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CSF 5-HIAA, serum cortisol, and age differentially predict vegetative and cognitive symptoms in depression
BIOL PSYCHIATRY 1990;27:311-318
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CSF 5-HIAA, Serum Cortisol, and Age Differentially Predict Vegetative and Cognitive Symptoms in Depression Williarn O. Faustman, Kym F. Faull, Harvey A. Whiteford, Catherine Borchert, and John G. Csernansky
Prior studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA) and serum cortisel levels are related to overall symptom severity in depression. In the present study, 30 unmedicated inpatients meeting Research Diagnostic Criteria (RDC) criteria for depression participuted in serum cortisol collection and a lumbar puncture for CSF. A multiple regression evaluated the ability of CSF 5HIAA, serum cortisol, and age to predict cognitive and vegetative symptom clusters of the Homilton Rating Scalefor Depression. The multiple regression to predict the vegetative symptom cluster was highly significant overall (p = 0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms. The regression to predict the cognitive cluster narrowly missed overall sign~cance (p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and 5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not predict cognitive symptoms. The results suggest a dissociation between serum cortisol levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters in depression.
Introduction A major goal of biological studies in mood disorders is the identification of measures that are related, and therefore may underlie, specific elements of psychopathology. The dexamethasone suppression test (DST) has been the subject of extensive research in mood disorders. Following administration of the exogenous steroid dexamethasone, a significant percentage of depressed patients fail to show normal cortisol suppression for the next 24 hr. This finding has provided the principal evidence for hypothalamic-pituitary-adrenal axis dysfunction in mood disorders. Several studies suggest that DST nonsuppression correlates with overall measures (e.g., the Hamilton Rating Scale for Depression--HRSD total score) of the severity of depressive symptoms (Kumar et al. 1986; Whiteford et al. IO86; Whitefi~rd et al. 1987a; Meador-Woodruff et al. 1987; Mea0or-Woodruff et al.
From the Departmeatof Psychiatry and BehavioralSciences, Stanford UniversitySchool of Medicine(W.O.F., K.F.F., C.B., J.G.C.); the Veterans AdministrationMedical Center, Palo Alto, California (W.O.F., J.G.C.); and the Division of Psychiatric Services, Queensland Departmentof Health, Brisbane, Australia (H.A.W.). Address reprint requests to William O. Faustman, Ph.D., PsychologyService 116B, Veterans Admit ~ ation Medical Center, 3801 Miranda Ave., Palo Alto, CA, 94304. Received February 24, 1989; revised May 16, 1989. This azticle is in the Public Domain.
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1988). Baseline (predexamethasone) cortisol levels also may correlate with the HRSD t¢~al score (Whiteford et al. 1987a). Further work has attempted to link the DST to specific depressive symptoms and disease subtypes. Miller and Nelson (1987) suggest that DST nonsuppression is related to HRSD measure~ of vegetative symptoms such as insomnia and weight loss. A relationship between nonsuppress:.on and vegetative symptoms has also been noted by others (Nasr and Gibbons 1983; Zimmerman et al. 1986). Some investigators (Miller and Nelson 1987; Nasr and Gibbons 1983) have failed to find a relationship between "psychological" or cognitive measures (e.g., guilt, suicidal ideation) and DST nonsuppression. Two recent works (Kumar et al. 1986; Whiteford et al. 1987a) suggested that although DST nonsuppression may correlate with measures of endogeneity, the relationship is not specific as DST nonsuppression correlates even more strongly with HRSD total scores. Serotonergic dysfunction in the CNS has also been postulated to occur in depression, as assessed by cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5HIAA, the major metabolite of serotonin, 5-HT). Asberg et al. (1984) demonstrated lower CSF 5-HIAA concentrations in melancholia patients when compared with nonpsychiatric controls. Tzaskman-Bendz ct a! (1984) found al~ increase in 5-HIAA after recovery from depression. Depressed patients with low 5-HIAA have been shown to require more frequent hospitalization than depressed patients with normal 5-HIAA values, suggesting that low 5-HIAA may predict depressive episodes (van Praag 1979). Similar to research involving the DST, several works suggest a relationship between CSF 5-HIAA and the severity of depression. The exact nature of this relationship remains to be clarified, as several workers (Davis et al. 1981; Peabody et al. 1987) have found an inverse correlation between 5-HIAA and severity and one group (Roy et al. 1985) obtained a posAive correlation between 5-HIAA and symptom severity in melancholic depression. Agren (1980) has linked CSF 5-HIAA to symptom clusters derived from the Schedule for Affective Disorders and Schizophrenia (SADS). Important findings have linked lower CSF 5-HIAA concentrations to suicide attempts (Asberg et al. 1976; Stanley et al. 1982) and clinical ratings of suicidal ideation (Lopez-lbor et al. 1985; Peabody et al. 1987). h addition, CSF-HIAA concentrations have been related to suicide attempts in personality-disordered patients (Brown et al. 1982) and self-report measures of hostility in normal ~olunteers (Roy et al. 1988). In summary, a growing literature suggests a role for 5-HT mechanisms in the expression of depression and of suicidal or impulsive ideation. In the present study, we report the ability of CSF 5-HIAA, age, and serum cortisol to predict vegetative and cognitive symptom clusters of the HRSD (Rhoades and Overall 1983). Baseline (i.e., predexamethasone) cortisol measures "~ere used because they are equivalently related to the total HRSD score, and postdexamethasone measures can be confounded by age-related differences in dexamethasone pharmacokinetics (Lowy and Meltzer 1987). Prior studies at our center (Peabody et al. 1987; Whiteford et al. 1987a) separately reported bivariate DST and 5-HIAA relationships with total HRSD scores. In the present work we used a sample of patients for whom both CSF and cortisol data were available.
