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Increased motor activity and recurrent manic episodes: Predictors of rapid relapse in remitted bipolar disorder patients after lithium discontinuation
BIOL PSYCHIATRY 1992;3 ! ~2"~9--284
279
Increased Motor Activity and Recurrent Manic Episodes: Predictors of Rapid Relapse in Remitted Bipolar Disorder Patients after Lithium Discontinuation E. Klein, P. Lavie, R. Meiraz, A. Sadeh, and R. H. Lenox*
Ten patients with remitted bipolar illness on lithium maintenance therapy underwent placebo-controlled lithium discontinuation. Clinical ratings and recording of sleep-wake activity using wrist-worn actigraphs were carried out before and after lithium discontinuation. Seven patients experienced relapse into mani~ or hypomania within the first 3 months after lithium discontinuation. Actigraphic recordings revealed that patients who relapsed had higher baseline levels of daytime motor activity than patients without relapse. This may suggest ithat motor activity can be a sensitive marker of subclinical manic tendencies and early relapse following lithium discontinuation.
Introduction Lithium plays an unequivocal role in the prophylactic treatment of bipolar disorder (BD) (Angst et al 1970; Baastmp and Schou 1967) and the management of acute manic agitation (Goodwin and Ebert 1973). Though the indications for initiation of fi~hium treatment in BD patients are relatively well defined, cessation of chronic lithium treatment is more ambiguous. Many clinicians would agree that even with complete clinical remission many patients require life-long treatment (Rifkin 1980). However, because of lithium's side effects and potential toxicity, discontinuation has to be considered in many cases. Few controlled studies of lithium discontinuation have been published, and these suggested relapse rates of 30%-50% over a l-year period (Baastmp et al 1970; Christodoulou and Lykouras 1982; Margo and McMahon 1982; Strober et al 1990). Furthermore, some of the studies indicate that early rebound may occur in some cases following lithium discontinuation (Lapierre et al 1980; Mander 1986). Changes in sleep and motor activity are well-known features of a developing affective episode. Depressed patients show characteristic changes in sleep (Foster and Kupfer 1975; Kupfer et al 1977), and tend to become hypoactive during daytime hours (Wolff et al
From the Department of Psychiatry, Rambam Medical Center, Haifa (EK, lOCI), Sleep Laboratory, Faculty of Medicine, Tochnion, Haifa (PL, AS), and the Depamnent of Psychiatry, Universi~ of Vermont, Vermont USA (PAIL). Address reprint requests to E. Klein, M.D., Department of Psychiatry, Rambam Medical Center, lOB 9602, Haifa 31096, Israel. Received November 20, 1990; revised July 27, 1991. *Preliminary data from this study were presented in pan at the 142rid Annual Meeting of the APA, San Francisco, May 6-I1, 1989. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
280
E. Klein et al
BIOL PSYCHIATRY 1992;31:279-284
Table 1. Patients's Clinical Characterh;fics° Number of patients Age Duration of illness Age on onset
I0 (6n~4f) 49.1 _ 1 2 . 4 y r 24.2 _ 9.6 yr 25.6 - 5.8 yr
Number of hospitalizations Before lithium treatment On lithium treatment
2.8 +- 1.6 0.3 +- 0.5
Number of affective episodes Before lithium treatment On lithium treatment
2.7 .4- 2.5 M / I . 7 -+ 1.8 D 0.1 +_ 0.3 M/0.2 ± 0.4 D
Duration of illness before lithium Duration on lithium treatment Duration of clinical remission (lithium only) Lithium dose Lithium blood level
15.2 +_ 8.2 (yr) 9.1 -+ 4.2 (yr) 7.2 _+ 4.4 (yr) 1005 __ 283 mg/day 0.75 _ 0.04 mEq/L
M = mania; D = depression. "Values given as means +_ SD.
