England has seen a modest rise in psychotic symptoms in recent years, while antipsychotic medication use doubled over the same period, according to a study by UCL and City, University of London researchers.
The findings, published in Schizophrenia Research, clarify that a previously-reported rise in psychosis rates is partly, but not entirely, due to changes in prescription rates, as symptoms themselves are increasing as well.
The researchers found that antipsychotic medication use approximately doubled between 2007 and 2014, from an estimated 0.5% to 1.2% of people in England. The proportion of people reporting psychotic symptoms, such as hallucinations and paranoia, increased from 5.6% in 2007 to 6.8% in 2014.
The study used data from over 20,000 people representative of the general population in England. Participants took part in one of three household surveys in 2000, 2007, and 2014.
While equivalent data is not yet available for more recent years, NHS data going up to 2017 suggests that prescriptions of antipsychotics continued to increase beyond 2014.
Some of the more common experiences identified in 2014 included hearing voices (1.3% of people surveyed), or feeling that people were plotting to cause them harm (almost 2%).
Experiencing some of these would not necessarily warrant a diagnosis of a psychotic disorder, and antipsychotic medication would not always be required.
Lead author Dr. Natalie Shoham (UCL Psychiatry) said: “The reasons for the disproportionate increase in antipsychotic medication use are difficult to explain. It might be because more people are being treated successfully for distressing symptoms, or that the medications are being used for other reasons, for example to treat depression or as anti-sickness medications.
“These figures also may reflect an over-medicalisation of psychotic symptoms. Some people might be taking these medications for longer, or people with relatively minor symptoms might be more likely to be prescribed antipsychotics.
Given the significant side effects of antipsychotics, it is important that prescriptions are reviewed regularly and that the impact of increased prescribing is carefully considered.”
Possible reasons for the increase in psychotic symptoms include greater stress caused by the economic recession or changes in recreational drug use such as a rise in typical THC levels in cannabis.
Co-author Sally McManus (City, University of London) said: “While the increase in the prevalence of psychotic symptoms in the population was small, it was significant and unexpected.
Clinicians should be aware of this rise and prepared to ask patients about such symptoms. It is important that in the context of the COVID-19 pandemic the range of mental health needs of the population – beyond anxiety and depression – are not overlooked.”‘
A gradual reduction in stigma could potentially also make people more comfortable disclosing psychotic symptoms. The researchers say it is also possible that an increase in survival rates for people with psychosis, who face a large but shrinking mortality gap compared to other people, could also increase the numbers of people who experience psychotic symptoms over time.
Drug-induced liver injury (DILI) is an adverse reaction to drugs and/or their metabolites that may result in permanent loss of liver function and death. DILI covers a broad spectrum of clinical manifestations, from asymptomatic abnormalities in the liver function tests (prothrombin time, albumin, direct and indirect bilirubin, the level of aspartate, and alanine transaminase in serum) to symptomatic acute liver disease, prolonged jaundice, and disability, or overt acute or subacute liver failure (Chalasani et al. 2008). DILI is commonly divided into two types: intrinsic and idiosyncratic.
Intrinsic DILI is dose-dependent, typically has a short latency period and predictable disease course, and is reproducible in animal models. Idiosyncratic DILI is a severe liver injury occurring very rarely and usually is not dose-dependent. It is characterized by unpredictable disease course, more varied manifestations, and is not reproducible in animal models (Ye et al. 2018).
Drugs that cause idiosyncratic DILI typically also cause a mild and asymptomatic liver injury—transient, asymptomatic elevations in serum alanine aminotransferase levels (Mosedale and Watkins 2017). The lack of specific serological markers makes DILI hard to diagnose.
The clinical symptoms are very diverse and may include tiredness, lack of appetite, nausea, vomiting, fever, joint and muscle pain, rash, and jaundice, while some patients remain asymptomatic. DILI is challenging not only concerning diagnosis but for the management as well. In most cases, the only treatment is to stop the drug administration and provide general supportive care (Navarro and Senior 2006).
The liver is the primary site for the metabolism of drugs, including antidepressants (ADs) and antipsychotics (APs). Thus, it is of great importance to understand how a specific drug and its metabolites affect the structure and function of this organ. Hepatotoxicity may result in hepatic steatosis (accumulation of fat in the liver), steatohepatitis (steatosis with inflammation), fibrosis (excessive accumulation of extracellular matrix proteins), and cirrhosis (formation of bridging fibrous septa and disruption of the standard architecture of the liver) (Aithal et al. 2011).
ADs and APs, used in treating different psychiatric disorders such as depression, schizophrenia, and anxiety, may display hepatotoxicity, even at therapeutic doses (reviewed in detail in the following sections). More than 160 psychotropic drugs have been shown to produce hepatic side-effects (Dumortier et al. 2002). A more recent study reported that psychotropic drugs were responsible for 7.6% of DILI cases in a cohort of 185 patients (Licata et al. 2017). Thus, the strategy behind the choice of a psychotropic drug must consider its hepatotoxicity, especially in patients with other risk factors, such as alcoholism, drug abuse, polymedication, obesity, and diabetes.
