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Q: Antidepressant and liver ( Answered,   1 Comment )
Subject: Antidepressant and liver
Category: Health > Medicine
Asked by: carlotta-ga
List Price: $100.00
Posted: 13 Jan 2005 10:15 PST
Expires: 12 Feb 2005 10:15 PST
Question ID: 456677
I'd like to which antidepressants, and in particular which SSRIs, may
be reasonably considered the least likely to possibly damage to the liver. 
My initial explorations seem to show at least the possibility of idiosyncratic
hepatic toxicity for every one(?).  Suppose minimizing possible threat to the
liver was a high priority ... what are the options?  I seen lots of relevant
studies (returned the obvious medline searches) , but nothing like a recent 
definitive comparison that would be useful in guiding choice.  Nor do I 
want to run down and evalute each of the hits from
"generic_name" | "brand_name ) &  (liver | hepatitis | hepatotoxicity)

[Ask an MD?: but truth is at at least the GP level they seem to be wondering
as well, or satisfied with the drug company's "rare"].  

I hope it is not inappropriate to add that if you aren't experienced with this 
kind of medical question the $100 I'm offereing probably won't cover the 
time it would take to get a satisfactory answer.  Though I guess I'm not
positive it's enough in any case.

Clarification of Question by carlotta-ga on 13 Jan 2005 10:21 PST
Of course I am also  looking for satisfyingly documented answer (URLs etc.).
Thanks!  And good luck!
Subject: Re: Antidepressant and liver
Answered By: crabcakes-ga on 13 Jan 2005 16:11 PST
Hello Carlotta,

  Before I get to your answer, I?d like to remind you that the
information contained in this answer is for informational purposes
only, and not intended to diagnose, treat, or replace sound medical
advice from a licensed physician. I have over 25 years experience in
health care as a Medical Technologist (M.T. ASCP), and felt qulaified
to answer your question.

   I attempted to organize the information by category, but as I
worked, too much data overlapped, and for this I apologize. I was able
to find two small charts, that were not inclusive of all
antidepressants.Comparison studies are few and do not incldue all
drugs. I'm wondering if because so few reports of hepatotoxicity are
reported, if large studies are even done. However, I have included
information about each class of drugs in my answer, along with my own
conclusion. You will, of course, need to discuss the proper selection
of drugs with your doctor. I agree with you that many GPs are not as
familiar with psychotropic drugs as a psychiatrist. If you had a
cardiac disorder, you would be treated by a cardiologist, and not by a
GP. While GPs can prescribe antidepressants, they do recommend seeing
a therapist while on medication, some of which do not have the ability
to prescribe.

Which Antidepressant is Best?
?The clear winner is the one that works best for that particular
individual. Because different people find relief from their symptoms
from different treatments, one cannot say ahead of time which among
many choices will help, or among those that end up helping which will
help most. However, if I were stranded on a desert island with exactly
the choice given, in what order would I prefer to try them? I would
first try the selective serotonin re-uptake inhibitor (SSRI, such as
fluoxetine [Prozac]), next a tricyclic (TCA, such as imipramine
[Tofranil]) and finally an antipsychotic (for example, olanzapine
[Zyprexa]). And the reason is simply likelihood of difficult side


?Comparative studies with these antidepressants are limited. Currently
there is not enough information to firmly recommend any one of these
antidepressants over another. Really, selection of antidepressant
therapy should be done on an individual basis. Drugs may work
differently for different people. What is effective for some may not
be effective for others. Your doctor will choose the best
antidepressant for you based on your depression symptoms, other
diseases or conditions you may have, other medications you may be
taking (to avoid potential drug interactions), and your prescription
benefits formulary. If one antidepressant doesn't work well for you,
then another can be tried.?,10621,46-11,00.html

It appears the risk of cardiotoxicity is greater than hepatotoxicity
with antidepressants other than SSRIs.

Head to head studies of antidepressants and hepatotoxicity are
incomplete and rare (As you know!)


In the chart found on this  page, from Queen?s University Faculty of
Health Sciences, you can see that SSRIs are known for rare

Page 2 of this document compares some antidepressants for
hepatobiliary effects, in 2 charts. Nefazodone (Serzone) is the
biggest culprit here, with Citalopram (Celexa), and Trazodone
(Desyrel) being the drugs that cause the fewer adverse effects.

?Serzone has a very low chance of causing serious liver damage, less
than 1 in 300,000 per year of use, but patients taking Serzone should
be aware of this risk and discuss it with a doctor.?