1985), whereas patients with mania show reduced need for sleep and increased rate of motor activity (Weiss et al 1979). Measurement and quantification of these changes have become simple and inexpensive with the recent advent of computerized wrist actigraphs (Redmond and Hegge 1985). This methodology allows continuous monitoring of sleep-wake cycle in the naturalistic environment of the patient's daily life. In the present study, lithium was discontinued blindly in 10 remitted bipolar patients using, in conjunction with the clinical assessment, wrist-worn actigraphs to monitor changes in sleep-wake cycles.
Methods
Patients Ten patients from our lithium outpatient clinic gave informed consent to their participation. All satisfied the DSM-III-R criteria (American Psychiatric Association 1987) for BD and were in a state of stable clinical remission on lithium as a single medication for at least 3 yeats. Data on the patients and the course of their illness are summarized in Table 1.
Study Design The study was of a double-blind single group crossover (nonrandomized) design in which all patients initially received lithium followed by placebo. During baseline, patiems received lithium at their previous dose for periods ranging from 3 to 8 weeks. The reason for the variable baseline period was to assure the blindness of the treating physician to the time of lithium replacement by placebo. Baseline clinical ratings included the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) and the Hamilton Depression Rating Scale (HDRS) (Hamilton 1960). Lithium blood levels were within therapeutic range in all patients. Following baseline, at a time unknown to either the patient or the
Motor Activity and Effects of Lithium Discontinuation
BIOL PSYCHIATRY 1992;3 ! :279-284
281
physician (RM), lithium was stopped abruptly and substituted by identical-looking placebo tablets. Patients continued regular visits to the clinic every other week, or more if necessary, and clinical ratings were performed. To further ensure the blindness of the treating physician, blood lithium levels were determined as before, and the physician was given fictitious results. In patients showing evidence of relapse, lithium treatment was reinstituted.
Actigraphic Monitoring Actigraphic recordings were performed during baseline and after lithium discontinuation for periods of 72 consecutive hr, using a computerized wrist actigraph as previously described (Sadeh et al 1989). In a previous study, we showed 80%-90% agreement between polysomnographic recordings and acdgraphic recordings with respect to determination of sleep and wakefulness in patients with sleep disorders and in normal controls (Sadeh et al 1989). In this study, movements were sampled at a constant rate of 10 Hz and were accumulated in the actigraph's memory every min. Actigraphic recordings were taken at baseline (while still on lithium) and following lithium discontinuation. During the baseline period every patient was recorded once, and after lithium discontinuation most patients were recorded 2-3 times. For those who relapsed, the recording closest to the relapse period was used for the analysis. The algorithm used to analyze the actigraphic recordings (Sadeh et al 1989) provided data on sleep duration, sleep efficiency, bedtime (sleep) activity, and daytime (wake) activity.
Data Analysis Statistical analysis of clinical ratings was performed by one-way analysis of variance (ANOVA) with repeated measures comparing the treatment conditions, that is, baseline on lithium, lithium discontinuation, and after restabilization on lithium for those who relapsed. For those who remained clinically stable on placebo, ratings were also obtained 3 and 6 months after cessation of lithium. Actigraphic data were analyzed by multiple analysis of variance (MANOVA) with repeated measures.
Results
Clinical Outcome Following lithium discontinuation, seven patients experienced a relapse into mania or hypomania within 3 months or less. The mean duration of the lithium baseline period was 41.5 - 17.6 days. In the seven patients who relapsed, the mean duration on placebo until relapse was 43 _ 31 days, and mean time for restabilization after lithium reinstitution was 2.~ _+ 21 days. Figure 1 shows the changes in the BPRS scores during the different treatment periods for the entire group. ANOVA revealed a significant treatment effect (on-off-on lithium) (F~27 - 19.09, p < 0.00001). Post hoc analysis revealed that BPRS scores during peak symptoms off-lithium were significantly higher than those during baseline (F,/~s - 22.66,
282
E. Klein et al
BIOL PSYCHIATRY 1992;31:279-284
30
4)
m
20
u
n_
On Lithium
Off Lithium
On Lithium
Figure 1. Mean BPRS scores at the different time points: before lithium discontinuation, after lithium discontinuation, and after restabilization on lithium for those who relapsed, or 6 months after lithium discontinuation for nonrelapsers.
p < 0.0003), and those during restabilization after restoration of lithium therapy (F,/,s = 16.44, p < 0.0008).
