Cholinergc drugs as diagnostic and therapeutic tools in affective disorders Berger M , Riemann D, Krieg C. Cholinergic drugs as diagnostic and therapeutic tools in affective disorders. Acta Psychiatr Scand 1991: Suppl 366: 52 60.
I
The hypothesis of a significant involvement of the cholinergic system in the pathogenesis of affective disorders still lacks strong experimentnl support. This is mainly because of missing specific peripheral markers of the central nervous activity of the cholinergic system and the lack of specific cholinergic agonists and antagonists without severe peripheral side effects. As the direct cholinergic agonist KS 86 seems to be more suitable because of its minor side effects, long half-life and oral applicability, it was tested for its antimanic property and its effect on the hypothalamo-pituitary adrenal system and the rapid eye movement (REM) sleep-generating system. RS 86 exhibited antimanic and KEM sleep-inducing properties, but failed to stimulate the cortisol system.
Janowsky & Davis ( I , 2) are regarded as the founders of the noradrenergic-cholinergic imbalance hypothesis of affective disorders. Some decades before, however, other authors (3-6) postulated an imbalance of the central nervous ergotrophic and trophotrophic system as the biological basis of affective disorders. Especially the relaxation oscillation model borrowed from the engineering fields of Selbach et al. ( 5 , 6) seems to be very differentiated and stimulating for relevant experimental studies. Janowsky et al. ( I , 2), however, deserve the credit for the first systematic experimental coverage of the imbalance model by pharmacological investigations. The authors, who intended an extension of the amino deficiency hypothesis, regarded regulation of the affective system by 2 reciprocal interacting systems as more likely than regulation by a single transmitter system. This would be in keeping with the fact that other important parts of the central nervous system (CNS), such as the extrapyramidal motor system, temperature regulation, sleep and REM-sleep regulation and the whole peripheral autonomic system, are regulated by reciprocally interacting transmitter systems. Analogous to other diseases such as Parkinson's disease, Huntington's chorea or tardive dyskinesia. whose origin seems to lie in an imbalance of the dopaminergic and cholinergic transmitter systems. affective disorders may be caused by an imbalance of noradrenergic and cholinergic transmitter systems. The authors based their theory, among other things, on the observations that cholinergic drugs 52
M. Berger', 0. Riernann', C. Krieg' 'Central Institute of Mental Health, Mannheim, 7 M a ~Planck Institute of Psychiatry, Munich, Federal Republic of Germany
Key words: affective disorder; cholinergic neurotransmission; REM sleep Mathias Berger, M.D., Psychiatric Clinic, University of Freiburg, Hauptstr. 5, D-7800 Freiburg, FRG
have a dysthymic effect in healthy subjects. that cholinergic agonists intensify depressive mood in patients with major depressive disorders. and that anticholinergics seem to possess antidepressant properties. Although the number of discovered neurotransmitters and neuromodulators is continuously increasing, rendering a two-factor interaction model somewhat reductionistic, a reciprocal interaction model seems more plausible than a one-transmitter deficiency model. Because of the multiple hints at an involvement of the serotonergic system in the pathogenesis of affective disorders, it meanwhile seems more fitting to speak of an aminergic-cholinergic imbalance model. Up until recently, however, there were significant obstacles to experimental testing of the role of the cholinergic system in affective disorders and use of these results for clinical purposes of diagnosis and therapy. On the one hand, there was no relevant peripheral marker for the CNS activity of the cholinergic system, and on the other, the very short half-life and the strong unpleasant side effects of such cholinergic drugs as physostigmine limited their application, for example, in the treatment of mania. It is difficult to treat depression by anticholinergics because of the strong overlap between the therapeutic and the toxic range. In the meantime, however. relevant approaches in this field seem feasible. Especially the rediscovery of the cholinomimetic drug RS 86 (2-ethyl-8-methyl-2,8-diazospiro-4,5-decan1,3dion hydrobromide) has provided researchers with an agonist that possesses a long half-life of about
Cholinergic drugs 8 h, can be applied orally and has only minor peripheral side effects, so that a peripheral antidote such as methylscopolamine is not warranted (7, 8). With this tool, it seems to be possible to clarify the question of whether cholinergic drugs indeed have an antimanic potency, or whether the short-lived antimanic effects of physostigmine were only caused by its significant unpleasant peripheral side effects such as nausea or vomiting. Additionally, animal experiments revealed that the best proven and most stable biological abnormalities in depressive disorders, hypercortisolism and the rapid eye movement (REM) sleep disinhibition at the beginning of the night, may be caused by cholinergic central nervous overactivity. At least in animals, both the hypothalamo-pituitary adrenal system and the REM regulation system can be activated by cholinergic agonists. Therefore, the hypothesis makes sense that both biological abnormalities are the consequence of an increased CNS cholinergic activity in depression and can be regarded as indirect markers for a CNS imbalance of the aminergic and cholinergic transmitter systems. These considerations promoted our experimental investigations. targeting the relevance of the cholinergic system in affective disorders. In 10 manic patients RS 86 was tested for its antimanic properties; second, we tested whether RS 86 causes an increased secretion of cortisol in healthy subjects; and third, we investigated whether, analogous to experimental studies in animals, RS 86 also stimulates REM sleep in healthy humans after different pretreatments and whether this REM sleepstimulating effect is more pronounced in depressed patients than in healthy controls and patients with other mental disorders. Parts of these investigations have been published already elsewhere (9-1 1) but have been completed by new data and are summariied here. Antimanic effect of RS 86 Material and methods
