Antidepressants in People With Chronic Liver Disease and Depression: When Are They Warranted and How to Choose the Suitable One?

Abstract

Most chronic medical illnesses are associated with significant psychiatric comorbidity, especially in the form of depression, anxiety, and suicidality. Chronic liver disease (CLD) is no exception to this and rather is placed uniquely as compared to other diseases because of its intersection with alcohol use disorder and other substance use, which in itself is a mental illness. Patients with CLD may have comorbid psychiatric illnesses; the pharmacokinetic concerns arising out of hepatic dysfunction which affects pharmacotherapy for depression and vice versa. The high prevalence of medical comorbidities with CLD may further complicate the course and outcome of depression in such patients, and diagnostic and management issues arise from special situations like transplant evaluation, alcohol use disorder, and hepatic encephalopathy or multifactorial encephalopathy seen in a disoriented or agitated patient with CLD. For this narrative review, we carried out a literature search in PubMed/PubMed Central and in Google Scholar (1980–2023) with the keywords “depression in cirrhosis”, “antidepressants in liver disease”, “anxiety in liver disease”, “depression in liver transplantation”, and “drug interactions with antidepressants”. This review presents a comprehensive view of the available research on the use of antidepressants in patients with CLD, including deciding to use them, choosing the right antidepressant, risks, drug interactions, and adverse reactions to expect, and managing the same. In addition, liver transplant fitness and the overlap of hepatic encephalopathy with neuropsychiatric illness will be discussed.

Graphical abstract

An estimated 3.8% of the general population experience depression, including 5% of all adults (4% among men and 6% among women), and up to 5.7% of adults older than 60 years. Overall, an estimated 280 million people in the world have depression.¹ Moreover, the COVID-19 pandemic led to a stark rise in depressive and anxiety disorders globally in 2020. The overall number of reported cases of mental disorders has increased, with additional 53.2 million and 76.2 million cases of anxiety and major depressive disorders (MDD), respectively.²

In the Indian context, the Global Burden of Disease study found 45.7 million (42.4–49.8) with depressive disorders and 44.9 million (41.2–48.9) with anxiety disorders. The contribution of mental disorders to the total DALYs in India increased from 2.5% (2.0–3.1) in 1990 to 4.7% (3.7–5.6) in 2017. In 2017, depressive disorders contributed the most to the total mental disorders DALYs (33.8%, 29.5–38.5), followed by anxiety disorders (19%, 15.9–22.4).³

Depression in Chronic Liver Disease: The Problem Statement

Chronic liver disease (CLD) refers to progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis, occurring over 6 months or longer.⁴ Depression is one of the most common psychiatric morbidities in persons suffering from CLD.^5,6 The occurrence of depression in CLD has also been seen to be dictated by the etiological cause. Notably, depression has been reported to be more common in those with hepatitis C virus (HCV) related CLD as compared to other causes. Recent studies have reported that about 25–50% of all HCV infected persons are seen to have underlying depression7, 8, 9, 10[1]. Depression with liver disease can be secondary to pharmacological agents used in the management of CLD, such as interferons for chronic hepatitis B or C virus infection, but is more often due to the psychological and emotional toll the illness takes on a person—owing to its chronicity, reduced quality of life, poor socio-occupational functioning, and often, poor prognosis.¹¹ With the availability of direct-acting antiviral agents (DAAs), improvement in depression and QoL scores can be expected, especially since interferon use has largely been phased out.¹²

Apart from HCV, other important causes of CLD associated with depression include metabolic dysfunction-related steatotic liver disease (MASLD),^13,14 hepatitis B virus (HBV),^15,16 and alcohol-associated liver disease(ALD).17, 18, 19 A 2011 study assessed 878 patients with CLD and found that 23.6% had a diagnosis of depression. Moreover, the authors found that patients with chronic liver disease, secondary to MASLD and HCV, had a greater prevalence of depression whereas the rates of depression in HBV patients do not differ significantly from those of the general population.²⁰ A recent large-scale multi-centric cohort study, TARGET-NASH, conducted in the United States, determined the presence of comorbid depression in patients with MASLD to be a strong predictor for opioid use and abuse.²¹ More recently, the concept of shared underlying mechanisms are being proposed by various authors—including gut-brain dysfunction, systemic inflammation, and metabolic derangements.^4,22 Further, studies have revealed that the presence of cirrhosis is a significant determinant to the development of depression as evident from a recent large population-based study in the United States that reviewed more than 50 million adults and found that patients with cirrhosis had a significantly higher prevalence of depression (23.93% vs 7.61%) as compared to those without cirrhosis.²³ Another large-scale longitudinal study from Korea studied the incidence of depression from before to after the diagnosis of cirrhosis (n = 7953), that reported the incidence rates before and after cirrhosis diagnosis as 3.56 and 7.54 per 100 person-year, respectively, and that the incidence-risk ratio (IRR) of developing depression mildly increased before the diagnosis of cirrhosis (IRR-1.14) and rapidly increased immediately after the diagnosis of cirrhosis (IRR-2.12). This pattern was also found to be similar across all age groups and gender.²⁴ Further, it has been reported that getting a diagnostic label of ‘cirrhosis’ or even ‘CLD’ has a marked impact on the quality of life of the individual and may lead to chronic depression.²⁵ Moreover, in the event of liver transplantation (LT) surgery, immunosuppressants as well as the long-term emotional and financial implications of LT are likely to predispose a person to stress and subsequent depression.²⁶ Studies have also suggested that depressive symptoms in the post-transplant period predict long-term survival as well as prognosis.^27,28

