Prolactin response to electroconvulsive therapy: Effects of electrode placement and stimulus dosage

Prolactin Response to Electroconvulsive Therapy: Effects of Electrode Placement and Stimulus Dosage Sarah H. Lisanby, D.P. Devanand, Joan Prudic, David Pierson, Mitchell S. Nobler, Linda Fitzsimons, and Harold A. Sackeim Background: It is unclear whether the serum prolactin (PRL) surge following electroconvulsive therapy (ECT) is a marker of optimal ECT administration. We investigated the relations among PRL surge, stimulus parameters, and outcome in major depressive disorder (MDD). Methods: Seventy-nine patients with MDD were randomized in a double-blind trial to right unilateral (RUL) or bilateral (BL), and to low-dose (just above seizure threshold) or high-dose (2.5 X threshold) ECT. Results: Change in PRL (APRL) varied among treatment groups, with significant effects of electrode placement (BL > RUL, p < .006), electrical dosage (high > low, p < .04), and gender (female > male, p < .005). There was no evidence that clinical improvement was associated with greater PRL surge. Conclusions: Although APRL varied with parameters impacting on response rates, these data indicate the PRL surge cannot serve as a useful index of clinically effective treatment. This finding does not support the view that diencephalic seizure propagation is necessary for ECT to exert therapeutic effects. Biol Psychiatry 1998;43: 146-155 © 1998 Society of Biological Psychiatry Key Words: Electroconvulsive therapy, prolactin, seizure, major depression, pituitary hormone

Introduction Pontaneous seizures and those induced by electroconvulsive therapy (ECT) result in marked postictal increases in serum prolactin (PRL) (Ohman et al 1976; Trimble 1978; Balldin 1982; Whalley et al 1982; Deakin et al 1983; Swartz and Abrams 1984; Abrams and Swartz 1985a). The neurobiological determinants and clinical significance of the ECT-induced PRL surge have not been

S

From the Department of Biological Psychiatry (SHL, DPD, JP, MSN, LF, HAS), New York State Psychiatric Institute, New York, New York, Department of Psychiatry (SHL, DPD, JP, MSN, HAS); and Department of Radiology, (HAS) College of Physicians and Surgeons, Columbia University, New York, New York; and the Nathan Kline Institute (DP), Orangeburg, NY. Address reprint requests to Dr. S. H. Lisanby, Department of Biological Psychiatry, New York State Psychiatric Institute, Unit 72, 722 West 168th Street, New York, NY 10032. Received February 19, 1996; revised June 17, 1996; accepted March 13, 1997.

© 1998 Society of Riological Psychiatry

well characterized. There is considerable interest in whether this hormonal response to ECT provides a useful marker of optimal ECT administration, and whether it may help elucidate the patterns of seizure spread that are necessary for antidepressant effects (Robin et al 1985; Zis et al 1996). The magnitude of the PRL surge is influenced by electrode placement and, perhaps, by electrical dosage. Several studies found that bilateral (BL) ECT produces a greater PRL surge than right unilateral (RUL) ECT (Papakostas et al 1984; Swartz and Abrams 1984; Papakostas et al 1986; Zis et al 1991; McCall et al 1996). There are also suggestions that high-dosage electrical stimuli result in greater PRL release than low-dosage stimuli (Abrams and Swartz 1985b; Robins et al 1985; Zis et al 1993, 1996). Recently it has been shown that bilateral electrode placement and high stimulus dosage interact in determining the efficacy of ECT (Sackeim et al 1993). Thus, the PRL surge has been linked to factors known to influence the antidepressant effects of this treatment, leading to the possibility that the magnitude of PRL release may predict clinical response and serve as a marker of treatment adequacy. Viewing diencephalic stimulation necessary and/or sufficient for antidepressant effects of ECT, some investigators have suggested that the differential effects of electrode placement and stimulus dosage on efficacy are due to varying degrees of diencephalic stimulation (Abrams and Taylor 1976; Fink and Ottosson 1980; Swartz and Abrams 1984; Abrams 1986; Zis et al 1996). The magnitude of the PRL surge with ECT has been utilized as an indirect measure of the degree of seizure generalization and diencephalic stimulation (Swartz and Abrams 1984; Abrams 1992; Zis et al 1996). Studies of epileptic patients argue against a straightforward association between the PRL surge and seizure generalization, but lend support for an association with limbic stimulation. Although substantial PRL release occurs with generalized tonic-clonic seizures (Trimble 1978), generalization and loss of consciousness are not always necessary for this hormonal response to occur with seizures (Pritchard et al 1983; Meierkord et al 1994). The PRL release found with some 0006-3223/98./519.00 Pll S0006-3223(97)00222-9

