University of Groningen. Pharmacological treatment of psychotic depression Wijkstra, Jakob

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1 University of Groningen Pharmacological treatment of psychotic depression Wijkstra, Jakob IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2010 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Wijkstra, J. (2010). Pharmacological treatment of psychotic depression: in search for evidence Utrecht: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Pharmacological treatment of psychotic depression In search for evidence Jaap Wijkstra

3 Cover design, type setting and layout: Proefschriftmaken Oisterwijk, the Netherlands Printed in the Netherlands by: Proefschriftmaken Oisterwijk, the Netherlands ISBN: Copyright: 2010 J. Wijkstra No part of this book may be reproduced in any form without permission of the author.

4 Rijksuniversiteit Groningen Pharmacological treatment of psychotic depression In search for evidence Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 13 januari 2010 om uur door Jakob Wijkstra geboren op 23 januari 1950 te Marum

5 Promotor Copromotor : Prof. Dr. W.A. Nolen : Dr. H. Burger Beoordelingscommissie : Prof. Dr. R.S. Kahn Prof. Dr. A.J.M. Loonen Prof. Dr. P. de Jonge

6 Contents Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Introduction Pharmacological treatment for unipolar psychotic depression Systematic review and meta-analysis Treatment of unipolar psychotic depression The use of evidence in practice guidelines Design of a randomized, double-blind, multicenter study with three treatment arms Treatment of unipolar psychotic depression A randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine Long-term response to successful acute pharmacological treatment of psychotic depression Treatment of unipolar psychotic depression An open study of lithium addition in refractory psychotic depression Summary and general discussion Samenvatting (Summary in Dutch) Dankwoord (Acknowledgements) List of publications Curriculum vitae

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8 Chapter 1 Introduction

9 10 Chapter 1 Psychotic depression In this thesis, the term psychotic depression is used to describe severe unipolar major depressive disorder accompanied by delusions and hallucinations, as reported in DSM-IV. The use of the term psychotic depression in this sense is relatively new; indeed, this generally accepted definition of psychotic depression 1 was first included in DSM-III, in Before then, the term psychotic depression was often used for endogenous depression or even melancholic depression. 3 The presence of psychotic features, such as hallucinations or delusions, was not considered a necessary component of psychotic, endogenous, or melancholic depression because the assumed biological cause of depression was considered more important than its phenomenology. Until 1980, the term delusional depression was mainly used for depression with delusions, and especially mood-congruent delusions. Hallucinations were considered insufficient grounds for the diagnosis delusional depression. Even when using the concept psychotic depression, it is still often difficult to distinguish between a depressive episode with psychotic features in the course of a bipolar disorder and a depressive episode with psychotic features in the course of a (recurrent) unipolar major depressive disorder. In the first major, and oftencitied, randomised double-blind study of patients with psychotic depression of Spiker et al, more than 20% of the patients had a bipolar disorder. 4 In DSM-III, psychotic depression is a subtype of major depressive episode, namely, a major depressive episode with psychotic features. These psychotic features can be both delusions and hallucinations. Interestingly, in the DSM-IV, the fifth-digit code of the classification makes a distinction between psychotic and non-psychotic features when classifying the severity of the episode, which can vary from mild and moderate, to severe without psychotic features and severe with psychotic features (with full or partial remission). Thus according to the DSM-IV, there is no such thing as a mild or moderate depressive episode with psychotic features. In addition, the fourthdigit code of the classification distinguishes between a depressive episode in the context of a unipolar major depressive disorder or a bipolar disorder. Even before 1980 there was discussion about whether psychotic depression was a severe form of depression or a distinct entity with a different cause, pathogenesis, and course. There was fervent support for both opinions. Those who supported the concept of psychotic depression being a distinct entity thought that it should be included in the DSM as a separate category. In comparison with non-

