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LETTER TO THE EDITOR |
Department of Psychiatry, Hospital Ramon y Cajal, Universidad de Alcal, Madrid, Spain and, Eastern State Hospital, Lexington, Kentucky
Prior studies have suggested that suicidal behavior may be more frequent in the perimenstrual weeks, before and after the menses (1). Hormonal determination seems to be required to avoid misclassification of female patients due to inaccuracies in self-estimates of the menstrual cycle (2). This letter explores the interaction of psychiatric diagnoses on the relationship between menstrual cycle phase and suicide attempts; we performed a new group of analyses on an already published study (2).
The study was performed in a general hospital that provides medical coverage for 500,000 people in a catchment area north of Madrid, Spain. We studied hormone levels in 90 fertile females who came to the emergency room of this hospital from January 1996 to December 1997 because of a suicide attempt (2). When the menstrual cycle was divided into three phases (follicular, mid-cycle, and luteal), we found that the number of suicide attempts in the follicular phase (51%) was significantly higher (p = .02) than the expected value (39%).
We now explore the mediating influence of psychiatric diagnosis on the relationship between suicide attempts and the phases of the menstrual cycle. The sample was divided into two categories based on the subjects’ history of absence or presence of any major axis I diagnosis except for adjustment disorders. The effect of personality disorder was also explored in a different analysis disregarding axis I diagnosis. Regardless of the inaccuracies introduced by the difficulty of diagnosing a personality disorder, these diagnoses were made without knowledge of the hormonal assessment and without any prior hypothesis.
For these new analyses, the menstrual cycle was divided into follicular, mid-cycle, and luteal phases as described previously (2). When the results were significant in a 
2 test, we eliminated the mid-cycle phase. There were a reduced number of subjects in this phase, and this elimination allowed a 2 x 2 comparison between the follicular and luteal phases and the calculation of odds ratios.
There was no significant difference in the relationship between menstrual cycle phases and current major axis I diagnosis (2 = 2.58, df = 2, p = .27). However, there was a significant difference in the frequency of suicide attempts among the three phases (follicular, mid-cycle, and luteal) (2 = 11.9, df = 2, p = .003) in subjects with a positive history of axis I diagnosis (current or past) vs. subjects with a negative history. After excluding the mid-cycle phase, 72% (34/47) of patients with a history of psychiatric illness attempted suicide during the follicular phase vs. 34% (12/35) of patients without history of a major psychiatric illness. This was a 5-times increase in suicide attempts in the follicular phase associated with a history of axis I diagnosis (odds ratio = 5.03, 95% confidence interval = 1.95–12.99; two-sided Fisher’s exact test, p = .001).
The analysis for the presence vs. absence of a personality disorder in relation to suicide attempts in the three menstrual cycle phases almost reached significance (2 = 5.47, df = 2, p = .065). During the follicular phase, suicide attempts decreased 3-fold in patients with a history of personality disorder compared with those without a personality disorder, 40% (12 of 30) vs. 65% (34 of 52) (odds ratio = 0.35, 95% confidence interval = 0.14–0.83; two-sided Fisher’s exact test, p = .037).
These results are limited by the naturalistic design of the study, the small sample size, the difficulty associated with making a psychiatric diagnosis in emergency situations, and the exploratory nature of a posteriori analyses. Moreover, the analyses somewhat overlap (eg, having a personality disorder does not exclude the history of a major axis I diagnosis). Several factors may make the vulnerable subject cross the threshold of suicidal behavior (3).
The differential influence of the follicular and luteal phases in suicide attempts may reflect the brain actions of sexual hormones. Low serotonergic function seems to increase suicide risk (3). Specifically, in the serotonergic system, estradiol may increase serotonin synthesis, modify serotonin receptor balance, increase the serotonin transporter, and decrease serotonin metabolism by inhibiting monoamine oxidase A (4). Thus, low levels of estrogens may be associated with a decrease in brain serotonin activity. Our first hypothesis is based on the idea that low estrogen levels during the early follicular phase may even further decrease serotonergic function in vulnerable women. We hypothesize that low serotonergic activity in patients with brain vulnerability to psychiatric illnesses may make them more prone to suicide attempts when there has been a further decrease in serotonergic function in the beginning of the follicular phase.
Progesterone does not seem to have major effects on the brain monoamine systems in animal or/and in vitro studies or in mood disorders in clinical studies. However, pregnenolone (a precursor of progesterone in the ovary) and allopregnanolone (a metabolite of progesterone) are neurosteroids that have been found to have specific actions on the 
-aminobutyric acid (GABA) system by a direct interaction with the GABA-A receptor. The predominance of one metabolic pattern or the other may be important because pregnenolone seems to be anxiogenic and allopregnanolone anxiolytic (5). Personality disorders are characterized by inappropriate reactions to life events. We hypothesize that the brain changes in GABA function associated with progesterone increases (or changes in its metabolites levels in the brain) during the luteal phase may make women with personality disorders more prone to react to stressful life events by attempting suicide. It is likely that brain response to an increase in plasma progesterone may vary among individuals because of the predominance of one metabolic pathway vs. the other (pregnenolone vs. allopregnanolone). Therefore, subjects with personality disorders, due to their genetic vulnerability and/or poor adjustment to the environment, may be more sensitive to the negative effects of these progesterone changes.
REFERENCES
This article has been cited by other articles:
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  E. Baca-Garcia, C. Diaz-Sastre, A. Ceverino, J. Saiz-Ruiz, F. J. Diaz, and J. de Leon Association Between the Menses and Suicide Attempts: A Replication Study Psychosom Med, March 1, 2003; 65(2): 237 - 244. [Abstract] [Full Text] [PDF]
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