Method Thirty male subjects (mean age 47.3 years, SD = 11.9 years, range 26-66), inpatients at the Stanford/V.A. Men~l Health Clinical Research Center, gave written informed consent for all procedures. All raet Research Diagnostic Criteria (RDC) (Spitzer et al.
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1977) for major depression. Twenty-eight of the patients were interviewed independently by two trained diagnosticians (a research assistant and a psychiatrist or psychologist), and diagnosed by consensus. Two patients were diagnosed by a psychiatrist alone. During the diagnostic assessment, the research assistant used the Schedule for Affective Disorder~ and Schizophrenia (SADS) (Endicott and Spitzer 1978), and the others used a semistructured clinical interview. Twenty-one of the 30 patients were included in a recent bivadat~ study of CSF measures and depressive symptoms (Peabody et al. 1987). Data from I l of the 30 subjects had been reported by Whiteford et al. (1987a).
CSF and Cortisol Collection CSF and serum were collected from all 30 patients. All patients h ~ been psychotherapeutic medication free (except for occasional 500-1000 mg doses of chloral hydrate) for at least 2 weeks prior to the CSF and serum collection; the serum was collected as part of a concurrent DST study. The lumbar puncture (LP) for CSF pn~:ceded the serum collection and DST in all cases, thereby avoiding any potential effects of dexamethasone on CSF 5-HIAA. The average period of time between the LP and serum collection was 6.1 days (SD = 6.0 days, median = 4.5 days, range = 0-25). Patients fasted and remained in bed overnight before the LP, which was performed in the lateral decubitus position at approximately 8.00 AM. CSF was collected in tubes containing ascorb~e acid, frozen immediately on dry ice, and stores at -80°C until later analysis. 5-HIAA was measured by gas chromatography/mass spectrome~' (Faull et al. 1979). lntercorrelation between CSF 5-HIAA and the major metabolites of other biogenic amines (homovanillic acid, 3-methoxy-4-hydroxyphenylglycol) usually occur, and are reported elsewhere (Jipson et al. 1989). The 4:00 PM baseline (predexamethasone) serum samples were selected from the DST study for cortisol analysis. Prior studies have suggested that postdexamethasone cortisol concentrations are confounded by both dexamethasone pharmacokinetics and age (Lowy and Meltzer 1987; Whiteford et al. 1987b). Furthermore, baseline cortisol levels correlate well with total HRSD scores (Whiteford et al. 1987a). All serum samples were frozen within 30 min of being drawn, and cortisol concentrations were assayed using a commercially available radioimmunoassay (New England Nuclear, Cambridge, MA) that employs a standard double antibody procedure.
Symptom Assessment All patients were interviewed to assess their symptoms using the HRSD (Hamilton 1960). Twenty-five of the 30 patients were rated by 2 independent raters who received extensive training in the HRSD, and the scores of these 2 raters were averaged. The remaining 5 patients were rated by a single interviewer. A rating prior to the cortisol collection was selected for the purpose of data analysis, often occurring in the time period between the LP and the cortisol collection. Depressive symptoms were assessed by the vegetative and cognitive HRSD super factors developed by Rhoades and Overall (1983). These factors are comprised of the following HRSD items: (1) vegetative (sleep disturbance, diurnal variation, genital symptoms, hyochondriasis, weight loss, somatic anxiety, som_~t.'_'c~ymptoms---general and GI); and (2) cognitive (suicidal ideation, guilt, psychic anxiety, insight, paranoia, depersonalization, work/activi*.ie~, ~epressed mood, retardation, agitation).
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Table 1. Results of Multiple Regression Analysis to Predict the Vegetative and Cognitive Super Factors of the HRSD Vegetative symptom cluster Variable
Coefficient
Standard error
T
p (2-tailed)
Intercept Age Baseline cortisol CSF 5-HIAA
- 0.707 0.118 0.163 - 0.050
1.985 0.031 0.080 0.048
- 0.356 3.797 2.054 - 1.041
0.725 0.001 0.051 0.308
3.749 - 0.136 1.906 - 2.305
0.001 0.893 0.068 0.029
Cognitive symptom cluster Intercept Age Baseline cortisol CSF 5-HIAA
4.208 - 0.003 0.090 - 0.067
1.122 0.019 0.047 0.029
Analysis Techniques A multiple regression model (Winer 1971) was used to evaluate the ability of 4:00 aM serum cortisol concentration, CSF 5-HIAA concentration, and age to predict the vegetative and cognitive super factors of the HRSD.
