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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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Incidence and Latency

The 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"), are often combined into a single, 1-dimensional "cure" model by means of survival-analytical techniques. This cure model incorporates non-responders in addition to modeling the time to an a priori defined clinical response. Patients who dropped out of the trial prior to the envisaged observation period are treated as "censored" data under the assumption of random censoring. The non-parametric generalized maximum likelihood for the model is obtained from the Kaplan-Meier (KM) product limit estimator. By contrast, when separating incidence and latency through a 2-dimensional cure model, tests become available [Kolmogorov-Smirnov, Cramer-von Mises] to explicitly compare the speed of improvement between treatments among improvers.

Latency Explains No More than 5% of Variance

Among patients who meet improvement or response criteria, the distribution of the individual onsets is slightly left-skewed, yet approximately normal, covering a wide range from early to late improvement/response with mean values around day 12-14 (improvement) and day 18-20 (response). Unexpectedly, there are almost no differences between treatment modalities in this respect, with differences between active compounds, and between active compounds and placebo, being reflected only by the total number of improvers and responders. The subtle differences in the "average" onset are likely the effect of non-standardized placebo washouts which may explain a ±2 day shift of baseline, or may relate to the dose titration differences in the first days of treatment.

No Gender Differences

Analyses carried out separately for male and female patients did not reveal major gender differences, except for mirtazapine and paroxetine, where sample sizes were small.

⇒ Meeting improvement criteria is highly predictive of later outcome, as typically >70% of the patients who show sustained improvement within the first 10-14 days of treatment ("early improvement") later become sustained responders by the end of a typical six-week drug trial. Inversely, more than 80% of sustained responders at the end of a six-week drug trial show sustained improvement within the first 10-14 days of treatment, thus suggesting that in more than two thirds of the patients, the time course of improvement is sustained once the recovery has started.

References

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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
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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]
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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 [submitted for publication]
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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 & 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. 2021 [submitted for publication]
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
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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]

 

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Response OR
Sustained response is much more likely among early improvers independent of treatment modality as indicated by odds ratios that exceed 3 for all drugs and placebo. The estimates were derived by fitting a random-effects model which accounted for the between-study variation. The dotted line indicates an odds ratio of 1.
Please note: (1) patients showing no improvement throughout the first 2 weeks of treatment have a probability of <15% to later become responders; (2) this probability drops below 8% after 3 weeks without improvement.
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