Lurasidone adjunctive with lithium or valproate for bipolar depression: A placebo-controlled trial utilizing prospective and retrospective enrolment cohorts

In this study, designed to evaluate the efficacy of lurasidone as adjunctive therapy with lithium or valproate, patients with bipolar I depression were randomized to 6 weeks of double-blind treatment with lurasidone (N = 180) or placebo (N = 176), added to background treatment with lithium or valproate. All patients were treated with lithium or valproate for a minimum of 4 weeks prior to screening. This was confirmed either by prospective treatment after study enrolment (run-in cohort), or retrospectively, with blood levels of lithium and valproate at screening (non-run-in cohort). Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP-S), respectively. Treatment with lurasidone was associated with non-significant improvement at week 6 vs. placebo for the MADRS total score (−11.8 vs −10.4; P = 0.176), and the CGI-BP-S score (−1.36 vs −1.13; P = 0.095). Significant separation from placebo was observed from weeks 2–5 for the MADRS and weeks 3–5 for the CGI-BP-S. Improvement in the placebo-subtracted MADRS total score was notably larger at week 6 for the non-run-in cohort compared to the run-in cohort (LS mean difference in endpoint change scores, −4.6; P = 0.009). Adverse events most frequently reported for lurasidone were akathisia, somnolence, and extrapyramidal side effects. In conclusion, lurasidone adjunctive with lithium or valproate demonstrated significant improvement in depressive symptoms based on the MADRS from weeks 2–5 but not at the primary week 6 endpoint.     

Effects of adjunctive inflammatory modulation on IL-1β in treatment resistant bipolar depression

BackgroundAdjunctive inflammatory modulation improved remission rates in treatment-resistant bipolar depression (TRBDD), but reliable biomarkers must be established to characterize the biosignature of TRBDD and the mechanisms underlying treatment response. In this molecular profiling study, we describe TRBDD and treatment response from the standpoint of interleukin-1 Beta (IL-1β) and KYN/TRP.Methods47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg–40 mg daily dose range) + celecoxib (CBX) (200 mg twice daily), or ESC (10 mg–40 mg daily dose range) + placebo (PBO) (twice daily). Plasma cytokine levels were measured in both treatment arms at baseline and week 8, and in a healthy control (HC) group of subjects (N = 43) once. A linear mixed model (LMM) was applied to evaluate whether clinical outcome is related to CBX and changes to biomarkers throughout treatment. A binary logistic regression model was formulated from this series to predict both the primary outcome of treatment response to CBX, and the secondary outcome of diagnosis of TRBDD using age, BMI, gender, and IL-1β at baseline.ResultsPatients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT = 3, and 15.300 times more likely to remit (p < 0.001) with NNT = 2, compared with ESC + PBO patients. Patient BMI (p = 0.003), baseline IL-1β (p = 0.004), and baseline KYN/TRP (p = 0.001) were most predictive of TRBDD diagnosis. By Week 8, responders showed a downtrend in IL-1β compared to non-responders in the ESC + CBX treatment arm. However, there was no statistical difference in the IL-1β or KYN/TRP change after treatment between placebo and ESC + CBX group responders/non-responders (p = 0.239, and p = 0.146, respectively). While baseline IL-1β was elevated in TRBDD compared to HC (p < 0.001), there was no difference in IL-1β between treatment responders at Week 8 compared to HC (p = 0.067).ConclusionsElevated IL-1β and low KYN/TRP at baseline are components of the TRBDD molecular signature. CBX but not baseline IL-1β or KYN/TRP predict treatment response. Change in IL-1β and KYN/TRP did not predict treatment response.     

Predicting placebo response in adolescents with major depressive disorder: The Adolescent Placebo Impact Composite Score (APICS)