In a double-blind study using a placebo-drug design, RS 86 was given to 10 patients (6 female. 4 male; aged: 19-22 years, mean=36+ll). Nine patients fulfilled the Research Diagnostic Criteria for mania, 1 for hypomania. According to ICD-9,7 patients had a bipolar affective disorder, 2 patients were monopolar manics and 1 patient was diagnosed as schizomanic. The length of the initial placebo phase and that inserted between the 2 drug phases varied from 2 to 7 d; the first drug phase lasted 6 d, and the second drug phase 4 d. Usually the daily RS 86 dosage consisted of a single 1mg dose distributed over the day, following the regimen 2-3-4-4-4-2 mg. Only in one nonresponder
was the dose increased to 6 mg per day. The degree of mania was assessed daily by 2 independent raters using the Inpatient Multidimensional Psychiatric Scale (IMPS) (12). The mean value of the 3 subscales excitement, hostile belligerence and grandiose expansiveness, most relevant for the evaluation of mania, were calculated. In 7 patients the blood concentration of RS 86 was measured by means of' gas chromatography-mass spectrometry; for this purpose blood samples were drawn on day 5 of the first drug phase directly before and 1 h after the 0800 intake of RS 86; the same was carried out on day 2 of the inserted placebo phase. Results
No improvement of the manic syndrome could be observed in 3 patients after the oral application of RS 86. Even an increase of the dose to 6 mg in 1 of these patients had no beneficial effect, but instead caused nausea. Two patients showed a marked improvement during the first drug phase, experienced a relapse during the following placebo phase and improved again in the second drug phase. Five patients displayed a continuous improvement in manic syndrome under RS 86 and did not experience a deterioration during the inserted placebo phase. The improvement of the manic syndrome was not only evidenced in the IMPS factors reflecting psychomotor disturbances, but also in the items evaluating superiority and grandiosity. Only minor side effects, such as increased sweating or salivation, could be observed, except for the nausea experiences by one of the 3 nonresponding patients, whose dosage had been increased to 6 mg. In the first drug phase, the RS 86 mean plasma concentration of the 3 nonresponders was lower (1 3.0 f 3.9 ng/ml) than that of the 4 responders in whom the plasma levels were determined (19.2k4.2 ng/ ml). In 2 of the 5 continuously improving responders, the assessed RS 86 plasma concentration was 4.3 and 3.7 ng/ml, respectively, on day 2 of the inserted placebo phase. In contrast to this, in the 1 responder who relapsed during the inserted placebo phase, the RS 86 concentration had dropped to an undetectable level at that time. Discussion
The study supports earlier findings that cholinomimetic agents possess antimanic properties (2, 13, 14). Convincing improvement of the manic symptoms of 7 patients could be observed during the application period of RS 86, The missing antimanic effect in the 3 nonresponding patients might be caused by individual differences in the pharmacokinetics of RS 86, especially since these nonrespond53
Berger et al.
ers showed lower mean serum concentrations than did the responders. But it might also be caused by a different pathogenetic mechanism of their manic disorder, which is not influenced by the muscarinic agonist RS 86. A surprising finding, however. was the fact that 5 of 7 responders did not show a relapse during the inserted placebo phase. Our limited data on RS 86 plasma concentrations suggested that the half-life of RS 86 may significant15 vary inter-individually. Therefore, some patients may have had an RS 86 plasma concentration during the inserted placebo phase that was still high enough to prevent a relapse. Another explanation for the phenomenon that the continuous improvement is not interrupted by the inserted placebo phase might be that an RS 86-induced “switchprocess” terminated the manic episode. A spontaneous remission occurring in each of the 5 patients during the first days of RS 86 medication is rather unlikely. In the meantime, another study has been published, with 6 manic patients treated in a similar design with up to 6 mg RS 86. Four manic patients completed the study; 2 improved, 2 were unaltered. The 2 remaining patients dropped out of the study after only 3 d of drug treatment. The results of this study neither support nor contradict the hypothesis of an antimanic property of cholinergic agonists (1 5). Effect of RS 86 on the limbic-hypothalamic-pituitaryadrenocortical (LHPA] system
Hypercortisolism in depression is believed to be caused by an overactivity of hypothalamic neurons secreting the corticotropin-releasing hormone (CRH). This assumption is corroborated by the finding of Nemeroff et al. (16), who observed an increased morning concentration of CRH in the cerebrospinal fluid of depressed patients. The release of CRH is mediated by a variety of neurotransmitters and neuropeptides, among them epinephrine, norepinephrine, serotonin. acetylcholine and gamma-aminobutyric acid. Thus, it could be demonstrated in animal studies that serotonin and acetylcholine are excitatory transmitters for the CRH-secreting neurons (1 7-21), whereas the alleged inhibitory role of norepinephrine (18, 20-22) has not yet been convincingly proven, since recent studies demonstrated an enhanced CRH secretion after the stimulation of alpha 1- and alpha 2-adrenergic receptors (23, 24). Without doubt, however, gamma-aniinobutyric acid plays an inhibitory role in CRH release into the pituitary portal circulation. Studies performed in humans with cholinomimetics such as physostigmine or arecoline resulted in an increase in serum cortisol levels (25-30). Fur54
thermore, Carroll et al. (31) and Doerr & Herger (32) demonstrated that, in healthy subjects, the injection of physostigmine induces an increase in plasma cortisol levels, even if the LHPA activity is suppressed by pretreatment with dexamethasone. These observations are in accordance with the assumption that centrally acting cholinergic agents augment cortisol secretion via an excitatory influence on the hypothalamic CRH-releasing neurons. Based on the above-mentioned findings, it was hypothesized that hypercortisolism in depression is caused by an overactivity of central cholinergic neurons, resulting in an increased CRH and (at least in the early phase of depression) ACTH secretion. A limitation of the physostigmine and arecoline experiments, however, is that these cholinergic agents frequently cause rather unpleasant side effects such as nausea or vomiting that, as stress stimuli. may indirectly activate the LHPA axis. resulting in the cortisol increase observed. We therefore used RS 86, which is a muscarinic agonist and has only minor side effects, to study the cholinergic influence on the LHPA axis.
