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Platelet and Whole Blood Serotonin Content in Depressed Inpatients: Correlations with Acute and Life-Time Psychopathology J. John Mann, P. Anne McBride, George M. Anderson, and Tammy A. Mieczkowski
Platelet or whole blood serotonin content did not differ significantly in patients with major depression compared to healthy controls, but within the patient group, platelet serotonin levels correlated negatively with severity of depression (r = -0.49, p = 0.007). Levels were 39% lower in patients who had made a suicide attempt compared to nonattempter patients (47.2 +_ 27.3 versus 77.6 +- 41.7 ng/lOs platelets, p = 0.04). Conversely, comorbid borderline personality disorder (85.3 +- 41.5 ng/lOs platelets) was associated with 31% greater platelet serotonin content than nonborderline patients (58.9 +- 31.1 ng/lOs platelets) and 27% greater than healthy controls (62.4 +- 19.8 ng/ l Os platelets ). A pronounced seasonal variation in whole blood and platelet serotonin content was found in both patients and controls, largely due to lower levels in summer. Excluding cases tested in the summer abolished the statistically significant differences in patients with and without comorbid borderline personality disorder (BPD ). Neve,'theless, BPD attempters had lower serotonin levels than BPD nonanempters but higher serotonin levels than non-BPD attempters. Current hostility and a life-time history of aggression were positively correlated with platelet serotonin content (r ffi 0.44, p ffi 0.04 and r = 0.41, p ffi 0.06). This study provides evidence for an association between lower platelet serotonin content and depression and suicidal behavior, and association of higher platelet serotonin content and comorbid borderline personality disorder and behavior traits such as aggressivity.
Introduction An association has been described between reduced serotonergic activity and depressive illness (Heninger et al 1984), suicidal behavior (Mann et al 1989a; Mann et al 1989b), and aggressive behavior (Brown et al 1979; Brown et al 1982a; Coccaro et al 1989; Virkkunen et al 1987; Virkkunen et al 1989a; Virkkunen et al 1989b). Neuroendocrine serotonin challenge tests, such as intravenous l-tryptophan (Heninger et al 1984)
Address reprint requests to Dr. J. John Mann, Laboratories of Neutopharmacology, Western Psychiatric Institute and Clinic,
University of Pittsburgh, 3811 O'Hata Street, Pittsburgh, PA., 15213. From the Laboratories of Neumpharmacology (JJM, TAM), Department of Psychiatry, University of Pittsburgh; Department of Psychiatry (PAM). Cornell University Medical College; and Child Study Center (GMA), Yale University School of Medicine. Received September 23, 1991; revised April 3, 1992. © 1992 Socie',y of Biological Psychiatry
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and oral fenfluramine (Coccaro et al 1989), stimulate a lower prolactin response in depressed patients. Similar results have also been reported regarding lower levels of CSF 5-hydroxyindeacetic acid (5-HIAA), a serotonin metabolite, in depressed patients (Asberg et al 1984). Suicidal or aggressive behavior also appear to be associated with low CSF 5-HIAA (Brown et al 1979; Brown et al 1982a; Brown et al 1982b; Asberg et ai 1986) ~,id a blunted prolactin response to fenfluramine (Coccaro et al 1989). Platelet serotonin content has been employed as an index of presynaptic serotonin function (Stahl 1977; Stahl et al 1982). Decreased whole blood or platelet serotonin content has been reported in patients with depression by some (Sarai and Kayano 1968; Takahashi 1976; Coppen et al 1976; Banki 1978; Born et al 1980; Quan-Bui et al 1984; Quintana 1992) but not all studies (Todrick et al 1960; Wirz-Justice and Piihringer 1978b; Stahl et al 1983; Meltzer et al 1986; Mtick-Seler et al 1991). Because serotonin reuptake inhibitors and 5-HTz receptor antagonists may decrease platelet serotonin content (WirzJustice and P~ihringer et al 1978b; Amstein et al 1988), previous psychotropic drug exposure, in addition to differences in diagnostic criteria, gender ratio, severity and subtypes of depression may have contributed to the discrepancies between these studies. Another factor that results in large variations in platelet serotonin content is seasonal variation (Wirz-Justice and Piihringer 1978a) and this has not been controlled for in most studies. The relaticnship between platelet serotonin content, aggressivity, and suicidality also warrants study bccause suicidal and aggressive behavior are associated with lower levels of CSF 5-HIAA (Asberg et al 1984; Asberg et al 1986; Virkkunen et al 1987; Virkkunen et al 1989a; Virkkunen et al 1989b) and a blunted prolactin response to the serotonin agonist fenfluramine (Coccaro et al 1989). Reduced serotonin levels have been reported by one study in suicidal female schizophrenics compared to nonsvicidal female schizophrenics or controls (Braunig et al 1989), but no differences in blood serotonin levels were lbund in suicide attempters versus nonattempters in another study (Meltzer and Arora 1986) that included a variety of diagnostic groups including depression and schizophrenia. In the present study, we have concurrently examined the relationship of suicidal behavior, depression, aggressivity, and season to whole blood and platelet serotonin content in drug-free depressed inpatients. Methods We studied 29 patients and 27 normal controls. Patients admitted to an acute care, private psychiatric hospital and meeting DSM-III-R criteria for a major depressive episode (Spitzer et al 1989) were admitted to the study. All patients and controls gave written informed consent as required by the Institutional Review Board. All patients and controls were off psychotropic drugs or drugs known to affect monoamines for at least 2 weeks prior to study. Chloral hydrate was permitted for distressing insomnia but was rarely used. The minimum drug-free period was 6 weeks in the case of fluoxetine and 1 month for oral antipsychotic medication. The mean drug-free period was 149.7 _ 163.2 days. The range of the drug-free period was recorded as 14 to 365 days because the maximum drug-free period was designated as 365 days. in the group of 12 recent suicide attempters, the mean time between suicide attempt and biological testing was 13.8 _ 12.3 days. Table 1 describes the clinical and demographic characteristics of the patients and control subjects. The patients had been recently hospitalized for evaluation and treatment of depression, and were studied prior to initiation of treatment. All were free from
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Table 1. Demographic and Clinical Variables in Depressed Patients and Normal Controls Depressed patients Number of Subjects Age (years) Sex (% Female) Age of onset of depression (years) History of depression in a first degree relative (%) Hamilton Depression Scale score, (24-item version) Hamilton Anxiety Scale Score GAS Score Unipolar (%) Bipolar (%) MelanchoLia (%) Psychotic Features (%) Recent Suicide Attempt (%) Concurrent diagnosis of Borderline Personality Disorder (%) Drug-Free Interval (days) "Depressed patients versus controls
t =
29 42.5 ~ ± 13.9 75.9 31.1 ± 15.8 27.6 31.2 ± 7.8 33.4 ± 10.3
Controlsubjects 27 35.6 ± 12.6 55.6
41.6 ± 9.8 86.2/13.8 62.1 13.8 41.4 27.6 149.7 --. 163.2
- 1.94, d f ffi 54, p ffi 0 . 0 6 .