ObjectiveThe aim of this study was to construct a composite scoring system to predict the probability of placebo response in adolescents with Major Depressive Disorder (MDD).MethodParticipants of the current study were 151 adolescents (aged 12–17 years) who were randomized to the placebo arm (placebo transdermal patches) of a randomized controlled trial (RCT) comparing the selegiline transdermal patch with placebo (DelBello et al., 2014). The primary outcome of response was defined as a CGI-I score of 1 or 2 (very much or much improved) at week 12 (study-end) or exit. As a first step, a multiple logistic mixed model was used to estimate the odds of placebo response from each predictor in the model, including age, CDRS-R total at baseline (depressive symptom severity), history of recurrent depression (yes vs. no), sex (female vs. male), and race (non-Caucasian vs. Caucasian). On the basis of the initial logistic mixed model analysis, we then constructed an Adolescent Placebo Impact Composite Score (APICS) that became the sole predictor in a re-specified Bayesian logistic regression model to estimate the probability of placebo response. Finally, the AUC for the APICS was tested against a nominal area of 0.50 to evaluate how well the APICS discriminated placebo response status.ResultsAmong the 151 adolescents, with a mean age of 14.6 years (SD = 1.6) and a mean baseline CDRS-R total of 60.6 (SD = 12.1), 68.2% were females, 50.3% was Caucasian, and 39.7% had a history of recurrent depression. Placebo response rate was 58.3%. Based on the logistic mixed model, the re-specified equation with the highest discriminatory ability to estimate the probability of placebo response was APICS = age + (0.32 × CDRS-R Total at baseline) + (−2.85 × if female) + (−5.50 × if history of recurrent depression) + (−5.85 × if non-Caucasian). The AUC for this model was 0.59 (p = .049). Within a Bayesian decision-theoretic framework, in 95.5% of the time, the 10,000 posterior Monte Carlo samples suggested that as APICS decreased the probability of placebo response increased. The observed APICS and related probability of responding to placebo in this adolescent sample ranged from 14.1 = 74.1% (in placebo responders) to 39.1 = 41.8% (in placebo non-responders).ConclusionThe APICS model estimates the probability of placebo response in adolescents with MDD with a modest degree of accuracy (AUC = 0.59) and with a reasonable degree of positive predictive value (74.5%), and is based on five previously identified patient characteristics of placebo response from prior meta-analytic studies (Bridge et al., 2009; Cohen et al., 2010) of randomized placebo-controlled trials of antidepressants in youth with MDD. Calculation of the APICS should be restricted to the range of the adolescent ages (12–17 years) and CDRS-R total scores (17–113); thus, the APICS can assume possible calculated values and related probability of responding to placebo ranging from about 3 (84%) to 53 (25%). The APICS Bayesian logistic model, based on a given aggregate patient profile, has a range of predicted probabilities of placebo response that is fairly wide, albeit truncated, but potentially meaningful for predicting the probability of placebo response among adolescent youth with MDD. The ability of the APICS to objectify the probability of placebo response in adolescents with MDD could be accounted for in the clinical research design of the trial itself and perhaps aid clinicians in treatment strategy for youth who are more likely to experience placebo response.     

Adjunctive lumateperone (ITI-007) in the treatment of bipolar depression: Results from a randomized placebo-controlled clinical trial

Objective

This phase 3, randomized, double-blind, placebo-controlled study (NCT02600507) evaluated the efficacy and safety of lumateperone adjunctive therapy to lithium or valproate in patients with bipolar depression.

Methods

Patients (18–75 years) with bipolar I or bipolar II disorder experiencing a major depressive episode (MDE), with inadequate therapeutic response to lithium or valproate, were randomized 1:1:1 to 6 weeks adjunctive therapy with lumateperone 28 mg (n = 176), lumateperone 42 mg (n = 177), or placebo (n = 176). The primary and key secondary efficacy endpoints were change from baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total score and the Clinical Global Impression Scale-Bipolar Version-Severity Scale (CGI-BP-S) depression subscore. Safety assessments included adverse events, laboratory evaluations, vital signs, extrapyramidal symptoms (EPS), and suicidality.

Results

Patients treated with adjunctive lumateperone 42 mg showed significantly greater improvement compared with adjunctive placebo in MADRS Total score (LS mean difference vs placebo [LSMD], −2.4; p = 0.02) and CGI-BP-S depression subscore (LSMD, −0.3; p = 0.01), while adjunctive lumateperone 28 mg showed numerical improvement in MADRS Total score (LSMD, −1.7; p = 0.10) and improvement in the CGI-BP-S depression subscore (LSMD, −0.3; p = 0.04). Adjunctive lumateperone treatment was well tolerated; treatment-emergent adverse events reported at rates >5% and twice placebo for lumateperone 42 mg were somnolence (11.3%), dizziness (10.7%), and nausea (8.5%), with minimal risk of EPS, metabolic abnormalities, or increased prolactin.

