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Psychosis and vulnerability to ECT-induced seizures
PSYCHIATRY RESEARCH Psychiatry Research 62 (1996) 191-201
Psychosis and vulnerability to ECT-induced seizures Rafiq Waziri *, Sankar Baruah, Stephan Arndt, Karen Baumert, Jon Cooney, Laura Christensen Psychiatry Research-MEB,
University of Iowa, Iowa City, IA 52242-1000, USA
Received 3 January 1995; revised 23 August 1995; accepted 8 December 1995
Abstract
Medical records of patients with major depressive disorders who had received electroconvulsive therapy (ECT) for the first time were studied to test the hypothesis that psychotic patients are more vulnerable to seizures than nonpsychotic patients. This hypothesis was based on studies suggesting a putative purinergic deficiency in psychosis. Results showed that the duration of.ECT-induced seizures as a measure of seizure vulnerability was significantly longer in psychotic than in nonpsychotic depressive patients. The association applied for the first ECT as well as for the course of eight ECTs. These findings were still present when covariates such as age, electrical energy applied, dosage of methohexital and succinylcholine, and psychotropic medications such as neuroleptics, benzodiazepines, and tricyclics were included in the statistical analysis. The results are discussed in the context of the role of neurotransmitters such as glutamate, y-aminobutyric acid, adenosine, and dopamine on seizure vulnerability and psychosis. Keywords: Electroconvulsive therapy, seizure duration; Affective disorder; Purines; Psychotic depression
1. Introduction
The application of electrical charge during electroconvulsive therapy (ECT) results in the longenduring synchronous depolarization of a large ensemble of neurons. These neurons activate adjacent and surrounding neurons as well as neurons that are one or two synapses distant from the site, resulting in a generalized seizure. Seizure vulnerability as measured by seizure duration and seizure threshold is affected by a multiplicity of factors such as age, gender, and use of medications. Also, there are the imposed factors that l Corresponding author, Tel: +1 319 3534444; Fax: +I 319 353-3003.
occur during treatment such as stimulus strength, doses of anesthetics and muscle relaxants, hyperventilation, and electrode placement. In addition, there are factors that are inherent in the brain. Paramount among these factors are the inhibitory neurotransmitter y-aminobutyric acid (GABA) (Wood, 1975; Lothman et al., 1986) and excitatory neurotransmitters such as aspartate and glutamate (Czuczwar et al., 1986; Engelson, 1986; Lothman et al., 1986; Meldrum and Chapman, 1986; Mody and Heinemann, 1987; Kish et al., 1988; Sherwin et al., 1988; Heinemann and Jones, 1991). Adenosine is another neurotransmitterneuromodulator that prevents the spread of seizures and helps in their termination (Whitcomb et al., 1990). The role of adenosine and other purines
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in the brain is mainly to reduce the response of neurons to excitatory input. They also decrease the release of neurotransmitters in general (Phillis and Wu, 1981). Adenosine analogues at the A, adenosine receptor can raise the seizure threshold (Murray et al., 1985; Murray and Szot, 1986) and can act as anticonvulsants (Dunwiddie and Worth, 1984; O’Brien, 1988). Because adenosine and other purine levels increase in the brain during and after the onset of seizures (Schultz and Lowenstein, 1978; Winn et al., 1979) and because adenosine and its analogues increase seizure threshold and decrease the spread and duration of seizures in animals, the hypothesis that adenosine may be an ‘endogenous anticonvulsant’ has been put forward (Dragenow et al., 1985; O’Brien, 1988; Eldridge et al., 1989). This hypothesis is strengthened by the finding that adenosine antagonists such as caffeine and theophylline have proconvulsive effects in humans (Peters et al., 1984; Hinkel et al., 1987; Coffey et al., 1990) and in animals (Murray and Szot, 1986). The synthesis of purines is largely dependent on the availability of l-carbon units provided by the interconversion of serine and glycine via the enzyme serine hydroxymethyltransferase (SHMT) (Henderson, 1972; Caperelli et al., 1980; Appling, 1991). Results of several studies on plasma and brains of patients and controls indicate that the activity of SHMT, which is important in the production of purines, is diminished in patients with psychosis (Waziri et al., 1983, 1984, 1985, 1989, 1990, 1992; Waziri and Mott, 1986, 1987). Pertinent to this study, the activity of SHMT is diminished in psychotic compared with nonpsychotic depressive patients (Waziri et al., 1985). Although direct measurements of adenosine in brains of psychotic patients in association with diminished activity of SHMT are not available, it is theoretically possible that psychotic patients could be deficient in brain adenosine and other purines. On the basis of these observations, we hypothesized that psychotic depressive patients receiving ECT would be more vulnerable to seizures than their nonpsychotic counterparts.
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2. Methods Charts of inpatients with the diagnosis of major depressive disorder with and without psychotic symptoms who had received a first course of ECT were reviewed. Diagnoses had been made according to DSM-III, DSM-III-R, and DSM-IV criteria (American Psychiatric Association, 1980, 1987, 1994) by the faculty of the University of Iowa Department of Psychiatry and were recorded in admission evaluations and discharge summaries. Admission history and mental status examinations had been obtained by medical students and psychiatric residents and evaluated by faculty before the patient’s interview by faculty-staff members. On the basis of history and mental status examination, presence or absence of psychosis had been determined. Psychotic symptoms had been described as mood-congruent and mood-incongruent delusions and believed hallucinations. The patients had been admitted between the years of 1984 and 1995. We selected only those patients who had received a course of ECT for the first time to avoid the controversy about whether previous ECTs permanently change subsequent responses to ECTs (Tomasson et al., 1992; Krueger et al., 1993). Excluded from data analysis were patients with organic brain syndromes, IQ scores below 75, Mini-Mental Status Examination scores below 24, abnormal electroencephalograms (EEGs), and treatment with theophylline or anticonvulsants such as diphenylhydantoin, carbamazepine, valproate, and clonazepam in the week before ECT. In our facility, it had been the general practice to withdraw patients from psychotropic medications as soon as a decision was made to give them ECT. After such a decision, a period of 24-72 h usually elapsed before treatments began. Short-acting benzodiazepines were infrequently given, mostly to psychotic patients for agitation only on a PRN basis, but rarely on the night before the treatments. Patients who had received caffeine for enhancement of seizures were not included. Also excluded were those who had been treated with benzodiazepines, tricyclic antidepressants, neuroleptics, and lithium in the 12
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h before ECT. The dosages of various benzodiazepines and neuroleptics that were administered during the week before ECT were recorded as diazepam (Perry et al., 1991) or chlorpromazine (Davis, 1974; Baldessarini et al., 1984) equivalents (where the last digits were rounded off to the nearest 5 or 0). Dosages of tricyclics were considered equivalent to imipramine, except for nortriptyline dosage, which was multiplied by a factor of 1.5. Treatments with nontricyclic antidepressants (fluoxetine, sertraline, paroxetine, trazodone, and bupropion) were too few and various to be included in data analysis. The total of 112 patients included in the study had received bilateral ECTs only. Conventional ECT procedures had been followed in all patients. After an overnight fast, 0.4 mg of atropine or 0.2 mg of glycopyrrolate was given subcutaneously just before treatment. Methohexital as the anesthetic and succinylcholine as the muscle relaxant were administered at doses approximately determined by the weight of the patient. Before, during, and sometimes after seizures, patients were ventilated with 100% OZ. The ECT instruments were MECTA Model D and Model SR-1 (MECTA Corporation, Lake Oswego, OR, USA) which were set to deliver a 2-s stimulus of 0.8 A, and pulses of 1S-1 6 ms duration at a frequency of 40-80 Hz. The energy delivered across the poles had been recorded as joules. Millicoulombs could not be calculated from records before 1986 because not all ECT parameters had been recorded in the charts. EEG seizure duration had been obtained with the fronto-mastoid lead and recorded in the strip of the MECTA instrument. The data from the strip were copied into the record by the resident physician who was rotating through the ECT service. We used the recorded seizure duration obtained from the EEG trace for data analysis because some of the records lacked the observed seizure duration and because the EEG provides a more objective measure of seizure duration. If at the first stimulus the patient had not seized, the value recorded for seizure duration was 0 s, which was included as such in the analysis. There was no information as to why a particular stimulus inten-
