Auditory hallucinations induced by atorvastatin and exacerbated by a rare case report

Authors: Daniele S. C. Ramsay, Harvey Stevenson, Waseem Jerjes

Abstract

Background

Auditory hallucinations, commonly associated with psychiatric conditions such as schizophrenia, can arise as side effects to certain medications. Several drug classes are commonly implicated in the causation of hallucinations, such as anticholinergics. Medication associated with disruption of steroid production may lead to neuropsychiatric disruption. One such drug class, statins, may also have psychiatric sequelae. Wide prescribing of common medication such as atorvastatin, allows the unveiling of uncommon medication-related adverse events.

Case Description

We detail a unique case-report of a 60-year-old man experiencing auditory hallucinations post-initiation of atorvastatin. The content of the hallucinations consisted of voices of deceased family members. These were frequently accompanied by predominantly frontal headaches. Subsequently, during the treatment of a chest infection utilizing cefalexin, the auditory hallucinations intensified in clarity and increased in frequency. Despite initial concerns related to a family history of meningiomas, magnetic resonance imaging ruled out structural abnormalities. Comprehensive viral screening excluded infectious as the causative factor and there were no signs of concurrent delirium. Following termination of the course of cefalexin, the hallucinations reduced in intensity. The cessation of atorvastatin led to the resolution of hallucinations.

Conclusions

This case emphasizes the importance of drug history evaluation in neuropsychiatric presentations and prompts further exploration into the neuropsychiatric effects of commonly prescribed drugs.

Introduction

Background

Auditory hallucinations are false perceptions of sound in the absence of an external stimulus (1). These can range from simple noises, like ringing or humming, to complex voices conversing or commenting on the individual’s thoughts or actions. Understanding the underlying causes of these hallucinations is crucial for effective management and treatment, particularly in the absence of a unifying psychiatric diagnosis or history.

The roots of auditory hallucinations in conditions such as schizophrenia are extensively studied, with disruptions in the brain’s auditory processing pathways, especially within the temporal lobe, playing a role (2). Furthermore, stress, anxiety, and depression can augment the risk of experiencing auditory hallucinations, pointing towards the multifaceted interplay between emotional experience and neurological elements.

Rationale and knowledge gap

These medications can cause hallucinations either during use, in overdose situations, or upon withdrawal. Better understanding of these mechanisms may shed light on the mechanisms underpinning hallucinations (1). Several classes of medications are known to precipitate auditory hallucinations, either during use, in overdose situations, or upon withdrawal.

Anticholinergic drugs, which act to block of the action of acetylcholine, are known to be implicated in hallucination development (3). Medications such as atropine and scopolamine can lead to a syndrome characterized by hallucinations, confusion, and agitation. Similarly, dopaminergic agents, like levodopa used in Parkinson’s disease, can also result in hallucinations (4). This aligns with the dopamine hypothesis of schizophrenia, which postulates that overactivity in the mesolimbic pathway is responsible for the positive symptoms of schizophrenia (5).

Another notable class is the sedative-hypnotics, including benzodiazepines and the so-called “Z-drugs” such as zolpidem (6). Withdrawal from or overdose of these agents can manifest with auditory hallucinations.

Objective

Herein, we present a unique case of a 60-year-old gentleman who, after commencing atorvastatin, developed auditory hallucinations that were further amplified following the addition of cefalexin for a chest infection. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-8/rc).

Case presentation

A 60-year-old male engineer, residing with his long-term partner, presented to our medical centre (North End Medical Centre) complaining that he could hear voices. He distinctively distinguished 2 or 3 separate voices during these episodes, of which one resembled a deceased family member.

He had a past medical history of essential hypertension and hypercholesterolaemia, managed with valsartan and atorvastatin respectively. The patient’s family history included multiple relatives diagnosed with meningiomas, which heightened his concern and anxiety about potential intracranial pathologies. This familial history initially led clinicians to prioritize ruling out structural abnormalities through imaging studies before considering medication-induced causes. His last consultation with his general practitioner (GP) at our centre was 5 days prior to this visit. In that session, he was diagnosed with a chest infection and was subsequently prescribed cefalexin.