Conclusions

Lumateperone 42-mg treatment adjunctive to lithium or valproate significantly improved depression symptoms and was generally well tolerated in patients with MDEs associated with either bipolar I or bipolar II disorder.     

Open-label lithium for the treatment of adolescents with bipolar depression

OBJECTIVES: To investigate the effectiveness and tolerability of lithium for the treatment of acute depression in adolescents with bipolar disorder. We hypothesized that patients receiving open-label treatment with lithium during a 6-week period would experience a statistically and clinically significant decrease in depressive symptoms and tolerate lithium treatment fairly well. METHOD: Twenty-seven adolescents (12-18 years old) with an episode of depression associated with bipolar disorder type I received open-label lithium 30 mg/kg (twice-daily dosing), which was adjusted to achieve a therapeutic serum level (1.0-1.2 mEq/L). Effectiveness measures included the Children's Depression Rating Scale-Revised (CDRS-R) and Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP). Adverse events were assessed weekly. RESULTS: Mean CDRS-R scores significantly decreased from baseline to endpoint (mean [SD] change = -25.5 (20.4); p < .001), resulting in a large effect size of 1.7. Response and remission rates (defined by a > or = 50% reduction in CDRS-R score from baseline to endpoint, and a CDRS-R score < or = 28 and a CGI-BP Improvement score of 1 or 2, respectively) were 48% and 30%. Side effects, which were generally mild to moderate in severity, included headache (74%), nausea/vomiting (67%), stomachache (30%), and abdominal cramps (19%). CONCLUSIONS: The findings of this study indicate that lithium may be effective and is relatively well tolerated for the treatment of an acute episode of depression in adolescents with bipolar disorder. Controlled studies of lithium in adolescent bipolar depression are needed.     

Vitamin D supplementation in bipolar depression: A double blind placebo controlled trial

ObjectiveBipolar depression is difficult to treat. Vitamin D supplementation is well tolerated and may improve mood via its neurotransmitter synthesis regulation, nerve growth factor enhancement and antioxidant properties. Vitamin D adjunct reduces unipolar depression, but has not been tried in bipolar depression.Methods18-70yos with DSM IV bipolar depression and Vitamin D deficiency (<30 ng/ml) were randomized in a controlled double blind trial of 5000IU Vitamin D₃ po qday supplementation versus placebo for twelve weeks. Change in Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), Young Mania Rating Scale (YMRS), medication, and tolerance were assessed q2weeks.Results16 VitD vs 17 placebo subjects did not differ in baseline characteristics (mean = 44 yo, SD = 13), VitD level (19.2 ± 65.8  g/ml vs 19.3 ± 5.5 ng/ml respectively) or mood ratings (MADRS 21.3 ± 6.4 vs 22.8 ± 6.9 respectively). At 12wks, the placebo group VitD levels remained unchanged, while the VitD group levels increased to 28 ng/ml. MADRS score decreased significantly in both placebo (mean = 6.42 (95% CI [2.28 to 10.56]) and VitD groups (mean = 9.54 (95% CI[3.51 to 15.56]) (p = 0.031), but there were no differences between treatment groups (time by treatment interaction estimate: 0.29, t₍₂₃₎ = 0.14, p = 0.89); VitD and placebo groups had similar reductions in YMRS and HAM-A. Vitamin D₃ was well tolerated.ConclusionsIn this small study, despite a greater rise in Vitamin D levels in the VitD supplementation group, there was no significant difference reduction in depressive symptoms. However both groups’ VitD levels remained deficient. Vitamin D₃ supplementation vs placebo did not improve reduction in mood elevation or anxiety symptoms.     

