Context Electroconvulsive therapy (ECT) is highly effective for treatment of
major depression, but naturalistic studies show a high rate of relapse after
discontinuation of ECT.
Objective To determine the efficacy of continuation pharmacotherapy with nortriptyline
hydrochloride or combination nortriptyline and lithium carbonate in preventing
post-ECT relapse.
Design Randomized, double-blind, placebo-controlled trial conducted from 1993
to 1998, stratified by medication resistance or presence of psychotic depression
in the index episode.
Setting Two university-based hospitals and 1 private psychiatric hospital.
Patients Of 290 patients with unipolar major depression recruited through clinical
referral who completed an open ECT treatment phase, 159 patients met remitter
criteria; 84 remitting patients were eligible and agreed to participate in
the continuation study.
Interventions Patients were randomly assigned to receive continuation treatment for
24 weeks with placebo (n = 29), nortriptyline (target steady-state level,
75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state
level, 0.5-0.9 mEq/L) (n = 28).
Main Outcome Measure Relapse of major depressive episode, compared among the 3 continuation
groups.
Results Nortriptyline-lithium combination therapy had a marked advantage in
time to relapse, superior to both placebo and nortriptyline alone. Over the
24-week trial, the relapse rate for placebo was 84% (95% confidence interval
[CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium,
39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium
occurred within 5 weeks of ECT termination, while relapse continued throughout
treatment with placebo or nortriptyline alone. Medication-resistant patients,
female patients, and those with more severe depressive symptoms following
ECT had more rapid relapse.
Conclusions Our study indicates that without active treatment, virtually all remitted
patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline
has limited efficacy. The combination of nortriptyline and lithium is more
effective, but the relapse rate is still high, particularly during the first
month of continuation therapy.
Electroconvulsive therapy (ECT) is usually administered to patients
with severe and medication-resistant major depression.1
The number of ECT procedures performed in the United States exceeds coronary
bypass, appendectomy, or hernia repair.2 While
the response rate to ECT in major depression is high,1,3
relapse is a key problem.4 Naturalistic studies
show that the relapse rate during the 6 to 12 months following ECT exceeds
50%.5-15
Electroconvulsive therapy is the only somatic treatment in psychiatry
that is typically discontinued following response, yet patients untreated
following ECT response have high rates of relapse.16-19
Studies in the 1960s suggested that continuation therapy with a tricyclic
antidepressant (TCA) or monoamine oxidase inhibitor markedly reduced the 6-month
post-ECT relapse rate.16-18
Post-ECT monotherapy with antidepressant medication is now standard.9,20-23
However, the evidence supporting this practice is flawed, and the recent naturalistic
studies document high relapse rates.
Post-ECT continuation pharmacotherapy has been based on 3 studies conducted
in the 1960s.16-18
A primary goal of those studies was to determine whether concurrent treatment
with TCAs or monoamine oxidase inhibitors reduced the number of ECT treatments
needed. Following ECT, patients continued taking active medication or placebo
or no subsequent treatment. Using 6-month follow-up periods, the findings
were consistent. Patients who received a TCA or monoamine oxidase inhibitor
during and following ECT had a relapse rate of approximately 20%, compared
with 50% in the control groups. There are major concerns about this research.4,24 At that time, ECT was a treatment
of first choice.25,26 Relevance
for continuation therapy in medication-resistant ECT responders is uncertain.
Second, some patients likely benefited from the concurrent antidepressant
during ECT, and continued to benefit from the medication as continuation therapy.
Since use of ECT now centers on medication-resistant patients,1,21,27
the relevance of this early research is questionable.
We conducted a randomized, double-blind, placebo-controlled trial of
continuation pharmacotherapy following ECT response. The treatments were a
TCA (nortriptyline hydrochloride), combination treatment with nortriptyline
and lithium carbonate, or placebo. A placebo-controlled trial following ECT
had never been conducted in the United States. This trial was justified since
the relapse rates in recent follow-up studies5-15
often exceeded those seen with placebo in the controlled investigations from
an earlier era.16-18
A placebo-controlled trial was also justified by our hypothesis that TCA monotherapy,
the best documented treatment in post-ECT relapse prevention,16-18
has limited efficacy. Monotherapy with nortriptyline was tested since (1)
early research suggested that TCA continuation therapy was effective in relapse
prevention16-18;
(2) concern that newer agents, such as selective serotonin reuptake inhibitors
(SSRIs), may be less effective than TCAs in treatment of the severe episodes
characteristic of ECT patients28-33;
and (3) given the widespread use of SSRIs and other newer agents as first-line
treatments, a low probability that ECT responders would have received an adequate
TCA trial during the episode.34 We hypothesized,
however, that the nortriptyline-lithium combination would be most efficacious,
given the evidence that combined TCA-lithium treatment is particularly effective
in medication-resistant major depression,35-41
and the supposition that regimens effective in the acute treatment of medication-resistant
major depression exert protective effects as continuation treatment. Nortriptyline-lithium
was also selected since few ECT remitters would have received this treatment
during the episode.34,42
Study Site and Study Participation
The study was conducted at the Carrier Foundation (Belle Meade, NJ),
a private psychiatric hospital, and at university-based psychiatric facilities
of the University of Iowa (Iowa City) and Western Psychiatric Institute and
Clinic (WPIC; Pittsburgh, Pa). The New York State Psychiatric Institute (NYSPI;
New York) was the coordinating and monitoring center. Using the Schedule for Affective Disorders and Schizophrenia,43
patients met the research diagnostic criteria44
for major depressive disorder. They had a pretreatment score of 21 or higher
on the Hamilton Rating Scale for Depression (HRSD; 24-item scale).45 Patients were excluded if they had a history of bipolar
disorder, schizophrenia, schizoaffective disorder, nonmood disorder psychosis,
neurological illness, alcohol or drug abuse within the past year, ECT within
the past 6 months, or severe medical illness that markedly increased the risks
of ECT (eg, unstable or severe cardiovascular conditions, aneurysm or vascular
malformation susceptible to rupture, severe chronic obstructive pulmonary
disease).