Actigraphic Recordings Table 2 summarizes the actigraphic data. Relapsers did not differ from nonrelapsers in their sleep efficiency or sleep activity, neither on lithium nor after lithium discontinuation. However, significant differences were found in daytime motor activity. MANOVA revealed a group main effect (relapsers versus nonrelapsers) with respect to daytime motor activity (FI/8 = 7.64, p < 0.03) without any evidence for an interaction. Relapsers had higher levels of activity when clinically euthymic on lithium, and after relapse, compared with nonrelapsers (181.3 _ 45.3 versus 131.9 __. 49.0 on lithium, and 210.8 -4" 21.9 versus 127.6 _+ 39.7 off lithium, respectively). Although sleep duration during baseline tended to be longer in relapsers, this difference was not statistically significant possibly due to the small number of nonrelapsers.
Table 2. Summary of Actigraphic Data On lithium
Daytime activity Sleep activity Sleep duration (min) Sleep efficiency (%)
Off lithium
Relapsers (n=7)
Nonrelaps. ( n = 3)
Relapsers (n = 7 )
Nom'elaps. (n-3)
181 ± 45 II ± 3 435 ± 25
132 ± 49 I0 -.+ 4 343 ± 9.•
211 ± ~,2 16 ± II 379 ± 78
128 ± 40 9 ± 4 341 ± 14
88 ± 4
81 ± I!
89 ± 7
91 ± 6
Motor Activity and Effects of Lithium Discontinuation
BIOL PSYCHIATRY 1992;31:279-284
283
Discussion In this study, 10 patients with BD, in long-term remission on lithium as the only treatment, were taken off lithium under double-blind conditions in a prospective study. Seven had a relapse, as defined by an operational criterion of a clinical change significant enough to justify renewal of lithium treatment according to the clinical judgment of two independent psychiatrists. Based on studies that have been published, it is estimated that approximately 30% of patients taken off chronic lithium are able to maintain long-term clinic~ remission (Baastrup et al 1970). Reports on controlled lithium discontinuation (Baastrup et al 1970; Chfistodoulou and Lykouas 1982; Margo :mr McMabon 1982; Strober et al 1990) indicate that over a l-year follow-up, 30%-50% of patients experience relapse while receiving placebo. These figures are 2-3-fold higher compared with lithium-treated patients. The relapse rate in our patients was higher (70%). From the "prelithium" clinical history of our patients, we predicted 6 relapsers o':er I year following lithium discontinuation. The fact that 4 relapses occurred within ? weeks and 7 within 3 months might suggest a rebound phenomenon, as has been implied by other investigators (Lapierre et al 1980; Mander and Loadin 1988). However, it is important to remember that lithium treatment in our patients was discontinued abruptly, a fact that might have contributed to the high relapse rate and rebound phenomena. Obviously, a comparison of abrupt discontinuation versus gradual tapering off is needed in order to further clarify this point. Predominance of previous manic episodes was evident in four of the patients who relapsed, and in none of those who remained euthymic. This, taken together with the fact that all relapsers were inte mania, may suggest that the manic manifestations of BD are more susceptible to lithium discontinuation. For obvious ethical reasons, treatment was reinstituted once clinical symptoms of relapse were evident without waiting for further deterioration. Thi~ resulted in relatively low rating scores during the relapse period (mean 12.7 _+ 7.7). The analysis of the actigraphic data using a conservative statistical procedure indicates that relapsers had significantly higher levels of daytime activity even while on lithium and clinically asymptomatic; this difference was further increased after lithium discontinuation. Comparison of the data of nonrelapsers before and after lithium discontinuation showed no evidence that lithium per se had any effect on actigraphic measurements, a finding in agreement with an earlier report (Heninger and Kirstein 1977). We propose that the level of motor activity may be a sensitive marker of the activity of the underlying bipolar process. Such subclinical manic traits evidenced by the increased activity could not be detected by our clinical ratings (BPRS). It is possible, however, that more specific rating scales for manic symptomatology would be more sensitive in detecting these trai~ts.