10 Introduction 11 psychotic depression, psychotic depression would be a more severe clinical entity, with more recurrences, longer episodes, hardly any response to placebo, a poorer response to antidepressants and a better response to antidepressants in combination with antipsychotics, a better response to electroconvulsive therapy (ECT), a greater familial burden of both depressive disorder and bipolar disorder, specific abnormalities in the pituitary adrenal axis, deviant findings on MRI and sleep EEG investigations, lower levels of serotonin metabolites in the CSF, and more frequent abnormal results in the dexamethasone suppression test. 5 Opponents of the distinct entity concept considered that these findings are also consistent with the view that psychotic depression is a more severe form of depression (APA, DSM-IV). The different operationalisations of psychotic depression make it difficult to interpret findings and results reported in the literature up to the mid-1980s. Thereafter, the DSM-III, DSM-III-R, and DSM-IV were used to classify patients in studies. However, even this classification has generated discussion. For example, an Italian study found monotherapy with a selective serotonin re-uptake inhibitor (SSRI) to be effective in a group of patients with DSM-III-R-diagnosed psychotic depression, 6 which prompted American authors to question whether the included patients did indeed suffer from psychotic depression. 7 Moreover, because mental health care and services differ substantially between different countries, it can be questioned to what extent the patients included in the various studies are similar. For example, an American study among patients with psychotic depression concerned mainly out-patients, 8 whereas the same diagnosis in the Netherlands in most cases leads to hospitalisation because of the difficult-to-assess increased risk of suicide. Moreover, nearly all of the patients of the American study responded within one week of treatment whereas this was not seen in the Dutch patients. This suggests that patient populations in the various studies are indeed different. Prevalence of psychotic depression It is not clear what proportion of patients with a (unipolar) depression have psychotic features. This question can be answered only if we can define depression (e.g. unipolar major depressive disorder) as well as psychotic features. The authors of the British NICE guideline on the treatment of depression emphasise that the main problem is the concept depression it is too heterogeneous and its validity is too limited. 9 Another important problem concerns what is understood by the terms delusion and hallucination. When are feelings of guilt overvalued ideas and when are they delusions? Depressed patients often express feelings of guilt and worry that they have done something wrong after all, depression colours how things or events are perceived and interpreted. In clinical practice, there is a smooth transition from worry to overvalued ideas, to delusional-type guilt feelings,

11 12 Chapter 1 and finally to definite delusions of guilt. Hallucinations are also not a clear-cut phenomenon. For example, what should be done with the patient who has heard sometimes as if voices inside his head for years, and who hears them now more often and with a more negative content since he or she became depressed? Using DSM-IV criteria, Ohayon and colleagues 10 reported in their population study a point prevalence of depressive disorder without psychotic features of 2% and a point prevalence of depressive disorder with psychotic features of 0.4%. Of patients with a depressive disorder, 18.2% also had psychotic symptoms. In hospitalised patients percentages of 20 25% has been found. 11,12 This difference is small, whereas one would expect that the prevalence would be much higher among hospitalised patients. These studies again raise the question whether delusions and hallucinations are diagnosed in the same way. Regardless of this, it can be concluded that psychotic depression is not uncommon, especially in clinical populations. Studies of the treatment of psychotic depression There have been few randomised controlled trials (RCTs) of the treatment of psychotic depression: we reviewed seven in our Cochrane review 13,14 and there have since been published three additional RCTs. 15,16,17 This relative lack of studies is probably due to a number of factors. The severity of the disorder makes it difficult to include patients in RCTs, and patients are often incapable of giving informed consent, partly because they are not competent to make the decision and partly because severe depression is accompanied by cognitive slowness and doubts so that some patients never reach at a decision about whether to participate or not. The legal representatives of patients, who are empowered to make such decisions, often find it difficult to view the patient s doubts and uncertainty as a symptom of depression. Moreover, they are often upset and concerned by the severity of the patient s symptoms and often do not dare to give their consent for inclusion in the trial. The decision is made even more difficult if the patient is not only doubtful but also suspicious. Randomisation is also a problem. The chance that the patient may be included in a possibly less effective treatment arm makes it difficult to agree to randomisation. The severe symptoms and suffering of affected individuals make patients, relatives, and often care professionals eager to do something as soon as possible. In the case of psychotic depression something is often medication or electroconvulsive therapy (ECT). An additional problem is that medication trials often require a medication-free period before the start of the trial. Most patients are already on, often poorly effective, medication, which has to be tapered off before the trial can start. This increases the risk of a further exacerbation of symptoms or the development of withdrawal symptoms.

