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J Affect Disord. Author manuscript; available in PMC Mar 1, 2012.
Published in final edited form as:
PMCID: PMC3036776
NIHMSID: NIHMS245868

A Tune in “A Minor” Can “B Major”: A Review of Epidemiology, Illness Course, and Public Health Implications of Subthreshold Depression in Older Adults

Thomas Meeks, M.D.,1,2 Ipsit Vahia, M.D.,1,2 Helen Lavretsky, M.D.,3 Ganesh Kulkarni,4 and Dilip Jeste, M.D.1,2

Abstract

BACKGROUND

With emphasis on dimensional aspects of psychopathology in development of the upcoming DSM-V, we systematically review data on epidemiology, illness course, risk factors for, and consequences of late-life depressive syndromes not meeting DSM-IV-TR criteria for major depression or dysthymia. We termed these syndromes subthreshold depression, including minor depression and subsyndromal depression.

METHODS

We searched PubMed (1980–Jan 2010) using the terms: subsyndromal depression, subthreshold depression, and minor depression in combination with elderly, geriatric, older adult, and late-life. Data were extracted from 181 studies of late-life subthreshold depression.

RESULTS

In older adults subthreshold depression was generally at least 2–3 times more prevalent (median community point prevalence 9.8%) than major depression. Prevalence of subthreshold depression was lower in community settings versus primary care and highest in long-term care settings. Approximately 8–10% of older persons with subthreshold depression developed major depression per year. The course of late-life subthreshold depression was more favorable than that of late-life major depression, but far from benign, with a median remission rate to non-depressed status of only 27% after ≥1 year. Prominent risk factors included female gender, medical burden, disability, and low social support; consequences included increased disability, greater healthcare utilization, and increased suicidal ideation.

LIMITATIONS

Heterogeneity of the data, especially related to definitions of subthreshold depression limit our ability to conduct meta-analysis.

CONCLUSIONS

The high prevalence and associated adverse health outcomes of late-life subthreshold depression indicate the major public health significance of this condition and suggest a need for further research on its neurobiology and treatment. Such efforts could potentially lead to prevention of considerable morbidity for the growing number of older adults.

INTRODUCTION

With the introduction of the DSM-III, psychiatry increased reliability of its diagnoses, including major depressive disorder (MDD) (Judd et al., 1994). The establishment of boundaries at which the frequency, duration, or severity of symptoms crossed a “threshold” sufficient to be labeled psychopathology was not simple, however. When possible, thresholds were based on empirical data, but otherwise, non-empirical “expert opinion” was involved in separating the “ill” from the “well.” With emphasis on dimensional aspects of psychopathology in development of the upcoming DSM-V, now may be an opportune time to explore the merits of better defining various continua of disorders such as depression. Subthreshold depression (SubD) has sometimes been divided into distinct categories (e.g. minor depression [MinD], recurrent brief depression, and subsyndromal depression [SSD]), but at other times studied as a single entity. Based on the diagnostic criteria used in studies, overlap among these constructs is common. We exclude dysthymia (DYS) as a type of SubD because it has well-defined DSM-IV-TR (First et al., 2002) criteria, and most SubD studies do not include it.

In 1992, Wells et al. (1989) reported that depressive symptoms not qualifying as MDD were associated with more social disability than many medical illnesses. Soon thereafter, Judd et al. (1994), in analyses from the Epidemiological Catchment Area (ECA) study (1982), reported a one-month prevalence of SSD in the general adult population of 11.8%. DSM-IV later listed criteria for MinD among its research diagnostic criteria in the section on Depression Not Otherwise Specified. These were similar to those for MDD except requiring only 2–4 symptoms and no prior history of MDD; however, subsequent research has shown that DSM-defined MinD misses a substantial number of people who suffer morbidity from other variants of SubD. For instance, Judd et al. noted that among the SubD subjects in the ECA study, less than a third met criteria for MinD because neither depressed mood nor anhedonia (MDD Criterion A symptoms) were present (Judd et al., 1994). The investigators found virtually no differences between SubD subjects with versus without Criterion A symptoms. Angst and colleagues (1990) proposed another variant of SubD—recurrent brief depression, in which the only reason for failing to meet MDD criteria was that symptoms did not persist uninterrupted for two consecutive weeks.

Despite variable definitions and criteria, “non-major” depressions consistently exact major consequences on affected individuals (e.g. increased disability, poorer quality of life) and on society (e.g. increased healthcare costs) (Broadhead et al., 1990; Hybels et al., 2001; Sptizer et al., 1995; Xavier et al., 2002; Koenig, 1998). The concept of SubD resonated strongly in geriatric psychiatry (Jeste et al., 1999; Jeste et al., 2005), along with a speculation that MDD prevalence among older adults was inaccurate in the ECA study because of diagnostic ascertainment procedures (Judd and Akiskal, 2002). Re-analyzing the ECA data, Judd and Kunovac (1998) found that among adults ≥65 years old, SubD (MinD + SSD) prevalence was 31.1%, versus 6.3% for MDD—a fivefold difference.