?Hepatotoxicity of psychotropic drugs occurs in a variable but small
proportion of users and therefore can be considered unpredictable or
idiosyncratic. When these uncommon adverse events occur
in association with rash, eosinophilia, and/or a rapid positive
rechallenge, sufficient circumstantial evidence exists to ascribe the
mechanism to an immune-mediated hypersensitivity reaction. Acute overt
reactions to drugs tend to have clinicopathological features of
hepatitis (destruction of liver parenchyma), cholestasis (impaired
bile secretion), or both. The hepatotoxic reactions to psychotropic
drugs conform to these general patterns. Furthermore, as with most
hepatotoxic drugs, individual psychotropic drugs have a characteristic
pattern of injury, i.e., cholestatic for some (e.g., chlorpromazine,
haloperidol, tricyclics), hepatitic for others (e.g., hydrazines, MAO
inhibitors, cocaine, ecstasy). On the chart on page 2 , you will see
that a liver enzyme called  ALT, released with liver damage is
slightly elevated, in rare cases, in Amitryptiline and Imiprimine use
(Tricyclics aka TCAs). Tacrine caused a more elevated ALT level, while
the SSRI Fluoxetine, caused rare elevated liver ALT.

Also on page 2 ?MAO Inhibitors. MAO inhibitors, which derive from
hydrazine, are all potential hepatotoxins. The experience with one,
iproniazid, was disastrous: overt hepatitis occurred in 1% with case
fatalities approaching 20%,32 and the drug was withdrawn. Hydrazines
can be metabolized by P450 to toxic intermediates. Their metabolism
and mechanism resemble that of isoniazid, also a hydrazine. One
substituted hydrazine MAO inhibitor remains available, namely
phenelzine; there have been case reports of hepatitis?	

?A full discussion is beyond the scope of this article.
Benzodiazepines illustrate the complexities of the question: some
exhibit altered clearance in liver disease, e.g., diazepam and
chlordiazepoxide, whereas others are unaffected, such as lorazepam,
oxazepam, and temazepam. Most psychotropic
drugs that have been studied have decreased clearance and increased
half-life in patients with liver disease, including midazolam,
triazolam, barbiturates, tricyclics, and fluoxetine. 69 However, even
if hepatic metabolism is not changed, effects of increased volume of
distribution (low albumin and ascites) and increased brain sensitivity
to sedation cannot be ignored, so that dose adjustments must be made
on an individual basis. However, the low risk of hepatotoxicity with
this class of drugs, coupled with a lack of evidence that underlying
liver disease would increase susceptibility to hepatotoxicity, should
provide reassurance that their use can follow the usual indications.
The major concern is oversedation, which must be avoided.?	

?Patients with chronic liver disease can have variably affected liver
function. In recommended dosages, most medications are safe in these
patients despite their altered metabolism and hepatic function.
However, patients with chronic liver disease may be at increased risk
for idiosyncratic drug reactions and less able to tolerate
hepatotoxicity when it occurs."

?Common drug classes with known hepatotoxicity include
antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs,
including cyclooxygenase-2 inhibitors), muscle relaxants,
psychotropics, anticonvulsants, lipid-lowering drugs, oral
antidiabetic agents, estrogens, anabolic steroids and antituberculous
agents. Drugs with a known potential for idiosyncratic reactions
include antibiotics, antifungals, antivirals, antiprotozoals and
NSAIDs? ?When treatment with a potentially hepatotoxic medication is
deemed necessary, the drug should be used with caution and under close

?Bupropion (Wellbutrin), trazodone (Desyrel), venlafaxine (Effexor),
and mirtazapine (Remeron) are a group of structurally unrelated
antidepressants that don't fit into any of the established
antidepressant drug classes of MAOIs, tricyclics, or SSRIs.?

?Wellbutrin, Effexor, Desyrel, and Remeron appear to cause fewer
serious side effects than MAO inhibitors or tricyclics. But because
these three drugs can cause a few unusual problems in some people,
chances are your psychiatrist will be far more likely to choose an
SSRI like Prozac or Zoloft at first.
The most common side effects shared by Wellbutrin, Effexor, and
Desyrel include agitation, dry mouth, insomnia, headache, nausea and
vomiting, constipation, and tremors. But many chronically depressed
people say they don't care. They're willing to pay the price of future
uncertainty to buy freedom from depression today.
"There are risks to these drugs," says Joan, whose training as a nurse
makes her more aware than most of the possible hazards. "They just
don't know what they do in the body. But after this many years of
being depressed, it's worth the risk to me. I've spent half my life in
hell, so taking a risk with antidepressants is well worth the effort.
As more years have gone by, I see the years I was depressed as wasted.
I don't want to waste any more."
?While there have been no reports that Wellbutrin caused liver damage,
animal studies have revealed a variety of liver problems with this

?Nine uncommon (<1% occurrence) but serious adverse effects were
associated with SSRIs: bradycardia, bleeding, granulocytopenia,
seizures, hyponatremia, hepatotoxicity, the serotonin syndrome,
extrapyramidal effects, and mania in unipolar depression.?

