Abstract
Objective: This study investigated the therapeutic potential of initiating treatment of generalized anxiety disorder (GAD) with alprazolam orally disintegrating tablets (ODT) in combination with an SSRI or SNRI, compared with SSRI/SNRI monotherapy.
Design: Subjects were randomized to eight weeks open-label treatment with alprazolam ODT (4 weeks treatment followed by a 3- to 4-week taper) combined with an SSRI or SNRI, or treatment with SSRI/SNRI alone.
Setting: The study was conducted at 43 primary care and 22 psychiatric practices under naturalistic conditions.
Participants: Subjects ≥ 18 years of age with a primary diagnosis of GAD.
Measurements: The primary efficacy measure was time to response, a ≥50-percent decrease from baseline in Hamilton Rating Scale for Anxiety (HAM-A) total score. Secondary variables included HAM-A total and sub-factor scores, and the Clinical Global Impression of Improvement (CGI-I) and Patient Global Impression (PGI) scales.
Results: The intent-to-treat population included 129 subjects. Discontinuation due to adverse events occurred in one subject in each group. There was no statistical difference between groups in the primary efficacy variable of time to response on the HAM-A. Combination treatment with alprazolam ODT and SSRI/SNRI was associated with statistically significant advantages on prespecified secondary variables including earlier improvement in the HAM-A total score and insomnia item and responses on the CGI-I and PGI scales.
Conclusion: Combination treatment did not differ from monotherapy on time to response but was associated with more rapid improvement in insomnia and global secondary measures.
Keywords: generalized anxiety disorder, SSRI, SNRI, alprazolam, naturalistic
Introduction
Generalized anxiety disorder (GAD) is a chronic disorder characterized by the cardinal feature of excessive, uncontrollable worry together with at least three of the following additional symptoms: Fatigue, insomnia, muscle tension, poor concentration, and irritability that are present on more days than not for a period of at least six months.1 Prevalence estimates range from 1.5 to 5.1 percent in the general population;2–4 however, GAD is the anxiety disorder that presents most frequently in primary care.5 GAD often occurs with other psychiatric conditions, particularly anxiety and depressive disorders.6–8 Lifetime comorbidity of GAD with mood disorders is estimated to be approximately 80 percent,9 and as many as 80 percent of patients with GAD have symptoms of depression.10
Benzodiazepines are generally regarded as beneficial for the acute treatment of anxiety disorders and have a rapid onset of effect,11 but their lack of antidepressant efficacy and concerns about the development of tolerance and risk of physical dependence limit the long-term use of these agents for the treatment of GAD.12,13 Antidepressants with anxiolytic properties have emerged as more suitable first-line pharmacotherapies. Specifically, the selective serotonin reuptake inhibitors (SSRIs) escitalopram and paroxetine and the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine have demonstrated short- and long-term safety and efficacy in the treatment of GAD,14–16 and are approved by the US Food and Drug Administration (FDA) for this indication.
The onset of therapeutic effect with SSRI and SNRI antidepressants requires at least several weeks of treatment; during this initial treatment phase the SSRI/SNRI may cause symptoms of anxiety and sleep disturbances to worsen. Adjunctive treatment with a benzodiazepine when initiating SSRI or SNRI therapy might be expected to moderate this risk and hasten therapeutic improvement. Indeed, combination therapy with benzodiazepines and antidepressants has become common in the clinical management of anxiety disorders17 despite limited evidence from controlled studies to support this approach. Two relatively small, placebo-controlled trials in panic disorder observed more rapid improvement in the first few weeks when initiating treatment with a benzodiazepine in addition to an SSRI,18,19 but to date no studies of this combination in the treatment of GAD have been published.
The purpose of the current study was to evaluate, in a naturalistic setting, the time to response of anxiety symptoms and overall tolerability of initiating treatment with alprazolam orally disintegrating tablets (Niravam™) in combination with an SSRI or SNRI, compared to antidepressant monotherapy, in subjects with a primary diagnosis of GAD. We hypothesized that combination therapy would result in a more rapid rate of improvement than antidepressant treatment alone.
