Journal of Psychiatric Research 44 (2010) 209–214
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Suicide attempts among women during low estradiol/low progesterone states Enrique Baca-Garcia a,b,g, Carmen Diaz-Sastre c,g, Antonio Ceverino b,g, M. Mercedes Perez-Rodriguez c,d,g, Rocio Navarro-Jimenez b, Jorge Lopez-Castroman b, Jeronimo Saiz-Ruiz c,g,e, Jose de Leon f, Maria A. Oquendo a,* a
Department of Psychiatry at the New York State Psychiatric Institute and Columbia University, NY, USA Department of Psychiatry, Fundacion Jimenez Diaz Hospital, Autonoma University of Madrid, Spain Department of Psychiatry, Ramon y Cajal Hospital, Madrid, Spain d Department of Psychiatry, Mount Sinai School of Medicine, New York, USA e Department of Psychiatry, University of Alcala, Madrid, Spain f Mental Health Research Center (MHRC) at Eastern State Hospital, Lexington, Kentucky, USA g Centro de Investigación Biomédica en Red en el área de Salud Mental (CIBERSAM), Madrid, Spain b c
a r t i c l e
i n f o
Article history: Received 11 May 2009 Received in revised form 29 July 2009 Accepted 4 August 2009
Keywords: Attempted suicide Menstrual cycle Gonadal steroid hormones Estrogen Progesterone Menstruation
a b s t r a c t The relationship between the menstrual cycle and risk for suicidal behaviors is not clear. The aim of this study is to determine whether perimenstrual phases in fertile women are associated with acute risk for suicide attempt and explore whether risk is elevated during low estradiol/low progesterone states. Women (N = 431) recruited within 24 h of a suicide attempt were assessed for psychopathology, suicidal behavior and LH, FSH, estradiol and progesterone blood levels. Among fertile women (N = 281/431), suicide attempts were more likely to occur during menses (26%, 72/281 observed vs. 15%, 43/281 expected attempts; p < 0.001). Compared to women whose attempts occurred during other phases, women who attempted suicide during low estradiol/low progesterone states (menstrual phase, amenorrhea and menopause) reported severe suicide intent, a measure that may be predictive of eventual suicide death. Suicide attempts among women are more likely when estrogen and progesterone levels are low and attempts made under these conditions are associated with greater severity. Low gonadal hormone levels may constitute a key factor in the neurobiological basis of suicidal behavior among women, suggesting a novel, testable hypothesis regarding the underpinnings of suicidal acts. ! 2009 Elsevier Ltd. All rights reserved.
1. Introduction Studies of the neurobiological basis of suicidal behavior have largely focused on the serotonergic system, but have also examined the hypothalamic–pituitary–adrenal (HPA) axis, and GABAergic and glutamatergic systems. Fewer studies have examined the hypothalamic–pituitary–gonadal axis, despite the fact that as early as 1926, publications described an association between the menstrual cycle and suicide attempts (Baca-Garcia et al., 2003a; Saunders and Hawton, 2006). Saunders and Hawton (Saunders and Hawton, 2006) reviewed studies of suicidal behavior and the menstrual cycle and found that 15 of 23 studies reported that suicide attempts tended to cluster around the premenstrual and menstrual phases of the cycle. The other eight studies found no association. Among these studies, they noted considerable variation in terms of the methodology used to
* Corresponding author. Address: Molecular Imaging and Neuropathology Division, NYS Psychiatric Institute and Columbia University, 1051 Riverside Drive, Office # 2725, 10032 New York, USA. Tel.: +1 212 543 5835; fax: +1 212 543 6017. E-mail address:
[email protected] (M.A. Oquendo). 0022-3956/$ - see front matter ! 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2009.08.004
determine the participants’ menstrual phase at the time of suicide attempt. Four studies used hormonal assessment, and only two of them combined menstrual history, hormonal assessments and psychiatric evaluation within 24 h of the index suicide attempt. In this study, we tested the hypothesis that low estradiol/low progesterone states are associated with suicide attempts during the menstrual cycle. To achieve this goal, we used a comprehensive assessment of blood hormonal levels among women who had recently attempted suicide. We also sought to determine whether the association extends to all low estradiol/low progesterone states such as menopause and amenorrhea. Such an association would suggest a novel biological pathway leading to risk for suicidal behavior in women and stimulate further investigation of the role of the HPG axis in suicidal behavior. Moreover, it may serve to alert the clinician to potential elevation in risk for suicidal behavior during low estradiol/low progesterone states among vulnerable women. 2. Materials and methods Women who attempted suicide (n = 431) were recruited and interviewed in the Emergency Departments of two general
