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REVIEW ARTICLE |
Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Centre, Utrecht, The Netherlands
Department of Psychiatry, Waterland Hospital, Purmerend, The Netherlands
Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Centre, Utrecht, The Netherlands
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
University Medical Centre Groningen, Department of Psychiatry, Groningen, The Netherlands
Correspondence: Dr J. Wijkstra, University Medical Centre Utrecht, HP B01.206, PO Box 85500, 3508 GA, Utrecht, The Netherlands. E-mail: j.wijkstra{at}azu.nl
Declaration of interest J.W. and W.N. are currently conducting a randomised controlled trial in patients with unipolar psychotic depression, which is financially supported by Wyeth and AstraZeneca.These organisations also financially supported the literature search for this review.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Aims To compare the clinical effectiveness of pharmacological treatments for patients with unipolar psychotic depression.
Method Systematic review and meta-analysis of randomised controlled trials.
Results Ten trials were included in the review. We found no evidence that the combination of an antidepressant with an antipsychotic is more effective than an antidepressant alone.This combination was statistically more effective than an antipsychotic alone.
Conclusions Antidepressant monotherapy and adding an antipsychotic if the patient does not respond, or starting with the combination of an antidepressant and an antipsychotic, both appear to be appropriate options for patients with unipolar psychotic depression.However, clinically the balance between risks and benefits may suggest the first option should be preferred for many patients. Starting with an antipsychotic alone appears to be inadequate.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Included studies
We included randomised controlled trials (RCTs) of the pharmacological
treatment of patients with psychotic depression, published in any language. We
expected to identify very few RCTs with the treatment of psychotic depression
as the primary focus. We therefore also selected RCTs including patients with
major depression with and without psychotic features, in which the effects in
the subgroup of patients with psychotic depression were reported separately.
The inclusion criteria for the review were as follows.
Participants
We included RCTs investigating patients in any setting (in-patient and
out-patient) with a unipolar major depressive disorder having a current major
depressive episode with psychotic features. If a trial had studied patients
with depressive episodes in the course of a bipolar disorder, it was only
included if the results in the non-bipolar depression group were reported
separately or if the percentage of patients with bipolar depression did not
exceed 20% of the total study population.
Interventions
We included RCTs making the following comparisons: antidepressant
v. antidepressant, antipsychotic v. antipsychotic,
antidepressant v. placebo, antipsychotic v. placebo,
antidepressant v. antipsychotic, antidepressant plus antipsychotic
v. antidepressant, antidepressant plus antipsychotic v.
antipsychotic, antidepressant plus antipsychotic v. placebo.
Search strategy for identification of studies
Bibliographic databases such as Medline do not have an indexing term for
psychotic depression. We therefore screened all RCTs that had included
patients with a unipolar major depressive disorder to identify those possibly
including patients with psychotic features. We searched the Cochrane Central
Register of Controlled Trials with the terms DEPRESSIVE DISORDER and DRUG
TREATMENT. In addition we searched Medline (1966 until April 2004) and EMBASE
(1980 until April 2004) using the following terms: (‘DEPRESSIVE
DISORDER/DRUG THERAPY’ [MESH] and ((‘DELUSIONS’
[MESH Terms] or DELUSIONS [Text Word]) or ((‘PSYCHOTIC
DISORDERS’ [MESH Terms] or PSYCHOTIC [Text Word]) and
FEATURES [All Fields]))) combined with a search strategy for RCTs.
In step 1 of the search process, all abstracts of the identified publications were screened independently by two authors (50% by both J.W. and J.L., 50% by both F.B. and W.N.) and studies were selected if they met the following criteria:
In case of any doubt or disagreement between the reviewers, the publication was included. Next, the full articles were obtained for the selected abstracts. In step 2, a trained medical student screened the full articles to select all trials in which: (a) patients with psychotic depression were not excluded; and (b) results in the subgroup of patients with psychotic depression were reported separately.
In case of any doubt the publication was included. In order to check the reliability of this procedure a random selection of 60 articles were also screened by J.W., which revealed no publication that had not been selected by the medical student. In addition, reference lists of included publications, related reviews and abstract books of recent congresses were searched and trials were identified through personal communication. In step 3, two authors (J.W. and F.B.) independently reviewed all identified publications according to the inclusion criteria. Any disagreement was resolved by consensus discussion with a third author (W.N.).
