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Cholinergic REM induction response: Separation of anxiety and depression
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Cholinergic REM Induction Response: Separation of Anxiety and Depression S. Dub6, N. Kumar, E. Ettedgui, R. Pohl, D. Jones, and N. Sitaram
Five groups of subjects underwent EEG sleep recordings, arecoline rapid eye movement (REM) induction response testing, and Schedule for Affective Disorders and Schizophrenia (SADS ) interview. Group I: 20 patients with primary major depressive disorder (MDD ) (endogenous) without any coexisting anxiety disorder; Group H: 19 primary MDD (endogenous) patients with secondary panic, GAD, or phobic disorders; Group Ili: 18 patients with primary anxiety disorder without coexisting MDD; Group IV: 14 patients with primary anxiety plus secondary MDD; Group V: 26 normal controls. Modified Research Diagnostic Criteria (RDC) were used for diagnosis, based on the SADS interview. There was considerable overlap of SADS scaled scores between patient groups, which is consistent with a heterogeneous clinical presentation of depressive and anxiety states. REM latency was significantly shorter in patients with primary MDD (without anxiety) as compared with that in patients with primary anxiety (no MDD ) and normals. Arecoline REM induction response time was significantly shorter in both primary affective groups (I and II) as compared with primary anxiety (no MDD) patients and normal controls. REM latency and arecoline REM induction time was not significantly different between the primary anxiety groups (III and IV) and normals. The study highlights the use of biological markers in differentiating between clinical syndromes confounded by mixed or overlapping phenomenology.
Introduction The clinical significance of the frequent occurrence of symptoms of anxiety, such as psychomotor agitation, nervousness, and tenseness in depressed patients (Overall et al. 1966; Paykel 1971; Prusoff and Paykel 1977), and the presence of depressive symptomatology in patients diagnosed as predominantly anxious remains unclear and poses problems in differential diagnosis (Klerman 1971). Longitudinal studies suggest a considerable
From the Affective Disorders Unit (S.D., D.J., N.S.) and the Anxiety Disorders Program (N.K., E.E., R.P.), Lafayette Clinic, Wayne State University, Detroit, MI. Supported by NIMH Grant MH 38342-01. Address reprint requests to Dr. S. DubS, Affective Disorders Unit, Lafayette Clinic, Wayne State University, 951 East Lafayette, DeAtoit, MI 48207. Received February 11, 1984; accepted October 3, 1984.
1985 Society of Biological Psychiatry
0006-32231851503.30
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overlap between symptoms of anxiety and depression in some patients (Cassidy et al. 1957; Kerr et al. 1969; Shapira et al. 1972; Downing and Rickels 1974; Akiskal et al. 1978; Raskin et al. 1982; Roth et al. 1982), leading to identification of an "anxious" subgroup of depressives by some investigators (Paykel 1971; Paykel and Fowles 1979). Are these disorders part of a continuum (Lewis 1934), with a shared pathophysiological substrate, or are they distinct conditions that often occur together? Recent family and genetic studies have yielded contradictory results. Noyes et al. (1978) Cloninger et al. (1981), and Crowe et al. (1983) found an increased risk for panic disorder, but not depression, in relatives of primary anxiety disorder probands compared with normal control probands. On the other hand, Leckman et al. (1983a,b) found a twofold increase in risk for both affective and anxiety disorders in relatives of probands with major depression with concurrent or antecedent panic or generalized anxiety disorder, as compared to probands with depression alone. Part of the discrepancy may be due to differences in diagnostic methods as well as selection of patient groups. For instance, Noyes et al. (1978), Cloninger et al. (1981), and Crowe et al. (1983) had anxious and normal control proband groups, but failed to include a major depressive disorder group in their study. Leckman et al. (1983a,b), on the other hand, did not have a primary anxiety disorder proband control group. The use of biological markers is a valid and potentially powerful tool to study this problem. Two recent studies (Reynolds et al. 1983; Akiskal et al. 1983) compared EEG sleep parameters of anxious and depressed patients. They reported that depressives had a shorter latency to onset of rapid eye movement sleep (REM latency) and greater REM sleep percent as compared to generalized anxiety disorder and panic disorder patients. The focus of the current study was the comparison of affective and anxious patients on both conventional sleep EEG variables (such as REM latency) and their sensitivity to cholinergic induction of REM sleep (Sitaram et al. 1980, 1982; Jones et al. 1983, 1984). The latter has been shown to be a putative "trait" marker of primary affective illness. The hypothesis of a shared diathesis between depression and anxiety disorders could be tested in part by determining whether or not a supersensitive cholinergic REM induction response--a putative affective vulnerability marker--is shared by the two illnesses.