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sity had been chosen for a particular patient. Repeated attempts in the same session at higher energy levels (at increments of 10 Hz), which produced seizures of various durations, were not included in the data analysis. Of the two measures of vulnerability, we had data only on seizure duration. Patients had not undergone procedures to establish seizure threshold (Sackeim et al., 1987). Information on several variables that influence seizure duration was available from the records. Among these were age (Abrams, 1988), dosage of methohexital and succinylcholine (Miller et al., 1985), and electrical energy (Rosenthal et al., 1962). Variables such as oxygenation (Holmberg et al., 1956) and electrode placement (Abrams, 1988) were considered to be similar and their differences randomly distributed in the two groups of patients. Anesthesiologists had administered the oxygen and had followed routines that may have varied on the basis of their preferences and patient characteristics. There was no information recorded about the volume of oxygen delivered during the procedure. However, all patients had been given enough oxygen to achieve >95% saturation as measured by pulse oximetry. 2.1. Statistics The association between the number of psychotic and nonpsychotic subjects who did and did not receive each of the four classes of medications before ECT was evaluated by x2 test. Student’s t tests and analysis of covariance (ANCOVA) were used to test the hypothesis that the seizure vulnerability of depressed patients with psychosis is different from that in those without psychosis. Thus, seizure duration (s) was used as the dependent variable. The main effects tested were diagnosis and gender, with age (years), energy (joules), methohexital dose/weight (mg/kg), and succinylcholine dose/weight (mg/kg) as covariates. After significant x2 test probabilities were obtained for neuroleptic and lithium treatment, these two medications at any dose were also included as covariates. Although benzodiazepine treatment did not yield a significant x2 test, it was included as a covariate to control for the fact that
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withdrawal from these medications may result in prolonged seizure durations. Although the means of none of the continuous variables were significantly different between the two diagnostic groups (Table l), each variable was considered to have an effect on seizure duration. To account for these effects, the above-mentioned variables were included in the analysis. The two-way interaction tested was gender x diagnosis, neuroleptic treatment x diagnosis, and energy x diagnosis. The adjusted mean seizure duration thus obtained from the ANCOVA was termed ‘predicted seizure duration’. 3. Results Comparison of variables such as age, dosages of methohexital, succinylcholine, and intensity of electrical stimulation showed no significant differences between the psychotic and nonpsychotic groups either in the first ECT session or throughout the course of ECT (Tables 1 and 2). However, seizure duration in the psychotic group was significantly longer during the first ECT than seizure duration in the nonpsychotic patients when males and females were combined (P < O.OOOl). For the first ECT, when males and females were analyzed separately, seizure duration was again significantly different (P < 0.005) between psychotic and nonpsychotic patients (Table 1). Seizure duration was also significantly longer in psychotic patients in the sum total of ECTs when
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males and females were combined (P < 0.0002) (Table 2). Whereas psychotic females were not significantly different (P < 0.059) from nonpsychotic females, psychotic males had significantly longer seizure durations (P < 0.0014) than nonpsychotic males (Table 2). Seizure duration did not differ significantly between males and females in either the psychotic or the nonpsychotic group. 3.1. Results of ANCO VA The overall statistical model (ANCOVA) testing all of the main effects of age, energy, anesthetic, muscle relaxant, neuroleptics, benzodiazepines, and lithium and the relevant interaction simultaneously was significant (F = 3.66, df = 12,99, P c 0.0001) for the first ECT. For the individual factors, only diagnosis (F = 17.73, df = 1,99, P < O.OOOl),age (F= 10.67, df = 1,99, P < 0.0015) and methohexital dose/weight (F = 6.86, df = 1,W, P < 0.0102) were significant. All other terms in the model, including gender x diagnosis, neuroleptics x diagnosis and energy x diagnosis interactions, were not statistically significant (P > 0.1).
Controlling for the effects of all the covariates, we obtained a ‘predicted seizure duration’ value that was significantly longer in psychotic depressive patients during the first ECT (Fig. 1). However, the adjusted means of seizure duration for the sum total of eight ECTs (Fig. 2) were significantly longer in male but not in female psychotic patients compared with nonpsychotic
Table 1 Raw means (SDS) of variables used in analysis of the first ECT session Gender
n
Age
Succinylcholine (weight, mgflrg)
Methohexital (weight, m&g)
Energy (i)
Seiire (s)
duration
32 25 57
45.5 (14.4) 48.0 (19.6) 46.6 (16.8)
0.79 (0.22) 0.89 (0.27) 0.84 (0.24)
1.33 (0.41) 1.45 (0.31) 1.39 (0.37)
34.7 (9.2) 29.1 (8.9) 32.23 (9.43)
54.6 (24.1) 57.4 (36.2) 55.8 (29.7)
27 28 55
49.3 (16.6) 42.3 (18.6) 45.7 (17.8)
0.76 (0.17) 0.77 (0.16) 0.76 (0.16)
1.49 (0.43) 1.37 (0.38) 1.43 (0.41)
32.3 (8.5) 27.2 (9.5) 29.7 (9.3)
89.1 (49. I)* 84.4 (34.2)* 86.7 (42.2)**
Nonpsychotic patients
Females Males Combined Psychotic patients
Females Males Combined l
= P c 0,005 and l * = P c 0.0001 by t test, comparison of nonpsychotic patients vs. psychotic patients for respective genders.
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Table 2 Raw means (SDS) of sums of variables during a course of 8 ECf sessions Gender
II
Age
Succinylcholine (weight, m&g)
MethohexitaJ (weight, mgfltg)
Energy (i)
Seizure duration (s)
32 25 57
45.5 (14.4) 48.0 (19.6) 46.6 (16.8)
5.93 (1.92) 7.41 (2.46) 6.58 (2.28)
10.16 (2.90) 11.18 (3.33) 10.61 (3.11)
241.4 (87.7) 217.0 (60.0) 234.0 (77.6)
337.2 (120.8) 343.5 (144.5) 340.0 (130.6)
27 28
49.3 (16.6) 42.3 (18.6)
5.65 (1.52) 7.01 (1.51)
11.11 (4.54)
233.3 (87.0)
409.0 (172.7)
Males
Combined
55
45.7 (17.8)
6.34 (1.65)
11.28 (3.17) 11.20 (3.87)
220.8 (71.1) 227.0 (78.8)
484.3 (174.3)* 447.3 (176.0)**
Nonpsychotic patients
Females Males Combined Psychotic patients
Females
* = P < 0.002 and l * = P < 0.0002 by t test, comparison of nonpsychotic patients vs. psychotic patients for respective genders.
and female patients, respectively. This apparent gender difference (although not a significant effect in the ANCOVA) is also evident in Fig. 3, which depicts the changes in the ‘predicted seizure duration’ through the course of eight ECTs. In general, these findings tend to validate the hypothesis of increased seizure vulnerability in psychotic depressive patients.
male
3.2. Effect of prior medications on seizure duration A significant effect (P < 0.05) for neuroleptic and lithium was demonstrated by x2 tests, based on a 2 x 2 contingency table for number of psychotic and nonpsychotic subjects who did and
did not receive various medications in the weeks before ECT. As shown in Table 3, very few nonpsychotic patients received neuroleptics whereas the numbers of psychotic patients who did and did not receive neuroleptics are quite comparable. However, the mean seizure durations of psychotic patients who did and did not receive neuroleptics are almost identical. The fact that neuroleptics did not affect seizure duration was confirmed by ANCOVA (F = 0.50, df = 1,99, P < 0.48) and there was no significant neuroleptic x diagnosis interaction effect. There was also no correlation between the dose of neuroleptics and seizure duration in the psychotic population: r = 0.105, P < 0.62, n = 25.
