DISCUSSION
bipolar I depression, manic, bipolar disorders, sleep disturbance, and reduced sleep, hypomanic, YMRS, bipolar disorder, depressive, bipolar depression, Sleep disturbance, MDD, irritability, DSM-5
DISORDER, REMISSION
We investigated “bridge” symptoms (overlapping symptoms that have cross-sectional and predictive associations with depressive and manic symptom clusters) using a network approach in children and adolescents with bipolar I depression based on a placebo-controlled, double-blind study of flexibly-dosed lurasidone 20-80 mg/d followed by a 2-year, open-label extension study of lurasidone treatment [Decreased need for sleep and irritability (“bridge”) symptoms are typically reported as common and disruptive in pediatric bipolar depression [Youth who had difficulty with sleep and decreased need for sleep had higher YMRS and CDRS-R total scores at baseline and at week-6 endpoints. The subgroup with irritability symptoms (both CDRS-R item 8 > 2 and YMRS item 5 > 0) had higher severity of depressive and manic symptoms at baseline and week-6 endpoints. These findings indicated that sleep disturbance and irritability (“bridge symptoms”) had robust and replicable associations with depressive and manic symptom clusters (Graphical Abstract).The predictive associations for the effects of “bridge” symptoms on the depressive and manic symptom clusters were demonstrated by a significant moderating effect of decreased need for sleep or decreased need for sleep combined with irritability (absent For participants who had no symptoms of decreased need for sleep and irritability at extension study baseline, low CDRS-R and high CGAS scores were maintained during lurasidone treatment over a 2-year follow-up period. Among youth with decreased need for sleep and/or irritability at extension study baseline, continued improvement in these symptoms, as well as overall CDRS-R and CGAS scores were observed over the 2-year, open-label study period.In youth treated with lurasidone during the acute and long-term treatment phases, resolution of “decreased need for sleep” (YMRS item 4 = 0 absent) and “irritability” (YMRS item 5 = 0 absent) symptoms at the week 6 endpoint predicted higher remission rates (CDRS-R total score ≤ 28).Significantly more participants without symptoms of decreased need for sleep and irritability at the end of the 6-week acute treatment period achieved sustained recovery criteria [Patients with persistent sleep and irritability symptoms at the extension study baseline showed lower rates of remission and functional recovery in the long-term extension study period. Further prospective studies should examine whether treatments to specifically ameliorate sleep disturbance and irritability symptoms could improve the speed and magnitude of overall symptom improvement in youth with bipolar depression.Collectively, these findings indicate that sleep disturbance and irritability (“bridge”) symptoms at study baseline were causally linked with changes in depressive and manic symptoms at study endpoint. Our findings are consistent with the existing body of evidence that sleep disturbance plays a central role in bipolar disorders and may be functioning as a causal factor in the progression of the disorder [Our work [Sleep disturbance often manifests itself as decreased need for sleep in participants with manic or hypomanic symptoms. Under the sleep-wake homeostasis process, increased periods of wakefulness result in an increased need for sleep. Thus, the co-occurrence of decreased need for sleep and reduced sleep may indicate a mismatched sleep-wake cycle in bipolar disorder [Results from the current study in children and adolescents with bipolar I depression are consistent with a prior study examining “bridge” symptoms that connected manic (11 YMRS items) and depressive (10 MADRS items) symptom clusters in adult participants with MDD presenting with two or three manic symptoms (DSM-5 mixed features specifier) [Both sleep disturbance and irritability were robustly linked to depressive and manic symptom clusters before and after randomized treatment. We show that replicable network association structures based on “bridge” symptoms may be useful for making causal inferences about their effects on short and long-term treatment outcomes. These findings are consistent with the “bridge” symptoms that linked decreased need for sleep and reduced sleep in adult participants with MDD presenting with mixed (subthreshold hypomanic) features [