Given the preponderance of SubD compared to MDD in older adults and the increasing research on late-life SubD, we believe an updated review of SubD in older adults is warranted. Specifically, we focus on the following aspects of late-life SubD, for which we know of no recently published comprehensive review: epidemiology, longitudinal time course, risk factors and public health consequences.

METHODS

We searched PubMed (1980– January 2010) using combinations of the following search terms: Group (A) subsyndromal depression, subthreshold depression, and minor depression with Group (B) elderly, geriatric, late-life, and older adult. Additional articles were identified via manual review of references in articles from database searches. We extracted data from articles in English conducted among older adults (age ≥ 55 years) that focused on any depressive condition with proposed criteria other than MDD, DYS, or bipolar depression. We included data on epidemiology only from studies with sample size ≥100. When two or more categories of SubD were assessed in the same study (e.g., MinD and SSD), we added their prevalences for a single estimate of SubD prevalence. We also calculated the prevalence ratio of SubD:MDD, and when available, calculated female:male prevalence ratios.

RESULTS

We identified 153 unique, potentially relevant articles by database searches (Figure 1). Although we used search terms geriatric, older adult, and late life for thoroughness, these terms yielded no articles other than those discovered with the search term elderly, hence the omission of these other search terms in Figure 1. An additional 28 studies of interest were identified via manual review of database-generated articles.

Figure 1
PubMed Search Results

EPIDEMIOLOGY

Community-based Studies

Table 1 summarizes epidemiological studies of late-life SubD. Twenty of the 37 investigations were at least partially community-based; five of these assessed mixed community-dwelling (CD) and long-term care (LTC) populations. Two studies (Kvaal et al., 2008; Geiselmann and Bauer, 2000) did not report what proportion of participants was CD versus LTC and were, therefore, excluded from composite data on CD epidemiology of SubD. In contrast, the other two mixed studies were included because one was predominantly community-based (87%) (Paivarinta et al., 1999) and the other reported findings which allowed separate analysis of CD vs. LTC data (Østbye et al., 2005); the fifth such study, while reporting the breakdown of CD vs. LTC participants, was excluded based on its unorthodox methodology (Steffens et al., 2009). Twelve of the 17 CD studies included for epidemiological estimates reported a point prevalence. SubD point prevalence in the community ranged from 4.0–22.9% (median prevalence 9.8%). All CD studies reported MDD or “syndromal depression” prevalence as well, and the ratio of SubD:MDD prevalence ranged from 1.1 to 6.9 (median 2.5). Studies assessing more than one variant of SubD (e.g., MinD and SSD) yielded higher than the median prevalence rates of SubD and ratios of SubD:MDD. The female preponderance seen in MDD (2:1) appeared somewhat reduced among CD older adults with SubD, with female:male prevalence ratios ranging from 1.0 to 2.4:1 (median 1.6:1), although many studies did not report these data.

Table 1
Epidemiological Studies of Subthreshold Depression in Older Adults

Four community-based investigations assessed 1-month prevalence: (a) SubD 31.1% (Judd and Kunovac, 1998) (DSM-IV MinD 13% + Judd et al. criteria (Judd et al., 1994) SSD 18.1%), (b) 16.5% SSD (Geriatric Mental State defined [a semi-structured interview]) (Geiselmann et al., 2001)—similar to SSD prevalence in the prior study using Judd et al. criteria, (c) 12.9% MinD (Beekman et al., 1995)—virtually identical to MinD prevalence in the first study, and (d) 8.8% SSD (Chen et al., 2007) (using the more stringent criteria of Lavretsky and Kumar (2002)).

Primary Care Studies

The prevalence of late-life SubD appears to be lower in the community as compared to primary care (PC) and inpatient hospitals, and is highest in institutional settings, similar to the epidemiological pattern of MDD. However, since these numbers are drawn from different populations, it is not conclusive that this represents a progressive increase in prevalence across such settings. Lyness and colleagues pioneered research of late-life SubD in PC settings (Lyness et al., 2009; Lyness et al., 2007; Lyness et al., 1999), with three studies reporting SubD point prevalence among older adults ranging from 15.1% to 35.9%. Two of these studies noted similar prevalences of DSM-defined MinD (5.2%–6.3%). All three studies assessed SSD, although with variable criteria; two evaluated SSD based on Hamilton Depression Rating Scale (HAMD) scores (>10) and reported prevalence of 9.9% and 20.4%. The latter prevalence (termed SSD-“A” in this study) is from a novel study comparing three different criteria for SSD, with the other two criteria being those espoused by Judd et al. (1994) (SSD-“B”: prevalence 16.2%), and alternative criteria proposed by Lyness et al. (SSD-“C”: prevalence 28.1%). (See Table 1 footnotes for details of these criteria). The final Lyness et al. PC study reported SubD prevalence as 35.9%, combining MinD, SSD-“C”, and also DYS; the individual prevalence of each diagnosis was not reported, but including DYS and using the most inclusive criteria for SSD (SSD-“C”) probably elevated prevalence rates (Lyness et al., 2009). Using a median prevalence of ~20% for SSD in combination with a prevalence of ~5% for MinD, SubD prevalence in PC is approximately 25% among Caucasian Americans. The SubD:MDD ratio among the Lyness et al. studies ranged from 2.3 to 7.5:1. The female:male prevalence ratio (2.1–2.3:1- based on 2 studies), was higher than that seen in the community—perhaps reflecting greater care-seeking behaviors by women.

