Augmentation of ECT seizures with caffeine

BIOL PSYCHIATRY 1987;22:631-649

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CASE REPORT

Augmentation of ECT Seizures with Caffeine C. Edward Coffey, Richard D. Weiner, Philip E. Hinkle, Martha Cress, Gordon Daughtry, and William H. Wilson

Introduction Over a course of electroconvulsive therapy (ECT) there is frequently a progressive rise in seizure threshold and an associated reduction in the duration of the electrically induced seizure (Sackeim et al. 1986). The recognition of brief ECT-induced seizures is of clinical importance because they may not be as effective as those of moderte duration and because they may herald the occurrence of missed seizures at subsequent ECT treatments (Ottosson 1960; Milstein and Small 1984; Sackeim et al. 1986). Techniques to maintain adequate seizure duration over a course of ECT are therefore of considerable clinical relevance. Because of the paucity of applicable clinical data, the definition of “adequate seizure duration” remains unclear. The proposal of a rather arbitrary cutoff of 25 set (Weiner 1979; Fink and Johnson 1982) has received wide clinical acceptance. The typical clinical approach to maintaining seizures of 25 set or greater during a course of ECT is to increase the intensity of the ECT stimulus when seizure duration becomes too brief (Fink 1979; Weiner 1979). A higher stimulus energy, however, may be associated with greater encephalopathic side effects (confusion, amnesia, EEG slowing) and obviously cannot be accomplished when the ECT device is already at maximal settings (Fink et al. 1958; Ottosson 1960). Recently, we (Hinkle et al. 1987) described six depressed inpatients receiving ECT whose seizure durations were declining despite maximal settings on three different commercially available ECT instruments. In each case, we found that the use of caffeine administered intravenously prior to the delivery of the ECT stimulus resulted in a marked lengthening of the seizure duration (mean increase of 107%), and all patients subsequently experienced a clinical remission of their depression (Hinkle et al. 1987). These findings raised the possibility that caffeine pretreatment could be used routinely to limit increases in electrical energy delivered during a course of ECT. We now describe a new series of depressed patients receiving ECT in whom pretreatment with caffeine reversed a pattern of declining seizure duration and reduced the need for frequent increases in ECT stimulus over the course of therapy.

From the Departments of Psychiatry (C.E.C., R.D.W., P.E.H., M.C., G.D.. W.H.W.) and Medicine (Neurology) (C.E.C.). Duke University Medical Center. and tlte Durham VA Medical Center (R.D.W.), Durbam, NC. Supported in pan by NIMH Grants MH30723,MH40159, and MH17632, and tlx North Carolina United Way. Address reprint requests to Dr. C. Edward Coffey, Box 3920, Duke University Medical Center, Durham, NC 27710. Presented in part at the Annual Meeting of the American Psychiabic Association, Washington, D.C., May 14, 1986. Received October 3, 1986; revised November 18, 1986.

0 1987 Society of Biological

Psychiatry

OCQ6-3223/87/$03.50

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Methods Subjects The 20 subjects were inpatients with DSM-III major depression who had been referred for ECT. There were 12 women and 8 men, with a mean age of 61 years (range 43-85 years). The majority of the patients were medically healthy, but seven were receiving medications for atherosclerotic cardiovascular disease with hypertension and/or diabetesthe dosages of these medications were held constant throughout the course of the ECT treatments. At the time of the ECT treatments, 12 patients were on no psychotropic medications; 3 patients were receiving benzodiazepines, 4 were receiving L-tryptophan, and 3 were receiving neuroleptic medications. In some patients, the dosages of these medications varied over the course of ECT; however, for all ECT treatments in which caffeine was compared to control, the dosages were held constant. Additionally, the hospital chart of each patient was reviewed to insure that pm dosage of these medications had not been administered.