Methods
This Phase IV randomized, open-label, naturalistic study was conducted at 43 primary care and 22 psychiatric practices in the US from November 11, 2005, through June 26, 2006.
Subjects. Adult subjects ≥18 years of age with a primary diagnosis of GAD (either first episode or recurrence) without panic disorder for whom treatment with an SSRI or SNRI was considered appropriate were eligible for inclusion in the study. Investigator diagnoses were confirmed by the Mental Health Screener® (MHS), a validated scale20 administered via a computer-assisted Interactive Voice Response System (IVRS), prior to randomization. The MHS was used to ensure that the diagnoses of GAD and comorbid psychiatric disorders were performed consistently in both primary care and psychiatric sites.
Subjects were ineligible to participate if they had received treatment with an SSRI or SNRI within one week (6 weeks for fluoxetine) or a short-acting, intermediate-acting, or long-acting benzodiazepine within two, four, or 10 days, respectively, of study entry. Those meeting criteria for schizophrenia, bipolar disorder, alcohol abuse/dependence, or any other psychiatric or medical condition that the investigator believed would compromise participation in the study also were excluded. Other exclusionary criteria included current suicide risk and any contraindication(s) or history of hypersensitivity to any SSRI, SNRI, or benzodiazepine. Subjects were not permitted to use any prescription hypnotic, antidepressant, anxiolytic, or benzodiazepine other than the study medication(s). Those initiating cognitive therapy within 60 days prior to this study were ineligible to participate, and beginning cognitive therapy was prohibited during the trial. Subjects participating in any clinical trial within the previous 30 days were excluded. Women who were pregnant or nursing were not eligible for inclusion, and those of child-bearing potential were required to use a medically accepted method of contraception.
All subjects provided written informed consent, and a central institutional review board approved the study protocol on behalf of all participating centers.
Study design. All subjects were to be prescribed an SSRI or SNRI, considered to be standard of care for the treatment of GAD. Subjects were then randomized by IVRS in a 1:1 ratio to receive eight-week, open-label treatment with alprazolam orally disintegrating tablets (ODT) in addition to the SSRI/SNRI or to receive the SSRI/SNRI alone. Alprazolam ODT and the SSRI/SNRI were to be administered as specified in the US product labeling. Gradual tapering of the alprazolam ODT dose was to begin after four weeks of treatment and be completed by the end of the study period.
Study participants were responsible for obtaining the prescribed SSRI/SNRI and adhering to the dosing regimen. Those randomized to alprazolam ODT received a unit dose pack to ensure that dosing began on the day of randomization, as well as a prescription and prescription card for use at a pharmacy of their choice.
Assessments. The initial visit included an assessment of study eligibility and collection of demographic information and medical history. During office visits at Weeks 2, 4, and 8, or upon early termination, subjects were assessed using the seven-point Clinical Global Impression of Improvement (CGI-I) scale.21 The 14-item Hamilton Rating Scale for Anxiety (HAM-A)22 was administered at baseline and weekly via the validated IVRS23,24 to provide evaluation consistency across multiple study sites and to minimize to the extent possible the inherent bias associated with an open-label study. The IVRS also was used weekly to query subjects' assessment of their improvement from baseline using the seven-point Patient Global Impression (PGI) scale.
The primary efficacy variable was time to response, with response defined as a ≥50-percent decrease in HAM-A total score from baseline. Secondary efficacy variables specified a priori included mean change from baseline in HAM-A total score, mean change from baseline in HAM-A insomnia, psychic, and somatic subscores, proportion of HAM-A responders, the physician-rated CGI-I and subject-rated PGI.
Safety assessments were performed at all visits, and the incidence and severity of spontaneously reported adverse events—including those spontaneously reported during telephone contact—were recorded. Dosage of the prescribed SSRI/SNRI was recorded at initiation of treatment and last visit, and alprazolam ODT dosage was recorded at initiation of treatment, initiation of taper, and at last visit if the taper was not completed.
