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Volume 11 No. 05
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Scientific Investigations

Risk of Psychiatric Disorders in Patients with Chronic Insomnia and Sedative-Hypnotic Prescription: A Nationwide Population-Based Follow-Up Study

Kuo-Hsuan Chung, MD1,2,3; Chung-Yi Li, PhD4,5; Shu-Yu Kuo, RN, PhD6; Trevor Sithole, RN, MSN7,8; Wen-Wei Liu, BS9; Min-Huey Chung, RN, PhD9
1Department of Psychiatry, Taipei Medical University Hospital, Taipei, Taiwan; 2Psychiatric Research Center, Taipei Medical University Hospital, Taipei, Taiwan; 3Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 5Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan; 6School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan; 7Maternity Department, Emkhuzweni Health Center, Swaziland; 8Customer Care Officer, Emkhuzweni Health Center, Swaziland; 9Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan

ABSTRACT

Study Objectives:

Previous epidemiological studies have established insomnia as a major risk factor for mood, anxiety, and substance use disorders. However, the associations between insomnia with sedative-hypnotic prescriptions and various psychiatric disorders have not been thoroughly examined. The current study involved evaluating the risk of psychiatric disorders, namely schizophrenia, mood, anxiety, somatoform, and substance-related disorders, over a 6-y follow-up period in three groups: patients with insomnia and sedative-hypnotic prescriptions (Inso-Hyp), those with insomnia and without sedative-hypnotic prescriptions (Inso-NonHyp), and those with neither insomnia nor sedative-hypnotic prescriptions (NonInso-NonHyp).

Methods:

We used a historical cohort study design to compare the risk of psychiatric disorders among the three groups. Data regarding these patients were derived from reimbursement claims recorded in Taiwan's National Health Insurance Research Database. Cox proportional hazards regression was used to compare the 6-y risk of subsequent psychiatric disorders among the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups.

Results:

Compared with the Inso-NonHyp and NonInso-NonHyp group patients, the Inso-Hyp group patients exhibited a higher risk of psychiatric disorders, particularly bipolar disorders (adjusted hazard ratio [AHR]: 7.60; 95% confidence interval [CI]: 5.31–10.89 and AHR: 14.69; 95% CI: 11.11–19.43, respectively). Moreover, among the Inso-Hyp patient group, insomnia prescribed with benzodiazepine, a longer duration of sedative-hypnotic action, and higher doses of sedativehypnotics were significantly associated with a higher risk of depressive and anxiety disorders.

Conclusion:

The Inso-Hyp group exhibited a higher risk of developing psychiatric disorders than did the Inso-NonHyp and NonInso-NonHyp groups. The results regarding patients with insomnia and sedative-hypnotic prescriptions associated with the risk of psychiatric disorders can serve as a reference for care providers when managing sleep disturbances.

Citation:

Chung KH, Li CY, Kuo SY, Sithole T, Liu WW, Chung MH. Risk of psychiatric disorders in patients with chronic insomnia and sedative-hypnotic prescription: a nationwide population-based follow-up study. J Clin Sleep Med 2015;11(5):543–551.


Insomnia is the most prevalent sleep disorder, with a prevalence ranging from 5% to 40% in Western and Asian counties,17 and exhibits wide variations depending on the definition of insomnia considered, populations studied, and research methodologies used. Approximately 5% to 12% of the general population experiences chronic insomnia,6,8 which is defined as the experience of an inability to obtain an adequate amount or quality of sleep for at least 3 nights per week for at least 1 mo.9 Insomnia is recognized as a growing public health concern with considerable personal and socioeconomic burdens8 and negative effects regarding the development of comorbid medical and psychiatric disorders.1012 Among patients with chronic insomnia, over half exhibit a comorbid medical condition, whereas one-fourth to half exhibits a comorbid psychiatric condition.1315

BRIEF SUMMARY

Current Knowledge/Study Rationale: Evidence has demonstrated that chronic insomnia may be associated with psychiatric comorbidities. However, the relationship between them is complex and includes bidirectional causation. In this study, we explored if we could identify whether there is an increased risk for emergence of psychiatric disorders among insomniacs with sedative-hypnotic prescriptions.

Study Impact: To our knowledge, this is the first nationwide population study using a historical cohort design to demonstrate that chronic Insomnia with sedative-hypnotics are risk factors for most common psychiatric disorders. These results led to the concept that chronic insomnia may have a common etiological or pathogenic influence on many psychiatric disorders.