ECT Treatment Technique The ECT treatment technique was similar for each patient. ECT was administered three mornings a week, on a Monday, Wednesday, and Friday schedule, in a special ECT treatment suite. Patients received anticholinergic premeditation with glycopyrrolate (Robinul, A.H. Robins, Co., Inc., Richmond, VA), 0.002 mg/lb im, at least 30 min prior to the ECT. Anesthesia was induced with methohexital (Brevital, Eli Lilly & Co., Indianapolis, IN), 1 mg/kg iv, followed by succinylcholine (Anectine Chloride, Burroughs Wellcome Co., NC), 1 mg/kg iv, to produce subtotal neuromuscular blockade. All patients were preoxygenated with 100% oxygen via mask, and once apneic, their respirations were maintained at 20-25/min with positive pressure ventilation by bag until spontaneous respirations returned. Blood pressure, pulse, and respiratory rate were measured immediately before administration of the anesthetic (baseline) and then at 30, 60, 180, and 300 set after the ECT stimulus. For each interval, the rate-pressure product (RPP), the product of pulse and systolic blood pressure, was calculated and the largest product during the 5-min interval was taken as the “maximal RPP.” All patients were monitored with electrocardiogram (ECG) and one-channel EEG. Choice of stimulus electrode placement was made by the attending physician. For unilateral nondominant (UL) ECT, the d’Elia placement technique (d’Elia 1970) was utilized. Eleven patients received UL ECT and five bilateral (BL) ECT. During the course of ECT, an additional two patients were switched from BL to UL ECT because of encephalopathic side effects, and two patients were switched from BL to UL ECT because of poor therapeutic response to the former. For these patients, however, stimulus electrode placement was always held constant for those ECT treatment pairs that compared caffeine pretreatment to control conditions. The total number of ECT treatment was determined by the attending physician-for 19 patients who received a full course, the average number of ECTs was 9.8 (range 7-13). One patient received only three ECT treatments, then left the hospital against medical advice (AMA). The brief-pulse ECT stimulus was delivered by one of two devices-the MECTA Model C or the Thymatron. These devices differ with respect to maximal charge at typical impedance of 220 ohm. The maximal charge is 336 mcoulombs for the MECTA Model C and 504 mcoulombs for the Thymatron. A “moderately suprathreshold” stimulus dosing

Caffeine Seizure Augmentation in ECT

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639

strategy was employed, in that parameters for each of the devices were chosen empirically to elicit seizures of between 30 and 60 set duration at the first ECT (Weiner 1979). For each ECT treatment, seizure duration was determined from the one-channel EEG using standard criteria (Weiner 1979). If a seizure of less than 30 set occurred, the stimulus parameters were increased one or two increments (IO%-25%) and the patient restimulated within 30-60 set of termination of the previous seizure. No more than two restimulations were administered during any one treatment session. After each ECT treatment, patients were assessed for recovery of pre-ECT orientation by trained nursing personnel using a standardized rating scale (Daniel and Crovitz 1986). Clinical response to the course of ECT was evaluated with a 4-point (none, slight, moderate, and marked) Global Clinical Impression Scale that was completed by the patient’s clinical treatment team. Caffeine Protocol Timing of Curiae

