In a double-blind study in psychiatric patients it was found that chlorpromazine 400 to 800mg daily,a dose that normally produced plasma levels of 100 to 300 nanograms/mL, only produced levels of 0 to 70 nanograms/mL when lithium carbonate was also given (See reference number 1).
Other studies confirm that normal therapeutic levels of lithium carbonate reduce plasma chlorpromazine levels (See reference number 2,3). The peak serum levels and AUC of chlorpromazine were reduced by 40 % and 26%,respectively, in healthy subjects given lithium carbonate (See reference number 2).
A paranoid schizophrenic taking chlorpromazine 200 to 600mg daily for 5 years with no extrapyramidal symptoms developed stiffness of his face,arms and legs, and parkinsonian tremor of both hands within one day of starting to take lithium 900mg daily. His lithium blood level after 3 days was 0.5 mmol/L. He was later given lithium 1.8 g daily (blood level 1.17 mmol/L),chlorpromazine 200mg daily and benzatropine 2mg daily, which improved his condition, but he still complained of stiffness and had a persistent hand tremor.(See reference number 4)
A number of other reports describe emergence of severe extrapyramidal adverse effects when chlorpromazine was given with lithium (See reference number 5-7). Ventricular fibrillation,thought to be caused by chlorpromazine toxicity, occurred in a patient taking lithium when both drugs were suddenly withdrawn (See reference number 8). Severe neurotoxicity has also been seen in a handful of other patients taking lithium and chlorpromazine (See reference number 9,10).
A large-scale retrospective study of literature over period 1966 to 1996 using Medline database identified 41 cases of neurotoxic adverse effects in 41 patients with low therapeutic concentrations of lithium. Of these patients,10 were taking haloperidol (See reference number 9).
Another retrospective study using both Medline and spontaneous reporting system of FDA in US, over period 1969 to 1994, identified 237 cases of severe neurotoxicity involving lithium, of which 59 also involved concurrent use of haloperidol (See reference number 11,12).
Other reports describe encephalopathic syndromes (lethargy,fever, tremulousness, confusion, extrapyramidal and cerebellar dysfunction),(See reference number 13)neuromuscular symptoms, impaired consciousness and hyperthermia,(See reference number 14)delirium, severe extrapyramidal symptoms and organic brain damage in patients taking haloperidol with lithium (See reference number 15-26). In one study it was found that of 13 patients who were taking haloperidol, 5 developed neurotoxic reactions, and they were receiving higher doses of haloperidol (average dose was 59 mg) than 8 patients who did not develop such symptoms (average dose was 34.9 mg) (See reference number 27). The sudden emergence of extrapyramidal or other adverse effects with lithium and haloperidol has also been described in other studies (See reference number 9,15,28).
In contrast to reports cited above, there are others describing successful and uneventful use (See reference number 13,29-32). A retrospective search of Danish hospital records found that 425 patients had taken both drugs and none of them had developed serious adverse reactions (See reference number 33).
A small rise in serum lithium levels occurs in presence of haloperidol, but it is almost certainly of little or no clinical significance (See reference number 34).
A large-scale retrospective study of literature over period 1966 to 1996 using Medline database identified 41 cases of neurotoxic adverse effects in 41 patients with low, therapeutic concentrations of lithium. Of these patients,51.2 % were also taking at least one antipsychotic drug (See reference number 9). Another retrospective study using both Medline and spontaneous reporting system of FDA in US, over period 1969 to 1994, identified 237 cases of severe neurotoxicity involving lithium, with 188 involving lithium with antipsychotics (See reference number 11,12). The sudden emergence of extrapyramidal or other adverse effects has also been described in other studies. The antipsychotics implicated in this interaction with lithium are
thioridazine,,trifluoperazine,zuclopenthixol (See reference number 9). Examples of some cases are cited in a little more detail below.
A study of 10 patients taking fluphenazine, haloperidol or tiotixene found that addition of lithium worsened their extrapyramidal symptoms (See reference number 43). Neurotoxicity (tremor,rigidity, ataxia, tiredness, vomiting, confusion) attributed to an interaction between lithium and fluphenazine has been described in another patient. He previously took haloperidol and later took chlorpromazine with lithium,without problem (See reference number 44). Irreversible brain damage has been reported in a patient taking fluphenazine decanoate and lithium (See reference number 45). Severe neurotoxic complications (seizures,encephalopathy, delirium, abnormal EEGs) developed in 4 patients taking thioridazine 400mg daily or more and lithium. Serum lithium levels remained below 1 mmol/L. Lithium and other phenothiazines had been taken by 3 of them for extended periods without problems, and fourth subsequently took lithium and fluphenazine without problems (See reference number 46). In one study concurrent use of lithium and chlorpromazine, perphenazine, or thioridazine was associated with sleep-walking episodes in 9 % of patients (See reference number 47). Somnolence,confusion, delirium, creatinine phosphokinase elevation and fever occurred in a man taking lithium when risperidone was given (See reference number 48). A retrospective review of 39 patients with a diagnosis of neurotoxicity caused by treatment with lithium and an antipsychotic,found that
Antipsychotics,Anxiolytics and Hypnotics 711
the onset of symptoms varied from 24 hrs to 3 months after taking two drugs together, with an average delay of 12.7 days (See reference number 28).
Not understood. One suggestion to account for reduced serum levels of chlorpromazine, which is based on animal studies,(See reference number 50,51) is that chlorpromazine can be metabolised in gut. Therefore, if lithium delays gastric emptying, more chlorpromazine will be metabolised before it reaches circulation. Just why severe neurotoxicity and other adverse effects sometimes develop in patients taking lithium and antipsychotics is not understood. It is subject of considerable discussion and debate (See reference number 9,11,12,52,53).
Information about reduction in chlorpromazine levels caused by lithium is limited, but it would seem to be an established interaction of clinical importance. Serum chlorpromazine levels below 30 nanograms/mL have been shown to be ineffective, whereas clinical improvement is usually associated with levels within 150 to 300 nanogram/mL range (See reference number 54). Thus a fall in levels to below 70 nanograms/mL,as described in one study, would be expected to result in a reduced therapeutic response to chlorpromazine. Therefore effects of concurrent use should be closely monitored and chlorpromazine dosage increased if necessary.
The development of severe neurotoxic or severe extrapyramidal adverse effects with combinations of antipsychotics and lithium appears to be uncommon and unexplained but be alert for any evidence of toxicity if lithium is given with any of these drugs. One recommendation is that onset of neurological manifestations, such as excessive drowsiness or movement disorders, warrants electroencephalography without delay and withdrawal of drugs, especially as irreversible effects have been seen. A review(See reference number 55) suggests that concurrent use of haloperidol seems to be safe if lithium levels are below 1 mmol/L. It is not known whether this also applies to other antipsychotics.
At moment there seems to be no way of identifying apparently small number of patients who are particularly at risk, but possible likely factors include a previous history of extrapyramidal reactions with antipsychotics and use of large doses of antipsychotic.
For interactions of atypical antipsychotics with lithium see amisulpride,; aripiprazole, ; clozapine, ; olanzapine, ; quetiapine, ; and ziprasidone, .
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