Methods Thirty-nine patients (inpatients and outpatients) who fulfilled the modified RDC criteria for major depressive disorder (Mazure and Gershon 1979) and endogenous subtype (Spitzer et al. 1978) formed one group. In addition, 32 patients who fulfilled the RDC criteria for anxiety disorders, i.e., generalized anxiety, panic, and phobic disorders, as their primary diagnoses were also included in the study. It should be noted that the RDC convention of not diagnosing an anxiety disorder that occurs in conjunction with a major depressive episode was disregarded in this study. These groups were subdivided into the following categories (Table 1): • Group I. Primary MDD (endogenous) (n = 20), without superimposed or concomitant anxiety disorder (Pri MDD-E). • Group II. Primary MDD (endogenous) with coexisting anxiety disorder meeting full RI)C criteria (n = 19) (Pri MDD + ANX). In 14 patients, MDD and anxiety disorder were always temporally associated. The remaining five patients met criteria
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for an anxiety disorder temporally separated from a major depressive episode by at least 2 months. • Group III. Primary anxiety disorders without MDD (n = 18) (Pri ANX). • Group IV. Primary anxiety disorders with secondary MDD (n = 14) (Pri ANX + See MDD). • Group V. Normal controls (n = 26). These subjects did not have any current or past history of major psychiatric or medical illness. Hereafter, the groups shall be referred to by their abbreviations. All subjects were administered a Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer et al. 1978) by experienced research clinicians whose interrater reliabi~y had been established. Both current and life-time diagnostic assessment of subjects (based on conventional or modified RDC criteria) were made using information from SADS Parts I and II, respectively. Raters were blind to sleep data, and the research assistant who scored the polygraphic sleep records was in turn unaware of the clinical data. All subjects received a complete physical and neurological examiniation, EKG, blood chemistry (SMA-17, T3, T4, CBC with differential) and urinalysis prior to inclusion in the study. They were free from any psychotropic agents or drugs that might influence that patient's mood or polygraphic data for at least 2 weeks prior to the study. An informed consent was obtained from every subject. Sleep Subjects underwent 3-4 nights of sleep recording, during which their EEG (C3-A2), EMG (submental electromyogram), and EOG (electrooculogram) were monitored as per standard criteria of Rechtschaffen and Kales (1968). Electrocardiogram (lead II) was also monitored throughout the night. The first night served to acclimatize the patient to sleeping with electrodes. During the second night, a regular polygraphic recording was obtained ("baseline" night). On nights 3 and 4, in addition to placement of polygraphic electrodes, subjects also slept with a 21-gauge scalp vein needle placed in a forearm vein attached to a 10-ft polyethylene tubing extending into an adjacent room. A continuous infusion of normal saline was maintained at the rate of approximately 0.25 ml/min (using an IVAC infusion pump) throughout the night to prevent blood coagulation. The intravenous set-up, as described above, permits discrete pharmacological challenges to be carried out safely during specific sleep stages or cycles without disturbing the sleeping subject. At the end of the first REM period, glycopyrrolate, a peripherally acting anticholinergic agent, was administered iv in a dose of 0.15 mg on both infusion nights. Approximately 25 min after the end of the first REM period, the patient received an infusion of either 0.5 mg arecoline or placebo (in a random order on nights 3 and 4). All infusions were administered over a 3-rain period.
Statistical Analysis The various groups were compared on sleep and SADS scale scores using one-way A_NOVA (independent groups) followed by post hoc Scheffe's Test. In addition, a priori contrasts between the following groups were set up and analyzed: 1. Pri MDD-E versus Pri MDD + ANX 2. (Pri MDD-E plus Pri MDD + ANX) versus (Pri ANX plus Pri ANX + Sec MDD)
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Table 1. Sample Characteristics
N
Age (yr) Mean sD
Range Sex Male Female RDC
Pri ANX + MDD
Sec
Pri MDD-E
Pri MDD-E + ANX
Pri ANX
20
19
18
14
26
46.6 21.7 22-83
40.0 16.4 21-47
32.2 7.7 22-51
32.8 10.7 23-38
36.4 16.1 20--87
8 12
7 12
8 10
4 10
11 15
----
13 4 2
13 3 2
10 3 1
3 17 16 1 3
1 18 14 4 1
------
2 12 14 0 0
Normal
diagnosis
Panic GAD
Phobia MDD
Psychotic Nonpsychotic Unipolar Bipolar I Bipolar II
B
3. Pri MDD-E versus Pri ANX 4. Pfi ANX versus Pri ANX + Sec MDD 5. Pri MDD + ANX versus Pfi ANX + Sec MDD 6. Pri MDD-E versus normals Statistical significance (probability) for the a priori contrasts was calculated by using separate, rather than pooled, variance estimates. This is a more conservative approach. All procedures were run using an SPSS statistical routine (Hull and Nie 1981).