Wats. For 16 patients (subjects 5-20), a trial of c~feine-s~ium benzoate was employed when a significant, progressive decline in seizure duration occurred during the course of ECT (n = 13 patients) or when patients required restimulation during the previous ECT treatment (n = 3 patients). In 8 of these patients (subjects 13-20)) caffeine was given only after increases in the stimlus intensity at prior treatments bad failed to reverse the pattern of declining seizure duration. For this group, caffeine was introduced on average at the eighth ECT (range 3-l 1). In the other 8 patients (subjects 5-12), caffeine was administered first, instead of increasing the stimlus intensity; for this group, caffeine was introduced on average at the sixth ECT (range 3-8). In four patients (subjects l-4), caffeine pretreatment was given at the second ECT treatment and then compared with placebo (4 cc normal saline) over the subsequent course of therapy. The procedure for administe~ng placebo was identical to that for caffeine (see below), and patients were not informed which agent they had received. Cafiine Dosage and Administration. Caffeine-sodium benzoate (Torigian Laboratories, Queens Village, NY) was obtained in ~-CCampules containing 250 mg of caffeine. Based on our previous experience (Hinkle et al. 1987), a starting dose of either 250 mg (n = IO) or 500 mg (n = 10) of caffeine was used. A typical brewed cup of coffee contains about 100 mg of caffeine. Although an equal number of patients was assigned to each dosage level, the choice of initial caffeine dosage was not systematically varied among patients. The caffeine was administered via iv push over 60 see after baseline vital signs had been obtained. Vital signs were then repeated 2 min after the caffeine infusion was completed; during this interval, patients were also observed for evidence of psychomotor agitation and questioned regarding any symptoms of anxiety or dysphoria. The anesthesia, muscle relaxant, and oxygen were then administered as described above. The delivery of the electrical stimlus was timed to occur 5 min after completion of the caffeine infusion. After the initial caffeine-ECT treatment, patients continued to receive caffeine at subsequent ECT treatments, unless significant adverse side effects occurred (see below). The dosage of caffeine at these treatments was titrated in 250 mg increments upward (to a maximum of 750 mg) or downward (to a minimum of 250 mg) to maintain seizure duration between 30 and 100 sec. As noted above, in four patients, caffeine was alternated with placebo over the course of ECT treatments.

Table I. Effects of Caffeine on ECT-Induced Seizure Duration and Maximal RPP Subject. electrode placement”

Seizure duration (set) ECT numbe? I+2

I RUL 2 RUL 3 RUL 4 RUL

63

i-+2

I 20

31

142

I26

40

I+?

202

89

3+4

202

56

748

202

93

2+3

Change

Control’

77

t

22.2%

18,060

mg) 58 (500 mg)

t

X7.l7c

18,315

t

7.5%

22,089

43 (250 mg) I85 (250 mg) I68 (250 mg) 140 (250 mg) II’

49

151

T 107.8%

26. I08

t 200%

14,507

1 5O.I%

23,920

T 128.6%

35.457

(250 mg) 344

ISI

I51

5-6

120

S-6

IO BL II RUL I2 BL

19 BL

233”

7 482.5%

25,500

33

(500 mg) I60

T 384.8%

20.340

40

(500 me) 97

t 142.5%

18,054

t

52.38

23.328

t

50.9%,

25,920

7 37.5%

25,160

T 62.5%)

24,824

i

9.1%

24.240

t ?-I 1.4%

17,728

1 s2.34

24.628

t 400.0%

36,348

t 191.4%

I 1,360

t

57.5%

28,224

1

IO.74

20,792

t

23.8%

24,800

t

21.7%

25,792

t 252.9%

16,215

b-7

I51

65

8-9

I.51

55 40

(250 mg) s5

90

6-7

13 RUL I4 RUL IS RUL I6 BL 17 RUL 18 RUL

40

(500 mg) 99 (250 mg) 83

b-7

202

40

7-8

90

55

I44

44

2-3

144

42

4-5

I20

24

10--t

II

5-6

96

3s

7-x

I44

40

IO-+

II

202

75

10-t

II

403

80

12-+

I3

403

60

IO-t

II

252

34

(500 mg) 6.5 (250 mg) 69 (500 mg) I37 (500 mg, 64 (500 mg) I20 (500 mg) bl (250 mg) b3 (250 mg) xi (250 mg) 9’) (250 mg) 73 (250 mg) I20 (500 mg) Mean change

bilateral

hemisphere;

bECT treatment ‘The immediately This

151

Caffeine (dose)

Controp

(250

5 RUL 6 BL I RUL 8 RUL 9 RUL

“BL,

Charge (mcoulombs)

