A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia.

This study assessed the efficacy and the safety of a dosing regimen that was revised from earlier studies for the investigational injectable atypical antipsychotic paliperidone palmitate (approved in the USA, August 2009) for adult patients with acutely exacerbated schizophrenia. The patients (N = 652) were randomly assigned (1:1:1:1) to paliperidone palmitate at 25, 100, or 150 mg eq. or placebo in this 13-week double-blind study. The patients received an injection of paliperidone palmitate at 150 mg eq. or placebo in the deltoid muscle on day 1 and the assigned fixed dose or placebo in the deltoid or gluteal [corrected] on day 8 and then once monthly (days 36 and 64). No oral supplementation was used. Target plasma levels were achieved by day 8 in all paliperidone palmitate groups. The mean change in Positive and Negative Syndrome Scale total score from baseline to end point improved significantly (P < or = 0.034) in all the paliperidone palmitate dose-groups versus placebo. Paliperidone palmitate treatment with this revised dosing regimen led to the achievement of rapid and consistent therapeutically effective plasma levels that were maintained by once-monthly dosing in either the deltoid or gluteal muscle. Common treatment-emergent adverse events (> or =2% of patients in any of the treatment groups) that occurred more frequently in the total paliperidone palmitate group versus the placebo group (with > or =1% difference) were injection-site pain (7.6% vs 3.7%), dizziness (2.5% vs 1.2%), sedation (2.3% vs 0.6%), pain in the extremity (1.6% vs 0.0%), and myalgia (1.0% vs 0.0%). The paliperidone palmitate treatment was efficacious and generally tolerated across the dose range (25, 100, or 150 mg eq.) in adult patients with acutely exacerbated schizophrenia.

Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder.

BACKGROUND: Treatment adherence is a significant problem in patients with bipolar disorder. This study was designed to determine the efficacy of risperidone long-acting injectable (LAI) in the maintenance treatment of bipolar I disorder. METHODS: Eligible patients with current or recent manic or mixed episodes (n = 559, aged 18-65 years) were treated with open-label oral risperidone for 3 weeks (period II) and open-label risperidone LAI for 26 weeks (n = 501; period III). Patients who maintained response (n = 303) were randomly allocated 1:1 to placebo injections (n = 149) or to continue risperidone LAI (n = 154) for up to 24 months (period IV). RESULTS: Most (77%) patients on risperidone LAI received a dose of 25 mg every 2 weeks during period IV. Time to recurrence for any mood episode (primary outcome variable) was significantly longer in the risperidone LAI group versus placebo (p < .001); the difference was significant for time to recurrence of elevated-mood episode (p < .001) but not time to recurrence of depressive episode (p = .805). Weight gains > or = 7% (compared with the period's baseline) occurred in 15% of patients in period III; in 12% of patients on risperidone LAI and 3% of patients on placebo in period IV. CONCLUSIONS: Risperidone LAI monotherapy significantly delayed the time to recurrence of mood episodes, versus placebo, in this controlled, randomized study in patients with bipolar I disorder. Risperidone LAI was tolerable and no new safety concerns emerged compared with previous studies of risperidone LAI.

Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of risperidone monotherapy for the treatment of an acute mixed or manic episode in children and adolescents with bipolar I disorder. METHODS: This randomized, placebo-controlled, double-blind, 3-arm study (N = 169) included children and adolescents (ages 10-17 years) with a DSM-IV diagnosis of bipolar I disorder, experiencing a manic or mixed episode. Study participants were randomized to placebo (n = 58), risperidone 0.5-2.5 mg/day (n = 50), or risperidone 3-6 mg/day (n = 61) for 3 weeks. The primary efficacy measure was change in Young Mania Rating Scale (YMRS) total score from baseline to end point. Safety assessments included adverse event (AE) monitoring and scores on extrapyramidal symptom rating scales. RESULTS: Improvement in mean YMRS total score was significantly greater in risperidone-treated subjects than in placebo-treated subjects [mean change (SD) -9.1 (11.0) for placebo; -18.5 (9.7) for risperidone 0.5-2.5 mg (p < 0.001); -16.5 (10.3) for risperidone 3-6 mg (p < 0.001)]. The most common risperidone-associated AEs were somnolence, headache, and fatigue. Mean (SD) weight gain was 0.7 (1.9) kg, 1.9 (1.7) kg, and 1.4 (2.4) kg in the placebo, risperidone 0.5-2.5 mg, and risperidone 3-6 mg groups, respectively, during this 3-week study. CONCLUSIONS: At daily doses of 0.5-2.5 mg and 3-6 mg, risperidone was effective and well tolerated in children and adolescents experiencing acute manic or mixed episodes of bipolar I disorder. Results indicate that risperidone 0.5-2.5 mg has a better benefit-risk profile than risperidone 3-6 mg.

Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-blind study.

BACKGROUND: Effective treatments for adolescent schizophrenia are needed. AIMS: To compare efficacy and safety of two dosing regimens of risperidone. METHOD: Double-blind, 8-week study. Patients, 13-17 years, with an acute episode of schizophrenia, randomised 1:1 to risperidone 1.5-6.0 mg/day (regimen A; n=125) or 0.15-0.6 mg/day (regimen B; n=132). TRIAL REGISTRATION NUMBER: NCT00034749. RESULTS: Mean total Positive and Negative Syndrome Scale (PANSS) score improved significantly (P<0.001; effect size=0.49) from baseline to end-point for regimen A (mean=96.4 (s.d.=15.39) to mean=72.8 (s.d.=22.52)) compared with regimen B (mean=93.3 (s.d.=14.14) to mean=80.8 (s.d.=24.33)). Treatment-emergent adverse events occurred in 74% (regimen A) and 65% (regimen B) of patients; 4% of patients overall discontinued for adverse events. Mean change in body weight was 3.2 kg (s.d.=3.49) for regimen A and 1.7 kg (s.d.=3.29) for regimen B. CONCLUSIONS: Adolescent patients in the regimen A group showed greater improvement in total PANSS compared with the regimen B group. Treatment was well tolerated.

Maintenance study for adolescent depression.

OBJECTIVE: Although recent studies and meta-analyses confirm the efficacy of antidepressants in the acute phase of treatment for adolescent depression, there are few data available to allow assessment of the value of continued use of antidepressants in depressed adolescents after acute response. This study examines the benefit of maintenance treatment with sertraline in adolescents aged 13-19 years with major depression using a multi-site randomized placebo controlled discontinuation design. METHODS: Subjects with a diagnosis of depression who responded to open-label treatment with sertraline in a 12-week acute phase and did not relapse with open-label continuation treatment for 24 weeks were randomized to placebo or continued treatment with sertraline for 52 weeks. RESULTS: Twenty-two subjects were randomized to maintenance treatment with sertraline (n = 13) versus placebo (n = 9). A higher proportion of subjects treated with sertraline (38%) remained well as compared to those on placebo (0%). Survival analyses found no significant differences between the groups (p = 0.17). CONCLUSIONS: This is the first study to examine the outcome to maintenance treatment for adolescents with major depression. Although the sample size was small, the findings suggest a possible benefit of maintenance treatment with sertraline over placebo. A larger clinical trial with adequate power is required to confirm or disconfirm these findings.

Pituitary gland volume in adolescent and young adult bipolar and unipolar depression.

OBJECTIVES: Few studies have examined pituitary gland size in mood disorders, particularly in adolescents. We hypothesized increase in the pituitary gland size in early-onset mood disorders. METHODS: Thirty subjects between the ages of 13 and 20 years participated in the study. Three groups (control, bipolar I depression and unipolar depression) of 10 subjects each (4 male, 6 female) underwent volumetric magnetic resonance imaging at 1.5 T. RESULTS: Analysis of covariance (covarying for age, sex and intracranial volume) revealed a significant difference in pituitary gland volume amongst the groups [F(2,24) = 7.092, p = 0.014]. Post hoc analysis revealed that controls had a significantly smaller pituitary gland volume than both bipolar patients (p = 0.019) and depressed patients (p = 0.049). Bipolar and depressed subjects did not differ significantly from each other with regard to pituitary gland volume (p = 0.653). Control females had larger pituitary glands than control males [F(1,8) = 10.523, p = 0.012], but no sex differences were noted in the mood disorder groups. CONCLUSIONS: Pituitary glands are enlarged in adolescents with mood disorders compared to controls. Healthy young females have larger pituitary glands than males, but such a difference is not evident in individuals with unipolar depression or bipolar disorder. These findings provide new evidence of abnormalities of the pituitary in early onset mood disorders, and are consistent with neuroendocrine dysfunction in early stages of such illnesses.

