Dependence on benzodiazepines in patients with panic disorder: A cross-sectional study

Authors

  • Kazuhito Fujii MD,

    1. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
    2. Azumabashi New Tower Clinic, Tokyo, Japan
    Search for more papers by this author
  • Hiroyuki Uchida MD, PhD,

    Corresponding author
    1. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
    2. Geriatric Mental Health Program, Centre for Addiction and Mental Health, Toronto, Canada
    • Correspondence: Hiroyuki Uchida, MD, PhD, Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: hiroyuki.uchida.hu@gmail.com

    Search for more papers by this author
  • Takefumi Suzuki MD, PhD,

    1. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
    2. Department of Psychiatry, Inokashira Hospital, Tokyo, Japan
    Search for more papers by this author
  • Masaru Mimura MD, PhD

    1. Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
    Search for more papers by this author

Abstract

Aims

The aim of this cross-sectional study was to examine the prevalence of psychological dependence on benzodiazepines in outpatients with panic disorder and elucidate demographic and clinical characteristics associated with this condition.

Methods

Subjects were eligible if they were outpatients in four clinics in Tokyo, Japan, aged 18 years or older and met the diagnostic criteria for panic disorder according to the ICD-10. The subjects received the following assessments: the Severity of Dependence Scale, Japanese Version (SDS), the Self-Report Version of Panic Disorder Severity Scale, Japanese Version (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version. The following information was also collected: age, sex, ethnicity, duration of illness, physical and psychiatric comorbidities, and details of prescribed psychotropic medications.

Results

The data from 51 outpatients showed that 31 patients (60.8%) showed psychological dependence (i.e. a total score of ≥5 in the SDS). The proportion of patients with dependence was significantly lower in remitted patients (i.e. a total score of ≤4 in the PDSS) (44.1%, n = 15/34) than those who were not (94.1%, n = 16/17) (Pearson χ2 = 11.9, P < 0.001). A multiple regression analysis showed that the PDSS scores showed a positive correlation with the SDS total scores (β = 0.60, 95% confidence interval = 0.30–0.90, P = 0.0001).

Conclusion

These findings emphasize the need for enhanced awareness about benzodiazepine dependence in patients and psychiatrists, as well as especially close attention to patients with panic disorder who present severe symptomatology.

Use of benzodiazepines has not been endorsed for the treatment of panic disorder in current treatment guidelines because of their potentially serious side-effects, which include dependence, withdrawal symptoms, psychomotor and cognitive impairments as well as drowsiness.[1-3] In contrast, selective serotonin reuptake inhibitors (SSRI) are recommended as first-line drugs for this condition. This notwithstanding, epidemiological data have shown that benzodiazepines are, in fact, widely used in the real world. For example, the use rate of benzodiazepine-derivative anxiolytics was approximately 70% in all decades of life without a group difference in 796 patients with neurotic disorders, including panic disorder.[4] Moreover, the prescription rate of benzodiazepines appears to be increasing at least in some countries, including Australia and the USA; the Australian Government Pharmaceutical Benefit's Scheme subsidized prescription of alprazolam increased by 93% from 1997 to 2007 to 386 350 prescriptions. Similar increases in prescription rates were observed in the USA with a 71% rise over the same period.[5] Thus, the evidence has clearly revealed the disparity between clinical practice and treatment guidelines.

The widespread use of benzodiazepines may be associated with psychiatrists' as well as patients' attitudes towards those medications. First, sufficient attention may not be paid to side-effects of benzodiazepines as many of the side-effects are invisible and therefore may not be well recognized. Second, benzodiazepines may be effective for the treatment of panic disorder in spite of the concerns, including dependence, raised by the treatment guidelines. In fact, there have been two double-blind, albeit small, randomized controlled trials that compared benzodiazepines with SSRI, which demonstrated comparable efficacy without any significant difference in side-effects.[6, 7]

Still, dependence on benzodiazepines is a major clinical and theoretical concern but the data on this clinically relevant issue are still scarce. Despite the widely accepted concerns on the dependence on benzodiazepines, the evidence on this issue has still been limited in panic disorder.[8] Data from a community-dwelling older adult population (aged 65 years or older) in Quebec, Canada in 2005 and 2006 showed prevalence rates of dependence on benzodiazepines of 2.3% in 2798 of a representative sample in the general population with mixed diagnoses (n = 64). In psychiatric hospitals of the Free University of Berlin and the Ludwig Maximilian University of Munich between 1980 and 1985, drug dependence and abuse were diagnosed in 6.6% (1009/15 296) of admitted patients with mixed diagnoses with benzodiazepines being involved in 4.7% (n = 726).[9] However, these studies included patients with various diagnoses and did not solely focus on panic disorder. In addition, demographic and clinical characteristics, including illness severity, that could influence the presence and degree of dependence have not been investigated. If those characteristics are identified specifically in patients with panic disorder, it will improve our understanding of dependence on benzodiazepines in this population and could improve clinical management for this frequently chronic condition.

