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Resistant depression: Patterns of treatment response
S. 09. Critical areas for the treatment of depression
$108
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Resistant depression: Patterns of treatment response
J. Mendlewicz, D. Souery. Department of Psychiatry, Erasmus Hospital, Free University of Brussels, Belgium Outcome studies have demonstrated that approximately one third of patients treated for major depression do not respond to antidepressant pharmacotherapy (Nierenberg and Amsterdam 1990). The key parameters that characterize and define treatment resistant depression (TRD) include the diagnostic criteria, the response to treatment, number of previous trials, adequacy of treatment and compliance to treatment. Diagnostic aspects include the need to reach an accurate diagnosis; to define various subtypes of depressive disorders; comorbidity with other psychiatric or personality disorders. The assessment of treatment response raises the problems of how to evaluate remission and recovery. Previous failed treatment trials remain the subject of controversy and refer to the number and type of adequate antidepressant treatment trials required before the question of resistance can be determined. Finally, treatment adequacy has to be considered in terms of dosage, duration and compliance. It appears that a number of variables commonly associated with treatment resistance, relate mainly to misdiagnosis and inadequate treatment and are independent of the characteristics of patients. A multicenter project has been initiated "Patterns of treatment resistant depression and switching strategies in unipolar affective disorders" in which these criteria are being validated. The objectives are to evaluate characteristics of patients with TRD using operational criteria, to compare responder and non-responder patients at the epidemiological level, to evaluate the rate of nonresponse to a 1st and 2nd antidepressant trial and to compare switching strategies of specific Noradrenergic and Serotoninergic treatments for depressed inpatients and outpatients. One thousand patients will be recruited in the epidemiological phase, an estimation of 400 will be included in the prospective phase. Preliminary results are available for 703 depressed patients (Major Depression). In this sample, 49.6% of patients are non-responders after receiving adequate dose and duration of antidepressant pharmacotherapy (baseline HAM-D17 /> 17). The following clinical variables were associated to non-response: female sex (p=0.007 OR=1.59), inpatient status (p=0.007), melancholia (p=0.0000013), suicidal risk (p=0.0000015) and severity (p=0.001). For the Group for the Study on Resistant Depression (GSRD): K. Demyttenaere, S. Kasper, Y. Lecrubier, I. Massat, J. Mendlewicz, S. Montgomery, A. Serretti, D. Souery, J. Zohar.
References [1] Nierenberg AA and Amsterdam JD: Treatment-resistant depression: definition and treatment approaches. J Clin Psychiatry 51(6):39~17, 1990. [2] Souery et al. TreatmentResistant Depression:methodologicaloverview and operationalcriteria. EuropeanNeuropsychopharmacology,9 (1999) 83-91.
15.09.051 Safety and efficacy of antidepressants in older people C. Katona, G. Livingston. University College London, London,
United Kingdom Depression in older people is common, causes considerable distress and increases health care costs. Many antidepressant drugs
are now available, newer drugs claiming to have fewer side effects and be safer in older people. The efficacy ofnewer drugs is usually claimed by manufacturers to be at least similar to that oftricyclics. It is however difficult to compare information from separate studies which vary widely in sample selection and outcome measures. In addition, results reported in terms of mean change scores give an inadequate impression of individual response patterns. A recentmeta-analysis of all published antidepressant studies listed on MEDLINE and EMBASE to 1996 (Mittmann et al 1997) concluded that there were no significant differences between antidepressant classes (tricyclics, SSRIs, MAOIs and atypicals) in respect of efficacy and tolerability. The authors conclusions were limited by lack of statistical power, lack of interchangeable instruments and poor outcome definition. It is difficult to extrapolate the likely clinical response in individual patients from this. The concept of 'Number Needed to Treat' (NNT) may be useful in rendering randomised controlled trial (RCT) data meaningful for clinical decision making since it conveys both statistical and clinical information intelligibly (Cook and Sacker 1995). The NNT is the number of patients who need to be treated with the treatment in question, compared to another treatment for one extra patient to gain a specified benefit. The lower the NNT, the better the drug. Where the clinical outcome being evaluated is adverse the same calculation can generate a Number Needed to Harm (NNH). Calculating NNTs and NNHs enables different trials