Maximal RPP

prolonged

RUL,

right

seiure

ECT

treatment

was terminated

21,294 (250 mg) I 1,970 (250 mg) 16.128 (250 mg) 28.034 (250 mg) 27.940 (250 mg) 29.137 (250 mg) 35,860 (2.50 mg) 39.010 (500 mg) 30.538 (500 mg) 3 1,050 (500 mg) 23,920 (250 mg) 22.660 (250 mg) 24,152 (500 mg) 28,060 (250 mg) 24.276 (500 mg) 23.875 (500 mg) 3b. I08 (500 mg) 35.298 (SO0 mg) 13,770 (250 mg) 31 .112 . (250 mg) 25,400 (250 mg) 16.926 (250 mg) 23,264 (250 mg) 30.046 (500 mg) Mean change

(nondominant) unilateral hemisphere.

numbers of the control-ECT preceding

t 127.0%

Caffeine (dose)

with

treatment

(first number)

not modified methohexital.

by caffeine

and the caffeiw-ECT

treatment

(second number1

Change r 17.9%, 134.6% 127.0% 1 7.4% T 92.6% 7 24.3% 7

i.ici;

r 53.oc/r 1 50.1% r 129 1 2.5% J 12.6% _1 3.0% r13.0%’ r

0.1%

r 34.71 r

4b.b’k

J

2.w

r 21.2%

r 10.6%

t 22.2%

131.8%

113.7%

r 85.3~~

T 17.8%

Caffeine Seizure Augmentationin ECT

BIOL

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Statistical Analysis Seizure duration and maximal RPP following the first caffeine pretreatment (Table 1) were compared to the corresponding parameters for the immediately preceding noncaffeine (control) ECT treatment using a paired t-test (two-tailed) on change scores expressed as a percent of control. Subjects were grouped according to an initial caffeine dosage of either 250 mg (n = 10) or 500 mg (n = 9) and analyzed separately. Differences in seizure duration and maximal RPP (expressed as a percent of change from control) between the 250-mg and 500-mg dose groups were analyzed with a standard t-test (two-tailed). In seven patients, an ECT treatment modified with caffeine was also followed during the course of therapy by a control ECT treatment with no caffeine (Table 2). For these patients, seizure duration and maximal RPP for this first control (no caffeine) ECT treatment were also compared to the corresponding parameters for the immediately preceding ECT treatment modified with caffeine (250 mg) using a paired t-test (two-tailed). There were too few subjects at the 500-mg and 750-mg dosage levels of caffeine to allow for meaningful statistical analysis. As noted above, for all caffeine+ontrol comparisions, stimulus charge and electrode placement were held constant.

Table 2. Effects of r)iscontinuingCaffeine Pretreatmenton ECT-Induced Seizure Maximal

Subject, electrode placement”

Seizure duration (set) ECT numbeS

I RUL

3-4

2 RUL 4 RUL

Caffeine (dose)

Control’

Change

151

57

28

ISI

(500 mg) 48

120

(500 me) 54

202

(750 mg) I85

202

(250 mg) I68

Charge (mcoulombs)

5-6 6-7 2-3 4-5 8-9 5 RUL 9 RUL

202

3-4

20 21 56 92

me) 140 (250mg)

7+8 9--t

II RUL 18 RUL

10

7-8 II --, 12

I51

II2

I51

(250 mg) 99

151

(250 mg) 83

202

(250 mg) 65

403

(250 mg) 99

Maximal RPP Caffeine (do=)

Control‘

Change

150.9%

22,932

21,106

1 7.9%

158.3%

(500 mg) 18,093

18,400

t

1.7%

161.1%

(500 mg) 16.087

17,019

t

5.8%

169.7%

(750 me) 28,034

14,507

148.3%

145.2%

(250 mg) 27,940

26,400

1 5.5%

15X.6%

(250 mg) 29,737

17,955

139.6%

1 6.3%

(250 mg) 35,860

35,208

1 1.8%

144.4%

(250 mg) 24,990

25,920

1 3.7%

175.9%

(250 mg) 22,660

26.520

r 17.0%

(250

58 I05 55 20

(250 mg) 45 60

130.8%

28,060

28,175

t

1 39.4%

(250 mg) 16,926

25,792

t 52.4%

(250 mg)

bilateral

hemisphere:

@ECT treatment The

immediately

RUL.

right (nondominant)

numbers of the caffeine-ECf succeeding

ECT

unilateral

treatment

rnzatmcnt not modified

0.4%

(250 mg) Mean change 149.1%

‘BL.