Quality assessment
Two reviewers (J.W. and J.L.) assessed the methodological quality of the
included trials, according to the criteria of the Cochrane Collaboration.
These criteria focus on randomisation procedures (especially allocation
concealment and randomisation); whether the study was double-blind,
single-blind or open randomised; analysis (stratification prior to treatment
or non-stratification of patients with psychotic v. non-psychotic
depression in the RCTs that did not have the treatment of psychotic depression
as their main focus); and other aspects, such as reporting of the number of
patients leaving the trial and the reasons for the withdrawals.
Types of outcome measures
The primary efficacy outcome used in the analysis was clinical response
based on observer-rated symptom reduction, for example a reduction of at least
50% on the Hamilton Rating Scale for Depression (HRSD) or any other
observer-rated depression severity rating scale, or a change score on the
Clinical Global Impression – Change (CGI–C) of ‘much
improved’ or ‘very much improved’. As secondary efficacy
outcomes, we investigated remission as defined in the reports and based on the
HRSD or other observer-rated depression severity scale or change in severity
on Clinical Global Impression – Severity (CGI–S); and quality of
life.
The primary harm outcome used in the analysis was overall withdrawal rate during acute treatment as a proxy measure of overall acceptability of treatment. We also analysed withdrawal rates resulting from adverse effects, all-cause mortality and suicide.
Data extraction
Data were extracted on participants’ characteristics, diagnosis
(diagnostic instrument, classification), intervention details and outcome
measures. Data were extracted independently by two reviewers (J.W. and
J.L.).
Data analysis
Data were entered into RevMan 4.2
(http://www.cc-ims.net/RevMan).
For binary efficacy outcomes a relative risk (with 95% confidence intervals)
was calculated for each comparison. When necessary, we converted response data
from the trials into intention-to-treat response data by using the total
number of randomised patients per group who had started with treatment as the
denominator.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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In seven of the ten studies the treatment of psychotic depression was the primary focus. From three studies we used data from the subgroup of patients with psychosis, which were reported separately (Spiker & Kupfer, 1988; Bruijn et al, 1996; Van den Broek et al, 2004). Five RCTs did not include only patients with unipolar psychotic depression. In the study by Zanardi et al (1996) it was possible to exclude the data relating to participants with bipolar disorder. The study by Anton & Burch (1990) reported 15.8% (6 out of 38) cases of bipolar disorder, and it is unclear how many of the 8 participants who left the study and whose data were excluded before analysis had bipolar disorder. To solve this problem we assumed a random withdrawal rate. In Spiker et al (1985) 15.5% of the patients in the results had bipolar disorder. In Bruijn et al (1996) and Zanardi et al (2000) we were able to exclude the data for patients with bipolar disorder with the help of additional information from the authors.
Outcome measures
It was not possible to transfer the authors’ defined response data
into rates based on one definition (e.g. 50% reduction of the HRSD score). In
addition, several authors used response definitions based on what is often
considered remission. In the absence of a better option, we decided to use
only response data as reported by the authors.
In eight of the ten studies we recalculated the intention-to-treat response rates using all randomised patients as the denominator. We thus included many patients who were excluded from analyses by the original researchers: from the study of Anton & Burch (1990), 8 patients who left the study before receiving 2 full weeks of active medication; 9 and 3 patients, respectively from the studies of Bruijn et al (1996) and Van den Brock et al (2004), who were treated with haloperidol; from the study of Mulsant et al (2001), 6 patients who left the trial after randomisation; 7% and 9% of the randomised patients respectively from the two trials of Rothschild et al (2004), who left the trial between baseline and the first visit after start of treatment at week 1; and finally 7 patients who left the studies of Spiker et al (1985) and Spiker & Kupfer (1988). Extracting continuous data of observer-rated depression severity scales for analysis was impossible because we were not able to convert these data according to an intention-to-treat analysis (Spiker et al, 1985; Spiker & Kupfer, 1988; Anton & Burch, 1990; Bruijn et al, 1996; Mulsant et al, 2001; Rothschild et al, 2004; Van den Broek et al, 2004), and in the two studies by Zanardi et al (1996, 2000) no continuous data were given. Other efficacy outcome measures (e.g. change in quality of life) could not be extracted from the trials.