600
0
M&S
Females s
Fig. 1. Seiire durations (mean f SD) for the Jst ECT as predicted from analysis of covariance.
Non psychotics
m
Psychotics
* p
Fig. 2. Sum of seizure durations (mean * SD) during a course of 8 ECTs as predicted from analysis of covariance.
1%
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Males and Females Combined +-Nonpsychotics -~-Psychotics * peo.05
* &
5
I
1
3
4
30 I
2
5
8
I
6
Males Only +Nonpsychotia +F’sychotics
I
p < 0.05
*
2
3
4
5
6
I
8
Females 110 3
* +Nonpsychotm
loo-
UPsychotia
.zt
90.
*
E
p < 0.05
‘Z 805
70.
t ‘$’
60.
z
*O-
.%
40 _
% 30 1
2
3
4
5
6
7
a
ECT Fig. 3. Changes in seizure durations during a course of ECT. Values shown are means and standard deviations as predicted from analysis of covariance.
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Table 3 Medications taken (during week before ECT) and seizure durations (of first ECT)
Nonpsychotic patients n ke Seiire
Ow)
duration (s)
Psychotic patients n Do= (ms)
!Seii
duration (s)
Neuroleptics
Benzodiazepines
Tricyclics
Yes
No
Yes
No
Yes
No
Yes
No
8 916 (1660) 63.1 (35.9)
49+ 0
27
30 0
32 519 (350) 62.3 (24.7)
25 0
16 2413 (1491) 55.6 (20.2)
41* 0
25 837 (818) 87.1 (42.8)
30* 0
25 356 (301) 92.5 (43.8)
30 0
:57) 46.9 (23.1)
86.4
22 ff6) 89.8 (43.3)
63.8++ (33.0)
33 0 84.7 (40.7)
Lithium
47.6 (33.9)
81.9 (41.5)
7 3086 (1517) 93.1 (42.9)
55.9 (33.0)
48* 0 85.8 (44.3)
Note. Values shown are raw means (SDS); l = P c 0.05 by x2 for proportion of psychotic patients to nonpsychotic patients; *+ = P
C 0.05 by t test comparing nonpsychotic yes to no.
Similarly in the case of lithium, there was no significant difference in the mean seizure duration of those who did and did not receive lithium treatment in either the psychotic or nonpsychotic group. The ANCOVA was also nonsignificant (F = 0.04, df = 1,99, P < 0.85). Effects of benzodiazepine treatment were different. As shown in Table 3, there was no difference in the use of this class of drugs between the two groups as confirmed by a x2 value of P < 0.432. Since withdrawal from benzodiazepines may result in prolonged seizures, a comparison of seizure duration between those who did and did not receive benzodiazepines in each group was made. Interestingly, the seizure duration of nonpsychotic patients who received benzodiazepines was significantly shorter than that of those who did not. There was no difference in seizure duration between those who did and did not receive benzodiazepines in the psychotic group. The ANCOVA was also nonsignificant (F= 0.03, df = 1,99, P < 0.86) and there was no benzodiazepines x diagnosis interaction effect. Thus, the use of or withdrawal from benzodiazepines did not have a confounding effect on the observed difference of seizure duration between psychotic patients and nonpsychotic patients.
3.3. Relationship between stimulus energy seizure duration
and
As mentioned earlier, stimulus energy supplied did not differ significantly in the two groups. However, there did appear to be a different trend in the relationship between energy applied and seizure duration in the two groups. Pearson’s correlation coeffkient between these two variables in the nonpsychotic patients was r = -0.142 (P < 0.294, n = 57) whereas in the psychotic group it was r = 0.251 (P < 0.064, n = 55). This difference in correlations, however, did not emerge as a significant effect in an energy x diagnosis interaction in the ANCOVA (F = 2.56, df = 1,99, P < 0.11). 4. Discussion
Both seizure duration and ‘predicted seizure duration’ clearly distinguished between psychotic and nonpsychotic depressive patients of both genders in the first ECT. When ‘predicted seizure duration’ was calculated cumulatively during the course of ECTs, only the males showed a significant difference between psychotic patients and nonpsychotic patients. It must be pointed out, however, that neither gender nor the gender x diagnosis interaction was significant in the AN-
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COVA. A lack of gender effects on seizure duration and seizure threshold has been previously reported, at least for the first ECT (Sackeim et al., 1987; Coffey et al., 1995). The statistical model that incorporates the effects of various medications - particularly neuroleptics, which were more commonly given to psychotic patients - did not show any significant effects on seizure duration. Although a major shortcoming of this study is the lack of information about seizure threshold as a measure of vulnerability, nevertheless, the ECT-induced seizure duration as a measure of vulnerability robustly differentiated between psychotic and nonpsychotic depressive patients. The brain mechanisms underlying these differences remain unclear. The basis for our hypothesis was the observation from many studies of reduced activity of the enzyme SHMT in plasma and brains of psychotic patients. SHMT is of crucial importance in providing l-carbon units required for the synthesis of purines and thereby adenosine, which has anticonvulsant effects. However, because there is no direct evidence for decreased levels of adenosine in brains of psychotic subjects and because vulnerability to seizures may involve the interplay of several neurotransmitters-neuromodulators, as well as structural abnormalities in the brain, these other variables could contribute to the observed differences between psychotic and nonpsychotic patients. Also it is possible that some unknown variable such as medications may have contributed to the observed differences. Potentially, treatment occasionally received by with neuroleptics, psychotic patients, could have been a variable contributing to this difference. However, psychotic patients who had received neuroleptics up to 12 h before ECT did not have significantly longer seizure durations than those who had not. Despite some suggestive findings (Sackeim et al., 1991), evidence for proconvulsant effects of these drugs remains equivocal. One study that compared thiothixene with placebo showed that thiothixene reduced seizure duration, on average, from 43 to 37 s (Small et al., 1982). Another study that examined seizure duration cumulatively over the course of ECT, while patients were being treated with various neuroleptics, also found that seizure duration was shortened by neuroleptics
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(Tomasson et al., 1992). There is even a report of some neuroleptics (thioridazine and pimozide) having anticonvulsant effects (Kamal et al., 1986). Glutamate and GABA, which have potent effects on seizures, have also been implicated in the etiology of psychosis. A decrease in glutamatergic neurotransmission has been hypothesized as an etiological basis for schizophrenic psychosis (Kim et al., 1980; Deutch et al., 1989). A number of studies on autopsied brains have supported this hypothesis (Nishikawa et al., 1983; Kerwin et al., 1988; Deakin et al., 1989; Sherman et al., 1991a, 1991b). Diminished GABAergic neurotransmission has also been considered as an etiological factor in schizophrenic psychosis. Studies on brain samples suggest the hypothesis of GABAergic deficiency in schizophrenic psychosis (Perry et al., 1979; Korpi et al., 1987; Simpson et al., 1989; Sherman et al., 1991a, 1991b). The hyperdopaminergic hypothesis of psychosis, which is supported by considerable clinical and indirect evidence, is widely accepted. While some studies on dopaminergic transmission have not found a significant role for this agent in epilepsy (Burly and Ferrendelli, 1984), other studies suggest that dopamine has anticonvulsant properties (Anlezark et al., 1981; Jobe and Laird, 1981; Loscher and Czuczwar, 1986). It appears that the anticonvulsant effects of dopamine are mediated via Dz receptors (Loscher and Czuczwar, 1986). Of the findings on these neurotransmitters, the paucity of GABAergic and purinergic neurotransmission in psychosis would explain the greater vulnerability of psychotic subjects to electrically induced seizures. Glutamatergic deficiency would theoretically reduce the excitatory drive for the activation of neurons and thereby reduce the vulnerability to seizures in psychotic patients, whereas excessive dopaminergic neurotransmission would reduce seizure vulnerability. Pharmacological and biochemical studies in animal brains provide evidence for a role of adenosine in seizures, and possibly in psychosis (Duncan and Morgan, 1990). In humans there is clinical and pharmacological evidence that large intake of adenosine antagonists, such as caffeine and theophylline, increases seizure susceptibility. These agents also increase psychotic symptoms (Lucas et al., 1990). In animals there is
