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Hello. This is Dr. Sydney LeFay, a consultation–liaison psychiatrist, here to discuss the safety of antipsychotics in liver disease. Chronic liver disease is rising in the general population, and our patients are especially vulnerable. Formulating a safe and effective plan can be challenging as we encounter more medically complex individuals in clinics and hospitals. Often, our decision isn’t about the best medication but rather which is the least risky, knowing that all medication have associated risks. In my practice, I face this dilemma frequently, so I was pleased to discover a 2023 review from the Academy of Consultation-Liaison Psychiatry that provides clear guidance.
The article begins by exploring the pathophysiology of drug-induced liver injury, which is divided into 2 subtypes: Intrinsic and idiosyncratic. Intrinsic injury is dose dependent and often occurs swiftly; consider acetaminophen as an example. Idiosyncratic injury is not related to dose and can manifest after months or even years of drug use. Generally, antipsychotics fall under the idiosyncratic category. Its exact cause remains elusive, but it’s likely a blend of genetics, environment, and immune response. Such injuries can present as hepatocellular, cholestatic, mixed, or hepatosteatotic. Predicting who will develop antipsychotic-induced liver injury is challenging; however, advanced stage nonalcoholic fatty liver disease, hepatitis, and polypharmacy likely increase the risk.
I want to emphasize the risk associated with hepatosteatosis. Although cholestatic, hepatocellular, or mixed injury can manifest relatively quickly, hepatosteatosis develops slowly but is reversible in its early stages. This often emerges in the context of metabolic syndrome, where elevated triglycerides accumulate in the liver. Therefore, it’s crucial to address and manage the metabolic side effects of our drugs. If unaddressed, this can lead to cirrhosis and carcinoma.
The review underscores a 3-year observational study wherein patients were randomly assigned to aripiprazole, risperidone, quetiapine, or ziprasidone. By study’s end, one-fourth exhibited signs of fatty liver disease, although none progressed to cirrhosis or full-blown nonalcoholic fatty liver disease. Interestingly, the study omitted metabolic heavyweights like olanzapine and clozapine. Looking broadly at all-cause antipsychotic-induced liver failure, the risk is minimal. A substantial 13-year observational study involving over 300,000 patients revealed that only 0.07% developed significant liver injury with transaminases exceeding 5 times the normal value. Transaminitis at the onset of an antipsychotic regimen is common. Its prevalence can range from 1% with paliperidone to 67% with clozapine. Typically, it is mild and resolves in days to weeks. However, if it lingers, worsens, or if other indicators of liver damage, such as elevated bilirubin or physical exam findings, emerge, the situation may be grave. In such cases, consultation with hepatology or a visit to the emergency department is necessary.
Although antipsychotics might be the culprit, other causes of liver injury should also be explored. A comprehensive evaluation is vital, especially for our clozapine patients. Depending on the risk–benefit analysis, we might be reluctant to discontinue clozapine immediately. If another cause for the liver injury is identified, we might consider continuing or eventually reintroducing clozapine. Generally, if a medication is suspected to be the cause, it should be halted while investigations continue. Ideally, as the paper suggests, liver function should be monitored 1–2 times weekly, followed by every 1–3 months until recovery. Once recuperated, one might consider reintroducing an antipsychotic with a lesser risk profile.
Often, I find myself in challenging situations where the patient’s psychosis demands treatment even before liver recovery. This paper mentions that haloperidol has been a preferred choice for delirious patients with liver injuries for decades. Other drugs might be considered based on the patient’s symptoms and past reactions to antipsychotics. When treating those with underlying liver disease, we must judiciously assess the risks because liver dysfunction adversely affects the pharmacokinetic process. Opting for liver-friendly medication and adopting a “start low, go slow” approach are prudent strategies. Minimizing polypharmacy is always my goal, but it’s especially vital when liver dysfunction impairs protein binding, excretion, and cytochrome P450 processing. This paper advises checking liver function at 6 weeks and then every three months for the first year when starting an antipsychotic in someone with existing liver disease. For those known to have had liver injuries from psychiatric drugs, more frequent monitoring might be appropriate. Personally, I’d likely consult with our GI colleagues.
