Abstract
Study Objectives
Chronic insomnia tends to “wax and wane” over lifetime. The presence of residual insomnia symptoms is common, especially among naturally remitted individuals. This study aims to examine the features of these residual symptoms and their potential association with future relapse.
Methods
A population-based data set on the natural history of insomnia was used for this secondary analysis. Residual insomnia symptoms were investigated in those who had insomnia symptoms/syndrome at baseline and achieved full remission (according to predetermined diagnostic algorithm) within the following 1 year. Cox regressions were used to determine the hazard ratio (HR) of each residual symptom for predicting relapse in the next 4 years. The nature and severity of residual symptoms were examined with an extended version of the Insomnia Severity Index (ISI), which incorporates additional items on sleep quality and specific sleep-related daytime impairments (on daytime fatigue, cognitive functioning, mood, interpersonal relationship, and daily activities). In addition, the presence of depressive symptoms and medical conditions were controlled for in investigating risks of insomnia relapse.
Results
A total of 434 participants were included in this study (age ranges from 18 to 94; 65.9% female); 248 of them had relapsed within 4 years. The response rate ranged from 78% to 83%. The most frequently reported residual symptoms with at least moderate severity (ISI items ≥2 on 0–4 ISI item scale) were poor “Quality of sleep” (39.2 %), followed by “difficulty maintaining sleep” (DMS; 27%). The most common residual daytime impairments related to insomnia were fatigue (24.7 %), mood disturbances (23%) and cognitive disturbances (22.6%). After controlling for baseline insomnia and depression severity and concurrent physical diseases, impairments of cognition (HR = 1.46), poor quality of sleep (HR = 1.43), disturbed mood (HR = 1.39), being female (HR = 1.36), DMS (HR = 1.35), and fatigue (HR = 1.24) were significantly associated with insomnia relapse in the next 4 years. Moreover, residual poor sleep quality and daytime insomnia symptoms were independent of DMS in predicting relapse. Subgroup regressions according to sex showed that for male participants, residual cognition impairments (HR = 1.98) was the most significant predictors of future relapse, whereas residual DMS (HR = 1.46) significantly predicted relapse for women only.
Conclusion
A wide range of residual symptoms exists in individuals with naturally remitted insomnia. Notably, residual DMS is the most common residual nighttime symptom and the only nighttime symptom associated with insomnia relapse. Additionally, perceived poor sleep quality and cognitive, mood, and somatic impairments attributed to sleep disturbances are also related to future relapse. Attention to these residual symptoms when initiating insomnia treatment is warranted to minimize future relapse.
Keywords: insomnia, natural remission, relapse, residual symptoms, natural history of insomnia
Statement of Significance.
This is the first longitudinal study investigating the relationship between residual insomnia symptoms and subsequent insomnia relapse. Residual symptoms commonly exist among those who had natural remission of insomnia, which might indicate refractory types of insomnia and risk future relapse. Among those symptoms, difficulty maintaining sleep, poor sleep quality as well as daytime impairments on cognition, mood, and fatigue are significant predictors for future relapse. These symptoms should be emphasized in prevention of insomnia relapse as well as in initial treatment. They could also be used to identify refractory phenotype of insomnia after natural remission. Sex differences in associations between residual symptoms and future relapse indicated potential role of sex hormone or different gender roles in family care, such as toddler night waking. It also requires more studies to investigate the impact of those persistent insomnia symptoms on courses of different mental illness.
Introduction
Chronic insomnia tends to either “wax and wane” or persist across the lifetime [1–3]. A naturalistic study of insomnia revealed that the relapse rate of insomnia is up to 26.7% over a 3 year period [2]. Unfortunately, little information is available regarding the relapse rate in individuals treated, a critical issue when treating insomnia in clinical practice. A recent study showed that individuals whose insomnia relapsed had more severe symptoms of anxiety and depression in comparison to those with remitted insomnia and even those with persistent insomnia [4].This calls for more studies to understand modulation of the course of insomnia and particularly on factors associated with persistence and relapse of insomnia. Especially, residual symptoms were easily overlooked when individual obtained a “remitted” status based on the general criteria.
Residual insomnia symptoms have been widely reported in successfully treated depression [5, 6], substance abuse [7], and post-traumatic stress disorder [8]. Even in remitted depression, 35.8% of the participants still had difficulties with initiating sleep (DIS); 55.8% continued to report difficulty maintaining sleep (DMS); 21.1% had residual early morning awakenings (EMA) [9]. The residual insomnia symptoms are also found to impair individuals’ normal daytime functioning after depression treatment [10, 11]. Accordingly, some studies have begun to address these residual insomnia symptoms by adding the adjunctive therapy of insomnia to the conventional management of depression [12, 13]. Despite the critical importance of understanding the residual insomnia symptoms, no study has examined these symptoms specifically in those with an insomnia disorder, and there has been no investigation of the relationship between these residual symptoms, probably also treatment resistant, and subsequent relapse of insomnia. It is not uncommon that insomnia patients who achieved partial or full remission with treatment continue experiencing some residual insomnia symptoms [14, 15], which confers potential risk for future relapse. Thus, study of residual symptoms in insomnia patients is highly pertinent for optimizing long-term outcomes among patients with insomnia as well as other mental illness, like depression.
