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Delta sleep-inducing peptide in CSF of patients with affective illness is elevated by lithium treatment
II2
UIOL
PSYCHlATR\r
Iwi:1‘&~Iox
Brief Reports
I I’
Thompson C. Mezey G, Corn T, Franey C. English J, Arendt J, Checkley S (1985):The effect of desipramine upon melatonin and cortisol secretion in depressed and normal sub.ject\. 61r J P.swhiurrv 147:X9-393. Wetterberg L. Beck-Friis J. Aperia B, et al. (1979): Melatonin/cortisol rario in depression. Lmcrr ii:1361.
Wirz-Justice A, Arendt J (1979) Diurnal, menstrual cycle and seasonal indole rhythms in man and their mod% cation. In Obiols J, Ballus G, Gonzales-Monclus E, et al. (eds). Biological Psychiatry Today. Vol. A. Amsterdam: Elsevier/North-Holland, p 294.
Delta Sleep-Inducing Peptide in CSF of Patients with Affective Illness is Elevated by Lithium Treatment G. Regnc511,E. Widerlijv, and R. Ekman
Introduction The treatment of mania with lithium was first introduced by Cade in 1949. Later, the prophylactic efficacy of lithium salts in both unipolar and bipolar manic-depressive illness was well documented (Baas&up et al. 1970; Coppen et al. 1971; Prien et al. 1973). The mode of action of lithium, however, still remains unclear. Delta sleep-inducing peptide (DSIP) is a nonapeptide that was first isolated and sequenced by Schoenenberger et al. (1978). The peptide was given its name because of its capacity to induce sleep and delta waves in the electroencephalogram of rabbits following intracerebroventricular infusion. However, a number of central and peripheral actions have later been attributed the peptide (for review, see Graf and Kastin 1986). Previous studies by our group
From the Department
of Psychiany,
Lund University
and the Department
of Psychiatry
Hospital.
of Lund (E.W.,
University
This work
was supported
of Lund; the Swedish
7517 R.E.
and No. 4803 R.6.);
Foundation chiatry, Received
(No.
reprint
Medical
St. Las
Sweden. of Medicine.
Research Council
(No.
the Bank of Sweden Tercentenary
85/77
E.W.):
and the Pfannenstill
requests
to Dr.
G.
Lund University April
R.E.).
by grants from the Faculty
University
Address
Hospital (G.R.).
and Neumchemistry
Hospital,
RegnCII, S-221
13. 1987; revised October
Foundation.
Department 85 Lund.
24.
19X7
of Psy-
Sweden.
(Lindstr(im et al. 1985; Wall&s et al. 1985) have indicated low concentrations of DSIP in both cerebrospinal fluid (CSF) and plasma from patients with major depression when compared with healthy volunteers. In the present investigation, we have examined the influence of chronic lithium treatment on CSF and plasma concentrations of the peptide in patients with major affective disorders.
