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Attrition factors in clinical trials of comorbid bipolar and substance-related disorders
Journal of Affective Disorders 112 (2009) 284 – 288 www.elsevier.com/locate/jad
Brief report
Attrition factors in clinical trials of comorbid bipolar and substance-related disorders Nicole Nomamiukor, E. Sherwood Brown ⁎ Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States Received 4 December 2007; received in revised form 4 April 2008; accepted 22 April 2008 Available online 29 May 2008
Abstract Background: This study analyzed and defined specific factors that account for attrition in clinical research for patients with bipolar and substance-related disorders. Methods: Data were analyzed from two completed studies: an open-label trial of lamotrigine in patients with bipolar disorder (BPD) and cocaine-related disorder, and a placebo-controlled trial of quetiapine in patients with BPD and alcohol-related disorders. Correlations and Independent sample t-tests were performed to assess the impact of baseline characteristics including on length of study participation. Significance was set at the p = 0.05 level. Results: In the lamotrigine-treated patients, the presence of an amphetamine-related disorder, in addition to cocaine-related disorders, was associated with a shorter time in the study. In the quetiapine-treated patients higher scores on the Addiction Severity Index Legal subscale were associated with shorter length in the study. The presence of panic disorder was associated with shorter time in both studies. Limitations: Although the data were taken from the two largest clinical trials, to date, in patients with BPD and substance-related disorders, the sample sizes were relatively modest. In addition, the baseline assessments were somewhat different in the two studies limiting our ability to make conclusions on differences between patients with BPD and cocaine use versus alcohol use. Conclusions: This study adds to an emerging literature on the significance of panic disorder in patients with BPD. © 2008 Elsevier B.V. All rights reserved. Keywords: Attrition; BPD; Cocaine; Alcohol
1. Introduction An estimated 22.2 million Americans age 12 or older have substance abuse/dependence. A problem in treating this population is treatment retention. Attrition rates up to 84% are observed in substance dependence ⁎ Corresponding author. UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas, 75390-8849, United States. Tel.: +1 214 645 6950; fax: +1 214 645 6951. E-mail address: [email protected] (E.S. Brown). 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.04.016
clinical trials (Lima et al., 2002). Younger age, minority ethnic/racial group, lower education, severity of substance use, concomitant psychiatric symptoms, and poor cognitive functioning are associated with higher rates of attrition (Sayre et al., 2002; McKellar et al., 2006; Gelkopf et al., 2006; Broome et al., 1999; Joe et al., 1995; Rees et al., 1984; Ryan et al., 1995; Mertens and Weisner, 2000). Medication side effects are a risk factor for treatment discontinuation (Lima et al., 2002). Limited research has been conducted on the treatment of bipolar disorder (BPD) and substance use disorders.
N. Nomamiukor, E.S. Brown / Journal of Affective Disorders 112 (2009) 284–288
Some studies show that patients with more severe psychiatric symptoms, particularly depression, tend to stay in treatment longer than those without (Nuttbrock et al., 1997; Gelkopf et al., 2006; Broome et al., 1999). Absence of substance use at baseline is associated with treatment retention in dual diagnosis patients (Laudet et al., 2003). We reported that baseline scores on the Barrett Impulsiveness Scale Non-Planning (Barratt and Patton, 1983) subscale negatively correlated (r = − .312, p b .05) with length of study participation in patients with BPD and cocaine-related disorders given lamotrigine (Akingbala et al., 2006). To explore factors associated with clinical trial attrition in patients with BPD and substance-related disorders we examined data from the two largest clinical trials in this population, reported to date. One study was a trial of lamotrigine in patients with BPD and cocaine abuse/dependence (Brown et al., 2006), and the other a trial of quetiapine in patients with BPD and alcohol abuse/dependence (Brown et al., 2008). 