Biological Psychiatry
Original Paper Neuropsychobiology 1992:25:11-13
P. Castrogiovanni /. Maremmatii A. Di Muro A. Rotondo D. Marazzili
Personality Features and Platelet 3H-lmipramine Binding
Institute of Psychiatry'. University of Pisa. Italy
Key Words
Abstract
Personality Minnesota Multiphasic Personality Inventory Serotonin Platelets 3H-imipramine binding Healthy condition
In an attempt to provide further information on the functions of the seroton ergic system in humans, we investigated the possible correlation between a peripheral serotonergic marker, such as platelet •’H-imipramine binding, and the Minnesota Multiphasic Personality Inventory (MMPI) items and scales in a group of 20 healthy subjects. The results showed the presence of significant positive correlation between the maximum binding capacity, a measure of the number of -'H-imipraminc sites, and 17 MMPI items suggestive of personality features of self-certainty, feeling of well-being and sense of reality.
of this proposed biological marker, which would appear to be linked with various psychopathological dimensions, across discrete diagnostic entities [ 19], The renewed interest in the biology of mental disorders has added a biological dimension also to the study of the personality, and this perspective represents an enrich ment. rather than a reductionist approach to the study of the physiology and of the biochemistry of higher mental functions [20], Furthermore, the study of the normal per sonality may provide useful information on the under standing of the pathophysiology of mental disorders, if. according to Griesinger, mental functions of both healthy and ill subjects are underlined by similar mechanisms. Our study aim was therefore to investigate the possible correlation between a peripheral marker of the 5HT-ergic system, i.e., platelet 3H-IMI binding, and the personality questionnaire Minnesota Multiphasic Personality Inven tory (MMPI) items and scales.
P. Castrogiovanni Institute of Psychiatry University of Pisa Via Roma 67 1-56100 Pisa (Italy)
© 1992 S. Kargcr AG, Basel 0302-282X/92/0251-00II $2.75/0
Downloaded by: MacQuarie University 137.111.162.20 - 2/14/2019 11:20:11 AM
During recent years, increasing interest has been di rected towards the investigation of biological correlates of mental disorders, for the availability of increasingly so phisticated research tools and of peripheral models able to reflect some central nervous system properties. Blood platelets represent a current, widely used peripheral model of presynaptic serotonergic (SHTergic) neurons [1, 2], Both platelets and neurons possess an active 5HT uptake and 3H-imipramine (3H-IMI) binding sites [3, 4] which are hypothesized to modulate allosterically the 5HT uptake mechanisms [5. 6], Several authors [7-10] have described a lowered 3H-IMI binding in platelets of depressed patients and such a decrease has been proposed either as a trait- or state-dependent biological marker for depression [11-14], The observation of decreased 3H-IMI binding sites in different disorders other than depression, such as panic disorder [ 15], eating disorders [ 16, 17], or obsessive-com pulsive disorder [18]. raises doubts about the specificity
Subjects and Methods Subjects A sample of 20 subjects ( 11 male and 9 female; mean age 28 ± 2.8 years) was included: they were recruited from the medical staff of the Psychiatric Institute at Pisa University, and thus belonged to similar socioeconomic and environmental conditions. All were com pletely psychotropic drug-free and showed no personality disorder, as documented by the normal MMPI profile. In addition, they had neither any somatic disease, nor family or personal history of major psychiatric disorders. All subjects gave informed consent to the study. Methods 3H-IM I Binding Assay. Thirty milliliters of venous blood were drawn from fasting subjects and transferred into plastic tubes con taining 4.5 ml of anticoagulant (93 mM trisodium-citrate. 213 mM citric acid, and 111 m M glucose). All samples were collected between 8 and 10 a.m. to avoid the possible influence of circadian rhythms, and during the months March-April to exclude a seasonal effect. Platelet membranes and 3H-IMI binding were performed accord ing to a protocol provided by the WHO. as already described [14], Briefly, platelet-rich plasma (PRP) was obtained by centrifugation at 200 g for 20 min at room temperature. PRP was then subjected to centrifugation at 10.000 and 20.000 g both twice for 10 min a t4 ° C . and the resulting pellet was homogenized by Potter Elvehjem. Plate let membranes were finally suspended in an assay buffer 50 m.V/Tris, 120 m.V/ NaCI. 5 m.V/ KC1 (pH 7.4), and homogenized as previously. The incubation mixture consisted of 0.1 ml of platelet membranes. 0.05 ml of 5H-IMI (specific activity 21.0 mCi/m.V/) at seven concen trations ranging from 0.1 to 8 nM. and 0.15 ml of assay buffer. All samples were assayed in duplicate and incubated at 0 °C for 1 h. The
incubation was stopped, while adding 5 ml of cold assay bull'er. The content of the tube was immediately filtered under vacuum through glass fiber filters GF/F (Whatman). 2.5 mm in diameter, and washed 3 times with 5 ml of assay buffer. The filters were dried overnight at 45 °C and counted by scintillation spectrometry after adding I0 ml of scintillation fluid. Specific binding was obtained as the binding remaining in the presence of l()0 g.V/desipramine (a gift from Ciba-Geigy. Milan, Ita ly). Tl-IMI binding parameters (Bmax in fmol/mg protein, and Kd in n.V/) were calculated after construction of the Scatchard plot. Pro teins were measured according to the method of Peterson [21]. Statistical Analyses. Bmax and Kj were correlated to single MMPI items and scales according to routine SPSS statistical methods.