It is also noteworthy that certain symptoms are of more concern than others when discussing the residual insomnia. For instance, difficulty maintaining sleep appears to be the most frequent and consistent residual symptom found in treated depression in comparison with the early and late night insomnia symptoms [5, 9, 16]. However, only few studies monitored individual insomnia symptoms when examining “residual insomnia.” Additionally, it is often the perceived daytime impairments attributed to insomnia, rather than the nocturnal insomnia symptoms per se, that prompt patients to seek treatment [17]. However, no study has examined the residual sleep-related daytime impairments among individuals with insomnia. A recent study found that insomnia-related daytime impairments was an important mediating factor between nighttime sleep quality (QoS) and depressive symptoms [18]. Therefore, the present study will evaluate the residual insomnia symptoms by dismantling symptoms in nighttime and daytime domains in order to identify particular patterns associated with relapse.
In view of those research gaps, study of these residual symptoms is pertinent to a better understanding of potential refractory phenotypes of insomnia. More importantly, those significant residual symptoms after natural remission should be the primary focus of interventions of insomnia. Therefore, the present study aims to study the residual insomnia symptoms in individuals with recent natural remission from insomnia. The objective was to identify the nature of nocturnal symptoms and sleep-specific daytime symptoms (on cognition, quality of life [QoL], fatigue, interpersonal relationship, and social activities) and investigate their prospective associations with insomnia relapse across 4 years. Using the data from a 5-year longitudinal study, participants were those with initial insomnia symptoms/syndrome at baseline who subsequently achieved full remission within the next 12 month follow-up. Given that little information is available on the residual symptoms in insomnia people, we also examined the residual symptoms by demographic groups and relevant clinical variables.
Methodology
Study context
This paper is based on a secondary analysis of data derived from a population-based epidemiological study of the natural history of insomnia, conducted in Canada (2008–2013). Initially, 12 000 adults were randomly selected to complete a telephone interview about their sleep. This study was conducted on 3005 eligible participants with or without insomnia (but excluded all respondents with diagnosed sleep disorders other than insomnia). The baseline assessment (T1) was conducted within 1 month after the phone interview. Six additional surveys were completed at 6 month (T2), 1 year (T3), 2 year (T4), 3 year (T5), 4 year (T6), and 5 year (T7) follow-ups. The ethical approval was received from the Ethics Committee of Université Laval and all participants provided written consent. More detailed information on the original study design and sample selection of the project were reported elsewhere [2, 17].
Sleep status categories
Patients were assigned at each assessment to one of three sleep status categories based on an algorithm that combined insomnia criteria from both DSM-IV-TR [19] and ICD-10 [20]. Screening questions were derived from the Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality index (PSQI).
Insomnia syndrome
Participants in syndrome status are those dissatisfied with their sleep and reporting initial, middle, or late insomnia symptoms at frequency of three or more nights per week for at least 1 month. In addition, they need to present daytime impairments or significant distress from their sleep difficulties. If a person takes prescribed sleeping medications at least three nights per week, he/she was also counted in the insomnia syndrome group regardless of other symptom manifestations.
Insomnia symptoms
Participants are considered to have insomnia symptoms if they present one or more insomnia symptoms at least three nights per week but do not meet the full criteria for insomnia syndrome. Those who are dissatisfied with their sleep or take prescribed sleeping medications more than one night per week but less than three nights per week were also classified as having insomnia symptoms regardless of other symptoms manifestations.
Good sleepers
Good sleepers were satisfied with their sleep, did not have insomnia symptoms, and did not use sleeping medication.
Definition of relapse event
A relapse was defined as the transition from an initial good sleeper status (at T2 or T3) to either insomnia symptoms or syndrome during the 4 years follow-up (T4–T7). Cases were censored after a first relapse without considering situation of multiple remission and relapse.
Participants
Given the focus of the current study on insomnia relapse, we selected only those participants (n = 1389) who presented either insomnia symptoms (n = 797) or an insomnia syndrome (n = 592) at baseline assessment and attained the full remission as good sleeper within 1 year of baseline assessment (at T2 and/or T3). There was a total of 301 participants who were classified as good sleeper at 6 month follow-up (T2) and an additional 133 participants who attained full remission at 1 year follow-up (T3). Thus, the final sample was composed of 434 individuals who presented insomnia symptoms/syndrome at entry point and were in full remission within 1 year (response rates of those 434 participants were 83% at the 2nd and 3rd year follow-ups; 80% and 78% for the 4th and 5th year follow-ups, respectively). These individuals were then followed over the next 4 years (T4–T7) to monitor changes in their sleep status and identify the timing of the first occurrence of insomnia relapse.
Measures
Demographic variables of age, gender, educational level, marital status, and occupation were derived from baseline assessment as were data about comorbid physical diseases. Physical diseases were surveyed by a list of 14 diseases with additional self-reported conditions. Question asked was “Currently, do you suffer from one or more of the following health problems.”
Extended version of ISI
The standard ISI instrument [21] is a seven-item scale measuring the severity of insomnia in terms of the nighttime DIS, DMS, and EMA. The remaining sleep items assessed the interference with daytime functioning (daytime impairments), noticeability of impact from insomnia (noticeable), worry about sleep (worry), and satisfaction with one’s sleep. Each item is rated on five-point Likert scale ranging from 0 (none) to 4 (very severe). This scale has been well validated in various populations [21–23].