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evidence that adenosine agonists for A2 receptors demonstrate a pharmacological profile quite similar to antipsychotic drugs (Heffner et al., 1989). These observations suggest that decreased adenosine may play a role in the genesis of both epilepsy and psychosis. Studies investigating the seizure proneness of psychotic populations, although few in number, tend to suggest a positive relationship between psychosis and epilepsy (Hill, 1957; Betts, 1981). The findings reported here provide support for a positive association between vulnerability to psychosis and vulnerability to seizures. There is an intriguing possibility that decreased adenosinergic input at the At receptor would increase vulnerability to seizures, while decreased input at the A2 receptor would increase vulnerability to psychosis. Whether this association is based on deficiencies either in adenosinergic neurotransmission-neuromodulation, GABAergic mechanisms, or both is unknown. Other brain mechanisms such as structural abnormalities observed in psychotic patients may also contribute to the observed differences in vulnerability between psychotic patients and nonpsychotic patients. Future studies should determine seizure threshold as well as seizure duration in assessing vulnerability in these patients. Studies on factors that make psychotic patients vulnerable to seizures would be important for the understanding of the etiology and the treatment of psychotic and epileptic disorders. Acknowledgments
We thank Dr. Raymond Crowe for his helpful comments and Ms. Julie Haugen for her diligent efforts in the preparation of this article. References Abrams, R. Eiectroconvulsive Therapy. (1988) Oxford University Press, New York. American Psychiatric Association. (1980) DSM-III: Diagnostic and Statistical Manual of Mental Disorders. 3rd edn. APA, Washington, DC. American Psychiatric Association. (1987) DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders. 3rd rev. edn. American Psychiatric Press, Washington, DC. American Psychiatric Association. (1994) DSM-IV: Diagnostic
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Betts, T.A. (1981) Epilepsy and the mental hospital. In: Reynolds, E.H. and Trimble, M.R. (Eds.), Epilepsy and Psychiatry. Raven Press, New York. Burley, E.S. and Ferrendelli, J.A. (1984) Regulatory effects of neurotransmitters on electroshock and pentylenetetraxol seizures. Fed Proc 43, 2521-2524. Caperelli, C.A., Benkovic, P.A., Chettur, G. and Bankovic, S.J. (1980) Purification of a complex folate cataloguing cofactor synthesis and transformulation in de novo purine biosynthesis. J Eiol Chem 255, 1885-1890. Coffey, C.E., Lucke, J., Weiner, R.D., Krystal, A.D. and Agne, M. (1995) Seizure threshold in electroconvulsive therapy (ECT): II. The anticonvulsant effects of ECI. Riol Psychiatry 37, 717-718. Coffey, C.E., Weiner, R.D. and Saunders, W.B.
(I 990)Caffeine augmentation of ECT. Am J Psychiatry 147, 579-585. Czucxwar, S.G., Frey, H.H. and Loscher. W. (1986) N-methylD,L aspartic acid induced convulsions in mice and their blockade by antiepileptic drugs and other agents. In: Nistico, G., Moreselli, P.L., Lloyd, K.G., Fariello, R.G. and Engle, J., Jr. (Eds.), Neurotransmitters, Seizures ana’ Epilepsy III. Raven Press, New York, pp. 235-246. Davis, J.M. (1974) Dose equivalence of antipsychotic drugs. J Psychiatr Res
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Duncan, M.G. and Morgan, P.F. (1990) Prospective role for adenosine and adenosinergic symptoms in psychiatric disorders. Psycho1 Med 20, 475-480. Dunwiddie, T.V. and Worth, T. (1984) Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J Pharmacol Exp Ther 227, 167-173.
Eldridge, F.L., Paydarfar, D., Scott, S.C. and Djowell, T.R. (1989) Role of endogenous adenosine in recurrent generaliied seizures. Exp Neurol 103, 179-185. Engelson, B. (1986) Neurotransmitter glutamate: its clinical importance. Acta Neural Scand 74, 337-355.
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Heffner, T.G., Wiley, J.N., Williams, A.E., Bruns, R.F., Conghenour, L.L. and Downs, D.A. (1989) Comparison of the behavioral effects of adenosine agonists and dopamine antagonists in mice. Psychophamurcology 98, 31-37. Heinemann, U. and Jones, R.S.G. (1991) Neurophysiology. In: Darr, M. and Gram, L. (Eds.) Comprehensive Epileptology. Raven Press, New York, pp. 17-42. Henderson, J.F. (1972) Regukztion of Purine Biosynthesis. (American Chemical Society Monograph 170) American Chemical Society, Washington, DC. Hill, D. (1957) Electroencephalogram in schizophrenia. In: Richter, D. (Ed.), Schizophrenia: Somatic Aspects. Macmillan, New York. Hinkel, P.E., Coffey, C.E., Weiner, R.D., Cress, M.F. and Christison, C. (1987) Use. of ECT to lengthen seizures in ECT. Am J Psychiatry 144, 1143-I 148. Hohnberg, G., Hard, G. and Ramquist, N. (1956) Experiments in the prolongation of convulsions induced by electric shock treatments. Acta Psychiatr Stand 69, 121-128. Jobe, P. and Laird, H.E. (1981) Neurotransmitter abnormalities as determinents of seixure susceptibility and intensity in the genetic models of epilepsy. Biochem Pharmacol 30, 3137-3141. Kamal, J.A., Janowsky, E.C., Risdi, SC. and Janowsky, D.S.
(1986) In: Smith, N.T. and Corbasio, A.N. (Eds.), Drag Interactions in Anesthesia. 2nd edn. Lea and Febiger, Philadelphia, pp. 261- 181. Kerwin, R.W., Patel, S., Meldrum, B.S., Czadek, C. and Reynolds, G.P. (1988) Asymmetrical loss of glutamate receptor subtype in left hippocampus in schizophrenia. Lancet I, 583-584. Kim, J.S., Komhuber, H.H., Schmid-Burgk, W. and Holtxmuller, B. (1980) Low cerebrospinal fluid gummate in schizophrenic patients and a new hypothesis of schizophrenia. Neurosci Lett 20, 379-382. Kish, S.J., Dixon, L.M. and Sherwin, A.L. (1988) Aspartic acid amino transferase activity is increased in actively spiking compared with non-spiking human epileptic focus. J Newel Neurosurg Psychiatry 51, 552-556. Korpi, E.R., Kleinman, J.E., Goodman, S.I. and Wyatt, R.J. (1987) Neurotransmitter amino acids in post-mortem brains of chronic schizophrenic patients. Psychiatry Res 22, 291-301.
Krueger, R.B., Fama, J.M., Devanand, D.P., Prudic, J. and Sackeim, H.A. (1993) Does ECT permanently alter seizure threshold? Biol Psychiatry 33, 272-276. Loscher, W. and Cxuczwar, S.J. (1986) Studies on the involvement of dopamine D-l and D-2 receptors in the anticonvulsant effect of dopamine agonists in various rodent models of epilepsy. Eur J Pharmacol 128, 55-65. Lothman, E.W., Bennett, J.P. and Perlin, J.B. (1986) Dynamic interactions of brain neurotransmitter amino acids during liibic seixures. In: Nistico, G., Moreselli, P.L., Lloyd, K.G., Fariello, R.G. and Engle, J., Jr. (Eds.), Nemotransmitters. Seizures and Epilepsy III. Raven Press, New York, pp. 349-419. Lucas, P.B., Pickar, D., Kelsoe, J., Rapaport, M., Pato, C. and
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Hommer, D. (1990) Effects of acute administration of caffeine in patients with schizophrenia. Biol Psychiatry 28, 35-40.