Sample Characteristics (Table 1) There was no significant difference between groups with respect to age and sex distribution. Psychotic and nonpsychotic depressive subtypes were equally represented. Patients in the Pfi MDD + ANX group had the following secondary diagnoses: panic disorder (13), generalized anxiety disorder (4), and phobia (2). The lafi ANX group was comprised of 13 patients with panic disorder, 3 of generalized anxiety disorder, and 2 with phobia; 10 patients with secondary panic comprised the Pri ANX + Sec MDD group. All patients included in the study were in a clinical episode at the time of investigation and had been in a drug-free state for a period of at least 2 weeks. Results Table 2 shows the means and standard deviations of SADS scaled scores between patient groups. Orthogonal contrasts and one-way ANOVA with post hoc Scheffe's Test were done between them to determine if they were significantly different from each other. As
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a whole, the primarily depressed groups (Pfi MDD-E, Pri MDD + ANX) and the primary anxiety groups (Pri ANX, Pri ANX + Sec MDD) were significantly different on scores of depressive mood and ideation (DMI), endogenous features (END), depressive associated features (DAF), and anxiety (ANX) ratings. A comparison of SADS scaled scores between Pri MDD + ANX and Pri ANX + MDD, on the other hand, revealed no significant differences on any SADS scales. Similarly, there were no significant differences between the Pri MDD-E and Pri ANX + MDD groups on any SADS scale item, except for ANX and suicidal ideation and behavior (SIB), which was higher in the latter. The pure groups, i.e., Pri MDD-E and Pri ANX, were significantly differentiated on the following SADS variables: END, DAF, ANX, and Global Assessment Scales (GAS). On the other hand, the Pri MDD + ANX group was significantly different from the Pri ANX group on the depression-related scales, i.e., DMI, END, DAF, SIB, and global severity of illness. The GAS ratings were significantly higher (p < 0.006) in the Pri ANX group, which suggested a lower functional impairment. The presence of anxiety features in mixed groups raises the Hamilton Scale for Depression (HAM) scores, as a result of an overlap of several anxiety subscales in the Hamilton scale. Table 3 shows the means and standard deviations of the sleep indices of the five groups. One-way ANOVA with a post hoc Scheffe's Test and orthogonal contrasts (separate variance estimates) were used for statistical comparison. The Pri MDD-E and Pri MDD + ANX groups arc significantly different (p < 0.05 or better) from the normal controls on the following variables: latency of first REM period, arecoline-induced REM-2 latency, and first REM densities of infusion night and average of 2 nights. The normals, however, were not significantly different from Pri ANX and Pri ANX + Sec MDD groups on any of these sleep variables. Pri MDD-E had a significantly shorter latency of first REM period, as well as a shorter arecoline
Figure 1. REM sleep and arecoline REM induction response parameters in depressed, anxious, and mixed groups. SUBfECT GROUPS (GR)
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GRII
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I~
LATENCYo*
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REM induction time (p < 0.001) than the Pri ANX group. REM time, however, was not significantly different between the groups. The primary MDD-E group also had a significantly shorter (p < 0.000) areeoline REM induction time than the Pri ANX + Sec MDD group. The lad MDD + ANX patients were significantly different from Pri ANX on parameters of REM latency, arecoline REM induction time, and first REM density. Comparison of sleep data between Pri MDD-E and Pfi MDD + ANX groups shows no significant differences between the groups. On the other hand, within the primarily anxious groups, there is a significantly shorter (p < 0.04) latency of the first REM period in Pri ANX + See MDD group as compared with the Pri ANX group (60.56 min versus 81.04 min). They were not different on other sleep variables. Patients with mixed symptoms, i.e., Pri MDD + ANX and Pri ANX + See MDD, did not differ from each other on any measure tested. Figure 1 shows the ANOVA results of significant differences (p < 0.05 or better) in REM latency, infusion REM-2 latency, and first REM time between the groups.
Discussion Nosological confusion between anxious and depressive states has been the subject of major concern during the last decade. This issue has been addressed by several investigators (Liebowitz and Klein 1979; Akiskal et al. 1980, 1982, 1983; Roth et al. 1982; Davidson et al. 1982). Sleep EEG studies have been used to address this issue by a number of investigators (Gillin et al. 1979; Kupfer et al 1980; Fienberg et al. 1982; Rush et al. 1982). The main findings of the present study were that EEG sleep physiological markers of primary endogenous depression, such as a shortened REM latency and increased first REM period density, as well as the recently described faster cholinergic REM induction, are not present in primary anxiety disorder. The primary anxiety group consisted mainly of panic and agoraphobic patients (15/18) who did not have secondary depression. These data fail to support a common pathophysiological substrate or vulnerability between primary endogenous depression and primary anxiety disorders. With respect to patients with mixed features of anxiety and depression, namely, groups Pri MDD + ANX and Pri ANX + See MDD, our data point toward a strong similarity between Pri MDD + ANX and lad MDD-E (without anxiety) on all biological variables tested. Similarly, Pri ANX and Pfi ANX + See MDD were not different from each other on any variable except REM latency, which was shorter in the latter. The Pfi ANX + Sec MDD differed significantly from lad MDD-E (without anxiety) on areeoline REM induction alone. It could not be distinguished from Pri MDD + ANX on any measure. The two anxiety groups (Pri ANX and lad ANX + See MDD) did not differ between themselves or from normal controls with respect to any variable. Cholinergic supersensitivity (as manifest by arecoline REM induction response) was specific to the Pri MDDE and Pfi MDD + ANX groups. Similar results with regard to REM latency and REM density between anxious depressives and normal controls were reported by Akiskal et al. (1983). Our results are at variance with those of Uhde et al. (1984), who found a significantly shorter REM latency and REM density in their panic disorder patients as compared to normal controls. The REM latency of their controls was, however, at the upper limit of the range of published norms. Further studies on these and other types of mixed groups with a larger sample size may lead to sharper psychobiological delineation.