References Angst J, Weiss P, Groff P, et al (1970): Lithium prophylaxis in recurrent affective disorder. Br J Psychiatry 116:601-611. American Psychiatric Association, Committee on Nonenclature and Statistics (1987): Diagnostic and StatisticalManualof Mental Disorders (ed) 3 revised. Washington DC: American Psychiatric Association. Baastrup PC (1980): Lithium in the prophylactic treatment of recurrent affective disorders. In Johnson FN (ed), Handbook of Lithium Therapy. Lancaster, England: MTP Press, pp 26-38.
284
BIOL PSYCHIATRY 1992;31:279-2~4
E. Klein et al
Baastrup PC, Schou M (1967): Lithium as a prophylactic agent: Its effect against recurrent depressions and mani¢-dcpres~ve psychosis. Arch Gen Psychiatry 16:162-172. Baastrup PC, Poulscn JC, Schou M, et al (1970): Prophylactic lithium: Double-blind discontinuation in manic-depress~ve and recurrent depressive disorders. Lancet 2:326-333. Christodoulou GN, Lykouras EP (1982): Abrupt lithium discontinuation in manic-depressive patients. Acta Psychiatr Scand 65:310-314. Foster FG, Kupfer DJ (1975): Psychomotor activity as a correlate of depression and sleep in acutely disturbed psychiatric inpatients. Am J Psychiatry 132:928-931. Goodwin FK, Ebert MH (1973): Lithium in mania: Clinical trials and controlled studies. In Gershon S, Shopsin B (eds), Lithium: Its Role in Psychiatric Research and Treatment. New York: Plenum Press, pp 237-252. Hamilton A (1960): A psychiatric rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Heninger GR, Kirstein MD (1977): Effects of lithium carbonate on motor activity in mania and depression. J Nerv Ment Dis 164:168-175. Kupfer DJ, Foster FG, Detre TP (1977): EEG sleep changes as predictors in depression. Am J Psychiatry 133:622-626. Lapierre YD, Gagnon A, Kokkinidis L (1980): Rapid recurrence of mania following lithium withdrawal. Biol Psychiatry 15:859-864. Mander AJ (1986): Is there a lithium withdrawal syndrome? Br J Psychiatry 149:498-501. Mander AJ, Loudin JB (1988): Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet 2:15-17. Margo A, McMahon P (1982): Lithium withdrawal triggers psychosis. Br J Psychiatry 141:407410. Overall JE, Gorham DR (1962): The brief psychiatric rating scale. Psvchol Rep 10:799-812. Redmond DP, Hegge FW (1985): Observations on the design and specifications of a wrist-worn human-activity-monitoring system. Behav Res Methods lnstrum Comput 17:659-669. Rifkin A (1980): Terminating lithium treatment, in Johnson FN (ed), Handbook of Lithium Therapy. Lancaster, England: MTP Press, pp 255-264. Sadeh A, AIster J, Urbach D, Lavie P (1989): Actigraphically based automatic bedtime sleep-wake scoring: Validity and clinical application. J Ambulatory Monitoring 2:209-216. Strober M, Morrell W, Lampert C, Burroughts J (1990): Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar I illness: A naturalistic study. Am J Psychiatry 147:457-461. Weiss BL, Foster FG, Reynolds CF, et al (1979): Psychomotor activity in mania. Arch Gen Psychiatry 31:379-383. Wolff EA, Putnam FW, Post RM (1985): Motor activity and affective illness. Arch Gen Psychiatry 42:288-294.
