BIGL PSYCHIATRY 1990;28:21-34
21
Differential Responses to Anxiogenic Challenge Studies in Patients with Major Depressive Disorder and Panic Disorder Steven D. Targum
Anxiogenic challenge studies (intravenous lactate infusion and oral fenfluramine challenge) were conducted in 17 patients with panic disorder (PD), 12 patients with major depressive disorder and a history of panic attacks (MDD-PD), 27 patients with major depression and no history of panic (MDD), and 12 normal controls. PD and MDD-PD patients revealed significantly greater anxiogenic responses to lactate infusion and fenfluramine administration than either MDD patients or controls. PD patients revealed the most robust anxiogenic responses to both challenges as well as associated significant prolactin and cortisol responses to fenfluramine. The findings suggest that the predisposition to panic attacks as seen in PD and MDD-PD patients may represent ~ distinct neurobiological diathesis which may coexist with a major depressive diathesis in some patients. The delineation of subgroups within the more heterogenous group of patients with MDD and/or PD will lead to greater precision in the development of clinical treatment strategies. Thus, MDD-PD patients (better called panic-depressives) may have a more severe illness than patients with MDD alone which must be accounted for in the course of pharmacotherapy and psychotherapy. The evolution of research in major depressive disorder (MDD) and panic disorder (PD) has lead to improved diagnostic precision between these entities as now defined in the DSM-III-R which allows for the concomitant use of both diagnoses in the same patient (APA 1987). However, the phenomenological, pharmacological, bioiogical, and familial similarities between these two putatively "distinct" clinical entities reveals a more complex interrelationship between them. In fact, it is not clear if MDD and PD are truly distinct illnesses or represent two states on a continuum of affective disorders (Schapira et al. 1972; Klerman 1980; Breier et al. 1984). The similarities between panic disorder and major depressive disorder are abundant. Phar~.acological studies have demonstrated equivalent therapeutic efficacy for imipramine ~ld MAO inhib~tors in the treatment of either disorder (Sheehan et .oi. 1980; Klein 1981; Breier et al. 1985). Neuroendocrine challenge studies have shown aberrant responses in PD patients which resemble those seen in patients with MDD (Sheehas~ et al. 1983;
F:o~','~ the ~L,~.,~:~~_.-.; .;., ".~vc~iatry, Crozer-Che~ter Medical Center, Upland, PA; and Hahnemann University, Philadelphia, PA. ~.'.*-~'-~s ~ep, i~.; : ~aes:s to Steven D. Targum, M.D., Crozer-Chester Medical Center, One Medical Center Blvd., POB 1, :;., ~ ~/., t~!,land, PA 19013-3995. ~,;2.: ,',~ July 22, 1989; revised November 2, 1989.
© 1990 Society of Biological P~ychiatry
0006.3223/90/$03.50
22
BIOL PSYCHIATRY 1990;28:21-34
S.D.
Targum
Targum et al. 1983; Gold et al. 1984; Hamlin et al. 1984; Avery et al. 1985; Roy-Byrne et al. 19850, 1985a, 1986; Grunhaus et al. 1987; Baumgarmer et al. 1988; Carson et al. 1988; Coryell et al. 1989). Some, but not all, family studies have demonstrated an increased incidence of MDD in the relatives of PD patients (Bowen and Kohout 1979; Ctowe et al. 1980, 1983; Harris et al. 1983; Munjack and Moss 1981; Noyes et al. 1986). Temporally distinct depressive episodes occurring either before or after the onset of panic attacks have been noted in 60%-88% of patients with panic disorder (Cloninger 1981; Pariser et al. 1978; Raskin et al. 1982; Breier et al. 1984, 1985). It is not clear whether patients who reveal MDD and PD at different times are revealing different clinical manifestations of the same psychopathological/biological condition or in fact have two distinct disorders (Klerman 1980; Breier et al. 1984; VanValkenburg et al. 1984). Leckman et al. (1983) suggested that those patients who have combined MDD-PD may have a partially shared underlying biological diathesis with PD patients and predicted that metabolic diffcreaces would exist that would dist.inguish patients with combined MDDPD from those with MDD without a panic disorder. Patients with PD are vulnerable to a number of diverse stimuli which can trigger anxiety and/or panic responses (Breier et al. 1985; Chamey et al. 1986; Gorman et al. 1989). Intravenous administration of isopmterenol or sodium lactate, oral ingestion of yohimbine, caffeine, or fenfluramine, hyperventilation, and inhalation of 5% carbon dioxide have all been shown to possess anxiogenic properties in PD patients (Boulenger et al. 1984; Liebowitz et al. 1984, 1985; Charney et al. 1984, 1986; Balon et al. 1988; Gaffney et al. 1988; Woods et al. 1988; Targum and Marshall 1989; Gorman et al. 1984, 1989). Infusion of sodium lactate has been shown to precipitate panic-like reactio~ts in 70%100% of patients with PD (Kelly et al. 1971; Pitts and McClure 1967; Liebowitz 1984; Rainey et al. 1984; Balon et al. 1988; Aronson et al. 1989). McGrath et al. (1988) found panic responses to lactate infusion in 15 of 29 depressed outpatients with a history of spontaneous panic attacks (52%) in contrast to I of 18 patients without a history of panic (×2 = 10.5; p < 0.002). Although they did not include panic disorder patients in their study, they did note that the likelihood of lactate-induced panic was greatest in depressed patients who wez~.cth-rently experiencing panic. Dager et al. (1987) found positive lactate responses in 34 of 43 PD patients (79%), 6 of 8 MDD-PD patients (75%), 2 of 9 MDD patients without panic (25%), and in none of 8 controls. Their findings suggested a common vulnerability between PD and MDD-PD patients. Fenfluramine, an indirect serotonergic.-rt~le~s:,ngand re-uptake blocking agent has been shown to precipitate anxiogenic responses in patients with PD (Targum and Marshall 1989). These investigators reported positive anxiogenic responses to fenflm'amine in 9 of 9 PD patients, 0 of 9 MDD patients with no history of panic, and 2 of 9 controls (X2 = 15.99; p < 0.0003). In addition, significant prolactin and cortisol responses to fenfluramine were observed in positive responders. Similarly, Lopez-Ibor (1988) reported a differential prolactin response to fenfluramine administration within subtypes of MDD patients such that those patients with a history of panic attacks (MDD-PD) had greater prolactin responses to fenfluramine than those patients without such a history. Further, Siever et al. (1984) have reported that MDD patients tend to have blunted prolactin responses to oral fenfluramine in contrast to controls, adding to the potential distinction between PD and MDD patients in the present study, two anxiogenic challenge studies were conducted (intrave,aous lactate infusion and oral fenfluramine administration) in age- and gender-matched groups
Panic and Depression: Anxiogenic Challenge
BIOL PSYCHIATRY 1990;28:21-34
23
Table i. Anxiogenic Challenge Studies in Patients with Major Depression and Panic Disorder Panic disorder n Age Gender Hamilton Scale Zung Scale
17 32.5 -4- 7.0 4: i 3 22.0 _ 7.8" 57.1 .4. 14.1 a
MDD-PD 12 32.8 _ 9.1 2:5 26.4 _ 6.9" 58.3 _+ 17.4 b
MDD
Controls
27 33.4 - 7.8 7:20 26.0 _.+ 6.9 ~ 51.5 .4- 9 . ~
12 35.7 ± 4.3 3:9 1.5 __ 1.3 43.8 __ 2.9
°p < 0.005 vs. controls; ~p < 0.01 vs. controls. MDD-PD = patients with major depressive disorder and a history of pa~aicattacks; MDD = patients with major depressive disorder and no history of panic attacks.
of patients with PD, MDD-PD, and MDD, and controls. The following questions have been asked: (1) Can anxiogenic challenge strategies distinguish PD from MDD patients vith or without a history of panic attacks? (2) Where do MDD-PD patients fit within the spectrum of major depressive and panic disorders?
Methods Anxiogenic challenge studies were performed as part of a comprehensive assessment of patients admitted to the psychobiological service of the Sarasota Palms Hospital between 1987 and 1989. Patients and normal volunteers consented to administration of both the intravenous lactate infusion and oral fenfluramine challenges. Subjects "sere free of all psychotropic, steroidal, and antihypertensive medications for a minimum of 2 weeks prior to entry into the study and were included only if they had no concurrent medical problems as confirmed by physical examination and had normal routine chemistries. Subjects were men and premenopausal women ranging in age between 19 and 48 years. There were no significant differences in age or gender distribution between diagnostic groups (see Table 1). Diagnoses were made using DSM-HI-R criteria via administration of structured interviews (Schedule for Affective Disorders and Schizophrenia-Lifetime Version and the Structured Clinical Interview for DSM-HI) by clinical staff who were blind to the results of biological studies (Endicott and Spitzer 1978; Spitzer and Williams 1983). Hamilton Depression Scales and Zung Anxiety Scales were also administered to all subjects (Hamilton 1960; Zung 1965). Seventeen patients met criteria for panic disorder (PD) as defined by DSM-IH-R, and 39 patient~ met criteria for major depressive disorder (MDD). PD patients did not meet criteria for MDD. Within the MDD group, 12 patients had a history of panic attacks which met DSM-HI-R criteria for panic disorder which had occurred at least 6 months prior to their current acute depressive episode, Thcse 12 patients were recategorized as a ~eparate group (MDD-PD) for this study, and the remaining 27 depressed patients were called MDD patients with no history of panic. The MDD-PD group was equally split between those patients who had a primary affective disorder versus those who had a primary panic disorder by history; tlff-:historical difference did not affect the biological results. All depressed subjects had a minimum Hamilton Score of 18 at the time of admission to the hospital. Twelve medically healthy normal volunteers with no previous psychiatric history also consented to participate in this study. The lactate infusion procedure was conducted i~ the morning after an ove~ght bedrest and fast according to methods described elsewhere (Liebowitz et al. 1984; Dager et al.
