Original Author: Paul Perry, Ph.D, BCPP
Latest Revisers: Vicki Ellingrod, Pharm.D., BCPP
Creation Date: 1996
Last Revision Date: February 2002
Peer Review Status: Internally Peer Reviewed
LITHIUM
INTRODUCTION
Lithium adverse effects are divided by therapeutic- (i.e., < 1.5 mEq/L) and toxic-related (i.e., > 1.5 mEq/L) levels. This handout primarily reviews lithium adverse effects that occur at therapeutic levels. Toxic signs and symptoms are reviewed later.
Incidence and Prevalence
The following studies are representative of several published lithium adverse effect assessment studies.
Schou et al (1970) retrospectively surveyed 30 charts and 100 charts for adverse effects in patients who had been receiving lithium for one week and one to two years, respectively. Adverse effect complaints after one week of lithium treatment included GI irritation (33%), tremor (53%), muscle weakness (40%), thirst and polyuria (60%), and weight gain > 5 kg (0%). Thirteen percent of patients had no complaints (13%). In the long-term group there were no gastrointestinal complaints or complaints of muscular weakness; 4% of the patients complained of tremor; weight gains of > 5 kg were listed in 11%; and polyuria and polydipsia were complaints in 24% of the patients. Sixty-five percent of patients had no complaints.
Vestergaard et al (1980) questioned 237 patients on long-term lithium. The following adverse effects were noted: polyuria and polydipsia, 70%; tremor, 45%; loose stools, 20%; weight gain > 10 kg, 20%; edema, 10%; dermatitis, 3%; and muscle weakness, 1.6%. He noted 25% of patients had > 3 complaints, 66% had > 1 complaint, and only 10% had no complaints.
Gastrointestinal
Milder GI complaints include epigastric bloating and slight abdominal pain. More severe symptoms such as nausea, vomiting, and anorexia may occur. The most serious problems are loose stools, diarrhea, and occasional bloody stools (Jefferson and Greist 1977, Vacaflor 1975). These side effects can produce water and electrolyte disturbances, most significantly loss of sodium, that may produce lithium retention and toxicity.
GI disturbances are usually transient in duration and often subside after the initial treatment period (Prien et al 1971). Early literature suggests that GI symptoms are related to the transient, rapid rise in serum lithium levels (Gattozi 1970, Trautner et al 1955). However, more recent work indicates nausea is the only GI side effect related to the rate of rise of the serum lithium level (Persson 1977).
Lithium should be administered with food to minimize GI adverse effects. Readjustment of the dosage schedule by dividing the total daily dose into small divided doses or utilizing a slow-release dosage form of lithium may reduce these disturbances (Vacaflor 1975). Lyskowski and Nasrallah (1981) reported a double-blind 4-week crossover study comparing side effects of Lithobid (a sustained-release product) and regular-release lithium in 29 patients. Overall, no significant differences in the incidence of nausea, diarrhea, or tremor were found between preparations. However, individually, some patients had less GI complaints on the sustained-release preparation. Diarrhea may be the result of unabsorbed lithium in the large intestine pulling water into the lumen by osmotic pressure (Jeppsson and Sjogren 1975). Therefore, diarrhea may appear or worsen when a patient changes from a standard to a slow-release preparation.
Bone et al noted when patients are manic or depressed their GI complaints related to lithium increase 2 - 20 times compared to their euthymic state (Bone et al 1980).
NEUROMUSCULAR
Tremor
Jarrett et al. (1975) reported 39 of 130 patients (30%) developed tremor, but this side effect did not often handicap their daily activities. The reported range is 10 to 65 percent (Carroll et al 1987).
Lithium tremor may occur both at rest and while moving, although the tremor may be aggravated by the performance of delicate hand movements (Carroll et al 1987). An exacerbation of the tremor or extension of the tremor to other parts of the body may signify impending lithium toxicity. Emotional stress and caffeine intake may also worsen the tremor. However, reducing caffeine intake may increase lithium levels and worsen tremor (Jefferson 1988).
Lithium tremor is not benefited by L-dopa or anticholinergic agents (Carroll et al 1987, Vacaflor 1975). A lowering of the lithium dose may be effective and it is reversible with drug discontinuation.
Case reports and controlled studies demonstrate propranolol to be effective in treating lithium-induced tremor (Vacaflor 1975). Kirk et al. (1973) conducted a single- blind, placebo-controlled study with ten patients, each treated with propranolol 30-80 mg/d for two weeks and with placebo for another two weeks. The propranolol was then restarted for two weeks followed by a further two weeks of placebo. The patients were questioned at the end of each treatment period about their preference to the two identical tablets. Five patients preferred propranolol in both propranolol treatment periods and an additional three patients showed preference to propranolol in one of the two propranolol treatment periods. In contrast, none of the patients preferred placebo at any time. The difference was statistically significant (p < 0.01).
Metoprolol, a cardioselective beta-blocker, can improve lithium-induced tremor (Gaby et al 1983). However, in one case bronchospasm occurred at doses required to improve the tremor (Zubenki et al 1984).
Lithium-induced tremor can be improved by lowering the lithium level. If this is not therapeutically possible or if it fails to produce improvement, propranolol can be instituted. Though propranolol's dose is low, exacerbation of depression should be considered before institution of this treatment.
Muscle Weakness
Muscle weakness has been reported as a transient side effect (Vestergaard et al 1980). Schou et al. (1970) noted 12 of 30 patients (40%) complained of muscle weakness during the first two weeks of lithium therapy. But this side effect was not observed in the 100 patients who had been on lithium for one to two years and in only 2 of the 100 patients in the follow-up study of Vestergaard (1980). Muscle weakness appears to be dose-related and disappears with reduction or discontinuation of lithium. Case reports of a severe neuromuscular disorder resembling myasthenia gravis during the treatment with lithium have been reported (Neil et al 1976). The symptom improved with lithium discontinuation.
ENDOCRINE
Weight Gain
Six studies have reported the prevalence of lithium-induced weight gain (Garland et al 1988). The duration of lithium treatment ranged from 6 months to 17 years. Four studies reported weight gain of >4.5 kg ranged from 11 to 64%. Two studies reported 20% of patients gained more than 10 kg. This compares to a weight gain of >4.5 kg in 8% of affective disorder patients treated with placebo. Overall, the range of weight gained was 3 to 28 kg with an average of 8.5 kg.
Factors associated with weight gain were increased thirst, a previous history of weight problems, and edema, though the latter is not a consistent finding (Garland et al 1988). It is of interest that lithium responders may gain more weight than non-responders.
The etiology of weight gain with lithium is not clear. Lithium may have a insulin-like effect to decrease blood glucose and inhibit adenyl cyclase to decrease lipolysis. Lithium is not contraindicated in diabetes, but adjustment of antidiabetic treatment maybe required because of improved glucose tolerance.
Weight gain can be minimized by caloric restriction and restriction of excessive fluid intake (Dempsey et al 1976). Once developed caloric restriction will promote weight loss. It is important to inform patients of the potential for weight gain and to avoid high calorie soft drinks in replacement of fluid loss secondary to polyuria.
Thyroid
Lithium has rarely been associated with thyrotoxicosis (Lazarus 1986, Salata and Klein 1987). One report found that the risk of thryotoxicosis was slightly, but significantly, elevated among lithium treated patients followed over an 18 year period compared to controls (Barcalay et al, 1994).
More commonly, the thyroid abnormality associated with lithium is hypofunction. Presentation includes abnormal laboratory tests (i.e., "chemical hypothyroidism"), goiter without hypothyroidism, and hypothyroidism.
The incidence of chemical hypothyroidism, if response to TRH stimulation tests is included, is approximately 50% (Lazarus 1986, Salata and Klein 1987). Therefore, abnormal thyroid function tests (TFT) without clinical consequences are common with lithium.
Emerson et al. evaluated 27 patients in whom lithium therapy was initiated after baseline data collection (Emerson et al 1973). The mean TSH increased for the first three months of therapy (p<0.001) and remained constant over the next 18 months, except in one patient who developed hypothyroidism after 13 months of lithium. Overall, approximately 15% of the patients had elevated TSH values in the range of 8-20 mU/ml. The TSH values remained stable over the next four years.
Two additional reports indicated early in treatment laboratory values may only be transiently changed. Smigan et al. studied 51 patients at baseline, 4 months, and 12 months after initiating lithium (Smigan et al 1984). After 4 months, the means T4 and T3 values decreased and the mean TSH increased. One patient developed clinical signs of hypothyroidism and received thyroid supplementation. After 12 months, the mean T4 and T3 values had returned to baseline and mean TSH values had decreased, but not to baseline.
