Five recent randomized controlled trials (RCTs) have demonstrated the efficacy of atypical antips... more Five recent randomized controlled trials (RCTs) have demonstrated the efficacy of atypical antipsychotics for treating bipolar disorder in children and adolescents, but 4 of these 5 trials remain unpublished. The lag time between the completion of these trials and publication of their results--typically 4 to 5 years (1)--leaves psychiatrists without important evidence to explain to families and critics (2) why they might recommend using these powerful medications in children with mental illness. [ILLUSTRATION OMITTED] This article previews the preliminary results of these 5 RCTs of atypical antipsychotics, offers a treatment algorithm supported by this evidence, and discusses how to manage potentially serious risks when using antipsychotics to treat children and adolescents with bipolar disorder (BPD). Where do atypical antipsychotics fit in? Details of the 5 industry-sponsored RCTs of atypical antipsychotics in children and adolescents with bipolar I manic or mixed episodes are summarized in Table 1 (page 24). (3-7) Only the olanzapine study (4) has been published; data from the other 4 trials were presented at medical meetings in 2007 and 2008. Table 1 RCTs of atypical antipsychotics in patients age 10 to 17 with bipolar I disorder * Antipsychotic and source Bipolar I Trial Dosage (mg/d) episode (# of duration subjects) (days) Risperidone Manic, mixed 21 0.5 to 2.5 Pandina et al (3) (169) 3 to 6 AACAP 2007 Olanzapine Manic, mixed 21 10.4 [+ or -] 4.5 Tohen et al (4) (161) Quetiapine Manic 21 400 DelBello et al (5) (284) 600 AACAP 2007 Aripiprazole Manic, mixed 28 10 Wagner et al (6) (296) 30 ACNP 2007 Ziprasidone Manic, mixed 28 80 to 160 DelBello et al (7) (238) APA 2008 Antipsychotic and source Response rate or NNT Mean weight YMRS score change gain (kg) Risperidone 59% 3.3 1.9 Pandina et al (3) 63% 3.5 1.4 AACAP 2007 Olanzapine 49% 4.1 3.7 Tohen et al (4) [+ or -] 2.2 Quetiapine 64% 4.4 1.7 DelBello et al (5) 58% 4.2 1.7 AACAP 2007 Aripiprazole 45% 4.1 0.9 Wagner et al (6) 64% 2.4 0.54 ACNP 2007 Ziprasidone -13.83 with 3.7 None DelBello et al (7) ziprasidone, APA 2008 -8.61 with placebo * Each trial included a 6-month open extension phase; results are pending AACAP: American Academy of Child and Adolescent Psychiatry; ACNP: American College of Neuropsychopharmacology; APA: American Psychiatric Association; NNT: number needed to treat; RCT: randomized controlled trial; YMRS: Young Mania Rating Scale Change in Young Mania Rating Scale (YMRS) score was the primary outcome measure in these 5 trials, and each compound was more effective than placebo. The trials demonstrated statistically significant and clinically relevant differences between each antipsychotic and a placebo. The number needed to treat (NNT)--how many patients need to be treated for 1 to benefit in a controlled clinical trial--ranged from 2 to 4. For comparison, the NNT for statins in the prevention of coronary events is 12 to 22, (8) and the NNT in an analysis of trials of selective serotonin reuptake inhibitors for pediatric major depressive disorder was 9. (9) Thus, an NNT of [less than or equal to] 4 represents a clinically significant effect. …
Journal of the American Academy of Child and Adolescent Psychiatry, 2022
OBJECTIVETo develop a new approach to prescribing guidelines as part of a pragmatic trial, Target... more OBJECTIVETo develop a new approach to prescribing guidelines as part of a pragmatic trial, Targeted and Safer Use of Antipsychotics in Youth (SUAY - ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03448575","term_id":"NCT03448575"}}NCT03448575) that supports prescribers in delivering high-quality mental health care to youth.METHODA nominal group technique was used to identify first to nth line treatments for target symptoms and potential diagnoses. The panel included US pediatricians, child and adolescent psychiatrists and psychopharmacology experts. Meeting materials included information about Medicaid review programs, systematic reviews, prescribing guidelines, and a description of the pragmatic trial. Afterwards, a series of four webinar discussions were held to achieve consensus on recommendations.RESULTSThe panel unanimously agreed that the guideline should focus on target symptoms rather than diagnoses. Guidance included recommendations for 1st- to nth-line treatment of target mental health symptoms, environmental factors to be addressed, possible underlying diagnoses that should first be considered and ruled out, and general considerations for pharmacological and therapeutic treatments.CONCLUSIONPrescribing guidelines are often ignored because they do not incorporate the real-world availability of first-line psychosocial treatments, comorbid conditions and clinical complexity. Our approach addresses some of these concerns. If the approach proves successful in our ongoing pragmatic trial, Targeted and Safer Use of Antipsychotics in Youth (SUAY), it may serve as a model to state Medicaid programs and health systems to support clinicians in delivering high-quality mental health care to youth.