Meldrum, B.S. and Chapman, A.G. (1986) Excitatory amino acid antagonists as anticonvulsant agents: receptor subtype involvement in different scixure models. In: Nistico, G., Moreselli, P.L., Lloyd, K.G., Fariello, R.G. and Engle, J., Jr. (Eds.), Nemotransmitters. Seizures and Epilepsy III. Raven Press, New York, pp. 223-232. Miller, A.L., Faber, R.A., Hutch, J.P. and Alexander, H.E. (1985) Factors affecting amnesia, seixure duration and efficacy of ECT. Am J Psychiatry 142, 692-696. Mody, I. and Heinemann, U. (1987) NMDA receptors of dentate gyrus granule cells participate in synaptic transmission following kindling. Nature 326, 701-704. Murray, T.F., Sylvester, D., Schulz, C.S. and Szot, P. (1985) Purinergic modulation of the seizure threshold for pentylenetetraxol. Neuropharmacology 24, 761-766. Murray, T.F. and Szot, P. (1986) A, adenosine receptor mediated modulation of seixure susceptibility. In: Nistico, G., Moreselli, P.L., Lloyd, K.G., Fariello, R.G. and Engle, J., Jr. @Is.), Neurotransmitters, Seizures and Epilepsy III. Raven Press, New York, pp. 341-353. Nishikawa, T., Takashima, M. and Tom, M. (1983) Increased [3H] kainic acid binding in the prefrontal cortex in schizophrenia. Neurosci Lett 40, 245-250. O’Brien, D.R. (1988) The adenosine hypothesis of epilepsy. Med Hypotheses 27, 28 l-284.
Perry, P.J., Alexander, B. and Liskow, B. (1991) Psychotropic Drug Hanabook. 6th edn. Perry, T.L., Kish, S.G., Buchannan, J. and Hansen, S. (1979) Gamma-aminobutyric acid deficiency in brains of schixophrenic patients. Lancer I, 237-239. Peters, S.G., Wochos, D.N. and Peterson, G.C. (1984) Status epilepticus as a complication of concurrent electroconvulsive and theophylline therapy. Mayo Chin Proc 59, 568-570.
Phillis, J.W. and Wu, P.H. (1981) The role of adenosine and its nucleotides in central synaptic transmission. Prog Neurobiol 16, 187-239. Rosenthal, F., Macey, R. and Timirus. P.S. (1962) Stimulus intensity and duration of electroshock response. Exp Neural 5, 292-301. Sackeim, H.A., Decina, P., Portnoy, S., Neely, P. and Malitz, S. (1987) Studies of dosage, seizure threshold and seizure duration in ECT. Biol Psychiatry 22, 249-268. Sackeim, H.A., Devanand, D.P. and Prudic, J. (1991) Stimulus intensity, seizure threshold and seizure duration impact on the efficacy and safety of electroconvulsive therapy. Psychiatr Chin North Am 14, 803-843.
Schultz, V. and Lowenstein, J.M. (1978) The purine nucleotide cycle. J Biol Chem 253, 1938-1943. Sherman, A.D., Davidson, A.T., Baruah, S., Hegwood, T. and Waxiri, R. (1991a) Evidence of ghnamatergic deficiency in schizophrenia. Neurosci L.ett121, 77-80. Sherman, A.D., Hegwood, T.S., Baruah, S. and Waxiri, R. (1991b) Deficient NMDA-mediated glutamate release from
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synaptosomes of schizophrenics. Biol Psychiatry 30, 1191-1198. Sherwin, A., Robitaille, Y., Quesney, F., Oliver A., Villemure, J., Leblanc, R., Feindel, W., Andermann, E., Gotman, J., Anderman, F., Etheir, E. and Klsh, S. (1988) Excitatory amino acids are elevated in human epileptic cerebral cortex. Neurology 38, 920-923. Simpson, M.D.C., Slater, P., De.akin, J.F., Roysten, M.C. and Skan, W.J. (1989) Reduced GABA uptake sites in temporal lobes in schizophrenia. Neurosci Lett 107, 211-215. Small, J.G., Milstein, V., Klapper, hi., Kellams, J.J. and Small, I.F. (1982) ECT combined with neuroleptics in the treatment of schizophrenia. Psychopharmacol Bull 18, 34-35. Tomasson, K., Winokur, G. and pfohl, B. (1992) Failed and short seizures associated with prior electroconvulsive therapy. Eur Arch Psychiatry Clin Neurosci 241, 307-313. Waziri, R., Baruah, S., Hegwood, T.S. and Sherman, A.D. (1990) Abnormal serine hydroxymethyltransferase activity in the temporal lobes of schizophrenics. Neurosci Lett 120, 237-240.
Waziri, R., Bamah, S. and Shennan, A.D. (1992) Abnormal serine-glycine metabolism in the brains of schizophrenics. Schizophr Res 8, 233-243.
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Waziri, R. and Mott, J. (1986) Drug effects on serine metabolism in psychiatric patients. Psychiatry Res 18, 119-126. Waziri, R. and Mott, J. (1987) A biochemical basis for psychotic symptoms in patients with brain dysfunction. Eur Arch Psychiatry Clin Neurosci 236, 251-255.
Waziri, R., Mott, J. and Wilcox, J. (1985) Differentiation of psychotic from non-psychotic depression by a biological marker. .J AIfect Disord 9, 175-180. Waziri, R., Wilson, R. and Sherman, A.D. (1983) Serine to cysteine ratio as a biological marker in psychosis. Br J Psychiatry 143, 69-73.
Waziri, R., Wilson, R., Sherman, A.D. and Mott, J. (1984) Serine metabolism and psychosis. Psychiatry Res 12, 121-136.
Whitcomb, K., Lupica, CR., Rosen, J.B. and Berman, R.F. (1990) Adenosine involvement in post-ictal events in amygdala kindled rats. Epilepsy Res 6, 171-179. Winn, H.R., Welsh, J.E., Bryner, C., Rubio, R. and Beme, R.M. (1979) Brain adenosine production during the initial 60 s of bicucullin seizures in rats. Acta Neural Stand 72(Suppl.), 536-537.
Wood, J.D. (1975) The role of y-aminobutyric acid in the mechanisms of seizures. Prog Neurobiol 17, l-36.
Psychosis and vulnerability to ECT-induced seizures Rafiq Waziri *, Sankar Baruah, Stephan Arndt, Karen Baumert, Jon Cooney, Laura Christensen Psychiatry Research-MEB,
University of Iowa, Iowa City, IA 52242-1000, USA
Received 3 January 1995; revised 23 August 1995; accepted 8 December 1995
Abstract
Medical records of patients with major depressive disorders who had received electroconvulsive therapy (ECT) for the first time were studied to test the hypothesis that psychotic patients are more vulnerable to seizures than nonpsychotic patients. This hypothesis was based on studies suggesting a putative purinergic deficiency in psychosis. Results showed that the duration of.ECT-induced seizures as a measure of seizure vulnerability was significantly longer in psychotic than in nonpsychotic depressive patients. The association applied for the first ECT as well as for the course of eight ECTs. These findings were still present when covariates such as age, electrical energy applied, dosage of methohexital and succinylcholine, and psychotropic medications such as neuroleptics, benzodiazepines, and tricyclics were included in the statistical analysis. The results are discussed in the context of the role of neurotransmitters such as glutamate, y-aminobutyric acid, adenosine, and dopamine on seizure vulnerability and psychosis. Keywords: Electroconvulsive therapy, seizure duration; Affective disorder; Purines; Psychotic depression
1. Introduction
The application of electrical charge during electroconvulsive therapy (ECT) results in the longenduring synchronous depolarization of a large ensemble of neurons. These neurons activate adjacent and surrounding neurons as well as neurons that are one or two synapses distant from the site, resulting in a generalized seizure. Seizure vulnerability as measured by seizure duration and seizure threshold is affected by a multiplicity of factors such as age, gender, and use of medications. Also, there are the imposed factors that l Corresponding author, Tel: +1 319 3534444; Fax: +I 319 353-3003.