In addition to its original seven items, this study incorporated additional items (using the same scaling) from an extended ISI version to examine more comprehensively the potential range of residual symptoms in remitted insomnia. The extended ISI includes additional items about the impact of insomnia on specific daytime impairments on general quality of life (QoL), fatigue (fatigue), cognition (concentration or memory; cognition), mood (mood) interpersonal relationship (interpersonal), and social activities (social activities), specifically attributed to sleep problems. A sample item is: “to what extent do you consider your sleep problem to cause daytime fatigue.” Other items from the extended version included evaluation of general quality of sleep (QoS) and refreshment in next morning (morning refreshment) on five-point Likert scale. Cronbach’s α of total fifteen items of extended ISI was 0.93. Reliability of eight new items was 0.85.
Beck Depression Inventory II
The Beck Depression Inventory II (BDI-II) comprises 21 items to rate intensity of depressive symptoms in the past 2 weeks on a four-point (0–3) Likert scale. Higher total score suggests a more severe depressive symptomatology. The French version of this scale has been well validated [24].
Statistical analyses
To identify the prevalence of significant residual symptoms, a series of binary (yes/no) variables were defined as a score of 2 or more (indicating moderate severity) for each individual ISI item at the 1 year follow-up (T3). A binary variable was also computed for participants with a BDI score ≥14 to identify individuals with at least mild depressive symptoms (Smarr et al., 2011) at the time of remission (T2 or T3). Subsequently, the Cox regression models were built to explore which linear combination of residual symptoms were associated with relapse during the follow-up years (T4–T7). The case was censored after the first occurrence of insomnia relapse. Three nighttime symptoms (DIS, DMS, and EMA) were introduced first into the model. Then, individual daytime symptoms and other items from ISI were added onto the nighttime model. Each daytime relevant ISI item was separately entered in the model in order to examine additional effects from daytime symptoms to nighttime symptoms. Control variables were age, gender, and sleep status at baseline (T1; insomnia symptoms or syndrome) and depressive symptoms at remission point (T2 or T3). We excluded the ISI sleep satisfaction item because that item was also a criterion used to define the three sleep status groups. Then, subgroup analyses of Cox regression by sex were performed to investigate the moderating effect of sex on the relationship between residual symptoms and relapse (i.e. potential different patterns of residual symptoms in predicting relapse). At last, we compared severity (not prevalence) of residual symptoms by demographic subgroups (including group with or without medical conditions) by using t-tests and analyses of variance (ANOVA) on raw scores of items from ISI_extended version over 1 year remission (at T2 or T3). All data analyses were conducted using SPSS version 21 [25] and standard α-level of 5% (95% confidential intervals [CIs]) was used to conclude about statistical significance.
Results
Table 1 shows the demographic characteristics of 434 participants. Participants were aged from 18 to 94 years old with a mean age of 48.1 (SD 15.0). Most of them were female (65.9%), married or cohabitating (61.1%), with the highest educational degree in-between high school and bachelor (41.2%) and studying or working full-time (54.4%). Of the participants, 23.5% reported one or more physical diseases. Spearman rank correlations among severity of residual insomnia symptoms measured by extended ISI are presented in Supplementary Table S1. The magnitudes of correlations were heterogenous. The correlations among nighttime insomnia symptoms were moderate and all statistically significant (ρ-ranging from 0.29 to 0.41, see Supplementary table S1).
Table 1.
Baseline characteristics of individuals who met criteria for insomnia remission at the 6 and 12 month follow-up (N = 434)
| Variables | n (percentage) |
|---|---|
| Age: 18–34 | 94 (21.7 %) |
| 35–49 | 135 (31.1%) |
| 50–59 | 99 (22.8 %) |
| 60–94 | 106 (24.4 %) |
| Sex: Female | 286 (65.9 %) |
| Male | 148 (34.1 %) |
| Marital status: Single | 81 (18.7 %) |
| Married/cohabit | 265 (61.1 %) |
| Separated/divorce/widow | 84 (19.4 %) |
| Education: Secondary level | 115 (26.5 %) |
| Degree below bachelor | 179 (41.2 %) |
| Bachelor or above | 132 (30.4 %) |
| Occupation: Full-time study/work | 236 (54. 4%) |
| Part-time work | 35 (8.1 %) |
| Retirement | 95 (21.9 %) |
| Others (unemployed; work at home without remuneration) | 61 (14.1 %) |
| Physical disease: None | 332 (76.5 %) |
| One or more | 102 (23.5 %) |
Table 2 shows the percentage of participants with significant residual insomnia symptoms for each ISI item. Among the three nighttime ISI symptoms, difficulty maintaining sleep (27%) was the most frequently reported nighttime residual symptom in remitted persons. After checking the possible combination of the nighttime symptoms, the standalone DMS symptom was still the most common residual symptom (9% versus 6.9% for the presence of all three nighttime symptoms). Regarding other ISI items, 39.2% of the remitted cases rated their QoS as fair or worse rather than excellent or good. Fatigue (24.7%), mood (23.0%), and cognition impairments (22.6 %) were the three most common residual daytime symptoms, respectively. Moreover, around 14% of participants had BDI greater than 13 at their timepoint of remission.
Table 2.
