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Early drop-outs, late drop-outs and completers
Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 415 – 419
Article
Early drop-outs, late drop-outs and completers: Differences in the continuation phase of a clinical trial Shamsah B. Sonawalla, M.D.*, Amy H. Farabaugh, Ph.D., Vinita M. Leslie, M.A., Joel A. Pava, Ph.D., John D. Matthews, M.D., Maurizio Fava, M.D. Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, WACC 812, 15 Parkman Street, Boston, MA 20114, USA
Abstract Objective: The purpose of this study was to assess the differences between early and late drop-outs and completers in the continuation phase of a clinical trial. Methods: The authors studied 119 outpatients who were treatment responders in an 8-week open trial with fluoxetine 20 mg/day, and who were then enrolled in a 26-week clinical trial comparing the efficacy of fluoxetine versus fluoxetine and cognitive behavior therapy (CBT). Patients were assessed using the Structured Clinical Interview for DSM-III-R — Axis I (SCID — Patient Edition), Hamilton Depression Rating Scale (HAMD-17) and the following self-rated scales: Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), Anxiety Sensitivity Index (ASI) and the Symptom Questionnaire (SQ) prior to starting the 26-week continuation phase. We defined ‘‘early drop-outs’’ (EDs) as patients who dropped out either at or prior to Visit 2 (which was at 2 months into the 6-month continuation phase); those dropping out at Visit 3 or later were defined as ‘‘late drop-outs’’ (LDs) (ED 2 months; LD > 2 months). The Kruskal – Wallis and the Mann – Whitney U tests were used for data analysis. Results: Of the 119 patients, 83 were completers (mean age: 42.1 ± 9.0 years; 46 [55%] women; age of onset of major depressive disorder [MDD] = 24.3 ± 12.5years), 11 were EDs (mean age: 38.1 ± 13.0 years; 4 [36%] women; age of onset of MDD = 22.0 ± 11.1 years) and 25 were LDs (mean age: 35.2 ± 10.4 years; 12 [48%] women; age of onset of MDD = 24.6 ± 11.6 years). LDs were significantly younger than completers ( P < .01). There was no significant difference in age between EDs and LDs, nor between EDs and completers. EDs were more likely to have been depressed for a longer period of time compared to LDs ( P < .05). EDs completers were depressed for a longer period of time compared to LDs ( P < .05). Conclusions: Our data suggest that late drop-outs are significantly younger than completers, although age is not a predictor between early drop-outs and late drop-outs. Further, early drop-outs are depressed for a longer duration compared to late drop-outs completers are depressed for a longer duration than late dropouts, and Early drop-outs have significantly more social impairment compared to completers. Our study identified some patient characteristics significantly associated with dropping out of a long-term clinical trial. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Age; Clinical trial; Completers; Early drop-outs; Late drop-outs; Major depression
1. Introduction In clinical trials, dropping out is a common occurrence, with drop-out rates ranging typically from 20% to 40% (Feighner and Boyer, 1992; Feighner et al., 1991). Patients Abbreviations: ASI, Anxiety Sensitivity Index; BHS, Beck Hopelessness Scale; CBT, cognitive behavioral therapy; ED, early drop-out; HAMD-17, Hamilton Depression Rating Scale; LD, late drop-out; MDD, major depressive disorder; SAS-SR, Social Adjustment Scale — Selfreport; SCID-P, Structured Clinical Interview for DSM-III-R — Axis I; SQ, Symptom Questionnaire * Corresponding author. Tel.: +1-617-726-9279; fax: +1-617-7243028. E-mail address: [email protected] (S.B. Sonawalla, M.D.).
may drop out of an ongoing clinical trial for several reasons. Claghorn and Feighner reported that the primary reasons for treatment discontinuation in the antidepressant treatment group of a clinical trial were adverse events and patients being lost to follow-up, and in the placebo group, ineffectiveness of treatment was noted (Claghorn and Feighner, 1991). A previous study from our group, reported differences between completers and drop-outs in the open phase of an 8-week clinical trial with fluoxetine (Tedlow et al., 1996). The study found a trend for higher scores on the Hamilton Depression Rating Scale (HAMD-17) (Hamilton, 1960) and on the Anxiety Sensitivity Index (ASI) (Peterson and Reiss, 1992) among those patients who dropped out of an acute phase of a treatment study (Tedlow et al., 1996).
