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Institute for Response-Genetics (e.V.)

Prof. Dr. Hans H. Stassen, Chairman

(Formerly Associated Institute of the University of Zurich)

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Improvement under Imipramine and Moclobemide versus Placebo

Response Criteria

The onset of action of antidepressant drugs was investigated on the basis of two independent multicenter, double-blind efficacy studies comparing amitriptyline (N=120), oxaprotiline (N=120), imipramine (N=506) and moclobemide (N=580) with placebo (N=189+191). The samples consisted of in- and out-patients diagnosed, according to DSM-III criteria, as suffering from major depressive disorder. Measures of efficacy were the Hamilton Depression (HAMD), Hamilton Anxiety (HAMA) and Zung Self-Rating scales. By using the "sustained relative improvement" criterion, onset of action was determined in each individual patient as that time point in the 30 day observation period, at which a 20% baseline score reduction was achieved without subsequent deterioration beyond achieved improvement score. Analogously, response to treatment was defined as sustained 50% baseline score reduction. Highly significant differences between active drugs and placebo were found with respect to the total number of improvers and responders.

Differences Between Treatment Modalities

Significant differences between treatment modalities surfaced in the percentage rate as well as the time distribution of premature withdrawals. Yet unexpectedly, among improvers, the time spans to onset of improvement turned out to be independent of treatment modality as indicated by virtually identical cumulative percentages of improvers over the full observation period. The picture was essentially the same for the HAMA and ZUNG assessments, except for a significant time lag between observer- and self-ratings. In particular, our analyses revealed no evidence for a delayed onset of action under various antidepressants with large biochemical and pharmacological differences in comparison to placebo. Moreover, the early onset of improvement was highly predictive of later outcome: on average, 70% of patients showing improvement within the first 14 days became responders.

Therapeutic Qualities of Antidepressants

Applying survical-analytical methods, we found that differences between active treatments and placebo emerged within the first 5 days and reached a point of maximum distinction around day 14. After this time point, differences between treatment modalities remained constant until the end of the observation period. According to our data, 20-25% of patients were, on average, "true" drug responders, thus suggesting that the therapeutic qualities of antidepressants does not lie in the suppression of symptoms, but rather related to their ability to elicit and maintain certain conditions which enable recovery in a subgroup of patients who would otherwise remain non-responders.