Comorbid sleep disorders and suicide risk among children and adolescents with bipolar disorder

Children and adolescents with bipolar disorder are at increased risk for suicide. Sleep disturbances are common among youth with bipolar disorder and are also independently implicated in suicide risk; thus, comorbid sleep disorders may amplify suicide risk in this clinical population. This study examined the effects of comorbid sleep disorders on suicide risk among youth with bipolar disorder. We conducted secondary analyses of baseline data from the Treatment of Early Age Mania (TEAM) study, a randomized controlled trial of individuals aged 6–15 years (mean ± SD = 10.2 ± 2.7 years) with DSM-IV bipolar I disorder (N = 379). Sleep disorders (i.e., nightmare, sleep terror, and sleepwalking disorders) and suicide risk were assessed via the WASH-U-KSADS and the CDRS-R, respectively. We constructed uncontrolled logistic regression models as well as models controlling for trauma history, a generalized anxiety disorder (GAD) diagnosis, and depression symptoms. Participants with a current comorbid nightmare disorder versus those without were nearly twice as likely to screen positive for suicide risk in an uncontrolled model and models controlling for trauma history, a GAD diagnosis, and depression symptoms. Neither a current comorbid sleep terror disorder nor a sleepwalking disorder was significantly associated with suicide risk. This pattern of findings remained consistent for both current and lifetime sleep disorder diagnoses. Youth with bipolar I disorder and a comorbid nightmare disorder appear to be at heightened suicide risk. Implications for assessment and treatment are discussed.     

Symptomatic efficacy of rasagiline monotherapy in early Parkinson's disease: Post-hoc analyses from the ADAGIO trial

BackgroundThe ADAGIO study included a large cohort of patients with early PD (baseline total-UPDRS = 20) who were initially randomized to rasagiline and placebo, thereby allowing analyses of symptomatic efficacy.MethodsPost-hoc analyses comparing the efficacy of rasagiline 1 mg/day (n = 288) versus placebo (n = 588) on key symptoms at 36 weeks, and on total-UPDRS scores over 72 weeks (completer population: rasagiline 1 mg/day n = 221, placebo n = 392) were performed.ResultsTreatment with rasagiline resulted in significantly better tremor, bradykinesia, rigidity and postural-instability-gait-difficulty scores at week 36 versus placebo. Whereas the placebo group experienced progressive deterioration from baseline (2.6 UPDRS points at week 36), patients in the rasagiline group were maintained at baseline values at week 60 (UPDRS-change of 0.3 points). At week 72, patients who had received continuous monotherapy with rasagiline experienced a worsening of only 1.6 points.ConclusionsTreatment with rasagiline maintained motor function to baseline values for at least a year with significant benefits observed in all key PD motor symptoms.     

A psychometric evaluation of the CDRS and MADRS in assessing depressive symptoms in children

OBJECTIVE: This study compared the psychometric properties of the Children's Depression Rating Scale-Revised (CDRS-R) and the Montgomery-Asberg Depression Rating Scale (MADRS) in children with major depressive disorder. METHOD: Children (N = 96; ages 8 to 11 years inclusive) with nonpsychotic major depressive disorder were enrolled. Participants were part of a multisite, outpatient, randomized, placebo-controlled, 9-week trial of fluoxetine (10 mg/day for the first week and 20 mg/day thereafter). The CDRS-R and MADRS were completed based on clinician interviews with both parents and children. Classic test theory and item response theory analyses were conducted. RESULTS: The MADRS and CDRS-R total scores were correlated at baseline (r = 0.51) and at study exit (r = 0.85). Cronbach's alpha was .86 (CDRS-R) and .82 (MADRS) at exit. The effect sizes for change from baseline to exit between the fluoxetine and placebo groups were 0.78 (CDRS-R) and 0.61 (MADRS). There was agreement between the CDRS-R and MADRS in the declaration of treatment response (50% improvement from baseline to exit) in 84.2% of children. Test information function favored the CDRS-R. CONCLUSIONS: The CDRS-R showed greater effect size for differentiating drug and placebo and better test information than the MADRS in this study of depressed children.     

Differential effects of venlafaxine in the treatment of major depressive disorder according to baseline severity

