Walter Deberdt

Olanzapine for the treatment of borderline personality disorder: variable dose 12-week randomised double-blind placebo-controlled study

BACKGROUND Despite the prevalence and clinical significance of borderline personality disorder, its treatment remains understudied. AIMS To evaluate treatment with variably dosed olanzapine in individuals with borderline personality disorder. METHOD In this 12-week randomised, double-blind trial, individuals received olanzapine (2.5-20 mg/day; n=155) or placebo (n=159) (trial registry: NCT00091650). The primary efficacy measure was baseline to end-point change on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) using last-observation-carried-forward methodology. RESULTS Both olanzapine and placebo groups showed significant improvements but did not differ in magnitude at end-point (-6.56 v. -6.25, P=0.661). Response rates (50% reduction in ZAN-BPD) were 64.7% with olanzapine and 53.5% with placebo (P=0.062); however, time to response was significantly shorter for olanzapine (P=0.022). Weight gain was significantly greater (2.86 v. -0.35 kg, P<0.001), with higher incidence of treatment-emergent abnormal high levels of prolactin for the olanzapine group. CONCLUSIONS Individuals treated with olanzapine and placebo showed significant but not statistically different improvements on overall symptoms of borderline personality disorder. The types of adverse events observed with olanzapine treatment appeared similar to those observed previously in adult populations.

Attention deficit hyperactivity disorder in the European adult population: prevalence, disease awareness, and treatment guidelines

Abstract Background: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobiological disorder with childhood onset and persistence into adolescence and adulthood. Methods: Our literature review reports scientific publications and guidelines on the treatment of adult ADHD, with a particular focus on European countries, identified by literature searches in Medline and Embase. The final literature search was performed in July 2012, incorporating literature from 1974 to 2012. The primary research parameters were ‘Europe’ (including single European countries), ‘ADHD’, ‘attention deficit disorder’, ‘attention deficit’, ‘attention disorder’, and ‘hyperactivity’. Secondary search parameters were ‘comorbid’, ‘epidemiology’ or ‘prevalence’, ‘disease management’, ‘drug therapy’, or ‘therapy’. The main searches were also limited to adults and English language publications. The papers identified by this literature review were selected for inclusion by consensus of the authors based on clinical relevance. Results: Appropriate resources for the diagnosis and treatment of adult ADHD in Europe are scarce, and many cases go untreated, particularly because of the frequent presence of psychiatric comorbidities. Apart from atomoxetine, and an extended-release form of methylphenidate in Germany, no other medications have been approved for starting treatment in adult ADHD patients in the European Union. However, a variety of stimulant and non-stimulant medications are used off-label, and a number of studies have confirmed that these medications are well tolerated and effective in adult patients with ADHD. Conclusions: Our results emphasize the need for broader access to effective treatments for adult ADHD patients in Europe.

Amantadine for weight gain associated with olanzapine treatment

Patients with schizophrenia (Sch), schizoaffective, schizophreniform, or bipolar (BP) I disorders [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)]; not manic or acutely psychotic [Brief Psychiatric Rating Scale (BPRS) total score < or =45]; treated with olanzapine for 1-24 months; and who had gained > or =5% of their initial body weight were examined to determine whether amantadine could attenuate weight gain or promote weight loss. Olanzapine (Olz; 5-20 mg/day) was co-administered with double-blind treatment of 100-300 mg/day amantadine (Olz+Amt, n=60) or placebo (Olz+Plc, n=65). Visit-wise analysis of weight showed that weight change from baseline [last-observation-carried-forward (LOCF)] in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 (P=0.042), 12 (P=0.029), and 16 (primary endpoint, mean+/-S.D.: -0.19+/-4.58 versus 1.28+/-4.26 kg, P=0.045). Mean BPRS total score, positive subscale, and anxiety-depression scores improved comparably in both groups, and Montgomery-Asberg Depression Rating Scale (MADRS) total score improved in the Olz+Amt group. Overall, amantadine was safe, was well tolerated, and attenuated weight gain or promoted weight loss in some patients who had gained weight during olanzapine therapy.

Early predictors of substantial weight gain in bipolar patients treated with olanzapine.

