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Catecholamine metabolism and affective disorders: Studies of MHPG excretion
CATECHOLAMINE METABOLISM AND AFFECTIVE DISORDERS: STUDIES OF MHPG EXCRETION JOSEPH J. SCHILDKRAUT Neuropsychopharmacology Laboratory, Massachusetts Mental Health Center, Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, U.S.A. STUDIES
of catecholamine metabolism in affective disorders (depressions and manias) have been one of the more productive areas of investigation in biological psychiatry during the past decade (SCHILDKRAUT, 1965, 1970; BUNNEY and DAVIS, 1965). Since the literature in this field has been reviewed recently (SCHILDKRAUT, 1973a), and because of space limitations, this paper will not provide another comprehensive review. Instead, I shall summarise aspects of our ongoing research in this area, focusing on recent studies of the urinary excretion of 3-methoxy-Chydroxyphenylglycol (MHPG), a metabolite of norepinephrine which may provide some index of the synthesis and metabolism of norepinephrine in the brain (SCHANBERG et al., 1968a, b; MAAS and LANDIS, 1968; MAAS et al., 1972a).* In one aspect of our research we have examined the changes in MHPG excretion which were associated with changes in affective state. The findings from our longitudinal studies of individual patients with naturally occurring or amphetamineinduced manic-depressive episodes indicate that levels of urinary MHPG are relatively lower during depressions and higher during manic or hypomanic episodes than after clinical remissions (GREENSPAN et al., 1970; SCHILDKRAUT et al., 1971, 1972b), and these findings have been confirmed by other investigators (BOND et al., 1972; JONES et al., 1973b) but not by all (BUNNEY et al., 1972). The relationship between MHPG excretion and clinical state that we have observed in manic-depressive patients, is illustrated in Table 1, which summarises the changes in MHPG excretion in a manicdepressive patient studied longitudinally through 5 successive periods which were defined by differences in clinical state. However, all depressed patients do not excrete comparably low levels of MHPG, and recent preliminary findings have suggested that MHPG excretion may provide a biological criterion for classifying the depressive disorders and for predicting the responses to specific forms of antidepressant pharmacotherapy (MAAS et al., 1968, 1972b; SCHILDKRAUT et al., 1972a; SCHILDKRAUT, 1973b). For example, in a preliminary study of a small group of depressed patients, we observed favorable responses to treatment with amitriptyline in depressed patients with relatively higher levels of urinary MHPG but not in patients with lower levels of MHPG (SCHILDKRAUT, 1973b).
In order to explore further the relationship between MHPG excretion and the clinical classification of depressive disorders, we recently compared the urinary excretion of MHPG in a small group of patients (6 men and 6 women) with various * While urinary MHPG may also derive, in part, from the peripheral sympathetic nervous system as well as the brain, recent studies in non-human primates suggest that an appreciable fraction of urinary MHPG may derive from norepinephrine originating in the brain (MAAS el al., 1972a).
977
JOSEPH J. SCHILDKRAUT TABLE 1. MHPG EXCRETIONAND AFFECTIVESTATEIN A MANIC-DEPRESSIVE PATIENT
Clincial state* Mildly depressed
Treatment None
Nt
MHPG @g/day)
5
1284 & 76
P$
MHPG &g/g treat.) 966 f 72
<0.05 Very depressed
None
4
PS
<0.05
817 f 176
609 & 105 <0.05
Decreasing depression
ECT
12
999 f 78
897 k 63
Mildly hypomanic
None
4
1500*70
1386 f 59
Mildly depressed
None
5
1384 f 58
1117 f 38
MHPG
EXCRETION
IN DEPRESSIVE
DISORDERS
2500 1
i250
2500
1250
0
SCHlZOAFFECTlVE
YANIC-
RECURRENT
CHRONIC
DEPRESSIVE
ENDOGENOUS
CRARACTEROL06lCAL
FIG. I.-MHPG excretion in depressive disorders. MHPG was determined in 3-10 separate 24-hr urine samples from each patient. These individual values were averaged to obtain an overall value for each subject; this value was then used in computing the means and standard errors of the means for the two groups (manic depressive and According to our diagnostic criteria chronic characterological depressions). SCHILDKRAUT, 1970 three of the patients with chronic characterological depressions and one of the patients with manic-depressive depressions had signs and symptoms suggesting possible involutional depressive syndr0mesd.g. agitation, somatic preoccupation, guilt, and paranoid ideation. and chronic *P < 0.05, **P < 0.02 for difference between manic-depressive characterological depressions. (Reproduced with permission from SCHILDKRAUTJ. J. K~ELERB. A., GRAB E. L., QNTROWICH J., HARWNN E. MHPG Excretion and Clinical Classification in Depressive Disorders, Lancer, 1973).
