Alimentary Pharmacology and Therapeutics
Review article: depression and the use of antidepressants in
patients with chronic liver disease or liver transplantation
B. H. Mullish, M. S. Kabir, M. R. Thursz & A. Dhar
Section of Hepatology, Faculty of
Medicine, Imperial College London, St
Mary’s Hospital Campus, Paddington,
London, UK.
Correspondence to:
Dr B. Mullish, Section of Hepatology
and Gastroenterology, Faculty of
Medicine, St Mary’s Hospital Campus,
Imperial College London, 10th floor,
QEQM building, South Wharf Road,
Paddington, London, UK.
E-mail: b.mullish@imperial.ac.uk
Publication data
Submitted 23 June 2014
First decision 14 July 2014
Resubmitted 23 July 2014
Resubmitted 27 July 2014
Accepted 28 July 2014
EV Pub Online 1 September 2014
This uncommissioned review article was
subject to full peer-review.
880
SUMMARY
Background
The scale of depression in patients with chronic liver disease (CLD) and
those who have received orthotopic liver transplantation (OLT) is poorly
characterised. Clinicians are uncertain of how best to manage depression
within these patients.
Aims
To review the literature evaluating both the prevalence and impact of depres-
sion in patients with CLD and post-OLT, and to assess the safety and effi-
cacy of antidepressant use within this context.
Methods
A PubMed search using the phrases ‘chronic liver disease’, ‘cirrhosis’, ‘liver
transplantation’, ‘depression’, ‘antidepressant’ and the names of specific
causes of liver disease and individual antidepressants.
Results
Over 30% of cirrhotic patients have depressive features, and they experience
worse clinical outcomes than nondepressed cirrhotic patients. CLD patients
with chronic hepatitis C are particularly prone to depression, partly related
to the use of interferon therapy. OLT patients with depression have higher
mortality rates than nondepressed patients; appropriate antidepressant use
reverses this effect. Selective serotonin reuptake inhibitors (SSRIs) and selec-
tive noradrenaline reuptake inhibitors (SNRIs) are effective and generally safe
in both CLD and OLT patients.
Conclusions
Depression is much more prevalent in CLD or OLT patients than is gener-
ally recognised, and it adversely affects clinical outcomes. The reasons for
this relationship are complex and multifactorial. Antidepressants are effective
in both CLD and post-OLT, although lower doses or a reduced dosing fre-
quency may be required to minimise side effects, e.g. exacerbation of hepatic
encephalopathy. Further research is needed to establish optimal management
of depression in these patients, including the potential role of nonpharmaco-
logical treatments.
Aliment Pharmacol Ther 2014; 40: 880–892
ª 2014 John Wiley & Sons Ltd
doi:10.1111/apt.12925
 Review: depression and antidepressants in liver disease or transplantation
INTRODUCTION
Depression currently represents the second most com-
mon cause worldwide of life-years lived with disability.1
It is now well-established that particular cohorts of
patients with chronic medical illness have a much greater
prevalence of affective disorders than the general popula-
tion.2 Furthermore, it has been demonstrated that these
patients experience worse health outcomes – including a
reduced quality of life and increased mortality – com-
pared to matched patients without depression.3, 4 Recent
studies suggest that the scale and impact of depression
in patients with CLD or OLT is comparable to that of
other chronic medical diseases, and that these adverse
effects may be reduced through the optimal use of an-
tidepressants.
METHODS
A search was performed for abstracts cited on PubMed
up to July 2014. The search terms used were ‘chronic
liver disease’, ‘cirrhosis’, ‘liver transplantation’, ‘depres-
sion’, ‘antidepressant’, the names of specific causes of
liver disease, and the names of individual antidepres-
sants, with these terms applied together in different logi-
cal combinations. The only restriction made on the
literature search was for English language abstracts only.
Following the identification of relevant titles, the
abstracts of these articles were read to decide if the study
contained material pertinent to the review, and the full
text article retrieved and reviewed if so. A manual
cross-reference search of bibliographies was also per-
formed to identify potentially relevant articles that may
have been missed by the initial search.
DEPRESSION IN PATIENTS WITH CHRONIC LIVER
DISEASE
Cirrhosis
The majority of studies aiming to establish the preva-
lence of depression within the population with liver dis-
ease have done so through the completion of Beck
Depression Inventory (BDI) questionnaires. These are a
widely used screen for depression of high internal con-
sistency and content validity, but have also been sub-
jected to a number of criticisms, including poor
discriminant validity against anxiety.5 By BDI criteria, at
least 30% of patients with cirrhosis have depressive
symptoms.6–8 Studies where cirrhotic patients have been
assessed for health-related quality of life (HRQOL) as
well as depression [the former typically also via ques-
tionnaires, such as the Short Form-36 (SF-36)] confirm
Aliment Pharmacol Ther 2014; 40: 880-892
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that depressed cirrhotic patients experience a signifi-
cantly reduced HRQOL in comparison to nondepressed
subjects.6, 9
Furthermore, cirrhotic patients with depression experi-
ence worse clinical outcomes than those without.