12 Introduction 13 Another explanation for the paucity of RCTs is the difficulty of attracting financial support for trials involving these patients. To date, registration authorities and thus also the pharmaceutical industry appears not to consider psychotic depression an important separate indication warranting the development of a medication or apart licensing, and other potential sponsors, such as government or non-profit organisations, have doubts about the achievability of such studies, particularly about the possibility to recruit a sufficient number of patients. Treatment of psychotic depression The paucity of RCTs on the treatment of psychotic depression means that it is not known how these patients can best be treated. A major treatment option is ECT; it has been found a very effective treatment especially for depressed patients with psychotic features, particularly in the short term. 18 However, not all patients want to undergo ECT and not all patients respond to ECT. Moreover, according the the Dutch ECT guideline, medication is always needed after ECT, to diminish the likelihood of recurrence 18. The other treatment option is pharmacotherapy. However, there have been only a few RCTs of pharmacotherapy for psychotic depression, 13,14 and surprisingly, ECT has never been compared with pharmacotherapy in a RCT. Regarding pharmacotherapy, study of the literature of the last 25 years shows there to be four main options: antidepressant monotherapy, antipsychotic monotherapy, combination therapy with an antidepressant plus an antipsychotic, and initial treatment with an antidepressant followed by addition of an antipsychotic if response to the antidepressant is insufficient. In a meta-analysis of 44 studies, Parker et al 19 concluded that combination therapy was not significantly better that monotherapy with a tricyclic antidepressant (TCA). However, most of the studies included in that review had methodological shortcomings, such as open treatment and lack of randomisation. In another review, Coryell et al 20 came to the conclusion that a TCA plus an antipsychotic was the most effective treatment. Wheeler Vega et al 21 considered antidepressant monotherapy to be indicated for mild cases and an SSRI plus an antipsychotic agent or olanzapine or amoxapine (an antidepressant with antipsychotic properties) to be indicated for severe cases. In general, American studies, 1,8,20,22 tend to use combination therapy and have rejected monotherapy with an antidepressant. However, in recent years monotherapy with an antipsychotic has become more common. 23 As mentioned before, there is very little good evidence to support these treatment choices. 13,14 The various guidelines make cautious but sometimes also decided recommendations. The American guideline 22 considers combination therapy with an antidepressant and an antipsychotic alongside ECT to be indicated. The British

13 14 Chapter 1 guideline 9 advises considering adding an antipsychotic to an antidepressant. The Dutch multidisciplinary guideline 24 is the most cautious and recommends starting with an antidepressant, with the addition of an antipsychotic if the treatment response is not satisfactory. It can only be concluded that the current literature is not unanimous on the pharmacological treatment of psychotic depression, a conclusion also drawn by Nolen 25 with regard to the treatment of depression in his thesis published in He then recommended further investigation of the combination of an antidepressant and an antipsychotic, a recommendation that after many years led to the studies described in this thesis. Overview of the thesis What is the best treatment for patients with psychotic depression? The studies described in this thesis were performed in an attempt to answer this question. The background of these studies is described in chapter 1. There have been very few RCTs resulting in the situation that clinically relevant questions, such as whether the combination of an antidepressant plus an antipsychotic is more effective than monotherapy with an antidepressant, remained unanswered. The Cochrane review described in chapter 2 investigated the evidence for the pharmacological treatment of psychotic depression and concluded that there is insufficient evidence to support the preferred treatment used in clinical practice, namely, a combination of an antidepressant plus an antipsychotic. On the basis of this evidence, a good option would be to start treatment with an antidepressant, and to add on an antipsychotic if the treatment response is not satisfactory. The study described in chapter 3 evaluated the main treatment guidelines and the evidence supporting treatment recommendations. It appeared that most treatment recommendations are not evidence based, even though it is sometimes emphatically claimed that this is the case. Because the design of our proposed double-blind multicentre study with three treatment arms with one of the antidepressants dose-titrated, was complex, we searched the literature for similar experimental designs. Because of the lack of such studies in the literature, the design of this double-blind, randomised multicentre study is described in depth in chapter 4. The results of this study, which compared antidepressant monotherapy (imipramine or venlafaxine) with combination therapy with an antidepressant plus an antipsychotic (venlaflaxine and quetiapine), are presented in chapters 5, 6, and 7. The main findings are discussed in chapter 8, which closes with conclusions drawn on the basis of our findings. Finally, a summary is given in Dutch, as are the acknowledgements.