In other American PC studies (Williams et al., 1995; Aranda et al., 2001) which included ≥50% Mexican-Americans or exclusively Latinos, the SubD prevalence (16.0–20.1%) and ratio of SubD:MDD (4.0–5.0:1) fell within the range reported in the aforementioned, predominantly Caucasian samples, despite use of more restrictive criteria.

An Italian PC study (Berardi et al., 2002) assessed point prevalence of International Classification of Disease (ICD) “current depressive episode” (CDE) (similar but not identical to DSM MDD) and found CDE almost twice as common as SSD. While not as drastically different from American PC studies, a Dutch PC study (Licht-Strunk et al., 2005) reported a notably lower point prevalence of SubD (10.2%) than that observed in American PC clinics. Differences in PC settings in Europe and the US, and absence of overlap in SubD criteria between American and European PC studies may partially explain these disparate epidemiological results.

Medical Inpatient Studies

We found only four epidemiological studies of SubD among older medical inpatients. Three of these reported higher point prevalences of SubD than MDD; the magnitude of difference was lower than in CD and American PC studies, likely because three of the four studies (Koenig et al., 1991; Koenig, 1997; McCusker et al., 2005) assessed MinD only. A fourth study by Schneider et al. (2000) examined SSD prevalence (determined by an ICD checklist) using inclusive versus exclusive approaches to depression diagnosis. The prevalences of MinD in two studies and SSD diagnosed via an inclusive approach were remarkably similar (29.2%, 27.9%, and 32.1%). SSD diagnosed via an exclusive approach decreased the prevalence (17.6%). The McCusker et al. (2005) study was anomalous in finding significantly higher rates of MDD than MinD in older medical inpatients, reporting a prevalence of MinD among patients in two hospitals of 7.9–9.4%. Notably, the prevalence of MDD varied by more than 30% between the two hospitals, indicating possible methodological issues in diagnostic ascertainment. Ratios of SubD:MDD in the first three studies ranged from 1.25 to 2.2:1. The SSD study was the only one to provide a female:male prevalence ratio (1.9:1) (Schneider et al., 2000).

Long-term Care (LTC) Studies

Several reports examined SubD point prevalence in LTC settings. Five of seven studies assessed MinD, although only two used DSM or Research Diagnostic Criteria (Jongenelis et al., 2004; Østbye et al., 2005; Morrow-Howell et al., 2008; Teresi et al., 2001; Parmelee et al., 1992; Parmelee et al., 1989). The prevalence of MinD ranged from 4.0% to 30.5 %, with the more rigorous criteria yielding similar rates of 16.8% and 14.1%. Østbye et al. (2005) reported a puzzling prevalence (4%) of MinD—lower than that seen in many CD studies, possibly due to lack of a singular focus on LTC or differences in the natures of the “institutions.”

The two investigations (Teresi et al., 2001; Jongenelis et al., 2004) with rigorous criteria for MinD along with one other American study assessed SSD or SubD defined based on symptom scale thresholds, and “non-MinD” SubD prevalence ranged from 19% to 44%; thus, in combination with rigorously defined MinD prevalences, approximately 33–61% of LTC residents experienced SubD at any given point in time. While many factors of institutional living may account for this high prevalence, it should be noted that most LTC studies did not exclude persons with cognitive disorders, which are prevalent in LTC and, as discussed later, themselves a risk factor for depressive disorders. Five of seven LTC studies found SubD more common than MDD, with SubD:MDD ratios ranging from 0.52 to 4.7:1 (median 2.5:1).

Only a few other settings have received epidemiological study of late-life SubD. RDC-defined MinD prevalence among older persons in hospice was reported as 9.2% (versus 16.9% for MDD); employing “Endicott criteria” (Endicott and Spitzer, 1979), which focus primarily on psychological depressive symptoms because neurovegetative symptoms among hospice patients are rampant, point prevalence was 12.3% for MinD and 10.3% for MDD (Chochinov et al., 1994). Three studies among older home healthcare recipients reported similar point prevalence of DSM-defined MinD (7.0, 8.2, and 10.8%) (Yewdell and Bennink, 1990; Fyffe et al., 2004).

LONGITUDINAL ILLNESS COURSE

Risk of Developing Major Depression

SubD diagnosed cross-sectionally may encompass a heterogeneity of depressive disorders, necessitating longitudinal data to yield a dynamic view of the condition over time. A focus of SubD illness course has been whether SubD serves as a prodrome to MDD. Two large studies in general adult populations found one-year and two-year rates of conversion to MDD to be 10% and 25%, respectively (Broadhead et al., 1990; Wells et al., 1992). Cuijpers et al. reviewed studies assessing risk of developing MDD among community-dwelling (CD) adults of all ages with SubD and found the relative risk (RR) ranged from 1.15 to 9.73 (median 4.43) (Cuijpers and Smit, 2004).