279
Increased Motor Activity and Recurrent Manic Episodes: Predictors of Rapid Relapse in Remitted Bipolar Disorder Patients after Lithium Discontinuation E. Klein, P. Lavie, R. Meiraz, A. Sadeh, and R. H. Lenox*
Ten patients with remitted bipolar illness on lithium maintenance therapy underwent placebo-controlled lithium discontinuation. Clinical ratings and recording of sleep-wake activity using wrist-worn actigraphs were carried out before and after lithium discontinuation. Seven patients experienced relapse into mani~ or hypomania within the first 3 months after lithium discontinuation. Actigraphic recordings revealed that patients who relapsed had higher baseline levels of daytime motor activity than patients without relapse. This may suggest ithat motor activity can be a sensitive marker of subclinical manic tendencies and early relapse following lithium discontinuation.
Introduction Lithium plays an unequivocal role in the prophylactic treatment of bipolar disorder (BD) (Angst et al 1970; Baastmp and Schou 1967) and the management of acute manic agitation (Goodwin and Ebert 1973). Though the indications for initiation of fi~hium treatment in BD patients are relatively well defined, cessation of chronic lithium treatment is more ambiguous. Many clinicians would agree that even with complete clinical remission many patients require life-long treatment (Rifkin 1980). However, because of lithium's side effects and potential toxicity, discontinuation has to be considered in many cases. Few controlled studies of lithium discontinuation have been published, and these suggested relapse rates of 30%-50% over a l-year period (Baastmp et al 1970; Christodoulou and Lykouras 1982; Margo and McMahon 1982; Strober et al 1990). Furthermore, some of the studies indicate that early rebound may occur in some cases following lithium discontinuation (Lapierre et al 1980; Mander 1986). Changes in sleep and motor activity are well-known features of a developing affective episode. Depressed patients show characteristic changes in sleep (Foster and Kupfer 1975; Kupfer et al 1977), and tend to become hypoactive during daytime hours (Wolff et al
From the Department of Psychiatry, Rambam Medical Center, Haifa (EK, lOCI), Sleep Laboratory, Faculty of Medicine, Tochnion, Haifa (PL, AS), and the Depamnent of Psychiatry, Universi~ of Vermont, Vermont USA (PAIL). Address reprint requests to E. Klein, M.D., Department of Psychiatry, Rambam Medical Center, lOB 9602, Haifa 31096, Israel. Received November 20, 1990; revised July 27, 1991. *Preliminary data from this study were presented in pan at the 142rid Annual Meeting of the APA, San Francisco, May 6-I1, 1989. © 1992 Society of Biological Psychiatry
0006-3223/92/$05.00
280
E. Klein et al
BIOL PSYCHIATRY 1992;31:279-284
Table 1. Patients's Clinical Characterh;fics° Number of patients Age Duration of illness Age on onset
I0 (6n~4f) 49.1 _ 1 2 . 4 y r 24.2 _ 9.6 yr 25.6 - 5.8 yr
Number of hospitalizations Before lithium treatment On lithium treatment
2.8 +- 1.6 0.3 +- 0.5
Number of affective episodes Before lithium treatment On lithium treatment
2.7 .4- 2.5 M / I . 7 -+ 1.8 D 0.1 +_ 0.3 M/0.2 ± 0.4 D
Duration of illness before lithium Duration on lithium treatment Duration of clinical remission (lithium only) Lithium dose Lithium blood level
15.2 +_ 8.2 (yr) 9.1 -+ 4.2 (yr) 7.2 _+ 4.4 (yr) 1005 __ 283 mg/day 0.75 _ 0.04 mEq/L
M = mania; D = depression. "Values given as means +_ SD.