Material and methods
Twelve healthy volunteers (2 female, 10 male; age 18-43 years, mean = 27 & 6) took part in the study. A weekly intervals and in a random design, each subject received placebo, 1.5 and 3 mg RS 86 at 1700. For cortisol analysis, blood samples were drawn at half-hourly intervals from 1600 to 2000. In addition, well-being was evaluated every hour with the Adjective Mood Scale (33) and possible side effects were assessed with a self-rating scale.
Results (Fig. 1)
After the intake of placebo, 1.5 and 3.0 mg RS 86 the mean plasma cortisol levels of all 3 experimental groups displayed a steady decline, reflecting the circadian secretion pattern of cortisol. N o statistically significant increase in mean plasma cortisol levels could be seen after the 1700 intake of 1.5 and 3.0 mg RS 86 respectively. On an individual level, 3 of the 12 subjects showed an activation of the LHPA system (cortisol increase > 20 pg/l) after placebo, 2 after 1.5 and 3 after 3.0 mg RS 86. Tivo of the 3 3.0-mg responders also experienced the greatest worsening in well-being and the most side effects. Regarding group differences, deterioration in well-being was most pronounced in the 3.0-mg RS 86 experimental group (P) of 12 healthy subjects prior to and after the intake of placebo, 1.5 and 3.0 mg RS 86 a t 1700.
Discussion
Contrary to the findings from physostigmine and arecoline. the intake of 1.5 and 3.0 mg RS 86 did not result in a stimulation of the LHPA axis. Since, after placebo, approximately the same number of subjects as in the RS 86 experiments displayed a cortisol increase, an RS 86-induced activation of the LHPA system is rather unlikely; rather, spontaneous secretory bursts have to be considered responsible for these individual findings. Furthermore. a nonspecific stress response activating the LHPA axis cannot be ruled out in some cases, especially since the subjects with a cortisol increase after 3.0 mg RS 86 also demonstrated the most pronounced deterioration in well-being, as well as the most side effects. Provided that, in humans, cholinergic agents have a stimulatory effect on the physiological regulation of LHPA activity. some considerations have to be made to explain the missing cortisol increase after RS 86. First, the dosage might not have been sufficient to stimulate the LHPA system. On the other hand, we convincingly demonstrated that a dosage of 1.5 mg RS 86 is sufficient to interfere with sleepregulating processes. Furthermore, a single-dose administration of more than 3.0 mg risks the appearance of unpleasant side effects which, as unspecific stress factors, had to be avoided. Second, endogenous counterregulating processes might have been able to overrule the phamacodynamic effects of RS 86 upon the LHPA axis. Third, the stimulatory effect of RS 86 may be absent because in humans, muscarinic receptors, different from those receptor subtypes RS 86 acts on, activate CRH-secreting neurons. Moreover, it is also likely that nicotinergic neurons, which are also stimulated by arecoline and physostigmine, activate the LHPA system. The
idea of a nicotinergic-mediated stimulation of the LHPA system is not preposterous, which can also be shown by animal studies (34) and by the fact that cigarette smoking increases plasma cortisol levels (35-37). But a combined muscarinic and nicotinic stimulation of the LHPA axis also has to be considered. as the central action of acetylcholine is only fully antagonized by the concomitant application of atropine and pempidine. a nicotinergic antagonist. Nevertheless. up to now, a hyperactivity of nicotinic neurons leading to an increased LHPA activity and thus to hypercortisolism has not yet been proven in depression. However, one also has to be aware of the fact that not only a muscarinic or nicotinic hyperactivity inay explain the increased LHPA activity in depression but also alterations in the activity of other central neurotransmitting and -modulating systems that are involved in the rather complex LHPA regulation (38). In this sense, the view that hypercortisolism in depression is caused by alterations in single distinct transmitter systems should be extended. The cholinergic system and REM sleep regulation
Shortening of REM latency (the time between sleep onset and the occurrence of the first REM period), prolongation of the first REM period and heightening of REM density are the most robust and prominent abnormalities of sleep in patients with a major depressive disorder (39). Animal studies in cats have shown that REM sleep is triggered and maintained by cholinergic neurons mainly located in the brain stem (40). The reciprocal interaction model of non-REM-REM regulation formulated by Hobson et al. (41, 42) postulates that aininergic neurons in the locus coeruleus and in the dorsal raphe inhibit REM sleep, whereas cholinergic neu-' rons in the pontine reticular formation are said to promote REM sleep. The reciprocal interaction between these transmitter systems is then assumed to be responsible for the temporal structure of nonREM and REM sleep. From this viewpoint, it seemed plausible to interpret REM sleep disinhibition in depression as further evidence of the cholinergic-aminergic imbalance hypothesis of depression (43). Sitaram et al. (44) demonstrated that intravenous administration of such cholinomimetics as physostigmine or arecoline led to an advanced onset or REM sleep in healthy volunteers. Similar effects were shown for RS 86 (7,45). Parallel investigations in depressed patients demonstrated that arecoline infusion prior to the second REM period led to a more pronounced REMinducing effect than in healthy subjects (44,46,47). In a study using 1.5 mg RS 86 we were able to show that this cholinergic drug provoked sleep on55