?Hepatotoxicity from serotonin reuptake inhibitors inhibitors such as
fluoxetine and paroxetine is reported but very rare?

Classes of Antidepressants:

- SSRI's (Selective Serotonin Reuptake Inhibitors)  These drugs
increase the brain's level of serotonin, thus improving mood.  SSRI's
have also been shown to be useful in the treatment of
obsessive-compulsive disorder and some forms of severe shyness.

They are generally well tolerated and effective.  Some common SSRI
side effects include: heartburn and drowsiness. They can sometimes
produce a transient loss of appetite.  SSRI medications can have drug
interactions.  You should consult with your doctor or pharmacist prior
to mixing them with other medications.

- Tricyclic Antidepressants get their name from their chemical
structure.  This class of drugs is very effective in combating
depression but is associated with troublesome side effects such as
drowsiness, dry mouth and constipation.
Tricyclic antidepressant medications can have drug interactions.  You
should consult with your doctor or pharmacist prior to mixing them
with other medications.

Other families of antidepressant drugs include the MAOI's (monoamine
oxidase Inhibitors).  MAOI's are very effective but have potentially
life-threatening drug interactions and food interactions.  If you are
taking a MAOI drug, it is important that you consult with your doctor
before you take any other medicines.  Your doctor will also tell you
which foods to avoid mixing with your medicine.
?The SSRI's, RIMA's and SNRI's are all relatively safe in overdose,
have little if any cardiotoxicity and hepatotoxicity and have little
effect on seizure threshold.?

From the FDA approved label for Lexapro
?Infrequent: decreased weight, hyperglycemia, thirst, bilirubin
increased, hepatic enzymes increased, gout, hypercholesterolemia.? 

SSRI's  include these commonly prescribed medications: 

Celexa (citalopram; Drug Family: SSRI - Forest Laboratories)

Lexapro (escitalopram HBr: Drug Family SSRI - Forest Laboratories)

Luvox (fluvoxamine; Drug Family: SSRI - Solvay)

Paxil, Paxil CR (paroxetine; Drug Family: SSRI - SmithKline)

Prozac, Prozac Weekly (fluoxetine; Drug Family: SSRI ? Lilly)

Zoloft (sertraline; Drug Family: SSRI - Pfizer)

Tricyclics (TCAs)

Amitriptyline; GENERIC (Drug Family: tricyclic - various manufacturers)

Desipramine; GENERIC (Drug Family: tricyclic - various manufacturers)

Nortriptyline; GENERIC (Drug Family: tricyclic - various manufacturers)

?The tricyclics have significant cardiotoxicity and hepatotoxicity is
not uncommon. They are dangerous in overdose and lower the seizure
threshold causing risk of seizures?
?The tricyclics have been used extensively for around forty years and
long term ill effects are remarkably absent.?

?Although other tricyclics (including amitriptyline, desipramine,
doxepin) rarely cause liver disease,
the reported cross-reactivity should preclude their use when
sensitivity to one has been suspected. Occasionally, hepatitis-like
injury has been reported with tricyclics.?
?Most tricyclic antidepressants are potentially hepatotoxic.?


Cymbalta ( Duloxetine; Drug Family: serotonin and norepinephrine uptake inhibitor )

Effexor, Effexor XR
(venlafaxine; Drug Family: serotonin and norepinephrine uptake
inhibitor - Wyeth Laboratories)

Nardil (phenelzine; Drug Family: MAOI - Parke-Davis)
Parnate (tranylcypromine; Drug Family: MAOI - SmithKline)

Remeron (mirtazepine; Drug Family: tetracyclic - Organon)

Serzone (removed from USA Market In June' 04)

Trazodone; GENERIC (Drug Family: triazolopyridine -  various manufacturers)

Wellbutrin, Wellbutrin SR ( twice a day)
Wellbiutrin XL ( Once a day)
(bupropion; Drug Family: aminoketone - Glaxo)

