Disorders - Bipolar Disorders
Findling, Robert L., McNamara, Nora K., Stansbrey, Robert J., Wynbrandt, Jaime L., Adegbite, Clara, Rowles, Brieana M., Demeter, Christine A., Frazier, Thomas W., Calabrese,
Joseph R.,
Background: This study evaluates the long-term efficacy of
aripiprazole compared to placebo in children with bipolar disorders. Method: Outpatients aged 4 to 9 years meeting DSM-IV criteria for a bipolar
disorder (I, II, not otherwise specified, cyclothymia) were eligible to receive up to 16 weeks of open-label treatment with aripiprazole (phase 1).
Patients were randomized into the 72-week double-blind phase of the study once they met a priori response criteria for stabilization (phase 2).
During phase 2, patients either remained on their current aripiprazole regimen or began a double-blind taper with aripiprazole discontinued and
switched to placebo. The primary outcome measure for phase 2 was time to discontinuation due to a mood event. Result: Patients were recruited between
May 2004 and November 2008. Following phase 1, in which 96 patients received aripiprazole, 30 patients (mean age = 7.1 years) were randomly assigned
to continue aripiprazole and 30 patients (mean age = 6.7 years) were randomly assigned to placebo. The mean (SD) dose of aripiprazole prior to
randomization for these patients was 6.4 (2.1) mg/d. Patients randomly assigned to aripiprazole were enrolled significantly longer until time to
study discontinuation due to a mood event (6.14 median weeks, SE ± 11.88 weeks; P = .005) and discontinuation for any reason (including mood events)
(4.00 median weeks, SE ± 3.91 weeks; P = .003) than those randomly assigned to placebo (mood event, 2.29 median weeks, SE ± 0.38 weeks; any reason,
2.00 median weeks, SE ± 0.31 weeks). Regardless of random assignment, both the aripiprazole and placebo groups showed substantial rates of withdrawal
from maintenance treatment over the initial 4 weeks (15/30 [50%] for aripiprazole; 27/30 [90%] for placebo), suggesting a possible nocebo effect (ie,
knowledge of possibly switching from active medication to placebo increasing concern about relapse). The most frequently reported adverse events
during double-blind aripiprazole therapy included stomach pain (n = 10, 33%), increased appetite (n = 9, 30%), and headaches (n = 9, 30%).
Conclusions: Despite the possibility of a nocebo effect, these results suggest that aripiprazole may be superior to placebo in the long-term
treatment of pediatric patients following stabilization with open-label aripiprazole. (PsycINFO Database Record (c) 2013 APA, all rights reserved)
(journal abstract)
Journal of Clinical Psychiatry, 73(1) : 57-63
- Year: 2012
- Problem: Bipolar Disorders
- Type: Randomised controlled trials
-
Stage: Relapse prevention
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation), Medication dose
reduction/discontinuation
Doey, T.
Background: Aripiprazole is an atypical
antipsychotic with unique pharmacological properties, used for a variety of indications, including psychotic and mood disorders in youth. Existing
literature was reviewed to summarize experience with this agent in that population. Methods: A review of relevant literature using the key words
aripiprazole, children, pediatric, all child, schizophrenia, bipolar disorder, and atypical antipsychotics was conducted. Results: A total of 140
articles and book chapters were identified, of which 7 reported double-blind controlled trials with aripiprazole, 5 were meta-analyses of pooled
data, 11 were open label trials, 10 were chart reviews, and 17 were case reports or case series. Limitations: Although every effort was made to
locate all available data, some information from posters or researchers was not available. Publication bias tends to report positive outcomes with a
treatment, while negative studies are less likely to be reported. Most trials are of short duration. Conclusions: Treatment with aripiprazole is
associated with significant reduction of the Positive and Negative Symptom Scale (PANSS) scores in youth with schizophrenia, and reductions in items
in the negative symptom scores at higher doses (30 mg/day). Significant reductions in the Young Mania Rating Scale (YMRS) have been demonstrated in
youth with bipolar disorder. In mixed populations, reductions in the Clinical Global Impressions Scale (CGI-S) have also been demonstrated when
compared with treatment with placebo. Head-to-head comparisons are fewer in number, and overall aripiprazole compares favorably with other atypical
antipsychotics (ATAs) in the populations studied. Treatment with aripiprazole is reported to have a lower incidence of weight gain, and less
elevation of prolactin. At higher doses, it appears more likely to result in extrapyramidal symptoms (EPS) and tremor. (copyright) 2012 Elsevier B.V.
