Addition
of Lithium
Carbonate
Hematological
Keith
G. Kramlinger,
to Carbamazepine:
and Thyroid
M.D.,
and
Robert
Effects
M.
commonly canbamazepine 10). Also,
Post,
M.D.
induces
a relative leukocytosis (8), whereas consistently decreases leukocytes (9, lithium is associated with a notable (7%-
In view of the increasing use of lithium-carbamazepine combination therapy for refractory psychiatric disorders, the authors assessed the clinical laboratory effects of adding lithium to carbamazepine in 23 patients with affective disorders. Lithium produced a robust reversal of carbamazepine-induced leukopenia, increasing WBCs, predominantly neutrophils, to levels significantly above placebo baseline values. The combination produced additive antithyroidal effects, resuiting in greater decreases in T4 and free T4 than with carbamazepine alone; the addition of lithium was associated with the emergence ofa modestly higher TSH level. The authors discuss clinical and theoretical implications of these findings. (Am J Psychiatry 1990; 147:615-620)
carbamazepine is not (13); although these drugs reduce peripheral thyroid hormone levels to similar degrees, lithium treatment is associated with increases of thyroid-stimulating hormone (TSH) levels (14) but carbamazepine is not (13). In view of these known and sometimes opposite dinical laboratory effects of lithium and canbamazepine when used alone and the increasing use of these two agents in combination in treatment-resistant patients, we investigated the effects of adding lithium carbonate to carbamazepine on hematological measures and thyroid indices.
L
METHOD
8%)
ithium carbonate is the treatment of choice for bipolar affective disorder. Carbamazepine, an anticonvulsant, is currently the most intensively studied treatment alternative to lithium, particularly for lithiumresistant bipolar disorder (1-4). The two drugs show a similar spectrum of clinical efficacy in the treatment of
The fective consent ciated
acute
history
mania
and
prophylaxis
against
recurrent
affective
episodes;
to a lesser extent, each drug used alone may be effective in the treatment of acute depression. Clinical efficacy of the combined use of canbamazepine and lithium, in instances when each drug used alone was ineffective, has been reponted in the treatment of acute mania and acute depression and in the prophylaxis
against
recurrent
affective
episodes
(for
re-
views see references S and 6). Despite infrequent neports of neurotoxicity associated with the canbamazepine-lithium combination, the majority of reports in the literature suggest that this combination is safe and well tolerated (7). When used alone, lithium and carbamazepine exert effects on physiologic systems that may be reflected in several clinical laboratory measures, including hematological and thyroid indices. For example, lithium
Received Feb. 15, 1989; revision received Oct. 25, 1989; accepted Nov. 21, 1989. From the Biological Psychiatry Branch, N1MH. Address reprint requests to Dr. Post, Biological Psychiatry Branch, NIMH, Bldg. 10, Rm. 3N212, 9000 Rockvitle Pike, Bethesda, MD 20892.
Am
J
Psychiatry
147:5,
May
1990
incidence
of
hypothyroidism
(11,
12),
patients met the DSM-III criteria for major afdisorder and gave oral and written informed for a clinical trial of carbamazepine and assoresearch procedures. A thorough neurological and
examination
and
a
pretreatment
helped rule out the presence of a seizure related medical condition. After a placebo period, treatment with pine was initiated on a double-blind basis 200-400
whereas
mg/day
and
slowly
increased
EEG
disorder
or
carbamazeat a dose
of
until
clinical
response occurred, side effects supervened, or a dose limit of 1600 mg/day was achieved. Plasma levels were generally between 4 and 12 iWrnl, but after initial findings indicated a poor relationship between blood levels and clinical response (15), blood levels were not used as a major determinant of dose adjustment. After chronic treatment for an acute episode, 15 depressed patients and seven manic patients with inadequate clinical
responses
were given lithium doses of 300-600 slowly increased effects supervened, of 1.2 meq/liter elsewhere (5, 6), six of the seven quate responses
to
canbamazepine
or
no
response
carbonate, also on a blind basis, at mg/day, and each patient’s dose was until clinical response occurred, side or a maximum plasma lithium level was attained. As discussed in detail eight of the 15 depressed patients and manic patients who had had madeto carbamazepine alone improved af-
615
ADDITION
OF LITHIUM
TO
CARBAMAZEPINE
ten the addition of lithium. We also included one euthymic patient who experienced occasional 1-2-day periods of hypomania while receiving carbamazepine only, bringing to 23 the total number of patients studied. There were 17 women and six men in the study, and their mean±SD age was 40.0±12.7 years (range, 20-60). Twenty-one patients had bipolar disorders (17 bipolar I and four bipolar II) and two had unipolar disorders. The duration of carbamazepine treatment before lithium supplementation ranged from 1 1 to 343 days; the median was 39 days, and the mean±SD was 67± 83 days. During the last week of carbamazepine monotherapy, the mean±SD carbamazepine dose was 1022±370 mg/day (range, 300-1600); the blood level was 8.8±2.5 p.g/ml (range, 3.1-12.4) at this time and did not change significantly during lithium supplementation. During the first week of combination treatment, the lithium dose was 809±310 mg/day (range, 171-1543) and the plasma lithium level was 0.61± 0.22 meq/liter (range, 0.1-1.1). Between the first and second weeks of combination treatment there were significant increases in both lithium dose (976±323 mg/ day) (t=S.01, df=22, p
of Lithium
Carbonate
Hematological
Keith
G. Kramlinger,
to Carbamazepine:
and Thyroid
M.D.,
and
Robert
Effects
M.