Maarbjerg et al. (1987) evaluated T4 and TSH at baseline, 6 months, and 12 months, then yearly after start of lithium in 430 patients. Mean T4 levels decreased and TSH increased at 6 months (p>0.05) and returned to baseline at 12 months. Thereafter, mean T4 increased and mean TSH decreased yearly (p<0.001). Clinical hypothyroidism developed in 8 patients after 6 months (N=3), 12 months (N=2), 2 years (N=1), and 3 years (N=2). All patients developing hypothyroidism were women and most were over 40 years of age.
In summary, many patients will develop abnormal TFT. These often present within 4 months of lithium initiation and normalize around 12 months. However, some patient's TFT remain abnormal throughout lithium treatment, without clinical consequences.
The prevalence of goiter without hypothyroidism ranges from 0 - 61% (mean 6%) in 4 studies (Lazarus 1986). The higher reported percentage is based on ultrasound findings, where the lower figures were made by clinical assessment (i.e., palpation).
Usually the goiter is diffuse, non-tender, and may spontaneously resolved with continued treatment. The goiter often is unnoticed unless the thyroid is examined prior to and during the course of lithium therapy. However, in 4 of 45 cases the enlarged thyroid gland produced difficult swallowing (Berens and Wolff 1975). No relationship has been demonstrated between lithium treatment and thyroid cancer.
Sixteen studies surveyed report a prevalence of hypothyroidism to range from 0 to 23% (mean 3.4%). These studies which included patient numbers >50 involved 4681 lithium-treated patients. Of hypothyroid patients the female/male ratio was 5:1. Age > 40 years been associated with a higher incidence of hypothyroidism. Lithium-induced hypothyroidism can occur anytime, but is more likely to occur early in treatment. Of 41 cases reporting time of onset, 36/41 (88%) occurred within the first four years of lithium therapy. Attempts to correlate the incidence and severity of hypothyroidism with serum lithium levels have not been successful (Berens and Wolff 1975).
The mechanism of lithium's effect on the thyroid gland is not fully known (Salata and Klein 1987). Lithium has been shown to reduce iodine uptake into the gland, inhibit iodine addition to tyrosine, reduce T3 and T4 release, reduce peripheral metabolism of thyroid hormones, and decrease the thyroid gland's sensitivity to TSH. It is unlikely that lithium has a direct effect on the hypothalamic-pituitary axis to reduce TSH release.
Seven studies report a higher incidence (10-33%, average 21%) of thyroid autoantibodies in patients receiving lithium compared to controls (10%) (Lazarus 1986). Lithium may accelerate the production of autoantibodies that are present prior to lithium initiation. Though pre-existing thyroid dysfunction is not a prerequisite for the development of lithium-induced hypothyroidism, patients with impaired function maybe at a higher risk. Autoimmune thyroiditis is not the sole cause of lithium-induced hypothyroidism as not all patients have thyroid antibodies. Also, increased levels of antibodies are observed in patients without hypothyroidism. It appears that thyroid failure due to lithium is usually but not necessarily dependent on antibody mediated damage.
Monitoring should include baseline free T4 and TSH. Repeat values should be obtained at six months, one year, and then yearly. Monitoring has been recommended in the literature for the duration of lithium treatment. However, since the majority of patients on lithium develop hypothyroidism within the first 3 years, routine laboratory monitoring after this period yields a low rate of return for considering the expense. Patients may develop symptoms between routine laboratory assessment. Therefore, patients should be questioned concerning signs and symptoms of hypothyroidism. This is especially true for women over 40 years of age on maintenance treatment.
Treatment may not be necessary as the majority of cases of lithium- induced thyroid abnormalities are transient and often without clinical symptoms (Lazarus 1986, Salata and Klein 1987). Despite the lack of a dose-response relationship, some clinicians report lowering the dose may reverse the hypothyroid symptoms. Goiter and the hypothyroid state can be reversed with thyroid supplementation (i.e., levothyroxine). Pre-existing hypothyroidism is not an absolute contraindication to lithium treatment. Lithium discontinuation will reverse the thyroid abnormalities.
DERMATOLOGIC EFFECTS
Lithium has been associated with a wide range of dermatological reactions of varying clinical significance (Deandrea et al 1982; Sarantidis and Waters, 1983). In one controlled study comparing the occurrence of cutaneous conditions between chronic lithium users and a control group of patients on minor tranquilizers or tricyclic antidepressants, the lithium patients experienced dermatologic adverse effects attributed to lithium in 34% (31/91) cases compared to 14% (6/44) in the control patients (Sarantidis and Waters, 1983). Maculopapular eruptions, which usually occur within one to three weeks of lithium initiation, may clear without discontinuation of lithium or any specific treatment. Acneiform eruptions may emerge or grow worse with lithium therapy, may be treatment resistant, and may require a decrease or discontinuation of the drug depending upon the patient. Sarantidis and Waters (1983) attributed acneiform eruptions to lithium in 11% (10/91) of lithium treated patients. Follicular eruptions may occur in one-third of patients, but go unnoticed due to lack of symptoms and spontaneous termination despite continued lithium treatment. Lithium may induce or, more commonly, exacerbate psoriasis, which may prove to be resistant to usual treatments and therefore require lithium discontinuation. Sarantidis and Waters (1983) attributed psoriatic exacerbations to lithium in 2% (2/91) of lithium treated patients. Exfoliative dermatitis exists as a rare, but potentially serious reaction to lithium. The mechanism of lithium-induced dermatological reactions is unknown.
HEMATOLOGIC EFFECTS
Hematologic effects are not related to age, sex, or psychiatric diagnosis (Prakash 1985). RBCs are not affected by lithium.
White Blood Cells
It is reported 75-100% of patients on lithium will demonstrate some leukocytosis (Joffe et al 1984). All WBCs are affected by lithium, with the exception of basophils (Prakash 1985). The increase in WBC count is usually 30-45% and is primarily due to neutrophilia. The maximum reported WBC count is 24,000. There is no shift to the left. The peak elevation typically occurs within one week and may be maintained long-term (Prakash 1985). One reports suggests that WBC count will gradually normalize over one year of treatment (Özdemir et al, 1994). Upon discontinuation the effect is reversible within 1 to 2 weeks. It does not appear to be dose-related.
The mechanism of action is unknown. However, the effect is not due simply to a redistribution of the granulocyte pool as increased production has been demonstrated.
Lithium has not been demonstrated to produce leukemia with long-term treatment.
Platelets
Eighty-one percent of patients have thrombocytosis with lithium (Joffe et al 1984). In one study after 4 weeks of treatment, platelet counts increased an average of 13%. Twenty-four percent of patients had platelet counts above the upper range of normal.
Two patients maintained an elevated platelet count 2 to 4 months after lithium discontinuation.
CNS EFFECTS
Organic changes may occur with therapeutic levels of lithium (Sansone and Ziegler 1985). These include distractibility, poor memory, disorientation, incoherence, poor concentration, and impaired judgment. These maybe accompanied by involuntary movements, ataxia, and dysarthria. The symptoms often appear insidiously and maybe unrecognized as lithium-related. Often the EEG is abnormal with minor asymmetries of alpha frequency or increase in 4-6 theta activities. With higher levels increasing episodes of intermittent high amplitude diffuse delta (below 4 Hz) waves with accentuation of previous focal abnormalities are common findings. Patients with organic or psychotic diagnoses maybe predisposed to this adverse effect (Shopsin et al 1970, Tucker et al 1965). Lithium-induced encephalopathy maybe reversed with dose-reduction or require discontinuation of the drug.
Neurotoxicity has been reported when lithium is combined with haloperidol, thioridazine, chlorpromazine, and fluphenazine (Sansome and Ziegler 1985). Three studies have not supported these case reports and many authors believe these represent cases of neuroleptic malignant syndrome related to antipsychotics.
CARDIAC EFFECTS
Lithium-induced T-wave flattening and inversion and widening of the QRS complex have been reported (Mitchell and Mackenzie 1982). T-wave changes are noted in 13-100% of patients. In healthy individuals, no clinical symptoms are related to these changes, they frequently disappear on continued treatment, and are readily reversible with lithium discontinuation. These appear to be related to replacement of intracellular potassium rather than a direct pharmacologic effect. Though little risk of an adverse event exits, patients with pre-existing conduction abnormalities should be monitored with an EKG after steady-state lithium levels are achieved. Sinus node dysfunction, in particular, may be frequently present in lithium treated patients. In one study of 45 chronic lithium treated patients, sinus node dysfunction, measured as sinus arrest > 1.5 seconds or heart rate < 50 beats/min, was more common among lithium patients versus controls (Rosenqvist et al, 1993). Among lithium patients (mean age 50.3 years old, range 34-72), sinus arrest and bradycardia occurred in 56% and 78%, respectively, compared to 30% and 30%, respectively, among age stratified controls, a significant difference. Clinically significant sinus node dysfunction, however, was very rare among lithium treated patients in this study.