In this meta-analysis, we compare the relative efficacy of venlafaxine to selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder classified according to baseline disease severity. Data from 31 double-blind randomised clinical trials comparing venlafaxine and SSRIs (intent-to-treat n = 6,492) were pooled. For this secondary analysis, patients were stratified into groups based on baseline HAM-D₁₇ total score (≥30, <30, ≥25, and <25). Remission rates (HAM-D₁₇ < 8) were analyzed for each subgroup using Fisher’s exact test to compare treatment effects between venlafaxine and SSRIs; last observation carried forward (LOCF) and observed cases (OC) data were analyzed. The number needed to treat (NNT) to benefit was determined for each analysis. Statistically significant remission rate differences, favoring venlafaxine, were seen in LOCF and OC analyses for each subgroup. In patients with baseline HAM-D₁₇ < 25 (n = 3,928) the differences were (LOCF) 7.3 [P < 0.001; NNT = 14] and (OC) 6.2 [P = 0.003; NNT = 16], and in patients with baseline HAM-D₁₇ ≥ 25 (n = 2,564) were (LOCF) 5.7 [P = 0.002; NNT = 17] and (OC) 6.7 [P = 0.009; NNT = 15]. In patients with baseline HAM-D₁₇ < 30 (n = 5,836) the differences were (LOCF) 6.4 [P < 0.001; NNT = 16] and (OC) 5.5 [P = 0.001; NNT = 18], and in patients with baseline HAM-D₁₇ ≥ 30 (n = 656) were (LOCF) 8.9 [P = 0.015; NNT = 11] and (OC) 14.8 [P = 0.003; NNT = 7]. In conclusion, these analyses demonstrate that venlafaxine may be superior to SSRIs in achieving remission in both mild/moderate and severely depressed patients. The greater difference in remission rates among patients with baseline HAM-D₁₇ ≥ 30 suggests a more pronounced clinical benefit that may be achieved with venlafaxine in severely depressed patients.     

Association between posttraumatic stress disorder and inflammation: A twin study

The association of posttraumatic stress disorder (PTSD) with cardiovascular disease risk may be mediated by inflammation. Our objective was to examine the association between PTSD and measures of inflammation and to determine whether these associations are due to shared familial or genetic factors. We measured lifetime history of PTSD using the Structured Clinical Interview for DSM-IV in 238 male middle-aged military veteran twin pairs (476 individuals), selected from the Vietnam Era Twins Registry, who were free of cardiovascular disease at baseline. We assessed inflammation using levels of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), fibrinogen, white blood cells, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 (ICAM-1). Geometric mean levels and percent differences by PTSD were obtained from mixed-model linear regression analyses with adjustment for potential confounders. Within-pair analysis was conducted to adjust for shared family environment and genetics (monozygotic pairs). Overall, 12.4% of participants had a lifetime history of PTSD. Adjusted mean levels of hsCRP and ICAM-1 were significantly higher among those with vs. without PTSD [hsCRP: 1.75 vs. 1.31 mg/l (33% difference); ICAM-1: 319 vs. 293 ng/ml (9% difference)]. Adjustment for depression rendered the association of PTSD with hsCRP non-statistically significant. For IL-6, no consistent association was seen. Within-pair analysis produced associations that were similar in direction for all three markers but lesser in magnitude for hsCRP and IL-6. There was no evidence of interaction by zygosity. Elevated hsCRP and ICAM-1 are associated with PTSD, and these associations may be confounded by shared non-genetic, antecedent familial and environmental factors.     

Improvements in metabolic abnormalities among overweight schizophrenia and bipolar disorder patients

PurposeAs weight-gain and metabolic abnormalities during treatment with psychotropic drugs are of great concern, we evaluated effects of psycho-education and medical monitoring on metabolic changes among severely mentally ill patients.Materials and methodsDuring repeated, systematic psycho-education about general health among 66 consecutive patients diagnosed with DSM-IV-TR schizophrenia (n = 33) or type-I bipolar disorder (n = 33), we evaluated (at intake 1, 2, 3, and 6 months) clinical psychiatric status, treatments and doses, recorded physiological parameters, and assessed attitudes about medication.ResultsAt intake, patients with schizophrenia vs bipolar disorder were receiving 3–7 times more psychotropic medication, with 14% higher initial body-mass index (BMI: 29.1 vs 25.6 kg/m2), 12 times more obesity, and significantly higher serum lipid concentrations. During 6-months follow-up, among bipolar disorder patients, polytherapy and serum lipid concentrations declined more than among schizophrenia patients (e.g., total cholesterol + triglycerides, by 3.21 vs 1.75%/month). BMI remained stable. Declining lipid levels were associated with older age, bipolar disorder, being unemployed, higher antipsychotic doses, and lower initial BPRS scores (all P ≤ 0.001).ConclusionsPsychotropic treatments were more complex, and metabolic measures more abnormal among bipolar disorder than schizophrenia patients. Intensive psycho-education, clinical monitoring, and encouragement of weight-control for six months were associated with improvements in metabolic measures (but not to BMI), and more realistic attitudes about medication.     