Statistical analysis. The primary measure of efficacy was time to response in relief of anxiety symptoms, defined as the first time point at which the response criterion of ≥50-percent decrease from baseline in HAM-A total score was met. Kaplan-Meier estimates25 were used to calculate the distribution for each treatment group, and the groups were compared using the Generalized Wilcoxon nonparametric survival statistic.26 A total sample size of 240 subjects was calculated to detect with 80-percent power a 13-percent difference between treatment groups at Week 1 in time to response.
Analysis of secondary variables, including mean change from baseline in HAM-A total score and subscores, was performed using an analysis of covariance (ANCOVA)27 model, with treatment as a fixed effect and the corresponding baseline HAM-A total or subscale score as a covariate. Cochran-Mantel-Haenszel tests28 were used to analyze distribution of CGI-I and PGI scores, and Pearson Chi-Square tests29 were used to compare treatment groups on the basis of proportion of responders.
All statistical tests were two-sided with a significance level of α=0.05 unless otherwise specified. Included in the safety population were all subjects who received at least one dose of the medication(s) they were prescribed (an SSRI or SNRI, with or without alprazolam ODT). Efficacy analyses were performed on the intent-to-treat (ITT) population, which included subjects who received at least one dose of the prescribed medication(s) and had at least one post-baseline assessment. A prospectively defined “per protocol” population was evaluated for outcome only on the primary efficacy variable of time to response. Efficacy data are presented by week for observed cases unless otherwise specified.
Results
Study population. The intent of the study was to randomize approximately 240 subjects with a primary diagnosis of GAD for whom treatment with an SSRI/SNRI would be considered standard of care. Six hundred and sixty-five subjects were screened. Due to an unexpectedly slow recruitment rate, the study was terminated after 143 subjects meeting eligibility criteria were randomized.
One subject randomized to the combination treatment group did not receive study medication; thus, the safety population comprised 71 subjects randomized to treatment with alprazolam ODT combined with an SSRI/SNRI and 71 subjects randomized to treatment with SSRI/SNRI alone. Efficacy analyses were performed on the ITT population, which included 67 subjects treated with alprazolam ODT combined with SSRI/SNRI, and 62 subjects treated with SSRI/SNRI alone. The per protocol population, which excluded subjects with major protocol violations, included 53 subjects treated with alprazolam ODT in combination with an SSRI/SNRI, and 49 subjects treated with SSRI/SNRI alone.
Baseline demographic and clinical characteristics of subjects in the ITT population are summarized in Table 1. There were no significant demographic differences between groups. Subjects were, in general, moderately ill at baseline, with mean HAM-A total scores of 23.4 in the combination treatment group, and 21.6 in the SSRI/SNRI monotherapy group. Psychiatric history and current clinical status were similar between groups, although a greater proportion of subjects randomized to treatment with alprazolam ODT in addition to an SSRI/SNRI met MHS criteria for comorbid mood disorders (predominantly major depressive disorder and/or dysthymia) compared to the group treated with an SSRI/SNRI alone, a difference that trended toward statistical significance (81% vs. 66%, χ2(1)=3.47, P=0.06).
Table 1.
Baseline demographic and clinical characteristics of subjects in the ITT population
| SSRI/SNRI plus alprazolam ODT N=67 | SSRI/SNRI alone N=62 | |
|---|---|---|
Age (years)
|
|
|
| Gender (% female) | 74.6% | 67.7% |
Ethnic origin (%)
|
|
|
Diagnosis of GAD (%)
|
|
|
Duration of GAD (years)
|
|
|
| Comorbid Disorders (%) |
|
|
HAM-A (mean score ± SD)
|
|
|
Predominantly obsessive-compulsive disorder and/or generalized social anxiety disorder
Predominantly major depressive disorder and/or dysthymia
Seventy-six percent of subjects randomized to combination treatment with an SSRI/SNRI plus alprazolam ODT completed the study compared with 69 percent of subjects randomized to treatment with SSRI/SNRI alone. This was not statistically significant. Reasons for premature discontinuation are shown in Table 2. Very few subjects in either treatment group withdrew for lack of efficacy or adverse events. The two most frequent reasons for not completing the study were subjects being lost to follow-up and (among subjects randomized to SSRI/SNRI monotherapy) withdrawal of consent. The mean number of days subjects remained in the study was statistically significantly greater in the group receiving alprazolam ODT in addition to an SSRI/SNRI compared with the group receiving SSRI/SNRI alone (52 vs. 46 days, F(1,141)=4.48, P<0.05).