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In addition to differences between completers and dropouts, there may be differences between early and late dropouts. For example, Linden and colleagues (1993) found that the main reasons for termination of antidepressant treatment were adverse drug effects, insufficient response and complete or sufficient response. They further reported that adverse drug effects led to early termination during the first few weeks, complete response resulted in termination after 4 to 8 weeks of treatment, and insufficient response caused treatment to be stopped almost linearly during the 12 weeks of observation (Linden et al., 1993). Lin and co-workers (1995) focused on predictors of early and late adherence to antidepressant therapy. Early adherence was defined as using antidepressants for at least 30 days after filling the initial prescription, while late adherence was defined as using antidepressants for at least 90 days after the initial prescription. They reported that 28% of patients dropped out within the first 2 weeks of treatment, while 44% dropped out after 90 days. They also found that dropping out early was related to severe side effects and not receiving an educational message, while dropping out late was significantly related to being on an antidepressant in the past (Lin et al., 1995). The present aim is to further examine predictors of early versus late drop-out during the continuation phase of a clinical trial.
2. Methods 2.1. Patient population The authors studied 119 outpatients between 18 and 65 years of age with major depressive disorder (MDD) who were treatment responders in an 8-week open treatment with fluoxetine 20 mg/day and who were entered into the continuation phase of a 26-week clinical trial comparing the efficacy of fluoxetine versus fluoxetine and cognitive behavior therapy (CBT). The initial sample in the acute phase consisted of 384 outpatients (55% female) between the ages of 18 and 65 years (mean age: 39.9 ± 10.5 years) who met criteria for MDD as measured by the Structured Clinical Interview for DSM-III-R — Patient Edition (SCID-P) (Spitzer et al., 1989), and had a HAMD-17 score 16 at baseline. 2.2. Study design Patients who met criteria for remitted depression, defined as a HAMD-17 score of 7 at week 8, were enrolled in the continuation phase, which lasted 26 weeks. Patients who entered the continuation phase were either randomized into a group that received fluoxetine 40 mg/day, or one that received fluoxetine 40 mg/day plus CBT. Fully trained and experienced psychologists in our program administered the CBT. Fifty-minute treatment sessions were conducted twice a week for the initial 4 weeks, then once a week for
12 weeks, and once every 2 weeks for the rest of the 26-week study. We defined ‘‘early drop-outs’’ (EDs) as patients who dropped out either at or prior to Visit 2 (which was at 2 months into the 6 month continuation phase); those dropping out at Visit 3 or later were defined as ‘‘late dropouts’’ (LDs) (ED 2 months; LD >2 months). The treatment trial was conducted by the Depression Clinical and Research Program at the Massachusetts General Hospital. After complete description of the study to subjects, written informed consent was obtained prior to participation in this study, which was approved by the Institutional Review Board of Massachusetts General Hospital. The following patients were excluded from the study: pregnant women, women of child-bearing potential who were not using either intrauterine device or a barrier device for contraception, women of child-bearing potential taking a birth control pill, lactating women, patients with serious suicidal risk, patients with a history of neurological illness including seizure disorder, serious medical illness, organic mental disorders, substance use disorders active within the last year, schizophrenia, delusional disorder, bipolar disorder or antisocial personality disorder, patients with mood congruent or mood incongruent psychotic features, history of multiple adverse drug reactions or allergy to the study drugs, current use of other psychotropic drugs, clinical or laboratory evidence of hypothyroidism, patients with a previous nonresponse to or intolerance of fluoxetine (60 –80 mg/day) or to the combination of fluoxetine and desipramine or fluoxetine and lithium, and patients who had failed to respond during the course of their current major depressive episode to at least one adequate antidepressant trial ( 6-weeks of treatment with either 150 mg of imipramine [or its tricyclic equivalent], 60 mg of fluoxetine or its selective serotonin reuptake inhibitor equivalent, or 60 mg of phenelzine [or its monoamine oxidase inhibitor equivalent]). 2.3. Assessment instruments At the beginning of the continuation phase (i.e., after the initial 8-week acute phase), patients were assessed using the depression module of the SCID-P, the HAMD-17, and the following self-rated scales: Beck Depression Inventory (BDI) (Beck et al., 1961), Beck Hopelessness Scale (BHS) (Beck and Steer, 1988), the Reiss-Epstein Gursky Anxiety Sensitivity Index (ASI) (Peterson and Reiss, 1992), Symptom Questionnaire (SQ) (Kellner, 1987) and Social Adjustment Scale — Self-report (SAS-SR) (Weissman and Bothwell, 1976). The BDI is a 21-item self-rated scale, which measures the behavioral manifestations of depression and has a sensitivity of 100% when a cut-off score of 16 is used to screen for major depression (Zich et al., 1990; Beck et al., 1961). The BHS is a 20-item, true/false inventory designed to assess pessimistic expectations, with higher scores indicating greater hopelessness (Beck and Steer, 1988). The ASI measures fear of anxiety and sensitivity to somatic cues (Peterson and Reiss, 1992). The SQ is a 92-item
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Table 1 Age, duration of MDD, and baseline SAS-SR scores of study completers, early drop-outs, and late drop-outs Completers (n = 83) Mean Age (years) Duration of MDD (years) SAS-SR a b c d
a
42.1 3.3b 2.5d
Early drop-outs (n = 11) S.D. 9.0 5.5 0.8
Mean 38.1 4.9c 3.3d
Late drop-outs (n = 25)
Kruskal – Wallis
S.D.