To address the gap in the literature, we performed a cross-sectional study to investigate the prevalence of dependence on benzodiazepines in outpatients with panic disorder and its association with demographic and clinical characteristics.

Method

Participants and questionnaires

This cross-sectional study was conducted from November 2012 to November 2013 in the following four psychiatric hospitals in Tokyo, Japan: Asakadai Mental Clinic, Oizumi Hospital, Oizumi Mental Clinic, and Azumabashi New Tower Clinic. The study was approved by the institutional review board at each participating site, and subjects provided written informed consent after receiving detailed information about the protocol. Subjects were eligible if they were 18 years of age or older, met the diagnostic criteria for panic disorder according to the ICD-10,[10] and visited one of the participating sites during the study period. Subjects were excluded if they had a psychiatric comorbidity or had a significant medical condition that required an immediate referral to specialists. The subjects received the following assessments: the Severity of Dependence Scale, Japanese Version (SDS),[11, 12] the Self-Report Version of Panic Disorder Severity Scale, Japanese Version (PDSS-SR),[13, 14] and the Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version (QIDS-SR).[15] The PDSS-SR is designed to evaluate the severity of panic disorder with a total score ranging from 0 to 28; a score of 4 or less indicates remission. The SDS is a self-rated questionnaire to assess psychological dependence on a given drug (benzodiazepines in this study) with a total score ranging from 0 to 15; a score of 5 or more indicates the presence of dependence. We also collected the following information: age, sex, ethnicity, duration of illness, physical and psychiatric comorbidities, and details of prescribed psychotropic medications. Daily doses of benzodiazepines and antidepressants were converted to diazepam and imipramine equivalents, respectively.[16]

Statistical analyses

Statistical analyses were carried out using ibm spss 20 (ibm, Armonk, NY, USA). Prevalence rates of dependence on benzodiazepines were compared between subjects in remission and those who were not by the χ2-test. In addition, a multiple regression analysis, using forced entry method, was performed to examine effects of age group (i.e. <40, 40–59, or ≥60 years), sex, duration of illness, total scores in the PDSS-SR, and QIDS-SR, diazepam-equivalent dose of benzodiazepines, and imipramine-equivalent dose of antidepressants on the SDS total scores. A binary multiple regression model was also used to evaluate effects of age group (i.e. <40, 40–59, or ≥60 years), sex, duration of illness, remission status in panic disorder (i.e. remitted or non-remitted), total scores in the QIDS-SR, diazepam equivalent dose of benzodiazepines, and imipramine equivalent dose of antidepressants on the presence of dependence to benzodiazepines. A P-value of <0.05 was considered statistically significant and all tests were two-tailed.

Results

Demographic and clinical characteristics of the subjects

A total of 52 patients were approached; of these, 51 subjects (98.1%) agreed to participate in this study. The subjects' demographic and clinical characteristics are summarized in Table 1. All patients were Japanese, and they were predominantly female, generally chronic with a mean duration of illness of approximately 5 years.

Table 1. Demographic and clinical characteristics of 51 subjects
CharacteristicsValues (n = 51)
  1. PDSS-SR, Self-Report Version of Panic Disorder Severity Scale, Japanese Version; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version; SDS, Severity of Dependence Scale, Japanese Version.
Sex: Male, n (%)17 (33.3%)
Age (years), mean ± SD (range)39.9 ± 11.1 (19–66)
<40 years n (%)26 (51.0%)
41–59 years n (%)22 (43.1%)
≥60 years n (%)3 (5.9%)
Duration of illness (months), mean ± SD (range)54.0 ± 73.9 (1–360)
SDS total score, mean ± SD (range)4.3 ± 2.7 (0.0–13.0)
PDSS-SR total score, mean ± SD (range)4.6 ± 4.9 (0.0–17.0)
QIDS-SR total score, mean ± SD (range)5.7 ± 5.1 (0.0–21.0)
Total diazepam equivalent dose of benzodiazepines, mg/day, mean ± SD7.8 ± 7.9
Total imipramine equivalent dose of antidepressants, mg/day, mean ± SD73.7 ± 73.5

Of all subjects, 66.7% (n = 34) were found to be in remission, and 60.8% (n = 31) demonstrated psychological dependence on benzodiazepines. The proportion of patients with dependence was significantly lower in remitted patients (44.1%, n = 15/34) than those who were not in remission (94.1%, n = 16/17) (Pearson χ2 = 11.9, d.f. = 1, P < 0.001).