Participants were recruited from those clinically referred for ECT.
Over a 6-year period (1993-1998), 349 patients consented and participated
in the pre-ECT screening (Figure 1).
Patients who met inclusion/exclusion criteria for the open ECT phase were
completers if they received at least 5 treatments or ended ECT earlier due
to response and did not receive any psychotropic medication during the ECT
course other than lorazepam (≤3 mg/d). Of the 59 patients who did not contribute
to ECT outcome data, 17 patients were dropped before ECT due to diagnostic
exclusions; 14 patients could not be withdrawn from psychotropics before (n
= 7) or during (n = 7) ECT; 12 patients terminated ECT against medical advice
prior to the fifth treatment; 9 developed an intercurrent illness so ECT was
not initiated (n = 2) or was interrupted (n = 7) (all before the fifth treatment);
6 patients withdrew consent before ECT; and 1 dropped below the inclusion
threshold (HRSD score of 21) before starting ECT. Only 2 of 59 dropouts (prohibited
medications) should have contributed to ECT efficacy analyses, but end point
evaluations were not obtained.
To enter the continuation trial, patients had to achieve at least a
60% reduction in HRSD scores relative to pre-ECT baseline, with a maximum
score of 10 both at an assessment within 2 days of ECT discontinuation and
reassessment 4 to 8 days following ECT termination, while free of psychotropic
medication. Since the extent of residual symptoms is predictive of relapse
following antidepressant treatment,46,47
the remitter criteria were particularly stringent. These criteria required
both a substantial symptomatic reduction and a low absolute score both immediately
and 4 to 8 days following ECT. Patients with medical contraindications to
nortriptyline or lithium were excluded. Patients provided separate informed
consent for participation in the ECT and continuation pharmacotherapy phases,
and capacity to consent was assessed at each time point. The institutional
review boards at each enrollment site and the NYSPI approved the study. Assuming
a relapse rate of 50% with placebo, the goal was to enroll at least 25 patients
in each randomized treatment condition to have at least an 80% probability
of detecting a significant advantage in relapse time for an active treatment
in a primary, intent-to-treat, parametric survival analysis.
Patients were withdrawn from psychotropic medications, other than lorazepam
(up to 3 mg/d) as needed, before starting ECT. Methohexital (0.75-1.0 mg/kg)
and succinylcholine chloride (0.75-1.0 mg/kg) were the anesthetic medications,
with preadministration of an anticholinergic agent (0.4-6 mg of atropine or
0.2-4 mg of glycopyrrolate). Based on clinical judgment, patients received
either right unilateral or bilateral ECT, using the d'Elia48
or bifrontotemporal21 placements, respectively.
Electroconvulsive therapy was given 3 times per week with a customized MECTA
SR1 device (MECTA Corp, Lake Oswego, Ore), which had double the maximal charge
output of commercial devices in the United States. Seizure threshold was quantified
at the first treatment using empirical titration.49
For right unilateral ECT, dosage at subsequent treatments exceeded initial
threshold by at least 150%. Patients who did not show substantial improvement
to right unilateral ECT within 5 to 8 treatments were switched to bilateral
ECT. To be considered adequate, minimal seizure duration was 20 seconds of
motor or 25 seconds of electroencephalogram manifestation.21
Length of the ECT course was determined on clinical grounds.
The ECT remitters were randomized to 3 continuation pharmacotherapy
groups, stratified by classification of the index episode as psychotic depression;
medication-resistant nonpsychotic depression; and nonpsychotic depression
without medication resistance. Medication resistance was rated using the Antidepressant
Treatment History Form.8,34,50
Medication-resistant nonpsychotic patients had to have received at least 1
adequate antidepressant trial prior to ECT. Patients with psychotic depression
were not further stratified by resistance classification since only 4 (4.3%)
of 92 such patients received an adequate combination antidepressant-antipsychotic
trial during the episode.42
Using a randomly permuted block procedure consisting of blocks of 6
patients (within site and the 3 strata), each treatment condition was equally
represented. The study psychiatrist who completed the Antidepressant Treatment
History Form communicated the patient classification to the pharmacist who
assigned the next available patient number within the stratum. Only the site
pharmacist, the study coordinator at NYSPI, and the NYSPI laboratory conducting
plasma level assays had access to the randomization code. The randomization
code was generated by the study coordinator at NYSPI based on the randomization
tables provided by Fleiss.51 Treatment teams,
outcome assessors, and data analysts were blind to treatment assignment.
