Journal of Affective Disorders

Journal of Affective Disorders 123 (2010) 238 242 Contents lists available at ScienceDirect Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad Research report Long-term response to successful acute pharmacological treatment of psychotic depression Jaap Wijkstra a,, Huibert Burger b,c, Walter W. van den Broek d, Tom K. Birkenhäger d, Joost G.E. Janzing f, Marco P.M. Boks a,c, Jan A. Bruijn d,e, Marc L.M. van der Loos g, Leonie M.T. Breteler h, Robbert J. Verkes f, Willem A. Nolen i a Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands b Interdisciplinary Center for Psychiatric Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands c Julius Center for Health Sciences and Primary care, University Medical Center Utrecht, Utrecht, The Netherlands d Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands e GGZ Regio Breda, Breda, The Netherlands f Department of Psychiatry, Radboud University Nijmegen Medical Centre, The Netherlands g Department of Psychiatry, Isala Klinieken, Location Sophia, Zwolle, The Netherlands h Department of Psychiatry, St. Antonius-Mesos Hospital, Utrecht, The Netherlands i Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands article info abstract Article history: Received 23 August 2009 Received in revised form 12 October 2009 Accepted 13 October 2009 Available online 31 October 2009 Keywords: Depression Psychosis Treatment Pharmacology Background: Data about follow-up after acute pharmacological treatment of psychotic depression are scarce. Methods: A 4 month open follow-up was done, preferentially with same medication as during acute treatment, of patients (n=59) with DSM-IV-TR major depressive disorder with psychotic features, aged 18 to 65 years, who had completed as responders an acute doubleblind 7 week trial with imipramine, venlafaxine or venlafaxine plus quetiapine. Main outcome measures were Hamilton Rating Scale for Depression and Clinical Global Impression Scale. Results: Six patients dropped out during the 4 month follow-up. Almost all patients (86.4%; 51/59) remained responder while remission rate increased from 59.3% (35/59) to 86.8% (46/53), independent of treatment. Relapse rate was low (3.8%; 2/53). Tolerability was good. Weight increased with all treatments. Limitations: Limitations were the limited sample size and consequent limited statistical power. The treatment during follow-up was not double-blind. Conclusions: Continuation treatment with the same medication that was effective in the acute treatment trial, remained effective during the 4 month follow-up in many patients leading to further improvement, and was well tolerated. 2009 Elsevier B.V. All rights reserved. 1. Introduction Although 20% of patients with an episode of major depressive disorder met criteria for psychotic depression (Coryell et al., This study protocol was registered at: http://www.controlled-trials. com/isrctn/trial ISRCTN36607067. Corresponding author. University Medical Center Utrecht, HP B01.206, PO. Box 85500, 3508 GA, Utrecht, The Netherlands. E-mail address: j.wijkstra@umcutrecht.nl (J. Wijkstra). 1984; Johnson et al., 1991; Wheeler Vega et al., 2000; Ohayon and Schatzberg, 2002) we found in a meta-analysis (up to 2004) only 10 randomized, double-blind trials (RCTs) studying its treatment. In this meta-analysis the combination of an antidepressant and an antipsychotic was found significantly more effective than an antipsychotic alone (3 studies;188 patients) but not significantly more effective than an antidepressant alone (2 studies; 77 patients) (Wijkstra et al., 2005; 2006). After having achieved response in psychotic depression, relapse rates are probably high (Rothschild and Duval, 2003). 0165-0327/$ see front matter 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2009.10.014