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hospitals within 24 h of a suicide attempt. These hospitals are part of the Spanish National Health Service, fully financed by taxes and providing free healthcare coverage for all Spanish citizens and legal immigrants. Suicide attempts were defined as ‘‘a self-destructive behavior with intent to end one’s life, independent of resulting damage” (Baca-Garcia et al., 2003a, 1998). Female suicide attempters were administered: (1) the Spanish version of the Mini-International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998); (2) Holmes and Rahe’s social adjustment scale (Holmes and Rahe, 1967; Gonzalez de Rivera and Morera, 1983); (3) Barratt Impulsiveness Scale (BIS), modified version (Oquendo et al., 2001); (4) Brown–Goodwin Aggression Scale (BGS) (Brown et al., 1979); and (5) Beck’s Suicidal Intent Scale (SIS) (Beck et al., 1974) to assess suicidal intent severity. Suicide intent was dichotomized into highand low-intent based on Harris and Hawton’s prospective report that a SIS cut-off value of 14 predicted future suicide death among females with a sensitivity 66.7% and specificity 75.3% (Harris and Hawton, 2005). The global score of life events index (LEI) provided by the Holmes and Rahe Scale for each patient was used to compare the total number of items (life events) between the groups. Based on a previous study with a sample of Spanish female suicide attempters, a score of 46.5 (75% sensitivity and 70% specificity) was used to define high levels of impulsivity with the BIS and a cut point of 9.5 (98% sensitivity and 100% specificity) was used to define high values in aggression with the BGS (Baca-García et al., 2006). Psychiatrists trained in the use of these research instruments conducted the assessment, which also included questions about the onset of the last menstrual period, duration of menses, cycle duration and regularity, and current use of oral contraceptive pills (OCP). Female healthy volunteers (n = 176) were recruited among blood donors. The General Health Questionnaire-12 (GHQ-12) was used to rule out psychopathology (Goldberg and Williams, 1988). Healthy controls were assessed with the same instruments as female suicide attempters, excluding the MINI. Volunteers with a history of psychiatric disorders, treatments, or admissions or with scores above the cut-off point on the GHQ-12 were excluded. General Health Questionnaire-12 (GHQ-12) scores >8 (Castle et al., 2004) indicate risk of psychiatric distress in the control sample. After description of the study, subjects gave written informed consent as approved by the Institutional Review Board. Some participants (n = 254) were the subject of previous reports (Baca-Garcia et al., 2000, 2003a). The study was in accordance with the Declaration of Helsinki. 2.1. Hormonal measures To determine the menstrual phase for each participant, serum luteinizing hormone (LH), follicular stimulating hormone (FSH), progesterone, and estradiol were measured within 24 h of the attempt as described in the endocrinology literature (Baca-Garcia et al., 1998, 2000, 2003a,b; Becker et al., 2005). Menstrual phase was determined with the following algorithm (Becker et al., 2005; Saunders and Hawton, 2006): those with progesterone levels >2.3 ng/ml were classified as being in the luteal phase; those with FSH levels between 5.7 and 20 mIU/ml, LH levels between 15 and 62 mIU/ml, and with low levels of progesterone (62.3 ng/ml) were classified as being in mid-cycle; those with low levels of FSH (65.7 mIU/ml), LH (615 mIU/ml), and progesterone (62.3 ng/ml) were classified as being in the follicular phase; OCP use was suspected when FSH levels were 14) (menopause 45% and amenorrhea 31%, respectively) at a rate comparable to that observed in menstruating women (v2 = 1.7, df = 2; p = 0.415), but significantly higher than what was seen during other menstrual cycle phases (v2 = 11.6, df = 2; p = 0.003). 4. Discussion Fertile women were more likely to attempt suicide during menses than in the follicular, mid-cycle, luteal phases of the menstrual cycle, despite the fact that other parameters associated with suicidal behavior such as aggression, impulsivity and life events (Oquendo et al., 2004) did not differ among women making attempts in different phases of the menstrual cycle. Suicide attempts were significantly more frequent during menses, when estrogen and progesterone levels are low, and in the first half of the cycle (combined menstrual and follicular phases), when estrogen and progesterone levels are low or rising. The increased frequency of suicide attempts during the first half of the cycle may be related to the time required for the action of steroids at the genome level (Rupprecht and Holsboer, 1999), which may delay the putative effects of gonadal steroids on the central nervous system. Moreover, women who attempted suicide during menses and in low estradiol/low progesterone states (amenorrhea and menopause) were more likely to make attempts with high intent scores, which may indicate risk for future suicide. These findings are consistent with the hypothesis that suicide risk increases when estrogen and pro-