Mean
S.D.
Overall P
df
13.0 6.1 1.0
a
10.4 2.0 0.8
.005 .04 .1
2 2 2
35.2 1.3b,c 2.7
Mann – Whitney U test: P <.01, completers vs. late drop-outs. Mann – Whitney U test: P <.05, completers vs. late drop-outs. Mann – Whitney U test: P <.05, early drop-outs vs. late drop-outs. Mann – Whitney U test: P =.05, completers vs. early drop-outs.
self-rated questionnaire, which assesses psychological wellbeing as well as symptoms of depression, anxiety, hostility and somatization (Kellner, 1987). The SAS-SR was used as a measure of social dysfunction (Weissman and Bothwell, 1976). It measures adjustment in major role areas of functioning, including: work outside the home, or at home or as a student; functioning in social and leisure activities; functioning in extended family, marital and parental roles; functioning within a family unit; and economic functioning. The SCID-P and HAMD-17 interviews were conducted by psychiatrists and clinicians affiliated with the Depression Clinical and Research Program who were fully trained in the use of these instruments through live and videotaped interviews. Although interrater reliability in the use of SCID-P was not formally assessed, participating clinicians established consensus with respect to the operational criteria required for Axis I disorders through interrater reliability sessions. 2.4. Data analysis The Kruskal – Wallis test was used to compare the continuous variable characteristics between completers, EDs, and LDs. The Mann –Whitney U test was then used for pairwise comparisons between groups. The chi-square method was used to compare the categorical demographic profiles across the three groups.
3. Results One hundred and twenty-nine patients had a HAMD-17 score 7 after 8 weeks of treatment with fluoxetine 20 mg/day and were enrolled in the continuation phase of the clinical trial comparing the efficacy of fluoxetine 40 mg/day versus fluoxetine 40 mg/day plus CBT. Ten patients relapsed, leaving 119 patients who were the subjects of this study. Of these 119 patients, 83 were completers (mean age: 42.1 ± 9.0 years; 46 [55%] women; age of onset of MDD = 24.3 ± 12.5years), 11 were EDs (mean age: 38.1 ± 13.0 years; 4 [36%] women; age of onset of MDD = 22.0 ± 11.1 years) and 25 were LDs (mean age: 35.2 ± 10.4 years; 12 [48%] women; age of onset of
MDD = 24.6 ± 11.6 years). Of the 83 completers, 41 patients received fluoxetine and CBT, and 42 patients received fluoxetine alone. Of the 36 drop-outs, 19 patients received fluoxetine and CBT and 17 patients received fluoxetine alone. Reasons for dropping out were as follows: lost to follow up (50%), noncompliance with medication (14%), adverse events (8%) and other (28%). The authors found a significant difference in age between completers, EDs, and LDs (Kruskal – Wallis; P < .01), with LDs being significantly younger than completers (Mann-Whitney; P < .01 (Table 1). We found a significant difference between completers, EDs and LDs in the duration of current episode of MDD (Kruskal – Wallis; P < .05); EDs were depressed for a longer period of time compared to LDs (Mann-Whitney; P < .05) and completers were depressed for a longer period of time compared to LDs (P < .05) (Table 1). EDs had significantly greater overall impairment in social adjustment compared to completers (Mann-Whitney; P < .05) (Table 1). There was no significant difference on the SQ subscales, ASI, BDI, HAMD-17, or BHS at the beginning of the continuation phase across the three groups. There was also no significant difference across EDs, LDs and completers in age of onset of MDD, and comorbid Axis I and Axis II disorders.