significant or active physical illness on the basis of physical examination and routine laboratory tests. The diagnosis of a major depressive episode (MDE) was generated by two research psychiatrists according to DSM-III-R criteria. Most patients had a major depressive (unipolar) disorder (86%), without psychotic features (86%). Almost twothirds of the patients (62%) met criteria for melancholia. The level of depression was moderately severe as indicated by a mean Hamilton Depression Scale (Hamilton 1960) score of 31.0 and the fact that 41% had made a recent suicide attempt. A categorical diagnosis of Borderline Personality Disorder (BPD) was made using a DSM-III-R checklist and the severity of BPD assessed using the Schedule for Interviewing Borderlines (SIB; Baron et al 1980). The percentage of patients who qualified for a diagnosis of BPD was 27.6%. In 22 of the 29 patients, general psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS) developed by Overall and Gorham (1962). Lifetime history of aggression was rated using the Brown-Goodwin Assessment for History of Lifetime Aggression (Brown et al 1979). Sensation-seeking behavior was assessed by the Zuckerman Interest and Preference Scale (Zuckerman 1971; Zuckerman 1978). Suicidal behavior was assessed by the Medical Damage or Lethality Scale (Beck et al 1975) and by the Suicide Intent Scale (Beck et al 1975). The method of suicide attempts included overdose of medications (n = 7), cutting self (n = 3), burning self (n = 1), and attempted hanging (n = 1). Controls were healthy adults recruited by advertisements or word of mouth from medical center staff and the neighborhood. All were free from physical and mental illness on the basis of a screening interview. All were totally drug-free including aspirin and other nonsteroidal anti-inflammatory drugs, for at least 2 weeks prior to testing. Blood samples were drawn between 8 and 9 AM into a glass Vacutainer tube (Becton Dickinson Vacutainer Systems, Rutherford, N J) containing EDTA as the anticoagulant, and a whole blood platelet count obtained. Ascorbic acid (50 ttl, 25%) and an internal standard, 5-HTP (100 ng), were added to 250 ttl of whole blood. Subsequently, 50 p,l of perchloric acid (3.5 tool/L) were added and the samples were vortexed for 10 sec and placed on ice for 10 min. The samples were then centrifuged at 10,000 g for 5 rain and the supernatant stored at -70°C untill shipped in dry ice to Yale University (GMA) for
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Table 2. Comparison of Whole Blood and Platelet Serotonin Content in Depressed Subjects Versus Normal Controls (ng/rnl and ng/10 8 platelets; mean -+ SD)
All subjects Platelet Whole Blood Males Platelet Whole Blood Females Platelet Whole Blood
Depressed (n)
Controls (n)
t
64.7 .4- 36.4 (29) 169,5 __ 74.5 (29)
62.4 ± 19.8 (25) 153.1 - 48.3 (27)
0.27 0.97
62,1 ± 29.0 (7) 159.9 -- 76.2 (7)
64.1 ± 22.9 (11) 144.7 ± 53.5 (12)
-0.16 0.51
65.5 ± 39,0 (14) 172.5 -*--75,5 (22)
61,2 ± 17.8 (14) 159.7 "*" 44.5 (15)
0.39 0.59
F 3.37 c 2.38 b !.59 2.03 4.82 c 2.88 t'
Patients versus controls:~p < 0.1; bp < 0,05; Cp < 0.01,
assay. Whole blood serotonin content was assayed by HPLC using our previously published method (Anderson et al 1987). The detection limit of the assay in less than 1 ng/ml and the day-to-day coefficient of variance (cv) for samples is 7.2%. The within-day cv is 3-5%. Because almost all serotonin in whole blood is located in cytoplasmic storage granules within the platelet (Sneddon 1973), results are expressed as platelet serotonin content (ng/10s platelets) as well as whole blood serotonin content (ng/ml ~hole blood). Group comparisons were performed using one-way and two-way analysis of variance. T-tests were used when only two groups were being compared. Pearson Product Moment Correlation coefficients were calculated to test for linear relationships between two variables. Whole blood serotonin content and platelet serotonin content were both normally distributed. The Kolmogorov-Smirnov statistic revealed no significant departures from normality for either of these variables. All data are reported as mean +_ standard deviation unless otherwise stated. Results
Comparison of Serotonin Content in Depressed Subjects Versus Normal Controls Mean whole blood serotonin content did not differ significantly between depressed subjects and normal controls in either the total pool of subjects or within subgroups defined by gender (see Table 2). However, there was a trend for platelet number to be higher in patients versus controls (2.9 _ 0.8 x 10S/ml versus 2.5 - 0.5 x 10e/ml, respectively; t = 1.87, df = 52, p = 0.07). This effect was significant in depressed males versus healthy male controls (2.6 _ 0.2 x 10S/ml versus 2.2 4._ 0.4 x 10~/ml; t = 2.5, df = 16, p = 0.02) and nonsignificant in female depressives versus female controis (2.9 _ 0.9 x 10S/ml versus 2.7 _ 0.6 x 10S/ml, t = 0.74, df = 34, p = 0.5). When mean whole blood serotonin content was corrected for platelet number, there was no significant difference in platelet serotonin content between depressed subjects and normal controls (see Table 2). Although mean whole blood and platelet serotonin content did not differ significantly between depressed subjects and normal controls, levels were significantly more variable in the depressed group compared to the control group (mean whole blood: F = 2.38, df = 28,26, p = 0.3; mean platelet serotonin content: F = 3.37, df =
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28,24, p = 0.003). In analyses by gender, whole blood and platelet serotonin levels were significantly more variable in the female depressed groups compared to female controls (F -- 2.88, df = 21,14, p = 0.05 and F - 4.82~ df = 21,13, p = 0.005, respectively) but not in male patients compared to male controls (F = 2.03, df ~6,11, p - 0.3 and F -- 1.59, df = 6,10, p - 0.5, respectively; see Table 2). Further analyses were done to explore other possible causes for the greater variability within the depressed group.