Residual symptoms of ISI_extended (by descending prevalence) among individuals with full remission (N = 434)
| Residual symptoms at remission | Percentage |
|---|---|
| Quality of sleep (≥2) | 39.2% |
| Difficulty maintaining sleep (≥2) | 27% |
| Fatigue (≥2) | 24.7% |
| General daytime impairments (≥2) | 23.5% |
| Mood (≥2) | 23% |
| Cognition impairments (≥2) | 22.6% |
| Early morning awakening (≥2) | 22.1% |
| Difficulty initialing sleep (≥2) | 21.9% |
| Daily activities (≥2) | 16.4% |
| Quality of life (≥2) | 15.7% |
| Interpersonal relationship (≥2) | 13.4% |
| Noticeability (≥2) | 13.1% |
| Morning refreshment (≤1) | 11.8% |
| Worry (≥2) | 9.9% |
Table 3 presents the residual symptoms by age and physical disease groups. Female participants reported more severe residual difficulty initialing sleep (t(395) = −2.71, p = 0.007) and general daytime impairments (t(395) = −2.20, p = 0.029) than their male counterparts. Table 3 also displays mean differences of residual symptoms across four age groups. In general, younger age group (18–34 and 35–49) showed higher daytime impairments on fatigue, cognition, mood, interpersonal relationship, daily activities as well as worries and higher expectations toward sleep than the other two groups (50–59 and 60–94). Contrary to one’s expectations, those with comorbid physical diseases tended to report less severe residual insomnia symptoms than those without physical disease. Significant differences were found on morning refreshment, noticeability, impairments on QoL, energy, cognition, worry about sleep, and BDI (all p < 0.05).
Table 3.
Comparison of the insomnia residual symptoms by subgroups of age and physical conditions at remission point (T2 or T3)
| Mean (SD) |
DIS | DMS | EMA | Daytime | MorRefr | Noticeable | Worry | QoS |
|---|---|---|---|---|---|---|---|---|
| Age: 18–34 | 0.88 (0.80) |
0.99 (0.88) |
0.90 (0.85) |
1.04 (0.85) |
2.19 (0.74) |
0.75 (0.75) |
0.61 (0.72) |
1.35 (0.82) |
| 35–49 | 0.85 (0.88) |
1.11 (0.81) |
0.98 (0.89) |
1.12 (0.90) |
2.14 (0.77) |
0.79 (0.82) |
0.61 (0.70) |
1.50 (0.78) |
| 50–59 | 0.94 (0.84) |
1.18 (0.89) |
1.02 (0.87) |
0.99 (0.80) |
2.31 (0.79) |
0.61 (0.70) |
0.58 (0.72) |
1.41 (0.73) |
| 60–94 | 0.93 (0.81) |
1.11 (0.82) |
1.07 (0.81) |
0.83 (0.85) |
2.55 (0.74) |
0.49 (0.73) |
0.47 (0.70) |
1.24 (0.67) |
| ANOVA: F | 0.26 | 0.75 | 0.62 | 2.12 | 5.74** | 3.38* | 0.93 | 2.28 |
| Physical disease(s) | ||||||||
| No | 0.93 (0.80) |
1.12 (0.85) |
1.00 (0.85) |
1.07 (0.85) |
2.27 (0.79) |
0.71 (0.78) |
0.60 (0.73) |
1.42 (0.76) |
| Yes | 0.80 (0.94) |
1.02 (0.82) |
1.00 (0.87) |
0.75 (0.84) |
2.37 (0.70) |
0.50 (0.70) |
0.45 (0.62) |
1.25 (0.73) |
| t-test: t | 1.18 | 0.98 | −0.03 | 3.12** | −1.06 | 2.26* | 1.74 | 1.86 |
| Mean (SD) | QoL | Fatigue | Cognition | Interpersonal | Mood | Activity | BDI-II | |
| Age: 18–34 | 0.85 (0.72) |
1.33 (0.90) |
1.08 (0.89) |
0.91 (0.92) |
1.34 (0.89) |
1.04 (0.71) |
8.75 (8.05) |
|
| 35–49 | 0.99 (0.84) |
1.30 (0.95) |
1.09 (0.94) |
0.84 (0.82) |
1.06 (0.99) |
0.94 (0.93) |
6.88 (7.10) |
|
| 50–59 | 0.78 (0.68) |
1.01 (0.77) |
0.80 (0.85) |
0.55 (0.72) |
0.87 (0.76) |
0.72 (0.71) |
7.95 (8.71) |
|
| 60–94 | 0.65 (0.69) |
0.85 (0.81) |
0.77 (0.92) |
0.38 (0.70) |
0.61 (0.72) |
0.59 (0.80) |
6.58 (5.80) |
|
| ANOVA: F | 3.96** | 6.94*** | 3.64* | 9.45*** | 11.53*** | 5.63** | 1.66 | |
| Physical disease(s) | ||||||||
| No | 0.87 (0.76) |
1.17 (0.90) |
0.99 (0.91) |
0.70 (0.82) |
0.97 (0.89) |
0.83 (0.85) |
7.85 (7.66) |
|
| Yes | 0.67 (0.71) |
0.94 (0.83) |
0.75 (0.93) |
0.57 (0.80) |
0.92 (0.89) |
0.76 (0.89) |
5.97 (6.47) |
|
| t-test: t | 2.26* | 2.15* | 2.20* | 1.30 | 0.51 | 0.73 | 2.09* |
*p < 0.5; **p < 0.01; ***p < 0.001.