Catecholamine
metabolism
and affective disorders:
Studies of MHPG excretion
979
clinically defined subtypes of depressive disorders* studied in hospital prior to treatment during drug free periods, and we examined our findings for possible relationships between urinary MHPG excretion and clinical measures of motor activity and anxiety (SCHILDKRAUTet al., 1973a, b). As shown in Fig. 1, MHPG excretion was significantly lower in 5 patients with manic-depressive depressions (i.e., bipolar disorders with histories of hypomanias or manias) than in 5 patients with chronic characterological depressions (i.e. dysphoric depressive syndromes with no history of hypomania or mania). In a patient with a schizoaffective depression, MHPG excretion was lower than the mean for the manic-depressive depressions, while in a patient with a recurrent endogenous depression (but no history of hypomania or mania) MHPG excretion fell between the means for manic-depressive and chronic characterological depressions. These differences in MHPG excretion may be related to the recent observations of other investigators that platelet monoamine oxidase activity was decreased in patients with bipolar affective disorders as well as schizophrenias but relatively increased in other types of depressive disorders (MURPHY and WYATT, 1972; MURPHY and WEISS, 1972; NIES et al., 1971). We also measured the urinary excretion of norepinephrine, normetanephrine, epinephrine, metanephrine and 3-methoxy-4-hydroxymandelic acid (VMA) in these patients. As indicated in Table 2, the urinary excretion of norepinephrine tended to be lower in manic-depressive than in chronic characterological depressions, but this difference was not statistically significant. There were no differences in normetanephrine, epinephrine, metanephrine or VMA excretion between these two groups. Thus, of the urinary catecholamines and metabolites that we measured, only MHPG showed significant differences when values in the manic-depressive and chronic characterological depressions were compared (Table 2). A correlation (of borderline statistical significance) between MHPG excretion and age was observed in the total group of 12 depressed patients. However, this may be related to the fact that the manic-depressives tended to be younger than the patients with chronic characterological depressionst, since other investigators found no correlation between MHPG excretion and age in a series of control subjects (DEKIRMENJIAN and MAAS, 1973). TABLET. EXCRETIONOPCATECHOLAMINESAND METAROLITESINMANICDEPRESSIVE AND CHRONIC CI-IARACTEROLOGICALDEPRESSIONS
Manic-dep. Norepinephrine* Normetanephrine* Epinephrine’ Metanephrine* VMA* MHPG*
21 * 180 f 10 f 190 k 3700 f 1240 *
5 30 2 30 310 160
Chron. char. dep.
P
36f 11 200 f 50 9I!c3 160 * 30 3590 & 230 1800 & 90
NS NS NS NS NS < 0.02
See caption to Fig. 1. * Expressed as means f S.E.M.in pg per day. * The clinical criteria used in the classification of the depressive disorders have been described previously (SCHILDKRAUT, 1970). t A s’milar difference in age has been noted in other studies, and may be explained by the fact that the age of onset is lower for manic-depressive disorders (bipolar) than for other types of depressive disorders (unipolar) (WINOKUR ef al.,1969).
980
JOSEPHJ. SCHILDKRAUT
Because it has been suggested recently that differences in physical activity or stress could conceivably account for the differences in MHPG excretion observed in patients with affective disorders (EBERT et al., 1972; MAAS er al., 1971; RUBIN et al., 1972), we examined our data in several different ways for possible relationships between MHPG excretion and clinical assessments of motor activity and anxiety as reflected by scores on a modified Hamilton Depression Rating Scale (HAMILTON, 1960). As shown in Table 3, there were no significant differences in scores for retardation, agitation and psychic or somatic anxiety between the manic-depressive and chronic characterological depressions. Moreover, when the entire group of 12 depressed patients were subdivided into the 4 with lowest, the 4 with intermediate and the 4 with highest scores on each of these items, no corresponding differences in MHPG excretion emerged (Tables 4 and 5). There were also no meaningful correlations between MHPG excretion and scores for retardation, agitation and psychic TABLE 3. HAMILTON DEPRESSIONRATING SCALE ITEMSIN MANICDEPRESSIVE AND CHRONIC CHARACTEROLOGICAL DEPRESSIONS
Hamilton item
Manic-dep.