Methods Patients Comparisons were made between two groups of patients with a DSM-III diagnosis of major affective disorder. The control group (n = 8) had no prophylactic treatment with lithium, and the experimental group (n = 15) received chronic lithium treatment. The patient characteristics are given in Table 1. Three of the patients in the first group were later instituted on lithium prophylaxis and were also examined following 2 months on lithium treatment. The remaining 12 lithium-treated patients had been on continued medication for l-18 years (mean ? SEM 8.9 ir 2.6 years). The steady-state serum lithium concentrations ranged from 0.4 to I .O
mmol/liter (mean + SEM 0.70 + 0.03 mmol/liter). The patients had not been randomly allocated to the control or lithium treatment group, but an individual decision whether or not to institute lithium prophylaxis had been made for each patient. However, besides the lithium treatment, the two patient groups were considered to be clinically similar enough to allow betweengroup comparisons. The patients had no history of alcohol or drug abuse, organic brain disorder, or any other somatic illness. The symptoms were rated using a lo-item Rating Scale for Depression (CPRS-D) (Montgomery and .&berg 1979). The low scores in both groups indicate that the patients were in remission when examined. In the lithium-treated group, 10 patients received lithium citrate (Litarex, Dumex), 2 had lithium sulphate (Lithionit, Astra), and 3 patients received lithium carbonate (Litiumkarbonat, Ace). Blood samples for assessment of the serum lithium concentrations were always taken 12 hr after the last dose. Lumbar Punctures and Blood Sampling All lumbar punctures were performed at 8:009:00 AM, after at least 8 hr fasting and bed rest. Twelve milliliters of CSF was drawn with the subject in a sitting position. To avoid contamination of cells, the CSF was centrifuged (1000 X g for 10 min). The supernatant was deposited in tubes containing trasylol (0.35 ml in a 7-ml tube; trasylol concentration 500 KIU/ml) and then divided into l-ml aliquots in polyethylene vials and kept frozen at - 70” C until the analysis of DSIP. After the lumbar puncture, a blood sample was drawn into tubes containing EDTA, and the plasma was separated, deposited in a trasylol tube, and frozen at - 70°C until assay. Radioimmunoassay (RIA) of DSIP Plasma and CSF samples were assayed for content of DSIP-like immunoreactivity using a previously described RIA and a rabbit antiserum (code No. A 42, batch 7911, MILAB, Malm6, Sweden), which recognizes the N-terminal amino
113
BIOL PSYCHIATRY 1988;24:112-116
Brief Reports
Table 1. Patient Characteristics Control patients Number of patients DSM-III diagnoses of major afective disorders Unipolar Bipolar Sex Females Males Age” (years) Range Mean + SEM CPRS-D score” Mean k SEM Duration of illness” (years) Range Mean k SEM Concomitant medication” Tricyclic antidepressants Other drugs
Lithium-treated patients
8
15
6
4 11
6 2
13 2
40-59 50.5 2 2.7
25-59 45.1 + 2.4
2.3 2 0.6
1.3 f 0.2
15-26 19.4 t 1.3
10-30 18.7 k 1.6
6
3 4
“No statistically significant difference between the two pups.
acid sequence of both bound and unbound peptide (Ekman et al. 1983). The antiserum was used at a final dilution 1:500,000. A p-hydroxyphenylpropionic acid derivative of DSIP was used for radioiodination by conventional chloramine-T oxidation. Each sample was assayed in serial dilutions. The intraassay variation was 5%, and the interassay variation was below lo%, in the range 200-1000 pg/ml.
Statistical Analysis The Mann-Whitney U-test (Siegel 1956) was used for statistical comparisons between groups, and the Spearman rank correlation test was used for the correlation analyses (Siegel 1956).
Results The CSF concentrations of DSIP in the two patient groups are demonstrated in Figure 1. In
Ii-1
UlOL PSYCHIATRY 19x8.24~1I2-116
Brief Reports
DSIP/CSF
pt.02 0 0
Normal range
cl
0'
Not on lithium
On lithium
N=8
N=lS
3 Females l
Males
Figure 1. DSIP-like immunoreactivity in cerebrospinai fluid. In three of the patients, CSF samples were taken both before and during lithium (connected by lines in the figure). Mean values t SEM are indicated. The normal range refers to a reference group of healthy volunteers (mean IT 2 SD) from our laboratory.