Medication was administered in sealed capsules containing 25 mg of nortriptyline,
300 mg of lithium, or microcrystalline cellulose (placebo). The capsules containing
nortriptyline or lithium were distinct in appearance, and each was matched
with placebo capsules identical in size, weight, appearance, and taste. Each
patient was given 2 sets of pills. On the first study day, 50 mg of nortriptyline
or its placebo and 600 mg of lithium or its placebo were administered. Blood
samples were obtained 24 hours later and estimates were determined for the
oral dose needed to produce steady-state levels of 100 ng/mL of nortriptyline
and 0.7 mEq/L of lithium.52-54
On days 3 and 4, depending on the estimate, oral doses were adjusted and maintained
until plasma levels were again taken on days 9 through 11. The goal was to
maintain nortriptyline levels between 75 and 125 ng/mL and lithium levels
between 0.5 and 0.9 mEq/L. During the 24-week trial, plasma levels were determined
on 10 occasions. A yoked-control procedure was used, with a psychiatrist at
NYSPI reporting simulated nortriptyline and lithium values for patients receiving
placebo, based on matching by sex, age, and weight with patients who were
receiving active medication.
Patients were evaluated at weekly intervals for the first 4 weeks, at
2-week intervals for the next 8 weeks, and at 4-week intervals for the remaining
12 weeks. They were contacted by telephone at weekly intervals between visits.
Clinical ratings during the continuation phase were obtained by the same blinded
evaluator (continuous rater) who evaluated patients throughout the ECT course.
During the continuation trial, a blinded study psychiatrist assessed adverse
effects and vital signs, adjusted medication or placebo dosage (based on plasma
levels reported by NYSPI and adverse effects), and completed clinical ratings.
To evaluate the adequacy of the blinding, patients guessed their treatment
assignment as placebo, nortriptyline, or nortriptyline-lithium at study exit.
Patients who dropped out of the study or relapsed were offered clinical care
by a psychiatrist at the research site not affiliated with the study or the
follow-up evaluation of the particular patient.
Time to relapse was the main outcome measure. The criteria for relapse
were a mean HRSD score (continuous rater and study psychiatrist) of at least
16 that was maintained for at least 1 week (over 2 consecutive visits) and
a mean absolute increase of at least 10 points at 2 consecutive visits relative
to continuation trial baseline. These criteria reflected a clinical worsening
for which most clinicians would abandon the current treatment in favor of
an alternative.
At the pre-ECT evaluation, a research nurse completed ratings on the
Cumulative Illness Rating Scale55 to assess
medical comorbidity. At all major time points (pre-ECT, post-ECT, start of
continuation trial [day 0], week 12, week 24, and relapse), the HRSD, Clinical
Global Impression,56 and Global Assessment
Scale43 scores were completed by the continuous
rater and the study psychiatrist. At each site, intraclass correlation coefficients
for the 2 raters exceeded 0.97, 0.93, and 0.90 for HRSD, Clinical Global Impression,
and Global Assessment Scale scores, respectively. A site-independent, time-blind
clinician at NYSPI rated 239 videotapes of continuous rater interviews conducted
at random intervals during the ECT and continuation phases. The intraclass
correlation coefficients were 0.97, 0.96, and 0.95 for HRSD, Clinical Global
Impression, and Global Assessment Scale scores, respectively. The HRSD, Clinical
Global Impression, and Global Assessment Scale scores reported below are the
continuous rater evaluations.
At each visit in the continuation phase, a blinded study psychiatrist
completed the Treatment Emergent Symptom Scale.56
Forty-eight possible adverse effects were rated for severity, relationship
to study medication, and action taken. Clinically significant adverse effects
were defined as those rated as moderate in severity, possibly related to study
medication, and, at minimum, those requiring increased surveillance.
Patients who met remitter criteria following ECT and who did or did
not participate in the continuation trial were compared in demographic, clinical,
and previous treatment features with t tests for
continuous measures and χ2 analyses for dichotomous variables.
The randomized continuation pharmacotherapy groups were compared on baseline
variables using analyses of variance or χ2 analyses.
The primary analysis of the continuation trial used survival analysis
for right-censored failure-time data. A simultaneous regression model was
fit to the relapse-time data using the Weibull distribution.10,15
Covariates in the regression model were the randomized treatment condition
(3 levels), strata (3 levels), sex, and HRSD score at the start of the trial.
In a secondary analysis, ECT treatment modality (right unilateral only vs
right unilateral and bilateral ECT vs bilateral ECT only) and number of ECT
treatments were added as additional covariates. To confirm the findings from
the parametric analysis regarding treatment group differences, nonparametric
estimates of the survival distribution function for each group were computed,
using the Kaplan-Meier method57 and contrasted
with the log-rank test (Mantel-Cox).58
Early in the study, 1 site (Carrier Foundation) was closed when the
hospital discontinued its research division, so another site (University of
Iowa) was added late. These 2 sites entered 21 patients in the continuation
trial compared with 63 patients at WPIC. To determine whether the effects
were not unique to WPIC, the Carrier Foundation and the University of Iowa
were pooled for analysis. A site term (WPIC vs Carrier Foundation and University
of Iowa) was entered into both secondary parametric and nonparametric survival
analyses.
To assess the adequacy of pharmacotherapy, separate analyses of variances
were conducted on the last plasma levels for nortriptyline and lithium obtained
in completers (24-week or time of relapse), using the assayed values for active
medication and the simulated values for placebo, and treatment group (3 levels)
and relapse status as between-subject factors. A logistic regression was conducted
on the patients' guess of treatment condition with relapse status and actual
treatment assignment as predictors.
Of the 290 patients who completed the ECT phase, 159 (54.8%) patients
were remitters (Table 1 and Figure 1). There was no difference among
the sites in remitter rate (χ22 = 3.75, P = .15). Immediately following ECT, 17 patients (5.9%) met initial
remitter criteria, but not at the 4- to 8-day reassessment. The remitter rate
may have been negatively influenced by the stringency of the remission criteria
and the fact that 262 patients (90.3%) started with right unilateral ECT,
with the minimum dosage only 150% above seizure threshold. Subsequent research
has shown that the efficacy of right unilateral ECT improves at a higher dosage
relative to seizure threshold.15,59
Of the 159 remitters, 84 (52.8%) patients entered the randomized continuation
trial. Of the 75 remitters who did not participate, 22.7% had medical exclusions
for nortriptyline or lithium; 26.7% had travel limitations; and 50.7% preferred
treatment by their referring physician, were receiving other medications or
ECT, or were unwilling to receive placebo.