1985), whereas patients with mania show reduced need for sleep and increased rate of motor activity (Weiss et al 1979). Measurement and quantification of these changes have become simple and inexpensive with the recent advent of computerized wrist actigraphs (Redmond and Hegge 1985). This methodology allows continuous monitoring of sleep-wake cycle in the naturalistic environment of the patient's daily life. In the present study, lithium was discontinued blindly in 10 remitted bipolar patients using, in conjunction with the clinical assessment, wrist-worn actigraphs to monitor changes in sleep-wake cycles.
Methods
Patients Ten patients from our lithium outpatient clinic gave informed consent to their participation. All satisfied the DSM-III-R criteria (American Psychiatric Association 1987) for BD and were in a state of stable clinical remission on lithium as a single medication for at least 3 yeats. Data on the patients and the course of their illness are summarized in Table 1.
Study Design The study was of a double-blind single group crossover (nonrandomized) design in which all patients initially received lithium followed by placebo. During baseline, patiems received lithium at their previous dose for periods ranging from 3 to 8 weeks. The reason for the variable baseline period was to assure the blindness of the treating physician to the time of lithium replacement by placebo. Baseline clinical ratings included the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) and the Hamilton Depression Rating Scale (HDRS) (Hamilton 1960). Lithium blood levels were within therapeutic range in all patients. Following baseline, at a time unknown to either the patient or the
Motor Activity and Effects of Lithium Discontinuation
BIOL PSYCHIATRY 1992;3 ! :279-284
281
physician (RM), lithium was stopped abruptly and substituted by identical-looking placebo tablets. Patients continued regular visits to the clinic every other week, or more if necessary, and clinical ratings were performed. To further ensure the blindness of the treating physician, blood lithium levels were determined as before, and the physician was given fictitious results. In patients showing evidence of relapse, lithium treatment was reinstituted.
Actigraphic Monitoring Actigraphic recordings were performed during baseline and after lithium discontinuation for periods of 72 consecutive hr, using a computerized wrist actigraph as previously described (Sadeh et al 1989). In a previous study, we showed 80%-90% agreement between polysomnographic recordings and acdgraphic recordings with respect to determination of sleep and wakefulness in patients with sleep disorders and in normal controls (Sadeh et al 1989). In this study, movements were sampled at a constant rate of 10 Hz and were accumulated in the actigraph's memory every min. Actigraphic recordings were taken at baseline (while still on lithium) and following lithium discontinuation. During the baseline period every patient was recorded once, and after lithium discontinuation most patients were recorded 2-3 times. For those who relapsed, the recording closest to the relapse period was used for the analysis. The algorithm used to analyze the actigraphic recordings (Sadeh et al 1989) provided data on sleep duration, sleep efficiency, bedtime (sleep) activity, and daytime (wake) activity.
Data Analysis Statistical analysis of clinical ratings was performed by one-way analysis of variance (ANOVA) with repeated measures comparing the treatment conditions, that is, baseline on lithium, lithium discontinuation, and after restabilization on lithium for those who relapsed. For those who remained clinically stable on placebo, ratings were also obtained 3 and 6 months after cessation of lithium. Actigraphic data were analyzed by multiple analysis of variance (MANOVA) with repeated measures.
Results
Clinical Outcome Following lithium discontinuation, seven patients experienced a relapse into mania or hypomania within 3 months or less. The mean duration of the lithium baseline period was 41.5 - 17.6 days. In the seven patients who relapsed, the mean duration on placebo until relapse was 43 _ 31 days, and mean time for restabilization after lithium reinstitution was 2.~ _+ 21 days. Figure 1 shows the changes in the BPRS scores during the different treatment periods for the entire group. ANOVA revealed a significant treatment effect (on-off-on lithium) (F~27 - 19.09, p < 0.00001). Post hoc analysis revealed that BPRS scores during peak symptoms off-lithium were significantly higher than those during baseline (F,/~s - 22.66,
282
E. Klein et al
BIOL PSYCHIATRY 1992;31:279-284
30
4)
m
20
u
n_
On Lithium
Off Lithium
On Lithium
Figure 1. Mean BPRS scores at the different time points: before lithium discontinuation, after lithium discontinuation, and after restabilization on lithium for those who relapsed, or 6 months after lithium discontinuation for nonrelapsers.
p < 0.0003), and those during restabilization after restoration of lithium therapy (F,/,s = 16.44, p < 0.0008).