J. Wijkstra et al. / Journal of Affective Disorders 123 (2010) 238 242 239 There are no double-blind studies on how to continue treatment after response. After response to antidepressant monotherapy, continuation with the same medication may be effective (Zanardi et al., 1997). However, it is unclear how to continue treatment after response to the combination of an antidepressant with an antipsychotic and for how long (Keck et al., 2000). As most relapses in psychotic depression appear to occur in the first 4 months after remission (Sackeim et al., 1990; Sackeim et al., 2001; Birkenhäger et al., 2005), continuation treatment should be at least 4 months. In a recent 7 week RCT comparing imipramine, venlafaxine and venlafaxine+quetiapine (Wijkstra et al., 2010) we found that significantly more patients responded to venlafaxine+quetiapine (27/41; 65.9%) than to venlafaxine alone (13/39; 33.3%), while the difference between venlafaxine+ quetiapine and imipramine (22/42; 52.4%) or between imipramine and venlafaxine was not statistically significant. Overall, tolerability was good. Weight increase was highest with venlafaxine+quetiapine. In this paper we report the results of a 4 month open continuation treatment of those patients who completed the acute trial as responder, with focus on the question as to what extent response and remission rates as well as tolerability were maintained during follow-up and whether this differed between treatment conditions. 2. Experimental procedures 2.1. Patients and study design The protocol of the acute trial has been described elsewhere (Wijkstra et al., 2010). In short, 122 patients with psychotic depression (SCID I, DSM-IV criteria) were randomized to a 7 week double-blind treatment with imipramine (plasma levels of 200 300ng/ml), venlafaxine (375 mg/day) or venlafaxine+ quetiapine (375 mg/day/600 mg/day). The present report concerns a 4 month follow-up among those patients who had achieved response ( 50% decrease and a final score 14 on the Hamilton Rating Scale for Depression 17-items (HAM-D) (Hamilton, 1960)). After the acute treatment phase (week 7) and after all data of that patient were monitored and entered into the database, patients and physicians were unblinded in order to inform the clinician how to proceed. Thus, all patients received open medication and it was advised to continue the same medication as in the acute treatment phase. During the 4 month follow-up, patients were seen after another 7 and 15 weeks (weeks 14 and 22). Severity of depressive symptoms was assessed using the HAM-D and the Clinical Global Impression (CGI) (Guy, 1976). Psychotic features, including whether they were mood-congruent or mood-incongruent, were documented as well. Vital signs were assessed, as were adverse events. The study was approved by the ethical review board and was performed according to the rules of Good Clinical Practice. All patients gave written informed consent. 2.2. Outcome measures The primary outcome measure was maintained response (maintaining 50% decrease in HAM-D score compared to baseline and a final HAM-D score of 14), while secondary outcome measures were remission rates (HAM-D 7) and relapse rates (<50% decrease in HAM-D scores compared to baseline or a HAM-D score of >14). Adverse events were measured on a 4-point scale (none light moderate severe). Because of the increasing importance of metabolic syndrome in patients treated with atypical antipsychotics, we also analyzed weight changes. 2.3. Statistical analysis Demographic and clinical characteristics of the study population at baseline (week 0) and start of follow-up (week 7) were described according to treatment condition. Next, maintenance of response and remission during follow-up were determined and expressed as percentages. The continuous HAM-D and CGI scores were calculated as change from week 7 to the first and second assessments during follow-up (weeks 14 and 22). Alterations in body weight during follow-up were calculated as change from baseline as well as from week 7 to week 22. Adverse events occurring during follow-up were considered present when they were of moderate or severe intensity and had shown an increase in severity from baseline to week 14 or to week 22 or from week 7 to week 14 or 22. The presence of any differences in baseline and outcome variables between treatment conditions was tested using Fisher's exact test for categorical variables and analysis of variance (ANOVA) for continuous variables. The significance level was set at 0.05, two sided. When a test yielded a p-value<0.05, post hoc pairwise comparisons were made using Bonferroni correction for multiple testing. For within subject mean changes in the continuous outcomes, we supplied a 95% confidence interval (95% CI). 