Baseline predictors of response to divalproex in conduct disorder

BACKGROUND: Successful treatment of conduct disorder remains difficult. On the basis of a positive response to divalproex among adolescent boys with conduct disorder, we conducted an analysis of the impact of baseline comorbid diagnoses and personality factors on the likelihood of treatment response to divalproex. METHOD: Seventy-one adolescent boys with conduct disorder (DSM-IV) and a history of at least 1 offense against persons were randomly assigned to receive high- or low-dose divalproex for 7 weeks. Evaluations included best estimate diagnoses, the Clinical Global Impressions-Severity of Illness scale (CGI-S) and CGI-Improvement scale (CGI-I), the 62-item Weinberger Adjustment Inventory (WAI-62) assessment of distress and restraint, the Response Evaluation Measure assessment of immature and mature defenses, and the Achenbach Youth Self-Report assessment of overall psychopathology. All were conducted at study entry and exit, and the WAI-62 was conducted weekly throughout the 7-week study period. Treatment response was defined as a rating of much improved or very much improved on the CGI-I. Data were collected from June 1997 to April 1998. RESULTS: Fifty-eight subjects completed the study and were eligible for inclusion in the analysis. Plasma divalproex level (p = .003) and immature defenses (p = .004) were significant positive predictors of treatment response, while restraint (p = .01) and level and range of psychopathology (p = .04) were significant predictors of nonresponse. Comorbidities or distress (p = .06) were not significantly associated with treatment outcome. CONCLUSION: Predictors of response to divalproex treatment for conduct disorder were identified, despite the small sample size in this study. The pattern of positive and negative predictors of response to divalproex, an antikindling agent, tends to support a model of kindling-reinforced reactive/affective/defensive/impulsive aggression among adolescent boys with conduct disorder. Additional studies are needed to identify more subtle predictors of treatment response and to clarify the mechanisms contributing to the development of conduct disorder.     

Divalproex Sodium for the Treatment of PTSD and Conduct Disordered Youth: A Pilot Randomized Controlled Clinical Trial

We examined the efficacy of divalproex sodium (DVP) for the treatment of PTSD in conduct disorder, utilizing a previous study in which 71 youth were enrolled in a randomized controlled clinical trial. Twelve had PTSD. Subjects (all males, mean age 16,␣SD 1.0) were randomized into high and low dose conditions. Clinical Global Impression (CGI) ratings for core PTSD symptoms (Intrusion, avoidance and hyper arousal) were primary outcome measures, weekly slopes of impulsivity secondary ones. Intent-to-treat analyses showed significant positive associations between receiving high dose of DVP CGI’s. Parallel analyses comparing outcome by drug level achieved strengthened the results.     

The Clinical Global Impressions scale: errors in understanding and use

Objective

The Clinical Global Impressions Severity and Improvement scales (CGI-S and CGI-I) are widely included as efficacy data in psychopharmacology new drug application submissions. This study was conducted to determine the extent to which clinical trials investigators included information unrelated to efficacy in their CGI ratings.

Method

Forty-five principal investigators provided CGI-S and CGI-I ratings of narratives of patients with major depressive disorder or generalized anxiety disorder. Investigators were blindly randomized to receive narratives that either did (experimental) or did not (control) contain indication-unrelated medical or psychiatric adverse events. Investigators then completed a survey assessing CGI-S and CGI-I rating patterns.

Results

CGI-S and CGI-I ratings were significantly more severe and less improved when the narratives contained medical and psychiatric adverse events unrelated to the diseases under study (major depressive disorder and generalized anxiety disorder) than when the narratives did not (Ps < .04). In response to the survey, 46% and 56% of investigators reported that a psychiatric adverse event unrelated to the disease under study would not affect their CGI-S and CGI-I ratings, respectively. Although 87% of investigators reported that their CGI-S and CGI-I ratings would not be affected by a medical adverse event, actual CGI-S ratings were significantly more severe when an unrelated medical adverse event was described as occurring than when it was not (P < .03).

Conclusion

Clinical trials investigators' inclusion of indication-irrelevant adverse events threatens the validity of the CGI as an efficacy measure and may contribute to failure to detect efficacy signals in psychopharmacology clinical trials.     

Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder

BACKGROUND: Posttraumatic stress disorder (PTSD) is a common illness associated with significant disability. Few large, placebo-controlled trials have been reported. METHODS: Outpatients with a DSM-III-R diagnosis of moderate-to-severe PTSD were randomized to 12 weeks of double-blind treatment with either sertraline (N = 100) in flexible daily doses in the range of 50 to 200 mg or placebo (N = 108). Primary outcome measures consisted of the Clinician-Administered PTSD Scale (CAPS-2) total severity score, the patient-rated Impact of Event Scale (IES), and the Clinical Global Impression-Severity (CGI-S) and -Improvement (CGI-I) ratings. RESULTS: Mixed-effects analyses found significantly steeper improvement slopes for sertraline compared with placebo on the CAPS-2 (t = 2.96, P =.003), the IES (t = 2.26, P =.02), the CGI-I score (t = 3.62, P<.001), and the CGI-S score (t = 4.40, P<.001). An intent-to-treat end-point analysis found a 60% responder rate for sertraline and a 38% responder rate for placebo (chi(2)(1) = 8.48, P =.004). Sertraline treatment was well tolerated, with a 9% discontinuation rate because of adverse events, compared with 5% for placebo. Adverse events that were significantly more common in subjects given sertraline compared with placebo consisted of insomnia (35% vs 22%), diarrhea (28% vs 11%), nausea (23% vs 11%), fatigue (13% vs 5%), and decreased appetite (12% vs 1%). CONCLUSION: The results of the current study suggest that sertraline is a safe, well-tolerated, and significantly effective treatment for PTSD.     

Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes

BACKGROUND: Divalproex sodium is a mood stabilizer used in the United States for the treatment of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical antipsychotic, was approved for the treatment of acute mania. This study compares the clinical, health-related quality of life (HRQL), and economic outcomes of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. METHOD: This 12-week, double-blind, double-dummy, randomized clinical trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for an acute manic episode recruited from 21 U.S. clinical centers. Subjects were randomly assigned to treatment with either divalproex or olanzapine and were followed in hospital for up to 21 days. If after 21 days clinical improvements (based on the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects showing clinical improvement were treated for up to 12 weeks. HRQL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and costs were collected over the 12-week study. RESULTS: A total of 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed beyond 21 days. No statistically significant differences between the treatment groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week outpatient medical costs were significantly lower for the divalproex-treated group (541 US dollars) compared with the olanzapine-treated group (1080 US dollars) (p =.004). There was no significant difference in total medical costs between the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars; p =.88). CONCLUSION: Divalproex is associated with lower 12-week outpatient costs compared with olanzapine. Divalproex and olanzapine have similar short-term effects on clinical or HRQL outcomes in bipolar disorder subjects.     

A preliminary double-blind, placebo-controlled trial of divalproex sodium in borderline personality disorder

BACKGROUND: Borderline personality disorder is characterized by affective instability, impulsivity, and aggression and is associated with considerable morbidity and mortality. Since anticonvulsant agents may be helpful in such symptomatology, we compared divalproex sodium with placebo in patients with borderline personality disorder. METHOD: A 10-week, parallel, double-blind design was conducted. Sixteen outpatients meeting Structured Clinical Interview for DSM-IV Axis II Personality Disorders criteria for borderline personality disorder were randomly assigned to receive placebo (N = 4) or divalproex sodium (N = 12). Change was assessed in global symptom severity (Clinical Global Impressions-Improvement Scale [CGI-I]) and functioning (Global Assessment Scale [GAS]) as well as in specific core symptoms (depression, aggression, irritability, and suicidality). RESULTS: There was significant improvement from baseline in both global measures (CGI-I and GAS) following divalproex sodium treatment. A high dropout rate precluded finding significant differences between the treatment groups in the intent-to-treat analyses, although all results were in the predicted direction. CONCLUSION: Treatment with divalproex sodium may be more effective than placebo for global symptomatology, level of functioning, aggression, and depression. Controlled trials with larger sample sizes are warranted to confirm these preliminary results.     