Results A result of regression analysis to predict the vegetative and cognitive factors are shown in ,table !. The regression to predict the vegetative factor was highly significant overall (Multiple R = 0.66, F3.25 = 6.50; p - 0.002; N = 29, as 1 patient with a large studentized residual was removed from the analysis) and found that age and c,misol but not CSF 5-H!AA predicted the HRSD vegetative factor. A multiple regression to predict the cognitive factor of the HRSD yielded a Multiple R of 0.49 (N = 30; F3.26 = 2.74; p = 0.063) that narrowly failed statistical significance. Age was not related to cognitive symptoms. Both CSF 5-HIAA and cortisol were related to cognitive symptoms and CSF~IIAA was somewhat more strongly predictive. Because prior works have shown a relationship between suicidality and CSF 5-HIAA, one could speculate that the current finding of a relationship between the cognitive symptom cluster and 5-HIAA was solely due to a strong relationship between 5-HIAA and the HRSD suicide item, and that other cognitive symptoms (e.~., psychic anxiety, guilt) were unrelated to 5-HIAA. Accordingly, the multiple regression to predict the cognitive cluster was recalculated following the removal of the suicide item from *.he cluster. This procedure resulted in a diminished level of significance for the overall model with a Multiple R of 0.45 (N = 30, F3.26 -" 2.19, p = 0.114). However, CSF, 5-HIbA continued to be related to cognitive symptoms at a significant level (t = - 2 . 1 , / : = 0.048) and with greater strength than serum cortisol (t = 1.7, p :-0.107). Age continued to be unrelated to cognitive symptoms (t = -0.26, p = 0.798). A bivariate Spearman correlation analysis demonstrated that plasma cortisol and CSF 5-HIAA were not correlated (rho = 0.!02). The vegetative and cognitive symptom clusters showed a small degree of correlation (rho = 0.285) suggesting only about 8%
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of shared variance. Age was not correlated with either CSF 5-HIAA (rho = -0.017) or plasma cortisol (rho - 0.143). Discussion The data suggest that serum cortisol concentrations, age, and CSF 5-HIAA concentrations differentially predict HRSD vegetative and cognitive symptom clusters in depre~;sion. Age and baseline cortisol, but not CSF 5-HIAA, predicted vegetative symptoms. Though both cortisol and CSF 5-HIAA predicted the cognitive symptom ,:luster, 5-HIAA was a stronger predictor. Age was unrelated to the HRSD cognitive symptom cluster. The relationship between cognitive symptoms and 5-HIAA was not due solely to a cone!ation with the HRSD suicide item, as cognitive symptoms were predicted by 5-HIAA when the analysis was repeated after the removal of the suicide item from the symptom cluster. These results confirm and extend several previous works. The relationship between 5HIAA and the cognitive dimension of depression supports previous studies in both depre.~sion and other disorders (Brown et al. 1982; Asberg 1976). Several works suggest that CSF 5-HIAA is related to the severity of depression (Davis et al. 1981), the presence of suicidal urges (Lopez-lbor et al. 1985), and suicidal behavior (Asberg et al. 1976). In addition, the ability of age to predict the severity of vegetative symptoms is consistent with prior work relating aging to symptom expression in depression (Blazer 1982). Some caution should be used in the interpretation of the current results as the patients were minimally 14 days medication free at the time of participation. Some authors (e.g., Szamek et al. 1987) haee noted that detectable amounts of psychiatric medications may be present 14 days after discontinuation. Though residual medication effects may have influenced cortisol or 5-HIAA concentrations, they would not have exerted a systematic bias leading to the current findings. Certain limitations should be noted in interpreting prior studies of the inter,flationship among depression, HPA function, and CSF 5-HIAA. First: many workers analyze DST results by grouping subjects ~s either DST suppressors or nonsuppressors, rather than by directly analyzing absolute cortisol values. Not only may such a division be arbitrary, but it also results in a significant loss of statistical power (Kumar et al. 1986). Second, age has repeatedly been shown to be a major determinant of postdexamethasone cortisol levels (Lewis et al. 1984; Whiteford et al. 1987b), and should be considered when assessing relationships between symptom presentation and DST findings. Third, a majority of prior studies have correlated biological measures with either total HRSD scores or numerous HRSD it~:ms; there are disadvantage:, to both of these strategies. The use of the total score offers no information for qualitative symptom assessmel~t, whereas the use of numerous items (e.g., Miller and Nelson 19~;7) yields so many correlations so as to make interpretation and p value protection difficult. One could interpret our multiple regression findings as suggesting that HPA axis function and brain 5-HT function, at least as reflected by CSF 5-HIAA, provide different contributions to the severity and quality of symptom expression in depression. In addition, the lack of bivariate correlation between baseline cortisol and CSF 5-HIAA concentrations does not support the hypothesis that an abnormality of 5-HT function causes HPA axis dysregulation in depressed patients. However. it should be kept in mind that the contributions of HPA and brain 5-HT dysfunction to depression may be dissociated across patients, or within individual patients. Our current data cannot discriminate these two possibilities.