BDI, Beck Depression Inventory; Daytime, ISI impairments daytime; DIS, difficulties with initiating sleep; DMS, difficulties maintaining sleep; EMA, early morning awakenings; MorRefr, ISI morning refreshment; QoL, quality of life; QoS, sleep quality.
Throughout 4 years, total 248 participants relapsed (183 into insomnia symptom; 65 into insomnia syndrome). To identify the predictors of insomnia symptom/syndrome relapse, three models were built by conducting survival analyses. All models were controlled for the insomnia severity at T1, age, sex, BDI at remission, and concurrent physical diseases. Table 4 shows hazard ratios (HRs) for predictors included in each model. Model 1 examined the associations between the three nighttime symptoms and the hazard of relapse after adjusting for covariates. Only difficulty maintaining sleep (HR = 1.35) was significantly associated with the prospective relapses. Moreover, being a female (HR = 1.36) and having a concurrent physical disease (HR = 0.78) were associated with a future relapse. Individual daytime symptoms were then added on separately into the basic model (model 1–model 3) to investigate additional predictors. After considering all the covariates, QoS (HR = 1.43) and cognition impairments (HR = 1.46) were found to be strongly predictive of the future relapse. When adding the QoS, the effect of difficulty maintaining sleep was no longer significant (95% CI HR: 0.95–1.40). Moreover, daytime fatigue (HR = 1.24), cognition impairment (HR = 1.46), and mood disturbances (HR = 1.39) attributed to insomnia were also associated with higher likelihood of relapse. All other daytime items were not significantly associated with relapse (all ps > 0.1; also see Supplementary Figures S1–S6). Furthermore, interaction analyses showed that there was significant moderating effect of sex on relationship between baseline insomnia severity (syndrome versus symptoms) and future relapse (sex × baseline insomnia severity: HR = 0.57; p = 0.012).
Table 4.
Cox regression models to predict first relapse of insomnia over 4 years
| Model 1 | B | SE | Sig. | HR† | 95% CI |
|---|---|---|---|---|---|
| Sex (female) | 0.31 | 0.10 | 0.002 | 1.36 | 1.12–1.65 |
| Age (at baseline) | 0.00 | 0.00 | 0.17 | 1.00 | 1.00–1.01 |
| BDI T2 or T3 (≥14) | 0.09 | 0.13 | 0.50 | 1.09 | 0.85–1.39 |
| Insomnia syndrome (at baseline) | 0.17 | 0.11 | 0.10 | 1.19 | 0.97–1.47 |
| Physical disease T4–T7 (no disease) | −0.25 | 0.12 | 0.04 | 0.78 | 0.62–0.99 |
| DIS (≥2) | −0.03 | 0.11 | 0.82 | 0.98 | 0.79–1.21 |
| DMS (≥2) | 0.30 | 0.10 | 0.002 | 1.35 | 1.11–1.63 |
| EMA (≥2) | −0.00 | 0.11 | 0.99 | 1.00 | 0.81–1.23 |
| Additional items* | |||||
| DMS (≥2) | 0.14 | 0.10 | 0.14 | 1.16 | 0.95–1.40 |
| QoS (≥2) | 0.36 | 0.10 | <0.001 | 1.43 | 1.18–1.75 |
| DMS (≥2) | 0.24 | 0.10 | 0.01 | 1.27 | 1.05–1.52 |
| Fatigue (≥2) | 0.21 | 0.10 | 0.04 | 1.24 | 1.01–1.52 |
| DMS (≥2) | 0.24 | 0.09 | 0.01 | 1.27 | 1.06–1.52 |
| Cognition (≥2) | 0.38 | 0.10 | <0.001 | 1.46 | 1.19–1.78 |
| DMS (≥2) | 0.25 | 0.09 | 0.006 | 1.29 |
1.08– 1.54 |
| Mood (≥2) | 0.33 | 0.11 | 0.002 | 1.39 | 1.13–1.71 |
*Controlling for age, sex, insomnia severity at baseline, BDI at residual time-point, concurrent physical disease.
†Hazard ratio is computed as exp(B). Each additional item was added separately into the basic model (model 1).
BDI, Beck Depression Inventory; DIS, difficulties with initiating sleep; DMS, difficulties maintaining sleep; EMA, early morning awakenings; QoS, sleep quality.
Based on results of interaction analyses, we further conducted survival analyses by subgroups of sex to see if the prediction pattern would be altered by sex. Baseline insomnia severity predicted relapse in male participants (insomnia syndrome was positively associated with future relapse). Further, as shown in Table 5, only residual symptom of perceived poor QoS (HR = 1.65) and daytime impairments in cognition (HR = 1.98) were significant predictors for future relapse in male participants. On the contrary, for female participants, baseline insomnia severity did not predict relapse. Rather, it was the difficulty maintaining sleep (HR = 1.46) that significantly predicted insomnia relapse. Moreover, relapse in female participants was also strongly predicted by poor QoS (HR = 1.30), cognition impairments (HR = 1.31), and mood (HR = 1.34, see Table 4). No additional residual symptoms were found significant in subgroup analyses.
Table 5.