Studies have also found some consistent risk factors for higher rates of depression in patients with CLD such as female gender, lower income, unemployment, widowed/being single, and advanced age.²⁹ Comorbid depression in CLD negatively impacts a person’s ability to properly adhere to treatment protocols, including lifestyle modifications and their motivation to seek and participate in treatment. Often under-diagnosed, untreated depression is associated with a poorer outcome of medical illness.^22,30 Therefore, proper assessment for early identification of depressive symptoms/depression and its management is crucial in patients with CLD and should be taken seriously.

Overlap With Hepatic Inflammatory States

A growing body of evidence suggests that inflammation is a key underlying mechanism in the pathophysiology of depression. This view is supported by elevated levels of pro-inflammatory cytokines (such as Tumour necrosis factor-α (TNF α), IL-1, and IL-6), chemokines, and acute phase reactants such as C-reactive protein. Certain postmortem studies have also identified neural inflammation and increased levels of inflammatory markers in the brain along with microglial activation.^4,22

The increased prevalence of depression with liver disease, especially in states like compensated advanced chronic liver disease, decompensated cirrhosis, MASLD, and acute-on-chronic liver failure, requires an explanation extending beyond psychosocial factors and disease severity—giving rise to a proposed unifying biological theory centred on the common underlying inflammatory pathway and immune dysregulation associated with both liver disease and neuropsychiatric changes.³¹

Overlap of Depression with Hepatic Encephalopathy

Hepatic encephalopathy (HE) or porto-systemic encephalopathy (PSE) is a reversible syndrome of impaired brain function occurring in patients with advanced liver failure. While the precise underlying mechanism remains elusive, the current widely held consensus focusses on systemic inflammation, degeneration of the blood–brain barrier and impaired neurotransmission.³²

One of the earliest manifestations of HE is an altered sleep–wake cycle, closely followed by cognitive disturbances and subtle personality changes. Patients may also have nonspecific symptoms like forgetfulness, common to both HE and depression. This holds significant diagnostic and treatment implications in the way of distinguishing depression from HE and identifying emerging HE in a patient already diagnosed with depression and liver disease. Interestingly, Single-photon emission computed tomography (SPECT) studies have demonstrated a neuropathological overlap between HE and depression which may further highlight neuroinflammation as the common denominator.²² Table 1 illustrates the differences between depression and HE. Figure 1 shows the differentials for HE in clinical settings where there are competing etiologies for altered mentation.

Table 1.

Differences Between Depression and Hepatic Encephalopathy.

	Hepatic encephalopathy	Depression
Onset	Acute to subacute	Insidious
Sleep disturbance	Alteration in sleep–wake cycle and circadian rhythm, drowsiness	Difficulty in initiation of sleep or early morning awakening
Sensorium	Altered	Clear
Depressive cognitions (such as hopelessness, helplessness, worthlessness, etc)	Absent	Present
Cognitive deficits	Generalised confusion, disorientation, and inattention	Decrease in attention and concentration, memory impairments reported are accompanied by subjective distress
Accompanying symptoms	Jaundice, ascites, asterixis (flapping tremor)	Disturbances in appetite and libido, anhedonia, pessimism, and reduced self-esteem, feelings of guilt and unworthiness, thoughts of suicide or self-harm
Laboratory findings	Elevated transaminases, elevated bilirubin, elevated serum ammonia levels, deranged coagulogram	Nonspecific

Figure 1.

Differentials for hepatic encephalopathy. Patients with chronic liver disease may have either overt or covert hepatic encephalopathy (HE), but not all altered mentation is attributed to HE. Psychiatric disorders may be responsible for cognitive defects and even mimic overt HE in CLD. Alcohol use disorder and the spectrum of neuropsychiatric changes associated with it are a concern for the clinician.

