Journal of Affective Disorders 162 (2014) 50–54
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Research report
Comparing outcomes of adjunctive treatment in depression: Aripiprazole versus Bupropion Suhayl Nasr a,b,c,d,n, Burdette Wendt a, Anand Popli a,b, John Crayton a a
Nasr Psychiatric Services, Michigan City, IN, United States Indiana University, Department of Psychiatry, Michigan City, IN, United States c University of Notre Dame, Department of Psychology, Notre Dame, IN, United States d Memorial Epworth Center, South Bend, IN 46617, United States b
art ic l e i nf o
a b s t r a c t
Article history: Received 13 March 2014 Accepted 14 March 2014 Available online 27 March 2014
Background: Adjunctive therapy in depression is often used in patients with an inadequate response to antidepressant therapy. Methods: Utilizing a chart review from a private, outpatient psychiatric clinic, patients with adjunctive medication added to their antidepressant were reviewed. Demographic information, diagnoses, medication history, and QIDS SR16 depression scores were collected and recorded at each visit and entered into a database. Results: Significant reductions were observed in the QIDS score of aripiprazole (n¼70) and bupropion (n¼83) patients after the first visit. At the first visit, 70% of aripiprazole patients had lower QIDS score compared to baseline visit, with 17% achieving remission, whereas 66% of bupropion users had lower scores at the first visit compared to baseline visit, with 23% achieving remission. At the end of the observation period 50% of patients on aripiprazole achieved remission compared to 33% of bupropion patients. Both groups of patients had significant reductions in their QIDS symptom scores of sadness, concentration, and general interest. In addition, aripiprazole patients had a decrease in the thoughts of death and suicide score while bupropion patients had decreases in the low energy score. None of the differences in QIDS line-item scores between aripiprazole and bupropion patients were statistically significant. Limitations: This study was a small scale, retrospective study that did not have a placebo control group. Conclusion: Aripiprazole and bupropion were comparable in significantly lowering patients’ QIDS SR16 scores and helping over 50% of the patients achieve remission. Differences in line-item QIDS score were also observed. & 2014 Elsevier B.V. All rights reserved.
Keywords: Aripiprazole Bupropion Adjunctive treatment Depression
1. Introduction Depression is a debilitating disease that affects over 13 million people in any one year (Kessler et al., 2003) and remission from this disease is known to increase functioning, productivity, and prognosis in the long-term (Miller et al., 1998; Paykel et al., 1995). The STARnD trial demonstrated that a low percentage (in STARnD trial 28%) of patients respond to an initial selective serotonin reuptake inhibitor (SSRI; (Trivedi et al., 2006a)). Furthermore, the longer patients stayed in the trial, the less likely they were to respond to medication (Fava et al., 2006; McGrath et al., 2006; Nierenberg et al., 2006; Rush et al., 2006; Thase et al., 2007; Trivedi et al., 2006a). Taken together, the results from the STARnD trial suggest that treatment of unresolved
n
Corresponding author at: 2814 Franklin St, Michigan City, IN 46360, USA. E-mail address:
[email protected] (S. Nasr).
http://dx.doi.org/10.1016/j.jad.2014.03.019 0165-0327/& 2014 Elsevier B.V. All rights reserved.
symptoms in depression is a challenge when treating depression and early intervention yields the most success. Because many depressed patients do not respond to only one medication, adjunctive use of one or more medications is required to give them relief from their distress. Adjunctive medication comes in several forms. First, the FDA has approved 2 atypical antipsychotics, aripiprazole and quetiapine, as adjunctive therapy for depression patients with an inadequate response to antidepressant therapy. These medications target the dopamine and serotonin systems by regulating receptor function (Pae et al., 2011; Sanford, 2011). Aripiprazole is a dopamine (D) 2, D3, and a serotonin (5HT) 1A partial agonist, as well as a 5HT2A antagonist (Burris et al., 2002; Jordan et al., 2002; Shapiro et al., 2003). In both open-label as well as randomized, placebo controlled studies, aripiprazole demonstrated efficacy as an adjunctive therapy to SSRIs in treating unresolved symptoms of
S. Nasr et al. / Journal of Affective Disorders 162 (2014) 50–54
depression (Adson et al., 2005; Berman et al., 2009, 2007; Marcus et al., 2008; Pae et al., 2007; Papakostas et al., 2005; Patkar et al., 2006; Simon and Nemeroff, 2005; Worthington et al., 2005). On the other hand, most clinicians are known to use off-label adjunctive treatment including bupropion (a dopamine norepinephrine reuptake inhibitor [DNRI]) and buspirone (a 5HT1A partial agonist and D2 antagonist), a practice that became popular after the dissemination of the STARnD Clinical Trial. Specifically, augmentation with bupropion and buspirone demonstrated success in real-world clinical practice, with some evidence to suggest bupropion provides greater benefit over buspirone (Moreira, 2011; Trivedi et al., 2006b). When clinicians decide to use adjunctive medication in depression, many factors enter to the choice, not only efficacy but also safety and cost. This retrospective study compares the effectiveness of aripiprazole and bupropion as adjunctive treatment of depression in a private psychiatric practice, using a patient-rated depression scale. This real-world setting allows for comparison of the two treatments based on a measurement-based care system. Although these two medications are not the only adjunctive medication used at the psychiatric clinic, patients who received adjunctive treatment with buspirone, stimulants, or quetiapine were not included because the number of patients was too small to offer meaningful comparisons.