References

Stassen HH, Bachmann S, Bridler R, Cattapan K, Herzig D, Schneeberger A, Seifritz E: Detailing the Effects of Polypharmacy in Psychiatry: Longitudinal Study of 320 Patients Hospitalized for Depression or Schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2021 [submitted for publication]
Moragrega I, Bridler R, Mohr C, Possenti M, Rochat D, Sanchez Parramon J, Stassen HH: Monitoring Mental Health and the Effects of Therapeutic Interventions through Self-Assessment Voice Analyses. Res Psychother. 2021 [submitted for publication]
Stassen HH, Bachmann S, Bridler R, Cattapan K, Herzig D, Schneeberger A, Seifritz E. Inflammatory Processes linked to Major Depression and Schizophrenic Disorders and the Effects of Polypharmacy in Psychiatry: Evidence from a longitudinal Study of 279 Patients under Therapy. Eur Arch Psychiatry Clin Neurosci. 2021; 271(3): 507-520 [get the article]
Pollak TA, Lennox B, Müller S, Benros ME, Prüss H, Tebartz van Elst L, Klein H, Steiner J, Frodl T, Bogerts B, Tian L, Groc L, Hasan A, Baune BT, Endres D, Haroon E, Yolken R, Benedetti F, Halaris A, Meyer J, Stassen H, Leboyer M, Fuchs D, Otto M, Brown DA, Vincent A, Najjar S, Bechter K: An international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin: the concept of autoimmune psychosis. Lancet Psychiatry 2020; 7(1): 93-108
Zhang M, Bridler R, Mohr C, Moragrega I, Sun N, Xu Z, Yang Z, Possenti M, Stassen HH: Early Detection of the Risk of Developing Psychiatric Disorders: A Study of 461 Chinese University Students under Chronic Stress. Psychopathology 2019; 52(6): 367-377 [get the article]
Bhake R, Kluckner V, Stassen HH, Russell GM, Leendertz J, Stevens K, Linthorst ACE, Lightman S: Continuous Free Cortisol Profiles — Circadian Rhythms in Healthy Men. J Clinical Endocrinology & Metabolism 2019; 104(12): 5935-5947
Stassen HH, Bachmann S, Bridler R, Cattapan K, Herzig D, Höppner K, Schneeberger A, Seifritz E, Wirth A, M. Weisbrod M: Polypharmacy in Psychiatry: Unwanted Side Effects and Inflammatory Response System — A Naturalistic Study of 195 Patients under Treatment. Eur Neuropsychopharmacology 2019; 29 Suppl 1: S345
Greil W, Zhang X, Stassen HH, Grohmann R, Bridler R, Hasler G, Toto S, Bleich S, Kasper S: Cutaneous adverse drug reactions to psychotropic drugs and their risk factors — a case-control study. Eur Neuropsychopharmacol. 2019; 29(1): 111-121 [get the article]
Stassen HH: Heterogeneity of schizophrenic disorders and link to chronically elevated IgM values. Neurology, psychiatry and brain research 2018; 29: 23-24
Stassen HH, Braun S, Bridler R, Seifritz E, Weisbrod M: Inflammatory Processes and Schizophrenia: Evidence from a Twin Study. Eur Neuropsychopharmacology 2017; 27 Suppl 4: S934-S935
Braun S, Bridler R, Müller N, Schwarz MJ, Seifritz E, Weisbrod M, Zgraggen A, Stassen HH: Inflammatory Processes and Schizophrenia: Two Independent Lines of Evidence from a Study of Twins Discordant and Concordant for Schizophrenic Disorders. European Archives of Psychiatry and Clinical Neuroscience 2017; 267: 377-389 [get the article]
Braun S, Annovazzi C, Botella C, Bridler B, Camussi E, Delfino JP, Mohr C, Moragrega I, Papagno C, Pisoni A, Soler C, Seifritz E, Stassen HH: Assessing Chronic Stress, Coping Skills and Mood Disorders through Speech Analysis. A Self-Assessment "Voice App" for Laptops, Tablets, and Smartphones. Psychopathology 2016; 49(6): 406-419 [get the article]
Delfino JP, Barragán E, Botella C, Braun S, Bridler R, Camussi E, Chafrat V, Lott P, Mohr C, Moragrega I, Papagno C, Sanchez S, Seifritz E, Soler C, Stassen HH: Quantifying Insufficient Coping Behavior under Chronic Stress. A cross-cultural study of 1,303 students from Italy, Spain, and Argentina. Psychopathology 2015; 48: 230-239
Mohr C, Braun S, Bridler R, Chmetz F, Delfino JP, Kluckner VJ, Lott P, Schrag Y, Seifritz E, Stassen HH: Insufficient Coping Behavior under Chronic Stress and Vulnerability to Psychiatric Disorders. Psychopathology 2014; 47: 235-243
Stassen HH, Delfino JP, Kluckner VJ, Lott P, Mohr C: Vulnerabilität und psychische Erkrankung. Swiss Archives of Neurology and Psychiatry 2014; 165(5): 152-157
Giegling I, Balzarro B, Porcelli S, Schäfer M, Hartmann AM, Friedl M, Konte B, Krämer P, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: Influence of ANKK1 and DRD2 polymorphisms in response to haloperidol. Eur Arch Psychiatry Clin Neurosci. 2013; 263(1): 65-74
Bridler R, Orosz A, Cattapan K, Stassen HH: In Need of Psychiatric Help - Leave a Message after the Beep. Psychopathology. 2013; 46(3): 201-205
Drago A, Giegling I, Schäfer M, Hartmann AM, Friedl M, Konte B, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: AKAP13, CACNA1, GRIK4 and GRIA1 genetic variations may be associated with haloperidol efficacy during acute treatment. Eur Neuropsychopharmacol. 2013; 23(8): 887-894
Drago A, Giegling I, Schäfer M, Hartmann AM, Möller HJ, De Ronchi D, Stassen HH, Serretti A, Rujescu D: No association of a set of candidate genes on haloperidol side effects. PLoS One. 2012; 7(10): e44853