Depressed patients with decompensated liver disease of
different aetiologies assessed for liver transplantation had
an increased mortality at 100 days post-assessment com-
pared to nondepressed patients,9 despite no significant
difference between groups in the incidence of specific
features of decompensation (including gastrointestinal
bleeding and hepatocellular carcinoma). While it might
be expected that this outcome could have reflected more
severe liver disease in the depressed patients, no signifi-
cant difference was found in Child-Pugh score between
groups. BDI score was a significant independent predic-
tor of mortality in this cohort.
There is also an association between the use of an-
tidepressants in depressed cirrhotic patients within the
pre-transplant period and post-OLT outcome. A retro-
spective analysis of patients with end-stage liver disease
of different aetiologies who received OLT demonstrated
that amongst patients with depression prior to surgery,
those taking antidepressants at the time of OLT experi-
enced significantly less acute cellular rejection (13%)
than depressed patients not receiving antidepressants
(40%).10 The group hypothesised that effective treat-
ment of depression was associated with increased com-
pliance with immunosuppressant medications. No
difference in time to death or incidence of graft dys-
function was observed between depressed and nonde-
pressed groups, consistent with other studies that have
also failed to show that pre-operative depression per se
is a risk factor for poor post-OLT outcome.9, 11, 12
However, the full impact of pre-operative depression on
post-OLT mortality may not have been fully appreciated
within these studies because although a proportion of
the cohort were using antidepressants, this was not
expressly recorded.
As both hepatic encephalopathy and depression may
present with comparable clinical features (including simi-
lar cognitive deficits and psychomotor impairment), fur-
ther research has explored the interplay between the two
conditions. The conditions certainly have overlap in their
pathological basis; for instance, single photon emission
computed tomography (SPECT) demonstrated areas of
hypoperfusion in the superior and middle frontal gyri13
and in the anterior cingulated gyrus in cirrhotic patients
with minimal hepatic encephalopathy,14 which are areas
also involved in other neuropsychological disorders.15
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B. H. Mullish et al.
However, recent research assessing for HRQOL and the
prevalence of affective disorders in cirrhotic patients of
mixed aetiologies shows no difference in psychological
scores for depressive disease between the 22 patients
with minimal hepatic encephalopathy (as diagnosed via
PHES testing16) compared to those without,8 supporting
the concept that hepatic encephalopathy and depression
may have overlapping features but are distinct clinical
entities.
Several different explanations have been proposed to
explain the high prevalence of depression in cirrhotic
patients. One postulation has been that cirrhotic patients
with depression may be more likely to have challenging
social circumstances than those without, with common
aetiologies of cirrhosis (especially alcohol misuse and
hepatitis C infection) often having a social underpinning.
However, none of the major lifestyle variables known to
contribute to depression (including level of social sup-
port, education level, income and marital status) were
found to different degrees between depressed and nonde-
pressed cirrhotic patients.9 Another suggestion has been
that medications commonly prescribed to patients with
cirrhosis (such as beta-blockers given as prophylaxis
against variceal bleeding) may be contributory; however,
a recent large systematic review of double-blinded rando-
mised controlled trials of beta-blockers vs. placebo in
patients with cardiac failure actually demonstrated signif-
icantly reduced rates of depression in patients given
beta-blockers in comparison to placebo.17
Both psychological and biological theories have been
proposed as explanations for the relationship between
depression in cirrhosis and increased mortality. Psycho-
logical theories focus on the finding that patients with
depression have high rates of noncompliance with medi-
cal regimens.18 Biological theories focus on the effect of
depression upon the immune system, including impaired
lymphocyte function19 and dysregulated secretion of
immunomodulatory cytokines20 that may increase the
propensity of patients with liver disease to decompensa-
tion.
