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Lithium treatment in a very elderly nursing home population
Lithium Treatment
in a Very Elderly Nursing Home Population
Matthew Bushey, Ulrich Rathey, and Malcolm B. Bowers, Jr.
L
ITTLE information regarding the use of lithium in very elderly patients is presently available. This paper deals with results of lithium treatment and occurrence of adverse effects in a closely monitored elderly nursing home population. Particular attention is focused on recent increased concern about lithium-induced renal toxicity and the more well-established side effect of hypothyroidism. The study group is unusual in that it consists of a very aged population monitored over a number of years in a nursing home environment under close, on-site medical staff supervision. METHOD The charts of patients who had received lithium following psychiatric consultation during the last Home and Hospital in Wallingford, Connecticut, were reviewed. The same psychiatrist (Malcolm B. Bowers, Jr.) diagnosed and followed the entire patient group throughout the study period. Information collected included sex, psychiatric and major medical diagnoses, age at beginning of lithium therapy, average serum lithium levels, overall response to therapy, and occurrence of side effects. Psychiatric diagnoses and responses to lithium therapy were evaluated by a single consulting psychiatrist who utilized observations of permanent medical staff members, combined with biweekly patient interviews over the 15-yr period. The following qualitative rating system was developed to grade response to lithium treatment: complete remission of manic and/or depressive symptoms; Excellent complete remission of mania with mild to moderate residual depression; Good incomplete remission of mania at usual therapeutic lithium levels (1.5 meqil); Fuir inadequate symptomatic remission or unacceptable toxicity at therapeutic lithium Poor levels. Monthly lithium levels were obtained throughout the duration of lithium therapy. Blood urea nitrogen (BUN), electrolytes, creatinine, and urinalysis were obtained at least quarterly. Electrocardiograms (EKG) and thyroid function studies were performed at least annually or when indicated by emergent clinical symptoms. 15 yr at Masonic
RESULTS Twelve patients consisting of nine females and three males comprised the study group (Table 1). The mean age at the beginning of lithium therapy was 77 (range 63 to 89). Duration of lithium therapy averaged 5.3 yr (range 1.5 to 15). The most common psychiatric diagnosis was bipolar disorder-manic, present in eight cases. Two patients were diagnosed as major depressive episode with psychotic features, one patient was diagnosed as manic episode, and one as From the Masonic Home and Hospital. Wallingjord. Conn. and Department (If University School of Medicine, New Haven. Conn. Matthew Bushey, P.A., B.A.: Masonic Home and Hospital; Ulrich Rathey, Home and Hospital: Malcolm B. Bowers, Jr.. M.D.: Department of Psychiatty. School of Medicine. Address reprint requests to Dr. Bobcsers, Yale Uni\zersity School of Medicine, New Haven. Conn. 06519. @ 1983 by Grune & Stratton, Inc. 0010440X/83/2404-0010$1.00/0 392
Comprehensive
Psychiatry,
Psychiatry,
Yale
M.D.: Masonic Yule lJniversih/ 25 Park Street,
Vol. 24, No. 4, (July/August), 1983
393
LITHIUM IN THE ELDERLY Table 1.