Berger et al. set periods (REM latency 1 2 5 min) in 14 of 16 depressed patients investigated (48, 49). Patients with personality disorders or an eating disorder. even with a concomitant major depression, showed REM sleep induction by RS 86 comparable to that of healthy controls and were clearly distinguishable from depressed subjects (49, 50). A pilot study in 9 depressive patients in remission seemed to indicate that pronounced REM induction in the cholinergic REM induction test with RS 86 may be a state marker but not a trait marker of major depression (51). To further elucidate the underlying mechanisms of REM sleep disinhibition in depression, we conducted 2 studies in healthy subjects (1 and 2) with the aim of testing the reciprocal interaction model of non-REM-REM regulation. Further, we investigated a new sample of depressed subjects with the cholinergic REM induction test with RS 86 and compared them with patients with anxiety disorders and schizophrenic disorders (study 3) to test the specificity of the REM sleep response to RS 86 for depressive disorders. Study 1
Ten young male healthy subjects with a mean age ( t- SD) of 27 k 2 years participated. After an adaptation and a baseline night, healthy volunteers were given scopolamine (6 pg!kg body weight) for a period of 3 d at 1000 via intramuscular injection. Additionally, 1.5 mg RS 86 was administered prior to sleep at 2200 on the third night of scopolamine administration. The design was double-blind placebo (NaC1)-controlled with a 1-week interval. Sleep was registered polysomnographically during all nights by standard procedures (52). The rationale for the design of this study was based on an investigation by Gillin et al. (53, 54), who showed that administration of the cholinergic antagonist scopolamine over a period of 3 d in the morning led to a hastening of the onset of REM sleep in the evening. The authors interpreted their results as evidence of the hypothesis that cholinergic blockade in the morning led to muscarinic supersensitivity in the evening. In our data analysis, we compared the influence of placebo (NaCI) pretreatment with the influence of scopolamine pretreatment on the baseline and the first 2 experimental nights. There was no effect on REM latency: in both conditions (NaC1 and scopolamine pretreatment), REM latency decreased slightly over the 3 d. After scopolamine treatment, however, the duration of the first REM period tended to increase (P10.06), the first REM density was significantly increased (PI 0.01) and REM density (Fig. 2) of the whole night was in56
creased ( P < 0.01) compared with NaCl pretreatment. Concerning the additional administration of RS 86 on the third night of scopolamine pretreatment, no additional effect on REM sleep could be demonstrated. The results of this study are presented in more detail elsewhere (55). Study 2
Twelve young male subjects with a mean age of 27+2 years took part. Healthy volunteers were treated with clonidine for 3 d (0.15 mg at 0900 and 1800) after an adaptation period of 3 d. Two or three days after cessation of clonidine administration, the volunteers were randomly assigned to a placebo or 1.5 mg RS 86 REM induction test. Sleep was registered throughout the whole experimental protocol. Clonidine tests according to standard procedures (56) were performed on the day before and after clonidine treatment, to test whether a noradrenergic subsensitivity. i.e., reduced growth hormone secretion, had been achieved. The aim of the study was to provoke a noradrenergic subsensitivity by 3 d of administration of clonidine, an a2 receptor agonist. Administration of clonidine led to a lengthening of REM latency. as expected (Fig. 3). After the first 6 volunteers, the design had to be changed, as there were still detectable plasma levels of clonidine after only one drug-free night. The main result of the study was that after clonidine treatment was ceased, REM latency returned to baseline values, which means that, before the RS 86 REM induction test, 1 more washout day was inserted. Additional cholinergic stimulation did not lead to a disinhibition of REM sleep. Clonidine hGH tests revealed that clonidine treatment had not provoked depression-like abnormalities of growth hormone secretion: clonidine treatment did not lead 1.5 mg R S 86
c
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29. N~;RNHI.:RGI:R JI. JIMERSONDt, SlhlhfONS-~I.l.lNG s et al. Behavioral. physiological, and neuroendocrine responses to arecoline in normal twins and “well state” bipolar patients. Psychiatry Res 1983: 9: 191. 30. JANOWSKY DS, RISCIISC, KENNIB)Y B, ZIIGLERM, HUEY L. Central muscarinic effects of physostigmine on mood. cardiovascular function, pituitary and adrenal ncuroendocrine release. Psychopharmacology 1986: 89: 150. 3 I . CARROILBJ, GREIXN JF, RUBISRT. HASKETT K, FEINBERG M, Scwriiix(imT D. Neurotransmitter mechanism of neuroendocrine disturbance in depression. Acta Endocrinol 1978: Suppl 220: 13. 32. DOERRP. BERGIR M. Physostigmine-induced escape from dexamcthasone suppression in normal adults. Biol l’sychiatry 1983: 18: 261. D. Clinical Self-Rating Scales (CSRS) of the 33. V o s ZERSSI~N Munich Psychiatric Information System (PSYCHIS Miinchcn). In: SATORIUSN. BAS TA, ed. Assessment of dcpression. Berlin: Springer. 1986: 270-303. 34. NARITA s. SIIIHATA 0, WAKIS . EGASHIRA K. Adrenal cortical secretion i n response to nicotine in conscious and anaesthetized dog. Q J Exp Physiol 1973: 58: 139. A, PAPPJOHN DJ. BEI.I.I.:TS, HlRABAYASIll M. 35. KERSHBA~JM SIIAFIIIIA H. lffect of smoking and nicotine on adrenocortical secretion. JAMA 1968: 203: 275-278. 