Prolactin Response to ECT

simple and complex partial seizures may depend on seizure propagation from limbic structures to the hypothalamus (Dana-Haeri et al 1983; Sperling et al 1986; Pritchard 1991). Depth electrode recording studies in epileptic patients have demonstrated that substantial PRL release is observed when high-frequency epileptic discharges are recorded in limbic areas (Sperling et al 1986; Sperling and Wilson 1986). There is conflicting evidence for an association between the magnitude of the PRL surge and antidepressant effects following ECT. Although some have found suggestions of an association (Scott et al 1986; Whalley et al 1987), other studies observed no relation (Deakin 1983; Clark et al 1995). Indeed, there is one report of a greater PRL surge being associated with inferior clinical outcome (Abrams and Swartz 1985a). These discrepancies may be related to the fact that the PRL surge is influenced by a large number of variables, including gender, concomitant medications, electrode placement, stimulus parameters, treatment number, and seizure duration (Zis et al 1991; Ben-Jonathan 1994). Furthermore, detecting a relation between PRL surge and clinical response may be difficult if the treatment groups have little variability in clinical outcome. We have reported that manipulations of electrode placement and stimulus dosage produced widely differing clinical response rates in major depression (Sackeim et al 1993). This provided an excellent opportunity to evaluate this issue and avoid the problem of truncated range of clinical response. The first goal of this study was to establish the effects of electrode placement and stimulus dosage on the PRL surge following ECT. The second goal was to investigate whether the magnitude of the PRL surge is related to clinical outcome following the ECT course. The relation between PRL surge and time to achieve reorientation during the acute postictal period was also assessed, providing the first exploration of whether an acute neuroendocrinological effect was associated with an acute cognitive effect during ECT.

Methods and Materials Patients The 79 patients included in this subsample (total n = 96) gave informed consent to participate in a double-blind, randomassignment, parallel-group protocol assessing the affective and cognitive consequences of ECT (Sackeim et al 1993). The protocol was approved by the Institutional Review Board at the New York State Psychiatric Institute. Patients were required to meet the Research Diagnostic Criteria for major depressive disorder, endogenous subtype, on the basis of interviews using the Schedule for Affective Disorders and Schizophrenia, and have pre-ECT 24-item Hamilton Depression Rating Scale

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(HDRS) scores of 18 or greater. Exclusion criteria included a history of schizophrenia, schizoaffective disorder, other functional psychosis, rapid-cycling bipolar disorder, organic mental syndrome, alcohol or substance dependence, alcohol or substance abuse within the previous year, neurological illness, serious concomitant medical condition, or ECT within the previous 6 months. All patients were free of psychotropic medication, other than lorazepam (up to 3 mg daily, as needed for anxiety or insomnia), from at least 5 days prior to the beginning of the ECT course until 1 week following the end of the ECT course. Using a 30-day upper limit, the average duration of medication washout prior to ECT was 16.9 _+ 7.9 days (mean _+ SD). Ten of the 79 patients had been exposed to neuroleptics within a month of ECT. The mean washout from neuroleptics in these l0 patients was 15.2 _+ 5.3 days, ranging from 11 to 29 days.

Electroconvulsive Therapy Subjects were randomly assigned to receive RUL (d'Elia placement) or BL ECT (bifrontotemporal placement) at either just above seizure threshold or at 2.5 times the initial seizure threshold. Seizure threshold was determined at the first treatment by empirical titration, using subconvulsive stimuli with preset increases in stimulus intensity until a seizure of adequate duration was elicited (Sackeim et al 1987a). ECT was administered three times per week, using a custom-modified MECTA SR-I. Atropine (0.4 mg IV) was given 2 min prior to anesthesia induction. Methohexital (0.75 mg/kg), and succinylcholine (0.50.75 mglkg) were used as the intravenous anesthetic agents. Patients were oxygenated from anesthetic administration until return of spontaneous respirations. Seizure duration was monitored with two frontal-mastoid electroencephalogram (EEG) channels, as well as motor manifestations using the cuff technique. Using conservative criteria (Sackeim et al 1993), generalized seizures of adequate duration were elicited at each treatment. There were no purely subconvulsive sessions. Further details of the treatment methods have been described (Sackeim et al 1993).

Clinical Evaluations A blind clinical evaluation team, composed of a research psychiatrist and social worker, rated each patient on the HDRS 2 days before the first treatment, twice a week during the acute ECT course, within 2 days after the end of the treatment course, and 1 week later. Interrater reliability coefficients for the total HDRS score exceeded .98 at all times. Analyses were based on mean scores across the two raters. To be classified as an initial responder within 2 days after the treatment course, patients had to meet two criteria: a minimum 60% decrease in HDRS scores from baseline, and a maximum post-ECT HDRS score of 16. To be classified as a final responder 1 week posttreatment, patients were required to maintain this level of improvement for at least 1 week after the ECT course. A minimum of 10 treatments was required before classification as a nonresponder. This requirement was reduced to eight treatments in cases of clinical urgency. In patients who showed clinical improvement, ECT was contin-

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ued until they were asymptomatic or had no further improvement over two additional treatments. Time to orientation recovery was assessed at each treatment (Sobin et al 1995). Once spontaneous respirations had returned, a technician asked the patient to open his or her eyes. Once the patient responded to this request, continuous assessment of orientation followed. This assessment included asking the patient to state his or her name, location, age, date of birth, and the day of the week. These queries were repeated continuously until correct responses were given or until 90 min had passed. The criterion for orientation recovery was correct responses to four out of the five queries. Patients failing to achieve this criterion within 90 min were given a score of 100 min.

normally distributed, so analyses were performed after logarithmic transformation. Analyses of covariance (ANCOVAs) (with electrode placement, dosage condition, and gender as between-subject factors) were used to test the association between PRL and other factors, including seizure duration, absolute dosage above threshold, time to reorientation, and percentage change in HDRS scores. Each of these factors were serially added as covariates. Dichotomous responder-nonresponder classification was added as a betweensubject factor in analyses testing the association between PRL and response status.