All rights reserved.
Journal of Affective
Disorders, 138(SUPPL.) : S15-S21
- Year: 2012
- Problem: Bipolar Disorders
- Type: Systematic reviews
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation)
Geller, Barbara, Luby, Joan L., Joshi, Paramjit, Wagner, Karen Dineen, Emslie, Graham, Walkup, John T., Axelson, David A., Bolhofner, Kristine, Robb, Adelaide, Wolf, Dwight V., Riddle, Mark A., Birmaher, Boris, Nusrat, Nasima, Ryan, Neal D., Vitiello, Benedetto, Tillman,
Rebecca, Lavori, Philip
Context:
There was a paucity of comparative pharmacological research for initial treatment of bipolar I disorder, manic or mixed phase, in children and
adolescents. Objective: To investigate which medication to administer first to antimanic medication - naive subjects. Design, Setting, and
Participants: The Treatment of Early Age Mania (TEAM) study recruited 6- to 15- year-old children and adolescents with DSM-IV bipolar I disorder
(manic or mixed phase) at 5 US sites from 2003 to 2008 into a controlled, randomized, no-patient-choice, 8-week protocol. Blinded, independent
evaluators conducted all baseline and end-point assessments. Interventions: Subjects received a titrated schedule of lithium, divalproex sodium, or
risperidone. Medications were increased weekly only if there was inadequate response, and no dose-limiting adverse effects, to maximum doses of
lithium carbonate (1.1-1.3 mEq/L), divalproex sodium (111-125 µg/mL), and risperidone (4-6 mg). Main Outcome Measures: Primary outcome measures were
the Clinical Global Impressions for Bipolar Illness Improvement - Mania and the Modified Side Effects Form for Children and Adolescents. Results:
There were 279 antimanic medication - naive subjects (mean [SD] age, 10.1 [2.8] years; 50.2% female) who had the following characteristics: 100%
elated mood and/or grandiosity, 77.1% psychosis, 97.5% mixed mania, 99.3% daily rapid cycling, and mean (SD) mania duration of 4.9 (2.5) years. The
mean (SD) titrated lithium level was 1.09 (0.34) mEq/L, and the mean (SD) divalproex sodium level was 113.6 (23.0) µg/mL. The mean (SD) titrated
risperidone dose was 2.57 (1.21) mg. Higher response rates occurred with risperidone vs lithium (68.5% vs 35.6%; ?²1=16.9, P<.001) and vs divalproex
sodium (68.5% vs 24.0%; ?²1=28.3, P<.001). Response to lithium vs divalproex sodium did not differ. The discontinuation rate was higher for lithium
than for risperidone (?²1=6.4, P=.011). Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium (F
[sub]1,212[/sub]=45.5, P<.001; F[sub]1,212[/sub]=39.1, P<.001; and F[sub]1,213[/sub]=191.4, P<.001, respectively) and vs divalproex sodium (F
[sub]1,212[/sub]=34.7, P<.001; F[sub]1,212[/sub]=45.3, P<.001; and F[sub]1,213[/sub]=209.4, P<.001, respectively). The thyrotropin level increased in
subjects taking lithium (t62=11.3, P<.001). Conclusions: Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment
of childhood mania but had potentially serious metabolic effects. (PsycINFO Database Record (c) 2013 APA, all rights reserved) (journal abstract)
Archives of General Psychiatry, 69(5) : 515-528
- Year: 2012
- Problem: Bipolar Disorders
- Type: Randomised controlled trials
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation), Anticonvulsants/mood stabilisers (excl. lithium), Lithium
Chiesa, A., Chierzi, F., De Ronchi,
D., Serretti, A.