36. WINTIIRNJTZ WW, Q N D. Acute hormonal response to Pharmacol 1977: 17: 389. cigarette smoking. J 37. WII.KINS JN. CARI.SON IIE. VUNAKISf I VAS. l i i i , i , .MA. GRrrz E, JARVIKME. Nicotine from cigarette smoking increases circulating levels of cortisol, growth hormone. and prolactin in male chronic smokers. I’sychopharmacology 1982: 78: 305. 38. €IOI.HOER F. Psychiatric implications of altered limbic-hypothalamic-pituitary-adrenocortical activity. Eur Arch Psychiatry Neurol Sci 1989: 238: 302-322. 39. REYNOLDS CF, KUPFI~R DJ. Sleep research in affective illness: state of the art circa 1987. Sleep 1987: 10: 199-215. 40. HOIWX JA, MCCARLEY RW. WYZINSKIPW. Sleep cycle oscillation: reciprocal discharge by t a o brainstem neuronal groups. Science 1975: 189: 55-58. 41. HOBSONJA, STERIADE iM. Neuronal basis of behavioral VB, BLOOMFE. CiEIGER state control. In: MOGNTCASTII. SR, cd. IIandbook of physiology, vol. 1V. Intrinsic regulatory systems of the brain. Bethesda, MI): Am Physiol Soc, 1986: 701-723. 42. Iiowm JA, L Y I K, ~ BAcmixwAN HA. Evolving concepts of sleep cycle generation: from brain centers to neuronal populations. Behav Brain Sci 1986: 9: 371488. 43. MCCARLEY RW. REM sleep and depression: common neuroendocrinology, vol. 8. Berlin: Springer, 1989: 141- 182. 44. SITARAM N. GII.L.INJC, BUNNEY WE. Cholinergic and catecholaminergic receptor sensitivity in affective illness: strategy and theory. In: POSTRM, BAIL ology of mood disorders. Baltimore: Williams & Willkins, 1984: 629- 651. 45. RIEMANSI>, JOY D, H6crn.1 D, LAUERCH, ZUILEY J. BERGERM. Influence of the cholinergic agonist RS 86 on normal sleep: sex and age effects. Psychiatry Res 1988: 24: 137 147. 46. GILLINJC, SITARAMN, MENL)BLSON WB. Acetylcholine. sleep and depression. IIum Neurobiol I: 21 1-219. 47. NURNBERGER J, BERRETTINI W, MENDELSON W, SACKD. GERSHON ES. Measuring cholinergic sensitivity. I. Arecoline effects in bipolar patients. Biol Psychiatry 1989: 25: 610. 48. BERGERM, HOCIKI D. ZULLEYJ, LAUERC, VON ZERSSEN. Cholinominietic drug RS 86, REM sleep and depression. Lancet 1985: 1: 1385-1386. 49. BERCERM, RIIMANND, H6c1nr D, SPIECELR. The cholin-
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I
The hypothesis of a significant involvement of the cholinergic system in the pathogenesis of affective disorders still lacks strong experimentnl support. This is mainly because of missing specific peripheral markers of the central nervous activity of the cholinergic system and the lack of specific cholinergic agonists and antagonists without severe peripheral side effects. As the direct cholinergic agonist KS 86 seems to be more suitable because of its minor side effects, long half-life and oral applicability, it was tested for its antimanic property and its effect on the hypothalamo-pituitary adrenal system and the rapid eye movement (REM) sleep-generating system. RS 86 exhibited antimanic and KEM sleep-inducing properties, but failed to stimulate the cortisol system.
Janowsky & Davis ( I , 2) are regarded as the founders of the noradrenergic-cholinergic imbalance hypothesis of affective disorders. Some decades before, however, other authors (3-6) postulated an imbalance of the central nervous ergotrophic and trophotrophic system as the biological basis of affective disorders. Especially the relaxation oscillation model borrowed from the engineering fields of Selbach et al. ( 5 , 6) seems to be very differentiated and stimulating for relevant experimental studies. Janowsky et al. ( I , 2), however, deserve the credit for the first systematic experimental coverage of the imbalance model by pharmacological investigations. The authors, who intended an extension of the amino deficiency hypothesis, regarded regulation of the affective system by 2 reciprocal interacting systems as more likely than regulation by a single transmitter system. This would be in keeping with the fact that other important parts of the central nervous system (CNS), such as the extrapyramidal motor system, temperature regulation, sleep and REM-sleep regulation and the whole peripheral autonomic system, are regulated by reciprocally interacting transmitter systems. Analogous to other diseases such as Parkinson's disease, Huntington's chorea or tardive dyskinesia. whose origin seems to lie in an imbalance of the dopaminergic and cholinergic transmitter systems. affective disorders may be caused by an imbalance of noradrenergic and cholinergic transmitter systems. The authors based their theory, among other things, on the observations that cholinergic drugs 52
M. Berger', 0. Riernann', C. Krieg' 'Central Institute of Mental Health, Mannheim, 7 M a ~Planck Institute of Psychiatry, Munich, Federal Republic of Germany
Key words: affective disorder; cholinergic neurotransmission; REM sleep Mathias Berger, M.D., Psychiatric Clinic, University of Freiburg, Hauptstr. 5, D-7800 Freiburg, FRG
have a dysthymic effect in healthy subjects. that cholinergic agonists intensify depressive mood in patients with major depressive disorders. and that anticholinergics seem to possess antidepressant properties. Although the number of discovered neurotransmitters and neuromodulators is continuously increasing, rendering a two-factor interaction model somewhat reductionistic, a reciprocal interaction model seems more plausible than a one-transmitter deficiency model. Because of the multiple hints at an involvement of the serotonergic system in the pathogenesis of affective disorders, it meanwhile seems more fitting to speak of an aminergic-cholinergic imbalance model. Up until recently, however, there were significant obstacles to experimental testing of the role of the cholinergic system in affective disorders and use of these results for clinical purposes of diagnosis and therapy. On the one hand, there was no relevant peripheral marker for the CNS activity of the cholinergic system, and on the other, the very short half-life and the strong unpleasant side effects of such cholinergic drugs as physostigmine limited their application, for example, in the treatment of mania. It is difficult to treat depression by anticholinergics because of the strong overlap between the therapeutic and the toxic range. In the meantime, however. relevant approaches in this field seem feasible. Especially the rediscovery of the cholinomimetic drug RS 86 (2-ethyl-8-methyl-2,8-diazospiro-4,5-decan1,3dion hydrobromide) has provided researchers with an agonist that possesses a long half-life of about