In older adults, two community-based Dutch investigations assessed MDD risk in late-life SubD. A six-year study reported that 20% of older adults with SSD (symptom scale threshold defined) developed a DSM-IV mood disorder: MDD (5.8%), DYS (12.3%), or comorbid MDD/DYS (1.9%) (Cuijpers et al., 2006). Data did not permit RR calculation, and it was not clear whether being diagnosed with SSD changed longitudinal depression treatment. The other Dutch study reported the 3-year RR of developing MDD among older adults with SSD (Geriatric Mental State defined) versus non-depressed (ND) peers to be 2.43 (3-year absolute risk 29.3%) (Schoevers et al., 2006). The absolute risk of 29.3% is significantly higher than the prior study, possibly due to different criteria for SSD, but this latter rate of approximately 10% per year is similar to reports among general adults cited above.

Several American investigations in PC settings examined future MDD risk in late-life SubD. Using PROSPECT study data, Lyness et al. (2006) reported that 8.8% of older adults with MinD or SSD had MDD after one year, consistent with a 16.2% two-year absolute risk of MDD in another PC study of late-life SubD (SSD + MinD) (Cui et al., 2008). These results were similar to the 10%/year conversion rate from SubD to MDD in another PC study (versus 2%/year MDD incidence among ND peers) (Lyness et al., 2002). Another group of investigators followed older adults in PC for 18 months, and among those with Structured Clinical Interview for DSM-IV (SCID) diagnosed MinD (with or without past MDD), 25% had developed MDD at study end. This yields a somewhat higher annual rate of conversion of 16.7% from SubD to MDD, perhaps because in contrast to the three prior studies, this study included only MinD—not any form of SSD (Vuorilehto et al., 2009). Lyness et al. (2009) later examined the risk of developing MDD in another PC sample of older adults with SubD (MinD + SSD) or DYS. Odds ratios (OR) for MDD diagnosis at one year compared to ND older adults were 12.1 for MinD and 6.1 for SSD. Another PC study addressed another issue—whether outcomes differed according to past history of MDD (Chopra et al., 2005). At three months, absolute risk of developing MinD, DYS, or MDD was 24.3% among SSD subjects with a history of MDD, significantly higher than that among those without prior MDD (10.1%), perhaps implying SSD was residual MDD in the former sub-sample.

Research on longitudinal MDD risk in other populations is limited. One study assessed post-myocardial infarction (MI) patients for MinD and noted that, after three months, 14% of persons with MinD had MDD versus only 6% among persons ND at baseline (Schleifer et al., 1989). Another investigation of persons with coronary heart disease (CHD) found that of the 17% of persons with MinD at baseline, 42% developed MDD at 1-year follow-up, indicating CHD may increase the risk for conversion from MinD to MDD above the average rate of 8–10% per year described above (Hance et al., 1996). Lastly, a study among senior community residents reported that among those with baseline MinD in “congregate apartment living,” 10% had MDD one year later, versus 23% among persons in traditional LTC (Parmelee et al., 1992).

Stability of longitudinal diagnosis

Aside from future risk of MDD, other longitudinal research on late-life SubD has focused on diagnostic stability. In the seminal Longitudinal Aging Study Amsterdam (LASA) (Beekman et al., 2002), CD older adults with MDD, DYS, and SubD (defined by Center for Epidemiological Studies Scale for Depression threshold scores) were evaluated at 14 time points over six years. Those with “double depression” (MDD/DYS) fared the worst, with only 5% achieving remission. While SubD had the best prognosis among the diagnoses assessed (26% remission rate), 61% of older adults with SubD had a chronic or chronic-intermittent course. Among PC patients in whom MinD and SSD were combined as a single category of SubD, stability of diagnosis at one year was similar to the LASA results (62–70%), with only 21.6–25.4% of older adults with SubD qualifying as ND after one year (Cui et al., 2008; Lyness et al., 2009). Strikingly similar numbers were reported from a very different population of mostly urban, CD African-Americans (65%) of Caribbean heritage (Cohen et al., 2009). SSD was defined by a score of 8–15 on the Center for Epidemiological Studies Scale for Depression (CES-D), whereas scores ≥16 were considered “syndromal depression” (SD). After 3 years, only 18% of those with baseline SSD were ND, while 59% had a stable diagnosis of SSD. Nonetheless, more of those with baseline SD had SD (50%) at follow-up than those with baseline SSD (23%). Study of SubD’s longitudinal course in PC has yielded a somewhat more favorable prognosis than in the community, although the number of studies are limited in both settings. One PC study reported that 48.8% of those with MinD/ SSD were ND at one year, still leaving more than half of such persons with depressive symptoms (Lyness et al., 2002). Another study in PC found a similar remission rate of 55% for MinD at 18-month follow-up (versus 38% remission for MDD) (Vuorilehto et al., 2009).

