The following warning is found in the package inserts of all Haloperidol and lithium preparations:
An encephalopathie syndrome (characterized by weakness, lethargy, lever, tremulousness and confusion, extrapyramidal symptoms, leueoeytosis. elevated serum enzymes, blood urea nitrogen, and lasting blood glueose) followed by irreversible brain damage has occurred in a few patients treated with lithium plus Haloperidol. A causal relationship between these events and the eoneomiiant administration ol lithium and Haloperidol has not been established; however patients reeeiving such combined therapy should be monitored closely lor early evidence of neurological toxicity and treatment discontinued promptly in Miehsigns appear.
A review of the literature shows many case reports and some brief reviews on the topic. Some ol these papers propose different possible explanations for this type of toxicity, but none Have reviewed the different hypotheses of mechanisms or given a comprehensive overview of this problem. This article is intended to fill this void and give the clinician an understanding ol the rationale for combined therapy. We also review different explanations oï action and highlight the implications for clinical practice.
Prior to the general use of lithium, neuroleptics were the major drug treatment available for mania. Qualitative differences were i'ound between the two classes of drugs (lithium r neuroleptics). Lithium was shown to be particularly effective in reducing affective and ideational signs and symptoms oi mania, such as elation, grandiosity, feelings of persecution, flight ol ideas, expansiveness. irritability, manipulaliveness. and anxiousness. In contrast, signs and symptoms of psychomotor activity were decreased carlier with neuroleptics. Lithium takes between b and IO days to have any appreciable antimanic effect, which explains a high drop-out rate with lithium treatment in severely ill patients. The qualitative differences in clinical efficacy of lithium and neuroleptics explain the different conclusions reached by different investigators. In the early phase of acute mania, neuroleptics seem to be more effective because of their effect on psychomotor activity.
Salient Features of Four Cases*
Because neuroleptics appear to be more effective than lithium in initially controlling the increased psychomotor activity of mania, it has become routine practice to initiate treatment of acute mania with lithium and a neuroleptic agent. Once lhe psychomotor activity has been controlled, the neuroleptic agent is tapered off and the patient is maintained on lithium therapy only. Of the neuroleptics, haloperidol is potent and has a rapid onset of action. It has a lower incidence oi autonomic and anticholinergic side effects than oilier neuroleptics and is, therefore, most frequently used in combination with lithium for the treatment oi acute episodes of mania.1
In 1974. Cohen and Cohen2 reported four cases ol a severe encephalopathy syndrome in patients treated with a combined regimen of lithium and haloperidol. The symptoms included lethargy, fever, tremulousness. confusion, and extrapyramidal and cerebellar dysfunction. Leucocytosis and elevated levels of serum enzymes, blood urea nitrogen, and fasting glucose also occurred. Two patients suffered widespread, severe, irreversible brain damage. Two others were left with persistent dyskinesis.
Cohen's report raised controversy about the merits of the combined use of lithium and haloperidol and is mainly responsible lor lhe warning in the drug inserts. A review oi these lour cases proves interesting (Table I).
All four patients began with an identical acute syndrome characterized by weakness, lethargy, fever, tremulousness. and increasing conlusion. Thereafter, severe extrapyramidal and cerebellar signs developed. Patients I and 2 suffered permanent sequelae with marked cerebellar-parkinsonian signs with indications of dementia. Patients 5 and 4 exhibited persistent dyskinesis and parkinsonism. The authors ruled out the possibility of viral or other infective encephalitis by laboratory screening. Their review of literature did not find any report of similar toxicity in patients on lithium or haloperidol therapy and hence they attributed it to the haloperidollithium combination therapy.
There were further reports on this complication of combined therapy. Baastrup et al5 retrospectively reviewed 425 patients who had been on lithium and Haloperidol combinalion therapy for varying lengths of time. Maximum lithium carbonate dosages were 500 mg/day to 5000 mg/day (median. 1550 mg), maximum serum lithium concentrations u etc 0.2 mEq L to 2.0 mEq/L (median, 1.0 mEq), maximum Haloperidol dosage ranged from I mg/day to bO mg/day (median, 9 mg), and the combined treatment period ranged from I day to 2900 days (median. 40 days). None of the patients developed neuromuscular symptoms, impairment of consciousness, hyperthermia, or the permanent neurological sequelae previously reported. However, their patients did show side effects of the type seen during treatment with lithium only and Haloperidol only. They concluded that combining the two drugs does not seem to increase the frequency or the intensity of side effects, and many clinicians share this view. However, like all retrospective studies on the incidence of adverse effects, this study suffers from the drawback that adverse effects are often missed and underreported, especially when the adverse reaction of the type being studied was not associated with the therapy al the time.