Hepatitis C
A significant proportion of patients infected with the
hepatitis C virus (HCV) develop neuropsychiatric symp-
toms, including cognitive impairment, fatigue, and/or a
‘brain fog’, that cannot be fully explained by the liver
disease associated with the infection.21, 22 Even account-
ing for these neuropsychiatric symptoms, depression per
se is more prevalent in hepatitis C patients than in the
general population. Major depression has been reported
882
in 15–49.5% of patients with chronic HCV infection,
independent of the use of anti-viral treatment,23–26 with
a mean prevalence of 38% found in a review across 10
studies.27 Of these patients, a significant proportion (up
to 72%) had not been identified as having depression
previously.26 Multi-variate regression analysis of a large
cohort of patients with chronic liver disease of different
aetiologies (HCV, hepatitis B (HBV), alcohol-related liver
disease and non-alcoholic fatty liver disease (NAFLD),
both cirrhotic and noncirrhotic), who were screened for
depression using the Patient Health Questionnaire-9
(PHQ-9) questionnaire, identified HCV only as an inde-
pendent risk factor for depression.28
There are a number of potential explanations for this
relationship. The stigmatisation of having a chronic
infectious disease is a risk factor for depression in
patients even without any pre-existing mental health
issues.26, 29 There is also a significant correlation
between psychiatric disorders and HCV infection; this
was proposed to be related to the higher prevalence of
injecting drug use and alcohol dependence in psychiatric
patients,30 although there is now evidence that this may
not be a strong contributory factor.23 The concept has
now arisen that HCV may have a specific biological role
in the development of depression, with recent research
suggesting that hepatitis C may have biological effects on
the brain itself,31 e.g. through dopamine and serotonin
transporter binding.27
Anti-viral treatment of hepatitis C with inter-
feron-alpha (IFN-a) also has a well-established role as a
contributory factor to depression. Mild to moderate
depression has been reported to develop in 45–60% of
HCV patients treated with IFN-a, moderate to severe
depression in 15–40%, and major depression in 15–
45%.27, 32–35 The type of interferon used (pegylated or
standard interferon) does not appear to have any differ-
ential impact on the prevalence of IFN-a-related depres-
sion; however, it does appear to be sensitive to dosage
and duration of treatment as well as pre-morbid
patient-related risk factors, including a previous history
of psychiatric disorders and female sex.33, 36 This phe-
nomenon has an increasingly well-characterised biologi-
cal basis, with activation of a pro-inflammatory cytokine
network and alterations in serotonin and dopamine neu-
rotransmitter metabolism being postulated to exert the
mood changes associated with IFN-a.27, 33 Specifically,
IFN-a induces expression of indoleamine (2,3)-dioxygen-
ase (IDO), which causes increased catabolism of the
serotonin precursor, tryptophan, resulting in reduced
peripheral serotonin levels.37 The potential role of newer
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 Review: depression and antidepressants in liver disease or transplantation
treatments (including direct-acting anti-virals and newer
forms of interferon) in the treatment of chronic HCV is
still being evaluated, but the data currently available for
interferon-lamba 1 suggest there may be fewer neuropsy-
chiatric complications resulting from its use compared to
IFN-a.38
Development of depression is the commonest reason
for HCV treatment discontinuation.36 A recent study
found that up to 10% of patients treated for HCV with
pegylated interferon and ribavirin had to prematurely
withdraw from treatment, and the majority (65%) of
these patients had developed features of major depres-
sion [as defined by total score >35 points on the Major
Depression Inventory (MDI)].36 15% of the patients who
did not achieve a sustained virological response (SVR)
had an on-treatment increase in their MDI score from
baseline by 35 points, as compared to the 2% who did
achieve SVR. One interpretation of these data is that the
development of major depression during therapy
adversely affects the outcome from HCV treatment,
although another explanation is that a risk factor for
depression in these patients was the failure to achieve vi-
rological suppression during therapy. 95% of the patients
in this cohort who had discontinued treatment due to
depression had not been initiated on antidepressant
medication during the study period.
Hepatitis B
Less than 5% of the population with chronic HBV infec-
tion have depression, comparable to the prevalence of
depression within the general population.39 However,
these patients do experience an increased rate of adverse
psychological effects. Noncirrhotic chronic HBV patients
who completed SF-36 questionnaires demonstrated sig-
nificant reductions in their scores for ‘mental health’ and
‘general health perception’ compared to healthy con-
trols.40 Patients with chronic HBV treated with peginter-
feron alpha-2a experienced depressive symptoms and
impairment to HRQOL, but to a much lesser degree
than patients with chronic HCV.41
Alcohol-related liver disease
Patients using alcohol to excess have an increased likeli-
hood of depression and anxiety disorders, as well as an
increased risk of both parasuicide and suicide, indepen-
dent of whether they have liver disease or not.42 In a
cohort of patients with biopsy-proven alcohol-related
liver disease (including both cirrhotic and noncirrhotic
patients), 40% were found to be depressed, although no
correlation was made between the degree of liver disease
Aliment Pharmacol Ther 2014; 40: 880-892
ª 2014 John Wiley & Sons Ltd
and likelihood of depression. Patients were equally as
likely to have developed depression before using alcohol
excessively as they were afterwards.43 Risk factors for
alcohol recidivism after OLT have been found to include
pre-operative depression and level of alcohol consump-
tion,44 with the evidence regarding the extent to which
duration of pre-transplant abstinence contributes being
contradictory.44, 45
Non-alcoholic fatty liver disease
Depressive symptoms occur in at least one-quarter of
patients with NAFLD,28, 39 but the evidence is contradic-
tory as to whether NAFLD is an independent risk factor
for depression, with some data sets supporting this,46
while others do not.28
A recent cross-sectional study assessed a cohort of
567 North American patients with biopsy-proven NA-
FLD, including patients with the entire spectrum of the
condition (i.e. steatosis, steatohepatitis and cirrhosis).
Patients were screened for depression with the Hospital
Anxiety and Depression Scale (HADS). After adjust-
ment for confounders, depression was significantly asso-
ciated with more severe hepatocyte ballooning (a
marker of histological severity) in a dose-dependent
manner.47 However, no evidence was found of an asso-
ciation between antidepressant use and histological
severity of disease.