occur during treatment such as stimulus strength, doses of anesthetics and muscle relaxants, hyperventilation, and electrode placement. In addition, there are factors that are inherent in the brain. Paramount among these factors are the inhibitory neurotransmitter y-aminobutyric acid (GABA) (Wood, 1975; Lothman et al., 1986) and excitatory neurotransmitters such as aspartate and glutamate (Czuczwar et al., 1986; Engelson, 1986; Lothman et al., 1986; Meldrum and Chapman, 1986; Mody and Heinemann, 1987; Kish et al., 1988; Sherwin et al., 1988; Heinemann and Jones, 1991). Adenosine is another neurotransmitterneuromodulator that prevents the spread of seizures and helps in their termination (Whitcomb et al., 1990). The role of adenosine and other purines
0165-1781/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SOl65-1781(96)02775-S
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in the brain is mainly to reduce the response of neurons to excitatory input. They also decrease the release of neurotransmitters in general (Phillis and Wu, 1981). Adenosine analogues at the A, adenosine receptor can raise the seizure threshold (Murray et al., 1985; Murray and Szot, 1986) and can act as anticonvulsants (Dunwiddie and Worth, 1984; O’Brien, 1988). Because adenosine and other purine levels increase in the brain during and after the onset of seizures (Schultz and Lowenstein, 1978; Winn et al., 1979) and because adenosine and its analogues increase seizure threshold and decrease the spread and duration of seizures in animals, the hypothesis that adenosine may be an ‘endogenous anticonvulsant’ has been put forward (Dragenow et al., 1985; O’Brien, 1988; Eldridge et al., 1989). This hypothesis is strengthened by the finding that adenosine antagonists such as caffeine and theophylline have proconvulsive effects in humans (Peters et al., 1984; Hinkel et al., 1987; Coffey et al., 1990) and in animals (Murray and Szot, 1986). The synthesis of purines is largely dependent on the availability of l-carbon units provided by the interconversion of serine and glycine via the enzyme serine hydroxymethyltransferase (SHMT) (Henderson, 1972; Caperelli et al., 1980; Appling, 1991). Results of several studies on plasma and brains of patients and controls indicate that the activity of SHMT, which is important in the production of purines, is diminished in patients with psychosis (Waziri et al., 1983, 1984, 1985, 1989, 1990, 1992; Waziri and Mott, 1986, 1987). Pertinent to this study, the activity of SHMT is diminished in psychotic compared with nonpsychotic depressive patients (Waziri et al., 1985). Although direct measurements of adenosine in brains of psychotic patients in association with diminished activity of SHMT are not available, it is theoretically possible that psychotic patients could be deficient in brain adenosine and other purines. On the basis of these observations, we hypothesized that psychotic depressive patients receiving ECT would be more vulnerable to seizures than their nonpsychotic counterparts.
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2. Methods Charts of inpatients with the diagnosis of major depressive disorder with and without psychotic symptoms who had received a first course of ECT were reviewed. Diagnoses had been made according to DSM-III, DSM-III-R, and DSM-IV criteria (American Psychiatric Association, 1980, 1987, 1994) by the faculty of the University of Iowa Department of Psychiatry and were recorded in admission evaluations and discharge summaries. Admission history and mental status examinations had been obtained by medical students and psychiatric residents and evaluated by faculty before the patient’s interview by faculty-staff members. On the basis of history and mental status examination, presence or absence of psychosis had been determined. Psychotic symptoms had been described as mood-congruent and mood-incongruent delusions and believed hallucinations. The patients had been admitted between the years of 1984 and 1995. We selected only those patients who had received a course of ECT for the first time to avoid the controversy about whether previous ECTs permanently change subsequent responses to ECTs (Tomasson et al., 1992; Krueger et al., 1993). Excluded from data analysis were patients with organic brain syndromes, IQ scores below 75, Mini-Mental Status Examination scores below 24, abnormal electroencephalograms (EEGs), and treatment with theophylline or anticonvulsants such as diphenylhydantoin, carbamazepine, valproate, and clonazepam in the week before ECT. In our facility, it had been the general practice to withdraw patients from psychotropic medications as soon as a decision was made to give them ECT. After such a decision, a period of 24-72 h usually elapsed before treatments began. Short-acting benzodiazepines were infrequently given, mostly to psychotic patients for agitation only on a PRN basis, but rarely on the night before the treatments. Patients who had received caffeine for enhancement of seizures were not included. Also excluded were those who had been treated with benzodiazepines, tricyclic antidepressants, neuroleptics, and lithium in the 12
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h before ECT. The dosages of various benzodiazepines and neuroleptics that were administered during the week before ECT were recorded as diazepam (Perry et al., 1991) or chlorpromazine (Davis, 1974; Baldessarini et al., 1984) equivalents (where the last digits were rounded off to the nearest 5 or 0). Dosages of tricyclics were considered equivalent to imipramine, except for nortriptyline dosage, which was multiplied by a factor of 1.5. Treatments with nontricyclic antidepressants (fluoxetine, sertraline, paroxetine, trazodone, and bupropion) were too few and various to be included in data analysis. The total of 112 patients included in the study had received bilateral ECTs only. Conventional ECT procedures had been followed in all patients. After an overnight fast, 0.4 mg of atropine or 0.2 mg of glycopyrrolate was given subcutaneously just before treatment. Methohexital as the anesthetic and succinylcholine as the muscle relaxant were administered at doses approximately determined by the weight of the patient. Before, during, and sometimes after seizures, patients were ventilated with 100% OZ. The ECT instruments were MECTA Model D and Model SR-1 (MECTA Corporation, Lake Oswego, OR, USA) which were set to deliver a 2-s stimulus of 0.8 A, and pulses of 1S-1 6 ms duration at a frequency of 40-80 Hz. The energy delivered across the poles had been recorded as joules. Millicoulombs could not be calculated from records before 1986 because not all ECT parameters had been recorded in the charts. EEG seizure duration had been obtained with the fronto-mastoid lead and recorded in the strip of the MECTA instrument. The data from the strip were copied into the record by the resident physician who was rotating through the ECT service. We used the recorded seizure duration obtained from the EEG trace for data analysis because some of the records lacked the observed seizure duration and because the EEG provides a more objective measure of seizure duration. If at the first stimulus the patient had not seized, the value recorded for seizure duration was 0 s, which was included as such in the analysis. There was no information as to why a particular stimulus inten-
193