Comparisons of remitters who did or did not enter the continuation trial
yielded no differences in pre- or post-ECT HRSD, Clinical Global Impression,
or Global Assessment Scale scores, number of episodes, duration of current
episode, number of ECT treatments, strength of the most potent antidepressant
trial during the index episode, sum or average potency of all trials, number
of trials, or number of adequate trials. The groups also did not differ in
sex, race, history of previous ECT, use of right unilateral or bilateral ECT,
or classification of medication resistance. Trial participants were younger
(mean [SD], 57.4 [17.2] years) than nonparticipants (64.2 [16.3] years) (t157 = 2.54; P = .01);
had more previous psychiatric hospitalizations (2.4 [2.6]) than nonparticipants
(1.5 [1.6]) (t157 = 2.82; P = .005); a higher rate of psychotic depression (41.7% vs 16.0%) (χ21 = 12.54, P <.001); and less
total medical burden (Cumulative Illness Rating Scale score, 6.1 [4.2] vs
8.0 [3.9]) (t157 = 2.91; P = .004). The medical exclusions for the continuation trial and travel
limitations likely accounted for the higher age and greater medical burden
of nonparticipants.
The continuation treatment groups were compared in demographic and clinical
features (Table 2). There were
no significant differences.
Eleven (13.1%) of the 84 patients dropped out of the trial before completing
24 weeks or meeting relapse criteria. The reasons for noncompletion are described
in Figure 1. Dropout rates were
evenly distributed among the 3 treatment groups (4 placebo, 2 nortriptyline,
and 5 nortriptyline-lithium).
The overall model in the parametric analysis on survival time was significant
(likelihood ratio, χ26 = 27.3; P<.001) (Table 3). The
treatment groups differed markedly (P<.001). Both
nortriptyline alone (P = .01) and nortriptyline-lithium
(P<.001) were superior to placebo in survival
time, and nortriptyline-lithium was superior to nortriptyline alone (P = .04).
The Kaplan-Meier survival function was computed for each treatment group
(Figure 2). Across the sample, 45
(61.6%) of 73 completers relapsed. This confirmatory nonparametric analysis
yielded a log-rank χ22 of 9.12 (P = .01). The relapse rates for completers were 84.0% (21/25) for placebo
(95% confidence interval [CI], 70%-99%); 60.0% (15/25) for nortriptyline (95%
CI, 41%-79%); and 39.1% (9/23) for nortriptyline-lithium (95% CI, 19%-59%).
Only 1 patient relapsed while taking nortriptyline-lithium after 5 weeks,
while relapse steadily continued with placebo and nortriptyline throughout
the 24-week trial (Figure 2). Nonparametric
survival analyses comparing each active treatment condition with placebo yielded
a significant effect for nortriptyline-lithium (χ21=
8.52; P = .004), but only a trend for nortriptyline
(χ21 = 3.33; P = .07).
The parametric survival analysis indicated that across the treatment
conditions, medication-resistant nonpsychotic patients had a higher relapse
rate than patients with psychotic depression. The relapse rates were 50.0%
for psychotic patients (n = 28), 55.6% for nonpsychotic patients without medication
resistance (n = 9), and 72.2% for nonpsychotic medication-resistant patients
(n = 36). The significant effect of sex was due to a higher relapse rate among
women (77.8%) than men (53.6%). Patients who relapsed had higher mean (SD)
HRSD scores at trial entry (6.0 [3.1]) than patients who did not relapse (5.0
[2.8]). There were no additional significant effects in the parametric survival
analysis when treatment with right unilateral, right unilateral and bilateral,
or bilateral ECT (P = .89), and number of ECT treatments
(P = .96) were entered as additional terms.
Study site (WPIC vs combined Carrier Foundation and University of Iowa)
was entered as a term in both the parametric and nonparametric survival analyses.
There were no site effects. The relapse rates at WPIC for placebo, nortriptyline,
and nortriptyline-lithium were 88.9%, 60.0%, and 41.2%, respectively, and
for the combined Carrier Foundation and University of Iowa they were 71.4%,
60.0%, and 33.3%, respectively.
The high rate of relapse across the treatments could have been due to
excessively sensitive relapse criteria. Clinical ratings at continuation trial
entry and end point were compared as a function of relapse status (Table 4). Relapsed patients showed marked
symptomatic worsening. Fifteen (33%) of the 45 relapsed patients were hospitalized
and received ECT, 6 patients (13%) received outpatient ECT, and all other
relapsed patients (53%) were switched to other pharmacotherapies. The severity
of relapse did not differ among the continuation treatments.
No effects approached significance in the analyses of variances of nortriptyline
and lithium levels on final visit. At final visit, the mean (SD) nortriptyline
level was 89.9 (38.2) ng/mL for the nortriptyline group, 89.2 (32.2) ng/mL
for the nortriptyline-lithium group, and the simulated levels reported for
the placebo group averaged 93.0 (27.5) ng/mL. For lithium, the levels were
0.59 (0.2) mEq/L for the nortriptyline-lithium group, with simulated levels
of 0.54 (0.2) mEq/L and 0.62 (0.2) mEq/L for the nortriptyline and placebo
groups, respectively. Relapse was not associated with nortriptyline or lithium
plasma levels.