Results
The Bmax (mean ± SD)was 1,073 ± 102 fmol/mg pro tein and the Kd (mean ± SD) was 1.56 ± 0.64 nM. The mean MMPI profile of all subjects was uniform, and the clinical scales were within the normal range (50 ± 6). Sta tistically significant and positive correlations were ob served between Bmax values and 17 MMPI items which are reported in table 1. On the other hand, no correlation between Bmax and MMPI scales were noted, nor were they noted between Kj and MMPI items or scales.
Discussion and Conclusions
12
MMPI item
True
170 415 443 447 163 340 341 414 11 300 244 252 253 440 441 453 516
-0.47 -0.45
False
0.57 -0.47 -0.63 0.45 0.63 -0.49 0.44 -0.45 -0.53 -0.46 0.47 -0.48 0.49 0.54 0.67
Castrogiovanni/Maremmani/ Di Muro/Rotondo/Marazziii
Personality and Serotonin
Downloaded by: MacQuarie University 137.111.162.20 - 2/14/2019 11:20:11 AM
Table 1. Correlations between MMPI items and Bmax values
The results of our study showed that all subjects included had Bmax values within the normal range, posi tively correlating with some MMPI items which delineate the following personality features: self-confidence (170, 415, 443, 447). feeling of well-being (163, 340, 341), no tolerance for the frustration (447,414) and sense of reality (II. 300) (table 1). The higher the Bmax. the more confi dent, concrete and realistic the subject. Therefore, it is possible to hypothesize that these features arc accen tuated by a higher level of functioning of the 5HTergic system, or at lest of that function reflected by 3H-IM1 binding. It is worth noting that these characteristics are opposite to those commonly seen in depressed patients, where in several studies the Bmax has been reported to be lower than in healthy controls [7-14]. Although our data are preliminary and derive from a small sample, they sug gest a link between the number of 3H-IMI binding sites and some personality traits, which permit to achieve selfconfidence, good social integration and good impulse control, particularly impaired with depression and even more with suicide attempts, where the peripheral 5HTer-
gic markers have been reported to be even more de creased than with depression [22-24], Naturally a single biological marker cannot reflect the complexity of a personality, however it may contribute to the development and subsequent functioning of some
traits, in balance with other systems and mechanisms. Future research should therefore be dedicated to the biol ogy of human personality and to the relationship between different neurotransmitters which might result in specific features.
References 10 Wacgner A, Aberg-Wistedt A. Asberg M. Ekquist B, Martenson B. Montero D: Lower 'H imipraminc binding in platelets from untreated depressed patients compared with healthy con trols. Psychiatry Res 1985:16:131-139. 11 Suranyi-Cadottc BE. Quirion R. McQuide P: Platelet 'H-imipramine binding: A state depen dent marker in depression. Prog. Neuropsychopharmacol Biol Psychiatry 1984;8:731-741. 12 Baron M, Barkai A. Grucn R. Peselow E. Ficve RR. Quitkin F: Platelet 'H-imipramine bind ing sites in affective disorders: Trait versus sta tus characteristics. Am J Psychiatry 1986:143: 711-717.