the li~ium-treated group (n = 15), the concentrations ranged from 449 to 1328 pg/ml (mean 5 SEM 794 t 65 pg/ml), and in the control group fn = 8), from 396 to 701 pglml (mean ? SEM 518 +- 35 pg/ml), which was significantly lower than in the lithium-treated group (p c 0.02; two-tailed). In the three patients recorded both before and after 2 months of lithium treatment, elevated CSF DSIP concentrations were noted following the lithium treatment (in one patient only slightly, in the other two patients 27% and 7 I%, respectively). The CPRS-D scores for these patients were almost identical at the two occasions. In Figure 2, the plasma DSIP concentrations for the two groups are presented. Due to methodological errors, three patients in the lithiumtreated group and one in the control group were
excluded in the c~c~ations. In the li~ium-its group (n = 12), the plasma DSIP concentrations ranged from 181 to 1077 pg/ml (mean k SEM 632 -r 88 pglml), and in the control group (n = 7), from 263 to 1080 pg/ml (mean + SEM 650 r4 106). Thus, no statistically significant difference was observed. No significant correlations were found between the CSF and plasma DSIP concentrations in either of the two groups. Furthermore, no significant correlations were found between the CSF or plasma DSIP concentrations and age, serum lithium c~centmtions, or duration of lithium treatment. Nor were there any significant differences in CSF or plasma DSIP concentration between patients with unipolar and bipolar affective illness in either of the two groups. Tricyclic antidepressant treatment did not affect
BIOL PSYCHIATRY 1988:24:112-116
Brief Reports
115
DSIP/plasma
NS
0
8
Not on lithium
On lithium
N=7
N=l2
Normal range
0 Females l
Males
Figure 2. DSIP-like inununoreactivity in plasma. Mean values 2 SEM are indicated. The normal range refers to a reference group of healthy volunteers (mean 2 2 SD) from our laboratory.
the plasma or CSF concentrations of DSIP in any of the two groups (data not shown).
Discussion Lindstriim et al. (1985) reported lower CSF DSIP concentrations in patients with schizophenia or major affective disorders when compared to healthy subjects. In a subsequent study (Wall&is et al. 1983, decreased concentrations of DSIP in both plasma and CSF of depressed patients were demonstrated. In the present study, we have examined patients with DSM-III major affective disorder during remission. The reference values for the normal controls indicated in Figures 1 and 2 are taken from these previous studies (Lindstrom et al. 1985; Wall&s et al. 1985) in which we used the same method with a small interassay variation. Therefore, we assume that
we can make reasonable comparisons between these studies. Again, our recovered patients demonstrated lower plasma and CSF DSIP concentrations than the controls (Figures 1 and 2). Particularly, the plasma DSIP levels were low, with 11 of 19 values in the two groups below the normal range. This finding indicates that plasma DSIP may be a trait marker of affective illness that is independent of the severity of the illness. A main finding was that the lithium-treated patients had significantly higher CSF DSIP concentrations than the control group. Furthermore, the three patients with DSIP assessments both before and after lithium treatment had higher CSF concentrations of the peptide during the lithium treatment. In contrast to the findings in CSF, lithium did not seem to affect the plasma concentrations of DSIP, sug-
116
BIOL PSYCHIATRY IYX8:24:112-II6
gesting that CSF and plasma DSIP belong to different compartments that react differently to the influence of lithium. A further support of this hypothesis is the observation that plasma and CSF concentrations of DSIP did not correlate in any of the two groups. This is in agreement with the previous report by Walleus and coworkers (1985). The question arises as to whether or not the increased CSF DSIP concentrations in our lithium-treated group could be explained by factors other than the lithium treatment. The patients in both groups were examined in a symptom-free state, and there were no differences in age or duration of the illness. In the present study, predominantly women were included (19 of 23 in the 2 groups). The few men included seemed to have lower plasma and CSF levels of DSIP than the women. However, in the reports by Lindstrom et al. (1985) and Wall&us et al. (1985), there were no sex differences in the groups of schizophrenics, depressives, or healthy volunteers. Therefore, we conclude that it is unlikely that a sex difference can account for the difference observed between the two groups in the present study. There were more bipolar patients in the lithium-treated than in the control group. However, no significant difference existed in CSF DSIP concentrations between unipolar and bipolar patients in the two groups. It is thus likely that the type of depression can be ruled out as the cause of elevated CSF levels in the lithium-treated group. As far as the concomitant medication is concerned, the antidepressant medication did not seem to affect the plasma or CSF concentrations of DSIP. It is known that lithium treatment induces a number of changes in central monoaminergic functions (for review, see Ahluwalia and Singhal 1983). Whether the lithium-induced elevation
Brief Reports
of CSF DSIP is a direct action on DSIP function or is mediated by alterations in monoaminergic or other neurotransmitter functions is presently not known.