Page 1. Clinical Manual for Management of Bipolar Disorder in Children and Adolescents Robert A. ... more Page 1. Clinical Manual for Management of Bipolar Disorder in Children and Adolescents Robert A. Kowatch, MD, Ph.D. Mary A. Fristad, Ph.D., ABPP Robert L Findling, MD Robert M. Post, MD Page 2. Clinical Manual for Management ...
This article provides pediatricians and other clinicians who treat children and adolescents with ... more This article provides pediatricians and other clinicians who treat children and adolescents with a working knowledge of mood stabilizers and their potential uses in children and adolescents with mood and behavior disorders. Mood stabilizers are ubiquitous agents that are often effective in the treatment of children and adolescents with bipolar disorders or conduct disorders and mentally retarded patients with aggressive behavior. The authors' also discuss mechanisms of action, pharmacokinetics, dosing, drug interactions, and potential uses. Following these medication details, specific information concerning the diagnosis and treatment of several child and adolescent mood and behavior disorders, and in which treatment with mood stabilizers may be helpful, is presented.
Journal of the American Academy of Child and Adolescent Psychiatry, May 1, 2001
To assess lifetime and current psychiatric disorders at least 1 year after traumatic brain injury... more To assess lifetime and current psychiatric disorders at least 1 year after traumatic brain injury (TBI) in children and adolescents. Forty-six youths who sustained a TBI between the ages of 6 through 15 years were evaluated at least 1 year post-TBI to identify the presence of lifetime and/or novel psychiatric disorders. Semistructured interviews of the parent and child and standardized parent self-report rating instruments were used. Attention-deficit/hyperactivity disorder and depressive disorders were the most common lifetime and novel diagnoses. A wide variety and high rate of novel psychiatric disorders were identified; 74% of these disorders persisted in 48% of the injured children. Internalizing disorders were more likely to resolve than externalizing disorders. Both interviews and parent ratings were sensitive to current externalizing behaviors; interviews more often detected internalizing disorders, whereas parent ratings also identified cognitive difficulties. Findings were generally consistent with previous research demonstrating the high rate of novel psychiatric disorders following pediatric TBI. Psychiatric interviews were sensitive in identifying both lifetime and novel disorders.
