Predicting Response to Psychopharmacological Treatment: Survey of Recent Results^{[ *]}

Abstract

Introduction:

Treatment with antidepressants and antipsychotics, though effective, is unspecific as agents that differ greatly in their biochemical and pharmacological actions have virtually the same efficacy. Half of the patients with initial improvement show incomplete response, while a large proportion of patients exhibit a refractory clinical picture which is resistant to all treatment modalities.

Methods:

Our analyses were based on a reference study of 2 848 depressive inpatients under monotherapeutic treatment with 7 different antidepressants or placebo, along with a naturalistic study of depressive and schizophrenic patients (296 inpatients, 363 outpatients) under today’s “standard” polypharmaceutic treatment regimens.

Results:

The empirical data suggested the following predictors of response: (1) severity at baseline, (2) early onset of improvement, (3) unwanted side-effects, and (4) medical comorbidity. A combination of these predictors with Therapeutic Drug Monitoring (TDM) methods has direct clinical relevance.

Discussion:

Evidence-based approaches to personalized treatment help improving the unsatisfactory situation patients and clinicians are faced with, given today’s incomplete treatments and the fact that the mechanisms by which antidepressants and antipsychotics ultimately exert their therapeutic effects are only marginally understood.

Key words

TDM - severity at baseline - early onset - side-effects - medical comorbidity - polypharmacy - inflammatory processes

^*

^* These data were presented during the Congress of the TDM group of the AGNP in Bolzano 2010 in Italy during a special lecture by Hans H. Stassen to honour Prof. Dr. Bruno Müller-Oerlinghausen who supported TDM in psychiatry effectively for many years.

