Olanzapine/Fluoxetine Combination in Patients With Treatment-Resistant Depression: Rapid Onset of Therapeutic Response and Its Predictive Value for Subsequent Overall Response in a Pooled Analysis of 5 Studies
ABSTRACT To characterize response profiles of olanzapine/fluoxetine combination therapy in treatment-resistant depression (TRD) and to investigate predictive relationships of early improvement with olanzapine/fluoxetine combination for subsequent response/remission during the acute phase of treatment.
Results were pooled from 5 outpatient studies comparing oral olanzapine/fluoxetine combination, fluoxetine, or olanzapine for a maximum of 8 weeks in patients with TRD who had at least 1 historical antidepressant treatment failure during the current episode and who failed a prospective antidepressant therapy during the study lead-in period. Mean Montgomery-Asberg Depression Rating Scale (MADRS) total and core mood items scores from the 8-week evaluation period were compared across treatment groups. Positive and negative predictive values (PPVs, NPVs) were computed from olanzapine/fluoxetine combination-treated patients demonstrating response and remission based on whether they demonstrated early improvement.
Mean olanzapine/fluoxetine combination MADRS score reductions were significantly greater than fluoxetine by week 0.5 and olanzapine by week 1. Significantly more olanzapine/fluoxetine combination patients demonstrated MADRS onset of response compared with fluoxetine and olanzapine patients (P < .001 for both MADRS total and core mood items). In olanzapine/fluoxetine combination patients, 38.1% exhibited MADRS total score response versus 26.9% of fluoxetine patients (P < .001) and 22.2% of olanzapine patients (P < .001). NPVs for MADRS total and core mood items response and remission ranged from 85.7% to 92.1%; PPVs ranged from 29.9% to 45.1%.
Olanzapine/fluoxetine combination is superior to fluoxetine and olanzapine in producing early improvement in patients with TRD. The absence of early improvement is highly predictive for overall response failure.
clinicaltrials.gov Identifier: NCT00035321.
- SourceAvailable from: PubMed Central
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- "Even when the antidepressant treatment effectively improves affective symptoms, residual cognitive symptoms may persist (Boeker et al., 2012) and the degree of cognitive impairment may determine treatment outcome, as for example schizophrenia and bipolar disorder (BPD) (Green, 1996; McCall and Dunn, 2003; Martinez-Aràn et al., 2004). Substantial clinical data support the adjunctive use of low to moderate doses of atypical antipsychotic drugs (APDs) in combination with SSRIs to rapidly enhance the antidepressant effect in treatment-resistant MDD and bipolar depression (see, e.g., Nelson and Papakostas, 2009; Cruz et al., 2010; Tohen et al., 2010). Preclinical studies have demonstrated increased outflow of both dopamine and noradrenaline in the medial prefrontal cortex (mPFC) by the combination of olanzapine or quetiapine with the noradrenaline reuptake inhibitor reboxetine or the SSRI fluoxetine (Zhang et al., 2000; Marcus et al., 2010; Björkholm et al., 2013), which has been suggested to contribute to the potent antidepressant effect observed with such drug combinations (Zhang et al., 2000). "
ABSTRACT: Substantial clinical data support the addition of low doses of atypical antipsychotic drugs (APDs) to SSRIs to rapidly enhance the antidepressant effect in treatment-resistant depression. Preclinical studies suggest that this effect is at least partly explained by an increased catecholamine outflow in the medial prefrontal cortex (mPFC). The present study, using in vivo microdialysis and in vitro intracellular recordings, shows that addition of low doses (0.05 and 0.1 mg/kg) of the novel atypical APD asenapine to the SSRI escitalopram (5 mg/kg) markedly enhances dopamine, noradrenaline and serotonin release in the rat mPFC as well as dopamine release in the nucleus accumbens. Moreover, this drug combination facilitated both NMDA- and AMPA-induced currents as well as electrically evoked EPSPs in pyramidal cells of the rat mPFC. Our results support the notion that the augmentation of SSRIs by atypical APDs in treatment-resistant depression may, at least in part, be related to enhanced catecholamine output in the PFC and that asenapine may be clinically used to achieve this end. In particular, the subsequent activation of the D1 receptor may be of importance for the augmented antidepressant effect as this mechanism facilitated both NMDA and AMPA receptor-mediated transmission in the mPFC. Our novel observation that the drug combination, like ketamine, facilitates glutamatergic transmission in the mPFC may contribute to explain the rapid and potent antidepressant effect obtained when atypical APDs are added to SSRIs. © The Author 2014. Published by Oxford University Press on behalf of CINP.The International Journal of Neuropsychopharmacology 10/2014; 18(3). DOI:10.1093/ijnp/pyu068 · 4.01 Impact Factor