Lithium Treatment In the Elchiy
Age sex F F
F
F
Dragnosis Bipolar- manic, hypertension Dementia with agitation, anemia Bipolar-manic, ASHD
LitMum Begun
DlJratiion Years
Average Level meqil
68
9
0.79
81
3
0.99
70
6
0.72
Range (0.40 to 1.45) (0.82 to 1.09) (0.27 to 1.48)
1.O)
Hypothyroidism Poor
Fair Levels < -1.0 Good Levels l.lV1.2 Good
Elevated BUN probably related to other causes Tremor, ataxia at higher lithium levels Bradycardia and ectopy None
Bipolar- manic, ASHD, rheumatoid arthritis Bipolar- manic, ASHD, bladder carcinoma
84
4
0.72
78
9
0.64
(0.30 to 0.80)
F
Bipolar- manic
81
15
0.66
(0.15 to 1.05)
Fair
M
Manic episode, ASHD, anemia, colon carcinoma Bipolar- manic
8.5
5
0.59
(0.30 to 1.40)
Good
Renal failure probably due to nephrotoxic antibiotics Bradycardia Disorientation that improved when lithium decreased None
72
4
0.86
Good
None
Major depressive episodde with psychotic features Bipolar- manic, ASHD Major depressive episode with psychotic features, intestinal resection Bipolar- manic
74
3
0.97
(0.50 to 1.14) (0.77 to 1.21)
Good
None
89
2
0.50
Good
63
1 112
0.72
(0.22 to 0.94) (0.1 to 1.1)
Tremor Disorientation Hypothyroidism Bradycardia Ectopy
84
2
0.72
(0.32 to 1.1)
Good
M
F F
M F
F
(0.5 to
TOXlClty
kSp0nS.Z
Poor
Disorientation Lethargy
dementia with agitation. The average lithium dose for the group was 500 mg per day and the most common dose was 300 mg twice a day (BID). In no case did a patient receive more than 300 mg three times a day (TID). The average serum level for the group based on regularly obtained monthly values was 0.74 meqil. The peak lithium level attained by any member of the group was 1.48 meqil. When the lithium response rating criteria previously described were utilized. the following treatment responses resulted: one excellent, seven good, two fair. and two poor. In the cases of poor responses to lithium therapy, one patient had a diagnosis of dementia and the other a major depressive episode with
394
BUSHEY ET AL.
psychotic features. In all cases except one in which the diagnosis was bipolar disorder-manic, the response to lithium therapy was either good or excellent. There were two cases of hypothyroidism that were apparently induced by lithium, both of which were well documented by T,, T,, and TSH levels and a clinical picture that was consistent with hypothyroidism. In these cases the laboratory values and clinical picture returned to normal after treatment with relatively small doses of thyroxine (Synthroid). Lithium treatment was discontinued in one of the cases in which treatment response was graded as poor. However, lithium was continued in the other case of hypothyroidism because the patient was having a good response. Concurrent treatment with thyroxine resulted in a rapid correction of abnormal T,, T4, and TSH as well as prompt resolution of clinical symptoms of hypothyroidism. Diabetes insipidus did not occur in any of the patients being treated with lithium. Although urinary output was not measured, frequently obtained urine specific gravities indicated no marked persistent concentrating defect. There were two cases of renal function impairment. One involved a very mild azotemia (BUN-31); the other consisted of acute renal failure and subsequent death. In the more serious instance, consultation with a nephrologist indicated that the most likely etiology for the acute renal failure was a drug-induced nephrotoxicity, because the patient had received a well-known nephrotoxic aminoglycoside antibiotic for a life-threatening infection just prior to the development of renal failure. He had been receiving maintenance lithium therapy for the preceding 8 yr without any discernible renal impairment detected by periodic BUN, creatinine, electrolytes, or urinalyses. In the case of the mild azotemia, there were a number of other acute medical problems that may have accounted for or contributed to the slightly elevated BUN. Among these were pneumonia, fever, urinary tract infection, and intermittent gastrointestinal bleeding. Two patients in the study developed sinus bradycardia without clinical or laboratory evidence suggestive of hypothyroidism during the course of maintenance lithium therapy. In these two cases, the implantation of a permanent cardiac pacemaker was required. Both these patients had preexisting cardiovascular disease and had received antipsychotic medication and/or tricyclic antidepressants with known cardiac side effects at some point prior to the development of severe bradycardia and ectopy. Another patient who had previously developed hypothyroidism while receiving lithium later developed a sinus bradycardia. It could not be determined conclusively whether the bradycardia was secondary to the hypothyroidism or unrelated. Infrequent episodes of mild tremor, ataxia, disorientation, and lethargy were experienced by four patients. The occurrence of these adverse effects seemed to be more frequent at higher serum levels and resolved in all cases when the lithium dose was decreased. There were no detectable adverse effects in four of the patients studied. DISCUSSION
Our experience suggests that lithium can be a relatively safe and useful agent for treatment of bipolar disorder-manic and manic episode in a very elderly
LITHIUM
IN THE ELDERLY
395
