Raloxifene as adjunctive treatment for chronic psychosis

Psychosis and mood symptoms are sometimes exacerbated  during times of hormonal flux in women such as postpartum and during menopause. Research from Australia has suggested that estradiol may ameliorate psychosis in women with schizoaffective disorder or schizophrenia. The same Australian team has recently published a randomized controlled trial of raloxifene in postmenopausal women with those diagnoses; raloxifene is an estrogen receptor modulator that may be safer than estradiol as it is less likely to provoke hormone-influenced cancers. However, it does entail an increased risk of thromboembolism.

The 56 subjects had a mean age of 53 years and a mean illness duration of 24 years, all were on antipsychotic therapy, and none was deemed at baseline to have elevated risk for thrombotic disease or evidence of reproductive cancers. They were randomly assigned to receive 120 mg of raloxifene or placebo for 12 weeks as cotreatment with their psychiatric medications; 8 patients were taking clozapine, 5 in the active treatment group. The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS); the investigators also monitored depression, movement disorder, cognitive function, and safety measures.

At the end of 12 weeks, the women receiving raloxifene had a significant reduction in the PANSS total and general scores, whether the diagnosis was schizophrenia or schizoaffective disorder; the PANSS positive and negative symptom subscales showed no significant improvement with raloxifene. Significantly more subjects who received raloxifene had a clinical response defined as a 20% reduction in PANSS total score (P = 0.01).  Measures of depression and cognition did not show any difference between the groups and adverse events were minimal; no thromboembolic events occurred in either group.

Raloxifene may help prevent osteoporosis and breast cancer, so it confers benefits beyond ameliorating symptoms of chronic psychosis. It has also been trialed in men cotreated with risperidone during an 8-week study in Iran; compared with placebo, the active treatment resulted in improvement in the PANSS total score and the negative and general subscale scores (2). Adverse effects did not occur more often with raloxifene, although the researchers admit that with longer-term treatment, gynecomastia and infertility would be possible which would greatly limit its utility in men.

References

1.Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial. Kulkarni J, Gavrilidis E, Gwini SM, et al. JAMA Psychiatry. 2016;73(9):947-354. Abstract

2.Khodaie-Ardakani MR, Khosravi M, Zarinfard R, et al. A placebo-controlled study of raloxifene added to risperidone in men with chronic schizophrenia. Acta Med Iran. 2015;53(6):337-345. Full text

 

Clinical Neurosciences Conference 2013

Treatment resistant schizophrenia (TRS) is a clinical challenge for mental health professionals, patients and families. Dr. Herbert Meltzer, Professor of Psychiatry at Northwestern Feinberg School of Medicine in Evanston, Illinois, spoke about his research on this disorder at the Clinical Neurosciences 2013 conference in Vancouver on March 8, 2013. Dr. Meltzer was an investigator in the 1988 pivotal U.S. clozapine trial. He emphasized that clozapine remains the best treatment and is greatly underutilized in North America. He shared data of a 15-year follow-up of clozapine-treated patients indicating that their reduction in psychosis and functional gains persisted and in some cases continued to improve. The one domain in which the outcomes were worse was cognition as measured by the Wisconsin Card Sort test.

For TRS patients who cannot tolerate clozapine, we need more options. Dr. Meltzer has recently investigated high-dose second-generation antipsychotics such as olanzapine, risperidone, and lurasidone. In a 2008 trial of high-dose olanzapine (mean dose 34 mg daily) compared with clozapine (mean dose 564 mg daily) in TRS, he found no difference between the treatments at 6 months, although olanzapine caused more weight gain. This may seem like a long time to wait, but full clozapine response may take as long or longer.

He has also examined high-dose risperidone for TRS in the form of risperidone microsphere depot injections, 100 mg every 2 weeks, compared with a more conventional dose of 50 mg every 2 weeks for 6 months. He found no difference between the doses, which had less robust outcomes than clozapine, but he added that the serum levels of risperidone were not higher than in oral dosing. Dr. Meltzer said that were he to investigate further, he would consider testing 150 mg of risperidone microspheres every 2 weeks.

In other presentations, Dr. Ofer Agid discussed the algorithm for first-episode schizophrenia that he and his team devised at the Centre for Addiction and Mental Health in Toronto. Drs. Debbie Thompson and Joing Wu presented their experience and data from the Fraser Health Psychosis Treatment Optimization Program. Dr. Bill MacEwan, who organizes the annual conference, discussed findings from the Vancouver Hotel Study, and Andrea Jones described distinguishing characteristics of substance-induced psychosis in polysubstance users.

The speaker who perhaps most captivated the audience was Erin Hawkes, a woman living with schizophrenia who discussed her experience as a patient in B.C. hospitals. She has courageously spoken and written about being psychotic, refusing medication, and being restrained and injected. Although she now accepts her diagnosis and treatment, what she underwent was at times degrading and traumatizing. She reminded the audience that small acts of kindness and a gentle approach can make a difference when someone is in great distress and turmoil.