gesterone levels are at their lowest (Baca-Garcia et al., 2003a). Of note, the putative underlying mechanism for higher suicide intent may be different during menses (in women with regular cycles) and in low estradiol/low progesterone states (amenorrhea and menopause), due to different hormonal states. The HPG axis may be involved in suicidal behavior through its interaction with the serotonergic system. Levels of free tryptophan, a key serotonin precursor, are higher when estrogen levels in women are low (Carretti et al., 2005) suggesting that the brain utilizes less tryptophan during hypoestrogenic periods which would result in lower CNS serotonin levels noted in suicidal behavior (Oquendo and Mann, 2001). Estradiol may increase serotonin by augmenting its synthesis, modifying serotonin receptor balance, and decreasing its metabolism via monoamine oxidase-A (MAO-A) inhibition (Berman et al., 2006; Fink et al., 1998; Gundlah et al., 2002; Hiroi et al., 2006). Estradiol also appears to increase the expression of serotonin transporter (5-HTT) mRNA in the dorsal raphe nucleus and the density of the 5-HTT binding sites in lateral septum, basolateral amygdala and ventromedial nucleus of hypothalamus of the female rat brain (McQueen et al., 1997). Altered serotonin transporter binding in the dorsal raphe nucleus has been implicated in suicide in human postmortem studies (Arango et al., 2001). Thus, low estradiol may contribute to decreased serotonergic neurotransmission, and may underlie the link between menses and suicidal behaviors observed here and elsewhere (Saunders and Hawton, 2006). Low progesterone levels are associated with higher suicidal ideation in female adolescents (Martin et al., 1997). Pregnenolone, a precursor of progesterone in the ovaries and a brain metabolite, is anxiogenic (Dubrovsky, 2005) and the progesterone metabolite allopregnanolone, a metabolite of progesterone, is anxiolytic (Dubrovsky, 2005). Both are neurosteroids that bind to the GABA-A receptor (Dubrovsky, 2005) and neurosteroid disturbances have been reported in suicidal behavior (Butterfield et al., 2005). Of course, relying on a single dimension of suicide risk such as gonadal hormone blood levels cannot adequately address propensity for a complex behavior such as suicide attempt. Cultural, social, biological and clinical factors likely modulate or add to the reported effect of sex hormones on suicidal acts (Dahlen and Canetto, 2002). For example, unwanted pregnancy has been cited as a risk factor for attempted suicide (Saunders and Hawton, 2006). However, in this sample, no patient reported fear of pregnancy as a trigger for suicide attempt. It is possible that in western societies, the use of oral contraceptives, changes in women’s roles and lower pregnancy rates may diminish sociocultural effects on the association between the menstrual cycle and suicidal behavior. On the other hand, stress and life events eventually leading to a suicide behavior are potential factors leading to sex steroids dysregulation (Girdler et al., 2001; Patchev and Almeida, 1998) and therefore, could mediate the findings in the present study. To our knowledge, this is the largest study to examine the association between suicide attempt and menstrual phase. It
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Table 2 Characteristics of women with suicide attempts in four phases of menstrual cycle. Menstrual phase (n = 72)
n
n
Mean (95% CI) [percent]
Follicular phase (n = 94) n
Mean (95% CI) [percent]
Mid-cycle phase (n = 15) n
Mean (95% CI) [percent]
Luteal phase (n = 100) n
Mean (95% CI) [percent]
Age
281
72
30.1 (27.9–32.1)
94
29.4 (27.5–31.2)
15
28.4 (24.0–32.8)
100
33.1 (31.4–34.8)
Married
280
19
[26]
23
[25]
3
[20]
36
[36]
History of psychiatric diagnosis
279
54
[76]
54
[58]
9
[60]
62
[62]
Mood disorder
229
14
[23]
16
[21]
3
[23]
27
[33]
Substance use disorder
229
10
[17]
5
[7]
1
[8]
9
[11]
History of psychiatric treatment
275
45
[62]
47
[53]
8
[53]
63
[64]
Suicide intent (High – Beck’s Suicide Intent Scale > 14)