Risperidone is the first second-generation antipsychotic (SGA) to receive FDA approval for treati... more Risperidone is the first second-generation antipsychotic (SGA) to receive FDA approval for treating children and adolescents with bipolar mania or schizophrenia. Specifically, the SGA is indicated for treating schizophrenia in patients age 13 to 17 and as monotherapy in short-term treatment of manic or mixed episodes of bipolar I disorder in patients age 10 to 17 (Table 1). Risperidone also is approved for: * schizophrenia in adults * acute mania or mixed episodes associated with bipolar I disorder in adults, alone or in combination with lithium or valproate * irritability associated with autistic disorder in patients age 5 to 16. Clinical implications Risperidone is widely used off-label to treat irritability in children with pervasive developmental disorders, (1,2) aggressive behaviors associated with conduct disorder, (3) psychotic disorders, (4) and bipolar disorder. (5) It also has been used off-label to treat pediatric schizophrenia and bipolar disorder for many years. These 2 new indications give clinicians additional support for using SGAs in children and adolescents with these serious psychiatric disorders. How it works Risperidone's therapeutic activity in schizophrenia seems to be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of risperidone's other therapeutic effects. Pharmacokinetics In children, the half-lives of risperidone and its major active metabolite 9-hydroxyrisperidone are 3 [+ or -] 2.3 hours and 22 [+ or -] 46 hours, respectively. (6) The pharmacologic activity of 9-hydroxyrisperidone is similar to that of risperidone. Risperidone is extensively metabolized in the liver by the cytochrome P-450 (CYP) 2D6 enzyme system. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by CYP 2D6. Food does not affect the rate or extent of the drug's absorption. (6) Efficacy studies In schizophrenia. Approval of the indication for pediatric schizophrenia was based on data from 2 short-term (6 and 8 weeks) randomized, double-blind, controlled trials involving a total of 416 patients age 13 to 17 who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute episode at enrollment. (7) In one study, patients received risperidone, 1 to 3 mg/d, 4 to 6 mg/d, or placebo. In the other study, dosages were 0.15 to 0.6 mg/d or 1.5 to 6 mg/d. Except for patients in the 0.15 to 0.6 mg group (who initially received 0.05 mg/d), most patients started risperidone at 0.5 mg/d. In both trials, starting dosages were titrated to the target range in approximately 7 days. Outcomes were measured as changes in total Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale scores. The multi-item PANSS inventory measures positive and negative schizophrenia symptoms, disorganized thoughts, uncontrolled hostility / excitement, and anxiety / depression. The PSP gauges personal and social functioning in socially useful activities (work and study), personal and social relationships, self-care, and disturbing/aggressive behaviors. Risperidone, 1 to 6 mg/d, improved schizophrenia symptoms significantly more than placebo, as measured by PANSS scores. Doses >3 mg/d did not show greater efficacy than lower doses, as evaluated by PANSS and PSP scores. Adverse reactions experienced by >5% of patients treated with risperidone included somnolence, parkinsonism, tremor, dystonia, dizziness, akathisia, increased salivation, and anxiety. (7) In bipolar I disorder. Risperidone's efficacy for short-term treatment of mania in children and adolescents was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multi-center study of 169 patients age 10 to 17 who were experiencing a manic or mixed episode of bipolar I disorder. …
In this chapter, we review the clinical characteristics, polysomnographic features, and treatment... more In this chapter, we review the clinical characteristics, polysomnographic features, and treatment of three common psychiatric disorders that may include nocturnal symptoms as part of their clinical presentation: nocturnal panic attacks (PAs), posttraumatic stress disorder (PTSD), and dissociative disorders (DD).
Journal of the American Academy of Child and Adolescent Psychiatry, May 1, 2009
To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day dou... more To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study. In the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 microg/mL. Sixty-six patients enrolled in the extension study. In the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER -8.8 [n = 74]; placebo -7.9 [n = 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting. The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.
Impairments in family functioning are associated with more severe depressive and manic symptoms, ... more Impairments in family functioning are associated with more severe depressive and manic symptoms, earlier recurrences, and more suicidal behaviors in early-onset bipolar disorder. This study examined whether family-focused treatment for adolescents (FFT-A) with BD I or II disorder led to greater increases in family cohesion and adaptability and decreases in conflict over 2 years compared to a briefer psychoeducational treatment (enhanced care, EC). Participants were 144 adolescents (mean age:15.6 ± 1.4 years) with BD I or II with a mood episode in the previous 3 months. Adolescents and parents were randomized to either FFT-A (21 sessions) or EC (three sessions). Patients received guideline-based pharmacotherapy throughout the 2-year study. Trajectories of adolescent- and parent-rated family cohesion, adaptability, and conflict were analyzed over 2 years. FFT-A had greater effects on adolescent-rated family cohesion compared to EC over 2 years. Participants in FFT-A and EC reported similar improvements in family conflict across the 2 years. In the FFT-A group, low-conflict families had greater adolescent-rated family cohesion throughout the study compared to high-conflict families. High-conflict families in both treatment groups tended to show larger reductions in conflict over 2 years than low-conflict families. Family psychoeducation and skills training may improve family cohesion in the early stages of BD. Measuring levels of family conflict at the start of treatment may inform treatment responsiveness among those receiving FFT-A.
