Anthony de Castella

Estrogen in Severe Mental Illness: A Potential New Treatment Approach

CONTEXT Accumulating evidence suggests that estrogens may have therapeutic effects in severe mental illnesses, including schizophrenia, via neuromodulatory and neuroprotective activity. OBJECTIVE To compare the efficacy of adjunctive transdermal estradiol with that of adjunctive placebo in the treatment of acute psychotic symptoms. DESIGN Randomized, double-blind study. SETTING Patients were recruited from inpatient acute hospital wards and outpatient clinics of 2 metropolitan Melbourne general hospitals. PARTICIPANTS One hundred two women of childbearing age with schizophrenia. All participants were in an acute or chronic phase of their illness; 73 participants were outpatients and the rest were inpatients. Intervention Patients were randomized to receive 100 microg of transdermal estradiol (n = 56) or transdermal placebo (n = 46) for 28 days. MAIN OUTCOME MEASURES Psychopathological symptoms were assessed weekly with the Positive and Negative Syndrome Scale. RESULTS The addition of 100 microg of transdermal estradiol significantly reduced positive (P < .05) and general psychopathological (P < .05) symptoms during the 28-day trial period compared with women receiving antipsychotic medication alone. CONCLUSION Estradiol appears to be a useful treatment for women with schizophrenia and may provide a new adjunctive therapeutic option for severe mental illness. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00206570.

A clinical trial of the effects of estrogen in acutely psychotic women.

This study was a preliminary open clinical trial aimed at exploring the hypothesis that estrogen may provide protection against schizophrenia in women. Eleven women with acute psychotic symptoms, as scored on the BPRS, SAPS and SANS, had 0.02 mg estradiol added to neuroleptic treatment for eight weeks. Their response was compared to seven women with similar symptom severity receiving neuroleptic treatment alone. Both groups had baseline hormonal assays of estrogen, progesterone, LH and FSH and underwent regular psychopathology ratings during the eight weeks. The group receiving the estradiol adjunct showed more rapid improvement in psychotic symptoms compared with the group receiving neuroleptics only. This difference was not sustained for the entirety of the trial. Both groups reached similar levels of recovery by the eighth week. These results suggest that estradiol may have antipsychotic properties and/or act as a catalyst for neuroleptic responsiveness in women with schizophrenia.

A pilot study of hormone modulation as a new treatment for mania in women with bipolar affective disorder

We tested and compared the use of two adjunctive hormonal agents, tamoxifen and medroxyprogesterone acetate (MPA), for the treatment of acute mania or hypomania. A total of 13 women with acute Bipolar Affective Disorder in the manic or hypomanic phase were recruited from a clinical population to participate in this 28-day, three-arm, double blind, placebo-controlled study. The women who received tamoxifen exhibited significant improvement in symptoms of mania from baseline to final assessment compared with the placebo group. The MPA group improved more than the placebo group. Further exploration of tamoxifen as a useful adjunct in the treatment of acute manic symptoms in women with Bipolar Affective Disorder is warranted.

Reduced plastic brain responses in schizophrenia: a transcranial magnetic stimulation study

BACKGROUND Abnormalities in brain plasticity, possibly related to abnormal cortical inhibition (CI), have been proposed to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation (TMS) provides a dynamic method for non-invasive study of plastic processes in the human brain. We aimed to determine whether patients with schizophrenia would exhibit an abnormal response to repetitive TMS (rTMS) applied to the motor cortex and whether this would relate to deficient cortical inhibition. METHODS Measures of motor cortical excitability and cortical inhibition were made before and after a single 15-min train of 1-Hz rTMS applied to the motor cortex in medicated and unmedicated patients with schizophrenia as well as healthy controls. RESULTS All three groups had equal motor cortical excitability prior to rTMS, although both patient groups had a shorter cortical silent period (CSP) and less cortical inhibition than the control group. Cortical excitability, as assessed by motor threshold levels, did not reduce in both medicated and unmedicated patients in response to rTMS as was seen in the control group. Significant differences were also seen between the groups in response to the rTMS for motor-evoked potential (MEP) size and cortical silent period duration. CONCLUSIONS Both medicated and medication free patients with schizophrenia demonstrated reduced brain responses to rTMS and deficits in cortical inhibition.

Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia.

Estrogen treatment may enhance the recovery of schizophrenia in women. However, adverse effects on uterine and breast tissue and other physical side effects may limit the long-term therapeutic use of estrogen. Raloxifene hydrochloride is a selective estrogen receptor modulator that acts as an estrogen antagonist in breast tissue and may have agonistic actions in the brain, potentially offering mental health benefits with few estrogenic side effects. To provide an indication of the potential therapeutic dose for raloxifene hydrochloride in postmenopausal women with schizophrenia, this study pools data from an ongoing randomized controlled trial of adjunctive 120 mg/day oral raloxifene hydrochloride (n=13) versus oral placebo (n=13), with data from a previous pilot study administering 60 mg/day raloxifene hydrochloride (n=9). Analysis of variance found significant interaction effects for total (p=.01) and general (p=.02) Positive and Negative Syndrome Scale (PANSS) symptomatology. Participants randomized to receive 120 mg/day raloxifene hydrochloride experienced a significantly more rapid recovery of total and general psychotic symptoms compared to both 60 mg/day raloxifene hydrochloride and placebo. The demonstrated benefit of adjunctive treatment with 120 mg/day raloxifene hydrochloride offers support for the potential role of this selective estrogen receptor modulator in treating postmenopausal women with schizophrenia.