Cholestatic and autoimmune liver diseases
A recent study of a cohort of patients with autoimmune
hepatitis identified symptoms consistent with major
depressive disorder in 10.8% of patients, as assessed by
PHQ-9. No association was found between the presence
of cirrhosis, the level of ALT, the level of IgG and
depressive symptoms, although a correlation was identi-
fied between use of prednisolone and the presence of
depression.48
One further question in this area has been whether
the fatigue commonly associated with cholestatic liver
diseases is a manifestation of depression. In a Dutch
cohort of 92 patients with primary biliary cirrhosis or
primary sclerosing cholangitis; patients were screened for
depressive symptoms through completion of BDI ques-
tionnaires, then completed structured psychiatric inter-
views and were assessed for depression by DSM-IV
criteria. 42% of patients had depressive symptoms based
on BDI criteria, but only 3.7% via DSM-IV criteria. The
authors hypothesised that this disparity relates to a large
proportion of patients having fatigue and other somatic
symptoms (which are assessed in BDI scores but not
883
B. H. Mullish et al.
DSM-IV), and concluded that the fatigue these patients
experience cannot be explained by depression.49
DEPRESSION IN PATIENTS WITH LIVER
TRANSPLANTS
Up to 40% of patients have features of depression fol-
lowing OLT.50 Patients with depression pre-operatively
are over twice as likely to experience post-transplant
depression as those without,10, 51 with other risk factors
for post-OLT depression including younger age, a lack of
spouse50 and unemployment.52 Patients transplanted for
HCV-related cirrhosis have higher rates of post-operative
depression than those transplanted for liver disease of
other aetiologies.52, 53 While both the physical and men-
tal components of HRQOL appear to improve signifi-
cantly within several weeks after liver transplantation,
only the physical component appears to be consistently
improved beyond 1 year post-operatively.54
There is now evidence from a number of sources
(including prospective longitudinal studies) that depres-
sive symptoms occurring in the early post-operative per-
iod in patients who have had OLT for alcohol-related
cirrhosis50 or cirrhosis of any cause55 predict long-term
mortality, with higher BDI scores being significantly
associated with increased mortality.55 In one study,
North American investigators followed 167 patients
transplanted for alcohol-related cirrhosis who developed
depressive symptoms (as assessed through BDI scores)
during their first post-operative year. They identified
three trajectories of depressive symptoms during this
time course: a group with consistently low depression
levels throughout the year (‘group 1’), a group with ini-
tially low depression levels that rose over time (‘group
2’), and a group with consistently high depression levels
(‘group 3’). 10 year survival rate post-OLT was 66% for
group 1, but 46% for group 2 and 43% for group 3.50
BDI scores were more strongly associated with survival
than MELD score, donor age or HCV status. No signifi-
cant difference in cause of death was found between
groups, including no difference in alcohol use and deaths
from alcohol-related liver disease.
This group subsequently evaluated the effect of antide-
pressants upon survival post-OLT for alcohol-related cir-
rhosis. Of the 167 patients, it was assessed that 41 of
those had depression that was being inadequately phar-
macologically treated (i.e. nontreated or insufficiently
treated, as assessed by Antidepressant Treatment History
Forms), with 31 having adequately treated depression. At
a median of 9.5 years post-transplant, depressed patients
who had been inadequately treated had an all-cause
884
mortality rate of 68%, which was significantly higher
than those receiving adequate antidepressants (48%) and
that of nondepressed patients (44%).56 Graft failure,
infection and cancer were the predominant causes of
death in the inadequately treated depressed group. There
was no significant difference in mortality between
patients receiving adequate antidepressant therapy and
nondepressed patients. Treatment of depression was
more strongly linked to survival than MELD score,
donor age or HCV status. The group with adequately
treated depression was predominantly taking selective
serotonin reuptake inhibitors (SSRIs), with other drugs
prescribed including mirtazapine and bupropion.
There have been a number of hypotheses offered to
explain the apparent association between depression, the
use of antidepressant therapy and post-OLT outcome.