Quetiapine has been proposed for depression in bipolar patients but a quantitative analysis is lacking. In the present paper, we
review and meta-analyze available data about the short-term and long-term efficacy and tolerability of quetiapine for the depressive phase of bipolar
disorder or bipolar depression. A literature research was carried out using three electronic databases. Studies providing measures of efficacy and
tolerability of quetiapine, either as monotherapy or as augmentation, for bipolar depression were considered. Seven short-term studies and four
maintenance studies were included. Short-term studies suggested that patients treated with quetiapine monotherapy were significantly more likely than
patients treated with placebo and further active comparators to achieve higher response and remission rates as well as more clinical improvements at
the endpoint. Such benefits were significant from the first weeks of treatment onward. Maintenance studies suggested that the combination of
quetiapine and mood stabilizers was significantly better than placebo plus mood stabilizers for the prevention of both depressive and manic relapses.
Quetiapine was generally well tolerated. Furthermore, several clinical variables moderated outcomes under investigation. In conclusion, quetiapine
could have some advantages over traditional treatments for the treatment of bipolar depression. (copyright) 2012 Wolters Kluwer Health | Lippincott
Williams & Wilkins.
International Clinical
Psychopharmacology, 27(2) : 76-90
- Year: 2012
- Problem: Bipolar Disorders
- Type: Systematic reviews
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation)
Biederman, J., Petty, C. R., Woodworth,
K. Y., Lomedico, A., O'Connor, K. B., Wozniak, J., Faraone, S. V.
Objective: To examine the informativeness of open-label trials
toward predicting results in subsequent randomized, placebo-controlled clinical trials of psychopharmacologic treatments for pediatric bipolar
disorder. Data Sources: We searched journal articles through PubMed at the National Library of Medicine using bipolar disorder, mania,
pharmacotherapy, treatment and clinical trial as keywords. This search was supplemented with scientific presentations at national and international
scientific meetings and submitted manuscripts from our group. Study Selection: Selection criteria included (1) enrollment of children diagnosed with
DSM-IV bipolar disorder; (2) prospective assessment of at least 3 weeks; (3) monotherapy of a pharmacologic treatment for bipolar disorder; (4) use
of a randomized placebo-controlled design or an open-label design for the same therapeutic compound; and (5) repeated use of the Young Mania Rating
Scale (YMRS) as an outcome. Data Extraction: The following information and data were extracted from 14 studies: study design, name of medication,
class of medication, dose of medication, sample size, age, sex, trial length, and YMRS mean and standard deviation baseline and follow-up scores.
Results: For both study designs, the pooled effect size was statistically significant (open-label studies, z = 8.88, P < .001; randomized placebo-
controlled studies, z = 13.75, P < .001), indicating a reduction in the YMRS from baseline to endpoint in both study designs. In a meta-analysis
regression, study design was not a significant predictor of mean change in the YMRS. Conclusions: We found similarities in the treatment effects
between open-label and randomized placebo-controlled studies in youth with bipolar disorder indicating that open-label studies are useful predictors
of the potential safety and efficacy of a given compound in the treatment of pediatric bipolar disorder. (copyright) Copyright 2011 Physicians
Postgraduate Press, Inc.
Journal of Clinical
Psychiatry, 73(3) : 358-365
- Year: 2012
- Problem: Bipolar Disorders
- Type: Systematic reviews
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation), Anticonvulsants/mood stabilisers (excl. lithium)
Davari-Ashtiani, R., Parvaresh, N., Akhondzadeh, S.
Objective: Pre-pubertal or early onset bipolar disorder commonly presents as a chronic and continuously cycling disorder with
high rates of mixed states. There are no good results for monotherapy in the people suffering from this disorder and a few controlled trials exist
for combined therapy in them. Some studies have been conducted about the role of gabapentin in the treatment of bipolar disorder in adults. So this
study was designed to investigate the efficacy of combined gabapentin and lithium treatment in youths with bipolar disorder. Methods: In an 8-week,
double-blind clinical trial, 31 adolescents with a diagnosis of bipolar disorder were randomized for treatment with lithium plus gabapentin (n = 16)
or lithium plus placebo (n = 15). The primary outcome measure was Young mania rating scale score. Anxiety and depression were measured bi weekly with
Hamilton rating scale and Beck depression inventory. Weight and side effects also were evaluated. Results: There was no significant difference
between the gabapentin and placebo groups in Young mania rating scale scores and the secondary outcome measures at any stage during the 8 week trial
(P> 0.05). Conclusion: Our findings do not support the efficacy of gabapentin as combination agent with lithium in the treatment of adolescents with
bipolar disorder.