PARATHYROID
Lithium can increase serum calcium, reduce serum phosphorous, and increase PTH (Salata and Klein 1987). Ten to fifteen percent of patients will develop slightly elevated Ca++ and PTH within 4 weeks of lithium initiation. These values may reverse within one week of lithium discontinuation and should be normal within 2 to 4 weeks.
It is unknown if lithium unmasks parathyroid pathology. Complications of primary hyperparathyroidism do not occur, though osteopenia has been reported.
The mechanism of lithium effect is not known. However, lithium may increase the threshold calcium level necessary to suppress PTH by preventing calcium binding to the parathyroid gland. A recent in vitro study indicated lithium increases the release of PTH at therapeutic concentrations (Birnbaum et al 1988).
RENAL
Anecdotal Data
The earliest reported cases of lithium nephrotoxicity were associated with lithium poisonings. Isolated case reports of uremia or acute renal failure began to appear in the literature in 1965 in patients with lithium intoxication (Achong et al 1975, Amkisen and Skoldborg 1969, Dias and Hocken 1973, Hawkins and Dorken 1969, Lavender et al 1973, Verbov et al 1965). In one of the fatal cases (Achong et al 1975), a renal biopsy was performed because of acute renal failure. The biopsy demonstrated damage mainly in the proximal tubules with less marked changes in the glomeruli and the interlobular arteries. Yet in another case (Lavender et al 1973), renal functional changes such as proteinuria, elevated BUN and hypokalemia occurred, but no significant pathological changes of the kidney were observed at autopsy. Schou et al in 1968 described moderate elevations of the BUN and/or serum creatinine in seven of eight poisoned patients. The highest observed BUN and serum creatinine were 80 mg% and 3.5 mg%, respectively. Clinical signs of uremia were not observed. Transient proteinuria occurred in three patients and reverted to normal upon reversal of the lithium intoxication. The authors felt that in humans, the central nervous system rather than the kidneys were the primary target organ affected by lithium intoxication. Thus, both functional and morphological changes of the kidneys have been reported in lithium-poisoned patients. Whether the renal impairments are due to a direct effect of the lithium on the kidneys or secondary to systemic toxicicity is not resolved. Although a direct toxic effect of lithium on the kidneys has been shown in animals, the renal failure could also result from hypotension and renal ischemia resulting from patients going into shock during lithium intoxications ( Dias and Hocken 1973, Hawkins and Dorken 1969, Verbov et al 1965).
The early reports suggest that lithium intoxication was a prerequisite for the occurrence of renal damage. Hestbech et al (1977) studied 14 chronic lithium users (duration of lithium therapy ranged between 1 2/3 to 14 years). These patients were referred to the nephrologist because of either acute lithium intoxication or lithium-induced diabetes insipidus. Renal biopsy specimens showed that 13 patients had a pronounced degree of focal nephron atrophy and/or interstitial fibrosis. Thirteen age-matched patients not on lithium were used as controls. The authors found significant differences between the two groups in the degree of focal cortical fibrosis, diffuse medullary fibrosis, distal tubular dilatation, and the presence of focal mononuclear cells. Although the majority (8) of the lithium-treated patients had lithium intoxication at the time of study, it was postulated that the chronic use of lithium also may have contributed to the chronic renal lesions in the five patients who had never been intoxicated. However, of the three patients who experienced a persisting reduction of creatinine clearance, all had been intoxicated. Despite these histological findings significant impairment of the GFR was not observed. The authors subsequently suggested that up to 26% of patients on maintenance lithium for greater than two years would develop pathological renal histolgical changes (chronic focal interstitial nephropathy) characterized functionally by progressive impairment of urinary concentrating ability. Hansen and Amdisen (1978) reported renal insufficiency (CrCl < 45 ml/min) occurring in 17 of the 23 patients intoxicated with lithium. Five of these cases did not regain normal renal function. In seven patients, renal biopsy studies suggested the presence of a chronic nephropathy. Although chronic lithium use had been implicated in the occurrence of lithium nephrotoxicity, the majority of the cases were still associated with intoxications.
Burrows et al in 1978 postulated that lithium could be nephrotoxic in chronic users, but the severity of the risk might be determined by the duration of lithium use. In their five cases of lithium-related renal lesions, two patients who had been treated for only a few months had the lesions mainly in the distal convoluted tubules and the collecting ducts with only minimal changes in the proximal tubules. In contrast, the three patients who had been taking lithium for over six years were found to have similar lesions in the distal tubules as well as more advanced changes including glomerular and interstitial cell involvements. None of these five patients had episodes of lithium intoxication.
Thus by 1978, anecdotal data was available that suggested that lithium intoxication was not a prerequisite for the occurrence of lithium nephrotoxicity. Chronic use of lithium also contributed to renal damage although the renal lesions seen in chronic lithium therapy were not as severe as those observed in lithium intoxications nor as frequent. In the next several years a number of case-control studies were conducted to assess the risk of lithium-induced nephrotoxicity.
Case Control Studies
Although the relationship between morphological changes observed on biopsy and functional impairment remains unclear, chronic renal damage is seen in a minority of patients on prophylactic lithium therapy. Rafaelson et al (1979) examined biopsies, creatinine clearance rates, and urine volumes in 37 patients treated with lithium longer than 5 years. Significant correlations were observed between urine volume or serum creatinine level to the presence of histological anomaly. Six of 37 (16%) renal biopsies were clearly pathological. Five of six pathological renal biopsies and seven of eleven borderline pathological biopsies came from patients who had a 24-hour urine volume >4000 ml or 24-hour creatinine clearance below 60 ml/min. Interestingly, nine patients had an increased serum creatinine. Of this group, six had been taking lithium on a divided daily dose schedule while three had been taking the drug once daily. Of the entire series, 80% of the patients were on a once-a-day dose, while most of the remainder were on a divided daily dose. Thus only 10% of patients on single daily dosing had abnormal biopsies while 86% of patients on divided daily dosing had abnormal biopsies. They hypothesized that an increase in 24-hour urine volume to greater than 3,000 ml during the first year of therapy may be the most easily observed warning signal of impending kidney damage.
Hullin (1979) examined urinary beta-microglobulins due to their sensitivity as an index of renal proximal tubular damage. No significant differences were found between lithium-treated patients and the control groups.
Kincaid-Smith et al (1979) compared the renal biopsies of 16 never intoxicated patients on lithium therapy for an average of 5.5 years to those of nine patients about to start lithium and a group of age- matched donor kidneys used for transplantation. There were no differences between the lithium and pre-lithium biopsies. However, there were significant histological differences between the affective disorder patients' biopsies and the donor kidneys. The authors raised the question as to whether the other psychotropic drugs used to treat affective illness could be nephrotoxic, such as TCAs.
In 1979, the World Psychiatric Association convened a meeting in Copenhagen to discuss lithium and renal effects. The consensus at this meeting was that the risk of lithium nephropathy in the absence of lithium toxicity is small. However, the patient with pre-existing renal damage or a history of renal disease placed on lithium should have renal function studies performed at regular intervals while on the drug (Anon 1979). Subsequent studies have reinforced the conclusion and recommendations of the WPA.
Gerner et al (1980) assessed the renal function in 43 manic-depressives who had taken lithium from 1-120 months (x = 27 mo.). All patients were euthymic at the time of the evaluation and had therapeutic lithium serum levels i.e., 0.6-1.2 mEq/L. None had diabetes, hypertension, autoimmune diseases, or renal disease before starting lithium. There was no significant correlation between decrease in creatinine clearance and duration of lithium treatment, and when creatinine clearance was corrected for age, the expected decrease with age was seen. BUN and uric acid were only slightly elevated in four and two patients, respectively. Minor elevations in urine methyl-histadine and glycine were seen in two and five patients, respectively, but were not sustained upon repeat urine amino acid chromatography and were postulated to be due to diet. Urinary lysozymes remained normal. The patients appeared to have a defect in maximal renal concentrating ability; their mean osmolality was 602 mOsm/kg (range = 100-965). There were no significant correlations of urine osmolality with duration of lithium treatment.