14 Introduction 15 References Carpenter LL, Price LH. Psychotic Depression: What Is It and How Should We Treat It? Harvard Rev Psychiatry 2000; 8:40-42 American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington DC: APA Kantor SJ, Glassman AH. Delusional depressions: natural history and response to treatment. Br J Psychiatry. 1977;131: Spiker DG, Cofsky Weiss J, Dealy RS et al. The pharmacological treatment of delusional depression. Am J Psychiatry 1985;142: Schatzberg AF, Rothschild AJ. Psychotic (delusional) major depression: should it be included as a distinct syndrome in DSM-IV? Am J Psychiatry 1992;149: Zanardi, R., Franchini, L., Gasperini, M, et al Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. American Journal of Psychiatry 1996;153: Rothschild AJ, Phillips KA. Selective serotonin reuptake inhibitors and delusional depression. (letter) Am J Psychiatry1999;156: (With reply) 8. Rothschild AJ, Williamson DJ, Tohen MF et al. A double-blind, randomized study of olanzapine and olanzapine/fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 2004;24: National Institute for Clinical Excellence. Depression: management of depression in primary and secondary care (Clinical Guideline 23) 2004 Ohayon MM, Schatzberg AF. Prevalence of depressive episodes with psychotic features in the general population. Am J Psychiatry 2002;159: Coryell W, Pfohl B, Zimmerman BA. The clinical and neuroendocrine features of psychotic depression. J Nerv Ment Dis 1984;172:

15 16 Chapter Johnson J, Horwath E, Weisman MM. The validity of major depression with psychotic features based on a community study. Arch Gen Psychiatry 1991;48: Wijkstra J, Lijmer J, Balk FJ et al. Pharmacological treatment for psychotic depression. The Cochrane Database of Systematic Reviews. 2005; Issue 4. Art. No.: CD pub2. OI: / CD pub2 Wijkstra J, Lijmer J, Balk FJ et al. Pharmacological treatment for unipolar psychotic depression: Systematic review and meta-analysis. Br J Psychiatry 2006;188: Künzel HE, Ackl N, Hatzinger M et al. Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol - A double-blind multicenter trial. J Psychiatr Res. 2008; Nov 25. [Epub ahead of print] 16. Meyer BS, Flint AJ, Rothschild AJ et al. A double-blind randomized controlled trial of olanzapine plus sertraline versus olanzapine plus placebo for psychotic depression - The STOP-PD study. Arch Gen Psychiatry 2009; submitted Wijkstra J, Burger H, Van den Broek WW et al. Journal of Clinical Psychiatry. Treatment of Unipolar Psychotic Depression. A randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psych Scandinavica 2009; submitted Nederlandse Vereniging voor Psychiatrie. Richtlijn ECT 2009 Parker G, Roy K, Hadzi-Pavlovic D et al. Psychotic (delusional) depression: a meta-analysis of physical treatments. J Affect Disord 1992;24:17-24 Coryell W. The treatment of psychotic depression. J Clin Psychiatry 1998;59(suppl 1):22-27;discussion Wheeler Vega JA, Mortimer AM, Tyson PJ. Somatic treatment of psychotic depression: review and recommendations for practice. J Clin Psychopharm 2000;20: American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision) 2000

16 Introduction Rothschild AJ. Challenges in the treatment of depression with psychotic features. Society Biol Psychiatry 2003;53: Dutch National Steering Committee Multidisciplinary Guideline Development Mental Health (Landelijke stuurgroep Multidisciplinaire Richtlijnontwikkeling in de GGZ) Multidisciplinary Guideline Depression. Trimbos-instituut. ISBN Nolen WA. Behandeling van depressie, strategieën bij de keuze van antidepressiva en andere biologische behandelmethoden. Academisch Proefschrift Leiden (thesis) 1986;Van Gorcum, Assen

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18 Chapter 2 Pharmacological treatment for unipolar psychotic depression Systematic review and meta-analysis Jaap Wijkstra MD, 1 Jeroen Lijmer MD PhD, 2 Ferdi J Balk MD, 1 John R Geddes MD FRCPsych, 3 Willem A Nolen MD PhD. 4 1 Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands 2 Department of Psychiatry, Waterland Hospital, Purmerend, The Netherlands 3 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, OX3 7JX, United Kingdom 4 University Medical Center Groningen, Department of Psychiatry, Groningen, The Netherlands The British Journal of Psychiatry (2006) 188:

19 20 Chapter 2 Abstract Objective: The optimal pharmacological treatment of unipolar psychotic depression is uncertain. Method: Systematic review and meta-analysis of randomised controlled trials (RCT). 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. Conclusion: 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 harms may suggest the first option should be preferred for many patients. Starting with an antipsychotic alone appears to be inadequate.

