Depression: A Retrospective Chart Analysis and Open Prospective Study on Its Efficacy and Safety versus Combined Treatment with Amitriptyline and Haloperidol

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Neuropsychobiology 2002;46(suppl 1):31–35DOI: 10.1159/000068017Nefazodone in Psychotic Unipolar and BipolarDepression: A Retrospective Chart Analysis andOpen Prospective Study on Its Efficacy andSafety versus Combined Treatment withAmitriptyline and HaloperidolHeinz Grunzea Alain Marcusea Lars O. Schärerb Christoph BornbJörg WaldenbDepartments of Psychiatry, aLMU Munich, Munich, and bUniversity of Freiburg, Freiburg, GermanyDr. H. GrunzePsychiatrische Klinik der LMUNussbaumstrasse 7D–80336 München (Germany)Tel. +49 89 51605335, Fax +49 89 51605330, E-Mail grunze@psy.med.uni-muenchen.de ABCFax + 41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 2002 S. Karger AG, Basel0302–282X/02/0465–0031$18.50/0Accessible online at:www.karger.com/npsKey WordsNefazodone W Amitriptyline W Haloperidol W Psychoticdepression W Delusional depressionAbstractAlthough atypical antipsychotics are on the rise, tradi-tional treatment of psychotic (or delusional) depressionmostly includes the addition of classical antipsychoticsto antidepressants. As there are only few data support-ing this approach compared with antidepressant mono-therapy, and almost no data comparing it with antide-pressants of the latest generation, we conducted a retro-spective chart analysis and a prospective, randomizedopen study on the efficacy and tolerability of nefazodonemonotherapy versus combined treatment with amitrip-tyline and haloperidol in psychotic depression. The re-sults suggest that the addition of classical antipsychoticsshould be reserved for those with very severe psychoticsymptoms, but may not be needed in milder forms.Copyright © 2003 S. Karger AG, BaselIntroductionPsychotic (or delusional) depression is characterizedby its greater severity, longer episodes, and greater inca-pacity compared with depression without psychotic fea-tures [1]. Since the landmark study of Spiker et al. [2],only few controlled trials have been published, and theappropriate pharmacological treatment of severe depres-sion with psychotic features remains a controversial prob-lem. The distinction between mood-congruent and mood-incongruent features does not seem to imply a differenceas far as the use of antipsychotics is concerned in clinicalpractice. Mood congruency of paranoid thoughts makesthem an endogenous part of the depressive syndromecharacterizing its severity. Thus, remission of depressionthrough treatment with antidepressants should also ame-liorate those psychotic symptoms. Nevertheless, classicalantipsychotics are often added to antidepressants in clini-cal practice. Traditionally, a combination of tricyclics,e.g. amitriptyline (AMI) combined with haloperidol(HAL), is widely used, as these drugs are effective, wellknown to the practitioner and inexpensive. However, thiscombination may yield several disadvantages, exertingadrenergic, antihistaminergic, anticholinergic and, forHAL, antidopaminergic side effects.32 Neuropsychobiology 2002;46(suppl 1):31–35 Grunze/Marcuse/Schärer/Born/WaldenOnly few data exist so far on the use of selective sero-tonin-reuptake inhibitors (SSRIs) for the treatment ofpsychotic depression. A small trial of the combination offluoxetine and perphenanzine suggested similar efficacyas the standard regimens tricyclic antidepressant (TCA) +antipsychotics or electroconvulsive therapy [3]. Interest-ingly, two trials with antidepressant monotherapy (ser-traline vs. paroxetine [4] and venlafaxine vs. fluvoxamine[5]) also showed efficacy of monotherapy with these newantidepressants in delusional depression in a double-blind and randomized design. However, it still remainsunclear how a new antidepressant as a monotherapywould perform in comparison with the traditional combi-nation therapy with a tricyclic and an antipsychotic.Nefazodone (NEF) is a dual-acting serotonergic drug.Presynaptically, it inhibits serotonine reuptake and post-synaptically, it blocks 5-HT2 receptors. Its affinity to oth-er receptors, i.e. alpha-adrenergic and cholinergic recep-tors, is very weak. This gives NEF a profile of high tolera-bility without side effects usually seen with classicalTCAs. Alpha-1-related side effects, such as dry mouth,blurred vision or constipation, may be observed, butclearly less frequent than with its precursor trazodone orwith TCAs, e.g. imipramine [6].The efficacy of NEF in treating major depressionappears comparable with typical SSRIs [7, 8] and estab-lished TCAs. Several studies comparing NEF with