Donker et al (1979) studied 30 patients on long-term lithium therapy of 39 + 3.6 months. The patients were subjected to an extensive battery of renal function testing that included urine concentration tests after water deprivation and intranasal administration of vasopressin; determination of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF); and measurement of minimal pH after an oral dose of ammonium chloride, and of urinary beta-2-microglobulin excretion. Urine osmolality during treatment and after 22h water deprivation was 845 mOsm/kg H2O (range 524-1078) as compared to that in normals of 1002 mOsm/kg H2O (range 712-1349). The mean GFR was 101 + 4ml/min, mean ERPF 360 + 18 ml/min, and mean minimal urine pH 4.95 + 0.06. Polyuria (>3000ml/24h) was present in 27% (8/30) of the patients, but only two of the patients' urine osmolality was abnormal. Serum levels of beta-2-microglobulins and lysozymes and urinary excretion of beta-2-microglobulins were normal in all patients. No correlations were established between urine osmolality and serum lithium levels. The GFR only correlated with age.
Coppen et al (1980) examined 101 patients maintained on slow-release lithium tablets for 1 to 12.5 years given as a single bedtime dose for the past seven years. A control group of patients matched for age and sex with affective illness who had never been treated with lithium were utilized as a control group. Creatinine clearance, serum creatinine, maximum urine osmolality after DDAVP (1-deamino-8-D-arginine vasopressin) administration, urine and plasma beta-2-microglobulins and the urinary excretion of N-acetyl-beta-glucosaminidase were not significantly different between patients on lithium and depressed patients never on lithium. The authors concluded that there was little evidence of serious renal functional impairment with lithium therapy.
Lokkegaard et al (1985) evaluated renal function of 153 manic-depressive patients treated with lithium for more than five years with a mean of ten years. The urine concentrating ability decreased and the 24-hour urine output of the patients increased as the dose increased. Interestingly, the glomerular filtration rate showed a slight decrease with was not projected as significant until after patients had been on lithium for a period of 17 years. This finding was independent of the daily dosing schedule.
Johnson et al (1984) showed that the impaired GFR in lithium patients correlated with episodes of acute toxicity rather than duration of stable maintenance lithium therapy. Overall, GFR fell within the established normal range based on sex and age, whereas measures of urinary concentrating ability were generally impaired. Additionally, he points out that in the few controlled studies of renal function that are available, measurements of GFR were similar between patients on maintenance lithium therapy and other patients with affective psychiatric disorders not on maintenance lithium therapy.
Despite reassurances that lithium does not cause severe renal dysfunction, reported reductions in GFRs ranged from 3-30%. DePaulo et al (1981) studied 99 lithium-treated patients, i.e. 32 + 35 months of therapy at a dose of 1198 + 407 mg/day, using several techniques to measure GFR. Eighty-six patients were suitable for the final analysis. Tests of the GFR were serum creatinine, creatinine clearance estimated by the Cockroft-Gault method, standard creatinine clearance determination, i.e. 24h urine collection, and insulin clearance. The Cockroft creatinine clearance (Ccr) was estimated by the equation (Cockroft and Gault 1976):
Ccr = (140-age) (weight in kg) / (72) (serum creatinine)
Ten of 86 (12%) patients who had no history of renal disease had mildly low creatinine clearance values. The mean serum creatinine was 1.25 mg% while the mean duration of therapy was 50 months in these ten patients. Modest but significant correlations of duration of lithium treatment with serum creatinine and creatinine clearance values suggested the possibility of an adverse effect of lithium on glomerular function. It should be noted, however, that 22 of the patients in this study had a history of lithium toxicity which may explain these findings. Also, in a subsequent longitudinal study DePaulo et al (1986) were unable to demonstrate a correlation between GFR and number of years on lithium. The authors recommended that clinicians initially perform duplicate classical and Cockroft creatinine clearance tests using the Cockroft value to confirm that standard creatinine clearance value.
The Cockroft-Gault equation is a practical means of monitoring lithium patients' renal function than creatinine clearances with 24-hour urine collections or urine concentrating tests. The complexity of these tests requires the physician to explain the potential problem to the patients. The patients may become unnecessarily worried with the result that they discontinue the lithium. On the other hand, the physician fearing noncompliance might treat the problem with benign neglect and not monitor patients' renal function. The Cockroft- Gault equation allows for both patient and physician concerns to be circumvented until a problem really exists.
In order to calculate the expected creatinine clearance by the Cockroft method so as to compare it to the apparent creatinine clearance for an individual, it is necessary to know the mean serum creatinine values for Cockroft's different age cohorts. The mean serum creatinines are as follows: 18-29 yo, 1.0 mg%; 30-39 yo, 1.1mg%; 40-49 yo, 1.2mg%, 50-59 yo, 1.5mg%; 60-69 yo, 1.4mg% and 70-79 yo, 1.8mg%. Thus as an example a 24 yo, 84 kg, male with serum creatinine of 1.9mg% is calculated to have an apparent creatinine clearance of 71 ml/min although according to Cockroft's norms he is expected to have a creatinine clearance of 135 ml/min. (Duplicate 24-hour creatinine clearances on this patient were 71 and 72 ml/min.)
Three important points to remember about the use of the above equation to insure its accuracy are: 1) the calculated CrCl should be reduced by 15% in women, 2) a correction to lean or ideal body weight is necessary in excessively fat or edematous patients, and 3) the serum creatinine value should be drawn in the fasting state.
The continuing appearance of new long-term studies suggesting little or no effect of lithium on GFR (Waller and Edwards 1988, Christensen and Aggernaes 1990) have lead Schou (1988) to state that "on the basis of the total evidence available today, one must conclude that lithium treatment does not, even when given for many years, lead to any change of GFR, let alone to renal failure." As a result, routine measurements of creatinine clearance and serum creatinine were thought hardly "worth the expenditure of time, effort, and money." It was stated that it is far more important to educate patients about signs of toxicity and risk situations such as physical illness with fever, rigorous slimming, and concurrent administration of diruetics or NSAIDS.
Most investigators agree the risk of renal dysfunction is far less than the risk of psychiatric morbidity. However, the present data suggests that it is imperative to avoid lithium intoxications. Thus routine measurement of urine volume (semi-annual) and serum creatinine (annual) and the education of patients to the signs and symptoms of lithium well are recommended as the current standard of care.
Lithium Induced Polyuria - Mechanism
Polyuria (urine output > 3 L/d) is currently recognized as the most bothersome effect of lithium on the kidneys. It occurs in 20-30% of patients on lithium, but it doesn't progress with time. It is also not immediately reversible upon lithium discontinuation and often persists for more than a year (Boton et al 1987) Lithium produces polyuria and polydipsia by disturbing ADH function through a number of inter-related mechanisms. The primary effect of lithium on the kidney is to block ADH-mediated water reabsorption by inhibiting ADH-sensitive adenylate cyclase production of cAMP in the collecting duct cells. Cyclic AMP ordinarily increases collecting duct permeability to allow reabsorption of free water (Christiansen et al 1985, Forrest et al 1974). As a result of the hypo-osmolality the pituitary will increase ADH secretion. The increased ADH level is known to elevate urinary prostaglandins which, similar to lithium, also inhibit ADH-sensitive adenylate cyclase (Grindlinger and Boylan 1987). It has also been shown that lithium increases thirst response to an osmotic load in non-polyuric lithium treated patients compared to patients not receiving lithium (Penney and Hampton 1990). This suggests that while much of the polydipsia seen is probably due to a secondary effect of the direct effect of lithium on the kidney, a primary component of increased thirst may also contribute.
Lithium Induced Polyuria--Management
Since 1977, several factors have been identified which probably affect the risk of adverse renal effects with lithium. These include the number of lithium doses ingested per day and the type of lithium product formulation being used.
Lithium is still being routinely administered in divided daily doses although the half-life is sufficiently long to permit once-a-day dosing. Perry et al (1981) assessed the feasibility of once-a-day in eight patients diagnosed as manic-depressives and under treatment with lithium by administering their entire 24 hour maintenance dose (1500 mg/d or less) at 8 PM for 12 consecutive days. Lithium half-life, steady-state serum lithium concentration, lithium clearance, serum creatinine and CrCl were unchanged. However, the mean 24 hour urine output was decreased from 2104 to 1566 ml/24h. Rafaelson et al (1979) as previously noted has found that urine outputs of > 3000 more likely to be associated with abnormal renal biopsies. It may be that significant polyuria is a harbinger of renal morphology. Alternatively, it may be that the polyuria results from changes in renal morphology.
