KIOS: A smartphone app for self-monitoring for patients with bipolar disorder.

OBJECTIVES: This study examined the use of a self-monitoring/self-management smartphone application (app) for patients with bipolar disorder. The app was specifically designed with patient-centered computational software system based on concepts from nonlinear systems (chaos) theory. METHODS: This was a randomized, active comparator study of use of the KIOS app compared to an existing free app that has high utilization rates known as eMoods, over 52 weeks, and performed in three academic centers. Patients were evaluated monthly utilizing the Bipolar Inventory of Symptoms Schedule (BISS). The primary outcome measure was the persistence of using the app over the year of the study. RESULTS: Patients assigned to KIOS persisted in the study longer than those assigned to eMoods; 57 patients (87.70%) in the KIOS group versus 42 (73.69%) in the eMoods group completed the study (p = 0.03). By 52 weeks, significantly more of KIOS group (84.4%) versus eMoods group (54%) entered data into their programs (χ2 = 14.2, df = 1, p = 0.0002). Patient satisfaction for KIOS was greater (F = 5.21, df = 1, 108, p = 0.025) with a standardized effect size (Cohen's d) of 0.41. There was no difference in clinical outcome at the end of the study between the two groups. CONCLUSIONS: This is the first randomized comparison study comparing two apps for the self-monitoring/self-management of bipolar disorder. The study revealed greater patient satisfaction and greater adherence to a patient-centered software program (KIOS) than a monitoring program that does not provide feedback (eMoods).

Inhaled loxapine for acute agitation in a psychiatric emergency service.

BACKGROUND: Rapid control of agitation in medical settings is necessary for safety and provision of care. Inhaled loxapine achieves peak plasma levels within 2 minutes of administration and is FDA-approved for managing acute agitation. METHODS: We examined the use of inhaled loxapine vs non-parenteral treatment as usual (TAU) in a psychiatric emergency service for consecutive patients with acute agitation or aggression. Data were collected retrospectively. T tests were used for continuous variables and Chi-square tests were used for categorical data. RESULTS: A total of 61 patients received inhaled loxapine and 29 received TAU. Time to outcome for patients receiving inhaled loxapine was 21 ± 21 minutes compared with 121 ± 206 minutes for TAU (t =-2.61; P = .014). At outcome, 89% of patients treated with loxapine experienced symptom resolution, compared with 69% of TAU (Chi-square = 17.4, P < .0001). Ten percent of patients receiving loxapine had no change in symptoms and 1% had worsening symptoms vs 14% in the TAU group who experienced no change in symptoms (z = 0.5, not significant), and 17% who described worsening symptoms (z = 6153.9, P < .0001). CONCLUSIONS: The rapid absorption of inhaled loxapine is associated with a 6-fold faster and more robust symptom control.

Anatomical Association Between Schizophrenia and Cerebellum.

The pathogenesis of schizophrenia is rarely attributed to dysfunction of the cerebellum. However, coordination of mental processes might involve the cerebellum and a cortico-cerebellar-thalamic-cortical circuit (CCTCC) that can mediate that process has been proposed. We present the case of a 31-year-old male patient with a family history of psychosis who developed schizophrenia in association with a slow-growing glioblastoma at the left posterior cerebellar pontine angle. Of interest is that his psychosis became refractory after surgical removal of the tumor that had no motor deficit consequences, suggesting that the greater disruption of the CCTCC due to surgical excision might be related to the worsening psychosis. The case supports the hypothesis of cognitive dysmetria and psychosis.

Asenapine in the Treatment of Bipolar Depression.

Objectives: Asenapine, a potent serotonin 7 (5-HT7) receptor antagonist, was examined for efficacy as an antidepressant in depressed bipolar subjects. It was predicted that subjects with the genetic variant of the short form of the serotonin transporter (5HTTR) would be more likely to respond. Experimental Design: A subset of patients participating in a randomized, placebo-controlled study of the efficacy of asenapine in bipolar I depression also underwent genetic testing for the 5HTTR. Montgomery Åsberg Depression Rating Scale (MADRS) score was ≥ 26 prior to randomization to asenapine or placebo for 8 weeks. Gene testing was performed before breaking the blind. Principal Observations: Nine patients completing the study also underwent gene testing. At study end, the average MADRS improvement was -19.80 ± SD 8.59 for the 4 people randomized to asenapine and -3.80 ± 9.01 for the 5 people receiving placebo (P = 0.021, t = 2.88). Anxiety, as measured by the Hamilton Anxiety Rating Scale (HAM-A), also improved in asenapine-treated patients (-15.40 ± 6.15 vs. -2.80 ± 7.95, P = 0.023, t = 2.803). Six participants had the short form of the 5HTTR, and it is believed they influenced the significant outcome in this small sample. Conclusions: While this is a very small sample, asenapine appears to have a beneficial effect on both depression and anxiety in depressed bipolar I patients compared to treatment with placebo. Due to the large fraction of subjects with the short form, the hypothesis that the SF-5HTTR might increase asenapine response could not be adequately tested.