Major depression in post-OLT patients is associated with
reduced compliance with medications,57 hence one psy-
chological perspective is that treatment of depression
may improve adherence with immunosuppression and
engagement with post-operative clinical follow-up,11
although the evidence regarding the strength of this
association is variable.58 Others have focused on social
theories, including that treating depression may help
minimise depression-related weight gain and physical
inactivity, in turn aiding post-operative rehabilitation.56
There is also an increasing evidence base for a biological
explanation. Specifically, depression appears to be associ-
ated with increased activity of the hypothalamic-pitui-
tary-adrenal axis and glucocorticoid resistance, which
may make patients vulnerable to graft rejection.59 Addi-
tionally, serotonin appears to act as a growth factor for
hepatocytes through actions on the 5HT-2b receptor60;
SSRIs work through the same receptor, with activation
of this receptor in murine models improving graft sur-
vival in small-for-size models of liver transplanta-
tion.61, 62
In practice, however, it may be more than one of
these factors working in tandem. For instance, sexual
dysfunction has a number of contributory biological and
psychosocial factors; although prevalence of the condi-
tion declines in the post-OLT period, sexual dysfunction
is correlated with depression within this cohort.63
USE OF ANTIDEPRESSANTS IN CHRONIC LIVER
DISEASE
Introduction
Given the crucial role that the liver plays in the pharma-
cokinetics of the majority of drugs, it is unsurprising that
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 Review: depression and antidepressants in liver disease or transplantation
CLD results in profound changes to drug metabolism via
a number of different routes. Firstly, liver dysfunction
results in marked changes in hepatic blood flow, includ-
ing the development of portal-systemic shunting; this
may substantially decrease the pre-systemic elimination
(i.e. ‘first pass’ effect) of high-extraction drugs following
their oral administration, in turn leading to a higher pro-
portion of drug distributed to the body.64 A second
mechanism is the reduction in synthesis of transport
proteins in liver disease which impacts upon drug distri-
bution and elimination.65 A further contributory factor is
the change in drug volume metabolism that occurs in
CLD, particularly related to development of peripheral
oedema and ascites. However, perhaps the most signifi-
cant means by which CLD impacts upon pharmacokinet-
ics is by reduced clearance of drugs eliminated by
hepatic metabolism or biliary excretion.66 The pattern of
loss of drug-metabolising abilities of the liver is depen-
dent upon the stage of disease, e.g. glucuronidation is
often considered to be affected to a lesser extent than
cytochrome P450-mediated reactions in mild cirrhosis,
but may be substantially impaired in patients with
advanced cirrhosis.66, 67 The aetiology of liver disease
also impacts upon the degree of change in hepatic
enzyme activity; acute viral hepatitis and alcohol-related
liver disease tends to initially affect the pericentral region
(where oxidative functions are focused), while primary
biliary cirrhosis predominantly involves the periportal
region.65 To add to the complexity, changes to pharma-
codynamics are also prevalent in patients with CLD; for
instance, increased sensitivity is found for the central
effects of opiates and benzodiazepines.68
Because of these effects, considerable anxiety exists
amongst clinicians regarding the risk of drug-induced
liver injury (DILI) and drug-related adverse effects when
prescribing in patients with CLD. With regards to DILI,
there is scant evidence that patients with pre-existing
liver disease are at any increased risk of DILI compared
to those with healthy livers following administration of
medications known to be associated with idiosyncratic
drug hepatotoxicity; conversely, pre-existing liver disease
may potentially protect against certain DILI in particular
circumstances by interrupting metabolite-generating
pathways.69
Part of the difficulty that clinicians face is that so few
of the medications they prescribe for medical conditions
that commonly co-exist with liver disease – including
antidepressants – have been adequately studied in this
setting, and personal experience and/or expert opinion
still contributes significantly to prescription patterns
Aliment Pharmacol Ther 2014; 40: 880-892
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within contemporary practice. Only relatively recently
have formal guidelines for the evaluation of pharmacoki-
netics and dosing adjustments in patients with existing
liver disease been proposed by both the Food and Drug
Administration (FDA)70 (since 2003) as well as the
European Medicines Agency (EMA)71 (since 2005).
However, many new drugs still lack this information as
patients with significant liver disease remain poorly rep-
resented in clinical drug trials. This next section summa-
rises what is currently understood about antidepressant
use in those with CLD.
Specific classes of antidepressants
Selective serotonin reuptake inhibitors and selective nor-
adrenergic reuptake inhibitors.
Use in patients with chronic liver disease. The current
consensus is that this category of drugs [and particularly
selective serotonin reuptake inhibitors (SSRIs)] are the
safest class of antidepressants for use in patients with
CLD,65, 67 principally based upon their relative lack of
side effects and high therapeutic index (Table 1). These
are currently the most common class of antidepressants
prescribed to patients with CLD.68
Side effects of these medications are rare, but include
nausea and vomiting, diarrhoea, hyponatraemia, changes
in cognition, sedation, apathy and – rarely – suicidal
thoughts. A further concern regarding the safety of SSRIs
is their apparent association with gastrointestinal bleed-
ing. Mechanistically, there are at least two possible expla-
nations for this. Firstly, SSRIs have been shown to
directly increase gastric acidity,82 which may increase the
risk of peptic ulcer disease. Secondly, SSRIs inhibit the
serotonin transporter that is responsible for the uptake
of serotonin into platelets, where it has a role in facilitat-
ing platelet aggregation in response to vascular injury.83
Clinically, while there is conflicting evidence as to the
extent to which SSRI use increases the risk of gastroin-
testinal bleeding, systematic review suggests that it
approximately doubles the risk, with the risk only lasting
for the duration of the medication intake.82 The evidence
is somewhat conflicting as to whether that risk differs
specifically in patients with liver disease; for example, no
increased risk was identified on a retrospective analysis
of patients with HCV with mixed degrees of liver disease
who were receiving interferon (itself hypothesised to be
an increased risk factor for haemorrhage),84 while a sys-
tematic review of patients with HCV-related cirrhosis
who had been administered SSRIs found that only
co-administration of anti-platelet medications appeared
to increase the risk of haemorrhage.85 As such,
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B. H. Mullish et al.