• References

• 1 Agid O, Kapur S, Arenovich T et al. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 2003; 60: 1228-1235
• 2 Agid O, Kapur S, Warrington L et al. Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders. Schizophr Res 2008; 102: 241-248
• 3 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: 93-100
• 4 Altamura AC, Bassetti R, Cattaneo E et al. Some biological correlates of drug resistance in schizophrenia: a multidimensional approach. World J Biol Psychiatry 2005; 6 (Suppl. 02) 23-30
• 5 Anghelescu IG, Bridler R, Lötscher K et al. Polypharmacy in psychiatry: clinical implications. Psychopharmacology 2011; in preparation
• 6 Bas S, Perneger TV, Seitz M et al. Diagnostic tests for rheumatoid arthritis: comparison of anti-cyclic citrullinated peptide antibodies, anti-keratin antibodies and IgM rheumatoid factors. Rheumatology 2002; 41: 809-814
• 7 Berckel van BN, Bossong MG, Boellaard R et al. Microglia activation in recent-onset schizophrenia: A quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 2008; 64: 820-822
• 8 Catena-Dell’Osso M, Bellantuono C, Consoli G et al. Inflammatory and neurodegenerative pathways in depression: a new avenue for antidepressant development?. Curr Med Chem 2011; 18: 245-255
• 9 Dawood T, Lambert EA, Barton DA et al. Specific serotonin reuptake inhibition in major depressive disorder adversely affects novel markers of cardiac risk. Hypertens Res 2007; 30: 285-293
• 10 De Berardis D, Conti CM, Serroni N et al. The effect of newer serotonin-noradrenalin antidepressants on cytokine production: a review of the current literature. Int J Immunopathol Pharmacol 2010; 23: 417-422
• 11 Ding K, Feng D, de Andrade M et al. Genomic regions that influence plasma levels of inflammatory markers in hypertensive sibships. J Hum Hypertens 2008; 22: 102-110
• 12 Eaton WW, Byrne M, Ewald H et al. Association of schizophrenia and autoimmune diseases: linkage of Danish national registers. Am J Psychiatry 2006; 163: 521-528
• 13 Fan X, Goff DC, Henderson DC. Inflammation and schizophrenia. Expert Rev Neurother 2007; 7: 789-796
• 14 Fornoni A, Ijaz A, Tejada T et al. Role of inflammation in diabetic nephropathy. Curr Diabetes Rev 2008; 4: 10-17
• 15 Fournier JC, DeRubeis RJ, Hollon SD et al. Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA 2010; 303: 47-53
• 16 Hanson DR, Gottesman II. Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Genet 2005; 6: 7
• 17 Henkel V, Seemüller F, Obermeier M et al. Does early improvement triggered by antidepressants predict response/remission? Analysis of data from a naturalistic study on a large sample of inpatients with major depression. J Affect Disord 2009; 115: 439-449
• 18 Hiemke C. Therapeutic drug monitoring in neuropsychopharmacology: does it hold its promises?. Eur Arch Psychiatry Clin Neurosci 2008; 258 (Suppl. 01) 21-27
• 19 Hoffman BM, Babyak MA, Craighead WE et al. Exercise and Pharmacotherapy in Patients With Major Depression: One-Year Follow-Up of the SMILE Study. Psychosom Med 2011; 73: 127-133
• 20 Hoffmann K, Planitz C, Rüschendorf F et al. A novel locus for arterial hypertension on chromosome 1p36 maps to a metabolic syndrome trait cluster in the Sorbs, a Slavic population isolate in Germany. J Hypertens 2009; 27: 983-990
• 21 Janssen DG, Caniato RN, Verster JC et al. A psychoneuroimmunological review on cytokines involved in antidepressant treatment response. Hum Psychopharmacol 2010; 25: 201-215
• 22 Jones AL, Mowry BJ, Pender MP et al. Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis?. Immunol Cell Biol 2005; 83: 9-17
• 23 Kaestner F, Hettich M, Peters M et al. Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity. J Affect Disord 2005; 87: 305-311
• 24 Kemp DE, Ganocy SJ, Brecher M et al. 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: 171-179
• 25 Khan A, Khan SR, Leventhal RM et al. 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: 113-118
• 26 Khan A, Khan SR, Leventhal RM et al. 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: 1449-1454
• 27 Khan AY, Preskorn SH. Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring. J Psychiatr Pract 2005; 11: 289-301
• 28 Kinon BJ, Chen L, Ascher-Svanum H et al. Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacol 2010; 35: 581-590
• 29 Kinon BJ, Chen L, Stauffer VL et al. Early onset of antipsychotic action in schizophrenia: evaluating the possibility of shorter acute efficacy trials. J Clin Psychopharmacol 2010; 30: 286-289
• 30 Kocsis JH, Gelenberg AJ, Rothbaum BO et al. Cognitive behavioral analysis system of psychotherapy and brief supportive psychotherapy for augmentation of antidepressant nonresponse in chronic depression: the REVAMP Trial. Arch Gen Psychiatry 2009; 66: 1178-1188