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The value of sleep EEG physiological and cholinergic markers is particularly highlighted when viewed against a background of the relatively poor discriminability between groups offered by phenomenological criteria. The mixed groups, i.e., Pri MDD + ANX and Pri ANX + Sec MDD, were not different from each other on any SADS item scores. The overall depression scores, as seen on HAM ratings, were higher in Pri MDD + ANX patients than in Pri MDD-E (without anxiety) and Pri ANX groups, but did not differ in other between-group comparisons, i.e., Pri ANX versus Pri ANX + Sec MDD, Pri MDD-E versus Pri ANX, and Pri MDD-E, Pri MDD + ANX versus Pri ANX, Pri ANX + Sec MDD. The mixed groups, Pri MDD + ANX and Pri ANX + Sec MDD, were the most severely ill patients, as revealed by their low scores on GAS ratings. Although phenomenological criteria were able to differentiate pure groups (Pri MDD-E and Pri ANX), the presence of overlapping or concurrent symptoms of anxiety and/or depression was associated with poor discriminability. The use of biological markers may therefore be a valid and potentially more promising tool than clinical criteria alone to differentiate syndromes with a mixed or overlapping symptomatology. Studies are underway to determine if the presence of a familial loading of affective illness is associated with cholinergic hypersensitivity and whether or not it explains some of the variance in cholinergic hypersensitivity in affective and/or anxious patients. The familial data may eventually offer greater precision in delineating patients with mixed or overlapping symptoms.
We thank the followingfor their assistance in preparation of this manuscript: Cadora Bush, R.N., Carol Muszkiewicz, M.S.W., Karen Ebersole, Alesia Brown, Edith Ross, and Cecile L. Ward.
References Akiskal HS (1980): External validating criteria for psychiatric diagnosis: Their application in affective disorders. J Clin Psychiatry 41:6-14. Akiskal HS, Bitar AH, Puzantian VR, Rosenthal TL, Walker PW (1978): The nosological status of neurotic depression. Arch Gen Psychiatry 35:756-766. Akiskal HS, King D, Rosenthal TL, Robinson D, Scott-Strauss A (1982): Chronic depressions: Part I. Clinical and familial characteristics in 137 probands. J Affect Dis 3:297-315. Akiskal HS, Lemmi H, Dickson H, King D, Yerevanian B, Van Valkenburg C (1983): Chronic depressions: Part 2. Sleep EEG differentiation of primary dysthymic disorders from anxious depressions. J Affect Dis 4:287-295. Cassidy WL, Flanagan NB, Spellman M, Cohen ME (1957): Clinical observations in manic depressive disease. JAMA 164:1535-1546. Cloninger CR, Martin RL, Clayton P, Guze SB (1981): A blind follow-up and family study of anxiety neurosis: Preliminary analysis of the St. Louis 500. In Klein DF, Rabkin J (eds), Anxiety: New Research and Changing Concepts. New York: Raven pp 137-155. Crowe RR, Noyes R, Pauls DL, Slymen D (1983): A family study of panic disorder. Arch Gen Psychiatry 40:1065-1069. Davidson JTR, Miller RD, TurnbuU CD, Sullivan JL (1982): Atypical depression. Arch Gen Psychiatry 39:527-534. Downing RW, Rickels K (1974): Mixed anxiety and depression. Arch Gen Psychiatry 30:312-317.
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Feinberg M, Gillin JC, Carroll BJ, Greden JF, Zis AP (1982): EEG studies of sleep in the diagnosis of depression. Biol Psychiatry 17:305-316. Gillin JC, Duncan WC, Pettigrew K (1979): Successful separation of depressed, normal, and insomniac subjects by EEG sleep data. Arch Gen Psychiatry 36:85-90. Hull CH, Nie NH (1981): SPSS Update 7-9: New Procedures and Facilities for Release 7-9. New York: McGraw-Hill. Jones D, Kelwala S, Pohl R, Dub6 S, Jackson E, Sitaram N (1983): Cholinergic REM sleep induction response as a marker of endogenous depression. In Hanin I (ed), Dynamics of Cholinergic Function. New York: Plenum (in press). Jones D, Kelwala S, Bell J, Sitaram N (1984): Cholinergic REM induction response I: Correlation with endogenous M.D.D. subtype. Psychiatr Res (in press). Kerr TA, Shapira K, Roth M (1969): The relationship between premature death and affective disorders. Br J Psychiatry 115:1277-1282. Klerman GL (1971): Clinical research in depression. Arch Gen Psychiatry 24:305-319. Kupfer DJ, Broudy D, Coble PA, Spiker 1)(3 (1980): EEG sleep and affective psychosis. J Affect Dis 2:17-25. Leckman JF, Merikangas KR, Pauls DL, Prusoff BA, Weissman MM (1983a): Anxiety disorders and depression: Contradictions between family study data and DSM HI conventions. Am J Psychiatry 140:880--882. Leckman JF, Weissman MM, Merikangas KR, Pauls DL, Prusoff BA (1983b): Panic disorder and major depression. Arch Gen Psychiatry 40:1055-1060. Lewis AJ (1934): A clinical study of depressive states. J Psychiatry 109:451--463. Liebowitz M, Klein D (1979): Hysteroid dysphoria. Psychiatr Clin North Am 2:555-575. Mazure C, Gershon ES (1979): Blindness and reliability in lifetime psychiatric diagnosis. Arch Gen Psychiatry 36:521-525. Noyes R Jr, Clancy