24
BIOL PSYCHIATRY 1990;28:21-34
S.D.
Targum
1987; Aronson et al. 1989). A slow intravenous infusion of D5W was given for 30 min and then changed under single blind conditions ~ 0o5 M sodium DL-lactate (warmed to body temperature) which was then infused over 20 min. Patients were rated every 5 min with the Acute Panic Inventory (AII) (Dillon et al. 1987) which asks the patient to rate 17 subjective items related to panic on a 0-3 scale with increasing severity. Scores ranged from 0 to 51. Lactate responses were considered positive if the patient reported the experience to be panic-like, had API scores exceeding 20 points, and had a minimum increment of 15 points from baseline on the API. Positive responses were invariably associated with concomitant tachycardia with increases greater than 20 beats/min. The oral fenfluramine challenge was administered on the day following the lactate infusion. In the morning, after an overnight bedrest and fast, all subjects received 60 mg of fenfluramine and completed a subjective rating scale hourly for 5 hr. Subjects were allowed mild ambulation in accordance with the method of Coccaro et al. (1987). A modification of the self-rated anxiety scale (SAS) developed by Sheehan (1986) was used and included 17 items from SAS Scale Part I and all 11 items from SAS Scale Part H which were rated 0-4 with increasing severity of anxiety symptoms. Total scores could vary from 0 to 112. Fenfluramine responses were considered positive if the patient reported the experience to be panic-like and their SAS scores increased by at least 25 points from baseline (ASAS >~ 25) ha accordance with the study of Targum and Marshall (1989). Collection of serem prolactin and cortisol was obtained during the course of the fenfluramine protocol as well. Serum prolactin was obtained at - 1 5 , 0, 60, i20, 180, 240, and 300 min and serum cortisol was obtained at baseline, 120, and 240 min. Baseline prolactin was determined as the average of the two pre~fenfluramine prolactin samples (Siever et al. 1984; Targum and Marshall 1989). Serum cortisol was measured by radioimmunoassay with a calculated assay sensitivity of 0.4 iol,g/dl. Intraassay coefficient of variation was 4.1% and interassay coefficient of variation was 1.0% for a sample of 15 ttg/dl. Serum prolactin was also measured by radioimmunoassay with an overall intraassay coefficient of variation of 3% and interassay coefficient of variation of 6%. Statistical analysis of the data included examination of each variable from each challenge study at each time point for each of the four study groups. The data were evaluated as pooled values for mean -+ standard deviation for each variable as well as by percentage of positive test responses in each study group. Statistical analysis included X2 test with Yate's co,-rection for continuity, one-way analysis of variance (ANOVA) with repeated measures (calculating the Greenhouse-Geisser effect), post hoc Student's t-test, and Spearman's rank correlation coefficient as appropriate. Results There were no age or gender differences between groups and controls as noted in Table 1. Hamilton depression scores and Zung anxiety scores reveal all patient groups (PD, MDD-PD, MDD) to be significantly more depressed and more anxious than the control group, but not significantly different from each other.
Lactate Infusion Response Responses to intravenous lactate are displayed in Figure 1. Analysis of the response curves revealed significant changes in PD patients (F = 30.42; df = 1, 57; p = 0.000), MDD-PD patients (F = 27.25; p - 0.000), MDD patients (F = 15.79; p = 0.000),
Panic and Depression: Anxiogenic Challenge
BIOL PSYCHIATRY 1990;28:21-34
25
25
2O
15 ANXIETY (API) 10
-A 0
.
-
', . . . . .
0
5
:
'
10
15
!
2O
TIME (MINUTES} "El"
PANIC
DISORDER
Figure 1. Anxiety response
~
tO
MDD-PANIC ATTACKS
-e- MDD
"~" CONTROLS
lactate infusion in patients with major depression and panic disorder.
but not in controls (F = 0.352; p = ns). PD and MDD-PD patients revealed more robust responses than MDD patients. Analysis of variance (ANOVA) with repeated measures revealed a significant interactive effect for diagnosis over time (F = 4.85; df = 1, 19; p = 0.038) with significant effects for diagnosis at all time points (Table 2). Post hoc t-tests (Table 2) ~flect that anxiogenic responses were significantly greater for all patient gcoups than controls at all time points. Within patient groups, PD patients' responses were significantly greater than MDD patients at all time points. Similarly, MDD-PD patients had significantly greater anxiogenic responses to lactate versus MDD patients at 15 min and 20 rain. PD and MDD-PD patients' responses did not differ significantly from each other. Using threshold criteria as described in Methods, 11 PD patients (65%), 7 MDD-PD patients (56%), 5 MDD patients (19%), and 0 controls had positive anxiogenic responses. PD patients had significantly more positive responses than MDD patients (X2 = 7.72; p = 0.005) and controls (X2 = 9.91; p = 0.002). MDD-PD patients had significantly greater positive responses than MDD patients (X2 = 4.45; p = 0.035) and controls (X2 = 7.26; p = 0.607). MDD patients did not differ from controls (X2 = 1.16; p = ns).
Fenfluramine Responses Anxiogenic and hormonal responses to 60 mg oral fenfluramine administration are displayed in Figures 2, 3, and 4. Analysis of the response curve for anxiogenic response to fenfluramine revealed significant changes over time for PD patients (F = 21.1; df = 1. 64; p = 0.000), MDD-PD patients (F = 11.36; p = 0.002), but not for MDD pafi~hts (D = 0.72; p = ns)or controls (F = 2.13; p = ns). PD and MDD-PD patients ,:,~,ealed significantly greater anxiogenic responses to fenfluramine than either MDD patients or controls, and panic disorder patients revealed significantly greater prolactin and cortisol responses as well.
26
BIOL PSYCHIATRY 1990;28:21-34
S.D. Targum
Table 2. Behavioral Responses to Lactate Infusion and Post Hoc t-Tests in Patients with Major Depression and Panic Disorder PD
MDD-PD
MDD
Controls
Mean baseline API t-tests: PD vs MDD-PD vs MI~D vs
5 Min-API PD vs MDD-PD vs MDD vs
1(, Min-API
7.0 4. 4.0
--
-10.4 _ 5.4 m
PD vs MDD-PD vs MDD vs
20 Min-API
16.6 _+ 9.9
t= t-
6.2 4. 5.0 2.6 ( p - - 0 . 0 1 5 ) 1.3 ( p - ns)
1.2 t=4.2 tffi 2.8 tffi 2.3
4. 1.2 (p=0.000) (p ffi 0.012) (p = 0 . 0 2 7 )
1.0 t = 5.1 t - 2.4 tffi3.0
4. 1.5 (/7 •0.000) ~p = 0.027) (p=0.005)
14.1 4. 12.3 t=0.6 (p--ns)
t-
9.5 4. 7.3 2.6 (p = 0 . 0 1 2 )
t-4.3
--
t-
1.4
( p = ns)
t-
--
--
t=
19.9 4. 10.8
21.2 4. 14.7 t=0.3 (p=ns) --
D
--
12.4 4. 8.5 tffi 2.5 (p ~ 0 . 0 1 9 ) t - - 2.2 (p = 0.033 --
21.2 __ 8.7
PD vs MDD-PD vs MDD ~,s One-way ANOVA:
9.4 4. 10.4 t=0.3 (p=ns)
4.2 4. 3.7 t=2.3 (p-0.027) t - - 1.2 (p = ns) --
--
PD vs MDD-PD vs MDD vs
15 Min-APl
6.7 4. 6.3 t-0.6 (p=ns)
21.5 4. 14.0 t =0.1
(p •ns)
-Baseline: 5 min 10 min 15 min 20 min
F --
5.81 6.19 6.81 9.34 10.65
df-
2.8 t=4.7 tffi 3.7 t - - 3.3
12.8 4. 9.7
_ 2.4 (p = 0 . 0 0 0 ) ( p - 0.002) (p = 0 . 0 0 2 )
3.0 4. 2.5
t=
2.8
( p ffi 0 . 0 0 8 )
t = 6.1
t-
2.1
(p-
t-
-3.57
2.3 4. 1.5 (p=0.000) 2.8 ( p = 0.011) 2.9 (p = 0.007)
0.039)
3.9
t = 3.0
( p ffi 0 . 0 0 0 )
(p ffi 0.001)
(p ffi 0.o06)
p -- 0.002 0.001 0.001 0.000 0.000
ANOVA for repeated measures revealed a significant interactive effect for diagnosis over time for anxiogen~c response to fenfluramine (F = 4.35; p -- 0.047). Table 3 summarizes the mean behavioral data to fenfluramine for all groups and presents post hoc t-tests as well. Fourteen PD patients (82%), 8 MDD-PD patients (67%), 2 MDD patients (7%), and 2 controls (16%) revealed positive anxiogenic responses. PD patients had significantly more positive responses than MDD patients (X2 = 22.18; p = 0.000), and controls (X2 : 9.76; p = 0.002). Similarly, MDD-PD patients had significantly more positive responses than MDD patients (Xe = 12.35; p = 0.000) and controls (7/2 = 4.29; p = 0.038). MDD patients did not differ from controls (X:~ = 0.09; p = ns). Analysis of the response curve for prolactin response to fenfluramine revealed significant changes in PD patients (F = 8.2; df = 1, 64; p = 0006), but not in MDD-PD patients (F = 2.75; p = 0.098), MDD patients (F = 2.08; p = ns), or controls (F = 1.75; p = ns). ANOVA for repeated measures revealed no significant interactive effect for diagnosis over time for prolactin (F : 1.26; p = ns). The absence of a significant interactive effect occurred because PD patients and both MDD groups had significantly greater serum prolactin responses to fenfluramine than controls at baseline, 60, oad 120
Panic and Depression: Anxiogenic Challenge
BIOL PSYCHIATRY
199o;28:21-34
45 40 35 X
30 ANXIETY (SAS)
25 20 15 10 5 0
I
I
60
120
' I
180
I
I
240
300
TIME (MINUTES)
PANIC DISORDER
~ MDD-PANIC ATTACKS
'~" MDD
"~" CONTROLS
Figure 2. Anxiety response to fenfluramine in patients with major depression and panic disorder.