Abstract: To determine predictors of substantial weight gain (SWG) during treatment of bipolar disorder with olanzapine, data were pooled from 4 long-term randomized, multicenter studies in patients with bipolar mania or mixed mania (N = 948 at initiation of olanzapine). SWG was defined as gaining 5 kg or 7% of initial weight in 30 ± 2 weeks. Logistic regression estimated odds ratios associated with early weight gain and baseline risk factors for predicting SWG. A classification system to identify patients at risk for SWG was constructed by recursive data partitioning. Baseline characteristics significantly associated with SWG included younger age, nonwhite ethnicity, lower body mass index (BMI), nonrapid cycling, and psychotic features. Weight gain of 2 or more kg in the first 3 weeks of therapy predicted SWG by 30 weeks (sensitivity = 57%; specificity = 71%). A classification system with thresholds for early weight gain, baseline BMI, and ethnicity further improved SWG predictability (sensitivity = 79%; specificity = 70%). In conclusion, patients with bipolar disorder who gained 2 to 3 kg during the first 3 weeks of treatment with olanzapine, SWG was predicted after 30 weeks of treatment. Patients with less pronounced early weight gain might still be at risk for later SWG if they have close to normal BMI (≤27 kg/m2) at treatment initiation.

Relationships among neurocognition, symptoms and functioning in patients with schizophrenia: a path-analytic approach for associations at baseline and following 24 weeks of antipsychotic drug therapy

BackgroundNeurocognitive impairment and psychiatric symptoms have been associated with deficits in psychosocial and occupational functioning in patients with schizophrenia. This post-hoc analysis evaluates the relationships among cognition, psychopathology, and psychosocial functioning in patients with schizophrenia at baseline and following sustained treatment with antipsychotic drugs.MethodsData were obtained from a clinical trial assessing the cognitive effects of selected antipsychotic drugs in patients with schizophrenia. Patients were randomly assigned to 24 weeks of treatment with olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Psychosocial functioning was assessed with the Heinrichs-Carpenter Quality of Life Scale [QLS], cognition with a standard battery of neurocognitive tests; and psychiatric symptoms with the Positive and Negative Syndrome Scale [PANSS]. A path-analytic approach was used to evaluate the effects of changes in cognitive functioning on subdomains of quality of life, and to determine whether such effects were direct or mediated via changes in psychiatric symptoms.ResultsAt baseline, processing speed affected functioning mainly indirectly via negative symptoms. Positive symptoms also affected functioning at baseline although independent of cognition. At 24 weeks, changes in processing speed affected changes in functioning both directly and indirectly via PANSS negative subscale scores. Positive symptoms no longer contributed to the path-analytic models. Although a consistent relationship was observed between processing speed and the 3 functional domains, variation existed as to whether the paths were direct and/or indirect. Working memory and verbal memory did not significantly contribute to any of the path-analytic models studied.ConclusionProcessing speed demonstrated direct and indirect effects via negative symptoms on three domains of functioning as measured by the QLS at baseline and following 24 weeks of antipsychotic treatment.

Retrospective Cohort Study of Diabetes Mellitus and Antipsychotic Treatment in a Geriatric Population in the United States

OBJECTIVES The objective of this study was to investigate risk of diabetes among elderly patients during treatment with antipsychotic medications. DESIGN We conducted a longitudinal, retrospective study assessing the incidence of new prescription claims for antihyperglycemic agents during antipsychotic therapy. SETTING Prescription claims from the AdvancePCS claim database were followed for 6 to 9 months. PARTICIPANTS Study participants consisted of patients in the United States aged 60+ and receiving antipsychotic monotherapy. The following cohorts were studied: an elderly reference population (no antipsychotics: n = 1,836,799), those receiving haloperidol (n = 6481) or thioridazine (n = 1658); all patients receiving any conventional antipsychotic monotherapy (n = 11,546), clozapine (n = 117), olanzapine (n = 5382), quetiapine (n = 1664), and risperidone (n = 12,244), and all patients receiving any atypical antipsychotic monotherapy (n = 19,407). MEASUREMENTS We used Cox proportional hazards regression to determine the risk ratio of diabetes for antipsychotic cohorts relative to the reference population. Covariates included sex and exposure duration. RESULTS New antihyperglycemic prescription rates were higher in each antipsychotic cohort than in the reference population. Overall rates were no different between atypical and conventional antipsychotic cohorts. Among individual antipsychotic cohorts, rates were highest among patients treated with thioridazine (95% confidence interval [CI], 3.1- 5.7), lowest with quetiapine (95% CI, 1.3-2.9), and intermediate with haloperidol, olanzapine, and risperidone. Among atypical cohorts, only risperidone users had a significantly higher risk (95% CI, 1.05-1.60; P = 0.016) than for haloperidol. Conclusions about clozapine were hampered by the low number of patients. CONCLUSION These data suggest that diabetes risk is elevated among elderly patients receiving antipsychotic treatment. However, causality remains to be demonstrated. As a group, the risk for atypical antipsychotic users was not significantly different than for users of conventional antipsychotics.