References Ahluwalia P, Singhal RL (1983): Lithium and central monoamine neurotransmitter systems. Drug Dev Res 3: I 1 I --
I??. Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A (1970): Prophylactic lithium: Double blind discontinuation in manic-depressive and recurrent depressive disorder. Lancer ii:326-330. Cade J (1949): Lithium salts in the treatment of psychotic excitement. Med J Australia 2~349-352. Coppen A, Noguera R, Bailey J (1971): Prophylactic lithium in affective disorders. Controlled trial. Lancer ii:2755 279. Ekman R, Larsson I, Malmquist M, Thorell JI (1983): Radioimmunoassay of delta sleep-inducing peptide using an iodinated p-hydroxyphenylpropionic acid derivative as tracer. Reg Peprides 6:371-378. Graf M, Kastin AJ (1986): Delta sleep-inducing (DSIP): An update. Peptides 7:1165-l 187.
peptide
Lindstrom LH, Ekman R, Walleus H. Widerlov E (1985): Delta-sleep inducing peptide in cerebrospinal fluid from schizophrenics, depressives and healthy volunteers. Pro(: Neuro-Psvchopharmacol
Montgomery designed
Biol Psyhiarry
9:83-90.
S, Asberg M (1979): A new depression scale to be sensitive to change. Br J Psychiatr)
134:382-389.
Prien R, Caffey EM, Klett CJ (1973): Prophylactic efficacy of lithium carbonate in manic-depressive illness. Arch Gen Psychiatry
28:337-341.
Schneider-Helmert D, Schoenenberger GA (1983): Effects of DSIP in man. Neuropsyhohiology 9: 197-206. Schoenenberger GA, Maier PF, Tobler KJ, Wilson K, Monnier M (1978): The delta-EEG (sleep)-inducing peptide (DSIP). XI. Amino acid analysis, sequence, synthesis and activity of the nonapeptide. Q%qersArrh 376: I19129.
Siegel S (1956): Nonparamefric Stafisticsfor Sriencer. New York: McGraw-Hill.
rhe Behaviorul
Walleus H, Widerlov E, Ekman R (1985): Decreased concentrations of delta-sleep inducing peptide in plasma and cerebrospinal fluid from depressed patients. Nerd Psv kiatr Tidsskr 39:63-67.
UIOL
PSYCHlATR\r
Iwi:1‘&~Iox
Brief Reports
I I’
Thompson C. Mezey G, Corn T, Franey C. English J, Arendt J, Checkley S (1985):The effect of desipramine upon melatonin and cortisol secretion in depressed and normal sub.ject\. 61r J P.swhiurrv 147:X9-393. Wetterberg L. Beck-Friis J. Aperia B, et al. (1979): Melatonin/cortisol rario in depression. Lmcrr ii:1361.
Wirz-Justice A, Arendt J (1979) Diurnal, menstrual cycle and seasonal indole rhythms in man and their mod% cation. In Obiols J, Ballus G, Gonzales-Monclus E, et al. (eds). Biological Psychiatry Today. Vol. A. Amsterdam: Elsevier/North-Holland, p 294.
Delta Sleep-Inducing Peptide in CSF of Patients with Affective Illness is Elevated by Lithium Treatment G. Regnc511,E. Widerlijv, and R. Ekman
Introduction The treatment of mania with lithium was first introduced by Cade in 1949. Later, the prophylactic efficacy of lithium salts in both unipolar and bipolar manic-depressive illness was well documented (Baas&up et al. 1970; Coppen et al. 1971; Prien et al. 1973). The mode of action of lithium, however, still remains unclear. Delta sleep-inducing peptide (DSIP) is a nonapeptide that was first isolated and sequenced by Schoenenberger et al. (1978). The peptide was given its name because of its capacity to induce sleep and delta waves in the electroencephalogram of rabbits following intracerebroventricular infusion. However, a number of central and peripheral actions have later been attributed the peptide (for review, see Graf and Kastin 1986). Previous studies by our group
From the Department
of Psychiany,
Lund University
and the Department
of Psychiatry
Hospital.
of Lund (E.W.,
University
This work
was supported
of Lund; the Swedish
7517 R.E.
and No. 4803 R.6.);
Foundation chiatry, Received
(No.
reprint
Medical
St. Las
Sweden. of Medicine.
