The results reported here are limited by the fact that the NCS-R used a fully-structured lay-administered diagnostic interview rather than a semi-structured clinician-administered diagnostic interview. However, the fact that good concordance was found between CIDI diagnoses with blinded SCID clinical diagnoses reduces this concern. In addition, irritability was defined as being “irritable, grouchy, or in a bad mood,” and this definition may be over-inclusive. Another limitation is that irritability was assessed with only a single question for a single worst lifetime episode, possibly leading to more imprecision in the distinction between irritable and non-irritable cases than if the assessment had been made using a more detailed assessment across a number of episodes. The base rate of “irritability” was not assessed in the entire sample, making it impossible to determine whether or not the high prevalence of irritability in MDD is different from the lifetime prevalence of irritability in the general population. However, the fact that irritability second was found to have a significant factor loading with the symptoms of MDE among respondents who endorsed a lifetime history of either dysphoria or anhedonia shows that irritability is associated with the symptoms of DSM-IV major depression. This finding is consistent with clinical evidence that irritability is more common among depressed vs. non-depressed subjects.23
The above limitations are likely to lead to the results regarding differences between irritable and non-irritable cases being conservative. An additional limitation, though, might have more complex effects: that respondents were not followed over time or assessed for a family history of bipolar disorder, raising the possibility that at least some of the respondents classified as having irritable MDD might actually be in the bipolar spectrum and might eventually convert to having bipolar disorder. Based on this limitation, the claim that the cases of irritable MDD seen here are non-bipolar should be seen as provisional.
A final noteworthy limitation is that the analysis was carried out exclusively among respondents who met DSM-IV criteria for major depression. This means that respondents with irritable depression were required to have six symptoms compared to five for respondents with non-irritable depression. It could be argued that not allowing irritability to be an alternative to sadness or lack of interest might have introduced a systematic bias toward a relatively more severe form of depression in our analysis. As noted above, though, only 28 additional cases would be classified as having irritable depression if we allowed irritability to be a diagnostic symptom of MDD. This means that any bias introduced in our analysis by requiring respondents with irritable depression to have at least six symptoms would likely be modest. This suspicion was confirmed by replicating all analyses reported above with these 28 respondents added to those considered to have irritable depression. The results were essentially unchanged (results available upon request). The only difference was that the rate of comorbid PTSD in irritable depression (16.6%) was no longer significantly higher than in non-irritable depression (11.3%)..
Within the context of the above limitations, our results provide the first nationally representative US general population prevalence estimates of irritable versus non-irritable MDD. Irritability was found in roughly half the cases of MDD, making it at least as common as a number of the DSM-IV Criterion A symptoms of MDD, including all the reverse vegetative symptoms combined (weight gain, hypersomnia, psychomotor agitation) and psychomotor retardation. This finding is consistent with previous evidence that irritability is more common among depressed than non-depressed subjects.23
The prevalence of irritability found here is somewhat higher than the 37%–40% irritability prevalence estimates reported in previous studies of depressed outpatients.4, 5
Recall, though, that these clinical studies considered only symptoms in the current episode whereas we considered symptoms in the worst lifetime episode. In addition, there was no consistency in any of these studies in the methods used to assess irritability.
We excluded respondents with a lifetime history of bipolar (BP) disorder as well as those with a history of either sub-threshold BP disorder24
or core hypomanic symptoms (i.e., a distinct period of abnormally and persistently elevated, expansive, or irritable mood lasting several days or longer with at least one other symptom of hypomania) in recognition of the fact that depression with anger has been conceptualized by some commentators as a bipolar spectrum disorder.25
As noted above, the fact that many of the NCS-R respondents are still in the age of risk of onset of BP disorder means that some unknown number of those with irritable MDD might have their diagnoses changed to BP disorder in the future. However, given the very high prevalence of irritability among respondents with lifetime MDD after excluding respondents in the BP spectrum, and taking into consideration that upper bound estimates put lifetime prevalence of BP spectrum disorder at no more than 5–7% of the population,26, 27
it is very likely that this sort of conversion will occur to a high proportion of the NCS-R respondents classified as having irritable MDD.
Based on the above considerations, our findings challenge the view that irritability in depression is a specific indicator of bipolarity.28, 29
The findings also raise the question whether the revised DSM and ICD criteria should include irritability as a symptom of non-bipolar depression. Not only did we find that irritability is a common feature of non-bipolar depression, but we also found that irritability was meaningfully related to a number of significant clinical features. Mean retrospectively reported age-of-onset of MDD is significantly earlier for irritable than non-irritable MDD. Although the shape of the age-of-onset (AOO) distribution is nonetheless generally consistent for the two sub-types, the earlier onset of irritable than non-irritable MDD is consistent with the one, small clinical study of which we are aware that examined this issue.30
It is unlikely that this is due to differential recall bias, as post hoc analysis shows that the same finding holds when we compare AOO of irritable and non-irritable MDD in sub-samples that are matched on age at interview. It is noteworthy, though, that it has long been known that early AOO of MDE is also often found in BP disorder,31
again raising a question about the possibility that some cases of irritable MDD are in the BP spectrum.
Another important clinical finding is the significantly greater persistence of irritable than non-irritable MDD, as defined by the proportion of lifetime cases who had a 12-month depressive episode. We are aware of no prior study that has examined this issue. As noted above, the greater persistence of irritable than non-irritable MDD was still present after we controlled for lifetime comorbidity. We also adjusted for differences in AOO, as irritable MDD had an earlier onset than non-irritable MDD, which might explain the more persistent course of irritable MDD, but we found that the significantly higher 12-month/lifetime prevalence ratio of irritable than non-irritable MDD persisted when this control was introduced along with controls for comorbidity. However, retrospectively reported mean number of years with any lifetime episode did not differ significantly for irritable and non-irritable MDD, demonstrating inconsistency in the finding regarding persistence depending on the indicator used to define persistence. As course of illness is a critical clinical feature, more definitive data are needed on differences between irritable and non-irritable MDD in this regard, ideally from prospective studies.