International Clinical
Psychopharmacology, 26 : e40
- Year: 2011
- Problem: Bipolar Disorders
- Type: Randomised controlled trials
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Anticonvulsants/mood stabilisers (excl. lithium), Lithium
Janicak, Philip G., Rado, Jeffrey T.
Introduction: Depression, in the
context of bipolar disorder, is more prevalent than hypomania or mania and accounts for most of the disability. Furthermore, the treatment of bipolar
depression is more complicated than the treatment of unipolar major depression. Finally, the evidence base for pharmacotherapy of bipolar depression
is much smaller than for unipolar depression or hypomania/mania.; Areas Covered: The article examines the mechanism of action and pharmacokinetics of
quetiapine, its evidence base as a treatment for bipolar depression and related issues of safety and tolerability.; Expert Opinion: In the context of
bipolar disorder, quetiapine is the only monotherapy approved for the treatment of hypomania/mania, depression and as an adjunctive maintenance
therapy. In addition to its antipsychotic properties, this broad mood stabilizing potential may uniquely benefit and simplify the management of some
bipolar patients who can tolerate this agent.; © 2011 Informa UK, Ltd.
Expert Opinion on Pharmacotherapy, 12(10) : 1643-
1651
- Year: 2011
- Problem: Bipolar Disorders
- Type: Systematic reviews
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation)
Gentile, S.
The onset of severe, chronic or
recurrent psychiatric illnesses, such as schizophrenia-spectrum and bipolar disorders, is a dramatic clinical event often detectable during
adolescence and even in childhood. At any age, pharmacotherapy, along with enhancement of social skills and family support, is the mainstay for the
management of such disorders. The aim of this review is to critically analyze findings from randomized controlled trials (RCTs) that have
investigated the clinical utility of second-generation antipsychotics (SGAs) for the treatment of early-onset schizophrenia and bipolar disorders.
Eighteen studies were considered, all of which were unfortunately impaired by methodologic limitations, such as the paucity of long-term data and
lack of a three-arm comparison (SGA vs SGA vs placebo).Nevertheless, the results of this review allow us to suggest the effectiveness of three SGAs
(aripiprazole, olanzapine, and risperidone) in the short-term treatment of both early-onset schizophrenia and bipolar mania, although such agents
show different safety profiles. The use of clozapine should be strictly limited to patients with non-affective, psychotic symptoms who do not respond
to any of these three SGAs. In contrast, the use of quetiapine and ziprasidone in young patients with either affective or non-affective psychosis is
not yet supported by evidence-based information.Given our findings, further studies are urgently required to identify the best treatment option(s)
for pediatric bipolar disorder (especially the depressive phase) and the long-term management of early-onset schizophrenia.
Pediatric Drugs, 13(5) : 291-302
- Year: 2011
- Problem: Bipolar Disorders, Psychosis Disorders
- Type: Systematic reviews
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation)
Fraguas,
D., Correll, C. U., Merchan-Naranjo, J., Rapado-Castro, M., Parellada, M., Moreno, C., Arango, C.
To review data on efficacy and safety of second-generation antipsychotics (SGAs) in children and adolescents with
psychotic and bipolar spectrum disorders. Methods: Medline. /PubMed/Google Scholar search for studies comparing efficacy and/or tolerability: (i)
between two or more SGAs; (ii) between SGAs and placebo; and (iii) between at least one SGA and one first-generation antipsychotic (FGA). The review
focused on three major side-effect clusters: 1. body weight, body mass index, and cardiometabolic parameters, 2. prolactin levels, and 3. neuromotor
side effects. Results: In total, 34 studies with 2719 children and adolescents were included. Studies lasted between 3. weeks and 12. months, with
most studies (79.4%) lasting 3. months or less. Nine studies (n = 788) were conducted in patients with schizophrenia, 6 (n = 719) in subjects with
bipolar disorder, and 19 (n = 1212) in a mixed population. Data on efficacy showed that, except for clozapine being superior for refractory
schizophrenia, there were no significant differences between SGAs. By contrast, safety assessments showed relevant differences between SGAs. Mean
weight gain ranged from 3.8. kg to 16.2. kg in patients treated with olanzapine (n = 353), from 0.9. kg to 9.5. kg in subjects receiving clozapine (n
= 97), from 1.9. kg to 7.2. kg in those on risperidone (n = 571), from 2.3. kg to 6.1. kg among patients taking quetiapine (n = 133), and from 0. kg
to 4.4. kg in those treated with aripiprazole (n = 451). Prolactin levels increased the most in subjects on risperidone (mean change ranging from
8.3. ng/mL to 49.6. ng/mL), followed by olanzapine (-1.5. ng/mL to +. 13.7. ng/mL). Treatment with aripiprazole was associated with decreased
prolactin levels, while clozapine and quetiapine were found to be mostly neutral. With respect to neuromotor side effects, SGAs were associated with
less parkinsonism and akathisia than FGAs. Most of the studies comparing neuromotor side effects between SGAs found no significant differences.
