Haloperidol with lithium

Marhold J, Zimanova J, Lachman M, Krai J, Vojtechovsky M. To the incompatibility of haloperidol with lithium salts. ActNerv Super (Praha) (1974) 16, 199-200. 

Fig. 15. Substantia nigra, pars compacta. Metabolic response to apomorphine (0.5 mg/kg) (expressed as percent change in cerebral glucose utilization from control animals) in four groups of animals which had been pretreated for 21 days with saline (SAL), haloperidol (HAL) (1 mg/kg/day), haloperidol with lithium in diet (Li /HAL), and lithium in diet (Li" ). Data are presented as mean SEM. The response to apomorphine in the animal chronically treated with haloperidol (HAL) differs significantly from that with all other treatments. Glucose utilization in control animals was 56 4 pmol/100 g/ min. (Data from McCulloch, Savaki, Pert, Bunney, and Sokoloff, unpublished.)...

Most psychotic and non-compliant patients are difficult to treat with lithium alone and need to be treated with neuroleptics. Haloperidol has been widely... 

Encephalopathic syndrome - An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness, confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, blood urea nitrogen, fasting blood sugar) has occurred in a few patients treated with lithium plus an antipsychotic (haloperidol). 

Campbell, M., Small, A.M., Green, W.H., Jennings, S.J., Perry, R., Bennett, W.G., and Anderson, L. (1984) Behavioral efficacy of haloperidol and lithium carbonate. A comparison in hospitalized aggressive children with conduct disorder. Arch Gen Psychiatry 41 650-656. 

Oxcarbazepine is a keto derivative of carbamazepine but offers several advantages over carbamazepine. Oxcarbazepine does not require blood cell count, hepatic, or serum drug level monitoring. It causes less cytochrome P450 enzyme induction than does carbamazepine (but may decrease effectiveness of oral contraceptives containing ethinyl estradiol and levonorgestrel). As opposed to carbamazepine, oxcarbazepine does not induce its own metabolism. These properties, combined with its similarity to carbamazepine, led many clinicians to use this medication for the treatment of bipolar disorder. Randomized controlled trials suggested efficacy in the treatment of acute mania compared with lithium and haloperidol, but these trials were quite small and did not include a placebo control (Emrich 1990). 

Verapamil Versus Other Psychotropics. Garza-Trevino et al. (258) conducted a 4-week, randomized, double-blind study comparing verapamil with lithium for acute mania and found no clinical or statistically significant differences between the two treatments. These results are difficult to interpret, however, because data about the amount and timing of rescue medication (i.e., haloperidol, lorazepam) were not presented. Further, more patients on verapamil required these agents. 

A 39-year-old woman who had overdosed with lithium and who took a single dose of haloperidol (195). 

A 30-year-old man with bipolar disorder who had previously taken haloperidol and lithium was also given trihexyphenidyl (benzhexol) because of rigidity, tremor, and akathisia, but persistent symptoms led to his being given olanzapine in place of haloperidol 6 days later he developed priapism (242). 

There is an increased frequency of neurotoxic symptoms in patients treated with lithium and antipsychotics (mainly described with lithium and haloperidol) or high-dose thioridazine. Marked electroencephalogram changes and tonic-clonic seizures have been observed when lithium has been combined with clozapine. ° ... 

K tt individualize dose for each patient. Transient dyskinesias may be caused by abrupt withdrawal. Enhances actions of CNS depressants, alcohol, anticonvulsants. Decreases actions of amphetamines. Severe hypotension with alcohol, epinephrine, antihypertensives. Antimuscarinics Increase intraocular pressure and reduce haloperidol effects. Lithium encephalopathic syndrome. ... 

Baastrup PC, Hollnagel P, SerensenR, SchouM. Adversereactionsin treatment with lithium carbonate and haloperidol. JAMA (1976) 236, 2645-6. 

A 59-year-old man who had been diagnosed with encephalopathy and confusion while taking a combination of carbamazepine, haloperidol and lithium (therapeutic lithium level), developed similar symptoms when he was later given lithium with olanzapine. Another elderly patient who had taken lithium for 7 years, developed severe delirium and extrapyramidal... 

