Over the years there have been multiple reports indicating that women with schizophrenia may experience worsening of their symptoms as they transition into the menopause.  In addition, while schizophrenia typically has its onset in young adulthood, there is a second peak in women around menopause.  Researchers have postulated that falling estrogen levels may modulate dopaminergic and serotonergic neurotransmitter systems and, in this manner, may lead to an increase in schizophrenia symptoms during these hormonal transitions.  While some women report increases in psychotic symptoms, the psychiatric symptoms most commonly reported during the menopausal transition are depression, anxiety, fatigue, and poor memory.

Other studies suggest that menopausal women may also become less responsive to antipsychotics.  In a small study, including 64 postmenopausal women with schizophrenia or schizoaffective disorder, 42 participants (66%) were found to be antipsychotic responders.  Decreased responsiveness to antipsychotics was associated with longer time since the onset of menopause.   In this study, smoking was associated with greater improvement in negative symptoms, depression, and cognition.  

We do not have any treatment guidelines regarding specific interventions for managing postmenopausal worsening of symptoms in women with schizophrenia.  While these data suggest that some women may become less responsive to antipsychotics, it is not clear if merely increasing the dose of antipsychotic medication leads to significant improvement.  Antipsychotic medications may help to alleviate positive symptoms; however, they may not help to improve negative symptoms, depression, fatigue, or cognitive problems.  If doses of antipsychotic medications are increased, one must be vigilant to the possibility of increased side effect burden.  

Several studies have suggested the possibility of using estrogenic compounds to augment antipsychotic medications in both pre- and postmenopausal women.  In one double-blind, placebo-controlled trial, women with schizophrenia received either a 100 mcg estradiol transdermal patch (n=54) or a placebo patch (n=46, no active hormone present), in addition to their regular antipsychotic medications and were followed for 28 days. Patients receiving estrogen showed significant improvement in positive symptoms (hallucinations, delusions), but no difference in negative symptoms (decreased range of emotional expression, poverty of speech, lack of motivation) was observed.

Another study explored the use of the selective estrogen receptor modulator (SERM), raloxifene, in a group of postmenopausal women.  Unlike estrogen, raloxifene (Evista) does not affect breast or uterine tissue, and thus may be a promising option for older women   Compared to women receiving placebo, women who were treated with raloxifene (60 mg/day) in addition to their regular antipsychotic treatment reported  significant reductions in negative, positive, and overall symptoms during this 12 week trial.  

The finding that smoking improved certain symptoms, including negative symptoms and cognitive functioning, has been demonstrated in other populations of male and female patients with schizophrenia.  While we obviously would not recommend smoking to manage breakthrough symptoms, there is some interesting research being done on agents that modulate nicotinic receptors and may increase the effectiveness of antipsychotic medications and may improve cognitive functioning.  

There have been mixed results regarding the effectiveness of estrogen-based treatments to reverse the cognitive deficits associated with schizophrenia.  While one study reported improvement in speech comprehension in schizophrenic women treated with 17?-estradiol using a transdermal patch, another study using 17?-estradiol patch failed to show any improvement in cognitive functioning.  Several studies using raloxifene have demonstrated improvements in cognitive functioning.  

While studies have shown that estrogen-based treatment may benefit menopausal women with schizophrenia, further study is necessary in order to weigh the benefits of treatment against the risks associated with exposure to prolonged hormone therapy in this population. 

Ruta Nonacs, MD PhD

 

Begemann MJ, Dekker CF, van Lunenburg M, Sommer IE.  Estrogen augmentation in schizophrenia: a quantitative review of current evidence.  Schizophr Res. 2012 Nov; 141(2-3):179-84.

González-Rodríguez A, Catalán R, Penadés R, Ruiz Cortés V, Torra M, Seeman MV, Bernardo M.  Antipsychotic Response Worsens With Postmenopausal Duration in Women With Schizophrenia.  J Clin Psychopharmacol. 2016 Sep 13. [Epub ahead of print]

Kulkarni J, de Castella A, Fitzgerald PB, Gurvich CT, Bailey M, Bartholomeusz C, Burger H. Estrogen in severe mental illness: a potential new treatment approach. Arch Gen Psychiatry. 2008 Aug;65(8):955-60.

Usall J, Huerta-Ramos, Iniesta R, et al. Raloxifene as Adjunctive Treatment for Postmenopausal Women with Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled trial. J Clin Psychiatry 2011; 72(11):15552-1557.