Actigraphic Recordings Table 2 summarizes the actigraphic data. Relapsers did not differ from nonrelapsers in their sleep efficiency or sleep activity, neither on lithium nor after lithium discontinuation. However, significant differences were found in daytime motor activity. MANOVA revealed a group main effect (relapsers versus nonrelapsers) with respect to daytime motor activity (FI/8 = 7.64, p < 0.03) without any evidence for an interaction. Relapsers had higher levels of activity when clinically euthymic on lithium, and after relapse, compared with nonrelapsers (181.3 _ 45.3 versus 131.9 __. 49.0 on lithium, and 210.8 -4" 21.9 versus 127.6 _+ 39.7 off lithium, respectively). Although sleep duration during baseline tended to be longer in relapsers, this difference was not statistically significant possibly due to the small number of nonrelapsers.
Table 2. Summary of Actigraphic Data On lithium
Daytime activity Sleep activity Sleep duration (min) Sleep efficiency (%)
Off lithium
Relapsers (n=7)
Nonrelaps. ( n = 3)
Relapsers (n = 7 )
Nom'elaps. (n-3)
181 ± 45 II ± 3 435 ± 25
132 ± 49 I0 -.+ 4 343 ± 9.•
211 ± ~,2 16 ± II 379 ± 78
128 ± 40 9 ± 4 341 ± 14
88 ± 4
81 ± I!
89 ± 7
91 ± 6
Motor Activity and Effects of Lithium Discontinuation
BIOL PSYCHIATRY 1992;31:279-284
283
Discussion In this study, 10 patients with BD, in long-term remission on lithium as the only treatment, were taken off lithium under double-blind conditions in a prospective study. Seven had a relapse, as defined by an operational criterion of a clinical change significant enough to justify renewal of lithium treatment according to the clinical judgment of two independent psychiatrists. Based on studies that have been published, it is estimated that approximately 30% of patients taken off chronic lithium are able to maintain long-term clinic~ remission (Baastrup et al 1970). Reports on controlled lithium discontinuation (Baastrup et al 1970; Chfistodoulou and Lykouas 1982; Margo :mr McMabon 1982; Strober et al 1990) indicate that over a l-year follow-up, 30%-50% of patients experience relapse while receiving placebo. These figures are 2-3-fold higher compared with lithium-treated patients. The relapse rate in our patients was higher (70%). From the "prelithium" clinical history of our patients, we predicted 6 relapsers o':er I year following lithium discontinuation. The fact that 4 relapses occurred within ? weeks and 7 within 3 months might suggest a rebound phenomenon, as has been implied by other investigators (Lapierre et al 1980; Mander and Loadin 1988). However, it is important to remember that lithium treatment in our patients was discontinued abruptly, a fact that might have contributed to the high relapse rate and rebound phenomena. Obviously, a comparison of abrupt discontinuation versus gradual tapering off is needed in order to further clarify this point. Predominance of previous manic episodes was evident in four of the patients who relapsed, and in none of those who remained euthymic. This, taken together with the fact that all relapsers were inte mania, may suggest that the manic manifestations of BD are more susceptible to lithium discontinuation. For obvious ethical reasons, treatment was reinstituted once clinical symptoms of relapse were evident without waiting for further deterioration. Thi~ resulted in relatively low rating scores during the relapse period (mean 12.7 _+ 7.7). The analysis of the actigraphic data using a conservative statistical procedure indicates that relapsers had significantly higher levels of daytime activity even while on lithium and clinically asymptomatic; this difference was further increased after lithium discontinuation. Comparison of the data of nonrelapsers before and after lithium discontinuation showed no evidence that lithium per se had any effect on actigraphic measurements, a finding in agreement with an earlier report (Heninger and Kirstein 1977). We propose that the level of motor activity may be a sensitive marker of the activity of the underlying bipolar process. Such subclinical manic traits evidenced by the increased activity could not be detected by our clinical ratings (BPRS). It is possible, however, that more specific rating scales for manic symptomatology would be more sensitive in detecting these trai~ts.