4. Discussion Dropping out of treatment can have profound consequences for patients and their families. It may lengthen a depressive episode, cause symptomatic relapse, disrupt the patient’s personal, family and professional life, increase repeated days out of work, increase suicides or suicide attempts and may generate major social costs for society (Montgomery and Kasper, 1998; Le Pen et al., 1994). Dropout rates in a clinical trial also have implications in research design and statistical analysis (Liang and Brown, 1997; Little and Yau, 1996; Lagakos et al., 1990). Our study found that LDs are significantly younger than completers, although age is not a predictor between EDs and LDs. Our findings are in agreement with those of Hillis and colleagues, who reported that younger individuals (20 years or under) were more likely to terminate treatment prema-
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turely, while those who were over 40 years of age were more likely to remain in treatment until its natural conclusion (Hillis et al., 1993). Heisler and coworkers reported that younger individuals (age < 20 years) were more likely to drop out of psychotherapeutic treatment compared to older patients (Heisler et al., 1982). Foulks et al. also found that older individuals were more compliant than younger individuals in a psychotherapy trial (Foulks et al., 1986). One might hypothesize that greater patience, maturity, and a greater degree of commitment to the therapeutic relationship may contribute towards greater compliance among older individuals. While a previous study from our group found differences in the ASI between drop-outs and completers (Tedlow et al., 1996), the current study did not find a difference in the ASI between EDs, LDs and completers. While we are not certain about the reasons for this difference, it is possible that anxiety sensitivity is more prominent in the earlier phase of a clinical trial and becomes less of an issue as patients get accustomed to the medication. In addition, we found that EDs have significantly greater social impairment compared to completers and EDs and completers are depressed for a longer duration compared to LDs.
not have the data on whether patients who dropped out continued in another study or received treatment elsewhere, there were no incentives for patients to drop out as they were receiving free medication and therapy if appropriate as part of the study.
5. Conclusions Our data suggest that LDs are significantly younger than completers, although age is not a predictor between EDs and LDs. Further, EDs and completers are depressed for a longer duration compared to LDs and EDs have significantly more social impairment compared to completers. Our study identified some patient characteristics significantly associated with dropping out of a long-term clinical trial.
Acknowledgments This study was supported by NIMH grant # R01-MH-48483-05.
4.1. Clinical implications References The main clinical implication of our study is that identification of possible predictors of dropping out from longterm antidepressant treatment may help identify individuals at risk of discontinuing treatment and increase the level of vigilance during follow-up care. By identifying patients who are likely to drop out, especially distinguishing between EDs and LDs, one can potentially use psychoeducation and appropriate interventions to enhance the likelihood that patients will continue in trials. It is possible that patients who are older and perhaps more mature, either because they have been ill for a longer period of time or have more experience with medication remain longer in clinical trials. Patients who are less ill may either drop out early or remain in trials because of improvement with study medication. LDs, being younger more naı¨ve to the seriousness of their illness may require more psychoeducation. However, our results are preliminary and further studies addressing this issue will be important to help distinguish when and why subjects drop out of studies. 4.2. Limitations Our study is limited by the fact that in the early versus late drop-out analyses, our sample size was rather small. We did not include relapsers in our analyses. Further, since this was a clinical trial with specific inclusion and exclusion criteria, sampling bias cannot be ruled out. In addition, our sample represent (patients who responded to medication and stayed in treatment during the first 8 weeks) hence a homogenous sample of initial responders. Although we do
Beck, A.T., Steer, R.A., 1988. Manual for the Beck Hopelessness Scale. Psychological Corporation, San Antonio, TX. Beck, A.T., Ward, C.E., Mendelson, M., 1961. An inventory for measuring depression. Arch. Gen. Psychiatry 4, 561 – 571. Claghorn, J.L., Feighner, J.P., 1991. A double-blind comparison of paroxetine with imipramine in the long-term treatment of depression. J. Clin. Psychopharmacol. 16, 23S – 27S. Feighner, J.P., Boyer, W.F., 1992. Paroxetine in the treatment of depression: a comparison with imipramine and placebo. J. Clin. Psychiatry 53, 44 – 47. Feighner, J.P., Gardner, E.A., Johnston, J.A., Batey, S.R., Khayrallah, M.A., Ascher, J.A., Lineberry, C.G., 1991. Double-blind comparison of bupropion and fluoxetine in depressed outpatients. J. Clin. Psychiatry 52, 329 – 335. Foulks, E.F., Persons, J.B., Merkel, R.L., 1986. The effect of patients’ beliefs about their illnesses on compliance in psychotherapy. Am. J. Psychiatry 143, 340 – 344. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56 – 62. Heisler, G.H., Beck, N.C., Fraps, C., McReynolds, W.T., 1982. Therapist ratings as predictors of therapy attendance. J. Clinical. Psychol. 38, 754 – 758. Hillis, G., Alexander, D.A., Eagles, J.M., 1993. Premature termination of psychiatric contact. Int. J. Soc. Psychiatry 39, 100 – 107. Kellner, R., 1987. A Symptom Questionnaire. J. Clin. Psychiatry 48, 268 – 274. Lagakos, S.W., Lim, L.Y., Robins, J.M., 1990. Adjusting for early treatment termination in comparative clinical trials. Stat. Med. 9, 1417 – 1424. Le Pen, C., Levy, E., Ravily, V., Beuzen, J.N., Meurgey, F., 1994. The cost of treatment drop-out in depression: a cost – benefit analysis of fluoxetine vs. tricyclics. J. Affective Disord. 31, 1 – 18. Liang, W.M., Brown, M.B., 1997. A median-based test under informative drop-out: the one-sample case. Control Clin. Trails 18, 445 – 459. Lin, E.H.B., Von Korff, M., Katon, W., Bush, T., Simon, G.E., Walker, E., Robinson, P., 1995. The role of the primary care physician in patients’ adherence to antidepressant therapy. Med. Care 33, 67 – 74.
