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Based on preliminary evidence of its usefulness in treatment-resistant depression (TRD), an olanzapine/fluoxetine combination (OFC) was examined in comparison with olanzapine, fluoxetine, and venlafaxine in a TRD population. In this 12-week double-blind study, 483 subjects with unipolar, nonpsychotic TRD, with historic failure on a selective serotonin reuptake inhibitor (SSRI) and prospective failure on open-label venlafaxine, were randomized to an OFC or to an olanzapine, fluoxetine, or venlafaxine monotherapy group. Venlafaxine was continued randomly in the double-blind acute phase to explore the benefits of continuation versus switching therapy. The Montgomery-Asberg Depression Rating Scale (MADRS) total change score at end point was the primary outcome measure. The OFC group had significantly greater improvement in depressive symptoms by week 1 of treatment (MADRS mean change =-7.2, baseline =29.6), in comparison to olanzapine (-4.8, P=.03), fluoxetine (-4.7, P=.03), or venlafaxine (-3.7, P=.002) groups and maintained its statistical separation from all three monotherapy groups through week 6. At end point, the OFC group was significantly different only from the olanzapine group (-14.1 vs. -7.7, P<.001). Analysis of a subgroup of subjects who had an SSRI failure in their current depressive episode (n=334) revealed statistical separation from both olanzapine and fluoxetine (but not venlafaxine) at end point: OFC (-14.6) versus olanzapine (-9.4, P<.001) versus fluoxetine (-10.7, P=.006) versus venlafaxine (-14.7, P=.98). The OFC had a safety profile comparable to its component monotherapies (i.e., olanzapine and fluoxetine), showed a rapid onset of antidepressant effect, and was effective in this TRD sample. At the study end point, OFC, fluoxetine, venlafaxine, and low-dose OFC all appeared to be similarly effective.

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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.

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 rema...