Malnutrition, Cirrhosis, and Depression

Patients with cirrhosis with or without comorbid depression often present with significant malnutrition needs separate attention and requires management. In recent times, the concept of frailty has been proposed. Frailty refers to a multidimensional condition characterised by loss of reserve and resistance to stressors (physical, environmental, and psychological) contributing to a decline in physical and mental vitality, resulting in increased vulnerability to poorer health outcomes.^33,34 It is frequently seen in those with chronic medical illnesses and is often an independent predictor of poorer prognosis as compared to those with similar illness but who are not medically frail.³⁴ Frailty can be understood from two perspectives—the phenotype model, which considers five variables: unintentional weight loss, weak grip strength, self-reported exhaustion, slow gait speed, and low physical activity; and the cumulative deficit model, which assesses a broad range of age-related deficits and forms the basis for frailty index.^35,36 Considering the chief features of frailty as a clinical condition, it is not surprising that there is significant overlap between depression and frailty—which often poses a diagnostic conundrum.³⁷ A recent retrospective study from Japan deduced the presence of a close correlation between frailty and depressive state in patients with CLD.³⁸

In the context of CLD characterised by decreased liver functional reserve, frailty can develop independent of age due to severe derangements in metabolism and nutrition.^38,39 Furthermore, cognitive and physical decline are marked in persons with liver cirrhosis.⁴⁰ There is also emerging evidence to suggest that frailty is common in patients with cirrhosis with prevalence ranging from 15% to 19%^41,42 and has been found to be strongly associated with self-reported symptom burden, disability, and psychological distress.⁴²

While challenging, it is important to distinguish between frailty and depression in persons with CLD so as to effectively manage the patient as well as potentially avoid unnecessary prescription of antidepressants and polypharmacy in a patient with already impaired pharmacokinetics.

Table 2 summarises some key points which can help clinicians to differentiate between the two conditions as well as areas of overlap which can lead to confusion.

Table 2.

Difference Between Frailty and Depression.

	Frailty	Depression
Common features	Loss of appetite and weight loss Cognitive deficits Slowness or psychomotor retardation Exhaustion or weakness
Depressive cognitions (such as pessimism about future, poor self-esteem, guilt, etc)	Absent	Present
Sleep disturbances	Absent	Present
Death wishes or suicidal ideations	Absent	Present
Loss of interest or anhedonia	Absent	Present

Depression and the Liver Transplant Patient

In cases of end-stage liver disease (ESLD) or liver cirrhosis, LT remains the only definitive treatment option. However, given the relatively high prevalence of depression in patients with ESLD, it is an issue that must be considered while considering transplant.43, 44, 45 It is estimated that around half of all patients, transplant patients experience at least one episode of anxiety or depression within the first two years of the post-transplant period.⁴⁶ Around one-fourth of the patients undergoing liver transplant also report symptoms of post-traumatic stress disorder.⁴⁷

Need for Assessment of Depression in Patients Awaiting Liver Transplant

Chronic illnesses, especially those as debilitating as end-stage liver disease, are associated with significant psychosocial stressors in the form of negative psychological impact of receiving the diagnosis and coming to terms with the prognosis, potential loss of employment and associated financial burden complicated by the cost of treatment and adverse reactions of family members, and poor social support; in addition to the major physical toll of the illness and often, accompanying loss of autonomy. When faced with the prospect of organ transplantation, the reality of limited life expectancy becomes starker and the difficult emotional process of accepting this is complicated by fears surrounding surgery, financial implications, uncertainty about the success of the procedure, and a rather demanding list of post-transplant care and precautions. In persons with end-stage liver disease secondary to chronic alcohol use, a sense of guilt may also weigh in to the process.^46,48 There is also the possibility of additional guilt of subjecting one’s own family member to a major surgery for donating a part of the liver in some cases of living donor LT. Few qualitative studies on patients waiting for a liver transplant have revealed uncertainty related to life and death, mental distress, and interdisciplinary communication problems.^49,50

Severe cases of depression may be associated with a wish to die, to not participate in medical treatment and to not get better. Moreover, cognitive decline and impaired decision making may be present due to a complex interplay of depression, frailty, and liver disease. This raises issues of capacity and consent.51, 52, 53, 54 Undiagnosed and untreated depression in the pre-operative period may bear negative consequences in peri- and post-operative periods and on the overall success of the transplant procedure and ensuing quality of life of the patient.⁵⁵