imip-ramine found equal efficacy [9–12]; the same holds truefor another study versus AMI [13].As mentioned, for psychotic depression, it is still con-troversial whether the addition of antipsychotics is reallyneeded, especially as depression-triggering effects of clas-sical antipsychotics have also been reported [14]. Similarto atypical antipsychotics, e.g. clozapine, olanzapine andrisperidone, NEF also binds to the 5-HT2A receptor. Bothagonist and antagonist binding to the 5-HT2A receptorfinally result in a downregulation [15]. These preclinicaldata may imply that NEF not only has an intrinsic anxio-lytic, but also antipsychotic action, probably making theaddition of classical antipsychotics unnecessary.The study described here was performed to test wheth-er monotherapy with NEF achieves similar improvementof psychotic depression as standard treatment with AMIand HAL. Tolerability of these treatments was a second-ary outcome parameter. The study consisted of two parts:first, we checked in a retrospective chart analysis whetherthere is sufficient evidence for comparable efficacy; next,we conducted an open, randomized prospective study in20 inpatients allocating 10 to each treatment arm.MethodsRetrospective Chart AnalysisThis analysis was done using the records of 20 inpatients of theDepartments of Psychiatry of the University of Munich and Frei-burg, Germany, with the documented clinical diagnosis of psychoticdepression and a Clinical Global Assessment Inventory (CGI) ratingof at least 5 (markedly ill). In contrast to the prospective study, bipo-larity was not an exclusion criterion. The allocation to treatmentarms was random in so far that the last 10 admissions treated witheither regimen (NEF vs. AMI-HAL) were chosen. Patients with acomedication other than short-term benzodiazepines for sleep distur-bances or biperiden were excluded. Patients were treated on differentwards of the hospital by different doctors according to their clinicalneeds, not with the intention of a study. However, as part of the hos-pital standard documentation system, the CGI was administered ona weekly basis. All patients had given their written consent at theentry to the hospital that data gathered during their stay can be usedfor post hoc scientific analysis.Comparison was made between the documented CGI scoresbefore treatment and after 4 weeks on either treatment.Prospective Open StudyThis 4-week, prospective trial was conducted in 20 adult inpa-tients of the Departments of Psychiatry of the University of Munichand Freiburg, Germany. Patients fulfilled the ICD-10 diagnostic crite-ria for severe depression with psychotic features (F32.3 or F33.3) andhad a score of at least 25 on the Hamilton depression scale, 21-itemversion (HAMD [16]). Exclusion criteria were a psychiatric diagnosisdifferent from F32.3 or F33.3, the need of continuous treatment withother antidepressants or mood stabilizer, electroconvulsive therapyduring the last month, depot antipsychotics within the last 2 months,suicidality and medical comorbidity. The only comedication allowedduring the 4-week trial were oxazepam and biperiden for the AMI-HAL group. After giving their informed written consent, the patientswere randomized on either treatment arm in the order of admission.Treatment success was documented by the HAMD and the BriefPsychiatric Rating Scale (BPRS), and the respective values at thebeginning and after 4 weeks were compared. Due to the small num-ber of patients in both groups, the results are descriptive, but notstatistically analyzed.ResultsRetrospective Chart AnalysisThe NEF group consisted of 8 female and 2 male, theAMI-HAL group of 6 female and 4 male patients. Age wascomparable between groups (mean B SD, 47 B 8.2 forNEF, 49.2 B 7.5 for AMI-HAL), as well as the meannumber of previous depressive episodes (3.2 for NEF vs.3.8 for AMI-HAL). Three patients in the NEF group werediagnosed as bipolar (F31.5), as well as 1 in the AMI-HALgroup (31.4), but all of them were without a mood stabi-lizer during the observation period. This difference maybe explained by the fact that clinicians consider it morehazardous to prescribe TCAs in bipolar depressed pa-Nefazodone in Psychotic Depression Neuropsychobiology 2002;46(suppl 1):31–35 33Table 1. Results of the retrospective chartanalysisa NEF groupPatientNo.ICD-10diagnosisNEF dosagemg/dayCGIbaselineCGI atday 281 32.2 200 5 12 32.3 400 7 53 32.3 400 7 614 31.5 350 7 35 32.3 400 6 56 32.2 400 6 47 31.5 500 7 48 31.5 400 7 49 32.3 500 7 710 32.3 400 7 6Mean B SD 395B83 6.6B0.7 4.5B1.7b AMI-HAL groupPatientNo.ICD-10diagnosisAMI dosagemg/dayHAL dosagemg/dayCGIbaselineCGI atday 2811 32.3 150 5 7 