A complex, bidirectional risk relationship exists between chronic insomnia and psychiatric disorders. Mai et al. suggested that insomnia can predict, cause, or be a prodromal symptom of other psychiatric disorders; moreover, insomnia might be secondary to or part of the primary psychiatric disorder or a separate or comorbid disorder.4 Despite the variety of possible reciprocal relationships between insomnia and comorbidities, studies have demonstrated that chronic insomnia can exacerbate certain comorbid conditions16,17 and is associated with an inadequate treatment response in patients with comorbid disorders.18 Medication management that targets comorbid insomnia may lead to improvements in insomnia as well as the treatment outcomes of comorbid disorders.18

Although psychological and behavioral interventions are effective in and recommended for treating chronic insomnia, the long-term use of hypnotic drugs may be indicated for severe or refractory insomnia or chronic comorbid illnesses.19 However, patients receiving hypnotic prescriptions exhibited four times greater mortality than did matched hypnotic drug-free control patients;20 patients who were prescribed hypnotic drugs at high doses exhibited an overall increase in the incidence of cancer.20 Moreover, a randomized placebo-controlled study using data released by the United States Food and Drug Administration suggested that hypnotic drugs are more likely to cause depression than to prevent it.21 These studies have reported a probable association between the use of hypnotic drugs and the risk of developing mortalities, cancer, and depression. Insomnia and hypnotics seem to independently increase the risks of psychiatric disorders; however, the risk of developing psychiatric disroders in patients with insomnia receiving sedative-hypnotic drugs need to be explored further.

Most studies examining whether chronic insomnia is a precedent risk factor for ensuing psychiatric disorders have focused on the correlation between chronic insomnia and depression,12,13,16,22,23 anxiety disorders,12,13,22 and alcohol abuse or dependence,8,13 and few studies have addressed the risk of developing other psychiatric disorders, such as schizophrenia, bipolar disorders, and somatoform disorders.2426 In addition, most longitudinal epidemiological studies have examined the evolution of psychiatric disorders in patients with chronic insomnia during follow-up periods ranging from 1 to 3 y.12,13,23,27 Considering the effect of sedative-hypnotic prescription on insomnia, we hypothesized that chronic insomnia prescribed with sedative-hypnotic drugs is a risk factor for most psychiatric disorders. Therefore, the current study explored whether patients with insomnia and sedative-hypnotic prescriptions (Inso-Hyp) exhibit an increased risk of developing psychiatric disorders compared with those with insomnia and without a sedative-hypnotic prescription (Inso-NonHyp) and those with neither insomnia nor sedative-hypnotic prescriptions (Non-Inso-NonHyp) by using a population-based, historical cohort design over a 6-y follow-up period.

METHODS

Database

The National Health Insurance (NHI) program initiated and maintained by the government is a compulsory, single-payer system. The NHI program has enrolled 98% of the residents of Taiwan and military employees. The program has a fee-for-service payment design, and all medical care providers are required to provide records on outpatient and inpatient services to NHI insurers to claim their fees. The medical claims include information regarding patient demographics (age and sex), clinical details (disease and procedure codes according to the International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]), and healthcare use (days in hospital, drug prescription, and charges). The National Health Research Institutes maintains and assesses the National Health Insurance Research Database (NHIRD) to ensure accurate coding. This study was exempted from full review by an institutional review board because the NHIRD contains deidentified secondary data that are released to scientists and clinicians for research purposes.

Participants

This historical cohort study examined two exposure groups and one unexposed group. The first exposure group comprised patients with insomnia who were prescribed sedative hypnotic (Inso-Hyp) medications. Insomnia was first diagnosed (ICD-9-CM Codes 307.40, 307.41, 307.42, 307.44, 307.49, or 780.52) by a physician between January 1, 2002 and December 31, 2004. Patients with insomnia were older than 18 y and had at least two service claims for insomnia visits within 1 y to ensure accurate coding. For each patient, the first ambulatory visit for insomnia treatment was assigned as the index date. In this study, patients for whom service claims were filed at > 1-mo intervals until a psychiatric disorder was diagnosed were considered to have chronic insomnia.