Clinical experience with anticonvulsant medication in pediatric epilepsy and comorbid bipolar spectrum disorder

Anticonvulsant drugs are first-line treatments for both bipolar mood disorder and epilepsy; however, few studies have explored treatment options when these disorders co-occur. The aim of this study was to identify bipolar disorder symptoms common in pediatric epilepsy and to determine whether anticonvulsant monotherapy might be a practical treatment consideration. A retrospective chart review identified 38 children with bipolar spectrum disorder and epilepsy comorbidity. Two mental health clinicians independently assessed psychiatric diagnoses, symptoms, and assigned retrospective CGI-I ratings for psychiatric symptoms. Common bipolar symptoms included impulsivity, psychomotor agitation, and explosive rage. Forty-two medication trials with 11 different anticonvulsants were identified. Of the 30 instances in which anticonvulsant monotherapy was attempted, carbamazepine, divalproex sodium, lamotrigine, and oxcarbazepine were associated with better psychiatric CGI-I ratings than other monotherapies (P<0.01). Results suggest that in many cases, selected anticonvulsants appeared to simultaneously treat both epilepsy and mood disorder. Controlled trials are necessary to further ascertain optimal anticonvulsant usage.     

A double-blind,placebo-controlled study of the efficacy and safety of controlled-release fluvoxamine in patients with obsessive-compulsive disorder

OBJECTIVE: The aim of this 12-week, double-blind, flexible-dose, placebo-controlled, parallel-arm, multicenter trial was to determine the safety and efficacy of fluvoxamine in a controlled-release (CR) formulation in adult outpatients with obsessive-compulsive disorder (OCD). METHOD: 253 adult outpatients with DSM-IV OCD were randomly assigned to receive 100 to 300 mg of fluvoxamine CR (N = 127) or placebo (N = 126) once daily for 12 weeks. Intent-to-treat analyses of efficacy assessments with the Yale-Brown Obsessive Compulsive Scale (YBOCS), Clinical Global Impressions-Severity of Illness scale (CGI-S), and Clinical Global Impressions-Improvement scale (CGI-I) were conducted. RESULTS: Fluvoxamine CR was significantly (p <.05) superior to placebo in decreasing YBOCS total score beginning at week 2. This early response was sustained at all subsequent visits. At endpoint, there was a mean decrease of 8.5 +/- 0.7 (31.7%) in the YBOCS total score compared with baseline in the fluvoxamine CR treatment group versus a mean decrease of 5.6 +/- 0.7 (21.2%) in the placebo group (p =.001). Fluvoxamine CR was also significantly superior to placebo in lowering the severity of illness (CGI-S, p =.002) and in producing clinical improvement (CGI-I, p <.01). At endpoint, significantly greater percentages of the fluvoxamine CR treatment group were responders (p =.002) and remitters (p =.019) compared with the placebo group. CONCLUSION: Over 12 weeks, fluvoxamine CR treatment was associated with a statistically significant and clinically relevant reduction in OCD severity and was found to be safe and well tolerated. The early onset of therapeutic effect, starting from week 2, was of particular interest.     

Divalproex sodium treatment of women with borderline personality disorder and bipolar II disorder: a double-blind placebo-controlled pilot study

BACKGROUND: The intent of this study was to compare the efficacy and safety of divalproex sodium and placebo in the treatment of women with borderline personality disorder and comorbid bipolar II disorder. METHOD: We conducted a placebo-controlled double-blind study of divalproex sodium in 30 female subjects aged 18 to 40 years who met Revised Diagnostic Interview for Borderlines and DSM-IV criteria for borderline personality disorder and DSM-IV criteria for bipolar II disorder. Subjects were randomly assigned to divalproex sodium or placebo in a 2:1 manner. Treatment duration was 6 months. Primary outcome measures were changes on the interpersonal sensitivity, anger/hostility, and depression scales of the Symptom Checklist 90 (SCL-90) as well as the total score of the modified Overt Aggression Scale (MOAS). RESULTS: Twenty subjects were randomly assigned to divalproex sodium; 10 subjects to placebo. Using a last-observation-carried-forward paradigm and controlling for baseline severity, divalproex sodium proved to be superior to placebo in diminishing interpersonal sensitivity and anger/hostility as measured by the SCL-90 as well as overall aggression as measured by the MOAS. Adverse effects were infrequent. CONCLUSION: The results of this study suggest that divalproex sodium may be a safe and effective agent in the treatment of women with criteria-defined borderline personality disorder and comorbid bipolar II disorder, significantly decreasing their irritability and anger, the tempestuousness of their relationships, and their impulsive aggressiveness.     