412 32.3 150 8 7 513 32.3 150 5 7 414 32.2 75 2 6 415 32.3 225 5 7 316 32.3 150 5 7 717 32.2 150 5 6 318 32.3 225 10 7 619 32.3 150 8 7 320 31.4 75 3 5 4Mean B SD 150B50 5.6B2.4 6.6B0.7 4.3B1.31 Premature discontinuation on day 14, LOCF.tients due to the high switch risk; however, none of thepatients in either group had a switch during the observa-tion period. Both NEF and AMI-HAL were dosed accord-ing to clinical needs, as patients were not part of a studyduring their individual treatment. The mean dosage ofNEF at the endpoint of the analysis (day 28) was 395 B83 mg/day, the mean dosage of AMI 150 B 50 mg/day,and of HAL 5.6 B 2.4 mg/day.Within 4 weeks, the mean of the CGI declined in theNEF group from 6.6 B 0.7 (range 5–7) to 4.5 B 1.7 (range1–7) with last observation carried forward (LOCF) fromone premature discontinuation. 6/10 patients were con-sidered as responders with a response criterion of a CGIimprovement of at least 2 points (with all 3 bipolarpatients being responders). One patient had the treatmentstopped after 2 weeks due to strong sedation after littleimprovement (CGI decrease from 7 to 6).For the AMI-HAL group, all patients remained for atleast 4 weeks on this treatment. The mean of the CGI atthe beginning was identical with the NEF group anddeclined from 6.6 B 0.7 (range 5–7) to 4.3 B 1.3 (range3–7). 7/10 patients were considered as responders with aresponse criterion of a CGI improvement of at least 2points (with the 1 bipolar patient not responding suffi-ciently).Table 1 shows the individual patient characteristicsand treatment response.Prospective Open StudyNEF or AMI-HAL were dosed at the clinicians’ discre-tion and the daily dosage did not appear different fromwhat was seen in the retrospective chart analysis. Two outof 10 patients of the NEF group discontinued prematurelyafter 1 and 2 weeks, respectively, 1 due to worsening of34 Neuropsychobiology 2002;46(suppl 1):31–35 Grunze/Marcuse/Schärer/Born/WaldenTable 2. Results of the prospective openstudy PatientNo.Medication HAMDbaselineHAMDday 28BPRSbaselineBPRSday 281 NEF 39 14 51 392 NEF 30 7 43 233 NEF 26 8 39 354 NEF 27 17 44 325 NEF 31 8 48 2461 NEF 25 31 41 487 NEF 28 6 50 2482 NEF 24 11 38 349 NEF 25 8 43 2910 NEF 25 10 43 37Mean B SD 28B4.5 12B7.5 44B4.4 32.5B7.911 AMI-HAL 30 12 47 29123 AMI-HAL 35 24 62 4613 AMI-HAL 30 6 46 26141 AMI-HAL 35 28 53 4515 AMI-HAL 33 5 50 20162 AMI-HAL 30 21 43 3517 AMI-HAL 33 17 56 3818 AMI-HAL 41 19 52 3219 AMI-HAL 28 7 44 1920 AMI-HAL 32 10 55 20Mean B SD 32.7B3.7 14.9B8.1 50.8B6 31B101 LOCF, discontinuation after day 14.2 LOCF, discontinuation after day 7.3 LOCF, discontinuation after day 21.symptoms, the other due to dizziness and nausea. In com-parison, 3/10 patients of the AMI-HAL group were drop-outs after 1, 2 and 3 weeks. The reasons included lack ofefficacy and intolerable EPMS in 2 patients, and drymouth and strong sedation in the third.Again, both NEF and AMI-HAL were dosed accordingto clinical needs. The mean dosage of NEF at the end-point of the analysis (day 28) was 425 B 45 mg/day,the mean dosage of AMI 175 B 37 and of HAL 7.2 B4.4 mg/day.At baseline, patients in the AMI-HAL group wereslightly more ill with an HAMD score of 32.7 B 3.7 and aBPRS score of 50.8 B 6 compared with 28 B 4.5(HAMD) and 44 B 4.4 (BPRS) for the NEF group. With-in 4 weeks, the mean of the HAMD in the AMI-HALgroup declined to 14.9 B 8.1 and in the NEF group to 12B 7.5 with LOCF in the 5 patients with premature dis-continuation. Defining a 50% reduction of the HAMD assufficient treatment response, 8/10 patients were respond-ers in the NEF group and 6/10 in the AMI-HAL group.Accordingly, the BPRS score declined to 31 B 10 inthe AMI-HAL group and to 32.5 B 7.9 in the NEFgroup.The individual results are shown in table 2. Figure 1 isa graphic depiction of the means of the HAMD and BPRSin both groups.Oxazepam was rarely needed in both groups. Only 2patients (1 in each group) received oxazepam for morethan 3 days during the observation period. However, 4/10patients in the AMI-HAL group needed biperiden (4 mg/day) for at least 14 days.DiscussionThe appropriate treatment of psychotic depression isstill a controversial topic. Treatment habit is the additionof antipsychotics, often typical antipsychotics such asHAL. As NEF may have an intrinsic antipsychotic com-ponent of action by its 5-HT2A antagonism, we investi-gated whether it may be a candidate drug efficient enoughNefazodone in Psychotic Depression Neuropsychobiology 2002;46(suppl 1):31–35 35Fig. 1. Prospective comparison of NEF vs. AMI-HAL in psychoticdepression. Results are LOCF for the dropouts (2 in the NEF groupand 3 in the AMI-HAL group).to