261
25
[36]
27
[31]
1
[8]
19
[21]
Barratt Impulsiveness Scale
207
56
60.0 (56.0–64.0)
67
58.0 (54.0–61.9)
13
59.2 (50.1–68.3)
71
59.2 (55.3–63.2)
Brown–Goodwin Aggression Scale
200
55
15 (13.6–16.3)
62
13.8 (12.7–15.0)
12
12.1 (10.7–13.5)
71
14.1 (12.9–15.3)
Holmes and Rahe’s social adjustment scale (life events index)
276
71
3.0 (2.6–3.4)
90
2.5 (2.1–2.8)
15
2.1 (1.4–2.9)
100
2.8 (2.5–3.1)
Statistical test
ANOVA F = 3.8 df = 3 p = 0.011 v2 = 4.0 df = 3 p = 0.258 v2 = 6.2 df = 3 p = 0.103 v2 = 3.4 df = 3 p = 0.338 v2 = 3.6 df = 3 p = 0.311 v2 = 2.9 df = 3 p < 0.415 v2 = 7.9 df = 3 p = 0.048 ANOVA F = 1.8 df = 3 p = 0.911 ANOVA F = 1.4 df = 3 p = 0.240 ANOVA F = 2.1 df = 3 p = 0.099
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addresses most of the methodological limitations of previous studies by (1) employing a clear definition of suicide attempts, (2) including measurements of gonadal hormone blood levels, and (3) ensuring psychiatric assessment within 24 h of the suicide attempt. As early as 1926, publications (n = 29) have described the association between the menstrual cycle and suicide attempts in a total of 1919 patients (Baca-Garcia et al., 2003a; Saunders and Hawton, 2006). Although four studies (n = 73; n = 68; n = 90; n = 52) used hormonal assessment, only two of them (n = 68; n = 90) combined menstrual history, hormonal assessments and psychiatric evaluation within 24 h of the attempt. Nonetheless, the present study has some limitations. Using a single hormone blood level determination to identify the menstrual cycle phase may be inaccurate given circadian (Saunders and Hawton, 2006) and intraindividual (Brown et al., 1995; Ojha et al., 2002) variations in hormone levels. However, combining hormonal patterns with a question to the patient about whether she is menstruating at the time of assessment addresses this limitation (Becker et al., 2005). In addition, other putative biological markers of suicide are likely to be relevant for suicide risk. Considering the reported association of high testosterone levels with aggression among women (Dabbs et al., 1997, 1988), endogenous testosterone could be a confounding factor in our study. However, Dougherty et al. (1997) stated that this relationship was inconsistent and that furthermore, menstrual cycle phase was not controlled for in most of the studies. We know that testosterone levels increase at ovulation (Epstein et al., 1975) and in the luteal phase (Oka et al., 1988), and new studies should address this question. Indeed, the effect of each putative risk factor for suicidal behavior is probably small, but the sum of all factors may ultimately determine whether an individual will attempt suicide. Given the complexity of suicidal behaviors and the variety of systems likely to be involved in their genesis, future studies that integrate measures of multiple candidate systems in the same sample of suicide attempters would be instructive. Prospective studies of the role of the menstrual cycle phase as a predictor of future suicide attempts in different sociocultural contexts are needed. The possible interaction between HPG related hormonal and genetic factors (Baca-Garcia et al., 2003b) also require further study. Nonetheless, in the context of the stress–diathesis model for suicidal behavior (Mann, 2003), neuroendocrine events related to female suicide should be considered as a stressor, and the predisposition of certain women to display increased sensitivity to low gonadal hormone levels would be the diathesis. This increased sensitivity might be at least partially mediated by genetic factors. In a prior study (Baca-Garcia et al., 2003b), we showed that, in women, carrying the L allele of the serotonin transporter gene increased the risk of suicide attempts only during periods characterized by low gonadal hormone levels, such as the menses and menopause. This observation may help increase patients’ and psychiatrists’ awareness of this high risk period for suicidal behaviors and ultimately decrease the morbidity and mortality associated with these behaviors.
Conflict of interest Dr. Baca-Garcia reports no conflict of interest. Dr. Diaz-Sastre reports no conflict of interest. Dr. Ceverino reports no conflict of interest. Dr. Perez-Rodriguez reports no conflict of interest. Dr. Navarro-Jimenez reports no conflict of interest. Dr. Lopez-Castroman reports no conflict of interest. Dr. Saiz-Ruiz reports no conflict of interest. Dr. de Leon reports no conflict of interest. Dr. Oquendo has received funding from NIMH, NIAAA, and American Foundation for Suicide Prevention, Moody’s Foundation, an unrestricted educational grant from Eli Lilly and has served as a consultant to Pfizer.