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Recent works have implicated the functioning of both limbic structures and frontal cortex in depression. HPA abnormalities and the vegetative dimension of depression may be derived from the dysfunction of limbic structures, in particular, the hippocampus (Greden 1987). Additionally, the effects of glucocorticoids on limbic/hippocampal function has been supported by innovative animal work (see Sapolsky et al. 1986, for a review). On the other hand, there is evidence for an abnormality of brain 5-HT function in the frontal cortex of depressed patients. Decreases in 5-HT2 receptors in the frontal cortex of suicide victims, many of whom were presumably depressed, have been noted (Stanley et al., 1982; Stanley and Mann 1983). Based on these findings, one could speculate that there are two biological dimensions of depression, one based on a limbic/hippocampal mechanism and the other based on 5-HT-related dysfunction of the frontal cortex. These two mechanisms could be differentially related to vegetative and cognitive symptom expression. In summary, our data support the idea that there may be more than one pathogenic mechanism related to depression. Cross-sectional studies of depressed patients may help decide whether or not different mechanisms exist independently in different patients, or if each patient is affected by these different mechanisms to a greater or lesser degree. However, much larger samples will be required, and cluster analytical techniques will have to be better validated. Longitudinal studies of individual patients may also be useful in that changes in CSF 5-HIAA and HPA function could be followed over the course of several depressive episodes to look for concurrent or dissociated change. Supported by grant MH-30854from the National Institute ot Mental Health to the Mental Health Clinical Research Center at Stanford University,and by the Research Serviceof the Veterans Administration.
References Agren H (1980): Symptom patterns in unipolar and bipolar depression correlating with monoamine metabolites in the cerebrospinal fluid, h General patterns. Psychiatry Res 3:211-223. Asberg M, Bertilsson L, Martensson B, Scalia-Tomba GP, Thoren P, Traskman-Bendz L (1984): CSF monamine metabolites in melancholia. Acta Psychiatr Scand 69:201-219. Asberg M, Traskman L, Thoren P (1976): 5-HIAA in the cerebrospinal fluid: A biochemical suicide predictor? Arch Gen Psychiatry 33:1193-1197. Blazer DG (1982): Depression in Late Life. St. Louis: CV Mosby Co. Brown GL, Ebert MH, Goyer PF, et al (1982): Aggression, suicide, and serotonin: Relationships to CSF amine metalr~lites. Am J Psychiatry 139:741-746. Davis KL, Hollister LE, Mathe AA, et al (1981): Neurt~endocrineand neumchemical measurements in depression. Am J Psychiatry 138:1555-f562. Endicott J, Spitzer R (1978): A diagnostic interview: A Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 35:837-844. Faull KF, Anderson PJ, Barehas JD, Berger PA (1979): Selected ion monitoring assay for biogenic amine metabolites and probenecid in human cerebmspinal fluid. Y Chromatogr 163:337-349. Greden JF (1987): The hypothalamic-pituitary-adrenal (HPA) system in depression: Paradigms and problems in research and practice. In U Halbreich (ed), Hormones and Depression. New York: Raven Press, pp 59-75. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62.
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Jipson MD, Faull KF, Csernansky JG (1989): Intercorrelation of CSF HVA, 5-HIAA, and MHPG before and after probenecid administration° Schizophr Res 2:155. Kumar A, Alcser K, Grunhaus L, Greden JF (1986): Relationships of the dexamethasone suppression test to clinical severity and degree of melancholia. Biol Psychiatry 21:436-444. Lewis DA, Pfohl B, Schlechte J, CoryeU W (1984): Influence of age on the co~isol response to dexamethasone. Psychiatry Res 13:213-220. Lopez-lbor JJ, Saiz-Ruiz J, Perez de los Cohos JC (1985): Biological correlations of suicide and aggresivity in major depressions (with melancholia): 5-Hydroxyindoleacetic acid and cortisol in cerebral spinal fluid, dexamethasone suppression test and therapeutic response to 5-hydroxytryptophan. Neuropsychobiology 14:67-74. Lowy MT, Meltzer HY (1987): Dexamethasone bioavailability: Implications for DST research. Biol Psychiatry 22:373-385. Meador-Woodruff JH, Greden JF, Grunhaus L, Haskett RF (1988): Dexamethasone suppression test and seveEty of depression. Biol Psychiatry 24:693-696. Meador-Woodruff JH, Haskett RF, Grunhaus L, Akil H, Watson SJ, Greden JF (1987): Postdexamethasone plasma cortisol and IB-endorphin levels in depression: Relationship to severity of illness. Biol Psychiatry 22:1137-1150. Miller KB, Nelson C (1987): Does the dexamethasone suppression test relate to subtypes, factors, symptoms, or severity? Arch Gen