treat psychotic depression without the addition ofantipsychotics.Both the retrospective chart analysis and the prospec-tive open trial suggest that the overall efficacy of NEF iscomparable with the one of the standard treatment withAMI and HAL. From the point of view of tolerability,more dropouts were observed in the AMI-HAL groupdespite the allowed use of biperiden. However, due to thesmall number of patients, this may also be by chance.Patients in the NEF group responded not as well forthe BPRS score as they did for the HAMD. Analysis of thesingle items of the BPRS revealed that those items associ-ated with psychotic features, item 4 (thought disorder), 10(hostility), 11 (paranoia), 12 (hallucinations), and 15 (un-usual thought content), responded less markedly thanthose focussing more on depressive symptoms and anxi-ety. Thus, in depression with severe and prominent psy-chotic features, the addition of antipsychotics to NEF stillappears to be needed. When using HAL, it has to be keptin mind that NEF increases the area under curve for HALplasma concentration by 36% after a one-time adminis-tration of HAL [17]. The pharmacological mechanism forthis is not yet understood. However, in clinical practice,this means that HAL should be reduced when coadminis-tered with NEF.In conclusion, these data do not support a monothera-py approach towards psychotic depression with NEF aslong as psychotic features are very prominent. For milderforms, an initial treatment with NEF monotherapy maybe an adequate option.References1 Coryell W: The treatment of psychotic depres-sion. J Clin Psychiatry 1998;59(suppl 1):22–27.2 Spiker DG, Weiss JC, Dealy RS, Griffin SJ,Hanin I, Neil JF, Perel JM, Rossi AJ, SoloffPH: The pharmacological treatment of delu-sional depression. Am J Psychiatry 1985;142:430–436.3 Rothschild AJ, Samson JA, Bessette MP, Cart-er-Campbell JT: Efficacy of the combination offluoxetine and perphenazine in the treatmentof psychotic depression. J Clin Psychiatry1993;54:338–342.4 Zanardi R, Franchini L, Gasperini M, Perez J,Smeraldi E: Double-blind controlled trial ofsertraline versus paroxetine in the treatment ofdelusional depression. Am J Psychiatry 1996;153:1631–1633.5 Zanardi R, Franchini L, Serretti A, Perez J,Smeraldi E: Venlafaxine versus fluvoxamine inthe treatment of delusional depression: A pilotdouble-blind controlled study. J Clin Psychia-try 2000;61:26–29.6 Lader MH: Tolerability and safety: Essentialsin antidepressant pharmacotherapy. J ClinPsychiatry 1996;57(suppl 2):39–44.7 Baldwin DS, Hawley CJ, Abed RT, MaragakisBP, Cox J, Buckingham SA, Pover GH, AscherA: A multicenter double-blind comparison ofnefazodone and paroxetine in the treatment ofoutpatients with moderate-to-severe depres-sion. J Clin Psychiatry 1996;57(suppl 2):46–52.8 Feiger A, Kiev A, Shrivastava RK, WisselinkPG, Wilcox CS: Nefazodone versus sertralinein outpatients with major depression: Focus onefficacy, tolerability, and effects on sexual func-tion and satisfaction. J Clin Psychiatry 1996;57(suppl 2):53–62.9 Cohn CK, Robinson DS, Roberts DL, Schwi-derski UE, O’Brien K, Ieni JR: Responders toantidepressant drug treatment: A study com-paring nefazodone, imipramine, and placeboin patients with major depression. J Clin Psy-chiatry 1996;57(suppl 2):15–18.10 Fontaine R, Ontiveros A, Elie R, Kensler TT,Roberts DL, Kaplita S, Ecker JA, Faludi G: Adouble-blind comparison of nefazodone, imip-ramine, and placebo in major depression. JClin Psychiatry 1994;55:234–241.11 Rickels K, Robinson DS, Schweizer E, MarcusRN, Roberts DL: Nefazodone: Aspects of effi-cacy. J Clin Psychiatry 1995;56(suppl 6):43–46.12 Rickels K, Schweizer E, Clary C, Fox I, WeiseC: Nefazodone and imipramine in major de-pression: A placebo-controlled trial. Br J Psy-chiatry 1994;164:802–805.13 Ansseau M, Darimont P, Lecoq A, De Nayer A,Evrard JL, Kremer P, Devoitille JM, DierickM, Mertens C, Mesotten F, et al: Controlledcomparison of nefazodone and amitriptyline inmajor depressive inpatients. Psychopharmaco-logy (Berl) 1994;115:254–260.14 Whitlock FA, Evans LE: Drugs and depression.Drugs 1978;15:53–71.15 Smith RL, Barrett RJ, Sanders-Bush E: Adap-tation of brain 5HT2 receptors after mianserintreatment: Receptor sensitivity, not receptorbinding, more accurately correlates with be-havior. J Pharmacol Exp Ther 1990;254:484–488.16 Hamilton M: Development of a rating scale forprimary depressive illness. Br J Soc Clin Psy-chol 1967;6:278–296.17 Barbhaiya RH, Shukla UA, Greene DS, BreulHP, Midha KK: Investigation of pharmacoki-netic and pharmacodynamic interactions aftercoadministration of nefazodone and haloperi-dol. J Clin Psychopharmacol 1996;16:26–34.

