STEP-BD investigators. antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients

Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, 501 East Broadway, MedCenter One, Suite 340, Louisville, Kentucky 40202, United States.
Journal of Affective Disorders (Impact Factor: 3.38). 07/2008; 111(2-3):372-7. DOI: 10.1016/j.jad.2008.03.025
Source: PubMed


It has been proposed that antidepressants can induce a chronic, dysphoric, irritable state in bipolar patients (called ACID for antidepressant-associated chronic irritable dysphoria). This phenomenon has only been described in case series format, and has not been prospectively validated.
Prospective data from the first 1500 patients (62.7% with bipolar I, 30.1% with bipolar II, and 7.2% with NOS) treated in the STEP-BD database were examined and those who were euthymic for at least one month at study entry, subsequently developed a depressive episode, and were then followed for one year were identified. Outcome of those who received an antidepressant for this depressive episode (n=27) was compared to those who did not (n=56), with particular attention given to the presence of the proposed symptom triad of ACID, namely dysphoria, irritability, and middle insomnia.
Patients treated with antidepressants were ten times more likely to develop ACID than those who were not (Hazard ratio=9.95, CI=1.103-89.717, P=0.04). However, the hazard ratio dropped to 1.05 (P=0.99) when corrected for significant covariates, notably past antidepressant-related manic switch and sex.
This study does not support the existence of ACID as an independent phenomenon. Rather, ACID appears to be part of a broader spectrum of antidepressant treatment-emergent affective switches.