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- "Recent research has explored predictors of treatment response in patients with MDD receiving antidepressants. Several studies in MDD suggest that improvement within the first two weeks is associated with endpoint treatment response (Nagayama et al., 1991; Katz et al., 1996; Stassen et al., 1993, 1996, 1999; Szegedi et al., 2009; Tohen et al., 2010; Nierenberg et al., 1995). In contrast, and despite its long history of safe clinical use in BD, little clinical evidence exists regarding predictors of initial treatment response-as opposed to maintenance treatment with lithium (Goodnick, 1996). "
ABSTRACT: OBJECTIVES: Despite lithium's clinical efficacy in treating mania in bipolar disorder (BD), studies evaluating early improvement and subsequent treatment response are sparse. This study investigated whether early improvement (within one week) to lithium monotherapy predicted later response and remission in individuals with BD mania. METHODS: BD-I patients (n=46) experiencing a manic episode received lithium monotherapy for four weeks (initial dose: 600mg/d, adjusted to therapeutic levels); individuals experiencing a mixed episode, rapid cyclers, previous non-responders to lithium, and those with current drug abuse/dependence were excluded. Symptoms were rated using the Young Mania Rating Scale (YMRS) at baseline and at Days 7, 14, 21, and 28. RESULTS: Thirty-three percent of the total sample responded to lithium within the first week of treatment, defined as a ≥50% decrease from baseline YMRS scores; 63% responded by study endpoint. In addition, 39% of the total sample showed early improvement (at least 20% decrease in YMRS scores) after one week of treatment. In this group, 79% responded to lithium by study endpoint. Among those showing less than 20% improvement at Week 1, only 23% responded to lithium by study endpoint. LIMITATIONS: History of episodes sequence was not assessed. CONCLUSIONS: Early improvement in response to lithium monotherapy in subjects with BD mania predicted later response and remission. Most patients who did not show early improvement in response to lithium during the first week of treatment showed no response after one month. The findings provide a valuable clinical tool for early identification of those patients most likely to benefit from lithium in clinical practice.Journal of Affective Disorders 08/2012; 144(1-2). DOI:10.1016/j.jad.2012.05.039 · 3.38 Impact Factor
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- "FLX alone or in combination with amantadine, an N-methyl-D-aspartate (NMDA) receptor antagonist, increased mRNA BDNF in the cerebral cortex (Rogóz et al., 2008). The combination of antidepressants within various pharmacological groups is used in the clinical environment to improve therapy (Shelton, 2006; Tohen et al., 2010). In basic experiments, the association of antidepressants with other drugs has showed a better effect than when used alone (Roman et al., 2009; Rogóz, 2010). "
ABSTRACT: Recently, several studies have emerged suggesting a role of the intracellular survival pathways in the treatment of mood disorders. In addition, the beneficial effects of using a combination of antipsychotics and antidepressants have been shown. With this in mind, we evaluated the effects of the acute administration of fluoxetine (FLX), olanzapine (OLZ) and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), cAMP response element-binding (CREB), Protein Kinase B (PKB, Akt), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated death promoter (BAD) in the rat brain. Adult Wistar rats received an acute injection of OLZ (3 or 6 mg/kg) and/or FLX (12.5 or 25 mg/kg), and were evaluated for Akt, BDNF, CREB, Bcl-2 and BAD protein levels in the prefrontal cortex, hippocampus and striatum. Our results showed that treatment with FLX and OLZ alone or in combination increased the Akt, CREB, BDNF, Bcl-2 and BAD levels in the prefrontal cortex, hippocampus and striatum. However, the combination of FLX and OLZ at high doses was associated with a greater increase in the levels of Akt in the prefrontal cortex, and did not have an effect on the levels of BAD in any of the brain areas that we evaluated. Finally, these findings further support the hypothesis that treatment with FLX and OLZ alone or in combination exert neuroprotective effects, and that intracellular survival pathways could be involved in the therapeutic effects of combining antipsychotic and antidepressant drugs in mood disorders.Journal of Psychiatric Research 05/2012; 46(8):1029-35. DOI:10.1016/j.jpsychires.2012.04.016 · 3.96 Impact Factor