20 Systematic review and meta-analysis 21 Introduction For unipolar psychotic depression, in which psychotic features appear in the context of a major depressive episode, electroconvulsive therapy (ECT) is considered by many clinicians to be the most effective and therefore the first line treatment. Pharmacotherapy is also often considered a suitable first line treatment, because many patients prefer drug therapy to ECT, and moreover, after a successful course of ECT subsequent treatment with medication is often needed to prevent relapse. If the choice is pharmacotherapy, it is unclear whether one can start with an antidepressant alone or should combine it with an antipsychotic. Some reviews suggest that one may consider antidepressant monotherapy before adding an antipsychotic. 1,2 However, recent US and British guidelines recommend the combination. 3,4 We report a systematic review of the evidence regarding the pharmacological treatment of unipolar psychotic depression. Method This review was performed as a Cochrane systematic review in co-operation with the Cochrane Collaboration Depression, Anxiety and Neurosis group, London, United Kingdom. 5 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 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: Participants We included RCTs investigating patients in any setting (in-patients and out-patients) 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 nonbipolar depression group were reported separately or if the percentage of patients with bipolar depression did not exceed 20% of the total study population.

21 22 Chapter 2 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 (CEN- TRAL) 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 JW and JL, 50% by both FB and WN) and studies were selected if they met the following criteria: (a) the study was a randomised controlled trial; (b) included patients with a major depressive disorder; (c) investigated the effectiveness of pharmacological treatment; and (d) concerned acute phase treatment. 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 these 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 number of 60 articles were also screened by JW, which revealed no publications 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 via personal communication. In step 3, two authors (JW, FB) independently reviewed

22 Systematic review and meta-analysis 23 all identified publications according to the inclusion criteria. Any disagreement was resolved by consensus discussion with another co-author (WN). Quality assessment Two reviewers (JW and JL) assessed the methodological quality of the included trials, according to the criteria of the Cochrane Collaboration. These criteria focus on randomisation procedure (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 psychotic v. non-psychotic patients in the RCTs which had not the treatment of psychotic depression as 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 from baseline in score on the HRSD or observer depression severity rating 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 participant s characteristic, diagnosis (diagnostic instrument, classification), intervention details, and outcome measures. Data were extracted independently by two reviewers (JW and JL). Data analysis Data were entered into RevMan 4.2. For binary efficacy outcomes a relative risk (with 95% confidence intervals) was calculated for each comparison. When neces-

23 24 Chapter 2 sary, 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. Results Description of the studies From the search in the Cochrane Central Register of Controlled Trials (CENTRAL) we identified 1782 publications. The searches in MEDLINE and EMBASE resulted in 720 and 831 publications, respectively. The first step of screening the abstracts of these publications resulted in 789 publications (749 from CENTRAL, 38 from MEDLINE, and 11 from EMBASE). The second step of screening the full articles resulted in the identification of 52 publications (47, 3 and 2 respectively). Handsearching of reference lists of relevant reviews resulted in one further publication, 6 whereas hand-searching of the included publications revealed in no other publication. The third step of reviewing these 53 publications resulted in seven included studies. Finally, we added two other publications from which we knew were then in press: one by Van den Broek et al 7 and one by Rothschild et al 8 reporting two similar trials. Thus, nine publications with a total of ten RCTs were included. (See table 1)