3. Results 3.1. Patient disposition After the acute trial (week 7) there were 59 out of 122 (48.4%) patients who had completed the trial as responders: 20 in the imipramine group, 13 in the venlafaxine group and 26 in the venlafaxine+quetiapine group. Characteristics at baseline (week 0) and at week 7 of these 59 patients are summarized in Table 1. Although not statistically different, the groups showed differences in duration of the depressive episode and in hallucinations. Six patients (10.2%) dropped out during follow-up: in the imipramine group one before week 14 because of a depressive relapse with psychotic symptoms, one after week 14 (still a responder) refusing to continue medication because of sexual adverse effects, and one after week 14 because of delirium (cause unknown); in the venlafaxine group one patient after week 14 because of switch to mild mania; and in the venlafaxine+quetiapine group one patient before week 14 because of severe illness of her husband, and one after week 14 because of removal to another city (both patients were still in remission at the time of drop out). 3.2. Medication Most patients continued their study medication. At week 14, 54/57 patients (94.7%) were still using study medication

240 J. Wijkstra et al. / Journal of Affective Disorders 123 (2010) 238 242 Table 1 Characteristics at baseline (week 0) and at start of follow-up (week 7) of those patients who completed the acute trial as responders. Characteristics (n=20) (n=13) +quetiapine (n=26) Female, n (%) 9 (45) 4 (30) 15 (58) 0.27 Age, years, mean (SD) 52.0 (9.6) 53.7 (6.8) 49.5 (11.5) 0.44 Number of previous episodes, mean (SD) 1.0 (1.4) 0.4 (0.7) 0.9 (1.2) 0.33 At baseline (week 0) Duration (weeks) of current episode (SD) 23.4 (33.0) 15.3 (12.5) 43.3 (121.6) 0.56 HAM-D score, mean (SD) 31.4 (5.7) 30.6 (3.9) 31.3 (5.6) 0.91 CGI-severity score, mean (SD) 5.5 (0.6) 5.4 (0.5) 5.3 (1.1) 0.75 Hallucinations, n (%) 4 (20) 1 (8) 3 (12) 0.70 Delusions, n (%) 18 (90) 13 (100) 26 (100) 0.16 At start of follow-up (week 7) HAM-D score, mean (SD) 7.6(4.1) 4.5 (2.8) 6.3 (3.9) 0.09 CGI-severity score, mean (SD) 2.6 (1.3) 2.2 (1.3) 2.0 (1.0) 0.23 Hallucinations, n (%) 0 (0) 0 (0) 0 (0) Delusions, n (%) 1 (5) 1 (8) 1 (4) 1.00 SD: standard deviation; HAM-D: Hamilton Rating Scale for Depression 17-item; CGI: Clinical Global Impression. p-values are from Fisher's exact tests for categorical variables and from analysis of variance for continuous variables. p-value and at week 22 49/53 patients (92.5%). In the imipramine group one patient (remitter at week 7) changed to amitriptyline at week 10 (remaining remitter at week 22) and one patient (remitter at week 7) stopped imipramine at week 18 (remaining remitter at week 22), while two other patients got lithium added to the study medication (one responder at week 7 with a relapse at week 22 and one responder at week 7 remaining remitter at week 22). In the venlafaxine group one patient (remitter at week 7) got lithium added to venlafaxine before week 14 (remaining remitter at week 22), and one patient (remitter at week 7) stopped venlafaxine at week 18 (also remaining remitter at week 22). In the venlafaxine+quetiapine group one patient (remitter at week 7) stopped venlafaxine+quetiapine at week 15 (remaining at week 22) and in three patients (responders at week 7) quetiapine was changed to another antipsychotic (two becoming remitters and one remaining responder at week 22). The reasons for these changes are unknown. 