The type of product formulation may influence renal effects as well. Because of its rapid absorption, a single oral dose of 600 mg of regular release lithium carbonate results in a peak serum level within usually 1 1/2 hours after drug administration. The US company, Rowell Laboratories have demonstrated, utilizing computer-simulated curves for a 600 mg po q 24h dose of lithium carbonate, that the peak serum lithium levels are decreased significantly when utilizing slow-release lithium carbonate (Greenwell 1980). Eleven patients received single 600 mg doses of the slow-release and regular-release lithium carbonation formulations in a cross-over design. The pharmacokinetic parameters were determined and then the computer-simulated curves were derived. The peak serum lithium level, occurring 1-2 h after ingestion of the regular release formulation, at steady state was 0.76 + 0.14 meq/l. The peak serum lithium level, occuring usually 4-6 h after ingestion of the slow-release formulation was 0.42 + 0.09 meq/l, a 45% decrease.
In a report using a British slow-release product, Wallin and Alling (1979) studied 56 patients receiving long-term lithium therapy (mean duration of treatment 63.5 months). Twenty-eight patients were treated with slow-release lithium while 28 received a regular-release formulation. Dosage administration schedules were not mentioned. Patients were matched for age, sex, and lithium intake. Urine osmolality was found to be significantly higher (846 mOsm/kg H2O versus 747 mOsm/kg H2O) in patients receiving the slow-release formulation. Unfortunately, this study failied to control for lithium concentration, duration of lithium treatment, or dosage schedule, three potentially important variables affecting urine concentrating ability, it is impossible to assess the efficacy of sustained release lithium in the prevention of polyuria. In addition, most published data suggests that once daily dosing and a low minimum lithium concentration resulting from once daily dosing are more important factors in the prevention of polyuria. Since sustained release dosage forms produce less peak/trough fluctuation than immediate-release dosage forms, it may be that sustained-release products are more likely to produce polyuria.
Of the two risk factors described above it appears that a number of daily doses may be more important than the product formulation based on recent study by Schou and coworkers (1982). He contrasted the effects on the kidney of lithium slow-release tablets being given twice daily to regular-release tablets being given once daily. For years, two Danish hospitals have used these two different treatment regimens. The regimens did not affect the glomerular filtration or proximal tubular reabsorption but distal tubular water reabsorption and polyuria were significantly less affected in patients given regular-release tablets once daily (median urine output = 2.38 1/2 4h) than in patients given slow-release tablets twice daily (median output = 2.83 1/2 4h). It is impossible to differentiate between the effect of slow-release tablets and dosage schedule in this study--either factor, or both, may have contributed to the results of the study.
An animal study by Plenge et al (1981) has explored the issue of dosage schedule more carefully. In this study, lithium was administered in equal doses to two groups of rats. One received lithium by daily intraperitoneal injections and thus had high peak and low trough serum lithium concentrations. The second group was given lithium with their food and had almost constant serum lithium concentrations. Noteworthy, is the fact that the first group of rats receiving bolus doses of lithium developed significantly less polyuria than the second group. Plenge et al (1982) studied renal structure and function in two groups of patients receiving long-term lithium. The drug was administered once daily between 8 and 10 p.m. or in a bid or tid dosage schedule. Kidney biopsy was performed and 24-h urine volume was measured in each patient. The function and structural changes were more pronounced in patients given their lithium in divided doses during the day. The mean daily urine output in the patients receiving the drug on the divided daily dosage schedule was 4.63 l/24 h versus 2.25 l/24 h in the patients on once daily dosing (p < 0.001). Additionally, the renal biopsies showed significant greater sclerotic glomeruli (14.5 vs 5.4%), fibrosis (9.5 vs 6.2%), and atropic tubules (14.4 vs 4.1%) in divided daily dosing group.
Mellerup et al (1988) have confirmed these findings. Serum lithium parameters were analyzed over a 24 hour period in patients receiving lithium once daily. Multiple linear regression analysis was performed using urine output as the independent variable and lithium dose, maximum serum lithium concentration, 12-hour serum lithium, minimum serum lithium concentration, length of treatment, and age of patients as the dependent variables. Only minimum serum lithium concentration and urine volume showed significant positive correlation. In a similar study, Hetmar et al (1986) found a highly significant positive correlation between urine volume and number of lithium doses per day. Although the lithium dose was 1.23 times higher in the multiple daily dose group, 12 hour lithium concentrations were similar between groups.
Two studies have been published that contradict the previously cited studies' suggestion that once daily lithium dosing prevents polyuria (Abraham et al, 1992; O'Donovan et al, 1993). In the Abraham et al study (1992), 20 chronic lithium-treated patients with an average duration of lithium treatment of 4.4 years were studied. Ten patients were on once daily dosing, the other 10 received lithium 2-4 times daily. After one month the subjects crossed over to the alternate schedule. While on once daily lithium, the mean urine volume and mean lithium concentrations were 2.4 L/dayand 0.69 mEq/L, respectively. While on multiple daily doses of lithium, the mean urine volume and mean lithium concentrations were 2.2 L/day and 0.64 mEq/L, respectively. Similarly, among 24 patients on multiple daily doses of lithium for at least one month, O'Donovan et al found no significant effect of dosing interval on 24 hour urine volume at 3 month's follow-up (1993). Lithium concentrations ranged from 0.62-0.73 mEq/L in this study. Although these studies have failed to confirm an effect of dosing interval on 24 hour urine volume, the conservative lithium concentrations they maintained may have prevented a difference from becoming apparent. This emphasizes the fact that at low concentrations, lithium is generally well tolerated.
If the use of single daily dosing lowering of the serum lithium level does not adequately control the lithium-induced polyuria the the use of thiazide diuretics or the potassium-sparing diurtetic amiloride is indicated.
Levy et al (1973) studied a 54 year-old woman with lithium-induced polyuria of 5500 ml/24 h. Following the addition of chlorothiazide 500 mg/d to her therapy, her previously stable serum lithium level increased from 1.2 to 2.5 mEq/l at a lithium carbonate maintenance dose of 1800 mg/d. The patient experienced a lithium neurotoxicity reaction manifested by dysarthria, ataxia, lethargy and tremor. When her maintenance dose was reduced to 1200 mg/d and the diuretic continued, the serum lithium concentration declined to 1.2 mEq/l. It is important to note that her urine output decreased to 2 liters/24 h on the diuretic. However, when the diuretic therapy was discontinued for 11 days, a > 5 liter/24 h polyuria recurred. Juhl et al (1976) described a 29 year old male with > 9 liter/24 h polyuria. Following the addition of hydrochlorothiazide 50 mg/d to his therapy, the polyuria decreased to < 3 liters/24 h. However, the patient's daily lithium carbonate dose of 2700 mg/d which produced a steady-state concentration of 0.85 mEq/l had to be reduced to 2100 mg/d to achieve a steady-state concentration of 1 mEq/l. The mechanism of action of the thiazide diuretics in reversing the symptoms of polyuria is hypothesized to be the result of the thiazides decreasing sodium reabsorption in the distal tubules thereby resulting in a compensatory increase in sodium and water reabsorption in the proximal tubules. Therefore less free water reaches the distal tubules. Bearing in mind the interaction of lithium and the thiazides, one should use caution when using the two drugs together. Serum lithium levels should be closely monitored and dosage adjustments probably will have to be made to avoid lithium intoxication. Serum potassium should be closely monitored for hypokalemia during the first 4 weeks of combined treatment.
The potassium-sparing diuretic, amiloride, may be a more preferable diuretic to treat lithium induced polyuria. Batlle et al (1985) studied the effect of amiloride on lithium-induced polyuria, i.e., 3.1-8.2 liters/24 h, in nine patients with affective illness being treated with prophylactic lithium therapy. Amiloride was selected because it is known to significantly improve the defect in free-water reabsorption in lithium-induced polyuria in animal models. All patients were receiving 20 mg/d within three weeks of the start of the study, except in the case of one subject who achieved this dose after three months. After an average course of 24 days of amiloride administration, the urine volume declined significantly from 4.7 to 3.1 liters/24 h. Additionally, the urine osmolality increased significantly from 228 to 331 mOsm/kg of H2O.