Results Prolactin Assessment

Characteristics of the Treatment Groups

Plasma for PRL assay was collected immediately prior to administration of anesthesia (about 5 min before electrical stimulation) to establish a baseline, and at three times points after seizure termination (5, 15, and 30 min post-seizure termination). These assessments were conducted at the second, sixth, and the penultimate ECT treatments. These time points were selected to sample PRL changes early and late in the treatment course, and to avoid sessions in which seizure threshold titration was performed (the first and last ECT treatments). At all time points, blood was collected at bed rest following an overnight fast. Blood was centrifuged, and plasma was separated and frozen at - 2 0 ° C until assay. PRL was measured via two-site immunoradiometric assay (Miles 1977). The intra- and interassay coefficients were 3.69% and 6.70% at 6.71 ng/mL and 5.38% and 6.60% at 25.68 ng/mL. The prolactin assays were performed blind to all patient information.

D e m o g r a p h i c and clinical characteristics o f the treatment groups are presented in Table 1. The t w o - w a y A N O V A s and log-linear analyses indicated that there were no significant differences a m o n g the treatment groups. T h e r e w e r e also no significant differences in the dosages o f anesthetic agents or in m e a s u r e s o f seizure duration (Table 2). Initial seizure threshold was h i g h e r with B L than R U L E C T ( F = 27.4, d f = 1,75, p < .0001). A v e r a g e charge per treatment was higher with B L than R U L E C T ( F = 39.1, d f = 1,75, p < .0001) and with high c o m p a r e d to low dosage ( F = 36.1, df = 1,75, p < .0001). Subconvulsive administrations occurred almost exclusively in low-dosage groups ( F = 46.4, df = 1,75, p < .0001). T i m e to orientation recovery took longer with B L relative to R U L E C T ( F = 35.7, df = 1,64, p < .0001) and with high compared to low dosage ( F = 7.1, df = 1,64, p < .01). Table 2 also presents the response rates and percent change in H D R S scores for the four treatment groups, i m m e d i a t e l y and 1 w e e k f o l l o w i n g the E C T course. As p r e v i o u s l y reported, clinical response varied as a function o f electrode p l a c e m e n t and dosage c o n d i t i o n ( S a c k e i m et al 1993). I m m e d i a t e l y after the E C T course, log-linear analysis r e v e a l e d a main effect o f electrode p l a c e m e n t (X2 = 4.12, df = 1, p < .04) and an interaction b e t w e e n electrode p l a c e m e n t and dosage group (X ~ = 3.69, d f = 1, p < .05) on clinical response rates. The l o w - d o s e R U L group had a particularly low response rate (Table 2). The percent change in H D R S i m m e d i a t e l y posttreatment was greater with B L relative to R U L E C T ( F = 8.0, d f = 1,75, p < .005) and with high relative to low dosage ( F = 4.4, d f = 1,75, p < .04). O n e w e e k posttreatment there continued to be a main effect of electrode p l a c e m e n t on clinical response rates (X 2 = 9.39, d f = 1, p < .002) and on percent change in H D R S ( F = 6.9, d f = 1,75,p < .01). The effect of dosage was no longer seen at 1 week, likely due to the high n u m b e r o f patients no longer m e e t i n g response criteria in the h i g h - d o s e R U L group. The percentage o f patients m e e t i n g criteria for clinical response in

Statistical Analysis The comparability of treatment groups in demographic variables and baseline measures was evaluated by conducting two-way (electrode placement by dosage condition) analyses of variance (ANOVAs) on continuous variables and by log-linear analysis on dichotomous variables. Values for seizure duration, absolute charge, and time to reorientation were calculated using data from the second, sixth, and penultimate treatments, which corresponded to treatment sessions when PRL was assessed. Treatments for which patients lacked PRL data at baseline or at 15 min posttreatment were excluded, since 15 rain has been the most commonly reported time for peak PRL levels after ECT (Whalley et al 1982). This occurred at 46 out of the total 215 ECT sessions examined (21 instances at ECT #2, 18 instances at ECT #6, and 7 instances at the penultimate treatment). At each treatment session, delta (A) PRL was computed by subtracting the pre-ECT baseline values (5 min pre-ECT) from the maximum postseizure value (either 5, 15, or 30 min post-seizure termination). The average peak change in PRL was also computed for each patient, taking the mean APRL across the second, sixth, and penultimate treatments. This averaged APRL served as the primary dependent measure for statistical analysis. PRL values, electrical variables, and seizure duration measures were not