nursing home population. Good to excellent treatment responses were obtained at moderate serum levels between 0.5 to 1.O meq/l. utilizing conservative doses of lithium carbonate averaging 500 mg per day. Treatment responses to lithium in disorders other than bipolar disorders-manic and manic episode seem to be variable. The development of probable lithium-induced hypothyroidism in 2 out of 12 patients without preexisting thyroid disease suggests that the very elderly may be at a higher risk for development of this complication than younger patients receiving lithium. Most studies indicate that approximately 5% of younger lithium patients develop a lithium-induced hypothyroidism.’ Severe renal functional impairment did not appear to be a significant problem in our experience. Neither of the two patients who developed impairment appeared to do so as a direct result of lithium therapy. In both cases, significant other disease processes could have explained the abnormal laboratory results we obtained. Renal damage appears more likely to occur at serum lithium levels considerably higher than those attained by any of the patients in our study. ‘,’ There may also be a correlation between significant functional renal improvement and the sporadic occurrence of serum lithium levels exceeding 1.5 meq/l, but our group never exceeded this level.” Our experience suggests that the potential benefit from lithium therapy in appropriately selected very elderly patients outweighs the potential risk from nephrotoxicity. The occurrence of significant sinus bradycardia and ectopy in three patients was a matter of concern. Prescribing information for lithium indicates that T-wave changes have been reported at high serum lithium levels and idiosyncratic EKG changes have also been observed. There have also been reports of sinus node dysfunction that is directly attributed to lithium therapy.h,7 We cannot directly relate the bradycardia and ectopy that some of our patients experienced to lithium therapy for several reasons. All patients who developed bradycardia were receiving or had received neuroleptics and/or tricyclic antidepressants as well as other medications that were possibly responsible t’o~ cardiotoxicity. In addition, two of the three patients who developed this complication had underlying coronary vessel disease. Whether or not lithium therapy played any significant role in the eventual development of the severe bradycardia cannot be definitively determined from our data. The question requires further study since the implication of lithium with cardiac side effects of this magnitude would significantly alter the present assessment of risk: benefit regarding lithium therapy. Only four patients were free of detectable side effects. Apart from the important exception of those patients who developed bradycardia, all other side effects potentially related to lithium therapy were considerably less dangerous and quickly reversible. It would appear from results of other studieh and our experience that the very elderly have some increased risk of adverse effects even at moderate serum lithium levels.’ However, in view of the good treatment responses to lithium in appropriately selected patients and the reversibility of the adverse effects encountered, the potential benefit of this treatment should not be denied to the very elderly due to unwarranted concern
BUSHEY ET AL.
396
about side effects. Close monitoring with attention to early signs of toxicity may be essential to minimize risk when lithium is utilized in a very elderly patient. SUMMARY
We studied the result of long-term lithium therapy in 12 very elderly nursing home residents. Good treatment results occurred most often when the diagnosis was bipolar disorder-manic or manic episode. Many of the side effects encountered were well known (tremor, ataxia, lethargy, disorientation, and hypothyroidism) and were easily reversible. The development of significant sinus bradycardia in 25% of the group raised a question concerning lithiuminduced cardiotoxicity. Nephrotoxicity was not apparent in spite of very advanced age and long duration of therapy. We conclude that the question of cardiotoxicity is important and requires further study. Other side effects were not sufficiently serious to contraindicate the use of lithium therapy in appropriately selected and well-monitored elderly patients. REFERENCES 1. Case records of the Massachusetts
General Hospital. Case 17-1981. N Engl J Med 304(17):1025, 1981 2. Depaulo JR, Correa E, Sapir D: Renal glomerular function and long-term lithium therapy. Am J Psychiatry 138: 324-327, 1981 3. Colt E. Kimbrell D, Fieve R: Renal impairment, hypercalcemia, and lithium therapy. Am J Psychiatry 138:106- 108, 1981 4. Lithium and the kidney: Grounds for cautious optimism (editorial). Lancet 2: 1056, 1979
5. Singer I: Lithium and the kidney. Kidney Int 19:374-387, 1981 6. Roose S, Nurnberger J, Dunner D, et al: Cardiac sinus node dysfunction during lithium treatment. Am J Psychiatry 136:804-806,
1979
7. Roose S, Bone S, et al: Lithium treatment in older patients. Am J Psychiatry 136:843-844, 1979 8. Smith RE, Helms PM: Adverse effects of lithium therapy in the acutely ill elderly patient. J Clin Psychiatry 43: 94-99, 1982
in a Very Elderly Nursing Home Population
Matthew Bushey, Ulrich Rathey, and Malcolm B. Bowers, Jr.
