After lithium augmentation: a retrospective follow-up of patients with antidepressant-refractory depression

Journal of Affectroe Dtsorders.

18

(1990)167m 175

167

Elsevier

JAD 00682

After lithium augmentation: a retrospective follow-up with antidepressant-refractory depression

of patients

Andrew A. Nierenberg *, Lawrence H. Price, Dennis S. Charney and George R. Heninger Department

OJ Pqrhrutty,

Yale University School of Medictne und Clrnicul Neuroscience Research Unrt. RthrcofJ Re.srurch Fuctlrtres, Connectrcut Mental Health Center, New Hacen. CT 06508. U.S.A. (Received 13 February 1989) (Accepted 20 July 1989)

Summary

There have been no systematic follow-up studies of depressed patients with documented refractoriness to antidepressants treated with lithium augmentation. To assess their longitudinal course, 66 (88%) of an original cohort of 75 such patients were followed in a retrospective, naturalistic design for 29.0 f SD 15.3 months. At follow-up, 29% had poor, 23% fair, and 48% good outcomes. An acute marked positive response to lithium augmentation predicted a good subsequent course. Acute partial and non-responders had a less benign outcome despite subsequent treatments. These findings indicate that outcomes of patients with documented refractory depression are heterogeneous. There is a suggestion that an acute marked response to lithium augmentation is sustained regardless of the duration of taking lithium, but this must be regarded as speculative.

Key

words:

Lithium

augmentation;

Refractory

depression;

Introduction

The long-term course of depressed patients who are refractory to antidepressant treatment is unknown, despite the occurrence of this problem in

Address for correspondence: Andrew A. Nierenberg, M.D.. 115 Mill Street, Belmont, MA 02178, U.S.A. Reprint requests to: Lawrence H. Price, M.D., 34 Park Street, New Haven. CT 06508, U.S.A. * Present address: Harvard University Medical School, McLean Hospital, 115 Mill Street, Belmont, MA 02178, U.S.A. 0165-0327/90/$03.50

0 1990 Elsevier Science Publishers

Course;

Outcome

about 20% of depressive episodes (Keller et al., 1984). The task of generating a systematic body of knowledge in this area has been complicated by the use of multiple definitions of refractoriness (Gelzer, 1986) reflecting in part the broad clinical spectrum of the phenomenon itself (Fawcett and Kravitz, 1984). The use of clinically relevant operational criteria to define refractoriness offers the possibility of creating clinically meaningful samples that can be studied longitudinally to clarify the course of such patients. The long-term course of refractory depression will depend, in part, on the efficacy of and com-

B.V. (Biomedical

Division)

16X

pliance with treatment strategies applied subsequent to the ascertainment of refractoriness. These strategies include: (1) optimrzu/ion of the current antidepressant trial (e.g.. increasing the dose or duration), (2) substitution of a different antidepressant (e.g., switching from a tricyclic to a monoamine troconvulsive

oxidase inhibitor therapy (ECT)),

(MAOI) or to elec(3) comhinution of

two different treatments that are each believed to possess some unique therapeutic effect (e.g., utilizing the antipsychotic effects of a neuroleptic in conjunction with the antidepressant effects of a tricyclic

in treating

psychotic depression). (4) UURor primary antidepressant by adding a second agent that is believed to interact in a specific way with the primary antidepressant to magnify or enhance its therapeutic

mentution of the initial

effect (Price, 1989). and MAOIs has been

Augmentation of tricyclics attempted with r.-tryptophan

(Pare, 1963), triiodothyronine (T,) (Goodwin et al., 1982). stimulants (Wharton et al.. 1971). and reserpine (Price et al., 1987). but findings have been most extensively reported with lithium (Price,

ported (Nelson and Byck. 19X2: Price. 1989). with additional preclinical studies further elaborating possible mechanisms of action (Blier et al.. 1987). The simplicity of the approach, and the familiarity of most psychiatrists with the agents employed, makes lithium augmentation an attractive clinical intervention. The acute efficacy of lithium augmentation highlights the dearth of information on the longterm outcome of antidepressant-refractory patients. There have been no systematic follow-up studies of patients treated with lithium augmentation subsequent to the assessment of initial response. To our knowledge. this is the first report of the longitudinal course of depressed patients with documented treatment. based

refractoriness to antidepressant on a followup of the largest

sample of patients thus far published

receiving lithium augmentation (Price et al.. 1986).

