What is the cause of muscle stiffness, weakness, and tremor in a patient taking lithium (lithium) and fluphenazine (fluphenazine, Prolixin)?

From the Guidelines

The patient's symptoms of muscle stiffness, weakness, and tremor while taking lithium and fluphenazine necessitate immediate medical evaluation to rule out extrapyramidal symptoms (EPS) or lithium toxicity, and the patient should contact their healthcare provider for an urgent assessment, including lithium level testing. The combination of these symptoms in a patient on lithium and fluphenazine suggests a medication-induced movement disorder, most likely EPS from fluphenazine or lithium toxicity 1. Fluphenazine, a typical antipsychotic, commonly causes EPS through dopamine receptor blockade, as described in the pathophysiology of neuroleptic malignant syndrome (NMS), where dopamine D2 receptor antagonism leads to manifestations including muscle rigidity and tremor 1. Lithium, on the other hand, has a narrow therapeutic window and can cause tremor even at therapeutic levels.

Key considerations in managing these symptoms include:

• Urgent assessment, including lithium level testing, to determine if the symptoms are due to lithium toxicity or EPS from fluphenazine.
• The patient should not abruptly stop medications but should be under close medical supervision.
• If symptoms are severe, an anticholinergic medication like benztropine (1-2mg twice daily) may be prescribed to manage EPS from fluphenazine, as suggested by guidelines for managing antipsychotic-induced side effects 1.
• Dose reduction of either medication might be necessary, considering the potential for significant side effects with typical antipsychotics like fluphenazine 1.
• For lithium-induced tremor, propranolol (10-40mg twice daily) may help, as it is sometimes used to manage tremors associated with lithium therapy.
• Hydration status, medication interactions, and renal function should be evaluated as they affect lithium levels, emphasizing the importance of regular monitoring of lithium levels (target 0.6-1.2 mEq/L), thyroid, and renal function to prevent toxicity, as recommended for patients on lithium therapy 1.

Given the potential for severe side effects and the complexity of managing patients on lithium and antipsychotics, close monitoring and adjustment of medications under the guidance of a healthcare provider are crucial to prevent morbidity and mortality.

From the FDA Drug Label

Information for the patients: Outpatients and their families should be warned that the patient must discontinue lithium therapy and contact his physician if such clinical signs of lithium toxicity as diarrhea, vomiting, tremor, mild ataxia, drowsiness, or muscular weakness occur Drug interactions: Combined use of haloperidol and lithium. An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leucocytosis, elevated serum enzymes, BUN and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol The possibility of similar adverse interactions with other antipsychotic medication exists.

The patient's symptoms of muscle stiffness, weakness, and tremor while on lithium and fluphenazine may be related to lithium toxicity or an adverse interaction between lithium and fluphenazine, an antipsychotic medication similar to haloperidol.

• Lithium toxicity can cause symptoms such as tremor and muscular weakness.
• The combination of lithium and antipsychotic medication may increase the risk of neurological toxicity.
• Patients receiving such combined therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear 2.

From the Research

Muscle Stiffness, Weakness, and Tremor in Patients on Lithium and Fluphenazine

• Muscle weakness is a common symptom that can result from dysfunction at any level of the neuraxis, and it is a cardinal feature of many neuromuscular disorders 3.
• The characteristics of muscle weakness include debility, loss of function, and asymmetry, with debility encompassing lack of strength, atrophy, and fatigue 4.
• Extrapyramidal symptoms (EPSs), such as muscle stiffness, weakness, and tremor, are adverse effects of antipsychotics, including fluphenazine 5, 6, 7.
• The incidence of EPSs with atypical antipsychotics is lower compared to conventional antipsychotics, but EPSs can still occur, particularly at high doses 6, 7.
• Fluphenazine, a first-generation antipsychotic, may have a higher risk of EPSs compared to some atypical antipsychotics 5.
• Lithium, a mood stabilizer, can also contribute to muscle weakness and tremor, particularly when used in combination with antipsychotics 3.
• A thorough neurologic examination and accurate diagnosis are essential to guide appropriate treatment and management of muscle stiffness, weakness, and tremor in patients on lithium and fluphenazine 3.

Possible Causes and Associations

• Muscle weakness can coexist with muscle tightness, and it is essential to consider both subjective and objective traits when assessing muscle weakness 4.
• The patient's age at symptom onset, any identified inciting factors, tempo of symptom progression, pattern of weakness, and associated symptoms and signs are all important diagnostic clues in the evaluation of a patient presenting with muscle weakness 3.
• EPSs, including muscle stiffness, weakness, and tremor, can be categorized as acute (dystonia, akathisia, and parkinsonism) and tardive (tardive dyskinesia and tardive dystonia) syndromes 6, 7.