Prolactin R e s p o n s e to E C T

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Table 1. D e m o g r a p h i c and Clinical Characteristics o f Patients Right unilateral ECT

n Age (years) Sex (% female) Education (years) Diagnostic subtype % bipolar % psychotic HDRS score pretreatment Length of current episode (weeks) ~ Length of washout period (days) t' Age at onset of affective disorder (years) No. of previous affective episodes C No. of prior psychiatric admissionsc Previous ECT (%)

Bilateral ECT

Low dose

High dose

Low dose

High dose

Total

20 54.9 - 15.0 65.0 13.4 ± 3.2

19 56.4 -+ 14.1 68.4 13.7 ± 3.8

17 59.4 ± 13.5 41.2 11,8 ± 3.5

23 53.9 ± 14.4 56.5 13.7 ± 2.4

79 55.9 ± 14.2 58.2 13.2 ± 3.2

30.0 40.0 35.2 - 8.6 46.4 ± 33.3 19.0 ± 8.1 37.8 ± 16.1 4.1 ± 3.5 2.3 ± 3.5 35.00

42.1 47.4 30.3 ± 6.7 34.5 ± 30.6 14.9 ± 7.7 41.2 ± 16.6 4.0 -+ 2.7 2.3 ± 2.6 47.37

17.7 41.2 34.1 ± 7.6 46.9 ± 35.7 15.8 ± 7.1 42.1 ± 20.9 2.8 ± 3.6 2.7 ± 4.8 47.06

30.4 43.5 31.7 ± 7.7 47.6 ± 36.0 17.4 ± 8.5 37.8 ± 17.3 4.2 + 3.9 2.6 + 3.5 39.13

30.4 44.3 32.8 ± 7.8 44.0 ± 33.8 16.9 ± 7.9 39.6 ± 17.5 3.8 ± 3.5 2.5 ± 3.6 42

Values are means + SD or percentages. °Capped at 104 weeks. hCapped at 30 days. ':Capped at 10.

this

subgroup

dropped

from

68.4%

immediately

after

s i o n s , t h e m e a n A P R L a f t e r E C T w a s 3 8 . 8 ___ 2 4 . 3 n g / m L ,

t r e a t m e n t to 3 6 . 8 % at 1 - w e e k f o l l o w - u p .

r e p r e s e n t i n g a 5 . 5 - f o l d i n c r e a s e o v e r b a s e l i n e (t = 6 2 . 3 8 , df = 78, p <

Prolactin Increases after ECT

. 0 0 0 1 ) . T h i s l a r g e P R L s u r g e w a s s e e n at

e a c h o f t h e t h r e e t r e a t m e n t s (all p s < . 0 0 0 1 ) , a n d w a s n o t

T h e m e a n P R L v a l u e p r i o r to e l e c t r i c a l s t i m u l a t i o n ( a v e r -

influenced by history of neuroleptic exposure within the

aged across the second, sixth, and penultimate treatments)

past month

w a s 8 . 7 _+ 3 . 9 n g / m L

measures

for the sample

baseline value did not differ among groups. Repeated-measures

ANOVA

as a w h o l e . T h i s

(t =

-1.17,

ANOVA

df =

revealed

77, p there

= was

.25). R e p e a t e d no

significant

the four treatment

c h a n g e in A P R L o v e r t h e s e c o n d , s i x t h , a n d p e n u l t i m a t e

indicated that there

treatments. These analyses were conducted pair-wise (sec-

w a s n o c h a n g e in b a s e l i n e P R L a c r o s s t h e t h r e e t r e a t m e n t

o n d to s i x t h , s i x t h to p e n u l t i m a t e , a n d s e c o n d to p e n u l t i -

sessions. Maximum

m a t e ) a n d a c r o s s all t h r e e t i m e s p o i n t s w i t h n o c h a n g e in

PRL values post-ECT ranged widely

f r o m 8 . 2 to 1 2 0 . 7 n g / m L , ng/mL.

When

averaged

with a mean of 47.5

results.

_+ 25.1

across the three treatment

There was no association between patient age and mean

ses-

Table 2. M e a s u r e m e n t s o f ECT, I n d u c e d Seizure, and Clinical R e s p o n s e Right unilateral ECT Low dose Methohexital dose (mg) Succinylcholine dose (mg) Initial seizure threshold (mC) Average charge per treatment (mC) Number of stimulations per treatment Duration of seizure (sec) Motor EEG Time to reorientation (rain) Response to treatment (% of patients) Immediate One week Percent change in HDRS Immediate One week Values are mean -+ SD or percentages.