Cox regression models to predict relapse of insomnia over 4 years (T4–T7) by gender
| Males | B | SE | Sig. | HR | 95% CI | |
|---|---|---|---|---|---|---|
| Model 2 | Age (at baseline) | 0.01 | 0.01 | 0.42 | 1.01 | 0.99–1.02 |
| BDI T2 or T3 (≥14) | 0.39 | 0.24 | 0.10 | 1.48 | 0.92–2.38 | |
| Insomnia syndrome (at baseline) | 0.54 | 0.19 | 0.00 | 1.72 | 1.19–2.49 | |
| Physical disease T4–T7 (no disease) | −0.26 | 0.23 | 0.24 | 0.77 | 0.49–1.20 | |
| DIS (≥2) | 0.08 | 0.24 | 0.76 | 1.08 | 0.67–1.73 | |
| DMS (≥2) | 0.08 | 0.21 | 0.68 | 1.09 | 0.73–1.63 | |
| EMA (≥2) | −0.01 | 0.22 | 0.97 | 0.99 | 0.64–1.53 | |
| Additional items* | QoS (≥2) | 0.50 | 0.18 | 0.00 | 1.65 | 1.16–2.36 |
| Cognition (≥2) | 0.68 | 0.20 | 0.00 | 1.98 | 1.34–2.94 | |
| Females | ||||||
| Model 3 | Age (at baseline) | 0.01 | 0.00 | 0.12 | 1.01 | 1.00–1.01 |
| BDI T2 or T3 (≥14) | −0.03 | 0.15 | 0.85 | 0.97 | 0.73–1.30 | |
| Insomnia syndrome (at baseline) | 0.02 | 0.13 | 0.90 | 1.02 | 0.79–1.32 | |
| Physical disease T4–T7 (no disease) | −0.19 | 0.15 | 0.18 | 0.82 | 0.62–1.10 | |
| DIS (≥2) | −0.06 | 0.12 | 0.66 | 0.95 | 0.74–1.21 | |
| DMS (≥2) | 0.38 | 0.11 | 0.00 | 1.46 | 1.17–1.82 | |
| EMA (≥2) | −0.00 | 0.12 | 0.74 | 1.00 | 0.78–1.27 | |
| Additional items* | DMS (≥2) | 0.24 | 0.12 | 0.05 | 1.27 | 1.00–1.59 |
| QoS (≥2) | 0.27 | 0.12 | 0.03 | 1.30 | 1.03–1.65 | |
| DMS (≥2) | 0.32 | 0.11 | 0.00 | 1.37 | 1.11–1.69 | |
| Cognition (≥2) | 0.27 | 0.12 | 0.03 | 1.31 | 1.03–1.66 | |
| DMS (≥2) | 0.32 | 0.11 | 0.00 | 1.37 | 1.11–1.70 | |
| Mood (≥2) | 0.30 | 0.12 | 0.02 | 1.34 | 1.05–1.72 |
*Controlling for age, sex, insomnia severity at baseline, BDI at residual time-point, concurrent physical disease. Each additional item was added separately.
BDI, Beck Depression Inventory; DIS, difficulties with initiating sleep; DMS, difficulties maintaining sleep; EMA, early morning awakenings; QoS, sleep quality.
Discussion
This is the first longitudinal study investigating the relationship between residual symptoms of insomnia and subsequent insomnia relapse. Our findings have important implications for prevention of relapse in patients treated for insomnia. They could also be useful to identify groups with refractory phenotype of insomnia who are at risk of relapse after natural remission, such as those with sleep maintenance problems. In general, residual symptoms were common amongst people whose insomnia was in remission (90.3% had at least one residual symptom), but only one nighttime residual symptom was significantly associated with relapse: difficulty staying asleep. Further, daytime residual symptoms, including fatigue, cognitive impairments, and mood disturbances, as well as poor QoS, all produced additional risks for future relapse. Interestingly, there were different prediction patterns between male and female participants. Relapse in men was mainly predicted by baseline insomnia severity and residual cognitive impairment and poor QoS, while DMS along with two daytime symptoms (mood and cognition impairments) and poor QoS predicted relapse in women.
Consistent with previous studies, difficulty maintaining sleep was more frequently reported than early and late nighttime symptoms of insomnia as the residual [5, 9, 16]. However contradicting with other longitudinal studies, which showed that mixed nighttime symptoms were the most common and stable insomnia phenotypes [26, 27], our study suggests that the most common and influential nighttime residual symptom is difficulty maintaining insomnia symptom. This suggests the existence of a residual insomnia subtype is different from the general insomnia subtypes revealed in previous epidemiological studies. Although there was no gender difference in the frequency of residual DMS symptoms, presence of residual DMS symptoms predicted future relapse only in females. More studies are required to understand this vulnerability carried by residual DMS in female remitters and its potential associations with sex hormone or different gender roles in family care, such as toddler night waking.
It should be noted that poor QoS also predicted relapse which also attenuated the effects of residual nighttime symptom. A previous study found that light or fragmented sleep was associated with complaints of poor QoS even when sleep duration was normal [28]. In effect, study found that subjective evaluation about QoS largely bear on feelings of fatigue, refreshment on waking, as well as nocturnal awakenings [29]. Therefore, poor QoS requires more attention in insomnia treatment and more efforts are needed to understand reasons and consequences of poor QoS. Moreover, other studies have also shown that the neurocognitive deficits produced by sleep loss tend to accumulate over time [30, 31]. In line with these findings, our study highlights the role of residual cognitive impairments in future relapse. Research has also identified two subgroups based on neurobehavioral performance after sleep deprivation: a resistant group and a vulnerable group, with the latter displaying more severe neurobehavioral deficits following sleep deprivation [32–34]. Together with our findings, this research suggests that certain residual symptoms (such as residual DSM, cognitive, mood, and somatic impairment) that are related to the more severe subtypes of insomnia may be more resistant to improvement. Especially, daytime residual symptoms should be further emphasized in insomnia treatments for preventing relapse. A recent community-based study showed that daytime symptoms, independent of nighttime insomnia symptoms, significantly associated with almost all depressive symptoms, and they were exclusively related to cognitive manifestation of depression [35]. Thus, it would be reasonable to include improvement of daytime symptoms to define a successful insomnia treatment outcome, which might also benefit depressive symptoms to a larger degree.