24 Systematic review and meta-analysis 25 Table 1 Characteristics of randomised, controlled trials of pharmacological treatment for psychotic depression Study and year N Randomisation/ Blinding Drug comparison Dose (blood level) Additional medication Treatment period Diagnosis Outcome Anton et al, 46 Not described/ Described Amoxapine vs amitriptyline + perphenazine mg versus mg mg. No blood levels. Lorazepam, oxazepam in low dose 4 weeks DSM-III: psychotic depressive episode > 50% reduction in Hamilton Rating Scale of Deprssion-17 Bruijn et al, 30 Not described/ Described Imipramine versus mirtazapine 37,5-450 mg ( ng/ml) vs mg (49-93 ng/ml) Valerian, lorazepam 1-5 mg, haloperidol 1-15 mg a day 4 weeks after reaching predefined blood levels DSM-III-R: depressive episode Subgroup: psychotic 50% reduction in HRSD-17 Mulsant et 36 Not described/ al, Described Nortriptyline vs nortriptyline + perphenazine Mean: 76 mg (101 ng/ml) vs 63 mg (120 ng/ml) + 19 mg (4 ng/ml) Lorazepam as needed After randomisation 2-16 weeks (at least 4 weeks) DSM-III-R: psychotic major depressive disorder HRSD-17 < 11 + Brief Psychiatric Raring Scale (11,12,15) 1 or 2 Rothschild et al, 2004 a Not described/ Not described Olanzapine vs olanzapine + fluoxetine Mean: 11.9 mg vs 12.4 mg mg vs placebo No blood levels 30 mg a day diazepam 8 weeks DSM-IV: major depression with psychotic features 50% reduction in HRSD-24 Rothschild et al, 2004 b Not described/ Not described Idem Mean: 14.0 mg vs 13.9 mg mg Idem Idem Idem Idem Described Spiker et al, 58 Partly described/ Perphenazine vs amitriptyline vs amitriptyline + perphenazine Mean 50 mg ( ng/ ml ) vs 218 mg (ami + nor ng/ml) vs 170 mg ( ng/ml) + 54 mg ( ng/ml) Benztropine mesylate 4 mg 4 weeks SADS and RDC major depressive disorder (only with delusions). HRSD-17 < 7 + Delusional Rating Score = 1 (6 point scale in the Schizophrenia and Affective Disorder Scale).

25 26 Chapter 2 Study and year N Randomisation/ Blinding Dose (blood level) Additional medication Treatment period Diagnosis Outcome Spiker et al, 27 Not described/ Described Drug comparison Amitriptyline versus placebo 3 days 50; 4 days 100; 7 days 150, 14 days 200 mg. No blood levels None 4 weeks (at least 3 weeks 150 mg) DSM III: major depressive disorder HRSD-17 <7 + not psychotic or = 6,5-9,5 + not psychotic + 1/3 entering score Van den Broek et al, Described/ Described Imipramine vs fluvoxamine mg (imi + desimi ng/ml). Vs mg ( ng/ml). Valerian, lorazepam 1-3 mg, haloperidol 1-10 mg a day 4 weeks after reaching predefined blood levels DSM-IV: major depressive disorder Subgroup: psychotic 50% reduction in HRSD-17 Zanardi et 32 Not described/ al, Not described Sertraline versus paroxetine 150 mg vs 50 mg from day 8. No blood levels Flurazepam <30 mg 5 weeks DSM-III-R: psychotic depressive episode HRSD-21 < 8 + not psychotic Zanardi et 22 Not described/ al, Not described Venlafaxine versus fluvoxamine 300 mg versus 300 mg. No blood levels Flurazepam <30 mg 5 weeks DSM-III-R: psychotic depressive episode HRSD-21 < 9 + not psychotic BPRS, Brief Rating Scale; HRSD, Hamilton Rating Scale for Depression; RDC, Research Diagnostic Criteria; SADS, Schedule for Affective Disorders and Schizophrenia

26 Systematic review and meta-analysis 27 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. 7,9,10 Five RCT did not include only patients with unipolar psychotic depression. In the study by Zanardi et al 11 it was possible to exclude the data relating to participants with bipolar disorder. The study by Anton & Burch 12 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 % of the patients in the results had bipolar disorder. In Bruijn et al 10 and Zanardi et al 14 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 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 & Buch 12 8 patients who left the study before receiving a 2 full weeks of active medication; 9 and 3 patients, respectively from the studies of Bruijn et al 10 and Van den Broek et al 7 who were treated with haloperidol; from the study of Mulsant et al 15 6 patient who left the trial after randomisation; 7% and 9% of the randomised patients respectively from the two trials of Rothschild et al, 8 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 13 and Spiker & Kupfer. 9 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, 7,8,9,10,12,13,15 and in the two other studies 11,14 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; 7,12,13,15 in three other studies these data were not based on an intention-to-treat analysis, 8,8,9 were not available in one study (SK 1988) and were the same as the overall withdrawal rates in two studies. 11,14 Withdrawals specifically owing to death or suicide were not reported in any of the studies.