A 1-way analysis of variance indicated that the treatment groups did
not differ in the average number of clinically significant adverse effects
(F2,80 = 0.13; P = .88). For the placebo,
nortriptyline, and nortriptyline-lithium groups, the mean (SD) number of significant
adverse effects per patient was 1.24 (1.8), 1.42 (1.7), and 1.21 (1.3), respectively.
An analysis of variance in the completer sample (with treatment group and
relapse status as between-subject factors) yielded no significant effects.
The mean (SD) number of significant adverse effects among patients who relapsed
(1.48 [1.7]) did not differ from nonrelapsed patients (1.32 [1.6]) (t70 = 0.39; P = .70). Table 5 presents the clinically significant
adverse effects experienced by at least 3 patients.
At study exit, 63 of the 73 completers guessed their treatment assignment.
The logistic regression analysis yielded a modest association between the
treatment assignment and the patients' guesses (χ24
= 9.68; P = .05) and a more robust association with
relapse status (χ22 = 8.17; P = .02). Only 1 (4%) of the 25 patients who did not relapse believed
he/she was treated with placebo, while this was true of 16 (42.1%) of the
38 patients who did relapse. Of the patients treated with placebo, 50% believed
they received only placebo, while 31.8% and 18.2% believed that they had received
nortriptyline and nortriptyline-lithium, respectively. For the nortriptyline
group, the guesses were 29.4% for placebo, 23.8% for nortriptyline, and 52.4%
for nortriptyline-lithium. For nortriptyline-lithium, these guesses were 5.0%,
30.0%, and 65.0%, respectively. While the patient blinding was imperfect,
relapse status was a more powerful determinant of the guesses. The distributions
overlapped considerably among patients treated with nortriptyline and nortriptyline-lithium.
Early research, based on first-choice use of ECT for major depression,
indicated that half of the patients remain well in the 6 months following
response without continuation therapy.16-18
We found that the relapse rate for placebo-treated patients was 84%. This
suggests that the prognosis following ECT is more guarded today. Given the
shift in use of ECT for severe, recurrent, and medication-resistant patients
with higher risk of relapse,8,15,60
almost universal relapse should be expected without effective continuation
therapy.
The early research suggested that continuation monotherapy with a TCA
reduced the relapse rate to approximately 20%.16-18
We found that the relapse rate with nortriptyline continuation monotherapy
was 60%, above the original projections for placebo. While TCAs are believed
to be among the most effective antidepressant agents,27,30,33
our findings indicate that the efficacy of post-ECT TCA continuation monotherapy
is not acceptable. Similarly, in a naturalistic study, Flint and Rifat61 found that continuation monotherapy with a TCA was
ineffective in preventing relapse in psychotically depressed patients who
responded to ECT.
The relapse rate for the combination of nortriptyline-lithium was 39.1%,
which was superior to placebo and nortriptyline monotherapy. Similar results
were reported in a naturalistic study at NYSPI, in which relapse rates over
1 year were markedly lower among ECT remitters who received TCA-lithium continuation
therapy (35.3%) compared with patients who received continuation treatment
with other pharmacological regimens (67.9%).15
It was noteworthy that the lithium levels in the present study were at the
low end of what is considered the therapeutic range for acute or maintenance
treatment (0.5-1.2 mEq/L).62,63
This suggests that in combination with nortriptyline, lithium levels may only
need to be greater than 0.5 mEq/L to prevent post-ECT relapse.
This study could not determine whether the advantage of the TCA-lithium
combination was due to lithium alone or the synergism of lithium with the
TCA. The only placebo-controlled trial of lithium following ECT in unipolar
patients found that lithium did not have protective effects during the first
6 months following ECT.64,65 Thus,
it is likely that the advantage of nortriptyline-lithium was due to additive
or synergistic effects and not lithium alone. Our findings encourage the use
of nortriptyline-lithium as post-ECT continuation therapy. It is unknown whether
similar protective effects would be obtained with a mood stabilizer other
than lithium or antidepressants other than nortriptyline (in combination with
lithium). This issue is important since SSRIs and other newer antidepressant
agents have better tolerability than TCAs and are now more commonly used.
Patients with higher HRSD scores at the start of the continuation trial
had shorter survival time. This is consistent with several studies of relapse
during continuation pharmacotherapy following response to antidepressant medications46,47 or ECT.8
Thus, concerted attempts should be made to maximize symptomatic improvement
in patients receiving ECT. Women were more prone to relapse during the continuation
phase. There is inconsistent evidence from naturalistic studies of a higher
relapse/recurrence rate among women.14,66-70
Studies of patients with psychotic depression suggested a high post-ECT relapse
rate.6,7 However, regardless of
the treatment producing remission, no previous controlled study has compared
relapse rates in psychotic and nonpsychotic depressed patients. We found that
psychotically depressed patients had a lower relapse rate than medication-resistant
nonpsychotic patients. Several studies have shown that medication resistance
is especially predictive of post-ECT relapse.8,15,60
It is also possible that compared with medication-resistant nonpsychotic patients,
patients with psychotic depression had less Axis II (personality disorder)
pathology and better interepisode function. There is evidence that the post-ECT
course is poorer in patients with significant Axis II pathology.71,72
The major finding was that treatment with the nortriptyline-lithium
combination produced a substantially lower relapse rate than treatment with
placebo or nortriptyline alone. Nonetheless, the relapse with nortriptyline-lithium
was high (39.1%). Two alternative strategies, which are not mutually exclusive,
should be tested.4 Both strategies are suggested
by the observations that relapse is heavily skewed to the period immediately
following ECT. During the acute treatment phase, there is a several week delay
before antidepressant and mood stabilizing agents exert therapeutic effects.73 Further, the abrupt discontinuation of effective
somatic treatment is associated with potentiation of relapse,74-76
which is standard in terminating an ECT course. One strategy is to taper ECT
over a few weeks, as is commonly done with pharmacological treatments, providing
symptom suppression during the most vulnerable period. Second, the antidepressant
medication used in continuation therapy may be started during the course of
ECT, followed by post-ECT addition of lithium. All controlled studies in which
ECT was combined with an antidepressant medication focused on whether response
to ECT was improved,16-19
and not whether this strategy reduced post-ECT relapse. Nonetheless, a low
post-ECT relapse rate was seen in studies in which patients began taking an
antidepressant at the start of the ECT course.16-19
Thus, these 2 adjunctive strategies raise the possibility that the advantage
seen with the nortriptyline-lithium therapy may be further improved and that
the problem of the high rate of early relapse with continuation pharmacotherapy
following ECT could be resolved.