Duration and

RPP

Mean change 1 2.0%

hemisphere.

(first number) by caffeine.

and the control-ECT

treatment

(second number).

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1601

THYMATRON A

90 CAFFEINE

80 70 60 50

PLACEBO

THYMATRON B Figure 1. Effects of caffeine and placebo on seizure duration over a course of ECT. Three patients were treated with the Thymatron device and one with the MECTA Model C. All patients received UL ECT (closed circle); one patient (B) was switched to BL ECT (open circle) at the seventh ECT. Stimulus settings are given under the relevant ECT treatment numbers. Note changes in the stimulus intensity during the course of ECT. At some treatments, patients required restimulation at higher stimulus intensities.

BIOL PSYCHL4TRY 1987;22:637-6)9

Caffeine Seizure Augmen~tion in ECT

PLACEBO

1

ECT NO. I

I

1

I

1

I

1

J

2

3

4

5

6

7

8

MECTA c 2OO180 160 140 120 100 80 60 40 -

PLACEBO

THYMATRON D

643

644

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Results The 20 patients in this study received a total of 188 ECT treatments, 66 of which were modified by caffeine pretreatment. All but one of the patients were felt by their attending physician and ward treatment team to have become euthymic or at least significantly improved (moderate or marked in the Global Clinical Impressions Scale) following the course of ECT. The one exception was the patient described above who left the hospital AMA after the third ECT treatment. Eflects of Cufeine Pretreatment on Seizure Duration Table 1 gives the seizure durations for all control and caffeine-modified ECT treatment comp~sons for which stimulus charge and electrode piacement were held constant (n = 24). Compared to the immediately preceding control (noncaffeine) ECT treatment, caffeine pretreatment produced a marked increase of 127.O% in mean seizure duration. An increase in seizure length was seen in every subject who received caffeine. To avoid statistical overrepresentation by subjects with multiple control-caffeine comparisons, only the first control-caffeine comparison for each subject was analyzed statistically. Caffeine pretreatment produced a significant increase in seizure duration at both the 250-mg and 500-mg dosage levels. At the 250-mg dosage level, caffeine increased seizure length by an average of 66.43% (t = 3.53, p 6 0.01); at 500 mg, mean seizure duration increased by 205.41% (t = 3.44, p s 0.01). This effect of increased seizure length was significantly greater (t = 2.32, p s 0.05) for the 500-mg dosage of caffeine than for the 250-mg dosage level. Table 2 compares the seizure durations for all caffeine-rn~i~ed ECT treatments followed by control (noncaffeine) ECT treatments for which stimulus charge and electrode placement were held constant (n = 11). Compared to the immediately preceding ECT treatments modified with caffeine, discontinuation of caffeine was associated with a marked decrease of 49.1% in mean seizure duration. This reduction in seizure length was seen in every subject. Again, taking only the first caffeine~ontro1 comparisons for analysis, the decline in seizure duration following discontinuation of caffeine was statistically significant at the 250-mg dosage level (t = 3.71, p S 0.05). There were too few subjects at other dosage levels to be analyzed. Figure 1 displays a course of ECT treatments in four representative patients who received caffeine. An example of the progressive decline in seizure duration that typically occurs during a course of ECT is evident in Figure 1A (subject 7). The relative effects on seizure duration of caffeine versus placebo are shown in Figure IB-D (subjects I, 2. and 4, respectively). In each of these patients, pretreatment with caffeine produced a marked lengthening of seizure duration without any increase in stimulus intensity. Reintroduction of placebo was associated with large reductions in seizure duration and occasionally brief seizures that required ~stimulation at higher stimulus settings (see ECT 4, 6, and 8 in Figure 1B and ECT 7 in Figure 1C). For all subjects who continued to received caffeine throughout their course of ECT (n = 15), seizure duration shortened over the course of therapy even when previously effective dosages of caffeine were employed. A larger dosage of caffeine and/or an increase in stimulus intensity were then required to reverse the pattern of declining seizure duration. The relative effects of caffeine pretreatment versus stimulus intensity on seizure length