Long-term outcome with divalproex in children and adolescents with bipolar disorder

OBJECTIVE: To assess the outcome and safety of divalproex treatment in children and adolescents with bipolar disorder. METHODS: We conducted a chart review of children and adolescents who were treated with divalproex and who met Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for bipolar disorder (dose 966 +/- 501 mg/day, level 79.4 +/- 23.1 micro g/mL, duration 1.4 +/- 1.5 years). Responders were defined as those showing moderate to marked response on the Clinical Global Impression-Improvement (CGI-I) scale. RESULTS: Eight of 15 (53%) patients responded to divalproex treatment for mixed episode (n = 6), disruptive behavior (n = 4), pure mania (n = 3), or depression (n = 2). Six of 15 (40%) discontinued divalproex, most due to side effects (n = 5). The most common side effect was weight gain (4/15, 27%). CONCLUSION: In children aged 4-18 years, divalproex treatment was related to improved outcome in the long-term treatment of bipolar disorder. One third of the patients discontinued treatment secondary to side effects, including a case of reversible liver enzyme elevation.     

Randomized controlled pilot study of quetiapine in the treatment of adolescent conduct disorder

OBJECTIVE: The aim of this study was to examine whether quetiapine is superior to placebo in the treatment of adolescents with conduct disorder. METHODS: This was a 7-week, randomized, double-blind, placebo-controlled pilot study with two parallel arms. Nine youths were randomly assigned to receive quetiapine, and 10 youths were randomly assigned to receive placebo. Patients were assessed weekly throughout the trial. Quetiapine was dosed twice daily, and medications could be titrated flexibly through the end of study week 5. The dose was fixed for the final 2 weeks of the study. The primary outcome measures were the clinician-assessed Clinical Global Impressions-Severity (CGI-S) and-Improvement (CGI-I) scales. Secondary outcome measures included parent-assessed quality of life, the overt aggression scale (OAS), and the conduct problems subscale of the Conners' Parent Rating Scale (CPRS-CP). RESULTS: The final mean dose of quetiapine was 294 +/- 78 mg/day (range 200-600 mg/day). Quetiapine was superior to placebo on all clinician-assessed measures and on the parent-assessed quality of life rating scale. No differences were found on the parent-completed OAS and CPRS-CP. Quetiapine was well tolerated. One patient randomized to quetiapine developed akathisia, requiring medication discontinuation. No other extrapyramidal side effects occurred in patients receiving active drug. CONCLUSIONS: This methodologically controlled pilot study provides data that quetiapine may have efficacy in the treatment of adolescents with conduct disorder. Because of the preliminary nature of the study, further research with larger samples is needed to confirm these findings.     

Efficacy of fluvoxamine in the treatment of major depression with comorbid anxiety disorders.

BACKGROUND: Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared with major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in depressive symptoms and anxiety levels in outpatients with major depression with comorbid anxiety disorder following 12 weeks of open treatment with fluvoxamine. METHOD: We enrolled 30 outpatients (mean +/- SD age = 39.4 +/- 11.3 years; 16 women and 14 men) with DSM-IV major depressive disorder accompanied by one or more current comorbid DSM-IV anxiety disorders in our study. Patients were treated openly with fluvoxamine initiated at 50 mg/day, with an upward titration to a maximum of 200 mg/day (mean +/- SD dose = 143 +/- 45 mg/day). Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and Clinical Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) scales for both depression and anxiety. Intent-to-treat analysis was used to assess outcome. RESULTS: The mean +/- SD number of comorbid anxiety disorders per patient was 2.1 +/- 1.1. Following fluvoxamine treatment, the mean +/- SD HAM-D-17 score dropped from 20.2 +/- 3.3 to 1 1.0 +/- 7.0 (p < .0001). The mean +/- SD depression CGI-S score dropped from 4.0 +/- 0.6 to 2.4 +/- 1.1 (p < .0001), and the mean +/- SD anxiety CGI-S score decreased from 4.1 +/- 0.8 to 2.5 +/- 1.2 (p < .0001). Eighteen (60%) of the 30 patients had CGI-I scores < or = 2 for both anxiety and depression at endpoint, with 53% showing a > or = 50% reduction in HAM-D-17 scores at endpoint. CONCLUSION: Although preliminary, our findings suggest that fluvoxamine is effective in treating outpatients with major depression with comorbid anxiety disorder, having a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are needed, in a larger sample, to confirm our findings.     

Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium

OBJECTIVE: The purpose of this study was to determine whether adjunctive use of a psychostimulant (mixed amphetamine salts) was safe and efficacious for treatment of symptoms of attention deficit hyperactivity disorder (ADHD) in pediatric outpatients with bipolar I or bipolar II disorder and concurrent ADHD whose manic symptoms had been stabilized through treatment with divalproex sodium. METHOD: An 8-week open-label trial of divalproex sodium to control manic symptoms and to discern the effect of divalproex sodium on ADHD was followed by a 4-week randomized, double-blind, placebo-controlled crossover trial to determine if mixed amphetamine salts was safe and effective for treatment of ADHD symptoms. Patients in the crossover trial continued to receive divalproex sodium. Diagnoses, made by clinical interview, were confirmed with the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. The Young Mania Rating Scale (for manic symptoms) and the Clinical Global Impression of improvement (for ADHD symptoms) were the primary outcome measures. RESULTS: Forty subjects ages 6-17 years with bipolar I disorder (77.5%) or bipolar II disorder (22.5%) and a Young Mania Rating Scale score > or =14 entered open treatment with divalproex sodium. With divalproex sodium, 32 subjects achieved > or =50% reduction in Young Mania Rating Scale baseline scores, but only three participants had significant improvement in ADHD symptoms. For the 30 subjects who entered the placebo-controlled crossover trial, mixed amphetamine salts was significantly more effective than placebo for ADHD symptoms. No significant side effects or worsening of manic symptoms was observed. CONCLUSIONS: Pediatric patients with bipolar disorder and concurrent ADHD can be safely and effectively treated with mixed amphetamine salts after their manic symptoms are stabilized with divalproex sodium. Divalproex sodium alone (8-week trial) is not an effective treatment for ADHD in the context of bipolar disorder.     

Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: This multicenter, randomized, fixed-dose, double-blind, placebo-controlled study evaluated efficacy of extended-release dexmethylphenidate (d-MPH-ER) in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: Randomized adults with ADHD (n=221) received once-daily d-MPH-ER 20 mg, 30 mg, or 40 mg or placebo for 5 weeks. The primary efficacy variable was change from baseline to final visit in DSM-IV ADHD Rating Scale (ADHD-RS) total score. Secondary efficacy parameters included the proportion of patients with improvement>or=30% in ADHD-RS total score and final scores on Clinical Global Impressions-Improvement (CGI-I) scale. RESULTS: Of 218 evaluable patients, 184 completed the study. All d-MPH-ER doses were significantly superior to placebo in improving ADHD-RS total scores. Placebo scores improved by 7.9; d-MPH-ER, 20 mg, improved by 13.7 (p=.006); d-MPH-ER, 30 mg, improved by 13.4 (p=.012); and d-MPH-ER, 40 mg, improved by 16.9 (p<.001). Overall distribution of CGI-I ratings at final visit was significantly better with each d-MPH-ER dosage than with placebo. There were no unexpected safety or tolerability concerns, based on experience with racemic methylphenidate (MPH) in adults and dexmethylphenidate (d-MPH) in children. CONCLUSIONS: Once-daily d-MPH-ER at 20 mg, 30 mg, or 40 mg is a safe and effective treatment for adults with ADHD.     

A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis

OBJECTIVE: To evaluate the efficacy and safety of extended-release divalproex sodium compared with placebo in prophylactic monotherapy treatment of migraine headache. METHODS: This was a double-blind, randomized, placebo-controlled, parallel-group study. Subjects with more than two migraine headache attacks during a 4-week baseline were randomly assigned in a 1:1 ratio at each center to receive either extended-release divalproex sodium or matching placebo once daily for 12 weeks. Subjects initiated treatment on 500 mg once daily for 1 week, and the dose was then increased to 1,000 mg once daily with an option, if intolerance occurred, to permanently decrease the dose to 500 mg during the second week. Reduction from baseline in 4-week migraine headache rate was the primary efficacy variable. Migraine headaches separated by a < 24-hour headache-free interval were counted as single migraines in calculating migraine headache rates. Tolerance and safety were also evaluated. RESULTS: The mean reductions in 4-week migraine headache rate were 1.2 (from a baseline mean of 4.4) in the extended-release divalproex sodium group and 0.6 (from a baseline mean of 4.2) in the placebo group (p = 0.006); reductions with extended-release divalproex sodium were significantly greater than with placebo in all three 4-week segments of the treatment period. No significant differences were detected between treatment groups in either the overall incidence or in the incidence of any specific treatment-emergent adverse event; 8% of subjects treated with extended-release divalproex sodium and 9% of those treated with placebo discontinued for adverse events. CONCLUSION: Extended-release divalproex sodium is an efficacious, well-tolerated, safe, and easy-to-use once-a-day prophylactic antimigraine medication.     