DILI represents a burden that has been heavily underestimated due to the limitations of clinical trials to identify such rare events. However, it is among the leading causes of late-stage drug development interruption and post-marketing drug withdrawal (Raschi and de Ponti 2015).
A systematic review which included 462 medical products withdrawn in the period 1953–2013 revealed that most products were withdrawn from the marketplace due to their hepatotoxicity (18%), followed by immune-related reactions (17%), neurotoxicity (16%), and cardiotoxicity (14%) (Onakpoya et al. 2016). DILI is the most common cause of acute liver failure (50%), ahead of viral infection or autoimmune hepatitis.
In developing countries, people are at higher risk of acute liver failure due to viral infections, while in Western Europe and the United States, most cases arise from DILI (Bernal et al. 2010). Epidemiology data regarding DILI are limited, given that the incidence and prevalence of this disorder are underestimated. In China, the incidence of DILI has been rising year by year and now is recognized as a major public health concern (Yu et al. 2017; Shen et al. 2019).
According to different national studies, summarized by Ahmad and Odin (2017), DILI incidence varies from 2 to 19 cases per 100,000 per year. However, despite low incidence, DILI should always be considered in acute liver injury cases when other possible aetiologies have been excluded.
DILI frequency varies according to age, gender, and socio-economic status. As for the age, the elderly are more affected, probably due to multiple drug use and low tolerability of the therapy. Also, women and wealthier classes are more affected than men and developing societies, respectively (Licata et al. 2017).
Given a large number of new cases of psychiatric patients each year, the need and use of psychotropic drugs are on the constant rise. In the case of depression, the total estimated number of affected people increased by 18.4% between 2005 and 2015 (WHO 2017).
Also, it is expected that the current worldwide health emergency caused by COVID-19 adversely affects mental health in many ways. It has already been established that COVID-19 survivors and frontline healthcare engaged with COVID-19 patients presented a high risk of developing symptoms of depression, anxiety, insomnia, fatigue, and post-traumatic stress disorder (Lai et al. 2020; Mazza et al. 2020; Rogers et al. 2020).
In addition, fear of infection, as well as unemployment, working from home, home-schooling of children, and lack of contact with family members and friends are risk factors for psychiatric disorders in the general population (WHO 2020). Thus, the current COVID-19 pandemic is expected to increase the use of psychotropic drugs further in the near future. With exploding rates of mental disorders and the growing use of psychotropic drugs, more and more evidences emerge on their hepatotoxic effects.
This review aims to: (1) provide a brief insight into the hepatic metabolism of psychotropic drugs; (2) evaluate the hepatotoxic effects of commonly prescribed ADs and APs; (3) summarize the roles of oxidative stress, inflammation, and lipid accumulation in the pathophysiology of DILI; and (4) review and discuss these pathophysiological mechanisms in the course of AD- and AP-induced hepatotoxicity.
The most important means of assessing a drug’s risk for hepatotoxicity is to review the published case reports, animal studies, and cell-based in vitro studies. We conducted a comprehensive literature search for case reports, original articles, and reviews published from 1960 to 2020 using the search terms “hepatotoxicity,” “DILI,” “liver injury,” “oxidative stress,” “hepatitis,” “steatosis,” and “fatty liver,” cross-referenced with “antidepressant” and “antipsychotic.”
This time interval was chosen, because the first ADs and APs were introduced in practice in the 1950s, while the first publications considering their hepatotoxic effects emerged in the 1960s. This approach cannot be used to compare the risks carried by different drugs, since many were introduced at different times and have been prescribed in different doses and rates.
It should also be borne in mind that the extent to which the results obtained by animal studies can reasonably be generalised to humans remains open to question. Given that even humans differ in their response to drugs, it is reasonable to suspect if animal models are good predictors of human response (Shanks et al. 2009; Bailey et al. 2014).
Thus, relevant in vitro studies with liver microsomes, hepatocytes, liver slices, and recombinant enzymes are very valuable and usually the only source of information reflecting the situation in humans (Martignoni et al. 2006). Taking all this into consideration, we made an effort to highlight the drugs associated with severe DILI cases, explain the potential molecular mechanisms underlying the phenomenon, and point out the ones which are less likely to cause DILI, reviewing relevant case studies, as well as in vivo and in vitro studies.
reference link: https://link.springer.com/article/10.1007/s00204-020-02963-4
More information: Natalie Shoham et al. Temporal trends in psychotic symptoms: Repeated cross-sectional surveys of the population in England 2000–14, Schizophrenia Research (2021). DOI: 10.1016/j.schres.2020.11.057