Online health promotion, early identification of difficulties, and help seeking in young people.

OBJECTIVE: To examine the use and impact of a dedicated health information Web site for adolescents. METHOD: Five hundred fifty-eight (27.2%) of all students in grades 7 through 12 from 4 schools logged onto the Web site; 1775 (86.4%) of all students in these grades completed a year-end health survey, with 455 (81.5%) of the students who used the Web site completing the survey. Dependent variables were help seeking and satisfaction ratings plus visits to specific Web site sections. Predictor variables were demographic characteristics, mental health, and psychosocial difficulties assessed at years' end. RESULTS: Students logged on >11,000 times during the year. Female students, students wanting professional help, those scoring higher on depressive vulnerability measures, and students reporting more severe mood problems were related to logging on frequently over longer periods of time, as well as viewing information sheets, posting and viewing questions and answers, and completing the symptom screen. Students accessing the Web site from 1 to 7 A.M. reported higher levels of distress than did students who accessed the Web site at other times of the day. Visits to the Web site were positively associated with visits to school health centers and guidance counselors and referrals to a health professional. CONCLUSIONS: Results are consistent with a health-needs model of utilization of this Internet-based health resource. A school-based health information Web site holds significant promise for health promotion and early self-identification for emotional problems.

Examining school health center utilization as a function of mood disturbance and mental health difficulties.

PURPOSE: We examined the presence and severity of mood disturbance and mental health difficulties as predictors of students' utilization of school health centers. METHODS: Mood disturbance and mental health difficulties were assessed through surveys completed at year end. Visits to school health centers were tracked prospectively over the year. RESULTS: Twenty-three percent of students with mental health difficulties visited the school health centers. Students reporting mood disturbance and difficulties were more likely to use school health centers and to use them more frequently than were students without such difficulties. More than half of all visitors were judged by health clinic staff to be experiencing impairment in functioning and reported difficulties, which typically lasted more than 6 months duration. CONCLUSIONS: Although the presence of mental health difficulties increases the probability of students' visiting school health centers, the majority of students with such difficulties do not avail themselves of this resource. Optimizing the effectiveness of school-based health services depends on understanding the interplay between availability and utilization of school-based services for students with mental health difficulties.

Choline in pediatric depression.

PURPOSE OF STUDY: The prefrontal cortex has been previously implicated in the neuropathology of major depressive disorder (MDD). Hence, we used proton magnetic resonance spectroscopy (1H-MRS) to examine choline levels in the prefrontal cortex of youth with major depression. BASIC PROCEDURES: Twelve age- and sex-matched case-control pairs were examined (age range 10 to 18 years, 7 females and 5 males in each group). All subjects were treatment naive at the time of the scan. A long echo 1H-MRS scan was acquired from the right prefrontal cortex (4cc) in all subjects. MAIN FINDINGS: Right prefrontal Choline/Creatine ratios were elevated in the youth with mood disorders (F1, 11=10.741, p=0.007) as compared with healthy controls. PRINCIPAL CONCLUSIONS: These findings suggest that prefrontal cytosolic choline may be increased in youth with MDD in comparison with healthy controls. This is consistent with reported findings in both adults and adolescents and suggests that MDD in youth is associated with alterations in choline metabolism in the prefrontal cortex.

Open-label adjunctive topiramate in the treatment of unstable bipolar disorder.

OBJECTIVE: To assess open-label adjunctive topiramate in the treatment of outpatients with unstable bipolar disorder (BD). METHOD: Outpatients with DSM-IV-defined BD (I or II) exhibiting mood instability were enrolled in this 16-week, open-label, multicentre study. Topiramate was added to existing mood stabilizers and other psychotropic treatments. The primary effectiveness measure was the Clinical Global Impression of Severity (CGI-S) scale; other scales included the Young Mania Rating Scale (YMRS) and the Montgomery-Asberg Depression Rating Scale (MADRS). Safety assessments included monitoring adverse events, measuring tremor, monitoring vital signs and weight, and laboratory indices. We also evaluated patient satisfaction with treatment. RESULTS: A total of 109 patients were enrolled. Intent-to-treat analysis showed significant improvement from baseline in the CGI-S, YMRS, and MADRS, starting at Week 2 (P < 0.001), with further accrual of benefit between Week 2 and Week 16 (P < 0.001). The mean modal dosage of topiramate during the stable dosing period was 180 mg daily. There was a mean 1.8 kg decrease in patient weight from topiramate initiation to Week 16 (P < 0.001). Topiramate was well tolerated by most patients; 11% withdrew from the study owing to adverse events. We noted a significant reduction in the mean severity score for preexisting tremor by Week 8 of treatment (P < 0.005); no notable changes in vital signs were observed. At Week 16, 50% of the patients were "completely satisfied" with topiramate treatment. CONCLUSIONS: Adjunctive topiramate treatment can reduce the severity of manic and depressive symptoms, as well as reducing tremor and weight in outpatients with BD I or II.