Chart review of the impact of attention-deficit/hyperactivity disorder comorbidity on response to lithium or divalproex sodium in adolescent mania

PURPOSE: Although adolescent onset of bipolar disorder is common, the optimal treatment approach for mania in this age group remains understudied. Comorbid attention-deficit/hyperactivity disorder (ADHD) has been reported to predict lithium resistance in adolescents with bipolar disorder. Little is known about response to dival-proex sodium in adolescents with bipolar disorder comorbid with ADHD. This study was conducted to evaluate comparative response rates to lithium and divalproex sodium in adolescent mania with and without this comorbidity. METHOD: Medical records were reviewed for 42 patients (ages 12-19 years) who were hospitalized for acute mania and discharged with a diagnosis of DSM-III-R or DSM-IV bipolar disorder on either lithium (N = 29) or divalproex sodium (N = 13) treatment. A clinician blinded to treatment status rated improvement on the basis of abstracted notes in each case utilizing the Clinical Global Impressions Scale modified for use in bipolar illness (CGI-BP). Response was defined as a discharge CGI-BP overall change score of 1 or 2 (much or very much improved). Data were collected from January 1992 through May 1999. RESULTS: 36/42 (85.7%) patients presented with mixed mania, and 14/41 (34.1%) patients had a history of ADHD. The overall response rate was 80.9% (34/42). 92.6% (25/27) of patients without ADHD were responders versus 57.1% (8/14) of subjects with comorbid ADHD (p =.007). There were no significant differences in response rates for lithium versus divalproex sodium in subjects with and without ADHD. CONCLUSION: These retrospective data suggest overall equivalent response rates for lithium and divalproex sodium in predominantly mixed adolescent mania. However, a history of ADHD was associated with a significantly diminished acute response to both divalproex sodium and lithium as a primary treatment for the manic phase of bipolar disorder.     

An open-label trial of escitalopram in children and adolescents with social anxiety disorder

Social anxiety disorder (SAD) is a highly prevalent and disabling disorder in children and adolescents. This study was designed to evaluate the efficacy and safety of a highly potent and selective serotonin reuptake inhibitor, escitalopram, in the treatment of SAD in children and adolescents. Twenty outpatients with a primary diagnosis of SAD were treated in a 12-week open trial with escitalopram. The primary outcome variable was the change from baseline to end point in Clinical Global Impression-Improvement scale (CGI-I). Secondary efficacy measures included the CGI-Severity scale (CGI-S), the Social Phobia and Anxiety Inventory for Children (SPAI-C), the Screen for Child and Anxiety Related Emotional Disorders (SCARED)-Child and Parent version, and The Youth Quality of Life Instrument-Research Version (Y-QOL-R). On the CGI-I scale, 13 of 20 patients (65%) had a score < or =2, meaning response to treatment. All symptomatic and quality of life measures showed improvements from baseline to week 12, with large effect sizes ranging from 0.9 to 1.9 (all p < 0.001). Escitalopram was generally well-tolerated. These results suggest that escitalopram may be an effective and safe treatment for pediatric SAD. Future double-blind, placebo-controlled, randomized clinical trials are warranted.     