The first exposure group was prescribed with sedative-hypnotic drugs at a defined daily dose (DDD) of at least 30 per year.28 The prescriptions of patients with ≥ 3-mo intervals between prescriptions were considered discontinued.29 The sedative-hypnotics were classified into two groups: benzodiazepines (BZDs) and non-BZDs. The BZDs were alprazolam, bromazepam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, fludiazepam, flunitrazepam, flurazepam, lorazepam, medazepam, midazolam, nitrazepam, nordazepam, oxazepam, and triazolam, whereas the non-BZDs were zolpidem, zopiclone, and zaleplon.30 Patients who were prescribed both BZDs and non-BZDs were excluded from the analysis of drug types. In general, sedative-hypnotic drugs can be divided into three groups according to their half-life values: short acting, intermediate acting, and long acting.31 Short-acting hypnotic drugs have a half-life of < 10 h, intermediate-acting hypnotic drugs have a half-life of approximately 10 to 35 h, and long-acting hypnotics have a half-life of > 35 h.31 Patients who switched from longer-acting sedative-hypnotics to shorter-acting drugs were categorized into the longer-acting group. Moreover, patients with a prescribed cumulative DDD of 7 to 30 per year were categorized as low-dose users, those with a prescribed cumulative DDD of 31 to 90 per year were categorized as medium-dose users, and those with a prescribed cumulative DDD of ≥ 91 were categorized as high-dose users.28

Insomnia was diagnosed in all patients in the second exposure group, and they received no sedative-hypnotic prescription (Inso-NonHyp). The definition of insomnia for the second exposure group was the same as that for the first exposure group. The exclusion criteria for both exposure groups were (1) a previous diagnosis of insomnia (ICD-9-CM Codes 307.40, 307.41, 307.42, 307.44, 307.49, or 780.52) between 1999 and 2001, and (2) a previous diagnosis of schizophrenia, bipolar disorder, depressive disorder, anxiety disorder, somatoform disorder, or substance-related disorder before the index date, and (3) substance-related disorder specifically related to BZD prescriptions.

The unexposed group comprised the remaining beneficiaries in the database who had no insomnia and did not receive a sedative-hypnotic prescription (NonInso-NonHyp) between 1999 and 2010. Only patients 18 y or older were included to limit the study to an adult population. The urbanization level of each patient's residence was defined as urban, suburban, or rural.32 Urbanization was evaluated to ensure that the patients had reasonably similar neighborhood and socioeconomic characteristics. Information regarding any preexisting comorbidities was acquired and evaluated using Charlson comorbidity index (CCI) scores. The CCI is a scoring system that assigns points between 1 and 6 to a range of diseases.33 In this study, the patients were classified into two groups according to the sum of their points: < 3 points (low comorbidity) and ≥ 3 points (high comorbidity). The exclusion criteria for patients in the unexposed group included a previous diagnosis of a psychiatric disorder and the prescription of sedative-hypnotics before the index visit. A patient's index visit was defined as their first use of medical care within the index year. The unexposed group comprised 22,700 patients (four for every patient with chronic insomnia) matched with those in the exposure cohorts according to age, sex, index year, and CCI score.

Variables of Interest

The risks of psychiatric disorders, namely schizophrenia (ICD-9-CM Code 295.xx), bipolar disorders (ICD-9-CM Codes 296.0x, 296.1x, 296.4x, 296.5x, 296.6x, 296.7x, 296.8x, and 296.9x), depressive disorders (ICD-9-CM Codes 296.2x, 296.3x, 300.4, and 311), anxiety disorders (ICD-9-CM Codes 300.3, 308.3, 300.00, 300.01, 300.02, 300.21, 300.22, 300.23, 300.29, and 309.81), somatoform disorders (ICD-9-CM Codes 300.7, 300.11, 300.81, 300.82, 307.80, and 307.89), and substance-related disorders (ICD-9-CM Codes 291.xx, 292.xx, 303.0x, 303.9x, 304.xx, and 305.xx) were evaluated for each patient. The patients were individually followed up for over 6 y from their index visit to the first diagnosis of a psychiatric disorder, death, or the end of the follow-up period between January 1, 2005, and December 31, 2010.

