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.


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


Partnership: People with schizophrenia, family members and clinicians talk about schizophrenia

Schizophrenia is a long-term but treatable brain condition. 1 in 100 people worldwide live with schizophrenia.

Dr. Diane Fredrickson is a psychiatrist who treats psychosis-related conditions including schizophrenia.

Gerhart Pahl is the father of four sons—three of whom it turns out suffer from schizophrenia.

Bryn Ditmars has a form of schizophrenia known as schizoaffective disorder.

Schizophrenia occurs most commonly between people between the ages of 15-25. It is the result of physical and biochemical changes in the brain. Symptoms may include:

  • Disordered thinking
  • Changes in emotion
  • Bizarre behaviour
  • Catatonia
  • Paranoia
  • Hallucinations
  • Delusions

60% of people with schizophrenia live with their families. Recovery takes time, a team, medication, and a healthy lifestyle.

Research has improved with brain imagery, but a cause and cure are still unknown.

Statistics about schizophrenia and suicide:

  • 50% attempt suicide.
  • 10-15% of people commit suicide.
  • Self-harm is more common than harm to others.

50% of people with schizophrenia have anosognosis, a condition in which they don’t know they’re ill. Early psychosis intervention (EPI), early diagnosis and treatment improve outcomes.

Stigma contributes to discrimination, which limits access to education, housing and employment. The media contribute to perpetuating myths that create skewed perceptions and unfounded fears.

The B.C. Schizophrenia Society (BCSS) Partnership Program provides mental health literacy. To increase your knowledge, book a presentation.
Call 604-270-7841
Toll Free: 1-888-888-0029
Email: community@bcss.org

Cognition in treatment resistance

Patients with treatment-resistant schizophrenia or schizoaffective disorder have the most severe form of the illness at least as determined by persistence of positive symptoms, but the other aspects, including negative and cognitive impairments, are typically not as well assessed clinically or in research. Most clinicians may assume that treatment-resistant patients, who often have profound functional deficits, have worse cognition than patients who respond to non-clozapine antipsychotics. This is an hypothesis that requires investigation, and a team from New Zealand have recently published such a study. They went further and also looked at the cognitive status of a group of clozapine-resistant (ultra-resistant) patients.

The 51 patients were recruited from outpatient and inpatient settings; 5 had schizoaffective disorder and the rest had schizophrenia. The control group comprised 22 healthy adults matched for age and sex. The mean age of the subjects was about 33 years. The researchers classified the patients into 3 groups based on treatment response: first-line antipsychotic responders (n=16), treatment-resistant but clozapine responders (n=20), and clozapine nonresponders (ultra-resistant; n=15). The latter group had a 8-week trial of monotherapy, and all ended up on at least 2 antipsychotics, most often clozapine and a another second-generation antipsychotic. Despite the designations, the 3 groups had no significant difference in PANSS total or subscale scores at the time of evaluation. The mean antipsychotic dose as measured in chlorpromazine equivalence was significantly greater in the clozapine-resistant group, but the mean duration of illness did not differ among groups. The control group had slightly greater mean educational attainment than the treatment-resistant group.

The cognitive assessments consisted of neuropsychologic tests covering the domains of the MATRICS Consensus Cognitive Battery developed by the U.S. National Institutes of Mental Health, considered the standard in psychosis cognitive evaluation. In this study, the testing was computerized and included such domains as executive function, social recognition, processing speed, and verbal and nonverbal learning and memory. The raw scores were converted to Z-scores normalized for age, sex and education.

The results showed that the patients overall had significant impairment in cognitive performance compared with healthy subjects, but the differences among the 3 patient groups were minimal. The treatment-resistant group, however, had a mean verbal fluency Z-score equal to that of the control group whereas the other patient groups had significantly worse performance in this domain, but subsequent analysis did not support a significant difference in verbal fluency performance in patient groups or controls. The researchers mention that pre-existing work has found that clozapine is associated with improvement in verbal fluency, an intriguing finding especially since in this study, verbal fluency was correlated with the negative-symptoms subscale of the PANSS in patients who responded to clozapine monotherapy.

The study is small, and the equivalent positive symptoms scores in the 3 patient groups raises questions about the distinctions based on treatment response, the findings tend to disconfirm the hypothesis that treatment resistance as defined by antipsychotic response necessarily indicates greater cognitive impairment.

Anderson VM, McIlwain ME, Kydd RR, Russell BR. Does cognitive impairment in treatment-resistant and ultra-treatment-resistant schizophrenia differ from that in treatment responders? Psychiatry Res. 2015; published online Oct 2015; http://dx.doi.org/10.1016/j.psychres.2015.10.036

Refugees in Canada have a high incidence of psychosis

A recent article which I reviewed found evidence for an increasing incidence of schizophrenia in Canada. The researcher speculated that Canada’s high rate of immigration may contribute to this finding. Studies from other industrialized countries have found that immigrants, both in the first and second generation, have an elevated risk of developing schizophrenia, but evidence of this in Canada is lacking. A group from the Centre for Addictions and Mental Health in Toronto estimated the incidence of schizophrenia and schizoaffective disorder in Ontario, the most populous and immigrant-rich province of Canada, by examining hospital and billing records with the records maintained by Canadian immigration authorities.

