Antiglucocorticoid and related treatments for psychosis

Psychosis is a broad term that includes several mental illnesses such as schizophrenia, schizophreniform disorder, schizoaffective disorder, psychotic depression and bipolar disorder with psychotic features. Psychotic disorders affect about 3% of the population and may cause high levels of disability, making it a significant public health problem both socially and economically.

Stress may result in the release of cortisol and has been linked with both onset and relapse of psychotic disorders. Elevated cortisol levels have been found in some people with psychosis, especially among those suffering with psychotic depression and those in earlier phases of psychosis. Antiglucocorticoid drugs have been reported to reduce the effects of cortisol and may be useful for people with psychotic depression and bipolar disorder. We reviewed all randomised trials comparing antiglucocorticoid and related drugs versus placebo in people with psychosis - prodromal psychosis or first episode of psychosis.

Eleven studies (involving 509 participants) were included in this review. Several antiglucocorticoid-related drugs were examined, including dehydroepiandrosterone (DHEA) (n = 5), mifepristone (n = 4), dexamethasone (n = 1) and ketoconazole (n = 1). All participants were adults with a diagnosis of schizophrenia, schizoaffective disorder or psychotic depression. Most trials examined giving antiglucocorticoid drugs as an additional part of regular treatment. Available data from these trials revealed no effects for overall psychotic symptoms, 'positive' symptoms or 'negative' symptoms. One large trial comparing mifepristone versus placebo as the sole treatment revealed a significant difference in the proportion of people responding to treatment with mifepristone versus placebo. This effect was not seen immediately but 21 days after the intervention was begun. Adverse effect data varied. When individual anticorticoids such as mifepristone and DHEA were compared with placebo, the incidence of side effects was similar between groups; however, pooled data on various antiglucorticoids given as an adjunct to combination treatment showed that antiglucocorticoids increased incidence of side effects than placebo. In summary, very few trials are under way, and most involve a small number of people. Limited available data do not provide enough evidence to support the use of antiglucocorticoid treatments for psychosis; additional trials are needed.

Authors' conclusions: 

Good evidence is insufficient to conclude whether antiglucocorticoid drugs provide effective treatment for psychosis. Some global state findings suggest a favourable effect for mifepristone, and a few overall adverse effect findings favour placebo. Additional large randomised controlled trials are needed to justify findings.

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Background: 

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in the development and relapse of psychotic disorders. Elevated cortisol secretion has been positively linked with symptom severity in people with psychosis. Antiglucocorticoid and related drugs that target the HPA axis may be useful for the treatment of individuals with psychosis.

Objectives: 

1. To determine the effects of antiglucocorticoid and related drugs for the treatment of psychosis, when used alone or in combination with antipsychotic medication.

2. To determine whether the effects of these medications differs between those in a prodromal phase or first episode of psychosis, and those with more established illness.

Search strategy: 

We searched the Cochrane Schizophrenia Group's Trials Register (August 2009 and April 2014).

Selection criteria: 

Randomised controlled trials (RCTs) comparing antiglucocorticoid and related drugs compared to placebo (either as a sole treatment or as an adjunct to atypical antipsychotics, typical antipsychotics, antidepressants or other combination treatment) for people with a primary diagnosis of a psychotic disorder, or for individuals at high risk of developing a psychotic disorder.

Data collection and analysis: 

Review authors independently selected trials, assessed methodological quality and extracted data. We used a fixed-effect meta-analysis. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) and standardised mean differences (SMDs) with 95% CIs for continuous measures. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table.

Main results: 

We included 11 studies that randomly assigned 509 people with schizophrenia, schizoaffective disorder or psychotic depression. No trials were conducted in patients at their first episode of psychotic illness and none included populations at high risk for developing psychosis. Our pre-stated outcomes of interest were mental state, global state, general functioning, adverse effects and quality of life.

Two trials compared antiglucocorticoid drugs (mifepristone) versus placebo as sole treatment. Limited data from one trial showed no difference in the proportion responding to mifepristone when mental state was assessed immediately post intervention using the Brief Psychiatric Rating Scale (BPRS) (n = 5, 1 RCT, MD -5.20, 95% CI -17.91 to 7.51; very low-quality evidence); depressive symptoms (Hamilton Rating Scale for Depression (HAMD) total) were also similar between groups (n = 5, 1 RCT, MD 1.67, 95% CI -16.44 to 19.78; very low-quality evidence). However, a significant difference favoured treatment at short-term follow-up for global state (30% reduction in total BPRS, n = 221, 1 RCT, RR 0.58, 95% CI 0.38 to 0.89; low-grade quality evidence). This effect was also seen for short-term positive psychotic symptoms (50% reduction in BPRS positive symptom subscale, n = 221, 1 RCT, RR 0.60, 95% CI 0.43 to 0.84; low-grade quality evidence). Participants receiving mifepristone experienced a similar overall number of adverse effects as those receiving placebo (n = 226, 2 RCTs, RR 0.92, 95% CI 0.77 to 1.09; moderate-quality evidence). No data on general functioning or quality of life were available.

One trial compared an antiglucocorticoid, dehydroepiandrosterone (DHEA), as an adjunct to atypical antipsychotic treatment to adjunctive placebo. Data for main outcomes of interest were of low quality, and analysis of useable data showed no significant effects of treatment on mental state or adverse effects. Data on global state, general functioning and quality of life were not available.

Data from six trials comparing antiglucocorticoid drugs as an adjunct to combination treatment versus adjunctive placebo showed no significant differences between groups in mean endpoint scores for overall psychotic symptoms (n = 171, 6 RCTs, SMD 0.01, 95% CI - 0.29 to 0.32) or positive psychotic symptoms (n = 151, 5 RCTs, SMD -0.07, 95% CI - 0.40 to 0.25). Data from three trials showed no differences between groups in mean endpoint scores for negative symptoms (n = 94, 3 RCTs, MD 2.21, 95% CI -0.14 to 4.55). One study found improvements in global state that were similar between groups (n = 30, 1 RCT, RR 0.58, 95% CI 0.32 to 1.06; very low-quality evidence). In this comparison, pooled results showed that antiglucorticoids caused a greater overall number of adverse events (n = 199, 7 RCTs, RR 2.66, 95% CI 1.33 to 5.32; moderate quality evidence), but no quality of life data were available.

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