Conclusions: SGAs do not behave as a homogeneous group in children and adolescents with psychotic and mood disorders. Except for clozapine, the
heterogeneity within the SGA group is mainly due to differences in the rates and severity of adverse events, especially regarding weight gain as a
proxy for the risk of cardiometabolic disturbances. (copyright) 2011.
European Neuropsychopharmacology, 21(8) : 621-645
- Year: 2011
- Problem: Bipolar Disorders
- Type: Systematic reviews
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation)
Garrett, A., Reiss, A., Miklowitz, D., Howe, M., Singh, M., Kelley, R., Taylor, D., George, E., Chang, K.
Background: Subthreshold forms of bipolar disorder (BD), such as BD NOS, cyclothymia,
and MDD with family history of BD, affect 3 - 9% of youth (Birmaher et al., 2009 ; Miklowitz et al., 2008). Without intervention, these youth are at
high risk for progressing to full BD. We recently demonstrated that a 12-week adaptation of Family Focused Therapy for youth at high risk for BD
(FFT-HR) reduced symptoms of depression and mania (Miklowitz et al., 2011). We therefore conducted a randomized trial of FFT-HR in 40 at-risk youth,
and conducted fMRI pre- and post-treatment in a subset of patients to study the neural correlates and predictors of clinical response. Because our
previous studies found that clinical improvement was associated with decreased amygdalar activation and increased DLPFC activation (Chang et al.,
2008; 2009), we hypothesized that improvements in symptom severity would be accompanied by changes in activation of the amygdala and prefrontal
cortex. Methods: Subjects: Twelve subjects at risk for BD were scanned (8 male; mean age = 14.1 yrs). Each participant was 9 to 17 years old, had at
least one first-degree relative with bipolar I disorder (confirmed by SCID interview), and had either BD-NOS, cyclothymia, or major depressive
disorder (by WASH-U-KSADS), and active depressive (CDRS-R>29) or manic (YMRS>11) symptoms in the last 2 weeks. Treatment: 6 subjects received FFT and
6 received TAU (one feedback session and up to 3 crisis sessions). MRI Acquisition: Subjects were scanned on a 3T GE Signa scanner using a custom-
built fMRI head coil. Thirty axial slices (4mm thick, .05 mm skip), parallel to the axis of anterior and posterior commisures, covering the entire
brain (FOV = 20cm, 64x64 matrix, in-plane spatial resolution = 3.4 mm) were acquired using a spiral pulse sequence with the following parameters: TR
= 2000 msec, TE = 30 msec, flip angle = 80 degrees and one interleave. Faces Task: Subjects performed a gender identification task while viewing
blocks of fearful, calm, and neutral faces, and scrambled images. There were 4 blocks for each condition. Each block included 8 pictures. Each
picture was presented for 3 sec, with no inter-stimulus interval. Data Analysis: Functional data were analyzed using SPM8. FMRI images were
reconstructed, spatially realigned to the third image, analyzed and repaired for motion, high-pass filtered, and spatially normalized into standard
stereotactic space using the individuals' anatomical scan and an age-appropriate group template (CCHMC) and smoothed with a 7 mm Gaussian filter.
Fearful minus scrabmbled faces was the main contrast used. Group analyses used a repeated measures ANOVA in SPM8 to identify clusters of activation
that changed significantly from baseline to follow-up. A dual threshold of p=0.01 height and k=40 cluster extent was used. Activation clusters were
localized using roimod2 spm toolbox, then superimposed on a single-subject high-resolution T1-weighted image to verify neuroanatomical locations.