Table 2.
Subject disposition
| SSRI/SNRI plus alprazolam ODT N (%) | SSRI/SNRI alone N (%) | |
|---|---|---|
| Randomized | 72 (100%) | 71 (100%) |
| Completed study | 55 (76.4%) | 49 (69.0%) |
Discontinued study
|
|
|
Medication doses. Table 3 lists the SSRIs and SNRIs that were prescribed in this study; escitalopram, sertraline, and venlafaxine extended release were prescribed most frequently. Mean starting doses and dose ranges for the SSRIs/SNRIs were generally consistent with labeling information for GAD (or major depression for those SSRIs/SNRIs without an FDA-approved indication for GAD), although mean doses at endpoint tended to be toward the lower end of the drugs' recommended dose ranges. There was no difference in time to response between the various SSRIs/SNRIs when adjusted for treatment and initial dose level of alprazolam ODT.
Table 3.
Mean ending doses of SSRIs and SNRIs in the ITT population
| SSRI/SNRI plus alprazolam ODT N=67 | SSRI/SNRI alone N=62 | |||
|---|---|---|---|---|
| n | Mean Dose (mg/day) | n | Mean Dose (mg/day) | |
SSRIs
|
|
|
|
|
SNRIs
|
|
|
|
|
| Othera | 4 | -- | 2 | -- |
| Not Availableb | 2 | -- | 3 | -- |
Subjects not receiving an SSRI/SNRI
Subjects for whom an endpoint dose was not recorded, including subjects receiving sertraline plus alprazolam ODT (n=1), venlafaxine plus alprazolam ODT (n=1), escitalopram alone (n=2), and paroxetine CR alone (n=1)
Mean, median, and distribution of alprazolam ODT doses used in the ITT population are summarized in Table 4. The mean starting dose was 0.81mg/day, given in divided doses; almost all subjects received starting doses of alprazolam ODT of 1.50mg/day. There were no statistically significant differences between psychiatric and primary care sites in dosages that were prescribed. At Week 4, the mean dose of alprazolam ODT was 0.94mg/day, given in divided doses.
Table 4.
Distribution of alprazolam ODT doses at Baseline, Week 4, and Endpoint
| Starting Dose ITT N=67 | Week 4 Dose ITT N=67 | Endpoint Dose ITT N=67 | Endpoint Dose Completers N=55 | |
|---|---|---|---|---|
| Mean (mg/day)a | 0.81 | 0.94 | 0.74 | 0.80 |
| Median (mg/day)a | 0.75 | 0.88 | 0.50 | 0.50 |
Range, n (%)
|
|
|
|
|
Means and medians calculated for subjects receiving any dose >0
Subjects for whom a dose was not recorded
Despite the protocol-directed taper of alprazolam ODT over the last four weeks of the study, not all subjects were tapered successfully. At study endpoint (completion or early termination), 61 percent of the ITT population had been completely tapered off alprazolam ODT; the mean dose of alprazolam ODT at endpoint for those subjects not fully tapered was 0.74mg/day. Among the subjects who completed the study (n=55), 67 percent were tapered off alprazolam ODT by Week 8. There was no correlation between alprazolam ODT dose at Week 4 and successful completion of taper by Week 8.
