31
Psychiatry Research, 43:3 l-42 Elsevier
Urinary
Catecholamines
and Cortisol
Catherine
Mancini
M. Brown
and Gregory
in Parasuicide
Received August 14, 1991; revised version received February 18, 1992; accepted April 19, 1992. Abstract. A relationship of urinary catecholamines and of urinary free cortisol with violent suicide attempts has been reported. We have reexamined this issue in patients within 24 hours of hospital admission. Suicide attempters had significantly higher norepinephrine (NE: mean + SD = 58.3 + 27.0 pg/24 hours; n = 27) than did control patients with suicidal ideation (mean + SD = 37.1 + 21.3; n = IO). Among suicide attempters, those who used physical means had the highest NE levels (mean & SD = 69.7 + 21.3) and those who took overdoses of antidepressants (mean f SD = 51.9 + 17.3; n = 6) benzodiazepines (mean + SD = 65.1 f 29.7; n = 5) or miscellaneous drugs (mean -t SD = 59. I + 36.5; n = 11) had lower NE values. In contrast to NE, urinary dopamine (mean & SD = 402.6 f 392 pg/24 hours, epinephrine (EPI: mean f SD = 14.3 f 4.0 pg/24 hours), the NE/EPI ratio (mean f SD = 8.3 + 0.9) urinary free cortisol (mean + SD = 157.9 * I I .5 ,ug/24 hours) and serum cortisol (mean +- SD = 35.0 + 13. I
did not differ between groups. There were no group differences in age (mean + SD = 36.3 ?c 16.5 years), Beck Depression Inventory score (mean f SD = 26.3 + 12.9), Beck Hopelessness Scale score (mean * SD = 10.0 & 5.6) Beck Scale for Suicidal Ideation score (mean * SD = 13.6 + 9.3), or Hamilton Rating Scale for Depression score (mean + SD = 19.5 * 9.8). In the four parasuicide
nM/l)
groups, there was no difference in suicide intent (mean + SD = 13.3 + 7.9). These findings indicate that there is increased NE output shortly after suicide attempts. Previous reports of a low NE/ EPI ratio in suicidal patients may reflect adaptive changes rather than the acute state of the patient at the time of the attempt. Key Words. Norepinephrine,
epinephrine,
dopamine,
cortisol,
depression.
Although suicide is a leading cause of death in North America, no biological indicator has been found that consistently predicts who will go on to commit suicide. A significant amount of research has been devoted to the study of the relationship of depression, suicidal behavior, and the biogenic amines-particularly, 5-hydroxyindoleacetic acid (SHIAA). Most studies have shown a decrease in serotonin activity in groups of people with suicidal ideation. Decreased concentrations of 5HlAA in cerebrospinal fluid (CSF) have been consistently found in depressed patients (Agren, 1980; van Praag, 1986; Asberg and Wagner, 1986). Several investigators have also demonstrated an association between low concentrations of CSF SHIAA and hospital-
Catherine Mancini, M.D., F.R.C.P.C., is an Assistant Professor, Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada, and Director of the Anxiety Disorders Clinic, McMaster University Medical Centre. Gregory M. Brown, M.D., Ph.D., is Professor of Psychiatric Research, Department of Psychiatry, University of Toronto, and Director of Research, Clarke Institute of Psychiatry, Toronto, Ontario, Canada. (Reprint requests to Dr. C. Mancini, McMaster University Medical Centre, 3G Clinic, Outpatient Psychiatry, Box 2000, Hamilton, ON L8N 325, Canada.) 01651781/92/$05.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd.
32 ized patients with a recent or a past history of suicide attempts (Asberg and Bertilsson, 1979; Banki and Arato, 1983; Banki et al., 1984). Trlskman and others (1981) found that the CSF SHIAA of nonviolent attempters did not differ significantly from control subjects, although an association was found between a low concentration of CSF SHIAA and violent suicide attempts. However, these findings have not been supported by others (Roy et al., 1986; Secunda et al., 1986). Also, post-mortem studies examining SHIAA levels (Beskow et al., 1976; Korpi et al., 1986), postsynaptic serotonin receptor number (Stanley et al., 1982) and platelet 3H-imipramine binding density (Meltzer and Arora, 1986) suggest that serotonergic transmission may be reduced in suicide victims. In contrast, little attention has focused on the noradrenergic system despite early work by Funkenstein et al. (1954). They studied the emotional reactions of college students to a stress-inducing laboratory situation and concluded that “anger in” or anger turned against the self was associated with epinephrine and “anger out” was associated with norepinephrine. Ostroff et al. (1982) noted an association between suicidal behavior and the ratio of norepinephrine-to-epinephrine in 24-hour urine samples collected during a study on the course of recovery in psychotic male patients. Two of the 22 patients went on to complete violent suicides, and one made a serious attempt. These three patients were found to have significantly lower norepinephrine-to-epinephrine ratios as well as higher levels of urinary free cortisol than did the other patients. In a subsequent study, 99 male inpatients with mixed diagnoses, including the original 22 patients, were divided into those with a history of suicide attempt and those without such a history. The ratio of norepinephrine-toepinephrine levels was significantly lower in the group with a history of sucide attempt (Ostroff et al., 1985). Prasad (1985) compared a group of 19 male wristslashers with 13 male patients who had used violent means of parasuicide (i.e., jumping from a height or hanging). The patients who had attempted suicide by violent means were found to have a significantly lower norepinephrine-toepinephrine ratio and a higher mean urinary free cortisol level. In a study of 65 depressed patients, Dajas et al. (1986) found an inverse relationship between the norepinephrine-to-epinephrine ratio and suicidal ideation (item 3 of the Hamilton Rating Scale for Depression; r = -0.31, p < 0.05). Other investigators have not confirmed the relationship between a decreased norepinephrine-to-epinephrine ratio and suicidality (Secunda et al., 1986). Roy et al. (1989) reported that depressed patients who had never attempted suicide and depressed patients who had attempted suicide both had significantly higher norepinephrine levels than controls but that suicidal behavior itself had no effect on urinary norepinephrine. Rockwell et al. (1978) reported a low output of norepinephrine, epinephrine, and 17-ketogenic steroids in a volunteer who committed suicide 2 weeks later. Low norepinephrine levels have been reported in the putamen of suicide victims (Beskow et al., 1976). Mann et al. (1986) have found a significant increase in /3-adrenergic receptor binding in the frontal cortex of suicide victims compared with controls. Measures of cerebrospinal fluid (CSF) norepinephrine and its metabolite, 3methoxy-4-hydroxyphenethyleneglycol (MHPG), in suicidal patients have given mixed results. Brown et al. (1979) found that CSF concentrations of MHPG were
33 positively correlated with suicidality in patients with personality disorders. However, this relationship was not found in patients with borderline personality disorders (Brown et al., 1982), although there was a significant positive correlation between aggression scores and CSF MHPG levels. Agren (1980, 1983) reported a significant negative correlation of CSF MHPG and suicidality in unipolar but not bipolar depression. Berrettini et al. (1985) found that norepinephrine and MHPG levels in the CSF of bipolar patients did not differentiate those who had made a past suicide attempt from those who had never made a suicide attempt. However, in the National Institute of Mental Health’s Collaborative Study on the Psychobiology of Depression, investigators found that patients who had never attempted suicide showed significantly higher plasma and urinary levels of MHPG, with a similar trend in CSF MHPG levels, than did patients who had attempted suicide (Secunda et al., 1986). A known biological marker for depressive illness is the excessive release of cortisol with high plasma levels and increased urinary excretion of cortisol. Several investigators have also demonstrated increased levels of 24-hour urinary 17hydroxycorticosteroids in patients who later went on to commit suicide (Bunney and Fawcett, 1965; Bunney et al., 1969; Krieger, 1970) or of urinary free cortisol in those who had a history of suicide attempts (Ostroff et al., 1982; Prasad, 1985). Others have failed to show such a relationship (Fink and Carpenter, 1976; Brown et al., 1986; Secunda et al., 1986). Conflicting results have also been reported with respect to the relationship between abnormal dexamethasone suppression test (DST) results and suicide attempts. Some investigators have shown a positive correlation between DST nonsuppression and suicide attempts (Coryell and Schlesser, 1981; Banki and Arato, 1983; Targum et al., 1983; Robbins and Alessi, 1985) and others have reported negative findings (Brown et al., 1986; Kocsis et al., 1986; Roy et al., 1986; Secunda et al., 1986). Several investigators (Barnes et al., 1983; Ostroff et al., 1985) have hypothesized that the noradrenergic and adrenal findings may be interrelated by a complex interaction between the hypothalamic-pituitary-adrenal system and the noradrenergic system. One major problem in this literature is that the length of time following suicide attempts is usually not specified despite the fact that dynamic changes in biological and clinical measures occur. Moreover, little effort has been made to assess suicidal intent separately from the lethality of the means used. Confounding effects of drug overdose or of other chemical agents (e.g., carbon monoxide) are also ignored. This prospective study was intended to test the hypothesis that the norepinephrineto-epinephrine ratio and urinary free cortisol may be biological markers of sucidal behavior and to relate these markers to specific clinical measures including suicidal intent, lethality of the attempt, and depression. The study compared patients who were hospitalized after a suicide attempt with a group of patients who were admitted with suicidal ideation but no suicide attempt.