Method

Putients

1989). Studies investigating the possibility that lithium-antidepressant combination treatment might possess greater efficacy than single-drug therapy were first reported in the early 1970s (Himmelhoch et al.. 1972), but the initial description of lithium augmentation per se appeared in 1981. DeMontigny et al. (1981) reported dramatic

The sample included 63 former inpatients and 12 former outpatients (46 female, 29 male), aged 23-74 years (mean & SD, 49 f 14 years). who had given voluntary informed consent for treatment at the Clinical Neuroscience Research Unit (CNRU). New Haven. CT. These 75 patients came from a larger sample of 84 refractory patients whose acute

improvement 48 h after

response reported

in eight of eight depressed patients addition of lithium to a previously

ineffective tricyclic regimen. They hypothesized that lithium-induced enhancement of presynaptic serotonin (5-HT) function interacted synergistically with the sensitization of postsynaptic 5-HT receptors caused by long-term tricyclic treatment (deMontigny and Aghajanian, 1978). Subsequent open (Nelson and Byck. 1982; Price et al.. 1983, 1986; Louie and Meltzer, 1984; deMontigny et al., 1985; Price, 1989) and placebo-controlled (deMontigny et al.. 1983; Heninger et al.. 1983) studies have confirmed the efficacy of lithium augmentation, although considerable variability appears to exist in the rate, quality, and latency of response (Price. 1989). The use of lithium augmentation with a variety of MAOIs and other non-tricyclic antidepressants has also been widely re-

to lithium augmentation (Price et al., 1986). Nine

was recently patients were

excluded from the study because they had been treated for less than 6 months at the start of the follow-up, a period deemed insufficient to provide meaningful information about long-term course. The original sample was derived from 301 patients consecutively treated for depression at the CNRU over a 5-year period. All were free of major medical illnesses. Diagnoses were made by consensus of three of the authors (L.H.P., D.S.C.. G.R.H.). based on residents’ assessments, nurses’ observations. family evaluation, medical records, and a structured interview with the Yale Depression Inventory (Mazure et al., 1986). All 75 patients met DSM-III criteria for major depression and eight also met criteria for bipolar disorder. More detailed diagnostic. clinical, and treatment data on

169

these patients are provided (Price et al., 1986). Initial

treatment

in the original

and ussessment

report

of acute response

At the time of the index admission of these patients to the CNRU. all psychotropic drugs were discontinued. Patients who had not recently received an adequate antidepressant trial were treated with desipramine, amitriptyline, nortriptyline, or trazodone. Patients who had previously been unresponsive to available drugs were treated with investigational antidepressants (adinazolam, bupropion, fluvoxamine, or mianserin). Patients were treated with 2-3 weeks of placebo followed by 446 weeks of active primary antidepressant. Patients, ward staff, and raters were blind to the sequence of placebo and active drug administration. In the four patients who worsened significantly during the primary antidepressant trial, the blind was opened and concurrent neuroleptic treatment was given. Criteria for refractoriness to the primary antidepressant trial included (1) a mean score of > 4 (4-6 = mild depressive symptoms) on the 15-point Short Clinical Rating Scale (SCRS) (Heninger et al., 1970) or a score of > 15 on the 25-item modified Hamilton Depression Rating Scale (HDRS) (Mazure et al., 1986), and (2) consensus of the treating psychiatrists that the patient was insufficiently improved to permit discharge. Upon determination of refractoriness, lithium carbonate was added to the ongoing antidepressant and continued for at least 10 days, initially at a dose of 900 mg/day and subsequently increased to 900-1500 mg/day to maintain serum levels of 0.5-1.3 mEq/l. For all but 15 patients previously reported (Heninger et al., 1983) lithium augmentation was open. Patients were classified as treatment responders to lithium augmentation if global function improved sufficiently on lithium-antidepressant alone to permit discharge from our inpatient or outpatient clinical research programs to mainteaftercare. Additionally, inpatient renance sponders underwent no major medication change for at least 4 weeks following discharge. These are robust measures of global improvement reflecting the treating staff’s best assessment, since treatment at our facility is provided free and patients