30
25
20 PROLACTIN (NO/ML)
15
-
>~
10
,.
0
60
120
I
I
180
240
- - 4
300
TIME (MINUTES) -El- P A N I C
DISORDER
")~ MDD-PANIC ATTACKS
Figure 3. Prolactin response to fenfluramine.
"if-MDD
"~" CONTROLS
27
28
S.D. Targum
BIOL PSYCHIATRY 1990;28:21-34
24
---
22
-
CORTISOL (UG/DL)
16
14
12 -
10
-
-
I
I
120
240
TIME (MINUTES) PANIC DISORDER ~ MDD-PANIC ATTACKS
~ MDD
~ CONTROLS
Figure 4. Serum cortisol response to fenfluramine.
rain. The A prolactin response to fenfluramine was calculated as the peak response over 5 hr less baseline. A prolactin values were 19.9 - 28.4 ng/ml in PD patients, 13.8 _+ 14.1 ng/ml in MDD-PD patients, 6.6 - l 1.1 ng/ml in MDD patients, and 7.2 -+ 7.0 ng/nd in controls. The A prolactin was significantly greater in PD versus MDD patients (t - 2.2; df = 42; p - 0.033), but not controls (t - 1.5; df = 27; p = ns). MDDPD patients A prolactin responses did not differ significantly from MDD patients (t = 1.7; d f - 37; p = n s ) o r controls (t = 1.4; p = ns). Analysis of the response curve for cortisol response to fenfluramine was not significantly changed over the three time points in panic disorder patients ( F = 2.68; df -= 1, 64; p = 0.10), but did diminish significantly in MDD-PD patients ( F = 6.04; p = 0.016), MDD patients (F = 13.62; p = 0.001), and controls (F = 5.14; p = 0.C,25)o ANOVA for repeated measures revealed a nonsignificant interactive effect fc~" ~iiaglcc~i~ over time for cortisol (F = 3.67; df - 1, 21.33; p = 0.065). Analysis of direct effects
Panic and Depression: Anxiogenic ChaUenge
BIOL PSYCHIATRY 199o;28:21-34
29
Table 3. Behavioral Response to Fenfluramine and Post Hoc t-Tests in Patients with Major Depression and Panic Disorder
Ba~eline SAS t-test (p) P D vs M D D - P D vs M D D vs
60 min-SAS
Panic disorder
MDD-PD
MDD
Controls
14.0 -4- 9.3
8.8 ± 8.8
9.7 __ 8.2
2.2 -4- 2.2
---
t=
_
P D vs M D D - P D vs M D D vs
180 min-SAS
2 5 . 6 ± 17.5 t--
4 0 . 5 ± 18.4 ---
P D vs M D D - P D vs M D D vs
t = 1.6 t = 0.3
--
t=
-38.5 ± 20.8 t=
-34.6 - 24.0 ---
d f f o r P D vs M D D - P D vs M D D vs controls for M D D - P D vs M D D vs controls for M D D vs controls
10.9 _ 11.0 2.6 (/7 = 0.016) w
22 42 27 32 17 37
t =4.3 t = 2.5 t=3.1
10.6 _ 9.7 t = 3.7 (p = 0 . 0 0 1 ) t = 0.1 (p = 0 . 9 3 5 ) --
27.8 ± 13.1 (p=0.041) ---
14.1 ± 12.5 (p=0.000) t = 3.1 (p = 0 . 0 0 4 ) ~
2.1
t=5.6
32.3 ± 29.1 0.7 (p = 0 . 5 1 2 )
(p = 0.00) (p = 0 . 0 1 9 ) (p = 0.004)
2.2 _ 3.3 t =4.6 (/7 = 0.000) t2.6 ( p - - 0.015) t
12.8 ± 10.4 t = 6.4 ( p = 0 . 0 0 0 ) t = 1.9 ( p - - 0.059) --
=
2.9
12.2 t = 4.4 t1.4 t--0.2
(p
=
0.~)06)
± 15.3 (p = 0.000) ( p - - 0.171) (p = 0.878)
9.7 ± 12.0
t-4.7
(p - O.O00)
t = 3.5 t = 1.0
(p = 0 . 0 0 2 ) (p=0.303)
~
12.7 ± 13.3 t = 5.0 (p = 0 . 0 0 0 ) t 2.9 ( p = 0 . 0 0 6 )
8.0 ± 12.4 t=4.5 (p = 0 . 0 0 0 ) t = 2.7 (p = 0.014)
~
--
t = 1.0 ( p = 0 . 3 0 4 ~
27.6 ± 2 6 . 0 t = 0.8 ( p = 0.457) h
11.3 ± 11.1 t = 4.4 (/7 = 0 . 0 0 0 ) t = 2.8 (p = 0.009)
--
= = = = =
(p = 0.115) (p = 0 . 7 6 6 ) h
20.8 ± 14.5 t = 3.1 (p = 0.005) ---
43.5 ± 22.6
P D vs M D D - P D vs M D D vs
300 min-SAS
0.144)
w
P D vs M D D - P D vs M D D vs
240 min-SA$
(p--_
P D vs M D D - P D vs M D D vs
120 min-SAS
1.5
One-way baseline 60 120 180 240 300
~
ANOVA F = 5.78 10.53 13.00 14.41 9.51 9.68
d f -- 3,64
4.1 t--- 4.3 t = 3.1 t --- 2.2
± (p (/7 (p
5.0 = 0.000) = 0.006) = 0.038)
p -- 0.001 0.000 0.000 0.000
0.000 0.000
was significant for diagnosis at 120 min (F = 3.40; df = 3, 64; p = 0.023). PD patients differed from MDD-PD patients at 120 min (t = 2.3; p = 0.033) and controls (t = 2.6; p = 0.015) but not MDD patients (t = 1.4; p = 0.18). Basal and post-fenfluramine cortisol responses in MDD-PD patients did not differ significantly from either MDD patients or control subjects at any point. A cortisol values were 2.8 --. 7.2 ttg/dl in PD patients, - 2 . 9 - 4.0 ixg/dl in MDDPD patients, - 3 . 0 - 5.7 p~g/dl in MDD patients, and - 4 . 6 -+ 4.2 Ixg/dl in controls. PD patients had significantly greater A cortisol values than MDD-PD patients (t = 2.5; df = 27; p = 0.02), MDD patients (t - 2.9; df -- 42; p = 0.005) and controls (t = 3.2; df = 27;p = 0.004). MDD-PD patients and MDD patients did not differ significantly from each other or the controls.
30
BIOL PSYCHIATRY 1990;28:21-34
S.D.
Targum
Thus, behavioral and hormonal responses to fenfiuramine challenge revealed different responsivities between PD, MDD-PD, and MDD patient groups and control subjects, with PD patients showing the most robust responses.