Methods Forty-three consenting patients who were consecutively admitted to the Liaison Unit at St. Joseph’s Hospital (Hamilton, Ontario, Canada) were evaluated. Experimental patients were those who had made a suicide attempt within the previous 24 hours. Control patients were those who were admitted with suicidal ideation but no suicide attempt within the last 6 months.
34 Exclusion criteria included age over 68 years, active drug or alcohol abuse, serious medical illness, and treatment with P-adrenergic blockers. The total group of subjects comprised 24 women and 20 men who ranged in age from 16 to 68 years. The patients were diagnosed using Research Diagnostic Criteria (Spitzer et al., 1978) and DSM-III-R criteria (American Psychiatric Association, 1987). Diagnostic information was obtained from the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer, 1978) and a clinical interview. A detailed psychiatric, medical, and drug history was obtained. Each patient was evaluated using the 17-item Hamilton Rating Scale for Depression (Hamilton, 1976) the Beck Depression Inventory (Beck et al., 1961) the Beck Hopelessness Scale (Beck et al., 19746) and the Scale for Suicidal Ideation (Beck et al., 1979). The Suicide Intent Scale (Beck et al., 1974~) and the Lethality of Suicide Attempt Scales (Smith et al., 1984) were completed for those
attempting suicide. Urine was collected
for a 24-hour period beginning at 7 a.m. on the day after admission. An aliquot for catecholamine determination was acidified to pH = 2 using 6 N HCI. A single blood sample was obtained at 2 a.m. on the night following admission for cortisol determination. Blood and urine samples were frozen at -20 “C until assay. Norepinephrine, epinephrine, and dopamine in urine were assayed by high performance liquid chromatography (HPLC) with electrochemical detection (Scheinin et al., 1983). Cortisol in urine and in blood was assayed by radioimmunoassay (Keane et al., 1975). Catecholamines and cortisol values were initially examined for their relationships to age. weight. and height in the overall patient group. Urinary cortisol was found to correlate with height and weight and urinary dopamine, with age. These effects were covaried out in subsequent analysis. The t test was used to compare suicide attempters (n = 32) and nonattempters (n = 12) on all variables. Then suicide attempters were subdivided into those who had used violent means (n = 8), tricyclic antidepressant overdose (n = 7) benzodiazepine overdose (n = 6) and other means (acetaminophen, carbon monoxide poisoning, chloral hydrate, aspirin with codeine, cogentin, and glyburide; n = I I). An analysis of variance was used to compare all groups. The correlations of the biochemical data with the clinical ratings were examined within each subgroup separately. Dose equivalents of tricyclic antidepressants and of benzodiazepines used for overdoses were calculated and their correlation with biochemical measures was examined. Correlations are reported only when significant. For catecholamine analysis, five subjects were excluded because acidified urine was not available and two subjects were excluded because of outlying data. One outlier had Parkinsonism, was being treated with t_-dopa, and had a urinary dopamine output of 4644pg/24 hours; the other subject, who took an overdose of maprotiline (750 mg; 5 times her usual dose), had a urinary epinephrine output of 37O,ug/24 hours, a value five-fold higher than that for any other subject. Two subjects were excluded from the urinary cortisol analysis because of the unavailability of urine and one from the serum cortisol analysis because of a missing blood sample.
Results Patient and Clinical Characteristics. Table 1 presents data for age, weight, and ratings for each group. There are no significant differences between groups in any of the variables, except for significantly higher lethality in those using physical means. Table 2 presents diagnostic information. Urinary Free Cortisol. Urinary free cortisol did not differ between the groups (Table 3). Urinary free cortisol showed no significant correlations with patient and clinical characteristics except for a correlation with height (r = 0.44, n = 41, p = 0.004) and weight (I = 0.40, n = 41,~ = 0.009). In a stepwise regression analysis, only the effect of height was significant. Levels of urinary free cortisol, calculated with the effect of height factored out, also did not differ between the groups.