L
ITTLE information regarding the use of lithium in very elderly patients is presently available. This paper deals with results of lithium treatment and occurrence of adverse effects in a closely monitored elderly nursing home population. Particular attention is focused on recent increased concern about lithium-induced renal toxicity and the more well-established side effect of hypothyroidism. The study group is unusual in that it consists of a very aged population monitored over a number of years in a nursing home environment under close, on-site medical staff supervision. METHOD The charts of patients who had received lithium following psychiatric consultation during the last Home and Hospital in Wallingford, Connecticut, were reviewed. The same psychiatrist (Malcolm B. Bowers, Jr.) diagnosed and followed the entire patient group throughout the study period. Information collected included sex, psychiatric and major medical diagnoses, age at beginning of lithium therapy, average serum lithium levels, overall response to therapy, and occurrence of side effects. Psychiatric diagnoses and responses to lithium therapy were evaluated by a single consulting psychiatrist who utilized observations of permanent medical staff members, combined with biweekly patient interviews over the 15-yr period. The following qualitative rating system was developed to grade response to lithium treatment: complete remission of manic and/or depressive symptoms; Excellent complete remission of mania with mild to moderate residual depression; Good incomplete remission of mania at usual therapeutic lithium levels (1.5 meqil); Fuir inadequate symptomatic remission or unacceptable toxicity at therapeutic lithium Poor levels. Monthly lithium levels were obtained throughout the duration of lithium therapy. Blood urea nitrogen (BUN), electrolytes, creatinine, and urinalysis were obtained at least quarterly. Electrocardiograms (EKG) and thyroid function studies were performed at least annually or when indicated by emergent clinical symptoms. 15 yr at Masonic
RESULTS Twelve patients consisting of nine females and three males comprised the study group (Table 1). The mean age at the beginning of lithium therapy was 77 (range 63 to 89). Duration of lithium therapy averaged 5.3 yr (range 1.5 to 15). The most common psychiatric diagnosis was bipolar disorder-manic, present in eight cases. Two patients were diagnosed as major depressive episode with psychotic features, one patient was diagnosed as manic episode, and one as From the Masonic Home and Hospital. Wallingjord. Conn. and Department (If University School of Medicine, New Haven. Conn. Matthew Bushey, P.A., B.A.: Masonic Home and Hospital; Ulrich Rathey, Home and Hospital: Malcolm B. Bowers, Jr.. M.D.: Department of Psychiatty. School of Medicine. Address reprint requests to Dr. Bobcsers, Yale Uni\zersity School of Medicine, New Haven. Conn. 06519. @ 1983 by Grune & Stratton, Inc. 0010440X/83/2404-0010$1.00/0 392
Comprehensive
Psychiatry,
Psychiatry,
Yale
M.D.: Masonic Yule lJniversih/ 25 Park Street,
Vol. 24, No. 4, (July/August), 1983
393
LITHIUM IN THE ELDERLY Table 1.