refractory to lithium augmentation are routinely treated with lithium-tranylcypromine, ECT, or additional investigational drugs. Responders were further categorized as marked or partial based on (1) change in objective ratings from the primary antidepressant trial to the lithium augmentation trial and (2) attainment of a cutoff score on the SCRS or the HDRS reflecting marked improvement in depressive symptoms. Marked responders had either (1) an SCRS decrease of > 1 (indicating clinically meaningful improvement) and a final mean score of < 4 or (2) an HDRS decrease of > 50% and a final score of < 15. Partial responders met only the discharge criterion of global improvement. Concordance between the SCRS and HDRS ratings in classifying patients as markedly or not markedly improved was 83% in the 35 patients who had both measures in the original report (Price et al.. 1986). Non-responders were so classified on the basis of having either failed to improve or worsened during lithium augmentation. All inpatients in this part of the study were rated twice daily by trained nurses using the SCRS global depression item. Most were also rated twice weekly by research nurses using the HDRS, but in some cases these ratings were not continued through the entire augmentation period. Outpatients were rated weekly on the HDRS throughout the entire trial but did not receive SCRS ratings. Response at the end of each treatment phase was assessed by averaging the SCRS and HDRS scores for (1) the last 6-day period of placebo administration. (2) the last 6-day period of primary antidepressant treatment, and (3) the last (or fourth, whichever came first) 6-day period of lithium augmentation. Following completion of treatment at our facility, patients were discharged to the care of private psychiatrists, community clinics, or long-term care facilities. Follow-up

study

Follow-up information was obtained on 66 (88%) of the 75 eligible patients using a modified version of the Longitudinal Interval Follow-up Evaluation (LIFE) scale (Keller et al., 1983). Diagnostic subtype and acute treatment response classifications of these patients are presented in

170

TABLE

1

ACUTE

RESPONSE

DIAGNOSTIC Diagnosis

Unipolar Non-melancholic

TO

LITHIUM

AUGMENTATION

BY

SUBTYPE Number

of patients

None

Partial

by response Marked

Total

6

8

7

21

6

6

10

22

Delusional

10

2

5

17

Total

22

26

22

Melancholic

Bipolar Non-melancholic

60 *

0

0

1

1

Melanchohc

1

0

0

1

Delusional

2

1

1

4

Total

3

1

2

6

* Mantel-Haenszel

x2 = 0.3;

P = 0.60.

time of onset for continuous refractory depression was arbitrarily defined as 1 month after discharge. A fuir outcome was defined as the return of depressive symptoms which persisted for at least 2 weeks and met criteria for either (1) minor depression (subjective distress which may or may not have been noted by friends and relatives, but was of sufficient intensity to be clearly differentiated from one’s normal mood state) or (2) moderate depression (mood dysregulation that resulted in a clearcut impairment in the patient’s functioning), as previously defined by Roy-Byrne et al. (1985). All patients with a fair outcome had at some point experienced significant improvement in their symptoms, mentation

whether in response or during subsequent

time course of a fair outcome because sufficiently reliable

to lithium treatment.