The longitudinal course of SubD in medical inpatients has been examined with variable results. A study among older medical inpatients indicated a fluctuant 1-year course for those with baseline MinD—4% maintained a stable diagnosis of MinD, 28% maintained stable ND recovery, and 68% vacillated between MDD, MinD, and ND (Cole et al., 2006). However, another investigation showed a relatively stable 1-year symptom course—measuring stability of depressive symptom severity (“minimal,” “mild,” or “moderate-severe” on the HAMD), rather than tracking categorical diagnoses (McCusker et al., 2007). Another study of inpatients with congestive heart failure reported more favorable rates of remission, 65% for MinD and 57% for MDD (statistically equivalent), but a trend for faster recovery time for MinD (3 weeks) versus MDD (20 weeks) (Koenig, 1998). Older inpatients with post-MI MinD had an intermediate rate of being ND at 3-month follow-up (64%) compared to those with post-MI MDD (23% ND) and those ND at baseline (83% ND) (Schleifer et al., 1989). A stable diagnosis of MinD occurred in only 22% of cases.

Evidence from other older populations supports the notion that MinD has a more favorable prognosis than MDD but that its course varies and is certainly less favorable than for ND elders. Among LTC residents, the rate of being depression-free one year after baseline assessment was 88% for a ND group versus only 3.3%–3.6% for those with MDD or MinD at baseline (Parmelee et al., 1992). In contrast, when screening new admissions to LTC (undergoing the acute stressor of moving), 45% of those who were depressed at baseline (75% of whom had SubD) were ND one year later (Morrow-Howell et al., 2008).

The longitudinal course of SubD has also been studied in the spousally-bereaved. Evaluations conducted 2–25 months after the loss showed that prognosis varied from best to worst in the following order: ND→SSD→MinD→MDD (Zisook et al., 1997). Over nearly 2 years, widows/widowers with baseline diagnoses in parentheses spent the following percentage of time non-depressed—84%(ND), 61%(SSD), 47%(MinD), and 24%(MDD) versus this percentage of time in major depression— 2.4%(ND), 6.4%(SSD), 6.6%(MinD), 38.4%(MDD). Despite having a better prognosis than MDD patients, spousally-bereaved older adults with SubD still spent more than 40% of their time in a persistent state of SubD over 2 years. In another at-risk group —persons with dementia—23.6% of patients had MinD at baseline, and they spent on average 25% of the next 9 months with symptomatic depression, although a significant minority had more persistent depressive symptoms (9.5% with MDD and 24% with ≥6 months of significant depression) (Ballard et al., 1996). Altogether, prospective studies of the course of late-life SubD of at least one year duration reported rates of remission to ND status ranging from 3.6 to 52% (median 27%).

HEALTH OUTCOMES: RISK FACTOR, CONSEQUENCE, OR BOTH?

Studies have demonstrated associations between SubD and multiple negative medical and psychosocial conditions in addition to MDD. A majority of investigations have been cross-sectional, limiting cause-and-effect interpretations. In some cases, it is likely that a certain adverse condition (e.g., functional disability) is both a risk factor for and a consequence of SubD, interacting in a vicious feed-forward cycle. Below, we first discuss cross-sectional evidence linking SubD with adverse health conditions, and subsequently we consider more conclusive prospective studies.

Cross-sectional Associations

Even in cross-sectional studies, certain variables are clearly risk factors rather than consequences, e.g. gender. Many of the epidemiological studies already summarized indicated female gender as a risk factor for late-life SubD (Beekman et al., 1995; Kvaal et al., 2008; Østbye et al., 2005; Xavier et al., 2002; Hybels et al., 2001; Lyness et al., 2007; Cohen et al., 2005; Schoevers et al., 2006). Other variables reported as risk factors include past history (Beekman et al., 1995; McCusker et al., 2005) and family history (Beekman et al., 1995) of depression/psychiatric illness.

Certain medical illnesses associated with MDD have been identified as possible risk factors for SubD, e.g. visual impairment (Horowitz et al., 2005), end-stage renal disease requiring hemodialysis (Drayer et al., 2006; Hinrichsen et al., 1989) Parkinson’s disease (Tandberg et al., 1996; Ehrt et al., 2007; Costa et al., 2006; Starkstein et al., 2008), cardiac disease/CHD (Penninx et al., 2001; Hance et al., 1996) and stroke (Eastwood et al., 1989; Saxena et al., 2008; Brodaty et al., 2007). Cognitive disorders also increase risk of SubD; four studies of cognitively impaired older adults (two with Alzheimer’s disease, two with mild cognitive impairment) reported similar point prevalences of MinD—17.2%, 26%, 26.5%, and 27% (versus median community prevalence of 9.8%) (Lyketsos et al., 1997; Kumar et al., 2006; Gabryelewicz et al., 2004; Starkstein et al., 2005). Although depressive symptoms likely result from neurobiological changes in dementia (Meeks et al., 2006; Brodaty et al., 2007), a reverse relationship in which depression is a possible risk factor for cognitive decline (Butters et al., 2008) complicates the interpretation of directionality (Saxena et al., 2008).