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compiled in a database. Patients were monitored for response to medication and remission from depression was defined as QIDSSR16 total score of five or lower. 2.3. Time to follow-up Patients QIDS-SR16 scores were assessed at baseline, then on every consecutive follow-up visit (up to 5 visits) to the psychiatrist. Data from patients not completing all 5 visits were analyzed using last observation carried forward (LOCF) imputation technique.
2.4. Statistics Statistical analyses were performed using SPSS v. 22.0. Changes in total QIDS-SR16 scores were compared over time, as well as between aripiprazole and bupropion groups at baseline, and visits 1 through 5. Individual QIDS-SR16 items were assessed for changes from baseline to the average of the 5 visits. Repeated measures ANCOVA were performed to examine differences in scores between adjunctive aripiprazole and adjunctive bupropion. Results are presented in mean 7SEM. 3. Results
2. Methods
3.1. Patient demographics
2.1. Chart review
Of the total 153 patients included in the study, 70 patients were prescribed aripiprazole and 83 patients were prescribed bupropion. The average age was similar between the aripiprazole group (44 715 years) and the bupropion group (45 715 years). Patients were on an average dose of 8 mg (7 6.1) of aripiprazole and 254 mg ( 788) of bupropion. The percentages of female and male patients were similar between the groups, with slightly more female patients in the bupropion group (66.25%) compared to the aripiprazole group (60%). The mean time from baseline to visit 5 for the aripiprazole group was 10.5 73.3 months, while it was 15 77.0 months for the bupropion group. Patients receiving adjunctive aripiprazole averaged 3.8 visits, with patients experiencing no improvement averaging 3.1 visits and patients with improvement averaging 4.3 visits. In contrast, patients receiving adjunctive bupropion averaged 3.5 visits, with patients experiencing no improvement averaging 2.8 visits and patients with improvement averaging 4.0 visits.
Patients for this study were obtained through a systematic chart review from a private, psychiatric outpatient clinic in Michigan City, IN, who received treatment from 2006 to 2011. Demographics collected were age and gender. Prior to initiation of therapy, informed consent was obtained for inclusion of any data collected from their treatment to be used in database chart review. Of (1936) patients reviewed, (153) patients were included in the study. Patients with the diagnosis of depression, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), who had an inadequate response to an antidepressant monotherapy, as determined by the clinical expertise of a board certified psychiatrist, were included in the study. Patients were excluded from the study if they had taken either aripiprazole or bupropion at any time. Permission was received from St. Antony Memorial Health Center's Institutional Review Board to conduct a non-identifying review of records. 2.2. QIDS SR16 scale Prior to each visit with the Psychiatrist, patients completed the quick inventory of depressive symptomatology (QIDS-SR16) in the waiting room. The QIDS-SR16 is effective at demonstrating severity of depression and is an advantageous tool because it is the patient who does the rating. This measurement-based tool used not only in research but also in psychiatric practice (Bernstein et al., 2009; Rush et al., 2003). Briefly, the QIDS-SR16 consists of 16 items, responses only based on the past 7 days, ranging from 0–3 points each, 0 indicating little impairment and 3 indicating extreme impairment. Items on the QIDS-SR16 include: falling asleep (early insomnia), sleep during the night (middle insomnia), waking up too early (late insomnia), sleeping too much (hypersomnia), sadness, decreased/increased appetite, decreased/ increased weight, concentration and decision making, view of one's self, thoughts of death and suicide, general interest, energy level, feeling slowed down, and feeling restless. QIDS-SR16 total score and line-item scores were recorded after each visit and
3.2. QIDS total score Both aripiprazole and bupropion significantly reduced mean QIDS-SR16 total score from baseline to treatment visit 5 (Fig. 1). At
Fig. 1. Mean change in QIDS-16 Score from baseline to visit 5 for aripiprazole and bupropion group. Mean 7SEM.
