The results reported here are limited in four ways. First, the assessments of MDE and GAD were based on fully-structured diagnostic interviews that are likely to be less accurate than clinician-administered diagnostic interviews. Second, AOO and persistence were assessed retrospectively. Third, although the risk factor data were gathered prospectively, they were based on retrospective reports. Fourth, although analyses were carried out in parallel to predict MDE and GAD, formal modelling procedures were not used to adjust for the influence of a latent “internalizing” variable so as to determine the extent to which the effects of predictors on MDE and GAD are mediated through such a construct.
The impact of the first of these limitations is reduced somewhat by evidence of good concordance between diagnoses based on the CIDI and those based on blinded clinical reappraisal interviews. The second and third limitations are inherent in the design, but are to some extent counterbalanced by the fact that we worked with prospective data. The fourth limitation needs to be addressed in future investigations, but should ideally be studied using a larger set of internalizing disorders (e.g., social phobia, panic disorder, PTSD). It is noteworthy, though, that the possibility of a latent factor completely explaining inter-temporal associations between two variables is inconsistent both with the magnitude of the cross-lagged associations between those two variables (i.e., the association between MDE at time 1 and GAD at time 2 and the association between GAD at time 1 and MDE at time 2) differing significantly from each other and with there being significant interactions involving differential associations of either time 1 variable with onset versus persistence of the other variable (Kessler, 1977
, Lazarsfeld, 1973
). Both these patterns are observed in our data. Specifically, the cross-lagged associations involving persistence are asymmetric, with GAD predicting MDE more strongly than MDE predicting GAD, and the time-lagged associations are stronger in predicting onset than persistence of both MDE and GAD. Both of these patterns argue against a latent variable explaining the associations, although formal evaluation of this possibility awaits future investigation.
These limitations notwithstanding, the study provides useful new information about MDE-GAD comorbidity and prospective predictors of MDE and GAD onset and persistence. The strong MDE-GAD comorbidity found here is consistent with much previous research (Belzer & Schneier, 2004
, Gorwood, 2004
, Kessler, 2000
, Noyes, 2001
), although our prospective data allowed us to decompose this cross-sectional association to document significant reciprocal cross-lagged relationships that vary with amount of time since the onset of the temporally primary disorder in predicting first onset. The most striking aspect of this time decay is the enormous same-year ORs. These same-year associations are so strong that more than one-third of all lifetime co-occurring MDE-GAD above that expected by chance occurs among cases in which both disorders started in the same year. We have no way to know what the strong association between time since onset and risk of comorbidity might mean, but it clearly implies that the temporally primary disorder is more than a mere marker of stable constitutional risk, as the latter would not be expected to produce an association between time since first onset of the temporally primary disorder and risk of the secondary disorder. The time decay also has implications for the argument in the literature that GAD might be nothing more than a prodrome or severity marker of MDE rather than an independent disorder (Brown et al., 1998
, Cloninger et al., 1990
, Offord et al., 1994
). If this argument were correct, the window of risk for secondary depression would be fairly short, which we find that it is not.
An alternative view of the causal processes linking temporally primary GAD with secondary MDE argues that secondary depression is an exhaustion response to unremitting anxiety (Akiskal, 1985
). Primary anxiety, in this view, can be conceptualized as a stressor that promotes secondary depression (Akiskal, 1990
, Durham et al., 1997
). If this were the case, though, we would expect that the OR for GAD predicting secondary MDE would become higher with the passage of time since onset of GAD. The fact that the opposite is the case argues against this interpretation. A more likely scenario is that the cross-lagged associations are due either to unmeasured common causes, to the effects of one disorder on the other, or to some combination of these two effects. We know that stable effects of the former sort exist. Indeed, as noted in the introduction, a number of population twin studies suggest that genetic influences are important common causes of MDE and GAD (Gorwood, 2004
, Kendler et al., 2007
). However, we can think of no biologically plausible mechanism whereby a genetic common cause would lead to a time decay of the sort seen in the NCS-2 data in the ORs linking onset of temporally primary disorders with subsequent onset of secondary disorders. Nor could common genetic causes account for all the observed comorbidity between MDE and GAD, as the latter is higher than would be predicted based solely on the heritability of MDE and GAD and the strength of the association between the genes for the MDE and GAD. This means that there must also be common environmental causes of MDE and GAD. The estimates in population twin studies suggest that the latter explain between one-third and two-thirds of the significant comorbidity between MDE and GAD, assuming that the joint effects of genetic and environmental causes are additive.
We investigated a number of potentially important prospective risk factors for MDE and GAD that might be considered common causes. Most of these were found to predict the first onset of both MDE and GAD, but fewer were significant prospective predictors of persistence. Statistical control for these common predictors only explained a small proportion of the observed cross-lagged associations between MDE and GAD involving either onset of persistence. This could mean that we simply failed to measure the common environmental causes that are important for explaining the cross-lagged associations between MDE and GAD. Another possibility is that the occurrence of one of these two disorders in itself might increase risk of the subsequent onset of the second disorder, possibly through some type of sensitization or kindling phenomenon (Post & Weiss, 1998
). An important implication of the possibility that temporally primary MDE or GAD might itself increase risk of the subsequent first onset of the other disorder is that successful treatment of the temporally primary disorder might be expected in such a case to reduce risk of onset of comorbidity. We are aware of no empirical research on this possibility. Given the high ORs associated with one of the two temporally primary disorders predicting the subsequent first onset of the other in the first few years after first onset, though, the sample size required to detect a preventive effect of this sort in an effectiveness trial framework with long-term (five-year) follow-up would not be prohibitive. It might be that this kind of experimental investigation is the only way to resolve the uncertainly regarding whether temporally primary MDE and GAD are causal risk factors for each other or only risk markers.
Even though the prospective risk factors considered here did not explain the time-lagged associations between MDE and GAD, they are important in documenting several differences in the environmental determinants of the two disorders. Most notable in this regard are associations of parental death, extroversion (negative), and openness to experiences on first onset of MDE but not GAD, and generally somewhat stronger and temporally more persistent associations of the majority of risk factors with MDE than GAD. Many of these differences, though, are small. We also found that MDE was not a significant predictor of persistence of GAD, while GAD was a significant predictor of persistence of MDE. This difference is consistent with an earlier finding based on the analysis of retrospective reports in the baseline NCS. This earlier finding was associated with an investigation of whether comorbidity is related more strongly to the persistence and severity of GAD than other anxiety or mood disorders (Kessler et al., 1994
). The rationale of this analysis was that if GAD was a prodrome, residual, or severity marker of MDE, as early commentators suggested (Brown et al., 1998
, Cloninger et al., 1990
, Offord et al., 1994
), the persistence-severity of GAD would be more strongly affected by comorbidity than would persistence-severity of depression. Yonkers et al. (1996)
reported a similar result in the prospective HARP study. These results provide concrete substantiation that MDE and GAD have partially distinct environmental determinants and add to the evidence from previous prospective studies of differences in the risk factors for MDE and GAD (Moffitt et al., 2007
) and differences in inter-temporal stability of these disorders that cannot be explained by a common underlying internalizing factor (Fergusson et al., 2006
). Future research needs to search for evidence of additional differences of this sort in an effort to expand our understanding of the distinction between common and distinct risk factors for MDE, GAD, and other internalizing disorder.