MAOIs (Monoamine Oxidase Inhibitors)

?Hepatic injury caused by the MAOIs is characteristically
hepatocellular and has the potential to progress to severe liver
necrosis. These hepatic injuries are usually caused by the hydrazine
MAOIs, i.e., phenelzine and isocarboxazid. Current evidence suggests
that hydrazine-linked liver damage results from a toxic metabolite
that is generated in rare susceptible individuals. It is hypothesized
that the toxicity may be related to the patients acetylator phenotype.
Women and the elderly may be more susceptible. The toxicity presents
as an acute or subacute hepatic necrosis with varying degrees of
cholestasis after 1-6 months of treatment with symptoms that include
anorexia, weakness, malaise, and jaundice of an insidious onset. The
bilirubin is elevated, AST and ALT are 8-10 times normal, and the
alkaline phosphatase is only slightly elevated. A bilirubin of > 20 mg
% is a bad prognostic marker. Fatalities occur in one in 5 effected
patients (Zimmerman and Ishak 1987).?

?MAO Inhibitors. MAO inhibitors, which derive from hydrazine, are all
potential hepatotoxins. The experience with one, iproniazid, was
disastrous: overt hepatitis occurred in 1% with case fatalities
approaching 20%,32 and the drug was withdrawn. Hydrazines can be
metabolized by P450 to toxic
intermediates. Their metabolism and mechanism resemble that of
isoniazid, also a hydrazine. One substituted hydrazine MAO inhibitor
remains available, namely phenelzine; there have been case reports of

The FDA?s consumer information sheet on  Celexa makes no mention of hepatotoxicity

However, the FDA approved label does state ?Infrequent: increased
hepatic enzymes, thirst, dry eyes, increased alkaline phosphatase,
abnormal glucose tolerance. Rare: bilirubinemia, hypokalemia ,
obesity, hypoglycemia, hepatitis, dehydration.?

?Selective serotonin reuptake inhibitors seemed to be better tolerated
than tricyclic antidepressants in this general practice observational
study. Despite methodological limitations of the study the results may
have important implications for cost effectiveness. A prospective
cohort study to examine the clinical and economic consequences of
differences in discontinuation rates and switches is required.?

Side Effects of Lexapro,3997,551371,00.html?DVHName=Lexapro

Side Effects of Effexor,3997,700,00.html?DVHName=Effexor

Side Effects of Paxil,3997,520,00.html?DVHName=Paxil

Side Effects of Wellbutrin,3997,88,00.html?DVHName=Wellbutrin

Side Effects of Desyrel,3997,678,00.html?DVHName=Desyrel

Side Effects of Zoloft,3997,606,00.html?DVHName=Zoloft

Side Effects of Celexa,3997,716,00.html?DVHName=Celexa

Side Effects of Prozac,3997,275,00.html?DVHName=Prozac

Nefazodone (Serzone) Now off the US market
This drug is contraindicated in anyone with liver disorders, and no
clinical trials have been run to compare it with SSRIs.

?Hepatotoxicity Associated With the New Antidepressants 
García-Pando AC, del Pozo JG, Sánchez AS, et al. 
Background: Safety profiles of classical and new antidepressants are
well established. Hepatotoxicity is known to occur. Recently, several
cases of severe hepatic injury associated with the new antidepressants
have been reported, prompting us to quantify this risk. Method: To
estimate the cumulative incidence of hepatic adverse reactions
associated with antidepressants, we used cases of hepatic damage
collected via spontaneous reporting and included in the Spanish
Pharmacovigilance System database; for exposure, we have used data
from drug sales to the Spanish National Health System. Results: The
estimated reported incidence did not show major differences for the
antidepressants studied, ranging from 1.28 cases per 100,000
patient-years for sertraline to 4.00 for clomipramine, except for
nefazodone, which was the agent that had the highest incidence with
28.96 cases per 100,000 patient-years. Conclusion: The reported
incidence of hepatic adverse reactions to nefazodone seems to be
higher than that estimated so far. Given the high prevalence of
depression and the widespread use of antidepressants, physicians
should be alert to the possibility that these medications cause
hepatitis and consider early discontinuation of an antidepressant if
the condition is suspected.?
(J Clin Psychiatry 2002;63:135-137)
Page 2

?The US Food and Drug Administration (FDA) recently included a black-box warning
in Serzone?s package insert, stating that the reported rate in the
United States of liver failure resulting in death or liver
transplantation is about 1 case per 250 000?300 000 patient-years of
Serzone treatment. This rate is about 3?4 times the estimated
background rate of liver failure. It is possibly an underestimate of
true risk because of underreporting?