27 28 Chapter 2 Efficacy analyses Only one RCT compared an antidepressant with a placebo. 9 In this study amitriptyline was not statistically significantly more effective than placebo (RR 8.40, 95% CI , P=0.14). In four studies, two different antidepressants were compared directly. In one study, 10 imipramine under plasma level control was statistically significantly more effective than mirtazapine (RR 3.00, 95% CI , P=0.05). In another, 7 imipramine under plasma level control was statistically significantly more effective than fluvoxamine (RR 2.10, 95% CI , P=0.03). In the first study by Zanardi et al 11 sertraline was statistically significantly more effective than paroxetine (RR 3.37, 95% CI , P=0.02); the second study by Zanardi et al, 14 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 to an antidepressant of another class (mirtazapine or fluvoxamine). After pooling these studies, 7,10 imipramine was statistically significant superior to the non-tca (RR 2.36, 95% CI , P=0.004) (Fig. 1). In three RCTs selective serotonin reuptake inhibitors (SSRI) were studied. Response rates to these SSRIs varied from 21.4% (paroxetine 11 ) and 30.4% (fluvoxamine 7 ) to 72.2% (sertraline 11 ) and 81.8% (fluvoxamine 14 ). In one of these studies 11 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 13 comparing antidepressant monotherapy (amitriptyline) with antipsychotic monotherapy (perphenazine) did not find a statistically significant difference (RR 2.09, 95% CI , P=0.22). We found two studies comparing antipsychotic monotherapy (olanzapine) with placebo. 8 Pooling these studies did not show a statistically significant difference (RR 1.13, 95% CI , P=0.57). In two studies the combination of an antidepressant (nortriptyline or amitriptyline) and an antipsychotic (perphenazine) was compared with antidepressant monotherapy. 13,15 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 , P=0.16) (Fig. 2).

28 Systematic review and meta-analysis 29 Review: Pharmacological treatment for psychotic depression Comparison: TCA versus non -TCA Outcome: Study defined outcome Study TCA Non-TCA RR (fixed) Weight RR (fixed) n/n n/n 95% CI % 95% CI Bruijn et al, /15 3/ [1.01, 8.95] Van den Broek et al, /25 7/ [1.06, 4.17] Total (95% CI) [1.32, 4.23] Total events: 25 (TCA), 10 (Non -TCA) Test for heterogeneity: Chi = 0.29, df = 1 (P = 0.59), I = 0% Test for overall effect: Z = 2.90 (P = 0.004) Favours non -TCA Favours TCA Figure 1 Efficacy of an tricyclic antidepressant (TCA) monotherapy v. non-tricyclic antidepressant (non-tca) monotherapy Review: Pharmacological treatment for psychotic depression Comparison: TCA + CAP versus TCA Outcome: Study defined outcome Study TCA + CAP TCA RR (fixed) Weight RR (fixed) n/n n/n 95% CI % 95% CI Spiker et al, /22 7/ [0.89, 3.37] Mulsant et al, /17 7/ [0.49, 2.53] Total (95% CI) [0.86, 2.41] Total events: 21 (TCA + CAP), 14 (TCA) Test for heterogeneity: Chi = 0.65, df = 1 (P = 0.42), I = 0% Test for overall effect: Z = 1.39 (P = 0.16) Favours TCA FavoursTCA+CAP Figure 2 Efficacy of the combination of an tricyclic antidepressant (TCA) + a classical antipsychotic (CAP) versus TCA monotherapy

29 30 Chapter 2 In three studies the combination of an antidepressant and an antipsychotic was compared with antipsychotic monotherapy. In one of these studies 13 the combination of amitriptyline plus perphenazine was statistically significantly superior to perphenazine alone (RR 3.61, 95% CI , P=0.02). In the other two studies comparing the combination of olanzapine plus fluoxetine 8 with olanzapine alone, pooling resulted in a significant advantage for the combination over the antipsychotic alone (RR 1.64, 95% CI , P=0.01) and over placebo (RR 1.86, 95% CI , P=0.003). Pooling the data from all three studies comparing the combination of an antidepressant plus an antipsychotic with an antipsychotic alone showed a statistically significant difference favouring the combination (RR 1.92, 95% CI , P=0.0007) (Figure 3).

