Adjunctive Antidepressant Use and Symptomatic Recovery Among Bipolar Depressed Patients With Concomitant Manic Symptoms: Findings From the STEP-BD

Harvard University, Cambridge, Massachusetts, United States
American Journal of Psychiatry (Impact Factor: 12.3). 09/2007; 164(9):1348-55. DOI: 10.1176/appi.ajp.2007.05122032
Source: PubMed


Practice guidelines have advised against treating patients with antidepressants during bipolar mixed states or dysphoric manias. However, few studies have examined the outcomes of patients with co-occurring manic and depressive symptoms who are treated with antidepressants plus mood stabilizing drugs.
The authors compared outcomes in patients with bipolar disorder who received a mood stabilizing agent with versus without an antidepressant for a bipolar depressive episode accompanied by > or = 2 concurrent manic symptoms. The 335 participants were drawn from the first 2,000 enrollees in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Kaplan-Meier survival curves and Cox regression models were used to compare time to recovery. General linear models examined the relationship between antidepressant use or mania symptom load at the study entry and mania or depression symptom severity at the 3-month follow-up.
Adjunctive antidepressant use was associated with significantly higher mania symptom severity at the 3-month follow-up. The probability of recovery at 3 months was lower among patients with higher baseline depression severity. Antidepressant use neither hastened nor prolonged time to recovery once potential confounding factors were covaried in a Cox regression model.
In bipolar depression accompanied by manic symptoms, antidepressants do not hasten time to recovery relative to treatment with mood stabilizers alone, and treatment with antidepressants may lead to greater manic symptom severity. These findings are consistent with those from the STEP-BD randomized trial for pure bipolar depression, in which adjunctive antidepressants did not yield higher recovery rates than did mood stabilizer monotherapy.