Risperidone reduces aggression in boys with a disruptive behaviour disorder and below average intelligence quotient: analysis of two placebo-controlled randomized trials.

The present study aimed to analyse the effect of risperidone on a priori defined core aggression items. Data were pooled from 163 boys (aged 5-12 years, with or without comorbid attention-deficit/hyperactivity disorder) with a DSM-IV diagnosis of either conduct disorder or oppositional defiant disorder who had participated in either of two identical, 6-week, randomized, double-blind, placebo-controlled trials. All received treatment with either placebo or oral risperidone solution (0.01-0.06 mg/kg/day). Subjects had below average intelligence [intelligence quotient (IQ) 36-84] and a score of > or =24 on the Conduct Problem subscale of the Nisonger Child Behaviour Rating Form (N-CBRF). An expert advisory panel selected six core aggression items from the N-CBRF, from which a total Aggression Score (AS, range 0-18) was constructed. Compared to those treated with placebo, risperidone-treated subjects experienced significantly greater mean decreases from baseline in the AS at each of weeks 1-6 (P<0.001). By study endpoint, aggression among risperidone-treated subjects had declined by 56.4% (mean baseline AS 10.1; mean endpoint AS 4.4), which was more than twice that of placebo-treated subjects (mean baseline AS 10.6; mean endpoint AS 8.3; 21.7% reduction). Risperidone was efficacious in reducing symptoms of aggression in boys of below average IQ with disruptive behaviour disorders.

Growth and sexual maturation during long-term treatment with risperidone.

OBJECTIVE: This study assessed the impact of risperidone on growth and sexual maturation. METHOD: The pooled database of five studies included 700 children ages 5-15 years with disruptive behavior disorders. All evaluable patients had received risperidone for 11 or 12 months. Those evaluable for growth also had baseline and 11- or 12-month height measurements (N=350); girls >/=9 years and boys >/=10 years who were evaluable for sexual maturation also had baseline and 11- or 12-month Tanner staging (N=222). RESULTS: Risperidone-treated children had a mean increase in height 1.2 cm greater than the reference population, and they experienced no delay in progression through Tanner staging. Transient increases in prolactin did not correlate with growth or sexual maturation. CONCLUSIONS: In this retrospective analysis, there was no evidence of statistically or clinically significant growth failure or delay in pubertal onset or progression in children treated for up to 1 year with risperidone.

Risperidone plus lithium versus risperidone plus valproate in acute and continuation treatment of mania.

This exploratory analysis was performed to compare the efficacy and tolerability of risperidone when added to two different mood stabilizers (lithium or valproate) for mania in bipolar disorder. Patients receiving lithium or valproate at baseline were drawn from the database of a 12-week, open-label risperidone study. The primary efficacy measure was the Young Mania Rating Scale (YMRS). Other assessments included the Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression (CGI) of improvement, and safety measures. The analysis included 33 patients on lithium plus risperidone and 46 patients on valproate plus risperidone. Both subgroups had comparable baseline YMRS scores (lithium 28.2, valproate 28.7) and both had significant reductions in score by week 1 (P<0.0001). Comparable reductions in score continued for both subgroups until the end of the study (YMRS scores at week 12: lithium 4.6 and valproate 6.7). There were no significant differences in response rates (> or =50% improvement on YMRS) or remission rates (YMRS score < or = 8) between the two subgroups. At week 12, 88% of the lithium plus risperidone patients and 80% of the valproate plus risperidone patients were in remission. Similarly, HAM-D scores were significantly and comparably reduced in both subgroups, and improvement in CGI was the same. There was no difference between subgroups in the incidence of adverse events or weight gain. These data suggest that risperidone can be safely combined with either lithium or valproate, and that the efficacy is similar regardless of the mood stabilizer used.

MRI study of the pituitary gland in adolescent depression.