Efficacy. There was no statistically significant difference between treatment groups in the primary efficacy variable of time to response in anxiety symptoms in the ITT population using the Generalized Wilcoxon survival test and Kaplan-Meier estimate of response (Figure 1). Analysis of the prospectively defined per protocol population also failed to detect a difference between treatment groups in time to response.
Figure 1.
Kaplan-Meier estimate of time to response in the ITT population
Analyses of secondary efficacy variables, however, suggested that combination treatment with alprazolam ODT and an SSRI/SNRI was associated with earlier improvement in global measures of response compared with SSRI/SNRI treatment alone. Both investigator-rated (Figure 2) and subject-rated (Figure 3) measures of global improvement favored combination treatment with SSRI/SNRI plus alprazolam ODT versus SSRI/SNRI alone at certain early time points. A significantly greater proportion of subjects treated with combination therapy versus monotherapy were considered much improved or very much improved on the CGI-I at Week 2 (43.9% vs. 21.1%, χ2(1)=7.21, P<0.01) and at Week 4 (63.3% vs. 41.3%, χ2(1)=5.08, P<0.05). Similarly, a greater proportion of subjects treated with SSRI/SNRI plus alprazolam ODT versus SSRI/SNRI alone considered themselves much improved or very much improved on the PGI at Week 2 (41.9% vs. 20.4%, χ2(1)=6.18, P<0.05), Week 3 (50.8% vs. 30.2%, χ2(1)=4.98, P<0.05), and Week 6 (70.0% vs. 43.8%, χ2(1)=6.89, P<0.01).
Figure 2.
Proportion of subjects rated “Very Much Improved” or “Much Improved” on the physician-rated Clinical Global Impression of Improvement scale
Figure 3.
Proportion of subjects rated “Very Much Improved” or “Much Improved” on the subject-rated Patient Global Impression scale
Analyses of mean change from baseline in HAM-A total and insomnia item scores also suggested that combination treatment with alprazolam ODT in addition to an SSRI/SNRI may be associated with earlier improvement in anxiety symptoms compared with SSRI/SNRI treatment alone. The difference between treatment groups trended toward significance at Week 1 (-7.8 vs. -4.6, F(1,117)=3.87, P=0.052) and was statistically significantly different at Week 2 (-10.0 vs. -6.1, F(1,111)=4.48, P<0.05) and Week 4 (-12.9 vs. -8.3, F(1,99)=5.32, P<0.05) with respect to mean change from baseline in HAM-A total score (Figure 4). On the HAM-A insomnia item (Figure 5), significant differences favoring combination treatment with SSRI/SNRI plus alprazolam ODT versus SSRI/SNRI alone were apparent at Weeks 1 and 2 (-1.0 vs. -0.5, F(1,117)=4.99, P<0.05, and -1.2 vs. -0.6, F(1,111)=6.50, P<0.05, respectively). There were no remarkable differences between treatment groups on mean change from baseline in HAM-A psychic or somatic factor subscales.
Figure 4.
Mean change from baseline in HAM-A total scores
Figure 5.
Mean change from baseline in HAM-A insomnia item scores
There was no evidence on any measure of an increase in anxiety symptoms among subjects in the combination treatment group during the alprazolam ODT taper over the last four weeks of the study.
Safety and tolerability. Both treatment regimens were generally well tolerated in this study. Discontinuation due to treatment emergent adverse events occurred in just one subject in each treatment group. Overall, 28 percent of subjects receiving alprazolam ODT in combination with an SSRI/SNRI reported experiencing at least one adverse event, compared with 20 percent of subjects receiving an SSRI/SNRI alone, a difference that was not statistically significant. The majority of adverse events (>95%) were classified as mild to moderate in nature. Adverse events reported by greater than two percent of subjects in either treatment group are shown in Table 5; fatigue and headache were the only adverse events reported by greater than five percent of subjects in either treatment group. Most adverse events were reported during the first four weeks of the study. Based on adverse event reporting, there was no evidence of withdrawal symptoms (such as insomnia, tinnitus, nausea, diarrhea) during the taper period. Serious adverse events, which required or prolonged hospitalization (cholecystitis and pneumonia), occurred in two subjects receiving SSRI/SNRI alone. They were unrelated to the study drug, and both subjects recovered. There were no serious adverse events in the combination group.
