S. Corya

Therapeutic Options for Treatment-Resistant Depression

Treatment-resistant depression (TRD) presents major challenges for both patients and clinicians. There is no universally accepted definition of TRD, but results from the US National Institute of Mental Health’s (NIMH) STAR*D (Sequenced Treatment Alternatives to Relieve Depression) programme indicate that after the failure of two treatment trials, the chances of remission decrease significantly.Several pharmacological and nonpharmacological treatments for TRD may be considered when optimized (adequate dose and duration) therapy has not produced a successful outcome and a patient is classified as resistant to treatment. Nonpharmacological strategies include psychotherapy (often in conjunction with pharmacotherapy), electroconvulsive therapy and vagus nerve stimulation. The US FDA recently approved vagus nerve stimulation as adjunctive therapy (after four prior treatment failures); however, its benefits are seen only after prolonged (up to 1 year) use. Other nonpharmacological options, such as repetitive transcranial stimulation, deep brain stimulation or psychosurgery, remain experimental and are not widely available.Pharmacological treatments of TRD can be grouped in two main categories: ‘switching’ or ‘combining’. In the first, treatment is switched within and between classes of compounds. The benefits of switching include avoidance of polypharmacy, a narrower range of treatment-emergent adverse events and lower costs. An inherent disadvantage of any switching strategy is that partial treatment responses resulting from the initial treatment might be lost by its discontinuation in favour of another medication trial. Monotherapy switches have also been shown to have limited effectiveness in achieving remission.The advantage of combination strategies is the potential to build upon achieved improvements; they are generally recommended if partial response was achieved with the current treatment trial. Various non-antidepressant augmenting agents, such as lithium and thyroid hormones, are well studied, although not commonly used. There is also evidence of efficacy and increasing use of atypical antipsychotics in combination with antidepressants, for example, olanzapine in combination with fluoxetine (OFC) or augmentation with aripiprazole. The disadvantages of a combination strategy include multiple medications, a broader range of treatment-emergent adverse events and higher costs.Several experimental pharmaceutical treatment alternatives for TRD are also being explored in combination with antidepressants or as monotherapy. These less studied alternative compounds include pindolol, inositol, CNS stimulants, hormones, herbal supplements, omega-3 fatty acids, S-adenosyl-L-methionine, folic acid, lamotrigine, modafinil, riluzole and topiramate.In summary, despite an increasing variety of choices for the treatment of TRD, this condition remains universally undefined and represents an area of unmet medical need. There are few known approved pharmacological agents for TRD (aripiprazole and OFC) and overall outcomes remain poor. This might be an indication that depression itself is a heterogeneous condition with a great diversity of pathologies, highlighting the need for careful evaluation of individuals with depressive symptoms who are unresponsive to treatment. Clearly, more research is needed to provide clinicians with better guidance in making those treatment decisions — especially in light of accumulating evidence that the longer patients are unsuccessfully treated, the worse their long-term prognosis tends to be.

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases

BackgroundAn advance in the treatment of schizophrenia is the development of long-acting intramuscular formulations of antipsychotics, such as olanzapine long-acting injection (LAI). During clinical trials, a post-injection syndrome characterized by signs of delirium and/or excessive sedation was identified in a small percentage of patients following injection with olanzapine LAI.MethodsSafety data from all completed and ongoing trials of olanzapine LAI were reviewed for possible cases of this post-injection syndrome. Descriptive analyses were conducted to characterize incidence, clinical presentation, and outcome. Regression analyses were conducted to assess possible risk factors.ResultsBased on approximately 45,000 olanzapine LAI injections given to 2054 patients in clinical trials through 14 October 2008, post-injection delirium/sedation syndrome occurred in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). Symptomatology was consistent with olanzapine overdose (e.g., sedation, confusion, slurred speech, altered gait, or unconsciousness). However, no clinically significant decreases in vital signs were observed. Symptom onset ranged from immediate to 3 to 5 hours post injection, with a median onset time of 25 minutes post injection. All patients recovered within 1.5 to 72 hours, and the majority continued to receive further olanzapine LAI injections following the event. No clear risk factors were identified.ConclusionsPost-injection delirium/sedation syndrome can be readily identified based on symptom presentation, progression, and temporal relationship to the injection, and is consistent with olanzapine overdose following probable accidental intravascular injection of a portion of the olanzapine LAI dose. Although there is no specific antidote for olanzapine overdose, patients can be treated symptomatically as needed. Special precautions include use of proper injection technique and a post-injection observation period.Trial RegistrationClinicalTrials.gov ID; URL: http://http//www.clinicaltrials.gov/: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.