Correlation Bet~'een Lactate and Fenfluramine Responses Using threshold criteria as described in Methods, 14 patients revealed positive responses to both the lactate infusion procedure and the oral fenfluramine challenge. Nine PD patients (53%) in contrast to 3 MDD-PD patients (25%) (X"~= 1.26; p = ns) and 2 MDD patients (7%) (X2 = 9.23; p < 0.003) had positive responses to both challenges. Correla~.lonal analysis of peak anxiogenic responses between lactate and fenfluramine challenges revealed significance in PD patients (r = 0.5; p = 0.03) but not in MDDPD patients (r = 0.1; p = ns) or MDD patients (r = 0.3; p = ns). Discussion This study has examined anxiogenic challenge responses to intravenous lactate infusion and oral fenfluramine administration in hospitalized patients with PD, MDD-PD, MDD, and a comparison group of nonpsychiatric control subjects. PD and MDD-PD patients had significantly greater anxiogenic responses to lactate infusion and to oral fenfiuramine administration compared with MDD patients or controls. These results are consistent with the studies of several other investigators (McGrath et al. 1988; Cowley et al. 1986; Dager et al. 1987; Lopez-Ibor et al. 1988; Targum and Marshall 1989) and reflect the predisposition of panic-prone patients to react to different panicogenic stimuli. Though the clarification of the boundaries between PD and MDD are still undecided (Coryell et al. 1988), the MDD-PD group of patients in this study clearly demonstrated a latent sensitivity to panic attacks which distinguished them from the MDD group. This suggests that the predisposition to a panic response is separate from the predisposition to depression. It must be emphasized that panic attacks as elicited by challenge studies are not synonymous with the DSM-III-R definition of panic disorder and that such attacks may be precipitated by many different factors an~Jor different psychiatric disorders (Dager et al. 1987; Aronson et al. 1989). However, the results of this study do suggest that major depressed patients with a history of panic attacks occurring more than 6 months prior to the study may share a neurobiological sensitivity with those patients who are currently having panic attacks and who have met DSM-III-R criteria for PD. The shared sensitivity may contribute to the overt expression of anxiogenic responses to either lactate or fenfluramine. The anxiogenic response may be diminished, but still measurable In patients who are not currently experiencing panic. Thus, it would appear that once an individual is "sensitized" to panic attacks~, he or she will remain vulnerable to panicogenic stimuli. These findings differ from those of McGrath et al. (1988) who suggested that the susceptibility to lactate-induced l?e~ie was related more to current state rather than to an underlying vulnerability. Alternatively, the findings are consistent with the study of Fyer et al. (1985) who reported that some PD patients retain their vulnerability to lactate infusion while in remission and after the discontinuation of medication. The PD patients and MDD-PD patients differed in two ways in their anxiogenic challenge responses. First, PD patients had more robust anxiogenic respoi~ses to both challenges than MDD-PD patients. For instance, PD patients had positive responses to both challenges significantly more often than MDD-PD patients. Further, correlational
Panic and Depre;~sion:Anxiogenic Challenge
BIOL P?VC!-I[L%TRY 1990;2~:21-34
31
analysis of peak anxiogenic responses between lactate and fenfluramiLe challenges reveaied significance in PD patients but not in MDD-PD patients. Second, PD patients revealed significant prolactin and cortisol responses to oral fenfluramine administration relative to MDD patients, whereas MDD-PD patients did not. These differences between PD and MDD-PD patients may be due to the conditioned "hyperresponse" seen in many I'D patients who have experienced recent acute panic episodes and have consequently developed a heightened anticipatory anxiety and the cognitive expectation of having more panic responses. A mechanism for this hyperresponse has been proposed by Gorman et al. (1989) who suggest that frequent brainstem stimulation occurring during recurrent panic attacks may lower the threshold to excitatory postsynaptic stimulation resulting in a sustal~led ("kindled") state of anticipatory anxiety; thus, a "hyperconditioned" patient may be more likely to react ve~ strongly to anxiogenic stimuli. Further, the kind~ed state ma:/also result in a reduced threshold for anxiogenic responsivity to more nonspecific ~unuli in these panic-prone individuals. Panic attacks occurring in PD and MDD-PD patients may be etiologically related to brainstem hypersensitivity, as suggested by Gorman et al. (1989), and may be indirectly related to MDD via associated limbic sys',em circuits. This common limbic system association may explain the complex interrelationships and comorbidity (the possibility that one disorder might contribute to the development of a second disorder) r ~ted between PD and MDD in many studies (Leckman et al. 1983; Coryell et al. 1988). Leckrnan et al. (1983) found that relatives of patients wi~. combine~l MDD and PD (MDD-;'D) were twice as likely to have major psychiatric disorders thou the relatives of patievts with MDD and no anxiety disorder. It is conceivable that the co-morbidity as reflected in the study of Leckman et al. might lower the threshold for overt expression of each disorder, but it does not rule out the possibility that the predisposition to develop panic attacks relates to a distinct neurobiological diathesis apart from MDD. The data of the present study would suggest that MDD-PD patients may have a combination of two distinct diatheses. There is some evidence to suggest that MDD-PD patients mey have a more severe disorder than either PD or MDD patients as characterized by earlier onset of illness and a more difficult treatment course (Leckman et al. 1983; VanValkenburg et al. 1984; Breier et al. 1985; Coryell et al. 1988). The clinical implications of this study cle~,,dy point to using therapeutic strategies that will treat patients with combined MDD-PD for both syndromes. In fact, it may be useful to consider individuals in the MDD-PD group as "panic-depressive" patients who are clinically separate from either PD patients or MDD patients.
References American Psychiatric Associ~:ion(1987): Diagnostic and Statistical Manual of ,'ffental Disease (ed 3, revised). Washington, DC: AmericanPsychiatric Association. Aronson TA, Whitaker-Azmitia,Caraseti I (1989): Differentialreactivity to lactate infusions:The relative role of biological, psychological, and conditioningvariables. Biol Psychiatry 25:469481. Avery DH, OsgoodTB, Ishiki DM, et al (1985): The DST in psychiatricoutpatientswithgeneralized anxiety disorder, panic disorder, or primary affective disorder. Am J Psychia~ 142:844-848. Balon R, Pohl R, Yeregani VK, et al (1988): The significanceof HPA axis dist~arbancein panic disorder. Psychiatry Res 23:153--160.
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Baumgartner A, Graf K-J, Kurten I, et al (1988): The hypothalamic-pituitary-thyroid axis in psychiatric patients and healthy subjects: Parts 1--4. Psychiatry Res 24:271-332. Boulenger JP, Uhde TW, Wolff EA HI, et al (1984): Increased sensitivity to caffeine in patients with panic disorder: Preliminary evidence. Arch Gen Psychiatry 4:1067-1071. Bowen RC, Kohout J (1979): The relationship between agoraphobia and primary affective disorders. Am J Psychiatry 24:317-322. Breier A, Chamey DS, Heninger GR (1984): Major depression in patients with agoraphobia and panic disorder. Arch Gen Psychiatry 41:1129-1135. Breier A, Charney DS, Heninger GR (1985): The diagnostic validity of anxiety disorders and their relationship to depressive illness. Am J Psychiatry 142:787-797. Carson SW, Halbreich V, Yeh C-M, et al (1988): Altered plasma dexamethasone and cortisol suppressibility in patients with panic disorders. Biol Psychiatry 24:56-62. Charney DS, Heninger GR, Breier A (1984): Noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psyclffa..'ry 4! "751-763. Charney DS, Heninger GR, Price LH, et al (1986): Major depression and panic disorder: Diagnostic and neurobiological relationships. Psychopharm Bull 22:503-511. Cloninger CR, Martin RL, Clayton P, et al (1981): A blind follow-up and family study of anxiety neurosis: Preliminary analysis of the St. Louis 500. In Klein DF, Rabkin J (,'As), Anxiety: New Research and Changing Concepts. New York: Raven Press. Coccaro EF, Siever LJ, Klar H, et al (1987): Diminished prolactin responses to repeated fenfluramine challenge in man. Psychiatry Res 22:257-259. Coryen W, Endicott J, Andreason NC, et al (1988): Depression and panic attacks: The significance of overlap as reflected in follow-up and family study data. Am J Psychiatry 145:293-300. CoryeU W, Noyes R Jr, Schlechte (1989): The significance of HPA axis disturbance in panic disorder. Biol Psychiatry 25:989-1~2. Cowley DS, Dager SR, Dunner DL (1986): Lactate-induced panic in primary affective disorder. Am J Psychiatry 143:646-648. Crowe RR, Noyes R, Pauls DL (1983): A family study of panic disorder. Arch Gen Psychiatry 40:1065-1069. Crowe RR, Pauls DL, Slymen DJ, Boyes R (1980): A family study of anxiety neurosis: Morbidity risk in families of patients with and without mitral valve prolapse. Arch Gen Psychiatry 37:7779. Dager SR, Cowley DS, Dunner DL (1987): Biological markers in panic states: Lactate-induced panic and mitral valve prolapse. Biol Psychiatry 22:339-359. Dillon DJ, Gorman JM, Liebowitz MR, et al (1987): Measurement of lactate-induced panic and anxiety. Psychiatry Res 20:97-105. Endicott J, Spitzer RL (1978): A diagnostic interview: The schedule for affective disorders and schizophrenia. Arch Gen Psychiatry 35:837--844. Fyer AJ, Liebowitz MR, Gorman JM, et al (1985): Lactate vulnerability of remitted panic patients. Psychiatry Res 14:143-148. Gaffaey FA, Fenton BJ, Lane LD, et al (1988): Hemodynamic, vcntilatory, and biochemical responses of panic patients and normal controls with sodium lactate infusion and spontaneous panic attacks. Arch Gen Psychia¢ry 45:53-61. Gold PW, Chrousos G, Kellner C, et al (1984): Psychia.t,ic implications of basic and clinical studies with corticotropin-releasing factor. Am J Psychiatry 141:619--627. Gorman JM, Askanazi J, Liebowitz MR, et al (1984): Response to hyperventilation in a group of patients with panic disorder. Am J Psychiatry 141:857-861. Gorman JM, Liebowitz MR, Fyer AJ, et al (1989): A neuroanatomical hypothesis for panic disorder. Am J Psychiatry 146:148-161.