Table 5.
Treatment emergent adverse events occurring in ≥2% of subjects treated with alprazolam ODT in combination with an SSRI or SNRI or an SSRI/SNRI alone
| SSRI/SNRI plus alprazolam ODT N=71 | SSRI/SNRI alone N=71 | |||
|---|---|---|---|---|
| n | % | n | % | |
| Fatigue | 5 | 7.0% | 1 | 1.4% |
| Headache | 4 | 5.6% | 4 | 5.6% |
| Nausea | 3 | 4.2% | 2 | 2.8% |
| Somnolence | 3 | 4.2% | 0 | 0 |
| Dry Mouth | 3 | 4.2% | 0 | 0 |
| Constipation | 2 | 2.8% | 2 | 2.8% |
| Diarrhea | 2 | 2.8% | 1 | 1.4% |
| Dizziness | 2 | 2.8% | 1 | 1.4% |
| Dysgeusia | 2 | 2.8% | 0 | 0 |
Discussion
To our knowledge, this is the first randomized study to evaluate the potential therapeutic benefits and overall tolerability of initiating treatment of GAD with a benzodiazepine in combination with an SSRI/SNRI. Despite the reportedly widespread practice of concomitant benzodiazepine and antidepressant use in patients with anxiety disorders,17 to date clinicians have had little empirical evidence on which to base such prescribing decisions. In this study, there was no significant difference between treatment with alprazolam ODT in combination with an SSRI/SNRI versus an SSRI/SNRI alone on the primary efficacy variable of time to response using the commonly accepted definition of ≥50-percent reduction from baseline in HAM-A total score. However, the smaller than planned sample size reduced the study's power from 80 percent to 52 percent to detect a 13-percent difference between treatment groups in time to response.
There were suggestions on several pre-specified secondary measures that combination treatment resulted in earlier improvement in at least some domains. Compared with SSRI/SNRI monotherapy, short-term treatment with alprazolam ODT in addition to an SSRI/SNRI was associated with more rapid global improvement as assessed both by investigator- and subject-rated outcome measures. The apparent agreement between investigators' and subjects' perceptions of global improvement suggests that these early differences were clinically meaningful. Additionally, greater improvement in the target symptom of insomnia was observed during the first few weeks of treatment in subjects treated with alprazolam ODT in combination with an SSRI/SNRI, compared with SSRI/SNRI treatment alone. This finding may be clinically important in facilitating rapport and adherence for patients troubled by sleep disturbance. The naturalistic design of this study, in which relatively few exclusion criteria were employed, would indicate these findings may be broadly applicable to patients with GAD who are seen in both primary care and specialty practices.
In contrast to results from earlier placebo-controlled trials in panic disorder,18,19 a more rapid onset of anxiolytic response with combination benzodiazepine and SSRI/SNRI treatment was not consistently evident in this study. However, there was some indication that subjects receiving alprazolam ODT in combination with an SSRI/SNRI had some additional benefit in global measures of anxiety. As previously noted, the current study may have been underpowered to detect small, yet clinically meaningful, differences in onset of symptom resolution.
The smaller than planned sample size was a result of an unusually high rate of screening failure. Roughly three out of four subjects that investigators had identified as potentially eligible for inclusion either failed to meet MHS diagnostic criteria for GAD, or met MHS criteria for both GAD and panic disorder, which was an exclusion criterion for this study. Our experience underscores both the value of using a structured and unbiased approach to diagnosis, as well as the difficulty of finding subjects in the “real world” who present with GAD that is not comorbid with panic.