Effects of Season of Year on Whole Blood and Platelet Serotonin Content To test for the effects of season, subjects were divided according to the date of biological testing into four categories: Mmch 21-June 21, June 21-September 21, September 21-December 21, and December 21-March 21. The groups were labeled spring, summer, fall, and winter, respectively. A two-way analysis of variance was performed to test if the variance in whole blood or platelet serotonin content could be explained by season, group membership (depressed versus control), or by an interaction of the two. A significant main effect for season was found for whole blood serotonin (F = 5.97, (if = 3,20, p - 0.004) and platelet serotonin content (F = 7.08, at -- 3,45, p - 0.001). Mean values of whole blood serotonin content were: spring 180.2 ± 60.6 (n -- 8), summer 107.6 __ 45.8 in - 14.), fall 178.4 -+ 63.3 (n = 10), and winter 183.0 _+ 56.8 (n = 23). Mean values of platelet serotonin content were: spring 73.6 -+ 24.4 in - 8), summer 39.9 _+ 20.2 (n -- 14), fall 71.8 -+ 21.2 in = 8), and winter 72.8 -- 31.8 in - 23). Thus, the main effect was largely due to the finding of lower levels in summer relative to the other seasons. However, there was no significant group effect or interaction effect.
Relationship Between Demographic and Clinical Variables and Whole Blood and Platelet Serotonin Content Effects of ABe and Gender. Whole blood serotonin content and age were not significantly correlated in the deplessed group (r -- 0.12, n - 29, p -- 0.55), or in the control group (r - 0.15, n = 27, p - 0.46). Similarly, platelet serotonin content and age were not significantly correlated (depressed subjects: r - 0.06, n -- 29, p = 0.75; control subjects: r -- - 0 . 0 4 , n - 25, p - 0.84). Values for whole blood serotonin content did not significantly differ between males and females in depressed subjects (159.9 __- 76.2 versus 172.5 --- 75.5 ng/ml, respectively; df = 27, t - - 0 . 3 8 , p = 0.70); normal controls (144.7 _ 53.5 versus 159.7 +_ 44.5 ng/ml, respectively; df - 25, t - - 0 . 8 0 , p -- 0.43); or in the combined group of depressed subjects and normal controls (150.3 -+ 61.2 versus 167.4 - 64.3 ng/ml; (If - 54, t = - 0 . 9 5 , p = 0.35). Values for platelet serotonin content did not differ significantly between males and females (depressed subjects: 62. I -29.0 versus 65.5 - 39.0, t -- - 0 . 2 1 , df = 27, p = 0.8; control subjects: 64.1 _ 22.9 versus 61.2 -+ 17.8, t = 0.36, df -- 23, p = 0.73; all subjects: 63.3 _+ 24.6 versus 63.8 __. 32.2, t = - 0 . 0 6 , df = 52, p = 0.95). Relationshipto DepressiveSubtype. Patients were assigned to the following categories: major depressive episode (MDE) with psychotic features; MDE with melancholia but without psychotic features; and MDE without psychotic features or melancholia. A oneway analysis of variance was performed, including the above subtypes and the normal
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Table 3. Whole Blood and Platelet Serotonin Content in Major Depression Episode (MDE): Effect of Subtypes of MDE, Psychotic Features, Borderline Personality Disorder or Suicidal Behavior
Group I. Subtypeof Depression MDE with Psychotic features MDE with melancholia without psychotic features MDE without melancholia or psychotic features 2. Comorbid Dorderline Personality Disorder MDE with Borderline personality Disorder (BPD) MDE without BPD 3. Recentsuicide attempt MDE & Suicide attempter (within 2 months) MDE & Suicide nonattempter (lifetime)
Whole blood serotonin content (ng/ml) Mean _+ SD (n)
Platelet serotonin content (ng/10s platelets)
138.5 -+ 118.0 (4)
48.4 +_ 37.9 (4)
170.5 -+ 60.4 (15)
65.7 ± 26.6 (15)
180.4 ± 80.0 (10)
69.6 ± 49.0 (IO)
214.7~ ± 40,8 (8)
58.9° ± 31.1 (20)
157.6 ± 75.9 (20)
85.3 ± 41.5 (8)
143,8 .4- 81,3 (12)
47.2b ± 27.3 02)
190,3 - 72.5 (14)
77.6 ± 41.7 04)
Op< 0.10; bp < 0.05.
control group. No significant main effects were found either when whole blood serotonin content (F = 0.72, df = 3,52, p = 0.5) or platelet serotonin content (F - 0.51, df = 3,50, p = 0.7) were analyzed (see Table 3). A second contrast was carried out, confined to patients having MDE with melancholia, MDE without melancholia, and normal controls, and again indicated no significant group differences (whole blood serotonin content: F = 0.46, df = 2,53, p = 0.6; platelet serotonin content: F = 0.04, df = 2,51, p = 0.96).
Relationship to Symptom Severity. Platelet serotonin content correlated negatively with the 24-item Hamilton Depression Scale total score, but not with the subscores (see Table 4). Whole blood serotonin content did not correlate significantly with scores from the Hamilton Depression Scale, although a trend (p = 0.08) for a negative correlation was also observed. Neither whole blood nor platelet serotonin content were correlated with the Hamilton Anxiety Scale score, There was a significant positive correlation of the Global Assessment Scale (GAS) score with whole blood serotonin content and with platelet serotonin content (see Table 4),
Reiationship to the Presence or Absence of Borderline Personality Disorder. Mean values of whole blood serotonin content were compared in depressed patients with and without coexistent Borderline Personality Disorder (BPD; see Table 3). The mean whole blood serotonin content appeared higher in the BPD patients compared to patients without this diagnosis (214.7 _ 40.8 versus 157.6 _ 75.9 ng/ml, respectively, t = 2.00, df = 26, p = 0.06), and compared to normal controls (214.7 +_ 40.8 versus 153.1 _ 48.3 ng/ml, t = - 3 . 3 , df = 33, p = 0.003). Of the non-BPD patients, 6 of 19 were tested in the summer as opposed to 1 of 8 BPD patients, which may have accounted for the lower lev-
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Table 4. Correlations Between Whole Blood and Platelet Serotonin Content and Scores on Scales Measuring Symptom Severity Whole blood serotonin content
Hamilton Depression Scale 24-item Total Psychomotor Agitation Subscale Score Psychomotor Retardation Subscalc Score Hamilton Anxiety Scale Global Assessment Scale
Platelet semtonin content
r
n
r
n
-0.33 a - 0.25 -0.18 0.08 0.49 c
29 29 29 22 29
-0.49 ~ - 0.25 -0.19 0.03 0.24 c
29 29 29 22 29
'*p < 0.10
~p < 0.05 ~p < O.OI
els of serotonin in the non-BPD group. To test this possibility, the above analysis was recomputed excluding subjects that were tested in the summer. Although the BPD group had a higher mean whole blood serotonin content (216.7 _+ 43.6) than those patients without this diagnosis (195.7 _+ 63.8), after excluding the cases tested in the summer the difference was no longer statistically significant (t ffi - 0.78, df = 18, p = 0.4). However, the difference between patients with BPD and healthy controls remained significant (216.7 __ 43.6versus 160.7 _+ 51.2, t = - 2 . 5 9 , df = 2 6 , p = 0.02). Platelet number expressed as l0 s platelets/ml did not differ significantly in the above groups (BPD patients, 2.9 - 0.95 versus patients without this diagnosis, 2.9 -+ 0.7, t = 0.06, df ffi 26, p = 0.96; and versus controls 2.5 - 0.5, t = - 1 . 1 8 , df = 31, p = 0.25). There was a trend for the BPD group to have higher platelet serotonin content than the non-BPD group (85.3 _+ 41.5 versus 58.9 -+ 31.1, t = - 1.84, df - 26, p = 0.08) and significantly higher platelet serotonin content versus controls (62.4 -+ 19.8, t 2 . 1 4 , df = 31, p = 0.04; see Table 3). When patients tested during the summer were excluded from the analysis (6 of 19 non-BPD patients, 1 of 8 BPD patients), the patients with BPD no longer had statistically significant higher mean platelet serotonin content (87.12 - 44.47) compared to those without BPD (75.09 4- 25.73; t = - 0 . 7 7 , df = 18, p = 0.4). Similarly, after excluding the cases tested during the summer (1 of 8 BPD patients and 6 of 27 controls), there was only a trend for those with BPD to have a higher mean platelet serotonin than the healthy controls (87.12 -+ 44.47 versus 65.78.4- 20.28, t-
-l.70,
df=
24, p = 0 . 1 0 ) .