Caffeine Seizure Aug~ntation in ECT

BIOLPSYCHIATRY 1987;22:637-649

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were not systematically examined in our clinical study. In four subjects, however, changes in caffeine dosage and stimulus intensity were made simultaneously, and the results are shown in Table 3. Caffeine pretreatment was associated with large increases in seizure duration even when stimulus intensity had been reduced in three patients (subjects 4, 8, and 20). In contrast, seizure length shortened when caffeine was discontinued, despite increases in stimulus intensity in two patients (subjects 4 and 12).

Side Egrets of Cu~e~~~~retreut~e~t During the caffeine infusion, two patients (subjects 4 and 13) complained of feelings of uneasiness and anxiety. In one patient (subject 13), these complaints occurred with the first caffeine pretreatment, but lessened as the depressive illness improved. In the other (subject 4), the complaints occurred at the third caffeine-ECT treatment and persisted; this patient also became agitated on the ward (see below), thus p~luding subsequent caffeine pretreatments. One patient (subject 11) developed anxiety, nausea, and wretching during the first caffeine infusion, and caffeine was not employed again during the ECT course. All three of these patients had marked psychomotor agitation and anxiety as prominent components of their depression prior to beginning ECT. No patient complained of pain or burning at the iv site during the caffeine infusion. Prolonged seizures of greater than 200 set (Kaufman et al. 1986) at the first caffeine-ECT treatment occurred in one patient, where the seizure was terminated with iv methohexita1 at 233 sec. A reduction in the dosage of caffeine and/or a reduction in stimulus intensity were effective at shortening the seizures at subsequent ECT treatments. The effects of caffeine pretreatment on the maximal RPP for caffeine-modified ECT treatments are shown in Tables 1 and 2. Caffeine pretreatment was associated with a nonsigni~c~t increase of 17.84% in mean maximal RPP compared to the immediately preceding control (noncaffeine) ECT treatments (Table 1). Analyzing only the first Table 3. Effects of Caffeine and Change in Stimulus Intensity of Em-Induced Seizure Duration Seizure duration (set) Subject, electrode placement 4

ECT number

Charge (mcoulombs)

Control

9

202

58

10

176

-

11 8

202 120

80 -

9

96

-

9

90

-

10

8

144 m4

44 31

9

126

-

Caffeine (dose)

Change

-

RUL

8 RUL

12

BL 20 BL

196 (500 mg) 76 (500 m8) 90 (750 mg) 63 (500 m8) 76

(500mg)

f 238% -1 59.2%

t 31.6%

J 30.2%

t 145.2%

646

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Coffey et al.

control+affeine comparisons for each subject, there was a trend for greater increases in maximal RPP with the 500-mg dose (mean increase of 29.52%) than with the 250-mg dose of caffeine (mean increase of 3.71%), although the difference did not reach a statistically significant level. Discontinuation of caffeine (Table 2) was associated with a nonsignificant reduction (2%) in the mean maximal RPP compared to the immediately preceding ECT treatments modified with caffeine. One patient (subject 4) was felt by the ward nursing staff to be somewhat more psychomotor agitated on the afternoon following her caffeine-ECT treatments. Again, this patient had significant anxiety and agitation as components of her depressive illness. and she had experienced anxiety during the caffeine infusion. Caffeine pretreatment was eventually discontinued. The patients’ time to reorientation after each ECT, as determined by formal nursing assessments, was not affected by pretreatment with caffeine. Specifically, patients recovered their pre-ECT level of orientation after an individual ECT treatment as quickly with caffeine pretreatment as without caffeine.

