Review Article: Depression and the Use of Antidepressants in Patients with Chronic Liver Disease
and Liver Transplantation.
Benjamin H Mullish1*, Misha S Kabir1, Mark R Thursz1, Ameet Dhar1.
1
Section of Hepatology, Faculty of Medicine, Imperial College London, St Mary’s Hospital Campus,
Paddington, London, W2 1NY, UK.
*Corresponding author. Contact Dr Benjamin Mullish via:
Telephone: +44 (0)203 312 6454
Fax: +44 (0)207 724 9369
Email: b.mullish@imperial.ac.uk
Mail address: 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.
Keywords: depression; antidepressant; chronic liver disease; cirrhosis; liver transplantation
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 depression in patients with CLD
and post-OLT, and to assess the safety and efficacy 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 non-depressed 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 non-depressed patients; appropriate antidepressant use reverses this effect.
Selective serotonin reuptake inhibitors (SSRIs) and selective 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 generally 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
frequency 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 non-pharmacological treatments.
1.
Introduction:
Depression currently represents the second most common cause worldwide of life-years lived with
disability1. 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 population2. Furthermore, it
has been demonstrated that these patients experience worse health outcomes - including a reduced
quality of life and increased mortality – compared to matched patients without depression3, 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 antidepressants.
2. 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’, ‘depression’, ‘antidepressant’, the names of
specific causes of liver disease, and the names of individual antidepressants, with these terms applied
together in different logical 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
performed to identify potentially relevant articles that may have been missed by the initial search.
3. Depression in patients with chronic liver disease:
3.1. Cirrhosis:
The majority of studies aiming to establish the prevalence of depression within the population with
liver disease have done so through the completion of Beck Depression Inventory (BDI) questionnaires.
These are a widely-used screen for depression of high internal consistency and content validity, but
have also been subjected to a number of criticisms, including poor discriminant validity against
anxiety5. By BDI criteria, at least 30% of patients with cirrhosis have depressive symptoms6,
7, 8
.
Studies where cirrhotic patients have been assessed for health-related quality of life (HRQOL) as well
as depression (the former typically also via questionnaires, such as the Short Form-36 (SF-36)) confirm
that depressed cirrhotic patients experience a significantly reduced HRQOL in comparison to nondepressed subjects6, 9.
Furthermore, cirrhotic patients with depression experience 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 compared to nondepressed patients9, despite no significant difference between groups in the incidence of specific
features of decompensation (including gastrointestinal bleeding and hepatocellular carcinoma).
Whilst it might be expected that this outcome could have reflected more severe liver disease in the
depressed patients, no significant difference was found in Child-Pugh score between groups. BDI
score was a significant independent predictor of mortality in this cohort.
There is also an association between the use of antidepressants in depressed cirrhotic patients within
the pre-transplant period and post-OLT outcome. A retrospective 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 experienced significantly
less acute cellular rejection (13%) than depressed patients not receiving antidepressants (40%)10. The
group hypothesised that effective treatment of depression was associated with increased compliance
with immunosuppressant medications.
No difference in time to death or incidence of graft
dysfunction was observed between depressed and non-depressed 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.
Since both hepatic encephalopathy and depression may present with comparable clinical features
(including similar cognitive deficits and psychomotor impairment), further 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 gyri 13 and in the anterior cingulated gyrus in
cirrhotic patients with minimal hepatic encephalopathy14, which are areas also involved in other
neuropsychological disorders15. However, recent research assessing for HRQOL and the prevalence of
affective disorders in cirrhotic patients of mixed aetiologies show no difference in psychological
scores for depressive disease between the 22 patients with minimal hepatic encephalopathy (as
diagnosed via PHES testing16) compared to those without8, 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 support, education level, income and marital status) were found to different degrees between
depressed and non-depressed cirrhotic patients9. 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
randomised controlled trials of beta-blockers versus placebo in patients with cardiac failure actually
demonstrated significantly reduced rates of depression in patients given beta-blockers in comparison
to placebo17.
Both psychological and biological theories have been proposed as explanations for the relationship
between depression in cirrhosis and increased mortality. Psychological theories focus on the finding
that patients with depression have high rates of non-compliance with medical regimens18. 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 decompensation.
