Jasmin Grigg

Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial

IMPORTANCE A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects. OBJECTIVE To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia. DESIGN, SETTING, AND PARTICIPANTS This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis. INTERVENTIONS Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed. RESULTS Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24 [11] years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = -6.37; 95% CI, -11.64 to -1.10; P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97; P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = -3.72; 95% CI, -6.83 to -0.61; P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, -1.92; 95% CI, -3.83 to 0.00; P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups. CONCLUSIONS AND RELEVANCE Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00361543.

Raloxifene for schizophrenia and symptoms of hyperprolactinaemia

Hyperprolactinaemia, a common adverse effect of antipsychotic medication, is a condition of elevated serum prolactin with multiple health consequences including sexual dysfunction, galactorrhoea and amenorrhoea that can result in osteoporosis. Hyperprolactinaemia was identified in Suzy, a 44-year-old woman with comorbid schizophrenia and pituitary microadenoma. The stable 3 mm adenoma, diagnosed 7 years previously, was treated with bromocriptine which appeared to induce her first psychotic episode. Key psychotic symptoms are frequent auditory and somatic hallucinations, delusional thinking and mild paranoia. Suzy also reported depression and memory difficulties. Previous antipsychotic treatment included olanzapine and clozapine, with unwanted side effects and perceived lack of symptom improvement. Suzy’s current treatment comprises zuclopenthixol decanoate injection 200 mg/fortnight, which has a propensity for prolactin elevation, and quetiapine 50 mg/day. Suzy reported 4 years of amenorrhoea since commencing the zuclopenthixol depot. Prior to this, serum prolactin levels were stable at 1502 mU/L and her periods were largely regular. Current serum prolactin level was 2270 mU/L (adjusted reference range: 109–557 mU/L). Minimal galactorrhoea has been reported. In line with emerging evidence of the psychoprotective effects of raloxifene (a selective oestrogen receptor modulator) for women with schizophrenia (Kulkarni et al., 2016), Suzy was trialled on 120 mg/day raloxifene for 12 weeks. She reported menstruating after 8 weeks of treatment with a progesterone level of 23 nmol/L, suggesting that ovulation had occurred. Menstruation occurred in the context of ongoing zuclopenthixol use and only a slight drop in prolactin level to 2217 mU/L (2202 mU/L after 12 weeks of raloxifene). Amenorrhoea resumed with cessation of raloxifene. Twelve weeks of raloxifene treatment improved Suzy’s psychotic symptoms (7-point change, Positive and Negative Syndrome Scale), mood (6-point change, Montgomery–Åsberg Depression Rating Scale) and cognitive functioning (8-point total scale change, Repeatable Battery for the Assessment of Neuropsychological Status). This is the first case to report resumption of menses with raloxifene in a woman with hyperprolactinaemia resulting from pituitary microadenoma plus antipsychotic use. While little is known about the effects of raloxifene in premenopausal women, it does appear to cause ovarian stimulation (Premkumar et al., 2007). Raloxifene has been shown to decrease prolactin levels in postmenopausal women (Cheng et al., 2004); however, this did not appear to be the case in our premenopausal patient. As patients taking prolactin-elevating antipsychotics are at high risk of bone mineral density depletion from hyperprolactinaemiainduced hypogonadism, raloxifene (currently indicated for the prevention and treatment of postmenopausal osteoporosis) may promote bone strength while reducing psychotic illness severity. Additional work is required to determine the effects of raloxifene in this patient group.

Adjunctive raloxifene for postmenopausal women with schizophrenia: A meta-analysis of randomized, double-blind, placebo-controlled trials

OBJECTIVE Raloxifene, a selective estrogen receptor modulator, has been used in treating postmenopausal women with schizophrenia with inconsistent results. This meta-analysis of randomized, double-blind, placebo-controlled trials (RCTs) examined its efficacy and safety for postmenopausal women with schizophrenia. METHOD Standardized mean differences (SMDs) and risk ratio (RR) together with their 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS The meta-analysis included 5 RCTs (n = 240) comparing raloxifene (n = 125, 60 or 120 mg/day) with placebo (n = 115). Adjunctive raloxifene outperformed placebo with regard to the Positive and Negative Syndrome Scale (PANSS) total psychopathology [n = 240, SMD:-0.64 (95%CI:-0.90, -0.37), P < 0.00001; I2 = 0%], positive symptoms [n = 240, SMD:-0.49 (95%CI:-0.81, -0.16), P = 0.003; I2 = 29%], negative symptoms [n = 240, SMD:-0.43 (95%CI:-0.68, -0.17), P = 0.001; I2 = 0%], and general psychopathology scores [n = 240, SMD:-0.66 (95%CI:-0.92, -0.39), P < 0.00001; I2 = 0%]. Both groups had similar rates of adverse events and discontinuation (n = 159, RR: 1.32 (95%CI: 0.65, 2.70), P = 0.44, I2 = 0%). CONCLUSION Adjunctive raloxifene appears to be effective and safe in improving psychotic symptoms for postmenopausal women with schizophrenia. Review registration: CRD 42017059946.

Establishing female-only areas in psychiatry wards to improve safety and quality of care for women.