Research Council
(No.
the Bank of Sweden Tercentenary
85/77
E.W.):
and the Pfannenstill
requests
to Dr.
G.
Lund University April
R.E.).
by grants from the Faculty
University
Address
Hospital (G.R.).
and Neumchemistry
Hospital,
RegnCII, S-221
13. 1987; revised October
Foundation.
Department 85 Lund.
24.
19X7
of Psy-
Sweden.
(Lindstr(im et al. 1985; Wall&s et al. 1985) have indicated low concentrations of DSIP in both cerebrospinal fluid (CSF) and plasma from patients with major depression when compared with healthy volunteers. In the present investigation, we have examined the influence of chronic lithium treatment on CSF and plasma concentrations of the peptide in patients with major affective disorders.
Methods Patients Comparisons were made between two groups of patients with a DSM-III diagnosis of major affective disorder. The control group (n = 8) had no prophylactic treatment with lithium, and the experimental group (n = 15) received chronic lithium treatment. The patient characteristics are given in Table 1. Three of the patients in the first group were later instituted on lithium prophylaxis and were also examined following 2 months on lithium treatment. The remaining 12 lithium-treated patients had been on continued medication for l-18 years (mean ? SEM 8.9 ir 2.6 years). The steady-state serum lithium concentrations ranged from 0.4 to I .O
mmol/liter (mean + SEM 0.70 + 0.03 mmol/liter). The patients had not been randomly allocated to the control or lithium treatment group, but an individual decision whether or not to institute lithium prophylaxis had been made for each patient. However, besides the lithium treatment, the two patient groups were considered to be clinically similar enough to allow betweengroup comparisons. The patients had no history of alcohol or drug abuse, organic brain disorder, or any other somatic illness. The symptoms were rated using a lo-item Rating Scale for Depression (CPRS-D) (Montgomery and .&berg 1979). The low scores in both groups indicate that the patients were in remission when examined. In the lithium-treated group, 10 patients received lithium citrate (Litarex, Dumex), 2 had lithium sulphate (Lithionit, Astra), and 3 patients received lithium carbonate (Litiumkarbonat, Ace). Blood samples for assessment of the serum lithium concentrations were always taken 12 hr after the last dose. Lumbar Punctures and Blood Sampling All lumbar punctures were performed at 8:009:00 AM, after at least 8 hr fasting and bed rest. Twelve milliliters of CSF was drawn with the subject in a sitting position. To avoid contamination of cells, the CSF was centrifuged (1000 X g for 10 min). The supernatant was deposited in tubes containing trasylol (0.35 ml in a 7-ml tube; trasylol concentration 500 KIU/ml) and then divided into l-ml aliquots in polyethylene vials and kept frozen at - 70” C until the analysis of DSIP. After the lumbar puncture, a blood sample was drawn into tubes containing EDTA, and the plasma was separated, deposited in a trasylol tube, and frozen at - 70°C until assay. Radioimmunoassay (RIA) of DSIP Plasma and CSF samples were assayed for content of DSIP-like immunoreactivity using a previously described RIA and a rabbit antiserum (code No. A 42, batch 7911, MILAB, Malm6, Sweden), which recognizes the N-terminal amino
113
BIOL PSYCHIATRY 1988;24:112-116
Brief Reports
Table 1. Patient Characteristics Control patients Number of patients DSM-III diagnoses of major afective disorders Unipolar Bipolar Sex Females Males Age” (years) Range Mean + SEM CPRS-D score” Mean k SEM Duration of illness” (years) Range Mean k SEM Concomitant medication” Tricyclic antidepressants Other drugs
Lithium-treated patients
8
15
6
4 11
6 2
13 2
40-59 50.5 2 2.7
25-59 45.1 + 2.4
2.3 2 0.6
1.3 f 0.2
15-26 19.4 t 1.3
10-30 18.7 k 1.6
6
3 4
“No statistically significant difference between the two pups.
acid sequence of both bound and unbound peptide (Ekman et al. 1983). The antiserum was used at a final dilution 1:500,000. A p-hydroxyphenylpropionic acid derivative of DSIP was used for radioiodination by conventional chloramine-T oxidation. Each sample was assayed in serial dilutions. The intraassay variation was 5%, and the interassay variation was below lo%, in the range 200-1000 pg/ml.