?Although the reported rate in the United States is about one case of
liver failure resulting in death or transplant per 250,000 to 300,000
patient-years of nefazodone treatment, clinicians still need to
consider this warning when using this medication (Aranda-Michel et
al., 1999; Carvajal et al., 2002; FDA, 2002). In addition,
nefazodone's profound inhibitory effects on CYP 3A4 (PDR, 2003) cannot
be overlooked.?

Additional Information

Drug Digest has a handy tool to let you enter a drug and see
interactions with other drugs.,4109,,00.html

An excerpt on the metabolism of  newer antidepressants

Hepatotoxicity and newer antidepressants

It seems the best information is costly! Here are articles for purchase:

If you have access to a medical library or a subscription to the
American Journal of Psychiatry, this article appears to be useful to
Hepatotoxicity Related to Citalopram
LÓPEZ-TORRES et al. Am J Psychiatry.2004; 161: 923-924.
For $15, you can have access to the article for 24 hours.

Acute and clinically relevant drug-induced liver injury: a population
based case-control study
?Idiopathic, acute and clinically relevant liver injury, which has the
use of drugs as the most probable aetiology, is a rare event in the
general population. The relative risks of 40 drugs/therapeutic classes
are provided, along with the crude incidence rates for 15 of them
where a statistical association was found.?
$38.40 to purchase the entire article.

?To review the risk of liver toxicity related to major
antidepressants, the authors have followed structural criteria
focusing on the underlying mechanism presumably involved and the role
of particular chemical structures. The clinicopathological expression
goes from transient increases in liver enzymes to fulminant liver
failure. Classical antidepressants such as monoamine oxidase
inhibitors (MAOIs) or tricyclic antidepressants (TCAs) seem to have
the highest potential to induce liver damage compared with the newer
drugs such as selective serotonin re-uptake inhibitors (SSRIs). The
potential for severe hepatotoxicity associated with nefazodone is
stressed. Guidelines for therapy and prevention of
antidepressant-induced hepatotoxicity are also discussed.? $65

Page 3



?Try an SSRI or bupropion SR. These appear to be the best medications
(with the least side effect burden) for pure dysthymia (and presumably
its variants), major depression without melancholia, and major
depression with melancholia that is not severe.?

Cytochrome P450 and Drug Metabolism
These antidepressants are CYP2D6, a form of cytochrome P450 inhibitors
Paroxetine > fluoxetine > 
sertraline (Zoloft) > fluvoxamine 
Nefazodone (Serzone),
Venlafaxine > clomipramine 
(Anafranil) > amitriptyline

?Approximately 7 to 10 percent of Caucasians are poor metabolizers of
drugs metabolized by CYP2D6.10 Individuals with normal CYP2D6 activity
are termed extensive metabolizers. Ethnic differences are indicated in
this genetic polymorphism, since Asians and blacks are less likely
than Caucasians to be poor metabolizers.11,12 Poor metabolizers are at
risk for drug accumulation and toxicity from drugs metabolized by this
?Many antidepressants are metabolized by CYP2D6, but other cytochrome
P450 isoforms can also contribute to their metabolism (Tables 1
through 6). The clinical importance of this "dual metabolism" will be
illustrated later. With respect to drugs inhibiting CYP2D6, cimetidine
(Tagamet), the selective serotonin reuptake inhibitors (SSRIs) and
some tricyclic antidepressants function as inhibitors of this P450
isoform.17-19 Of the antidepressants, paroxetine (Paxil) appears to
have the greatest ability to inhibit the metabolism of CYP2D6
substrates. This is followed by fluoxetine (Prozac) and norfluoxetine;
sertraline (Zoloft) and desmethylsertraline; fluvoxamine (Luvox),
nefazodone (Serzone) and venlafaxine (Effexor); clomipramine
(Anafranil), and amitriptyline (Elavil).19 This ranking is based on in
vitro data, however, and the choice of an antidepressant should be
based on factors other than the propensity to inhibit CYP2D6. Although
sertraline appears to be less likely than the other SSRIs to inhibit
CYP2D6, inhibition may still occur at doses greater than 50 mg. The
clinical significance of the inhibition of tricyclics by SSRIs or
cimetidine is subject to variation in enzyme activity between
individuals, the degree to which the patient metabolizes and
co-ingestion of other enzyme inhibitors.?