Table 1. Patient and clinical characteristics
Physical means (n= 8)
Antidepressant overdose (n= 7)
Benzodiazepine overdose (n= 6)
Other means (n= 11)
Suicidal ideation/ no suicide attempt (n = 11)
39.9
34.3
42.7
32.7
35.3
Suicide attempters
Age
Mean
Height (cm)
Mean SD
Weight (kg)
Mean SD
21.0
20.4
16.9
15.0
10.9
Mean
22.1
31.0
29.2
26.2
25.1
SD
16.8
7.7
15.6
14.0
10.7
9.6
11.4
9.5
9.7
10.1
SD
Beck Depression Inventory
16.5
13.0
10.7
14.1
16.0
168.3
168.3
169.4
165.0
172.0
12.3
12.9
10.0
9.8
13.0
72.5
71.7
71.3
74.3
72.4
Hopelessness
Mean SD
6.0
4.2
8.2
6.3
4.3
Suicidal Ideation
Mean
8.4
15.9
14.7
14.4
14.5
SD Hamilton Rating Scale for Depression Suicidal Intent Lethality
8.0
8.5
10.0
10.7
9.3
Mean
19.0
22.0
21.5
17.3
19.5
SD
13.1
8.4
8.1
10.9
8.9
Mean
11.1
12.1
15.5
14.5
NA
SD
9.7
3.9
6.8
9.2
Mean
6.1’
3.5
1.9
3.5
SD
1.9
2.3
0.9
2.7
Significance NS NS NS NS NS NS NS NS
NA
F = 4.56 df=
3,31
p = 0.01 Men
4
2
4
3
7
Women
4
5
2
8
4
Note. NA = not applicable. 1. Differs from other groups (p < 0.05)
36
Table 2. Diagnosis using Research Diagnostic Criteria Physical means Minor depression
3
Major depression
1
Recurrent major depression
2
Primary situational depression
1
Not currently ill (adjustment disorder, DSA&///-R)
1
Antidepressant
overdose
Major depression
2
Recurrent major depression
2
Intermittent depressive disorder
1
Not currently ill (adjustment disorder, DSM-III-R)
1
Schizophrenia
1
Benzodiazepine
overdose
Bipolar disorder, depressed Intermittent depressive
1
disorder
1
Primary situational major depression
2
Not currently ill (alcoholism in remission)
1
Not currently ill (adjustment disorder with depressed
mood, DW-WR)
1
Other means Minor depression
3
Major depression
1
Recurrent major depression
2
Schizoaffective
1
disorder-depressed
Chronic schizophrenia
1
Cyclothymic
1
personality disorder
Labile personality disorder
1
Not currently ill (adjustment disorder, DSM-III-R)
1
Suicidal ideation but no suicide attempt Minor depression
1
Major depression
4
Recurrent major depression
1
Primary situational major depression
1
Antisocial personality disorder
1
Not currently ill (adjustment disorder with depressed
mood, DSM-III-R)
3
Table 3. Urinary free cortisol (pg/24 hours) n
Mean
SD
Physical
8
158.6
98.6
7
170.4
96.0
6
192.0
67.8
11
148.6
67.9
9
143.7
39.5
means
Antidepressant Benzodiazepine
overdose overdose
Other means Suicidal ideation-no
suicide attemot
Note. No significant difference between groups (analysis of variance: F = 0.48; df = 4.40; p = 0.7).
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38
Table 6. Norepinephrinelepinephrine
ratio
Group
n
Mean f SD)
7
12.1 F 6.4
6
8.8 + 5.0
Physical
means
Antidepressant Benzodiazepine
overdose overdose
Other means Suicidal ideation-no
suicide attempt
4
7.3 f 3.5
10
8.4 + 5.7
9
7.9 i 5.2
Note. No significant difference between groups (F = 0.8; df = 4, 35; p = 0.53).
Discussion Studies of the biological correlates of suicide are important as they have the potential to be predictive markers. For that reason we have attempted to replicate and extend previous studies on catecholamines and adrenal function in suicide. Previous reports suggested an association of a low norepinephrine-to-epinephrine ratio with violent means of suicide (Ostroff et al., 1982), history of suicide attempt (Ostroff et al., 1985; Prasad, 1985) and suicide ideation on item 3 of the Hamilton Rating Scale for Depression (Dajas et al., 1986), although other investigators (Secunda et al., 1986) have failed to find such a relationship. In our study, we also failed to confirm this relationship but instead found a higher urinary norepinephrine output in those attempting suicide when compared with control subjects. One difference between our study and previous ones is that patient investigations and urine collections began within 24 hours following the suicide attempt and biochemical changes may reflect the state at that time. In most of the other studies, the time elapsed between suicide attempts and biochemical measurements was not given, although Kosten et al. (1987), in a study of posttraumatic stress disorder that used the same protocol used by Ostroff et al. (1985) noted that urine collection began 2 to 7 days after hospital admission. A “cathartic effect” of attempted suicide has been reported by van Praag and Plutchik (1985) in a study of depression scores before and after suicide attempts. They demonstrated a significant decrease in depression 3 to 6 days after admission. Thus, the timing of the clinical assessment in relation to the suicide attempt is extremely important. This is likely to be so not only for the clinical assessment but for those biologic measures that may be related to the clinical state of the individual instead of being trait markers. It is therefore difficult to relate our findings to those of other studies following a suicide attempt where the timing of measurements was not given (Ostroff et al., 1985; Prasad, 1985) or to studies that preceded suicide attempts where the findings may be trait dependent rather than state dependent (Ostroff et al., 1982). In normal volunteers admitted to a research ward, urinary epinephrine and norepinephrine were higher on admission than 1 week later (Tolson et al., 1965). The initial elevation was attributed to novelty and unpredictability. In two studies of patients in which urine was sampled over 24 hours at 2-week intervals throughout their entire hospitalization, it was shown that levels of both norepinephrine and epinephrine fell during the course of hospitalian initial zation (Ostroff et al., 1985; Kosten et al., 1987). In suicide attempters, elevation followed by a decrease over time would be expected due to an “admission”
39 effect. A decrease would also be expected related to the “cathartic effect” of their suicide attempt. The high output of norepinephrine that we found in patients who attempted suicide indicates that this group is characterized by a substantial activation of the sympathetic nervous system as compared with the control subjects. Norepinephrine excretion has been shown to be increased during emotional arousal (Mason, 1968; Levi, 1972; Frankenhaeuser, 1975). Those attempting suicide were likely more emotionally aroused than control subjects who did not attempt suicide. It is of interest that the suicide attempt groups had similar norepinephrine levels except for those who used physical means. The group who used physical means showed a trend toward higher levels that might have been significant if larger numbers of subjects had been studied. Thus, not only did the present study fail to confirm a low norepinephrine-to-epinephrine ratio in suicide attempters who used violent means, it also indicated that norepinephrine output was as high or higher in those who used physical means as in other attempters. We found no differences between groups in the output of urinary free cortisol. The mean levels that we found are higher than the means that were found in previous studies by Ostroff et al. (1982) and Prasad (1985). As noted above, in those studies the time after the suicide attempt was not given, and in our study urine collection began within 24 hours following admission. Previous studies of normal volunteers in a research ward have shown a clear effect of hospital admission with a substantial increase in 17-hydroxycorticosteroids on the admission day and fall by the end of the first week (Fishman et al., 1962). These changes were attributed to the novelty of admission followed by rapid adaptation. Higher levels of urinary free cortisol in our study may well be due to this initial novelty effect. It is also possible that the cortisol elevation secondary to admission could obscure differences between the groups. In our study, 2 a.m. serum cortisol levels also did not distinguish between groups. It is clear that studies of biologic factors in relation to suicide attempts reflect both the biologic and clinical state of the individual at the time of study as well as possibly being trait markers. Given the evidence of rapid changes in depression after suicide attempts (van Praag and Plutchik, 1985) and the dynamic changes in biologic indexes, it is apparent that future studies should take these changes into account by examination of biologic measures and clinical ratings immediately after suicide attempts and by repeated studies at intervals throughout the hospital stay. Acknowledgments. The authors are grateful for financial assistance from the Ontario Mental Health Foundation and technical assistance from J. McKeen, E. Johansson, and M.C. Brown. G.M. Brown is an Ontario Mental Health Foundation Research Associate.