Antidepressant discontinuation in treatment resistant depression.

Treatment-resistant depression (TRD) is a growing problem in psychiatric practice with some 15-20% of depressed patients becoming chronically depressed and perhaps as many as 40% in tertiary settings. Several groups have championed the idea that TRD may be attributed to the long-term treatment with antidepressant drugs (AD). Subjects with the short form of the serotonin transporter gene (both heterozygotes and homozygotes) have an increased risk for depression in the setting of adversity compared to people with the long form. Moreover, these same individuals have a reduced likelihood of responding well to antidepressants, with reports of no response, delayed response, and increased side effects. This hypothesis needs to be examined in a randomized clinical trial. The study will examine the effect of discontinuation versus continuation of serotonergic antidepressants on disease progression in patients with treatment resistant depression. We will recruit 30 subjects and assess the depressive symptoms and disease progression. Genetic testing will be performed to optimize clinical outcome in both groups, but will also be used to evaluate if the short form of the serotonin transporter predicts disease progression and long-term antidepressant treatment response.

Resource Utilization with the Use of Seclusion and Restraint in a Dedicated Emergency Psychiatric Service.

OBJECTIVES: There is a dearth of data regarding the use of emergency interventions in dedicated emergency psychiatric service settings, and reliable data are needed. This article describes the frequency and duration of the use of seclusion and restraint for imminent or existing agitation, aggression, or violence in a dedicated emergency psychiatric service located within an academic university hospital and staffed by sufficient numbers of trained personnel. METHODS: We performed a retrospective chart review of 6 months' visits to a dedicated emergency psychiatric service. RESULTS: Men outnumbered women with a 1.6 ratio of visits. Of 2843 subjects, 425 (14.6%) received emergent medication for anxiety (n = 90), substance withdrawal (n = 28), or agitation (n = 290). Physical interventions were used in 3.4%; 96 (3.3%) were secluded, and 9 (0.3%) were restrained. The average duration of seclusion was (mean ± standard deviation) 58.7 ± 37.4 minutes and for restraint 63.2 ± 23.4 minutes. Each episode of seclusion or restraint required approximately 3 hours of staff time. CONCLUSIONS: The use of an intervention such as seclusion in >3% and restraint in 0.3% of patients represents the use of seclusion and restraint in a dedicated psychiatric emergency service with personnel trained to minimize the use of seclusion and restraint.

Acute antidepressant response and plasma levels of bupropion and metabolites in a pediatric-aged sample: an exploratory study.

Studies examining associations between antidepressant response and plasma levels of bupropion and its metabolites have yielded contradictory findings. There have been no such studies in youth. This study explored such associations in 8 boys and 8 girls, age 11 to 17 years, all prescribed bupropion sustained release (SR) for major depression (n = 6) or depressive disorder not otherwise specified (n = 10) as part of a pharmacokinetic (PK) study. All were started on morning doses of bupropion SR of 100 mg/day, and most eventually had doses increased to 200 mg/day because of inadequate clinical response. After taking prescribed dose of bupropion SR at least 14 days (median = 21 days), subjects had steady-state serial plasma levels of bupropion and its metabolites measured during a 24-hour period after morning doses. A total of 9 subjects underwent these PK assessments on doses of 100 mg/day, and 6 underwent these on doses of 200 mg/day, with 4 studied on both doses. In this 24-hour assessment, the treating psychiatrist rated subjects' antidepressant response using the Clinical Global Impression's Improvement scale (CGI-I), blind to plasma levels, but informed by child and parent rating scales of depressive symptoms and clinical interviews. Relative to 7 nonresponders, 9 responders (CGI-I < or = 2) had significantly higher mean areas under concentration curves for bupropion (P = 0.03), threohydrobupropion (P = 0.02), and erythrohydrobupropion (P = 0.02), and especially hyroxybupropion (P = 0.006). Plasma levels 7.5 hours after morning doses reaching the following cut points discriminated responders from nonresponders: bupropion > or = 37 ng/mL (P = 0.001), hydroxybupropion > or = 575 ng/mL (P = 0.003), threohydrobupropion > or = 240 ng/mL (P = 0.009), or erythrohydrobupropion > or = 45 ng/mL (P = 0.009). These preliminary findings suggest that plasma levels of bupropion and metabolites, particularly hydroxybupropion, may predict acute antidepressant response in depressed youths taking bupropion SR.