S.B. Sonawalla et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 415–419 Linden, M., Osterheider, M., Nickelsen, T., Schaaf, B., 1993. Three types of early termination of antidepressant drug treatment. Int. Clin. Psychopharmacol. 8, 345 – 346. Little, R., Yau, L., 1996. Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics 52, 1324 – 1333. Montgomery, S.A., Kasper, S., 1998. Side effects, drop-outs from treatment and cost consequences. Int. Clin. Psychopharmacol. 13, S1 – S5. Peterson, R.A., Reiss, S., 1992. Anxiety Sensitivity Index Revised Test Manual. Intern Diagnostic Services, Worthington. Spitzer, R.L., Williams, J.B.W., Gibbon, M., First, M.B., 1989. Structured
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Clinical Interview for DSM-III-R—Patient Edition (SCID-P). Biometrics Research Department, New York. Tedlow, J.R., Fava, M., Uebelacker, L.A., Alpert, J.E., Nierenberg, A.A., Rosenbaum, J.F., 1996. Are study drop-outs different from completers? Biol. Psychiatry 40, 668 – 670. Weissman, M.M., Bothwell, S., 1976. Assessment of social adjustment by patient self-report. Arch. Gen. Psychiatry 33, 1111 – 1115. Zich, J.M., Attkisson, C.C., Greenfield, T.K., 1990. Screening for depression in primary care clinics: the CES-D and the BDI. Int. J. Psychiatry Med. 20 (3), 259 – 277.
Article
Early drop-outs, late drop-outs and completers: Differences in the continuation phase of a clinical trial Shamsah B. Sonawalla, M.D.*, Amy H. Farabaugh, Ph.D., Vinita M. Leslie, M.A., Joel A. Pava, Ph.D., John D. Matthews, M.D., Maurizio Fava, M.D. Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, WACC 812, 15 Parkman Street, Boston, MA 20114, USA
Abstract Objective: The purpose of this study was to assess the differences between early and late drop-outs and completers in the continuation phase of a clinical trial. Methods: The authors studied 119 outpatients who were treatment responders in an 8-week open trial with fluoxetine 20 mg/day, and who were then enrolled in a 26-week clinical trial comparing the efficacy of fluoxetine versus fluoxetine and cognitive behavior therapy (CBT). Patients were assessed using the Structured Clinical Interview for DSM-III-R — Axis I (SCID — Patient Edition), Hamilton Depression Rating Scale (HAMD-17) and the following self-rated scales: Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), Anxiety Sensitivity Index (ASI) and the Symptom Questionnaire (SQ) prior to starting the 26-week continuation phase. We defined ‘‘early drop-outs’’ (EDs) as patients who dropped out either at or prior to Visit 2 (which was at 2 months into the 6-month continuation phase); those dropping out at Visit 3 or later were defined as ‘‘late drop-outs’’ (LDs) (ED 2 months; LD > 2 months). The Kruskal – Wallis and the Mann – Whitney U tests were used for data analysis. Results: Of the 119 patients, 83 were completers (mean age: 42.1 ± 9.0 years; 46 [55%] women; age of onset of major depressive disorder [MDD] = 24.3 ± 12.5years), 11 were EDs (mean age: 38.1 ± 13.0 years; 4 [36%] women; age of onset of MDD = 22.0 ± 11.1 years) and 25 were LDs (mean age: 35.2 ± 10.4 years; 12 [48%] women; age of onset of MDD = 24.6 ± 11.6 years). LDs were significantly younger than completers ( P < .01). There was no significant difference in age between EDs and LDs, nor between EDs and completers. EDs were more likely to have been depressed for a longer period of time compared to LDs ( P < .05). EDs completers were depressed for a longer period of time compared to LDs ( P < .05). Conclusions: Our data suggest that late drop-outs are significantly younger than completers, although age is not a predictor between early drop-outs and late drop-outs. Further, early drop-outs are depressed for a longer duration compared to late drop-outs completers are depressed for a longer duration than late dropouts, and Early drop-outs have significantly more social impairment compared to completers. Our study identified some patient characteristics significantly associated with dropping out of a long-term clinical trial. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Age; Clinical trial; Completers; Early drop-outs; Late drop-outs; Major depression
1. Introduction In clinical trials, dropping out is a common occurrence, with drop-out rates ranging typically from 20% to 40% (Feighner and Boyer, 1992; Feighner et al., 1991). Patients Abbreviations: ASI, Anxiety Sensitivity Index; BHS, Beck Hopelessness Scale; CBT, cognitive behavioral therapy; ED, early drop-out; HAMD-17, Hamilton Depression Rating Scale; LD, late drop-out; MDD, major depressive disorder; SAS-SR, Social Adjustment Scale — Selfreport; SCID-P, Structured Clinical Interview for DSM-III-R — Axis I; SQ, Symptom Questionnaire * Corresponding author. Tel.: +1-617-726-9279; fax: +1-617-7243028. E-mail address: [email protected] (S.B. Sonawalla, M.D.).