Psychiatry 44:769-774. Nasr SJ, Gibbons RD (1983): Depressive symptoms associated with dexamethasone resistance. Psychiatry Res 10:183-189. Peabody CA, Faull KF, King RJ, Whiteford HA, Barchas JD, Berger PA (1987): CSF amine metabolites and depression. Psychiatry Res 21:1-7. Rhoades HM, Overall JE (1983): The Hamilton Depression Scale: Factor scoring and profile classification. Psychopharm Bull 19:91-96. Roy A, Adinoff B, Linnoila M (1988): Acting out hostility in normal volunteers: Negative correlation with levels of 5-HIAA in cerebrospinal fluid. Psychiatry Res 24:187-194. Roy A, Pickar D, Linnoila M, Doran AR, Ninan P, Paul SM (1985): Cerebrospinal fluid monoamine and monoamine metabolite concentrations in melancholia. Psychiatry Res 15:281-292. Sapolsky RM, Krey LC, McEwen BS (1986): The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocr ltev 7:284-301. Spitzer RL, Endicott J, Robins E (1977): Research Diagnostic Criteria for a Selected Group of Functional Disorders. New York: New York State Psychiatric Institute. Sramek J, Herrera J, Costa J, Heh C (1987): Persistence of plasma neuroleptic levels after drvg discontinuation. J Clin Psychopharmacol 7:436-437. Stanley M, Mann JJ (1983): Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet 2:214-216. Stanley M, Virgilio J, Gershon S (1982): Tritiate~! imipramine binding sites are decreased in the frontal cortex of suicides. Science 216:1337-1339. Traskman-Bendz L, As~erg M, Bertilsson L, Thoren P (1984): CSF monoamine metabolites of depressed patients d~mng illness and after recovery. Acta Psychiatr Scand 69:333-342. van Praag HM Haan de S (1979): Central serotonin metabolism and frequency of depression. Psychiatry Res 1:219-224 Whiteford HA, Peabody CA, Csemansky JG, Berger PA (1986): The severity of depression and nonsuppression on the DST. Am J Psychiatry 143:1634-1635. Whiteford HA, Peabody CA, Csemansky JG, Warner MD, Berger PA (1987a): E!evated baseline and postdexamethasone cortisol levels: A reflection of se~e~i~y :a-~e.~geaeity? J Affect Dis 12:199-202. Whiteford HA, Peabody CA, Thiemann S, Kraemer HC, Csemansky JG, Berger PA (1987b): The
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effect of age on baseline and postdexamethasone cortisol levels in major depressive disorder.
Biol Psychiatry 22:1029-.1032. Winer BJ (1971): Statistical Principles in Exl~erimental Design New York: Mcgraw-Hill. Zimmerman M, Coryell W, Pfohl B (1986): The validity of the dexamethasone suppression test as a marker for endogenous depression. Arch Gen Psychiatry 43:347-355.
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CSF 5-HIAA, Serum Cortisol, and Age Differentially Predict Vegetative and Cognitive Symptoms in Depression Williarn O. Faustman, Kym F. Faull, Harvey A. Whiteford, Catherine Borchert, and John G. Csernansky
Prior studies have shown that both cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA) and serum cortisel levels are related to overall symptom severity in depression. In the present study, 30 unmedicated inpatients meeting Research Diagnostic Criteria (RDC) criteria for depression participuted in serum cortisol collection and a lumbar puncture for CSF. A multiple regression evaluated the ability of CSF 5HIAA, serum cortisol, and age to predict cognitive and vegetative symptom clusters of the Homilton Rating Scalefor Depression. The multiple regression to predict the vegetative symptom cluster was highly significant overall (p = 0.002) and found that age and cortisol but not 5-HIAA predicted vegetative symptoms. The regression to predict the cognitive cluster narrowly missed overall sign~cance (p = 0.06). Both CSF 5-HIAA and serum cortisol predicted cognitive symptoms and 5-HIAA predicted the cognitive cluster more strongly than cortisol. Age did not predict cognitive symptoms. The results suggest a dissociation between serum cortisol levels and CSF 5-HIAA in predicting vegetative and cognitive symptom clusters in depression.
Introduction A major goal of biological studies in mood disorders is the identification of measures that are related, and therefore may underlie, specific elements of psychopathology. The dexamethasone suppression test (DST) has been the subject of extensive research in mood disorders. Following administration of the exogenous steroid dexamethasone, a significant percentage of depressed patients fail to show normal cortisol suppression for the next 24 hr. This finding has provided the principal evidence for hypothalamic-pituitary-adrenal axis dysfunction in mood disorders. Several studies suggest that DST nonsuppression correlates with overall measures (e.g., the Hamilton Rating Scale for Depression--HRSD total score) of the severity of depressive symptoms (Kumar et al. 1986; Whiteford et al. IO86; Whitefi~rd et al. 1987a; Meador-Woodruff et al. 1987; Mea0or-Woodruff et al.
