One-Year Follow-up of Children and Adolescents with Major Depressive Disorder: Relationship between Clinical Variables and Abcb1 Gene Polymorphisms

Abstract

Introduction: Differences in response to fluoxetine (FLX) may be influenced by certain genes that are involved in FLX transportation (ABCB1). We examined remission and recovery from the index episode in a cohort of patients treated with FLX, and also investigated associations between genetic variants in ABCB1 and remission, recovery, and suicide risk.

Methods: This was a naturalistic 1-year follow-up study of 46 adolescents diagnosed with major depressive disorder (MDD). At 12 months they underwent a diagnostic interview with the K-SADS-PL.

Results: It was found that remission was around 69.5% and recovery 56.5%. Remission and recovery were associated with lower scores on the CDI at baseline, with fewer readmissions and suicide attempts, and with lower scores on the CGI and higher scores on the GAF scale. No relationship was found between ABCB1 and remission or recovery. However, a significant association was observed between the G2677T ABCB1 polymorphism and suicide attempts.

Conclusion: Other factors such as stressful events, family support, and other genetic factors are likely to be involved in MDD outcome.

Key words

fluoxetine - recovery - remission - suicide attempts - ABCB1

• References

• 1 Birmaher B, Ryan ND, Williamson DE. et al. Childhood and adolescent depression: a review of the past 10 years: part I. J Am Acad Child Adolesc Psychiatry 1996; 35: 1427-1439
• 2 Costello E, Pine DS, Hammen C. et al. Development and natural history of mood disorders. Biol Psychiatry 2002; 52: 529-542
• 3 Lewinsohn PM, Clarke GN, Seeley JR. et al. Major depression in community adolescents: age at onset, episode duration and time to recurrence. Acad Child Adolesc Psychiatry 1994; 33: 809-818
• 4 Carr A. Depression in young people: description, assessment and evidence-based treatment. Dev Neurorehabil 2008; 11: 3-15
• 5 Birmaher B, Arbelaez C, Brent D. Course and outcome of child and adolescent major depressive disorder. Child Adolesc Psychiatr Clin N Am 2002; 11: 619-637
• 6 Gould MS, Velting D, Kleinman M. et al. Teenagers’ attitudes about coping strategies and help-seeking behavior for suicidality. J Am Acad Child Adolesc Psychiatry 2004; 43: 1124-1133
• 7 Glied S, Pine DS. Consequences and correlates of adolescent depression. Arch Pediatr Adolesc Med 2002; 156: 1009-1114
• 8 Dopheide JA. Recognizing and treating depression in children and adolescents. Am J Health Syst Pharm 2002; 63: 233-243
• 9 Lewinsohn PM, Allen NB, Seeley JR. et al. First onset versus recurrence of depression: differential processes of psychosocial risk. J Abnorm Psychol 1999; 108: 483-489
• 10 Fombonne E, Wostear G, Cooper V. et al. The Maudsley long-term follow-up of child and adolescent depression. Psychiatric outcomes in adulthood. Br J Psychiatry 2001; 179: 210-217
• 11 Emslie GJ. Improving outcome in pediatric depression. Am J Psychiatry 2008; 165: 1-3
• 12 Emslie GJ, Heiligenstein JH, Hoog SL. et al. Fluoxetine treatment for prevention of relapse of depression in children and adolescents: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 2004; 43: 1397-1405
• 13 Kennard BD, Emslie GJ, Mayes TL. et al. Relapse and recurrence in pediatric depression. Child Adolesc Psychiatr Clin N Am 2006; 15: 1057-1079
• 14 Kovacs M, Gatsonis C, Paulauskas SL. et al. Depressive disorders in childhood: IV. A longitudinal study of comorbidity with and risk for anxiety disorders. Arch Gen Psychiatry 1989; 46: 776-782
• 15 Essau CA. Course and outcome of major depressive disorder in non-referred adolescents. J Affect Disord 2007; 99: 191-201
• 16 Thase ME. Preventing relapse and recurrence of depression: a brief review of therapeutic options. CNS Spectr Suppl 2006; 15: 12-21