Retardation Agitation Anxiety (Psychic) Anxiety (Somatic)
0.75 1.01 2.50 0.80
TABLE 4. MHPG WITH
A.
LOW
* * i &
0.59 1.20 244 1.08
0.28 0.17 0.15 0.34
EXCRETIONIN
AND
HIGH
Retardation
* 0.20 f ,0.06 & 0.18 i 0.42
DEPRESSIVE
RETARDATION
H.D.R.S.*
N.S. N.S. N.S. N.S.
DISORDERS
OR AGITATION
Score
0.21 + 0.09 0.49 + 0.03 1.24 i 0.10
Low (N = 4) Middle (N = 4) High (N = 4)
P
Chron. char. dep.
MHPG (!tg/day) 1510 i 280 1290 f 180 1620 i It0 MHPG
B.
Agitation
H.D.R.S.*
0.77 f 0.10 1.16 * 0.01 1.44 i 0.06
Low (N = 4) Middle (N = 4) High (N = 4) * H.D.R.S. TABLE
5.
Score
= Hamilton Depression
MHPG WITH
EXCRETION LOW
A. Anxiety (Psychic) Low (N = 4) Middle (N = 4) High (N = 4)
AND
IN HIGH
H.D.R.S.*
&/day) 1510 f 150 1510 f 70 1390 i. 360
Rating Scale
DEPRESSIVE
DISORDERS
ANXIETY
Score
2.11 5 0.01 2.40 j, 0.12 2.83 + 0.07
MHPG (pg/day) 1510 & 140 1400 * 210 1500 f 290 MHPG
B. Anxiety (Somatic) Low (N = 4) Middle (N = 4) High (N = 4) * H.D.R.S.
H.D.R.S.*
Score
0.22 i 0.08 0.83 & 0.15 1.83 2 0.17
= Hamilton Depression
@g/day) 1440 + 120 1460 * 200 1510 f 320
Rating Scale
Catecholamine
metabolism
and effective disorders:
Studies of MHPG excretion
981
TABLE 6. CORRELATIONS BETWEEN HAMILTON DEPRESSION RATING SCALE AND ITEMS MHPG EXCRETION
Hamilton item
Retardation Agitation Anxiety (Psychic) Anxiety (Somatic)
Correlation coefficient
0.24 -0.19 -0.19 0.11
P
N.S. N.S. N.S. N.S.
or somatic anxiety (Table 6). Other investigators have recently made similar observations concerning the absence of an association between MHPG excretion and marked retardation or agitation in depressed patients (JONES et al., 1973a). These findings thus provide no support for the suggestion that differences in MHPG excretion in patients with affective disorders reflect only differences in activity or stress. In interpreting these data, one cannot exclude the possibility that these Hamilton Depression Rating Scale items were not specific or sensitive enough to detect differences in retardation, agitation or anxiety which may have been related to MHPG excretion. However, this possibility is weakened by the fact that we did observe meaningful relationships between several of these Hamilton Depression Rating Scale items and certain other biochemical variables. For example, patients with high scores on retardation excreted significantly less epinephrine and tended to excrete less metanephrine than patients with low retardation scores, whereas patients with high scores on somatic anxiety excreted significantly more metanephrine than did patients with low scores on this item. In collaboration with Dr. Ernest Hartmann, we also examined the relationship of MHPG excretion, in these depressed patients, to certain aspects of central nervous system activity as reflected by all-night electroencephalographic sleep recordings. We were particularly interested in the relationship between MHPG excretion and the amount of time spent in desynchronised-i.e., REM-sleep (D-time), since pharmacological studies in animals and man suggest that there may be an inverse relationship between central catecholaminergic activity and D-time (HARTMANN, 1970; HARTMANN et al., 1971a, b; WYATT, 1972; KUPFER and BOWERS, 1972), although this has not been confirmed in all studies (JOUVET, 1968; KING, 1971). As shown in Table 7, when the data from the total group of 12 depressed patients were examined, there were no statistically significant correlations between MHPG excretion and total sleep time or slow-wave sleep time. However, a statistically significant inverse correlation was observed between MHPG excretion and D-time. When the subgroups of depressive disorders were examined separately the inverse correlation between MHPG excretion and D-time was high and significant in the TABLET. CORRELATIONSBETWEEN MHPG EXCRETION AND SLEEP MEASURES IN DEPRESSIVE DISORDERS