The influence of baseline severity on efficacy of escitalopram and citalopram in the treatment of major depressive disorder: an extended analysis

OBJECTIVE: To determine the differences between escitalopram and citalopram in the treatment of patients with major depressive disorder across a range of baseline severity of depression using trend analysis. METHODS: Data from the three placebo-controlled studies comparing escitalopram to citalopram were analyzed. The pre-specified primary outcome variable was MADRS total score; secondary outcomes included Clinical Global Impression-Severity (CGI-S) and -Improvement (CGI-I) scores. All analyses were based on an intent-to-treat (ITT) population and all direct comparisons were done by ANCOVA adjusting for baseline value and centre. RESULTS: Analyses of the pooled data (N=1203) show that, while the difference between citalopram and placebo was approximately constant across the range of baseline severity, the difference between escitalopram and placebo (p=0.0010 for no trend) and between escitalopram and citalopram (p=0.0012 for no trend) became greater, the more severely depressed the patients were at baseline. A similar pattern was apparent with the CGI-S and CGI-I results. There was a significant superiority of escitalopram over citalopram in response rate (defined as > or = 50% decrease in MADRS total score), and this difference increased with increasing baseline severity. CONCLUSION: These trend analyses thus indicate that the superiority of escitalopram over citalopram is more apparent as the baseline severity of depression increases.     

Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder

OBJECTIVE: To evaluate the efficacy and tolerability of sertraline and imipramine in patients with comorbid panic disorder and major depressive disorder. METHOD: Outpatients meeting a DSM-IV diagnosis of panic disorder and concurrent major depressive disorder were randomized in a 2:1 ratio to 26 weeks of double-blind treatment with either sertraline, in daily doses of 50 to 100 mg, or imipramine, in daily doses of 100 to 200 mg. Primary outcome measures were panic attack frequency (derived from patient diaries) and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: 138 patients were treated with sertraline (76% female; mean age = 40 years) and 69 with imipramine (70% female; mean age = 40 years). The symptoms of both major depressive disorder and panic disorder responded significantly and equivalently to both drugs. Endpoint improvement with sertraline versus imipramine, respectively, on the MADRS was 11.1 +/- 10.8 versus 11.2 +/- 10.4, and on the Clinical Global Impressions-Improvement scale (CGI-I) was 2.1 +/- 1.3 versus 2.4 +/- 1.6. Among study completers, CGI-I responder rates were 88% with sertraline and 91% with imipramine. Treatment outcome was concordant for both diagnoses in approximately 70% of patients and discordant in approximately 30%. Overall, sertraline was significantly better tolerated with significantly fewer discontinuations due to adverse events (11% vs. 22%; chi(2) = 4.39, df = 1, p =.04). CONCLUSION: Both sertraline and imipramine were found to be highly effective treatments for both major depressive disorder and panic disorder, with sertraline showing significantly greater tolerability and compliance during long-term treatment than imipramine.     

An efficacy/effectiveness study of cognitive-behavioral treatment for adolescents with comorbid major depression and conduct disorder

OBJECTIVE: To evaluate effectiveness of the Adolescent Coping With Depression (CWD-A) course, a cognitive-behavioral group intervention for depressed adolescents with comorbid conduct disorder. METHOD: Between 1998 and 2001, 93 nonincarcerated adolescents (ages 13-17 years) meeting criteria for major depressive disorder and conduct disorder were recruited from a county juvenile justice department and randomly assigned to the CWD-A or a life skills/tutoring control condition. Participants were assessed post-treatment and at 6- and 12-month follow-up. Dichotomous outcomes were analyzed with logistic regression; dimensional measures were analyzed using random effects regression. RESULTS: Major depressive disorder recovery rates post-treatment were greater in CWD-A (39%) compared with life skills/tutoring control (19%) (odds ratio 2.66, 95% confidence interval = 1.03-6.85). CWD-A participants reported greater reductions in Beck Depression Inventory-II (r2 = 0.055, p =.033) and Hamilton Depression Rating Scale (r2 = 0.047, p =.039) scores and improved social functioning (r2 = 0.064, p =.019) post-treatment. Group differences in major depressive disorder recovery rates at 6- and 12-month follow-up were nonsignificant, as were differences in conduct disorder both post-treatment and during follow-up. CONCLUSIONS: This is the first randomized, controlled trial of a psychosocial intervention with adolescents with major depressive disorder and conduct disorder. Although the CWD-A appears to be an effective acute treatment for depression in adolescents with multiple disorders, findings emphasize the need to improve long-term outcomes for depressed adolescents with psychiatric comorbidity and imply that interventions for comorbid populations focus directly on each specific disorder.