References Agren, H. Symptom patterns in unipolar and bipolar depression correlating with monoamine metabolites in the cerebrospinal fluid: II Suicide. Psychiatry Research, 3:225-236, 1980. Agren, H. Life at risk: Markers of suicidality in depression. Psychiatric Developments, 1:87-104, 1983. Asberg, M., and Bertilsson, L. Serotonin in depressive illness: Studies of 5-HIAA. In: Salem, B., ed. Neuropsychopharmacology. New York: Pergamon Press, 1979. pp. 105-l 15.
40
Asberg, M., and Wagner, A. Biochemical effects of antidepressant treatment-studies of monoamine metabolites in cerebrospinal fluid and platelet [3H] imipramine binding. Ciba Foundation Symposium, 12357-83, 1986. Banki, C.M., and Arato, M. Amine metabolites and neuroendocrine responses related to depression and suicide. Journal of Affective Disorders, 5223-232, 1983. Banki, C.M.; Arato, M.; Papp, Z.; and Kurca, M. Biochemical markers in suicidal patients: Investigations with cerebrospinal fluid amine metabolites and neuroendocrine tests. Journal of Affective Disorders, 6:341-350, 1984. Barnes, R.F.; Veith, R.C.; Borson, S.; Verhey, J.; Raskind, M.A.; and Holter, J.B. High levels of plasma catecholamines in dexamethasone-resistant depressed patients. American Journal of Psychiatry, 140:1623-1625, 1983. Beck, A.T.; Kovac, M.; and Weisman, A. Suicidal intention: The scale for suicidal ideation. Journal of Consulting and Clinical Psychology, 471343-352, 1979. Beck, A.T.; Schuyler, D.; and Herman, I. Development of suicide intent scales. In: Beck, A.T.; Resmik, H.L.D.; and Lettieri, D.J., eds. The Prediction of Suicide. Baltimore: Charles Press, 1974a. pp. 45-56. Beck, A.T.; Ward, C.H.; Mendolson, M.; Mock, J.; and Erbaugh, J. An inventory for measuring depression. Archives of General Psychiatry, 4:567-571, 1961. Beck, A.T.; Weisman, A.; Lester, D.; and Trexler, L. The measurement of pessimism: The Hopelessness Scale. Journal of Consulting and Clinical Psychology, 42:861-865, 19746. Berrettini, W.H.; Nurnberger, J.I., Jr.; Scheinin, M.; Seppala, T.; Linnoila, M.; Narrow, W.; Simmons-Alling, S.; and Gershon, E.S. Cerebrospinal fluid and plasma monoamines and their metabolites in euthymic bipolar patients. Biological Psychiatry, 20:257-269, 1985. Beskow, J.; Gottfries, C.G.; Roos, B.E.; and Winblld, B. Determination of monoamine and monoamine metabolites in the human brain: Post-mortem studies in a group of suicides and in a control group. Acta Psychiatrica Scandinavica, 53:7-20, 1976. Brown, G.L.; Ebert, M.H.; Goyer, P.F.; Jimerson, D.C.; Klein, W.J.; Bunney, W.E.; and Goodwin, F.K. Aggression, suicide, and serotonin: Relationships to CSF amine metabolites. American Journal of Psychiatry, 139:74 l-746, 1982. Brown, G.L.; Goodwin, F.K.; Ballenger, J.C.; Goyer, P.F.; and Major, L.F. Aggression in humans correlates with cerebrospinal fluid amine metabolies. Psychiatry Research, 1: 13 1- 139, 1979. Brown, R.; Mason, B.; Stoll, P.; Brizer, D.; Kocsis, J.; Stokes, P.E.; and Mann, J.J. Adrenocortical function and suicidal behavior in depressive disorders. Psychiatry Research, 17:317-323, 1986. Bunney, W.E., Jr., and Fawcett, J.A. Possibility of a biochemical test for suicidal potential. Archives of General Psychiatry, 13:232-239, 1965. Bunney, W.E., Jr.; Fawcett, J.A.; Davis, J.M.; and Gifford, S. Further evaluation of urinary 17-hydroxycorticosteroids in suicidal patients. Archives of General Psychiatry, 21:138-150, 1969. Coryell, W., and Schlesser, M.A. Suicide and the dexamethasone suppression test in unipolar depression. American Journal of Psychiatry, 138: 1120-l 121, 1981. Dajas, F.; Barbeito, L.; and Cervenansky, C. An association between norepinephrine-toepinephrine ratio and suicidal ideation in depression. American Journal of Psychiatry, 143:683, 1986. Endicott, J., and Spitzer, R.L. The Schedule for Affective Disorders and Schizophrenia. Archives of General Psychiatry, 35:837-844, 1978. Fink, E.B., and Carpenter, W.T. Further examination of a biochemical test for suicide potential. Diseases of the Nervous System, 37~34 l-343, 1976. Fishman, J.R.; Hamburg, D.A.; Handlon, J.H.; Mason, J.W.; and Sachar, E. Emotional and adrenal cortical responses to a new experience. Archives of General Psychiatry, 61271-278, 1962.
41
Frankenhaeuser, M. Experimental approaches to the study of catecholamines and emotions. In: Levi, L., ed. Emotions-Their Parameters and Measurement. New York: Raven Press, 1975. pp. 209-234. Funkenstein, D.H.; King, S.H.; and Drolette, M. The direction of anger during a laboratory stress-inducing situation. Psychosomatic Medicine, 16:404-413, 1954. Hamilton, M. Hamilton Depression Scale. In: Guy, W., ed. ECDEU Assessment Manual for Psychopharmacology. (DHEW Pub]. No. ADM 76-338) Washington, DC: Superintendent of Documents, U.S. Government Printing Office, 1976. pp. 180-192. Keane, P.M.; Stuart, J.; Mendez, J.; Barbadoro, S.A.; and Walker, W.H.C. Rapid specific assay for plasma cortisol by competitive protein binding. Clinical Chemistry, 21:1474-1478, 1975. Kocsis, J.H.; Kennedy, S.; Brown, R.D.; Mann, J.J.; and Mason, B. Suicide and adrenocortical function. Psychopharmacology Bulletin, 22:650-655, 1986. Korpi, E.R.; Kleinman, J.E.; and Goodman, S.I. Serotonin and 5-hydroxyindoleacetic acid in brains of suicide victims: Comparison in chronic schizophrenic patients with suicide as cause of death. Archives of General Psychiatry, 43:594-600, 1986. Kosten, T.R.; Mason, J.W.; Giller, E.L.; Ostroff, R.B.; and Harkness, L. Sustained urinary norepinephrine and epinephrine elevation in post-traumatic stress disorder. Psychoneuroendocrinology, 12: 13-20, 1987. Krieger, G. Biochemical predictors of suicide. Diseases of the Nervous System, 31:237-240, 1970. Levi, L. Stress and distress in response to psychosocial stimuli: Laboratory and real life studies on sympathoadrenomedullary and related reactions. Acta Medica Scandinavica, Suppl. 528: l-666, 1972. Mann, J.; Stanley, M.; McBride, A.; and McEwen, B. Increased serotonin, and fiadrenergic receptor binding in the frontal cortices of suicide victims. Archives of General Psychiatry, 43:954-959, 1986. Mason, J. W. A review of psychoendocrine research on the sympathetic-adrenal medullary system. Psychosomatic Medicine, 30:631-653, 1968. Meltzer, H.Y., and Arora, R.C. Platelet markers for suicidality. Annals of the New York Academy of Sciences, 487:271-280, 1986. Ostroff, R.; Giller, E.; Bonese, K.; Ebersole, E.; Harkness, L.; and Mason, J. Neuroendocrine risk factors of suicidal behavior. American Journal of Psychiatry, 139: 13231325, 1982. Ostroff, R.B.; Giller, E.; Harkness, L.; and Mason, J. The norepinephrine-to-epinephrine ratio in patients with a history of suicide attempts. American Journal of Psychiatry, 142:224227, 1985. Prasad, A.J. Neuroendocrine differences between violent and nonviolent para-suicides. Neuropsychobiology, 13:157-159, 1985. Robbins, D.R., and Alessi, N.E. Suicide and the dexamethasone suppression test in adolesence. Biological Psychiatry, 20: 107-I 10, 1985. Rockwell, D.A.; Winget, C.M.; Rosenblatt, L.S.; Higgins, E.A.; and Hetherington, N.W. Biological aspects of suicide: Circadian disorganization. Journal of Nervous and Mental Disease, 166:851-858, 1978. Roy, A.; Pickar, D.; DeJong, J.; Karoum, F.; and Linnoila, M. Suicidal behavior in depression: Relationship to noradrenergic function. Biological Psychiatry, 25:341-350, 1989. Roy, A.; Agren, H.; Pickar, D.; Linnoila, M.; Doran, A.R.; Cutler, N.R.; and Paul, SM. Reduced CSF concentrations of homovanillic acid and homovanillic acid to 5hydroxyindoleacetic acid ratios in depressed patients: Relationship to suicidal behavior and dexamethasone nonsuppression. American Journal of Psychiatry, 143:1539-1545, 1986. Scheinin, M.; Chang, W.; Kirk, K.; and Linnoila, M. Simultaneous determination of 3methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid and homovanillic acid in cerebrospinal fluid with higher performance liquid chromatography using electrochemical detection. Annals of Biochemistry, I3 11246-253, 1983.