Five recent randomized controlled trials (RCTs) have demonstrated the efficacy of atypical antips... more Five recent randomized controlled trials (RCTs) have demonstrated the efficacy of atypical antipsychotics for treating bipolar disorder in children and adolescents, but 4 of these 5 trials remain unpublished. The lag time between the completion of these trials and publication of their results--typically 4 to 5 years (1)--leaves psychiatrists without important evidence to explain to families and critics (2) why they might recommend using these powerful medications in children with mental illness. [ILLUSTRATION OMITTED] This article previews the preliminary results of these 5 RCTs of atypical antipsychotics, offers a treatment algorithm supported by this evidence, and discusses how to manage potentially serious risks when using antipsychotics to treat children and adolescents with bipolar disorder (BPD). Where do atypical antipsychotics fit in? Details of the 5 industry-sponsored RCTs of atypical antipsychotics in children and adolescents with bipolar I manic or mixed episodes are summarized in Table 1 (page 24). (3-7) Only the olanzapine study (4) has been published; data from the other 4 trials were presented at medical meetings in 2007 and 2008. Table 1 RCTs of atypical antipsychotics in patients age 10 to 17 with bipolar I disorder * Antipsychotic and source Bipolar I Trial Dosage (mg/d) episode (# of duration subjects) (days) Risperidone Manic, mixed 21 0.5 to 2.5 Pandina et al (3) (169) 3 to 6 AACAP 2007 Olanzapine Manic, mixed 21 10.4 [+ or -] 4.5 Tohen et al (4) (161) Quetiapine Manic 21 400 DelBello et al (5) (284) 600 AACAP 2007 Aripiprazole Manic, mixed 28 10 Wagner et al (6) (296) 30 ACNP 2007 Ziprasidone Manic, mixed 28 80 to 160 DelBello et al (7) (238) APA 2008 Antipsychotic and source Response rate or NNT Mean weight YMRS score change gain (kg) Risperidone 59% 3.3 1.9 Pandina et al (3) 63% 3.5 1.4 AACAP 2007 Olanzapine 49% 4.1 3.7 Tohen et al (4) [+ or -] 2.2 Quetiapine 64% 4.4 1.7 DelBello et al (5) 58% 4.2 1.7 AACAP 2007 Aripiprazole 45% 4.1 0.9 Wagner et al (6) 64% 2.4 0.54 ACNP 2007 Ziprasidone -13.83 with 3.7 None DelBello et al (7) ziprasidone, APA 2008 -8.61 with placebo * Each trial included a 6-month open extension phase; results are pending AACAP: American Academy of Child and Adolescent Psychiatry; ACNP: American College of Neuropsychopharmacology; APA: American Psychiatric Association; NNT: number needed to treat; RCT: randomized controlled trial; YMRS: Young Mania Rating Scale Change in Young Mania Rating Scale (YMRS) score was the primary outcome measure in these 5 trials, and each compound was more effective than placebo. The trials demonstrated statistically significant and clinically relevant differences between each antipsychotic and a placebo. The number needed to treat (NNT)--how many patients need to be treated for 1 to benefit in a controlled clinical trial--ranged from 2 to 4. For comparison, the NNT for statins in the prevention of coronary events is 12 to 22, (8) and the NNT in an analysis of trials of selective serotonin reuptake inhibitors for pediatric major depressive disorder was 9. (9) Thus, an NNT of [less than or equal to] 4 represents a clinically significant effect. …
Journal of the American Academy of Child and Adolescent Psychiatry, 2022
OBJECTIVETo develop a new approach to prescribing guidelines as part of a pragmatic trial, Target... more OBJECTIVETo develop a new approach to prescribing guidelines as part of a pragmatic trial, Targeted and Safer Use of Antipsychotics in Youth (SUAY - ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03448575","term_id":"NCT03448575"}}NCT03448575) that supports prescribers in delivering high-quality mental health care to youth.METHODA nominal group technique was used to identify first to nth line treatments for target symptoms and potential diagnoses. The panel included US pediatricians, child and adolescent psychiatrists and psychopharmacology experts. Meeting materials included information about Medicaid review programs, systematic reviews, prescribing guidelines, and a description of the pragmatic trial. Afterwards, a series of four webinar discussions were held to achieve consensus on recommendations.RESULTSThe panel unanimously agreed that the guideline should focus on target symptoms rather than diagnoses. Guidance included recommendations for 1st- to nth-line treatment of target mental health symptoms, environmental factors to be addressed, possible underlying diagnoses that should first be considered and ruled out, and general considerations for pharmacological and therapeutic treatments.CONCLUSIONPrescribing guidelines are often ignored because they do not incorporate the real-world availability of first-line psychosocial treatments, comorbid conditions and clinical complexity. Our approach addresses some of these concerns. If the approach proves successful in our ongoing pragmatic trial, Targeted and Safer Use of Antipsychotics in Youth (SUAY), it may serve as a model to state Medicaid programs and health systems to support clinicians in delivering high-quality mental health care to youth.