2. Methods Data were obtained from two clinical trials in which the primary analysis have been previously published (Brown et al., 2008, 2006). Detailed descriptions of experimental methods can be found in the primary papers (Brown et al., 2008, 2006). All participants completed an IRB approved informed written consent process. Participants in both studies were assessed with the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998), 17-item Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960), and Young Mania Rating Scale (YMRS) (Young et al., 1978) and substance use was quantified. One study was an open-label trial of lamotrigine in 80 adults with bipolar I, II or NOS disorders and current cocaine or amphetamine abuse/dependence. In addition to the MINI, HAM-D and YMRS, outcomes included the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962), urine drug screens, amount of cocaine use, and the Cocaine Craving Questionnaire (CCQ) (Tiffany et al., 1993). The other study was a randomized, placebocontrolled trial of quetiapine in adults with BPD and alcohol-related disorders. Inclusion criteria for the participants were diagnoses of bipolar I or bipolar II, and current alcohol abuse/ dependence. In addition to the MINI, HAM-D and YMRS, assessments included alcohol use, Somatic Symptom Scale (Thase et al., 1996) to assess medication side effects, Addiction Severity Index (ASI) (Mclellan et al., 1980) and Barratt
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Impulsiveness Scale Non-Planning subscale (Barratt and Patton, 1983). In both studies some participants were receiving concomitant psychiatric medications. Changes in concomitant medications were made when clinically necessary. For additional information on specific concomitant medications used in the two studies see the primary papers (Brown et al., 2008, 2006). Statistical analyses were performed on SPSS. Continuous variables (i.e. age) were correlated with the length of study participation using Pearson's Correlation Coefficient. Categorical variables (i.e. gender) were assessed by comparing the means between the groups using 2-tailed independent sample t-test. Variables with multiple groups were analyzed using a one way between group analysis of variance (ANOVA). Significance was defined as a p ≤ 0.05. 3. Results The lamotrigine trial (n = 80) included Caucasians (69%), African Americans (24%), Hispanics (6%) and Native Americans (1%). The mean age was 36.2 ± Table 1 Correlations of length of study participation with demographics, drug use severity, and psychiatric variables A. Lamotrigine/stimulant Length of study participation (baseline) Variable Age HAM-D YMRS BPRS CCQ Days of stimulant use/week Dollars spent on stimulants/week
r-score .116 −.303 ⁎ −.087 −.218 ⁎ −.181 −.110 .096
B. Quetiapine/alcohol Length of Study participation (baseline) Variable Age HAM-D YMRS ASI alcohol composite ASI drug composite score ASI employment ASI family/social composite score ASI legal composite score ASI medical composite ASI psychiatric composite score Somatic Symptoms Scale (side effects) Days of alcohol use/week Total # of standard drinks/week ⁎ Correlation significant at ⁎p ≤ 0.05.
r-score .178 −.149 .065 −.052 −.054 −.030 −.200 −.235 ⁎ −.032 −.023 −.117 −.097 .017
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8.7 years, with an equal number of men (n = 40) and women (n = 40). The attrition rate was 69% (55/80) in the 12 week acute phase. Scores in the HAM-D and BPRS correlated negatively with length of participation. No other correlations were significant (Table 1A). Patients with panic disorder had significantly (p = .039) lower mean weeks of participation than those without panic disorder (Table 2A). Of those with panic disorder who did not complete the 12 week acute phase all but one was discontinued due to need for emergency/inpatient care, side effects or lost to follow-up. One discontinued themselves because they wanted to start valproate under the care of an outside physician. ANOVA showed no significant difference on BPD diagnosis (bipolar I, bipolar II, bipolar NOS), race/ethnicity (Caucasian, African American, Hispanic, Other), or baseline mood state (euthymic, depressed, manic, mixed, depressed and hypomanic, hypomanic). The ANOVA revealed differences in time in the study based on substance use diagnosis of cocaine dependence only (n = 66, 6.26 ± 4.80 weeks) amphetamine dependence (n = 7, 7.43 ±
4.96 weeks) and both cocaine and amphetamine dependence (n = 7, 1.71 ± 1.25 weeks) (p = 0.038). In the quetiapine study, patient demographics (n = 115) included a mean age of 37.72 ± 9.542 years, 60% Caucasian, 27% African American, 9.5% Hispanic, 66% male and 34% female, with an attrition rate of 61% (70/115). The only significant correlation with length of time in study was baseline ASI legal score (Table 1B.) Patients with panic disorder had significantly lower mean weeks in the study. Reasons for withdrawal in the panic disorder group included incarceration, moving out of area, desire for open-label treatment, worsening of symptoms, side effects and lost to follow-up. Patients with obsessive-compulsive disorder had significantly higher mean number of weeks in the study. Bipolar I patients had a significantly shorter time in the study than bipolar II patients. An ANOVA did not reveal significance differences in time in the study based on race/ethnicity (Caucasian, African American, Hispanic, Other) or mood state (euthymic, depressed, manic, mixed, depressed and hypomanic).