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.

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.

Open-label treatment with olanzapine for patients with borderline personality disorder.

Abstract This report presents efficacy and safety outcomes for patients with borderline personality disorder (BPD) treated with olanzapine for up to 24 weeks. In 2 concurrent studies, patients received open-label olanzapine for 12 weeks after 12 weeks of double-blind olanzapine or placebo. Open-label dosing started at 2.5 or 5 mg/d and could be increased up to 20 mg/d (study 1) or 15 mg/d (study 2). The primary efficacy measure was open-label baseline–to–endpoint change in Zanarini Rating Scale for BPD (ZAN-BPD) total score. Of 472 patients who completed the double-blind acute phase, 444 entered and 320 (72.1%) completed 12 weeks of open-label extension treatment. Mean ZAN-BPD total scores at the start of the acute phase were approximately 17, indicating moderate symptom severity. Mean ZAN-BPD total scores ranged from 7.8 to 10.5 at the start of the open-label treatment and decreased to 5.7 to 6.5, indicating mild symptom severity, by the end of the open-label treatment. Patients taking placebo during the acute phase showed increases in weight, prolactin level, and other laboratory values during open-label olanzapine treatment similar in magnitude to increases seen in olanzapine-treated patients during the acute phase. Patients proceeding from olanzapine during the acute phase to open-label olanzapine showed smaller changes in weight and laboratory values. In conclusion, these results suggest that continued therapy with olanzapine may sustain and build upon improvements seen with acute olanzapine treatment of patients with BPD. However, no medication is currently approved for treatment of BPD, and physicians should carefully weigh potential benefits and risks of antipsychotic treatment in this population.

Metabolic parameters in patients treated with olanzapine or other atypical antipsychotics.

The relative risk of changes in metabolic parameters during treatment with atypical antipsychotics has not been fully investigated. Baseline-to-endpoint mean and anytime-categorical changes in metabolic parameters were evaluated in Lilly active comparator-controlled clinical trials. Olanzapine-treated patients gained significantly more baseline-to-endpoint weight versus risperidone- (3.3 kg [N = 713; median exposure [ME, days] = 68] versus 1.8 kg [N = 697; ME = 65], p < 0.001), ziprasidone- (2.8 kg [N = 463; ME = 168] versus −1.3 kg [N = 443; ME = 89], p < 0.001), and aripiprazole-treated patients (3.7 kg [N = 273; ME = 104] versus 0.5 kg [N = 275; ME = 187], p < 0.001). Significantly more olanzapine-treated patients gained ≥7% of their baseline weight versus risperidone- (30.6% [N = 713; ME = 169] versus 20.2% [N = 697; ME = 140], p < 0.001), ziprasidone- (30.0% [N = 463; ME = 147] versus 6.5% [N = 443; ME = 165], p < 0.001), and aripiprazole-treated patients (40.3% [N = 273; ME = 170] versus 16.4% [N = 275; ME = 154], p < 0.001). Olanzapine-treated patients had significantly greater baseline-to-endpoint changes in fasting triglycerides compared with ziprasidone- (0.24 mmol/L [N = 365; ME = 168] versus −0.24 mmol/L [N = 316; ME = 140], p < 0.001) and aripiprazole-treated patients (0.28 mmol/L [N = 215; ME = 195] versus −0.19 mmol/L [N = 210; ME = 194], p < 0.001). Olanzapine-treated patients had significantly greater baseline-to-endpoint changes in fasting glucose than ziprasidone- (0.25 mmol/L [N = 379; ME = 168] versus −0.04 mmol/L [N = 333; ME = 133], p = 0.016) and aripiprazole-treated patients (0.27 mmol/L [N = 227; ME = 195] versus 0.04 mmol/L [N = 220; ME = 194], p = 0.048). The study concluded that there are changes with varying frequencies and magnitude in some metabolic parameters in patients treated with olanzapine compared with other atypical antipsychotics.