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Smith, K.; Conroy, Life Threatening
R.W.; and Ehler, B.D. Lethality
Behavior,
1412 13-24
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I, 1984.
Spitzer, R.L.; Endicott, J.; and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of General Psychiatry, 35:773-782, 1978. Stanley, M.; Virgilio, J.; and Gershon, S. Tritiated imipramine binding sites are decreased in the frontal cortex of suicides. Science, 2 16: 1337-l 339, 1982. Targum, S.D.; Rosen, L.; and Capodanno, A.E. The dexamethasone suppression test in suicidal patients with unipolar depression. American Journal of Psychiatry, 140:877-879. 1983.
Tolson, W.W.; Mason, J.W.; Sachar, E.J.; Hamburg, D.A.; Handlon, J.H.; and Fishman, J.R. Urinary catecholamine responses associated with hospital admission in normal human subjects. Journal o Psychosomatic Research, 8:365-372, 1965. Traskman, L.; d sberg, M.; Bertilsson, L.; and Sjiistrand, L. Monoamine metabolites in cerebrospinal fluid and suicidal behavior. Archives of General Psychiatry, 38:63 l-637, 198 I. van Praag, H.M. lndoleamines in depression and suicide. Progress in Brain Research, 65:59-71,
1986.
van Praag, H.M., and Plutchik, R. An empirical study attempted suicide. Psychiatry Research, 16: 123-130, 1985.
on the “cathartic
effect”
of
Psychiatry Research, 43:3 l-42 Elsevier
Urinary
Catecholamines
and Cortisol
Catherine
Mancini
M. Brown
and Gregory
in Parasuicide
Received August 14, 1991; revised version received February 18, 1992; accepted April 19, 1992. Abstract. A relationship of urinary catecholamines and of urinary free cortisol with violent suicide attempts has been reported. We have reexamined this issue in patients within 24 hours of hospital admission. Suicide attempters had significantly higher norepinephrine (NE: mean + SD = 58.3 + 27.0 pg/24 hours; n = 27) than did control patients with suicidal ideation (mean + SD = 37.1 + 21.3; n = IO). Among suicide attempters, those who used physical means had the highest NE levels (mean & SD = 69.7 + 21.3) and those who took overdoses of antidepressants (mean f SD = 51.9 + 17.3; n = 6) benzodiazepines (mean + SD = 65.1 f 29.7; n = 5) or miscellaneous drugs (mean -t SD = 59. I + 36.5; n = 11) had lower NE values. In contrast to NE, urinary dopamine (mean & SD = 402.6 f 392 pg/24 hours, epinephrine (EPI: mean f SD = 14.3 f 4.0 pg/24 hours), the NE/EPI ratio (mean f SD = 8.3 + 0.9) urinary free cortisol (mean + SD = 157.9 * I I .5 ,ug/24 hours) and serum cortisol (mean +- SD = 35.0 + 13. I
did not differ between groups. There were no group differences in age (mean + SD = 36.3 ?c 16.5 years), Beck Depression Inventory score (mean f SD = 26.3 + 12.9), Beck Hopelessness Scale score (mean * SD = 10.0 & 5.6) Beck Scale for Suicidal Ideation score (mean * SD = 13.6 + 9.3), or Hamilton Rating Scale for Depression score (mean + SD = 19.5 * 9.8). In the four parasuicide
nM/l)
groups, there was no difference in suicide intent (mean + SD = 13.3 + 7.9). These findings indicate that there is increased NE output shortly after suicide attempts. Previous reports of a low NE/ EPI ratio in suicidal patients may reflect adaptive changes rather than the acute state of the patient at the time of the attempt. Key Words. Norepinephrine,
epinephrine,
dopamine,
cortisol,
depression.
Although suicide is a leading cause of death in North America, no biological indicator has been found that consistently predicts who will go on to commit suicide. A significant amount of research has been devoted to the study of the relationship of depression, suicidal behavior, and the biogenic amines-particularly, 5-hydroxyindoleacetic acid (SHIAA). Most studies have shown a decrease in serotonin activity in groups of people with suicidal ideation. Decreased concentrations of 5HlAA in cerebrospinal fluid (CSF) have been consistently found in depressed patients (Agren, 1980; van Praag, 1986; Asberg and Wagner, 1986). Several investigators have also demonstrated an association between low concentrations of CSF SHIAA and hospital-
Catherine Mancini, M.D., F.R.C.P.C., is an Assistant Professor, Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada, and Director of the Anxiety Disorders Clinic, McMaster University Medical Centre. Gregory M. Brown, M.D., Ph.D., is Professor of Psychiatric Research, Department of Psychiatry, University of Toronto, and Director of Research, Clarke Institute of Psychiatry, Toronto, Ontario, Canada. (Reprint requests to Dr. C. Mancini, McMaster University Medical Centre, 3G Clinic, Outpatient Psychiatry, Box 2000, Hamilton, ON L8N 325, Canada.) 01651781/92/$05.00
@ 1992 Elsevier Scientific
Publishers
Ireland
Ltd.