Objective: Our aim was to assess the impact of creating a female-only area within a mixed-gender inpatient psychiatry service, on female patient safety and experience of care. Method: The Alfred hospital reconfigured one of its two psychiatry wards to include a female-only area. Documented incidents compromising the safety of women on each ward in the 6 months following the refurbishment were compared. Further, a questionnaire assessing perceived safety and experience of care was administered to female inpatients on both wards, and staff feedback was also obtained. Results: The occurrence of documented incidents compromising females’ safety was found to be significantly lower on the ward containing a female-only area. Women staying on this ward rated their perceived safety and experience of care significantly more positively than women staying where no such gender segregation was available. Further, the female-only area was identified by the majority of surveyed staff to provide a safer environment for female patients. Conclusions: Establishing female-only areas in psychiatry wards is an effective way to improve the safety and experience of care for female patients.

Borderline personality disorder and polycystic ovary syndrome: A review of the literature:

Objective: This review examines the existing evidence for the relationship between borderline personality disorder and polycystic ovary syndrome, and to identify commonalities in etiological mechanisms of borderline personality disorder and polycystic ovary syndrome that might explain the relationship between these seemingly disparate disorders. Methods: A search of Medline, EMBASE and Cochrane Central was undertaken on 5 December 2016 to identify studies investigating women with borderline personality disorder and polycystic ovary syndrome (or symptoms and markers specific to polycystic ovary syndrome). Results: Nine studies were identified, including three cross-sectional studies investigating symptoms of polycystic ovary syndrome in women with borderline personality disorder, two cross-sectional and one cohort study examining the prevalence of psychiatric diagnoses in women with polycystic ovary syndrome and three case reports of comorbid borderline personality disorder and polycystic ovary syndrome. Conclusion: Overall, the literature shows women with borderline personality disorder to have higher than expected serum androgen levels and incidence of polycystic ovaries, which can be key features of polycystic ovary syndrome. However, this research is still in its infancy, which limits our understanding of this potential comorbid phenomenon. Given the emerging anecdotal and empirical evidence to date, a theoretical discussion of the potential psychoneuroendocrinological mechanism underlying the borderline personality disorder and polycystic ovary syndrome comorbidity is provided. Further rigorous studies using standardized diagnostic criteria for polycystic ovary syndrome are warranted. Specifically, the use of prospective controlled cohort studies may be able to determine the causality and temporality of observed comorbid borderline personality disorder and polycystic ovary syndrome.

Oestradiol treatment for mood stabilisation in borderline personality disorder

In women, low and fluctuating levels of oestradiol are shown to underpin vulnerability to stress-related psychiatric disorders, as well as treatment response (Maeng and Milad, 2015), though studies rarely control for menstrual cycle phase, oral contraceptive use or basal hormone levels. Alice, a 21-year old patient, was diagnosed with borderline personality disorder (BPD) 3 years previously. BPD is a complex, severe and highly stigmatised psychiatric illness that can result from childhood trauma plus genetic vulnerability, evoking a stress response that promotes pathophysiological processes. Alice presented at our tertiary clinic for women’s mental health with severe emotional dysregulation, self-harm and suicidality. Current medications were quetiapine immediate release (IR) 200 mg/day plus extended release (XR) 50 mg twice daily, lamotrigine 200 mg twice daily and duloxetine 120 mg/day. In line with emerging evidence of oestradiol’s psychoprotective effects (e.g. Kulkarni et al., 2015), our Professor of Psychiatry (J.K.) in consultation with our Endocrinologist (specialising in psychoneuroendocrine aspects of women’s mental health) commenced Alice on daily oral oestradiol 1.5 mg/nomegestrol acetate 2.5 mg, and 1 month later added transdermal oestradiol (titrated to 37 μg/ day). Adverse effects were monitored fortnightly. At 8 weeks of treatment, substantial improvements in Alice’s overall symptom severity (7-point change, Zanarini Rating Scale for Borderline Personality Disorder), affect dysregulation (14-point change, Difficulty in Regulation of Emotions Scale) and self-reported negative thoughts, emotions and behaviours (17-point change, Borderline Evaluation of Severity over Time) were observed. Due to irritant contact dermatitis of increasing severity, transdermal oestradiol was substituted with oral oestradiol valerate 1 mg/day and then increased to 2 mg/ day to improve response. Over a 12-month period of treatment and monitoring, Alice reports her mood to have stabilised with a significant reduction in anger. Most notably, her previously prominent suicidal tendencies have been near absent for 9–12 months – even in the context of worsening life stresses. A sustained dose reduction of quetiapine (IR) to 125 mg/day has also been achieved. This is the first case to report improvement of BPD symptoms with oestradiol use. While little is currently known about oestradiol’s role in modifying neural function in BPD, oestrogen levels have been demonstrated to play a critical role in vulnerability to stress and fear responses in extrapolative post-traumatic stress disorder research (Glover et al., 2015). Co-administration with a progestin (as we did with nomegestrol acetate) can reduce risks associated with unopposed oestradiol on reproductive tissue. Oestrogen modulation holds promise in advancing treatment of BPD, and clinical research to examine efficacy and dose-dependent effects is now warranted.