Institute for Response-Genetics (e.V.)

Chairman: Prof. Dr. Hans H. Stassen

Psychiatric Hospital (KPPP), University of Zurich

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Between-Drug Differences

There are two central aspects of psychotropic drug response: the proportion of patients in whom a therapeutic response is induced ("incidence"), and the time to onset of improvement ("latency"). These two aspects can be detailed through 2-dimensional cure models and particularly enable statistical tests [Kolmogorov-Smirnov, Cramer-von Mises] to explicitly compare the speed of improvement between treatments. It turns out that almost all (>90%) of the observed differences in efficacy between drugs, which are beyond clinical relevance among effective compounds, can be explained by incidence, while less than 10% of the differences can be attributed to latency. In fact, cumulative rates of improvers/responders are virtually identical under antidepressants of large pharmacological and biochemical differences (e.g., imipramine [TCA], moclobemide [MAOI], fluoxetine [SSRI]) at standard drug trial days 3, 7, 10, 14, 21, 28, 35 and 42. These striking between-drug similarity of these cumulative rates are independent of improvement criteria.

Between-Drug Differences in Efficacy Beyond Clinical Relevance

Differences between drugs relate exclusively to the percentage of improvers (78%-83% under active compounds; 58% under placebo) or responders (48% under fluoxetine and moclobemide). If one drug displays better efficacy than another, it apparently converts throughout the entire observation period a higher proportion of patients to responders who otherwise would remain nonresponders. A finding which is compatible with results in the literature on early drug-placebo separation [Posternak and Zimmerman, 2005], and with results derived through the "average patient approach", where differences among drugs are found to be marginal at best, rarely reaching statistical significanc even with sample sizes of >1000 patients.

Highly Significant Differences for Side Effects

By contrast, active compounds display significant differences with respect to their unwanted side effects. Newer treatments have generally better tolerability and safety profiles than the older substances. This is demonstrated in Figure 1, where the time characteristics of premature withdrawal were detailed for the older TCA amitriptyline, the investigational compound oxaprotiline, and placebo. Premature withdrawals occur early under placebo — patients implicitly associate "no side effect" with "no drug effect" — while drop-outs under amitriptyline typically occur after one week of treatment when dosages reach therapeutical levels. Under the newer compound oxaprotiline, on the other hand, drop-outs occur at similar rates over the entire observation period.

Ethnic Variation in Dose, Blood-Level, Weight Gain

It is worth noting that the inter-individual variation in dose, blood-level, weight gain and other side effects is ethnicity-specific, whereas response rates are very similar across ethnicities, suggesting that drug-induced therapeutic effects are ethnicity-independent. Here, the term "ethnicity" is meant in the biological sense of a distinct individuality in certain genetic patterns as reflected, for example, by the inter-individual variation of the cytochrome P450 system.