13 Langer SZ, Sechter D. Loo H. Raisman R.
14
15
16
17
Zarifian E: Electroconvulsive shock therapy and maximum binding of platelet tritiated imipramine binding in depression. Arch Gen Psychiatry 1986:43:949-952. Marazziti D, Perugi G. Deltito J. Lenzi A. Maremmani I. Placidi GF. Cassano GB: Higliaffinity 'H-imipramine binding sites: A possi ble state-dependent marker for major depres sion. Psychiatry Res 1988:23:229-237. Lewis DA, Noyes RJ, Coryell W. Clancy S: Triliated imipramine binding to platelets is de creased in patients with agoraphobia. Psychia try Res 198 5;6:2-9. Wcizman A, Carmi M. Tyano S, Apter A, Rehavi M: ’H-imipramine binding and sero tonin uptake to platelets of adolescent females suffering from anorexia nervosa. Life Sci 1986; 38:1235-1242. Maraz.z.iti D. Macchi E. Rotondo A. Placidi GF. Cassano GB: Involvement of serotonin system in bulimia. Life Sci 1988:43:2123— 2126.
18 Weizman R. Carmi M. Hermesh H, Shahar A. Apter A, Tyano S, Rehavi M: High-affinity imipramine binding and serotonin uptake in platelets of eight adolescent and ten adult ob sessive-compulsive patients. Am J Psychiatrv 1986:143:335-339. 19 Van Praag HM, Kahn RS, Asnis GM. Wetzler S. Brown SL. Bleich A. Korn ML: Dcnosologization of biological psychiatry or the specificity of 5-HT disturbances in psychiatric disorders. J Affective Disord 1987:13:1-8. 20 Goodwin FK. Rov-Byme PP: Future direc tions in biological psychiatry; in Meltzer HY fed): Psychopharmacology: The Third Genera tion of Progress. New York, Raven Press. 1987. pp 1691-1698. 21 Peterson GL: A simplification of the protein assavmethod of Lowry et al which is more gen erally applicable. Anal Biochem 1977:83:366— 356. 22 Asberg M. Traskman L, Thoren P: 5-HIAA in the cerebrospinal fluid: A biochemical suicide predictor? Arch Gen Psychiatry 1976:33: 1193-1197. 23 Traskman L. Asberg M. Bertilsson L, Sjostrand L: Monoamine metabolites in CSF and suicidal behavior. Arch Gen Psychiatry 1981:38:631636. 24 Marazziti D, De Leo D, Conti L: Further evi dence supporting the role of the serotonin sys tem in suicidal behaviour. Acta Psychiat Scand 1989.80:322-324.
13
Downloaded by: MacQuarie University 137.111.162.20 - 2/14/2019 11:20:11 AM
1 Sneddon MJ: Blood platelets as a model for monoamine-containing neurons. Prog Neurobiol 1973;1:151-198. 2 Stahl SM: The human platelets. A diagnostic and research tool for the study of biogenic amines in psychiatric and neurological disor ders. Arch Gen Psychiatry 1977;34:509-516. 3 Briley MS. Langer SZ. Raisman R: Human platelets possess high-affinity binding sites for 'H-imipraminc. Eur J Pharmacol I979;58: 347-348. 4 Paul SM. Rehavi M, Skolnick P. Goodwin FK: Demonstration of specific high-affinity bind ing sites for 'H-imipramine in human platelets. LifeSci 1980;26:953-959. 5 Wennogle LP, Meyerson LR: Serotonin modu lates the dissociation of ’H-imipramine from human platelet recognition sites. Eur J Phar macol 1984:86:303-307. 6 Meyerson LR. leni JR. Wennogle LP: Alloste ric interaction between the site labelled by 'Himipramine and the serotonin transporter in human platelets. J Neurochcm 1987:48:560— 565. 7 Briley MS. Langer SZ. Raisman R. Sechtcr D. Zarifian E: Tritiatcd imipramine binding sites are decreased in platelets from untreated de pressed patients. Science 1980:209:303-305. 8 Raisman R. Briley MS. Bouchami F, Sechter D. Zarifian E. Langer SZ: 'H-imipramine bind ing and serotonin uptake in platelets from un treated depressed patients and control volun teers. Psychopharmacology 1982:77:332—335. 9 Baron M. Barkai A. Grucn R. Kowalik S. Quitkin F: ’H-imipramine binding sites in unipolar depression. Biol Psychiatry 1983; 18:1403— 1409.