Reviews of Patients on Combined Therapy
In a retrospective study of 28 manic patients on haloperidollithium combination therapy by Krishna el al.4 five patients showed tremor and rigidity, eight showed only rigidity, and one showed only tremor. One female patient developed a temporary syndrome of confusion, fever, rigidity, and incontinence of urine, which remitted without sequelae when the drugs were discontinued. Other reports indicate no differences in side effects and complications between patients treated with Haloperidol only and those treated with a combination ol Haloperidol and lithium.5,9 However, in one recent study of 10 patients on combination therapy, five were reported to show symptoms of neurotoxicity, including delirium, extrapyramidal symptoms, and ataxia.10 The only difference between the patients with toxicity and those without was the high dose of Haloperidol in the group with toxicity (mean dose. 40.7 mg): for the group without toxicity, the mean dose was 16.2 mg. A summary of these studies is provided in Table 2. These studies suffer from the following drawbacks:
* The numbers of patients were too small to delect adverse effects of low incidence.
* Haloperidol and lithium were used in low doses.
* No rating scales were used to assess adverse reactions before, during, and after therapy.
The report of Cohen and Cohen is noi an isolated one. and cases of severe adverse reactions associated with haloperidol-lilhium therapy are reported almost even year. Some ol these reports are summarized in Table 5.11-21
Case Reports of Toxicity with Combination Therapy
A review of the literature indicates that the issue is far from resolved. Although cases of severe adverse reactions associated with haloperidol-lilhium therapy are reponed every year, prospective studies, some retrospective studies, and clinical experience reports have failed to document any increased risk with combination therapy. We have seen in our clinical practice many cases of toxicity in patients on haloperidol-lithium combination therapy, bin none of them were of the type described by Cohen and Cohen.
Because adverse read ions reported with the combined therapy might be due to the lithium, haloperidol, possible synergism between lithium and haloperidol. or causes other than drug toxicity, a consideration ol the adverse reactions associateti with each of these drugs is indicated.
Lithium can produce a variety of neurotoxic effects, which may he mild, as in tremors or cogwheel rigidity, or serious, as in drowsiness, confusion, disorientation, muscle fasciculation. ataxia, extrapyramidal symptoms, and seizures, liven death can occur. Severe side effects are usually associated with serum lithium levels greater than 2.0 mEq/L. However, some cases of this syndrome have been reported in patients with serum lithium levels within the therapeutic range (0.6 mliq/L to 1.2 mEq/L).22,25 Schon24 has described 40 eases of lithium intoxication with long-lasting neurological sequelae. Recent reports have reemphasized irreversible lithium-induced neurotoxity.25,26 Neurotoxicity correlates with cerebrospinal fluid (CSF) lithium level.27 and (here could be a subpopulaiion of patients who have higher CSf lithium levels in the therapeutic range. In none ol the reports of toxicity with combination therapy were CSK levels measured, and thus lithium neurotoxicity due to high CSE levels cannot he ruled out as a basis of encephalopathy.
Haloperidol can also produce a variety of neurotoxic effects. The most serious adverse reaction associated with haloperidol given in high doses is the neuroleptic malignant syndrome, which consists ol muscular rigidity, hyperpyrexia, fluctuating consciousness. leucocytosis. and altered LIiG patterns.28 The incidence of neuroleptic malignant syndrome is reported lo be 0.5% to 1%.29 This syndrome usually evolves over 24 to 72 hours and can occur from hours to months after the initiation of neuroleptic drug therapy. The syndrome is not specifically confined to haloperidol and has been reported with other neurolepties.30,31 Some to the patients showing adverse reactions during combined haloperidol-lilhium treatment may be manifesting the signs and symptoms of this syndrome, with or without lithium neurotoxicity. Concurrent administration of lithium and haloperidol has been reported to result in higher haloperidol levels in brain and plasma of guinea pigs.32 an appropriate model for Human Haloperidol metabolism and may account for enhanced Haloperidol toxicity.
Another explanation for the encephalopathy is the synergism between lithium and Haloperidol. Lithium may enhance the dopamineblocking effects of Haloperidol." Friedman and Gershon'4 have demonstrated that lithium inhibits striatal dopamine synthesis in the rat, thereby increasing the effect of dopamine-receptor blockade by neuroleptics. It could be that Cohen's patients developed a lithium-enhanced malignant neuroleptic syndrome.
