Comorbidities of psychiatric and headache disorders in Nepal: implications from a nationwide population-based study

The term “comorbidity” refers to the coexistence of any additional ailment in a person with an index disease [1]. Headache disorders such as migraine and tension-type headache (TTH) and psychiatric disorders such as anxiety and depression are all very common among general populations worldwide. Accordingly, some level of comorbidity between them will arise by chance. However, epidemiological studies over 25 years have consistently indicated that headache disorders and anxiety and depression are excessively comorbid [2‐20], with bidirectional [6] or syndromal [7] associations. Although most such studies have selectively considered migraine [8‐11], some have looked at TTH [12], “chronic daily headache” (CDH) [13] or headache in general [14]. Furthermore there are studies showing associations between headache disorders and neuroticism [21, 22], a personality trait closely interlinked with psychological distress [23].

Headache disorders, anxiety and depression are collectively viewed as the major disorders of the brain (MDBs) [24], each occupying a place among the top ten causes of disability in the world [25, 26]. From a public-health perspective, worrying consequences for overall disease burden arise from these disorders being comorbid. Firstly, comorbidity increases morbidity, perhaps synergistically. For example, headache associated with psychopathology has exaggerated effects on quality of life (QoL) and disability [23, 27, 28]. Secondly, comorbid disorders may be mutually aggravating. Again for example, comorbid psychiatric illnesses are risk factors for headache becoming chronic [29]. Thirdly, comorbid headache and psychiatric disorders pose significant management challenges: treatment of each may be hindered by the other, with worse outcomes likely and increased health-care liabilities [30]. Fourthly, there is the possibility of causal relationships, in either or both directions.

Most data on this subject come from the western world. However, MDBs appear to be prevalent and burdensome everywhere. The Global Burden of Disease Study 2013 (GBD2013) extrapolations to South Asia indicated that years of life lost to disability (YLDs) in this Region from these conditions were in line with global rankings [25]. Our study from Nepal, the only nationwide study in this region so far, showed high prevalences of both headache and psychiatric disorders, including a much higher prevalence of migraine than the global mean [31] and prevalences of anxiety above and of depression at the upper limit of their respective global ranges [32]. Both anxiety and depression correlated positively with neuroticism and negatively with QoL [32]. The probability of comorbidity between these disorders in Nepal, and the implications arising therefrom, are consequently matters of considerable public-health importance and of interest to health policy.

Therefore, our aims were to examine the extent to which the common headache disorders (migraine, TTH and the group of headache disorders characterised by headache occurring on ≥15 days/month) and psychiatric disorders (anxiety and depression) are comorbid in Nepal, a country with unique geocultural diversity [33], and to look also for associations between these headache disorders and neuroticism. Our objective was to establish the public-health implications of any associations discovered. Our purpose was to guide national health policy.

There were 2100 participants, with a participation rate of 99.6 % (males: 861 [41.0 %]; females: 1239 [59.0 %]; mean age 36.4 ± 12.8 years). The majority (1328; 63.2 %) were rural inhabitants, and over one fifth (470; 22.4 %) lived at an altitude of ≥2000 m. Well over one third (822; 39.1 %) were in the lowest category of annual household consumption. A detailed description of the sample characteristics has been reported previously [34].

Having any headache was significantly associated with HADS-A caseness (17.2 %) compared with having no headache (10.5 %; AOR 1.6; 95 % CI: 1.1–2.3; p = 0.024) (Table 1). In relation to headache types, the strongest association with HADS-A was observed for headache on ≥15 days/month (AOR 3.2) followed by migraine (AOR 1.7); there was no significant association between TTH and HADS-A (Table 1). No interaction effects were seen with any of the factors analysed.

There were no significant associations between having headache and HADS-D caseness (Table 2).

Having any headache was significantly associated with HADS-cAD caseness (7.0 %) compared with having no headache (3.6 %; AOR 1.9; 95 % CI: 1.0–3.6; p = 0.050) (Table 3). Again the strongest association with HADS-cAD was seen for headache on ≥15 days/month (AOR 2.7) followed by migraine (AOR 2.3), and there was no significant association between TTH and HADS-cAD.