References

Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60(12): 1228-1235
Agid O, Seeman P, Kapur S. The "delayed onset" of antipsychotic action--an idea whose time has come and gone. J Psychiatry Neurosci. 2006; 31(2): 93-100
Agid O, Kapur S, Warrington L, Loebel A, Siu C. Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders. Schizophr Res. 2008; 102(1-3): 241-248
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
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. Eur Arch Psychiatry Clin Neurosci 2017; 267: 377-389 [get the article]
Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 2004; 16(1): 15-25
Chwastiak LA, Rosenheck RA, McEvoy JP, Keefe RS, Swartz MS, Lieberman JA. Interrelationships of psychiatric symptom severity, medical comorbidity, and functioning in schizophrenia. Psychiatr Serv. 2006; 57(8): 1102-1109
Correll CU, Malhotra AK. Pharmacogenetics of antipsychotic-induced weight gain. Psychopharmacology 2004; 174(4): 477-489
Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, Mortensen PB. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006; 163(3): 521-528
Fleischhacker WW, Cetkovich-Bakmas M, De Hert M, Hennekens CH, Lambert M, Leucht S, Maj M, McIntyre RS, Naber D, Newcomer JW, Olfson M, Osby U, Sartorius N, Lieberman JA. Comorbid somatic illnesses in patients with severe mental disorders: clinical, policy, and research challenges. J Clin Psychiatry. 2008;69(4): 514-519
Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000; 321(7273): 1371-1376
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
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]
Greil W, de Bardeci M, Seifert J, Bernegger X, Cattapan K, Stassen HH, Wagner AL, Sieberer M, Grohmann R, Toto S: Treatment of depression: Are psychotropic drugs appropriately dosed in women and in the elderly? Dosages of psychotropic drugs by sex and age in routine clinical practice. Hum Psychopharmacol. 2022; 37(1): e2809 [get the article]
Greil W, de Bardeci M, Müller-Oerlinghausen B, Nievergelt N, Stassen HH, Hasler G, Erfurth A, Cattapan K, Rüther E, Seifert J, Toto S, Bleich S, Schoretsanitis G. Controversies regarding lithium-associated weight gain: case-control study of real-world drug safety data. Int J Bipolar Disord. 2023; 11(1): 34. doi: 10.1186/s40345-023-00313-8 [get the article]
Häfner H. Ist die Diagnose Schizophrenie noch sinnvoll? Psychiat Prax 2007; 34: 175-180
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
Khan A, Khan SR, Leventhal RM, Brown WA. Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: a replication analysis of the Food and Drug Administration Database. Int J Neuropsychopharmacol 2001; 4(2): 113-118
Khan A, Khan SR, Leventhal RM, Brown WA. Symptom reduction and suicide risk among patients treated with placebo in antipsychotic clinical trials: an analysis of the food and drug administration database. Am J Psychiatry 2001; 158(9): 1449-1454
Laska EM, Meisner MJ. Nonparametric estimation and testing in a cure model. Biometrics 1992; 48(4): 1223-1234
Lett HS, Blumenthal JA, Babyak MA, Sherwood A, Strauman T, Robins C et al. Depression as a risk factor for coronary artery disease: evidence, mechanisms, and treatment. Psychosom Med 2004; 66(3): 305-315
Leucht S, Pitschel-Walz G, Abraham D, Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res 1999; 35(1): 51-68
Leucht S, Busch R, Kissling W, Kane JM. Early prediction of antipsychotic nonresponse among patients with schizophrenia. J Clin Psychiatry. 2007; 68(3): 352-360
Li M, Fletcher PJ, Kapur S. Time course of the antipsychotic effect and the underlying behavioral mechanisms. Neuropsychopharmacology. 2007; 32(2): 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
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
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, 24(3): 250-262 [get the article]
Motivala SJ, Sarfatti A, Olmos L, Irwin MR. Inflammatory markers and sleep disturbance in major depression. Psychosom Med. 2005; 67(2): 187-194
Papakostas GI, Perlis RH, Scalia MJ, Petersen TJ, Fava M. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006; 26(1): 56-60
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 HH, 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
Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005; 66(2): 148-158
Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biol Psychiatry 2003; 54: 227-240
Skilton MR, Moulin P, Terra JL, Bonnet F. Associations between anxiety, depression, and the metabolic syndrome. Biol Psychiatry. 2007; 62(11): 1251-1257
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, Anghelescu IG, Braun S, Hoffmann K, Rujescu D, Scharfetter C, Szegedi A, Tadic A: Vulnerability to major psychiatric disorders, response to treatment and medical comorbidity — shared genetic factors? Eur Neuropsychopharmacol. 2009; 19 (Suppl. 3): 262
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
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
Stassen HH: Heterogeneity of schizophrenic disorders and link to chronically elevated IgM values. Neurology, psychiatry and brain research 2018; 29: 23-24
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]
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. 2022; 272(4): 603-619 [get the article]
Stassen HH, Bachmann S, Bridler R, Cattapan K, Seifritz E. Polypharmacy in Psychiatry and Weight Gain: Longitudinal Study of 832 Patients Hospitalized for Depression or Schizophrenia, along with Data of 3,180 Students from Europe, the U.S., South America, and China. Eur Arch Psychiatry Clin Neurosci. 2024; https://doi.org/10.1007/s00406-024-01767-2 (Epub ahead of print) [get the article]
Stassen HH, Bachmann S, Bridler R, Cattapan K, Hartmann AM, Rujescu D, Seifritz E, Weisbrod M, Scharfetter C: Genetic Determinants of Antidepressant and Antipsychotic Drug Response: A molecular-genetic study of 902 patients over 6 weeks. Psychiatry Res. 2024 [submitted for publication]
Stassen HH, Bachmann S, Bridler R, Cattapan K, Hartmann AM, Rujescu D, Seifritz E, Weisbrod M, Scharfetter C. Analysis of genetic diversity in patients with major psychiatric disorders versus healthy controls: A molecular-genetic study of 1698 subjects genotyped for 100 candidate genes (549 SNPs). Psychiatry Res. 2024; 333: 115720. doi: 10.1016/j.psychres.2024.115720 [get the article]
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
Tamura RN, Faries DE, Feng J. Comparing time to onset of response in antidepressant clinical trials using the cure model and the Cramer-von Mises test. Stat Med 2000; 19(16): 2169-2184
Thase ME. Comparing the methods used to compare antidepressants. Psychopharmacol Bull 2002; 36 Suppl 1: 1-17
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]

 

vSpacer Premature withdrawals: drop-out rates
Cumulative rates of premature withdrawals under amitriptyline (TCA; yellow triangles) and oxaprotiline (investigational noradrenaline uptake inhibitor; green circles) versus placebo (red squares). Premature withdrawals occur early under placebo (lack of effect), while drop-outs under amitriptyline typically occur after one week of treatment when dosages reach therapeutical levels. This in contrast to the reduced, unspecific side effect profile of oxaprotiline, where premature withdrawals occur at a constant rate over the entire observation period.
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