Alternatively, Haloperidol may interlere with lithium transport. Pandey et al33 have shown that neuroleptics enhance intracellular lithium levels through changes in the cell membranes. This enhancement is associated with thioridazine particularly. However. Haloperidol has not been found to interfere with the lithium to red blood cell/plasma ratio."'11 Schaf 1er et al·7 have reported an increase in steady-slate lithium levels of manic patients after the addition of 20 mg of Haloperidol to the regular dose of lithium. It may be that Haloperidol blocks the dopamine receptors in the kidney, resulting in a decrease in renal excretion of lithium.38 Patients on combination therapy were found to Have more pronounced kidney histopathologieal changes and lower concentrating capacity than patients on lithium alone.39
West and Meltzer" reported that the Heightened metabolism of patients in acute manic states makes them more susceptible to toxicity from lithium, neuroleptics, or a combination of these agents. Various physical stresses often associated with mania (eg, physical exhaustion, dehydration) may increase the risk of lithium toxicity. Likewise, lever, negative sodium balance, and dehydration with increased intracellular lithium level may increase the risk of lithium toxicity.40
In a retrospective study by Miller and Menninger.10 five of 10 patients became neurotoxic. The mean peak dose of Haloperidol for the patients with neurotoxicity was 41 mg and for those without toxicity. 16 mg. There was a statistically significant difference between the dose of Haloperidol of the patients with toxicity and those without, indicating the role of high doses of Haloperidol in the incidence of neurotoxicity.
Addy et al20 reported two patients who showed both pholomyoclonic and photoparoxysmal responses on the LEG while on combined lithiumhaloperidol treatment. They suggested that these EEG abnormalities reflected early stages of neurotoxicity and recommended LEG monitoring for all patients on combined therapy.
There seems to be a liability to severe adverse reactions in patients on a haloperidol-lithium combination, particularly during the acute manic phase, but the incidence and etiology remain controversial and unresolved. The clinical manifestations of this toxic lithium-haloperidol interaction seem to be different from the reactions to toxicity of either drug alone. The two drugs may act in an additive or synergistic fashion. Wc believe that this combination in mania increases patients' susceptibility to neurotoxicity due to lithium and neuroleptic malignant syndrome due to Haloperidol : we may have been seeing the superimposition of one toxicity over another. In a recent survey of publications from 1959 to 1987 representing 202 case reports, Haloperidol was involved in 99 (49.5%) of all the episodes of neuroleptic malignant syndrome.41
Although haloperidol-lithium combination Has been reported most frequently as producing neurotoxic stales, there have been reports of other neuroleptic-lithium combinations producing identical syndromes. Fluphenazine,42,43 thioridazine.44 perphenazine.4"' and chlorpromazine42 in combination with lithium have also been associated with neurotoxic states. Frequent use of Haloperidol as an antimanic drug in combination with lithium may account for High incidence oï neurotoxicity. Any conclusion drawn and recommendations made Here are equally valid for any neuroleptic-lithium combination.
It is important for clinicians to be aware of the potential risks involved with combined haloperidol-lithium therapy and be familiar with the side effects of both drugs. All staff involved in the treatment and followup of acute manic patients should become familiar with the early signs and symptoms oï the adverse reactions to these drugs so that they can be reported to the physicians as early as possible. Wc recommend the following actions:
* An inservice training program be conducted by the psychiatrist for nurses and other primary therapists on the signs and symptoms of adverse reactions to Haloperidol and lithium and the neurotoxicity seen with combination therapy.
* A statement be made in the chart indicating that the patient's clinical status requires combination therapy and any sign or symptom of toxicity be reported immediately to the attending psychiatrist.
* As Haloperidol controls acute psychomotor symptoms and lithium controls the core symptoms oí mania, which takes about a week, lithium should be used initially in low dosage and be carefully titrated while the dose of neuroleptic is gradually tapered ou. We have been using a two-point method for predicting lithium maintenance dosage, with good results.46
* At the first indication of drug toxicity, both drugs should be discontinued and patients started on alternative therapy, such as carbamazepine or clonazepam, until the signs of toxicity disappear, at which point lithium can be initiated as a single drug therapy.
* Treatment is mainly supportive. If the serum lithium level is more than 2.5 mEq/L. the patient should undergo Hemodialysis.47 If muscle rigidity persists or progresses after neuroleptics have been withdrawn, the muscle relaxant dantrolene or the dopamine agonist bromocriptine may be initiated.48-49
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Salient Features of Four Cases*
Reviews of Patients on Combined Therapy
Case Reports of Toxicity with Combination Therapy