Differential diagnosis, comorbidity, and treatment of attention-deficit/hyperactivity disorder in relation to bipolar disorder or borderline personality disorder in adults

Abstract Background: Attention-deficit/hyperactivity disorder (ADHD) in adults can resemble, and often co-occurs with, bipolar disorder (BD) and borderline personality disorder (BPD). This can lead to mistaken diagnoses and ineffective treatment, resulting in potentially serious adverse consequences. All three conditions can substantially impair well-being and functioning, while BD and BPD are associated with suicidality. Objectives: To update clinicians on the overlap and differences in the symptomatology of ADHD versus BD and BPD in adults; differential diagnosis of ADHD from BD and BPD in adults; and diagnosis and treatment of adults with comorbid ADHD-BD or ADHD-BPD. Methods: We searched four databases, referred to the new Diagnostic and Statistical Manual of Mental Disorders, 5th edition, used other relevant literature, and referred to our own clinical experience. Results: ADHD coexists in ∼20% of adults with BD or BPD. BD is episodic, with periods of normal mood although not necessarily function. In patients with comorbid ADHD-BD, ADHD symptoms are apparent between BD episodes. BPD and ADHD are associated with chronic trait-like symptoms and impairments. Overlapping symptoms of BPD and ADHD include impulsivity and emotional dysregulation. Symptoms of BPD but not ADHD include frantically avoiding real/imagined abandonment, suicidal behavior, self-harm, chronic feelings of emptiness, and stress-related paranoia/severe dissociation. Consensus expert opinion recommends that BD episodes should be treated first in patients with comorbid ADHD, and these patients may need treatment in stages (e.g. mood stabilizer[s], then a stimulant/atomoxetine). Data is scarce and mixed about whether stimulants or atomoxetine exacerbate mania in comorbid ADHD-BD. BPD is primarily treated with psychotherapy. Principles of dialectical behavioral treatment for BPD may successfully treat ADHD in adults, as an adjunct to medication. No fully evidence-based pharmacotherapy exists for core BPD symptoms, although some medications may be effective for individual symptom domains, e.g. impulsivity (shared by ADHD and BPD). In our experience, treatment of ADHD should be considered when treating comorbid personality disorders. Conclusions: It is important to accurately diagnose ADHD, BD, and BPD to ensure correct targeting of treatments and improvements in patient outcomes. However, there is a shortage of data about treatment of adults with ADHD and comorbid BD or BPD.