Sleep measure Total sleep Slow wave sleep D-Time
Correlation coefficient -0.35 -0.15 -0.66
P
N.S. N.S. <0.02
982
JOSEPH J. SCHILDKRAUT
patients with manic-depressive depressions. In addition, MHPG excretion was higher and D-time was lower in two patients studied during hypomanic episodes than in any of the patients with manic-depressive disorders studied during depressive episodes (SCHILDKRAUT et al., 1973b). Taken in conjunction with pharmacological observations that have suggested an inverse relationship between D-time and central catecholaminergic activity, these findings appear to support the view that MHPG excretion may reflect central noradrenergic activity, particularly in patients with manic-depressive disorders. In summary, during several longitudinal studies of individual patients we have observed that MHPG excretion was higher during hypomanias or manias, intermediate during well intervals and lower during depressions in patients with naturally occurring or amphetamine-induced manic-depressive disorders. Moreover, in a recent cross-sectional comparison of a small group of patients with various clinically defined subtypes of depressive disorders examined prior to treatment with antidepressant drugs or electroconvulsive therapy, we observed that MHPG excretion was significantly lower in patients with manic-depressive depressions than in patients with chronic characterological depressions. MHPG excretion did not appear to be related to the degree of retardation, agitation or anxiety in these depressed patients; but MHPG excretion was inversely related to the time spent in desynchronised-i.e. REM-sleep (D-time), particularly in the patients with manic-depressive disorders. In the aggregate, these findings provide further evidence that alterations in central norepinephrine metabolism may be of importance in the underlying pathophysiology of at least some types of depressive disorders. Moreover, these findings suggest that MHPG excretion may provide a clinically useful biochemical criterion for classifying the depressive disorders and possibly also for predicting responses to specific forms of antidepressant pharmacotherapy. work was supported in part by USPHS National Institute of Mental Health.
Acknowledgements--This
Grant No. MH 15,413 from the
REFERENCES P. A., JENNER F. A. and SAMPSONG. A. (1972) Psychological Med. 2,&U-85. BUNNEY W. E., JR. and DAVIS J. M. (1965) Archs. Gem Psychiat. 13,483-494. BUNNEY W. E., JR., GOODWIN F. K., MURPHY D. L., HOUSE K. M. and GO-N BOND
E. K. (1972)
Archs. Gem Psychiat. 27, 304-309. DEKIRMENJIANH. and MAAS J. W. (1973) presented at the AMU~I Meeting, American Psychiatric Association, Honolulu, May, 1973. EBERT M. H., POST R. M. and GOODWINF. K. (1972) Lancer II, 766. GREENSPANK., SCHILDKRAIJTJ. J., GORWN E. K., BAER L., ARONOFFM. S. and DURELL J. (1970.
J. Psychiat. Res. 7, 171-183. HAMILTONM. (1960) J. Neural. Neurosurg. Psychiat. 23,56-62. HARTMANNE. (1970) In: Sleep and Dreaming. (E. HARTMANN,Ed.) pp. 308-328, Little, Brown & Co., Boston. HARTMANNE., BRIDWELL T. J. and SCHILDKRAUTJ. J. (1971a) Psychopharmacologia @xl.) 21, 157-164. HARTMANNE.. CHUNG R.. DRASK~CZY P. R. and SCHILDKRAUTJ. J. (1971b) Nature. Lond. 233.
425-427. JONES F. D., DEKIRMENJIANH. and MAAS J. W. (1973a) presented at the annual meeting of the American Psychosomatic Society, Denver, Colorado, April, 1973. JONES F. D., MAAS J. W., DEKIRMENJIANH. and FAWCE~ J. A. (1973b) Science 179,300-302. JOUVET M. (1968) Science 163. 3241. KING C. D. (197i) Adu. Pharmacol. & Chemother. 9, 1-91. KUFTER D. J. and BOWERS M. B., JR. (1972) Psychopharmacologia (Berl.) 27, 183-240. MAAS J. W. and LANDIS D. H. (1968) J. Pharmacol. Exp. Ther. 163, 147-162.