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Gq~nhaus L, Hegel P, Haskett RF, et al (1987): Serial dexamethasone suppression tests in simultaneous panic and depressive disorders. Biol Psychiatry 22:332-338. Hamilton M (1960): A rating sc.~!efor depress~.n. J ~,'eurol Neurosurg Psychiatry 23:56-62. Hamlin CL, Dackis CA, Martin DM, et al (1984): Blunted thyrotmpin-releasing hormone stimulation test in panic disorder. Presented at 137th annual meeting of the American Psychiatric Association, May 8. Harris EL, Noyes R, Crowe RR, et al (1983): Family study of agoraphobia. Arch Gen Psychiatry 40:1061-1064. Kelly D, Mitchell-Heggs N, Sherman D (1971): Anxiety and the effects of sodium lactate assessed clinically and physiologically. Br J Psychiatry 119:129-141. ICdein DF (1981): Anxiety reconceptualized: In Klein DF, Rabkin J (eds), Anxiety: New Research and Changing Concepts. New York: Raven Press. Klerman GL (1980): Anxiety and depression. In Burrouws GD, Davis B (eds), Handbook of Studies on Anxiety. New York: Elsevier. Leckman JF, Weissman MM, Merikangas KR, et al (1983): Panic disorder and major depression: Increased risk of depression, alcoholism, panic, and phobic disorders in families of depressed probands with panic disorder. Arch Gen Psychiatry 40:1055-1060. Liebowitz MR, Fyer AJ, Gorman JM, et al (1984): Lactate provocation of panic attacks. I. Clinical and behavioral findings. Arch Gen Psychiatry 41:764-770. Liebowitz MR, Gorman JM, Fyer AJ, et al (1985): Lactate provocation of panic attacks. II. Biochemic~ and physiological findings. Arch Gen Psychiatry 42:709-719. Lopez-lbor JJ, Saiz-Ruiz J, Iglesias LM (1988): The fenfluramine challenge test in the affective spectrum: A possible marker for endogeneity and severity. Pharmacopsychiatry 21:9-14. McGrath P, Stewart J, Liebowitz MR, et al (1988): Lactate provocation of panic attacks in depressed outpatients. Psychiatry Res 25:41-47. Munjack DJ, Moss HB (1981): Affective disorder and alcoholism in families of agoraphobics. Arch Gen Psychiatry 38:869-871. Noyes R, Crowe RR, Harris EL, et al (1986): Relationship between panic disorder and depression. Arch Gen Psychiatry 43:227-232. Pariser S, Pinta E, Jones B (1978): Mitral valve prolapse syndrome and anxiety neurosis/panic disorder. Am J Psychiatry 135:240-247. Pitts FN, McClure JN (1967): Lactate metabolism in anxiety neurosis. N Engl 3 Med 277:13291336. Rainey JM Jr, Pohl RB, Williams M, et al (1984): A comparison of lactate and isoproterenol anxiety states. Psychopathology 17(Suppl 1):74-82. Raskin M, Peeke HVS, Dickman W, et al (1982): Panic and generalized anxiety disorders: Developmental antecedents and precipitants. Arch Gen Psychiatry 39:687-689. Roy-Byrne PP, Bierer LM, Uhde TW (1985a): The dexamethasone suppression .test in panic disorder: Comparison with normal controls. Biol Psychiatry 20:1234-1237. Roy-Byme PP, Uhde TW, Gold PW, et al (1985b): Neuroendocrine abnormalities in panic disorder. Psychopharmacol Bull 21:546-550. Roy-Byrne PP, Uhde TW, Rubinow DR, et al (1986): Reduced TSH and prolactin responses to TRH in patients with panic disorder. Am J Psychiatry 143:503-507. Schapira K, Roth M, Kerr TA, et al (1972): Prognosis of affective disorders: The differentiation of anxiety states from depressive illnesses. Br J Psychiatry 121:175-181. Sheehan DV (1986): The Anxiety Disease. New York: Bantam Books. Sheehan DV, Ballenger J, Jacobsen G (1980): Treatment of endogenous anxiety with phobic, hysterical and hypochondriacal symptoms. Arch Gen Psychiatry 37:51-59. Sheehan DV, Claycomb JB, Surman OS, Baer L, Colleman J, Gelles L (1983): Panic attacks and the Dexamethasone Suppression Test. Am J Psychiatry 140:1063-1064.
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Siever LJ, Murphy DL, Slater S, et al (1984): Plasm~ pmlactin changes following fenfluramine in depressed patients compared to controls: An evolution of central semtonergic responsivity in depression. Life Sci 34:1029-1039. Spitzer RL, Williams aBW (1983): Structured clinical interview for DSM-III. New York: Biometrics Research Department, New York State Psychiatric Institute. Targum SD, Marshall LE (1989): Fenfluramine provocation of anxiety in patients with panic disorder. Psychiatry Res 28:295-306. Targum SD, Sullivan AC, Bymes SM (1983): Neuroendocrine interrelationships in major depressive disorder. Am J Psychiatry 139:282-286. VanValkenburg C, Akiskal HS, Puzantian V, Rosenthal T (1984): Anxious depressions: Clinical, family history, and naturalistic outcome--comparisons with panic and major depressive disorders. J Affective Dis 6:67-82. Woods SW, Charney DS, Coodman WK, Heninger GR (1988): Carbon dioxide-induced anxiety. Arch Gen Psychiatry 45:43-52. Zung WWK (1965): A self-rating depression scale. Arch Gen Psychiatry 12:63-70.
21
Differential Responses to Anxiogenic Challenge Studies in Patients with Major Depressive Disorder and Panic Disorder Steven D. Targum
Anxiogenic challenge studies (intravenous lactate infusion and oral fenfluramine challenge) were conducted in 17 patients with panic disorder (PD), 12 patients with major depressive disorder and a history of panic attacks (MDD-PD), 27 patients with major depression and no history of panic (MDD), and 12 normal controls. PD and MDD-PD patients revealed significantly greater anxiogenic responses to lactate infusion and fenfluramine administration than either MDD patients or controls. PD patients revealed the most robust anxiogenic responses to both challenges as well as associated significant prolactin and cortisol responses to fenfluramine. The findings suggest that the predisposition to panic attacks as seen in PD and MDD-PD patients may represent ~ distinct neurobiological diathesis which may coexist with a major depressive diathesis in some patients. The delineation of subgroups within the more heterogenous group of patients with MDD and/or PD will lead to greater precision in the development of clinical treatment strategies. Thus, MDD-PD patients (better called panic-depressives) may have a more severe illness than patients with MDD alone which must be accounted for in the course of pharmacotherapy and psychotherapy. The evolution of research in major depressive disorder (MDD) and panic disorder (PD) has lead to improved diagnostic precision between these entities as now defined in the DSM-III-R which allows for the concomitant use of both diagnoses in the same patient (APA 1987). However, the phenomenological, pharmacological, bioiogical, and familial similarities between these two putatively "distinct" clinical entities reveals a more complex interrelationship between them. In fact, it is not clear if MDD and PD are truly distinct illnesses or represent two states on a continuum of affective disorders (Schapira et al. 1972; Klerman 1980; Breier et al. 1984). The similarities between panic disorder and major depressive disorder are abundant. Phar~.acological studies have demonstrated equivalent therapeutic efficacy for imipramine ~ld MAO inhib~tors in the treatment of either disorder (Sheehan et .oi. 1980; Klein 1981; Breier et al. 1985). Neuroendocrine challenge studies have shown aberrant responses in PD patients which resemble those seen in patients with MDD (Sheehas~ et al. 1983;
F:o~','~ the ~L,~.,~:~~_.-.; .;., ".~vc~iatry, Crozer-Che~ter Medical Center, Upland, PA; and Hahnemann University, Philadelphia, PA. ~.'.*-~'-~s ~ep, i~.; : ~aes:s to Steven D. Targum, M.D., Crozer-Chester Medical Center, One Medical Center Blvd., POB 1, :;., ~ ~/., t~!,land, PA 19013-3995. ~,;2.: ,',~ July 22, 1989; revised November 2, 1989.