The identified cohort was all Ontario residents who were age 14 to 40 years at the beginning of the 10-year period from 1999-2008. Because of the universal health-care system, all people who come to medical attention have their diagnosis recorded in a provincial data set. All those listed as an immigrants by the federal ministry of citizenship were classified as such whereas all those not listed were classified as non-immigrants. The investigators also noted which immigrants were admitted under refugee status, an indication of a more vulnerable and likely trauma-exposed group.

The rate of new-onset psychosis in the general population was 55.6 (95% CI 54.9–56.4) per 100 000 person-years and 51.7 (95% CI 49.2–54.4) per 100 000 person-years in first-generation immigrants; these rates are not significantly different. Among the immigrants classified as refugees, the rate was higher: 72.8 (95% CI 67.1– 78.9) per 100 000 person-years, but this is not significantly different from the other rates. Closer examination found that immigrants of various origins had differing rates; those from the Caribbean and Bermuda had significantly higher risk whereas those from northern and southern Europe and east Asia had significantly lower risk than the general population. Among refugees, those from east Africa and south Asia had significantly greater risk of psychosis than the general population.

The shortcomings of this kind of study are considerable, mainly the retrospective design and the reliance on administrative-level diagnostic data. Furthermore, the general population included second-generation immigrants who could not be identified by the study methods but who also probably have a higher risk of psychosis. Moreover, the researchers mention that refugees often have other mental illnesses such as posttraumatic stress disorder which may be misdiagnosed as psychosis. Despite these sources of bias, the findings support an emerging theoretical framework in which those immigrants most subject to discrimination, often because of their race, may be most vulnerable to onset of psychosis. Socioeconomic factors and trauma also likely play a role. Early intervention programs may increase their effectiveness by taking this into consideration. The findings also underline the significance of the federal role in health-care funding for refugees, a highly vulnerable population.

Anderson KK, Cheng J, Susser E, McKenzie KJ, Kurdyak P. Incidence of psychotic disorders among first-generation immigrants and refugees in Ontario. CMAJ. 2015;17:e279-e286. Article

Supersensitivity psychosis in treatment resistance

Guy Chouinard proposed the concept of dopamine supersensitivity psychosis (DSP) in 1978, a consequence of chronic antagonism of dopamine D-2 receptors which also is posited to cause tardive dyskinesia (1). The proposed mechanism is upregulation of D2 receptors in the basal ganglia, and tardive dyskinesia is itself considered one of the markers of the condition, also characterized by tolerance to increasing doses of antipsychotic. Supersensitivity psychosis patients may therefore represent a subtype of treatment resistance. In this study from Japan, the investigators examined this hypothesis in a group of patients with chronic psychosis (2).

The 147 patients enrolled had treatment-resistant schizophrenia or schizoaffective disorder as defined by failure of at least 2 antipsychotics at a dose equivalent to 600 mg chlorpromazine for 4 weeks. Although specifics of antipsychotic therapy were not provided, none of the patients was on clozapine. Their mean duration of illness was about 23 years. Supersensitivity was diagnosed if a patient met one of 3 criteria, which were adopted from Chouinard:

  • Antipsychotic tolerance indicated by relapse while on medication and failure to improve despite 20% or more increase in dosage
  • Rebound psychosis manifested by swift relapse with reduction or discontinuation of medication; the psychosis may involve new symptoms for a patient
  • Presence of tardive dyskinesia

The investigators found that 106 or 72.1% of the patients met at least one criterion for DSP; 56% had tolerance, 44% had tardive dyskinesia, and 42% had rebound psychosis. The patients were also classified by the presence or absence of deficit syndrome, defined by prominent negative symptoms assessed by standardized rating instruments. Of 55 patients judged to have deficit syndrome, the majority did not meet criteria for DSP; hence, DSP was significantly negatively associated with prominent deficit symptoms.

Although the researchers evaluated the present state of each subject, the main limitation of the study was reliance on chart reviews for the longitudinal course of patients’ illness. Furthermore, relapse of symptoms due to nonadherence could not be reliably distinguished from antipsychotic tolerance. The findings however suggest that supersensitivity psychosis may be an important contributor to treatment resistance, and that investigations using functional imaging and other techniques are warranted to validate the concept of DSP.