Page 1. Clinical Manual for Management of Bipolar Disorder in Children and Adolescents Robert A. ... more Page 1. Clinical Manual for Management of Bipolar Disorder in Children and Adolescents Robert A. Kowatch, MD, Ph.D. Mary A. Fristad, Ph.D., ABPP Robert L Findling, MD Robert M. Post, MD Page 2. Clinical Manual for Management ...
This article provides pediatricians and other clinicians who treat children and adolescents with ... more This article provides pediatricians and other clinicians who treat children and adolescents with a working knowledge of mood stabilizers and their potential uses in children and adolescents with mood and behavior disorders. Mood stabilizers are ubiquitous agents that are often effective in the treatment of children and adolescents with bipolar disorders or conduct disorders and mentally retarded patients with aggressive behavior. The authors' also discuss mechanisms of action, pharmacokinetics, dosing, drug interactions, and potential uses. Following these medication details, specific information concerning the diagnosis and treatment of several child and adolescent mood and behavior disorders, and in which treatment with mood stabilizers may be helpful, is presented.
Journal of the American Academy of Child and Adolescent Psychiatry, May 1, 2001
To assess lifetime and current psychiatric disorders at least 1 year after traumatic brain injury... more To assess lifetime and current psychiatric disorders at least 1 year after traumatic brain injury (TBI) in children and adolescents. Forty-six youths who sustained a TBI between the ages of 6 through 15 years were evaluated at least 1 year post-TBI to identify the presence of lifetime and/or novel psychiatric disorders. Semistructured interviews of the parent and child and standardized parent self-report rating instruments were used. Attention-deficit/hyperactivity disorder and depressive disorders were the most common lifetime and novel diagnoses. A wide variety and high rate of novel psychiatric disorders were identified; 74% of these disorders persisted in 48% of the injured children. Internalizing disorders were more likely to resolve than externalizing disorders. Both interviews and parent ratings were sensitive to current externalizing behaviors; interviews more often detected internalizing disorders, whereas parent ratings also identified cognitive difficulties. Findings were generally consistent with previous research demonstrating the high rate of novel psychiatric disorders following pediatric TBI. Psychiatric interviews were sensitive in identifying both lifetime and novel disorders.