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Contributors Enrique Baca-Garcia, Carmen Diaz-Sastre and Antonio Ceverino conceived and designed the study and drafted the manuscript. Enrique Baca-Garcia, Carmen Diaz-Sastre, Antonio Ceverino and M. Mercedes Perez-Rodriguez managed the literature searches and analyses. Enrique Baca-Garcia performed the statistical analysis and analyzed and interpreted the data. M. Mercedes PerezRodriguez, Rocio Navarro-Jimenez, Jorge Lopez-Castroman, Jeronimo Saiz-Ruiz, Jose de Leon and Maria A. Oquendo participated in the statistical analysis and helped to draft the manuscript and to analyze and interpret the data. M. Mercedes Perez-Rodriguez, Rocio Navarro-Jimenez, Jorge Lopez-Castroman, Jeronimo Saiz-Ruiz, Jose de Leon, Maria A. Oquendo. All authors read and approved the final manuscript. There is no one else who fulfils the criteria but has not been included as an author. Role of funding source This study was supported by a National Alliance for Research on Schizophrenia and Affective Disorders (NARSAD) Young Investigator Award to Dr. Baca-Garcia and by the Spanish Health Ministry (FIS 01/0077-01, and Instituto de Salud Carlos III, CIBERSAM). Acknowledgements This study was conducted at the Ramon y Cajal and Puerta de Hierro Hospitals in Madrid, Spain. The statistical analyses described in this article were conducted without external support. The authors thank Dianne Currier, Ph.D. and Lorraine Maw, M.A., for editorial assistance. References Arango V, Underwood MD, Boldrini M, Tamir H, Kassir SA, Hsiung S, et al. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology 2001;25:892–903. Baca-Garcia E, Sanchez-Gonzalez A, Gonzalez Diaz-Corralero P, Gonzalez Garcia I, de Leon J. Menstrual cycle and profiles of suicidal behaviour. Acta Psychiatrica Scandinavica 1998;97:32–5. Baca-Garcia E, Diaz-Sastre C, De Leon J, Saiz-Ruiz J. The relationship between menstrual cycle phases and suicide attempts. Psychosomatic Medicine 2000;62:50–60. Baca-Garcia E, Diaz-Sastre C, Ceverino A, Saiz-Ruiz J, Diaz FJ, De Leon J. Association between the menses and suicide attempts: a replication study. Psychosomatic Medicine 2003a;65:237–44. Baca-Garcia E, Vaquero C, Diaz-Sastre C, Ceverino A, Saiz-Ruiz J, Fernandez-Piquera J, et al. A pilot study on a gene–hormone interaction in female suicide attempts. European Archives of Psychiatry and Clinical Neuroscience 2003b;253:281–5. Baca-García E, Oquendo MA, Saiz-Ruiz J, Mann JJ, de Leon JA. A pilot study on differences in aggression in New York City and Madrid, Spain, and their possible impact on suicidal behavior. The Journal of Clinical Psychiatry 2006;67(3):375–80. Beck AT, Resnik HLP, Lettieri DJ. The prediction of suicide. Charles Press Publishers; . Becker JB, Arnold AP, Berkley KJ, Blaustein JD, Eckel LA, Hampson E, et al. Strategies and methods for research on sex differences in brain and behavior. Endocrinology 2005;146:1650–73. Berman NE, Puri V, Chandrala S, Puri S, Macgregor R, Liverman CS, et al. Serotonin in trigeminal ganglia of female rodents: relevance to menstrual migraine. Headache 2006;46:1230–45. Brown GL, Goodwin FK, Ballenger JC, Goyer PF, Major LF. Aggression in humans correlates with cerebrospinal fluid amine metabolites. Psychiatry Research 1979;1:131–9. Brown JR, Liu HC, Sewitch KF, Rosenwaks Z, Berkeley AS. Variability of day 3 folliclestimulating hormone levels in eumenorrheic women. Journal of Reproductive Medicine 1995;40:620–4. Butterfield MI, Stechuchak KM, Connor KM, Davidson JR, Wang C, MacKuen CL, et al. Neuroactive steroids and suicidality in posttraumatic stress disorder. American Journal of Psychiatry 2005;162:380–2. Carretti N, Florio P, Bertolin A, Costa CV, Allegri G, Zilli G. Serum fluctuations of total and free tryptophan levels during the menstrual cycle are related to gonadotrophins and reflect brain serotonin utilization. Human Reproduction 2005;20:1548–53.
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