Statistical Analysis

All statistical analyses were performed using the SAS statistical package (SAS systems for Windows, Version 9.2; Cary, NC, USA). Demographic information regarding age, sex, income, residential region, and urbanization level was acquired from each patient's file in the NHI insurance database. The patients were divided into four age groups: younger than 30 y, 30–44 y, 45−64 y, and 65 y or older. The average monthly income was divided into three groups: < US $640 (New Taiwan Dollars [NTD] 20,000), US $640−$1,280 (NTD 20,000–39,999), and ≥ US $1,281 (≥ NTD 40,000). The residential areas of the patients were divided according to the four administrative regions of Taiwan: Northern, Central, Southern, and Eastern. An incident case was considered when a new diagnosis of a psychiatric disorder was made in a patient using the NHI services for the first time during 2002 to 2004 and there had been no previous diagnosis of a psychiatric disorder. The incidence density was calculated as the number of incident cases relative to the number of person-years contributed by the study patients. A univariate Cox proportional hazard regression analysis was conducted to estimate the crude hazard ratios (CHRs) of psychiatric disorders related to chronic insomnia. After we controlled for the potential confounders of psychiatric disorders, including patient income, region, and CCI score, a multivariate Cox proportional hazard regression model was applied to calculate the adjusted hazard ratios (AHRs), which indicated the effects of chronic insomnia treated with sedative-hypnotics prescription on the risk of psychiatric disorders. In addition, the Kaplan–Meier method and log-rank test were used to assess the differences in the survival rates and curves of the development of psychiatric disorders between the exposure and the unexposed groups, respectively. A p value of < 0.05 was considered statistically significant.

RESULTS

Table 1 summarizes the demographic characteristics of the patients in the Inso-Hyp (N = 2,295), Inso-NonHyp (N = 5,675), and NonInso-NonHyp (N = 22,700) groups between 2002 and 2004. Compared with the Inso-NonHyp and NonInso-NonHyp groups, a higher number of Inso-Hyp patients were between 45 and 64 y of age (39.61%), were male (48.80%), had lower incomes (76.12%), and resided in Northern Taiwan (52.77%) (p < 0.001). In addition, the Inso-NonHyp group exhibited significantly lower CCIs than did the patients from the other two groups (p < 0.001).

Demographic characteristics of patients in the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups.

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Table 1

Demographic characteristics of patients in the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups.

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Table 2 lists the incidence density as well as the CHRs and AHRs for psychiatric disorders in all patients. Compared with the NonInso-NonHyp group, the Inso-Hyp and Inso-NonHyp groups exhibited higher hazard ratios for psychiatric disorders (CHR: 5.82, 95% confidence interval [CI]: 5.45–6.22; CHR: 1.99, 95% CI: 1.87–2.12, respectively). After adjustment for age, sex, income, residential region, urbanization, and CCI, the Inso-Hyp and Inso-NonHyp groups still exhibited higher hazard ratios for psychiatric disorders (AHR: 6.07, 95% CI: 5.68–6.50; AHR: 2.19, 95% CI: 2.05–2.33, respectively) than did the NonInso-NonHyp group. In addition, patients at least age 30 y and younger than 65 y exhibited significantly higher incidence densities of psychiatric disorders than did those younger than 30 y. In addition, the incidence densities of psychiatric disorders were significantly higher in patients with CCI scores ≥ 3 than in those with CCI scores < 3.

Crude and adjusted hazard ratios for psychiatric disorders in patients in the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups.

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Table 2

Crude and adjusted hazard ratios for psychiatric disorders in patients in the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups.

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The Inso-Hyp patients with BZD prescriptions exhibited a higher risk of developing depressive (p < 0.001; AHR: 3.33; 95% CI: 1.83–6.07) and anxiety (p < 0.001; AHR: 2.25; 95% CI: 1.61–3.15) disorders than did the Inso-Hyp patients with non-BZD prescriptions (Table 3). When categorized according to the half-life of the sedative-hypnotics prescribed, patients with long-acting BZD prescriptions exhibited a higher risk of developing bipolar (p < 0.001; AHR: 8.24; 95% CI: 2.61–26.08), depressive (p < 0.001; AHR: 13.06; 95% CI: 7.17–23.78), and anxiety (p < 0.001; AHR: 5.08; 95% CI: 3.71–6.95) disorders than did those with short-acting sedative-hypnotic prescriptions. Moreover, compared with patients with insomnia and low-dose sedative-hypnotic prescriptions, those with high-dose sedative-hypnotic prescriptions exhibited significantly higher risks of developing all six aforementioned psychiatric disorders. Furthermore, compared with patients with low-dose sedative-hypnotic prescriptions, those with medium-dose sedative-hypnotic prescriptions exhibited significantly higher risks of developing depressive (p < 0.001; AHR: 1.60; 95% CI: 1.30–1.97), anxiety (p < 0.001; AHR: 1.31; 95% CI: 1.13–1.51), and substance-related (p < 0.05; AHR: 1.48; 95% CI: 1.04–2.10) disorders.