3.3. Effectiveness Most patients remained responders (51/59, 86.4%), being 96.2% (51/53) of those who completed the follow-up: 16/17 (94%) on imipramine, 12/12 (100%) on venlafaxine and 23/24 (96%) on the combination (p=1.00). Thus, in addition to one relapse among the drop outs, two patients relapsed: one on imipramine and one on venlafaxine+quetiapine. Remission rate increased during follow-up from 35 out of 59 responders (59.3%) at weeks 7 to 46 out of 53 responders (86.8%) at week 22: 1517 (88%) on imipramine, 11/12 (92%) on venlafaxine and 20/24 (83%) on venlafaxine+quetiapine (p=0.88). The HAM-D decreased from week 7 to week 22 in all groups (imipramine 3.2 (95% CI 0.9 5.6) points, venlafaxine 2.1 (0.5 3.6), venlafaxine+quetiapine 1.8 points ( 0.6 4.1)). Decreases during follow-up were statistically significant except for the venlafaxine+quetiapine group, while there were no significant differences between treatment groups (p=0.61). For the CGI the same pattern was observed. Relapse rate was 2/53 (3.8%), one in the imipramine group and one in the combination group. 3.4. Psychotic features Neither at week 7 nor at weeks 14 and 22 did any of the patients have hallucinations. At week 7 three patients (5.1%, one in each group) still had a mood-congruent delusion, which had disappeared at week 14. Another two patients (3.4%) developed mood-congruent delusions between weeks 7 and 14: one of them was still in remission of his depression at week 22; the other patient dropped out at week 17 because of a switch to mild mania. 3.5. Adverse events (Table 2) Occurrence of adverse events was slightly lower than in the acute trial. Patients receiving venlafaxine+quetiapine in the acute treatment trial (n=122) had a significant greater (p<0.01) increase in weight (mean 3.8 kg; SD 4.0; all patients, LOCF) than patients receiving imipramine or venlafaxine (mean 0.4 kg; SD 3.0 and mean 0.5 kg; SD 4.0, respectively). During follow-up weight further increased in all groups. 4. Discussion The major finding of this study is that almost all patients (86.4%; 51/59) who had completed the acute double-blind trial as responders, remained responder after follow-up of another 15 weeks during which almost all of them (88.7%;47/53) continued the same medication. Relapse rate during these 4 months (3.8%; 2/53) was low and comparable with 0% relapse rates in previous studies (4 months continuation treatment with fluoxetine and perphenazine (Rothschild and Duval, 2003), and 6 months continuation treatment with fluvoxamine (Zanardi et al., 1997)). The effect on depression paralleled the effect on psychotic features. Almost all responders were also free of psychotic features, both at the end of the acute trial

J. Wijkstra et al. / Journal of Affective Disorders 123 (2010) 238 242 241 Table 2 Occurrence (%) of adverse events (at least moderate and in more than 10% of patients in any group) and weight changes among patients still using study medication compared to baseline (week 0) and to start of follow-up (week 7). Adverse events n=15 n=11 +quetiapine n=20 Compared to baseline (week 0) Cold hands 20.0 9.1 0 0.11 Constipation 20.0 18.2 10.0 0.67 Dry mouth 20.0 0 10.0 0.34 Restlessness 0 18.2 0 0.05 Somnolence 6.7 0 15.0 0.54 Strange taste 13.3 0 0 0.16 Transpiration 6.7 18.2 0 0.10 Other 6.7 27.3 5.0 0.14 Compared to start of follow-up (week 7) Cold hands 13.3 0 0 0.16 Constipation 13.3 18.2 10.0 0.86 Dry mouth 13.3 0 15.0 0.59 Somnolence 6.7 0 20 0.28 Strange taste 13.3 0 0 0.16 Transpiration 6.7 18.2 0 0.10 Other 6.7 18.2 5.0 0.44 Weight change n=14 n=11 +quetiapine n=19 Weight change, mean kg (95%CI) Week 0 week 7 1.4 ( 0.7; 3.5) 2.4 (0.5; 4.4) 5.2 (4.1; 6.3) 0.002 Week 7 week 22 5.3 (2.8; 7.9) 4.0 (0.2; 7.7) 5.0 (2.9; 7.1) 0.76 Week 0 week 22 6.7 (3.2; 10.3) 6.4 (1.4; 11.4) 10.1 (7.4; 12.9) 0.20 Weight increase >7% relative to week 0, n (%) Week 7 1 (7) 2 (18) 8 (42) 0.07 Week 22 8 (57) 6 (55) 16 (84.) 