Catecholamine
metabolism and affective disorders:
Studies of MHPG excretion
MAAS J. W., FAWCE~ J. A., DEKIRMENJUN H. (1968) Archs. Gen. Psych&. 19, 129-134. MAAS J. W., DEKIRMENJIANH. and FAWCIYIT J. (1971) Nature, Lond. 230, 330-331. MAAS J. W., DEKIRMENJIANH., GARVER D.. REDMONDD. E,. JR. and LANDIS H. D. (1972a)
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Res. 41, iO7-511. MAAS J. W., FAWC~ J. A. and DEKIRMENJIANH. (1972b) Archs. Gen. Psychiut. 26,252-262. MURPHY D. L. and WEISS R. (1972) Am. J. Psvchiut. 128. 1351-1357. MURPHY D. L. and WYAW R.. J. (1972) Nut&, Lond. US, 225-226. Nns A., ROBIN~~ND. S., RAVARISC. L. and DAVIS J. M. (1971) Psychosomatic Med. 33,470. RUBIN R. T., MILLER R. G., CLARK B. R., POLAND R. E. and ARTHUR R. J. (1972) Psychosomutic
Med. 32,589-597. SCHANBERGS. M., SCHILDKRAUTJ. J., BREESE G. R. and KOPIN I. J. (1968a) Biochem. Phurmucol.
17,247-254. SCHANBERGS. M., BREESEG. R., SCHILDKRALJT J. J., GORDONE. K. and KOPIN I. J. (1968b) Biochem.
Phurmucol. 17, 2006-2008. J. (1965) Am. J. Psychiut. 122, 509-522. J. (1970) Neuropsychophurmucology and the Affective Disorders Little, Brown & Co.,
SCHILDKRAUTJ. SCHILDKRAUTJ. Boston. SCHILDKRAUTJ. SCHILDKRAUTJ. SCHILDKRAUTJ. SCHILDKRALJT J.
J. (1973a) Ann. Rev. Pharm. 13,427-+54. J. (1973b) Am J. Psychiut. 130, 695-699. J., WATSON R., DRA~K~CZY P. R. and HARTMANNE. (1971) Luncet ii, 485-486. J., KEELER B. A., ROGERSM. P. and DRASKOCZY P. R. (1972b) Psychosomatic Med.
34,470. SCHILDKRAUTJ. J., DRASK~CZY P. R., GER~HONE. S., REICH P. and GRAB E. L. (1972a) J. Psychiut.
Res. 9, 173-175. SCHILDKRAUTJ. J., KEELER B. A., I, 1251-1252. SCHILDKRAUTJ. J., KEELER B. A., WINOKURG., CLAYTONP. J. and WYATT R. J. (1972) Biol. Psychiut.
GRAB E. L., KANTROWICHJ. and HARTMANNE. (1973a) Lancer PAPOUSEKM. and HARTMANNE. (1973b) Science 181,762-764. REICH T. (1969) Manic-Depressive Illness C. V. Mosby, St. Louis.
5, 33-64.
of catecholamine metabolism in affective disorders (depressions and manias) have been one of the more productive areas of investigation in biological psychiatry during the past decade (SCHILDKRAUT, 1965, 1970; BUNNEY and DAVIS, 1965). Since the literature in this field has been reviewed recently (SCHILDKRAUT, 1973a), and because of space limitations, this paper will not provide another comprehensive review. Instead, I shall summarise aspects of our ongoing research in this area, focusing on recent studies of the urinary excretion of 3-methoxy-Chydroxyphenylglycol (MHPG), a metabolite of norepinephrine which may provide some index of the synthesis and metabolism of norepinephrine in the brain (SCHANBERG et al., 1968a, b; MAAS and LANDIS, 1968; MAAS et al., 1972a).* In one aspect of our research we have examined the changes in MHPG excretion which were associated with changes in affective state. The findings from our longitudinal studies of individual patients with naturally occurring or amphetamineinduced manic-depressive episodes indicate that levels of urinary MHPG are relatively lower during depressions and higher during manic or hypomanic episodes than after clinical remissions (GREENSPAN et al., 1970; SCHILDKRAUT et al., 1971, 1972b), and these findings have been confirmed by other investigators (BOND et al., 1972; JONES et al., 1973b) but not by all (BUNNEY et al., 1972). The relationship between MHPG excretion and clinical state that we have observed in manic-depressive patients, is illustrated in Table 1, which summarises the changes in MHPG excretion in a manicdepressive patient studied longitudinally through 5 successive periods which were defined by differences in clinical state. However, all depressed patients do not excrete comparably low levels of MHPG, and recent preliminary findings have suggested that MHPG excretion may provide a biological criterion for classifying the depressive disorders and for predicting the responses to specific forms of antidepressant pharmacotherapy (MAAS et al., 1968, 1972b; SCHILDKRAUT et al., 1972a; SCHILDKRAUT, 1973b). For example, in a preliminary study of a small group of depressed patients, we observed favorable responses to treatment with amitriptyline in depressed patients with relatively higher levels of urinary MHPG but not in patients with lower levels of MHPG (SCHILDKRAUT, 1973b).
