Effects of ECT on the TRH stimulation test

Psychoneuroendocrinology, Vol. 12, No. 1, pp. 29 34, 1987.

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EFFECTS OF ECT ON THE TRH STIMULATION TEST PAOLO DECINA,* HAROLD A. SACKEIM, DAVID A. KAHN, DAVID PIERSON, NANCY HOPKINS and SIDNEY MALITZ Department of Biological Psychiatry, New York State Psychiatric Institute; the Department of Psychiatry, College of Physicians and Surgeons of Columbia University; and the Department of Psychology,New York University (Dr Sackeim) (Received 27 November 1985; in final form 4 February 1986) SUMMARY The prognostic value of the TRH stimulation test was evaluated in 23 inpatients with major depressive disorder before and after a trial of ECT. In contrast to previous reports, the peak TSH response to TRH was sign;ficantiy decreased after treatment compared with before treatment. This effect was consistent across individuals and subgroups (responders/nonresponders; unilateral/bilateral ECT). The particular ECT technique used in the study may account for the discrepancies between these findings and those previously reported by other authors. I NTRODUCTION THE THYROTROPIN (TSH) response to thyrotropin-releasing hormone (TRH) has been used to investigate neuroendocrine abnormalities of the h y p o t h a l a m u s - p i t u i t a r y thyroid system in affective disorders. Compared to controls, a subgroup of euthyroid depressed patients show a diminished TSH response to TRH. About one-quarter of depressed patients evidence a maximum TSH increase from baseline (A TSH) after T R H administration equal to or less than 5 I~U/ml (Loosen & Prange, 1982). There has been only limited study of the relation between TSH response to T R H and treatment outcome, and of the effects of somatic treatment on the TSH response. Primarily in patients treated with antidepressants, some investigators have reported that the diminished TSH response before treatment increased with recovery (Gregoire et al., 1977; Hatotani et al., 1977; Brambilla et al., 1978; Asnis et al., 1981). Others have reported no change in TSH response despite clinical recovery (Coppen et al., 1974), while others observed both patterns (Kirkegaard et al., 1975; Linkowsky et al., 1981). In much of this work, patients were receiving antidepressant medication while tested during recovery (Asnis et al., 1981). The change in TSH response to T R H from pre-treatment to post-treatment has been suggested as a predictor of outcome of somatic treatment (Langer et al., 1980) or of relapse (Kirkegaard & Carroll, 1980). Langer et al. (1980) claimed that in patients treated with clomipramine, post-treatment depression scores were associated with the change in A TSH values from pre- to post-treatment. Higher post-treatment A TSH values were associated with positive therapeutic outcome. They did not find that the change in TSH values predicted later relapse.

*Address correspondence to: Dr Paolo Decina, Department of Biological Psychiatry, New York State Psychiatric Institute, 722 West 168th Street, New York, NY 10032, U.S.A. 29

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A series of studies conducted by Kirkegaard and colleagues gave a strong indication that comparison of post- and pre-treatment A TSH values in ECT patients may predict the likelihood of depressive relapse. These studies (Kirkegaard et al., 1975, 1977; Kirkegaard & Carroll, 1980) found that A.,- A, TSH values, i.e. A TSH post-treatment minus A TSH pre-treatmenl, equal to or less than 2 gU/ml predicted a high likelihood of relapse. These data prompted Kirkegaard et al. (1983) to assign patients to maintenance medication conditions or not, depending on change in TSH response. The same investigative group has claimed that relapse not only can be predicted by the test but also prevented by antidepressant pharmacotherapy (Krog-Meyer et al., 1984). There has been little study of these effects by other investigators. Coppen et al. (1980) reported on five patients tested pre- and post-ECT. At the post-ECT testing there was a significant reduction in basal TSH and non-significant reductions in post-TRH levels of TSH. No data on relapse were presented. Papakostas et al. (1981) tested seven patients pre- and post-ECT. There was no overall change in TSH response in the sample and no apparent relation to outcome or relapse. The present study investigated the prognostic value of the TRH test in ECT-treated depressed patients and was conducted in the context of a larger double blind, random assignment trial contrasting the relative efficacies and cognitive consequences of bilateral and right unilateral ECT.