Cholinergic drugs 8 h, can be applied orally and has only minor peripheral side effects, so that a peripheral antidote such as methylscopolamine is not warranted (7, 8). With this tool, it seems to be possible to clarify the question of whether cholinergic drugs indeed have an antimanic potency, or whether the short-lived antimanic effects of physostigmine were only caused by its significant unpleasant peripheral side effects such as nausea or vomiting. Additionally, animal experiments revealed that the best proven and most stable biological abnormalities in depressive disorders, hypercortisolism and the rapid eye movement (REM) sleep disinhibition at the beginning of the night, may be caused by cholinergic central nervous overactivity. At least in animals, both the hypothalamo-pituitary adrenal system and the REM regulation system can be activated by cholinergic agonists. Therefore, the hypothesis makes sense that both biological abnormalities are the consequence of an increased CNS cholinergic activity in depression and can be regarded as indirect markers for a CNS imbalance of the aminergic and cholinergic transmitter systems. These considerations promoted our experimental investigations. targeting the relevance of the cholinergic system in affective disorders. In 10 manic patients RS 86 was tested for its antimanic properties; second, we tested whether RS 86 causes an increased secretion of cortisol in healthy subjects; and third, we investigated whether, analogous to experimental studies in animals, RS 86 also stimulates REM sleep in healthy humans after different pretreatments and whether this REM sleepstimulating effect is more pronounced in depressed patients than in healthy controls and patients with other mental disorders. Parts of these investigations have been published already elsewhere (9-1 1) but have been completed by new data and are summariied here. Antimanic effect of RS 86 Material and methods
In a double-blind study using a placebo-drug design, RS 86 was given to 10 patients (6 female. 4 male; aged: 19-22 years, mean=36+ll). Nine patients fulfilled the Research Diagnostic Criteria for mania, 1 for hypomania. According to ICD-9,7 patients had a bipolar affective disorder, 2 patients were monopolar manics and 1 patient was diagnosed as schizomanic. The length of the initial placebo phase and that inserted between the 2 drug phases varied from 2 to 7 d; the first drug phase lasted 6 d, and the second drug phase 4 d. Usually the daily RS 86 dosage consisted of a single 1mg dose distributed over the day, following the regimen 2-3-4-4-4-2 mg. Only in one nonresponder
was the dose increased to 6 mg per day. The degree of mania was assessed daily by 2 independent raters using the Inpatient Multidimensional Psychiatric Scale (IMPS) (12). The mean value of the 3 subscales excitement, hostile belligerence and grandiose expansiveness, most relevant for the evaluation of mania, were calculated. In 7 patients the blood concentration of RS 86 was measured by means of' gas chromatography-mass spectrometry; for this purpose blood samples were drawn on day 5 of the first drug phase directly before and 1 h after the 0800 intake of RS 86; the same was carried out on day 2 of the inserted placebo phase. Results
No improvement of the manic syndrome could be observed in 3 patients after the oral application of RS 86. Even an increase of the dose to 6 mg in 1 of these patients had no beneficial effect, but instead caused nausea. Two patients showed a marked improvement during the first drug phase, experienced a relapse during the following placebo phase and improved again in the second drug phase. Five patients displayed a continuous improvement in manic syndrome under RS 86 and did not experience a deterioration during the inserted placebo phase. The improvement of the manic syndrome was not only evidenced in the IMPS factors reflecting psychomotor disturbances, but also in the items evaluating superiority and grandiosity. Only minor side effects, such as increased sweating or salivation, could be observed, except for the nausea experiences by one of the 3 nonresponding patients, whose dosage had been increased to 6 mg. In the first drug phase, the RS 86 mean plasma concentration of the 3 nonresponders was lower (1 3.0 f 3.9 ng/ml) than that of the 4 responders in whom the plasma levels were determined (19.2k4.2 ng/ ml). In 2 of the 5 continuously improving responders, the assessed RS 86 plasma concentration was 4.3 and 3.7 ng/ml, respectively, on day 2 of the inserted placebo phase. In contrast to this, in the 1 responder who relapsed during the inserted placebo phase, the RS 86 concentration had dropped to an undetectable level at that time. Discussion
The study supports earlier findings that cholinomimetic agents possess antimanic properties (2, 13, 14). Convincing improvement of the manic symptoms of 7 patients could be observed during the application period of RS 86, The missing antimanic effect in the 3 nonresponding patients might be caused by individual differences in the pharmacokinetics of RS 86, especially since these nonrespond53
Berger et al.