The NCS-R finding that irritability is more prevalent in MDD among respondents in the age range 18–44 and among students is consistent with the finding of a decreasing prevalence of irritability in MDD with age in the STAR*D clinical sample4
It is conceivable that the comparatively early age-of-onset and young age at interview of respondents with irritable MDE are related to the fact that irritability is such a commonly occurring symptom in child and adolescent depression.1, 2
Another possibility is that irritability is becoming a more common feature of depressive episodes in recent cohorts.
The finding that severity of illness, as indicated by the QIDS-SR and the Sheehan Disability Scales, did not differ between irritable and non-irritable MDD diverges from the STAR*D finding that patients with irritable MDD had greater illness severity than those with non-irritable MDD.4
This discrepancy may be due, at least in part, to our finding that people with very severe, irritable MDD were significantly more likely to obtain psychiatric treatment than people with very severe, non-irritable MDD, leading to an over-representation of very severe cases of irritable MDD in specialty treatment samples.
NCS-R respondents with irritable MDD reported a higher prevalence of fatigue, self-reproach and morbid thoughts of death than those with non-irritable MDD. The elevated prevalence of morbid thoughts of death is indirectly consistent with the association between past history of suicide attempts and irritable MDD in the STAR*D study.4
The elevated prevalence of self-reproach in NCS-R irritable MDD might be part of the pattern, as self-reproach has been linked to suicidal ideation.32
It is noteworthy that similar symptom differences were found in the STAR*D sample, but these differences were explained by overall illness severity.4
It is striking that this is not the case in the NCS-R, as these symptom differences were found despite irritable and non-irritable MDD not differing in overall illness severity. This suggests that symptoms of self-reproach and morbid thoughts of death, and possibly fatigue (which was not elevated among STAR*R patients with irritable MDD) provide some genuine differentiation between irritable and non-irritable MDD. Clearly, though, these differences need to be examined in independent samples controlling for overall illness severity before we can conclude that they are due to more than idiosyncratic features of a single study.
The significantly higher prevalence of comorbid anxiety disorders among people with irritable than non-irritable MDD is in agreement with the observation that MDD outpatients with anxious depression in the STAR*D study were significantly more likely to report irritability than were MDD outpatients without anxious features.33
As no previous study investigated comorbidity of irritable vs. non-irritable MDD with impulse-control disorders, our finding that impulse-control disorders are comorbid only with irritable MDD is unique. This is potentially important as it is the most dramatic difference we found in the clinical correlates of irritable vs. non-irritable MDD. The association of irritable MDD with impulse-control disorders might account for the thus far unexplored finding in the Epidemiologic Catchment Area Survey that depression was related to violent behavior.34
The findings that irritability is a common symptom of MDD and that irritable MDD is associated with distinctive clinical features raises the possibility that the presence of irritability might be a useful MDD sub-typing distinction. Whether this turns out to be the case, though, will require further investigation of differential risk factors, family aggregation, and treatment response. A more detailed investigation of family aggregation of comorbid impulse-control disorders might turn out to be especially illuminating in this regard in light of the unique comorbidity of irritable MDD with impulse-control disorders.
Finally, the association in MDD of irritability with specific symptom clusters and comorbidities may reflect a psychopathological endophenotype that might defy the current DSM-IV nosology and, in fact, cut across DSM-IV clinical entities such as mood and anxiety disorders. A related example of such a cross-cutting distinction exists in the reduction in serotonergic neurotransmission, as suggested by blunted prolactin responses to fenfluramine challenges, reported in patients with both unipolar and bipolar depression,35
anxiety disorders such as PTSD36
and personality disorder patients with impulsive aggression.37
Consistent with these observations, we have found that patients with MDD, irritability and anger attacks had a significantly greater blunting of the prolactin response to fenluramine challenge than MDD patients without irritability and anger attacks.38
One could hypothesize that this particular endophenotype may share signs of serotonergic dysregulation, in addition to the clinical characteristics that we have identified, although further studies would need to be carried out to assess the specificity and temporal stability of this possibility. .
With regard to differential treatment response, no study has ever investigated whether irritability is a moderator of antidepressant treatment response. However, the fact that MDD patients with irritability and anger attacks have been shown to have distinctive neurobiological features, such as blunting of the prolactin response to fenfluramine challenge38
and a distinctive pattern of regional cerebral blood flow in the left ventromedial prefrontal cortex and left amygdala during anger induction39
raises the possibility that there might be distinctive responsiveness to antidepressant treatment. This is an issue that clearly warrants additional investigation in light of the results presented in the current report.
Even before further studies of risk factors and consequences are carried out, though, the results reported here raise the question whether irritability should be included as a symptom of MDD in the revised DSM-V and IDC-11 diagnostic systems. We saw that irritability is as strongly related as other DSM-IV symptoms with the underlying dimension of depression symptomatology in factor analysis. We saw that the prevalence of irritable MDD would be increased by roughly one-fifth (from 5.3% to 6.4% lifetime prevalence), but not dramatically, by including irritability as a core Criterion A symptom of MDD. Thorough evaluation of the extent to which these additional cases would have similar treatment response and correlates to cases that meet current DSM-IV criteria for irritable MDD is beyond the scope of this report. However, the apparent importance of irritability in MDD documented here suggests that clinical studies are needed of the people who would be conferred a diagnosis of MDD if irritability were added as a core symptom in DSM-V and ICD-11.