The authors reviewed data from 1946–2022 and focused on 15 agents, grading them from low to high risk in terms of risk categorization. Low-risk drugs reported fewer than 10 incidents of hepatotoxicity with no liver failures, whereas high-risk ones had over 50 such cases, with or without liver failure. Some newer drugs seem to have reduced hepatotoxicity, although their shorter market presence might account for fewer reports. Loxapine, paliperidone, aripiprazole, ziprasidone, and lurasidone are low-risk staples. Newer drugs like brexpiprazole, cariprazine, and lumateperone also join this list. Chlorpromazine, clozapine, and olanzapine are moderate-to-high–risk medications. Regarding long-acting injectables, paliperidone, which undergoes minimal liver metabolism, might be the safest option.
In conclusion, although anyone could be susceptible to antipsychotic-induced liver injury, predicting it is arduous. Thankfully, the chances of severe injury are low. In cases of acute damage, the medication usually should be stopped, and an investigation for other causes should be initiated. We might be hesitant with clozapine, depending on individual circumstances. We must be vigilant with our patients known to have metabolic syndrome, as they are particularly prone to hepatosteatosis. When choosing medication for those at high risk or with existing liver disease, paliperidone, aripiprazole, ziprasidone, and some newer drugs should be prioritized, whereas chlorpromazine, olanzapine, and clozapine should generally be avoided. Pharmacology isn’t one-size-fits-all. Reviews like this guide us in navigating information and facilitate our risk–benefit dialogues with fellow professionals and patients. Ultimately, we should always adhere to the principle of start low, go slow.
Abstract
Antipsychotic Safety in Liver Disease: A Narrative Review and Practical Guide for the Clinician
Matthew Gunther, Julie A Dopheide
Background: Clinicians treating psychiatric disorders in medically ill patients need a comprehensive resource for comparing the risk and types of liver injury associated with antipsychotic therapy.
Objective: We conducted a narrative review aimed at developing a comprehensive resource comparing antipsychotics with regard to risk of inducing or worsening liver injuries, types of liver injury, associated pharmacokinetic changes, dosing, monitoring, and patient counseling recommendations.
Methods: We conducted database searches of LiverTox.nih.gov, DailyMed.nlm.nih.gov, and PubMed through June of 2022. Sources describing premarketing data, observational studies, case reports and case series of antipsychotic-induced liver injuries, types of hepatic dysfunction, interventions, recovery, and treatment for 15 antipsychotics were included. Duplicate reports were excluded. Antipsychotics were graded as low, low to moderate, moderate, moderate to high, or high risk for causing or worsening a liver disease.
Results: Of the 1861 publications, 21 papers met criteria and were included. Evidence shows antipsychotic-induced liver dysfunction is uncommon to rare. Chlorpromazine, clozapine, and olanzapine pose the greatest risk of hepatoxicity; quetiapine and risperidone pose a moderate risk with haloperidol considered to pose low to moderate risk. Paliperidone, aripiprazole, lurasidone, and loxapine are lower-risk agents with no reports of liver failure. Transaminitis that is mild and self-limiting is the most common antipsychotic-induced liver injury followed by hepatocellular disease, steatosis, and mixed liver injury. A careful risk-benefit analysis should guide the decision to discontinue the antipsychotic in cases of severe liver disease. Dose adjustments and careful monitoring are recommended for a mild to moderate disease when the benefits of treating psychosis outweigh the risks. Patients without an existing liver disease initiating a treatment with a higher-risk antipsychotic should be counseled to report symptoms of liver injuries along with regular lab monitoring.
Conclusions: Antipsychotic selection, dosing, monitoring, and counseling should be individualized based on whether a patient has an existing liver disease and if they are receiving an agent that poses a higher risk of liver injury. The consultation-liaison psychiatry provider can guide the primary team in management through thoughtful integration of the known pathophysiologic changes in hepatic disease and risk-benefit analysis of antipsychotic safety profiles.
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Reference
Gunther, M., & Dopheide, J. A. (2023). Antipsychotic safety in liver disease: A narrative review and practical guide for the clinician. Journal of the Academy of Consultation-Liaison Psychiatry, 64(1), 73–82.