1.American Psychiatric Association Committee on Electroconvulsive Therapy. The Practice of Electroconvulsive Therapy: Recommendations
for Treatment, Training, and Privileging. 2nd ed. Washington, DC: American Psychiatric Association; 2001.
2.Thompson JW, Weiner RD, Myers CP. Use of ECT in the United States in 1975, 1980, and 1986.
Am J Psychiatry.1994;151:1657-1661.Google Scholar 3.Sackeim HA, Devanand DP, Nobler MS. Electroconvulsive therapy. In: Bloom F, Kupfer D, eds. Psychopharmacology:
The Fourth Generation of Progress. New York, NY: Raven; 1995:1123-1142.
4.Sackeim HA. Continuation therapy following ECT: directions for future research.
Psychopharmacol Bull.1994;30:501-521.Google Scholar 5.Karlinsky H, Shulman KI. The clinical use of electroconvulsive therapy in old age.
J Am Geriatr Soc.1984;32:183-186.Google Scholar 6.Spiker DG, Stein J, Rich CL. Delusional depression and electroconvulsive therapy: one year later.
Convulsive Ther.1985;1:167-172.Google Scholar 7.Aronson TA, Shukla S, Hoff A. Continuation therapy after ECT for delusional depression: a naturalistic
study of prophylactic treatments and relapse.
Convulsive Ther.1987;3:251-259.Google Scholar 8.Sackeim HA, Prudic J, Devanand DP.
et al. The impact of medication resistance and continuation pharmacotherapy
on relapse following response to electroconvulsive therapy in major depression.
J Clin Psychopharmacol.1990;10:96-104.Google Scholar 9.Malcolm K, Dean J, Rowlands P, Peet M. Antidepressant drug treatment in relation to the use of ECT.
J Psychopharmacol.1991;5:255-258.Google Scholar 10.Sackeim HA, Prudic J, Devanand DP.
et al. Effects of stimulus intensity and electrode placement on the efficacy
and cognitive effects of electroconvulsive therapy.
N Engl J Med.1993;328:839-846.Google Scholar 11.Grunhaus L, Shipley JE, Eiser A.
et al. Shortened REM latency post-ECT is associated with rapid recurrence
of depressive symptomatology.
Biol Psychiatry.1994;36:214-222.Google Scholar 12.Lemstra A, Leentjens AF, van den Broek WW. Temporary results only in electroconvulsive therapy in therapy-resistant
depression: retrospective study.
Ned Tijdschr Geneeskd.1996;140:260-264.Google Scholar 13.O'Leary DA, Lee AS. Seven-year prognosis in depression: mortality and readmission risk
in the Nottingham ECT cohort.
Br J Psychiatry.1996;169:423-429.Google Scholar 14.Flint AJ, Rifat SL. Two-year outcome of psychotic depression in late life.
Am J Psychiatry.1998;155:178-183.Google Scholar 15.Sackeim HA, Prudic J, Devanand DP.
et al. A prospective, randomized, double-blind comparison of bilateral and
right unilateral electroconvulsive therapy at different stimulus intensities.
Arch Gen Psychiatry.2000;57:425-434.Google Scholar 16.Seager CP, Bird RL. Imipramine with electrical treatment in depression: a controlled trial.
J Ment Sci.1962;108:704-707.Google Scholar 17.Imlah NW, Ryan E, Harrington JA. The influence of antidepressant drugs on the response to electroconvulsive
therapy and on subsequent relapse rates.
Neuropsychopharmacology.1965;4:438-442.Google Scholar 18.Kay DW, Fahy T, Garside RF. A seven-month double-blind trial of amitriptyline and diazepam in ECT-treated
depressed patients.
Br J Psychiatry.1970;117:667-671.Google Scholar 19.Lauritzen L, Odgaard K, Clemmesen L.
et al. Relapse prevention by means of paroxetine in ECT-treated patients with
major depression: a comparison with imipramine and placebo in medium-term
continuation therapy.
Acta Psychiatr Scand.1996;94:241-251.Google Scholar 20.Abou-Saleh MT, Coppen AJ. Continuation therapy with antidepressants after electroconvulsive therapy.
Convulsive Ther.1988;4:263-268.Google Scholar 21.American Psychiatric Association Committee on Electroconvulsive Therapy. The Practice of Electroconvulsive Therapy: Recommendations
for Treatment, Training and Privileging. Washington, DC: American Psychiatric Association; 1990.