• 17 Emslie GJ, Heiligenstein JH, Wagner KD. et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry 22 24: 377-383
• 18 Usala T, Clavenna A, Zuddas A. et al. Randomised controlled trials of selective serotonin reuptake inhibitors in treating depression in children and adolescents: a systematic review and meta-analysis. Eur Neuropsychopharmacol 2008; 18: 62-73
• 19 Kronenberg S, Frisch A, Rotberg B. et al. Pharmacogenetics of selective serotonin reuptake inhibitors in paediatric depression and anxiety. Pharmacogenomics 2008; 9: 1725-1736
• 20 Treatment for Adolescents with Depression Study Team. The treatment for adolescents with depression study (TADS): outcomes over 1 year of naturalistic follow-up. Am J Psychiatry 2009; 166: 1141-1149
• 21 Emslie GJ, Kennard BD, Mayes TL. et al. Fluoxetine versus placebo in preventing relapse of major depression in children and adolescents. Am J Psychiatry 2008; 165: 459-467
• 22 Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry 2010; 15: 473-500
• 23 Gassó P, Rodríguez N, Mas S. et al. Effect of CYP2D6, CYP2C9 and ABCB1 genotypes on fluoxetine plasma concentrations and clinical improvement in children and adolescent patients. Pharmacogenomics J 2014;
• 24 Uhr M, Grauer MT, Yassouridis A. et al. Blood-brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls. J Psychiatr Res 2007; 41: 179-188
• 25 Dong C, Wong ML, Licinio J. Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-Americans. Mol Psychiatry 2009; 14: 1105-1118
• 26 Menu P, Gressier F, Verstuyft C. Antidepressants and ABCB1 gene C3435T functional polymorphism: a naturalistic study. Neuropsychobiology 2010; 62: 193-197
• 27 Uhr M, Steckler T, Yassouridis A. et al. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption. Neuropsychopharmacology 2000; 22: 380-387
• 28 Uhr M, Tontsch A, Namendorf C. et al. Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression. Neuron 2008; 57: 203-209
• 29 de Klerk OL, Nolte IM, Bet PM. et al. ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder. Pharmacogenomics J 2013; 13: 349-353 doi:10.1038/tpj.2012.16 Epub 2012 May 29
• 30 Breitenstein B, Brückl TM, Ising M. et al. ABCB1 gene variants and antidepressant treatment outcome: A meta-analysis. Am J Med Genet B Neuropsychiatr Genet 2015; 168B: 274-283
• 31 Peñas-Lledó E, Guillaume S, Delgado A. et al. ABCB1 gene polymorphisms and violent suicide attempt among survivors. J Psychiatr Res 2015; 61: 52-56 doi:10.1016/j.jpsychires.2014.12.005
• 32 Noordam R, Aarts N, Hofman A. et al. Association between genetic variation in the ABCB1 gene and switching, discontinuation, and dosage of antidepressant therapy: results from the Rotterdam Study. J Clin Psychopharmacol 2013; 33: 546-550
• 33 Fabbri C, Serretti A. Pharmacogenetics of major depressive disorder: top genes and pathways toward clinical applications. Curr Psychiatry Rep 2015; 17: 50 doi:10.1007/s11920-015-0594-9
• 34 Fujii T, Ota M, Hori H. et al. Association between the functional polymorphism (C3435T) of the gene encoding P-glycoprotein (ABCB1) and major depressive disorder in the Japanese population. J Psychiatr Res 2012; 46: 555-559
• 35 Blázquez A, Mas S, Plana MT. et al. Plasma fluoxetine concentrations and clinical improvement in an adolescent sample diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder. J Clin Psychopharmacol 2014; 34: 318-326
• 36 Ulloa RE, Ortiz S, Higuera F. et al. [Interrater reliability of the Spanish version of Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime version (K-SADS-PL)]. Actas Esp Psiquiatr 2006; 34: 36-40
• 37 Kaufman J, Birmaher B, Brent D. et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 1997; 36: 980-998
• 38 Frank E, Prien RF, Jarrett RB. et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991; 48: 851-855