Multiple regression analyses

A multiple regression analysis showed that the PDSS scores and prescribed antidepressant dose showed a positive correlation with the SDS total scores; the standardized partial regression coefficient for the PDSS score was almost twice as high as that for the antidepressant dose (0.60 and 0.31, respectively) (Table 2). A binary regression model demonstrated that the absence of remission increased the risk of dependence on benzodiazepines (odds ratio [OR] = 122.8, 95% confidence interval [CI] = 3.0–5036.8, P = 0.01) as well as the duration of illness (OR = 1.03, 95%CI = 1.00–1.06, P = 0.04) (Table 3).

Table 2. Multiple regression analysis to identify variables associated with SDS total scorea
Variablesβt valueP-value95%CI
  1. aDependent variable, SDS; one-way analysis of variance showed significant validity of the model selection (F(7, 43) = 6.718, P = 0.0001); coefficient of determination showed the model with high predictive power (R = 0.723, adjusted-R2 = 0.445).
  2. β, standardized partial regression coefficient; CI, confidence interval; PDSS-SR, Self-Report Version of Panic Disorder Severity Scale, Japanese Version; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version; SDS, Severity of Dependence Scale, Japanese Version.
Age, years−0.09−0.750.46−0.34–0.16
Female, sex0.221.880.07−0.02–0.45
Duration of illness, years0.191.630.110.16–0.21
PDSS-SR total score0.604.030.00010.30–0.90
QIDS-SR total score−0.24−1.750.09−0.51–0.04
Total diazepam equivalent dose of benzodiazepines, mg/day0.02−0.170.87−0.21–0.25
Total imipramine equivalent dose of antidepressants, mg/day0.312.650.010.07–0.55
Table 3. Binary regression model to identify variables associated with benzodiazepine dependencea
VariablesOdd ratiosP-value95%CIβ (SE)Wald
  1. aDependent variable, SDS.
  2. CI, confidence interval for the estimated odds ratio; PDSS-SR, Self-Report Version of Panic Disorder Severity Scale, Japanese version; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Report, Japanese Version; SDS, Severity of Dependence Scale, Japanese Version; SE, standard error.
Age, years0.990.710.91–1.070.040.14
Female, sex6.390.110.67–61.371.162.58
Duration of illness, years1.030.041.00–1.060.024.35
PDSS-SR122.810.013.00–5036.761.906.45
QIDS-SR total score0.910.420.72–1.150.120.66
Total diazepam equivalent dose of benzodiazepines, mg/day0.890.270.72–1.100.111.23
Total imipramine equivalent dose of antidepressants, mg/day1.020.061.00–1.030.013.51

Discussion

To our knowledge, this is the first study that evaluated the prevalence of psychological dependence on benzodiazepines specifically in patients with panic disorder. Approximately 60% of the subjects were found to be dependent on those medications in this population. Of note, the proportion of patients with dependence was significantly higher in non-remitters compared to remitters. Subsequent regression analyses have corroborated this finding; severer symptomatology in panic disorder was associated with a greater risk of developing dependence on benzodiazepines. These findings emphasize the need for enhanced awareness about benzodiazepine dependence in patients and psychiatrists, as well as for especially close attention to patients with severe symptomatology of panic disorder who are more likely to become dependent on those medications.

The percentage of psychological dependence on benzodiazepines was found to be significantly higher in patients who showed severe symptomatology; this finding was also supported by subsequent regression analyses. One plausible explanation for this finding is that patients with severer symptomatology may more frequently develop psychological dependence on benzodiazepines in an effort to alleviate anxiety symptoms. One large observational cohort study in the Netherlands found that preoccupation with the availability of benzodiazepines was significantly related with anxiety severity in 401 users of those medications.[17] Another possibility is that severer patients may receive a larger amount of doses, which could result in a higher chance to develop dependence/tolerance in light of the previously reported correlation between dose and dependence;[18-20] however, the dose was not a significant factor in the present study. Moreover, a longer duration of treatment has been reported to increase the risk of physiological dependence;[21] it was also associated with benzodiazepine dependence in a binary regression model in our study, which however failed to be replicated in a multiple regression. Another potential reason is the possibility that benzodiazepine dependence inhibits recovery from panic disorder although this speculative contention needs to be confirmed in future investigations. Thus, in light of the paucity of the data, dependence on benzodiazepines should receive sufficient attention, irrespective of their dose and treatment duration.