Although there is some evidence that poor physical health is a risk factor for sleep disturbances [36], our study suggests the opposite pattern amongst those who have already suffered insomnia. We found that individuals without physical comorbidities presented more severe residual symptoms and had higher hazard of relapse (in model 1). It has been postulated that the attribution of sleep problems is different in people with and without comorbid physical disease. Physically healthy people with insomnia worry more about their QoS and ruminate more about their insomnia symptoms [5], whereas people with physical comorbidities are more likely to connect their insomnia with their physical disease and worry more about the disease per se rather than what they perceive as secondary insomnia. Hence, relapse is more likely in people without physical comorbidities because reactivation of the perpetuating factors is more likely.
As for the demographic variables, residual symptoms were more frequent and more severe in women than in men. This is in line with other epidemiological studies showing that women are at higher risk of insomnia than men [37–38]. However, different prediction patterns suggested that certain physiological and social factors may underpin this sex differences. More studies are required to investigate the nature and significance of those residual symptoms for men and women, respectively (e.g. DMS for women and cognitive impairments for men). It is also worth noting that younger people tended to report more residual daytime symptoms than older people, although their frequency of nighttime symptoms was similar. It is usually the daytime distress associated with insomnia that prompts individuals to consult a health care professional about their sleep problems. This finding adds to the evidence that treating sleep-related daytime malfunctions should be a priority in insomnia [39–41], especially in younger people, for whom insomnia exerts significant daytime burdens on work or study.
Limitation and future studies
Despite some interesting findings, this study has several limitations. First, residual symptoms were measured with a single self-report scale, the ISI, which evaluates the perceived severity of the various insomnia symptoms. In future studies, it would be useful to include variables derived from actigraphy or Polysomnography to improve the quantification of residual insomnia symptoms. We found that the residual symptom that best predicted subsequent relapse was difficulty maintaining sleep and further investigation of residual sleep fragmentation using both subjective and objective measures should be carried out. In addition, this study did not consider the temporal pattern of multiple remissions and relapses over the 4 years. More rigorous investigation of interactions between residual symptoms and the timing and frequency of relapse are needed. Finally, we did not use a standardized diagnostic procedure to identify individuals with depression. Given the potential reciprocal relationship between depression and residual insomnia symptoms, future studies are required to examine the interrelationships between episodes of depression diagnosed according to standardized criteria, residual symptoms of insomnia, and insomnia relapse.
Funding
This study was supported by a Canadian Institutes of Health Research grant (42504). Charles M. Morin has received research grant from Idorsia.
Conflict of interest statement. Charles M. Morin has served on advisory board for Abbott, Merck and Phillips; he has received research grant from Idorsia.
Supplementary Material
References
- 1. Jindal RD, et al.. Maintenance treatment of insomnia: what can we learn from the depression literature? Am J Psychiatry. 2004;161(1):19–24. [DOI] [PubMed] [Google Scholar]
- 2. Morin CM, et al.. The natural history of insomnia: a population-based 3-year longitudinal study. Arch Intern Med. 2009;169(5):447–453. [DOI] [PubMed] [Google Scholar]
- 3. Savard J, et al.. Natural course of insomnia comorbid with cancer: an 18-month longitudinal study. J Clin Oncol. 2011;29(26):3580–3586. [DOI] [PubMed] [Google Scholar]
- 4. Chen PJ, et al.. Relapse insomnia increases greater risk of anxiety and depression: evidence from a population-based 4-year cohort study. Sleep Med. 2017;38:122–129. [DOI] [PubMed] [Google Scholar]
- 5. Carney CE, et al.. A comparison of rates of residual insomnia symptoms following pharmacotherapy or cognitive-behavioral therapy for major depressive disorder. J Clin Psychiatry. 2007;68(2):254–260. [DOI] [PubMed] [Google Scholar]
- 6. Taylor DJ, et al.. Which depressive symptoms remain after response to cognitive therapy of depression and predict relapse and recurrence? J Affect Disord. 2010;123(1–3):181–187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Brower KJ, et al.. Sleep disturbance as a universal risk factor for relapse in addictions to psychoactive substances. Med Hypotheses. 2010;74(5):928–933. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Zayfert C, et al.. Residual insomnia following cognitive behavioral therapy for PTSD. J Trauma Stress. 2004;17(1):69–73. [DOI] [PubMed] [Google Scholar]