From the Departmeatof Psychiatry and BehavioralSciences, Stanford UniversitySchool of Medicine(W.O.F., K.F.F., C.B., J.G.C.); the Veterans AdministrationMedical Center, Palo Alto, California (W.O.F., J.G.C.); and the Division of Psychiatric Services, Queensland Departmentof Health, Brisbane, Australia (H.A.W.). Address reprint requests to William O. Faustman, Ph.D., PsychologyService 116B, Veterans Admit ~ ation Medical Center, 3801 Miranda Ave., Palo Alto, CA, 94304. Received February 24, 1989; revised May 16, 1989. This azticle is in the Public Domain.
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1988). Baseline (predexamethasone) cortisol levels also may correlate with the HRSD t¢~al score (Whiteford et al. 1987a). Further work has attempted to link the DST to specific depressive symptoms and disease subtypes. Miller and Nelson (1987) suggest that DST nonsuppression is related to HRSD measure~ of vegetative symptoms such as insomnia and weight loss. A relationship between nonsuppress:.on and vegetative symptoms has also been noted by others (Nasr and Gibbons 1983; Zimmerman et al. 1986). Some investigators (Miller and Nelson 1987; Nasr and Gibbons 1983) have failed to find a relationship between "psychological" or cognitive measures (e.g., guilt, suicidal ideation) and DST nonsuppression. Two recent works (Kumar et al. 1986; Whiteford et al. 1987a) suggested that although DST nonsuppression may correlate with measures of endogeneity, the relationship is not specific as DST nonsuppression correlates even more strongly with HRSD total scores. Serotonergic dysfunction in the CNS has also been postulated to occur in depression, as assessed by cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5HIAA, the major metabolite of serotonin, 5-HT). Asberg et al. (1984) demonstrated lower CSF 5-HIAA concentrations in melancholia patients when compared with nonpsychiatric controls. Tzaskman-Bendz ct a! (1984) found al~ increase in 5-HIAA after recovery from depression. Depressed patients with low 5-HIAA have been shown to require more frequent hospitalization than depressed patients with normal 5-HIAA values, suggesting that low 5-HIAA may predict depressive episodes (van Praag 1979). Similar to research involving the DST, several works suggest a relationship between CSF 5-HIAA and the severity of depression. The exact nature of this relationship remains to be clarified, as several workers (Davis et al. 1981; Peabody et al. 1987) have found an inverse correlation between 5-HIAA and severity and one group (Roy et al. 1985) obtained a posAive correlation between 5-HIAA and symptom severity in melancholic depression. Agren (1980) has linked CSF 5-HIAA to symptom clusters derived from the Schedule for Affective Disorders and Schizophrenia (SADS). Important findings have linked lower CSF 5-HIAA concentrations to suicide attempts (Asberg et al. 1976; Stanley et al. 1982) and clinical ratings of suicidal ideation (Lopez-lbor et al. 1985; Peabody et al. 1987). h addition, CSF-HIAA concentrations have been related to suicide attempts in personality-disordered patients (Brown et al. 1982) and self-report measures of hostility in normal ~olunteers (Roy et al. 1988). In summary, a growing literature suggests a role for 5-HT mechanisms in the expression of depression and of suicidal or impulsive ideation. In the present study, we report the ability of CSF 5-HIAA, age, and serum cortisol to predict vegetative and cognitive symptom clusters of the HRSD (Rhoades and Overall 1983). Baseline (i.e., predexamethasone) cortisol measures "~ere used because they are equivalently related to the total HRSD score, and postdexamethasone measures can be confounded by age-related differences in dexamethasone pharmacokinetics (Lowy and Meltzer 1987). Prior studies at our center (Peabody et al. 1987; Whiteford et al. 1987a) separately reported bivariate DST and 5-HIAA relationships with total HRSD scores. In the present work we used a sample of patients for whom both CSF and cortisol data were available.
Method Thirty male subjects (mean age 47.3 years, SD = 11.9 years, range 26-66), inpatients at the Stanford/V.A. Men~l Health Clinical Research Center, gave written informed consent for all procedures. All raet Research Diagnostic Criteria (RDC) (Spitzer et al.
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1977) for major depression. Twenty-eight of the patients were interviewed independently by two trained diagnosticians (a research assistant and a psychiatrist or psychologist), and diagnosed by consensus. Two patients were diagnosed by a psychiatrist alone. During the diagnostic assessment, the research assistant used the Schedule for Affective Disorder~ and Schizophrenia (SADS) (Endicott and Spitzer 1978), and the others used a semistructured clinical interview. Twenty-one of the 30 patients were included in a recent bivadat~ study of CSF measures and depressive symptoms (Peabody et al. 1987). Data from I l of the 30 subjects had been reported by Whiteford et al. (1987a).