Depressive Symptoms and Clinical Status During the Treatment of Adolescent Suicide Attempters (TASA) Study

ObjectiveTo examine the course of depression during the treatment of adolescents with depression who had recently attempted suicide.MethodAdolescents (N = 124), ages 12 to 18 years, with a 90-day history of suicide attempt, a current diagnosis of depressive disorder (96.0% had major depressive disorder), and a Children's Depression Rating Scale-Revised (CDRS-R) score of 36 or higher, entered a 6-month treatment with antidepressant medication, cognitive-behavioral therapy focused on suicide prevention, or their combination (Comb), at five academic sites. Treatment assignment could be either random or chosen by study participants. Intent-to-treat, mixed effects regression models of depression and other relevant ratings were estimated. Improvement and remission rates were computed with the last observation carried forward.ResultsMost patients (n = 104 or 84%) chose treatment assignment, and overall, three fourths (n = 93) received Comb. In Comb, CDRS-R declined from a baseline adjusted mean of 49.6 (SD 12.3) to 38.3 (8.0) at week 12 and to 27.0 (10.1) at week 24 (p < .0001), with a Clinical Global Impression -defined improvement rate of 58.0% at week 12 and 72.2% at week 24 and a remission (CDRS-R ≤28) rate of 32.5% at week 12 and 50.0% at week 24. The CDRS-R and the Scale for Suicidal Ideation scores were correlated at baseline (r= 0.43, p < .0001) and declined in parallel.ConclusionsWhen vigorously treated with a combination of medication and psychotherapy, adolescents with depression who have recently attempted suicide show rates of improvement and remission of depression that seem comparable to those observed in nonsuicidal adolescents with depression.     

Short-term efficacy and safety of lurasidone versus placebo in antipsychotic-naïve versus previously treated adolescents with an acute exacerbation of schizophrenia

BackgroundTo evaluate the efficacy of short-term lurasidone in antipsychotic treatment-naïve (TN) adolescents with schizophrenia versus those treated previously (TP) with antipsychotics.MethodsPatients aged 13–17 with schizophrenia, and a Positive and Negative Symptom Scale (PANSS) score ≥ 70 and < 120, were randomized to 6 weeks of double-blind treatment with lurasidone (40 or 80 mg/day) or placebo. In a post-hoc, pooled-dose analysis, efficacy was evaluated for TN (criteria: never received antipsychotic treatment) versus TP at the time of the study. Treatment response criteria: ≥20% reduction in PANSS total score.ResultsAltogether, 57 TN and 269 TP patients enrolled in the 6-week DB study. Mean endpoint change in PANSS total score was significantly greater for lurasidone versus placebo in both the TN group (−25.0 vs. -14.4; p < 0.02; effect size = 0.75), and in the TP group (−17.3 vs. -10.0; p < 0.001; effect size = 0.45); and responder rates were higher for lurasidone versus placebo in both the TN group 84.6% versus 38.9%; number needed to treat [NNT] = 3 and in the TP group (60% vs. 42%; NNT = 6). Rates of treatment-emergent adverse events, and mean changes in body weight and metabolic parameters were similar for the TN and TP groups.ConclusionsIn a 6-week, placebo-controlled trial, lurasidone demonstrated significant efficacy in adolescents with schizophrenia regardless of previous antipsychotic therapy status; however, the effect size was notably larger in the TN patient group. In both the TN and TP groups, minimal effects were noted on weight, metabolic parameters, or prolactin.     