Adjusted hazard ratios for psychiatric disorders in the Inso-Hyp group according to the type, half-life, and doses of sedative-hypnotic drugs.

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Table 3

Adjusted hazard ratios for psychiatric disorders in the Inso-Hyp group according to the type, half-life, and doses of sedative-hypnotic drugs.

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Table 4 summarizes the incidence densities of psychiatric disorders in the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups over a 6-y follow-up period. The proportion of anxiety disorders in the Inso-Hyp group was 43.40%, and the incidence density of anxiety disorders was 82.31 per 1000 person-years, which was higher than the incidence densities of other psychiatric disorders. Overall, the incidence densities of psychiatric disorders were higher in the Inso-Hyp group than in the Inso-NonHyp and NonInso-NonHyp groups. A log-rank test revealed that the Inso-Hyp group exhibited significantly lower psychiatric-disorder-free survival rates than did the Inso-NonHyp and NonInso-NonHyp groups (p < 0.001). Figure 1 shows the overall 6-y psychiatric-disorder-free survival curves for the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups that were created using the Kaplan–Meier method. After adjustment for age, sex, income, residential region, urbanization, and CCI scores, the Inso-Hyp group exhibited a higher probability of developing all six aforementioned psychiatric disorders than did the Inso-NonHyp and NonInso-NonHyp groups, whereas the Inso-NonHyp group exhibited a significantly higher risk of psychiatric disorders than did the NonInso-NonHyp group. In addition, according to the results of the Cox proportional hazard regression analysis, the Inso-Hyp group exhibited significantly higher AHRs for bipolar disorders (AHR: 14.69; 95% CI: 11.11–19.43) than did the NonInso-NonHyp group. Furthermore, the Inso-Hyp group exhibited a higher risk of depressive disorders than did the Inso-NonHyp and NonInso-NonHyp groups (AHR: 5.02, 95% CI: 4.39–5.75; AHR: 11.86, 95% CI: 10.58–13.29, respectively).

Incidence densities and crude and adjusted hazard ratios for psychiatric disorders in the patients in the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups.

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Table 4

Incidence densities and crude and adjusted hazard ratios for psychiatric disorders in the patients in the Inso-Hyp, Inso-NonHyp, and NonInso-NonHyp groups.

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Psychiatric disorder-free survival rates of patients with insomnia and sedative-hypnotic prescriptions (Inso-Hyp), those with insomnia and without sedative-hypnotic prescriptions (Inso-NonHyp), and those with neither insomnia nor sedative-hypnotic prescriptions (NonInso-NonHyp).

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Figure 1

Psychiatric disorder-free survival rates of patients with insomnia and sedative-hypnotic prescriptions (Inso-Hyp), those with insomnia and without sedative-hypnotic prescriptions (Inso-NonHyp), and those with neither insomnia nor sedative-hypnotic prescriptions (NonInso-NonHyp).

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DISCUSSION

The Inso-Hyp group exhibited higher risks of developing psychiatric disorders than did the Inso-NonHyp and NonInso-NonHyp groups, particularly bipolar disorders (Table 4). A possible explanation for this result is that the Inso-Hyp group had a more severe form of insomnia than did the Inso-NonHyp group. BZDs are the most commonly prescribed medicines for patients with bipolar disorders, but only a few studies have evaluated the effectiveness of BZDs in treating bipolar disorders after the acute phase.34 Evidence has suggested that sleep disruption might be an underlying trigger for manic episodes and that total sleep time might be a predictor of future manic episodes.35 A study that investigated the prodromal symptoms of mania determined that sleep disturbances were the most commonly reported prodromal symptoms before a manic episode, which occurred in approximately 77% of the patients.25 Wehr et al. suggested that all triggers of mania, including biological causes, psychosocial stressors, and direct disturbances of sleep schedules, might be associated with the occurrence of mania caused by reduced sleep.36 However, according to the risk of devloping bipolar disorders in our results (Table 3), particular caution is warranted with the prescription of long-acting or high-dose sedative-hypnotics.