Overall rates of withdrawal were available for all studies. Rates of withdrawal because of adverse effects were available in four studies (Spiker et al, 1985; Anton & Burch, 1990; Mulsant et al, 2001; Van den Broek et al, 2004); in three other studies these data were not based on an intention-to-treat analysis (two in Rothschild et al, 2004; one in Bruijn et al, 1996), were not available in one study (Spiker & Kupfer, 1988) and were the same as the overall withdrawal rates in two studies (Zanardi et al, 1996, 2000). Withdrawals specifically owing to death or suicide were not reported in any of the studies.
Efficacy analyses
Only one RCT compared an antidepressant with a placebo
(Spiker & Kupfer, 1988).
In this study amitriptyline was not statistically significantly more effective
than placebo (RR=8.40, 95% CI 0.50–142.27; P=0.14). In four
studies two different antidepressants were compared directly. In one study
(Bruijn et al, 1996),
imipramine under plasma level control was statistically significantly more
effective than mirtazapine (RR=3.00, 95% CI 1.01–8.95; P=0.05).
In another (Van den Broek et al,
2004), imipramine under plasma level control was statistically
significantly more effective than fluvoxamine (RR=2.10, 95% CI
1.06–4.17; P=0.03). In the first study by Zanardi et
al (1996), sertraline was
statistically significantly more effective than paroxetine (RR=3.37, 95% CI
1.19–9.57; P=0.02); the second
(Zanardi et al, 2000)
did not find a statistically significant difference between fluvoxamine and
venlafaxine.
In two studies the tricyclic antidepressant (TCA) imipramine given under plasma level control was compared with an antidepressant of another class (mirtazapine or fluvoxamine). After pooling these studies (Bruijn et al, 1996; Van den Broek et al, 2004) imipramine was statistically significantly superior to the non-TCA (RR=2.36, 95% CI 1.32–4.23, P=0.004) (Fig. 1).
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In three RCTs selective serotonin reuptake inhibitors (SSRIs) were studied. Response rates to these SSRIs varied from 21.4% (paroxetine in Zanardi et al, 1996) and 30.4% (fluvoxamine in Van den Broek et al, 2004) to 72.2% (sertraline in Zanardi et al, 1996) and 81.8% (fluvoxamine in Zanardi et al, 2000). In one of these studies (Zanardi et al, 1996) there was a statistically significant difference between two SSRIs, favouring sertraline. Combining the studies with SSRIs led to a mean response rate to SSRIs of 51.5%. A pooled comparison of SSRIs with other antidepressants was not possible.
One study (Spiker et al, 1985) comparing antidepressant monotherapy (amitriptyline) with antipsychotic monotherapy (perphenazine) did not find a statistically significant difference (RR=2.09, 95% CI 0.64–6.82; P=0.22).
We found two studies comparing antipsychotic monotherapy (olanzapine) with placebo (Rothschild et al, 2004). Pooling these studies did not show a statistically significant difference (RR=1.13, 95% CI 0.74–1.73; P=0.57).
In two studies the combination of an antidepressant (nortriptyline or amitriptyline) and an antipsychotic (perphenazine) was compared with antidepressant monotherapy (Spiker et al, 1985; Mulsant et al, 2001). Pooling these two studies did not show a statistically significant difference between a TCA plus an antipsychotic and a TCA alone (RR=1.44, 95% CI 0.86–2.41; P=0.16) (Fig. 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Underinvestigation of unipolar psychotic depression
That we identified only ten RCTs in psychotic depression illustrates that
this most severe form of depression is seriously underinvestigated. One
probable reason for this is that it is difficult to conduct RCTs in patients
with psychotic depression. These patients not only have a psychotic illness,
but often also are very anxious or physically ill. In addition, they are often
offered ECT directly because many clinicians assume that ECT is more effective
than pharmacotherapy. Patients with psychotic depressive illness may be unable
to give informed consent or may tend to withdraw from trials. Furthermore
– until the recent trials by Rothschild et al
(2004) – pharmaceutical
companies were not interested in conducting trials in psychotic depression
because this subgroup of depression is not considered a separate indication
for treatment by the regulatory authorities and therefore is commercially
unattractive.
