Lithium with Flupenthixol Interaction Details

Brand Names Associated with Lithium

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 21, 2023

Interaction Effect

Weakness, dyskinesias, increased extrapyramidal symptoms, encephalopathy, and brain damage

Interaction Summary

An encephalopathic syndrome followed by irreversible brain damage has occurred in a few patients treated with lithium plus a DOPamine-2 antagonist, particularly haloperidol. A causal relationship between these events and the concomitant administration of a DOPamine-2 antagonist and lithium has not been established. Coadministration of lithium and a number of antipsychotic drugs has caused a wide variety of encephalopathic symptoms, brain damage, extrapyramidal symptoms, and dyskinesias in isolated case reports. In most cases, these effects have occurred with therapeutic lithium levels . However, many series and trials have reported using such combinations with no severe adverse consequences . The mechanism is not fully understood, but chronic lithium treatment decreases neostriatal DOPaminergic activity, probably through a direct action on the G protein and the capacity of the G proteins, once activated, to stimulate adenyl cyclase . Hyperglycemic reactions have also occurred during combined phenothiazine and lithium use .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Monitor patients closely for any signs of toxicity or extrapyramidal symptoms, especially if high doses of DOPamine-2 antagonists, particularly haloperidol, and lithium are used. Serum lithium levels should be monitored periodically. Some clinicians advocate maintaining levels in the low therapeutic range.

Mechanism Of Interaction

Unknown

Literature Reports

A) Concomitant haloperidol and lithium therapy has resulted in symptoms of encephalopathy, confusion, extrapyramidal symptoms, and fever in several patients with mania . Irreversible neurological injuries have been reported .

B) Seizures, encephalopathy, delirium, and abnormal EEG occurred in four patients during combined lithium and thioridazine therapy . Serum lithium levels were below 1 mEq/L at the time of the toxic reaction in all cases. All patients had previously tolerated lithium in combination with another phenothiazine. Three of these patients developed symptoms within eight days of initiating combination therapy.

C) The addition of lithium to neuroleptic therapy exacerbated extrapyramidal symptoms (EPS) in a small study . The patients had received at least five days of treatment with either oral thiothixene, haloperidol, or fluphenazine in mean doses of 607.5 chlorpromazine equivalents prior to initiation of the lithium and were experiencing drug-induced extrapyramidal symptoms. Oral lithium was added when clinically indicated in sufficient doses to achieve a therapeutic serum concentration. The maximum levels attained were 0.65 to 1.27 mEq/L. The EPS ratings increased in all ten patients following the addition of lithium. However, only three patients developed marked symptoms and no patient developed lithium toxicity. Significantly increased symptoms included gait, shoulder shaking, elbow rigidity, and tremor.

D) Ten patients treated with clozapine and lithium were studied . Of the ten patients, four experienced significant neurologic effects, including jerking of limbs, facial spasms and tics, tremor of hands and arms, tongue twitching, and stumbling gait. One of these also experienced delirium. These effects reversed when lithium was discontinued or given at a lower dose. On rechallenge, one of two patients suffered recurrence of symptoms. By keeping serum lithium no greater than 0.5 mEq/L, clozapine could be safely coadministered.

E) Chlorpromazine serum levels can be significantly reduced in the presence of lithium treatment. If used concurrently, abrupt cessation of lithium may result in rebound elevation of chlorpromazine levels, resulting in chlorpromazine toxicity. In patients on a lithium-chlorpromazine combination, abrupt withdrawal of the lithium may precipitate chlorpromazine cardiotoxicity. In this report, such toxicity was manifested as sudden ventricular fibrillation associated with prolongation of the QTc interval. Hypotension and EPS are also possible in this situation .

F) However, other data do not support that such adverse events are frequent or indeed causally related to combination therapy. Combination of DOPamine antagonist antipsychotic drugs and lithium have been used successfully in many patients with manic-depressive illness. It has been proposed that the interaction may only become significant with very high doses of one or both drugs or with failure to discontinue dosing in the presence of toxic symptoms .

G) A 69-year-old patient with oxygen-dependent chronic obstructive pulmonary disorder and a 25-year history of bipolar disorder was started on risperidone 3 mg for the treatment of new-onset auditory and visual hallucinations. She had also been maintained on a regimen of lithium (450 mg daily) for more than 10 years. In addition, she was given amantadine (100 mg twice daily) for tremor. Three weeks after the start of risperidone, the patient experienced a decline in mental status in addition to dizziness, worsening tremors, nausea and vomiting, polyuria, depression, and visual and auditory hallucinations. She was then admitted to the hospital for delirium. Her lithium serum level was 1.36 mEq/L at the time of the admission. All medications were discontinued. Although her lithium level decreased to 0.41 mEq/L, she continued to experience profound delirium, tremors, lethargy, and hallucinations for almost one week. After she started to respond to commands, she was restarted on lithium (300 mg at bedtime) because of the onset of mild hypomania. Five days later, she was discharged with a regimen of lithium and low-dose lorazepam for treatment of insomnia. It is suggested that delirium could have been caused by the concurrent use of lithium and risperidone. Other factors could also have caused delirium, such as the patient's serum lithium level and the underlying pulmonary pathology. In addition, amantadine, which facilitates the release of presynaptic DOPamine and has a mild anticholinergic effect, may have contributed .

Lithium Overview

• Lithium is used to treat and prevent episodes of mania (frenzied, abnormally excited mood) in people with bipolar disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Lithium is in a class of medications called antimanic agents. It works by decreasing abnormal activity in the brain.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.