Lithium Treatment In the Elchiy
Age sex F F
F
F
Dragnosis Bipolar- manic, hypertension Dementia with agitation, anemia Bipolar-manic, ASHD
LitMum Begun
DlJratiion Years
Average Level meqil
68
9
0.79
81
3
0.99
70
6
0.72
Range (0.40 to 1.45) (0.82 to 1.09) (0.27 to 1.48)
1.O)
Hypothyroidism Poor
Fair Levels < -1.0 Good Levels l.lV1.2 Good
Elevated BUN probably related to other causes Tremor, ataxia at higher lithium levels Bradycardia and ectopy None
Bipolar- manic, ASHD, rheumatoid arthritis Bipolar- manic, ASHD, bladder carcinoma
84
4
0.72
78
9
0.64
(0.30 to 0.80)
F
Bipolar- manic
81
15
0.66
(0.15 to 1.05)
Fair
M
Manic episode, ASHD, anemia, colon carcinoma Bipolar- manic
8.5
5
0.59
(0.30 to 1.40)
Good
Renal failure probably due to nephrotoxic antibiotics Bradycardia Disorientation that improved when lithium decreased None
72
4
0.86
Good
None
Major depressive episodde with psychotic features Bipolar- manic, ASHD Major depressive episode with psychotic features, intestinal resection Bipolar- manic
74
3
0.97
(0.50 to 1.14) (0.77 to 1.21)
Good
None
89
2
0.50
Good
63
1 112
0.72
(0.22 to 0.94) (0.1 to 1.1)
Tremor Disorientation Hypothyroidism Bradycardia Ectopy
84
2
0.72
(0.32 to 1.1)
Good
M
F F
M F
F
(0.5 to
TOXlClty
kSp0nS.Z
Poor
Disorientation Lethargy
dementia with agitation. The average lithium dose for the group was 500 mg per day and the most common dose was 300 mg twice a day (BID). In no case did a patient receive more than 300 mg three times a day (TID). The average serum level for the group based on regularly obtained monthly values was 0.74 meqil. The peak lithium level attained by any member of the group was 1.48 meqil. When the lithium response rating criteria previously described were utilized. the following treatment responses resulted: one excellent, seven good, two fair. and two poor. In the cases of poor responses to lithium therapy, one patient had a diagnosis of dementia and the other a major depressive episode with
394
BUSHEY ET AL.
psychotic features. In all cases except one in which the diagnosis was bipolar disorder-manic, the response to lithium therapy was either good or excellent. There were two cases of hypothyroidism that were apparently induced by lithium, both of which were well documented by T,, T,, and TSH levels and a clinical picture that was consistent with hypothyroidism. In these cases the laboratory values and clinical picture returned to normal after treatment with relatively small doses of thyroxine (Synthroid). Lithium treatment was discontinued in one of the cases in which treatment response was graded as poor. However, lithium was continued in the other case of hypothyroidism because the patient was having a good response. Concurrent treatment with thyroxine resulted in a rapid correction of abnormal T,, T4, and TSH as well as prompt resolution of clinical symptoms of hypothyroidism. Diabetes insipidus did not occur in any of the patients being treated with lithium. Although urinary output was not measured, frequently obtained urine specific gravities indicated no marked persistent concentrating defect. There were two cases of renal function impairment. One involved a very mild azotemia (BUN-31); the other consisted of acute renal failure and subsequent death. In the more serious instance, consultation with a nephrologist indicated that the most likely etiology for the acute renal failure was a drug-induced nephrotoxicity, because the patient had received a well-known nephrotoxic aminoglycoside antibiotic for a life-threatening infection just prior to the development of renal failure. He had been receiving maintenance lithium therapy for the preceding 8 yr without any discernible renal impairment detected by periodic BUN, creatinine, electrolytes, or urinalyses. In the case of the mild azotemia, there were a number of other acute medical problems that may have accounted for or contributed to the slightly elevated BUN. Among these were pneumonia, fever, urinary tract infection, and intermittent gastrointestinal bleeding. Two patients in the study developed sinus bradycardia without clinical or laboratory evidence suggestive of hypothyroidism during the course of maintenance lithium therapy. In these two cases, the implantation of a permanent cardiac pacemaker was required. Both these patients had preexisting cardiovascular disease and had received antipsychotic medication and/or tricyclic antidepressants with known cardiac side effects at some point prior to the development of severe bradycardia and ectopy. Another patient who had previously developed hypothyroidism while receiving lithium later developed a sinus bradycardia. It could not be determined conclusively whether the bradycardia was secondary to the hypothyroidism or unrelated. Infrequent episodes of mild tremor, ataxia, disorientation, and lethargy were experienced by four patients. The occurrence of these adverse effects seemed to be more frequent at higher serum levels and resolved in all cases when the lithium dose was decreased. There were no detectable adverse effects in four of the patients studied. DISCUSSION
Our experience suggests that lithium can be a relatively safe and useful agent for treatment of bipolar disorder-manic and manic episode in a very elderly
LITHIUM
IN THE ELDERLY