3.2. Hepatitis C:
A significant proportion of patients infected with the hepatitis C virus (HCV) develop neuropsychiatric
symptoms, 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 accounting for these
neuropsychiatric symptoms, depression per se is more prevalent in hepatitis C patients than in the
general population. Major depression has been reported in 15 - 49.5% of patients with chronic HCV
infection, independent of the use of anti-viral treatment23-26, with a mean prevalence of 38% found in
a review across ten studies27. Of these patients, a significant proportion (up to 72%) had not been
identified as having depression previously26. 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 non-cirrhotic), who were
screened for depression using the Patient Health Questionnaire-9 (PHQ-9) questionnaire, identified
HCV only as an independent 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 issues26, 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 factor23. The principle 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 itself31, e.g. through dopamine and serotonin transporter binding27.
Anti-viral treatment of hepatitis C with interferon-alpha (IFN-) 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-α, 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 differential impact on the prevalence of IFN-α-related depression; however, it
does appear to be sensitive to dosage and duration of treatment as well as pre-morbid patientrelated risk factors, including a previous history of psychiatric disorders and female sex33, 36. This
phenomenon has an increasingly well-characterised biological basis, with activation of a proinflammatory cytokine network and alterations in serotonin and dopamine neurotransmitter
metabolism being postulated to exert the mood changes associated with IFN-α27, 33. Specifically, IFNα induces expression of indoleamine (2,3)-dioxygenase (IDO), which causes increased catabolism of
the serotonin precursor, tryptophan, resulting in reduced peripheral serotonin levels37. The potential
role of newer treatments (including direct-acting antivirals and newer forms of interferon) in the
treatment of chronic HCV is still being evaluated, but the data currently available for interferon-lamba
1 suggests there may be fewer neuropsychiatric complications resulting from its use compared to IFN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 depression (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 ontreatment 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 virological 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.
3.3. Hepatitis B:
Less than 5% of the population with chronic HBV infection have depression, comparable to the
prevalence of depression within the general population 39. However, they do experience an increased
rate of adverse psychological effects. Non-cirrhotic chronic HBV patients who completed SF-36
questionnaires demonstrated significant reductions in their scores for ‘mental health’ and ‘general
health perception’ compared to healthy controls40.
Patients with chronic HBV treated with
peginterferon alpha-2 experienced depressive symptoms and impairment to HRQOL, but to a much
lesser degree than patients with chronic HCV41.
3.4. Alcohol-related liver disease:
Patients using alcohol to excess have an increased likelihood of depression and anxiety disorders,as
well as an increased risk of both parasuicide and suicide, regardless of whether they have liver disease
or not42. In a cohort of patients with biopsy-proven alcohol-related liver disease (including both
cirrhotic and non-cirrhotic patients), 40% were found to be depressed, although no correlation was
made between the degree of liver disease 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 consumption44, with the evidence regarding the extent to which duration of pre-transplant
abstinence contributes being contradictory44, 45.
3.5. Non-alcoholic fatty liver disease (NAFLD):
Depressive symptoms occur in at least one-quarter of patients with NAFLD28, 39, but the evidence is
contradictory as to whether NAFLD is an independent risk factor for depression, with some data sets
supporting this46, whilst others do not28.
A recent cross-sectional study assessed a cohort of 567 North American patients with biopsy-proven
NAFLD, 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 adjustment for confounders, depression was significantly associated with more severe
hepatocyte ballooning (a marker of histological severity) in a dose-dependent manner47. However, no
evidence was found of an association between antidepressant use and histological severity of disease.
3.6. 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 identified 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 questionnaires, then completed structured psychiatric interviews 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 DSM-IV), and concluded that the fatigue these patients experience cannot be
explained by depression49.
4. Depression in patients with liver transplants:
Up to 40% of patients have features of depression following OLT 50. Patients with depression preoperatively 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
unemployment52. Patients transplanted for HCV-related cirrhosis have higher rates of post-operative
depression than those transplanted for liver disease of other aetiologies 52, 53. Whilst both the physical
and mental components of HRQOL appear to improve significantly within several weeks after liver
transplantation, only the physical component appears to be consistently improved beyond one year
post-operatively54.
There is now evidence from a number of sources (including prospective longitudinal studies) that
depressive symptoms occurring in the early post-operative period 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 initially 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 350. BDI scores were more strongly associated with survival than MELD score, donor age or
HCV status. No significant 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 antidepressants upon survival post-OLT for alcoholrelated cirrhosis. Of the 167 patients, it was assessed that 41 of those had depression that was being
inadequately pharmacologically-treated (i.e. non-treated 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 mortality rate of 68%, which was significantly higher than those receiving adequate
antidepressants (48%) and that of non-depressed 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
non-depressed patients. Treatment of depression was more strongly linked to survival than MELD
score, donor age or HCV status. The group with adequately-treated depression were 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 medications57, hence one psychological
perspective is that treatment of depression may improve adherence with immunosuppression and
engagement with post-operative clinical follow-up11, although the evidence regarding the strength of
this association is variable58.