Giegling I, Drago A, Dolzan V, Plesnicar BK, Schäfer M, Hartmann AM, Sander T, Toliat MR, Möller HJ, Stassen HH, Rujescu D, Serretti A: Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. Pharmacogenet Genomics. 2011; 21(4): 206-216
Kemp DE, Ganocy SJ, Brecher M, Carlson BX, Edwards S, Eudicone JM, Evoniuk G, Jansen W, Leon AC, Minkwitz M, Pikalov A, Stassen HH, Szegedi A, Tohen M, Van Willigenburg AP, Calabrese JR: Clinical value of early partial symptomatic improvement in the prediction of response and remission during short-term treatment trials in 3369 subjects with bipolar I or II depression. J Affect Disord. 2011; 130(1-2): 171-179
Stassen HH, Anghelescu IG, Angst J, Böker H, Lötscher K, Rujescu D, Szegedi A, Scharfetter C: Predicting Response to Psychopharmacological Treatment. Survey of Recent Results. Pharmacopsychiatry 2011; 44: 263-272
Lötscher K, Anghelescu IG, Braun S, Bridler R, Stassen HH: Polypharmacy in psychiatry: clinical practice versus empirical evidence. Eur Neuropsychopharmacol. 2010; 20 (Suppl. 3): 378-379
Szegedi A, Jansen WT, Van Willigenburg AP, Van der Meulen E, Stassen HH, Thase ME: Early improvement as a predictor of treatment outcome in patients with major depressive disorder: Why the first 2 weeks really matter - evidence from 6562 patients. J Clin Psychiatry 2009; 70(3): 344-353
Stassen HH, Angst J, Hell D, Scharfetter C, Szegedi A: Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. J Clin Psychiatry 2007; 68(8): 1195-1205
Stassen HH, Scharfetter C: Vulnerability, resilience and response to psychotropic drugs: shared genetic factors? Am J Med Genetics 2006; 141: 707-708
Lavergne F, Berlin I, Gamma A, Stassen H, Angst J: Onset of improvement and response to mirtazapine in depression: a multicenter naturalistic study of 4771 patients. Neuropsychiatric Disease and Treatment 2005; 1(1): 59-68
Stassen HH, Angst J, Scharfetter C, Szegedi A: Therapie mit Antidepressiva: Erfolg von genetischen Faktoren abhängig? Leading Opinions, Neurologie & Psychiatrie 2005; 6: 25-27
Stassen HH, Angst J: Wirkung und Wirkungseintritt in der Antidepressiva-Behandlung. Medizinspektrum 2004; 15: 15-17
Stassen HH, Dahmen N, Hell D, Nürnberg P, Sander T, Toliat MR, Szegedi A: Genetic predisposition of antidepressant drug response. Am J Med Genetics 2003; 122: 123-124
Montgomery SA, Bech P, Blier P, Moller HJ, Nierenberg AA, Pinder RM, Quitkin FM, Reimitz PE, Rosenbaum JF, Rush AJ, Stassen HH, Thase ME: Selecting methodologies for the evaluation of differences in time to response between antidepressants. J Clin Psychiatry 2002; 63(8): 694-699
Stassen HH, Angst J, Delini-Stula A: Fluoxetine versus moclobemide: cross-comparison between the time course of improvement. Pharmacopsychiatry 1999; 32: 56-60
Stassen HH, Kuny S,. Hell D: The speech analysis approach to determining onset of improvement under antidepressants. Eur Neuropsychopharmacology 1998; 8,4: 303-310
Stassen HH, Angst J, Delini-Stula A: Onset of improvement under fluoxetine and moclobemide. Eur Psychiatry 1998; 13,3: 128-133
Angst J, Stassen HH: Methodische Probleme der Prüfung von Antidepressiva. In: Stieglitz RD, Fähndrich E, Möller HJ (eds): Syndromale Diagnostik psychischer Störungen. Hogrefe, Göttingen 1998: 5-12
Stassen HH, Angst J, Delini-Stula A: Delayed onset of action of antidepressant drugs? Survey of results of Zurich meta-analyses. Eur Psychiatry 1997; 12: 166-176
Stassen HH, Angst J, Delini-Stula A: Delayed onset of action of antidepressant drugs? Survey of results of Zurich meta-analyses. Pharmacopsychiatry 1996; 29: 87-96
Kuny S, Stassen HH: Cognitive performance in patients recovering from depression. Psychopathology 1995; 28: 190-207
Stassen HH, Angst J: Methods of estimating onset of improvement. Eur Neuropsychopharmacology 1994; 4,3: 284-285
Stassen HH, Angst J, Delini-Stula A: Severity at baseline and onset of improvement in depression. Meta-analysis of Imipramine and Moclobemide vs Placebo. Eur Psychiatry 1994; 9: 129-136
Stassen HH, Delini-Stula A, Angst J: Time course of improvement under antidepressant treatment: a survival-analytical approach. Eur Neuropsychopharmacol 1993; 3: 127-135
Angst J, Delini-Stula A, Stabl M, Stassen HH: Is a cutoff score a suitable measure of treatment outcome in short-term trials in depression? A methodological meta-analysis. Human Psychopharmacology 1993; 8: 311-317
Angst J, Stassen HH, Woggon B: Effect of neuroleptics on positive and negative symptoms and the deficit state. Psychopharmacology 1989; 99: 41-46

 

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Improvement under Imipramine and Moclobemide versus Placebo
Cumulative rates of improvers as a function of time under imipramine (n=506), moclobemide (n=580) and placebo (n=191). Improvement is defined as a 20% sustained baseline score reduction. It is worth noting that the time characteristics of improvement are virtually identical under all three treatment modalities.
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