Methods and Areas of Assessment

In addition to looking out for symptoms of depression as per the standard nosological systems, assessment should also focus on knowledge and perception of patient and family members regarding illness, need for transplant, surgical procedure and potential risks, chances of success vs organ rejection, need for lifelong post-transplant care and precautions, post-transplant lifestyle changes; ongoing and past substance use which can impact the transplant procedure and success; financial constraints, insurance coverage of the procedure and any associated stress and any worries or concerns about the procedure. Various tools have been used for pre-transplant assessment of patients awaiting liver transplant aimed at screening and appropriate diagnosis of a psychiatric disorder, such as, Mini International Neuropsychiatric Interview plus, Beck Depression Inventory, Hospital Depression and Anxiety Scale, etc. Further, in liver transplant patients with alcohol use disorder, additional risk assessment tools include Alcohol Use Identification Test, Stanford Integrated Psychosocial Assessment for Transplant, Sustained Alcohol Use Post-Liver Transplant Score, and Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-AR). However, the assessment should not be limited to these tools and as far as possible, such evaluation should involve a psychiatrist working in tandem with the hepatology team.⁵⁶

Management of Depression in Liver Transplant Patients

Education and open discussion between patient and clinician is key—with focus on addressing and resolving worries and concerns on part of the patient centred on the transplant procedure and post-transplant care and precautions. In mild to moderate cases, psychotherapy in the form of supportive psychotherapy or cognitive behavioural therapyshould be offered as first-line treatments with resources permitting. Pharmacokinetic considerations are key when planning pharmacological management of depression in those with end-stage liver disease planned for LT. Selective serotonin reuptake inhibitors (SSRIs) are usually well tolerated, although are usually given at lower doses in patients with hepatic impairments.⁵⁷ This is discussed later in this article.

Depression in CLD & Management Issues

Managing depression in patients with medical/physical illness has always been a challenge due to a multitude of factors. Some of these are diagnosing depression (symptoms of depression often overlap with somatic symptoms of the illness per se), safety profile of the antidepressants, severity of the medical illness restricting the use of usual dosage of the antidepressants, compromised physical state of the patient, issues related to drug–drug interactions, delayed response of the antidepressants and increased risk of side-effects of antidepressants (electrolytes imbalance, constipation, bleeding tendencies, etc.).^58,59

Issues Related to Diagnosing and Treating Depression in CLD

As per the diagnostic guidelines of major diagnostic systems (Diagnostic and Statistical Manual of Mental disorders, 5th Edition [DSM-5] and International Classification of Diseases-11th edition[ICD-11]),^60,61 symptoms of persistent and pervasive sadness of mood, loss of interest in pleasurable activities or anhedonia, and easy fatigability along with disturbances in biofunctions, cognitive issues, and feelings of low self-esteem and pessimism, lasting for a period of 2 weeks or more warrants the consideration of a diagnosis of depression. However, in case of any chronic medical illness such as CLD, care must be taken to rule out hepatic encephalopathy and/or delirium which may closely resemble depression in terms of disturbances in biofunctions such as early morning awakening, diurnal variation in mood, lethargy, and loss of interest; before making a diagnosis of depression.⁵⁸ Further, symptoms commonly seen in depression such as loss of appetite and easy fatigability are core symptoms of CLD, and hence the approach to diagnose depression should be slightly different. Further, the symptoms suggestive of depression such as weight loss, fatigue, hypersomnia or decreased sleep, confusion and decreased concentration, etc. can also be attributable to the medications used for the treatment of CLD(62). Further, in cholestatic disorders like primary biliary cholangitis and primary sclerosing cholangitis, more than two-third of patients may experience pruritus during the course, which results in skin pigmentation, rash, hyperpigmentation, and causes sleep disturbances. These symptoms may also be observed in other diseases like cholangiocarcinoma, inherited disorders such as progressive familial intrahepatic cholestasisor even intrahepatic cholestasis of pregnancy,^63,64 and contribute to depression and fatigue.

In this regard, the substitutive approach should be followed to diagnose depression (as was proposed by Endicott) in which the four of the symptoms confounded by medical illness (CLD in this case), i.e. fatigue, reduced appetite, sleep disturbances, and decreased concentration are replaced by four alternative symptoms, i.e. tearfulness/depressed appearance, social withdrawal/reduced talkativeness, brooding/self-pity or pessimism and cannot be cheered up/doesn’t smile/no response to any good or positive news.⁵⁴ Some other authors have also suggested failure to participate in medical treatment despite the ability to do so and functioning at a lower level than the medical condition warrants or failure to progress in recovery despite improvement in the medical condition to be explored for diagnosing depression in patients with medical illnesses.^65,66 Therefore, before diagnosing depression in a patient with CLD, care must be taken to observe the patient closely, evaluate the depressive cognitions properly, and then reach to a conclusive diagnosis of depression.

