A Pilot Study of Antidepressant-Induced Mania in Pediatric Bipolar Disorder: Characteristics, Risk Factors, and the Serotonin Transporter Gene

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305-5540, USA.
Biological Psychiatry (Impact Factor: 10.26). 12/2006; 60(9):1005-12. DOI: 10.1016/j.biopsych.2006.06.010
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Antidepressant-induced mania (AIM) has been described in bipolar disorder (BD) and has been associated with the short-allele of the serotonin transporter gene (5-HTT). We wished to investigate the frequency of and risk factors for AIM in pediatric patients with or at high risk for BD.
Fifty-two children and adolescents (30 with BD and 22 with subthreshold manic symptoms, 15.1 +/- 3.4 years old), all with a parent with BD, were interviewed with their parents for manic/depressive symptoms occurring before and after past antidepressant treatment. The 47 subjects with serotonin reuptake inhibitor (SSRI) exposure were genotyped for the 5-HTT polymorphism.
Fifty percent of subjects were AIM+ and 25.5% had new onset of suicidal ideation. The AIM+ and AIM- groups did not differ significantly in relation to allele (p = .36) or genotype (p = .53) frequencies of the 5-HTT polymorphism. The AIM+ subjects were more likely to have more comorbidities (3.2 vs. 2.4; p = .02) and be BD type I (p = .04) than AIM- subjects.
Youth with or at high risk for BD may be particularly vulnerable to SSRI AIM and thus should be monitored if given SSRIs. In this preliminary study, we did not find that the 5-HTT polymorphism significantly influenced vulnerability to AIM.

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    • "Most definitions of antidepressant-induced mood-switching have focused on the time between antidepressant initiation and the development of moodswitching . Although 8 weeks (Altshuler et al., 1995; Goldberg and Truman, 2003; Joffe et al., 2002), intermediate to other definitions of 4 weeks (Serretti et al., 2004) or 12 weeks (Baumer et al., 2006; Goldberg and Whiteside, 2002; Manwani et al., 2006), has been the most common period of time, recent studies have expanded the definition of antidepressant-induced mood-switching to any mood-switching occurring during antidepressant treatment Fig. 2. Kaplan–Meier survival curve for days to incidence of mood-switching plotted by agitated feature. During the follow-up period, mood-switching occurred in 15 (20.3%) of the 74 agitated patients and eight (7.0%) of the 115 non-agitated patients. "
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    ABSTRACT: Background The relationship between psychomotor agitation in unipolar depression and mood-switching from depression to manic, hypomanic and mixed states has been controversial. We investigated the future risk of initial mood-switching as a function of psychomotor agitation in unipolar depression. Methods We identified 189 participants diagnosed with major depressive disorder (MDD). We divided all patients with MDD into two categories (1) agitated patients (n=74), and (2) non-agitated patients (n=115). These groups were prospectively followed and compared by time to mood-switching. Kaplan–Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazard ratio estimates for a multivariate model were conducted to examine the risk of mood-switching by psychomotor agitation. Results During follow-up, mood-switching occurred in 20.3% of the agitated patients and 7.0% of the non-agitated patients. In the Kaplan–Meier survival estimates for time to incidence of mood-switching with agitated or non-agitated patients, the cumulative probability of developing mood-switching for agitated patients was higher than those for non-agitated patients (log-rank test: χ2=7.148, df=1, p=0.008). Survival analysis was also performed using Cox proportional hazards regression within a multivariate model. The agitation remained significantly associated with incidence of mood-switching (HR=2.98, 95% CI: 1.18–7.51). Limitations We did not make a clear distinction between antidepressant-induced mood-switching and spontaneous switching. Conclusions The main finding demonstrated that MDD patients with agitation were nearly threefold as likely to experience mood-switching, suggesting that psychomotor agitation in MDD may be related to an indicator of bipolarity.
    Journal of Affective Disorders 01/2015; 170:185–189. DOI:10.1016/j.jad.2014.09.001 · 3.38 Impact Factor
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    • "Adolescents who have not manifested the manic component of a bipolar disorder may be particularly vulnerable to SSRI antidepressant-induced mania or hypomania (Frye et al., 2009). Although preliminary studies showed conflicting results regarding the association between 5-HTTLPR polymorphism and antidepressant-induced mania (Mundo et al., 2001; Rousseva et al., 2003; Serretti et al., 2004; Baumer et al., 2006; Masoliver et al., 2006; Ferreira Ade et al., 2009), a recent meta-analysis indicated a higher incidence of antidepressant-induced mania in patients with the “s” variant of 5-HTTLPR (Daray et al., 2010). Likelihood of SSRI monotherapy response is deemed low once failure of the “SSRI challenge” test has been observed in this category. "
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    ABSTRACT: First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are less than 50%. The authors examine the putative biological substrates underlying “Treatment Refractory Depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin (5-HT) system becomes impervious to the desired enhancement of 5-HT neurotransmission by SSRI’s. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple 5-HT deficit state but rather an excess of midbrain peri-raphe 5-HT and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in 5-HT-mediated neuroplasticity. Glutamate, 5-HT, noradrenaline and histamine are activated by stress and exert an inhibitory effect on 5-HT outflow, in part by “flooding” 5-HT1A autoreceptors by 5-HT itself. Certain factors putatively exacerbate this scenario- presence of the short arm of the serotonin transporter gene, early life adversity and comorbid bipolar disorder- each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing 5-HT neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on 5-HT neurons. Future studies are recommended to test this biologically based approach for TRD.
    Frontiers in Behavioral Neuroscience 05/2014; 8:189. DOI:10.3389/fnbeh.2014.00189 · 3.27 Impact Factor
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    • "Nonetheless, some medications (i.e., antidepressants) should be monitored closely. Although many suggested that antidepressant-induced bipolar symptoms may occur uncommonly (e.g., [140, 141]), some children and adolescents may be susceptible to such symptoms [142]. "
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    ABSTRACT: Although bipolar disorder historically was thought to only occur rarely in children and adolescents, there has been a significant increase in children and adolescents who are receiving this diagnosis more recently (Carlson, 2005). Nonetheless, the applicability of the current bipolar disorder diagnostic criteria for children, particularly preschool children, remains unclear, even though much work has been focused on this area. As a result, more work needs to be done to further the understanding of bipolar symptoms in children. It is hoped that this paper can assist psychologists and other health service providers in gleaning a snapshot of the literature in this area so that they can gain an understanding of the diagnostic criteria and other behaviors that may be relevant and be informed about potential approaches for assessment and treatment with children who meet bipolar disorder criteria. First, the history of bipolar symptoms and current diagnostic criteria will be discussed. Next, assessment strategies that may prove helpful for identifying bipolar disorder will be discussed. Then, treatments that may have relevance to children and their families will be discussed. Finally, conclusions regarding work with children who may have a bipolar disorder diagnosis will be offered.
    02/2014; 2014(4):928685. DOI:10.1155/2014/928685
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