164
Serotoninergic Dysfunction in Bipolar Disorder Donatella Marazziti, A. Lenzi, G. B. Cassano Institute of Psychiatry, U niversity of Pisa, Pisa, Italy
The recent discovery of peripheral markers of central neurotransmitter systems has broadened the scope of biological research in psychiatry. Human platelets resemble presynaptic serotoninergic neurons and permit us to investigate the involvement of the serotonin system in the pathophysiology of mood disorders. In particular, platelets show an active uptake of serotonin and the related 3H-imipramine eH-IMI), similar to cerebral binding sites. - We evaluated 3H-IMI binding in a group of 30 bipolar patients as compared with healthy controls. In 20 patients, platelet 14C-5HT uptake was also measured. The results showed no difference in IMI binding parameters between bipolar patients and healthy controls. However, the patients showed a lower Vmax of 14C-5HT uptake than the controls. These findings suggest that bipolarity influences one of the main components of the 5HT transporter complex in platelets.
Introduction Although no specific biological markers have yet been discovered in subtypes of mood disorders, there is a growing interest in indices of serotonin (5HT) function in view of its possible involvement in the pathophysiology of these disorders. Human platelets resemble presynaptic 5HTergic neurons and have been widely used as a peripheral marker of the 5HTergic system. In particular, they possess high-affinity binding sites for 5HT and the associated 3H-imipramine eH-IMI) (Stahl, 1977; Briley et al., 1979). Various studies have shown areduction in the number of uptake sites in platelets of depressed patients as compared with healthy controls (Tuomisto and Tukiainen, 1976; Coppen et al., 1978; Meltzer et al., 1981). A similar decrease has also been observed in the number of 3H-IMI sites (Briley et al., 1980; Baron et al., 1983, 1986; Lewis and McChesney, 1985; Waegner et al., 1985), which has been proposed as a biologi-
Phannacopsychiat. 24 (1991) 164-167 © Georg Thieme Verlag Stuttgart . N ew York
Serotoninergiscbe Dysfunktion bei bipolaren Störungen Die neuerdings verfügbaren peripheren Marker des zentralen Neurotransmittersystems haben die Möglichkeiten der biologischen Forschung auf dem Gebiet der Psychiatrie erweitert. Die menschlichen Thrombozyten verhalten sich ähnlich wie präsynaptische Serotonin-Neuronen und ermöglichen eine Erforschung der Beteiligung des Serotoninsystems bei der Pathophysiologie affektiver Störungen. Insbesondere können Thrombozyten aktiv Serotonin (5HT) aufnehmen. Ihre 3H-Imipramin(3H-IMI)-Bindungsstellen ähneln den entsprechenden Bindungsstellen im Gehirn. - Wir haben daher die 3H-IMI-Bindung in einer Patientengruppe von 30 Patienten mit bipolaren Störungen untersucht und diese mit gesunden Probanden verglichen. Bei 20 Patienten wurde ebenfalls die aktive Aufnahme von 14C-5HT durch die Thrombozyten gemessen. Es ergaben sich keine Unterschiede hinsichtlich der IMI-Bindungsparameter zwischen den Patienten mit bipolaren Störungen und den gesunden Probanden, jedoch zeigten die Patienten ein niedrigeres Vmax der 14c-5HT-Aufnahme als die Probanden. Diese Befunde scheinen darauf hinzudeuten, daß bipolare Störungen die wichtigsten hochaffinen 5HT-Bindungsstellen der Thrombozyten beeinflussen.
cal marker for depression. Some authors found a significant reduction between patients and controls, whereas other researches found no difference at all or a slight increase (Mellerup et al., 1982; Braddock et al., 1986; Carstens et al., 1986). Methodological factors, such as the possible existence of seasonal rhythms (Egrise et al., 1986; Galzin et al., 1986; Goziotis and Tang, 1988), differences in platelet storage, preparation and assay, or the effects of varying protein concentrations (Mellerup et al., 1982; Friedl and Propping, 1983), might have contributed to the discrepancies between these results. Previous pharmacotherapy and different wash-out periods might influence the binding parameters, although no drug effect on IMI binding has been reported (Nankai et al., 1986). In view of the conflicting data currently available, our study aimed at evaluating 3H-IMI binding parameters in a clinically well-eharacterised group of bipolar
Received: 11. 2.1991 Revised version: 3.6.1991 8.7.1991 Accepted:
Downloaded by: University of Iowa Libraries. Copyrighted material.