Original Paper Neuropsychobiology 1992:25:11-13
P. Castrogiovanni /. Maremmatii A. Di Muro A. Rotondo D. Marazzili
Personality Features and Platelet 3H-lmipramine Binding
Institute of Psychiatry'. University of Pisa. Italy
Key Words
Abstract
Personality Minnesota Multiphasic Personality Inventory Serotonin Platelets 3H-imipramine binding Healthy condition
In an attempt to provide further information on the functions of the seroton ergic system in humans, we investigated the possible correlation between a peripheral serotonergic marker, such as platelet •’H-imipramine binding, and the Minnesota Multiphasic Personality Inventory (MMPI) items and scales in a group of 20 healthy subjects. The results showed the presence of significant positive correlation between the maximum binding capacity, a measure of the number of -'H-imipraminc sites, and 17 MMPI items suggestive of personality features of self-certainty, feeling of well-being and sense of reality.
of this proposed biological marker, which would appear to be linked with various psychopathological dimensions, across discrete diagnostic entities [ 19], The renewed interest in the biology of mental disorders has added a biological dimension also to the study of the personality, and this perspective represents an enrich ment. rather than a reductionist approach to the study of the physiology and of the biochemistry of higher mental functions [20], Furthermore, the study of the normal per sonality may provide useful information on the under standing of the pathophysiology of mental disorders, if. according to Griesinger, mental functions of both healthy and ill subjects are underlined by similar mechanisms. Our study aim was therefore to investigate the possible correlation between a peripheral marker of the 5HT-ergic system, i.e., platelet 3H-IMI binding, and the personality questionnaire Minnesota Multiphasic Personality Inven tory (MMPI) items and scales.
P. Castrogiovanni Institute of Psychiatry University of Pisa Via Roma 67 1-56100 Pisa (Italy)
© 1992 S. Kargcr AG, Basel 0302-282X/92/0251-00II $2.75/0
Downloaded by: MacQuarie University 137.111.162.20 - 2/14/2019 11:20:11 AM
During recent years, increasing interest has been di rected towards the investigation of biological correlates of mental disorders, for the availability of increasingly so phisticated research tools and of peripheral models able to reflect some central nervous system properties. Blood platelets represent a current, widely used peripheral model of presynaptic serotonergic (SHTergic) neurons [1, 2], Both platelets and neurons possess an active 5HT uptake and 3H-imipramine (3H-IMI) binding sites [3, 4] which are hypothesized to modulate allosterically the 5HT uptake mechanisms [5. 6], Several authors [7-10] have described a lowered 3H-IMI binding in platelets of depressed patients and such a decrease has been proposed either as a trait- or state-dependent biological marker for depression [11-14], The observation of decreased 3H-IMI binding sites in different disorders other than depression, such as panic disorder [ 15], eating disorders [ 16, 17], or obsessive-com pulsive disorder [18]. raises doubts about the specificity
Subjects and Methods Subjects A sample of 20 subjects ( 11 male and 9 female; mean age 28 ± 2.8 years) was included: they were recruited from the medical staff of the Psychiatric Institute at Pisa University, and thus belonged to similar socioeconomic and environmental conditions. All were com pletely psychotropic drug-free and showed no personality disorder, as documented by the normal MMPI profile. In addition, they had neither any somatic disease, nor family or personal history of major psychiatric disorders. All subjects gave informed consent to the study. Methods 3H-IM I Binding Assay. Thirty milliliters of venous blood were drawn from fasting subjects and transferred into plastic tubes con taining 4.5 ml of anticoagulant (93 mM trisodium-citrate. 213 mM citric acid, and 111 m M glucose). All samples were collected between 8 and 10 a.m. to avoid the possible influence of circadian rhythms, and during the months March-April to exclude a seasonal effect. Platelet membranes and 3H-IMI binding were performed accord ing to a protocol provided by the WHO. as already described [14], Briefly, platelet-rich plasma (PRP) was obtained by centrifugation at 200 g for 20 min at room temperature. PRP was then subjected to centrifugation at 10.000 and 20.000 g both twice for 10 min a t4 ° C . and the resulting pellet was homogenized by Potter Elvehjem. Plate let membranes were finally suspended in an assay buffer 50 m.V/Tris, 120 m.V/ NaCI. 5 m.V/ KC1 (pH 7.4), and homogenized as previously. The incubation mixture consisted of 0.1 ml of platelet membranes. 0.05 ml of 5H-IMI (specific activity 21.0 mCi/m.V/) at seven concen trations ranging from 0.1 to 8 nM. and 0.15 ml of assay buffer. All samples were assayed in duplicate and incubated at 0 °C for 1 h. The
incubation was stopped, while adding 5 ml of cold assay bull'er. The content of the tube was immediately filtered under vacuum through glass fiber filters GF/F (Whatman). 2.5 mm in diameter, and washed 3 times with 5 ml of assay buffer. The filters were dried overnight at 45 °C and counted by scintillation spectrometry after adding I0 ml of scintillation fluid. Specific binding was obtained as the binding remaining in the presence of l()0 g.V/desipramine (a gift from Ciba-Geigy. Milan, Ita ly). Tl-IMI binding parameters (Bmax in fmol/mg protein, and Kd in n.V/) were calculated after construction of the Scatchard plot. Pro teins were measured according to the method of Peterson [21]. Statistical Analyses. Bmax and Kj were correlated to single MMPI items and scales according to routine SPSS statistical methods.