In order to explore further the relationship between MHPG excretion and the clinical classification of depressive disorders, we recently compared the urinary excretion of MHPG in a small group of patients (6 men and 6 women) with various * While urinary MHPG may also derive, in part, from the peripheral sympathetic nervous system as well as the brain, recent studies in non-human primates suggest that an appreciable fraction of urinary MHPG may derive from norepinephrine originating in the brain (MAAS el al., 1972a).
977
JOSEPH J. SCHILDKRAUT TABLE 1. MHPG EXCRETIONAND AFFECTIVESTATEIN A MANIC-DEPRESSIVE PATIENT
Clincial state* Mildly depressed
Treatment None
Nt
MHPG @g/day)
5
1284 & 76
P$
MHPG &g/g treat.) 966 f 72
<0.05 Very depressed
None
4
PS
<0.05
817 f 176
609 & 105 <0.05
Decreasing depression
ECT
12
999 f 78
897 k 63
Mildly hypomanic
None
4
1500*70
1386 f 59
Mildly depressed
None
5
1384 f 58
1117 f 38
MHPG
EXCRETION
IN DEPRESSIVE
DISORDERS
2500 1
i250
2500
1250
0
SCHlZOAFFECTlVE
YANIC-
RECURRENT
CHRONIC
DEPRESSIVE
ENDOGENOUS
CRARACTEROL06lCAL
FIG. I.-MHPG excretion in depressive disorders. MHPG was determined in 3-10 separate 24-hr urine samples from each patient. These individual values were averaged to obtain an overall value for each subject; this value was then used in computing the means and standard errors of the means for the two groups (manic depressive and According to our diagnostic criteria chronic characterological depressions). SCHILDKRAUT, 1970 three of the patients with chronic characterological depressions and one of the patients with manic-depressive depressions had signs and symptoms suggesting possible involutional depressive syndr0mesd.g. agitation, somatic preoccupation, guilt, and paranoid ideation. and chronic *P < 0.05, **P < 0.02 for difference between manic-depressive characterological depressions. (Reproduced with permission from SCHILDKRAUTJ. J. K~ELERB. A., GRAB E. L., QNTROWICH J., HARWNN E. MHPG Excretion and Clinical Classification in Depressive Disorders, Lancer, 1973).
Catecholamine
metabolism
and affective disorders:
Studies of MHPG excretion
979
clinically defined subtypes of depressive disorders* studied in hospital prior to treatment during drug free periods, and we examined our findings for possible relationships between urinary MHPG excretion and clinical measures of motor activity and anxiety (SCHILDKRAUTet al., 1973a, b). As shown in Fig. 1, MHPG excretion was significantly lower in 5 patients with manic-depressive depressions (i.e., bipolar disorders with histories of hypomanias or manias) than in 5 patients with chronic characterological depressions (i.e. dysphoric depressive syndromes with no history of hypomania or mania). In a patient with a schizoaffective depression, MHPG excretion was lower than the mean for the manic-depressive depressions, while in a patient with a recurrent endogenous depression (but no history of hypomania or mania) MHPG excretion fell between the means for manic-depressive and chronic characterological depressions. These differences in MHPG excretion may be related to the recent observations of other investigators that platelet monoamine oxidase activity was decreased in patients with bipolar affective disorders as well as schizophrenias but relatively increased in other types of depressive disorders (MURPHY and WYATT, 1972; MURPHY and WEISS, 1972; NIES et al., 1971). We also measured the urinary excretion of norepinephrine, normetanephrine, epinephrine, metanephrine and 3-methoxy-4-hydroxymandelic acid (VMA) in these patients. As indicated in Table 2, the urinary excretion of norepinephrine tended to be lower in manic-depressive than in chronic characterological depressions, but this difference was not statistically significant. There were no differences in normetanephrine, epinephrine, metanephrine or VMA excretion between these two groups. Thus, of the urinary catecholamines and metabolites that we measured, only MHPG showed significant differences when values in the manic-depressive and chronic characterological depressions were compared (Table 2). A correlation (of borderline statistical significance) between MHPG excretion and age was observed in the total group of 12 depressed patients. However, this may be related to the fact that the manic-depressives tended to be younger than the patients with chronic characterological depressionst, since other investigators found no correlation between MHPG excretion and age in a series of control subjects (DEKIRMENJIAN and MAAS, 1973). TABLET. EXCRETIONOPCATECHOLAMINESAND METAROLITESINMANICDEPRESSIVE AND CHRONIC CI-IARACTEROLOGICALDEPRESSIONS
Manic-dep. Norepinephrine* Normetanephrine* Epinephrine’ Metanephrine* VMA* MHPG*
21 * 180 f 10 f 190 k 3700 f 1240 *
5 30 2 30 310 160
Chron. char. dep.