A Dose Comparison of Olanzapine for the Treatment of Borderline Personality Disorder: A 12-Week Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVE To examine the efficacy and safety of olanzapine at low and moderate doses for the treatment of borderline personality disorder. METHOD In this 12-week randomized double-blind placebo-controlled trial, 451 outpatients aged 18-65 years with DSM-IV borderline personality disorder received olanzapine 2.5 mg/d (n = 150), olanzapine 5-10 mg/d (n = 148), or placebo (n = 153). The trial was conducted from February 2004 through January 2006 at 59 community-based and academic study centers in 9 countries (United States, Italy, Poland, Romania, Turkey, Chile, Peru, Argentina, and Venezuela). The primary efficacy measure was mean change from baseline to last-observation-carried-forward endpoint on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) total score. Secondary measures included the Montgomery-Asberg Depression Rating Scale, the Modified Overt Aggression Scale, the Global Assessment of Functioning, the Symptom Checklist-90-Revised, and the Sheehan Disability Scale. RESULTS An overall mean baseline ZAN-BPD total score of 17.2 (SD = 4.9) indicated moderate symptom severity. Only treatment with olanzapine 5-10 mg/d was associated with significantly greater mean change from baseline to endpoint in ZAN-BPD total score relative to placebo (-8.5 vs -6.8, respectively; P = .010; effect size = 0.29; 95% CI, 0.06-0.52). Response rates (response indicated by ≥ 50% decrease from baseline in ZAN-BPD total score) were significantly higher for olanzapine 5-10 mg/d (73.6%) versus olanzapine 2.5 mg/d (60.1%; P = .018) and versus placebo (57.8%; P = .006). Time to response was also significantly shorter for patients taking olanzapine 5-10 mg/d than for placebo-treated patients (P = .028). Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, fatigue, increased appetite, and weight increase (all P values < .05). Mean weight change from baseline to endpoint was significantly greater for olanzapine-treated than for placebo-treated patients (olanzapine 2.5 mg/d: 2.09 kg; olanzapine 5-10 mg/d: 3.17 kg; placebo: 0.02 kg; P < .001). The overall completion rate for the 12-week double-blind treatment period was 65.2% (ie, 64.7% for olanzapine 2.5 mg/d, 69.6% for olanzapine 5-10 mg/d, and 61.4% for placebo). CONCLUSIONS Olanzapine 5-10 mg/d showed a clinically modest advantage over placebo in the treatment of overall borderline psychopathology. This advantage in effectiveness should be weighed against the risk of adverse events (particularly weight gain), which were consistent with the known safety profile of olanzapine. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00088036.

Efficacy of atomoxetine in adults with attention deficit hyperactivity disorder: an integrated analysis of the complete database of multicenter placebo-controlled trials.

Persistence of attention deficit hyperactivity disorder (ADHD) into adulthood can be disabling or lead to substantial impairment. Several clinical trials of atomoxetine (ATX) in adults with ADHD have been reported following the National Institute for Health and Clinical Excellence (NICE) guidelines issued in 2008. We performed an integrated analysis of all Eli Lilly-sponsored, randomized, double-blind, placebo-controlled studies of ATX in adults with ADHD completed as of May 2012. Individual patient data were pooled from six short-term (10–16 week) studies (1961 patients) and three longer-term (six-month) studies (1413 patients). In the short-term analysis, ATX patients achieved a significantly greater mean reduction in ADHD symptoms than placebo patients (−12.2 vs −8.1; Conners’ Adult ADHD Rating Scale–Investigator-Rated: Screening Version (CAARS-Inv: SV); p<0.001). In the longer-term analysis, respective improvements after six months were −13.2 vs −9.7 (p<0.001). Response rates at study endpoints for ATX vs placebo, based on CAARS-Inv: SV improvement ≥30% and Clinical Global Impressions of ADHD-Severity (CGI-ADHD-S) ≤3 were 34.8% vs 22.3% in the short-term and 43.4% vs 28.0% after six months, and CAARS-Inv: SV improvements ≥40% were 41.3% vs 25.3% in the short-term and 44.0% vs 31.4% after six months (all p<0.001). Overall, ATX had a clinically significant effect in adults with ADHD, with reductions in core symptoms and clinically meaningful responder rates.

Defining “good” and “poor” outcomes in patients with schizophrenia or schizoaffective disorder: A multidimensional data-driven approach

The studys goal was to characterize the typology of patient outcomes based on social and occupational functioning and psychiatric symptoms following antipsychotic drug treatment, and to explore predictors of group membership representing the best/worst outcomes. A hierarchical cluster analysis was used to define groups of patients (n=1449) based on endpoint values for psychiatric symptoms, social functioning, and useful work measured up to 30 weeks of treatment. Stepwise logistic regression was used to construct predictive models of cluster membership for baseline predictors, and with 2/4/8 weeks of treatment. Five distinct clusters of patients were identified at endpoint (Clusters A-E). Patients in Cluster A (25.6%, best outcome) had minimal psychiatric symptoms and mild functional impairment, while patients in Cluster D (14.3%) and E (14.8%) (worst outcome) had moderate-to-severe symptoms and severe functional impairment. Occupational functioning, disorganized thinking, and positive symptoms were sufficient to describe the clusters. Membership in the best/worst clusters was predicted by baseline scores for functioning and symptom severity, and by early changes in symptoms with treatment. Psychiatric symptoms and functioning provided complementary information to describe treatment outcomes. Early symptom response significantly improved the prediction of outcome, suggesting that early monitoring of treatment response may be useful in clinical practice.