augThe

was not examined data could not be

obtained retrospectively. A good outcome was defined as a course in which criteria for a poor or Table 1. Nine patients (13%) (four marked, two partial, and three non-responders to lithium augmentation) either refused to participate or could not be located. Patients were evaluated by one of the authors (A.A.N.) who was blind to details of their initial treatment. including diagnosis, primary antidepressant. and response status. Sources of information included face-to-face or telephone interviews with the patient, family members, and/or current treating clinician, as well as medical records. Thirty-eight (58%) of the 66 contacted patients were interviewed face-to-face and rated with the Yale Depression Inventory. The mean f SD duration of follow-up after completion of the lithium augmentation trial was 29.0 f 15.3 (range 1.1-59.3) months. A poor outcome was defined as either hospitalization, suicide attempt, death by suicide, or death as a complication of antidepressant treatment. These criteria were selected on the basis of their clinical relevance and their ability to be easily operationalized in the context of a retrospective study. Non-responders to lithium augmentation who also failed to improve significantly during subsequent treatment (in the judgement of the follow-up rater and the patient, family, or current treating clinician) were diagnosed as having ‘continuous refractory depression’, and were also classified as having a poor outcome. The discrete

fair outcome

were

not met.

Duta unalvsis Mantel-Haenszel chi square was used for rectangular tables (Mantel and Haenszel. 1959). Stepwise discriminant analysis was used to determine the relationship between baseline variables and outcome (SPSS. 1983). Life table and survival analysis methods (Kaplan and Meier, 1958; Cox. 1972) were used to estimate the cumulative probability of a poor outcome only. These methods allow the probability of a given outcome to be estimated independently of variations in the duration of follow-up. Differences between strata were determined using the generalized Wilcoxon (Breslow) test for stratified life table data with varied censored times (Breslow, 1970). Since the discrete onset of a fair outcome could not be determined reliably, and life table analysis requires discrete times. only the proportion of patients with fair outcomes was calculated. Statistical significance was set at P < 0.05 (all tests two-tailed). Data analysis utilized SPSS-X (SPSS, 1983) and BMDP (Dixon, 1981) programs. Results Of the entire sample of 66 contacted 29% had poor, 23% fair, and 48% good

patients, outcomes

171 TABLE

2

LONGITUDINAL TYPE

TABLE 4 OUTCOME

Diagnosis

of patients

Poor

Fair

4 7 6

SUB-

Total

7 5 2

10 IO 9

21 22 17

17

14

29

60 *

0 0 2

1 0 0

0 1 2

1 1 4

2

1

3

6

Total

x2 = 0.3: P = 0.57.

(without accounting for differences in duration of follow-up). Fifty-three percent (10/19) of the poor outcome patients (15% of the entire sample) were characterized as having continuous refractory depression. Table 2 presents outcome as a function of diagnostic subtype. There were no significant differences. In addition, comparisons of all melancholic vs. all non-melancholic patients and all psychotic vs. all non-psychotic patients revealed no significant differences. Stratification by acute response to lithium augmentation (Table 3) showed that, of those patients with a poor outcome, 58% (11/19) had been non-responders, 32% (6/19) partial, and 11% (2/19) marked responders. Of those with a fair

TABLE

3

LONGITUDINAL OUTCOME LITHIUM AUGMENTATION

BY ACUTE

RESPONSE

Acute response

Number

Good

Total

None

Partial Marked

11 6 2

3 5 7

11 6 15

25 17 24

Total

19

15

32

66 *

* Mantel-Haenszel

x2 = 4.8; P = 0.03.

Poor

of patients Fair

STEPWISE CLINICAL COME

DISCRIMINANT PREDICTORS

OF

ANALYSIS OF POSSIBLE LONGITUDINAL OUT-

by outcome Good

Bipolar Non-melancholic Melancholic Delusional

* Mantel-Haenszel

DIAGNOSTIC

Number

Unipolar Non-melancholic Melancholic Delusional Total

BY

by outcome

TO

Variable

R=

F

P

Acute response Number of prior hospitalizations Number of prior suicide attempts Dysthymia Age Sex