The decrease in urine output was sustained for six months. After the addition of amiloride 10 mg/d, serum lithium levels measured 7-14 days later increased insignficantly from a mean of 1.1 mEq/l to 1.2 MEq/l. In one patient, however, an asymptomatic rise in the serum lithium level from 0.8 to 2.0 mEq/l was observed, at which time the daily lithium dose was decreased by 50%. The authors hypothesized that amiloride might have caused a volume contraction which decreased the glomerular filtration rate, thereby increasing lithium levels. Another patient required the lithium dose to be halved because the serum lithium level increased to 1.8 mEq/l by the end of the second month of amiloride. Serum potassium remained in the normal range throughout the study period. Kosten and Forrest (1986) replicated the finding that amiloride is effective in treating lithium-induced nephrogenic diabetes insipidus. Eight patients being treated with hydrochlorothiazide 50-150 mg/d for polyuria were switched to amiloride 10-20 mg/d. Within 4-6 days of amiloride the polyuria decreased significantly from 5906 ml/24 h to 5.1 l/24 h. Two of the eight patients who were continued on the drug for an additional 2-3 months had their polyuria decrease from 4.5 to 1.8 l/24 h. However, the data suggest that the chances are only 1 in 3 that a polyuria decrease of greater than 1 l/24 h will be observed. The mechanism whereby amiloride reduced urine volume in these patients is suggested to be prevention of lithium uptake into the collecting duct cells, thereby preventing lithium's inhibitory action on adenyl cyclase. Though amiloride is less likely to increase lithium levels than thiazide diuretics, the potential exists. Therefore, serum lithium and potassium levels (for hyperkalemia) should be monitored frequently during the first 4 weeks of combined treatment or after amiloride dose increases.
In an unpublished cross-over study coordinated by Bruce Alexander, Pharm.D. and Brian Cook, D.O. at the Univerity of Iowa, placebo, hydrochlorothiazide (HCTZ), and amiloride were compared in the treatment of lithium-induced polyuria. In general, both HCTZ and amiloride porduced a one liter reduction in 24 hour urine volume compared to placebo. Response was variable, with some patients responding better to one treatment over another. Although HCTZ was more likely to produce significant changes in lithium concentration, this effect did not occur in all patients on HCTZ. For amiloride, significant elevations in lithium concentration also occurred, although less frequently. Both drugs affected potassium concentration. When patients were on HCTZ, they were more likely to experience hypokalemia and require potassium supplementation. When patients were on amiloride, hyperkalemia was more likely. Therefore, in terms of potential adverse effects and drug interactions, HCTZ and amiloride were comparable. Lithium and potassium concentrations must be monitored for either drug.
It has been consistently demonstrated that lithium decreases urinary concentrating ability to produce a nephrogenic diabetes insipidus as a result of the drug's inhibition of vasopressin to produce the symptoms of polyuria and polydipsia. These symptoms usually are most pronounced in pateints who have experienced lithium intoxications. This effect is usually reversible on discontinuation of the drug. Although histological changes have been described in the literature, no long-term studies have been able to associate a decrease in the glomerular filtration rate with the biopsy changes. The focal interstial nephropathy that has been reported is only associated with lithium intoxications. Thus the risk of renal damage and dysfunction appears to be extremely small in patients on stable maintenance lithium treatment who have no prior history of lithium intoxication.
PREGNANCY AND LACTATION
Teratogenicity of Lithium
Lithium has traditionally, been considered a significant human teratogen (Schou et al 1973b). Most of the data that supports this assertion, however, comes retrospective studies, a conservative approach that overestimates the true incidence of malformations. More recent cohort and case-control studies suggest that the risk of teratogenicity due to lithium has been substantially less than initially thought (Cohen et al, 1994).
In animal studies, lithium has been shown to be teratogenic when administered in high doses (Weinstein and Goldfield 1975a). Because of difficulties in experimental design, a direct link between lithium at therapeutic levels and teratogenicity has not been definitely established. Chromosome studies suggest that lithium carbonate has no significant adverse effect in therapeutic concentrations (Weinstein and Goldfield 1975a).
In humans, indirect evidence of the effect of lithium on the fetus initially came from the International Register of Lithium Babies, a collaborative program developed by Schou et al (Weinstein and Goldfield 1975a, Schou et al 1973a, Schou et al 1973b, Weinstein and Goldfield 1975b). The Register requested physicians report any pregnant patients treated with lithium at least during the first trimester. The authors acknowledged that deviation from normal are more likely to be reported to the register than are reports of normal babies. This may result in an over-estimation of the incidence figure.
Overall, malformation rate estimates in humans range between 1 and 7%, with 3% being average. As of 1980, 225 lithium babies had been reported to the Register. Twenty-five newborns (11.1%) had malformations, of which 18 (8%) involved the cardiovascular system (Weinstein 1980). The cardiovascular abnormalities included Ebstein's anomaly--a rare malformation consisting of a distorted tricuspid valve with secondary abnormalities of the right ventricle and atrium as well as other major cardiovascular malformations. Atrial septal defect of the patent foramen ovale is also reported.
The incidence of all cardiovascular abnormalities in the general population is 0.004%, compared to 8% in the Lithium Registry. In 1975 the reported incidence of Ebstein's anomaly in lithium babies was 2.8%. Through 1985, with more exposures reported, the figure dropped to 1.0%, (Elia et al 1987). This contrasts with a normal incidence of 0.0005% (Weinstein and Goldfield 1975). An incidence of Ebsein's anomaly of 1% among lithium exposures is approximately 200-400 times greater than normal (Cohen et al, 1994, Zalzstein et al, 1990). Therefore, the Registry's data suggest that a fetus exposed to lithium has an increased risk of a congenital abnormality, especially of the cardiovascular system
In addition to the reports of in utero exposure, 60 "lithium children" who did not have malformations at birth were identified (Schou and Amdisen 1975). At a mean age of 7.3 years, there was no difference in the incidence of physical or mental abnormalities in the lithium children as compared to siblings who had not been exposed to lithium. It is important to note this information was obtained by survey and not direct examination of the children.
The Cohen et al review (1994), however, suggests that the Lithium Registry's retrospective data dramatically overestimates the true incidence of lithium teratogenicity. Among the four case control studies, no cases of lithium exposure were identified among 207 cases of Ebstein's anomaly. Each of the studies had a power of at least 97% to identify a risk of Ebstein's anomaly 400 times greater than normal among lithium treated mothers. Therefore, it would be very unlikely for each of these studies to fail to find a link between Ebstein's anomaly and lithium exposure during pregnancy. In one report, the risk of Ebstein's anomaly was no more than 28 times normal at an a = 0.05 and b = 0.8 (Zalzstein et al, 1990) Between two additional studies cited, there was less than a 2.5% chance of an 8.4-fold increase of congenital heart defects (Kallen, 1991) and an eight-fold increase of congenital anomalies, overall (Czeizel and Racz, 1990), in mothers treated with lithium during pregnancy.
In the two cohort studies cited by Cohen et al (1994), a significant risk of congenital anomalies (all types) and cardiac anomalies was found in one study (Kallen and Tandberg, 1983). In this study, the relative risk of all types of congenital anomalies and cardiac anomalies was three times and 7.7 times control, respectively. The other study failed to find a similar relationship, but, of interest, one case of Ebstein's anomaly occurred in the lithium-exposed group (Jacobson et al, 1992).
Lithium Administration During Pregnancy
Cohen et al have published guidelines for lithium use in women with bipolar affective disorder (1994):
If administered during the second or third trimesters, the lithium dosage should be adjusted to avoid high serum levels. It is important to note salt restriction and diuretics potentially may increase lithium levels. Serum concentrations of lithium in neonates have been found to be equal to that in the mother (Schou and Amdisen 1975). Woody et al (1971) reported a case of lithium intoxication in a neonate that showed signs of sedation and listlessness. Thyroid function disturbances have also been found in infants of mothers treated with lithium (Karlsson et al 1975, Schou et al 1968).
Schou et al. (1973) reported renal lithium clearance increase 50-100% during gestation, which may necessitate dosage increases to maintain a desired level. Lithium clearance returns to baseline at delivery (Schou et al 1973). Maternal lithium intoxication has been reported a few hours before delivery (Vacaflor et al 1970, Wilbanks et al 1970). Weinstein and Goldfield (1975) recommend reducing the daily lithium dose by 50% in the last week of gestation, discontinuing the drug entirely at the onset of labor, and reinstituting it at the pre-pregnancy dose immediately after delivery. Lithium levels should be monitored more frequently (weekly or bi-weekly) as the woman approaches delivery.