Table 2 Between group comparisons (t-test) with length of study participation
4. Discussion
A. Lamotrigine/stimulant
Attrition rates were high in both studies underscoring the challenges of research in patients with BPD and substance use disorders. Perhaps the most interesting finding is the relationship between panic disorder and attrition observed in both studies. Panic disorder is common in patients with BPD with rates of 21-35% reported in community-based studies (Chen and Dilsaver, 1995; Goodwin and Hoven, 2002). We previously reported a lifetime prevalence of panic disorder of 54% in patients with BPD and alcohol abuse/dependence and 42% in BPD and cocaine abuse/dependence (Mitchell et al., 2007). Thus, panic disorder is a common comorbid condition in BPD that until recently has been the focus of little attention. MacKinnon and Zamoiski (2006) suggested that deficits in conditioning processes within the amygdala may explain what they termed the “manic-panic connection”. Masi et al. (2007) reported that panic disorder is also common in children and adolescents with BPD (23%). Panic disorder appears to be associated with an increased risk of suicidal ideation in adolescents with BPD (Dilsaver et al., 2006), and may be more common in patients presenting with mixed versus pure mania (Dilsaver and Chen, 2003). Our studies did not show a relationship between amount of substance use at baseline and study attrition, although the combined use of cocaine and amphetamines was associated with early withdrawal in the lamotrigine study. We also did not observe the relationship between
Length of study participation (weeks) (±SD) Male (n = 40) Female (n40) 6.03 ± 5.03 5.74 ± 4.52 PTSD (n = 26) PTSD absent (n50) 6.28 ± 4.61 4.88 ± 4.83 Panic disorder (n = 31) Panic disorder absent (n43) ⁎ 4.16 ± 4.30 6.86 ± 4.81 Social phobia (n = 20) Social Phobia absent (n54) 4.445 ± 4.27 6.500 ± 4.74 OCD (n = 9) OCD absent (n66) 5.67 ± 4.33 5.894 ± 78 Antisocial personality (n = 43) Antisocial Personality absent (n34) 5.81 ± 4.72 5.97 ± 4.80 B. Quetiapine/alcohol Length of study participation (weeks) (±SD) Male (n = 76) Female (n39) 7.14 ± 4.78 7.21 ± 4.45 PTSD (n = 31) PTSD absent (n83) 7.52 ± 4.39 6.98 ± 4.76 Panic disorder (n = 51) Panic disorder absent (n63) ⁎ 6.16 ± 4.76 7.90 ± 4.45 Social phobia (n = 59) Social phobia absent (n55) 7.39 ± 4.679 6.84 ± 4.642 OCD (n = 40) OCD absent (n73) ⁎ 8.35 ± 4.336 6.53 ± 4.694 Antisocial personality (n = 50) Antisocial personality absent (n63) 7.14 ± 4.77 7.16 ± 4.61 Bipolar I (n = 57) Bipolar II (n58) ⁎ 6.05 ± 4.561 8.26 ± 4.513 ⁎ p ≤ 0.05.
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impulsivity, as assessed by the BIS NP subscale, and attrition in the quetiapine that we previously reported in a subset of patients in the lamotrigine study. Severity of depression was previously reported to be associated with less attrition (Nuttbrock et al., 1997; Gelkopf et al., 2006; Broome et al., 1999). However, in our lamotrigine trial, higher HAM-D and BPRS scores were associated with earlier withdrawal from the study, although, categorical diagnosis of baseline mood state was not associated with attrition. Thus, it appears that severity of psychiatric symptoms, but not manic/hypomanic versus depressed mood state, is associated with attrition in patients with BPD and cocaine-use disorders. Interestingly, patients with OCD remained in the study longer than those without OCD in the quetiapine study. Although somewhat different factors were related to attrition in the two studies, it may not be accurate to conclude that the differences are related to differences in persons with stimulant use versus those with alcohol use since many participants used both substances in the studies. In addition, one study was open-label and the other placebo controlled and different medications with potentially different spectrums of efficacy and side effects were used. To our knowledge, the relationship between panic disorder and treatment adherence or attrition in people with BPD has not been previously explored. The findings suggest that greater attention should be paid to comorbid panic disorder in dual diagnosis patients. Role of funding source The studies from which the data for this paper were derived were funded by the Stanley Medical Research Institute and an investigatorinitiated grant from AstraZeneca. In addition, GlaxoSmithKline provided lamotrigine for one study. AstraZeneca provided feedback on the design of the quetiapine trial. Sponsors were not involved in the data analysis or interpretation of the findings presented in this report. Conflict of interest Dr. E. Sherwood Brown has research grants from AstraZeneca, Forest Laboratories, GlaxoSmithKline, McNeil, NIAAA, and the Stanley Medical Research Institute. Nicole Nomamiukor has no conflict of interest to disclose.
Acknowledgment Funded by the Stanley Medical Research Institute and AstraZeneca and medication for one study provided by GlaxoSmithKline. References Akingbala, F., Dhanani, N., Brown, E.S., 2006. Impulsivity in patients with BPD and cocaine or amphetamine dependence given lamotrigine. J. Dual Diagn. 2, 73–83.