30 Systematic review and meta-analysis 31 Review : Pharmacological treatment for psychotic depression Co mparison: AP + AD versus AP Outcome: Study defined outcome Study AP + AD AP RR (fixed) Weight RR (fixed) n/n n/n 95% CI % 95% CI Spiker et al, /22 3/ [1.23, 10.56] Rothschild et al, /25 15/ [1.04, 3.09] Rothschild et al, /23 17/ [0.84, 2.66] Total (95% CI) [1.32, 2.80] Total events: 39 (antipsych+antidepr), 35 (antipsychotics) Test for heterogeneity: Chi = 2.11, df = 2 (P = 0.35), I = 5.4% Test for overall effect: Z = 3.38 (P = ) Favours AP Favours AP + AD Figure 3 Efficacy of the combination of an antipsychotic (AP) + an antidepressant (AD) versus antipsychotic monotherapy

31 32 Chapter 2 Other analyses The rates of withdrawal from the studies varied from 9% to 41%. In the two multicentre trials with olanzapine/fluoxetine 8 the rate was 102 out of 249 (41%), and these authors reported even higher non-completion rates (completers: 110 out of 249 = 44%, thus the non-completion rate was 56%). There was no statistically significant difference in the overall dropout rates between any of the treatments, either in individual studies or after pooling of studies. Discussion Despite our extensive search of the literature, we identified very few RCTs investigating the pharmacological treatment of patients with a unipolar major depressive episode with psychotic features (psychotic depression). In addition to seven trials 8,8,11,12,13,14,15 in which the treatment of patients with a psychotic depression was the major focus of the study, we were able to find three other trials, 7,9,10 that reported on the effects in a subgroup of patients with psychotic depression separately. The authors of two of these studies of both psychotic and non-psychotic depression provided us with additional information on the results in the subgroups of patients with psychotic depression. Because of the numbers involved, we were not able to approach the authors of all RCTs comprising depressed patients to request similar information. However, if data from other RCTs on the subgroup of people with psychotic depressions are available, we invite the authors of these trials to provide us with the relevant data, so that we may update this systematic review. 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 a psychotic depression. These patients not only have a psychotic illness, but often also 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 also be unable to give informed consent or may tend to withdraw from trials. Furthermore - until the recent trials by Rothschild et al 8 - 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 commercially unattractive.

32 Systematic review and meta-analysis 33 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 7, imipramine, 10 sertraline, 11 fluvoxamine as well as venlafaxine. 14 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 7 and mirtazapine 10 respectively, suggesting that a tricyclic antidepressant is to be preferred over non-tricyclic drug in patients with a psychotic depression. This finding is in line with the three Danish studies among hospitalised depressed patients in which clomipramine was more effective than citalopram, 16 paroxetine 17 or moclobemide, 18 respectively. 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, 11 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 14 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 3 and British 4 guidelines that in psychotic depression the combination should be preferred over an antidepressant alone is not reliably evidence based, if not necessarily incorrect. Clinically, the balance between risks and harms 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 13 and was also found in one of the studies comparing fluoxetine plus olanzapine v. olanzapine alone. 8 Moreover, it was confirmed in the pooled analysis of these studies. Therefore, it is concluded that one should not start with antipsychotic monotherapy. Limitations Our review has several limitations. First, none of the studies with antidepressant monotherapy had a sample size exceeded 25 patients per group. The only two rela-

33 34 Chapter 2 tive large studies were the studies sponsored by Eli Lilly 8 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 response rate based on one definition (e.g. HRSD- 17 scores), as many studies used other 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 11,14 reported high responses rates (above 50%) to SSRIs (with the exception of paroxetine), and in both the Dutch studies 7,10 the response rate was above 50% to imipramine (but not to mirtazapine and fluvoxamine). In contrast, the US studies reported response rates below 50%. 9,13,15 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, 7,10,13,15 and only one of these trials 10 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. Acknowledgements The authors are grateful for the support from the Cochrane Collaboration Depression, Anxiety and Neurosis Group. We thank Dr. J. Bruijn, Dr. W.W. van den Broek and Dr. R. Zanardi for additional data from their studies.