0.14 0.00 0.02 0.04 0.03 0.04

4.7 0.0 0.6 1.3 0.8 1.5

0.01 0.96 0.54 0.29 0.47 0.23

outcome, 20% (3/15) had been non-responders, 33% (S/15) partial, and 47% (7/15) marked responders. Of patients with a good outcome, 34% (11/32) had been non-responders, 19% (6/32) partial, and 47% (15/32) marked responders. These differences were statistically significant (P < 0.03). Stepwise discriminant analysis revealed that, aside from acute response to lithium augmentation, outcome could not be predicted on the basis of any of the other variables examined (i.e., sex, age, number of prior hospitalizations, number of prior suicide attempts, prior history of dysthymia) (Table 4). Using the Kaplan-Meier method, life table analysis estimated a cumulative probability of 36% that a patient would meet criteria for a poor outcome, with mean time until the occurrence of a poor outcome = 40.6 + 25 months. Stratifying by acute response to lithium augmentation showed that by 37 months after discharge, the cumulative probability of a poor outcome was 66% for nonresponders, 36% for partial, and 12% for marked responders (Fig. 1). For the three acute response categories, mean times until a poor outcome occurred were 25.5 _t 22.7 months, 29.6 +_ 21.5 months, and 52.9 + 18.7 months, respectively. Significant differences were present in comparing the life table curves of marked vs. non-responders (Wilcoxon-Breslow statistic = 11.24, Q”= 1, P < 0.001) and marked vs. the combined group of partial plus non-responders (statistic = 10.38, df= 1, P = 0.001). None of the marked responders had a poor outcome occur until 19 months after discharge. Stepwise Cox regression analysis using a maximum partial likelihood ratio test showed that acute response to lithium augmentation was the

172 TABLE

5

SUBSEQUENT

TREATMENTS

Discharge medicatmns

FOR LITHIUM

No change

TC‘A alone I?=1 TCA + Li N= 3 MAO1 alone II=1 MAO1 + LI n=9 LI alone n=4 LI + ALP II=1 Li + AntIpsych ?I=2 Other n=4 Total n = 25

AUGMENTATION

NON-RESPONDERS

T(‘A

MAOI

Antlpsych

EC‘T

Other

0

1

0

1

0

I (TRZ)

0

0

2

2

2

I (CARB)

1

0

0

0

(1

0

6

2

0

3

I

0

3

1

0

0

0

0

1

0

0

0

0

0

1

0

2

0

0

1 (BUP)

2

0

2

0

I

1 (BUP)

14

4

6

6

4

4

TCA. trlcyclic; LI. lithium: ALP. alprazolam: Antipsych. antlpsychotx: Other, fluvoxamine, mianxerin. or bupropion. The total number of trials IS greater than n because some individuals

BUP. bupropion;

TRZ. trazodone;

had more than one subsequent

CARB.

carbamazepine;

trial,

only predictor of a poor outcome when marked responders were compared to the combined group of partial and non-responders (global x2 = 8.04, df= 1, P = 0.005for the model; improvement in xZ with the addition of lithium response = 9.54,

viding the entire sample into quartiles showed that, early in follow-up. times to discontinuation of antidepressant or lithium were similar for a given proportion of patients: 25% had discontinued the antidepressant by 6 months and lithium

P = 0.002).

by 4 months, and 50% had discontinued the antidepressant by 15 months and lithium by 13 months. However, while 75% had stopped the antidepressant by 24 months, the same proportion did not stop lithium until 36 months. Interestingly, 25% of the marked responders stopped their medications within 6 months. but only one of these six patients relapsed (with a fair outcome). Non-responders to the acute trial of lithium augmentation were subsequently treated by us with other drugs in an effort to induce some clinical improvement (Table 5). Fifty-six percent of these patients (14/25) had no changes in their medications subsequent to their discharge from our program; of these. 50% (7/14) were taking an MAOI (alone or with lithium), 36% (5/14) lithium (alone, with alprazolam, or with a neuroleptic) and 14% (2/14) fluvoxamine with lithium and a neuroleptic. The remainder had subsequent trials of

Life table continuation lithium did

analysis

showed

that

the duration

treatment with an antidepressant not predict subsequent course.

of or Di-

Fig. 1. Life table analysis showing time to poor longitudinal outcome for patients grouped by acute marked, partial, or non-response to lithium augmentatmn. See text for discuwon.