P
36f 11 200 f 50 9I!c3 160 * 30 3590 & 230 1800 & 90
NS NS NS NS NS < 0.02
See caption to Fig. 1. * Expressed as means f S.E.M.in pg per day. * The clinical criteria used in the classification of the depressive disorders have been described previously (SCHILDKRAUT, 1970). t A s’milar difference in age has been noted in other studies, and may be explained by the fact that the age of onset is lower for manic-depressive disorders (bipolar) than for other types of depressive disorders (unipolar) (WINOKUR ef al.,1969).
980
JOSEPHJ. SCHILDKRAUT
Because it has been suggested recently that differences in physical activity or stress could conceivably account for the differences in MHPG excretion observed in patients with affective disorders (EBERT et al., 1972; MAAS er al., 1971; RUBIN et al., 1972), we examined our data in several different ways for possible relationships between MHPG excretion and clinical assessments of motor activity and anxiety as reflected by scores on a modified Hamilton Depression Rating Scale (HAMILTON, 1960). As shown in Table 3, there were no significant differences in scores for retardation, agitation and psychic or somatic anxiety between the manic-depressive and chronic characterological depressions. Moreover, when the entire group of 12 depressed patients were subdivided into the 4 with lowest, the 4 with intermediate and the 4 with highest scores on each of these items, no corresponding differences in MHPG excretion emerged (Tables 4 and 5). There were also no meaningful correlations between MHPG excretion and scores for retardation, agitation and psychic TABLE 3. HAMILTON DEPRESSIONRATING SCALE ITEMSIN MANICDEPRESSIVE AND CHRONIC CHARACTEROLOGICAL DEPRESSIONS
Hamilton item
Manic-dep.
Retardation Agitation Anxiety (Psychic) Anxiety (Somatic)
0.75 1.01 2.50 0.80
TABLE 4. MHPG WITH
A.
LOW
* * i &
0.59 1.20 244 1.08
0.28 0.17 0.15 0.34
EXCRETIONIN
AND
HIGH
Retardation
* 0.20 f ,0.06 & 0.18 i 0.42
DEPRESSIVE
RETARDATION
H.D.R.S.*
N.S. N.S. N.S. N.S.
DISORDERS
OR AGITATION
Score
0.21 + 0.09 0.49 + 0.03 1.24 i 0.10
Low (N = 4) Middle (N = 4) High (N = 4)
P
Chron. char. dep.
MHPG (!tg/day) 1510 i 280 1290 f 180 1620 i It0 MHPG
B.
Agitation
H.D.R.S.*
0.77 f 0.10 1.16 * 0.01 1.44 i 0.06
Low (N = 4) Middle (N = 4) High (N = 4) * H.D.R.S. TABLE
5.
Score
= Hamilton Depression
MHPG WITH
EXCRETION LOW
A. Anxiety (Psychic) Low (N = 4) Middle (N = 4) High (N = 4)
AND
IN HIGH
H.D.R.S.*
&/day) 1510 f 150 1510 f 70 1390 i. 360
Rating Scale
DEPRESSIVE
DISORDERS
ANXIETY
Score
2.11 5 0.01 2.40 j, 0.12 2.83 + 0.07
MHPG (pg/day) 1510 & 140 1400 * 210 1500 f 290 MHPG
B. Anxiety (Somatic) Low (N = 4) Middle (N = 4) High (N = 4) * H.D.R.S.
H.D.R.S.*
Score
0.22 i 0.08 0.83 & 0.15 1.83 2 0.17
= Hamilton Depression
@g/day) 1440 + 120 1460 * 200 1510 f 320
Rating Scale
Catecholamine
metabolism
and effective disorders:
Studies of MHPG excretion
981
TABLE 6. CORRELATIONS BETWEEN HAMILTON DEPRESSION RATING SCALE AND ITEMS MHPG EXCRETION
Hamilton item
Retardation Agitation Anxiety (Psychic) Anxiety (Somatic)
Correlation coefficient
0.24 -0.19 -0.19 0.11
P
N.S. N.S. N.S. N.S.