Largactil is a proprietary preparation of chlorpromazine, an aliphatic antipsychotic with marked sedation and moderate antimuscarinic and extrapyramidal side-effects. Serenace is a proprietary preparation of haloperidol, a butyrophenone antipsychotic with marked extrapyramidal side-effects, moderate sedation but not very likely to cause hypotension. Tegretol is a proprietary preparation of carbamazepine, an anti-epileptic drug indicated in partial and secondary generalised tonic-clonic seizures, primary generalised tonic-clonic seizures, trigeminal neuralgia and in the prophylaxis of bipolar disorder unresponsive to lithium. 

Antipsychotic drugs, such as flupentixol and haloperidol are the mainstay of treatment for acute attacks of mania. Lithium is not indicated as it may take a few days before the drug exerts an effect. Lithium may be given concomitantly with an antipsychotic drug. 

Aggravation of the extrapyramidal effects of antipsychotic agents have been described and it has been reported that the use of lithium in combination with haloperidol may result in irreversible neurological toxicity. Lithium can increase the hypothyroid effects of antithyroid agents or iodides. 

For more than 40 years, Li+ has been used to treat mania. While it is relatively inert in individuals without a mood disorder, lithium carbonate is effective in 60 to 80% of all acute manic episodes within 5 to 21 days of beginning treatment. Because of its delayed onset of action in the manic patient, Li+ is often used in conjunction with low doses of high-potency anxiolytics (e.g., lo-razepam) and antipsychotics (e.g. haloperidol) to stabilize the behavior of the patient. Over time, increased therapeutic responses to Li+ allow for a gradual reduction in the amount of anxiolytic or neuroleptic required, so that eventually Li+ is the sole agent used to maintain control of the mood disturbance. 

Of the atypical antipsychotics, clozapine, olanzapine, and risperidone have been studied the most. Clozapine was used to treat 10 treatment refractory acutely manic patients and 15 schizomanic patients. Using reduction in the YMRS score as the outcome measure, 72% improved (non-rapid cycling, bipolar patients). Comparison of olanzapine (5-20 mg) with placebo showed significant reduction of the YMRS in 49% vs. 24% of subjects by 3 weeks, with significant change evident by the first week. In a trial comparing risperidone at 6 mg with haloperidol at 10 mg and low-dose lithium (800-1200 mg/day) efficacy was similar over the 28 days of the trial. 

Freeman TW, Clothier JL, Pazzaglia P, et al A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 149 108-111,1992 Frenchman IB, Prince T Clinical experience with risperidone, haloperidol, and thioridazine for dementia-associated behavioral disturbances. Int Psychogeriatr 9 431-435, 1997... 

Another use of the laboratory is for therapeutic drug monitoring (TDM) of psychotropics with defined optimal ranges, narrow therapeutic indices, or both. Although TDM is not essential for many psychotropics, it is for others, including lithium, several TCAs, valproate, and carbamazepine. It may also be helpful to optimize the use of certain antipsychotics (e.g., haloperidol, clozapine) ( 7). 

Limited evidence indicates that carbamazepine plus an antipsychotic may also benefit some schizophrenic patients. This is an interesting possibility in view of the similar antimanic properties of lithium and carbamazepine (375). This area requires further research, especially to clarify the indications for combining anticonvulsants with an antipsychotic. For example, mania complicated by psychotic features may benefit from lithium, valproate, or carbamazepine augmented by antipsychotics. Because carbamazepine induces the metabolism of at least some antipsychotics (e.g., haloperidol, thiothixene), dose adjustment based on TDM may be necessary to achieve the optimal effect. 

Lorazepam. Lenox et al. (118) found lorazepam and haloperidol comparable in efficacy when used as adjuncts to lithium in a double-blind study of 20 acutely manic patients. Interestingly, another report comparing lorazepam with clonazepam found a better outcome with lorazepam, using mean doses of 12 to 13 mg (119). 

Approximately 50 subjects were randomized to each group. Open lithium or VPA treatment was also used. Those patients treated with risperidone or haloperidol had a substantially greater decrease from baseline YMS scores than those on placebo (i.e., 14 for risperidone and 13 for haloperidol versus 8 points for the placebo group (p=0.009). Further, 57% of the risperidone group achieved at least a 50% decrease from the YMS baseline score, compared with 38% in the placebo group. This study demonstrates that the addition of risperidone or haloperidol produced a better response than that achieved with a mood stabilizer alone. 

The question of increased neurotoxic reactions with the combination of lithium and an antipsychotic (especially haloperidol) has been vigorously debated since the report of Cohen and Cohen (346, 347, 348 and 349). Possible explanations have included the following ... 

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