32 ized patients with a recent or a past history of suicide attempts (Asberg and Bertilsson, 1979; Banki and Arato, 1983; Banki et al., 1984). Trlskman and others (1981) found that the CSF SHIAA of nonviolent attempters did not differ significantly from control subjects, although an association was found between a low concentration of CSF SHIAA and violent suicide attempts. However, these findings have not been supported by others (Roy et al., 1986; Secunda et al., 1986). Also, post-mortem studies examining SHIAA levels (Beskow et al., 1976; Korpi et al., 1986), postsynaptic serotonin receptor number (Stanley et al., 1982) and platelet 3H-imipramine binding density (Meltzer and Arora, 1986) suggest that serotonergic transmission may be reduced in suicide victims. In contrast, little attention has focused on the noradrenergic system despite early work by Funkenstein et al. (1954). They studied the emotional reactions of college students to a stress-inducing laboratory situation and concluded that “anger in” or anger turned against the self was associated with epinephrine and “anger out” was associated with norepinephrine. Ostroff et al. (1982) noted an association between suicidal behavior and the ratio of norepinephrine-to-epinephrine in 24-hour urine samples collected during a study on the course of recovery in psychotic male patients. Two of the 22 patients went on to complete violent suicides, and one made a serious attempt. These three patients were found to have significantly lower norepinephrine-to-epinephrine ratios as well as higher levels of urinary free cortisol than did the other patients. In a subsequent study, 99 male inpatients with mixed diagnoses, including the original 22 patients, were divided into those with a history of suicide attempt and those without such a history. The ratio of norepinephrine-toepinephrine levels was significantly lower in the group with a history of sucide attempt (Ostroff et al., 1985). Prasad (1985) compared a group of 19 male wristslashers with 13 male patients who had used violent means of parasuicide (i.e., jumping from a height or hanging). The patients who had attempted suicide by violent means were found to have a significantly lower norepinephrine-toepinephrine ratio and a higher mean urinary free cortisol level. In a study of 65 depressed patients, Dajas et al. (1986) found an inverse relationship between the norepinephrine-to-epinephrine ratio and suicidal ideation (item 3 of the Hamilton Rating Scale for Depression; r = -0.31, p < 0.05). Other investigators have not confirmed the relationship between a decreased norepinephrine-to-epinephrine ratio and suicidality (Secunda et al., 1986). Roy et al. (1989) reported that depressed patients who had never attempted suicide and depressed patients who had attempted suicide both had significantly higher norepinephrine levels than controls but that suicidal behavior itself had no effect on urinary norepinephrine. Rockwell et al. (1978) reported a low output of norepinephrine, epinephrine, and 17-ketogenic steroids in a volunteer who committed suicide 2 weeks later. Low norepinephrine levels have been reported in the putamen of suicide victims (Beskow et al., 1976). Mann et al. (1986) have found a significant increase in /3-adrenergic receptor binding in the frontal cortex of suicide victims compared with controls. Measures of cerebrospinal fluid (CSF) norepinephrine and its metabolite, 3methoxy-4-hydroxyphenethyleneglycol (MHPG), in suicidal patients have given mixed results. Brown et al. (1979) found that CSF concentrations of MHPG were
33 positively correlated with suicidality in patients with personality disorders. However, this relationship was not found in patients with borderline personality disorders (Brown et al., 1982), although there was a significant positive correlation between aggression scores and CSF MHPG levels. Agren (1980, 1983) reported a significant negative correlation of CSF MHPG and suicidality in unipolar but not bipolar depression. Berrettini et al. (1985) found that norepinephrine and MHPG levels in the CSF of bipolar patients did not differentiate those who had made a past suicide attempt from those who had never made a suicide attempt. However, in the National Institute of Mental Health’s Collaborative Study on the Psychobiology of Depression, investigators found that patients who had never attempted suicide showed significantly higher plasma and urinary levels of MHPG, with a similar trend in CSF MHPG levels, than did patients who had attempted suicide (Secunda et al., 1986). A known biological marker for depressive illness is the excessive release of cortisol with high plasma levels and increased urinary excretion of cortisol. Several investigators have also demonstrated increased levels of 24-hour urinary 17hydroxycorticosteroids in patients who later went on to commit suicide (Bunney and Fawcett, 1965; Bunney et al., 1969; Krieger, 1970) or of urinary free cortisol in those who had a history of suicide attempts (Ostroff et al., 1982; Prasad, 1985). Others have failed to show such a relationship (Fink and Carpenter, 1976; Brown et al., 1986; Secunda et al., 1986). Conflicting results have also been reported with respect to the relationship between abnormal dexamethasone suppression test (DST) results and suicide attempts. Some investigators have shown a positive correlation between DST nonsuppression and suicide attempts (Coryell and Schlesser, 1981; Banki and Arato, 1983; Targum et al., 1983; Robbins and Alessi, 1985) and others have reported negative findings (Brown et al., 1986; Kocsis et al., 1986; Roy et al., 1986; Secunda et al., 1986). Several investigators (Barnes et al., 1983; Ostroff et al., 1985) have hypothesized that the noradrenergic and adrenal findings may be interrelated by a complex interaction between the hypothalamic-pituitary-adrenal system and the noradrenergic system. One major problem in this literature is that the length of time following suicide attempts is usually not specified despite the fact that dynamic changes in biological and clinical measures occur. Moreover, little effort has been made to assess suicidal intent separately from the lethality of the means used. Confounding effects of drug overdose or of other chemical agents (e.g., carbon monoxide) are also ignored. This prospective study was intended to test the hypothesis that the norepinephrineto-epinephrine ratio and urinary free cortisol may be biological markers of sucidal behavior and to relate these markers to specific clinical measures including suicidal intent, lethality of the attempt, and depression. The study compared patients who were hospitalized after a suicide attempt with a group of patients who were admitted with suicidal ideation but no suicide attempt.
Methods Forty-three consenting patients who were consecutively admitted to the Liaison Unit at St. Joseph’s Hospital (Hamilton, Ontario, Canada) were evaluated. Experimental patients were those who had made a suicide attempt within the previous 24 hours. Control patients were those who were admitted with suicidal ideation but no suicide attempt within the last 6 months.