to be compared directly. We (Katona and Livingston 2001) have examined all available placebo controlled data in terms of NNTs and NNHs. We also searched systematically for new studies since 1996 to update the conclusions of Mittmann et al (1997) using their search strategy which involved searching Medline (1966-1999) and Embase (1994-1999). In summary we used the keywords antidepressant agent, tricyclic antidepressant (TCA), selective serotonin uptake inhibitors (SSR/), monamine oxidase inhibitor (MAOI), antidepressive agent, second generation (ATYP), and individual antidepressant drugs by non-proprietary name. Searches were limited by age (65 and over; 80 and over). The inclusion criteria that the study was double-blind, randomised and controlled; efficacy measures, numbers of patients in each group and percentage of responders were reported; the diagnosis of major depressive disorder or unipolar depression using defined criteria. The main exclusions were case reports, open studies, and studies of less than four weeks duration. We also contacted the manufacturers of all antidepressants asking them for their data on antidepressant trials with older people. We did not identify any studies published before 1997 that met our inclusion criteria and had not been identified by Mittmann et al (1997). We were able to identify two relevant papers published subsequent to their search. Hoyberg et al (1996) compared mirtazapine (15-45mg/day) and amitriptyline (30-90mg) in 114 patients with major depression aged 60-85 years who had failed to respond during a twoweek placebo washout period. Response rates (Clinical Global Impression much or very much improved) were similar for mirtazapine and amitriptyline (74% and 81%) as were withdrawal rates (26% vs 19%). Mahapatra and Hackett (1997) report a safety and efficacy comparison between venlafaxine (150 mg/day) and dothiepin (150 mg/day) in 92 subjects with major depression aged between 64 and 87 years. Response rates (defined by HAMD reduction of at least 50%) were 60% in each group. Withdrawal rates were also similar (20%vs 15%). There were no new placebo controlled antidepressant trials published since 1996. Our analysis suggests that the majority of antidepressants evaluated by placebo controlled trial in older people are effective, with relatively small NNTs similar to those reported in younger
$108
•
Resistant depression: Patterns of treatment response
J. Mendlewicz, D. Souery. Department of Psychiatry, Erasmus Hospital, Free University of Brussels, Belgium Outcome studies have demonstrated that approximately one third of patients treated for major depression do not respond to antidepressant pharmacotherapy (Nierenberg and Amsterdam 1990). The key parameters that characterize and define treatment resistant depression (TRD) include the diagnostic criteria, the response to treatment, number of previous trials, adequacy of treatment and compliance to treatment. Diagnostic aspects include the need to reach an accurate diagnosis; to define various subtypes of depressive disorders; comorbidity with other psychiatric or personality disorders. The assessment of treatment response raises the problems of how to evaluate remission and recovery. Previous failed treatment trials remain the subject of controversy and refer to the number and type of adequate antidepressant treatment trials required before the question of resistance can be determined. Finally, treatment adequacy has to be considered in terms of dosage, duration and compliance. It appears that a number of variables commonly associated with treatment resistance, relate mainly to misdiagnosis and inadequate treatment and are independent of the characteristics of patients. A multicenter project has been initiated "Patterns of treatment resistant depression and switching strategies in unipolar affective disorders" in which these criteria are being validated. The objectives are to evaluate characteristics of patients with TRD using operational criteria, to compare responder and non-responder patients at the epidemiological level, to evaluate the rate of nonresponse to a 1st and 2nd antidepressant trial and to compare switching strategies of specific Noradrenergic and Serotoninergic treatments for depressed inpatients and outpatients. One thousand patients will be recruited in the epidemiological phase, an estimation of 400 will be included in the prospective phase. Preliminary results are available for 703 depressed patients (Major Depression). In this sample, 49.6% of patients are non-responders after receiving adequate dose and duration of antidepressant pharmacotherapy (baseline HAM-D17 /> 17). The following clinical variables were associated to non-response: female sex (p=0.007 OR=1.59), inpatient status (p=0.007), melancholia (p=0.0000013), suicidal risk (p=0.0000015) and severity (p=0.001). For the Group for the Study on Resistant Depression (GSRD): K. Demyttenaere, S. Kasper, Y. Lecrubier, I. Massat, J. Mendlewicz, S. Montgomery, A. Serretti, D. Souery, J. Zohar.