Mean activation in clusters that fell in apriori hypothesized regions were extracted to SPSS. In SPSS, Spearman's correlations were conducted
between activation and CDRS and YMRS scores. Results: CDRS and YMRS scores decreased significantly following treatment (p=0.007), but not
differentially by treatment group (p=0.53). For all subjects, whole-brain analysis showed that activation in the right amygdala declined and in the
right DLPFC increased significantly from baseline to follow-up. Greater activation in the amygdala at baseline was associated with greater
improvement in depression severity following treatment by FFT, but not TAU (p=0.001; Figure 1). For both treatment groups, greater increases in DLPFC
from baseline to follow-up was associated with greater improvement in mania severity following treatment (p=0.02). Two of the subjects in the FFT
group and four in the TAU groups were taking medications, which had no discernible effect on amygdala or DLPFC activations. Discussion: This is the
first study to demonstrate neural predictors of response to famil therapy in youth at high-risk for BD. Decreased amygdala activation following both
active and comparator treatments may reflect overall improved regulation of amygdala reactivity to emotion-related stimuli. Greater activation in the
amygdala at baseline may predict better response to FFT. Increased DLPFC activation following both treatments may reflect improved executive control
over emotional responses. Limitations of this study include the small sample size and medications taken by the subjects. Future studies with larger
samples are needed to confirm these findings and explore further neural mechanisms of response to psychotherapy in this population.
Neuropsychopharmacology, 36 : S401
- Year: 2011
- Problem: Bipolar Disorders
- Type: Randomised controlled trials
-
Stage: At risk (indicated or selected prevention)
-
Treatment and intervention: Psychological Interventions
(any), Family therapy
Findling, R. L., Youngstrom, E. A., McNamara, N. K., Stansbrey,
R. J., Demeter, C. A., Rowles, B. M., Frazier, T. W., Calabrese, J. R.
Background:
Aripiprazole (APZ) is an atypical antipsychotic indicated by the United States Food and Drug Administration for the acute treatment of manic or mixed
episodes associated with bipolar I disorder as monotherapy and adjunctive to lithium or valproate in pediatric patients ages 10-17. Owing to the
severity and chronicity of pediatric bipolar disorder in children younger than 10 years of age, safe and effective long-term interventions are needed
for that patient population. This study tested the long-term efficacy of APZ compared to placebo in children under age 10 suffering from a bipolar
disorder. Methods: Medically healthy outpatients, ages 4-9 years, meeting DSM-IV criteria for a bipolar disorder were eligible to receive up to 16
weeks of open-label treatment with APZ (Phase I) (Findling et al., in press). Patients ended participation in Phase I and were randomized into the
double-blind phase of the study, Phase II, once they met a priori response criteria (treatment with APZ for a minimum of 6 weeks and 3 of 4
consecutive weeks with: Children's Depression Rating Scale-Revised (CDRS-R)o29; Young Mania Rating Scale (YMRS)o10; and Children's Global
Assessment Scale (CGAS)4 50). Phase II, the primary focus of this poster, was a randomized, double-blind clinical trial in which stabilized patients
received either ongoing APZ treatment or placebo for up to 72 weeks. Patients either remained on their current APZ dose, or began a double-blind
taper during which APZ was discontinued and replaced by placebo. The treatment groups were compared on demographics, psychiatric diagnoses, weeks
enrolled in Phase II, symptom ratings at time of randomization, adverse events, weight gain, and changes in safety laboratory values. Treatment
efficacy was examined using two separate Kaplan-Meier survival analyses: one used nulldiscontinuation for any reasonnull as the event of interest,
and the other used nulldiscontinuation due to the development of a mood episodenull to quantify risk of discontinuation. Cox regression analyses were
computed to examine the effects of covariates. For all analyses, significance was set at p<0.05. Results: Thirty patients were randomized to APZ
while receiving an average daily dose of 0.23 (0.07) mg/kg/day after a mean of 14.3 (2.8) weeks of open-label treatment with APZ. Also, 30 patients
who were being treated with 0.22 (0.07) mg/kg/day of APZ were randomized to placebo after 14.2 (2.4) weeks of open-label treatment. The two groups
did not significantly differ in the time until stabilization and randomization in Phase I (p=0.88). The APZ group did not significantly differ from
the placebo group in mean weight adjusted total daily dose at randomization (p=0.64). No significant differences were observed between treatment
groups at baseline for any demographic, diagnostic, or symptom rating variables (all p values 4 0.05). Six patients randomized to receive APZ and 0
patients randomized to placebo completed the entire 72 weeks of Phase 2. For patients randomized to continued APZ therapy, time to study
discontinuation for any reason and as a result of a mood event was longer compared to those randomized to placebo (any reason: p=0.003; mood event:
p=0.005).Regardless of randomized assignment, both APZ and placebo showed substantial rates of withdrawal from maintenance treatment over the initial
4 weeks (15/30, 50% for APZ; 27/30, 90% for placebo) suggesting a possible nocebo effect. Children treated with APZ were more likely to report both
stomach (n=10 (33%) vs. n=1 (3%)) and musculoskeletal pain (n=8 (27%) vs. 0) than those who received placebo (both p<0.01). There was a significant
difference in weight gain from time of randomization between patients who received APZ (mean=2.61 kg, S.D.=3.88 kg) versus those that received
placebo (mean=0.42 kg, S.D.= 1.26 kg; p=0.006). There was a significant time-treatment interaction in prolactin levels (F=19.76, df=1, 56, p<0.001).