Summary
Pharmacopsychiat. 24 (1991)
Serotoninergic Dysfunction in Bipolar Disorder
Subjects
c
Thirty healthy drug-free subjects (27 females and 3 males, age between 26 and 52, mean±SD: 34.8±8.18) served as the control group. They had neither family nor past personal history of psychiatric disorders (Table I). In 20 patients out of a total of 30 (all females and all bipolar I in manic or depressive phase) and in 20 healthy volunteers (17 females and 3 males) the measurement of 14C-5HT uptake was also performed.
All patients and volunteers gave informed consent to the study.
IMI and 5HT binding assay Forty millilitres of venous blood were drawn from the fasting subject and transferred into plastic tubes containing 6 ml anticoagulant (93 mM trisodium citrate, 213 mM citric acid, and 111 mM glucose). All the sampies were collected between 8 and 10 a. m. to avoid the possible influence of circadian rhythms, and during the months March-May, to avoid seasonal rhythms. IMI binding tests were performed according to a protocol provided by the World Health Organization, as previously described (Marazziti et al., 1989). Specific binding was defined as the binding remaining in the presence of 100~M desipramine. 3H-IMI
0
e
0
g'
1200
ctflo
900
0j 0
-oE 0
Thirty patients (29 females and I male, age between 22 and 57, mean±SD: 39.7± 10.33), who had been admitted to the Psychiatric Institute at the University of Pisa, were studied. All patients were diagnosed as being afTected by bipolar disorder according to DSMIII-R criteria (American Psychiatric Association, 1987) and the results of the Semistructured Interview for Mood Disorders (SID, Cassano et al., 1988). Twenty-one were bipolar I in the manic phase (4 had mood-congruent psychotic features, 2 mood-incongruent psychotic features, I was in a mixed state, and the rest were pure manic). Seven patients were bipolar I in the depressed phase (2 were melancholic and I had mood-congruent psychotic symptoms). The other two patients were bipolar 11 depressives with melancholia. The patients had been free from antidepressant drugs for at least one year. Fifteen (all bipolar I and manie) were being given carbamazepine andjor lithium salts as a prophylactic treatment, plus neuroleptics (haloperidol, chlorpromazine) according to individual needs.
x a E
CD
•
0
~ 1500 0.
Materials and Methods
Table 1
1800
8
iI
0 0 0
0
'VC:8J
8
ifl
Serotoninergic Dysfunction in Bipolar Disorder Donatella Marazziti, A. Lenzi, G. B. Cassano Institute of Psychiatry, U niversity of Pisa, Pisa, Italy
The recent discovery of peripheral markers of central neurotransmitter systems has broadened the scope of biological research in psychiatry. Human platelets resemble presynaptic serotoninergic neurons and permit us to investigate the involvement of the serotonin system in the pathophysiology of mood disorders. In particular, platelets show an active uptake of serotonin and the related 3H-imipramine eH-IMI), similar to cerebral binding sites. - We evaluated 3H-IMI binding in a group of 30 bipolar patients as compared with healthy controls. In 20 patients, platelet 14C-5HT uptake was also measured. The results showed no difference in IMI binding parameters between bipolar patients and healthy controls. However, the patients showed a lower Vmax of 14C-5HT uptake than the controls. These findings suggest that bipolarity influences one of the main components of the 5HT transporter complex in platelets.
Introduction Although no specific biological markers have yet been discovered in subtypes of mood disorders, there is a growing interest in indices of serotonin (5HT) function in view of its possible involvement in the pathophysiology of these disorders. Human platelets resemble presynaptic 5HTergic neurons and have been widely used as a peripheral marker of the 5HTergic system. In particular, they possess high-affinity binding sites for 5HT and the associated 3H-imipramine eH-IMI) (Stahl, 1977; Briley et al., 1979). Various studies have shown areduction in the number of uptake sites in platelets of depressed patients as compared with healthy controls (Tuomisto and Tukiainen, 1976; Coppen et al., 1978; Meltzer et al., 1981). A similar decrease has also been observed in the number of 3H-IMI sites (Briley et al., 1980; Baron et al., 1983, 1986; Lewis and McChesney, 1985; Waegner et al., 1985), which has been proposed as a biologi-
Phannacopsychiat. 24 (1991) 164-167 © Georg Thieme Verlag Stuttgart . N ew York
Serotoninergiscbe Dysfunktion bei bipolaren Störungen Die neuerdings verfügbaren peripheren Marker des zentralen Neurotransmittersystems haben die Möglichkeiten der biologischen Forschung auf dem Gebiet der Psychiatrie erweitert. Die menschlichen Thrombozyten verhalten sich ähnlich wie präsynaptische Serotonin-Neuronen und ermöglichen eine Erforschung der Beteiligung des Serotoninsystems bei der Pathophysiologie affektiver Störungen. Insbesondere können Thrombozyten aktiv Serotonin (5HT) aufnehmen. Ihre 3H-Imipramin(3H-IMI)-Bindungsstellen ähneln den entsprechenden Bindungsstellen im Gehirn. - Wir haben daher die 3H-IMI-Bindung in einer Patientengruppe von 30 Patienten mit bipolaren Störungen untersucht und diese mit gesunden Probanden verglichen. Bei 20 Patienten wurde ebenfalls die aktive Aufnahme von 14C-5HT durch die Thrombozyten gemessen. Es ergaben sich keine Unterschiede hinsichtlich der IMI-Bindungsparameter zwischen den Patienten mit bipolaren Störungen und den gesunden Probanden, jedoch zeigten die Patienten ein niedrigeres Vmax der 14c-5HT-Aufnahme als die Probanden. Diese Befunde scheinen darauf hinzudeuten, daß bipolare Störungen die wichtigsten hochaffinen 5HT-Bindungsstellen der Thrombozyten beeinflussen.