Discussion In our 20 patients, caffeine pretreatment produced a sizeable increase in ECT-induced seizure duration. In previous work done in a separate group of patients (Hinkle et al. 1987), we have demonstrated that caffeine can lengthen ECT seizures in patients with declining seizure durations on maximal (for a given device) stimulus settings. The present findings confirm and extend these observations, in that caffeine reversed a pattern of declining seizure duration and lengthened seizures in patients at moderate (and certainly less than maximal) dosages of stimulus intensity. Our results raise the possibility that caffeine augmentation of ECT-induced seizure duration may obviate the need for increases in stimulus intensity during a course of ECT. Several clinically observed trends were also noted in these data. First, caffeine appeared to be effective at increasing seizure duration even in patients taking medications (benzodiazepines, L-tryptophan) that have anticonvulsant effects (Prince and Zimmer 1985; Standish-Barry et al. 1985). Second, caffeine appeared to be effective at lengthening seizures at all stages of the ECT treatment course. Third, caffeine did not appear to affect the tendency for seizure duration to shorten over the course of ECT, in that seizure duration continued to decline even when previously effective dosages of caffeine were employed. This finding is in agreement with that of Shapira et al. (personal communication). Nevertheless, seizure duration could still be increased by employing higher dosages of caffeine (e.g., up to 750 mg). Finally, in a small number of patients examined (Table 3), caffeine appeared to have a greater impact on seizure duration than changes in stimulus intensity. We are currently investigating these various issues in prospective studies. In general, caffeine was well tolerated by most of our patients. The major side effects observed were increased anxiety and psychomotor agitation, prolonged seizures, and enhanced hemodynamic changes associated with the ECT treatment. Three patients experienced increased anxiety during the caffeine infusion; one of these was also felt by the nursing staff to exhibit increased psychomotor agitation on the afternoon following the ECT treatments. All of these patients had anxiety and marked psychomotor agitation as prominent components of their depression prior to beginning ECT. These observations are consistent with recent data that indicate that caffeine is associated with increased

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BlOL PSYCHIATRY 1981;22:637-649

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anxiogenic effects in patients with prominent symptoms of anxiety relative to “lessanxious” controls (Chamey et al. 1985; Lee et al. 1986). More work is needed to determine whether or not marked anxiety is a contraindication to the use of caffeine during ECT and whether or not the anxiogenic effects of caffeine could be ameliorated with lower dosages of the drug without loss of its beneficial effects on seizure duration. A prolonged seizure of greater than 200 set (Kaufman et al. 1986) occurred in only one patient during the first ECT treatment modified with caffeine. This seizure was easily terminated at 4 min with methohexital. At subsequent ECT treatments, prolonged seizures were avoided by a reduction in the dosage of caffeine and/or a reduction in the stimulus intensity. Thus, we do not feel that prolonged seizures are a contraindication to the subsequent use of caffeine during a course of ECT. As theoretically, a prolonged seizure may increase the risk of acute encephalopathic effects from ECT, such patients should be carefully observed for increased confusion and/or agitation in the postictal period. It should be noted that despite significant increases in seizure duration with caffeine in our patients, nursing assessments of reorientation following ECT revealed no evidence of prolonged disorientation. Caffeine pretreatment was associated with a nonsignificant increase in maximal RPP of 18%. This effect was highly variable, however. Some patients actually experienced decreases in the maximal RPP, whereas others exhibited large increases in maximal RPP with caffeine. Still, none ever complained of chest pain or palpitations, and significant cardiac arrhythmias were not observed. In every case, vital signs returned to baseline levels within 5 min of the ECT treatment. A preliminary review of the data did not reveal any association between large increases in maximal RPP with caffeine and advanced age, the presence of atherosclerotic/hypertensive cardiovascular disease, or the use of antihypertensive medications. Of interest in our patients was the apparent dosage-dependent relationship of the caffeine response. The 500-mg dosage of caffeine produced a greater increase in seizure duration than the 250-mg dosage. In contrast, there was a trend for the increase in maximal RPP to be less with the 250-mg dosage of caffeine than for the 500-mg dosage. These observations suggest that careful clinical titration of the caffeine dose may allow for an increase in seizure duration, while at the same time minimizing the hemodynamic effects of the pretreatment. A study with subjects assigned randomly to these (and possibly other) dosage levels and blind assessment of behavioral response measures is needed to test this procedure. Chronic administration of caffeine elevates the number of adenosine receptors, a finding that has been used to account for tolerance to caffeine in chronic users (Snyder and Sklar 1984). We did not obtain information regarding baseline caffeine consumption in our patients, but clearly, future studies should attempt to determine whether or not differences in daily consumption of caffeine correlate with the observed dose-dependent effects of caffeine pretreatment in ECT. The mechanism of action of caffeine in lengthening seizure duration in ECT is unknown and was not examined in our clinical study. The suggestion of Shapira et al. (1985) that caffeine may lengthen seizure duration by inhibition of adenosine at the central A, receptor is supported by studies of adenosine antagonists, such as theophylline, which exert an augmenting effect on seizure duration in animals (Murray et al. 1984). A high serum level of theophylline has also been linked to the occurrence of status epilepticus in a 71year-old patient who received ECT (Peters et al. 1984). Furthermore, adenosine antagonists tend to shorten seizure duration (Murray et al. 1984). However, most agents that