sity had been chosen for a particular patient. Repeated attempts in the same session at higher energy levels (at increments of 10 Hz), which produced seizures of various durations, were not included in the data analysis. Of the two measures of vulnerability, we had data only on seizure duration. Patients had not undergone procedures to establish seizure threshold (Sackeim et al., 1987). Information on several variables that influence seizure duration was available from the records. Among these were age (Abrams, 1988), dosage of methohexital and succinylcholine (Miller et al., 1985), and electrical energy (Rosenthal et al., 1962). Variables such as oxygenation (Holmberg et al., 1956) and electrode placement (Abrams, 1988) were considered to be similar and their differences randomly distributed in the two groups of patients. Anesthesiologists had administered the oxygen and had followed routines that may have varied on the basis of their preferences and patient characteristics. There was no information recorded about the volume of oxygen delivered during the procedure. However, all patients had been given enough oxygen to achieve >95% saturation as measured by pulse oximetry. 2.1. Statistics The association between the number of psychotic and nonpsychotic subjects who did and did not receive each of the four classes of medications before ECT was evaluated by x2 test. Student’s t tests and analysis of covariance (ANCOVA) were used to test the hypothesis that the seizure vulnerability of depressed patients with psychosis is different from that in those without psychosis. Thus, seizure duration (s) was used as the dependent variable. The main effects tested were diagnosis and gender, with age (years), energy (joules), methohexital dose/weight (mg/kg), and succinylcholine dose/weight (mg/kg) as covariates. After significant x2 test probabilities were obtained for neuroleptic and lithium treatment, these two medications at any dose were also included as covariates. Although benzodiazepine treatment did not yield a significant x2 test, it was included as a covariate to control for the fact that
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withdrawal from these medications may result in prolonged seizure durations. Although the means of none of the continuous variables were significantly different between the two diagnostic groups (Table l), each variable was considered to have an effect on seizure duration. To account for these effects, the above-mentioned variables were included in the analysis. The two-way interaction tested was gender x diagnosis, neuroleptic treatment x diagnosis, and energy x diagnosis. The adjusted mean seizure duration thus obtained from the ANCOVA was termed ‘predicted seizure duration’. 3. Results Comparison of variables such as age, dosages of methohexital, succinylcholine, and intensity of electrical stimulation showed no significant differences between the psychotic and nonpsychotic groups either in the first ECT session or throughout the course of ECT (Tables 1 and 2). However, seizure duration in the psychotic group was significantly longer during the first ECT than seizure duration in the nonpsychotic patients when males and females were combined (P < O.OOOl). For the first ECT, when males and females were analyzed separately, seizure duration was again significantly different (P < 0.005) between psychotic and nonpsychotic patients (Table 1). Seizure duration was also significantly longer in psychotic patients in the sum total of ECTs when
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males and females were combined (P < 0.0002) (Table 2). Whereas psychotic females were not significantly different (P < 0.059) from nonpsychotic females, psychotic males had significantly longer seizure durations (P < 0.0014) than nonpsychotic males (Table 2). Seizure duration did not differ significantly between males and females in either the psychotic or the nonpsychotic group. 3.1. Results of ANCO VA The overall statistical model (ANCOVA) testing all of the main effects of age, energy, anesthetic, muscle relaxant, neuroleptics, benzodiazepines, and lithium and the relevant interaction simultaneously was significant (F = 3.66, df = 12,99, P c 0.0001) for the first ECT. For the individual factors, only diagnosis (F = 17.73, df = 1,99, P < O.OOOl),age (F= 10.67, df = 1,99, P < 0.0015) and methohexital dose/weight (F = 6.86, df = 1,W, P < 0.0102) were significant. All other terms in the model, including gender x diagnosis, neuroleptics x diagnosis and energy x diagnosis interactions, were not statistically significant (P > 0.1).
Controlling for the effects of all the covariates, we obtained a ‘predicted seizure duration’ value that was significantly longer in psychotic depressive patients during the first ECT (Fig. 1). However, the adjusted means of seizure duration for the sum total of eight ECTs (Fig. 2) were significantly longer in male but not in female psychotic patients compared with nonpsychotic
Table 1 Raw means (SDS) of variables used in analysis of the first ECT session Gender
n
Age
Succinylcholine (weight, mgflrg)
Methohexital (weight, m&g)
Energy (i)
Seiire (s)
duration
32 25 57
45.5 (14.4) 48.0 (19.6) 46.6 (16.8)
0.79 (0.22) 0.89 (0.27) 0.84 (0.24)
1.33 (0.41) 1.45 (0.31) 1.39 (0.37)
34.7 (9.2) 29.1 (8.9) 32.23 (9.43)
54.6 (24.1) 57.4 (36.2) 55.8 (29.7)
27 28 55
49.3 (16.6) 42.3 (18.6) 45.7 (17.8)
0.76 (0.17) 0.77 (0.16) 0.76 (0.16)
1.49 (0.43) 1.37 (0.38) 1.43 (0.41)
32.3 (8.5) 27.2 (9.5) 29.7 (9.3)
89.1 (49. I)* 84.4 (34.2)* 86.7 (42.2)**
Nonpsychotic patients
Females Males Combined Psychotic patients
Females Males Combined l
= P c 0,005 and l * = P c 0.0001 by t test, comparison of nonpsychotic patients vs. psychotic patients for respective genders.
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195
Table 2 Raw means (SDS) of sums of variables during a course of 8 ECf sessions Gender
II
Age
Succinylcholine (weight, m&g)
MethohexitaJ (weight, mgfltg)
Energy (i)
Seizure duration (s)
32 25 57
45.5 (14.4) 48.0 (19.6) 46.6 (16.8)
5.93 (1.92) 7.41 (2.46) 6.58 (2.28)
10.16 (2.90) 11.18 (3.33) 10.61 (3.11)
241.4 (87.7) 217.0 (60.0) 234.0 (77.6)
337.2 (120.8) 343.5 (144.5) 340.0 (130.6)
27 28
49.3 (16.6) 42.3 (18.6)
5.65 (1.52) 7.01 (1.51)
11.11 (4.54)
233.3 (87.0)
409.0 (172.7)
Males
Combined
55
45.7 (17.8)
6.34 (1.65)
11.28 (3.17) 11.20 (3.87)
220.8 (71.1) 227.0 (78.8)
484.3 (174.3)* 447.3 (176.0)**
Nonpsychotic patients
Females Males Combined Psychotic patients
Females
* = P < 0.002 and l * = P < 0.0002 by t test, comparison of nonpsychotic patients vs. psychotic patients for respective genders.
and female patients, respectively. This apparent gender difference (although not a significant effect in the ANCOVA) is also evident in Fig. 3, which depicts the changes in the ‘predicted seizure duration’ through the course of eight ECTs. In general, these findings tend to validate the hypothesis of increased seizure vulnerability in psychotic depressive patients.
male
3.2. Effect of prior medications on seizure duration A significant effect (P < 0.05) for neuroleptic and lithium was demonstrated by x2 tests, based on a 2 x 2 contingency table for number of psychotic and nonpsychotic subjects who did and
did not receive various medications in the weeks before ECT. As shown in Table 3, very few nonpsychotic patients received neuroleptics whereas the numbers of psychotic patients who did and did not receive neuroleptics are quite comparable. However, the mean seizure durations of psychotic patients who did and did not receive neuroleptics are almost identical. The fact that neuroleptics did not affect seizure duration was confirmed by ANCOVA (F = 0.50, df = 1,99, P < 0.48) and there was no significant neuroleptic x diagnosis interaction effect. There was also no correlation between the dose of neuroleptics and seizure duration in the psychotic population: r = 0.105, P < 0.62, n = 25.
600
0
M&S
Females s
Fig. 1. Seiire durations (mean f SD) for the Jst ECT as predicted from analysis of covariance.
Non psychotics
m
Psychotics
* p
Fig. 2. Sum of seizure durations (mean * SD) during a course of 8 ECTs as predicted from analysis of covariance.
1%
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Males and Females Combined +-Nonpsychotics -~-Psychotics * peo.05
* &
5
I
1
3
4
30 I
2
5
8
I
6
Males Only +Nonpsychotia +F’sychotics
I
p < 0.05
*
2
3
4
5
6
I
8
Females 110 3
* +Nonpsychotm
loo-
UPsychotia
.zt
90.
*
E
p < 0.05
‘Z 805
70.
t ‘$’
60.
z
*O-
.%
40 _
% 30 1
2
3
4
5
6
7
a
ECT Fig. 3. Changes in seizure durations during a course of ECT. Values shown are means and standard deviations as predicted from analysis of covariance.