J, Crowe R, Hoenk PR, Slymen DJ (1978): The familial prevalence of anxiety neurosis. Arch Gen Psychiatry 35:1057-1059. Overall JE, Hollister LE, Johnson M, Pennington V (1966): Nosology of depression and differential response to drugs. JAMA 195:946--948. Paykel ES (1971): Classification of depressed patients: A cluster analysis derived grouping. Br J Psychiatry 118:275-288. Paykel ES, Fowles DC (1979): Neurotic depression: The concept of anxious depression. In Depue RH (ed): The Psychobiology of the Depressive Disorders: Implications for Effects of Stress, Orlando, FL: Academic pp 81-104. Prusoff BA, Paykel ES (1977): Typological prediction of response to amitryptyline: A replication study. Int Pharmacopsychiatry 2:153-159. Raskin M, Peeke HVS, Dickman W, Pinsker H (1982): Panic and generalized anxiety disorders: Developmental antecedents and precip itants. Arch Gen Psychiatry 39:687-689. Rechtschaffen A, Kales A (1968): A Manual for Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Publication 234. Washington D.C.: Department of Health, Education and Welfare. Reynolds CF III, Shaw DH, Newton TF, Coble PA, Kupfer DJ (1983): EEG sleep in outpatients with generalized anxiety: A preliminary comparison with depressed outpatients. Psychiatr Res 8:81-89. Roth M, Mountjoy CQ, Caetano D (1982): Further investigations into the relationship between depressive disorders and anxiety state. Pharmacopsychiatry 15:135-141. Rush AJ, Giles GE, Roffwarg HP, Parker CF (1982): Sleep EEG and dexamethasone suppression test findings in outpatients with unipolar major depressive disorders. Biol Psychiatry 17:327-341. Shapira K, Roth M, Kerr TA, Gurney C (1972): The prognosis of affective disorders: The differentiation of anxiety states from depressive illness. Br J Psychiatry 121:175-181.
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Sitaram N, Nurnberger JI, Gershon ES, Gillin JC (1980): Faster cholinergic REM sleep induction in euthymic patients with primary affective illness. Science 208:200-202. Sitaram N, Nurnberger JI, Gershon ES, Gillin JC (1982): Cholinergic regulation of mood and REM sleep: A potential model and marker for vulnerability to depression. AmJPsychiatry 20:470-477. Spitzer FL, Endicott J, Robins E (1978): Research and diagnostic criteria: Rationale and reliability. Arch Gen Psychiatry 35:773-782. Uhde TW, Roy-Byme P, Gillin JC, Mendelson WB, Boulenger J-P, Vittone BJ, Post RM (1984): The sleep of patients with panic disorder: A preliminary report. Psychiatr Res 12:251-259.
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Cholinergic REM Induction Response: Separation of Anxiety and Depression S. Dub6, N. Kumar, E. Ettedgui, R. Pohl, D. Jones, and N. Sitaram
Five groups of subjects underwent EEG sleep recordings, arecoline rapid eye movement (REM) induction response testing, and Schedule for Affective Disorders and Schizophrenia (SADS ) interview. Group I: 20 patients with primary major depressive disorder (MDD ) (endogenous) without any coexisting anxiety disorder; Group H: 19 primary MDD (endogenous) patients with secondary panic, GAD, or phobic disorders; Group Ili: 18 patients with primary anxiety disorder without coexisting MDD; Group IV: 14 patients with primary anxiety plus secondary MDD; Group V: 26 normal controls. Modified Research Diagnostic Criteria (RDC) were used for diagnosis, based on the SADS interview. There was considerable overlap of SADS scaled scores between patient groups, which is consistent with a heterogeneous clinical presentation of depressive and anxiety states. REM latency was significantly shorter in patients with primary MDD (without anxiety) as compared with that in patients with primary anxiety (no MDD ) and normals. Arecoline REM induction response time was significantly shorter in both primary affective groups (I and II) as compared with primary anxiety (no MDD) patients and normal controls. REM latency and arecoline REM induction time was not significantly different between the primary anxiety groups (III and IV) and normals. The study highlights the use of biological markers in differentiating between clinical syndromes confounded by mixed or overlapping phenomenology.
Introduction The clinical significance of the frequent occurrence of symptoms of anxiety, such as psychomotor agitation, nervousness, and tenseness in depressed patients (Overall et al. 1966; Paykel 1971; Prusoff and Paykel 1977), and the presence of depressive symptomatology in patients diagnosed as predominantly anxious remains unclear and poses problems in differential diagnosis (Klerman 1971). Longitudinal studies suggest a considerable
From the Affective Disorders Unit (S.D., D.J., N.S.) and the Anxiety Disorders Program (N.K., E.E., R.P.), Lafayette Clinic, Wayne State University, Detroit, MI. Supported by NIMH Grant MH 38342-01. Address reprint requests to Dr. S. DubS, Affective Disorders Unit, Lafayette Clinic, Wayne State University, 951 East Lafayette, DeAtoit, MI 48207. Received February 11, 1984; accepted October 3, 1984.