22.Royal College of Psychiatrists. The ECT Handbook: The Second Report of the Royal
College of Psychiatrists' Special Committee on ECT. London, England: Royal College of Psychiatrists; 1995.
23.Abrams R. Electroconvulsive Therapy. 3rd ed. New York, NY: Oxford University Press; 1997.
24.Sackeim HA, Prudic J, Devanand DP. Treatment of medication-resistant depression with electroconvulsive
therapy. In: Tasman A, Goldfinger SM, Kaufmann CA, eds. Annual Review of Psychiatry. Vol 9. Washington, DC: American Psychiatric
Press; 1990:91-115.
25.Medical Research Council. Clinical trial of the treatment of depressive illness: report to the
Medical Research Council by its Clinical Psychiatry Committee.
BMJ.1965;1:881-886.Google Scholar 26.Sargant W, Slater E. An Introduction to Physical Methods of Treatment
in Psychiatry. Baltimore, Md: Williams & Wilkins; 1964.
27.Flint AJ, Rifat SL. The effect of sequential antidepressant treatment on geriatric depression.
J Affect Disord.1996;36:95-105.Google Scholar 28.Danish University Antidepressant Group (DUAG). Citalopram: clinical effect profile in comparison with clomipramine:
a controlled multicenter study.
Psychopharmacology.1986;90:131-138.Google Scholar 29.Andersen IM, Tomenson BM. The efficacy of selective serotonin reuptake inhibitors in depression:
a meta-analysis of studies against tricyclic antidepressants.
J Psychopharmacol.1994;8:238-249.Google Scholar 30.Roose SP, Glassman AH, Attia E, Woodring S. Comparative efficacy of selective serotonin reuptake inhibitors and
tricyclics in the treatment of melancholia.
Am J Psychiatry.1994;151:1735-1739.Google Scholar 31.Reimherr F, Wood D, Byerley B, Brainard J, Grosser B. Characteristics of responders to fluoxetine.
Psychopharmacol Bull.1984;20:70-72.Google Scholar 32.Tignol J, Stoker M, Dunbar G. Paroxetine in the treatment of melancholia and severe depression.
Int Clin Psychopharmacol.1992;7:91-94.Google Scholar 33.Danish University Antidepressant Group (DUAG). Paroxetine: a selective serotonin reuptake inhibitor showing better
tolerance, but weaker antidepressant effect than clomipramine in a controlled
multicenter study.
J Affect Disord.1990;18:289-299.Google Scholar 34.Prudic J, Haskett RF, Mulsant B.
et al. Resistance to antidepressant medications and short-term clinical response
to ECT.
Am J Psychiatry.1996;153:985-992.Google Scholar 35.de Montigny C, Cournoyer G, Morissette R, Langlois R, Caille G. Lithium carbonate addition in tricylic antidepressant-resistant unipolar
depression.
Arch Gen Psychiatry.1983;40:1327-1334.Google Scholar 36.Dinan TG, Barry S. A comparison of electroconvulsive therapy with a combined lithium and
tricyclic combination among depressed tricyclic nonresponders.
Acta Psychiatr Scand.1989;80:97-100.Google Scholar 37.Bruijn JA, Moleman P, Mulder PG, van den Broek WW. Comparison of 2 treatment strategies for depressed inpatients: imipramine
and lithium addition or mirtazapine and lithium addition.
J Clin Psychiatry.1998;59:657-663.Google Scholar 38.Heninger GR, Carney DS, Sternberg DE. Lithium carbonate augmentation of antidepressant treatment: an effective
prescription for treatment-refractory depression.
Arch Gen Psychiatry.1983;40:1335-1342.Google Scholar 39.Joffe RT, Singer W, Levitt AJ, MacDonald C. A placebo-controlled comparison of lithium and triiodothyronine augmentation
of tricyclic antidepressants in unipolar refractory depression.
Arch Gen Psychiatry.1993;50:387-393.Google Scholar 40.Kantor D, McNevin S, Leichner P, Harper D, Krenn M. The benefit of lithium carbonate adjunct in refractory depression:
fact or fiction?
Can J Psychiatry.1986;31:416-418.Google Scholar 41.Thase ME, Kupfer DJ, Frank E, Jarrett DB. Treatment of imipramine-resistant recurrent depression, II: an open
clinical trial of lithium augmentation.
J Clin Psychiatry.1989;50:413-417.Google Scholar 42.Mulsant BH, Haskett RF, Prudic J.
et al. Low use of neuroleptic drugs in the treatment of psychotic major depression.
Am J Psychiatry.1997;154:559-561.Google Scholar 43.Endicott J, Spitzer RL. A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia.
Arch Gen Psychiatry.1978;35:837-844.Google Scholar 44.Spitzer RL, Endicott J, Robins E. Research diagnostic criteria: rationale and reliability.
Arch Gen Psychiatry.1978;35:773-782.Google Scholar 45.Hamilton M. Development of a rating scale for primary depressive illness.
Br J Soc Psychol.1967;6:278-296.Google Scholar 46.Prien R, Kupfer D. Continuation drug therapy for major depressive episodes: how long should
it be maintained?
Am J Psychiatry.1986;143:18-23.Google Scholar 47.Prien RF, Koscis JH. Long-term treatment of mood disorders. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology:
The Fourth Generation of Progress. New York, NY: Raven; 1995:1067-1080.
48.d'Elia G. Unilateral electroconvulsive therapy.