Table 1 | Summary of pharmacokinetic data and dosing recommendations for commonly prescribed antidepressants
in patients with CLD
Class of antidepressant
Selective serotonin reuptake
inhibitor (SSRI)
Selective noradrenergic
reuptake inhibitor (SNRI)
Tricyclic antidepressant (TCA)
886
Pharmacokinetics in patients with
Specific drug CLD
Citalopram Approximate doubling of half-life
and 36% reduction in clearance
after single administration to
patients with liver disease of
mixed aetiology and Child–Pugh
score.72
Escitalopram Increase in AUC by 51% in those
with Child-Pugh A cirrhosis and
69% in those with Child-Pugh B
cirrhosis after single
administration.73
Fluoxetine Approximate tripling of half-life
and 50% reduction in plasma
clearance in those with alcohol-
related cirrhosis.74, 75
Paroxetine Approximate doubling of trough
drug concentration, AUC and
half-life when administered over
14 days to those with alcohol-
related cirrhosis.76
Sertraline 70% reduction in clearance and
significant prolongation of half-
life after single administration to
those with Child-Pugh A/B
cirrhosis.77
Duloxetine 85% reduction in clearance and
tripling of half-life when
administered to Child-Pugh B
cirrhotics.67
Venlafaxine 40% reduction in clearance in
Child-Pugh A/B cirrhotics and
up to 90% in Child-Pugh C
cirrhotics.78
Amitriptyline Plasma levels and AUC
approximately tripled.79
Suggested prescribing advice for
patients with CLD
● No change in loading/initial dose,
but aim for maintenance dose of
50% that used in healthy patients,
and titrate based on balance of
efficacy and side effects.
● Aim to minimise co-administration
of SSRIs with anti-platelet/non-
steroidal anti-inflammatories
where possible because
of increased risk of bleeding,
including gastrointestinal
haemorrhage.
● Ensure close monitoring of QT
segment on ECG for prolongation,
especially when co-administered
with other medications known to
affect the QTc.
● Reduce both initial and
maintenance doses to
approximately 50% of normal with
cautious titration based on balance
of efficacy and side effects.
● Aim to minimise co-administration
of SSRIs with anti-platelet/non-
steroidal anti-inflammatories
where possible because
of increased risk of bleeding,
including gastrointestinal
haemorrhage.
● Ensure close monitoring of QT
segment on ECG for prolongation,
especially when co-administered
with other medications known to
affect the QTc.
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 Review: depression and antidepressants in liver disease or transplantation

Table 1 | (Continued)
Class of antidepressant
Atypical
Noradrenaline reuptake
inhibitor (NRI)
Serotonin antagonist and
reuptake inhibitor (SARI)
Noradrenergic and specific
serotonergic antidepressant
(NaSSA)
Pharmacokinetics in patients with
Specific drug CLD
Bupropion No significant change in
pharmacokinetics in Child-Pugh
A/B cirrhosis, although tripling
of AUC, 40% increase in half-life
and peak plasma concentration
increased by 70% in Child-Pugh
C cirrhosis.
Reboxetine Half-life increased 150% and AUC
92% after single administration
to those with alcohol-related
cirrhosis.80
Trazadone No published studies in liver
disease.
Mirtazapine At least 33% reduction in plasma
clearance and 33% increase in
half-life in those with CLD.81
Suggested prescribing advice for
patients with CLD
● Use at a reduced dose in those
with Child-Pugh A/B cirrhosis
and avoid in Child-Pugh C
cirrhosis.
● Ensure particular care when
administering to patients with
hepatic encephalopathy because
of confusion as a recognised
side effect.
● Start with 50% of normal dose
and titrate based on balance of
efficacy and side effects.
● Ensure particular care in patients
with hepatic encephalopathy
because of side effects of
sedation.
● Start with 50% of normal dose,
with carefully titration based
on balance of efficacy and
side effects.
● Ensure particular care with
co-administration of other
medications affecting serotonergic
pathways (e.g. SSRIs) because
of risk of serotonin syndrome.

AUC, area under curve.

conventional advice is that SSRIs should be administered
with attempts to minimise co-administration of
anti-platelet medications and nonsteroidal anti-inflam-
matory drugs (NSAIDs) if at all possible.
The pharmacokinetic profile of these medications is as
summarised in Table 1. Typically, they have a prolonged
half-life and reduction in drug clearance in patients with
CLD compared to healthy subjects. As such, no change
is required in the loading/initial dose for these medica-
tions, but the maintenance dose may need to be
reduced.86 Consensus advice, therefore, is to aim for a
maintenance dose of 50% of that which would be aimed
for in healthy patients, with subsequent titration based
upon the balance of efficacy and side effects.
SSRIs and selective noradrenergic reuptake inhibitors
(SNRIs) have been associated with hepatoxicity in iso-
lated reports in non-CLD patients which reversed on dis-
continuation of the drug, including venlafaxine,78
citalopram,87 and fluoxetine, paroxetine and sertraline.88
In a series of seven cases of duloxetine-induced liver
injury, three had pre-existing chronic liver disease and
one had acute decompensation with jaundice and asci-
tes.89 Both duloxetine and sertraline have also been asso-
ciated with fatal hepatotoxicity.90 No serious liver injury
has been reported with the use of escitalopram; however,
this may be related to it being a relatively new medica-
tion and lack of long-term follow-up data. As it is an
S-enantiomer of citalopram, it may be expected to dem-
onstrate similar adverse effects.