173

tricyclic antidepressants, MAOIs, neuroleptics, and other atypical antidepressants (bupropion, trazodone. carbamazepine). Only 16% (4/25) of non-responders to lithium augmentation were ever treated with ECT. Two of these were treated within 3 months of the lithium augmentation trial, while the other two were not treated with ECT until at least 12 months later. In the sample of 38 patients interviewed faceto-face on follow-up. the mean total score of the modified 25-item HDRS was 14.5 f 12.3 (range O-43). Fifty-eight percent of these patients had scores of < 15, the criterion for marked improvement in the acute phase of this study. Seven of the 10 patients considered to have a continuous refractory depression were evaluated with the HDRS. Six of these seven had HDRS scores of > 20. Discussion

In this sample of depressed patients with documented refractoriness to antidepressant treatment, 29% had a poor outcome, 23% had a fair outcome, and 48% had a good outcome within 37 months after lithium augmentation. These findings are in accord with those reported in a recent comprehensive literature review of the longitudinal course of relapses in affective disorders (Lavori et al., 1984). Lavori et al. (1984) using life table methods to re-analyze data from five studies with sufficient data. found a median ‘survival’ rate (i.e., good outcome) of 40% after 36 months. Patients in these studies were unselected in terms of treatment response. Thus, our data suggest that even if patients are refractory to an antidepressant alone, their course after lithium augmentation may be similar to that of unselected depressed patients. Of the patients in this study who initially had a marked response to lithium augmentation, none had a poor outcome until 19 months after discharge. By 37 months, statistically significant differences were evident between marked responders and other treatment response groups. This suggests that acute response to lithium augmentation may have prognostic importance for the long-term course of antidepressant refractory depression. Marked responders appear to have better outcomes than partial and non-responders, even when

the effects of response to subsequent treatments are taken into account. Although in this study the outcomes of partial and non-responders to lithium augmentation did not differ from each other, this must be interpreted cautiously because of limited power. The outcomes (five good, one fair) of the six marked responders who took medication for < 6 months are particularly intriguing, and reminiscent of the observation of remissions sustained for at least 5 days following discontinuation of lithium given for only 48 h in some rapid responders to augmentation (deMontigny et al.. 1983). Prien and Kupfer (1986) found that the greatest vulnerability to recurrence in unselected depressed patients is within the first 4-5 months after recovery, with recurrence rates of 50% during placebo and 20% during active drug treatment. On the basis of these findings, a substantial number of poor outcomes would have been expected in our drug-free refractory patients. However, reviews of longitudinal studies of depression point out that prediction of recurrence is highly problematic at best, complicated by the tendency of some patients to suffer ‘bursts’ of episodes interspersed with long periods of remission (Coryell and Winokur, 1982; Jablenski, 1987). These data did not permit a systematic evaluation of the differential efficacy of subsequent treatments given to patients who were acute nonresponders to lithium augmentation. However, 34% of these patients had a good outcome, and our impression was that this more often reflected response to a subsequent treatment trial rather than spontaneous remission. Other studies suggest that some non-responders to lithium augmentation of heterocyclic antidepressants will respond to treatment with a lithium-MAO1 combination (Price et al., 1985) or to lithium augmentation of a potent and selective serotonin reuptake inhibitor (Delgado et al., 1988). Of note in the present data is the suggestion that ECT may be underutilized in the treatment of such patients. This study suggests that the outcomes of patients with documented refractory depression are heterogeneous. An initial marked response to lithium augmentation appears to predict a good outcome, whereas partial and non-responders resemble each other in having a less benign course.

174

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