A: A multicenter double-blind comparison of nefazodone and paroxetine in the treatment of outpatients with moderate-to-severe depression.

Carter-Campbell JT: Efficacy of the combination of fluoxetine and perphenazine in the treatment of psychotic depression.

CS: Nefazodone versus sertraline in outpatients with major depression: Focus on efficacy, tolerability, and effects on sexual function and satisfaction.

Development of a rating scale for primary depressive illness.

Drugs and depression.

et al: Controlled comparison of nefazodone and amitriptyline in major depressive inpatients. Psychopharmacology (Berl)

Faludi G: A double-blind comparison of nefazodone, imipramine, and placebo in major depression.

Ieni JR: Responders to antidepressant drug treatment: A study comparing nefazodone, imipramine, and placebo in patients with major depression.

Midha KK: Investigation of pharmacokinetic and pharmacodynamic interactions after coadministration of nefazodone and haloperidol.

Nefazodone and imipramine in major depression: A placebo-controlled trial.

Roberts DL: Nefazodone: Aspects of efficacy.

Sanders-Bush E: Adaptation of brain 5HT2 receptors after mianserin treatment: Receptor sensitivity, not receptor binding, more accurately correlates with behavior.

Smeraldi E: Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression.

Smeraldi E: Venlafaxine versus fluvoxamine in the treatment of delusional depression: A pilot double-blind controlled study.

Soloff PH: The pharmacological treatment of delusional depression.

The treatment of psychotic depression.

Tolerability and safety: Essentials in antidepressant pharmacotherapy.

Nefazodone in psychotic unipolar and bipolar depression: A retrospective chart analysis and open prospective study on its efficacy and safety versus combined treatment with amitriptyline and haloperidol