395
nursing home population. Good to excellent treatment responses were obtained at moderate serum levels between 0.5 to 1.O meq/l. utilizing conservative doses of lithium carbonate averaging 500 mg per day. Treatment responses to lithium in disorders other than bipolar disorders-manic and manic episode seem to be variable. The development of probable lithium-induced hypothyroidism in 2 out of 12 patients without preexisting thyroid disease suggests that the very elderly may be at a higher risk for development of this complication than younger patients receiving lithium. Most studies indicate that approximately 5% of younger lithium patients develop a lithium-induced hypothyroidism.’ Severe renal functional impairment did not appear to be a significant problem in our experience. Neither of the two patients who developed impairment appeared to do so as a direct result of lithium therapy. In both cases, significant other disease processes could have explained the abnormal laboratory results we obtained. Renal damage appears more likely to occur at serum lithium levels considerably higher than those attained by any of the patients in our study. ‘,’ There may also be a correlation between significant functional renal improvement and the sporadic occurrence of serum lithium levels exceeding 1.5 meq/l, but our group never exceeded this level.” Our experience suggests that the potential benefit from lithium therapy in appropriately selected very elderly patients outweighs the potential risk from nephrotoxicity. The occurrence of significant sinus bradycardia and ectopy in three patients was a matter of concern. Prescribing information for lithium indicates that T-wave changes have been reported at high serum lithium levels and idiosyncratic EKG changes have also been observed. There have also been reports of sinus node dysfunction that is directly attributed to lithium therapy.h,7 We cannot directly relate the bradycardia and ectopy that some of our patients experienced to lithium therapy for several reasons. All patients who developed bradycardia were receiving or had received neuroleptics and/or tricyclic antidepressants as well as other medications that were possibly responsible t’o~ cardiotoxicity. In addition, two of the three patients who developed this complication had underlying coronary vessel disease. Whether or not lithium therapy played any significant role in the eventual development of the severe bradycardia cannot be definitively determined from our data. The question requires further study since the implication of lithium with cardiac side effects of this magnitude would significantly alter the present assessment of risk: benefit regarding lithium therapy. Only four patients were free of detectable side effects. Apart from the important exception of those patients who developed bradycardia, all other side effects potentially related to lithium therapy were considerably less dangerous and quickly reversible. It would appear from results of other studieh and our experience that the very elderly have some increased risk of adverse effects even at moderate serum lithium levels.’ However, in view of the good treatment responses to lithium in appropriately selected patients and the reversibility of the adverse effects encountered, the potential benefit of this treatment should not be denied to the very elderly due to unwarranted concern
BUSHEY ET AL.
396
about side effects. Close monitoring with attention to early signs of toxicity may be essential to minimize risk when lithium is utilized in a very elderly patient. SUMMARY
We studied the result of long-term lithium therapy in 12 very elderly nursing home residents. Good treatment results occurred most often when the diagnosis was bipolar disorder-manic or manic episode. Many of the side effects encountered were well known (tremor, ataxia, lethargy, disorientation, and hypothyroidism) and were easily reversible. The development of significant sinus bradycardia in 25% of the group raised a question concerning lithiuminduced cardiotoxicity. Nephrotoxicity was not apparent in spite of very advanced age and long duration of therapy. We conclude that the question of cardiotoxicity is important and requires further study. Other side effects were not sufficiently serious to contraindicate the use of lithium therapy in appropriately selected and well-monitored elderly patients. REFERENCES 1. Case records of the Massachusetts
General Hospital. Case 17-1981. N Engl J Med 304(17):1025, 1981 2. Depaulo JR, Correa E, Sapir D: Renal glomerular function and long-term lithium therapy. Am J Psychiatry 138: 324-327, 1981 3. Colt E. Kimbrell D, Fieve R: Renal impairment, hypercalcemia, and lithium therapy. Am J Psychiatry 138:106- 108, 1981 4. Lithium and the kidney: Grounds for cautious optimism (editorial). Lancet 2: 1056, 1979
5. Singer I: Lithium and the kidney. Kidney Int 19:374-387, 1981 6. Roose S, Nurnberger J, Dunner D, et al: Cardiac sinus node dysfunction during lithium treatment. Am J Psychiatry 136:804-806,
1979
7. Roose S, Bone S, et al: Lithium treatment in older patients. Am J Psychiatry 136:843-844, 1979 8. Smith RE, Helms PM: Adverse effects of lithium therapy in the acutely ill elderly patient. J Clin Psychiatry 43: 94-99, 1982