The mean whole blood serotonin content in depressed patients without coexistent Borderline Personality Disorder did not differ significantly from normal controls (157.6 _+ 75.9 versus 153.1 +- 48.3 ng/ml, t -- 0.25, df = 45, p = 0.8) but the variance of the depressed group was significantly larger than the normal controls (F = 2.47, df 19,26, p = 0.03). The increased variance in the patient group was stiil present at~er adjusting for platelet number, but was no longer present when the analysis was done excluding the summer cases. The Schedule for Interviewing Borderlines (SIB) total score assessed severity of BPD and was available for 20 of the 29 patients. The SIB score was positively correlated with whole blood serotonin levels, btlt the result was not statistically significant (r = 0.24, n = 20, p = 0.3).
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Relationship to Suicidal Behavior. Platelet serotonin content was significantly lower in depressed patients who had recently auempted suicide (within the previous 2 months) compared to patients who had never a~empted suicide (47.2 ± 27.3 versus 77.6 -.- 41.7 ng/108 platelets, t = 2.16, df = 24, p = 0.04). Although mean whole blood serotonin content appeared lower in recent suicide attempters compared to patients without a history of a suicide attempt, the difference was not statistically significant (143.8 _+ 81.3 versus 190.3 - 72.5 ng/ml, t = 1.54, df = 24, p = 0.14). Because 6 of the 12 recent attempters and only 2 of the 13 nonattempters were tested during the summer, additional analyses were performed excluding these cases. Comparison of whole blood and platelet serotonin content in recent attempters versus life-time nonattempters suggested lower levels in attempters, but the difference in the means did not reach statistical significance for whole blood serotonin content (190.43 -+ 76.22 versus 217.45 ± 52,29, t = 0.87, df = 15, p = 0.4), or platelet serotonin content (61.35 - 26.23 versus 90.58 ± 36.85, t = 1.71, df = 15, p = 0.11). Among the recent suicide attempters, there was no correlation between whole blood or platelet serotonin content and medical damage or lethality of the suicide attempt rated using the Medical Lethality Scale (r - 0.19, n -- 12, p = 0.6; r - - 0 . 0 4 , n - 12, p = 0.9). There was also no correlation between whole blood or platelet serotonin content and an overall objective rating of suicidal planning behavior as derived by a factor analysis of the Suicide Intent Scale (r = 0.19, n = 12, p = 0.6; r = 0.01, n = 12, p = 0.97, respectively). Platelet number was not related to either the medical lethality nor degree of planning behavior. There was no difference in platelet count in attempters as comp~a'ed to nonattempters (3.16 ± 0.84 × 108 platelets/ml versus 2.68 ± 0.71 × 108 platelets/ml, t = 1.57, df = 24, p = 0.13). When recent suicide attempters with a concurrent diagnosis of BPD were compared to those who had a diagnosis of BPD but never attempted suicide, there was a trend for the suicide attempters with BPD to have lower whole blood serotonin content (211.3 17.6 versus 263.5 ± 46.0, t = 2.19, df - 4, p -- 0.09) and lower platelet serotonin content (65.75 ± 19.9 versus 137.8 ± 58.8, t = 2.44, df = 4, p - 0.07). When patients with BPD and a life.time history of a suicide attempt were compared to those with BPD and no life-time history of suicide attempt, there was a significant difference in whole blood serotonin content (198.4 ± 25.1 versus 263.5 ± 46.0, t - 2.69, df 6 , p - 0.04) and platelet serotonin content (67.78 ± 15.8 versus 137.8 4. 58.8, t = 3.07, df -- 6, p = 0.02). Even excluding those subjects tested during the summer, the above results remained the same. When BPD attempters were compared to non-BPD attempters, the BPD attempter group had significantly higher whole blood serotonin content than the non-BPD attempter group (198.37 ± 25.12 versus 117.94 _ 78.28, ': = 2.41, df = 13, p = 0.03). There was also a trend for platelet serotonin content to be higher in BPD attempters compared to non-BPD attempters (67.78 ± 15.75 versus 42.36 ± 28.20, t = 1,99, df = 13, p = 0.07). Because 5 of the 9 non-BPD attempters and only 1 of the 6 BPD attempters were tested during the summer, another analysis was performed excluding all of those tested during the summer. Although the BPD attempters had higher whole blood and platelet serotonin content, the results were no longer statistically significant (whole blood serotonin content: 198.04 ± 28.08 versus 169.78 ± 91.0, t = 0.67, df = 7, p = 0.53; platelet serotonin content: 66.85 ± 17.42 versus 63.87 ± 29.15, t = 0.19, df = 7, p - 0.85). Two-way analysis of variance was performed to simultaneously test for main effects and an interaction between a BPD diagnoses and lifetime suicide attempt history. Sig-
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Table 5. Correlations Between Whole Blood and Platelet Serotonin Content and Scores on Scales Measuring Aggressivity and Impulsivity
BPRS Total Anxiety and Depression Anergia Thought disorder Activity disturbance Hostility Aggression History Scale (n = 21) Total Zuckerman Sensation Seeking Total Thrill and Adventure Experience Seeking Disinhibiton Boredom Susceptibility
Whole blood serotonin (ng/ml) (n = 22)
Platelet serotonin content (rig/10 s platelets) (n = 22)
r
r
-0.06 0.02 -0.36 a - 0.32 -0.02 0.44 b
-0.15 -0.24 -0.43 b - 0.25 -0.09 0.41 a
0.4P 0.12 0.03 0.22 - 0.004 0.08
0.42 a 0.28 0.13 0.38 0. ! 7 0.09
"p
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Platelet and Whole Blood Serotonin Content in Depressed Inpatients: Correlations with Acute and Life-Time Psychopathology J. John Mann, P. Anne McBride, George M. Anderson, and Tammy A. Mieczkowski
Platelet or whole blood serotonin content did not differ significantly in patients with major depression compared to healthy controls, but within the patient group, platelet serotonin levels correlated negatively with severity of depression (r = -0.49, p = 0.007). Levels were 39% lower in patients who had made a suicide attempt compared to nonattempter patients (47.2 +_ 27.3 versus 77.6 +- 41.7 ng/lOs platelets, p = 0.04). Conversely, comorbid borderline personality disorder (85.3 +- 41.5 ng/lOs platelets) was associated with 31% greater platelet serotonin content than nonborderline patients (58.9 +- 31.1 ng/lOs platelets) and 27% greater than healthy controls (62.4 +- 19.8 ng/ l Os platelets ). A pronounced seasonal variation in whole blood and platelet serotonin content was found in both patients and controls, largely due to lower levels in summer. Excluding cases tested in the summer abolished the statistically significant differences in patients with and without comorbid borderline personality disorder (BPD ). Neve,'theless, BPD attempters had lower serotonin levels than BPD nonanempters but higher serotonin levels than non-BPD attempters. Current hostility and a life-time history of aggression were positively correlated with platelet serotonin content (r ffi 0.44, p ffi 0.04 and r = 0.41, p ffi 0.06). This study provides evidence for an association between lower platelet serotonin content and depression and suicidal behavior, and association of higher platelet serotonin content and comorbid borderline personality disorder and behavior traits such as aggressivity.