Acta Psychiatr Scand.1970;215(suppl):1-98.Google Scholar 49.Sackeim HA, Decina P, Prohovnik I, Malitz S. Seizure threshold in electroconvulsive therapy: effects of sex, age,
electrode placement, and number of treatments.
Arch Gen Psychiatry.1987;44:355-360.Google Scholar 50.Prudic J, Sackeim HA, Devanand DP. Medication resistance and clinical response to electroconvulsive therapy.
Psychiatry Res.1990;31:287-296.Google Scholar 51.Fleiss JL. The Design and Analysis of Clinical Experiments. New York, NY: John Wiley & Sons; 1986.
52.Cooper TB, Simpson GM. Prediction of individual dosage of nortriptyline.
Am J Psychiatry.1978;135:333-335.Google Scholar 53.Cooper TB, Simpson GM. The 24-hour lithium level as a prognosticator of dosage requirements:
a 2-year follow-up study.
Am J Psychiatry.1976;133:440-443.Google Scholar 54.Cooper TB, Simpson GM. Issues related to the prediction of optimum dosage. In: Cooper TB, Gershon S, Kline NS, Schou M, eds. Lithium: Controversies and Unresolved Issues. Amsterdam, the Netherlands:
Excerpta Medica; 1979:346-353.
55.Miller MD, Paradis CF, Houck PR.
et al. Rating chronic medical illness burden in geropsychiatric practice and
research: application of the Cumulative Illness Rating Scale (CIRS).
Psychiatry Res.1992;41:237-248.Google Scholar 56.Guy W. ECDEU Assessment Manual for Psychopharmacology. Washington, DC: Superintendent of Documents, US Government Printing
Office, US Dept of Health, Education, and Welfare; 1976. Publication 76-338.
57.Kalbfleisch JD, Prentice RL. Survival Models and Data Analysis. New York, NY: John Wiley; 1980.
58.Peto R, Peto J. Asymptomatically efficient rank invariant procedure.
J R Stat Soc Ser A.1972;135:185-207.Google Scholar 59.McCall WV, Reboussin DM, Weiner RD, Sackeim HA. Titrated moderately suprathreshold vs fixed high-dose right unilateral
electroconvulsive therapy: acute antidepressant and cognitive effects.
Arch Gen Psychiatry.2000;57:438-444.Google Scholar 60.Shapira B, Gorfine M, Lerer B. A prospective study of lithium continuation therapy in depressed patients
who have responded to electroconvulsive therapy.
Convuls Ther.1995;11:80-85.Google Scholar 61.Flint AJ, Rifat SL. The effect of treatment on the two-year course of late-life depression.
Br J Psychiatry.1997;170:268-272.Google Scholar 62.Steering Committee of the American Psychiatric Association. The Expert Consensus Guideline Series: treatment of bipolar disorder.
J Clin Psychiatry.1996;57(suppl 12A):3-88.Google Scholar 63.American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder.
Am J Psychiatry.1994;151(12 suppl):1-36.Google Scholar 64.Coppen A, Abou-Saleh MT, Milln P.
et al. Lithium continuation therapy following electroconvulsive therapy.
Br J Psychiatry.1981;139:284-287.Google Scholar 65.Abou-Saleh MT. How long should drug therapy for depression be maintained?
Am J Psychiatry.1987;144:1247-1248.Google Scholar 66.Sargeant JK, Bruce ML, Florio LP, Weissman MM. Factors associated with 1-year outcome of major depression in the community.
Arch Gen Psychiatry.1990;47:519-526.Google Scholar 67.Black DW, Goldstein RB, Nasrallah A, Winokur G. The prediction of recovery using a multivariate model in 1471 depressed
inpatients.
Eur Arch Psychiatry Clin Neurosci.1991;241:41-45.Google Scholar 68.Ernst C, Angst J. The Zurich Study, XII: sex differences in depression: evidence from
longitudinal epidemiological data.
Eur Arch Psychiatry Clin Neurosci.1992;241:222-230.Google Scholar 69.Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey, I: lifetime
prevalence, chronicity and recurrence.
J Affect Disord.1993;29:85-96.Google Scholar 70.Simpson HB, Nee JC, Endicott J. First-episode major depression: few sex differences in course.
Arch Gen Psychiatry.1997;54:633-639.Google Scholar 71.Zimmerman M, Coryell W, Pfohl B, Corenthal C, Stangl D. ECT response in depressed patients with and without a
DSM-III personality disorder.
Am J Psychiatry.1986;143:1030-1032.Google Scholar 72.Sareen J, Enns MW, Guertin JE. The impact of clinically diagnosed personality disorders on acute and
one-year outcomes of electroconvulsive therapy.
J ECT.2000;16:43-51.Google Scholar 73.Hyman SE, Nestler EJ. Initiation and adaptation: a paradigm for understanding psychotropic
drug action.
Am J Psychiatry.1996;153:151-162.Google Scholar 74.Suppes T, Baldessarini RJ, Faedda GL, Tohen M. Risk of recurrence following discontinuation of lithium treatment in
bipolar disorder.
Arch Gen Psychiatry.1991;48:1082-1088.Google Scholar 75.Baldessarini RJ, Tondo L, Faedda GL, Suppes TR, Floris G, Rudas N. Effects of the rate of discontinuing lithium maintenance treatment
in bipolar disorders.
J Clin Psychiatry.1996;57:441-448.Google Scholar 76.Reynolds III CF, Frank E, Perel JM.
et al. High relapse rate after discontinuation of adjunctive medication for
elderly patients with recurrent major depression.
Am J Psychiatry.1996;153:1418-1422.Google Scholar