References Continue reading

Riverview Refractory Psychosis Data Presented at International Psychiatry Congress



View the poster in a PDF file here


Treatment-resistant psychosis is a challenge to psychiatry and a substantial burden to health-care systems. The province of British Columbia in Canada has publicly funded, universal health care, and patients with treatment-resistant psychosis may receive care in a specialized residential program. Between 1993 and 2011, 663 patients were admitted to this program; this cohort contains one of the largest known series of patients with treatment-resistant schizoaffective disorder.

All patients were evaluated by a psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist. Records from previous hospital admissions were reviewed and all information was presented at a multidisciplinary conference. This resulted in a consensus DSM-III or -IV multiaxial diagnosis and a detailed treatment plan. Ratings of symptoms and functioning at admission and discharge included the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning Scale, the Social and Occupational Functioning Scale, and the Clinical Global Impression of Severity. A research psychologist compiled all data at the time of each patient’s hospitalization.

Patients who did not complete treatment or had a diagnosis other than schizophrenia (SZ), schizoaffective (SZA) or mood disorder (MD) were excluded; the following describes 551 included patients (SZ = 63%, SZA = 29%, MD = 8%). More than half were male (59%), and the mean duration of hospitalization was 30 weeks. The proportion receiving clozapine increased from 21% at admission to 61% at discharge. Those with a MD were less likely to receive clozapine than either SZ or SZA (SZ = 64%, SZA = 61%, MD = 41%). In each diagnostic group, both antipsychotic polypharmacy and the ratio of prescribed daily dose to defined daily dose (PDD/DDD) of antipsychotic medication decreased during hospital stay (polypharmacy: SZ: 52% to 16%, SZA: 52% to 14%, MD: 43% to 0%; PDD/DDD: SZ: 2.1 to 1.6, SZA: 2.1 to 1.4, MD: 1.6 to 1.1). The use of mood stabilizers declined in all groups, but antidepressant use declined only in SZ and SZA. Mean total PANSS score declined in all diagnostic groups, but most in MD, least in SZ, and intermediate in SZA.

In an intensive inpatient program for treatment-resistant psychosis, aggregate improvement occurred despite global reduction in medications while clozapine use nearly tripled. Lower total antipsychotic dose correlated with greater improvement at discharge.

Estradiol for treatment-resistant schizophrenia

Researchers from Australia have conducted the first controlled trial of estrogen in premenopausal women with treatment-resistant psychosis (1). They recruited 183 women with schizophrenia or schizoaffective disorder who were not pregnant, lactating, or postmenopausal; and who had no history of breast cancer, endocrine disorders, migraine with aura, or thromboembolism. Patients with acute mania were excluded. Patients were randomly assigned to receive either transdermal estradiol 100 mcg daily, transdermal estradiol 200 mcg daily, or placebo patch. The primary outcome measure during the 56-day trial was the Positive and Negative Syndrome Scale (PANSS). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Repeatable Battery of Neuropsychological Status, adverse-effects monitoring, and serum estradiol concentration at the baseline and during treatment.

The baseline demographic, illness, and treatment characteristics did not differ among the placebo, 100 mcg-estradiol, and 200-mcg estradiol groups. Most subjects were outpatients, and the three groups had mean PANSS total scores of 72-75. Compared with the placebo group, both treatment groups had significant increases in serum estradiol concentration; and greater decreases in mean PANSS positive, general, and total scores. The effect size for positive symptoms, however, was 0.0 for the 100 mcg group and 0.44 for the 200 mcg group, which reflected a mean 3.3-point reduction in PANSS-positive score with the higher dose. No significant treatment effect was found for negative symptoms or cognition. The only significant adverse effect was an increase of irregular menses in the 200 mcg group compared with the placebo group.

The investigators acknowledge that this trial was short-term and that the risks of thromboembolism and endometrial carcinoma may accumulate during longer-duration therapy. Raloxifene, a selective estrogen receptor modulator, entails a lower risk of these adverse effects. In 2011, investigators from Spain reported on a randomized trial of 16 postmenopausal women who had significant mean reduction of positive, negative, and general symptoms compared with a comparable placebo group (2). Case reports exist of raloxifene use in premenopausal women with treatment-resistant schizophrenia (3,4), but controlled trials in this population have not been published.


1. Kulkarni J, Gavrilidis E, Wang W. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age. Molecular Psychiatry. Published online 15 Apr 2014. Abstract

2. Usall J, Huerta-Ramos E, et al. Raloxifene as an adjunctive treatment for postmenopausal women with schizophrenia: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011;72(11):1552-1557. Abstract

3. Raveendranathan D, Shivakumar V, Jayaram N, Rao NP, Venkatasubramanian G. Beneficial effects of add-on raloxifene in schizophrenia. Arch Womens Ment Health. 2012;15(2):147-148. Abstract

4. Shivakumar V, Venkatasubramanian G. Successful use of adjuvant raloxifene treatment in clozapine-resistant schizophrenia. Indian J Psychiatry. 2012;54(4):394. Full text