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Barratt, E.S., Patton, J.H., 1983. Impulsivity: cognitive, behavioral, and psychophysiological correlates. In: Zuckerman, M. (Ed.), Biological Basis of Sensation-Seeking, Impulsivity, and Anxiety. Lawrence Erlbaum Associates, Hillsdale, NJ, pp. 77–116. Broome, K., Flynn, P., Simpson, D., 1999. Psychiatric comorbidity measures as predictors of retention in drug abuse treatment programs. Health Serv. Res. 34, 791–806. Brown, E.S., Perantie, D.C., Dhanani, N., Beard, L., Orsulak, P., Rush, A.J., 2006. Lamotrigine for BPD and comorbid cocaine dependence: a replication and extension study. J. Affect. Disord. 93, 219–222. Brown, E.S., Garza, M., Carmody, T., 2008. A randomized, doubleblind, placebo-controlled trial of quetiapine in outpatients with BPD and alcohol use disorders. J. Clin. Psychiatry. Chen, Y.W., Dilsaver, S.C., 1995. Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area Survey. Am. J. Psychiatry 152, 280–282. Dilsaver, S.C., Chen, Y.W., 2003. Social phobia, panic disorder and suicidality in subjects with pure and depressive mania. J. Affect. Disord. 77, 173–177. Dilsaver, S.C., Akiskal, H.S., Akiskal, K.K., Benazzi, F., 2006. Doseresponse relationship between number of comorbid anxiety disorders in adolescent bipolar/unipolar disorders, and psychosis, suicidality, substance abuse and familiality. J. Affect. Disord. 96, 249–258. Gelkopf, M., Weizman, T., Melamed, Y., Adelson, M., Bleich, A., 2006. Does psychiatric comorbidity affect drug abuse treatment outcome? A prospective assessment of drug abuse, treatment tenure and infectious diseases in an Israeli methadone maintenance clinic. Isr. J. Psychiatry Relat. Sci. 43, 126–136. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. Goodwin, R.D., Hoven, C.W., 2002. Bipolar-panic comorbidity in the general population: prevalence and associated morbidity. J. Affect. Disord. 70, 27–33. Joe, G.W., Brown, B.S., Simpson, D.D., 1995. Psychological problems and client engagement in methadone treatment. J. Nerv. Ment. Dis. 183, 704–710. Laudet, A., Magura, S., Cleland, C., Vogel, H., Knight, E., 2003. Predictors of retention in dual-focus self-help groups. Community Ment. Health J. 39, 281–297. Lima, M., Soares, O.B., Reisser, P.A., Farell, M., 2002. Pharmacological treatment of cocaine dependence: a systematic review. Addiction 97, 931–949. MacKinnon, D.F., Zamoiski, R., 2006. Panic comorbidity with BPD: what is the manic–panic connection? Bipolar. Diosord. 8, 648–664. Masi, G., Perugi, G., Millepiedi, S., Toni, C., Mucci, M., Nicoletta, B., Pfanner, Berloffa, S., Pari, Akiskal, K., Akiskal, H.S., 2007. Clinical and research implications of panic-bipolar comorbidity in children and adolescents. Psychiatry Res. 153, 47–54. McKellar, J., Kelly, J., Harris, J., Moos, R., 2006. Pretreatment and during treatment risk factors for dropout among patients with substance use disorders. Addict. Behav. 31, 450–460. McLellan, A.T., Luborsky, L., Woody, G.E., O'Brien, C.P., 1980. An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index. J. Nerv. Ment. Dis. 168, 26–33. Mertens, J.R., Weisner, C.M., 2000. Predictors of substance abuse treatment retention among women and men in an HMO. Alcohol Clin. Exp. Res. 24, 1525–1533. Mitchell, J.D., Brown, E.S., Rush, A.J., 2007. Comorbid disorders in patients with bipolar and concomitant substance dependence. J. Affect. Disord. 102, 281–287.
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Nuttbrock, L., Ng-Mak, D., Rahav, M., Rivera, J., 1997. Pre- and postadmission attrition of homeless, mentally ill chemical abusers referred to residential treatment programs. Addiction 92 (10), 1305–1315. Overall, J., Gorham, D., 1962. The brief psychiatric rating scale. Psychol. Rep. 10, 799–812. Rees, D., Beech, H., Hore, B., 1984. Some factors associated with compliance in the treatment of alcoholism. Alcohol Alcohol. 19, 303–307. Ryan, R., Plant, R., O'Malley, S., 1995. Initial motivations for alcohol treatment: relations with patient characteristics, treatment involvement and drop out. Addict. Behav. 20, 279–297. Sayre, S.L., Schmitz, J.M., Stotts, A.L., Averill, P.M., Rhoades, H.M., Grabowski, J.J., 2002. Determining predictors of attrition in an outpatient substance abuse program. Am. J. Drug Alcohol Abuse 24, 55–72.
Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The miniinternational neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59, 22–33. Thase, M.E., Fava, M., Halbreich, U., Kocsis, J.H., Koran, L., Davidson, J., Rosenbaum, J., Harrison, W., 1996. A placebocontrolled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch. Gen. Psychiatry 53, 777–784. Tiffany, S.T., Singleton, E., Haertzen, C.A., Henningfield, J.E., 1993. The development of a cocaine craving questionnaire. Drug Alcohol Depend. 34, 19–28. Young, R., Biggs, J., Meyer, D., 1978. A rating scale for mania: reliability, validity, and sensitivity. Br. J. Psychiatry 133, 429–435.