55.6 40.7 79.0 92.7 1.5

÷ ± ± ± +

13.0 13.8 29.8 39.7 0.3

Bilateral ECT

High dose 51.2 33.1 69.0 161.3 1.0

± ± ± ± ±

12.5 10.5 27.3 61.7 0.0

Low dose 59.1 40.1 119.2 171.6 1.5

± 20.4 ± 7.6 _+ 49.0 ± 90.1 ± 0.4

High dose 58.4 --- 12.4 43.8 ± 16.8 128.6 ± 68.8 314.4 ± 156.4 1 . 1 _+ 0.2

Total 56.1 39.6 99.7 190.7 1.2

± 14.7 ± 13.4 ± 53.7 ± 130.7 ~- 0.3

46.0 + 17.2 57.3 ± 23.7 11.6 _+ 8.2

45.2 ± 12.6 58.1 ± 17.2 21.1 ± 13.7

48.4 ± 12.8 56.7 ± 13.6 32.6 -+ 17.3

44.7 ± 11.8 58.3 -+ 17.3 44.1 ± 25.7

46.0 ± 13.5 57.6 ± 18.0 28.0 ± 21.6

25.0 20.0

68.4 36.8

70.6 70.6

69.6 65.0

58.2 45.6

35.8 ± 37.5 33.0 ± 37.6

57.6 _+ 26.9 43.4 ± 36.4

62.9 ± 35.7 60.8 ± 35.0

71.1 - 26.3 59.4 ± 38.1

57.2 ± 33.9 49,2 + 38.0

150

BIOL PSYCHIATRY 1998;43:146-155

S.H. Lisanby et al

70

[7

RUL low d¢me

D RULhigh doee

•

m. ~g~ a m

significant at the sixth and the penultimate treatments ( F = 6.0, df = 1,51,p < .01 and F = 5.99, df = 1,50,p < .02, respectively). The main effect of dosage condition was significant at all three time points ( F --- 9.5, df = 1,53, p < .003; F = 4.9, df = 1,51, p < .03; and F = 4.2, df = 1,50, p < .05, respectively).

--~ 30L

Absolute Electrical Dose and Dose above Threshold

< 20100

i

#2

#6 Penultimate ECT Treatment Number

i

Mean of ell treatments

Figure 1. The ECT treatment groups differed in mean APRL across the three treatment sessions, with main effects of electrode placement (BL > RUL, p < .006) and dosage group (high > low dose, p < .04). The main effect of dosage condition was seen at all three time points, and the main effect of electrode placement was seen at the sixth and penultimate treatments. *Lower than high-dose RUL and high-dose BL ECT, ps < .008. **Lower than both BL groups, ps < .03. *Lower than the other three groups, ps < .05. APRL (r = .12, p < .3), and age was not a significant correlate of mean APRL after controlling for the effects of electrode placement and dosage group. W o m e n had significantly higher mean APRL than men (45.5 _+ 26.9 ng/mL in women, 29.5 -+ 16.5 in men, t = 2.45, df = 78, p < .02). Gender remained a significant contributor to the variance in mean APRL values after controlling for the effects of electrode placement and dosage group ( F = 8.5, df = 1,74, p < .005). Consequently, gender, but not age, was used as a term in all subsequent analyses. There was no interaction between age and gender. When examined by individual treatment session, the main effect of gender was significant only at the second treatment ( F = 13.0, df = 1,53, p < .0007), but there was no gender by time interaction in repeated-measures A N O V A s .

Effect of Electrode Placement and Dosage on PRL The treatment groups differed in the magnitude of mean APRL. An A N O V A with electrode placement, dosage, and gender as between-subject factors yielded main effects of electrode placement (BL > RUL, F = 8.2, df = 1,74, p < .006) and dosage condition (high > low dose, F = 4.7, df = 1,74, p < .04) and no interaction (Figure 1). These main effects remained significant after excluding the 10 patients with prior neuroleptic exposure (BL > RUL, F = 4.87, df = 1,64, p < .03; high > low dose, F = 4.61, df = 1,64, p < .04; no significant interaction). Low-dose R U L ECT produced a smaller PRL surge than each of the other groups (ps < .05). When examined by individual treatment session, the main effect of electrode placement was

Across the sample as a whole, there was a modest correlation between absolute electrical dose and mean APRL (r = .26, p < .02). This effect was due primarily to dosage condition assignment, which defined the degree to which electrical dose exceeded the seizure threshold. The absolute electrical dose administered was fully determined by the patient's initial seizure threshold and dosage condition assignment, since absolute stimulus charge was a specified percentage of the initial threshold (either just above or 2.5 times threshold). A N C O V A was used to test the impact of absolute electrical dose on PRL release. Between-subject factors were electrode placement, dosage group, and gender. Initial seizure threshold served as a covariate. Main effects of electrode placement ( F = 5.1, df = 1,73, p < .03), dosage condition ( F = 4.7, df = 1,73, p < .03), and gender ( F = 8.4, df = 1,73, p < .005) were unaltered, while there was no effect of initial seizure threshold on mean APRL (p = .65). These analyses were repeated for each treatment session separately. At all three time points, the main effect of dosage condition was unaltered (ps < .04), and in no case was initial seizure threshold related to APRL. Thus, APRL was related to charge above threshold and not to absolute electrical dose.