Family conflict moderates response to pharmacological intervention in pediatric bipolar disorder

OBJECTIVE: Family conflict affects the expression of psychopathology in youth. This study investigated whether family conflict moderates response to medication in youth with bipolar disorder. METHODS: Youth ages 5-17 years diagnosed with bipolar I or II disorder were recruited from a trial of combination therapy with divalproex and lithium. Mania and depression were assessed at baseline and after 8 weeks of treatment using the Young Mania Rating Scale (YMRS) and the Children's Depression Rating Scale-Revised (CDRS-R). Parents completed the Family Assessment Device (FAD). Ordinary least-squares regression evaluated whether family conflict contributed to YMRS/CDRS-R outcomes controlling for severity of baseline mood. RESULTS: In 55 youths, the model examining family conflict and CDRS-R outcomes showed that family conflict variables accounted for 10% of the variance in CDRS-R scores after 8 weeks of treatment. The final model was statistically significant. The FAD Problem Solving subscale was the only uniquely significant predictor of CDRS-R scores after 8 weeks of treatment. Family conflict did not predict YMRS outcomes. CONCLUSION: There is a significant relationship between family problem solving and depressive symptoms that persist despite pharmacotherapy. Although depression severity was mild at baseline, it persisted despite pharmacological treatment in youths whose families endorsed higher levels of conflict.     

Benefits and harms of low and high second-generation antipsychotics doses for bipolar depression: A meta-analysis

The aim of this systematic review and meta-analysis was testing whether low versus high doses of second-generation antipsychotics (SGAs) are associated with different clinical benefits and harms for the acute treatment of bipolar depression. We included clinical trials comparing different doses of the same SGA monotherapy for bipolar depression. SGAs defined daily doses were used to define high and low doses. Clinical benefit outcomes included improvement, response and remission rates on Montgomery-Asberg Depression Rating Scale. Clinical harm outcomes included all-cause and adverse effect-related discontinuation rates. Data from seven clinical trials testing high and low doses of quetiapine (4 trials), cariprazine, lurasidone, and ziprasidone (1 trial each), showed no differences between lower and higher doses of selected SGAs on improvement, response and remission rates, without significant heterogeneity across studies (I² = 0%). Subgroup analyses based on single SGAs confirmed the clinical benefit comparability between low and high doses. However, clinical harm favorable differences for low doses on all-cause (p = 0.01) and adverse effects-related discontinuation (p = 0.001) were found.In sum, this meta-analysis showed that, although no benefits were found in terms of symptoms improvement, response and remission rates, there were clear disadvantages in prescribing higher rather than lower doses of selected SGAs. The uniform methodological strength of studies increases confidence in our findings. These data need to be integrated with individual patient characteristics (e.g., clinical urgency and adverse effect sensitivity) to optimize management of acute bipolar depression.     

Efficacy and safety of lurasidone in adolescents and young adults with schizophrenia: A pooled post hoc analysis of double-blind,placebo-controlled 6-week studies

BackgroundThe aim of this pooled analysis was to evaluate the efficacy and safety of lurasidone in the treatment of an acute exacerbation of schizophrenia in adolescents and young adults.MethodsThe six pooled studies in this analysis used similar study designs and outcome measures. Patients (aged 13–25 years) were randomized to 6 weeks of double-blind, placebo-controlled treatment with lurasidone in fixed doses of 40, 80, 120, or 160 mg. The primary efficacy endpoint was Week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score; secondary efficacy endpoints included Week 6 change in the Clinical Global Impression–Severity scale.ResultsThe safety population consisted of 537 patients (mean age: 18.1 years); 82.6% of patients completed the studies. Treatment with lurasidone was significantly better than placebo at all doses (p < 0.001) for change in the PANSS total score at Week 6. Placebo-adjusted PANSS scores ranged from −9.4 to −16.1 (effect sizes: 0.53–0.90), with effect sizes increasing at higher doses. For lurasidone (combined doses), three adverse events occurred with a frequency of ≥5% (nausea: 13.5%; somnolence: 12.1%; akathisia: 10.1%). At last observation carried forward (LOCF)-endpoint weight gain of ≥7% was similar for lurasidone versus placebo (3.6 vs. 4.7%). Minimal median changes were observed at endpoint in cholesterol, −2.0 mg/dL; triglycerides, 0.0 mg/dL; and glucose, 0.0 mg/dL.ConclusionsIn adolescents and young adults with schizophrenia, treatment with lurasidone in doses of 40–160 mg/d was a safe, well-tolerated, and effective treatment. Short-term treatment with lurasidone was associated with minimal effects on weight and metabolic parameters.     