• 31 Kurz T, Altmueller J, Strauch K et al. A genome-wide screen on the genetics of atopy in a multiethnic European population reveals a major atopy locus on chromosome 3q21.3. Allergy, Eur J of Allergy and Clinical Immunology 2005; 60: 192-199
• 32 Lencz T, Malhotra AK. Pharmacogenetics of antipsychotic-induced side effects. Dialogues Clin Neurosci 2009; 11: 405-415
• 33 Lencz T, Robinson DG, Napolitano B et al. DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet Genomics 2010; 20 (09) 569-572
• 34 Leucht S, Arbter D, Engel RR et al. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 2009; 14: 429-447
• 35 Leucht S, Shamsi SA, Busch R et al. Predicting antipsychotic drug response – replication and extension to six weeks in an international olanzapine study. Schizophr Res 2008; 101: 312-319
• 36 Levine SZ, Leucht S. Elaboration on the early-onset hypothesis of antipsychotic drug action: treatment response trajectories. Biol Psychiatry 2010; 68 (01) 86-92
• 37 Lötscher K, Anghelescu IG, Braun S et al. Polypharmacy in psychiatry: clinical practice versus empirical evidence. Eur Neuropsychopharmacol 2010; 20 (Suppl. 03) 378-379
• 38 Müller N, Myint AM, Schwarz MJ. Inflammatory Biomarkers and Depression. Neurotox Res 2011; 19: 308-318
• 39 Müller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 2007; 12: 988-1000
• 40 Müller N, Schwarz MJ. A psychoneuroimmunological perspective to Emil Kraepelins dichotomy: schizophrenia and major depression as inflammatory CNS disorders. Eur Arch Psychiatry Clin Neurosci 2008; 258 (Suppl. 02) 97-106
• 41 Müller N, Schwarz MJ. Immune System and Schizophrenia. Curr Immunol Rev 2010; 6: 213-220
• 42 Papakostas GI, Perlis RH, Scalia MJ et al. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006; 26: 56-60
• 43 Plenge RM, Seielstad M, Padyukov L et al. TRAF1-C5 as a risk locus for rheumatoid arthritis – a genomewide study. N Engl J Med 2007; 357: 1199-1209
• 44 Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005; 66 (02) 148-158
• 45 Prapotnik M, Waschgler R, König P et al. Therapeutic drug monitoring of trazodone: are there pharmacokinetic interactions involving citalopram and fluoxetine?. Int J Clin Pharmacol Ther 2004; 42: 120-124
• 46 Savoia C, Schiffrin EL. Reduction of C-reactive protein and the use of anti-hypertensives. Vasc Health Risk Manag 2007; 3: 975-983
• 47 Shankar A, Li J. Positive association between high-sensitivity C-reactive protein level and diabetes mellitus among US non-Hispanic black adults. Exp Clin Endocrinol Diabetes 2008; 116: 455-460
• 48 Shelton RC, Miller AH. Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Prog Neurobiol 2010; 91: 275-299
• 49 Sicard MN, Zai CC, Tiwari AK et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics 2010; 11: 1561-1571
• 50 Stassen HH, Angst J, Hell D et al. Is there a common resilience mechanism underlying antidepressant drug response? Evidence from 2848 patients. J Clin Psychiatry 2007; 68: 1195-1205
• 51 Stassen HH, Kuny S, Hell D. The speech analysis approach to determining onset of improvement under antidepressants. Eur Neuropsychopharmacology 1998; 8 (04) 303-310
• 52 Stassen HH, Szegedi A, Scharfetter C. Modeling Activation of Inflammatory Response System. A Molecular-Genetic Neural Network Analysis. BMC Proceedings 2007; 1 (Suppl. 01) S61 1–6
• 53 Stolk P, Ten Berg MJ, Hemels ME et al. Meta-analysis of placebo rates in major depressive disorder trials. Ann Pharmacother 2003; 37: 1891-1899
• 54 Strous RD, Shoenfeld Y. Schizophrenia, autoimmunity and immune system dysregulation: a comprehensive model updated and revisited. J Autoimmun 2006; 27 (02) 71-80
• 55 Szegedi A, Jansen WT, Van Willigenburg AP et al. Early improvement as a predictor of treatment outcome in patients with major depressive disorder: Why the first 2 weeks really matter – evidence from 6 562 patients. J Clin Psychiatry 2009; 70: 344-353
• 56 Tadic A, Rujescu D, Dahmen N et al. Association Analysis between Variants of the Interleukin-1β and the Interleukin-1 Receptor Antagonist Gene and Antidepressant Treatment Response in Major Depression. Neuropsychiatr Dis Treat 2008; 4: 269-276
• 57 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: 2169-2184
• 58 Tiwari AK, Zai CC, Likhodi O et al. A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia. Neuropsychopharmacol 2010; 35: 1315-1324
• 59 Tsai TC, Lu JH, Chen SJ et al. Soluble interleukin-10 and transforming growth factor-beta in children with acute exacerbation of allergic asthma. J Asthma 2009; 46: 21-24
• 60 Waldschmitt C, Vogel F, Pfuhlmann B et al. Duloxetine serum concentrations and clinical effects. Data from a therapeutic drug monitoring (TDM) survey. Pharmacopsychiatry 2009; 42 (05) 189-193
• 61 Warrier MR, Hershey GK. Asthma genetics: personalizing medicine. J Asthma 2008; 45 (04) 257-264