Subconvulsive Stimulations These analyses indicated that PRL release was particularly low with low-dosage R U L ECT. Subconvulsive stimuli occurred almost exclusively in the low-dose RUL and BL groups. Therefore we examined the possibility that R U L placement coupled with subconvulsive stimulation might be responsible for lower PRL release. The number of subconvulsive stimulations given prior to the convulsive stimulation at each treatment was not correlated with APRL when assessed across the entire sample, as well as when each electrode placement group was tested separately. To assess possible within-subject effects of subconvulsive stimulation, a subgroup of low-dose patients were selected on the basis of having at least one subconvulsive stimulation preceding the convulsive stimulation during a treatment session. The subgroup consisted of 16 patients (7 RUL and 9 BL ECT). The APRL at each session having

Prolactin Response to ECT

at least one subconvulsive stimulation was compared with the APRL at a treatment without a subconvulsive stimulation within the same patients. The order of the treatment pairs selected was counterbalanced to control for any decline in APRL with subsequent treatment. The absolute charge administered at each of the two sessions within each pair was comparable (t = - 1 . 4 , df = 15, p < .2). Repeated-measures A N O V A revealed a trend toward an interaction between the presence of a subconvulsive stimulation and electrode placement (p < .08). The APRL of patients receiving BL ECT showed no difference with or without subconvulsive stimulation, whereas those receiving RUL ECT tended to show higher APRL following treatments preceded by at least one subconvulsive stimulation (t = 2.3, df = 6, p < .07). Consequently, the low APRL values in the low-dosage RUL ECT group could not be attributed to effects of subconvulsive stimuli.

Effect of Seizure Duration on PRL Surge Neither motor nor E E G measures of mean seizure duration differed among the treatment groups. When averaged across the three sessions, seizure duration was positively correlated with mean APRL (r = .27, p < .02 for EEG; r = .25, p < .03 for motor). Both motor and EEG measures of seizure duration accounted for additional variance in mean APRL after controlling for electrode placement, dosage condition, and gender ( F = 6.0, df = 1,72, p < .02 for E E G length; F = 8.8, df = 1,73, p < .004 for motor length). Repeated-measures A N O V A showed that seizure length decreased across the treatment course ( F = 7.4, df = 2,48, p < .001 for EEG; F = 29.8, df = 2,61, p < .0001 for motor). When analyzed by individual treatment session, an effect of EEG seizure length on APRL was seen only at the sixth treatment ( F = 11.4, df = 1,47, p < .002), whereas an effect of motor seizure duration was seen at the second and sixth treatments ( F = 4.8, df = 1,52, p < .03; F = 10.9, df = 1,50, p < .002, respectively). The main effects of electrode placement and dosage group on APRL remained unchanged after covarying for seizure length at each of the three sessions.

Time to Reorientation Time to reorientation was positively correlated with mean APRL across the entire sample (r = .39, p < .001). This effect was due primarily to the R U L ECT groups, which had a correlation of r = .49 (p < .003), whereas there was no association within the BL ECT groups (p < .4). A N C O V A with electrode placement, dosage group, and gender as the between-subject factors and time to orientation as the covariate revealed a trend toward an associ-

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ation between time to reorientation and mean APRL ( F = 3.1, df = 1,62, p < .08). When analyses were conducted separately for each electrode placement group, the association reached significance for patients receiving R U L ECT ( F = 5.5, df = 1,30, p < .03), but not BL ECT. To test whether the association between ApRL and time to reorientation in patients receiving RUL ECT was attributable to differences in seizure duration, a second set of analyses used E E G seizure duration as an additional covariate. Across the sample, when controlling for seizure duration, the relation between mean APRL and time to reorientation was not significant; however, when analyses were conducted separately for each electrode placement, there was a trend for a positive association among patients treated with R U L ECT ( F = 3.4, df = 1,28, p < .07), but not BL ECT. When the analyses were conducted separately for each of the three treatment time points, this trend was significant for patients receiving RUL ECT at the second treatment ( F = 5.2, df = 1,11, p < .04) and at the penultimate treatment ( F = 7.8, df = !,12, p < .02).

Relationship between Prolactin Surge to ECT and Clinical Response Before controlling for the contribution of treatment conditions, there was no correlation between mean APRL and any clinical outcome measure immediately after the ECT course. After controlling for treatment condition effects, mean APRL was also not related to response status ( A N O V A with electrode placement, dosage group, gender, and responder status as the between-subject factors). These results were unaltered when excluding patients with neuroleptic exposure in the prior month, and when excluding women from the analysis to remove variance due to reproductive cycle status. Likewise, there was no association between mean APRL and the change in HDRS scores. When analyses were conducted separately at each of the three treatments, there was no association between APRL and response at the second or sixth treatment, whereas there was a main effect of initial response status on APRL at the penultimate treatment. Initial responders had lower APRL than nonresponders at the penultimate treatment ( F = 5.7, df = 1,49, p < .02). Repeatedmeasures A N O V A (electrode placement, dosage group, gender, and initial response status as the between-subject factors) also suggested different changes in APRL between responders and nonresponders. There was a trend toward an interaction between initial response status and time point in the treatment course ( F = 3.9, df = 1,33, p < .06). This trend was also seen after controlling for the total number of treatments ( F = 3.8, df = 1,32, p < .06) and after controlling for the percentage change in seizure threshold from the beginning to the end of the treatment