cal marker for depression. Some authors found a significant reduction between patients and controls, whereas other researches found no difference at all or a slight increase (Mellerup et al., 1982; Braddock et al., 1986; Carstens et al., 1986). Methodological factors, such as the possible existence of seasonal rhythms (Egrise et al., 1986; Galzin et al., 1986; Goziotis and Tang, 1988), differences in platelet storage, preparation and assay, or the effects of varying protein concentrations (Mellerup et al., 1982; Friedl and Propping, 1983), might have contributed to the discrepancies between these results. Previous pharmacotherapy and different wash-out periods might influence the binding parameters, although no drug effect on IMI binding has been reported (Nankai et al., 1986). In view of the conflicting data currently available, our study aimed at evaluating 3H-IMI binding parameters in a clinically well-eharacterised group of bipolar
Received: 11. 2.1991 Revised version: 3.6.1991 8.7.1991 Accepted:
Downloaded by: University of Iowa Libraries. Copyrighted material.
Summary
Pharmacopsychiat. 24 (1991)
Serotoninergic Dysfunction in Bipolar Disorder
Subjects
c
Thirty healthy drug-free subjects (27 females and 3 males, age between 26 and 52, mean±SD: 34.8±8.18) served as the control group. They had neither family nor past personal history of psychiatric disorders (Table I). In 20 patients out of a total of 30 (all females and all bipolar I in manic or depressive phase) and in 20 healthy volunteers (17 females and 3 males) the measurement of 14C-5HT uptake was also performed.
All patients and volunteers gave informed consent to the study.
IMI and 5HT binding assay Forty millilitres of venous blood were drawn from the fasting subject and transferred into plastic tubes containing 6 ml anticoagulant (93 mM trisodium citrate, 213 mM citric acid, and 111 mM glucose). All the sampies were collected between 8 and 10 a. m. to avoid the possible influence of circadian rhythms, and during the months March-May, to avoid seasonal rhythms. IMI binding tests were performed according to a protocol provided by the World Health Organization, as previously described (Marazziti et al., 1989). Specific binding was defined as the binding remaining in the presence of 100~M desipramine. 3H-IMI
0
e
0
g'
1200
ctflo
900
0j 0
-oE 0
Thirty patients (29 females and I male, age between 22 and 57, mean±SD: 39.7± 10.33), who had been admitted to the Psychiatric Institute at the University of Pisa, were studied. All patients were diagnosed as being afTected by bipolar disorder according to DSMIII-R criteria (American Psychiatric Association, 1987) and the results of the Semistructured Interview for Mood Disorders (SID, Cassano et al., 1988). Twenty-one were bipolar I in the manic phase (4 had mood-congruent psychotic features, 2 mood-incongruent psychotic features, I was in a mixed state, and the rest were pure manic). Seven patients were bipolar I in the depressed phase (2 were melancholic and I had mood-congruent psychotic symptoms). The other two patients were bipolar 11 depressives with melancholia. The patients had been free from antidepressant drugs for at least one year. Fifteen (all bipolar I and manie) were being given carbamazepine andjor lithium salts as a prophylactic treatment, plus neuroleptics (haloperidol, chlorpromazine) according to individual needs.
x a E
CD
•
0
~ 1500 0.
Materials and Methods
Table 1
1800
8
iI
0 0 0
0
'VC:8J
8
ifl