Lithium and Breast-Feeding
Lithium is present in breast milk at a concentration about 30-100% of the mother's serum (Schou and Amdisen 1973, Weinstein and Goldfield 1975). A similar concentration of lithium has been found in the serum of the infant breast-fed by a lithium-treated mother (Schou and Amdisen 1973). It can be argued that breast-feeding need not be restricted since the infant has been exposed to the same concentration of lithium before birth. It is the opinion of most authors, however, this practice is hazardous to the infant because the infant's regulatory and excretory mechanisms are not well developed (Ananth 1978, Weinstein and Goldfield 1975). The infant may be especially susceptible to alterations in fluid-electrolyte imbalance and lithium toxicity. Tunnessen and Hertz (1972) reported that a breast- fed baby with a serum level of 0.6 mEq/L developed cyanosis and poor muscle tone. The infant also manifested T wave changes on EKG.
The evidence linking lithium and birth defects is equivocal based on available data. Conservative clinical judgment suggests the drug be discontinued at least during the first trimester of pregnancy. Lithium needs close monitoring during the second and third trimesters and, especially, at the time of delivery. Breast-feeding may produce significant lithium concentrations in the infant.
RATIONAL PRESCRIBING OF LITHIUM TO REDUCE ADRS
1. Lithium should be given as a single dose if the lithium carbonate dose is less than 1,800 mg/day and twice daily if the dose is greater then 1,800 mg/day. It is recommended that lithium carbonate be given with food.
2. Lithium formulation of choice depends on side effects and cost considerations. Most patients prefer capsules rather than tablets due to the latter's unpleasant taste. The use of and SR form of lithium may reduce nausea and tremor, but increase the incidence of diarrhea and loose stools.
3. SR products are more expensive than immediate release ones. It is recommended that patients initially be treated with immediate release lithium carbonate. Lithium citrate syrup might also be used in patients who are suspected or found to be "cheeking" solid dosage forms of the drug.
4. Maintaining maintenance levels of lithium around 0.4 - 0.6 mEq/L will help reduce the incidence of GI side effects.
5. Patients with preexisting cardiac conduction abnormalities should be monitored with an ECG after steady state lithium levels are achieved.
6. Monitoring of TSH, free T4, and renal function (Scr) should occur at baseline, 6 months and then yearly.
VALPROATE
CARDIOVASCULAR
Pitting edema has been infrequently reported with valproate (McElroy and Keck 1993, Pugh and Garnett 1991).
DERMATOLOGICAL
Transient alopecia has been reported in 4 - 12% of patients receiving valproate (Barnes and Bower 1975, Sherard et al 1980).
ENDOCRINE
Weight Gain
Approximately 13 - 20% of patients receiving valproate will experience a > 12 pound weight gain during treatment. This weight gain and increased appetite is not related to changes in either basal metabolism or thyroid activity. Dietary counseling is recommended, although calorie restriction will not always reverse the weight gained (Penry and Dean 1989).
Idiosyncratic Pancreatitis
This potentially fatal condition usually occurs within the first 6 months of treatment Wyllie et al 1984). Abdominal pain associated with an increased amylase level necessitates drug discontinuation.
GASTROINTESTINAL
GI problems are fairly common with valproate use (Barnes and Bower 1975, Penry and Dean 1989, Sherard et al 1980). Most commonly, patients experience anorexia (11.6%), indigestion, heartburn, and nausea (13.8%), vomiting (19.2%), and transient diarrhea (1.7%0. Administering the drug with food, slowing titrating the dose, and or switching to an enteric coated dosage form (i.e. Depakote) can minimize the incidence of these ADRS. In a study by Pugh and Garnett 1991, 85% of patients unable to tolerate the soft gelatin formulation of valproate were successfully switched to the enteric-coated form. It is important to note that the enteric coated formations are more expensive than the soft gelatin formulations. The addition of a histamine -2 blocker (i.e. ranitidine) has also been reported to reduce GI complaints (McElroy and Keck 1993).
HEMATOLOGICAL
Thrombocytopenia and neutropenia and the most common hematological abnormalities associated with valproate. In 45 children followed for more than 1 year, neutropenia and thrombocytopenia were observed in 27% and 33% of the population, respectively (Barr et al 1982). Drug discontinuation was not necessary for both conditions to resolve. Prolongation of bleeding time has also occurred and is correlated with both dosage and drug serum concentration (Gidal et al 1994). A baseline CBC with differential should be obtained for patients starting valproate treatment. Some authors have suggested that patients will affective disorders receiving these tests monthly for the first 3 months of drug therapy and every 6 - 24 months thereafter (McElroy and Keck 1993). All patients should be instructed to contact the prescriber if signs of hematological dysfunction occur (i.e., high fever, extremely sore throat, easy bruising).
HEPATIC
Enzyme Elevations
An elevation in liver enzymes has been reported in 2 - 44% of patients receiving valproate (McElroy and Keck 1993) and are not associated with more-serious liver complications. The enzymes typically will return to baseline with drug discontinuation, dosage reduction, or drug continuation. A baseline liver evaluation is recommended before starting therapy and some authors recommended that patients with affective disorders receive these tests monthly for three months and then every 6 - 24 months thereafter (McElroy and Keck 1993). Patients should be instructed to contact the prescriber if signs or symptoms of hepatic dysfunction occur (i.e. abdominal pain, nausea/vomiting, and change in conjunctiva color).
Fatal Hepatotoxicity
Fatal hepatotoxicity, although rare, has been reported with valproate use (McElroy and Keck 1993, Pugh and Garnett 1991) and is most commonly seen in the first 6 months of treatment initiation. The onset of this reaction is proceeded by symptoms of vomiting, lethargy, anorexia, and weakness. Risk factors include age less than 2 years, mental retardation, use of multiple anticonvulsants, and refractory seizures. Although no fatalities in patients older than 10 have occurred from valproate monotherapy, one case report has been published on a 13 year old girl that died of valproate induced liver disease after abnormalities in her liver function tests were ignored (Clin-Alert 1994).
Hyperammonemia
Hyperammonemia has been reported in patients receiving valproate for bipolar disorder (Raby 1997, Panikkar and Gilman 1999). The incidence of this adverse effect in bipolar patients has not been reported. Two mechanisms have been proposed (Raskind and El-Chaar 2000). Valproate increases ammonia release in the kidney due to stimulation of glutaminase in the renal cortex. Valproate can also induce carnitine deficiency. This can cause ammonia accumulation due to a disturbance in mitochondrial function in the liver that inhibits the urea cycle. This second mechanism contributes more to hyperammonemia. Carnitine deficiency is most likely to occur in children less than 2 years old, those with inborn errors of metabolism (such as urea cycle disorders), and those with a restricted dietary intake of carnitine (such as vegetarians) (Raby 1997).
Hyperammonemia can present as mental status change, lethargy, somnolence, reversible cognitive deficits, or delirium (Panikkar and Gilman 1999). When a patient receiving valproate develops lethargy, cognitive slowing, or a general feeling of malaise, liver function tests as well as serum ammonia levels should be monitored (Raby 1997). Hyperammonemia may resolve with a reduction in valproate dose and will resolve if the drug is discontinued (Panikkar and Gilman 1999). Carnitine supplementation, 1 g bid, has also been used, with resolution of symptoms occurring in 10-14 days (Raby 1997). Symptom reduction was associated with a reduction in ammonia levels to the normal range.
NEUROLOGICAL
Approximately 4% of patients will complain of sedation while receiving valproate (Volzke and Doose 1973). Less commonly experienced ADRS include confusion, fatigue, dizziness, and headache. Minimal or no effect son cognitive skills have been reported with valproate (Gerner 1993, Pugh and Garnett 1991). Essential tremor has also been reported with valproate use, is usually occurs within one month of treatment for 7 of 10 adult patients, and is dose related (Karas et al 1982, Pugh and Garnett 1991).
PREGNANCY AND LACTATION
Teratogenicity
There is a 1 - 2% increased risk of neural tube defects in children exposed to valproate during the first trimester of pregnancy (Jeavons 1982). Minor facial defects are also associated with valproate exposure (Briggs et al 1994). Women taking valproate during days 17 through 30 of gestation should consult their physician about prenatal testing (Briggs et al 1994). Valproate is rating a pregnancy category D.
Breast Feeding
No ADRs from valproate exposure in the nursing infant have been reported (Briggs et al 1994). The drug is considered compatible with breast feeding (Committee on Drugs 1994).
RATIONAL PRESCRIBING OF VALPROATE TO REDUCE ADRS
1. Baseline hepatic and hematologic tests should be obtained. Patients should be instructed of the signs and symptoms of infection and liver disease.