Although insomnia can be regarded as a prodromal symptom and a comorbid condition of schizophrenia, few studies have evaluated the incidence of chronic insomnia before the onset of schizophrenia.24,37 Patients with schizophrenia might exhibit a positive clinical response to antipsychotic drugs but continue to experience a certain degree of insomnia.38 In schizophrenia treatment, BZDs are prescribed for symptoms such as insomnia, anxiety, and panic attacks.39 The current study provides the evidence that chronic insomnia may occur before the presence of psychosis, and all of these results imply that sleep disturbances may be inherent in the pathophysiology of schizophrenia. Furthermore, the high-dose sedative-hypnotic prescriptions were associated with increased risk of developing schizophrenia.

The Inso-Hyp group exhibited higher risks of depressive and anxiety disorders than did the Inso-NonHyp and NonInso-NonHyp groups (Table 4); these results are consistent with those reported in previous studies, which indicate that chronic insomnia is an independent predictor of subsequent depression in Western and Asian populations.8,13,23 Chronic sleep disruption-related negative emotional consequences40 and “learned helplessness” can partially explain the manner in which chronic insomnia leads to a depressed mood.41 This study determined an association between the long-term use of BZD sedative-hypnotic drugs and subsequent depression, thereby supporting an indirect causal relationship between these variables. Kripke reported that the use of hypnotic drugs in depressed patients exerted a minimal effect on depressed moods, but increased the incidence of exacerbations of depression.21 Nevertheless, Neckelmann et al. suggested that the association between the use of hypnotics and depression or anxiety disorders is a result of subsyndromal anxiety or depression.12 A meta-analytical evaluation of longitudinal epidemiological studies indicated that compared with people without sleep disturbances, nondepressed people with insomnia exhibit a twofold higher risk of developing depression.16 The primary limitation mentioned in this meta-analytical study was that the studies analyzed did not compare the effects of insomnia with or without hypnotic drugs on psychiatric outcomes. This study demonstrated that chronic insomnia and chronic insomnia with sedative-hypnotics prescription are risk factors for depressive and anxiety disorders.

Somatoform disorders are a heterogeneous category of psychiatric disorders with several classification shortcomings, such as ambiguity of definition, lack of clearly defined thresholds, failure to achieve established standards of reliability, and incompatibility with non-Western cultures.42 In addition, a high risk of medically unexplained somatic complaints might affect the assessment or management of increased physical illnesses following chronic insomnia,4 emphasizing the association between chronic insomnia and somatoform disorders. A previous study evaluating 259 adolescent patients and their parents revealed that insomnia and poor sleep quality are strongly associated with pain and somatic symptoms and indicated that a shared genetic predisposition might underlie these associations.43 The current study also support that the Inso-Hyp group exhibited higher risk of developing somatoform disorders than did the Inso-NonHyp and NonInso-NonHyp groups (Table 4).

Sedative-hypnotic drugs are commontly prescribed for treating insomnia. The long-term use of sedative-hypnotic drugs can help patients induce sleep; however, this sedative effect may lead to tolerance and thus contribute to chronic insomnia.44 BZD dependence has been considered a substance-use disorder, and certain psychological factors such as depression, anxiety, and substance-use disorder can cause BZD addiction.45 This trend might be related to coping with insomnia through self-medication.8 In the current study, we elucidated the higher risk of developing substance-related disorders in the Inso-Hyp group than did the Inso-NonHyp and NonInso-NonHyp groups (Table 4). These results are consistent with the findings of a previous study, which suggested that the benefit–risk ratio of hypnotics is questionable. Moreover, based on the reported association between addiction, long-term use, and signs of tolerance46 (i.e., using higher doses), patients with chronic insomnia exhibited higher risks of addiction and psychopathology. Our results only indicated that the Inso-Hyp group with higher doses of sedative-hypnotic drugs exhibited a significantly higher risk of substance-related disorders than did the corresponding patients with lower doses of sedative-hypnotic drugs (Table 3). Therefore, to safely prevent the development of substance-related disorders, low-dose sedative-hypnotic drugs may be prescribed.