METHODS Twenty-three mpatients with major depressive disorder (21 primary) were studied before and after a trial of ECT. The sample comprised 12 females (mean age = 57 years, SD = l 1, nine post-menopausal) and l I males (mean age = 55 years, SD = 10). Psychiatric diagnosis was made according to the Research Diagnostic Criteria (Spitzer el al., 1978) based on structured interviews with the Schedule for Affective Disorders and Schizophrenia (Endicott & Spitzer, 1978). Severity of depresmon was assessed with the 24-item Hamilton Depression Scale (HAM-D) (Hamilton, 1960), and a minimum pre-treatment score of 18 was required to be included in the study. The diagnostic composition of the group was 19 unipolars and four bipolars (BP I), with five patients preseming with psychotic features. A substantial proportion of patients (78%) had been resistant to previous pharmacological treatments, based on a criterion of at least 5 weeks continuous administration of a tricyclic, with at least 2 weeks at a daily dose of 250 mg equivalents of imipramine. The patients were assigned to unilateral (n = I l) or bilateral (n = 12) ECT treatment conditions with a constant current device (MECTA) and titration of stimulus electrical intensity to just above seizure threshold. The MECTA device produces a bidirectional, square wave, brief pulse stimulus. During each pulse, a 800 mA constant current is passed+ The frequency and width of pulses may be varied, as well as the duration of the pulse train. The titration and anesthesia procedures have been described in detail elsewhere (Malitz et al., 1982). Either thiopental ot methohexital was used as the anesthetic, with within-patient random assignment to an agent at each treatment session. The mean dose of thiopental was 120 mg; the mean dose of methohexital was 52 mg. Succinylcholine was administered as a muscle relaxant (mean dose = 35 mg). Atropine (0.4 m g / w a s administered approx 2 min prior to the anesthetic. The standard bifrontotemporal and d'Elia electrode placements were used for bilateral and right unilateral ECT, respectively. A method of limits procedure was designed to titrate dosage to' just alz.,,]e seizure threshold, In the first session, a dosage value (pulse frequency--20 Hz, pulse width--l.5 msec. duration I sec) was used that rarely elicited a seizure. Following a subconvulsive administration, a minimum interval of 40 sec was required prior to readministration at increased intensity. The settings for subsequent administrations were 40 Hz frequency-l sec duration. 70 Hz frequency--1 sec duration, and 70 Hz frequency--2 sec duration, all at a pulse ~vidthof 1.5 msec. In all patients, a generalized seizure, lasting at least 25 sec in motor manifestations, was elicited by the fourth stimulation. in the second treatment session, the dosage level that previously resulted m a seizure was again administered. If again a seizure was produced at that dosage, charge was decreased at the next session. This procedure was followed throughout the treatment course.