1985 Society of Biological Psychiatry
0006-32231851503.30
Cholinergic REM Induction Response
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409
1985;20:408--418
overlap between symptoms of anxiety and depression in some patients (Cassidy et al. 1957; Kerr et al. 1969; Shapira et al. 1972; Downing and Rickels 1974; Akiskal et al. 1978; Raskin et al. 1982; Roth et al. 1982), leading to identification of an "anxious" subgroup of depressives by some investigators (Paykel 1971; Paykel and Fowles 1979). Are these disorders part of a continuum (Lewis 1934), with a shared pathophysiological substrate, or are they distinct conditions that often occur together? Recent family and genetic studies have yielded contradictory results. Noyes et al. (1978) Cloninger et al. (1981), and Crowe et al. (1983) found an increased risk for panic disorder, but not depression, in relatives of primary anxiety disorder probands compared with normal control probands. On the other hand, Leckman et al. (1983a,b) found a twofold increase in risk for both affective and anxiety disorders in relatives of probands with major depression with concurrent or antecedent panic or generalized anxiety disorder, as compared to probands with depression alone. Part of the discrepancy may be due to differences in diagnostic methods as well as selection of patient groups. For instance, Noyes et al. (1978), Cloninger et al. (1981), and Crowe et al. (1983) had anxious and normal control proband groups, but failed to include a major depressive disorder group in their study. Leckman et al. (1983a,b), on the other hand, did not have a primary anxiety disorder proband control group. The use of biological markers is a valid and potentially powerful tool to study this problem. Two recent studies (Reynolds et al. 1983; Akiskal et al. 1983) compared EEG sleep parameters of anxious and depressed patients. They reported that depressives had a shorter latency to onset of rapid eye movement sleep (REM latency) and greater REM sleep percent as compared to generalized anxiety disorder and panic disorder patients. The focus of the current study was the comparison of affective and anxious patients on both conventional sleep EEG variables (such as REM latency) and their sensitivity to cholinergic induction of REM sleep (Sitaram et al. 1980, 1982; Jones et al. 1983, 1984). The latter has been shown to be a putative "trait" marker of primary affective illness. The hypothesis of a shared diathesis between depression and anxiety disorders could be tested in part by determining whether or not a supersensitive cholinergic REM induction response--a putative affective vulnerability marker--is shared by the two illnesses.
Methods Thirty-nine patients (inpatients and outpatients) who fulfilled the modified RDC criteria for major depressive disorder (Mazure and Gershon 1979) and endogenous subtype (Spitzer et al. 1978) formed one group. In addition, 32 patients who fulfilled the RDC criteria for anxiety disorders, i.e., generalized anxiety, panic, and phobic disorders, as their primary diagnoses were also included in the study. It should be noted that the RDC convention of not diagnosing an anxiety disorder that occurs in conjunction with a major depressive episode was disregarded in this study. These groups were subdivided into the following categories (Table 1): • Group I. Primary MDD (endogenous) (n = 20), without superimposed or concomitant anxiety disorder (Pri MDD-E). • Group II. Primary MDD (endogenous) with coexisting anxiety disorder meeting full RI)C criteria (n = 19) (Pri MDD + ANX). In 14 patients, MDD and anxiety disorder were always temporally associated. The remaining five patients met criteria
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BIOL PSYCI-KATRY 1985;20:408--418
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for an anxiety disorder temporally separated from a major depressive episode by at least 2 months. • Group III. Primary anxiety disorders without MDD (n = 18) (Pri ANX). • Group IV. Primary anxiety disorders with secondary MDD (n = 14) (Pri ANX + See MDD). • Group V. Normal controls (n = 26). These subjects did not have any current or past history of major psychiatric or medical illness. Hereafter, the groups shall be referred to by their abbreviations. All subjects were administered a Schedule for Affective Disorders and Schizophrenia (SADS) (Spitzer et al. 1978) by experienced research clinicians whose interrater reliabi~y had been established. Both current and life-time diagnostic assessment of subjects (based on conventional or modified RDC criteria) were made using information from SADS Parts I and II, respectively. Raters were blind to sleep data, and the research assistant who scored the polygraphic sleep records was in turn unaware of the clinical data. All subjects received a complete physical and neurological examiniation, EKG, blood chemistry (SMA-17, T3, T4, CBC with differential) and urinalysis prior to inclusion in the study. They were free from any psychotropic agents or drugs that might influence that patient's mood or polygraphic data for at least 2 weeks prior to the study. An informed consent was obtained from every subject. Sleep Subjects underwent 3-4 nights of sleep recording, during which their EEG (C3-A2), EMG (submental electromyogram), and EOG (electrooculogram) were monitored as per standard criteria of Rechtschaffen and Kales (1968). Electrocardiogram (lead II) was also monitored throughout the night. The first night served to acclimatize the patient to sleeping with electrodes. During the second night, a regular polygraphic recording was obtained ("baseline" night). On nights 3 and 4, in addition to placement of polygraphic electrodes, subjects also slept with a 21-gauge scalp vein needle placed in a forearm vein attached to a 10-ft polyethylene tubing extending into an adjacent room. A continuous infusion of normal saline was maintained at the rate of approximately 0.25 ml/min (using an IVAC infusion pump) throughout the night to prevent blood coagulation. The intravenous set-up, as described above, permits discrete pharmacological challenges to be carried out safely during specific sleep stages or cycles without disturbing the sleeping subject. At the end of the first REM period, glycopyrrolate, a peripherally acting anticholinergic agent, was administered iv in a dose of 0.15 mg on both infusion nights. Approximately 25 min after the end of the first REM period, the patient received an infusion of either 0.5 mg arecoline or placebo (in a random order on nights 3 and 4). All infusions were administered over a 3-rain period.