Introduction An association has been described between reduced serotonergic activity and depressive illness (Heninger et al 1984), suicidal behavior (Mann et al 1989a; Mann et al 1989b), and aggressive behavior (Brown et al 1979; Brown et al 1982a; Coccaro et al 1989; Virkkunen et al 1987; Virkkunen et al 1989a; Virkkunen et al 1989b). Neuroendocrine serotonin challenge tests, such as intravenous l-tryptophan (Heninger et al 1984)
Address reprint requests to Dr. J. John Mann, Laboratories of Neutopharmacology, Western Psychiatric Institute and Clinic,
University of Pittsburgh, 3811 O'Hata Street, Pittsburgh, PA., 15213. From the Laboratories of Neumpharmacology (JJM, TAM), Department of Psychiatry, University of Pittsburgh; Department of Psychiatry (PAM). Cornell University Medical College; and Child Study Center (GMA), Yale University School of Medicine. Received September 23, 1991; revised April 3, 1992. © 1992 Socie',y of Biological Psychiatry
0006-3223/92/$05.00
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and oral fenfluramine (Coccaro et al 1989), stimulate a lower prolactin response in depressed patients. Similar results have also been reported regarding lower levels of CSF 5-hydroxyindeacetic acid (5-HIAA), a serotonin metabolite, in depressed patients (Asberg et al 1984). Suicidal or aggressive behavior also appear to be associated with low CSF 5-HIAA (Brown et al 1979; Brown et al 1982a; Brown et al 1982b; Asberg et ai 1986) ~,id a blunted prolactin response to fenfluramine (Coccaro et al 1989). Platelet serotonin content has been employed as an index of presynaptic serotonin function (Stahl 1977; Stahl et al 1982). Decreased whole blood or platelet serotonin content has been reported in patients with depression by some (Sarai and Kayano 1968; Takahashi 1976; Coppen et al 1976; Banki 1978; Born et al 1980; Quan-Bui et al 1984; Quintana 1992) but not all studies (Todrick et al 1960; Wirz-Justice and Piihringer 1978b; Stahl et al 1983; Meltzer et al 1986; Mtick-Seler et al 1991). Because serotonin reuptake inhibitors and 5-HTz receptor antagonists may decrease platelet serotonin content (WirzJustice and P~ihringer et al 1978b; Amstein et al 1988), previous psychotropic drug exposure, in addition to differences in diagnostic criteria, gender ratio, severity and subtypes of depression may have contributed to the discrepancies between these studies. Another factor that results in large variations in platelet serotonin content is seasonal variation (Wirz-Justice and Piihringer 1978a) and this has not been controlled for in most studies. The relaticnship between platelet serotonin content, aggressivity, and suicidality also warrants study bccause suicidal and aggressive behavior are associated with lower levels of CSF 5-HIAA (Asberg et al 1984; Asberg et al 1986; Virkkunen et al 1987; Virkkunen et al 1989a; Virkkunen et al 1989b) and a blunted prolactin response to the serotonin agonist fenfluramine (Coccaro et al 1989). Reduced serotonin levels have been reported by one study in suicidal female schizophrenics compared to nonsvicidal female schizophrenics or controls (Braunig et al 1989), but no differences in blood serotonin levels were lbund in suicide attempters versus nonattempters in another study (Meltzer and Arora 1986) that included a variety of diagnostic groups including depression and schizophrenia. In the present study, we have concurrently examined the relationship of suicidal behavior, depression, aggressivity, and season to whole blood and platelet serotonin content in drug-free depressed inpatients. Methods We studied 29 patients and 27 normal controls. Patients admitted to an acute care, private psychiatric hospital and meeting DSM-III-R criteria for a major depressive episode (Spitzer et al 1989) were admitted to the study. All patients and controls gave written informed consent as required by the Institutional Review Board. All patients and controls were off psychotropic drugs or drugs known to affect monoamines for at least 2 weeks prior to study. Chloral hydrate was permitted for distressing insomnia but was rarely used. The minimum drug-free period was 6 weeks in the case of fluoxetine and 1 month for oral antipsychotic medication. The mean drug-free period was 149.7 _ 163.2 days. The range of the drug-free period was recorded as 14 to 365 days because the maximum drug-free period was designated as 365 days. in the group of 12 recent suicide attempters, the mean time between suicide attempt and biological testing was 13.8 _ 12.3 days. Table 1 describes the clinical and demographic characteristics of the patients and control subjects. The patients had been recently hospitalized for evaluation and treatment of depression, and were studied prior to initiation of treatment. All were free from
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Table 1. Demographic and Clinical Variables in Depressed Patients and Normal Controls Depressed patients Number of Subjects Age (years) Sex (% Female) Age of onset of depression (years) History of depression in a first degree relative (%) Hamilton Depression Scale score, (24-item version) Hamilton Anxiety Scale Score GAS Score Unipolar (%) Bipolar (%) MelanchoLia (%) Psychotic Features (%) Recent Suicide Attempt (%) Concurrent diagnosis of Borderline Personality Disorder (%) Drug-Free Interval (days) "Depressed patients versus controls
t =
29 42.5 ~ ± 13.9 75.9 31.1 ± 15.8 27.6 31.2 ± 7.8 33.4 ± 10.3
Controlsubjects 27 35.6 ± 12.6 55.6
41.6 ± 9.8 86.2/13.8 62.1 13.8 41.4 27.6 149.7 --. 163.2
- 1.94, d f ffi 54, p ffi 0 . 0 6 .