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Table 3 Medications taken (during week before ECT) and seizure durations (of first ECT)
Nonpsychotic patients n ke Seiire
Ow)
duration (s)
Psychotic patients n Do= (ms)
!Seii
duration (s)
Neuroleptics
Benzodiazepines
Tricyclics
Yes
No
Yes
No
Yes
No
Yes
No
8 916 (1660) 63.1 (35.9)
49+ 0
27
30 0
32 519 (350) 62.3 (24.7)
25 0
16 2413 (1491) 55.6 (20.2)
41* 0
25 837 (818) 87.1 (42.8)
30* 0
25 356 (301) 92.5 (43.8)
30 0
:57) 46.9 (23.1)
86.4
22 ff6) 89.8 (43.3)
63.8++ (33.0)
33 0 84.7 (40.7)
Lithium
47.6 (33.9)
81.9 (41.5)
7 3086 (1517) 93.1 (42.9)
55.9 (33.0)
48* 0 85.8 (44.3)
Note. Values shown are raw means (SDS); l = P c 0.05 by x2 for proportion of psychotic patients to nonpsychotic patients; *+ = P
C 0.05 by t test comparing nonpsychotic yes to no.
Similarly in the case of lithium, there was no significant difference in the mean seizure duration of those who did and did not receive lithium treatment in either the psychotic or nonpsychotic group. The ANCOVA was also nonsignificant (F = 0.04, df = 1,99, P < 0.85). Effects of benzodiazepine treatment were different. As shown in Table 3, there was no difference in the use of this class of drugs between the two groups as confirmed by a x2 value of P < 0.432. Since withdrawal from benzodiazepines may result in prolonged seizures, a comparison of seizure duration between those who did and did not receive benzodiazepines in each group was made. Interestingly, the seizure duration of nonpsychotic patients who received benzodiazepines was significantly shorter than that of those who did not. There was no difference in seizure duration between those who did and did not receive benzodiazepines in the psychotic group. The ANCOVA was also nonsignificant (F= 0.03, df = 1,99, P < 0.86) and there was no benzodiazepines x diagnosis interaction effect. Thus, the use of or withdrawal from benzodiazepines did not have a confounding effect on the observed difference of seizure duration between psychotic patients and nonpsychotic patients.
3.3. Relationship between stimulus energy seizure duration
and
As mentioned earlier, stimulus energy supplied did not differ significantly in the two groups. However, there did appear to be a different trend in the relationship between energy applied and seizure duration in the two groups. Pearson’s correlation coeffkient between these two variables in the nonpsychotic patients was r = -0.142 (P < 0.294, n = 57) whereas in the psychotic group it was r = 0.251 (P < 0.064, n = 55). This difference in correlations, however, did not emerge as a significant effect in an energy x diagnosis interaction in the ANCOVA (F = 2.56, df = 1,99, P < 0.11). 4. Discussion
Both seizure duration and ‘predicted seizure duration’ clearly distinguished between psychotic and nonpsychotic depressive patients of both genders in the first ECT. When ‘predicted seizure duration’ was calculated cumulatively during the course of ECTs, only the males showed a significant difference between psychotic patients and nonpsychotic patients. It must be pointed out, however, that neither gender nor the gender x diagnosis interaction was significant in the AN-
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COVA. A lack of gender effects on seizure duration and seizure threshold has been previously reported, at least for the first ECT (Sackeim et al., 1987; Coffey et al., 1995). The statistical model that incorporates the effects of various medications - particularly neuroleptics, which were more commonly given to psychotic patients - did not show any significant effects on seizure duration. Although a major shortcoming of this study is the lack of information about seizure threshold as a measure of vulnerability, nevertheless, the ECT-induced seizure duration as a measure of vulnerability robustly differentiated between psychotic and nonpsychotic depressive patients. The brain mechanisms underlying these differences remain unclear. The basis for our hypothesis was the observation from many studies of reduced activity of the enzyme SHMT in plasma and brains of psychotic patients. SHMT is of crucial importance in providing l-carbon units required for the synthesis of purines and thereby adenosine, which has anticonvulsant effects. However, because there is no direct evidence for decreased levels of adenosine in brains of psychotic subjects and because vulnerability to seizures may involve the interplay of several neurotransmitters-neuromodulators, as well as structural abnormalities in the brain, these other variables could contribute to the observed differences between psychotic and nonpsychotic patients. Also it is possible that some unknown variable such as medications may have contributed to the observed differences. Potentially, treatment occasionally received by with neuroleptics, psychotic patients, could have been a variable contributing to this difference. However, psychotic patients who had received neuroleptics up to 12 h before ECT did not have significantly longer seizure durations than those who had not. Despite some suggestive findings (Sackeim et al., 1991), evidence for proconvulsant effects of these drugs remains equivocal. One study that compared thiothixene with placebo showed that thiothixene reduced seizure duration, on average, from 43 to 37 s (Small et al., 1982). Another study that examined seizure duration cumulatively over the course of ECT, while patients were being treated with various neuroleptics, also found that seizure duration was shortened by neuroleptics
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(Tomasson et al., 1992). There is even a report of some neuroleptics (thioridazine and pimozide) having anticonvulsant effects (Kamal et al., 1986). Glutamate and GABA, which have potent effects on seizures, have also been implicated in the etiology of psychosis. A decrease in glutamatergic neurotransmission has been hypothesized as an etiological basis for schizophrenic psychosis (Kim et al., 1980; Deutch et al., 1989). A number of studies on autopsied brains have supported this hypothesis (Nishikawa et al., 1983; Kerwin et al., 1988; Deakin et al., 1989; Sherman et al., 1991a, 1991b). Diminished GABAergic neurotransmission has also been considered as an etiological factor in schizophrenic psychosis. Studies on brain samples suggest the hypothesis of GABAergic deficiency in schizophrenic psychosis (Perry et al., 1979; Korpi et al., 1987; Simpson et al., 1989; Sherman et al., 1991a, 1991b). The hyperdopaminergic hypothesis of psychosis, which is supported by considerable clinical and indirect evidence, is widely accepted. While some studies on dopaminergic transmission have not found a significant role for this agent in epilepsy (Burly and Ferrendelli, 1984), other studies suggest that dopamine has anticonvulsant properties (Anlezark et al., 1981; Jobe and Laird, 1981; Loscher and Czuczwar, 1986). It appears that the anticonvulsant effects of dopamine are mediated via Dz receptors (Loscher and Czuczwar, 1986). Of the findings on these neurotransmitters, the paucity of GABAergic and purinergic neurotransmission in psychosis would explain the greater vulnerability of psychotic subjects to electrically induced seizures. Glutamatergic deficiency would theoretically reduce the excitatory drive for the activation of neurons and thereby reduce the vulnerability to seizures in psychotic patients, whereas excessive dopaminergic neurotransmission would reduce seizure vulnerability. Pharmacological and biochemical studies in animal brains provide evidence for a role of adenosine in seizures, and possibly in psychosis (Duncan and Morgan, 1990). In humans there is clinical and pharmacological evidence that large intake of adenosine antagonists, such as caffeine and theophylline, increases seizure susceptibility. These agents also increase psychotic symptoms (Lucas et al., 1990). In animals there is
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evidence that adenosine agonists for A2 receptors demonstrate a pharmacological profile quite similar to antipsychotic drugs (Heffner et al., 1989). These observations suggest that decreased adenosine may play a role in the genesis of both epilepsy and psychosis. Studies investigating the seizure proneness of psychotic populations, although few in number, tend to suggest a positive relationship between psychosis and epilepsy (Hill, 1957; Betts, 1981). The findings reported here provide support for a positive association between vulnerability to psychosis and vulnerability to seizures. There is an intriguing possibility that decreased adenosinergic input at the At receptor would increase vulnerability to seizures, while decreased input at the A2 receptor would increase vulnerability to psychosis. Whether this association is based on deficiencies either in adenosinergic neurotransmission-neuromodulation, GABAergic mechanisms, or both is unknown. Other brain mechanisms such as structural abnormalities observed in psychotic patients may also contribute to the observed differences in vulnerability between psychotic patients and nonpsychotic patients. Future studies should determine seizure threshold as well as seizure duration in assessing vulnerability in these patients. Studies on factors that make psychotic patients vulnerable to seizures would be important for the understanding of the etiology and the treatment of psychotic and epileptic disorders. Acknowledgments
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