In tests for interaction, we found only a weakly significant effect of gender (p = 0.047) with any headache. A subgroup analysis, however, suggested that the association of any headache with HADS-cAD was specific to females (AOR 4.3 [95 % CI: 1.3–13.8] versus AOR 1.0 [95 % CI: 0.4–2.2] in males). Numbers were low in the reference group in these analyses. No significant interactions were seen with any of the headache types.

Linear regression analysis showed a significant association between all headache and neuroticism score (B = 0.9; 95 % CI: 0.5–1.2; p < 0.001). Among headache types, headache on ≥15 days/month showed the strongest association (B = 1.6; 95 % CI: 0.9–2.2; p < 0.001), followed by migraine (B = 1.3; 95 % CI: 0.8–1.7; p < 0.001); the association between TTH and neuroticism was weak, although significant (B = 0.4; 95 % CI: 0.02–0.8; p = 0.040). All these analyses were adjusted for age, gender, household consumption, habitation, altitude and use of alcohol and marijuana. Tests for interaction revealed no significant effects with regard to any headache. However, in relation to migraine, the association with neuroticism demonstrated some gender-specificity, being stronger among males (B = 1.9; 95 % CI: 1.3–2.5) than females (B = 0.8; 95 % CI: 0.1–1.4).

Tables 4 and 5 summarise the data from Tables 1, 2 and 3, presenting them from a clinical management perspective: what was the probability (expressed as a percentage and AOR) that a patient with either headache (of a specific type) or psychiatric disorder (as HADS caseness) had the other as a comorbid condition? HADS-A was the most prevalent HADS caseness comorbid with each of the headache types: a patient with headache on ≥15 days/month had almost 30 % probability (AOR 3.2) of also having HADS-A. Migraine was the most prevalent headache comorbid with each of HADS-A, HADS-D and HADS-cAD: a patient with HADS-cAD had 46.7 % probability (AOR 2.5) of also having migraine.

Tables 6 and 7 show how the effects of comorbid headache and HADS caseness interacted on QoL, being additive (reducing WHOQOL score) in almost all cases. The only exceptions were that the presence or absence of TTH made little difference to QoL in those with HADS-A or HADS-cAD. In general, the additive effects of comorbid HADS caseness were highly significant; those of HADS-cAD were strongest and those of HADS-A least strong. None of the effects of the headache types were significant although, apart from those of TTH, they were consistent; headache on ≥15 days/month had, numerically, the strongest effect (Table 7).

This is the first nationwide, population-based survey in any country of South Asia to explore the comorbidity of headache and psychiatric disorders, which are both highly prevalent in Nepal [31, 32]. Comorbidity occurred more than was expected by chance, at least with regard to migraine and headache on ≥15 days/month on the one hand, and HADS-A and HADS-cAD on the other, the associations thereby indicated (with AORs in the range 1.7–3.2) likely to be bidirectional. There were also significant associations between headache, especially headache occurring on ≥15 days/month, and neuroticism. There were no associations between any headache and HADS-D, and none between TTH and any HADS caseness. Additive and possibly synergistic effects of comorbid headache and HADS caseness were evident on QoL, highly significantly so when migraine or TTH was the index disorder and HADS caseness the comorbid disorder.

Before considering the implications of these findings, we would compare them with others as a test of veracity; but as we have noted, there are none from this Region. Outside South Asia, most studies exploring psychiatric associations with headache disorders have focused on migraine [3‐11]. A Zürich cohort study first demonstrated strong relationships between migraine and both anxiety and depression [3], which were subsequently reported in the United States (US) [4, 9] and Canada [42]. Other US studies found that people with migraine had high levels of neuroticism [43, 44]. In Nepal, we found strong associations between migraine and HADS-A, HADS-cAD and neuroticism, but not HADS-D.

There is relatively little evidence regarding psychiatric associations with episodic TTH [45]. A large Swiss epidemiological study found no associations with depressive or anxiety disorders [7], and neither did we. Episodic TTH is usually a less painful disorder than migraine, and less troublesome since it lacks the range of associated symptoms that contribute to the burden of migraine [35]. Hence people with episodic TTH may not express the same extent of subjective emotional experiences as those with migraine [46].