significant or active physical illness on the basis of physical examination and routine laboratory tests. The diagnosis of a major depressive episode (MDE) was generated by two research psychiatrists according to DSM-III-R criteria. Most patients had a major depressive (unipolar) disorder (86%), without psychotic features (86%). Almost twothirds of the patients (62%) met criteria for melancholia. The level of depression was moderately severe as indicated by a mean Hamilton Depression Scale (Hamilton 1960) score of 31.0 and the fact that 41% had made a recent suicide attempt. A categorical diagnosis of Borderline Personality Disorder (BPD) was made using a DSM-III-R checklist and the severity of BPD assessed using the Schedule for Interviewing Borderlines (SIB; Baron et al 1980). The percentage of patients who qualified for a diagnosis of BPD was 27.6%. In 22 of the 29 patients, general psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS) developed by Overall and Gorham (1962). Lifetime history of aggression was rated using the Brown-Goodwin Assessment for History of Lifetime Aggression (Brown et al 1979). Sensation-seeking behavior was assessed by the Zuckerman Interest and Preference Scale (Zuckerman 1971; Zuckerman 1978). Suicidal behavior was assessed by the Medical Damage or Lethality Scale (Beck et al 1975) and by the Suicide Intent Scale (Beck et al 1975). The method of suicide attempts included overdose of medications (n = 7), cutting self (n = 3), burning self (n = 1), and attempted hanging (n = 1). Controls were healthy adults recruited by advertisements or word of mouth from medical center staff and the neighborhood. All were free from physical and mental illness on the basis of a screening interview. All were totally drug-free including aspirin and other nonsteroidal anti-inflammatory drugs, for at least 2 weeks prior to testing. Blood samples were drawn between 8 and 9 AM into a glass Vacutainer tube (Becton Dickinson Vacutainer Systems, Rutherford, N J) containing EDTA as the anticoagulant, and a whole blood platelet count obtained. Ascorbic acid (50 ttl, 25%) and an internal standard, 5-HTP (100 ng), were added to 250 ttl of whole blood. Subsequently, 50 p,l of perchloric acid (3.5 tool/L) were added and the samples were vortexed for 10 sec and placed on ice for 10 min. The samples were then centrifuged at 10,000 g for 5 rain and the supernatant stored at -70°C untill shipped in dry ice to Yale University (GMA) for
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Table 2. Comparison of Whole Blood and Platelet Serotonin Content in Depressed Subjects Versus Normal Controls (ng/rnl and ng/10 8 platelets; mean -+ SD)
All subjects Platelet Whole Blood Males Platelet Whole Blood Females Platelet Whole Blood
Depressed (n)
Controls (n)
t
64.7 .4- 36.4 (29) 169,5 __ 74.5 (29)
62.4 ± 19.8 (25) 153.1 - 48.3 (27)
0.27 0.97
62,1 ± 29.0 (7) 159.9 -- 76.2 (7)
64.1 ± 22.9 (11) 144.7 ± 53.5 (12)
-0.16 0.51
65.5 ± 39,0 (14) 172.5 -*--75,5 (22)
61,2 ± 17.8 (14) 159.7 "*" 44.5 (15)
0.39 0.59
F 3.37 c 2.38 b !.59 2.03 4.82 c 2.88 t'
Patients versus controls:~p < 0.1; bp < 0,05; Cp < 0.01,
assay. Whole blood serotonin content was assayed by HPLC using our previously published method (Anderson et al 1987). The detection limit of the assay in less than 1 ng/ml and the day-to-day coefficient of variance (cv) for samples is 7.2%. The within-day cv is 3-5%. Because almost all serotonin in whole blood is located in cytoplasmic storage granules within the platelet (Sneddon 1973), results are expressed as platelet serotonin content (ng/10s platelets) as well as whole blood serotonin content (ng/ml ~hole blood). Group comparisons were performed using one-way and two-way analysis of variance. T-tests were used when only two groups were being compared. Pearson Product Moment Correlation coefficients were calculated to test for linear relationships between two variables. Whole blood serotonin content and platelet serotonin content were both normally distributed. The Kolmogorov-Smirnov statistic revealed no significant departures from normality for either of these variables. All data are reported as mean +_ standard deviation unless otherwise stated. Results
Comparison of Serotonin Content in Depressed Subjects Versus Normal Controls Mean whole blood serotonin content did not differ significantly between depressed subjects and normal controls in either the total pool of subjects or within subgroups defined by gender (see Table 2). However, there was a trend for platelet number to be higher in patients versus controls (2.9 _ 0.8 x 10S/ml versus 2.5 - 0.5 x 10e/ml, respectively; t = 1.87, df = 52, p = 0.07). This effect was significant in depressed males versus healthy male controls (2.6 _ 0.2 x 10S/ml versus 2.2 4._ 0.4 x 10~/ml; t = 2.5, df = 16, p = 0.02) and nonsignificant in female depressives versus female controis (2.9 _ 0.9 x 10S/ml versus 2.7 _ 0.6 x 10S/ml, t = 0.74, df = 34, p = 0.5). When mean whole blood serotonin content was corrected for platelet number, there was no significant difference in platelet serotonin content between depressed subjects and normal controls (see Table 2). Although mean whole blood and platelet serotonin content did not differ significantly between depressed subjects and normal controls, levels were significantly more variable in the depressed group compared to the control group (mean whole blood: F = 2.38, df = 28,26, p = 0.3; mean platelet serotonin content: F = 3.37, df =
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28,24, p = 0.003). In analyses by gender, whole blood and platelet serotonin levels were significantly more variable in the female depressed groups compared to female controls (F -- 2.88, df = 21,14, p = 0.05 and F - 4.82~ df = 21,13, p = 0.005, respectively) but not in male patients compared to male controls (F = 2.03, df ~6,11, p - 0.3 and F -- 1.59, df = 6,10, p - 0.5, respectively; see Table 2). Further analyses were done to explore other possible causes for the greater variability within the depressed group.