Platelet serotonin reuptake inhibition and response to SSRIs in depressed adolescents.

OBJECTIVE: The authors examined platelet serotonin reuptake inhibition and response to selective serotonin reuptake inhibitor (SSRI) treatment in depressed adolescents. METHOD: Twenty-three depressed adolescents participating in pharmacokinetic studies of SSRIs had platelet serotonin reuptake measured before and after 14-28 days of treatment. The Clinical Global Impression (CGI) improvement rating was determined on the basis of all clinical information and was performed blind to the platelet data. RESULTS: Improvement in depressive symptoms as rated with the CGI improvement subscale was significantly associated with the percentage change in platelet serotonin reuptake inhibition from pre- to posttreatment. Improvement in depression was also associated with absolute decrease in platelet serotonin reuptake when adjusted for the magnitude of baseline reuptake. CONCLUSIONS: Platelet serotonin reuptake inhibition may be an appropriate surrogate biological marker for the pharmacodynamic activity of SSRIs in depressed adolescents.

Steady-state pharmacokinetics of bupropion SR in juvenile patients.

OBJECTIVE: To examine the steady-state pharmacokinetic properties of bupropion sustained release (SR) and their potential developmental differences in youths. METHOD: Eleven boys and eight girls aged 11 to 17 years old were prescribed bupropion SR monotherapy for attention-deficit/hyperactivity disorder (n = 16) and/or depressive disorders (n = 16). Bupropion SR was given in morning doses of 100 mg/day (n = 11) or 200 mg/day (n = 8) for 14 days or less, with five subjects studied on both doses. All subjects had blood draws from an intravenous port every 1 to 3 hours for 24 hours after their usual morning doses. Pharmacokinetic variables were determined by noncompartmental and compartmental analyses for bupropion and metabolites, respectively. RESULTS: Bupropion and its metabolites exhibited linear pharmacokinetics. Areas under the concentration curves for the hydroxybupropion, threohydrobupropion, and erythrohydrobupropion were 20, 12, and 2.7 times higher, respectively, than for bupropion. Relative to adults, the mean half-lives of bupropion (12.1 hours) and threohydrobupropion (26.3 hours) were significantly shorter, and areas under the concentration curve ratios of metabolites to bupropion were 19% to 80% higher. CONCLUSIONS: Youths metabolize bupropion SR faster to hydroxybupropion and other active metabolites than adults. Until the clinical importance of bupropion's metabolites is clarified, bupropion SR should be given in divided doses to youths, as the manufacturer recommends for adults taking higher doses.

Sertraline pharmacokinetics and dynamics in adolescents.

OBJECTIVE: To determine the pharmacokinetics of sertraline in adolescents and assess its effect on a surrogate marker of serotonin transport. METHOD: Pharmacokinetic parameters of a single 50-mg dose of sertraline were determined in 10 adolescents. Steady-state withdrawal kinetics were determined in 12 adolescents taking 50 mg/day and in 6 adolescents taking 100 to 150 mg/day. Platelet serotonin reuptake was measured before and after 2 weeks of daily 50-mg dosing. RESULTS: The mean steady-state half-life of 50 mg was significantly shorter (15.3 +/- 3.5 hours) than the single-dose half-life (26.7 +/- 5.2 hours; t = 6.4, p < .001) and the steady-state half-life at 100 to 150 mg/day (20.4 +/- 3.4 hours; t = 2.9, p = .01). Platelet serotonin reuptake was inhibited by 61 +/- 15% after approximately 2 weeks of sertraline 50 mg/day. CONCLUSIONS: The half-life of sertraline 50 mg becomes significantly shorter from the initial dose to steady-state, and many adolescents may benefit from twice-per-day dosing. The steady-state half-life increases as the dose increases. The moderate levels of platelet reuptake inhibition at 50 mg/day indicate that most adolescents may need sertraline doses higher than 50 mg/day to attain a therapeutic response.