Universität München: Elektronischen Publikationen

Neuropsychobiology 2002;46(suppl 1):31–35
DOI: 10.1159/000068017
Nefazodone in Psychotic Unipolar and Bipolar
Depression: A Retrospective Chart Analysis and
Open Prospective Study on Its Efficacy and
Safety versus Combined Treatment with
Amitriptyline and Haloperidol
Heinz Grunzea Alain Marcusea Lars O. Schärerb Christoph Bornb
Jörg Waldenb
Departments of Psychiatry, aLMU Munich, Munich, and bUniversity of Freiburg, Freiburg, Germany
Dr. H. Grunze
Psychiatrische Klinik der LMU
Nussbaumstrasse 7
D–80336 München (Germany)
Tel. +49 89 51605335, Fax +49 89 51605330, E-Mail grunze@psy.med.uni-muenchen.de 
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2002 S. Karger AG, Basel
0302–282X/02/0465–0031$18.50/0
Accessible online at:
www.karger.com/nps
Key Words
Nefazodone W Amitriptyline W Haloperidol W Psychotic
depression W Delusional depression
Abstract
Although atypical antipsychotics are on the rise, tradi-
tional treatment of psychotic (or delusional) depression
mostly includes the addition of classical antipsychotics
to antidepressants. As there are only few data support-
ing this approach compared with antidepressant mono-
therapy, and almost no data comparing it with antide-
pressants of the latest generation, we conducted a retro-
spective chart analysis and a prospective, randomized
open study on the efficacy and tolerability of nefazodone
monotherapy versus combined treatment with amitrip-
tyline and haloperidol in psychotic depression. The re-
sults suggest that the addition of classical antipsychotics
should be reserved for those with very severe psychotic
symptoms, but may not be needed in milder forms.
Copyright © 2003 S. Karger AG, Basel
Introduction
Psychotic (or delusional) depression is characterized
by its greater severity, longer episodes, and greater inca-
pacity compared with depression without psychotic fea-
tures [1]. Since the landmark study of Spiker et al. [2],
only few controlled trials have been published, and the
appropriate pharmacological treatment of severe depres-
sion with psychotic features remains a controversial prob-
lem. The distinction between mood-congruent and mood-
incongruent features does not seem to imply a difference
as far as the use of antipsychotics is concerned in clinical
practice. Mood congruency of paranoid thoughts makes
them an endogenous part of the depressive syndrome
characterizing its severity. Thus, remission of depression
through treatment with antidepressants should also ame-
liorate those psychotic symptoms. Nevertheless, classical
antipsychotics are often added to antidepressants in clini-
cal practice. Traditionally, a combination of tricyclics,
e.g. amitriptyline (AMI) combined with haloperidol
(HAL), is widely used, as these drugs are effective, well
known to the practitioner and inexpensive. However, this
combination may yield several disadvantages, exerting
adrenergic, antihistaminergic, anticholinergic and, for
HAL, antidopaminergic side effects.
32 Neuropsychobiology 2002;46(suppl 1):31–35 Grunze/Marcuse/Schärer/Born/Walden
Only few data exist so far on the use of selective sero-
tonin-reuptake inhibitors (SSRIs) for the treatment of
psychotic depression. A small trial of the combination of
fluoxetine and perphenanzine suggested similar efficacy
as the standard regimens tricyclic antidepressant (TCA) +
antipsychotics or electroconvulsive therapy [3]. Interest-
ingly, two trials with antidepressant monotherapy (ser-
traline vs. paroxetine [4] and venlafaxine vs. fluvoxamine
[5]) also showed efficacy of monotherapy with these new
antidepressants in delusional depression in a double-
blind and randomized design. However, it still remains
unclear how a new antidepressant as a monotherapy
would perform in comparison with the traditional combi-
nation therapy with a tricyclic and an antipsychotic.
Nefazodone (NEF) is a dual-acting serotonergic drug.
Presynaptically, it inhibits serotonine reuptake and post-
synaptically, it blocks 5-HT2 receptors. Its affinity to oth-
er receptors, i.e. alpha-adrenergic and cholinergic recep-
tors, is very weak. This gives NEF a profile of high tolera-
bility without side effects usually seen with classical
TCAs. Alpha-1-related side effects, such as dry mouth,
blurred vision or constipation, may be observed, but
clearly less frequent than with its precursor trazodone or
with TCAs, e.g. imipramine [6].
The efficacy of NEF in treating major depression
appears comparable with typical SSRIs [7, 8] and estab-
lished TCAs. Several studies comparing NEF with imip-
ramine found equal efficacy [9–12]; the same holds true
for another study versus AMI [13].
As mentioned, for psychotic depression, it is still con-
troversial whether the addition of antipsychotics is really
needed, especially as depression-triggering effects of clas-
sical antipsychotics have also been reported [14]. Similar
to atypical antipsychotics, e.g. clozapine, olanzapine and
risperidone, NEF also binds to the 5-HT2A receptor. Both
agonist and antagonist binding to the 5-HT2A receptor
finally result in a downregulation [15]. These preclinical
data may imply that NEF not only has an intrinsic anxio-
lytic, but also antipsychotic action, probably making the
addition of classical antipsychotics unnecessary.
The study described here was performed to test wheth-
