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 Chapter 1 Introduction

3 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-

4 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,

5 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.

6 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

7 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.

8 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:

9 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

10 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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