A longitudinal study of patient- and observer-rated quality of life in schizophrenia

Patient-rated life satisfaction and observer-rated quality of life (ORQOL) appear to have different determinants in patients with schizophrenia, although most studies conducted to date have used cross-sectional methods or related clinical dimensions at one time point with quality of life (QOL) measured at another. The aim of this study was to investigate the relationship between changes in patient-rated QOL (PRQOL) and ORQOL over time and changes in clinical variables. Two hundred and thirty-one patients taking part in the Schizophrenia Care Assessment Program (SCAP) study at Dandenong in Australia were included in this analysis. Subjective ratings of several domains of social functioning and life satisfaction were taken from the SCAP instrument and comparisons made with data from the QOL Scale rated by research staff, as well as several psychopathology measures. Changes in these scores over 1 year were correlated to investigate relationships between measures. Weak correlations were seen between changes in PRQOL and ORQOL domains. Patient-rated domains related most closely to depressive symptoms (Montgomery-Asberg Depression Rating Scale scores) whereas observer-rated domains related to both negative symptoms and depressive symptoms. Positive psychotic symptoms had little effect on either domain. Longitudinal data appear to confirm that PRQOL and ORQOL are not closely related and may have differing determinants in patients with schizophrenia. They should be considered as separate and complementary outcome variables and utilized accordingly.

Repetitive transcranial magnetic stimulation reveals abnormal plastic response to premotor cortex stimulation in schizophrenia.

BACKGROUND Schizophrenia may be characterized by abnormal plastic modulation in cortical neuronal circuits. Activation of premotor cortex using repetitive transcranial magnetic stimulation (rTMS) produces suppression of cortical excitability in primary motor cortex. We hypothesized that premotor rTMS would cause less suppression of motor cortical excitability in patients with schizophrenia than in control subjects. METHODS Twelve patients diagnosed with schizophrenia and twelve healthy control subjects underwent subthreshold rTMS to the premotor area in a 15-min conditioning train. Measurements of primary motor cortical excitability (motor evoked potential; MEP), the resting motor threshold (RMT), and cortical inhibition (CI) were taken before and after the rTMS. RESULTS There was no difference in RMT between groups at baseline, although the patient group had less CI than the control group at baseline. Following rTMS, the change in both MEP size and RMT between groups was significant. After rTMS, MEP size was suppressed in the control group and increased in the patient group, whereas RMT increased in the normal control group and decreased in the patient group. CONCLUSIONS Patients with schizophrenia demonstrate abnormal brain responses to rTMS applied to the premotor cortex that appear to relate to reduced motor cortical inhibition.

Estrogens and men with schizophrenia: Is there a case for adjunctive therapy?

Adjunctive use of estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia in women. In men, consideration of estrogen therapy has been impacted by concerns of feminising side effects, however, clinical trials of the use of estrogen in treating prostate cancer, bone density loss and even aggression and psychosis in dementia or traumatic brain injury, show this to be a safe and effective therapy. The current 14-day randomised placebo-controlled trial in 53 men with schizophrenia was conducted to evaluate the efficacy of 2 mg oral estradiol valerate as an adjunct to atypical antipsychotic treatment. Results demonstrated for estradiol participants a more rapid reduction in general psychopathology that occurred in the context of greater increases in serum estrogen levels and reductions in FSH and testosterone levels. Approximately 28% of estradiol participants did not achieve an increase (at least a 50% from baseline) in serum estrogen suggesting that further research is needed to refine the type, dose and administration route for estrogen therapy in men. Findings do, however, suggest further exploration of a therapeutic role for adjunctive estradiol treatment in men with schizophrenia is warranted.

A functional magnetic resonance imaging study of the effects of low frequency right prefrontal transcranial magnetic stimulation in depression.

The study aimed to explore the biological effects of low-frequency repetitive transcranial magnetic stimulation (LFR-TMS) treatment applied to the right prefrontal cortex, comparing this with the effects of high-frequency left-sided (HFL-TMS) in patients with treatment-resistant depression. Twenty-six patients with treatment-resistant depression were randomized to receive either daily LFR-TMS or HFL-TMS treatment for 3 weeks and underwent functional magnetic resonance imaging during a planning task before and after treatment. Patients responded clinically to both forms of treatment with no difference in the degree of response (F1,24 = 0.65;P > 0.05). Low-frequency repetitive transcranial magnetic stimulation resulted in no overall change in task-related activation. However, responders to LFR-TMS demonstrated a bilateral decrease in activity in middle frontal gyrus. In contrast, HFL-TMS produced an increase in activation in left precuneus with responders showing increased activation in several additional regions. Response to LFR-TMS is associated with a bilateral reduction in frontal activation that does not seem to be a nonspecific effect of treatment and differs from the response to HFL-TMS.

A prospective study of the impact of smoking on outcomes in bipolar and schizoaffective disorder

BACKGROUND Tobacco smoking is more prevalent among people with mental illnesses, including bipolar disorder, than in the general community. Most data are cross-sectional, and there are no prospective trials examining the relationship of smoking to outcome in bipolar disorder. The impact of tobacco smoking on mental health outcomes was investigated in a 24-month, naturalistic, longitudinal study of 240 people with bipolar disorder or schizoaffective disorder. METHOD Participants were interviewed and data recorded by trained study clinicians at 9 interviews during the study period. RESULTS Comparisons were made between participants who smoked daily (n = 122) and the remaining study participants (n = 117). During the 24-month study period, the daily smokers had poorer scores on the Clinical Global Impressions-Depression (P = .034) and Clinical Global Impressions-Overall Bipolar (P = .026) scales and had lengthier stays in hospital (P = .012), compared with nonsmokers. LIMITATIONS Smoking status was determined by self-report. Nicotine dependence was not measured. CONCLUSION These findings suggest that smoking is associated with poorer mental health outcomes in bipolar and schizoaffective disorder.