Brief report
Attrition factors in clinical trials of comorbid bipolar and substance-related disorders Nicole Nomamiukor, E. Sherwood Brown ⁎ Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, United States Received 4 December 2007; received in revised form 4 April 2008; accepted 22 April 2008 Available online 29 May 2008
Abstract Background: This study analyzed and defined specific factors that account for attrition in clinical research for patients with bipolar and substance-related disorders. Methods: Data were analyzed from two completed studies: an open-label trial of lamotrigine in patients with bipolar disorder (BPD) and cocaine-related disorder, and a placebo-controlled trial of quetiapine in patients with BPD and alcohol-related disorders. Correlations and Independent sample t-tests were performed to assess the impact of baseline characteristics including on length of study participation. Significance was set at the p = 0.05 level. Results: In the lamotrigine-treated patients, the presence of an amphetamine-related disorder, in addition to cocaine-related disorders, was associated with a shorter time in the study. In the quetiapine-treated patients higher scores on the Addiction Severity Index Legal subscale were associated with shorter length in the study. The presence of panic disorder was associated with shorter time in both studies. Limitations: Although the data were taken from the two largest clinical trials, to date, in patients with BPD and substance-related disorders, the sample sizes were relatively modest. In addition, the baseline assessments were somewhat different in the two studies limiting our ability to make conclusions on differences between patients with BPD and cocaine use versus alcohol use. Conclusions: This study adds to an emerging literature on the significance of panic disorder in patients with BPD. © 2008 Elsevier B.V. All rights reserved. Keywords: Attrition; BPD; Cocaine; Alcohol
1. Introduction An estimated 22.2 million Americans age 12 or older have substance abuse/dependence. A problem in treating this population is treatment retention. Attrition rates up to 84% are observed in substance dependence ⁎ Corresponding author. UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas, 75390-8849, United States. Tel.: +1 214 645 6950; fax: +1 214 645 6951. E-mail address: [email protected] (E.S. Brown). 0165-0327/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2008.04.016
clinical trials (Lima et al., 2002). Younger age, minority ethnic/racial group, lower education, severity of substance use, concomitant psychiatric symptoms, and poor cognitive functioning are associated with higher rates of attrition (Sayre et al., 2002; McKellar et al., 2006; Gelkopf et al., 2006; Broome et al., 1999; Joe et al., 1995; Rees et al., 1984; Ryan et al., 1995; Mertens and Weisner, 2000). Medication side effects are a risk factor for treatment discontinuation (Lima et al., 2002). Limited research has been conducted on the treatment of bipolar disorder (BPD) and substance use disorders.
N. Nomamiukor, E.S. Brown / Journal of Affective Disorders 112 (2009) 284–288
Some studies show that patients with more severe psychiatric symptoms, particularly depression, tend to stay in treatment longer than those without (Nuttbrock et al., 1997; Gelkopf et al., 2006; Broome et al., 1999). Absence of substance use at baseline is associated with treatment retention in dual diagnosis patients (Laudet et al., 2003). We reported that baseline scores on the Barrett Impulsiveness Scale Non-Planning (Barratt and Patton, 1983) subscale negatively correlated (r = − .312, p b .05) with length of study participation in patients with BPD and cocaine-related disorders given lamotrigine (Akingbala et al., 2006). To explore factors associated with clinical trial attrition in patients with BPD and substance-related disorders we examined data from the two largest clinical trials in this population, reported to date. One study was a trial of lamotrigine in patients with BPD and cocaine abuse/dependence (Brown et al., 2006), and the other a trial of quetiapine in patients with BPD and alcohol abuse/dependence (Brown et al., 2008). 