Implications of the study
Despite the paucity of RCTs, a few clinically relevant conclusions can be
drawn. First, there is no evidence for the clinical belief that an
antidepressant alone is ineffective in psychotic depression. In seven of the
ten studies there was at least one treatment arm with an antidepressant as
monotherapy, with in total 11 treatment arms. In 5 of these treatment arms the
antidepressant was effective in more than 50% of the patients: imipramine in
Bruijn et al (1996)
and Van den Broek et al
(2004), sertraline in Zanardi
et al (1996) and
fluvoxamine and venlafaxine in Zanardi et al
(2000). In three studies there
was even a statistically significant difference between two antidepressants.
In two of these studies imipramine (under plasma level control) was more
effective than fluvoxamine (Van den Broek
et al, 2004) and mirtazapine
(Bruijn et al, 1996)
respectively, suggesting that a tricyclic antidepressant is to be preferred
over a non-tricyclic drug in patients with psychotic depression. This finding
is in line with three studies among hospitalised, depressed patients in which
clomipramine was found to be more effective than citalopram, paroxetine or
moclobemide respectively (Danish University Antidepressant Group,
1986,
1990,
1993). In these three studies
patients with psychotic depression were also included; unfortunately, however,
it is not possible to identify which patients these were, as this information
was not systematically recorded. In the third trial finding a difference
between two antidepressants (Zanardi
et al, 1996), more patients responded to sertraline than
to paroxetine, probably related to more patients withdrawing from the
paroxetine group. It is difficult to draw a conclusion from this study, as in
another study (Zanardi et al,
2000) the same group found good response rates to another SSRI,
fluvoxamine, as well as to venlafaxine.
Second, there is no evidence that the combination of an antidepressant with an antipsychotic is more effective than an antidepressant alone. Therefore, it can be concluded that the recommendation in the US and British guidelines (American Psychiatric Association, 2000; National Institute for Clinical Excellence, 2004) that in psychotic depression the combination therapy should be preferred over an antidepressant alone is not reliably evidence-based, if not necessarily incorrect. Clinically, the balance between risks and benefits may suggest that initial monotherapy with an antidepressant should be the preferred option for many patients.
Finally, there is evidence that the combination of an antidepressant with an antipsychotic is more effective than an antipsychotic alone. This was the major result of the study comparing amitriptyline plus perphenazine v. perphenazine alone (Spiker et al, 1985) and was also found in one of the studies comparing fluoxetine plus olanzapine v. olanzapine alone (Rothschild et al, 2004). Moreover, it was confirmed in the pooled analysis of these studies. Therefore, it is concluded that treatment should not begin with antipsychotic monotherapy.
Limitations of the study
Our review has several limitations. First, none of the studies with
antidepressant monotherapy had a sample size exceeding 25 patients per group.
The only two relative large studies were the studies sponsored by Eli Lilly
(Rothschild et al,
2004) with around 50 patients per group (olanzapine 48 and 53
patients, and placebo 51 and 49 patients respectively), but with fewer
patients in the group receiving olanzapine plus fluoxetine (25 and 23
respectively). As with all systematic reviews, publication bias is a
potentially serious source of error. There were too few studies –
especially too few larger studies – to investigate further the
possibility of publication bias, and so it cannot be ruled out. Additionally,
the relative high proportion of these small studies (5 out of 10) reporting a
significant difference between two treatments suggests publication bias.
Second, we could only use one outcome measure regarding efficacy: the response rates as defined by the authors. It was impossible to recalculate these response rates into a standard rate based on one definition (e.g. HRSD score), as many studies used different versions of the HRSD or actually reported only remission rates. As some of these authors’ response definitions may actually be considered remission, this might have had an influence on the results of our meta-analysis.