Variables cross-sectionally associated with late-life SubD which may be antecedents, consequences, or both include the following: (a) being unmarried (Schneider et al., 2000; Beekman et al., 1995; Hybels et al., 2001), (b) low socioeconomic status (Blazer and William, 1980; Adams and Moon, 2009; Mechakra-Tahiri et al., 2009), (c) Lower education (Blazer and William, 1980; Adams and Moon, 2009) (d) executive function and verbal recall impairments (McCusker et al., 2005; Parmelee et al., 1992; Xavier et al., 2002; Chuan et al., 2008; Elderkin-Thompson et al., 2003; Elderkin-Thompson et al., 2006), (e) increased medical burden (Beekman et al., 1995; Parmelee et al., 1992; Chuan et al., 2008; Geiselmann et al., 2001; Hybels et al., 2001; Lyness et al., 2007; Penninx et al., 1999), (f) disability (Beekman et al., 1995; McCusker et al., 2005; Parmelee et al., 1992; Schneider et al., 2000; Chuan et al., 2008; Eastwood et al., 1989; Geiselmann et al., 2001; Hybels et al., 2001; Lyness et al., 1999; Lyness et al., 2007; Penninx et al., 1999), (g) decreased social support/loneliness/conflicted relationships (Beekman et al., 1995; Adams and Moon, 2009; Mechakra-Tahiri et al., 2009; Morrow-Howell et al., 2008; Blazer and William, 1980; McCusker et al., 2005; Schneider et al., 2000; Hybels et al., 2001; Pasternak et al., 1992) and (g) negative life events and loss (Beekman et al., 1995; Adams and Moon, 2009; Morrow-Howell et al., 2008; Ormel et al., 2001). These are consistent with a recent meta-analysis of risk factors for late-life depression (variably defined, not generally referring to SubD) (Cole, 2005). Other reported associations include decreased quality of life (Chachamovich et al., 2008; Geiselmann and Bauer, 2000; Williams et al., 1995), more negative attitudes toward aging (Chachamovich et al., 2008), personality traits such as increased neuroticism (Lyness et al., 2002; Weiss et al., 2009; Aben et al., 2002) or decreased conscientiousness (Weiss et al., 2009), and lower intrinsic religiosity (Koenig et al., 1998).

Prospective Studies: Risk Factors

A prospective investigation has identified medical burden, functional disability, and decreased social support as risk factors for persistence or worsening of MinD among older medical inpatients followed for three months (Koenig et al., 2006). Similarly, among depressed medical inpatients (37% with MinD), negative life events predicted lack of recovery at 1-year (Koenig, 1998). Cui et al. (2008) conducted a 2-year observational cohort study among older PC patients with MDD, SubD (SSD + MinD), and ND. The authors identified six different illness trajectories, two being germane to this discussion. One trajectory involved ND→SubD; risk factors for this outcome included medical burden and past depression history. Another trajectory was SubD→MDD, predicted by higher medical burden, greater disability, and less social support. These findings were partly replicated in a later study of SubD in PC patients—i.e., increased MDD risk and severity at one year predicted by more disability and less social support (Lyness et al., 2009).

Prospective Studies: Consequences

Several prospective studies have demonstrated significant adverse public health outcomes in late-life SubD. Four of six relevant studies reported that late-life SubD increased healthcare utilization. Supportive reports included: (a) 1-year follow-up of medical inpatients with either MDD or MinD (Koenig, 1998), (b) 10-year follow-up of CD older adults with SubD, who used more home health and social services than ND peers (Beekman et al., 1997), (c) a study of stroke rehabilitation patients with MDD or MinD, who had longer hospital stays than ND controls (Eastwood et al., 1989), and (d) a 5-month follow-up of older medical inpatients assessing mixed symptoms of depression and anxiety in which subthreshold symptoms increased healthcare costs (Creed et al., 2002).

At the individual level, prospective investigations of late-life SubD have identified the following adverse consequences in comparison with ND older adults: (a) increased cognitive impairment at 1-year follow-up among cognitively intact medical inpatients with MinD (Han et al., 2008) as well as elevated risk of dementia or cognitive disorder NOS over 3 years in a sample of primary care outpatients (Boyle et al., 2010) and (b) poorer physical health among CD older adults with MinD in the 10-year LASA study (Beekman et al., 1997). Perhaps most impressive is the evidence that SubD increases risk for future functional disability. This was demonstrated in at least eight studies, with findings such as the following: (i) slower recovery among hospitalized rehabilitation patients (Allen et al., 2004), (ii) increased bed-days and decreased activity due to health in the LASA study (Beekman et al., 1997), (iii) more impairment in activities of daily living (ADLs) among CD older adults and those in home healthcare (Li and Conwell, 2009; Hybels et al., 2009; Weinberger et al., 2009; Hybels et al., 2009), (iv) during a 4-year study of CD older adults, objective decline on physical performance tests (e.g., balance and walking speed) that correlated linearly with depression severity beginning with “subclinical” levels of depression (Penninx et al., 1998), and (v) over nine years of follow-up, a linear relationship between depression severity as measured by the CES-D and progression to mild disability starting with CES-D scores of zero, as well as CES-D scores (10–19) usually considered under the threshold for significant depression predicting mild and severe disability in ADLs (Barry et al., 2009).