Effects of Season of Year on Whole Blood and Platelet Serotonin Content To test for the effects of season, subjects were divided according to the date of biological testing into four categories: Mmch 21-June 21, June 21-September 21, September 21-December 21, and December 21-March 21. The groups were labeled spring, summer, fall, and winter, respectively. A two-way analysis of variance was performed to test if the variance in whole blood or platelet serotonin content could be explained by season, group membership (depressed versus control), or by an interaction of the two. A significant main effect for season was found for whole blood serotonin (F = 5.97, (if = 3,20, p - 0.004) and platelet serotonin content (F = 7.08, at -- 3,45, p - 0.001). Mean values of whole blood serotonin content were: spring 180.2 ± 60.6 (n -- 8), summer 107.6 __ 45.8 in - 14.), fall 178.4 -+ 63.3 (n = 10), and winter 183.0 _+ 56.8 (n = 23). Mean values of platelet serotonin content were: spring 73.6 -+ 24.4 in - 8), summer 39.9 _+ 20.2 (n -- 14), fall 71.8 -+ 21.2 in = 8), and winter 72.8 -- 31.8 in - 23). Thus, the main effect was largely due to the finding of lower levels in summer relative to the other seasons. However, there was no significant group effect or interaction effect.
Relationship Between Demographic and Clinical Variables and Whole Blood and Platelet Serotonin Content Effects of ABe and Gender. Whole blood serotonin content and age were not significantly correlated in the deplessed group (r -- 0.12, n - 29, p -- 0.55), or in the control group (r - 0.15, n = 27, p - 0.46). Similarly, platelet serotonin content and age were not significantly correlated (depressed subjects: r - 0.06, n -- 29, p = 0.75; control subjects: r -- - 0 . 0 4 , n - 25, p - 0.84). Values for whole blood serotonin content did not significantly differ between males and females in depressed subjects (159.9 __- 76.2 versus 172.5 --- 75.5 ng/ml, respectively; df = 27, t - - 0 . 3 8 , p = 0.70); normal controls (144.7 _ 53.5 versus 159.7 +_ 44.5 ng/ml, respectively; df - 25, t - - 0 . 8 0 , p -- 0.43); or in the combined group of depressed subjects and normal controls (150.3 -+ 61.2 versus 167.4 - 64.3 ng/ml; (If - 54, t = - 0 . 9 5 , p = 0.35). Values for platelet serotonin content did not differ significantly between males and females (depressed subjects: 62. I -29.0 versus 65.5 - 39.0, t -- - 0 . 2 1 , df = 27, p = 0.8; control subjects: 64.1 _ 22.9 versus 61.2 -+ 17.8, t = 0.36, df -- 23, p = 0.73; all subjects: 63.3 _+ 24.6 versus 63.8 __. 32.2, t = - 0 . 0 6 , df = 52, p = 0.95). Relationshipto DepressiveSubtype. Patients were assigned to the following categories: major depressive episode (MDE) with psychotic features; MDE with melancholia but without psychotic features; and MDE without psychotic features or melancholia. A oneway analysis of variance was performed, including the above subtypes and the normal
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Table 3. Whole Blood and Platelet Serotonin Content in Major Depression Episode (MDE): Effect of Subtypes of MDE, Psychotic Features, Borderline Personality Disorder or Suicidal Behavior
Group I. Subtypeof Depression MDE with Psychotic features MDE with melancholia without psychotic features MDE without melancholia or psychotic features 2. Comorbid Dorderline Personality Disorder MDE with Borderline personality Disorder (BPD) MDE without BPD 3. Recentsuicide attempt MDE & Suicide attempter (within 2 months) MDE & Suicide nonattempter (lifetime)
Whole blood serotonin content (ng/ml) Mean _+ SD (n)
Platelet serotonin content (ng/10s platelets)
138.5 -+ 118.0 (4)
48.4 +_ 37.9 (4)
170.5 -+ 60.4 (15)
65.7 ± 26.6 (15)
180.4 ± 80.0 (10)
69.6 ± 49.0 (IO)
214.7~ ± 40,8 (8)
58.9° ± 31.1 (20)
157.6 ± 75.9 (20)
85.3 ± 41.5 (8)
143,8 .4- 81,3 (12)
47.2b ± 27.3 02)
190,3 - 72.5 (14)
77.6 ± 41.7 04)
Op< 0.10; bp < 0.05.
control group. No significant main effects were found either when whole blood serotonin content (F = 0.72, df = 3,52, p = 0.5) or platelet serotonin content (F - 0.51, df = 3,50, p = 0.7) were analyzed (see Table 3). A second contrast was carried out, confined to patients having MDE with melancholia, MDE without melancholia, and normal controls, and again indicated no significant group differences (whole blood serotonin content: F = 0.46, df = 2,53, p = 0.6; platelet serotonin content: F = 0.04, df = 2,51, p = 0.96).
Relationship to Symptom Severity. Platelet serotonin content correlated negatively with the 24-item Hamilton Depression Scale total score, but not with the subscores (see Table 4). Whole blood serotonin content did not correlate significantly with scores from the Hamilton Depression Scale, although a trend (p = 0.08) for a negative correlation was also observed. Neither whole blood nor platelet serotonin content were correlated with the Hamilton Anxiety Scale score, There was a significant positive correlation of the Global Assessment Scale (GAS) score with whole blood serotonin content and with platelet serotonin content (see Table 4),
Reiationship to the Presence or Absence of Borderline Personality Disorder. Mean values of whole blood serotonin content were compared in depressed patients with and without coexistent Borderline Personality Disorder (BPD; see Table 3). The mean whole blood serotonin content appeared higher in the BPD patients compared to patients without this diagnosis (214.7 _ 40.8 versus 157.6 _ 75.9 ng/ml, respectively, t = 2.00, df = 26, p = 0.06), and compared to normal controls (214.7 +_ 40.8 versus 153.1 _ 48.3 ng/ml, t = - 3 . 3 , df = 33, p = 0.003). Of the non-BPD patients, 6 of 19 were tested in the summer as opposed to 1 of 8 BPD patients, which may have accounted for the lower lev-
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Table 4. Correlations Between Whole Blood and Platelet Serotonin Content and Scores on Scales Measuring Symptom Severity Whole blood serotonin content
Hamilton Depression Scale 24-item Total Psychomotor Agitation Subscale Score Psychomotor Retardation Subscalc Score Hamilton Anxiety Scale Global Assessment Scale
Platelet semtonin content
r
n
r
n
-0.33 a - 0.25 -0.18 0.08 0.49 c
29 29 29 22 29
-0.49 ~ - 0.25 -0.19 0.03 0.24 c
29 29 29 22 29
'*p < 0.10
~p < 0.05 ~p < O.OI
els of serotonin in the non-BPD group. To test this possibility, the above analysis was recomputed excluding subjects that were tested in the summer. Although the BPD group had a higher mean whole blood serotonin content (216.7 _+ 43.6) than those patients without this diagnosis (195.7 _+ 63.8), after excluding the cases tested in the summer the difference was no longer statistically significant (t ffi - 0.78, df = 18, p = 0.4). However, the difference between patients with BPD and healthy controls remained significant (216.7 __ 43.6versus 160.7 _+ 51.2, t = - 2 . 5 9 , df = 2 6 , p = 0.02). Platelet number expressed as l0 s platelets/ml did not differ significantly in the above groups (BPD patients, 2.9 - 0.95 versus patients without this diagnosis, 2.9 -+ 0.7, t = 0.06, df ffi 26, p = 0.96; and versus controls 2.5 - 0.5, t = - 1 . 1 8 , df = 31, p = 0.25). There was a trend for the BPD group to have higher platelet serotonin content than the non-BPD group (85.3 _+ 41.5 versus 58.9 -+ 31.1, t = - 1.84, df - 26, p = 0.08) and significantly higher platelet serotonin content versus controls (62.4 -+ 19.8, t 2 . 1 4 , df = 31, p = 0.04; see Table 3). When patients tested during the summer were excluded from the analysis (6 of 19 non-BPD patients, 1 of 8 BPD patients), the patients with BPD no longer had statistically significant higher mean platelet serotonin content (87.12 - 44.47) compared to those without BPD (75.09 4- 25.73; t = - 0 . 7 7 , df = 18, p = 0.4). Similarly, after excluding the cases tested during the summer (1 of 8 BPD patients and 6 of 27 controls), there was only a trend for those with BPD to have a higher mean platelet serotonin than the healthy controls (87.12 -+ 44.47 versus 65.78.4- 20.28, t-
-l.70,
df=
24, p = 0 . 1 0 ) .