To summarize, if it were up to me,(and it is not), I would select
Lexapro (escitalopram) as the safest antidepressant. TCAs and MAOIs
have far more effects than SSRIs. You should discuss this with your
doctor, however. Factors such as  a person?s age, overall health,
other medications to be taken concurrently, and even race, will
determine which antidepressant would be best for you. I have known
patients who have previously had hepatitis take Lexapro with no sign
of hepatotoxicity. No drug is completely free of side effects, some of
which manifest themselves more so in some patients. Your doctor can
decide, with your input, on a course of therapy for you.

On  Lexapro:
?Safety: To date, no serious adverse effects have been associated with
escitalopram. One study demonstrated a slightly greater likelihood of
activation of mania/hypomania in the treatment group as compared with
the placebo group (0.1 percent versus zero percent). Therefore, as
with other antidepressants, escitalopram should be used with caution
in patients with a history of mania or hypomania. Escitalopram has not
been evaluated in patients with seizure disorder or in patients with
recent myocardial infarction or unstable heart disease. Because
escitalopram has weak or negligible effects on the cytochrome P450
system, the potential for drug interactions is low. However, as with
other SSRIs, escitalopram should not be used in combination with a
monoamine oxidase inhibitor (MAOI), or within 14 days of discontinuing
an MAOI. It also should not be given with citalopram because it is the
active isomer of that drug. Escitalopram is classified in pregnancy
category C, and there have been no studies evaluating the risk of its
use in nursing mothers.?

?In healthy volunteers and in patients escitalopram did not cause
clinically significant changes in vital signs, ECGs, or laboratory
Escitalopram is metabolised in the liver to the demethylated and
didemethylated metabolites. Alternatively, the nitrogen may be
oxidised to form the N-oxide metabolite. Both parent and metabolites
are partly excreted as glucuronides. Unchanged escitalopram is the
predominant compound in plasma. After multiple dosing the mean
concentrations of the demethyl and didemethyl metabolites are usually
28-31% and <5% of the escitalopram concentration, respectively.
Biotransformation of escitalopram to the demethylated metabolite is
mediated by a combination of CYP2C19, CYP3A4 and CYP2D6.
The elimination half-life (t½ ?) after multiple dosing is about 30
hours and the oral plasma clearance (Cloral) is about 0.6 L/min.
Escitalopram and major metabolites are - like racemic citalopram -
assumed to be eliminated both by the hepatic (metabolic) and the renal
routes with the major part of the dose excreted as metabolites in
urine. Hepatic clearance is mainly by the P450 enzyme system.
The pharmacokinetics of escitalopram are linear over the clinical
dosage range. Steady state plasma levels are achieved in about 1 week.
Average steady state concentrations of 50 nmol/L (Range 20 to 125
nmol/L) are achieved at a daily dose of 10 mg.

Reduced hepatic function

There is no data on the use of escitalopram in reduced hepatic
function. However, based on data for racemic citalopram, escitalopam
is expected to be eliminated more slowly in patients with reduced
hepatic function. The half-life of escitalopam is expected to be about
twice as long and steady state escitalopam concentrations at a given
dose will be about twice as high as in patients with normal liver

Reduced renal function

While there is no specific data, the use of escitalopram in reduced
renal function may be extrapolated from that of racemic citalopram.
Escitalopam is expected to be eliminated more slowly in patients with
mild to moderate reduction of renal function with no major impact on
the escitalopram concentrations in serum. At present no information is
available for the treatment of patients with severely reduced renal
function (creatinine clearance < 20 mL/min).

I hope my answer has enabled you to distinguish the adverse effects of
various antidepressants. Please request an Answer Clarification before
rating this answer, if anything is unclear. Doing so will enable me to
assist your further, if possible.


Search Terms
Psychotropic drugs + hepatotoxicity
Psychotropic drugs + adverse effects
incidence hepatotoxicity + antidepressants
hepatotoxicity + ssri
compare hepatotoxicity ssri
compare hepatotoxicity anti-depressants
ssri + adverse effects
comparing side effects antidepressants
comparing hepatotoxicity antidepressants
SSRI caused hepatotoxicity
Effects psychotropic drugs  liver

Clarification of Answer by crabcakes-ga on 13 Jan 2005 16:16 PST
It's me again! I really CAN spell "qualified"! Sorry for the typo--I
get fumblefingered at times!