References Angst J, Weiss P, Groff P, et al (1970): Lithium prophylaxis in recurrent affective disorder. Br J Psychiatry 116:601-611. American Psychiatric Association, Committee on Nonenclature and Statistics (1987): Diagnostic and StatisticalManualof Mental Disorders (ed) 3 revised. Washington DC: American Psychiatric Association. Baastrup PC (1980): Lithium in the prophylactic treatment of recurrent affective disorders. In Johnson FN (ed), Handbook of Lithium Therapy. Lancaster, England: MTP Press, pp 26-38.
284
BIOL PSYCHIATRY 1992;31:279-2~4
E. Klein et al
Baastrup PC, Schou M (1967): Lithium as a prophylactic agent: Its effect against recurrent depressions and mani¢-dcpres~ve psychosis. Arch Gen Psychiatry 16:162-172. Baastrup PC, Poulscn JC, Schou M, et al (1970): Prophylactic lithium: Double-blind discontinuation in manic-depress~ve and recurrent depressive disorders. Lancet 2:326-333. Christodoulou GN, Lykouras EP (1982): Abrupt lithium discontinuation in manic-depressive patients. Acta Psychiatr Scand 65:310-314. Foster FG, Kupfer DJ (1975): Psychomotor activity as a correlate of depression and sleep in acutely disturbed psychiatric inpatients. Am J Psychiatry 132:928-931. Goodwin FK, Ebert MH (1973): Lithium in mania: Clinical trials and controlled studies. In Gershon S, Shopsin B (eds), Lithium: Its Role in Psychiatric Research and Treatment. New York: Plenum Press, pp 237-252. Hamilton A (1960): A psychiatric rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Heninger GR, Kirstein MD (1977): Effects of lithium carbonate on motor activity in mania and depression. J Nerv Ment Dis 164:168-175. Kupfer DJ, Foster FG, Detre TP (1977): EEG sleep changes as predictors in depression. Am J Psychiatry 133:622-626. Lapierre YD, Gagnon A, Kokkinidis L (1980): Rapid recurrence of mania following lithium withdrawal. Biol Psychiatry 15:859-864. Mander AJ (1986): Is there a lithium withdrawal syndrome? Br J Psychiatry 149:498-501. Mander AJ, Loudin JB (1988): Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet 2:15-17. Margo A, McMahon P (1982): Lithium withdrawal triggers psychosis. Br J Psychiatry 141:407410. Overall JE, Gorham DR (1962): The brief psychiatric rating scale. Psvchol Rep 10:799-812. Redmond DP, Hegge FW (1985): Observations on the design and specifications of a wrist-worn human-activity-monitoring system. Behav Res Methods lnstrum Comput 17:659-669. Rifkin A (1980): Terminating lithium treatment, in Johnson FN (ed), Handbook of Lithium Therapy. Lancaster, England: MTP Press, pp 255-264. Sadeh A, AIster J, Urbach D, Lavie P (1989): Actigraphically based automatic bedtime sleep-wake scoring: Validity and clinical application. J Ambulatory Monitoring 2:209-216. Strober M, Morrell W, Lampert C, Burroughts J (1990): Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar I illness: A naturalistic study. Am J Psychiatry 147:457-461. Weiss BL, Foster FG, Reynolds CF, et al (1979): Psychomotor activity in mania. Arch Gen Psychiatry 31:379-383. Wolff EA, Putnam FW, Post RM (1985): Motor activity and affective illness. Arch Gen Psychiatry 42:288-294.