Further, in many cases, if depression is not adequately treated, then it often leads to worsening of quality of life of patients with CLD and they fail to follow the restrictions/instructions needed to be followed to remain stable, thus worsening the prognosis. Hence utmost care is to be taken for regular follow-up of patients with CLD with comorbid depression to prevent frequent relapse.

Once a diagnosis of depression is clear, the next step is to assess the severity of depression as well as of the liver disease, the latter to anticipate pharmacokinetics. Conditions that can result in higher serum drug levels (such as porto-systemic shunting, alteration in volume of distribution, hepatic and/or biliary excretion, and presence of cirrhosis) will warrant dose adjustment if pharmacotherapy is planned.^58,59

In case of mild to moderate depression, the current recommendations are to opt for selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs) or psychotherapy as the first-line of treatment and observe for response over 4–6 weeks. In case of no response, further strategies include dose optimisation and augmentation with psychotherapy or pharmacotherapy, as applicable has been suggested.⁵⁸

Although the use of electroconvulsive therapy (ECT) is restricted, in rare cases with severe depression with high suicidality, this therapy may be considered after taking due precaution for risk of portal hypertension-related bleeding and possible coagulation dysfunction.⁶⁷ Therefore, this therapy can only be offered in advanced care settings with expert multidisciplinary care from psychiatry, neurology, critical care, and hepatology, as the procedure sedation and organ support. Most patients with advanced disease are therefore not eligible for this modality. Where suicidality is not a pressing issue, a combination of SSRI/SNRI and psychotherapy can be opted for⁵⁸ ECT can be performed safely in patients with comorbid liver disease with proper precautions.⁶⁸

Liver Safety Profile of Antidepressants

Minor hepatic dysfunction in the form of mild liver function tests (LFT) derangements are seen in less than 1% of patients treated with second-generation antidepressants (SSRIs and SNRIs) and up to 3% of those treated with monoamine-oxidase (MAO) inhibitors and tricyclic antidepressants (TCAs). The incidence of antidepressant-induced liver toxicity requiring hospitalisation is 1.28–4 cases per 100,000 patient-years, with the exception of nefazodone, for which the incidence is higher at 29 cases per 100,000 patient-years.69, 70, 71, 72 Antidepressant-induced liver injury is usually an idiosyncratic and dose-independent, but few authors have also postulated metabolic, immunologic/immune-allergic mechanism, and hypersensitivity reaction for the same.^72,73 There are no well-established risk factors for antidepressant-induced liver injury, although polypharmacy with more than one antidepressants resulting in CYP450 enzyme-based drug interactions seems to increase the risk of developing hepatic injury. Similarly, elderly patients, presumably with comorbidities, are at an elevated risk of antidepressant-induced liver injury. Pre-existing liver disease, alcohol use/dependence, illicit substance use, and chronic liver disease are other risk factors which can precipitate antidepressant-induced liver injuries.⁷² Antidepressant-induced liver injury is similar to liver injury, secondary to other causes in its clinical and biochemical/laboratory presentation and is usually a diagnosis of exclusion.⁷² The estimated prevalence of antidepressant-induced liver injury, reported liver injuries, and their mechanism of action for liver injuries from published data has been listed in Table 3.

Table 3.

Prevalence of Antidepressant-induced Liver Injury Along With Reported Liver Injuries.^53,62, 63, 64

Antidepressant class/individual antidepressant	Estimated prevalence rate64 (in %)	Reported liver injuries as available form case reports63	Suspected mechanism for liver toxicity/injury as per different authors63
SSRIs (overall) Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline	0.08 0.02 0.01 0.02 0.05 0.06 0.05	Acute hepatitis Acute fatal hepatitis Cholestatic hepatitis Transaminitis Hepatocellular injury	Idiosyncratic reaction Immuno-allergic mechanism Immunologic mechanism Metabolic
SNRIs (Overall) Venlafaxine Duloxetine	0.08 0.09 0.04	Acute hepatitis Fulminant hepatic failure Cholestatic hepatitis	Idiosyncratic reaction
MAO inhibitors	0.08	Severe hepatitis and cholestatic lesion Liver angiosarcoma	Metabolic and genetic origin
TCAs (Overall) Amitriptyline Nortriptyline Doxepin Clomipramine	0.14 0.08 0.09 0.06 0.23	Cholestatis and fibrosis Toxic hepatitis Fulminant hepatitis Acute hepatitis	Direct toxic effect or hypersensitive reaction Immuno-allergic mechanism
Other 2nd Antidepressants Mirtazapine Reboxetine Agomelatine Trazodone	0.09 0.03 0.33 0.01	Transaminitis Acute hepatitis Cholestasis	Idiosyncratic reaction

SSRI: Selective serotonin reuptake inhibitors; SNRI: Serotonergic-noradrenergic reuptake inhibitors; TCA: Tricyclic antidepressants; MAO: Monoamine-oxidase inhibitors.