2. Methods Data were obtained from two clinical trials in which the primary analysis have been previously published (Brown et al., 2008, 2006). Detailed descriptions of experimental methods can be found in the primary papers (Brown et al., 2008, 2006). All participants completed an IRB approved informed written consent process. Participants in both studies were assessed with the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998), 17-item Hamilton Rating Scale for Depression (HAM-D) (Hamilton, 1960), and Young Mania Rating Scale (YMRS) (Young et al., 1978) and substance use was quantified. One study was an open-label trial of lamotrigine in 80 adults with bipolar I, II or NOS disorders and current cocaine or amphetamine abuse/dependence. In addition to the MINI, HAM-D and YMRS, outcomes included the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962), urine drug screens, amount of cocaine use, and the Cocaine Craving Questionnaire (CCQ) (Tiffany et al., 1993). The other study was a randomized, placebocontrolled trial of quetiapine in adults with BPD and alcohol-related disorders. Inclusion criteria for the participants were diagnoses of bipolar I or bipolar II, and current alcohol abuse/ dependence. In addition to the MINI, HAM-D and YMRS, assessments included alcohol use, Somatic Symptom Scale (Thase et al., 1996) to assess medication side effects, Addiction Severity Index (ASI) (Mclellan et al., 1980) and Barratt
285
Impulsiveness Scale Non-Planning subscale (Barratt and Patton, 1983). In both studies some participants were receiving concomitant psychiatric medications. Changes in concomitant medications were made when clinically necessary. For additional information on specific concomitant medications used in the two studies see the primary papers (Brown et al., 2008, 2006). Statistical analyses were performed on SPSS. Continuous variables (i.e. age) were correlated with the length of study participation using Pearson's Correlation Coefficient. Categorical variables (i.e. gender) were assessed by comparing the means between the groups using 2-tailed independent sample t-test. Variables with multiple groups were analyzed using a one way between group analysis of variance (ANOVA). Significance was defined as a p ≤ 0.05. 3. Results The lamotrigine trial (n = 80) included Caucasians (69%), African Americans (24%), Hispanics (6%) and Native Americans (1%). The mean age was 36.2 ± Table 1 Correlations of length of study participation with demographics, drug use severity, and psychiatric variables A. Lamotrigine/stimulant Length of study participation (baseline) Variable Age HAM-D YMRS BPRS CCQ Days of stimulant use/week Dollars spent on stimulants/week
r-score .116 −.303 ⁎ −.087 −.218 ⁎ −.181 −.110 .096
B. Quetiapine/alcohol Length of Study participation (baseline) Variable Age HAM-D YMRS ASI alcohol composite ASI drug composite score ASI employment ASI family/social composite score ASI legal composite score ASI medical composite ASI psychiatric composite score Somatic Symptoms Scale (side effects) Days of alcohol use/week Total # of standard drinks/week ⁎ Correlation significant at ⁎p ≤ 0.05.
r-score .178 −.149 .065 −.052 −.054 −.030 −.200 −.235 ⁎ −.032 −.023 −.117 −.097 .017
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8.7 years, with an equal number of men (n = 40) and women (n = 40). The attrition rate was 69% (55/80) in the 12 week acute phase. Scores in the HAM-D and BPRS correlated negatively with length of participation. No other correlations were significant (Table 1A). Patients with panic disorder had significantly (p = .039) lower mean weeks of participation than those without panic disorder (Table 2A). Of those with panic disorder who did not complete the 12 week acute phase all but one was discontinued due to need for emergency/inpatient care, side effects or lost to follow-up. One discontinued themselves because they wanted to start valproate under the care of an outside physician. ANOVA showed no significant difference on BPD diagnosis (bipolar I, bipolar II, bipolar NOS), race/ethnicity (Caucasian, African American, Hispanic, Other), or baseline mood state (euthymic, depressed, manic, mixed, depressed and hypomanic, hypomanic). The ANOVA revealed differences in time in the study based on substance use diagnosis of cocaine dependence only (n = 66, 6.26 ± 4.80 weeks) amphetamine dependence (n = 7, 7.43 ±
4.96 weeks) and both cocaine and amphetamine dependence (n = 7, 1.71 ± 1.25 weeks) (p = 0.038). In the quetiapine study, patient demographics (n = 115) included a mean age of 37.72 ± 9.542 years, 60% Caucasian, 27% African American, 9.5% Hispanic, 66% male and 34% female, with an attrition rate of 61% (70/115). The only significant correlation with length of time in study was baseline ASI legal score (Table 1B.) Patients with panic disorder had significantly lower mean weeks in the study. Reasons for withdrawal in the panic disorder group included incarceration, moving out of area, desire for open-label treatment, worsening of symptoms, side effects and lost to follow-up. Patients with obsessive-compulsive disorder had significantly higher mean number of weeks in the study. Bipolar I patients had a significantly shorter time in the study than bipolar II patients. An ANOVA did not reveal significance differences in time in the study based on race/ethnicity (Caucasian, African American, Hispanic, Other) or mood state (euthymic, depressed, manic, mixed, depressed and hypomanic).