• 39 Kovacs M. The Children’s Depression Inventory Manual. New York: Multi-Health Systems; 1992
• 40 Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. Bethesda MD: United States Department of Health, Education, and Welfare; 1976
• 41 Luborsky L. Clinician’s judgments of mental health: A proposed scale. Arch Gen Psychiatry 1962; 7: 407-417
• 42 Shaffer D, Gould MS, Brasic J. et al. A children’s global assessment scale (CGAS). Arch Gen Psychiatry 1983; 40: 1228-1231
• 43 Dunn V, Goodyer IM. Longitudinal investigation into childhood and adolescence-onset depression: psychiatric outcome in early adulthood. Br J Psychiatry 2006; 188: 216-222
• 44 March J, Silva S, Vitiello B. The Treatment for Adolescents with Depression Study (TADS): methods and message at 12 weeks. J Am Acad Child Adolesc Psychiatry 2006; 45: 1393-1403
• 45 Kennard BD, Silva SG, Tonev S. et al. Remission and recovery in the Treatment for Adolescents with Depression Study (TADS): acute and long-term outcomes. J Am Acad Child Adolesc Psychiatry 2009; 48: 186-195
• 46 Gledhill J, Garralda ME. The short-term outcome of depressive disorder in adolescents attending primary care: a cohort study. Soc Psychiatry Psychiatr Epidemiol 2011; 46: 993-1002
• 47 Tsapakis EM, Soldani F, Tondo L. et al. Efficacy of antidepressants in juvenile depression: meta-analysis. Br J Psychiatry 2008; 193: 10-17
• 48 Emslie GJ, Rush AJ, Weinberg WA. et al. Fluoxetine in child and adolescent depression: acute and maintenance treatment. Depress Anxiety 1998; 7: 32-39
• 49 Melvin GA, Dudley AL, Gordon MS. What happens to depressed adolescents? A follow-up study into early adulthood. J Affect Disord 2013; 151: 298-305
• 50 Lewinsohn PM, Clarke GN, Seeley JR. Major depression in community adolescents: age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry 1994; 33: 809-818
• 51 Harrington R, Fudge H, Rutter M. et al. Adult outcomes of childhood and adolescent depression: I. Psychiatric status. Arch Gen Psychiatry 1991; 47: 465-473
• 52 Geller B, Zimmerman B, Williams M. Adult psychosocial outcome of prepubertal major depressive disorder. J Am Acad Child Adolesc Psychiatry 2001; 40: 673-677
• 53 Kovacs M, Goldston D, Gatsonis C. Suicidal behaviors and childhood-onset depressive disorders: a longitudinal investigation. J Am Acad Child Adolesc Psychiatry 1993; 32: 8-20
• 54 Williams JMG, Crane C, Barnhofer T. Recurrence of suicidal ideation across depressive episodes. J Affect Disord 2006; 91: 189-194
• 55 Eichelbaum M, Fromm MF, Schwab M. Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit 2004; 26: 180-185
• 56 Nikisch G, Eap CB, Baumann P. Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study. Pharmacol Res 2008; 58: 344-347
• 57 Singh AB, Bousman CA, Ng CH. ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression. Transl Psychiatry 2012;
• 58 Sarginson JE, Lazzeroni LC, Ryan HS. et al. ABCB1 (MDR1) polymorphisms and antidepressant response in geriatric depression. Pharmacogenet Genomics 2010; 20: 467-475 doi:10.1097/FPC.0b013e32833b593a
• 59 Niitsu T, Fabbri C, Bentini F. et al. Pharmacogenetics in major depression: a comprehensive meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2013; 45: 183-194
• 60 Perroud N, Bondolfi G, Uher R. et al. Clinical and genetic correlates of suicidal ideation during antidepressant treatment in a depressed outpatient sample. Pharmacogenomics 2011; 12: 365-377
• 61 Boiso Moreno S, Zackrisson AL, Jakobsen Falk I. et al. ABCB1 gene polymorphisms are associated with suicide in forensic autopsies. Pharmacogenetics 2013; 23: 463-469
• 62 Charlier C, Broly F, Lhermitte M. et al. Polymorphisms in the CYP2D6 gene: Association with plasma concentrations of fluoxetine and paroxetine. Ther Drug Monit 2003; 25: 738-742