commonly canbamazepine 10). Also,
Post,
M.D.
induces
a relative leukocytosis (8), whereas consistently decreases leukocytes (9, lithium is associated with a notable (7%-
In view of the increasing use of lithium-carbamazepine combination therapy for refractory psychiatric disorders, the authors assessed the clinical laboratory effects of adding lithium to carbamazepine in 23 patients with affective disorders. Lithium produced a robust reversal of carbamazepine-induced leukopenia, increasing WBCs, predominantly neutrophils, to levels significantly above placebo baseline values. The combination produced additive antithyroidal effects, resuiting in greater decreases in T4 and free T4 than with carbamazepine alone; the addition of lithium was associated with the emergence ofa modestly higher TSH level. The authors discuss clinical and theoretical implications of these findings. (Am J Psychiatry 1990; 147:615-620)
carbamazepine is not (13); although these drugs reduce peripheral thyroid hormone levels to similar degrees, lithium treatment is associated with increases of thyroid-stimulating hormone (TSH) levels (14) but carbamazepine is not (13). In view of these known and sometimes opposite dinical laboratory effects of lithium and canbamazepine when used alone and the increasing use of these two agents in combination in treatment-resistant patients, we investigated the effects of adding lithium carbonate to carbamazepine on hematological measures and thyroid indices.
L
METHOD
8%)
ithium carbonate is the treatment of choice for bipolar affective disorder. Carbamazepine, an anticonvulsant, is currently the most intensively studied treatment alternative to lithium, particularly for lithiumresistant bipolar disorder (1-4). The two drugs show a similar spectrum of clinical efficacy in the treatment of
The fective consent ciated
acute
history
mania
and
prophylaxis
against
recurrent
affective
episodes;
to a lesser extent, each drug used alone may be effective in the treatment of acute depression. Clinical efficacy of the combined use of canbamazepine and lithium, in instances when each drug used alone was ineffective, has been reponted in the treatment of acute mania and acute depression and in the prophylaxis
against
recurrent
affective
episodes
(for
re-
views see references S and 6). Despite infrequent neports of neurotoxicity associated with the canbamazepine-lithium combination, the majority of reports in the literature suggest that this combination is safe and well tolerated (7). When used alone, lithium and carbamazepine exert effects on physiologic systems that may be reflected in several clinical laboratory measures, including hematological and thyroid indices. For example, lithium
Received Feb. 15, 1989; revision received Oct. 25, 1989; accepted Nov. 21, 1989. From the Biological Psychiatry Branch, N1MH. Address reprint requests to Dr. Post, Biological Psychiatry Branch, NIMH, Bldg. 10, Rm. 3N212, 9000 Rockvitle Pike, Bethesda, MD 20892.
Am
J
Psychiatry
147:5,
May
1990
incidence
of
hypothyroidism
(11,
12),
patients met the DSM-III criteria for major afdisorder and gave oral and written informed for a clinical trial of carbamazepine and assoresearch procedures. A thorough neurological and
examination
and
a
pretreatment
helped rule out the presence of a seizure related medical condition. After a placebo period, treatment with pine was initiated on a double-blind basis 200-400
whereas
mg/day
and
slowly
increased
EEG
disorder
or
carbamazeat a dose
of
until
clinical
response occurred, side effects supervened, or a dose limit of 1600 mg/day was achieved. Plasma levels were generally between 4 and 12 iWrnl, but after initial findings indicated a poor relationship between blood levels and clinical response (15), blood levels were not used as a major determinant of dose adjustment. After chronic treatment for an acute episode, 15 depressed patients and seven manic patients with inadequate clinical
responses
were given lithium doses of 300-600 slowly increased effects supervened, of 1.2 meq/liter elsewhere (5, 6), six of the seven quate responses
to
canbamazepine
or
no
response
carbonate, also on a blind basis, at mg/day, and each patient’s dose was until clinical response occurred, side or a maximum plasma lithium level was attained. As discussed in detail eight of the 15 depressed patients and manic patients who had had madeto carbamazepine alone improved af-
615
ADDITION
OF LITHIUM
TO
CARBAMAZEPINE
ten the addition of lithium. We also included one euthymic patient who experienced occasional 1-2-day periods of hypomania while receiving carbamazepine only, bringing to 23 the total number of patients studied. There were 17 women and six men in the study, and their mean±SD age was 40.0±12.7 years (range, 20-60). Twenty-one patients had bipolar disorders (17 bipolar I and four bipolar II) and two had unipolar disorders. The duration of carbamazepine treatment before lithium supplementation ranged from 1 1 to 343 days; the median was 39 days, and the mean±SD was 67± 83 days. During the last week of carbamazepine monotherapy, the mean±SD carbamazepine dose was 1022±370 mg/day (range, 300-1600); the blood level was 8.8±2.5 p.g/ml (range, 3.1-12.4) at this time and did not change significantly during lithium supplementation. During the first week of combination treatment, the lithium dose was 809±310 mg/day (range, 171-1543) and the plasma lithium level was 0.61± 0.22 meq/liter (range, 0.1-1.1). Between the first and second weeks of combination treatment there were significant increases in both lithium dose (976±323 mg/ day) (t=S.01, df=22, p