Statistical Analysis The various groups were compared on sleep and SADS scale scores using one-way A_NOVA (independent groups) followed by post hoc Scheffe's Test. In addition, a priori contrasts between the following groups were set up and analyzed: 1. Pri MDD-E versus Pri MDD + ANX 2. (Pri MDD-E plus Pri MDD + ANX) versus (Pri ANX plus Pri ANX + Sec MDD)
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Table 1. Sample Characteristics
N
Age (yr) Mean sD
Range Sex Male Female RDC
Pri ANX + MDD
Sec
Pri MDD-E
Pri MDD-E + ANX
Pri ANX
20
19
18
14
26
46.6 21.7 22-83
40.0 16.4 21-47
32.2 7.7 22-51
32.8 10.7 23-38
36.4 16.1 20--87
8 12
7 12
8 10
4 10
11 15
----
13 4 2
13 3 2
10 3 1
3 17 16 1 3
1 18 14 4 1
------
2 12 14 0 0
Normal
diagnosis
Panic GAD
Phobia MDD
Psychotic Nonpsychotic Unipolar Bipolar I Bipolar II
B
3. Pri MDD-E versus Pri ANX 4. Pfi ANX versus Pri ANX + Sec MDD 5. Pri MDD + ANX versus Pfi ANX + Sec MDD 6. Pri MDD-E versus normals Statistical significance (probability) for the a priori contrasts was calculated by using separate, rather than pooled, variance estimates. This is a more conservative approach. All procedures were run using an SPSS statistical routine (Hull and Nie 1981).
Sample Characteristics (Table 1) There was no significant difference between groups with respect to age and sex distribution. Psychotic and nonpsychotic depressive subtypes were equally represented. Patients in the Pfi MDD + ANX group had the following secondary diagnoses: panic disorder (13), generalized anxiety disorder (4), and phobia (2). The lafi ANX group was comprised of 13 patients with panic disorder, 3 of generalized anxiety disorder, and 2 with phobia; 10 patients with secondary panic comprised the Pri ANX + Sec MDD group. All patients included in the study were in a clinical episode at the time of investigation and had been in a drug-free state for a period of at least 2 weeks. Results Table 2 shows the means and standard deviations of SADS scaled scores between patient groups. Orthogonal contrasts and one-way ANOVA with post hoc Scheffe's Test were done between them to determine if they were significantly different from each other. As
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a whole, the primarily depressed groups (Pfi MDD-E, Pri MDD + ANX) and the primary anxiety groups (Pri ANX, Pri ANX + Sec MDD) were significantly different on scores of depressive mood and ideation (DMI), endogenous features (END), depressive associated features (DAF), and anxiety (ANX) ratings. A comparison of SADS scaled scores between Pri MDD + ANX and Pri ANX + MDD, on the other hand, revealed no significant differences on any SADS scales. Similarly, there were no significant differences between the Pri MDD-E and Pri ANX + MDD groups on any SADS scale item, except for ANX and suicidal ideation and behavior (SIB), which was higher in the latter. The pure groups, i.e., Pri MDD-E and Pri ANX, were significantly differentiated on the following SADS variables: END, DAF, ANX, and Global Assessment Scales (GAS). On the other hand, the Pri MDD + ANX group was significantly different from the Pri ANX group on the depression-related scales, i.e., DMI, END, DAF, SIB, and global severity of illness. The GAS ratings were significantly higher (p < 0.006) in the Pri ANX group, which suggested a lower functional impairment. The presence of anxiety features in mixed groups raises the Hamilton Scale for Depression (HAM) scores, as a result of an overlap of several anxiety subscales in the Hamilton scale. Table 3 shows the means and standard deviations of the sleep indices of the five groups. One-way ANOVA with a post hoc Scheffe's Test and orthogonal contrasts (separate variance estimates) were used for statistical comparison. The Pri MDD-E and Pri MDD + ANX groups arc significantly different (p < 0.05 or better) from the normal controls on the following variables: latency of first REM period, arecoline-induced REM-2 latency, and first REM densities of infusion night and average of 2 nights. The normals, however, were not significantly different from Pri ANX and Pri ANX + Sec MDD groups on any of these sleep variables. Pri MDD-E had a significantly shorter latency of first REM period, as well as a shorter arecoline
Figure 1. REM sleep and arecoline REM induction response parameters in depressed, anxious, and mixed groups. SUBfECT GROUPS (GR)
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GRII
14DD ÷ ANX
I~
LATENCYo*
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1985;20:408-418
REM induction time (p < 0.001) than the Pri ANX group. REM time, however, was not significantly different between the groups. The primary MDD-E group also had a significantly shorter (p < 0.000) areeoline REM induction time than the Pri ANX + Sec MDD group. The lad MDD + ANX patients were significantly different from Pri ANX on parameters of REM latency, arecoline REM induction time, and first REM density. Comparison of sleep data between Pri MDD-E and Pfi MDD + ANX groups shows no significant differences between the groups. On the other hand, within the primarily anxious groups, there is a significantly shorter (p < 0.04) latency of the first REM period in Pri ANX + See MDD group as compared with the Pri ANX group (60.56 min versus 81.04 min). They were not different on other sleep variables. Patients with mixed symptoms, i.e., Pri MDD + ANX and Pri ANX + See MDD, did not differ from each other on any measure tested. Figure 1 shows the ANOVA results of significant differences (p < 0.05 or better) in REM latency, infusion REM-2 latency, and first REM time between the groups.