Finally, there was considerable clinical heterogeneity between the trials, illustrated by substantial differences in response rates to antidepressant monotherapy between the European and the US studies. Two Italian studies (Zanardi et al, 1996, 2000) reported high response rates (above 50%) to SSRIs (with the exception of paroxetine), and in the Dutch studies (Bruijn et al, 1996; Van den Broek et al, 2004) the response rate was above 50% to imipramine (but not to mirtazapine and fluvoxamine). In contrast, the US studies reported response rates below 50% (Spiker et al, 1985; Spiker & Kupfer, 1988; Mulsant et al, 2001). One likely reason for this US–European discrepancy is differences between the study populations. Although all studies required that patients fulfilled diagnostic criteria according to a specified diagnostic classification, the reliability of diagnosis may have been limited in some – if not most – of the trials. Only four trials used a semi-structured interview (Spiker et al, 1985; Bruijn et al, 1996; Mulsant et al, 2001; Van den Broek et al, 2004), and only one of these trials (Bruijn et al, 1996) reported the specific psychotic features for all patients. This leaves open the possibility that the conclusion that in a particular patient (for instance) a feeling of guilt was actually a delusion was drawn differently across the trials in this review. A similar problem may have played a part in the judgement as to whether a patient had a psychotic depression in the course of unipolar disorder or bipolar disorder.
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Clinical Implications and Limitations |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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American Psychiatric Association (2000) Practice Guideline for the Treatment of Patients with Major Depressive Disorder (Revision).Washington, DC: APA.
Bellini, L., Gasperini, M., Gatti, F., et al (1994) A double blind study with fluvoxamine vs. desipramine combined with placebo or haloperidol in delusional depression. Critical Issues in the Treatment of Affective Disorders, 9, 32 –36.
Bruijn, J. A., Moleman, P., Mulder, P. G., et al (1996) A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients. Psychopharmacology, 127, 231 –237.[Medline]
Danish University Antidepressant Group (1986) Citalopram: clinical effect profile in comparison with clomipramine. A controlled multicenter study. Psychopharmacology, 90, 131 –138.[CrossRef][Medline]
Danish University Antidepressant Group (1990) Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicenter study. Journal of Affective Disorders, 18, 289 –299.[CrossRef][Medline]
Danish University Antidepresasnt Group (1993) Moclobemide: a reversible MAO-A inhibitor showing weaker antidepressant effect than clomipramine in a controlled multicenter study. Journal of Affective Disorders, 28, 105 –116.[CrossRef][Medline]
Mulsant, B. H., Sweet, R. A., Rosen, J., et al (2001) A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. Journal of Clinical Psychiatry, 62, 597 –604.[Medline]
National Institute for Clinical Excellence (2004) Depression: Management of Depression in Primary and Secondary Care. Clinical Guideline 23. London: NICE.
Nelson, E. B. & McElroy, S. L. (1997) Psychotic depression: a guide to drug choice. CNS drugs, 8, 457 –473.
Rothschild, A. J., Williamson, D. J., Tohen, M. F., et al (2004) A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. Journal of Clinical Psychopharmacology, 24, 365 –373.[CrossRef][Medline]
Spiker, D. G.& Kupfer, D. J. (1988) Placebo response rates in psychotic and nonpsychotic depression. Journal of Affective Disorders, 14, 21 –23.[CrossRef][Medline]
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Van den Broek, W.W., Birkenhäger, T. K., Mulder, P. G. H., et al (2004) A double blind study comparing imipramine with fluvoxamine in depressed inpatients. Psychopharmacology, 175, 481 –486.[Medline]
Wijkstra, J., Lijmer, J., Balk, F., et al (2005) Pharmacological treatment for psychotic depression. The Cochrane Database of Systematic Reviews, Issue 4. article no. CD004044.pub2. doi: 10.1002/14651858.CD004044.pub2
Wheeler Vega, J. A., Mortimer, A. M., & Tyson, P. J. (2000) Somatic treatment of psychotic depression: review and recommendations for practice. Journal of Clinical Psychopharmacology, 20, 504 –519.[Medline]
Zanardi, R., Franchini, L., Gasperini, M., et al
(1996) Double-blind controlled trial of sertraline versus
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Zanardi, R., Franchini, L., Serrett, A., et al (2000) Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. Journal of Clinical Psychiatry, 61, 26 –29.
Received for publication February 25, 2005. Revision received May 23, 2005. Accepted for publication June 16, 2005.
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