er monotherapy with NEF achieves similar improvement
of psychotic depression as standard treatment with AMI
and HAL. Tolerability of these treatments was a second-
ary outcome parameter. The study consisted of two parts:
first, we checked in a retrospective chart analysis whether
there is sufficient evidence for comparable efficacy; next,
we conducted an open, randomized prospective study in
20 inpatients allocating 10 to each treatment arm.
Methods
Retrospective Chart Analysis
This analysis was done using the records of 20 inpatients of the
Departments of Psychiatry of the University of Munich and Frei-
burg, Germany, with the documented clinical diagnosis of psychotic
depression and a Clinical Global Assessment Inventory (CGI) rating
of at least 5 (markedly ill). In contrast to the prospective study, bipo-
larity was not an exclusion criterion. The allocation to treatment
arms was random in so far that the last 10 admissions treated with
either regimen (NEF vs. AMI-HAL) were chosen. Patients with a
comedication other than short-term benzodiazepines for sleep distur-
bances or biperiden were excluded. Patients were treated on different
wards of the hospital by different doctors according to their clinical
needs, not with the intention of a study. However, as part of the hos-
pital standard documentation system, the CGI was administered on
a weekly basis. All patients had given their written consent at the
entry to the hospital that data gathered during their stay can be used
for post hoc scientific analysis.
Comparison was made between the documented CGI scores
before treatment and after 4 weeks on either treatment.
Prospective Open Study
This 4-week, prospective trial was conducted in 20 adult inpa-
tients of the Departments of Psychiatry of the University of Munich
and Freiburg, Germany. Patients fulfilled the ICD-10 diagnostic crite-
ria for severe depression with psychotic features (F32.3 or F33.3) and
had a score of at least 25 on the Hamilton depression scale, 21-item
version (HAMD [16]). Exclusion criteria were a psychiatric diagnosis
different from F32.3 or F33.3, the need of continuous treatment with
other antidepressants or mood stabilizer, electroconvulsive therapy
during the last month, depot antipsychotics within the last 2 months,
suicidality and medical comorbidity. The only comedication allowed
during the 4-week trial were oxazepam and biperiden for the AMI-
HAL group. After giving their informed written consent, the patients
were randomized on either treatment arm in the order of admission.
Treatment success was documented by the HAMD and the Brief
Psychiatric Rating Scale (BPRS), and the respective values at the
beginning and after 4 weeks were compared. Due to the small num-
ber of patients in both groups, the results are descriptive, but not
statistically analyzed.
Results
Retrospective Chart Analysis
The NEF group consisted of 8 female and 2 male, the
AMI-HAL group of 6 female and 4 male patients. Age was
comparable between groups (mean B SD, 47 B 8.2 for
NEF, 49.2 B 7.5 for AMI-HAL), as well as the mean
number of previous depressive episodes (3.2 for NEF vs.
3.8 for AMI-HAL). Three patients in the NEF group were
diagnosed as bipolar (F31.5), as well as 1 in the AMI-HAL
group (31.4), but all of them were without a mood stabi-
lizer during the observation period. This difference may
be explained by the fact that clinicians consider it more
hazardous to prescribe TCAs in bipolar depressed pa-
Nefazodone in Psychotic Depression Neuropsychobiology 2002;46(suppl 1):31–35 33
Table 1. Results of the retrospective chart
analysis
a NEF group
Patient
No.
ICD-10
diagnosis
NEF dosage
mg/day
CGI
baseline
CGI at
day 28
1 32.2 200 5 1
2 32.3 400 7 5
3 32.3 400 7 61
4 31.5 350 7 3
5 32.3 400 6 5
6 32.2 400 6 4
7 31.5 500 7 4
8 31.5 400 7 4
9 32.3 500 7 7
10 32.3 400 7 6
Mean B SD 395B83 6.6B0.7 4.5B1.7
b AMI-HAL group
Patient
No.
ICD-10
diagnosis
AMI dosage
mg/day
HAL dosage
mg/day
CGI
baseline
CGI at
day 28
11 32.3 150 5 7 4
12 32.3 150 8 7 5
13 32.3 150 5 7 4
14 32.2 75 2 6 4
15 32.3 225 5 7 3
16 32.3 150 5 7 7
17 32.2 150 5 6 3
18 32.3 225 10 7 6
19 32.3 150 8 7 3
20 31.4 75 3 5 4
Mean B SD 150B50 5.6B2.4 6.6B0.7 4.3B1.3
1 Premature discontinuation on day 14, LOCF.
tients due to the high switch risk; however, none of the
patients in either group had a switch during the observa-
tion period. Both NEF and AMI-HAL were dosed accord-
ing to clinical needs, as patients were not part of a study
during their individual treatment. The mean dosage of
NEF at the endpoint of the analysis (day 28) was 395 B
83 mg/day, the mean dosage of AMI 150 B 50 mg/day,
and of HAL 5.6 B 2.4 mg/day.
Within 4 weeks, the mean of the CGI declined in the
NEF group from 6.6 B 0.7 (range 5–7) to 4.5 B 1.7 (range
1–7) with last observation carried forward (LOCF) from
one premature discontinuation. 6/10 patients were con-
sidered as responders with a response criterion of a CGI
improvement of at least 2 points (with all 3 bipolar
patients being responders). One patient had the treatment
stopped after 2 weeks due to strong sedation after little
improvement (CGI decrease from 7 to 6).
For the AMI-HAL group, all patients remained for at
least 4 weeks on this treatment. The mean of the CGI at
the beginning was identical with the NEF group and
