Overt Irritability/Anger in Unipolar Major Depressive Episodes Past and Current Characteristics and Implications for Long-term Course

Department of Psychiatry, University of California, San Diego, La Jolla.
JAMA Psychiatry (Impact Factor: 12.01). 09/2013; 70(11). DOI: 10.1001/jamapsychiatry.2013.1957
Source: PubMed


IMPORTANCE Although symptoms of irritability or anger are not central to the diagnosis of unipolar major depressive episodes (MDEs), these symptoms have been found, in cross-sectional studies, to be highly prevalent and associated with increased comorbidity and depressive illness burden. OBJECTIVE To determine the prevalence of overtly expressed irritability/anger and its effect on intake presentation and the long-term course of illness. DESIGN A prospective, naturalistic investigation of patients with unipolar MDEs, studied systematically at intake and during up to 31 years of follow-up. SETTING Five US academic medical centers. PARTICIPANTS Patients entered the National Institute of Mental Health Collaborative Depression Study during an MDE in 1978, 1979, 1980, or 1981. Patients with unipolar MDE at intake (n = 536) were divided into those with and those without current comorbid overtly expressed irritability/anger. EXPOSURE In this observational, longitudinal study, patients received treatment that was recorded but not controlled. MAIN OUTCOMES AND MEASURES Groups were compared on illness severity and chronicity, psychosocial impairment, quality of life, suicidal behavior, lifetime comorbid diagnoses, impulse control, and measures associated with bipolarity. RESULTS Overt irritability/anger was present in 292 of 536 participants with a unipolar MDE at study intake (54.5%). It was associated with significantly increased depressive severity, longer duration of the index MDE, poorer impulse control, a more chronic and severe long-term course of illness, higher rates of lifetime comorbid substance abuse and anxiety disorder, more antisocial personality disorders, greater psychosocial impairment before intake and during follow-up, reduced life satisfaction, and a higher rate of bipolar II disorder in relatives. No association was found with increased suicidal ideation or behavior. Results were not explained by comorbidity or other manic spectrum symptoms. CONCLUSIONS AND RELEVANCE This study extends results of cross-sectional investigations and indicates that irritability/anger during MDEs is a highly prevalent clinical marker of a more severe, chronic, and complex depressive illness. Findings have important implications for assessment and treatment.

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    • "The only vulnerability factor associated with CORT/CRP and not moderated by gender was anger. Although irritability is no longer a diagnostic symptom of MDD in adults, studies have shown that among adults with MDD, approximately 50% report increased irritability (Fava et al., 2010; Judd et al., 2013). Increased irritability/ anger in patients with MDD has been associated with anxiety, early age of onset, and lifetime persistence (Fava et al., 2010), observations recently replicated and extended by Judd et al. (2013). "
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    ABSTRACT: We examined whether the ratio of cortisol (CORT) to high-sensitivity C-reactive protein (hsCRP), an index that captures the integrity of homeostatic regulation between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory processes, is associated with vulnerability to depression in a gender specific manner and whether glucocorticoid receptor (GR) sensitivity plays a role in these associations. Fasting blood samples were collected between 0845 and 0915 and assayed for CORT, hsCRP, and leukocyte count in 213 healthy, medication-free men and women. The NEO-Personality Inventory was used to assess neuroticism, extraversion and anxiety. We used the Hamilton Depression Interview to assess depressive symptoms, the Buss-Perry anger subscale to measure anger, and the Pittsburgh Sleep Quality Index to evaluate subjective sleep quality and its components. Log-transformed CORT/CRP values were analyzed using multiple regression with Holms' adjusted p-values and age, body mass index (BMI), and race as covariates. GR sensitivity was estimated using the log-transformed ratio of neutrophils (N)-to-monocytes (M). The log-transformed ratio of CORT/CRP did not differ between men and women but was significantly and negatively associated with age and BMI. Severity of depressive symptoms, extraversion, anxiety, and sleep quality were associated with the CORT/CRP ratio in a gender-specific manner. For women, decreasing CORT/CRP ratios, suggestive of an insufficient release of CORT coupled with a heightened inflammatory state, were associated with increasing severity of depressive symptoms, decreasing quality of sleep, increasing frequency of sleep disturbance, and decreasing extraversion. For men, increasing frequency of daytime disturbance and levels of anxiety were associated with increasing CORT/CRP ratio, suggestive of an enhanced release of CORT relative to attenuated levels of hsCRP. For both genders, increasing anger was associated with decreasing CORT/CRP ratios. Although results suggested GR downregulation in women but not men, such differences did not mediate the observed associations. With the use of the CORT/CRP ratio, we showed that vulnerability factors for depression are associated with a loss of normal regulatory controls resulting in gender-specific patterns of neuro-immune dysregulation. That GR downregulation did not influence these associations suggests that the loss of regulatory controls in at risk individuals is primarily at the level of the hormone. Beyond the individual contribution of each component of the CORT/CRP ratio, disruption of normal neuroimmune regulatory feedback provides a plausible biological framework useful in understanding biobehavioral vulnerabilities to depression in a gender specific manner. The CORT/CRP ratio may be a viable biomarker not only for delineating risk for MDD but also progression and treatment responses among patients with MDD; possibilities that are testable in future studies.
    Brain Behavior and Immunity 09/2014; 44. DOI:10.1016/j.bbi.2014.09.008 · 5.89 Impact Factor
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    • "Major depressive disorder (MDD) is a common and major psychiatric disorder that affects as many as about 20% of individuals within their lifetime [1-3]. A wide variety of pharmaceuticals are available for treating depression, including tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors (SSRIs). "
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    ABSTRACT: Background We investigated the association between serum proBDNF, a precursor of brain-derived neurotrophic factor (BDNF), and response to fluvoxamine in patients with major depressive disorder (MDD) using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR): physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders. Methods Fifty-one patients with MDD (M/F, 19:32; age, 38 ± 19 years) and 51 healthy controls (M/F, 22:29; age, 34 ± 17 years) were studied using DSM-IV-TR: physically healthy and free of current alcohol or drug abuse, comorbid anxiety, or personality disorders. Serum levels of proBDNF and MDNF were measured by sandwich enzyme-linked immunosorbent assay (ELISA). Results Serum mature BDNF levels in the MDD patients were significantly lower than those in the healthy controls (t = 3.046, p = 0.0018). On the other hand, no difference was found in serum proBDNF between the MDD patients and the healthy controls (t = −0.979, p = 0.833). A trend of negative correlation was found between baseline serum BDNF and baseline scores of the 17 items of the Hamilton Rating Scale for Depression (HAMD17) (r = −0.183, p = 0.071). No correlation was however found between HAMD17 scores and proBDNF at baseline (r = 0.092, p = 0.421). Furthermore, no correlation was observed between baseline HAMD17 scores and baseline proBDNF/BDNF (r = −0.130, p = 0.190). No changes were observed in serum levels of proBDNF and BDNF during the treatment periods. Conclusions These results suggest that there is no association between serum proBDNF/BDNF and fluvoxamine response in MDD patients at least within 4 weeks of the treatment.
    Annals of General Psychiatry 07/2014; 13(1):19. DOI:10.1186/1744-859X-13-19 · 1.40 Impact Factor
  • JAMA Psychiatry 10/2013; 70(11). DOI:10.1001/jamapsychiatry.2013.3493 · 12.01 Impact Factor
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