0.12 95% CI: 95% confidence interval. p-values are from Fisher's exact tests for categorical variables and from analysis of variance for continuous variables. Weight data are missing from 2 patients. p-values for pairwise comparisons are 1.000 (imipramine vs. venlafaxine), 0.002 (imipramine vs. venlafaxine +quetiapine) and 0.054 (venlafaxine vs. venlafaxine+quetiapine), corrected for multiple comparisons. p-value (94.9%) and at end of follow-up (96.3%). Thirty-five (59.3%) patients who completed the acute trial as responder, had also achieved remission. Remission rate increased among those who completed the follow-up (86.8%, 46/53), suggesting that after the first 7 weeks of treatment further improvement remains possible. Overall, the results during follow-up appeared not different between the three treatments, thus preserving only the difference already obtained during the acute trial. This suggests that continuation of treatment with the same medication (an antidepressant with or without an antipsychotic) on which acute response has been achieved, is sufficient. In general, tolerability during both the acute trial and followup was good. A problem however was weight gain: during the acute trial, weight increased in all groups, but especially in the combination group. During follow-up weight increased further, but now about the same in all three groups. From a clinical perspective, weight increase should therefore be a point of attention during acute treatment and during follow-up. Our study has two major limitations. First, due to limited sample size, the power to detect group differences was low and, consequently, the statistical test results must be interpreted with caution. Second, treatment during followup was not double-blind. Strength of the study is the relative low drop out rate and given the open and naturalistic design of this part of the study that most patients continued their study medication. Our study did not address the question whether the combination should be continued after response or that the antipsychotic might be tapered off. We are aware of only one open study by Rothschild and Duval (2003) which followed 30 patients with psychotic depression who had responded to a combination of fluoxetine and perphenazine. After 4 months they tapered perphenazine and found that 8 patients (27%) had a relapse with 2 months. This high relapse rate clearly illustrates that further studies addressing this question are warranted. In conclusion, the results of this open follow-up study are hopeful. Response achieved after 7 weeks acute treatment of patients with psychotic depression with imipramine, venlafaxine or venlafaxine+quetiapine, was maintained during the 4 month follow-up and medication was well tolerated, although weight increase appeared as a clinical problem. These results suggest that successful treatment either an antidepressant alone or the combination of an antidepressant with an antipsychotic should be continued for at least 4 months. Role of funding source The study was supported by grants from AstraZeneca and Wyeth Pharmaceuticals, both of which also provided the study medication. They had the opportunity to review the manuscript. AstraZeneca and Wyeth had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

242 J. Wijkstra et al. / Journal of Affective Disorders 123 (2010) 238 242 Conflicts of interest J. Wijkstra Grants: AstraZeneca, Wyeth Honoraria/Speaker's fees: AstraZeneca, Wyeth H. Burger Grants: Stanley Medical Research Institute W.W. van den Broek Grants: Hersenstichting Honoraria/Speaker's fees: Servier, Wyeth R.J. Verkes Grants: ZonMw, Astra Zeneca, Eli Lilly, Pfizer, Wyeth, Organon, NWO Honoraria/Speaker's fees: Astra Zeneca, Eli Lilly, Lundbeck, Wyeth, Organon, BMS Advisory boards: Eli Lilly, Servier, Organon, Lareb T.K. Birkenhäger Grants: Wyeth Honoraria/Speaker's fees: Wyeth, Servier J.G.E. Janzing Grants: Hersenstichting Honoraria/Speaker's fees: Bristol-Myers Squibb M.P.M. Boks