On the other hand, the proportion of psychological dependence was lower in remitted patients compared to others; the prevalence rate was 44.1%. This figure may be considered high. However, looking at this fact from a different angle, it can also be said that more than half of remitted patients with panic disorder in this study did not show evidence of psychological dependence on benzodiazepines on the measures used. Consistent with this finding, Rickels et al. reported that 62.1% (23/37) of the alprazolam-treated patients achieved remission, and none developed any tolerance to benzodiazepines in a double-blind, 2-month, placebo-controlled trial of alprazolam and imipramine followed by a 6-month naturalistic follow up.[22] Andersch et al. conducted a 15-year naturalistic follow up of outpatients with panic disorder who had originally participated in an 8-week double-blind randomized controlled trial that had compared alprazolam with imipramine. While 53 of 62 patients (85.5%) received alprazolam at the baseline, only 10 of 55 patients (18.2%) were still taking the medication 15 years later although prescription details for seven dropouts were not provided in the report.[23] This result may suggest that a significant proportion of patients with panic disorder receiving benzodiazepines successfully discontinue them eventually in the long run. Thus, there may be a possibility that benzodiazepines can be safely utilized without a significant risk of psychological dependence at least in a sizeable proportion of patients with panic disorder. However, given that benzodiazepines are known to cause other numerous side-effects, such as ataxia, sedation, cognitive and psychomotor impairment and withdrawal syndrome,[24-27] a thoroughly balanced assessment of the benefits and risks associated with benzodiazepine use should be exercised in every instance.[24]

There are several limitations to be noted in the present study. First, although this is the largest study to examine psychological dependence on benzodiazepines in patients with panic disorder so far, the sample size of 51 is still very small. Second, as the data in the present study were derived from outpatients in one psychiatric hospital and three clinics in Japan, generalization of the findings to other population groups may be limited. Third, due to the cross-sectional study design, any causality remains a matter of speculation. Moreover, even in patients who did not show evidence of psychological dependence on benzodiazepines, their future risk of developing dependence has to be acknowledged. Fourth, the relative usefulness and risks of benzodiazepines in comparison with the gold standard medications, SSRI, are unknown as this was not our topic herein. Finally, psychological dependence on benzodiazepines should be interpreted in a context of many factors, such as personality and lifestyle,[28-30] which were not assessed in our study. Thus, the preliminary nature of this cross-sectional study clearly warrants future methodologically rigid investigations with larger sample sizes.

In conclusion, these findings underscore the need for closer attention to possible psychological dependence on benzodiazepines in patients with panic disorder; this may be especially the case for those with severe symptomatology irrespective of dose and treatment duration. On the other hand, it is also noted that a majority of remitters did not show psychological dependence on those medications, which highlights a possible role for benzodiazepines in the management of panic disorder despite their risks. In light of inconsistencies between suggestions by the treatment guidelines and the actual use of benzodiazepines in the real world, further studies, such as prospective trials or follow-up studies to elucidate any causal relation between the use of benzodiazepines and incidence of and/or recovery from dependence on those medications, are needed. In the meantime, balanced discussions regarding the pros and cons of those medications are needed for the front-line clinicians.

Acknowledgments

This study was partially funded by an Inokashira Hospital Research Grant. The authors thank Drs Hirano, Mizuno, Sawada, Tsuboi, and Yoshida for their continuous support and Ms Ai Ohtani for her administrative support. Dr Fujii has nothing to disclose. Dr Uchida has received grants from Pfizer, Astellas Pharmaceutical, Eisai, Otuka Pharmaceutical, GlaxoSmithKline, Shionogi, Dainippon-Sumitomo Pharma, Eli Lilly, Mochida Pharmaceutical, Meiji-Seika Pharma, Janssen Pharmaceutical, and Yoshitomi Yakuhin and speaker's honoraria from Otuka Pharmaceutical, Eli Lilly, Shionogi, GlaxoSmithKline, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, Meiji-Seika Pharma, Abbvie, and Janssen Pharmaceutical within the past 3 years. Dr Suzuki has received manuscript or speaker's fees from Astellas, Dainippon Sumitomo, Eli Lilly, Elsevier Japan, Meiji Seika, Novartis, Otsuka, and Weily Japan within the past 3 years. Dr Mimura has received grants and/or speaker's honoraria from Asahi Kasei Pharma, Astellas Pharmaceutical, Daiichi Sankyo, Dainippon-Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Meiji-Seika Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, Takeda, Tanabe Mitsubishi Pharma, and Yoshitomi Yakuhin within the past 3 years.

Ancillary