Use in patients with chronic hepatitis C infection. SSRIs
are the best studied and most frequently-used antide-
pressants within this context. The majority of studies
have focused on interferon-related depression, but an
open-label trial of mainly untreated chronic HCV
patients without decompensated cirrhosis demonstrated
that an 8-week course of 10–20 mg escitalopram signifi-
cantly reduced the mean 17-item Hamilton Rating Scale
for Depression Scores (HAM-D-17) to a third of the
baseline mean scores, with no adverse effect on liver
function.91 Similarly, a 50% reduction in BDI scores with
the use of 20–60 mg citalopram daily was demonstrated

Aliment Pharmacol Ther 2014; 40: 880-892 887

ª 2014 John Wiley & Sons Ltd
B. H. Mullish et al.
in 85% of chronic HCV patients who had developed a
major depressive disorder on interferon treatment.35
Kraus et al. demonstrated in a randomised, placebo-con-
trolled trial, that 20 mg citalopram daily was significantly
superior to placebo in reducing interferon-related depres-
sive symptoms after 2 and 4 weeks.92 A significant
improvement in major depression was found in inter-
feron-treated HCV patients managed concomitantly with
20 mg paroxetine,93 allowing 79% of the subjects who
had developed depression to complete interferon treat-
ment. Certainly, SSRI use in chronic HCV patients does
not appear to have any additional adverse effects in most
case series and trials.34, 91
Tricyclic antidepressants. A major concern regarding
Tricyclic antidepressants (TCAs) is their extensive side
effect profile, including anticholinergic symptoms, ortho-
static hypotension, cardiac dysrhythmia (particularly dis-
ordered atrio-ventricular conduction) and neurological
side effects (including sedation and seizures).94 Given
that these drugs normally have high hepatic extraction,
their plasma clearance will decrease with the develop-
ment of CLD and its associated extra- and intrahepatic
portosystemic shunting of blood. Amitriptyline was
shown to have an increased sedative effect when admin-
istered to a patient with cirrhosis and portocaval anasto-
mosis.79 Amitriptyline interacts with a number of drugs
including certain antibiotics; a recent report described
cirrhotic patients developing long QTc syndrome after
co-administration of amitriptyline and trimethoprim-sul-
famethoxazole.68 There are no published trials of nor-
triptyline, clomipramine, dibenzepin, imipramine or
trimipramine use in patients with liver disease, and only
occasional reports of DILI associated with their use.95
Consensus advice is for initial doses of TCAs to not
exceed 50% of standard starting doses, with subsequent
titration dependent upon the balance of efficacy and
adverse effects. Particular caution must be given in their
prescription to patients with hepatic encephalopathy
given their potentially sedative effects.
Monoamine oxidase inhibitors. Iproniazid, a hydrazine
derivative, was amongst the first Monoamine oxidase
inhibitors (MAOI) developed. It was withdrawn from
use in 1978 because of the recognition that its use was
associated with a significant risk of hepatocellular injury
when used even in healthy patients, with serum transam-
inases rising up to 10-fold above the upper range of
normal and jaundice occurring in 1% of patients. This
typically occurred during the first 3 months of treat-
888
ment, and resulted in death in up to one-fifth of all
affected patients.96 Scarce data are available about the
pharmacokinetics of more modern MAOIs in liver dis-
ease; however, the half-life and systemic clearance of
tranylcypromine (a nonhydrazine, irreversible, nonselec-
tive MAOI) and moclobemide (a reversible and selec-
tive inhibitor of MAO-A) is prolonged in cirrhotic
patients in comparison to healthy controls.97 Given
their side effect profile (including nausea, dizziness,
headache and occasional anticholinergic effects), associ-
ation with hepatoxicity and apparent pharmacokinetic
changes in CLD, some authorities would suggest that
MAOIs should be avoided altogether within this popu-
lation.98 However, if they are to be used, moclobemide
is preferred because of its reversibility, and the recom-
mended starting dose should be reduced by 50% or
dosage interval doubled.
Other antidepressants. Bupropion (an atypical antide-
pressant) has several well-recognised side effects, includ-
ing agitation, confusion, nausea and vomiting, and
seizures. As such, particular care should be used when
administering this to patients with hepatic encephalopa-
thy. Its pharmacokinetics are as summarised in Table 1.
Recommendations are that bupropion is used with cau-
tion in Child-Pugh A and B cirrhosis, and avoided in
those with Child-Pugh C cirrhosis; dosing should start at
the smallest available dose (typically 50% of the usual
dose), and a reduced frequency of administration should
be considered.67, 95
There are also a number of other antidepressants
that are established in clinical use that may be of use
in this population (see Table 1 for further details). Re-
boxetine has altered pharmacokinetics in those with
CLD compared to healthy controls, but there are no
reports of DILI in association with its use at present.