Discussion Nosological confusion between anxious and depressive states has been the subject of major concern during the last decade. This issue has been addressed by several investigators (Liebowitz and Klein 1979; Akiskal et al. 1980, 1982, 1983; Roth et al. 1982; Davidson et al. 1982). Sleep EEG studies have been used to address this issue by a number of investigators (Gillin et al. 1979; Kupfer et al 1980; Fienberg et al. 1982; Rush et al. 1982). The main findings of the present study were that EEG sleep physiological markers of primary endogenous depression, such as a shortened REM latency and increased first REM period density, as well as the recently described faster cholinergic REM induction, are not present in primary anxiety disorder. The primary anxiety group consisted mainly of panic and agoraphobic patients (15/18) who did not have secondary depression. These data fail to support a common pathophysiological substrate or vulnerability between primary endogenous depression and primary anxiety disorders. With respect to patients with mixed features of anxiety and depression, namely, groups Pri MDD + ANX and Pri ANX + See MDD, our data point toward a strong similarity between Pri MDD + ANX and lad MDD-E (without anxiety) on all biological variables tested. Similarly, Pri ANX and Pfi ANX + See MDD were not different from each other on any variable except REM latency, which was shorter in the latter. The Pfi ANX + Sec MDD differed significantly from lad MDD-E (without anxiety) on areeoline REM induction alone. It could not be distinguished from Pri MDD + ANX on any measure. The two anxiety groups (Pri ANX and lad ANX + See MDD) did not differ between themselves or from normal controls with respect to any variable. Cholinergic supersensitivity (as manifest by arecoline REM induction response) was specific to the Pri MDDE and Pfi MDD + ANX groups. Similar results with regard to REM latency and REM density between anxious depressives and normal controls were reported by Akiskal et al. (1983). Our results are at variance with those of Uhde et al. (1984), who found a significantly shorter REM latency and REM density in their panic disorder patients as compared to normal controls. The REM latency of their controls was, however, at the upper limit of the range of published norms. Further studies on these and other types of mixed groups with a larger sample size may lead to sharper psychobiological delineation.
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The value of sleep EEG physiological and cholinergic markers is particularly highlighted when viewed against a background of the relatively poor discriminability between groups offered by phenomenological criteria. The mixed groups, i.e., Pri MDD + ANX and Pri ANX + Sec MDD, were not different from each other on any SADS item scores. The overall depression scores, as seen on HAM ratings, were higher in Pri MDD + ANX patients than in Pri MDD-E (without anxiety) and Pri ANX groups, but did not differ in other between-group comparisons, i.e., Pri ANX versus Pri ANX + Sec MDD, Pri MDD-E versus Pri ANX, and Pri MDD-E, Pri MDD + ANX versus Pri ANX, Pri ANX + Sec MDD. The mixed groups, Pri MDD + ANX and Pri ANX + Sec MDD, were the most severely ill patients, as revealed by their low scores on GAS ratings. Although phenomenological criteria were able to differentiate pure groups (Pri MDD-E and Pri ANX), the presence of overlapping or concurrent symptoms of anxiety and/or depression was associated with poor discriminability. The use of biological markers may therefore be a valid and potentially more promising tool than clinical criteria alone to differentiate syndromes with a mixed or overlapping symptomatology. Studies are underway to determine if the presence of a familial loading of affective illness is associated with cholinergic hypersensitivity and whether or not it explains some of the variance in cholinergic hypersensitivity in affective and/or anxious patients. The familial data may eventually offer greater precision in delineating patients with mixed or overlapping symptoms.
We thank the followingfor their assistance in preparation of this manuscript: Cadora Bush, R.N., Carol Muszkiewicz, M.S.W., Karen Ebersole, Alesia Brown, Edith Ross, and Cecile L. Ward.
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