Results
The Bmax (mean ± SD)was 1,073 ± 102 fmol/mg pro tein and the Kd (mean ± SD) was 1.56 ± 0.64 nM. The mean MMPI profile of all subjects was uniform, and the clinical scales were within the normal range (50 ± 6). Sta tistically significant and positive correlations were ob served between Bmax values and 17 MMPI items which are reported in table 1. On the other hand, no correlation between Bmax and MMPI scales were noted, nor were they noted between Kj and MMPI items or scales.
Discussion and Conclusions
12
MMPI item
True
170 415 443 447 163 340 341 414 11 300 244 252 253 440 441 453 516
-0.47 -0.45
False
0.57 -0.47 -0.63 0.45 0.63 -0.49 0.44 -0.45 -0.53 -0.46 0.47 -0.48 0.49 0.54 0.67
Castrogiovanni/Maremmani/ Di Muro/Rotondo/Marazziii
Personality and Serotonin
Downloaded by: MacQuarie University 137.111.162.20 - 2/14/2019 11:20:11 AM
Table 1. Correlations between MMPI items and Bmax values
The results of our study showed that all subjects included had Bmax values within the normal range, posi tively correlating with some MMPI items which delineate the following personality features: self-confidence (170, 415, 443, 447). feeling of well-being (163, 340, 341), no tolerance for the frustration (447,414) and sense of reality (II. 300) (table 1). The higher the Bmax. the more confi dent, concrete and realistic the subject. Therefore, it is possible to hypothesize that these features arc accen tuated by a higher level of functioning of the 5HTergic system, or at lest of that function reflected by 3H-IM1 binding. It is worth noting that these characteristics are opposite to those commonly seen in depressed patients, where in several studies the Bmax has been reported to be lower than in healthy controls [7-14]. Although our data are preliminary and derive from a small sample, they sug gest a link between the number of 3H-IMI binding sites and some personality traits, which permit to achieve selfconfidence, good social integration and good impulse control, particularly impaired with depression and even more with suicide attempts, where the peripheral 5HTer-
gic markers have been reported to be even more de creased than with depression [22-24], Naturally a single biological marker cannot reflect the complexity of a personality, however it may contribute to the development and subsequent functioning of some
traits, in balance with other systems and mechanisms. Future research should therefore be dedicated to the biol ogy of human personality and to the relationship between different neurotransmitters which might result in specific features.
References 10 Wacgner A, Aberg-Wistedt A. Asberg M. Ekquist B, Martenson B. Montero D: Lower 'H imipraminc binding in platelets from untreated depressed patients compared with healthy con trols. Psychiatry Res 1985:16:131-139. 11 Suranyi-Cadottc BE. Quirion R. McQuide P: Platelet 'H-imipramine binding: A state depen dent marker in depression. Prog. Neuropsychopharmacol Biol Psychiatry 1984;8:731-741. 12 Baron M, Barkai A. Grucn R. Peselow E. Ficve RR. Quitkin F: Platelet 'H-imipramine bind ing sites in affective disorders: Trait versus sta tus characteristics. Am J Psychiatry 1986:143: 711-717.