CSF and Cortisol Collection CSF and serum were collected from all 30 patients. All patients h ~ been psychotherapeutic medication free (except for occasional 500-1000 mg doses of chloral hydrate) for at least 2 weeks prior to the CSF and serum collection; the serum was collected as part of a concurrent DST study. The lumbar puncture (LP) for CSF pn~:ceded the serum collection and DST in all cases, thereby avoiding any potential effects of dexamethasone on CSF 5-HIAA. The average period of time between the LP and serum collection was 6.1 days (SD = 6.0 days, median = 4.5 days, range = 0-25). Patients fasted and remained in bed overnight before the LP, which was performed in the lateral decubitus position at approximately 8.00 AM. CSF was collected in tubes containing ascorb~e acid, frozen immediately on dry ice, and stores at -80°C until later analysis. 5-HIAA was measured by gas chromatography/mass spectrome~' (Faull et al. 1979). lntercorrelation between CSF 5-HIAA and the major metabolites of other biogenic amines (homovanillic acid, 3-methoxy-4-hydroxyphenylglycol) usually occur, and are reported elsewhere (Jipson et al. 1989). The 4:00 PM baseline (predexamethasone) serum samples were selected from the DST study for cortisol analysis. Prior studies have suggested that postdexamethasone cortisol concentrations are confounded by both dexamethasone pharmacokinetics and age (Lowy and Meltzer 1987; Whiteford et al. 1987b). Furthermore, baseline cortisol levels correlate well with total HRSD scores (Whiteford et al. 1987a). All serum samples were frozen within 30 min of being drawn, and cortisol concentrations were assayed using a commercially available radioimmunoassay (New England Nuclear, Cambridge, MA) that employs a standard double antibody procedure.
Symptom Assessment All patients were interviewed to assess their symptoms using the HRSD (Hamilton 1960). Twenty-five of the 30 patients were rated by 2 independent raters who received extensive training in the HRSD, and the scores of these 2 raters were averaged. The remaining 5 patients were rated by a single interviewer. A rating prior to the cortisol collection was selected for the purpose of data analysis, often occurring in the time period between the LP and the cortisol collection. Depressive symptoms were assessed by the vegetative and cognitive HRSD super factors developed by Rhoades and Overall (1983). These factors are comprised of the following HRSD items: (1) vegetative (sleep disturbance, diurnal variation, genital symptoms, hyochondriasis, weight loss, somatic anxiety, som_~t.'_'c~ymptoms---general and GI); and (2) cognitive (suicidal ideation, guilt, psychic anxiety, insight, paranoia, depersonalization, work/activi*.ie~, ~epressed mood, retardation, agitation).
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Table 1. Results of Multiple Regression Analysis to Predict the Vegetative and Cognitive Super Factors of the HRSD Vegetative symptom cluster Variable
Coefficient
Standard error
T
p (2-tailed)
Intercept Age Baseline cortisol CSF 5-HIAA
- 0.707 0.118 0.163 - 0.050
1.985 0.031 0.080 0.048
- 0.356 3.797 2.054 - 1.041
0.725 0.001 0.051 0.308
3.749 - 0.136 1.906 - 2.305
0.001 0.893 0.068 0.029
Cognitive symptom cluster Intercept Age Baseline cortisol CSF 5-HIAA
4.208 - 0.003 0.090 - 0.067
1.122 0.019 0.047 0.029
Analysis Techniques A multiple regression model (Winer 1971) was used to evaluate the ability of 4:00 aM serum cortisol concentration, CSF 5-HIAA concentration, and age to predict the vegetative and cognitive super factors of the HRSD.
Results A result of regression analysis to predict the vegetative and cognitive factors are shown in ,table !. The regression to predict the vegetative factor was highly significant overall (Multiple R = 0.66, F3.25 = 6.50; p - 0.002; N = 29, as 1 patient with a large studentized residual was removed from the analysis) and found that age and c,misol but not CSF 5-H!AA predicted the HRSD vegetative factor. A multiple regression to predict the cognitive factor of the HRSD yielded a Multiple R of 0.49 (N = 30; F3.26 = 2.74; p = 0.063) that narrowly failed statistical significance. Age was not related to cognitive symptoms. Both CSF 5-HIAA and cortisol were related to cognitive symptoms and CSF~IIAA was somewhat more strongly predictive. Because prior works have shown a relationship between suicidality and CSF 5-HIAA, one could speculate that the current finding of a relationship between the cognitive symptom cluster and 5-HIAA was solely due to a strong relationship between 5-HIAA and the HRSD suicide item, and that other cognitive symptoms (e.~., psychic anxiety, guilt) were unrelated to 5-HIAA. Accordingly, the multiple regression to predict the cognitive cluster was recalculated following the removal of the suicide item from *.he cluster. This procedure resulted in a diminished level of significance for the overall model with a Multiple R of 0.45 (N = 30, F3.26 -" 2.19, p = 0.114). However, CSF, 5-HIbA continued to be related to cognitive symptoms at a significant level (t = - 2 . 1 , / : = 0.048) and with greater strength than serum cortisol (t = 1.7, p :-0.107). Age continued to be unrelated to cognitive symptoms (t = -0.26, p = 0.798). A bivariate Spearman correlation analysis demonstrated that plasma cortisol and CSF 5-HIAA were not correlated (rho = 0.!02). The vegetative and cognitive symptom clusters showed a small degree of correlation (rho = 0.285) suggesting only about 8%