Compared to the randomization time point, prolactin levels decreased at EOS in the APZ group, while prolactin levels at EOS in th placebo group
increased. Discussion: Results from this double-blind, placebo-controlled maintenance trial suggest that APZ may be beneficial in the longterm
treatment of pediatric patients with a bipolar disorder following stabilization with open-label APZ. Considering the low completion rate, further
treatment research is needed in order improve long term outcomes in this population.
Neuropsychopharmacology, 36 : S349-S350
- Year: 2011
- Problem: Bipolar Disorders
- Type: Randomised controlled trials
-
Stage: Relapse prevention
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation), Medication dose
reduction/discontinuation
Cohen, D., Bonnot, O., Bodeau, N., Consoli, A., Laurent, C.
Objective: In adults, second-generation antipsychotics (SGAs) have shown a good benefice/risk ration in bipolar
disorder (BD) and low frequency of extrapyramidal syndrome (EPS) and a moderate frequency of metabolic adverse effects. Here we aimed to assess this
ratio in children and adolescents. Methods: We searched for relevant studies MEDLINE and EMBASE (1996-2010), FDA and EMEA clinical trial registries,
reference list of review articles. We found 41 were short-term (3-12 weeks) controlled studies that evaluated SGAs adverse effects in youths,
including 12 in youths with BD. Using Bayesian meta-analysis, we analyzed odds ratios (OR) or mean average effects. Results: Numbers of arms
(subjects) in the 41 trials were: aripiprazole: 10 (N = 671); olanzapine: 14 (N = 413); quetiapine: 10 (N = 446); risperidone: 25 (N = 1,040);
ziprasidone: 4 (N = 228); clozapine: 5 (N = 79); placebo/untreated: 23 (N = 1,138); totaling 93 arms (4,015 patients). Clozapine was only assessed
for weight gain and somnolence. Compared to placebo, significant treatment-related increases were observed for: weight gain with olanzapine,
clozapine, risperidone, quetiapine, and aripiprazole; glucose levels with risperidone and olanzapine; cholesterol levels with quetiapine and
olanzapine; triglyceride levels with olanzapine and quetiapine; hyperprolactinemia with risperidone, olanzapine and ziprasidone; and EPS with
ziprasidone, olanzapine, aripiprazole, risperidone. All SGAs increased the risk of somnolence/sedation. Regarding efficacy on BD, aripiprazole,
olanzapine, quetiapine, risperidone and ziprasidone were superior to placebo in one or more large placebo controlled trial. Conclusion: In youths
treated with SGAs, short-term metabolic effects and EPS are frequent, despite evidence of efficacy in youth BD. SGAs have diverse profiles of
secondary effects, which should be considered in making treatment decisions and optimizing benefice/risk ratio.
European
Neuropsychopharmacology, 21 : S206
- Year: 2011
- Problem: Bipolar Disorders
- Type: Systematic reviews
-
Stage: Disorder established (diagnosed disorder)
-
Treatment and intervention: Biological Interventions
(any), Atypical Antipsychotics (second
generation)