Table 2 Between group comparisons (t-test) with length of study participation
4. Discussion
A. Lamotrigine/stimulant
Attrition rates were high in both studies underscoring the challenges of research in patients with BPD and substance use disorders. Perhaps the most interesting finding is the relationship between panic disorder and attrition observed in both studies. Panic disorder is common in patients with BPD with rates of 21-35% reported in community-based studies (Chen and Dilsaver, 1995; Goodwin and Hoven, 2002). We previously reported a lifetime prevalence of panic disorder of 54% in patients with BPD and alcohol abuse/dependence and 42% in BPD and cocaine abuse/dependence (Mitchell et al., 2007). Thus, panic disorder is a common comorbid condition in BPD that until recently has been the focus of little attention. MacKinnon and Zamoiski (2006) suggested that deficits in conditioning processes within the amygdala may explain what they termed the “manic-panic connection”. Masi et al. (2007) reported that panic disorder is also common in children and adolescents with BPD (23%). Panic disorder appears to be associated with an increased risk of suicidal ideation in adolescents with BPD (Dilsaver et al., 2006), and may be more common in patients presenting with mixed versus pure mania (Dilsaver and Chen, 2003). Our studies did not show a relationship between amount of substance use at baseline and study attrition, although the combined use of cocaine and amphetamines was associated with early withdrawal in the lamotrigine study. We also did not observe the relationship between
Length of study participation (weeks) (±SD) Male (n = 40) Female (n40) 6.03 ± 5.03 5.74 ± 4.52 PTSD (n = 26) PTSD absent (n50) 6.28 ± 4.61 4.88 ± 4.83 Panic disorder (n = 31) Panic disorder absent (n43) ⁎ 4.16 ± 4.30 6.86 ± 4.81 Social phobia (n = 20) Social Phobia absent (n54) 4.445 ± 4.27 6.500 ± 4.74 OCD (n = 9) OCD absent (n66) 5.67 ± 4.33 5.894 ± 78 Antisocial personality (n = 43) Antisocial Personality absent (n34) 5.81 ± 4.72 5.97 ± 4.80 B. Quetiapine/alcohol Length of study participation (weeks) (±SD) Male (n = 76) Female (n39) 7.14 ± 4.78 7.21 ± 4.45 PTSD (n = 31) PTSD absent (n83) 7.52 ± 4.39 6.98 ± 4.76 Panic disorder (n = 51) Panic disorder absent (n63) ⁎ 6.16 ± 4.76 7.90 ± 4.45 Social phobia (n = 59) Social phobia absent (n55) 7.39 ± 4.679 6.84 ± 4.642 OCD (n = 40) OCD absent (n73) ⁎ 8.35 ± 4.336 6.53 ± 4.694 Antisocial personality (n = 50) Antisocial personality absent (n63) 7.14 ± 4.77 7.16 ± 4.61 Bipolar I (n = 57) Bipolar II (n58) ⁎ 6.05 ± 4.561 8.26 ± 4.513 ⁎ p ≤ 0.05.
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impulsivity, as assessed by the BIS NP subscale, and attrition in the quetiapine that we previously reported in a subset of patients in the lamotrigine study. Severity of depression was previously reported to be associated with less attrition (Nuttbrock et al., 1997; Gelkopf et al., 2006; Broome et al., 1999). However, in our lamotrigine trial, higher HAM-D and BPRS scores were associated with earlier withdrawal from the study, although, categorical diagnosis of baseline mood state was not associated with attrition. Thus, it appears that severity of psychiatric symptoms, but not manic/hypomanic versus depressed mood state, is associated with attrition in patients with BPD and cocaine-use disorders. Interestingly, patients with OCD remained in the study longer than those without OCD in the quetiapine study. Although somewhat different factors were related to attrition in the two studies, it may not be accurate to conclude that the differences are related to differences in persons with stimulant use versus those with alcohol use since many participants used both substances in the studies. In addition, one study was open-label and the other placebo controlled and different medications with potentially different spectrums of efficacy and side effects were used. To our knowledge, the relationship between panic disorder and treatment adherence or attrition in people with BPD has not been previously explored. The findings suggest that greater attention should be paid to comorbid panic disorder in dual diagnosis patients. Role of funding source The studies from which the data for this paper were derived were funded by the Stanley Medical Research Institute and an investigatorinitiated grant from AstraZeneca. In addition, GlaxoSmithKline provided lamotrigine for one study. AstraZeneca provided feedback on the design of the quetiapine trial. Sponsors were not involved in the data analysis or interpretation of the findings presented in this report. Conflict of interest Dr. E. Sherwood Brown has research grants from AstraZeneca, Forest Laboratories, GlaxoSmithKline, McNeil, NIAAA, and the Stanley Medical Research Institute. Nicole Nomamiukor has no conflict of interest to disclose.
Acknowledgment Funded by the Stanley Medical Research Institute and AstraZeneca and medication for one study provided by GlaxoSmithKline. References Akingbala, F., Dhanani, N., Brown, E.S., 2006. Impulsivity in patients with BPD and cocaine or amphetamine dependence given lamotrigine. J. Dual Diagn. 2, 73–83.