There are mixed results regarding increased mortality with SubD. SubD increases suicidal ideation (Angst et al., 1990; Chopra et al., 2005; Montross et al., 2008), and one retrospective “psychological autopsy” study found that among completed suicides versus control subjects, OR for completed suicide among persons age ≥75 was significantly elevated (OR=42.3) for those diagnosed by collateral history with MinD (Waern et al., 2003). In another study in Sweden conducted among older persons seeking treatment for suicide attempts in emergency rooms, MinD was associated with elevated risk (OR=2.6) (Wiktorsson et al., 2010). Depression has been linked to increased non-suicide mortality among several late-life disorders (Katon et al., 2008). Of these, CHD (Whang et al., 2009; Williams et al., 2004) has received the most attention. Three studies (Carney et al., 2008; Romanelli et al., 2002; Penninx et al., 2001) reported that older adults with MinD vs. ND peers had increased CHD-related mortality (OR 4.8, hazard ratio [HR] 1.7, and RR 2.1) with follow-up periods from 4 months to 5 years. In a 6–8 year cohort study of older persons after coronary artery bypass graft (CABG), DSM-IV MinD increased long-term risk for “coronary events” (angina, MI, or cardiac death) (Rafanelli et al., 2006), whereas a similar study among older adults without baseline CHD, found no increase in ischemic coronary events among persons with SubD (symptom-scale defined) followed on average for 7.2 years (Bremmer et al., 2006). Similarly, MinD failed to predict mortality among patients with congestive heart failure over a 2.5-year period (Faller et al., 2007). However, another study found that CHF patients with MinD had a significantly increased risk of adverse cardiovascular events (HR = 4.36) at 2-month follow-up, while those with MDD did not (Rafanelli et al., 2009).

In a study of mortality among patients with diabetes mellitus, Lin et al. (2009) noted that in a 5-year cohort, after adjustment for demographics, clinical characteristics, health habits and treatment-related measures, MinD was associated with increased all-cause mortality (HR = 1.52). In a cross-sectional study of older adults with diabetes mellitus, Egede et al. (2009) noted that presence of MinD or MDD was associated with poor adherence to self-care recommendations (most notably physical activity and smoking cessation) as well as lower scores on quality of care indicators (notably receipt of flu shots and receipt of eye examinations). One could posit such poor self-care is at least one significant mediator of the increased risk of mortality in diabetes patients with MinD in the prior study.

Penninx et al. (1999) as part of the LASA study examined overall mortality risk among older adults with MDD and “MinD” (defined by symptom scale thresholds) longitudinally for approximately 50 months. After adjusting for possible confounds, the increased risk was significant for MDD (RR 1.68) and for males with MinD (RR 1.45). There was no link between MinD/depressive symptoms and mortality in two studies of LTC residents, whereas MDD increased mortality in both studies (Rovner et al., 1991; Parmelee et al., 1992). A similar lack of an association between late-life SubD and mortality has been reported in other studies of CD older adults and older medical inpatients, with one report even showing lower mortality among women with SubD versus ND women (Hybels et al., 2002; McCusker et al., 2006). However, several studies of SubD in older adults with specific medical conditions (e.g. diabetes mellitus, dementia, end-stage renal disease, and stroke [2 studies]) have found that SubD significantly increased mortality (HR 1.7, OR 4.3, HR 4.1, OR 3.7, and HR 2.0, respectively) (Janzing et al., 1999; Drayer et al., 2006; Katon et al., 2005; Morris et al., 1993; Endicott and Spitzer, 1979).

DISCUSSION

The evidence reviewed above strongly suggests that late-life SubD, howsoever defined, is prevalent, worsens quality of life and health of older adults, and impacts healthcare systems via increased service utilization and cost expenditure. Epidemiological research on late-life SubD demonstrated a pattern observed in late-life MDD: increasing prevalence moving from community to PC to LTC settings (community [10%], PC [25%], medical inpatients [30%+], LTC [c. 45–50%]). SubD was consistently at least 2–3 times more prevalent than MDD across all settings. When gender data were reported, the female:male diagnostic ratio was similar to but perhaps slightly lower than the 2:1 ratio in MDD. When assessed simultaneously, SSD prevalence was generally higher than MinD prevalence. The most consistently identified risk factors for late-life SubD in prospective studies were increased medical burden, disability, decreased social support, female gender, and neurological illnesses (e.g. Parkinson’s disease, stroke, AD).

Research on the longitudinal course of late-life SubD indicates risk of developing MDD to be generally 8–10% per year, with possibly higher risk in LTC and among persons with CHD. Studies from various settings indicate the prognosis (e.g., odds of remission) are better for late-life SubD than for MDD, although a majority (median 73%) of older adults with SubD remained symptomatic during follow-up. Some studies indicated the diagnostic stability of late-life SubD categories was relatively low but did not suggest either that SubD has a benign course or that it is an invalid diagnosis. Indeed, a fluctuant course is similar to results from a study of the 12-year course of MDD among adults aged up to 79 which demonstrated that affected persons were symptomatic 60% of the 12-year period, and when symptomatic, 73% met criteria for SubD, not MDD (Judd et al., 1998).