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course ( F = 3.45, df = 1,30, p < .07). Patients who were responders immediately after treatment showed a significant drop in APRL from the second to the penultimate treatment ( F = 6.0, df = 1,17, p < .03). Nonresponders had no change (t7 < .9). Similarly, patients showing greater improvement on HDRS immediately after treatment had significantly lower APRL at the sixth and penultimate treatments ( F = 4.0, df = 1,50, p < .05; F = 6.4, df = 1,49, p < .01, respectively). Repeated-measures A N C O V A with electrode placement, dosage group, and gender as the between-subject factors, and percent change in HDRS as the covariate, revealed a significant interaction between time point in treatment and change in HDRS ( F = 5.6, df = 1,33, p < .02). Patients showing greater improvement on HDRS immediately after treatment had a greater drop in APRL from the second to the penultimate treatment. This relationship held when controlling for the total number of treatments ( F = 5.5, df = 1,32, p < .03). The preceding analyses on the association between APRL and clinical response were repeated using the outcome measures obtained 1 week following ECT with no change in results. Again, there was no association between mean APRL and any clinical outcome measure. When analyses were conducted separately at each treatment, patients showing greater improvement on HDRS had significantly lower APRL at the sixth and penultimate treatments ( F = 4.8, df = 1,50, p < .03; F = 5.5, df = 1,49, p < .02, respectively). Repeated-measures A N O V A revealed a significant interaction between l - w e e k response status and time point in the treatment course ( F = 7.9, df = 1,33, p < .008). This relationship held when controlling for the total number of treatments ( F = 7.7, df = 1,32, p < .009) and after controlling for the percentage change in seizure threshold from the beginning to the end of the treatment course ( F = 6.98, df = 1,30, p < .01). As shown in Figure 2, responders at 1 week post-ECT showed a significant drop in APRL from the second to the penultimate treatment ( F = 9.0, df = 1,15, p < .009), whereas nonresponders had no change (p < .6). The drop in APRL across the treatment course in responders immediately and 1 week after the treatment course could not be attributed to the progressive decrease in seizure length across the course. Seizure length decreased the same amount in responders and nonresponders. Repeated-measures A N O V A s with seizure length (EEG or motor) as the dependent measure showed no interaction between responder status (initial or at 1 week) and time point. Nor could the difference between responders and nonresponders in the drop in APRL across the treatment course be attributed to a differential change in seizure threshold. There was no significant correlation between change in APRL from the second to the penultimate treatment and the change in seizure threshold across

55

ECT~

50-

~ A

45.

_~40. o

~35 -

3025

Nonresponders Reeponders Clinical Response 1 week poit-ECT

Figure 2. ECT responders at 1 week posttreatment showed a significant drop in APRL from the second to the penultimate treatment by repeated-measures ANOVA (p < .009). Nonresponders did not show a significant change (p < .6).

the ECT course. The interaction between response status and time in the treatment course was not altered when using the change in seizure threshold as a covariate in the repeated-measures A N C O V A (see above).

Discussion The acute prolactin surge following ECT was greater with BL than RUL placement and with suprathreshold compared to threshold electrical stimulation. Despite the fact that these aspects of ECT administration strongly determined antidepressant effects, there was no evidence that clinical improvement with ECT was associated with a greater PRL surge. Consequently, it is unlikely that the acute PRL surge covaries with the neurobiological alterations that mediate clinical response to ECT. In line with many previous studies, we found that the PRL surge was greater with BL ECT than with RUL ECT (Papakostos et al 1984, 1986; Swartz and Abrams 1984; Zis et al 1991; McCall et al 1996). There was also a greater PRL surge in the high- compared to the low-dosage conditions. These effects were independent of seizure duration and gender, other variables that displayed significant associations with the PRL surge. Although the low-dosage groups received more subconvulsive stimulation than the high-dosage groups, there was no evidence that subconvulsive stimulation prior to seizure induction resulted in a smaller postseizure PRL surge. Early work had been inconclusive concerning the relationship between the PRL surge and electrical dosage, possibly due to the contounding of dosage manipulation with variation in electrical waveform and by the use of