ECT - TRH TEST

31

On average, patients received 1.5 electrical administrations per treatment session. The average percent of treatment sessions with one or more subconvulsive administrations was 44%. The length of the course of ECT was naturalistically determined on a double-blind basis by a clinical evaluation team and based on therapeutic response. A reduction of at least 50°7o from pre-treatment HAM-D scores was reauired for designation of successful response. A minimum of 10 treatments was required for patients to be classified as non-responders to a particular modality. The modalities did not differ in average number of treatments (bilateral E C T - - m e a n = 9.4, right unilateral E C T - - m e a n = 9.2), or EEG seizure duration (bilateral E C T - - m e a n = 63 sec, right unilateral E C T - - m e a n = 58 sec). The modalities differed in response rate. Of the bilateral ECT patients, eight out of 12 were classified as responders, while only one of I 1 unilateral ECT patients were so classified Lo < 0.005). All responders were followed by biweekly telephone interviews for the first 2 months after treatment termination, and monthly thereafter for an additional 10 months. During these interviews, the HAM-D was administered to identify potentially relapsed patients. Relapse was defined by an increase in HAM-D of at least 50°7o from post-treatment, with a minimum score of 14, and was confirmed by direct interview with patients. • Follow-up was conducted to further evaluate the prognostic value of the TRH test in predicting likelihood of relapse after initial positive response to ECT. Patients were excluded from the study if they had definite or suspected history of endocrinopathies or hormone replacement therapy, lithium therapy within the previous 2 months, or ECT within the previous year. All patients were free of significant medical illnesses, had normal blood levels of thyroxine, triiodothyronine and TSH, and had negative histories for organic brain syndrome or substance abuse. The TSH response to TRH was assessed during the pre-treatment washout period and within a week from the last ECT treatment. The time interval between the two tests was approximately one month. Patients were medication-free throughout this period except for lorazepam (up to 2 mg/day, as needed). The pre-ECT medication washout lasted for an average of five days. Smokers (n = 6) were tested before their first cigarette of the day. The test procedures were based, with modification, on those detailed by Loosen & Prange (1980). Following an overnight fast, an intravenous catheter was inserted at 0800 hr, and 30 min later synthetic TRH (500 ~tg) was injected over a 1 min period. Blood was sampled at - 30, - 15, 0, 15, 30, 45, and 60 min relative to injection. All samples from a patient were measured in duplicate in the same assay. Modification of the double antibody TSH radioimmunoassay procedure of Odell et al. (1966) was used. The lower detection limit of the assay was 0.5 laU/ml. The intrassay coefficient of variation was 4.5°7o, and the interassay coefficient of variation was 5°7o. Two measures of the TSH response were analyzed. The A TSH at pre- and post-treatment was determined by calculating the difference between the peak TSH value post-TRH infusion and the mean of the values obtained prior to TRH infusion. Secondly, a measure of change in area under the curve was determined by computing the difference between the mean of all TSH values post-TRH infusion and the mean of the baseline pre-infusion values. ECT responders and non-responders were compared on pre- and post-treatment test measures by analysis of variance. RESULTS

Figure 1 depicts the pre- and post-ECT TSH curve response for the total sample. Table I presents s u m m a r y TSH data for the total sample and as a function of response classification and E C T modality. The principal finding of this study was that across the sample A T S H decreased after treatment compared to pre-treatment ( F = 9.70, d.f. = 21, p = 0.006). The reduction of A T S H was mirrored by a reduction in the total area under the curve ( F = 9.80, d.f. = 21, p = 0.006). This effect was consistent across individuals and subgroups. Particularly, the reduction of post-ECT & T S H was almost identical in unilaterally and bilaterally treated patients, as well as in responders and non-responders, ruling out the possibility that the difference in efficacy between treatment modalities accounted for the findings. Two patients displayed small increases in A TSH, one displayed no change, and in 20 patients A TSH decreased post-treatment. No patient displayed an increase in A TSH that reached Kirkegaard's criterion of > 2.0 IxU/ml as a predictor of good remission. None of the eight patients (35°-/o of the sample) who had a blunted T S H response (i.e., a A max T S H < 5.0 txUl/ml) pre-treatment showed post-treatment normalization. In three cases,

32

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FK;. 1. Pre- and post-ECT TSH response to TRH.

Table 1. Pre- and post-ECT Hamilton scores (HAM-D), and TSH response to ECT Pre-ECT

Group Total sample

Mean

(n = 23)

SD

Outcome: Responder

Mean

(n = 9)

SD

Post-ECT

Basal

A,

HAM-D

TSH

TSH

HAM-D

Basal TSH

A2 TSH

A2--A, TSH

29.83 7.24

2.33 0.79

7.05 4.02

18.35 10.22

2.22 0.47

4.96 2.82

- 2,09 2.92

30.44 6.77

2.01 1.02

7.52 4.21

7.33 4.88

2.20 0.48

5.52 3.45

- 1.99 2.90

Non-responder

Mean

(n = 14)

SD

29.43 7.5

2.53 0.51

6.75 3.87

25.43 5.32

2.23 0.42

4.60 2.26

- 2. t 6 2.92

Uni, right (n = 11)