© 1990 Society of Biological P~ychiatry
0006.3223/90/$03.50
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Targum
Targum et al. 1983; Gold et al. 1984; Hamlin et al. 1984; Avery et al. 1985; Roy-Byrne et al. 19850, 1985a, 1986; Grunhaus et al. 1987; Baumgarmer et al. 1988; Carson et al. 1988; Coryell et al. 1989). Some, but not all, family studies have demonstrated an increased incidence of MDD in the relatives of PD patients (Bowen and Kohout 1979; Ctowe et al. 1980, 1983; Harris et al. 1983; Munjack and Moss 1981; Noyes et al. 1986). Temporally distinct depressive episodes occurring either before or after the onset of panic attacks have been noted in 60%-88% of patients with panic disorder (Cloninger 1981; Pariser et al. 1978; Raskin et al. 1982; Breier et al. 1984, 1985). It is not clear whether patients who reveal MDD and PD at different times are revealing different clinical manifestations of the same psychopathological/biological condition or in fact have two distinct disorders (Klerman 1980; Breier et al. 1984; VanValkenburg et al. 1984). Leckman et al. (1983) suggested that those patients who have combined MDD-PD may have a partially shared underlying biological diathesis with PD patients and predicted that metabolic diffcreaces would exist that would dist.inguish patients with combined MDDPD from those with MDD without a panic disorder. Patients with PD are vulnerable to a number of diverse stimuli which can trigger anxiety and/or panic responses (Breier et al. 1985; Chamey et al. 1986; Gorman et al. 1989). Intravenous administration of isopmterenol or sodium lactate, oral ingestion of yohimbine, caffeine, or fenfluramine, hyperventilation, and inhalation of 5% carbon dioxide have all been shown to possess anxiogenic properties in PD patients (Boulenger et al. 1984; Liebowitz et al. 1984, 1985; Charney et al. 1984, 1986; Balon et al. 1988; Gaffney et al. 1988; Woods et al. 1988; Targum and Marshall 1989; Gorman et al. 1984, 1989). Infusion of sodium lactate has been shown to precipitate panic-like reactio~ts in 70%100% of patients with PD (Kelly et al. 1971; Pitts and McClure 1967; Liebowitz 1984; Rainey et al. 1984; Balon et al. 1988; Aronson et al. 1989). McGrath et al. (1988) found panic responses to lactate infusion in 15 of 29 depressed outpatients with a history of spontaneous panic attacks (52%) in contrast to I of 18 patients without a history of panic (×2 = 10.5; p < 0.002). Although they did not include panic disorder patients in their study, they did note that the likelihood of lactate-induced panic was greatest in depressed patients who wez~.cth-rently experiencing panic. Dager et al. (1987) found positive lactate responses in 34 of 43 PD patients (79%), 6 of 8 MDD-PD patients (75%), 2 of 9 MDD patients without panic (25%), and in none of 8 controls. Their findings suggested a common vulnerability between PD and MDD-PD patients. Fenfluramine, an indirect serotonergic.-rt~le~s:,ngand re-uptake blocking agent has been shown to precipitate anxiogenic responses in patients with PD (Targum and Marshall 1989). These investigators reported positive anxiogenic responses to fenflm'amine in 9 of 9 PD patients, 0 of 9 MDD patients with no history of panic, and 2 of 9 controls (X2 = 15.99; p < 0.0003). In addition, significant prolactin and cortisol responses to fenfluramine were observed in positive responders. Similarly, Lopez-Ibor (1988) reported a differential prolactin response to fenfluramine administration within subtypes of MDD patients such that those patients with a history of panic attacks (MDD-PD) had greater prolactin responses to fenfluramine than those patients without such a history. Further, Siever et al. (1984) have reported that MDD patients tend to have blunted prolactin responses to oral fenfluramine in contrast to controls, adding to the potential distinction between PD and MDD patients in the present study, two anxiogenic challenge studies were conducted (intrave,aous lactate infusion and oral fenfluramine administration) in age- and gender-matched groups
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23
Table i. Anxiogenic Challenge Studies in Patients with Major Depression and Panic Disorder Panic disorder n Age Gender Hamilton Scale Zung Scale
17 32.5 -4- 7.0 4: i 3 22.0 _ 7.8" 57.1 .4. 14.1 a
MDD-PD 12 32.8 _ 9.1 2:5 26.4 _ 6.9" 58.3 _+ 17.4 b
MDD
Controls
27 33.4 - 7.8 7:20 26.0 _.+ 6.9 ~ 51.5 .4- 9 . ~
12 35.7 ± 4.3 3:9 1.5 __ 1.3 43.8 __ 2.9
°p < 0.005 vs. controls; ~p < 0.01 vs. controls. MDD-PD = patients with major depressive disorder and a history of pa~aicattacks; MDD = patients with major depressive disorder and no history of panic attacks.
of patients with PD, MDD-PD, and MDD, and controls. The following questions have been asked: (1) Can anxiogenic challenge strategies distinguish PD from MDD patients vith or without a history of panic attacks? (2) Where do MDD-PD patients fit within the spectrum of major depressive and panic disorders?
Methods Anxiogenic challenge studies were performed as part of a comprehensive assessment of patients admitted to the psychobiological service of the Sarasota Palms Hospital between 1987 and 1989. Patients and normal volunteers consented to administration of both the intravenous lactate infusion and oral fenfluramine challenges. Subjects "sere free of all psychotropic, steroidal, and antihypertensive medications for a minimum of 2 weeks prior to entry into the study and were included only if they had no concurrent medical problems as confirmed by physical examination and had normal routine chemistries. Subjects were men and premenopausal women ranging in age between 19 and 48 years. There were no significant differences in age or gender distribution between diagnostic groups (see Table 1). Diagnoses were made using DSM-HI-R criteria via administration of structured interviews (Schedule for Affective Disorders and Schizophrenia-Lifetime Version and the Structured Clinical Interview for DSM-HI) by clinical staff who were blind to the results of biological studies (Endicott and Spitzer 1978; Spitzer and Williams 1983). Hamilton Depression Scales and Zung Anxiety Scales were also administered to all subjects (Hamilton 1960; Zung 1965). Seventeen patients met criteria for panic disorder (PD) as defined by DSM-IH-R, and 39 patient~ met criteria for major depressive disorder (MDD). PD patients did not meet criteria for MDD. Within the MDD group, 12 patients had a history of panic attacks which met DSM-HI-R criteria for panic disorder which had occurred at least 6 months prior to their current acute depressive episode, Thcse 12 patients were recategorized as a ~eparate group (MDD-PD) for this study, and the remaining 27 depressed patients were called MDD patients with no history of panic. The MDD-PD group was equally split between those patients who had a primary affective disorder versus those who had a primary panic disorder by history; tlff-:historical difference did not affect the biological results. All depressed subjects had a minimum Hamilton Score of 18 at the time of admission to the hospital. Twelve medically healthy normal volunteers with no previous psychiatric history also consented to participate in this study. The lactate infusion procedure was conducted i~ the morning after an ove~ght bedrest and fast according to methods described elsewhere (Liebowitz et al. 1984; Dager et al.
24
BIOL PSYCHIATRY 1990;28:21-34
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Targum
1987; Aronson et al. 1989). A slow intravenous infusion of D5W was given for 30 min and then changed under single blind conditions ~ 0o5 M sodium DL-lactate (warmed to body temperature) which was then infused over 20 min. Patients were rated every 5 min with the Acute Panic Inventory (AII) (Dillon et al. 1987) which asks the patient to rate 17 subjective items related to panic on a 0-3 scale with increasing severity. Scores ranged from 0 to 51. Lactate responses were considered positive if the patient reported the experience to be panic-like, had API scores exceeding 20 points, and had a minimum increment of 15 points from baseline on the API. Positive responses were invariably associated with concomitant tachycardia with increases greater than 20 beats/min. The oral fenfluramine challenge was administered on the day following the lactate infusion. In the morning, after an overnight bedrest and fast, all subjects received 60 mg of fenfluramine and completed a subjective rating scale hourly for 5 hr. Subjects were allowed mild ambulation in accordance with the method of Coccaro et al. (1987). A modification of the self-rated anxiety scale (SAS) developed by Sheehan (1986) was used and included 17 items from SAS Scale Part I and all 11 items from SAS Scale Part H which were rated 0-4 with increasing severity of anxiety symptoms. Total scores could vary from 0 to 112. Fenfluramine responses were considered positive if the patient reported the experience to be panic-like and their SAS scores increased by at least 25 points from baseline (ASAS >~ 25) ha accordance with the study of Targum and Marshall (1989). Collection of serem prolactin and cortisol was obtained during the course of the fenfluramine protocol as well. Serum prolactin was obtained at - 1 5 , 0, 60, i20, 180, 240, and 300 min and serum cortisol was obtained at baseline, 120, and 240 min. Baseline prolactin was determined as the average of the two pre~fenfluramine prolactin samples (Siever et al. 1984; Targum and Marshall 1989). Serum cortisol was measured by radioimmunoassay with a calculated assay sensitivity of 0.4 iol,g/dl. Intraassay coefficient of variation was 4.1% and interassay coefficient of variation was 1.0% for a sample of 15 ttg/dl. Serum prolactin was also measured by radioimmunoassay with an overall intraassay coefficient of variation of 3% and interassay coefficient of variation of 6%. Statistical analysis of the data included examination of each variable from each challenge study at each time point for each of the four study groups. The data were evaluated as pooled values for mean -+ standard deviation for each variable as well as by percentage of positive test responses in each study group. Statistical analysis included X2 test with Yate's co,-rection for continuity, one-way analysis of variance (ANOVA) with repeated measures (calculating the Greenhouse-Geisser effect), post hoc Student's t-test, and Spearman's rank correlation coefficient as appropriate. Results There were no age or gender differences between groups and controls as noted in Table 1. Hamilton depression scores and Zung anxiety scores reveal all patient groups (PD, MDD-PD, MDD) to be significantly more depressed and more anxious than the control group, but not significantly different from each other.
Lactate Infusion Response Responses to intravenous lactate are displayed in Figure 1. Analysis of the response curves revealed significant changes in PD patients (F = 30.42; df = 1, 57; p = 0.000), MDD-PD patients (F = 27.25; p - 0.000), MDD patients (F = 15.79; p = 0.000),
Panic and Depression: Anxiogenic Challenge
BIOL PSYCHIATRY 1990;28:21-34
25
25
2O
15 ANXIETY (API) 10
-A 0
.
-
', . . . . .
0
5
:
'
10
15
!