may drop out of an ongoing clinical trial for several reasons. Claghorn and Feighner reported that the primary reasons for treatment discontinuation in the antidepressant treatment group of a clinical trial were adverse events and patients being lost to follow-up, and in the placebo group, ineffectiveness of treatment was noted (Claghorn and Feighner, 1991). A previous study from our group, reported differences between completers and drop-outs in the open phase of an 8-week clinical trial with fluoxetine (Tedlow et al., 1996). The study found a trend for higher scores on the Hamilton Depression Rating Scale (HAMD-17) (Hamilton, 1960) and on the Anxiety Sensitivity Index (ASI) (Peterson and Reiss, 1992) among those patients who dropped out of an acute phase of a treatment study (Tedlow et al., 1996).
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In addition to differences between completers and dropouts, there may be differences between early and late dropouts. For example, Linden and colleagues (1993) found that the main reasons for termination of antidepressant treatment were adverse drug effects, insufficient response and complete or sufficient response. They further reported that adverse drug effects led to early termination during the first few weeks, complete response resulted in termination after 4 to 8 weeks of treatment, and insufficient response caused treatment to be stopped almost linearly during the 12 weeks of observation (Linden et al., 1993). Lin and co-workers (1995) focused on predictors of early and late adherence to antidepressant therapy. Early adherence was defined as using antidepressants for at least 30 days after filling the initial prescription, while late adherence was defined as using antidepressants for at least 90 days after the initial prescription. They reported that 28% of patients dropped out within the first 2 weeks of treatment, while 44% dropped out after 90 days. They also found that dropping out early was related to severe side effects and not receiving an educational message, while dropping out late was significantly related to being on an antidepressant in the past (Lin et al., 1995). The present aim is to further examine predictors of early versus late drop-out during the continuation phase of a clinical trial.
2. Methods 2.1. Patient population The authors studied 119 outpatients between 18 and 65 years of age with major depressive disorder (MDD) who were treatment responders in an 8-week open treatment with fluoxetine 20 mg/day and who were entered into the continuation phase of a 26-week clinical trial comparing the efficacy of fluoxetine versus fluoxetine and cognitive behavior therapy (CBT). The initial sample in the acute phase consisted of 384 outpatients (55% female) between the ages of 18 and 65 years (mean age: 39.9 ± 10.5 years) who met criteria for MDD as measured by the Structured Clinical Interview for DSM-III-R — Patient Edition (SCID-P) (Spitzer et al., 1989), and had a HAMD-17 score 16 at baseline. 2.2. Study design Patients who met criteria for remitted depression, defined as a HAMD-17 score of 7 at week 8, were enrolled in the continuation phase, which lasted 26 weeks. Patients who entered the continuation phase were either randomized into a group that received fluoxetine 40 mg/day, or one that received fluoxetine 40 mg/day plus CBT. Fully trained and experienced psychologists in our program administered the CBT. Fifty-minute treatment sessions were conducted twice a week for the initial 4 weeks, then once a week for
12 weeks, and once every 2 weeks for the rest of the 26-week study. We defined ‘‘early drop-outs’’ (EDs) as patients who dropped out either at or prior to Visit 2 (which was at 2 months into the 6 month continuation phase); those dropping out at Visit 3 or later were defined as ‘‘late dropouts’’ (LDs) (ED 2 months; LD >2 months). The treatment trial was conducted by the Depression Clinical and Research Program at the Massachusetts General Hospital. After complete description of the study to subjects, written informed consent was obtained prior to participation in this study, which was approved by the Institutional Review Board of Massachusetts General Hospital. The following patients were excluded from the study: pregnant women, women of child-bearing potential who were not