ers showed lower mean serum concentrations than did the responders. But it might also be caused by a different pathogenetic mechanism of their manic disorder, which is not influenced by the muscarinic agonist RS 86. A surprising finding, however. was the fact that 5 of 7 responders did not show a relapse during the inserted placebo phase. Our limited data on RS 86 plasma concentrations suggested that the half-life of RS 86 may significant15 vary inter-individually. Therefore, some patients may have had an RS 86 plasma concentration during the inserted placebo phase that was still high enough to prevent a relapse. Another explanation for the phenomenon that the continuous improvement is not interrupted by the inserted placebo phase might be that an RS 86-induced “switchprocess” terminated the manic episode. A spontaneous remission occurring in each of the 5 patients during the first days of RS 86 medication is rather unlikely. In the meantime, another study has been published, with 6 manic patients treated in a similar design with up to 6 mg RS 86. Four manic patients completed the study; 2 improved, 2 were unaltered. The 2 remaining patients dropped out of the study after only 3 d of drug treatment. The results of this study neither support nor contradict the hypothesis of an antimanic property of cholinergic agonists (1 5). Effect of RS 86 on the limbic-hypothalamic-pituitaryadrenocortical (LHPA] system
Hypercortisolism in depression is believed to be caused by an overactivity of hypothalamic neurons secreting the corticotropin-releasing hormone (CRH). This assumption is corroborated by the finding of Nemeroff et al. (16), who observed an increased morning concentration of CRH in the cerebrospinal fluid of depressed patients. The release of CRH is mediated by a variety of neurotransmitters and neuropeptides, among them epinephrine, norepinephrine, serotonin. acetylcholine and gamma-aminobutyric acid. Thus, it could be demonstrated in animal studies that serotonin and acetylcholine are excitatory transmitters for the CRH-secreting neurons (1 7-21), whereas the alleged inhibitory role of norepinephrine (18, 20-22) has not yet been convincingly proven, since recent studies demonstrated an enhanced CRH secretion after the stimulation of alpha 1- and alpha 2-adrenergic receptors (23, 24). Without doubt, however, gamma-aniinobutyric acid plays an inhibitory role in CRH release into the pituitary portal circulation. Studies performed in humans with cholinomimetics such as physostigmine or arecoline resulted in an increase in serum cortisol levels (25-30). Fur54
thermore, Carroll et al. (31) and Doerr & Herger (32) demonstrated that, in healthy subjects, the injection of physostigmine induces an increase in plasma cortisol levels, even if the LHPA activity is suppressed by pretreatment with dexamethasone. These observations are in accordance with the assumption that centrally acting cholinergic agents augment cortisol secretion via an excitatory influence on the hypothalamic CRH-releasing neurons. Based on the above-mentioned findings, it was hypothesized that hypercortisolism in depression is caused by an overactivity of central cholinergic neurons, resulting in an increased CRH and (at least in the early phase of depression) ACTH secretion. A limitation of the physostigmine and arecoline experiments, however, is that these cholinergic agents frequently cause rather unpleasant side effects such as nausea or vomiting that, as stress stimuli. may indirectly activate the LHPA axis. resulting in the cortisol increase observed. We therefore used RS 86, which is a muscarinic agonist and has only minor side effects, to study the cholinergic influence on the LHPA axis.
Material and methods
Twelve healthy volunteers (2 female, 10 male; age 18-43 years, mean = 27 & 6) took part in the study. A weekly intervals and in a random design, each subject received placebo, 1.5 and 3 mg RS 86 at 1700. For cortisol analysis, blood samples were drawn at half-hourly intervals from 1600 to 2000. In addition, well-being was evaluated every hour with the Adjective Mood Scale (33) and possible side effects were assessed with a self-rating scale.
Results (Fig. 1)
After the intake of placebo, 1.5 and 3.0 mg RS 86 the mean plasma cortisol levels of all 3 experimental groups displayed a steady decline, reflecting the circadian secretion pattern of cortisol. N o statistically significant increase in mean plasma cortisol levels could be seen after the 1700 intake of 1.5 and 3.0 mg RS 86 respectively. On an individual level, 3 of the 12 subjects showed an activation of the LHPA system (cortisol increase > 20 pg/l) after placebo, 2 after 1.5 and 3 after 3.0 mg RS 86. Tivo of the 3 3.0-mg responders also experienced the greatest worsening in well-being and the most side effects. Regarding group differences, deterioration in well-being was most pronounced in the 3.0-mg RS 86 experimental group (P) of 12 healthy subjects prior to and after the intake of placebo, 1.5 and 3.0 mg RS 86 a t 1700.
Discussion
Contrary to the findings from physostigmine and arecoline. the intake of 1.5 and 3.0 mg RS 86 did not result in a stimulation of the LHPA axis. Since, after placebo, approximately the same number of subjects as in the RS 86 experiments displayed a cortisol increase, an RS 86-induced activation of the LHPA system is rather unlikely; rather, spontaneous secretory bursts have to be considered responsible for these individual findings. Furthermore. a nonspecific stress response activating the LHPA axis cannot be ruled out in some cases, especially since the subjects with a cortisol increase after 3.0 mg RS 86 also demonstrated the most pronounced deterioration in well-being, as well as the most side effects. Provided that, in humans, cholinergic agents have a stimulatory effect on the physiological regulation of LHPA activity. some considerations have to be made to explain the missing cortisol increase after RS 86. First, the dosage might not have been sufficient to stimulate the LHPA system. On the other hand, we convincingly demonstrated that a dosage of 1.5 mg RS 86 is sufficient to interfere with sleepregulating processes. Furthermore, a single-dose administration of more than 3.0 mg risks the appearance of unpleasant side effects which, as unspecific stress factors, had to be avoided. Second, endogenous counterregulating processes might have been able to overrule the phamacodynamic effects of RS 86 upon the LHPA axis. Third, the stimulatory effect of RS 86 may be absent because in humans, muscarinic receptors, different from those receptor subtypes RS 86 acts on, activate CRH-secreting neurons. Moreover, it is also likely that nicotinergic neurons, which are also stimulated by arecoline and physostigmine, activate the LHPA system. The