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fixed stimulus intensities that were not titrated to seizure threshold (Robin and De Tissera 1982; Abrams and Swartz 1985b; Robin et al 1985). More recent work, although limited by small sample size, has found a greater PRL surge in patients who received electrical doses that were known to be substantially suprathreshold by the use of the titration method. In a within-subject study, Zis et al (1993) administered electrical doses that were just above the seizure threshold or 3.6 times the threshold to 8 patients. They found a greater PRL surge in the high-dose condition, pooling data across patients treated with BL or RUL ECT. In a subsequent within-subject study of 10 patients, Zis et al (1996) found a greater PRL surge with high-dosage relative to threshold RUL ECT. McCall et al (1996) did not find an association between APRL and stimulus intensity in 22 patients; however, their withinsubject design could not test the independent effect of dosage group without the confound of treatment order, since high-dosage treatments always followed threshold treatments. Our design allowed for the first evaluation of the simultaneous contributions of electrode placement and stimulus dosage, demonstrating that electrode placement and dosage above threshold both determine the magnitude of the PRL surge. Our findings on two dosage groups (just above threshold and 2.5 times threshold) indicated that dosage group relative to seizure threshold is a more important determinant of the PRL surge than the absolute dosage administered. Prior work on the relationship between the PRL surge and clinical response to ECT produced conflicting results (Deakin et al 1983; Abrams and Swartz 1985a; Scott et al 1986; Whalley et al 1987; Clark et al 1995). The four forms of ECT administered in this study differed markedly in therapeutic effects, decreasing the likelihood of type 2 error due to a truncated range of clinical outcome. As indicated, the PRL surge was greater with BL electrode placement and high-dosage stimulation. These same factors were associated with superior efficacy (Sackeim et al 1993). Nonetheless, both across the sample and when controlling for the contributions of treatment conditions, there was no evidence of a positive association between the magnitude of the PRL surge and short-term clinical outcome following ECT. In fact, we found a significant negative association between the PRL surge and clinical response, with responders demonstrating a decrease in their PRL surge as the ECT course progressed. This diminution in the PRL surge could not be fully explained by a decrease in the relative electrical dose above threshold that responders received, secondary to ECT-induced increases in seizure threshold over the treatment course (Sackeim et al 1987b). It has been suggested that stimulation of the diencephalon mediates the efficacy of ECT (Abrams and Taylor

1976; Fink and Ottosson 1980; Abrams 1986; Fink and Nemeroff 1989), and that high-dosage and BL treatments are more effective due to greater stimulation of deep structures. This study demonstrates that, indeed, high electrical dose and BL treatments produce a greater PRL surge, which is suggestive of greater hypothalamic stimulation; however, the PRL surge was independent of clinical outcome, or negatively associated. Similarly, in other work we have observed that BL electrode placement and high-dosage stimulation result in greater short-term amnesic effects, without any associations between the magnitude of the adverse cognitive effects and clinical outcome (Sackeim et al 1993; McElhiney et al 1995). The lack of a positive association between the PRL surge and clinical response suggests that the mechanisms or pathways responsible for the PRL release are not essential to the therapeutic effects of ECT. In contrast, a greater PRL surge was associated with longer time to reorient following RUL ECT. This suggests that the ECT-induced mechanisms leading to PRL release may be associated with an acute cognitive effect, but not the antidepressant effect, of ECT. These findings argue against the theory of hypothalamic mediation of the therapeutic effects of ECT. It must be remembered, however, that the mediation of PRL release is complex, and PRL is only an indirect measure of diencephalic activity. Swartz (1991) suggested that PRL levels would be unrelated to therapeutic response due to the influence of factors outside the central nervous system. Multiple inhibiting and releasing factors regulate PRL levels, and prolactin responsivity can vary a great deal between individuals (Ben-Jonathan 1994). The seizure-mediated release of PRL is likewise a complicated process (Pritchard 1991). It was previously thought PRL release was measure of "generalization" of the seizure, and thus would only be released after generalized seizures with bilateral involvement and loss of consciousness (Johansson and von Knorring 1987). Video-EEG monitoring has demonstrated that PRL can be released by a simple partial seizure before secondary generalization and loss of consciousness occur (Meierkord et al 1994). Further, PRL is not always released with prolonged generalized seizures such as during some types of status epilepticus, and this may not be simply due to cellular depletion of PRL (Tomson et al 1989; Lindbom et al 1993; Bauer et al 1994). Studies with intracranial electrodes have shed light on these apparent discrepancies, and suggest that a prerequisite for PRL release with any type of seizure is high-frequency epileptic activity in limbic areas (Sperling et al 1986; Sperling and Wilson 1986). Inferences about current pathways and seizure propagation in ECT based on PRL levels must be made in light of these multiple contributing factors. In conclusion, although there was a robust PRL surge

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with ECT, and its magnitude varied in relation with treatment parameters that impact on response rates, these data indicate that the PRL surge cannot serve as a useful index o f clinically effective treatment. The PRL surge has been used as a rough estimate o f the magnitude of diencephalic stimulation with ECT. These data suggest that diencephalic stimulation, at least as estimated by PRL levels, does not mediate the therapeutic effect o f ECT. Furthermore, variation in the magnitude of diencephalic stimulation may not account for the dramatic differences in ECT clinical outcome attributable to manipulations of electrode placement and stimulus intensity.

Supported in part by NIMH grant MH35636 to H.A.S.

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