34 Exclusion criteria included age over 68 years, active drug or alcohol abuse, serious medical illness, and treatment with P-adrenergic blockers. The total group of subjects comprised 24 women and 20 men who ranged in age from 16 to 68 years. The patients were diagnosed using Research Diagnostic Criteria (Spitzer et al., 1978) and DSM-III-R criteria (American Psychiatric Association, 1987). Diagnostic information was obtained from the Schedule for Affective Disorders and Schizophrenia (Endicott and Spitzer, 1978) and a clinical interview. A detailed psychiatric, medical, and drug history was obtained. Each patient was evaluated using the 17-item Hamilton Rating Scale for Depression (Hamilton, 1976) the Beck Depression Inventory (Beck et al., 1961) the Beck Hopelessness Scale (Beck et al., 19746) and the Scale for Suicidal Ideation (Beck et al., 1979). The Suicide Intent Scale (Beck et al., 1974~) and the Lethality of Suicide Attempt Scales (Smith et al., 1984) were completed for those
attempting suicide. Urine was collected
for a 24-hour period beginning at 7 a.m. on the day after admission. An aliquot for catecholamine determination was acidified to pH = 2 using 6 N HCI. A single blood sample was obtained at 2 a.m. on the night following admission for cortisol determination. Blood and urine samples were frozen at -20 “C until assay. Norepinephrine, epinephrine, and dopamine in urine were assayed by high performance liquid chromatography (HPLC) with electrochemical detection (Scheinin et al., 1983). Cortisol in urine and in blood was assayed by radioimmunoassay (Keane et al., 1975). Catecholamines and cortisol values were initially examined for their relationships to age. weight. and height in the overall patient group. Urinary cortisol was found to correlate with height and weight and urinary dopamine, with age. These effects were covaried out in subsequent analysis. The t test was used to compare suicide attempters (n = 32) and nonattempters (n = 12) on all variables. Then suicide attempters were subdivided into those who had used violent means (n = 8), tricyclic antidepressant overdose (n = 7) benzodiazepine overdose (n = 6) and other means (acetaminophen, carbon monoxide poisoning, chloral hydrate, aspirin with codeine, cogentin, and glyburide; n = I I). An analysis of variance was used to compare all groups. The correlations of the biochemical data with the clinical ratings were examined within each subgroup separately. Dose equivalents of tricyclic antidepressants and of benzodiazepines used for overdoses were calculated and their correlation with biochemical measures was examined. Correlations are reported only when significant. For catecholamine analysis, five subjects were excluded because acidified urine was not available and two subjects were excluded because of outlying data. One outlier had Parkinsonism, was being treated with t_-dopa, and had a urinary dopamine output of 4644pg/24 hours; the other subject, who took an overdose of maprotiline (750 mg; 5 times her usual dose), had a urinary epinephrine output of 37O,ug/24 hours, a value five-fold higher than that for any other subject. Two subjects were excluded from the urinary cortisol analysis because of the unavailability of urine and one from the serum cortisol analysis because of a missing blood sample.
Results Patient and Clinical Characteristics. Table 1 presents data for age, weight, and ratings for each group. There are no significant differences between groups in any of the variables, except for significantly higher lethality in those using physical means. Table 2 presents diagnostic information. Urinary Free Cortisol. Urinary free cortisol did not differ between the groups (Table 3). Urinary free cortisol showed no significant correlations with patient and clinical characteristics except for a correlation with height (r = 0.44, n = 41, p = 0.004) and weight (I = 0.40, n = 41,~ = 0.009). In a stepwise regression analysis, only the effect of height was significant. Levels of urinary free cortisol, calculated with the effect of height factored out, also did not differ between the groups.
Table 1. Patient and clinical characteristics
Physical means (n= 8)
Antidepressant overdose (n= 7)
Benzodiazepine overdose (n= 6)
Other means (n= 11)
Suicidal ideation/ no suicide attempt (n = 11)
39.9
34.3
42.7
32.7
35.3
Suicide attempters
Age
Mean
Height (cm)
Mean SD
Weight (kg)
Mean SD
21.0
20.4
16.9
15.0
10.9
Mean
22.1
31.0
29.2
26.2
25.1
SD
16.8
7.7
15.6
14.0
10.7
9.6
11.4
9.5
9.7
10.1
SD
Beck Depression Inventory
16.5
13.0
10.7
14.1
16.0
168.3
168.3
169.4
165.0
172.0
12.3
12.9
10.0
9.8
13.0
72.5
71.7
71.3
74.3
72.4
Hopelessness
Mean SD
6.0
4.2
8.2
6.3
4.3
Suicidal Ideation
Mean
8.4
15.9
14.7
14.4
14.5
SD Hamilton Rating Scale for Depression Suicidal Intent Lethality
8.0
8.5
10.0
10.7
9.3
Mean
19.0
22.0
21.5
17.3
19.5
SD
13.1
8.4
8.1
10.9
8.9
Mean
11.1
12.1
15.5
14.5
NA
SD
9.7
3.9
6.8
9.2
Mean
6.1’
3.5
1.9
3.5
SD
1.9
2.3
0.9
2.7
Significance NS NS NS NS NS NS NS NS
NA
F = 4.56 df=
3,31
p = 0.01 Men
4
2
4
3
7
Women
4
5
2
8
4
Note. NA = not applicable. 1. Differs from other groups (p < 0.05)
36
Table 2. Diagnosis using Research Diagnostic Criteria Physical means Minor depression
3
Major depression
1
Recurrent major depression
2
Primary situational depression
1
Not currently ill (adjustment disorder, DSA&///-R)
1
Antidepressant
overdose
Major depression
2
Recurrent major depression
2
Intermittent depressive disorder
1
Not currently ill (adjustment disorder, DSM-III-R)
1
Schizophrenia
1
Benzodiazepine
overdose
Bipolar disorder, depressed Intermittent depressive
1
disorder
1
Primary situational major depression
2
Not currently ill (alcoholism in remission)
1
Not currently ill (adjustment disorder with depressed
mood, DW-WR)
1
Other means Minor depression
3
Major depression
1
Recurrent major depression
2
Schizoaffective
1
disorder-depressed
Chronic schizophrenia
1
Cyclothymic
1
personality disorder
Labile personality disorder
1
Not currently ill (adjustment disorder, DSM-III-R)
1
Suicidal ideation but no suicide attempt Minor depression
1
Major depression
4
Recurrent major depression
1
Primary situational major depression
1
Antisocial personality disorder
1
Not currently ill (adjustment disorder with depressed
mood, DSM-III-R)
3
Table 3. Urinary free cortisol (pg/24 hours) n
Mean
SD
Physical
8
158.6
98.6
7
170.4
96.0
6
192.0
67.8
11
148.6
67.9
9
143.7
39.5
means
Antidepressant Benzodiazepine
overdose overdose
Other means Suicidal ideation-no
suicide attemot
Note. No significant difference between groups (analysis of variance: F = 0.48; df = 4.40; p = 0.7).
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lueag$?!s aq 0% pun03 put2 pauy?xa alojalaqlSBM sa1oas uo!ssaldaa 103 aleas 8U~lE~ UOll~""H put?a% 30 uO~~e!aosseaqL '(roo()'() > d ‘9 = u ‘Lb.0= 1) sa1oas uo!ssaldaa 103 aleas 8ugea uo~~put?~ q1!~ pale]alJoaauIr.uedopput? (10'0 > s,d yloq :9 = u :LIaylaadsal‘06'0 = 1 pue 68'0 = 1) a% qy!~ palyalJoa aytuedop pur! au!Iqdau!dalou d.wuy 30 slaaal ‘dnoJ8 asoplalzo luessaldapyue aql UI .dno.# wq~ u! punojalaM suogtqalloa ~ueag!u%!s~aq~oON '(I()'()> s,d qloq f~ =u~61aA~1aadsal‘au!wedop%o1loj98'0- =.i pue gfj'o-= 1) aytuedop ~I!M sa1oas aleas SSaUSSaIadOg yaaa put? dloluar\uI uo!ssaldaa yaaH JO uo!le[alloaa$@au luea!j@?!s e SBM alay ‘sueatu le+tyd icq ap!a!ns palduralw oqM sluayd aql UI .au!uwdop JO auuqdautda JO s]aAalu! ~ajj~ploup!psdno.Baql .pasnspoq$awaqliCqpap!a!pqnsa~aMs~aldwaw aq)uaqM sdnol%aqluaaMlaq aaua~a3j!pw2a~3@?~s ou seMalaql apqM‘(o'LZ + E'gS 'shE'Iz f
smoq pz/%ti I ‘/_f = as T ueatu) slalduram ap!D!ns u! ueql slaldwaueuou d~luex3!u8!s S'I?M(s a[qel) au!lqdau!da_Ioudleyln 'sau!ure~oy~a~e~ ‘(OL’O= d
u! IaMoI AJeu!Jn
:cp‘p = upts9.0= j :axe!m ~0s!sAleue)SdnoJduaawaq amaJay!p jwmyu6!s 0~ .ajoN
L’OE
P'O
O‘OP
6’ZZ
Y&E
Z’9
b’9E
0’0 1
1’SE
P’S1
)dLuaUe apgns
11
ou-uo!leap!