Request for Answer Clarification by carlotta-ga on 13 Jan 2005 19:21 PST
I won't have a chance to look at this closely until tomorrow morning,
but from even a quick look I get the impression that you, like me,
weren't able to find what one would have thought would be easy to
find, as it would be so obviously useful:

Column 1: name of anti-depressant 
Column 2: incidence of reported problems*

*not report totals, incidence.

Or, alternatively, a classification just fine enough that is doesn't
assign the same description ("rare"!!!) to *every* single SSRI! (are
we in Lake Wobegon?)

Or at the very least some expert saying, recently: hey, to minimize
liver risk I'd go with... or ...

Grrr. If I were a MD in a rush to make a prescribing decision I'd be
pretty irritated after plowing through though these promising but in
the end mostly really unhelpful articles. But this isn't your (the
researcher's) fault, just the way it is.  They all sound like they are
going to be helpful, but then in the end just tell you to be careful,
be aware, investigate, etc.   That's disingenuous, at best.  (Again, I
mean of them of course not you).

Anyway I'll sit down and look more closely tomorrow and try to follow
some of the references to licensed artices if I can.  A couple of
those do have promising titles.

(apologies if "request for answer clarification" isn't supposed to be
used for general comments; I'm new to this)

Request for Answer Clarification by carlotta-ga on 13 Jan 2005 19:26 PST
me again.  Wish I had started by saying Thanks!  And especially thanks
for being so quick.

Clarification of Answer by crabcakes-ga on 13 Jan 2005 19:39 PST

   Take your time reviewing the answer--there is no rush!  :-)

  You placed your clarification exactly where it should go. We do not
get notification of "comments" but we are made aware of

  I honestly believe a better chart is not available for free, if
indeed such a thing exists. I also believe since SSRIs are not known
for causing liver damage, there is not a perceived reason to run
comparison studies. Personally, I would be more fearful of taking
acetaminophen than an SSRI! I've witnessed the effects of
acetaminophen on livers.

"The danger of hepatotoxicity in association with acetaminophen use
has been well recognized.  Acetaminophen induced hepatotoxicity is
caused by a toxic metabolite of the parent compound and can lead to
liver failure, which may result in liver transplant or death.  The
purpose of the advisory committee meeting was to review the data on
unintentional overdose and determine whether additional measures
should be taken to decrease the risk of these events."

It took me just two minutes to locate the above links. In contrast, it
took me over 5 hours to ferret out what I found on antidepressants.  I
will continue seeking more data for you, but am doubtful I'll find


Clarification of Answer by crabcakes-ga on 13 Jan 2005 19:51 PST
Apparently, clinical trial data was not released, at least not in totality!

I'm still searching!


Request for Answer Clarification by carlotta-ga on 13 Jan 2005 20:13 PST
Right.  the incidence is low, and the problem is "idiosyncratic".
So at the general public health level it isn't much of a problem at all.
But as you know from the searches every SSRI seems
to have confirmed serious hepatotoxicity incidents, and the
rates do seem to vary. 

So if one wanted to adapt a therapy to a case, as some of
general suggest one ought, finding an SSRI whose
incidence of hepatoxicity is low sounds like the thing to do.
Only, from what I can tell so far, it can't be done.

Clarification of Answer by crabcakes-ga on 13 Jan 2005 21:59 PST
  This is not useful to you, but I'm posting this weel done article to
emphasize how there is a dearth of hepatotoxicity data about

This chart is only slightly better than the ones in the original answer

I'm calling it a night, but if I should happen across this Holy
Hepatotoxicity Grail of Antidepressants, I will post, post haste.


Clarification of Answer by crabcakes-ga on 14 Jan 2005 14:09 PST

PAges 41-44 have some information on SSRIs and liver enzymes.

2 SSRIs are implicated in hepatic function on this chart

 Antidepressant-induced hepatotoxicity, $65 USD

General Information.

I have to conclude that the lack of hard data on hepatotoxicity is, at
least partially, due to the fact that it is not a huge concern of most
SSRIs. Becoming suicidal with some antidepressants is the main
concern, followed by cardiotoxicity and whether a drug crosses into
breast milk.


Additional Search Terms
hepatic dysfunction + antidepressants
hepatotoxicity + statistics + antidepressants
antidepressants + table + hepatotoxicity

Request for Answer Clarification by carlotta-ga on 14 Jan 2005 20:00 PST
Thanks for these last bits.  The weather kept me away from work, where
I could follow links to licensed databases. I'll do that tomorrow
though, or Sunday.  I'll report on what I find there in an answer
clarification before I wrap everything up.  -- Carlotta

Clarification of Answer by crabcakes-ga on 14 Jan 2005 21:51 PST
Hello Carlotta,

I found more reading for you tonight:
"As all of the SSRIs are extensively metabolized in the liver, they
must be used with caution in "those with liver dysfunction". That is,
people already having liver disorders. Page 6 shows a table of some
SSRIs and their effect on liver cytochrome enzymes.