2. Gastrointestinal adverse effects are dose-related and may be benefited by changing to a coated dosage form.
CARBAMAZEPINE
CARDIAC
Carbamazepine can suppress both atrioventricular (AV) conduction and ventricular automaticity. These changes have been reported only in patients with pre-existing conduction disturbances can occur at therapeutic or mildly elevated serum concentrations, and are more common in elderly women. Similar to tricyclic antidepressants, carbamazepine is contraindicated in patients with bundle branch block (Boesen et al 1983, Kasarskis et al 1992).
DERMATOLOGICAL
Dermatological conditions associated with carbamazepine use occur in 2 - 13% of patients (Denicoff et al 1994, Livingston et al 1974). Generally the onset is within 2 weeks to 5 months of treatment initiation. The maculopapular rash is the most common reaction and will usually resolve with drug discontinuation (Denicoff et al 1994) but may also resolve with drug continuation. Oral antihistamines and prednisone may help alleviate some of the symptoms of this rash. In one series of carbamazepine challenges after the rash occurrence, 4 of 7 patients had a reoccurrence (Livingston et al 1974). Of note is that some authors feel that the development of a rash may be a harbinger of bone-marrow suppression (Silverstein et al 1983) and suggest obtaining a CBC if a rash develops. Other dermatological side effects are rare and include rashes with edema, systemic lupus erythematosis, dermatomyostitis, erythema multiforme, and Stevens-Johnson syndrome. This last condition requires drug discontinuation with no rechallenge.
ENDROCRINE/METABOLIC
Carbamazepine is a vasopressin agonist and has been reported to cause hyponatremia and water intoxication in 5% of patients (Brewerton and Jackson 1994, Uhde and Post 1983). Serum sodiums have been reported to decrease to 117 mEq/L. In six patients, demeclocycline 600 mg BID has been reported to prevent this decrease in sodium (Brewerton and Jackson 1994). When carbamazepine is coadministered with lithium, hyponatremia has precipitated lithium toxicity, thus serum sodium should be measured when patients are treated with this combination (Chaudhry and Waters 1983, Shulka et al 1984).
GASTROINTESTINAL
Nausea and vomiting are the adverse reactions most commonly experienced by patients during carbamazepine initiation and titration (Mattson et al 1992). If this occurs, the next dose can be held and the total daily dosage reduced by 200 mg. Once the symptoms have resolved, a dosage increase may then be reattempted, but at a slower rate. Less frequent GI side effects include diarrhea and abdominal cramps.
HEMATOLOGICAL
Aplastic anemia, agranulocytosis, thrombocytopenia, leukopenia, eosinophilia, leukocytosis, red-cell aplasia, hemolytic anemia, and reticulocytosis have been reported with carbamazepine use (Sobotka et al 1990). With the exception of leukopenia, these blood dyscrasias are rare and do not warrant routine hematological monitoring.
Leukopenia develops in approximately 12% of adults and 7% of children receiving carbamazepine (Sobotka et al 1990). Its onset is usually within the first 3 months of treatment with those at risk having a low or low-normal pretreatment WBC or neutrophil count. Most patients will have a 25% decrease in WBC, however in almost all cases the WBC will return to normal with drug continuation. In a few cases the leukopenia will continue, but without adverse hematological or medical consequences. In some patients with decline in WBC is reversible with dose reduction. Recommended monitoring for patients receiving carbamazepine is as follows:
1. Obtain a baseline CBC. If all indices are in the middle or upper-normal range, no further laboratory checks are necessary. The patient should be further educated to report signs and symptoms of leukopenia (i.e. fever, sore throat, easy bruising, and ulcers in the mouth) to the prescriber.2. Patients with low-normal or below-normal WBCs and neutraphil counts should be monitored every 2 weeks for the first 3 months of treatment. Subsequent monitoring should be individualized based on the previous blood counts.
3. If the WBC falls below 3000/mm2, or the neutrophil count drops below 1000/mm2, the dosage should be decreased or, if necessary the drug should be discontinued. The risks and benefits of carbamazepine use should be evaluated in patients with dangerously low counts (Hart and Easton 1982, Silverstein et al 1983, Sobotka et al 1990).
HEPATIC
Benign Hepatic Elevation
Approximately 20% of patients receiving carbamazepine have elevated liver enzymes, primarily the alkaline phosphatase (Soffer et al 1983). These enzymes often stabilize and do not require dosage adjustment.
Hepatotoxicity
Cholestatic jaundice, hepatic necrosis, and granulomatosis hepatitis has been reported to occur rarely with carbamazepine use (Ballinger 1988, Pugh and Garnett 1991). Twelve cases of hepatotoxicity have been reviewed (Howrie et al 1983). Ten of these occurred within 4 weeks of treatment initiation an two occurred at 2 and 6 months. Signs and symptoms included fever, jaundice, rash, liver tenderness or enlargement, anorexia, and/or nausea. In one case the bilirubin was increased to 3.5 mg% and mild elevation of other enzymes was noted. Carbamazepine discontinuation leads to rapid improvement in clinical symptoms, although laboratory abnormalities remained elevated for months. Two fatalities occurred. Because hepatotoxicity is believed to be a hypersensitivity reaction, patients who experience this ADR should not be rechallenged (Howrie et al 1983).
NEUROLOGICAL
Sedation/Ataxia
The most common CNS effects associated with carbamazepine use are vertigo, drowsiness, unsteadiness, and dizziness. These ADRs occur transiently during the first few weeks of therapy (Killian and Fromm 1968, Pugh and Garnett 1991). To overcome these effects, the dosage can be temporarily reduced until symptoms subside or the rate of increase can be reduced. Serum carbamazepine epoxide (CBZE) concentrations greater than 2.2 mcg/ml are directly correlated with acute CNS toxicity (Patsalos et al 1985). This metabolite is not routinely measured.
Dystonic Reactions
Dystonic reactions have been associated with carbamazepine use in children are possibly due to its antagonism of dopamine (Crosley and Swender 1979). These reactions usually occur 2- 3 weeks after the drug is started.
Neurotoxicity
Neurotoxicity usually occurs with the combination of carbamazepine and lithium at therapeutic doses. Although most patients are able to tolerate this combination, approximately 12% may experience muscle fasciculation, nystagmus, confusion, disorientation, hyperreflexia, slurred speech, and/or incoordination (Ballinger 1988).
OPHTHALMOLOGICAL
Rare dose dependant visual disturbances have been reported at carbamazepine dosages less then 1200 mg/day (Livingston et al 1974).
PSYCHAITRIC
Behavioral
Delirium and hallucinations have been reported with carbamazepine use (Silverstein et al 1983). Additionally, difficulty sleeping, agitation, irritability, and emotional liability have occur occurred (Pugh and Garnett 1991). If these occur, the drug should be stopped and reinitiated at lower dosages. These reactions are most likely due to carbamazepine's anticholinergic activity.
Cognitive
Although little cognitive impairment can occur at therapeutic doses, carbamazepine has been associated with impairment at high doses (Pugh and Garnett 1991). This impairment does not correlatd with dose or plasma concentration.
RENAL
Carbamazepine has been reported to cause proteinuria, which resolved upon drug discontinuation (Livingston et al 1974).
PREGNANCY AND LACTATION
Teratogenicity
Physical Effects: A recent study using retrospective data found that of 35 children born to women treated with carbamazepine alone, 11% had craniofacial deficits, 26% had fingernail hypoplasia, 1% had spina bifida, and 20% had developmental delays (Jones et al 1989, Scolink et al 1994). Carbamazepine is rated a pregnancy category C.
Intellectual Effects: Carbamazepine has not been found to adversely effect the global IQs of children born to mothers treated with the drug (Scolnik et al 1994).
Breast Feeding
The milk-to-plasma ratio of carbamazepine ranges from 0.24 to 0.69 (Briggs et al 1994). Carbamazepine in breast milk produced non-toxic plasma concentrations that averaged 0.4 mcg/ml (Inoue and Unno 1984). This drug is considered compatible with breast feeding (Committee on Drugs 1994).
RATIONAL PRESCRIBING OF CARBAMAZEPINE TO REDUCE ADRS
1. A baseline complete blood count should be obtained on each patient.
2. Except for leukopenia, all CBZ-associated hematologic adverse effects should be monitored with signs and symptoms (i.e., sore throat, mucosal ulcers, fever, easy bruising) (Sobotka et al 1990). Leukopenia should be monitored if the patient has a low or low-normal white blood cell count (WBC). If the neutrophil count is <1000/mm3 or the WBC count is <3000/mm3, then the CBZ dose should be decreased or the drug discontinued.
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