Risperidone is the first second-generation antipsychotic (SGA) to receive FDA approval for treati... more Risperidone is the first second-generation antipsychotic (SGA) to receive FDA approval for treating children and adolescents with bipolar mania or schizophrenia. Specifically, the SGA is indicated for treating schizophrenia in patients age 13 to 17 and as monotherapy in short-term treatment of manic or mixed episodes of bipolar I disorder in patients age 10 to 17 (Table 1). Risperidone also is approved for: * schizophrenia in adults * acute mania or mixed episodes associated with bipolar I disorder in adults, alone or in combination with lithium or valproate * irritability associated with autistic disorder in patients age 5 to 16. Clinical implications Risperidone is widely used off-label to treat irritability in children with pervasive developmental disorders, (1,2) aggressive behaviors associated with conduct disorder, (3) psychotic disorders, (4) and bipolar disorder. (5) It also has been used off-label to treat pediatric schizophrenia and bipolar disorder for many years. These 2 new indications give clinicians additional support for using SGAs in children and adolescents with these serious psychiatric disorders. How it works Risperidone's therapeutic activity in schizophrenia seems to be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of risperidone's other therapeutic effects. Pharmacokinetics In children, the half-lives of risperidone and its major active metabolite 9-hydroxyrisperidone are 3 [+ or -] 2.3 hours and 22 [+ or -] 46 hours, respectively. (6) The pharmacologic activity of 9-hydroxyrisperidone is similar to that of risperidone. Risperidone is extensively metabolized in the liver by the cytochrome P-450 (CYP) 2D6 enzyme system. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by CYP 2D6. Food does not affect the rate or extent of the drug's absorption. (6) Efficacy studies In schizophrenia. Approval of the indication for pediatric schizophrenia was based on data from 2 short-term (6 and 8 weeks) randomized, double-blind, controlled trials involving a total of 416 patients age 13 to 17 who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute episode at enrollment. (7) In one study, patients received risperidone, 1 to 3 mg/d, 4 to 6 mg/d, or placebo. In the other study, dosages were 0.15 to 0.6 mg/d or 1.5 to 6 mg/d. Except for patients in the 0.15 to 0.6 mg group (who initially received 0.05 mg/d), most patients started risperidone at 0.5 mg/d. In both trials, starting dosages were titrated to the target range in approximately 7 days. Outcomes were measured as changes in total Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale scores. The multi-item PANSS inventory measures positive and negative schizophrenia symptoms, disorganized thoughts, uncontrolled hostility / excitement, and anxiety / depression. The PSP gauges personal and social functioning in socially useful activities (work and study), personal and social relationships, self-care, and disturbing/aggressive behaviors. Risperidone, 1 to 6 mg/d, improved schizophrenia symptoms significantly more than placebo, as measured by PANSS scores. Doses >3 mg/d did not show greater efficacy than lower doses, as evaluated by PANSS and PSP scores. Adverse reactions experienced by >5% of patients treated with risperidone included somnolence, parkinsonism, tremor, dystonia, dizziness, akathisia, increased salivation, and anxiety. (7) In bipolar I disorder. Risperidone's efficacy for short-term treatment of mania in children and adolescents was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multi-center study of 169 patients age 10 to 17 who were experiencing a manic or mixed episode of bipolar I disorder. …
In this chapter, we review the clinical characteristics, polysomnographic features, and treatment... more In this chapter, we review the clinical characteristics, polysomnographic features, and treatment of three common psychiatric disorders that may include nocturnal symptoms as part of their clinical presentation: nocturnal panic attacks (PAs), posttraumatic stress disorder (PTSD), and dissociative disorders (DD).
Journal of the American Academy of Child and Adolescent Psychiatry, May 1, 2009
To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day dou... more To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study. In the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 microg/mL. Sixty-six patients enrolled in the extension study. In the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER -8.8 [n = 74]; placebo -7.9 [n = 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting. The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.
Impairments in family functioning are associated with more severe depressive and manic symptoms, ... more Impairments in family functioning are associated with more severe depressive and manic symptoms, earlier recurrences, and more suicidal behaviors in early-onset bipolar disorder. This study examined whether family-focused treatment for adolescents (FFT-A) with BD I or II disorder led to greater increases in family cohesion and adaptability and decreases in conflict over 2 years compared to a briefer psychoeducational treatment (enhanced care, EC). Participants were 144 adolescents (mean age:15.6 ± 1.4 years) with BD I or II with a mood episode in the previous 3 months. Adolescents and parents were randomized to either FFT-A (21 sessions) or EC (three sessions). Patients received guideline-based pharmacotherapy throughout the 2-year study. Trajectories of adolescent- and parent-rated family cohesion, adaptability, and conflict were analyzed over 2 years. FFT-A had greater effects on adolescent-rated family cohesion compared to EC over 2 years. Participants in FFT-A and EC reported similar improvements in family conflict across the 2 years. In the FFT-A group, low-conflict families had greater adolescent-rated family cohesion throughout the study compared to high-conflict families. High-conflict families in both treatment groups tended to show larger reductions in conflict over 2 years than low-conflict families. Family psychoeducation and skills training may improve family cohesion in the early stages of BD. Measuring levels of family conflict at the start of treatment may inform treatment responsiveness among those receiving FFT-A.
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Papers by Robert Kowatch