Interactive effects of systemic inflammation and life stressors on treatment response of depressive disorders

Inflammation is an important contributor in the pathophysiology of depression and recent evidence suggests that systemic inflammation and life stressors have interactive roles in depression onset. The aim of the present study was to investigate the individual and interactive effects of systemic inflammation and life stressors with short- and long-term treatment responses in outpatients with depressive disorders in a naturalistic one-year prospective design.Serum high-sensitivity C-reactive protein (hsCRP) levels were measured and number of stressful life events (SLEs) during the last 3 months were ascertained from 1094 patients at baseline. These patients received initial antidepressant monotherapy, then, for patients with an insufficient response or uncomfortable side effects, next treatment with alternative strategies were administered at every 3 weeks in the acute treatment phase (3, 6, 9, and 12 weeks) and at every 3 months in the continuation treatment phase (6, 9, and 12 months). 12-week and 12-month remission was estimated, defined as a Hamilton Depression Rating Scale score of ≤ 7.In multivariable logistic regression analyses, individual effects were found only between higher baseline serum hsCRP levels (≥1.0 vs. < 1.0 mg/L) and 12-week non-remission. Significant interactive effects between higher hsCRP levels and higher number of SLEs (≥2 vs. < 2) on both 12-week and 12-month non-remission were observed.Combining serum hsCRP levels and number of SLEs might therefore be a useful predictor for short- and long-term treatment responses in patients with depressive disorders receiving pharmacotherapy.     

Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression

BACKGROUND: Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression. OBJECTIVE: To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. DESIGN: Double-blind, 8-week, randomized controlled trial. SETTING: Eighty-four sites (inpatient and outpatient) in 13 countries.Patients A total of 833 randomized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20.Intervention Patients were randomly assigned to receive placebo (n = 377); olanzapine, 5 to 20 mg/d (n = 370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86). MAIN OUTCOME MEASURE: Changes in MADRS total scores using mixed-effects model repeated-measures analyses. RESULTS: During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group (P<.001 for all). The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8. At week 8, MADRS total scores were lower than at baseline by 11.9, 15.0, and 18.5 points in the placebo, olanzapine, and olanzapine-fluoxetine groups, respectively. Remission criteria were met by 24.5% (87/355) of the placebo group, 32.8% (115/351) of the olanzapine group, and 48.8% (40/82) of the olanzapine-fluoxetine group. Treatment-emergent mania (Young Mania Rating Scale score <15 at baseline and > or =15 subsequently) did not differ among groups (placebo, 6.7% [23/345]; olanzapine, 5.7% [19/335]; and olanzapine-fluoxetine, 6.4% [5/78]). Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea. CONCLUSIONS: Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.     

Efficacy of ferric carboxymaltose (FCM) 500 mg dose for the treatment of Restless Legs Syndrome

IntroductionThere have been four randomized, placebo-controlled, double-blinded studies of intravenous (IV) iron in Restless Legs Syndrome (RLS), all of which delivered a final total dose of 1000 mg of iron. The purpose of this study was to evaluate effects of a lesser total dose (500 mg of iron).MethodsSubjects with idiopathic RLS were enrolled in a randomized, double-blinded, placebo-controlled study. Subjects received either 500 mg ferric carboxymaltose (FCM) or placebo as a single infusion (Phase I). Subjects who were previously on medication were off any RLS medications for at least two weeks prior to baseline assessment. The primary outcome variable was a change-from-baseline at week six on the International RLS Severity Scale (IRLSS) and a subject-completed Visual Analog Scale of Severity (VAS). Phase II of the study involved long-term (30 weeks) follow-up after completing the six week efficacy phase.ResultsAt week six post infusion, FCM, compared to placebo recipients, showed no significantly greater change-from-baseline for both primary outcome measures (IRLSS scale, FCM 500 mg vs. placebo: −8.3 ± 7.5 vs. −4.8 ± 8.7, p = 0.100; VAS, FCM 500 mg vs. placebo: −23.4 ± 24.1 vs. −13.3 ± 23.1, p = 0.077). None of the secondary outcome variables showed a significant difference at week six. Seven (21.9%) of the 32 subjects treated with iron in Phase I remained free from further RLS medications at 30 weeks. No serious adverse effects were found in this study.ConclusionsThis study did not show significant benefit from a single 500 mg FCM treatment for RLS symptoms. The two previous, well-controlled, trials of 1000 mg FCM showed significant treatment benefits which suggested that there may have been a clinically relevant total dose required to achieve a clinical response.