For management of pruritus, anion-exchange resins like cholestyramine, ursodeoxycholic acid, rifampicin, opioid receptor antagonist rifampicin, and the SSRI Sertraline has been used with varying success,^74,75 although the mechanism of action and interference in the lysophosphatidic acid and autotaxin mediators of cholestatic itch may ameliorate symptoms.

All antidepressants may potentially cause liver injury, even at therapeutic doses. However, it should be noted that antidepressant-induced liver injury is a rare event.⁷² Among the commonly used antidepressants, higher risk for hepatotoxicity is with the usage of TCAs and MAO inhibitors. SSRIs (mostly escitalopram, citalopram, fluoxetine) seem to have the least potential for hepatic damage/injury.^72,73 Recent data also suggest less risk of liver injury as well as very low risk of drug–drug interactions with desvenlafaxine, hence it can be used in patients with hepatic impairment with minimal or no dose modifications.^76,77 Medical personnel caring for patients with liver disease should be cognisant of the dose modifications and interactions of these agents in CLD.

Choosing an Antidepressant in Patients With Depression and Chronic Liver Disease

After the diagnosis of depression has been established in patients with CLD, choosing an appropriate antidepressant needs to be done with due consideration of the hepatotoxic potential or those which would not affect the liver status in the long run (as antidepressants have to be advised for at least a minimum duration of 6–8 months or more for complete resolution of depressive symptoms and to prevent relapse of depression). In this regard, studies have shown that SSRIs and SNRIs are the preferred pharmacotherapeutic agents due to their relatively low hepatotoxic potential (0.5–1%).^59,78 Although there are isolated case reports of SSRI- and SNRI-induced hepatoxicity in non-CLD subjects, which got reversed on discontinuation of the drug (antidepressant), these can be considered as rare adverse effects and should be considered as a deterrent to use SSRIs and SNRIs in patients with depression and CLD.⁵⁹

There is no difference between SSRIs and SNRIs with respect to efficacy.^79,80 However, there exists an elevated risk of gastrointestinal bleed with SSRIs/SNRIs which is a cause for concern in patients with CLD since they are predisposed to esophageal variceal bleeds.⁵⁹ Therefore, concomitant use of proton pump inhibitors can be considered in those with higher risk of variceal bleed. Further, the SSRI/SNRI antidepressants should be started at low doses and slowly titrated upward to usual therapeutic doses. Generally, a maintenance dose in patients with CLD would be half of the usual dose in those without hepatic impairment.^58,59 As with usual course of treatment, in case of non-response to first agent, change to second agent of same or different class can be considered.¹¹ If response is still inadequate, augmenting agents such as buspirone (for anxiety) or pregabalin and first-generation antihistamines like hydroxyzine (for sleep disturbances) can be considered.^58,59 Psychotherapy (cognitive behaviour therapy and supportive psychotherapy) has also been tried as an augmenting agent to antidepressants or in case if the patient is unfit or severely compromised to start any antidepressant (due to multiple physical conditions).^81,82 However, psychotherapy or counselling has its own constraints of resources and time, hence integrated care in special liver units in which both mental health, substance abuse, and hepatic issues are taken care have been established in recent times.⁸²

Benzodiazepines are usually used as an add-on to reduce anxiety symptoms and sleep disturbances. However, they should be prescribed with caution (with the exception of lorazepam), as they carry risk of accumulation and subsequent use has been reported to cause cholestatic liver injury in case reports.⁸³ Further, benzodiazepines have been found to precipitate or worsen hepatic encephalopathy or delirium, warranting judicious use and monitoring when prescribed.^84,85

We have summarised the dosing recommendations and metabolism of commonly used antidepressants in CLD in Table 4 and the summarised flowchart is demonstrated in Figure 2.^11,86 Further, we have documented the drug–drug interactions of commonly used antidepressants with the commonly used drugs in patients with CLD in Table 5.

Table 4.