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    • "In the STEP-BD study, approximately 15% of bipolar patients receiving long-term treatment with antidepressants developed a chronic irritable dysphoric state (ACID syndrome). The study indicated that the risk of developing ACID symptoms was linked to a previous history of antidepressant-induced affective switch, and to female gender [67]. Finally, the use of antidepressants may significantly increase the risk of suicidal ideation [68]. "
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    ABSTRACT: Many new approaches have been adopted for the treatment of bipolar disorder (BD) in the past few years, which strived to produce more positive outcomes. To enhance the quality of care, several guideline recommendations have been developed. For study purposes, we monitored the prescription of psychotropic drugs administered to bipolar patients who had been referred to tertiary care services, and assessed the degree to which treatment met specific guidelines. Between December 2006 and February 2009, we assessed 113 individuals suffering from BD who had been referred to the Royal Ottawa Mental Health Centre (ROMHC) Mood Disorders Program by physicians within the community, mostly general practitioners. The Structured Clinical Interview for DSM-IV-TR was used to assess diagnosis. The prescribed treatment was compared with specific Canadian guidelines (CANMAT, 2009). Univariate analyses and logistic regression were used to assess the contribution of demographic and clinical factors for concordance of treatment with guidelines. Thirty-two subjects had BD type I (BD-I), and 81 subjects had BD type II (BD-II). All subjects with BD-I, and 90% of the BD-II group were given at least one psychotropic treatment. Lithium was more often prescribed for subjects with BD-I (62%) than those with BD-II (19%). Antidepressants were the most frequently prescribed class of psychotropics. Sixty-eight percent of subjects received treatment concordant with guidelines by medication and dose. The presence of a current hypomanic episode was independently associated with poorer concordance to guidelines. In more than half the cases, the inappropriate use of antidepressants was at the origin of the non concordance of treatment with respect to guidelines. Absence of psychotropic treatment in bipolar II patients and inadequate dosage of mood stabilizers were the two other main causes of non concordance with guidelines. The factors related to treatment not concordant with guidelines should be further explored to determine appropriate strategies in implementing the use of guidelines in clinical practice.
    Full-text · Article · Aug 2013 · BMC Psychiatry
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    • "For example, elements of activation—anxiety, inner tension, psychomotor hyperactivity—during a depressive episode (i.e., a mixed depressive state) may hamper treatment response and lead to treatment resistance, thus negatively affecting outcome (Goldberg et al., 2007; Rihmer and Gonda, 2011; Rybakowski, 2012). Furthermore, antidepressant use in such states may even worsen depression (Goldberg et al., 2007; El-Mallakh et al., 2008; Koukopoulos et al., 2007), or increase suicidality (Pacchiarotti et al., 2011; Valentí et al., 2011; Balá zs et al., 2006; Goldberg et al., 2009; Algorta et al., 2011). Similarly, the presence of depressive features during a manic episode may lead to poor responses to lithium (Swann et al., 1997), or may increase the risk of antipsychotic-induced post-manic depression (Zarate et al., 2001; Vieta, 2005b). "
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    ABSTRACT: Objective: The nature of mixed mood episodes is still a matter of controversy amongst experts. Currently, the approach to this syndrome is mainly categorical and very restrictive. The factor-structure of bipolar mood episodes has not been studied yet. We performed a dimensional analysis of the structure of bipolar episodes aimed at identifying a factor deconstructing mixed episodes; furthermore, we analyzed correlations of factors emerging from the factorial analysis of the Brief Psychiatric Rating Scale (BPRS) with Temperament Evaluation of Memphis-Pisa-Paris-San Diego (TEMPS-A) and predominant polarity. Method: 187 consecutive bipolar I inpatients hospitalized for DSM-IV-TR acute mood episodes (depressive, manic or mixed) underwent a standardized assessment, including the 24-item Brief Psychiatric Rating Scale (BPRS 4.0), the 21-item Hamilton Depression Rating Scale (HDRS-21), the Young Mania Rating Scale (YMRS) and the TEMPS-A. Principal factor analysis was performed on BPRS-24 items. Results: This analysis revealed five factors corresponding to "psychosis", "euphoric mania", "mixity", "dysphoria" and "inhibited depression", capturing 71.89% of the rotated variance. The mixity factor was characterized by higher rates of suicidal ideation, more mixed episodes, higher frequencies of antidepressant (AD) use, depressive predominant polarity and anxious temperament. Discussion: The factor-structure of the BPRS in inpatients with bipolar I disorder with an acute episode of any type is pentafactorial; one factor identified is the mixity factor, which is independent from other factors and characterized by anxiety and motor hyperactivity and by the absence of motor retardation. Our results should prompt reconsideration of proposals for DSM-5 diagnostic criteria for the mixed features specifier. Limitations of the study include the relative small sample, the absence of drug-naïve patients and the use of rating scales no specific for mixed states.
    Full-text · Article · Feb 2013 · Journal of Affective Disorders
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    • "Recently, data from the first 1500 subjects treated in the STEP-BD (Goldberg et al., 2007) study confirmed patients taking antidepressant medications being 10 times more likely to develop ACID than those not taking antidepressant drugs (HR; 9.95, 95% CI = 1.10–89.72) (El-Mallakh et al., 2008). El-Mallakh et al. (2011) have hypothesized that since multiple AD exposures have been related to the incidence of this symptoms, the ACID syndrome may be better explained as a part of a broader spectrum of antidepressant treatment emergent affective switches. "
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    ABSTRACT: There is increasing awareness that, in some cases, long-term use of antidepressant drugs (AD) may enhance the biochemical vulnerability to depression and worsen its long-term outcome and symptomatic expression, decreasing both the likelihood of subsequent response to pharmacological treatment and the duration of symptom-free periods. A review of literature suggesting potential side effects during long treatment with antidepressant drugs was performed. Studies were identified electronically using the following databases: Medline, Cinahl, PsychInfo, Web of Science and the Cochrane Library. Each database was searched from its inception date to April 2010 using "tolerance", "withdrawal", "sensitization", "antidepressants" and "switching" as key words. Further, a manual search of the psychiatric literature has been performed looking for articles pointing to paradoxical effects of antidepressant medications. Clinical evidence has been found indicating that even though antidepressant drugs are effective in treating depressive episodes, they are less efficacious in recurrent depression and in preventing relapse. In some cases, antidepressants have been described inducing adverse events such as withdrawal symptoms at discontinuation, onset of tolerance and resistance phenomena and switch and cycle acceleration in bipolar patients. Unfavorable long-term outcomes and paradoxical effects (depression inducing and symptomatic worsening) have also been reported. All these phenomena may be explained on the basis of the oppositional model of tolerance. Continued drug treatment may recruit processes that oppose the initial acute effect of a drug. When drug treatment ends, these processes may operate unopposed, at least for some time and increase vulnerability to relapse. Antidepressant drugs are crucial in the treatment of major depressive episodes. However, appraisal and testing of the oppositional model of tolerance may yield important insights as to long-term treatment and achievement of enduring effects.
    Full-text · Article · Aug 2011 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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