Safety and Effectiveness of Antidepressants in Medicaid-Enrolled Pediatric Bipolar Depression

Pediatric bipolar disorder (I and II) patients suffer from recurrent episodes of depression and mania or hypomania (American Psychiatric Association, 1994), or mixed episodes with rapid cycling (Findling et al., 2001; Geller et al., 2002). Worldwide prevalence of bipolar disorder was 5% (Tondo et al., 2003), and in the USA was 2.6% in adults and 0-3% in adolescents (Bipolar Disorder). Early-onset bipolar disorder in childhood was associated with a higher number of lifetime episodes of manic and depressive phases, more comorbidities such as anxiety and substance abuse, rapid cycling between different phases, and higher incidence of suicide attempts compared to adulthood onset of bipolar disorder (Potter et al., 2009; Leverich et al., 2007; Perlis et al., 2004). Lifetime prevalence of the depressive phase among bipolar disorder patients is 3-fold higher than the mania phase (Post et al., 2003). Untreated bipolar depression among all the phases of bipolar disorder, particularly in children and adolescents, is associated with a high risk of suicidality (Tondo et al., 1998), substance abuse, functional disability, and poor academic and social performance among children and adolescents (Baldessarini et al., 2008; Angst et al., 2002; Frye et al., 2006; Thase, 2006; Dutta et al., 2007; Huxley and Baldessarini, 2007; Tondo and Baldessarini, 2007). Despite a higher prevalence of the depressive phase and associated risk of morbidity and mortality among bipolar disorder patients, research on the bipolar depressive phase is limited (Bhangoo et al., 2003). Although medication regimens includingmood stabilizers, antidepressants, and antipsychotics for treating bipolar depression in adults is well established (Lin et al., 2006), similar treatment guidelines for bipolar depression in younger populations are unavailable. Efficacy of different classes of medications in treating pediatric bipolar depression has been examined in several randomized trials or observational studies and documented (Kowatch et al., 2005), but psychiatric practice for children and adolescents in this regard is mostly extrapolated from adult guideline, expert consensus, or clinicians’ experience. Accordingly, mood stabilizers and second-generation antipsychotics (SGA) are considered to be the 1st line therapy for pediatric bipolar depression, while antidepressants selective serotonin reuptake inhibitors (SSRI) and bupropion are recommended only as adjunct therapy when 1st line treatment is ineffective (Kowatch et al., 2005). However, the utilization pattern of medications in treating bipolar depression in pediatric population is mostly unexplored. Subsequently, real-world safety and effectiveness of psychotropic medications in pediatric bipolar depression is also limited. Controversy prevails over the safety of using antidepressants in bipolar depression patients due to the concerns about possible manic or hypomanic switching, rapid cycling, and long-term mood destabilization. Although a potential risk of mood destabilization with the use of antidepressants has been suggested historically, critical evaluation of those clinical trials suggested presence of bias and a lack of control groups to accurately address the issue. Quantitative real-world data on comparative safety of antidepressants, antipsychotics, and mood stabilizers, in terms of risk of short-term manic switch among pediatric bipolar depression patients, is limited as well. Effectiveness of psychotropic pharmacotherapy in bipolar disorder is examined for outcomes such as response, remission, recovery, and relapse of the depressive phase. Such outcomes are measured using mania and depression rating scales, such as Young’s mania rating scale, Montgomery-Asberg depression rating scale, etc. Unavailability of such severity scales in administrative data hinders direct assessment of comparative effectiveness of psychotropic medications in real-world patients. Overall, numerical data on comparative effectiveness of antidepressants, antipsychotics, and mood stabilizers in pediatric bipolar depression is limited. Considering the prevalence of bipolar depression among children and adolescents and the associated risk of morbidity and mortality, and paucity of knowledge regarding drug utilization pattern, and comparative safety and effectiveness of antidepressant pharmacotherapy in this patient population, the specific aims of this study will be- Aim I: To assess adherence to psycho-pharmacotherapeutic regimens during 6 months after the initial bipolar depression diagnosis among Medicaid-enrolled children and adolescents, in terms of- (1) Continuation of antidepressant monotherapy, antipsychotic monotherapy, mood stabilizer monotherapy, antidepressant polytherapy (with antipsychotic or mood stabilizer), antipsychotic-mood stabilizer polytherapy, and 3-class polytherapy regimens during 6 months after initial bipolar depression diagnosis, (2) Augmentation pattern with a new class of medications among antidepressant, antipsychotic, and mood stabilizer monotherapy; and antidepressant, and antipsychotic-mood stabilizer polytherapy regimens during the 6 months of follow up after initial bipolar depression diagnosis, (3) Switch from initial treatment regimen including antidepressant, antipsychotic, and mood stabilizer monotherapy; and antidepressant, antipsychotic-mood stabilizer, and 3-class polytherapy to regimens inclusive of other therapeutic classes, during the 6 months of follow up after initial bipolar depression diagnosis, (4) All medication class discontinuation patterns in antidepressant, antipsychotic, and mood stabilizer monotherapy; and antidepressant, antipsychotic-mood stabilizer, and 3-class polytherapy regimens, during 6 the months of follow up after initial bipolar depression diagnosis. Aim II: To examine the risk of manic switch with the use of antidepressant in Medicaid-enrolled pediatric bipolar depression patients – (1) To assess comparative safety of antidepressant monotherapy against antipsychotic monotherapy, in terms of risk of manic switch in pediatric bipolar depression population, (2) To assess comparative safety of antidepressant monotherapy against mood stabilizer monotherapy, in terms of risk of manic switch in pediatric bipolar depression population, (3) To assess comparative safety of antidepressant polytherapy against antipsychotic-mood stabilizer polytherapy, in terms of risk of manic switch in pediatric bipolar depression population. Aim III: To evaluate the effectiveness of antidepressant pharmacotherapy among Medicaid enrolled children and adolescents with bipolar depression - (1) To assess risk of treatment augmentation in pediatric bipolar depression patients, comparing (i) Antidepressant monotherapy vs. antipsychotic monotherapy, (ii) Antidepressant monotherapy vs. mood stabilizer monotherapy, (iii) Antidepressant polytherapy vs. antipsychotic-mood stabilizer polytherapy. (2) To assess risk of mental-health related hospitalization in pediatric bipolar depression patients, comparing (i) Antidepressant monotherapy vs. antipsychotic monotherapy, (ii) Antidepressant monotherapy vs. mood stabilizer monotherapy, (iii) Antidepressant polytehrapy vs. antipsychotic-mood stabilizer polytherapy