As observed in Table 2, patients with CCI scores ≥ 3 exhibited higher incidence densities of psychiatric disorders than did those with CCI scores < 3. In addition, patients with chronic insomnia exhibited comorbid disorders; this observation is consistent with the findings of a previous study regarding hospital readmission among older adults with depressive symptoms.47 Moreover, a previous study indicated that older patients with higher CCI scores exhibited a significantly higher risk of hospital readmission.47 Furthermore, older patients (age 30 y or older and younger than 65 y) exhibited higher incidence densities of psychiatric disorders than did those younger than 30 y; this result is consistent with results of a previous study that indicated that elderly people exhibit a higher tendency to develop insomnia and that insomnia is often comorbid with psychiatric disorders.48 Thus, both age and CCI scores may have modified the risk of psychiatric disorders.

The current study had several limitations. First, we used a nationwide population-based design with data derived from an Asian population; therefore, our results might not be generalizable to other ethnic groups. Second, the diagnoses of insomnia and the examined psychiatric disorders were determined according to administrative claims data that were obtained from the Taiwan NHI program and reported by physicians and hospitals and were not based on objective measures. Moreover, not all types of insomnia may have been reported in this study. Although the dataset and statistics may be as accurate and comprehensive as possible, differences in the definition of insomnia and misclassification of psychiatric disorders within the registry system could have exerted confounding effects on our results. However, the validity of the diagnoses of chronic insomnia was enhanced by the requirement of at least two service claims for ambulatory care within 1 y and the diagnosis of insomnia by physicians. Third, the study database lacked information regarding several variables, such as stressful psychosocial life events, dietary habits, physical activity, and other nonpharmacological treatments, all of which could have contributed to the associations among Inso-Hyp, insomnia, and subsequent psychiatric disorders. Fourth, we did not analyze other psychotropic medications because of the complexity of regimen combinations and prescription durations for each psychiatric disorder. These factors could have exerted mediating effects on the association between Inso-Hyp and psychiatric disorders. However, we evaluated a large sample in Taiwan, and the study design represents a reliable model of this association. In addition, this study focused on the relationship between insomnia and psychiatric disorders; therefore, we evaluated the risk of psychiatric disorders in patients with insomnia who were and those who were not receiving sedative-hypnotic drugs. The current study did not report findings for sedative-hypnotic drugs alone, and the actual interactions were not assessed. Moreover, the isolated associations between psychiatric outcomes and hypnotics alone in patients without insomnia and the interaction between hypnotic drugs and insomnia require further examination. Finally, the follow-up period for this historical cohort study was over 6 y. Although this follow-up period is longer than those used in most studies on chronic insomnia and the development of psychiatric disorders, future studies with longer follow-up periods are warranted to confirm this association and to clarify the long-term interactions and association of chronic insomnia with sedative-hypnotic drugs.

CONCLUSION

Compared with the Inso-NonHyp and NonInso-NonHyp groups, the study results provide evidence that the Inso-Hyp group exhibited a higher risk of developing several psychiatric disorders. In addition, the Inso-Hyp group with BZD prescriptions, with longer-acting medications, and with higher doses of sedative-hypnotic drugs exhibited significantly higher risks of depressive and anxiety disorders than did corresponding patients with non-BZD prescriptions, shorter-acting medications, and lower doses of sedative-hypnotics. Age and differences in CCI scores markedly influenced the risk of psychiatric disorders. These results emphasize that managing sleep disturbances may be a fundamental priority for preventing ensuing psychiatric comorbidities. Thus, clinicians must have a thorough understanding of the various causes of sleep disturbances in patients with chronic insomnia and develop practical interventions based on a systematic approach involving pharmacological and nonpharmacological strategies for managing sleep disturbances.

DISCLOSURE STATEMENT

This was not an industry supported study. This study was supported by a grant (100TMU-TMUH-16) from Taipei Medical University and Taipei Medical University Hospital. The authors have indicated no financial conflicts of interest.

ABBREVIATIONS

AHRs

adjusted hazard ratios

BZDs

benzodiazepines

CCI

Charlson comorbidity index

CHRs

crude hazard ratios

CI

confidence interval

DDD

defined daily dose

Inso-Hyp

with insomnia and sedative-hypnotic prescriptions

Inso-NonHyp

with insomnia and without sedative-hypnotic prescriptions

NHI

National Health Insurance

NHIRD

National Health Insurance Research Database

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