- 9. Nierenberg AA, et al.. Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychol Med. 2010;40(1):41–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Li SX, et al.. Residual sleep disturbances in patients remitted from major depressive disorder: a 4-year naturalistic follow-up study. Sleep. 2012;35(8):1153–1161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Romera I, et al.. Residual symptoms and functioning in depression, does the type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013;13:51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Manber R, et al.. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep. 2008;31(4):489–495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Watanabe N, et al.. Brief behavioral therapy for refractory insomnia in residual depression: an assessor-blind, randomized controlled trial. J Clin Psychiatry. 2011;72(12):1651–1658. [DOI] [PubMed] [Google Scholar]
- 14. Buysse DJ, et al.. Efficacy of brief behavioral treatment for chronic insomnia in older adults. Arch Intern Med. 2011;171(10):887–895. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Morin CM, et al.. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. JAMA. 2009;301(19):2005–2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. McClintock SM, et al.. Residual symptoms in depressed outpatients who respond by 50% but do not remit to antidepressant medication. J Clin Psychopharmacol. 2011;31(2):180–186. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Morin CM, et al.. Epidemiology of insomnia: prevalence, self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Med. 2006;7(2):123–130. [DOI] [PubMed] [Google Scholar]
- 18. Ji XW, et al.. Integrative body-mind-spirit intervention for concurrent sleep and mood disturbances: sleep-specific daytime functioning mediates sleep and mood improvements. J Sleep Res. 2018;27(1):56–63. [DOI] [PubMed] [Google Scholar]
- 19. Association of American Psychiatry. Diagnostic and Statistical Manual of Mental Disorders. 4th ed (Text Revision). Washington, DC: APA; 2000. [Google Scholar]
- 20. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Diagnostic Criteria for Research. Geneva: World Health Organization 1993. [Google Scholar]
- 21. Bastien CH, et al.. Validation of the insomnia severity index as an outcome measure for insomnia research. Sleep Med. 2001;2(4):297–307. [DOI] [PubMed] [Google Scholar]
- 22. Morin CM, et al.. The Insomnia Severity Index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep. 2011;34(5):601–608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Savard MH, et al.. Empirical validation of the insomnia severity index in cancer patients. Psychooncology. 2005;14(6):429–441. [DOI] [PubMed] [Google Scholar]
- 24.Lahlou-Laforêt K, et al. Validity of Beck Depression Inventory for the assessment of depressive mood in chronic heart failure patients. J Affect Disord. 2015;184:256–260. [DOI] [PubMed] [Google Scholar]
- 25.IBM Corp. IBM SPSS Statistics for Windows, Version 21.0. Armonk, NY: IBM Corp.; 2012. [Google Scholar]
- 26. Léger D, et al.; EQUINOX (Evaluation of daytime QUality Impairment by Nocturnal awakenings in Outpatient’s eXperience) Survey Investigators Characteristics of insomnia in a primary care setting: EQUINOX survey of 5293 insomniacs from 10 countries. Sleep Med. 2010;11(10):987–998. [DOI] [PubMed] [Google Scholar]
- 27. Pillai V, et al.. The nature of stable insomnia phenotypes. Sleep. 2015;38(1):127–138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Fernandez-Mendoza J, et al.. Sleep misperception and chronic insomnia in the general population: role of objective sleep duration and psychological profiles. Psychosom Med. 2011;73(1):88–97. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Harvey AG, et al.. The subjective meaning of sleep quality: a comparison of individuals with and without insomnia. Sleep. 2008;31(3):383–393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Curcio G, et al.. Sleep loss, learning capacity and academic performance. Sleep Med Rev. 2006;10(5):323–337. [DOI] [PubMed] [Google Scholar]
- 31. Durmer JS, et al.. Neurocognitive consequences of sleep deprivation. Semin Neurol. 2005;25(1):117–129. [DOI] [PubMed] [Google Scholar]
- 32. Basner M, et al.. Sleep deprivation and neurobehavioral dynamics. Curr Opin Neurobiol. 2013;23(5):854–863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Galliaud E, et al.. Sharp and sleepy: evidence for dissociation between sleep pressure and nocturnal performance. J Sleep Res. 2008;17(1):11–15. [DOI] [PubMed] [Google Scholar]
- 34. Goel N, et al.. Circadian rhythms, sleep deprivation, and human performance. Prog Mol Biol Transl Sci. 2013;119:155–190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Ji X, et al.. Disassembling insomnia symptoms and their associations with depressive symptoms in a community sample: the differential role of sleep symptoms, daytime symptoms, and perception symptoms of insomnia. Sleep Health. 2019; doi: 10.1016/j.sleh.2018.12.009 (in press). [DOI] [PubMed] [Google Scholar]
- 36. Smagula SF, et al.. Risk factors for sleep disturbances in older adults: evidence from prospective studies. Sleep Med Rev. 2016;25:21–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Li RH, et al.. Gender differences in insomnia–a study in the hong kong chinese population. J Psychosom Res. 2002;53(1):601–609. [DOI] [PubMed] [Google Scholar]
- 38. Zhang B, et al.. Sex differences in insomnia: a meta-analysis. Sleep. 2006;29(1):85–93. [DOI] [PubMed] [Google Scholar]
- 39. Kyle SD, et al.. Insomnia and health-related quality of life. Sleep Med Rev. 2010;14(1):69–82. [DOI] [PubMed] [Google Scholar]
- 40. Shekleton JA, et al.. Searching for the daytime impairments of primary insomnia. Sleep Med Rev. 2010;14(1):47–60. [DOI] [PubMed] [Google Scholar]
- 41. Buysse DJ, et al.. Daytime symptoms in primary insomnia: a prospective analysis using ecological momentary assessment. Sleep Med. 2007;8(3):198–208. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.