using either intrauterine device or a barrier device for contraception, women of child-bearing potential taking a birth control pill, lactating women, patients with serious suicidal risk, patients with a history of neurological illness including seizure disorder, serious medical illness, organic mental disorders, substance use disorders active within the last year, schizophrenia, delusional disorder, bipolar disorder or antisocial personality disorder, patients with mood congruent or mood incongruent psychotic features, history of multiple adverse drug reactions or allergy to the study drugs, current use of other psychotropic drugs, clinical or laboratory evidence of hypothyroidism, patients with a previous nonresponse to or intolerance of fluoxetine (60 –80 mg/day) or to the combination of fluoxetine and desipramine or fluoxetine and lithium, and patients who had failed to respond during the course of their current major depressive episode to at least one adequate antidepressant trial ( 6-weeks of treatment with either 150 mg of imipramine [or its tricyclic equivalent], 60 mg of fluoxetine or its selective serotonin reuptake inhibitor equivalent, or 60 mg of phenelzine [or its monoamine oxidase inhibitor equivalent]). 2.3. Assessment instruments At the beginning of the continuation phase (i.e., after the initial 8-week acute phase), patients were assessed using the depression module of the SCID-P, the HAMD-17, and the following self-rated scales: Beck Depression Inventory (BDI) (Beck et al., 1961), Beck Hopelessness Scale (BHS) (Beck and Steer, 1988), the Reiss-Epstein Gursky Anxiety Sensitivity Index (ASI) (Peterson and Reiss, 1992), Symptom Questionnaire (SQ) (Kellner, 1987) and Social Adjustment Scale — Self-report (SAS-SR) (Weissman and Bothwell, 1976). The BDI is a 21-item self-rated scale, which measures the behavioral manifestations of depression and has a sensitivity of 100% when a cut-off score of 16 is used to screen for major depression (Zich et al., 1990; Beck et al., 1961). The BHS is a 20-item, true/false inventory designed to assess pessimistic expectations, with higher scores indicating greater hopelessness (Beck and Steer, 1988). The ASI measures fear of anxiety and sensitivity to somatic cues (Peterson and Reiss, 1992). The SQ is a 92-item
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Table 1 Age, duration of MDD, and baseline SAS-SR scores of study completers, early drop-outs, and late drop-outs Completers (n = 83) Mean Age (years) Duration of MDD (years) SAS-SR a b c d
a
42.1 3.3b 2.5d
Early drop-outs (n = 11) S.D. 9.0 5.5 0.8
Mean 38.1 4.9c 3.3d
Late drop-outs (n = 25)
Kruskal – Wallis
S.D.
Mean
S.D.
Overall P
df
13.0 6.1 1.0
a
10.4 2.0 0.8
.005 .04 .1
2 2 2
35.2 1.3b,c 2.7
Mann – Whitney U test: P <.01, completers vs. late drop-outs. Mann – Whitney U test: P <.05, completers vs. late drop-outs. Mann – Whitney U test: P <.05, early drop-outs vs. late drop-outs. Mann – Whitney U test: P =.05, completers vs. early drop-outs.
self-rated questionnaire, which assesses psychological wellbeing as well as symptoms of depression, anxiety, hostility and somatization (Kellner, 1987). The SAS-SR was used as a measure of social dysfunction (Weissman and Bothwell, 1976). It measures adjustment in major role areas of functioning, including: work outside the home, or at home or as a student; functioning in social and leisure activities; functioning in extended family, marital and parental roles; functioning within a family unit; and economic functioning. The SCID-P and HAMD-17 interviews were conducted by psychiatrists and clinicians affiliated with the Depression Clinical and Research Program who were fully trained in the use of these instruments through live and videotaped interviews. Although interrater reliability in the use of SCID-P was not formally assessed, participating clinicians established consensus with respect to the operational criteria required for Axis I disorders through interrater reliability sessions. 2.4. Data analysis The Kruskal – Wallis test was used to compare the continuous variable characteristics between completers, EDs, and LDs. The Mann –Whitney U test was then used for pairwise comparisons between groups. The chi-square method was used to compare the categorical demographic profiles across the three groups.