10 Reads
  • Source
    • "Accurately identifying mixed depression is essential for successful treatment; the first randomized clinical trial (RCT) of MxD showed a significant benefit with ziprasidone vs. placebo after six weeks of treatment (Patkar et al., 2012). These RCT findings confirmed the clinical impression of many renowned physicians that patients suffering from mixed depression need different treatments compared to those with non-mixed depressive states (Koukopoulos and Koukopoulos, 1999; Akiskal and Mallya, 1987; Prien et al., 1988; Koukopoulos et al., 1992; Akiskal and Pinto, 1999; Akiskal et al., 2005a, 2005b; Krüger et al., 2005; Goldberg et al., 2007). Strengths of this study include a large sample size, careful clinical evaluation, generalizability to multiple clinical sites across different countries and cultures, and assessment of explicit diagnostic criteria for MxD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Mixed depression (MxD) is one subtype of depressive experiences within the depressive spectrum. MxD definition is debated among experts. Koukopoulos' proposed diagnostic criteria focused primarily on psychic agitation, marked irritability, and intense mood lability as markers of a mixed depressive episode. The present study validates Koukopoulos' criteria as diagnostic for MxD. Methods A sample of 435 patients from the International Mood Network (IMN), multi-center, international network of sites, and the Centro LucioBini of Rome was analyzed. Koukopoulos' criteria were assessed in all patients. Results The most prevalent MxD criteria were "absence of psychomotor retardation" (84%), "mood lability or marked reactivity" (78%), and "psychic agitation or inner tension" (75%). Multivariable predictors of a MxD (+) diagnosis were: higher current CGI (OR=1.23, 95% CI 1.23, 2.84), lower rates of previous bipolar type I diagnosis (OR=0.54, 95% CI-3.28,-0.13), mixed symptoms on the index episode (OR=10.02, 95% CI 2.32, 24.12), rapid cycling course (OR=2.6 95% CI 1.45, 3.56), past substance abuse (OR=3.02, 95% CI 2.01, 5.67) and lower education status (OR=0.44, 95% CI-3.23,-0.98). This model showed a sensitivity of 76.4%, specificity of 86.3%, negative predictive value of 75%, and positive predictive value of 86%. Limitations An external validation of these criteria in an independent sample is warranted. Conclusion A broad definition of mixed depression was internally validated with multiple diagnostic validators and was sensitively and specifically predicted. Contrary to DSM-5, Koukopoulos' broad criteria include agitation, irritability and mood lability as core features.
    Journal of Affective Disorders 08/2014; 164C:14-18. DOI:10.1016/j.jad.2014.03.054 · 3.38 Impact Factor
  • Source
    • "Au niveau pronostique, ces EDM mixtes sont associés à des troubles de l'humeur à début plus précoce [21], à évolution plus sévère et à cycle plus rapide [15] [16] [19] et augmentent le risque suicidaire [15] et d'impulsivité [22]. Sur le plan pharmacologique ces EDM mixtes présentent un facteur de mauvais pronostic pour la réponse aux antidépresseurs qui peuvent aggraver la symptomatologie [3] [23]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epidemiological studies of major depressive episodes (MDE) highlighted the frequent association of symptoms or signs of mania or hypomania with depressive syndrome. Beyond the strict definition of DSM-IV, epidemiological recognition of a subset of MDE characterized by the presence of symptoms or signs of the opposite polarity is clinically important because it is associated with pejorative prognosis and therapeutic response compared to the subgroup of "typical MDE". The development of DSM-5 took into account the epidemiological data. DSM-5 opted for a more dimensional perspective in implementing the concept of "mixed features" from an "episode" to a "specification" of mood disorder. As outlined in the DSM-5: "Mixed features associated with a major depressive episode have been found to be a significant risk factor for the development of bipolar I and II disorder. As a result, it is clinically useful to note the presence of this specifier for treatment planning and monitoring of response to therapeutic". However, the mixed features are sometimes difficult to identify, and neurophysiological biomarkers would be useful to make a more specific diagnosis. Two neurophysiological models make it possible to better understand MDE with mixed features : i) the emotional regulation model that highlights a tendency to hyper-reactive and unstable emotion response, and ii) the vigilance regulation model that highlights, through EEG recording, a tendency to unstable vigilance. Further research is required to better understand relationships between these two models. These models provide the opportunity of a neurophysiological framework to better understand the mixed features associated with MDE and to identify potential neurophysiological biomarkers to guide therapeutic strategies.
    L Encéphale 12/2013; 39 Suppl 3:149-56. · 0.70 Impact Factor
  • Source
    • "In this regard, the results of the present study support the use of lamotrigine as a mood stabilizer, as it appears to make a significant difference and is more commonly used in the sub-threshold mixed state than in the pure depressive state. Antidepressants have limited efficacy and can potentially harm patients with a bipolar mixed state (Goldberg et al., 2007; Rybakowski, 2012). These findings are similar to the data in the present study showing a trend toward less frequent antidepressant use for the depressive mixed state than the pure depressive state. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We compared the time to achieve remission and the clinical characteristics of patients with bipolar depressive mixed state and those with bipolar depressive non-mixed state. The subjects (N=131) were inpatients diagnosed between 2006 and 2012 with bipolar I or II disorder, depression and were classified into the following three groups: "pure depressive state" (PD, n=70), "sub-threshold mixed state" (SMX, n=38), and "depressive mixed state" (DMX, n=23). Diagnosis of a DMX was in accordance with Benazzi's definition: three or more manic symptoms in a depressive episode. The subjects' charts were retrospectively reviewed to ascertain the time to achieve remission from the index episode and to identify other factors, such as demographic and clinical characteristics, specific manic symptoms, and pharmacological treatment, that may have contributed to remission. The time to achieve remission was significantly longer in the DMX (p=0.022) and SMX (p=0.035) groups than in the PD group. Adjustment for covariates using a Cox proportional hazards model did not change these results. Clinically, subjects with a DMX were more likely to have manic symptoms in the index episode, especially inflated self-esteem and psychomotor agitation than those in the PD. We investigated only inpatients and therefore could not comment on outpatients. These findings showed that sub-syndromal manic symptoms in bipolar depression had different clinical characteristics and a more severe illness course, including a longer time to achieve remission, than did a pure depressive state.
    Journal of Affective Disorders 10/2013; 152(1). DOI:10.1016/j.jad.2013.09.035 · 3.38 Impact Factor
Show more


10 Reads
Available from