Dose Recommendations and Metabolism of Commonly Prescribed Antidepressants in Patients With Depression and CLD.^7,75

Class of drug	Hepatic metabolism	Dosing in hepatic impairment	Remarks/points to note
SSRIs
Fluoxetine	Reduced clearance, prolonged half-life, greater time taken to attain steady-state concentration; metabolised extensively by CYP2D6, CYP2C9, and CYP3A4	Initiate at 5–10 mg daily, titrate slowly, and do not exceed 40 mg	Long half-life —tends to accumulate in compensated cirrhosis
Sertraline	Extensively metabolised by CYP3A4 and CYP2B6; prolonged half-life and increased systemic exposure	Initiate at 25 mg daily and titrate gradually; Do not exceed 100 mg daily in mild disease. Dose reduction by 50% or alternate day dosing in cirrhosis.	Slightly greater risk of gastrointestinal bleeding, use of proton-pump inhibitors is advisable
Fluvoxamine	Extensively metabolised by CYP2D6; prolonged half-life	Initiate at 25 mg daily, titrate slowly, and do not exceed 100 mg daily	Less commonly used for major depression, mostly preferred for obsessive compulsive disorder
Paroxetine	Extensively metabolised by CYP2D6. Prolonged half-life and increased systemic exposure	Initiate at 10 mg daily and titrate slowly. Do not exceed more than 40 mg/day	Asymptomatic rise in serum aminotransferase levels can be seen which are usually self-limited and do not require dose modification or discontinuation of therapy.
SNRI
Duloxetine	Extensively metabolised in liver and clearance markedly reduced (85%) even in mild impairment	Avoid in any degree of hepatic impairment	Reports of hepatocellular injury and jaundice (deranged liver function tests) and isolated case report of fulminant hepatic failure. Contraindicated in hepatic impairment.
Venlafaxine/desvenlafaxine	Extensively metabolised by CYP2D6, raised oral bioavailability and half-life	Initiate at 37.5 mg daily, titrate gradually, do not exceed 150 mg daily Dose reduction to 50% in mild-to-moderate hepatic impairment	Rare cases of hepatitis Avoid in decompensated liver disease or those at risk of seizures
TCiAs (Amitryptiline, imipramine)	All are hepatically metabolised and tend to accumulate in case of dysfunction (reduced clearance)	No guidelines available on dose recommendations. If required, start at the lowest possible dose with careful escalation.	Avoid sedative TCAs such as imipramine, trimipramine, dosulepin (dothiepin), amitriptyline Prefer second-generation tricyclics such as nortriptyline or desipramine
NDRI—Bupropion	Half-life increased by 70% in patients with severe liver disease Good tolerability with no side-effects in mild -moderate liver disease	Mild to moderate liver disease—Maximum dose −75 mg/day (immediate release preparation) or 150 mg (extended release) every alternate day	Asymptomatic rise in LFTs—0.1–1% Rare cases of acute liver injury which is usually self-limiting76
NaSSA—Mirtazapine	Reduced clearance by 33% in patients with CLD	Initial dose reduction by 50% Avoid co-prescribing with other serotonergic agents	Asymptomatic rise in LFTs (up to 3 times) has been seen in 2% cases. Few cases of cholestatic and hepatocellular damage Used in some liver units owing to effects on sleep and appetite
SARI—Trazodone	Data not available	No guidelines currently available; avoid in hepatic impairment in view of sedative property	Does not seem to be associated with hepatotoxicity

SSRI: Selective serotonin reuptake inhibitors, SNRI: Serotonergic noradrenergic reuptake inhibitors, TCAs: Tricyclic antidepressants, NDRI: Noradrenergic dopaminergic reuptake inhibitors, NaSSA: Noradrenergic and specific serotonergic antidepressant, SARI: Serotonin antagonist and reuptake inhibitor, LFT: Liver function tests.

Figure 2.

Management pathway and choice of antidepressants in chronic liver disease.

Table 5.

Interactions of Antidepressants With Commonly Used Drugs in Hepatology Settings.⁷⁷