Statistical Analysis The Mann-Whitney U-test (Siegel 1956) was used for statistical comparisons between groups, and the Spearman rank correlation test was used for the correlation analyses (Siegel 1956).
Results The CSF concentrations of DSIP in the two patient groups are demonstrated in Figure 1. In
Ii-1
UlOL PSYCHIATRY 19x8.24~1I2-116
Brief Reports
DSIP/CSF
pt.02 0 0
Normal range
cl
0'
Not on lithium
On lithium
N=8
N=lS
3 Females l
Males
Figure 1. DSIP-like immunoreactivity in cerebrospinai fluid. In three of the patients, CSF samples were taken both before and during lithium (connected by lines in the figure). Mean values t SEM are indicated. The normal range refers to a reference group of healthy volunteers (mean IT 2 SD) from our laboratory.
the li~ium-treated group (n = 15), the concentrations ranged from 449 to 1328 pg/ml (mean 5 SEM 794 t 65 pg/ml), and in the control group fn = 8), from 396 to 701 pglml (mean ? SEM 518 +- 35 pg/ml), which was significantly lower than in the lithium-treated group (p c 0.02; two-tailed). In the three patients recorded both before and after 2 months of lithium treatment, elevated CSF DSIP concentrations were noted following the lithium treatment (in one patient only slightly, in the other two patients 27% and 7 I%, respectively). The CPRS-D scores for these patients were almost identical at the two occasions. In Figure 2, the plasma DSIP concentrations for the two groups are presented. Due to methodological errors, three patients in the lithiumtreated group and one in the control group were
excluded in the c~c~ations. In the li~ium-its group (n = 12), the plasma DSIP concentrations ranged from 181 to 1077 pg/ml (mean k SEM 632 -r 88 pglml), and in the control group (n = 7), from 263 to 1080 pg/ml (mean + SEM 650 r4 106). Thus, no statistically significant difference was observed. No significant correlations were found between the CSF and plasma DSIP concentrations in either of the two groups. Furthermore, no significant correlations were found between the CSF or plasma DSIP concentrations and age, serum lithium c~centmtions, or duration of lithium treatment. Nor were there any significant differences in CSF or plasma DSIP concentration between patients with unipolar and bipolar affective illness in either of the two groups. Tricyclic antidepressant treatment did not affect
BIOL PSYCHIATRY 1988:24:112-116
Brief Reports
115
DSIP/plasma
NS
0
8
Not on lithium
On lithium
N=7
N=l2
Normal range
0 Females l
Males
Figure 2. DSIP-like inununoreactivity in plasma. Mean values 2 SEM are indicated. The normal range refers to a reference group of healthy volunteers (mean 2 2 SD) from our laboratory.
the plasma or CSF concentrations of DSIP in any of the two groups (data not shown).