The patient recalled that approximately 5 weeks post-initiation of atorvastatin (which was started six months before) he began experiencing non-distinct auditory sensations. Initially, these occurred predominantly during nocturnal hours. He initially dismissed them, uncertain of their association with the medication. Over the following months, these auditory events became more pronounced and frequent, particularly following the initiation of cefalexin for a chest infection. Though sporadic, these became more pronounced and were frequently accompanied by headaches, primarily localised in the frontal region. Initially, the auditory hallucinations occurred infrequently, roughly 2–3 times per week, often during the night. Over the next 5 months, the frequency increased to almost daily occurrences. The hallucinations were often triggered by periods of stress and were partially alleviated by rest and relaxation. Specific examples include hearing indistinct murmurs which evolved into clearer, distinct voices. One of which was recognized as a deceased family member, which would comment on his actions or have nonsensical conversations. An example includes hearing a voice say, ‘You left the door open,’ when no one else was in the house. There were no delusions associated with the hallucinations. The headaches were intermittent and pulsating. These headaches often coincided with the auditory hallucinations, suggesting a possible link. Stress and lack of sleep appeared to exacerbate both the headaches and the hallucinations. The headaches were somewhat alleviated by over-the-counter pain medication and rest. The patient was diagnosed with a chest infection, presenting with symptoms of productive cough, fever, and malaise. He was prescribed cefalexin (500 mg four times a day for 7 days) to treat this infection. The auditory hallucinations notably intensified within 48 hours of starting cefalexin, persisting throughout the course of the antibiotic and gradually subsiding after its completion. During this period, the patient did not exhibit any signs of delirium. The timing augmentation in auditory hallucinations, 48 hours after cefalexin initiation and persisting throughout the 7-day course of treatment, strongly suggests a correlation with cefalexin use rather than the pulmonary infection itself.

Physical examination revealed the patient was oriented to time, place and person, with vital signs within normal limits. His memory was sharp, with immediate recall and recognition intact. A thorough mental health assessment showed no signs of cognitive impairments, mood disorders, or any underlying social stressors. His Montreal Cognitive Assessment (MOCA) score was 29 out of 30, reinforcing the absence of cognitive dysfunction.

Given his symptoms and family history, a comprehensive work-up was warranted. His haematology, biochemical and viral screening were reported as normal. Within 2 weeks of halting atorvastatin, the patient revisited our clinic, reporting a significant reduction in the intensity of his hallucinations, which now reverted to vague auditory murmurs at night.

An audiogram evaluation did not reveal any hearing deficits. Most importantly, cranial magnetic resonance imaging (MRI) was performed to rule out any structural abnormalities, especially meningiomas, and it returned with no remarkable findings. Autoimmune encephalitis was not considered in the differential diagnosis. The patient did not exhibit any additional neurological symptoms suggestive of encephalitis. A lumbar puncture was not indicated.

Considering the chronological relationship between the atorvastatin initiation and the emergence of these auditory symptoms, the clinical decision was to discontinue atorvastatin. Simultaneously, he was referred to a mental health specialist for a more comprehensive assessment. The hallucinations subsided following the discontinuation of atorvastatin. The cessation of the statin led to a complete resolution of the auditory hallucinations and associated headaches within two weeks (Figure 1).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case underscores the importance of keen pharmacovigilance, patient history analysis, and the potential for atypical presentations linked to commonly prescribed medications. Auditory hallucinations, often regarded as a hallmark of certain psychiatric disorders, can occasionally arise from unexpected sources, such as drug-related side effects. Statins, including atorvastatin, are widely prescribed for hyperlipidaemia, and their side effects are predominantly documented within the scope of muscle and liver disturbances (7). However, the central nervous system manifestations, including auditory hallucinations, are rarely considered.

In our patient, the chronology of the onset of auditory symptoms in conjunction with the commencement of atorvastatin raises important questions about the drug’s neuropsychiatric safety profile. Notably, sporadic reports have begun to emerge, linking statins with cognitive disturbances (8,9). While cognitive complaints associated with statin use are largely reversible upon discontinuation, the occurrence of auditory hallucinations is seldom documented, making this case an intriguing addition to the literature. Potential mechanisms for atorvastatin-induced hallucinations may involve its impact on cholesterol synthesis and membrane fluidity in neuronal cells, potentially affecting neurotransmitter function. Cefalexin may exacerbate these effects through possible neurotoxicity or drug-drug interactions, although the exact mechanism remains unclear. Further research into these biochemical pathways could provide insights into the neuropsychiatric side effects of these medications.

Cefalexin, an antibiotic employed in the treatment of bacterial infections, is not conventionally linked to neuropsychiatric side effects (10). Yet, in our patient, the amplification of auditory hallucinations upon its initiation merits consideration. It is conceivable that an underlying drug-drug interaction or a potential synergistic neurotoxic effect may have exacerbated the auditory distortions. There are sporadic reports of hallucinations and delirium associated with its use. These cases suggest a potential, though rare, neurotoxic effect that warrants further investigation (11). However, further exploration and larger studies are essential to ascertain this hypothesis.

The patient’s genuine concern regarding the familial history of meningiomas complicated the clinical scenario. Such concerns can be a powerful catalyst for the nocebo effect, where the mere apprehension about potential adverse outcomes can contribute to the perceived symptoms (12). Nevertheless, with the resolution of auditory hallucinations post discontinuation of atorvastatin, the drug’s role as the primary culprit becomes more likely.

Conclusions

This case underscores the key role of a thorough drug history in the evaluation of neuropsychiatric symptoms. As our inventory of pharmacological agents grows, so does the potential for unexpected drug-related side effects. It is vital for clinicians to remain vigilant, especially when dealing with commonly prescribed medications, and consider the possibility of rare or atypical presentations.

Supplementary