Drug	Propranolol	Carvedilol	Nadolol	Rifaximin	Aldactone	Furosemide	Torsemide	Albumin	Tenofovir	Daclatasvir	Sofosbuvir/Velpatasvir	Metformin	Glimepiride	Sitagliptin	Pioglitazone
Fluoxetine	Increased level of propranolol via CYP2D6	Increased level of carvedilol via CYP2D6a	No interaction	No interaction	No interaction	Possible additive hyponatremiac	Possible additive hyponatremiac	No interaction	No interaction	No interaction	No interaction	Increased effect of metforminc	Increased effect of glimepiridec	No interaction	No interaction
Sertraline	Increased level of propranolol via CYP2D6 (more pronounced in CAD patients)	Increased level of carvedilol via CYP2D6b	No interaction	No interaction	No interaction	Possible additive hyponatremiac	Possible additive hyponatremiac	No interaction	No interaction	No interaction	No interaction	Increased effect of metforminc	No interaction	No interaction	No interaction
Fluvoxamine	No interaction	Increased level of carvedilol via CYP2C9/10c	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	Increased level of sofosbuvir/velpatasvir via CYP2B6c	Increased effect of metforminc	No interaction	No interaction	No interaction
Paroxetine	Increased level of propranolol via CYP2D6a	Increased level of carvedilol via CYP2D6a	No interaction	No interaction	No interaction	Possible additive hyponatremiac	Possible additive hyponatremiac	No interaction	No interaction	No interaction	No interaction	Increased effect of metformincc	No interaction	No interaction	No interaction
Duloxetine	Increased level of propranolol via CYP2D6b	Increased level of carvedilol via CYP2D6c	No interaction	No interaction	No interaction	Possible additive hyponatremiac	Possible additive hyponatremiac	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction
Venlafaxine	Increased level of propranolol via CYP2D6b	Increased level of carvedilol via CYP2D6b	No interaction	No interaction	No interaction	Possible additive hyponatremiac	Possible additive hyponatremiac	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction
Desvenlafaxine	Increased level of propranolol via CYP2D6b	Increased level of carvedilol via CYP2D6b	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction
Amitriptyline	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	Increased effect of metforminc	Increased effect of glimepiridec	Increased effect of sitagliptinc	Increased effect of pioglitazonec
Imipramine	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	Increased effect of metforminc	Increased effect of glimepiridec	Increased effect of sitagliptinc	Increased effect of pioglitazonec
Bupropion	Increased level of propranolol via CYP2D6b	Increased level of carvedilol via CYP2D6b	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction
Mirtazapine	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction	No interaction
Trazodone	No interaction	No interaction	No interaction	No interaction	No interaction	Possible additive hyponatremiac	Possible additive hyponatremiac	No interaction	No interaction	No interaction	No interaction	Increased effect of metforminc	Increased effect of glimepiridec	Increased effect of sitagliptinc	Increased effect of pioglitazonec

^aSerious drug interaction—consider using alternative agent.

^bClose monitoring needed.

^cminor drug interaction—unknown or nonspecific mechanism.

Cirrhosis is associated with symptoms like fatigue and muscle cramps. Fatigue is a common compliant in patients with CLD patients, with a prevalence ranging between 50% and 85%.⁸⁷ Various non-pharmacological strategies and medications have been tried to manage fatigue in patients with CLD, but are with limited evidence and efficacy.⁸⁸ More recently, the use of ademetionine for treatment of fatigue in CLD has been evaluated in several randomised controlled trials, but further studies are needed to prove its efficacy in the long run.⁸⁹ Muscle cramps are also a common complaint (prevalence – 22–88%) in patients with liver cirrhosis and causes sleep disturbances and poor QoL.⁹⁰ Many trials have evaluated the role of various medications to treat muscle cramps in this group of patients and branch chain amino-acids (BCAAs), pregabalin, baclofen, and vitamin D have been found to be beneficial for muscle cramps.^90,91 The symptoms contribute to poor quality of life and should be managed appropriately.

Along with managing depression and anxiety in patients with CLD, those with alcohol-related cirrhosis need effective counselling and medication-assisted therapies (MATs) which have been found to be quite effective in reducing relapse rates and maintaining alcohol abstinence,⁹² thereby enhancing overall treatment outcome in patients with liver cirrhosis.

In conclusion, patients with CLD have various physical health and psychological issues which may lead to development of depression. Prompt identification of depressive symptoms and their management by considering the severity level, drug–drug interactions and hepatotoxicity of antidepressants can help in better and holistic management of depression in patients with CLD. Depression should be treated early and adequately in patients with chronic physical illness to improve their quality of life as well as to ensure adherence to treatment for the physical problem. With regard to CLD, there are overlapping symptoms of CLD which can mimic depression; hence a proper assessment is warranted by mental health professionals and cautious and judicious use of antidepressants (preferably SSRIs) are recommended with careful monitoring of side-effects.

Credit authorship contribution statement

Concept was developed by Swapnajeet Sahoo and M Premkumar. Eepsita Mishra and Swapnajeet Sahoo drafted the primary manuscript. M Premkumar edited the revised version.

Conflicts of interest

All authors have none to declare.

Acknowledgements

The support provided by Ms Prerna Sharma is acknowledged for the preparation of this manuscript.

Funding

None.