The mean whole blood serotonin content in depressed patients without coexistent Borderline Personality Disorder did not differ significantly from normal controls (157.6 _+ 75.9 versus 153.1 +- 48.3 ng/ml, t -- 0.25, df = 45, p = 0.8) but the variance of the depressed group was significantly larger than the normal controls (F = 2.47, df 19,26, p = 0.03). The increased variance in the patient group was stiil present at~er adjusting for platelet number, but was no longer present when the analysis was done excluding the summer cases. The Schedule for Interviewing Borderlines (SIB) total score assessed severity of BPD and was available for 20 of the 29 patients. The SIB score was positively correlated with whole blood serotonin levels, btlt the result was not statistically significant (r = 0.24, n = 20, p = 0.3).
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Relationship to Suicidal Behavior. Platelet serotonin content was significantly lower in depressed patients who had recently auempted suicide (within the previous 2 months) compared to patients who had never a~empted suicide (47.2 ± 27.3 versus 77.6 -.- 41.7 ng/108 platelets, t = 2.16, df = 24, p = 0.04). Although mean whole blood serotonin content appeared lower in recent suicide attempters compared to patients without a history of a suicide attempt, the difference was not statistically significant (143.8 _+ 81.3 versus 190.3 - 72.5 ng/ml, t = 1.54, df = 24, p = 0.14). Because 6 of the 12 recent attempters and only 2 of the 13 nonattempters were tested during the summer, additional analyses were performed excluding these cases. Comparison of whole blood and platelet serotonin content in recent attempters versus life-time nonattempters suggested lower levels in attempters, but the difference in the means did not reach statistical significance for whole blood serotonin content (190.43 -+ 76.22 versus 217.45 ± 52,29, t = 0.87, df = 15, p = 0.4), or platelet serotonin content (61.35 - 26.23 versus 90.58 ± 36.85, t = 1.71, df = 15, p = 0.11). Among the recent suicide attempters, there was no correlation between whole blood or platelet serotonin content and medical damage or lethality of the suicide attempt rated using the Medical Lethality Scale (r - 0.19, n -- 12, p = 0.6; r - - 0 . 0 4 , n - 12, p = 0.9). There was also no correlation between whole blood or platelet serotonin content and an overall objective rating of suicidal planning behavior as derived by a factor analysis of the Suicide Intent Scale (r = 0.19, n = 12, p = 0.6; r = 0.01, n = 12, p = 0.97, respectively). Platelet number was not related to either the medical lethality nor degree of planning behavior. There was no difference in platelet count in attempters as comp~a'ed to nonattempters (3.16 ± 0.84 × 108 platelets/ml versus 2.68 ± 0.71 × 108 platelets/ml, t = 1.57, df = 24, p = 0.13). When recent suicide attempters with a concurrent diagnosis of BPD were compared to those who had a diagnosis of BPD but never attempted suicide, there was a trend for the suicide attempters with BPD to have lower whole blood serotonin content (211.3 17.6 versus 263.5 ± 46.0, t = 2.19, df - 4, p -- 0.09) and lower platelet serotonin content (65.75 ± 19.9 versus 137.8 ± 58.8, t = 2.44, df = 4, p - 0.07). When patients with BPD and a life.time history of a suicide attempt were compared to those with BPD and no life-time history of suicide attempt, there was a significant difference in whole blood serotonin content (198.4 ± 25.1 versus 263.5 ± 46.0, t - 2.69, df 6 , p - 0.04) and platelet serotonin content (67.78 ± 15.8 versus 137.8 4. 58.8, t = 3.07, df -- 6, p = 0.02). Even excluding those subjects tested during the summer, the above results remained the same. When BPD attempters were compared to non-BPD attempters, the BPD attempter group had significantly higher whole blood serotonin content than the non-BPD attempter group (198.37 ± 25.12 versus 117.94 _ 78.28, ': = 2.41, df = 13, p = 0.03). There was also a trend for platelet serotonin content to be higher in BPD attempters compared to non-BPD attempters (67.78 ± 15.75 versus 42.36 ± 28.20, t = 1,99, df = 13, p = 0.07). Because 5 of the 9 non-BPD attempters and only 1 of the 6 BPD attempters were tested during the summer, another analysis was performed excluding all of those tested during the summer. Although the BPD attempters had higher whole blood and platelet serotonin content, the results were no longer statistically significant (whole blood serotonin content: 198.04 ± 28.08 versus 169.78 ± 91.0, t = 0.67, df = 7, p = 0.53; platelet serotonin content: 66.85 ± 17.42 versus 63.87 ± 29.15, t = 0.19, df = 7, p - 0.85). Two-way analysis of variance was performed to simultaneously test for main effects and an interaction between a BPD diagnoses and lifetime suicide attempt history. Sig-
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Table 5. Correlations Between Whole Blood and Platelet Serotonin Content and Scores on Scales Measuring Aggressivity and Impulsivity
BPRS Total Anxiety and Depression Anergia Thought disorder Activity disturbance Hostility Aggression History Scale (n = 21) Total Zuckerman Sensation Seeking Total Thrill and Adventure Experience Seeking Disinhibiton Boredom Susceptibility
Whole blood serotonin (ng/ml) (n = 22)
Platelet serotonin content (rig/10 s platelets) (n = 22)
r
r
-0.06 0.02 -0.36 a - 0.32 -0.02 0.44 b
-0.15 -0.24 -0.43 b - 0.25 -0.09 0.41 a
0.4P 0.12 0.03 0.22 - 0.004 0.08
0.42 a 0.28 0.13 0.38 0. ! 7 0.09
"p