Abnormalities in pituitary function have been described in major depressive disorder (MDD) and may reflect neurodevelopmental abnormalities. We hypothesized alterations in the pituitary in early onset MDD. We measured the volume of the pituitary gland in 17 MDD (mean+/-S.D.=16.67+/-1.83 years; 8M, 9F) patients and 17 age and sex matched healthy controls (mean+/-S.D.=16.23+/-1.61 years; 8M, 9F) using 1.45 mm thick T(1)-weighted coronal MRI images. A trained rater blind to diagnosis did all measurements. ANCOVA covarying for age, sex and intracranial volume (ICV) revealed a significant difference between the two groups (F=6.43, df=1, 29, P=0.02; MDD subjects demonstrated a 25% increase in pituitary gland volume). Age was significantly correlated with pituitary volume in the healthy controls (r=0.62, P=0.008) but not the MDD group. No significant relationships between pituitary size and clinical severity were found in the MDD patients. To our knowledge, this is the first study that reports larger pituitary volumes in early onset major depression. These findings provide new evidence of abnormalities of the pituitary in early onset MDD, possibly related to neuroendocrine dysfunction.

Hippocampal volume in early onset depression.

BACKGROUND: Abnormalities in limbic structures have been implicated in major depressive disorder (MDD). Although MDD is as common in adolescence as in adulthood, few studies have examined youth near illness onset in order to determine the possible influence of atypical development on the pathophysiology of this disorder. METHODS: Hippocampal volumes were measured in 17 MDD subjects (age = 16.67 +/- 1.83 years [mean +/- SD]; range = 13 - 18 years) and 17 age- and sex-matched healthy controls (16.23 +/- 1.61 years [mean +/- SD]; 13 - 18 years) using magnetic resonance imaging (MRI). RESULTS: An analysis of covariance revealed a significant difference between MDD and control subjects (F = 8.66, df = 1, 29, P = 0.006). This was more strongly localized to the left hippocampus (P = 0.001) than the right hippocampus (P = 0.047). CONCLUSIONS: Our findings provide new evidence of abnormalities in the hippocampus in early onset depression. However, our results should be considered preliminary given the small sample size studied.

International consensus statement on attention-deficit/hyperactivity disorder (ADHD) and disruptive behaviour disorders (DBDs): clinical implications and treatment practice suggestions.

Researchers and clinicians worldwide share concerns that many youngsters with attention-deficit/hyperactivity disorder (ADHD) and/or disruptive behaviour disorders (DBDs) do not receive appropriate treatment despite availability of effective therapies. At the request of Johnson and Johnson (sponsor), 11 international experts in child and adolescent psychiatry were selected by Professor Stan Kutcher (chair) to address these concerns. This paper describes the experts' consensus conclusions, including treatment practice suggestions for physicians involved in the early treatment of youngsters with ADHD (or hyperkinetic disorder, in countries preferring this classification) and/or DBDs internationally: suggested first-line treatment for ADHD without comorbidity is psychostimulant medication aided by psychosocial intervention. For ADHD with comorbid conduct disorder (CD), psychosocial intervention combined with pharmacotherapy is suggested. For primary CD, suggested first-line treatment is psychosocial intervention, with pharmacotherapy considered as an 'add-on' when aggression/impulsivity is marked and persistent. Pharmacotherapy requires careful titration; full-day coverage is the suggested goal. Regular long-term follow-up is recommended.

Prolactin levels during long-term risperidone treatment in children and adolescents.

BACKGROUND: This analysis was designed to investigate prolactin levels in children and adolescents on long-term risperidone treatment and explore any relationship with side effects hypothetically attributable to prolactin (SHAP). METHOD: Data from 5 clinical trials (total N = 700) were pooled for this post hoc analysis. Children and adolescents aged 5 to 15 years with subaverage intelligence quotients and conduct or other disruptive behavior disorders received risperidone treatment (0.02-0.06 mg/kg/day) for up to 55 weeks. Outcome measures analyzed included serum prolactin levels, reported adverse events, and the conduct problem subscore of the Nisonger Child Behavior Rating Form. RESULTS: Mean prolactin levels rose from 7.8 ng/mL at baseline to a peak of 29.4 ng/mL at weeks 4 to 7 of active treatment, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 (N = 358) and 13.0 ng/mL at weeks 52 to 55 (N = 42). There was no relationship between pro-lactin levels and age. Females returned to a mean value within the normal range (

Risperidone in acute and continuation treatment of mania.