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the baseline visit, the mean QIDS-SR16 score for the aripiprazole group was 12.6 70.6 and the bupropion group was 11.9 70.5. By the first visit after initiating therapy with either aripiprazole or bupropion, there was a significant decrease in the QIDS-SR16 total score (po0.0001; Fig. 1), with 66% of patients in the aripiprazole group decreasing their score at the first visit, and 70% of the bupropion group decreasing their score. Over the course of treatment, both groups significantly decreased the average QIDSSR16 total score (p o0.0001), with the average score in the aripiprazole group being 10.6 70.3 and bupropion group being 9.4 70.3. At the final visit, the average QIDS-SR16 score for the aripiprazole group was 9.17 0.7 and for the bupropion group was 9.17 0.6.
remission at any time during treatment. Similarly, in the bupropion group, 23% of patients achieved remission by the first visit, with 55% of patients achieving remission at any time during the study. At the end of the observation period, 50% of aripiprazole patients were considered to be in remission compared to 33% of bupropion patients.
3.3. QIDS line item results
4. Discussion
Results from the individual line item of the QIDS-SR16 are displayed in Table 1. Significant decreases in line item scores were observed in the aripiprazole group in the early insomnia, sadness, concentration, self-view, thoughts of suicide and death, and general interest (p o0.01). Significant differences in line item scores were observed in the bupropion group in the hypersomnia, sadness, concentration, self-view, general interest, and energy level (po 0.01). No statistically significant differences in line item scores between the aripiprazole group and the bupropion group were observed. Of note, neither aripiprazole nor bupropion demonstrated a patient-perceived change in appetite or weight. Similarly, neither aripiprazole nor bupropion increased the restlessness line item in the QIDS-SR16.
In this study, both aripiprazole and bupropion were effective for treating depression as an adjunctive therapy. Both aripiprazole and bupropion significantly improved patient's perception of their sadness, concentration, self-worth, and general interest. Patients on aripiprazole showed additional significant improvement in patient's perception of early insomnia and thoughts of suicide, while patients on bupropion showed additional improvement on patient's perception of hypersomnia and energy level. Interestingly, neither group experienced a perceived change in appetite, weight, or restlessness. Furthermore, 50% of aripiprazole patients achieved remission at any time during the treatment and 55% of bupropion patients achieved remission during this time. However, at the end of the treatment, 50% of aripiprazole patients were in remission and 33% of bupropion patients were in remission. These results indicate that both aripiprazole and bupropion are effective as an adjunctive treatment for depression in a real-world clinical setting and may help specific aspects of the symptom relief. Although both are effective, aripiprazole and bupropion have different theoretical mechanisms of action. Aripiprazole is a D2/ D3/5HT1A receptor partial agonist and 5HT2A antagonist while bupropion is a DNRI. Typical antidepressant therapies target the serotonin system, however, more data suggests that the other neurotransmitter systems are involved in the progression of depression (Blier and Blondeau, 2011; Haenisch and Bonisch, 2011). While the exact neurobiological mechanism of depression is unknown, data suggests that disruption of the dopamine and norepinephrine systems may play a role in the progression of the disease (Haenisch and Bonisch, 2011; Trivedi et al., 2008). Moreover, data suggest that modulation of the 5HT1A receptor may play a crucial role in antidepressant actions (Noro et al., 2010; Rausch et al., 2006; Theodore et al., 2007). By using adjunctive therapy, more neurotransmitter systems can be targeted, increasing the clinical efficacy, ultimately providing relief to depression patients. A difference in improvement based on medication prescribed was observed in the line-item analysis of the QIDS-SR16. As previously mentioned, both aripiprazole and bupropion were effective at decreasing line-item scores in 4 of the 16 items. Interestingly, aripiprazole and bupropion showed a significant difference in an additional two line-items that had significance based on the treatment group. An unmeasured side effect in this particular study could be altered cognitive function. Bupropion alters the acetylcholine system (Salin-Pascual et al., 2003), where receptors are hypothesized to have an integral role in cognitive function (Bubser et al., 2012; dos Santos Coura and Granon, 2012). Conversely, aripiprazole has no appreciable affinity for acetylcholine receptors (Burris et al., 2002; Jordan et al., 2002; Shapiro et al., 2003). This data may indicate that aripiprazole and bupropion have differential effects on some symptoms associated with depression, information that could aid prescribers when deciding which medication is appropriate for their
3.4. Patients achieving remission Similar percentages of patients achieved remission during this study (Table 2). In the aripiprazole group, 17% of patients achieved remission by the first visit, with 50% of patients achieving Table 1 QIDS line-item results. Baseline 1. Early insomnia 2. Middle insomnia 3. Late insomnia 4. Hypersomnia 5. Sadness 6. Decreased appetite 7. Increased appetite 8. Weight loss 9. Weight gain 10. Concentration 11. Self-view 12. Thoughts of suicide/death 13. General interest 14. Energy level 15. Feeling slowed down 16. Feeling restless TOTAL QIDS SR16 n
Aripiprazole
Baseline
Bupropion
1.4 1.8 0.8 0.8 1.6 0.4 0.6 0.5 0.7 1.3 1.4 0.7 1.2 1.1 0.7 1.1
1.0n 1.7 0.8 0.7 1.0n 0.3 0.6 0.4 0.9 1.0n 1.1n 0.3n 0.9n 1.0 0.7 1.0
1.3 1.8 0.6 1.0 1.4 0.4 0.4 0.5 0.6 1.4 1.2 0.5 1.2 1.4 0.6 0.8
1.0 1.5 0.5 0.7n 0.9n 0.4 0.3 0.5 0.4 0.9n 0.8n 0.2 0.8n 0.9n 0.5 0.7
12.6
9.1n
11.9
9.1n
po 0.05.
