Research Group 'Psychiatric Genetics', Head: Prof. Dr. Hans H. Stassen

Department of Psychiatry, Psychotherapy and Psychosomatics

Psychiatric Hospital, University of Zurich


Severity at Baseline Determines Drug Effect

Placebo-Drug Differences

Placebo-drug differences are generally modest for all classes of pychotropic drugs, although their onset of action is immediate [e.g., Angst and Stassen 2001; Agid et al 2003]. Differences between active compounds and placebo evolve from the very beginning of treatment, achieving over 65% of the maximal difference within the first two weeks, while differences among active compounds remain marginal throughout a typical drug trial of six weeks. There is no distinct increase in the number of patients benefitting from treatment after 3-4 weeks as postulated by the "delayed onset-of-action hypothesis". For the "average patient", response rates under active compounds are in the range of 55% while those under placebo lie around 30%.

The "Average Patient"

However, the "average patient" is rarely encountered in the treatment of psychiatric disorders and single case analyses reveal that there is a lot of between-patient variation. For example, the efficacy of antidepressants in the treatment of MDD depends essentially on the severity of depression at baseline [Figure 3], with drug-placebo differences hardly ever reaching significance in mild MDD cases. For this reason, clinical drug trials typically require a minimum baseline score of at least 15 points on the 17-item HAM-D scale at entry into study (after washout), whereas Figure 3 suggests a minimum baseline score > 18 as inclusion criterion.

⇒ For mild depression the patients' benefits from antidepressant drug treatment are marginal and rarely outweigh the burden of the drugs' side effects.

Alternative Treatments in Mild Depression

Seeing a doctor should always be the patient's first step in dealing with depression, but there are some ways patients can deal with depression on a daily basis. Though it may seem impossible, exercise is one of the best ways to deal with mild depression. In fact, several studies have reported more depressive symptoms in physically inactive individuals. Regular exercise has also been shown to protect against relapse to previous levels of depression and a 16-week exercise intervention found exercise to be as effective as antidepressants in treating older patients with depression.


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
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
Häfner H. Ist die Diagnose Schizophrenie noch sinnvoll? Psychiat Prax 2007; 34: 175-180
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
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
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
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
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
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
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


Severity at baseline
Response to treatment under imipramine (circles, n=506), moclobemide (triangles, n=580) and placebo (squares, n=191) as a function of HAM-D17 baseline score after placebo washout. The 4-week response rates (50% baseline score reduction) are plotted along the y-axis for baseline scores 15 (HAM-D17 ≤ 15), 18 (15 < HAM-D17 ≤ 18), 21 (18 < HAM-D17 ≤ 21),… 33 (30 < HAM-D17), indicating that placebo-drug differences reach 30% for HAM-D17 baseline scores >27.
Please note: (1) placebo-drug differences rarely ever reach statistical statistical significance in mild cases (HAM-D17 ≤ 18); (2) placebo-drug differences are highly significant and largely independent of baseline scores for moderately to severely ill patients (HAM-D17 > 20).
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