2O
TIME (MINUTES} "El"
PANIC
DISORDER
Figure 1. Anxiety response
~
tO
MDD-PANIC ATTACKS
-e- MDD
"~" CONTROLS
lactate infusion in patients with major depression and panic disorder.
but not in controls (F = 0.352; p = ns). PD and MDD-PD patients revealed more robust responses than MDD patients. Analysis of variance (ANOVA) with repeated measures revealed a significant interactive effect for diagnosis over time (F = 4.85; df = 1, 19; p = 0.038) with significant effects for diagnosis at all time points (Table 2). Post hoc t-tests (Table 2) ~flect that anxiogenic responses were significantly greater for all patient gcoups than controls at all time points. Within patient groups, PD patients' responses were significantly greater than MDD patients at all time points. Similarly, MDD-PD patients had significantly greater anxiogenic responses to lactate versus MDD patients at 15 min and 20 rain. PD and MDD-PD patients' responses did not differ significantly from each other. Using threshold criteria as described in Methods, 11 PD patients (65%), 7 MDD-PD patients (56%), 5 MDD patients (19%), and 0 controls had positive anxiogenic responses. PD patients had significantly more positive responses than MDD patients (X2 = 7.72; p = 0.005) and controls (X2 = 9.91; p = 0.002). MDD-PD patients had significantly greater positive responses than MDD patients (X2 = 4.45; p = 0.035) and controls (X2 = 7.26; p = 0.607). MDD patients did not differ from controls (X2 = 1.16; p = ns).
Fenfluramine Responses Anxiogenic and hormonal responses to 60 mg oral fenfluramine administration are displayed in Figures 2, 3, and 4. Analysis of the response curve for anxiogenic response to fenfluramine revealed significant changes over time for PD patients (F = 21.1; df = 1. 64; p = 0.000), MDD-PD patients (F = 11.36; p = 0.002), but not for MDD pafi~hts (D = 0.72; p = ns)or controls (F = 2.13; p = ns). PD and MDD-PD patients ,:,~,ealed significantly greater anxiogenic responses to fenfluramine than either MDD patients or controls, and panic disorder patients revealed significantly greater prolactin and cortisol responses as well.
26
BIOL PSYCHIATRY 1990;28:21-34
S.D. Targum
Table 2. Behavioral Responses to Lactate Infusion and Post Hoc t-Tests in Patients with Major Depression and Panic Disorder PD
MDD-PD
MDD
Controls
Mean baseline API t-tests: PD vs MDD-PD vs MI~D vs
5 Min-API PD vs MDD-PD vs MDD vs
1(, Min-API
7.0 4. 4.0
--
-10.4 _ 5.4 m
PD vs MDD-PD vs MDD vs
20 Min-API
16.6 _+ 9.9
t= t-
6.2 4. 5.0 2.6 ( p - - 0 . 0 1 5 ) 1.3 ( p - ns)
1.2 t=4.2 tffi 2.8 tffi 2.3
4. 1.2 (p=0.000) (p ffi 0.012) (p = 0 . 0 2 7 )
1.0 t = 5.1 t - 2.4 tffi3.0
4. 1.5 (/7 •0.000) ~p = 0.027) (p=0.005)
14.1 4. 12.3 t=0.6 (p--ns)
t-
9.5 4. 7.3 2.6 (p = 0 . 0 1 2 )
t-4.3
--
t-
1.4
( p = ns)
t-
--
--
t=
19.9 4. 10.8
21.2 4. 14.7 t=0.3 (p=ns) --
D
--
12.4 4. 8.5 tffi 2.5 (p ~ 0 . 0 1 9 ) t - - 2.2 (p = 0.033 --
21.2 __ 8.7
PD vs MDD-PD vs MDD ~,s One-way ANOVA:
9.4 4. 10.4 t=0.3 (p=ns)
4.2 4. 3.7 t=2.3 (p-0.027) t - - 1.2 (p = ns) --
--
PD vs MDD-PD vs MDD vs
15 Min-APl
6.7 4. 6.3 t-0.6 (p=ns)
21.5 4. 14.0 t =0.1
(p •ns)
-Baseline: 5 min 10 min 15 min 20 min
F --
5.81 6.19 6.81 9.34 10.65
df-
2.8 t=4.7 tffi 3.7 t - - 3.3
12.8 4. 9.7
_ 2.4 (p = 0 . 0 0 0 ) ( p - 0.002) (p = 0 . 0 0 2 )
3.0 4. 2.5
t=
2.8
( p ffi 0 . 0 0 8 )
t = 6.1
t-
2.1
(p-
t-
-3.57
2.3 4. 1.5 (p=0.000) 2.8 ( p = 0.011) 2.9 (p = 0.007)
0.039)
3.9
t = 3.0
( p ffi 0 . 0 0 0 )
(p ffi 0.001)
(p ffi 0.o06)
p -- 0.002 0.001 0.001 0.000 0.000
ANOVA for repeated measures revealed a significant interactive effect for diagnosis over time for anxiogen~c response to fenfluramine (F = 4.35; p -- 0.047). Table 3 summarizes the mean behavioral data to fenfluramine for all groups and presents post hoc t-tests as well. Fourteen PD patients (82%), 8 MDD-PD patients (67%), 2 MDD patients (7%), and 2 controls (16%) revealed positive anxiogenic responses. PD patients had significantly more positive responses than MDD patients (X2 = 22.18; p = 0.000), and controls (X2 : 9.76; p = 0.002). Similarly, MDD-PD patients had significantly more positive responses than MDD patients (Xe = 12.35; p = 0.000) and controls (7/2 = 4.29; p = 0.038). MDD patients did not differ from controls (X:~ = 0.09; p = ns). Analysis of the response curve for prolactin response to fenfluramine revealed significant changes in PD patients (F = 8.2; df = 1, 64; p = 0006), but not in MDD-PD patients (F = 2.75; p = 0.098), MDD patients (F = 2.08; p = ns), or controls (F = 1.75; p = ns). ANOVA for repeated measures revealed no significant interactive effect for diagnosis over time for prolactin (F : 1.26; p = ns). The absence of a significant interactive effect occurred because PD patients and both MDD groups had significantly greater serum prolactin responses to fenfluramine than controls at baseline, 60, oad 120
Panic and Depression: Anxiogenic Challenge
BIOL PSYCHIATRY
199o;28:21-34
45 40 35 X
30 ANXIETY (SAS)
25 20 15 10 5 0
I
I
60
120
' I
180
I
I
240
300
TIME (MINUTES)
PANIC DISORDER
~ MDD-PANIC ATTACKS
'~" MDD
"~" CONTROLS
Figure 2. Anxiety response to fenfluramine in patients with major depression and panic disorder.
30
25
20 PROLACTIN (NO/ML)
15
-
>~
10
,.
0
60
120
I
I
180
240
- - 4
300
TIME (MINUTES) -El- P A N I C
DISORDER
")~ MDD-PANIC ATTACKS
Figure 3. Prolactin response to fenfluramine.
"if-MDD
"~" CONTROLS
27
28
S.D. Targum
BIOL PSYCHIATRY 1990;28:21-34
24
---
22
-
CORTISOL (UG/DL)
16
14
12 -
10
-
-
I
I
120
240
TIME (MINUTES) PANIC DISORDER ~ MDD-PANIC ATTACKS
~ MDD
~ CONTROLS
Figure 4. Serum cortisol response to fenfluramine.