648

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C.E.

Coffey et al.

have a potentiating effect on seizure duration and/or threshold are also cerebral stimulants, e.g., caffeine, amphetamine, theophylline, direct administration of epinephrine and norepinephrine, and even the convulsant pentylenetetrazol. Thus, it remains unclear as to whether these agents act on seizure duration via their known monoaminergic effects or whether some other mechanism (e.g., adenosine) is involved. We have previously reviewed the options available to the clinician when faced with brief/missed seizures or declining seizure duration during a course of ECT (Hinkle et al. 1987). Seizure duration may be decreased by a number of drugs (e.g., lidocaine, benzodiazepines, L-tryptophan), and these should be discontinued (Ottosson 1960; Price and Zimmer 1985; Standish-Barry et al. 1985). However, in patients with epilepsy who require anticonvulsant medications (e.g., phenytoin, carbamazepine), this may not be possible. A reduction in the dosage of barbiturate anesthetics (e.g., thiopental, methohexital) used for ECT may also help lengthen seizures. A switch to the nonbarbiturate anesthetic ketamine is another option, but its use may be associated with delirium and dissociative states (Guerra 1980). The convulsant agent pentylenetetrazol was previously used as an adjunct for lengthening ECT seizures (Thigpen and Cleckley 1984), but it is no longer commercially available. Hyperventilation can also be used to prolong seizure duration, with its action derived through a decrease in PC02 (Bergsholm et al. 1984). In the present series of patients, care was taken to provide uniform respiratory assistance across all ECT treatments so as to minimize the confounding effects of this variable. The use of higher stimulus energies may be effective at maintaining adequate seizure duration, but this procedure carries the risk of increased encephalopathic side effects and is obviously not an option when maximal machine settings have been reached. Although older model ECT devices differed with respect to energy output, it should be noted that the presently marketed pulse ECT machines by MECTA (SR and JR) and Somatics (Thymatron) are equivalent in terms of maximal energy output. Our studies suggest that pretreatment with caffeine-sodium benzoate may be an effective and safe technique to augment ECT and increase seizure duration. The use of caffeine pretreatment should be considered when the measures described above are not effective at maintaining seizure duration during a course of ECT. We recommend a starting dose of 250 mg of caffeine, with subsequent titration of the dose as determined by seizure duration. By lessening the need for increases in electrical energy during the treatment course, caffeine may become an important tool for reducing the encephalopathic effects of the therapy.

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