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of shared variance. Age was not correlated with either CSF 5-HIAA (rho = -0.017) or plasma cortisol (rho - 0.143). Discussion The data suggest that serum cortisol concentrations, age, and CSF 5-HIAA concentrations differentially predict HRSD vegetative and cognitive symptom clusters in depre~;sion. Age and baseline cortisol, but not CSF 5-HIAA, predicted vegetative symptoms. Though both cortisol and CSF 5-HIAA predicted the cognitive symptom ,:luster, 5-HIAA was a stronger predictor. Age was unrelated to the HRSD cognitive symptom cluster. The relationship between cognitive symptoms and 5-HIAA was not due solely to a cone!ation with the HRSD suicide item, as cognitive symptoms were predicted by 5-HIAA when the analysis was repeated after the removal of the suicide item from the symptom cluster. These results confirm and extend several previous works. The relationship between 5HIAA and the cognitive dimension of depression supports previous studies in both depre.~sion and other disorders (Brown et al. 1982; Asberg 1976). Several works suggest that CSF 5-HIAA is related to the severity of depression (Davis et al. 1981), the presence of suicidal urges (Lopez-lbor et al. 1985), and suicidal behavior (Asberg et al. 1976). In addition, the ability of age to predict the severity of vegetative symptoms is consistent with prior work relating aging to symptom expression in depression (Blazer 1982). Some caution should be used in the interpretation of the current results as the patients were minimally 14 days medication free at the time of participation. Some authors (e.g., Szamek et al. 1987) haee noted that detectable amounts of psychiatric medications may be present 14 days after discontinuation. Though residual medication effects may have influenced cortisol or 5-HIAA concentrations, they would not have exerted a systematic bias leading to the current findings. Certain limitations should be noted in interpreting prior studies of the inter,flationship among depression, HPA function, and CSF 5-HIAA. First: many workers analyze DST results by grouping subjects ~s either DST suppressors or nonsuppressors, rather than by directly analyzing absolute cortisol values. Not only may such a division be arbitrary, but it also results in a significant loss of statistical power (Kumar et al. 1986). Second, age has repeatedly been shown to be a major determinant of postdexamethasone cortisol levels (Lewis et al. 1984; Whiteford et al. 1987b), and should be considered when assessing relationships between symptom presentation and DST findings. Third, a majority of prior studies have correlated biological measures with either total HRSD scores or numerous HRSD it~:ms; there are disadvantage:, to both of these strategies. The use of the total score offers no information for qualitative symptom assessmel~t, whereas the use of numerous items (e.g., Miller and Nelson 19~;7) yields so many correlations so as to make interpretation and p value protection difficult. One could interpret our multiple regression findings as suggesting that HPA axis function and brain 5-HT function, at least as reflected by CSF 5-HIAA, provide different contributions to the severity and quality of symptom expression in depression. In addition, the lack of bivariate correlation between baseline cortisol and CSF 5-HIAA concentrations does not support the hypothesis that an abnormality of 5-HT function causes HPA axis dysregulation in depressed patients. However. it should be kept in mind that the contributions of HPA and brain 5-HT dysfunction to depression may be dissociated across patients, or within individual patients. Our current data cannot discriminate these two possibilities.
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Recent works have implicated the functioning of both limbic structures and frontal cortex in depression. HPA abnormalities and the vegetative dimension of depression may be derived from the dysfunction of limbic structures, in particular, the hippocampus (Greden 1987). Additionally, the effects of glucocorticoids on limbic/hippocampal function has been supported by innovative animal work (see Sapolsky et al. 1986, for a review). On the other hand, there is evidence for an abnormality of brain 5-HT function in the frontal cortex of depressed patients. Decreases in 5-HT2 receptors in the frontal cortex of suicide victims, many of whom were presumably depressed, have been noted (Stanley et al., 1982; Stanley and Mann 1983). Based on these findings, one could speculate that there are two biological dimensions of depression, one based on a limbic/hippocampal mechanism and the other based on 5-HT-related dysfunction of the frontal cortex. These two mechanisms could be differentially related to vegetative and cognitive symptom expression. In summary, our data support the idea that there may be more than one pathogenic mechanism related to depression. Cross-sectional studies of depressed patients may help decide whether or not different mechanisms exist independently in different patients, or if each patient is affected by these different mechanisms to a greater or lesser degree. However, much larger samples will be required, and cluster analytical techniques will have to be better validated. Longitudinal studies of individual patients may also be useful in that changes in CSF 5-HIAA and HPA function could be followed over the course of several depressive episodes to look for concurrent or dissociated change. Supported by grant MH-30854from the National Institute ot Mental Health to the Mental Health Clinical Research Center at Stanford University,and by the Research Serviceof the Veterans Administration.
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