declined from 6.6 B 0.7 (range 5–7) to 4.3 B 1.3 (range
3–7). 7/10 patients were considered as responders with a
response criterion of a CGI improvement of at least 2
points (with the 1 bipolar patient not responding suffi-
ciently).
Table 1 shows the individual patient characteristics
and treatment response.
Prospective Open Study
NEF or AMI-HAL were dosed at the clinicians’ discre-
tion and the daily dosage did not appear different from
what was seen in the retrospective chart analysis. Two out
of 10 patients of the NEF group discontinued prematurely
after 1 and 2 weeks, respectively, 1 due to worsening of
34 Neuropsychobiology 2002;46(suppl 1):31–35 Grunze/Marcuse/Schärer/Born/Walden
Table 2. Results of the prospective open
study Patient
No.
Medication HAMD
baseline
HAMD
day 28
BPRS
baseline
BPRS
day 28
1 NEF 39 14 51 39
2 NEF 30 7 43 23
3 NEF 26 8 39 35
4 NEF 27 17 44 32
5 NEF 31 8 48 24
61 NEF 25 31 41 48
7 NEF 28 6 50 24
82 NEF 24 11 38 34
9 NEF 25 8 43 29
10 NEF 25 10 43 37
Mean B SD 28B4.5 12B7.5 44B4.4 32.5B7.9
11 AMI-HAL 30 12 47 29
123 AMI-HAL 35 24 62 46
13 AMI-HAL 30 6 46 26
141 AMI-HAL 35 28 53 45
15 AMI-HAL 33 5 50 20
162 AMI-HAL 30 21 43 35
17 AMI-HAL 33 17 56 38
18 AMI-HAL 41 19 52 32
19 AMI-HAL 28 7 44 19
20 AMI-HAL 32 10 55 20
Mean B SD 32.7B3.7 14.9B8.1 50.8B6 31B10
1 LOCF, discontinuation after day 14.
2 LOCF, discontinuation after day 7.
3 LOCF, discontinuation after day 21.
symptoms, the other due to dizziness and nausea. In com-
parison, 3/10 patients of the AMI-HAL group were drop-
outs after 1, 2 and 3 weeks. The reasons included lack of
efficacy and intolerable EPMS in 2 patients, and dry
mouth and strong sedation in the third.
Again, both NEF and AMI-HAL were dosed according
to clinical needs. The mean dosage of NEF at the end-
point of the analysis (day 28) was 425 B 45 mg/day,
the mean dosage of AMI 175 B 37 and of HAL 7.2 B
4.4 mg/day.
At baseline, patients in the AMI-HAL group were
slightly more ill with an HAMD score of 32.7 B 3.7 and a
BPRS score of 50.8 B 6 compared with 28 B 4.5
(HAMD) and 44 B 4.4 (BPRS) for the NEF group. With-
in 4 weeks, the mean of the HAMD in the AMI-HAL
group declined to 14.9 B 8.1 and in the NEF group to 12
B 7.5 with LOCF in the 5 patients with premature dis-
continuation. Defining a 50% reduction of the HAMD as
sufficient treatment response, 8/10 patients were respond-
ers in the NEF group and 6/10 in the AMI-HAL group.
Accordingly, the BPRS score declined to 31 B 10 in
the AMI-HAL group and to 32.5 B 7.9 in the NEF
group.
The individual results are shown in table 2. Figure 1 is
a graphic depiction of the means of the HAMD and BPRS
in both groups.
Oxazepam was rarely needed in both groups. Only 2
patients (1 in each group) received oxazepam for more
than 3 days during the observation period. However, 4/10
patients in the AMI-HAL group needed biperiden (4 mg/
day) for at least 14 days.
Discussion
The appropriate treatment of psychotic depression is
still a controversial topic. Treatment habit is the addition
of antipsychotics, often typical antipsychotics such as
HAL. As NEF may have an intrinsic antipsychotic com-
ponent of action by its 5-HT2A antagonism, we investi-
gated whether it may be a candidate drug efficient enough
Nefazodone in Psychotic Depression Neuropsychobiology 2002;46(suppl 1):31–35 35
Fig. 1. Prospective comparison of NEF vs. AMI-HAL in psychotic
depression. Results are LOCF for the dropouts (2 in the NEF group
and 3 in the AMI-HAL group).
to treat psychotic depression without the addition of
antipsychotics.
Both the retrospective chart analysis and the prospec-
tive open trial suggest that the overall efficacy of NEF is
comparable with the one of the standard treatment with
AMI and HAL. From the point of view of tolerability,
more dropouts were observed in the AMI-HAL group
despite the allowed use of biperiden. However, due to the
small number of patients, this may also be by chance.
Patients in the NEF group responded not as well for
the BPRS score as they did for the HAMD. Analysis of the
single items of the BPRS revealed that those items associ-
ated with psychotic features, item 4 (thought disorder), 10
(hostility), 11 (paranoia), 12 (hallucinations), and 15 (un-
usual thought content), responded less markedly than
those focussing more on depressive symptoms and anxi-
ety. Thus, in depression with severe and prominent psy-
chotic features, the addition of antipsychotics to NEF still
appears to be needed. When using HAL, it has to be kept
in mind that NEF increases the area under curve for HAL
plasma concentration by 36% after a one-time adminis-
tration of HAL [17]. The pharmacological mechanism for
this is not yet understood. However, in clinical practice,
this means that HAL should be reduced when coadminis-
tered with NEF.
In conclusion, these data do not support a monothera-
py approach towards psychotic depression with NEF as
long as psychotic features are very prominent. For milder
forms, an initial treatment with NEF monotherapy may
be an adequate option.
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Nefazodone in psychotic unipolar and bipolar depression: A retrospective chart analysis and open prospective study on its efficacy and safety versus combined treatment with amitriptyline and haloperidol

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