"Although SSRI overdose can cause toxic effects, fatality rates are
substantially lower than with TCA overdose. The drugs have varying
potential for drug interactions via hepatic cytochrome P450 enzymes,
with escitalopram (Lexapro)having the lowest potential for


Clarification of Answer by crabcakes-ga on 15 Jan 2005 11:10 PST
Content and Format of the Adverse Reactions Section of Labeling for
Human Prescription Drugs and Biologics

"In general, there is no need to present less informative data in a
table. For example, if placebo-controlled data are adequate, there is
no need to present active-controlled data, single-arm trial data or
the overall database in a table, even if they are larger databases. If
lower quality data sources contribute a critical element not found in
the more rigorous trials (e.g., prolonged duration of therapy or
important comparative data on a specific adverse reaction), these data
can be discussed in the commentary subsection following the table (see
section II.B.5; see section III for specific guidance on presenting
adverse reaction data in a table)." Scroll almost to the middle of the

"The ADVERSE REACTIONS section should also discuss significant adverse
reactions that occur less commonly than those presented in the table
or tables (i.e., at rates below the frequency cut-off for inclusion in
the table). These reactions may be identified from any source in the
overall safety database or from spontaneous reports received after the
drug has been marketed. Long and exhaustive lists of adverse events,
including those that are infrequent, commonly observed in the absence
of drug therapy, or not plausibly related to drug therapy, should be

Because it is very difficult to establish that very low frequency
adverse events are caused by a drug, events included should be limited
to those that are serious, that are typical of drug-induced reactions
(e.g., liver necrosis, agranulocytosis, Stevens-Johnson syndrome),
that have a relatively strong causal relationship, such as a positive
re-challenge, or that are particularly plausible in light of the
drug_s pharmacology. In general, events that would be expected to
occur in the observed or studied population at a similar frequency
absent drug therapy (e.g., acute infarctions in the elderly,
palpitations, upper respiratory infections, minor symptomatic
complaints such as headaches, diarrhea, nausea, and dry mouth) should
be omitted. In contrast, events that are serious but very unusual in
the absence of drug therapy (e.g., liver failure, agranulocytosis,
significant hemolytic anemia, thrombocytopenia, rhabdomyolysis,
idiopathic thrombocytopenic purpura, intussusception, acute renal
failure) should be included, even if there are only one or two
Subject: Re: Antidepressant and liver
From: sgopal-ga on 27 Mar 2005 06:56 PST
> I won't have a chance to look at this closely until tomorrow morning,
> but from even a quick look I get the impression that you, like me,
> weren't able to find what one would have thought would be easy to
> find, as it would be so obviously useful:
> Column 1: name of anti-depressant 
> Column 2: incidence of reported problems*
> *not report totals, incidence.

Well let me try to explain the reason why this information will never
be publicly available.

- To calculate incidence, you generally need to know the # of events over time. 
- Most clinical trials submitted to the FDA are placebo controlled and
generally SHORT term (usually 6-8 weeks).
- Severe liver injury or hepatitis does generally NOT appear to any
great extent in such short term studies.
- Long term studies generally are NOT placebo controlled and
considered to be "open-label"
- Incidence rates can be calculated in open-label trial but they are
not meaningful because there is no placebo group.

The FDA makes most drug companies do some sort of pooled analysis on
liver damage whenever they submit a new NDA, but again the # of
patients are fairly limited (no more than 1000-2000 patients per NDA).
This type of information is confidential and generally not released
publicly by the FDA (it can be obtained by FOI or subpoena but is not
an easy process)

To see a rare event like liver failure, you would need hundreds of
thousands of patients exposed for long term before you saw a signal.
These type of studies are known as "epidemiologic" and by nature are
not placebo controlled. Since epidemiologic studies take a long time
to do, and cost a lot of money, there aren't that many of them being
done. Thats why in the package insert of most SSRIs you simply see a
case count, without relative incidence compared to placebo.

One alternative to getting at your question is to see if there were
any "meta-analyses" or compilation works of different SSRI trials
together by a scientific organization. The Cochrane Collaboration is
one such place that I know of which does these sort of things.

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