Raloxifene and mood

Estrogens affect not only the bones and the breast but also the brain. So the question of how raloxifene changes mood is entirely natural. The editorial team has examined the clinical study data — from large programs in postmenopausal women to experimental work in psychiatry — and separated the facts from the assumptions.

Estrogens and the brain: briefly on the mechanism

Estrogen receptors of the two main types, ERα and ERβ, are present in many areas of the brain: the hypothalamus, hippocampus, amygdala and prefrontal cortex. Through them, estradiol affects the synthesis and metabolism of serotonin, dopamine and norepinephrine, neuroplasticity, and the resistance of neurons to stress.

It is precisely fluctuations in estrogen that are linked to women's increased vulnerability to depressive symptoms at certain times: in the premenstrual phase, after childbirth, in perimenopause. That is why any drug that modulates estrogen receptors could theoretically alter the emotional state.

Raloxifene crosses the blood-brain barrier much less well than estradiol, and its action in the brain depends on the specific region and receptor type. In some structures it may behave as a weak agonist, in others as an antagonist. There is little direct data on the distribution of raloxifene in the human brain.

Because of this complexity, it is impossible to predict the effect on mood "from theory". Only clinical studies, in which mood was measured with standardized scales and compared with placebo, provide the answer.

What is known about mood while taking raloxifene

One of the first systematic assessments was carried out by Nickelsen and colleagues (1999). In a randomized study of postmenopausal women, raloxifene was compared with placebo and estrogen therapy, measuring cognitive function and mood. The authors found no negative effect of raloxifene on mood compared with placebo.

Large osteoporosis studies, in particular MORE, recorded side effects according to a standard scheme. Depression and anxiety did not stand out among the reactions whose frequency significantly exceeded placebo; the most common specific effects were hot flashes, leg cramps and edema.

At the same time, raloxifene should not be regarded as an antidepressant or a means of improving mood. Unlike menopausal hormone therapy, it does not relieve vasomotor symptoms, which often underlie poor sleep and irritability during this period.

So, for postmenopausal women, the available data are generally reassuring: the drug probably does not worsen mood, but it should not be prescribed with the aim of improving it.

Cognitive function: the MORE data

Mood is closely linked to cognitive function, so data on memory and attention are important. Yaffe and colleagues (2001) analyzed cognitive tests in the MORE participants after three years of treatment. No overall difference was found between raloxifene and placebo, although a trend toward less deterioration in certain measures was observed in the raloxifene group.

A further analysis of the same cohort (Yaffe et al., 2005) found that in women receiving the higher of the studied doses, the risk of mild cognitive impairment was lower than in the placebo group. For dementia as such there was no significant difference. The authors emphasized that the cognitive results were secondary endpoints.

These data are important primarily from the standpoint of safety: long-term use of raloxifene, at least in postmenopausal women, was not associated with a decline in thinking. However, the claim that raloxifene "protects the brain" does not currently have sufficient evidence base.

It is also worth remembering that the studies were conducted in a specific population of elderly women with osteoporosis. Transferring these conclusions to young people or to men without additional data is incorrect.

Raloxifene in psychiatric research

The most interesting and most active line of research is the use of raloxifene as an add-on treatment in schizophrenia. The hypothesis is that estrogens have a certain antipsychotic action, and a SERM makes it possible to obtain this without the risks of estrogen therapy to the uterus and the breast.

In the randomized study by Kulkarni and colleagues (2016), published in JAMA Psychiatry, adding raloxifene to antipsychotics in women with treatment-resistant schizophrenia was associated with a greater reduction in symptoms compared with placebo. Other studies, in particular in men, gave conflicting results.

• Populations studied: mostly postmenopausal women with schizophrenia, with some studies in men.
• Outcomes assessed: positive and negative symptoms, general psychopathology, cognitive function.
• State of the evidence: heterogeneous results; raloxifene has no official psychiatric indication.

This line of research is important because it shows that the effect of a SERM on the mind is real and measurable. But it is specific to certain conditions, and it does not follow that raloxifene improves mood in healthy people.

A few small studies examined raloxifene in postmenopausal depression, but there is no convincing data that would allow us to speak of an antidepressant effect.

Indirect factors and caveats

In practice, mood during any therapy often changes because of indirect factors. For raloxifene these are primarily hot flashes, especially at night, which disrupt sleep. Chronic lack of sleep naturally worsens emotional stability, concentration and motivation.

Another factor is health anxiety. Warnings about thrombosis and stroke in the prescribing information can heighten worry in sensitive people. An open conversation with a doctor about the real size of the risk usually helps.

In the sports community, raloxifene is sometimes used by men, combining it with anabolic steroids or after them. In such a situation, mood fluctuations are almost always caused by changes in androgen and estrogen levels, not by raloxifene itself. There is no systematic data on the effect of raloxifene on the mind of male athletes, and any "observations" from forums cannot be considered evidence.

If persistently low mood, loss of interest in usual activities, sleep disturbance or thoughts of hopelessness appear during treatment, this requires seeing a doctor regardless of whether it is related to the drug.

Editorial conclusions

In randomized studies of postmenopausal women, raloxifene did not worsen mood and cognitive function compared with placebo.

There is not enough data to consider it a means of improving mood or protecting the brain, and for men such data is essentially nonexistent.

The most real pathways of effect on well-being are indirect: hot flashes, sleep disturbance, anxiety about side effects.

We also recommend reading our articles on the history of raloxifene's creation, on raloxifene and libido, and on how estrogens affect the male mind.

References

1. Nickelsen T, Lufkin EG, Riggs BL, et al. Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology. 1999;24(1):115–128.
2. Yaffe K, Krueger K, Sarkar S, et al. Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med. 2001;344(16):1207–1213.
3. Yaffe K, Krueger K, Cummings SR, et al. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry. 2005;162(4):683–690.
4. Kulkarni J, Gavrilidis E, Gwini SM, et al. Effect of adjunctive raloxifene therapy on severity of refractory schizophrenia in women: a randomized clinical trial. JAMA Psychiatry. 2016;73(9):947–954.
5. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282(7):637–645.
6. U.S. Food and Drug Administration. EVISTA (raloxifene hydrochloride) tablets: prescribing information. Eli Lilly and Company.
7. World Anti-Doping Agency. The Prohibited List. Montreal: WADA; чинна редакція.