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 rehabilitation56. There is also an increasing evidence base for a biological explanation.
Specifically, depression appears to be associated with increased activity of the hypothalamicpituitary-adrenal axis and glucocorticoid resistance, which may make patients vulnerable to graft
rejection59. Additionally, 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 survival in small-for-size models of liver transplantation61, 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 condition declines in the post-OLT period, sexual dysfunction is correlated with
depression within this cohort63.
5. Use of antidepressants in chronic liver disease:
5.1. Introduction:
Given the crucial role that the liver plays in the pharmacokinetics of the majority of drugs, it is
unsurprising that 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, including 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 proportion 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 distribution and
elimination65. 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 significant means by which CLD impacts upon pharmacokinetics 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 dependent 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 cirrhosis66, 67. The aetiology of liver disease also
impacts upon the degree of change in hepatic enzyme activity; acute viral hepatitis and alcoholrelated liver disease tends to initially affect the pericentral region (where oxidative functions are
focused), whilst primary biliary cirrhosis predominantly involves the periportal region65. To add to the
complexity, pharmacodynamics changes 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 druginduced 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 metabolitegenerating pathways69.
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 within contemporary practice. Only relatively recently have
formal guidelines for the evaluation of pharmacokinetics 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 represented in clinical drug trials.
This next section summarises what is currently understood about antidepressant use in those with
CLD.
5.2. Specific classes of antidepressants:
5.2.1.
Selective serotonin reuptake inhibitors (SSRIs) and selective noradrenergic reuptake
inhibitors (SNRIs):
5.2.1.1. Use in patients with chronic liver disease:
The current consensus is that this category of drugs (and particularly SSRIs) are the safest class of
antidepressants for use in patients with CLD65, 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 CLD68.
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 bleeding.
Mechanistically, there are at least two possible explanations for this. Firstly, SSRIs have been shown
to directly increase gastric acidity82, 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 facilitating platelet aggregation in response to vascular injury 83. Clinically, whilst
there is conflicting evidence as to the extent to which SSRI use increases the risk of gastrointestinal
bleeding, systematic review suggests that it approximately doubles the risk, with the risk only lasting
for the duration of the medication intake82. 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, whilst a systematic
review of patients with HCV-related cirrhosis who had been administered SSRIs found that only coadministration of anti-platelet medications appeared to increase the risk of haemorrhage85. As such,
conventional advice is that SSRIs should be administered with attempts to minimise co-administration
of anti-platelet medications and non-steroidal anti-inflammatory 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 medications, but the maintenance
dose may need to be reduced86. 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 SNRIs have been associated with hepatoxicity in isolated reports in non-CLD patients which
reversed on discontinuation of the drug, including venlafaxine78, citalopram87, and fluoxetine,
paroxetine, and sertraline88. 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 ascites 89.
Both duloxetine and sertraline have also been associated 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 medication and lack of long-term follow up data. Since it is an S-enantiomer of
citalopram, it may be expected to demonstrate similar adverse effects.
5.2.1.2. Use in patients with chronic hepatitis C infection:
SSRIs are the best studied and most frequently use antidepressants 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 eight week course of 10
- 20 mg escitalopram significantly 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 - 60mg citalopram daily was demonstrated
in 85% of chronic HCV patients who had developed a major depressive disorder on interferon
treatment35. Kraus et al demonstrated in a randomised, placebo-controlled trial, that 20mg
citalopram daily was significantly superior to placebo in reducing interferon-related depressive
symptoms after two and four weeks92. A significant improvement in major depression was found in
interferon-treated HCV patients managed concomitantly with 20mg paroxetine93, allowing 79% of the
subjects who had developed depression to complete interferon treatment. Certainly, SSRI use in
chronic HCV patients does not appear to have any additional adverse effects in most case series and
trials34, 91.