There are currently no clinical studies of the use of
trazadone in patients with liver disease. While there
are only a few reports of DILI in patients with healthy
livers associated with trazadone use, those that do exist
are serious, including a healthy patient who developed
fulminant hepatic failure 4 months into a course of
venlafaxine and trazadone and required OLT.99 Traza-
done is commonly associated with sedation, so caution
is particularly required for its prescription to patients
with hepatic encephalopathy.65 There are rare cases of
mirtazapine-related DILI associated with prolonged
jaundice, taking up to three months to resolve on
drug withdrawal.100 There have been three reports of
serotonin syndrome when mirtazapine was co-adminis-
Aliment Pharmacol Ther 2014; 40: 880-892
ª 2014 John Wiley & Sons Ltd
 Review: depression and antidepressants in liver disease or transplantation
tered with another medication (fluoxetine, tramadol
and venlafaxine), so care must particularly be taken
with co-administration of mirtazapine with other medi-
cations that also act on serotonin pathways.101
USE OF ANTIDEPRESSANTS IN LIVER TRANSPLANT
PATIENTS
Whilst the anxiety about use of antidepressants in the
CLD population relates predominantly to pharmacoki-
netic changes, the concern about their use in the post--
OLT setting is different, focusing particularly on
medication tolerability and interactions with other medi-
cations, most notably immunosuppressive medications.
As in the CLD population, there is a scarcity of data,
reflecting the rarity with which transplant patients are
included in the clinical trials of antidepressants.
The side effect and drug interaction profiles of TCAs
and MAOIs mean that they are used only very rarely in
the post-transplant setting. It is SSRIs and SNRIs that
are of most common use in this population, predomi-
nantly reflecting their relative lack of side effects and
high therapeutic index.56, 94 However, care must be
taken regarding the possibility of drug interaction
between SSRIs/SNRIs and immunosuppressant medica-
tions. Caution should particularly be taken with the use
of fluoxetine and paroxetine, both of which inhibit the
cytochrome P450 3A4 enzyme metabolisation of the cal-
cineurin inhibitors (ciclosporin and tacrolimus) and
mammalian target of rapamycin (mTOR) inhibitor siroli-
mus, hence raising their plasma concentrations when
co-administered.33, 102, 103 Citalopram, escitalopram,
sertraline, venlafaxine, mirtazapine and bupropion
appear to have few effects on cytochrome P450 3A4 and
therefore would not expect to significantly alter metabo-
lism of these immunosuppressants. A small study failed
to show any effect of citalopram upon ciclosporin levels
in OLT patients.104 While some studies have demon-
strated an elevation in ciclosporin levels when co-admin-
istered with sertraline,105 others have not,106 and
clarification is needed.
In keeping with the known neurocognitive side effects
of the medication, a retrospective analysis of cohort of
patients receiving liver transplants for different patholo-
gies used multivariate analysis to identify that high-dose
corticosteroid use is an independent risk factor for the
mental health component of HRQOL in the post-OLT
population.107 As such, efforts should be made to
minimise exposure to corticosteroids where possible
within depressed liver transplant patients.
Aliment Pharmacol Ther 2014; 40: 880-892
ª 2014 John Wiley & Sons Ltd
Mycophenolate mofetil is not metabolised by the cyto-
chrome P450 enzyme system but by glucuronyl transfer-
ase, making drug interactions less common.
CONCLUSIONS
Depression is under-recognised when occurring in patients
with CLD and OLT, and its presence can adversely affect
patient outcomes. This phenomenon cannot be attributed
to the degree of a patient’s liver disease alone and is not
purely an atypical manifestation of hepatic encephalopathy.
The evidence for optimal pharmacotherapy reducing
adverse outcomes associated with depression within these
populations is compelling. As such, hepatologists should
seek to apply the same level of vigour to recognising and
treating depression in their patients as they do in their man-
agement of decompensated liver disease and immunosup-
pression regimens. They should have a low threshold to
suspect the condition, should investigate carefully to distin-
guish depression from hepatic encephalopathy, and should
have no hesitation in employing the safe and effective phar-
macotherapy that exists.
Nevertheless, this is a complex area in which consid-
erable uncertainty still exists. There are to our knowl-
edge no professional guidelines within this area, likely
reflecting the fact that the current evidence base for
assessment and management of depression within this
population is still hampered by a lack of data. Some
aspects of depression care in those with liver disease
remain virtually unexplored, such as examination of the
efficacy of nonpharmacological interventions for depres-
sion in this population, including psychotherapy. Fur-
ther studies are urgently merited to close the evidence
gaps in this area and to give clinicians support in this
challenging area.
AUTHORSHIP
Guarantor of the article: Dr Ameet Dhar.
Author contributions: Dr Dhar and Prof Thursz were
responsible for the concept of the article. Dr Mullish and
Dr Kabir performed the literature review and wrote the
article. All authors reviewed and approved the final ver-
sion of the manuscript.
ACKNOWLEDGEMENTS
Declaration of personal interests: None.
Declaration of financial interests: The Section is supported
by the National Institute of Health Research (NIHR)
Biomedical Research Centre based at Imperial College
Healthcare NHS Trust and Imperial College London.
889
B. H. Mullish et al.
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