287
Barratt, E.S., Patton, J.H., 1983. Impulsivity: cognitive, behavioral, and psychophysiological correlates. In: Zuckerman, M. (Ed.), Biological Basis of Sensation-Seeking, Impulsivity, and Anxiety. Lawrence Erlbaum Associates, Hillsdale, NJ, pp. 77–116. Broome, K., Flynn, P., Simpson, D., 1999. Psychiatric comorbidity measures as predictors of retention in drug abuse treatment programs. Health Serv. Res. 34, 791–806. Brown, E.S., Perantie, D.C., Dhanani, N., Beard, L., Orsulak, P., Rush, A.J., 2006. Lamotrigine for BPD and comorbid cocaine dependence: a replication and extension study. J. Affect. Disord. 93, 219–222. Brown, E.S., Garza, M., Carmody, T., 2008. A randomized, doubleblind, placebo-controlled trial of quetiapine in outpatients with BPD and alcohol use disorders. J. Clin. Psychiatry. Chen, Y.W., Dilsaver, S.C., 1995. Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area Survey. Am. J. Psychiatry 152, 280–282. Dilsaver, S.C., Chen, Y.W., 2003. Social phobia, panic disorder and suicidality in subjects with pure and depressive mania. J. Affect. Disord. 77, 173–177. Dilsaver, S.C., Akiskal, H.S., Akiskal, K.K., Benazzi, F., 2006. Doseresponse relationship between number of comorbid anxiety disorders in adolescent bipolar/unipolar disorders, and psychosis, suicidality, substance abuse and familiality. J. Affect. Disord. 96, 249–258. Gelkopf, M., Weizman, T., Melamed, Y., Adelson, M., Bleich, A., 2006. Does psychiatric comorbidity affect drug abuse treatment outcome? A prospective assessment of drug abuse, treatment tenure and infectious diseases in an Israeli methadone maintenance clinic. Isr. J. Psychiatry Relat. Sci. 43, 126–136. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. Goodwin, R.D., Hoven, C.W., 2002. Bipolar-panic comorbidity in the general population: prevalence and associated morbidity. J. Affect. Disord. 70, 27–33. Joe, G.W., Brown, B.S., Simpson, D.D., 1995. Psychological problems and client engagement in methadone treatment. J. Nerv. Ment. Dis. 183, 704–710. Laudet, A., Magura, S., Cleland, C., Vogel, H., Knight, E., 2003. Predictors of retention in dual-focus self-help groups. Community Ment. Health J. 39, 281–297. Lima, M., Soares, O.B., Reisser, P.A., Farell, M., 2002. Pharmacological treatment of cocaine dependence: a systematic review. Addiction 97, 931–949. MacKinnon, D.F., Zamoiski, R., 2006. Panic comorbidity with BPD: what is the manic–panic connection? Bipolar. Diosord. 8, 648–664. Masi, G., Perugi, G., Millepiedi, S., Toni, C., Mucci, M., Nicoletta, B., Pfanner, Berloffa, S., Pari, Akiskal, K., Akiskal, H.S., 2007. Clinical and research implications of panic-bipolar comorbidity in children and adolescents. Psychiatry Res. 153, 47–54. McKellar, J., Kelly, J., Harris, J., Moos, R., 2006. Pretreatment and during treatment risk factors for dropout among patients with substance use disorders. Addict. Behav. 31, 450–460. McLellan, A.T., Luborsky, L., Woody, G.E., O'Brien, C.P., 1980. An improved diagnostic evaluation instrument for substance abuse patients. The Addiction Severity Index. J. Nerv. Ment. Dis. 168, 26–33. Mertens, J.R., Weisner, C.M., 2000. Predictors of substance abuse treatment retention among women and men in an HMO. Alcohol Clin. Exp. Res. 24, 1525–1533. Mitchell, J.D., Brown, E.S., Rush, A.J., 2007. Comorbid disorders in patients with bipolar and concomitant substance dependence. J. Affect. Disord. 102, 281–287.
288
N. Nomamiukor, E.S. Brown / Journal of Affective Disorders 112 (2009) 284–288
Nuttbrock, L., Ng-Mak, D., Rahav, M., Rivera, J., 1997. Pre- and postadmission attrition of homeless, mentally ill chemical abusers referred to residential treatment programs. Addiction 92 (10), 1305–1315. Overall, J., Gorham, D., 1962. The brief psychiatric rating scale. Psychol. Rep. 10, 799–812. Rees, D., Beech, H., Hore, B., 1984. Some factors associated with compliance in the treatment of alcoholism. Alcohol Alcohol. 19, 303–307. Ryan, R., Plant, R., O'Malley, S., 1995. Initial motivations for alcohol treatment: relations with patient characteristics, treatment involvement and drop out. Addict. Behav. 20, 279–297. Sayre, S.L., Schmitz, J.M., Stotts, A.L., Averill, P.M., Rhoades, H.M., Grabowski, J.J., 2002. Determining predictors of attrition in an outpatient substance abuse program. Am. J. Drug Alcohol Abuse 24, 55–72.
Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The miniinternational neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59, 22–33. Thase, M.E., Fava, M., Halbreich, U., Kocsis, J.H., Koran, L., Davidson, J., Rosenbaum, J., Harrison, W., 1996. A placebocontrolled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch. Gen. Psychiatry 53, 777–784. Tiffany, S.T., Singleton, E., Haertzen, C.A., Henningfield, J.E., 1993. The development of a cocaine craving questionnaire. Drug Alcohol Depend. 34, 19–28. Young, R., Biggs, J., Meyer, D., 1978. A rating scale for mania: reliability, validity, and sensitivity. Br. J. Psychiatry 133, 429–435.