The negative health consequences associated with late-life SubD are on par with those seen in many chronic medical and psychiatric conditions, including increased healthcare utilization and expenditure, cognitive impairment, physical health decline, increased disability, and increased suicidal ideation. Most studies among general populations of older adults do not support an association between SubD and increased mortality, although SubD has been linked to increased mortality in certain medical conditions. Disability emerged as a robust risk factor for and consequence of late-life SubD. Please see Bruce (2001) for a review of the complex interplay between depression and disability.

Data also suggest that SubD exists on a spectrum with established depressive disorders (MDD and DYS). Similarities between late-life MDD and SubD have been demonstrated in gender ratio (Beekman et al., 1995), affective disorder family history (Beekman et al., 1995), and associations with a number of similar adverse outcomes (Hybels et al., 2001). Also, variables, such as cognitive impairments (Costa et al., 2006; Elderkin-Thompson et al., 2003), worse symptomatic and functional outcomes (Lyness et al., 2006), ADL impairments (Schneider et al., 2000), and lack of social support (McCusker et al., 2005), which were associated with late-life depression diagnoses, demonstrated levels of correlation with SubD intermediate between correlations reported for MDD and ND.

Some limitations of this review warrant discussion. We could not conduct a meta-analysis due to data heterogeneity (especially in the criteria used to define “less than major” depression) which complicated data synthesis. The DSM-IV criteria for MinD were the most replicable and consistent among the various criteria of SubD reviewed, although several studies did not apply these criteria rigorously. Aside from MinD, the most common diagnosis used was SSD, defined based on various criteria (Judd et al., 1994; Lavretsky and Kumar, 2002; Lyness et al., 2007), or scoring above an established threshold on a depression rating scale.

Concerns for the effects of heterogeneous SSD criteria on conclusions in this review are partially tempered by a study (Lyness et al., 2007) demonstrating a preponderance of similarities in variables associated with three different criteria for SSD. Our review did not include data on early or middle adulthood SubD, limiting extrapolation of findings to other age groups.

As psychiatry moves toward DSM-V, establishing consensus on terminology, definitions and criteria for SubD should be an important goal. This will allow for creating an agenda on future SubD research. Priority areas should include studies of incidence, prevalence, and longitudinal course of SubD in various clinical settings, diverse geographical areas, and cultural/socioeconomic groups. While some late-life SubD risk factors (e.g., female gender, medical illness, functional disability, and poor social support) seem well established, others remain to be identified, in order to guide effective prevention efforts (Reynolds, 2008). More sophisticated health economic studies of the effects of SubD would assist in formulating optimal healthcare policy. Based on existing literature, there is certainly evidence to make a case for developing interventions targeted at prevention of SubD (van't Veer-Tazelaar et al., 2009; Vahia et al., 2010). This could potentially be a simple and low-cost means of reducing global morbidity and mortality among older adults.

It would be important to ascertain whether late-life SubD is associated with other forms of psychopathology as a risk factor, consequence, or comorbidity. Existing studies suggest that SubD is associated with both threshold and subthreshold anxiety disorders (Kvaal et al., 2008; Palmer et al., 1997) in older adults—Geisselmann et al. (2001) reported that 32% of older adults with SSD experienced significant anxiety symptoms (though not specifically DSM disorders). SubD is also prevalent among older persons with schizophrenia (Zisook et al., 2007; Diwan et al., 2007). While.a comprehensive review of comorbidity of SubD and sunsyndromal anxiety or other psychiatric conditions is beyond the scope of this work, we believe that an exploration of the course of illness and outcomes associated with psychiatric cormorbidity is warranted. Depressive symptoms have also been associated with higher cardiovascular and cerebrovascular morbidity, as well as higher mortality in the elderly, These associations may have plausible biological underpinnings that merit further research (Schulz et al., 2000; Schulz et al., 2009).

As SubD becomes a focus of increased research, our understanding of the continuum of mood pathology from “normal” to major depression will be enhanced. Based on existing research, a need to clarify the terminology associated with subsyndromal forms of depression is clear. This will be an important step in facilitating more valid and reliable research in this area. Finally, research advances in understanding the neurobiology of late-life SubD and development of psychosocial and pharmacological treatments are necessary to guide evidence-based treatment algorithms. Such advances could save millions of older adults from the morbidity associated with depressive symptoms that, in spite of their notable prevalence and impact, are often overlooked, under-diagnosed, and under-treated.

Acknowledgement

This work was supported in part by grants from the National Institute on Mental Health (P30 MH080002), the National Institute on Aging (T35 AG26757), and The US Health Resources and Services Administration (Geriatric Academic Career Award), the UCSD Sam and Rose Stein Institute for Research on Aging, the John A. Hartford Center of Excellence in Geriatric Psychiatry, and the Department of Veterans Affairs.

Footnotes

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Conflict of Interests

Dr. Lavretsky has a research grant from the Forest research Institute.

AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Janssen donate medication to Dr. Jeste’s NIMH-funded research grant, “Metabolic Effects of Newer Antipsychotics in Older Pts.”

No other authors have any conflicts of interest.

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