The dosing regimen used in this trial of brief treatment with low doses of alprazolam ODT in combination with an SSRI/SNRI followed by a gradual taper appeared to be well tolerated, with a very low rate of drop-outs due to adverse events, and no evidence of rebound anxiety during the taper. It must be noted, however, that some subjects who were lost to follow-up may have experienced intolerable adverse events, and not all subjects completed the protocol-directed taper by Week 8. It is unclear whether those not completing the taper required continued treatment with alprazolam ODT to manage persistent symptoms of anxiety, or whether some individuals may require a more extended period of titration during benzodiazepine discontinuation. An intriguing post hoc finding is that the combination of alprazolam ODT with an SSRI/SNRI was associated with a significantly longer mean duration of treatment than SSRI/SNRI monotherapy. While SSRI and SNRI antidepressants remain the preferred pharmacotherapeutic choice for chronic treatment of GAD,30 initial co-administration of alprazolam ODT with an SSRI or SNRI may provide early relief of symptoms, which might account for longer-term adherence to an antidepressant regimen. Whether initiating treatment with an SSRI/SNRI in combination with a benzodiazepine truly improves adherence to the SSRI/SNRI regimen should be evaluated in a prospective manner.
A major limitation of the current study is its open-label design, as investigators and subjects may have had increased expectations of a positive response among those assigned to receive combination treatment compared with the group assigned to treatment with SSRI/SNRI alone. Further investigation employing a double-blind, placebo-controlled design to confirm and extend the observations in this trial appears warranted. Future studies are also needed to compare the relative efficacy and tolerability of alternative benzodiazepine-antidepressant combination regimens (e.g., early vs. later treatment in the face of partial response or nonresponse to antidepressants), as well as to identify subgroups of patients who may respond preferentially to combination versus monotherapy in the treatment of GAD. Another limitation is that investigators in this trial prescribed relatively low doses of both alprazolam ODT and the SSRIs and SNRIs. While higher medication dosages might have produced more robust responses and be more consistent with the dose ranges commonly reported in clinical trials and recommended in treatment guidelines, the doses used in this study may more accurately reflect dosing strategies used in practice. A third limitation with this naturalistic study is the paucity of information about the approximately one third of subjects treated with alprazolam ODT in combination with an antidepressant who did not follow the taper protocol and remained on combination therapy. We do not know if this represents subject preference, inadequate response to the antidepressant, or some type of prescriber bias. Further investigation of this observation is warranted in a more rigorously controlled study.
In conclusion, four weeks concomitant treatment with alprazolam ODT followed by a gradual taper did not differentiate from SSRI/SNRI therapy alone on the primary measure, but still may prove a useful strategy for initiating SSRI or SNRI treatment for some patients with GAD. Administration of alprazolam ODT in combination with an SSRI/SNRI appears to be safe and well tolerated. Compared with SSRI/SNRI monotherapy, the combination of alprazolam ODT with an SSRI/SNRI may lead to early relief at least from symptoms of insomnia, and may be associated with a more rapid onset of global improvement. These observations merit further study under double-blind, placebo-controlled conditions.
Acknowledgments
The authors gratefully acknowledge each of the investigators who contributed data to this study, and Mary Susan Prescott, MS, who provided editorial assistance in development of the manuscript.
Contributor Information
Mark Hyman Rapaport, Dr. Rapaport is from the Department of Psychiatry, Cedars-Sinai Medical Center, and from the Department of Psychiatry and Behavioral Neurosciences, David Geffen School of Medicine and Biobehavioral Sciences at UCLA, Los Angeles, California.
Steve B. Skarky, Dr. Skarky is from Paradigm Research Professionals, LLP, Oklahoma City, Oklahoma.
David J. Katzelnick, Dr. Katzelnick is from Healthcare Technology Systems, Inc., and from the Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Jeffrey N. DeWester, Dr. DeWester is from DeWester, Dicks, & DeWester Family Medicine, Indianapolis, Indiana.
James M. Harper, Dr. Harper is from the Department of Biometrics, Omnicare Clinical Research, King of Prussia, Pennsylvania.
Kay E. McCrary, Dr. McCrary is from Schwarz Pharma, Inc., Mequon, Wisconsin..
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