Mean SD

29.64 8.27

2.44 0.48

6.73 3.63

25.55 6.88

2.25 0.47

4.66 2.35

- Z08 2.98

Bilateral

Mean

(n = 12)

SD

30.00 6.14

2.23 0.98

7.34 4.33

11.75 8.12

2.20 0.49

5.24 3.17

- 2.11 2.86

Modality:

pre-treatment non-blunted levels fell into the blunted range after treatment. Consistent with previous observations, there were indications that women showed a greater magnitude of TSH response than men at both assessments (data not shown). DISCUSSION

The most critical finding of the present study was that in depressed patients during the week following a course o f ECT, the TSH response to TRH became significantly more blunted. The absence of a single patient who met Kirkegaard's criterion of A TSH increase > 2.0 ttU/ml was remarkable. We cannot attribute this effect to the absence of subjects who responded and showed good remission. Of the nine treatment responders, one relapsed at 2 months, and one at 8 months. The others have been followed up for at least 12 months post-treatment without relapse. Further, although possible, it is unlikely that our sample, composed of 7507o tricyclic non-responder patients, may account for the postECT test findings.

ECT - TRH TEST

33

We also believe that differences in test procedures could not explain the discrepancies between our findings and those previously reported. The major procedural difference between our study and those of Kirkegaard and colleagues involves the TRH challenge dose used. In these latter studies, 200 ~tg of TRH was administered. We used a challenge dose of 500 ltg of TRH, as it may produce more reliable assessment of TSH response. It is unlikely, however, that such procedural differences account for the discrepant findings. Papakostas et al. (1981) also used a 500 Ixg dose; approximately one-third of their patients demonstrated a A2- A, TSH of more than 2.0 I~U/ml. This may suggest that differences in ECT procedures, rather than variation in clinical outcome or TRH test procedures, may account for the discrepancy between our study and prior research. The ECT technique we used was designed to minimize electrical dosage by titrating electrical stimulus intensity to just above each patient's seizure threshold. To quantify and track seizure threshold, subconvulsive administrations were delivered in approximately 40-50°7o of sessions. There is evidence that these procedures may be associated with decreased therapeutic efficacy, particularly with unilateral electrode placement. In the present sample, less than 10°70 of unilaterally treated patients and 66070 of patients treated with bilateral ECT responded to treatment. In the larger parent study involving 52 patients, these procedures were associated with a response rate of approximately 7807o in the bilateral group and 40°7o in the right unilateral group (Malitz et al., in press). Moreover, there are indications in the literature that even with bilateral electrode placement, low dosage techniques may be less therapeutically effective than traditional high dosage ECT (Cronholm & Ottosson, 1962; Robin & De Tissera, 1982). The possible impact of ECT electrical dosage on efficacy supports the speculation that the treatment technique we used may have produced neurochemical changes that differ from those obtained with traditional fixed dosage methods. More particularly, our technique may have had a pronounced effect on the secretory activity of TRH brain cells and resulted in hypersecretion of endogenous TRH. Kubek et al. (1984, 1985) examined the effects of subconvulsive and convulsive electrical stimulation on TRH in rat brain and found that both types of electrical stimulation resulted in increased regional cerebral TRH concentrations. As noted, in our study one or more subconvulsive administr~ tions were delivered in almost 5007o of treatment sessions. This may have resulted in a higher secretion of TRH than that obtained with traditional methods, where subconvulsive administrations are relatively rare events. Possibly due to down-regulation of pituitary receptors, the pituitary may have become less responsive to exogenous TRH administration. In summary, our study suggests that with low dosage, titrated ECT, the TSH response to TRH decreases post-treatment, regardless of electrode placement, clinical response to treatment, or post-treatment relapse or recurrence. In this context, the TRH stimulation test lacked predictive value. Nonetheless, the highly consistent pattern of post-treatment reduction suggests that the test may be useful as a research tool for probing the mechanisms of action of ECT.

This investigation was supported in part by grant MH 35636 from the National Institute of Mental Health, and by BRSG grant SO7RR E625Q.

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