3. Results One hundred and twenty-nine patients had a HAMD-17 score 7 after 8 weeks of treatment with fluoxetine 20 mg/day and were enrolled in the continuation phase of the clinical trial comparing the efficacy of fluoxetine 40 mg/day versus fluoxetine 40 mg/day plus CBT. Ten patients relapsed, leaving 119 patients who were the subjects of this study. Of these 119 patients, 83 were completers (mean age: 42.1 ± 9.0 years; 46 [55%] women; age of onset of MDD = 24.3 ± 12.5years), 11 were EDs (mean age: 38.1 ± 13.0 years; 4 [36%] women; age of onset of MDD = 22.0 ± 11.1 years) and 25 were LDs (mean age: 35.2 ± 10.4 years; 12 [48%] women; age of onset of
MDD = 24.6 ± 11.6 years). Of the 83 completers, 41 patients received fluoxetine and CBT, and 42 patients received fluoxetine alone. Of the 36 drop-outs, 19 patients received fluoxetine and CBT and 17 patients received fluoxetine alone. Reasons for dropping out were as follows: lost to follow up (50%), noncompliance with medication (14%), adverse events (8%) and other (28%). The authors found a significant difference in age between completers, EDs, and LDs (Kruskal – Wallis; P < .01), with LDs being significantly younger than completers (Mann-Whitney; P < .01 (Table 1). We found a significant difference between completers, EDs and LDs in the duration of current episode of MDD (Kruskal – Wallis; P < .05); EDs were depressed for a longer period of time compared to LDs (Mann-Whitney; P < .05) and completers were depressed for a longer period of time compared to LDs (P < .05) (Table 1). EDs had significantly greater overall impairment in social adjustment compared to completers (Mann-Whitney; P < .05) (Table 1). There was no significant difference on the SQ subscales, ASI, BDI, HAMD-17, or BHS at the beginning of the continuation phase across the three groups. There was also no significant difference across EDs, LDs and completers in age of onset of MDD, and comorbid Axis I and Axis II disorders.
4. Discussion Dropping out of treatment can have profound consequences for patients and their families. It may lengthen a depressive episode, cause symptomatic relapse, disrupt the patient’s personal, family and professional life, increase repeated days out of work, increase suicides or suicide attempts and may generate major social costs for society (Montgomery and Kasper, 1998; Le Pen et al., 1994). Dropout rates in a clinical trial also have implications in research design and statistical analysis (Liang and Brown, 1997; Little and Yau, 1996; Lagakos et al., 1990). Our study found that LDs are significantly younger than completers, although age is not a predictor between EDs and LDs. Our findings are in agreement with those of Hillis and colleagues, who reported that younger individuals (20 years or under) were more likely to terminate treatment prema-
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turely, while those who were over 40 years of age were more likely to remain in treatment until its natural conclusion (Hillis et al., 1993). Heisler and coworkers reported that younger individuals (age < 20 years) were more likely to drop out of psychotherapeutic treatment compared to older patients (Heisler et al., 1982). Foulks et al. also found that older individuals were more compliant than younger individuals in a psychotherapy trial (Foulks et al., 1986). One might hypothesize that greater patience, maturity, and a greater degree of commitment to the therapeutic relationship may contribute towards greater compliance among older individuals. While a previous study from our group found differences in the ASI between drop-outs and completers (Tedlow et al., 1996), the current study did not find a difference in the ASI between EDs, LDs and completers. While we are not certain about the reasons for this difference, it is possible that anxiety sensitivity is more prominent in the earlier phase of a clinical trial and becomes less of an issue as patients get accustomed to the medication. In addition, we found that EDs have significantly greater social impairment compared to completers and EDs and completers are depressed for a longer duration compared to LDs.
not have the data on whether patients who dropped out continued in another study or received treatment elsewhere, there were no incentives for patients to drop out as they were receiving free medication and therapy if appropriate as part of the study.
5. Conclusions Our data suggest that LDs are significantly younger than completers, although age is not a predictor between EDs and LDs. Further, EDs and completers are depressed for a longer duration compared to LDs and EDs have significantly more social impairment compared to completers. Our study identified some patient characteristics significantly associated with dropping out of a long-term clinical trial.
Acknowledgments This study was supported by NIMH grant # R01-MH-48483-05.
4.1. Clinical implications References The main clinical implication of our study is that identification of possible predictors of dropping out from longterm antidepressant treatment may help identify individuals at risk of discontinuing treatment and increase the level of vigilance during follow-up care. By identifying patients who are likely to drop out, especially distinguishing between EDs and LDs, one can potentially use psychoeducation and appropriate interventions to enhance the likelihood that patients will continue in trials. It is possible that patients who are older and perhaps more mature, either because they have been ill for a longer period of time or have more experience with medication remain longer in clinical trials. Patients who are less ill may either drop out early or remain in trials because of improvement with study medication. LDs, being younger more naı¨ve to the seriousness of their illness may require more psychoeducation. However, our results are preliminary and further studies addressing this issue will be important to help distinguish when and why subjects drop out of studies. 4.2. Limitations Our study is limited by the fact that in the early versus late drop-out analyses, our sample size was rather small. We did not include relapsers in our analyses. Further, since this was a clinical trial with specific inclusion and exclusion criteria, sampling bias cannot be ruled out. In addition, our sample represent (patients who responded to medication and stayed in treatment during the first 8 weeks) hence a homogenous sample of initial responders. Although we do
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