Discussion Lindstriim et al. (1985) reported lower CSF DSIP concentrations in patients with schizophenia or major affective disorders when compared to healthy subjects. In a subsequent study (Wall&is et al. 1983, decreased concentrations of DSIP in both plasma and CSF of depressed patients were demonstrated. In the present study, we have examined patients with DSM-III major affective disorder during remission. The reference values for the normal controls indicated in Figures 1 and 2 are taken from these previous studies (Lindstrom et al. 1985; Wall&s et al. 1985) in which we used the same method with a small interassay variation. Therefore, we assume that
we can make reasonable comparisons between these studies. Again, our recovered patients demonstrated lower plasma and CSF DSIP concentrations than the controls (Figures 1 and 2). Particularly, the plasma DSIP levels were low, with 11 of 19 values in the two groups below the normal range. This finding indicates that plasma DSIP may be a trait marker of affective illness that is independent of the severity of the illness. A main finding was that the lithium-treated patients had significantly higher CSF DSIP concentrations than the control group. Furthermore, the three patients with DSIP assessments both before and after lithium treatment had higher CSF concentrations of the peptide during the lithium treatment. In contrast to the findings in CSF, lithium did not seem to affect the plasma concentrations of DSIP, sug-
116
BIOL PSYCHIATRY IYX8:24:112-II6
gesting that CSF and plasma DSIP belong to different compartments that react differently to the influence of lithium. A further support of this hypothesis is the observation that plasma and CSF concentrations of DSIP did not correlate in any of the two groups. This is in agreement with the previous report by Walleus and coworkers (1985). The question arises as to whether or not the increased CSF DSIP concentrations in our lithium-treated group could be explained by factors other than the lithium treatment. The patients in both groups were examined in a symptom-free state, and there were no differences in age or duration of the illness. In the present study, predominantly women were included (19 of 23 in the 2 groups). The few men included seemed to have lower plasma and CSF levels of DSIP than the women. However, in the reports by Lindstrom et al. (1985) and Wall&us et al. (1985), there were no sex differences in the groups of schizophrenics, depressives, or healthy volunteers. Therefore, we conclude that it is unlikely that a sex difference can account for the difference observed between the two groups in the present study. There were more bipolar patients in the lithium-treated than in the control group. However, no significant difference existed in CSF DSIP concentrations between unipolar and bipolar patients in the two groups. It is thus likely that the type of depression can be ruled out as the cause of elevated CSF levels in the lithium-treated group. As far as the concomitant medication is concerned, the antidepressant medication did not seem to affect the plasma or CSF concentrations of DSIP. It is known that lithium treatment induces a number of changes in central monoaminergic functions (for review, see Ahluwalia and Singhal 1983). Whether the lithium-induced elevation
Brief Reports
of CSF DSIP is a direct action on DSIP function or is mediated by alterations in monoaminergic or other neurotransmitter functions is presently not known.
References Ahluwalia P, Singhal RL (1983): Lithium and central monoamine neurotransmitter systems. Drug Dev Res 3: I 1 I --
I??. Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A (1970): Prophylactic lithium: Double blind discontinuation in manic-depressive and recurrent depressive disorder. Lancer ii:326-330. Cade J (1949): Lithium salts in the treatment of psychotic excitement. Med J Australia 2~349-352. Coppen A, Noguera R, Bailey J (1971): Prophylactic lithium in affective disorders. Controlled trial. Lancer ii:2755 279. Ekman R, Larsson I, Malmquist M, Thorell JI (1983): Radioimmunoassay of delta sleep-inducing peptide using an iodinated p-hydroxyphenylpropionic acid derivative as tracer. Reg Peprides 6:371-378. Graf M, Kastin AJ (1986): Delta sleep-inducing (DSIP): An update. Peptides 7:1165-l 187.
peptide
Lindstrom LH, Ekman R, Walleus H. Widerlov E (1985): Delta-sleep inducing peptide in cerebrospinal fluid from schizophrenics, depressives and healthy volunteers. Pro(: Neuro-Psvchopharmacol
Montgomery designed
Biol Psyhiarry
9:83-90.
S, Asberg M (1979): A new depression scale to be sensitive to change. Br J Psychiatr)
134:382-389.
Prien R, Caffey EM, Klett CJ (1973): Prophylactic efficacy of lithium carbonate in manic-depressive illness. Arch Gen Psychiatry
28:337-341.
Schneider-Helmert D, Schoenenberger GA (1983): Effects of DSIP in man. Neuropsyhohiology 9: 197-206. Schoenenberger GA, Maier PF, Tobler KJ, Wilson K, Monnier M (1978): The delta-EEG (sleep)-inducing peptide (DSIP). XI. Amino acid analysis, sequence, synthesis and activity of the nonapeptide. Q%qersArrh 376: I19129.
Siegel S (1956): Nonparamefric Stafisticsfor Sriencer. New York: McGraw-Hill.
rhe Behaviorul
Walleus H, Widerlov E, Ekman R (1985): Decreased concentrations of delta-sleep inducing peptide in plasma and cerebrospinal fluid from depressed patients. Nerd Psv kiatr Tidsskr 39:63-67.