rain. The A prolactin response to fenfluramine was calculated as the peak response over 5 hr less baseline. A prolactin values were 19.9 - 28.4 ng/ml in PD patients, 13.8 _+ 14.1 ng/ml in MDD-PD patients, 6.6 - l 1.1 ng/ml in MDD patients, and 7.2 -+ 7.0 ng/nd in controls. The A prolactin was significantly greater in PD versus MDD patients (t - 2.2; df = 42; p - 0.033), but not controls (t - 1.5; df = 27; p = ns). MDDPD patients A prolactin responses did not differ significantly from MDD patients (t = 1.7; d f - 37; p = n s ) o r controls (t = 1.4; p = ns). Analysis of the response curve for cortisol response to fenfluramine was not significantly changed over the three time points in panic disorder patients ( F = 2.68; df -= 1, 64; p = 0.10), but did diminish significantly in MDD-PD patients ( F = 6.04; p = 0.016), MDD patients (F = 13.62; p = 0.001), and controls (F = 5.14; p = 0.C,25)o ANOVA for repeated measures revealed a nonsignificant interactive effect fc~" ~iiaglcc~i~ over time for cortisol (F = 3.67; df - 1, 21.33; p = 0.065). Analysis of direct effects
Panic and Depression: Anxiogenic ChaUenge
BIOL PSYCHIATRY 199o;28:21-34
29
Table 3. Behavioral Response to Fenfluramine and Post Hoc t-Tests in Patients with Major Depression and Panic Disorder
Ba~eline SAS t-test (p) P D vs M D D - P D vs M D D vs
60 min-SAS
Panic disorder
MDD-PD
MDD
Controls
14.0 -4- 9.3
8.8 ± 8.8
9.7 __ 8.2
2.2 -4- 2.2
---
t=
_
P D vs M D D - P D vs M D D vs
180 min-SAS
2 5 . 6 ± 17.5 t--
4 0 . 5 ± 18.4 ---
P D vs M D D - P D vs M D D vs
t = 1.6 t = 0.3
--
t=
-38.5 ± 20.8 t=
-34.6 - 24.0 ---
d f f o r P D vs M D D - P D vs M D D vs controls for M D D - P D vs M D D vs controls for M D D vs controls
10.9 _ 11.0 2.6 (/7 = 0.016) w
22 42 27 32 17 37
t =4.3 t = 2.5 t=3.1
10.6 _ 9.7 t = 3.7 (p = 0 . 0 0 1 ) t = 0.1 (p = 0 . 9 3 5 ) --
27.8 ± 13.1 (p=0.041) ---
14.1 ± 12.5 (p=0.000) t = 3.1 (p = 0 . 0 0 4 ) ~
2.1
t=5.6
32.3 ± 29.1 0.7 (p = 0 . 5 1 2 )
(p = 0.00) (p = 0 . 0 1 9 ) (p = 0.004)
2.2 _ 3.3 t =4.6 (/7 = 0.000) t2.6 ( p - - 0.015) t
12.8 ± 10.4 t = 6.4 ( p = 0 . 0 0 0 ) t = 1.9 ( p - - 0.059) --
=
2.9
12.2 t = 4.4 t1.4 t--0.2
(p
=
0.~)06)
± 15.3 (p = 0.000) ( p - - 0.171) (p = 0.878)
9.7 ± 12.0
t-4.7
(p - O.O00)
t = 3.5 t = 1.0
(p = 0 . 0 0 2 ) (p=0.303)
~
12.7 ± 13.3 t = 5.0 (p = 0 . 0 0 0 ) t 2.9 ( p = 0 . 0 0 6 )
8.0 ± 12.4 t=4.5 (p = 0 . 0 0 0 ) t = 2.7 (p = 0.014)
~
--
t = 1.0 ( p = 0 . 3 0 4 ~
27.6 ± 2 6 . 0 t = 0.8 ( p = 0.457) h
11.3 ± 11.1 t = 4.4 (/7 = 0 . 0 0 0 ) t = 2.8 (p = 0.009)
--
= = = = =
(p = 0.115) (p = 0 . 7 6 6 ) h
20.8 ± 14.5 t = 3.1 (p = 0.005) ---
43.5 ± 22.6
P D vs M D D - P D vs M D D vs
300 min-SAS
0.144)
w
P D vs M D D - P D vs M D D vs
240 min-SA$
(p--_
P D vs M D D - P D vs M D D vs
120 min-SAS
1.5
One-way baseline 60 120 180 240 300
~
ANOVA F = 5.78 10.53 13.00 14.41 9.51 9.68
d f -- 3,64
4.1 t--- 4.3 t = 3.1 t --- 2.2
± (p (/7 (p
5.0 = 0.000) = 0.006) = 0.038)
p -- 0.001 0.000 0.000 0.000
0.000 0.000
was significant for diagnosis at 120 min (F = 3.40; df = 3, 64; p = 0.023). PD patients differed from MDD-PD patients at 120 min (t = 2.3; p = 0.033) and controls (t = 2.6; p = 0.015) but not MDD patients (t = 1.4; p = 0.18). Basal and post-fenfluramine cortisol responses in MDD-PD patients did not differ significantly from either MDD patients or control subjects at any point. A cortisol values were 2.8 --. 7.2 ttg/dl in PD patients, - 2 . 9 - 4.0 ixg/dl in MDDPD patients, - 3 . 0 - 5.7 p~g/dl in MDD patients, and - 4 . 6 -+ 4.2 Ixg/dl in controls. PD patients had significantly greater A cortisol values than MDD-PD patients (t = 2.5; df = 27; p = 0.02), MDD patients (t - 2.9; df -- 42; p = 0.005) and controls (t = 3.2; df = 27;p = 0.004). MDD-PD patients and MDD patients did not differ significantly from each other or the controls.
30
BIOL PSYCHIATRY 1990;28:21-34
S.D.
Targum
Thus, behavioral and hormonal responses to fenfiuramine challenge revealed different responsivities between PD, MDD-PD, and MDD patient groups and control subjects, with PD patients showing the most robust responses.
Correlation Bet~'een Lactate and Fenfluramine Responses Using threshold criteria as described in Methods, 14 patients revealed positive responses to both the lactate infusion procedure and the oral fenfluramine challenge. Nine PD patients (53%) in contrast to 3 MDD-PD patients (25%) (X"~= 1.26; p = ns) and 2 MDD patients (7%) (X2 = 9.23; p < 0.003) had positive responses to both challenges. Correla~.lonal analysis of peak anxiogenic responses between lactate and fenfluramine challenges revealed significance in PD patients (r = 0.5; p = 0.03) but not in MDDPD patients (r = 0.1; p = ns) or MDD patients (r = 0.3; p = ns). Discussion This study has examined anxiogenic challenge responses to intravenous lactate infusion and oral fenfluramine administration in hospitalized patients with PD, MDD-PD, MDD, and a comparison group of nonpsychiatric control subjects. PD and MDD-PD patients had significantly greater anxiogenic responses to lactate infusion and to oral fenfiuramine administration compared with MDD patients or controls. These results are consistent with the studies of several other investigators (McGrath et al. 1988; Cowley et al. 1986; Dager et al. 1987; Lopez-Ibor et al. 1988; Targum and Marshall 1989) and reflect the predisposition of panic-prone patients to react to different panicogenic stimuli. Though the clarification of the boundaries between PD and MDD are still undecided (Coryell et al. 1988), the MDD-PD group of patients in this study clearly demonstrated a latent sensitivity to panic attacks which distinguished them from the MDD group. This suggests that the predisposition to a panic response is separate from the predisposition to depression. It must be emphasized that panic attacks as elicited by challenge studies are not synonymous with the DSM-III-R definition of panic disorder and that such attacks may be precipitated by many different factors an~Jor different psychiatric disorders (Dager et al. 1987; Aronson et al. 1989). However, the results of this study do suggest that major depressed patients with a history of panic attacks occurring more than 6 months prior to the study may share a neurobiological sensitivity with those patients who are currently having panic attacks and who have met DSM-III-R criteria for PD. The shared sensitivity may contribute to the overt expression of anxiogenic responses to either lactate or fenfluramine. The anxiogenic response may be diminished, but still measurable In patients who are not currently experiencing panic. Thus, it would appear that once an individual is "sensitized" to panic attacks~, he or she will remain vulnerable to panicogenic stimuli. These findings differ from those of McGrath et al. (1988) who suggested that the susceptibility to lactate-induced l?e~ie was related more to current state rather than to an underlying vulnerability. Alternatively, the findings are consistent with the study of Fyer et al. (1985) who reported that some PD patients retain their vulnerability to lactate infusion while in remission and after the discontinuation of medication. The PD patients and MDD-PD patients differed in two ways in their anxiogenic challenge responses. First, PD patients had more robust anxiogenic respoi~ses to both challenges than MDD-PD patients. For instance, PD patients had positive responses to both challenges significantly more often than MDD-PD patients. Further, correlational
Panic and Depre;~sion:Anxiogenic Challenge
BIOL P?VC!-I[L%TRY 1990;2~:21-34
31
analysis of peak anxiogenic responses between lactate and fenfluramiLe challenges reveaied significance in PD patients but not in MDD-PD patients. Second, PD patients revealed significant prolactin and cortisol responses to oral fenfluramine administration relative to MDD patients, whereas MDD-PD patients did not. These differences between PD and MDD-PD patients may be due to the conditioned "hyperresponse" seen in many I'D patients who have experienced recent acute panic episodes and have consequently developed a heightened anticipatory anxiety and the cognitive expectation of having more panic responses. A mechanism for this hyperresponse has been proposed by Gorman et al. (1989) who suggest that frequent brainstem stimulation occurring during recurrent panic attacks may lower the threshold to excitatory postsynaptic stimulation resulting in a sustal~led ("kindled") state of anticipatory anxiety; thus, a "hyperconditioned" patient may be more likely to react ve~ strongly to anxiogenic stimuli. Further, the kind~ed state ma:/also result in a reduced threshold for anxiogenic responsivity to more nonspecific ~unuli in these panic-prone individuals. Panic attacks occurring in PD and MDD-PD patients may be etiologically related to brainstem hypersensitivity, as suggested by Gorman et al. (1989), and may be indirectly related to MDD via associated limbic sys',em circuits. This common limbic system association may explain the complex interrelationships and comorbidity (the possibility that one disorder might contribute to the development of a second disorder) r ~ted between PD and MDD in many studies (Leckman et al. 1983; Coryell et al. 1988). Leckrnan et al. (1983) found that relatives of patients wi~. combine~l MDD and PD (MDD-;'D) were twice as likely to have major psychiatric disorders thou the relatives of patievts with MDD and no anxiety disorder. It is conceivable that the co-morbidity as reflected in the study of Leckman et al. might lower the threshold for overt expression of each disorder, but it does not rule out the possibility that the predisposition to develop panic attacks relates to a distinct neurobiological diathesis apart from MDD. The data of the present study would suggest that MDD-PD patients may have a combination of two distinct diatheses. There is some evidence to suggest that MDD-PD patients mey have a more severe disorder than either PD or MDD patients as characterized by earlier onset of illness and a more difficult treatment course (Leckman et al. 1983; VanValkenburg et al. 1984; Breier et al. 1985; Coryell et al. 1988). The clinical implications of this study cle~,,dy point to using therapeutic strategies that will treat patients with combined MDD-PD for both syndromes. In fact, it may be useful to consider individuals in the MDD-PD group as "panic-depressive" patients who are clinically separate from either PD patients or MDD patients.
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