In a prospective study, we examined the efficacy of risperidone added-on to mood stabilizers in the acute and continuation treatment of mania over a 12-week period. Patients (n=108) with a DSM-IV diagnosis of bipolar disorder, manic or mixed episode requiring treatment with an antipsychotic were recruited. All subjects were on one or two mood stabilizers at the time of initiation of risperidone (range 0.5-4 mg). No other antipsychotic medication or ongoing benzodiazepine therapy was allowed. There was a significant decrease in mean Young Mania Rating Scale (YMRS) scores from baseline (27.5+/-7.5) to week 1 (-10.8, P<0.0001), week 3 (-17.7, P<0.0001) and to week 12(-22.6, P<0.0001). When response was defined as > or = 50% reduction in YMRS scores from baseline, 32%, 68% and 90% of patients met criteria at week 1, week 3 and week 12, respectively. Significant decreases in mean 21-item Hamilton Depression Rating Scale scores from baseline (12.2+/-7.7) to week 3 (-5.7, P<0.0001) and week 12 (-5.7, P<0.0001) were also observed. No significant changes in extrapyramidal symptoms were noted between baseline and endpoint. The mean daily dose of risperidone was 2 mg with a median of 1.8 mg. These findings support the results of the two previous double-blind, randomized trials and indicate that the addition of risperidone to mood stabilizers is a safe and effective treatment for acute and continuation treatment of mania. Risperidone add-on does not induce depressive symptoms and, furthermore, risperidone may have efficacy in treating comorbid depressive symptoms in bipolar patients.

Methodological issues and controversies in clinical trials with child and adolescent patients with bipolar disorder: report of a consensus conference.

OBJECTIVE: To achieve consensus among researchers, pharmaceutical industry representatives, federal regulatory agency staff, and family advocates on a template for clinical trials of acute mania/bipolar disorder in children and adolescents. METHOD: The American Academy of Child and Adolescent Psychiatry, in collaboration with Best Practice, convened a group of experts from the key stakeholder communities (including adult psychiatrists with expertise in bipolar disorder) and assigned them to workgroups to examine core methodological issues surrounding the design of clinical trials and, ultimately, to generate a consensus statement encompassing: (1) inclusion/exclusion criteria, (2) investigator training needs and site selection, (3) assessment and outcome measures, (4) protocol design and ethical issues unique to trials involving children/adolescents, and (5) regulatory agency perspectives on these deliberations. RESULTS: Conference participants reached agreement on 18 broad methodological questions. Key points of consensus were to assign priority to placebo-controlled studies of acute manic episodes in children and adolescents aged 10-17 years, who may or may not be hospitalized, and who may or may not suffer from common comorbid psychiatric disorders; to require that specialist diagnostic "gatekeepers" screen youths' eligibility to participate in trials; to monitor interviewer and rater competency over the course of the trial using agreed upon standards; and to develop new tools for assessment, including scales to measure aggression/rage and cognitive function, while using the best available instruments (e.g., Young Mania Rating Scale) in the interim. CONCLUSIONS: Methodologically rigorous, large-scale clinical trials of treatment of acute mania are urgently needed to provide information regarding the safety and efficacy, in youth, of diverse agents with potential mood-stabilizing properties.

Bipolar depression: criteria for treatment selection, definition of refractoriness, and treatment options.

OBJECTIVE: This paper reviews controlled studies of bipolar depression, outlines criteria for choosing treatment, defines refractoriness in bipolar depression, and provides options for treatment of refractory bipolar depression. METHODS: Controlled studies that examined the efficacy of treatments for acute and long-term treatment of bipolar depression were located through electronic searches of several databases and by manual crosssearch of references and proceedings of international meetings. RESULTS: Lithium comes close to fulfilling the proposed criteria for first-line treatment for bipolar depression, and those not responding to lithium should be considered to have refractory bipolar depression. Options for such patients include addition of lamotrigine or a second mood stabilizer, or a newer-generation antidepressant such as a serotonin re-uptake inhibitor or bupropion, or the atypical antipsychotic olanzapine. CONCLUSIONS: Although there is a paucity of research in the treatment of refractory bipolar depression, available data could be used for providing rational treatment options for such patients. However, further studies are urgently needed to determine which options are most appropriate for which type of patients.