References [1] Nierenberg AA and Amsterdam JD: Treatment-resistant depression: definition and treatment approaches. J Clin Psychiatry 51(6):39~17, 1990. [2] Souery et al. TreatmentResistant Depression:methodologicaloverview and operationalcriteria. EuropeanNeuropsychopharmacology,9 (1999) 83-91.
15.09.051 Safety and efficacy of antidepressants in older people C. Katona, G. Livingston. University College London, London,
United Kingdom Depression in older people is common, causes considerable distress and increases health care costs. Many antidepressant drugs
are now available, newer drugs claiming to have fewer side effects and be safer in older people. The efficacy ofnewer drugs is usually claimed by manufacturers to be at least similar to that oftricyclics. It is however difficult to compare information from separate studies which vary widely in sample selection and outcome measures. In addition, results reported in terms of mean change scores give an inadequate impression of individual response patterns. A recentmeta-analysis of all published antidepressant studies listed on MEDLINE and EMBASE to 1996 (Mittmann et al 1997) concluded that there were no significant differences between antidepressant classes (tricyclics, SSRIs, MAOIs and atypicals) in respect of efficacy and tolerability. The authors conclusions were limited by lack of statistical power, lack of interchangeable instruments and poor outcome definition. It is difficult to extrapolate the likely clinical response in individual patients from this. The concept of 'Number Needed to Treat' (NNT) may be useful in rendering randomised controlled trial (RCT) data meaningful for clinical decision making since it conveys both statistical and clinical information intelligibly (Cook and Sacker 1995). The NNT is the number of patients who need to be treated with the treatment in question, compared to another treatment for one extra patient to gain a specified benefit. The lower the NNT, the better the drug. Where the clinical outcome being evaluated is adverse the same calculation can generate a Number Needed to Harm (NNH). Calculating NNTs and NNHs enables different trials to be compared directly. We (Katona and Livingston 2001) have examined all available placebo controlled data in terms of NNTs and NNHs. We also searched systematically for new studies since 1996 to update the conclusions of Mittmann et al (1997) using their search strategy which involved searching Medline (1966-1999) and Embase (1994-1999). In summary we used the keywords antidepressant agent, tricyclic antidepressant (TCA), selective serotonin uptake inhibitors (SSR/), monamine oxidase inhibitor (MAOI), antidepressive agent, second generation (ATYP), and individual antidepressant drugs by non-proprietary name. Searches were limited by age (65 and over; 80 and over). The inclusion criteria that the study was double-blind, randomised and controlled; efficacy measures, numbers of patients in each group and percentage of responders were reported; the diagnosis of major depressive disorder or unipolar depression using defined criteria. The main exclusions were case reports, open studies, and studies of less than four weeks duration. We also contacted the manufacturers of all antidepressants asking them for their data on antidepressant trials with older people. We did not identify any studies published before 1997 that met our inclusion criteria and had not been identified by Mittmann et al (1997). We were able to identify two relevant papers published subsequent to their search. Hoyberg et al (1996) compared mirtazapine (15-45mg/day) and amitriptyline (30-90mg) in 114 patients with major depression aged 60-85 years who had failed to respond during a twoweek placebo washout period. Response rates (Clinical Global Impression much or very much improved) were similar for mirtazapine and amitriptyline (74% and 81%) as were withdrawal rates (26% vs 19%). Mahapatra and Hackett (1997) report a safety and efficacy comparison between venlafaxine (150 mg/day) and dothiepin (150 mg/day) in 92 subjects with major depression aged between 64 and 87 years. Response rates (defined by HAMD reduction of at least 50%) were 60% in each group. Withdrawal rates were also similar (20%vs 15%). There were no new placebo controlled antidepressant trials published since 1996. Our analysis suggests that the majority of antidepressants evaluated by placebo controlled trial in older people are effective, with relatively small NNTs similar to those reported in younger