Haloperidol neurologic effects

The global efficacy of olanzapine was not substantially different from that of haloperidol in two of three comparative trials involving 2500 patients, according to a comprehensive review of the safety and efficacy of olanzapine in addition, the only relevant comparative trial failed to demonstrate superiority of olanzapine over risperidone (52). Olanzapine has fewer adverse neurological effects than haloperidol, but there is no evidence that it differs from other atypical neuroleptic drugs in this respect. 

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. 

Nevertheless, this condition is responsive to treatment with dopamine-2 receptor antagonists. Hence, this condition is one of the clearest childhood indications for treatment with these medications. In theory, any dopamine-2 blocking receptor antagonist could be used. Haloperidoi has been the most extensively tested and used medication for this condition (167). The typical dose for children aged 3 to 12 years old is 0.2 mg/kg per day. More recently, in a double-blind study of 36 boys with Tourette s syndrome, risperidone was effective in reducing tics in 88% versus 60% for haloperidol (197), perhaps making risperidone a better option than a neuroleptic in terms of neurological adverse effects. 

Chlorpromazine, the first modern drug to be used in the treatment of schizophrenia and other psychotic disorders, was introduced into psychiatry in 1952 [61]. It was followed by a number of other drugs for the treatment of these conditions (e.g., haloperidol, thioridazine). These were also called neuroleptics because of their neurological side effects, such as parkinsonian syndrome and tardive dyskinesia. Tardive dyskinesia is a movement disorder characterized by involuntary movements of the face and limbs. The antipsychotic properties of these drugs were inseparable from the extrapyramidal effects. 

Erythrocyte/plasma lithium concentration ratios were lower in patients taking phenothiazines or haloperidol than in those taking lithium alone (620,621), and the former group had a higher incidence of neurological and renal adverse effects (621). 

Adverse effects can result from increased plasma concentrations of haloperidol during itraconazole treatment. This has been observed in 13 schizophrenic patients treated with haloperidol 12 or 24 mg/day who took itraconazole 200 mg/day for 7 days (51). Plasma concentrations of haloperidol were significantly increased and neurological adverse effects were more common. Itraconazole is a potent inhibitor of CYP3A4. 

Meibach RC, Mazurek MF, Rosebush P. Neurologic side effects in neuroleptic-naive patients treated with haloperidol or risperidone. Neurology 2000 55(7) 1069. 

Other, chemically distinct dopamine blockers were then developed, such as thiothixene, haloperidol, loxapine, molindone, and pimozide. All of these antipsychotics are potent dopamine blockers and collectively were called neuroleptics because they inadvertently cause certain neurological side effects (discussed below). More recently, atypical antipsychotic medications have been developed (clozapine and risperidone), which are effective antipsychotics yet are weak dopamine blockers and cause minimal neurological side effects. This group is discussed separately below. 

The development of severe neurotoxic or severe extrapyramidal adverse effects with comhinations 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 the onset of neurological manifestations, such as excessive drowsiness or movement disorders, warrants electroencephalography without delay and withdrawal of the drugs, especially as irreversible effects have been seen. A review suggests that the concurrent use of haloperidol seems to be safe if lithium levels are helow 1 mmol/L. It is not known whether this also applies to other antipsychotics. 

The clinical significance of the raised levels is unclear, although one study found an increase in neurological adverse effects with haloperidol. It may be prudent to monitor concurrent use, decreasing the haloperidol or bromperidol dose if adverse effects become troublesome. This interaction may be of more importance in those patients have less active CYP2D6, the predominant isoenzyme involved in the metabolism of haloperidol, as CYP3A4, which is inhibited by itraconazole, will then become more important. It is likely that other azoles that are potent inhibitors of CYP3A4, such as ketoconazole, would interact similarly, but this needs confirmation. 

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