People with chronic TTH, on the other hand, demonstrate strong psychiatric associations [47]: in the US, almost half had either a depressive or an anxiety disorder [48] while those in a Norwegian study had high levels of neuroticism [22]. We did not analyse chronic TTH specifically because it could not reliably be diagnosed by lay interviewers using a questionnaire [35], but among our participants with other headache on ≥15 days/month would have been some with this disorder. The category of headaches occurring on ≥15 days/month corresponds with what is elsewhere referred to as “CDH” [49], which has been associated with high frequencies of both depressive and anxiety symptoms [13, 50]. We found, in the Nepalese population, that headache on ≥15 days/month was associated with HADS-A, HADS-cAD and neuroticism, but not HADS-D.

Our findings, therefore, are not entirely in accord with others regarding depression. The explanation may be methodological. We found no association between HADS-D and any headache type, in line with French [27] and Norwegian studies [51] that also used HADS to establish psychiatric caseness. The studies from Switzerland [3], the US [4] and Canada [42], which found strong associations between depression and headache, instead used structured interviews based on Diagnostic and Statistical Manual (DSM) criteria [52]. A recent study from South Korea [53] obtained similar findings using the self-administered Patient Health Questionnnaire-9 (PHQ-9) [54], as did another US study [48] using the Beck Depression Inventory (BDI) [55]. Cultural factors determining how moods are expressed [56] may contribute: in many Asian countries, depression is often manifested somatically [57, 58], while HADS does not capture the somatic domains of depression so well [38]. HADS may therefore underestimate any association of depression alone with headache.

However, as was pointed out in a recent review [20] and revealed in the French study [27], depression in migraine rarely occurs alone but is almost always comorbid with anxiety. A stronger association of migraine with combined anxiety-depression than with either independently was seen in the early Zürich study [3], and similar findings in relation to the other headache types came later in Norway [51]. In our study, HADS-cAD occurred twice as often among all headache sufferers and those with migraine, and almost three times in those with headache on ≥15 days/month. Hence the association of headache with depression in our population, though not apparent in HADS-D, may have manifested in HADS-cAD. There was, however, a gender influence in this association: for any headache, the association with HADS-cAD appeared specific to females (AOR 4.3 versus 1.0 in males).

Summarising these arguments, we believe use of HADS – a screening rather than diagnostic instrument for depression – is valid among people with headache although it may underestimate caseness prevalence. We could not establish any association between headache disorders and HADS-D in Nepal, but this limitation should be taken into account.

We also note other limitations. It is a general limitation of cross-sectional studies that, while associations can be demonstrated, causality cannot. However, public-health purposes are served in the first instance by uncovering these relationships, which have important policy implications; subsequent research can investigate causation. It is a limitation of HADS that it cannot go beyond detecting caseness of anxiety or depression, which encompass heterogeneous mental disorders. This renders it difficult to identify and make provision in health-service planning for issues that might be related to particular types of these disorders. By a similar token, our headache diagnostic questionnaire captured episodic migraine and TTH, while all chronic cases were subsumed under headache on ≥15 days/month [35]. Comorbidities associated with these subtypes were likely to be different in view of their high-frequency, long-duration, intractable symptoms coupled with problems in management, but the prevalence of each would have been about 1 % or less. Categorically assessing these multiple types and subtypes would have been a cumbersome exercise requiring much greater investment. We believe that our approach, with simple validated interviewer-administered culturally-validated instruments, was a more practical option in a population with high illiteracy, and it best served our public-health purpose. Furthermore, our study had notable strengths: tried and tested methodology [33‐35, 59], large sample size, high participation rate and good representativeness of the diverse population of Nepal [33, 34].

Headache disorders, highly prevalent in Nepal, are excessively comorbid with anxiety and associated with neuroticism, and these relationships aggravate their negative impact on QoL. These findings call for reciprocal awareness, and a holistic coordinated approach to management and in the health service. Care for common headache and common psychiatric disorders should be integrated in primary care.