13 Langer SZ, Sechter D. Loo H. Raisman R.
14
15
16
17
Zarifian E: Electroconvulsive shock therapy and maximum binding of platelet tritiated imipramine binding in depression. Arch Gen Psychiatry 1986:43:949-952. Marazziti D, Perugi G. Deltito J. Lenzi A. Maremmani I. Placidi GF. Cassano GB: Higliaffinity 'H-imipramine binding sites: A possi ble state-dependent marker for major depres sion. Psychiatry Res 1988:23:229-237. Lewis DA, Noyes RJ, Coryell W. Clancy S: Triliated imipramine binding to platelets is de creased in patients with agoraphobia. Psychia try Res 198 5;6:2-9. Wcizman A, Carmi M. Tyano S, Apter A, Rehavi M: ’H-imipramine binding and sero tonin uptake to platelets of adolescent females suffering from anorexia nervosa. Life Sci 1986; 38:1235-1242. Maraz.z.iti D. Macchi E. Rotondo A. Placidi GF. Cassano GB: Involvement of serotonin system in bulimia. Life Sci 1988:43:2123— 2126.
18 Weizman R. Carmi M. Hermesh H, Shahar A. Apter A, Tyano S, Rehavi M: High-affinity imipramine binding and serotonin uptake in platelets of eight adolescent and ten adult ob sessive-compulsive patients. Am J Psychiatrv 1986:143:335-339. 19 Van Praag HM, Kahn RS, Asnis GM. Wetzler S. Brown SL. Bleich A. Korn ML: Dcnosologization of biological psychiatry or the specificity of 5-HT disturbances in psychiatric disorders. J Affective Disord 1987:13:1-8. 20 Goodwin FK. Rov-Byme PP: Future direc tions in biological psychiatry; in Meltzer HY fed): Psychopharmacology: The Third Genera tion of Progress. New York, Raven Press. 1987. pp 1691-1698. 21 Peterson GL: A simplification of the protein assavmethod of Lowry et al which is more gen erally applicable. Anal Biochem 1977:83:366— 356. 22 Asberg M. Traskman L, Thoren P: 5-HIAA in the cerebrospinal fluid: A biochemical suicide predictor? Arch Gen Psychiatry 1976:33: 1193-1197. 23 Traskman L. Asberg M. Bertilsson L, Sjostrand L: Monoamine metabolites in CSF and suicidal behavior. Arch Gen Psychiatry 1981:38:631636. 24 Marazziti D, De Leo D, Conti L: Further evi dence supporting the role of the serotonin sys tem in suicidal behaviour. Acta Psychiat Scand 1989.80:322-324.
13
Downloaded by: MacQuarie University 137.111.162.20 - 2/14/2019 11:20:11 AM
1 Sneddon MJ: Blood platelets as a model for monoamine-containing neurons. Prog Neurobiol 1973;1:151-198. 2 Stahl SM: The human platelets. A diagnostic and research tool for the study of biogenic amines in psychiatric and neurological disor ders. Arch Gen Psychiatry 1977;34:509-516. 3 Briley MS. Langer SZ. Raisman R: Human platelets possess high-affinity binding sites for 'H-imipraminc. Eur J Pharmacol I979;58: 347-348. 4 Paul SM. Rehavi M, Skolnick P. Goodwin FK: Demonstration of specific high-affinity bind ing sites for 'H-imipramine in human platelets. LifeSci 1980;26:953-959. 5 Wennogle LP, Meyerson LR: Serotonin modu lates the dissociation of ’H-imipramine from human platelet recognition sites. Eur J Phar macol 1984:86:303-307. 6 Meyerson LR. leni JR. Wennogle LP: Alloste ric interaction between the site labelled by 'Himipramine and the serotonin transporter in human platelets. J Neurochcm 1987:48:560— 565. 7 Briley MS. Langer SZ. Raisman R. Sechtcr D. Zarifian E: Tritiatcd imipramine binding sites are decreased in platelets from untreated de pressed patients. Science 1980:209:303-305. 8 Raisman R. Briley MS. Bouchami F, Sechter D. Zarifian E. Langer SZ: 'H-imipramine bind ing and serotonin uptake in platelets from un treated depressed patients and control volun teers. Psychopharmacology 1982:77:332—335. 9 Baron M. Barkai A. Grucn R. Kowalik S. Quitkin F: ’H-imipramine binding sites in unipolar depression. Biol Psychiatry 1983; 18:1403— 1409.