or somatic anxiety (Table 6). Other investigators have recently made similar observations concerning the absence of an association between MHPG excretion and marked retardation or agitation in depressed patients (JONES et al., 1973a). These findings thus provide no support for the suggestion that differences in MHPG excretion in patients with affective disorders reflect only differences in activity or stress. In interpreting these data, one cannot exclude the possibility that these Hamilton Depression Rating Scale items were not specific or sensitive enough to detect differences in retardation, agitation or anxiety which may have been related to MHPG excretion. However, this possibility is weakened by the fact that we did observe meaningful relationships between several of these Hamilton Depression Rating Scale items and certain other biochemical variables. For example, patients with high scores on retardation excreted significantly less epinephrine and tended to excrete less metanephrine than patients with low retardation scores, whereas patients with high scores on somatic anxiety excreted significantly more metanephrine than did patients with low scores on this item. In collaboration with Dr. Ernest Hartmann, we also examined the relationship of MHPG excretion, in these depressed patients, to certain aspects of central nervous system activity as reflected by all-night electroencephalographic sleep recordings. We were particularly interested in the relationship between MHPG excretion and the amount of time spent in desynchronised-i.e., REM-sleep (D-time), since pharmacological studies in animals and man suggest that there may be an inverse relationship between central catecholaminergic activity and D-time (HARTMANN, 1970; HARTMANN et al., 1971a, b; WYATT, 1972; KUPFER and BOWERS, 1972), although this has not been confirmed in all studies (JOUVET, 1968; KING, 1971). As shown in Table 7, when the data from the total group of 12 depressed patients were examined, there were no statistically significant correlations between MHPG excretion and total sleep time or slow-wave sleep time. However, a statistically significant inverse correlation was observed between MHPG excretion and D-time. When the subgroups of depressive disorders were examined separately the inverse correlation between MHPG excretion and D-time was high and significant in the TABLET. CORRELATIONSBETWEEN MHPG EXCRETION AND SLEEP MEASURES IN DEPRESSIVE DISORDERS
Sleep measure Total sleep Slow wave sleep D-Time
Correlation coefficient -0.35 -0.15 -0.66
P
N.S. N.S. <0.02
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JOSEPH J. SCHILDKRAUT
patients with manic-depressive depressions. In addition, MHPG excretion was higher and D-time was lower in two patients studied during hypomanic episodes than in any of the patients with manic-depressive disorders studied during depressive episodes (SCHILDKRAUT et al., 1973b). Taken in conjunction with pharmacological observations that have suggested an inverse relationship between D-time and central catecholaminergic activity, these findings appear to support the view that MHPG excretion may reflect central noradrenergic activity, particularly in patients with manic-depressive disorders. In summary, during several longitudinal studies of individual patients we have observed that MHPG excretion was higher during hypomanias or manias, intermediate during well intervals and lower during depressions in patients with naturally occurring or amphetamine-induced manic-depressive disorders. Moreover, in a recent cross-sectional comparison of a small group of patients with various clinically defined subtypes of depressive disorders examined prior to treatment with antidepressant drugs or electroconvulsive therapy, we observed that MHPG excretion was significantly lower in patients with manic-depressive depressions than in patients with chronic characterological depressions. MHPG excretion did not appear to be related to the degree of retardation, agitation or anxiety in these depressed patients; but MHPG excretion was inversely related to the time spent in desynchronised-i.e. REM-sleep (D-time), particularly in the patients with manic-depressive disorders. In the aggregate, these findings provide further evidence that alterations in central norepinephrine metabolism may be of importance in the underlying pathophysiology of at least some types of depressive disorders. Moreover, these findings suggest that MHPG excretion may provide a clinically useful biochemical criterion for classifying the depressive disorders and possibly also for predicting responses to specific forms of antidepressant pharmacotherapy. work was supported in part by USPHS National Institute of Mental Health.
Acknowledgements--This
Grant No. MH 15,413 from the
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