5.2.2. Tricyclic antidepressants (TCAs):
A major concern regarding TCAs is their extensive side effect profile, including anticholinergic
symptoms, orthostatic hypotension, cardiac dysrhythmia (particularly disordered 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 development of
CLD and its associated extra- and intrahepatic portosystemic shunting of blood. Amitriptyline was
shown to have an increased sedative effect when administered to a patient with cirrhosis and portocaval anastomosis79. 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-sulfamethoxazole68. There are no published trials of nortriptyline,
clomipramine, dibenzepin, imipramine or trimipramine use in patients with liver disease, and only
occasional reports of DILI associated with their use95. 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.
5.2.3. Monoamine oxidase inhibitors (MAOIs):
Iproniazid, a hydrazine derivative, was the first 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 transaminases rising up to 10-fold above the upper
range of normal and jaundice occurring in 1% of patients. This typically occurred during the first three
months of treatment, and resulted in death in up to one-fifth of all affected patients96. Scarce data is
available about the pharmacokinetics of more modern MAOIs in liver disease; however, the half-life
and systemic clearance of tranylcypromine (a non-hydrazine, irreversible, non-selective MAOI) and
moclobemide (a reversible and selective inhibitor of MAO-A) is prolonged in cirrhotic patients in
comparison to healthy controls97.
Given their side effect profile (including nausea, dizziness,
headache and occasional anticholinergic effects), association with hepatoxicity and apparent
pharmacokinetic changes in CLD, some authorities would suggest that MAOIs should be avoided
altogether within this population98. However, if they are to be used, moclobemide is preferred
because of its reversibility, and the recommended starting dose should be reduced by 50% or dosage
interval doubled.
5.2.4. Other antidepressants:
Bupropion (an atypical antidepressant) has several well-recognised side effects, including agitation,
confusion, nausea and vomiting, and seizures.
As such, particular care should be used when
administering this to patients with hepatic encephalopathy. Its pharmacokinetics are as summarised
in Table 1. Recommendations are that bupropion is used with caution 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). Reboxetine 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. Whilst 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 four months into a course of venlafaxine and trazadone and required OLT 99.
Trazadone is commonly associated with sedation, so caution is particularly required for its
prescription to patients with hepatic encephalopathy65. There are rare cases of mirtazapine-related
DILI associated with prolonged jaundice, taking up to three months to resolve on drug withdrawal100.
There have been three reports of serotonin syndrome when mirtazapine was co-administered with
another medication (fluoxetine, tramadol and venlafaxine), so care must particularly be taken with
co-administration of mirtazapine with other medications that also act on serotonin pathways 101.
6. Use of antidepressants in liver transplant patients:
Whilst the anxiety about use of antidepressants in the CLD population relates predominantly to
pharmacokinetic changes, the concern about their use in the post-OLT setting is different, focusing
particularly on medication tolerability and interactions with other medications, 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, predominantly reflecting their relative lack of side effects and high therapeutic index56, 94.
However, care must be taken regarding the possibility of drug interaction between SSRIs/ SNRIs and
immunosuppressant medications. Caution should particularly be taken with the use of fluoxetine and
paroxetine, both of which inhibit the cytochrome P450 3A4 enzyme metabolisation of the calcineurin
inhibitors (ciclosporin and tacrolimus) and mammalian target of rapamycin (mTOR) inhibitor
sirolimus, hence raising their plasma concentrations when co-administered33,
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 metabolism of these
immunosuppressants. A small study failed to show any effect of citalopram upon ciclosporin levels in
OLT patients104. Whilst some studies have demonstrated an elevation in ciclosporin levels when coadministered with sertraline105, others have not106, 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 pathologies 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 population107. As such, efforts should be made to minimise
exposure to corticosteroids where possible within depressed liver transplant patients.
Mycophenolate mofetil is not metabolised by the cytochrome P450 enzyme system but by glucuronyl
transferase, making drug interactions less common.
7. Conclusion:
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 management of
decompensated liver disease and immunosuppression regimens. They should have a low threshold to
suspect the condition, should investigate carefully to distinguish depression from hepatic
encephalopathy, and should have no hesitation in employing the safe and effective pharmacotherapy
that exists.
Nevertheless, this is a complex area in which considerable uncertainty still exists. There are to our
knowledge 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 non-pharmacological interventions for depression
in this population, including psychotherapy.
Further studies are urgently merited to close the
evidence gaps in this area and to give clinicians support in this challenging area.
Ethics:
Declaration of personal interests: None.
Declaration of funding interests: None.
Authorship:
Guarantor of 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 version of the manuscript.
Figures:
Table 1: Summary of pharmacokinetic data and dosing recommendations for commonly-prescribed
antidepressants in patients with CLD. Abbreviations: AUC = area under curve.
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