Grants: ZonMw J.A. Bruijn None M.L.M. van der Loos Grants: GSK Honoraria/Speaker's fees: Astra Zeneca Advisory boards: BMS L.M.T. Breteler None W.A. Nolen Grants: Netherlands Organisation for Health Research and Development, Stanley Medical Research Institute, Astra Zeneca, Eli Lilly, GlaxoSmithKline, Wyeth Honoraria/Speaker's fees: Astra Zeneca, Eli Lilly, Pfizer, Servier, Wyeth Advisory boards: Astra Zeneca, Cyberonics, Eli Lilly, GlaxoSmithKline, Pfizer, Servier Acknowledgments The authors thank the following for their support: J.P. Selten, R. van Ojen,.I Klijn: independent psychiatrist for medication G. Hugenholtz, H. Wassens, C. Stuivenberg, T. Gerbranda: central distribution of medication F. Ververs: laboratory (plasma levels imipramine) E.A. Wijnia, K. Nijssen, J.W. van de Maaskant, Julius Center J. Verploegh, J. Leijtens: research nurses F. Kruisdijk, psychiatrist, Symfora, Amersfoort M.F. de Vries, L.J. Vos, I. Sommer, C. Schubart, UMC Utrecht N.P.J.T. van Schayk, I. Vosjan, I. van Geel, I. Kop, AstraZeneca H. Kornaat, M. Kanters-van Buren, E. Ides, M. Griekspoor, Wyeth AstraZeneca and Wyeth for financial support and providing the study medication. References Birkenhäger, T.K., Van den Broek, W.W., Mulder, P.G., De Lely, A., 2005. Oneyear outcome of psychotic depression after successful electroconvulsive therapy. J. ECT 21, 221 226. Coryell, W., Pfohl, B., Zimmerman, B.A., 1984. The clinical and neuroendocrine features of psychotic depression. J. Nerv. Ment. Dis. 172, 521 528. Guy, W., 1976. Clinical global impression. ECDEU Assessment Manual for Psychopharmacology, Revised. National Institute of Mental Health, Rockville. Hamilton,M.,1960.Aratingscalefordepression.J.Neurol.Neurosug.Psychiatry. 23, 56 62. Johnson, J., Horwath, E., Weisman, M.M., 1991. The validity of major depression with psychotic features based on a community study. Arch. Gen. Psychiatry 48, 1075 1081. Keck, P.E., McElroy, S.L., Strakowski, S.M., Soutullo, C.A., 2000. Antipsychotics in the treatment of mood disorders and risk of tardive dyskinesia. J. Clin. Psychiatry 61, 33 38. Ohayon, M.M., Schatzberg, A.F., 2002. Prevalence of depressive episodes with psychotic features in the general population. Am. J. Psychiatry 159, 1855 1861. Rothschild, A.J., Duval, S.E., 2003. How long should patients with psychotic depression stay on the antipsychotic medication? J. Clin. Psychiatry 64, 390 396. Sackeim, H.A., Prudic, J., Devanand, D.P., Decina, P., Kerr, B., Malitz, S., 1990. The impact of medication resistance and continuation pharmacotherapy on relapse following response to electroconvulsive therapy in major depression. J. Clin. Psychopharmacol. 10, 96 104. Sackeim, H.A., Haskett, R.F., Mulsant, B.H., Thase, M.E., Mann, J.J., Pettinati, H.M., Greenberg, R.M., Crowe, R.R., Cooper, T.B., Prudic, J., 2001. Continuation pharmacotherapy in the prevention of relapse following ECT. JAMA 285, 1299 1307. Wheeler Vega, J.A., Mortimer, A.M., Tyson, P.J., 2000. Somatic treatment of psychotic depression: review and recommendations for practice. J. Clin. Psychopharmacol. 20, 504 519. Wijkstra,J.,Lijmer,J.,Balk,F.J.,Geddes,J.R.,Nolen,W.A.,2005.Pharmacological treatment for psychotic depression. The Cochrane Database of Systematic Reviews. Issue 4. Art.No.: CD004044.pub2. OI:10.1002/14651858.CD004044. pub2. Wijkstra, J., Lijmer, J., Balk, F.J., Geddes, J.R., Nolen, W.A., 2006. Pharmacological treatment for unipolar psychotic depression: systematic review and meta-analysis. Br. J. Psychiatry 188, 410 415. Wijkstra, J., Burger, H., Van den Broek, W.W., Birkenhäger, T.K., Janzing, J.G.E., Boks, M.P.M., Bruijn, J.A., Van der Loos, M.L.M., Breteler, L.M.T., Ramaekers, G.M.G.I., Verkes, R.J., Nolen, W.A., 2010. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatrica Scand. Zanardi, R., Franchini, L., Gasperini, M., Smeraldi, E., Perez, J., 1997. Long-term treatment of psychotic (delusional) depression with fluvoxamine: an open pilot study. Int. Clin. Psychopharmacol. 12, 195 197.