Table 2 Comparison of aripiprazole and bupropion.
Improved score at first visit Remission at first visit Remission at any time of treatment
Aripiprazole
Bupropion
46/70 (66%) 12/70 (17%) 35/70 (50%)
58/83 (70%) 19/83 (23%) 46/83 (55%)
3.5. Intolerance and adverse events During this chart review, no tolerability or adverse events were noted in the charts that were severe enough to discontinue treatment.
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patients. Furthermore, these results indicate that neither treatment group had a perceived increase in weight, appetite, or restlessness, all of which are noted as possible side effects for both medications (Moreira, 2011; Pae et al., 2011). During this study, 50% of aripiprazole patients achieved remission at any time during the study and 50% of aripiprazole patients were considered “in remission” at the end of the study. Conversely, 55% of bupropion patients achieved remission at any time during the study, but only 33% of bupropion patients were considered “in remission” at the end of the study. Although it may be an artifact by limitations in the study, it also may show a difference between a DNRI and a receptor modulator as treatment. Specifically, when considering the mechanism of action, reuptake inhibitors require time to achieve therapeutic effect due to their hypothetical initiation of synaptic plasticity (Krishnan and Nestler, 2008; Mathew et al., 2008; Millan, 2006). Moreover, the reuptake inhibitors also potentially limit neurotransmitter regulation because of other presynaptic negative feedback mechanisms (Andres et al., 2005; Millan, 2006). On the other hand, targeted receptor modulators may not be subject to the same compensatory mechanisms as reuptake inhibitors due to the mechanism of action (Jordan et al., 2004; Tamminga and Carlsson, 2002). Another possibility is that the underlying neurobiology in depression varies from patient to patient, thus medications may have differential effects depending on the patient (Palazidou, 2012; Saveanu and Nemeroff, 2012). 4.1. Limitations Although valuable data is gleamed from this study, there are limitations that should be considered. First, there was no placebo control group, thus spontaneous remission from depression cannot be excluded from the possible outcomes. Second, the study size was limited to a private, outpatient psychiatric clinic and did not have the large numbers of some multi-center studies. Next, as the medication was not randomly assigned to patients, but rather prescribed based on clinical judgment of an expert psychiatrist, there is a possibility of selection bias. Finally, there was a baseline difference in total QIDS-SR16 score. This may have contributed to the selection bias, as patients prescribed aripiprazole had numerically higher QIDS-SR16 scores, although not statistically higher than bupropion scores. Nevertheless, patients in both groups had a statistically significant decrease in the QIDS score with treatment. In light of these limitations, this study assessed a real-world clinical setting. In this type of setting, clinicians prescribe medication for each individual patient based on their expertise and clinical judgment. Also, private practice psychiatrists typically do not have the time to perform a time-consuming series of psychiatric evaluations as observed frequently in large scale clinical trials. On the other hand, some psychiatrists use clinician or patientrated scales to assess depression severity and find the scales to be useful (Duffy et al., 2008; Nasr, 2008; Williams et al., 2010). Thus, a patient-rated scale, similar to the one described here, could be easily implemented into any practice, simply by handing the scale to the patients in the waiting room prior to seeing their physician, and could easily be compared to the data observed here. Outcomes data, from a real-world setting, can provide valuable information to prescribers when deciding which medication to prescribe. In conclusion, both aripiprazole and bupropion are effective as adjunctive treatment to an inadequate response to antidepressant therapy as assessed by the patient-rated QIDS-SR16 scale. There were slight differences in the line-item scores between baseline and treatment, although there were no statistically significant differences between treatment groups. Furthermore, over half of the patients achieved remission from depression during the course of the study. A better understanding of the exact mechanism of depression symptomatology, and the medications that treat
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depression, can connect the right medication to each individual patient.
Role of funding source This study was self funded with no outside financial support.
Conflict of interest Dr Nasr was on the speakers bureau for Bristol-Myers at the time of the study. All other authors declare that they have no conflicts of interest.
Acknowledgement No acknowledgements to report.
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