idea of a nicotinergic-mediated stimulation of the LHPA system is not preposterous, which can also be shown by animal studies (34) and by the fact that cigarette smoking increases plasma cortisol levels (35-37). But a combined muscarinic and nicotinic stimulation of the LHPA axis also has to be considered. as the central action of acetylcholine is only fully antagonized by the concomitant application of atropine and pempidine. a nicotinergic antagonist. Nevertheless. up to now, a hyperactivity of nicotinic neurons leading to an increased LHPA activity and thus to hypercortisolism has not yet been proven in depression. However, one also has to be aware of the fact that not only a muscarinic or nicotinic hyperactivity inay explain the increased LHPA activity in depression but also alterations in the activity of other central neurotransmitting and -modulating systems that are involved in the rather complex LHPA regulation (38). In this sense, the view that hypercortisolism in depression is caused by alterations in single distinct transmitter systems should be extended. The cholinergic system and REM sleep regulation
Shortening of REM latency (the time between sleep onset and the occurrence of the first REM period), prolongation of the first REM period and heightening of REM density are the most robust and prominent abnormalities of sleep in patients with a major depressive disorder (39). Animal studies in cats have shown that REM sleep is triggered and maintained by cholinergic neurons mainly located in the brain stem (40). The reciprocal interaction model of non-REM-REM regulation formulated by Hobson et al. (41, 42) postulates that aininergic neurons in the locus coeruleus and in the dorsal raphe inhibit REM sleep, whereas cholinergic neu-' rons in the pontine reticular formation are said to promote REM sleep. The reciprocal interaction between these transmitter systems is then assumed to be responsible for the temporal structure of nonREM and REM sleep. From this viewpoint, it seemed plausible to interpret REM sleep disinhibition in depression as further evidence of the cholinergic-aminergic imbalance hypothesis of depression (43). Sitaram et al. (44) demonstrated that intravenous administration of such cholinomimetics as physostigmine or arecoline led to an advanced onset or REM sleep in healthy volunteers. Similar effects were shown for RS 86 (7,45). Parallel investigations in depressed patients demonstrated that arecoline infusion prior to the second REM period led to a more pronounced REMinducing effect than in healthy subjects (44,46,47). In a study using 1.5 mg RS 86 we were able to show that this cholinergic drug provoked sleep on55
Berger et al. set periods (REM latency 1 2 5 min) in 14 of 16 depressed patients investigated (48, 49). Patients with personality disorders or an eating disorder. even with a concomitant major depression, showed REM sleep induction by RS 86 comparable to that of healthy controls and were clearly distinguishable from depressed subjects (49, 50). A pilot study in 9 depressive patients in remission seemed to indicate that pronounced REM induction in the cholinergic REM induction test with RS 86 may be a state marker but not a trait marker of major depression (51). To further elucidate the underlying mechanisms of REM sleep disinhibition in depression, we conducted 2 studies in healthy subjects (1 and 2) with the aim of testing the reciprocal interaction model of non-REM-REM regulation. Further, we investigated a new sample of depressed subjects with the cholinergic REM induction test with RS 86 and compared them with patients with anxiety disorders and schizophrenic disorders (study 3) to test the specificity of the REM sleep response to RS 86 for depressive disorders. Study 1
Ten young male healthy subjects with a mean age ( t- SD) of 27 k 2 years participated. After an adaptation and a baseline night, healthy volunteers were given scopolamine (6 pg!kg body weight) for a period of 3 d at 1000 via intramuscular injection. Additionally, 1.5 mg RS 86 was administered prior to sleep at 2200 on the third night of scopolamine administration. The design was double-blind placebo (NaC1)-controlled with a 1-week interval. Sleep was registered polysomnographically during all nights by standard procedures (52). The rationale for the design of this study was based on an investigation by Gillin et al. (53, 54), who showed that administration of the cholinergic antagonist scopolamine over a period of 3 d in the morning led to a hastening of the onset of REM sleep in the evening. The authors interpreted their results as evidence of the hypothesis that cholinergic blockade in the morning led to muscarinic supersensitivity in the evening. In our data analysis, we compared the influence of placebo (NaCI) pretreatment with the influence of scopolamine pretreatment on the baseline and the first 2 experimental nights. There was no effect on REM latency: in both conditions (NaC1 and scopolamine pretreatment), REM latency decreased slightly over the 3 d. After scopolamine treatment, however, the duration of the first REM period tended to increase (P10.06), the first REM density was significantly increased (PI 0.01) and REM density (Fig. 2) of the whole night was in56
creased ( P < 0.01) compared with NaCl pretreatment. Concerning the additional administration of RS 86 on the third night of scopolamine pretreatment, no additional effect on REM sleep could be demonstrated. The results of this study are presented in more detail elsewhere (55). Study 2
Twelve young male subjects with a mean age of 27+2 years took part. Healthy volunteers were treated with clonidine for 3 d (0.15 mg at 0900 and 1800) after an adaptation period of 3 d. Two or three days after cessation of clonidine administration, the volunteers were randomly assigned to a placebo or 1.5 mg RS 86 REM induction test. Sleep was registered throughout the whole experimental protocol. Clonidine tests according to standard procedures (56) were performed on the day before and after clonidine treatment, to test whether a noradrenergic subsensitivity. i.e., reduced growth hormone secretion, had been achieved. The aim of the study was to provoke a noradrenergic subsensitivity by 3 d of administration of clonidine, an a2 receptor agonist. Administration of clonidine led to a lengthening of REM latency. as expected (Fig. 3). After the first 6 volunteers, the design had to be changed, as there were still detectable plasma levels of clonidine after only one drug-free night. The main result of the study was that after clonidine treatment was ceased, REM latency returned to baseline values, which means that, before the RS 86 REM induction test, 1 more washout day was inserted. Additional cholinergic stimulation did not lead to a disinhibition of REM sleep. Clonidine hGH tests revealed that clonidine treatment had not provoked depression-like abnormalities of growth hormone secretion: clonidine treatment did not lead 1.5 mg R S 86
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