An 8-Week Open-Label Trial of a 6-Day Course of Mifepristone for the Treatment of Psychotic Depression

183

104

Psychotic major depression (PMD) is found to be a relatively common psychiatric condition that affects up to nearly 20% of patients with major depression. Previous studies by our group have shown rapid reversal of psychotic symptoms in some PMD patients treated with mifepristone, in addition to restoring a more normal afternoon cortisol release. The rationale for treating patients with PMD with a glucocorticosteroid receptor antagonist is further discussed. In total, 30 patients with PMD were treated with either 600 mg/day mifepristone or placebo for 8 days in a randomized double-blind manner. The Hamilton Depression Rating Scale (HDRS) and the Brief Psychiatric Rating Scale (BPRS) were administered at baseline and again after 8 days of treatment. Cortisol and ACTH were measured hourly from 1800 to 0900 at baseline and after 8 days of treatment. Significantly, more patients in the mifepristone group (seven of 15) showed a 50% or greater decline on the BPRS positive symptom subscale, an index of psychotic symptoms, as compared to the placebo group (two of 15). Patients who received mifepristone had lower HDRS and BPRS scores at study completion compared to those who received placebo, but these differences were not statistically significant. In addition, mifepristone significantly elevated cortisol and ACTH levels and steepened ascending slopes from 1800 to 0100 and from 0100 to 0900 as compared to placebo. Clinical and biological effects of mifepristone were comparable among males and females. Age was found to significantly and positively correlate with changes in cortisol and ACTH. These results suggest that short-term use of mifepristone may be effective in the treatment of PMD and may reregulate the HPA axis. Additional blinded studies are warranted.

Section: Discussionsupporting

confidence: 92%

Clinical and Biological Effects of Mifepristone Treatment for Psychotic Depression

Flores

Kenna

Keller

et al. 2005

183

104

“…The time course of the effects by RU 38486 on Ca-currents is comparable to that of the ameliorating effects by this compound seen in patients with psychotic or bipolar depression (Belanoff et al, 2001;Young et al, 2004;Simpson et al, 2005;Flores et al, 2006). Thus, in individuals with psychotic depression it was found that significantly more patients in the group treated for 4-7 days with RU 38486 showed a 50% or greater decline on a positive symptom subscale which serves as an index of psychotic symptoms (Belanoff et al, 2001;Flores et al, 2006).…”

Section: Ru 38486 Treatmentmentioning

confidence: 55%

“…In the present study, we focused on two questions regarding this model: (i) we examined if 21 days of unpredictable stress affect Ca-currents in CA1 pyramidal neurons, a property that so far has not been studied after chronic stress; and (ii) if so, whether this can be normalized by 4-days treatment with the GR-antagonist RU 38486, a compound that was recently described to rapidly ameliorate symptoms of bipolar or psychotic depression in humans (Belanoff et al, 2001;Young et al, 2004;Simpson et al, 2005;Flores et al, 2006). Our data unequivocally indicate that chronic stressFparticularly under conditions that low levels of corticosterone circulateFenhances the total Ca-influx into CA1 pyramidal neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Also, the normalization of hormone levels upon treatment predicts for relapse probability (Ribeiro et al, 1993;Zobel et al, 2001). Finally, patients with bipolar or psychotic depression show improvement of their symptoms already within a week of treatment with the GR-antagonist RU 38486 (Belanoff et al, 2001;Young et al, 2004;Simpson et al, 2005;Flores et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Brief RU 38486 Treatment Normalizes the Effects of Chronic Stress on Calcium Currents in Rat Hippocampal CA1 Neurons

Karst

Joëls

2007

Chronic stress alters many properties in rat brain, like serotonin responsiveness and dendritic morphology. In the present study, we examined (i) whether unpredictable stress during 21 days affects calcium (Ca) currents of CA1 pyramidal neurons recorded on day 22; and (ii) if so, whether this change is normalized by treatment with the glucocorticoid receptor-antagonist RU 38486 during days 18-21. At 3 weeks of unpredictable stress increased the amplitude of the peak and sustained calcium current components, determined in hippocampal slices prepared from animals under rest (ie, with low corticosterone levels). The increased Ca-current amplitude was associated with an enhanced cell capacitance; current density was not significantly affected by chronic stress. In slices from stressed rats that received RU 38486, no stress-induced enhancement of calcium current amplitude was seen, while RU 38486 by itself did not alter calcium currents in handled controls. We confirmed earlier observations that brief in vitro treatment with 100 nM corticosterone, thus substantially activating the low-affinity glucocorticoid receptors, increases Ca-current amplitude recorded 1-4 h later in slices from naïve rats. However, Ca-current amplitude was not affected by corticosterone applied to slices from handled controls and currents were even decreased by corticosterone given to slices from chronically stressed rats, suggesting that corticosterone effects depend on the history of the animal. In conclusion, the data indicate that chronic stress, RU 38486 treatment as well as acute rises in corticosterone level strongly modulate calcium influx into CA1 neurons. This could have consequences for the viability of these neurons.

“…Several investigations suggest that mifepristone leads to the rapid amelioration of psychotic depression (Belanoff et al, 2001(Belanoff et al, , 2002Simpson et al, 2005;Flores et al, 2006). Another clinical study showed mifepristone improves cognition and mood in patients with bipolar disorder (Young et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression

Han

Wang

et al. 2007

Clinical investigations present much evidence that the glucocorticoid receptor (GR) antagonist mifepristone leads to a rapid amelioration of depression. The molecular mechanisms of mifepristone involved in the treatment of depression are not fully understood. Depression is associated with hippocampal plasticity, for which increased excitatory amino acid (EAA) release in CA3 induced by chronic stress is responsible, and glucocorticoids have a permissive role and act synergistically with EAAs in producing neuronal damage. Moreover, glucocorticoids increase synapsin I, which has a key role in the release of neurotransmitter, including EAAs. Hereby, we hypothesize that major depression involves synapsin I alteration and that mifepristone blocks this alteration. In the present study, we observed both the expression of hippocampal synapsin I and depression-associated behavior in a rat model of depression induced by chronic unpredictable mild stress (CUMS). The result showed that a region-dependent synapsin I alteration occurs in the rat hippocampus after 21 days of CUMS, that is, it increases in dentate gyrus (DG)/CA3 and decreases in the CA1 region. Correlation analysis indicated that the decrease of synapsin I in CA1 is highly correlated with the increase in the DG/CA3 subfield. Simultaneously, the region-dependent alteration of synapsin I is correlated with depression-associated behaviors. Both the alteration of synapsin I and the depression-associated behavior were rapidly restored after treatment with mifepristone for 1 week. The result suggests that the molecular mechanism underlying the treatment of depression with mifepristone is associated with the rapid repair of the synaptic alteration.