)epyng
sueaw
01
Jatj10
asopJaho au!daze!pozuag
9
asoplaA0
L
~ueSSaJdap!JiJif sueaku )e3!sAqd
8
uea((y
as
u (I/WU)
‘(I()‘()>
(OS!$JO3 lunlas
‘p alqel
d‘L = 2.4 ‘88'0 = ~)~~J~u~!saq 01 punoj put?pauyvxa
~uaI~A!nba-au!ure~dyuII
qyM ~os~uo~jo
SBM a%sop uoyla_IJoa aql ‘a&sop 01 pa]eIals!Algeqlal
sv '(IO.0> d‘L = 2.4 ‘pg.0= 1) 6lgeqlaI ql!M uoyZ~a.I.Io:, luea!jy%!s12SBM a.Iaql ‘dno.Bqns asoplaao wssa~dapyue pc?apu1aput? wayed
aql u!qvM
.dno.G IIZJ~AOaql u! sa!ls!.Iaw?.wqa
ql!M suoye~a~~oa ~uea!j!u%!sou paMoqs
a[qeL) sdnol% aql uaamaq
~osp~oa cutwas '(p
m3j!p IOU pip *UI*Bz w IOS!IJODumJas
umJas
yos!yo=)
Lf
38
Table 6. Norepinephrinelepinephrine
ratio
Group
n
Mean f SD)
7
12.1 F 6.4
6
8.8 + 5.0
Physical
means
Antidepressant Benzodiazepine
overdose overdose
Other means Suicidal ideation-no
suicide attempt
4
7.3 f 3.5
10
8.4 + 5.7
9
7.9 i 5.2
Note. No significant difference between groups (F = 0.8; df = 4, 35; p = 0.53).
Discussion Studies of the biological correlates of suicide are important as they have the potential to be predictive markers. For that reason we have attempted to replicate and extend previous studies on catecholamines and adrenal function in suicide. Previous reports suggested an association of a low norepinephrine-to-epinephrine ratio with violent means of suicide (Ostroff et al., 1982), history of suicide attempt (Ostroff et al., 1985; Prasad, 1985) and suicide ideation on item 3 of the Hamilton Rating Scale for Depression (Dajas et al., 1986), although other investigators (Secunda et al., 1986) have failed to find such a relationship. In our study, we also failed to confirm this relationship but instead found a higher urinary norepinephrine output in those attempting suicide when compared with control subjects. One difference between our study and previous ones is that patient investigations and urine collections began within 24 hours following the suicide attempt and biochemical changes may reflect the state at that time. In most of the other studies, the time elapsed between suicide attempts and biochemical measurements was not given, although Kosten et al. (1987), in a study of posttraumatic stress disorder that used the same protocol used by Ostroff et al. (1985) noted that urine collection began 2 to 7 days after hospital admission. A “cathartic effect” of attempted suicide has been reported by van Praag and Plutchik (1985) in a study of depression scores before and after suicide attempts. They demonstrated a significant decrease in depression 3 to 6 days after admission. Thus, the timing of the clinical assessment in relation to the suicide attempt is extremely important. This is likely to be so not only for the clinical assessment but for those biologic measures that may be related to the clinical state of the individual instead of being trait markers. It is therefore difficult to relate our findings to those of other studies following a suicide attempt where the timing of measurements was not given (Ostroff et al., 1985; Prasad, 1985) or to studies that preceded suicide attempts where the findings may be trait dependent rather than state dependent (Ostroff et al., 1982). In normal volunteers admitted to a research ward, urinary epinephrine and norepinephrine were higher on admission than 1 week later (Tolson et al., 1965). The initial elevation was attributed to novelty and unpredictability. In two studies of patients in which urine was sampled over 24 hours at 2-week intervals throughout their entire hospitalization, it was shown that levels of both norepinephrine and epinephrine fell during the course of hospitalian initial zation (Ostroff et al., 1985; Kosten et al., 1987). In suicide attempters, elevation followed by a decrease over time would be expected due to an “admission”
39 effect. A decrease would also be expected related to the “cathartic effect” of their suicide attempt. The high output of norepinephrine that we found in patients who attempted suicide indicates that this group is characterized by a substantial activation of the sympathetic nervous system as compared with the control subjects. Norepinephrine excretion has been shown to be increased during emotional arousal (Mason, 1968; Levi, 1972; Frankenhaeuser, 1975). Those attempting suicide were likely more emotionally aroused than control subjects who did not attempt suicide. It is of interest that the suicide attempt groups had similar norepinephrine levels except for those who used physical means. The group who used physical means showed a trend toward higher levels that might have been significant if larger numbers of subjects had been studied. Thus, not only did the present study fail to confirm a low norepinephrine-to-epinephrine ratio in suicide attempters who used violent means, it also indicated that norepinephrine output was as high or higher in those who used physical means as in other attempters. We found no differences between groups in the output of urinary free cortisol. The mean levels that we found are higher than the means that were found in previous studies by Ostroff et al. (1982) and Prasad (1985). As noted above, in those studies the time after the suicide attempt was not given, and in our study urine collection began within 24 hours following admission. Previous studies of normal volunteers in a research ward have shown a clear effect of hospital admission with a substantial increase in 17-hydroxycorticosteroids on the admission day and fall by the end of the first week (Fishman et al., 1962). These changes were attributed to the novelty of admission followed by rapid adaptation. Higher levels of urinary free cortisol in our study may well be due to this initial novelty effect. It is also possible that the cortisol elevation secondary to admission could obscure differences between the groups. In our study, 2 a.m. serum cortisol levels also did not distinguish between groups. It is clear that studies of biologic factors in relation to suicide attempts reflect both the biologic and clinical state of the individual at the time of study as well as possibly being trait markers. Given the evidence of rapid changes in depression after suicide attempts (van Praag and Plutchik, 1985) and the dynamic changes in biologic indexes, it is apparent that future studies should take these changes into account by examination of biologic measures and clinical ratings immediately after suicide attempts and by repeated studies at intervals throughout the hospital stay. Acknowledgments. The authors are grateful for financial assistance from the Ontario Mental Health Foundation and technical assistance from J. McKeen, E. Johansson, and M.C. Brown. G.M. Brown is an Ontario Mental Health Foundation Research Associate.
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on the “cathartic
effect”
of
