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
University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. The Journal of Clinical Psychiatry
(Impact Factor: 5.5).
02/2010; 71(4):451-62. DOI: 10.4088/JCP.08m04984gre
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.
Available from: Torgny H Svensson
- "olanzapine ) may augment the effect of antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs; e.g. fluoxetine ) in TRD (Nelson and Papakostas, 2009) with a rapid onset, i.e. 4–5 days as opposed to the several weeks of treatment needed with SSRIs alone (Tohen et al., 2010). Part of the explanation for these synergistic effects may be that such drug combinations enhance catecholamine output in the mPFC (Zhang et al., 2000). "
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ABSTRACT: Preclinical studies indicate that the rapid antidepressant effect of ketamine is dependent on activation of AMPA receptors in the medial prefrontal cortex (mPFC) resulting in a prolonged enhancement of glutamatergic transmission in the mPFC. In similarity, addition of atypical antipsychotic drugs (APDs) to SSRIs has also been found to induce a rapid and potent antidepressant effect. Using intracellular recordings in layer V/VI pyramidal cells of the rat mPFC in vitro, we found that a combination of low, clinically relevant concentrations of the atypical APD olanzapine and the SSRI fluoxetine facilitated NMDA and AMPA-induced currents in pyramidal cells via activation of dopamine D1 receptors. A single ketamine injection (10mg/kg, 24h before the experiment) enhanced AMPA-and apparently to some extent also NMDA-induced currents. Our results propose that the rapid and potent antidepressant effects of both treatments may be related to a common mechanism of action, namely facilitation of glutamatergic, in particular AMPA receptor-mediated transmission, in the mPFC.
Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
Available from: Carl Bjorkholm
- "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). "
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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.
Available from: Rodrigo Machado-Vieira
- "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). "
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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.
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