646234

research-article2016
APY0010.1177/1039856216646234Australasian PsychiatryParker

Australasian
Regular Article Psychiatry
Australasian Psychiatry

Managing patients who are 2

1
The Royal Australian and
New Zealand College of Psychiatrists 2016

ultra-rapid metabolisers of Reprints and permissions:

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DOI: 10.1177/1039856216646234
antidepressant medications apy.sagepub.com

Gordon Parker Scientia Professor, School of Psychiatry, University of New South Wales, Sydney, NSW, and; Professorial
Fellow, Black Dog Institute, Prince of Wales Hospital, Randwick, NSW, Australia

Abstract
Objective: The objective of this study was to increase recognition of ultra-rapid metabolising status as a cause of
treatment-resistant depression and consider management options.
Conclusions: The incidence of ultra-rapid metabolising status is not rare in patients who fail to report improvement
with antidepressant medication. Two broad options are available for identifying ultra-metabolising status. While
there are several management options available to the clinician, combination therapy is likely of low utility while
there are risks associated with mega-prescribing. As the literature is limited, clinician observations about alternate
strategies would be welcomed.

Keywords: ultra-rapid metabolising status, genotyping, treatment-resistant depression

W
hile there are many reasons for patients fail-
ing to respond to antidepressant medication,
one ultra-rapid metabolising status is
particularly worthy of recognition as it potentially able
to be addressed if identified. The phenomenon tends
to be rarely discussed by clinicians or considered in the
literature, raising questions as to whether it is commonly
suspected in formulating reasons for a treatment-resist-
ant depressive disorder. In addition, options for attempt-
ing to redress it are rarely considered in the literature.
As detailed by Laine et al.,1 the ultra-rapid metaboliser
phenotype was originally described in the early 1990s,
reflects the impact of multiple active CYP2D6 alleles and,
while ranging widely in its prevalence across differing
races, is estimated to affect 15% of Caucasians and up to
30% of some other races. Thus, it is unlikely to be a rare
clinical phenomenon, although rates would be expected
to be higher in psychiatric than in primary physician
practice and highest in psychiatric facilities weighted to
those with a generic diagnosis of treatment-resistant
depression, as those with such a condition would be
expected to be referred to more specialised services. It is
particularly worthy of consideration in those with a
melancholic depression where, in my view, antidepres-
sant medication is the principal treatment modality.
There is one key clinical indicator of the possibility. In
addition to the patient reporting a failure to respond to
several or multiple antidepressant medications of differing
classes, the most useful diagnostic signal in my view is the
patient reporting no side-effects to recommended doses
of all or nearly all antidepressants trialled. When further
questioned, a percentage will affirm failing to obtain ben-
efits from analgesic medication, especially codeine.
This sparse overview is designed both to determine how
to clarify such a possibility and to consider management
options. In reviewing the literature the most distinctive
impression was the paucity of papers on the topic. The
most informative overview found was a paper published
by Kraus et al. nearly two decades ago.2 The current
paper therefore builds on that paper and several other
reports, while adding personal observations in relation
to patients with melancholic depression.
Clarification of metabolising status might ideally emerge
from drug-gene testing. Two cytochrome P450 (CYP)
liver enzymes (CYP2D6 or 2D6 and CYP2C19 or C19)
metabolise most antidepressant medications and their
genotyping might ideally identify rapid or ultra-rapid
metabolisers. In the last decade a number of genotyping
tests have been developed. In 2004, the US Food and
Drug Administration approved the AmpliChip CYP450
test. This test, as for other relevant genotyping tests,
assesses both the CYP2D6 and CYP2C19 genotype but
not the phenotype, and thus disallows or compromises
precision in application. This is understandable when, as
De Leon et al. have noted,3 the activity of the 2D6
enzyme is extremely variable due to it having more than
50 genetic variations, while ultra-rapid metabolisers have
three or more copies of the active 2D6 gene, helping to
explain why some 80% of ultra-metabolisers are missed
by genetic testing.
Corresponding author:
Gordon Parker, Black Dog Institute, Prince of Wales Hospital,
Randwick, NSW 2031, Australia.
Email: g.parker@unsw.edu.au

1
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A second option nominated by Kraus et al. (and one which
I find more useful clinically than pharmacogenetic testing)
for determining whether a patient is an ultra-rapid metab-
oliser is to test the serum level of a tricyclic antidepressant
(TCA),2 as the serum level of most other antidepressant
medications has not been shown to correlate with the
drugs concentration in the brain,4 and therefore not cor-
relate with clinical efficacy. Thus, my practice is to com-
mence a patient suspected as being a rapid metaboliser on
a TCA (if they are not already receiving one) and, once a
daily dose of 150 mg has been achieved, undertake a serum
tricyclic level. If the serum level is low and all other clinical
markers are supportive of the likelihood that the patient
has ultra-rapid metabolising status (and, for tricyclic medi-
cations, reflecting 2D6 status principally), the first clinical
task is to determine if the patient is taking any other medi-
cations known to quicken cytochrome isoenzyme activity
such as phenytoin) and determine if any such medications
can be withdrawn or substituted to redress the problem.
In terms of managing such patients, De Leon et al. sug-
gested that patients identified as CYP2D6 ultra-metabolis-
ers are likely to have low plasma levels of TCA and perhaps
of venlafaxine,3 and therefore their treatment should pri-
oritise antidepressants not dependent on CYP2D6 (e.g.
bupropion, citalopram, escitalopram, sertraline, mirtazap-
ine). I have not so used bupropion but have had little suc-
cess with the other four antidepressant medications.
I generally favour using a TCA, however, as the primary
antidepressant in those with ultra-metabolising status as
I can monitor the serum level in conjunction with
assessing clinical progress. This generally involves
increasing the dose of the tricyclic slowly but consider-
ably beyond the general endpoint of 150 mg/day, and
often in collaboration with a cardiologist. In several of
my patients the tricyclic dose has reached 600 mg/day
before the serum level is near to or within the clinical
range, and which is generally required before the patient
reports some degree of improvement and, rarely, remis-
sion. In some patients such a dose remains associated
with a sub-threshold serum level. Kraus et al. detailed
this as one of two strategies that can be employed,2 but
observed that this strategy (of megaprescribing) can be
hazardous in that metabolites of the antidepressants
(especially hydroxylated compounds) can, while not
contributing to the efficacy (or here inefficacy) of the
antidepressant, lead to cardiac and neurological toxicity.
A second strategy considered by Kraus et al. is to inhibit
the enzymatic metabolism of the antidepressant,2 so as to
create an increased concentration of the active drug and a
decreased concentration of the hydroxymetabolites.
Those authors nominated several drugs and compounds
having that propensity, in particular, two serotonin reup-
take inhibitors (i.e. fluoxetine and paroxetine). In their
own study they reported on 12 patients who were identi-
fied as rapid metabolisers and who were prescribed desip-
ramine and then subsequently had either fluoxetine or
paroxetine added, with the combination being well toler-
ated, with ten achieving a desipramine level in the thera-
peutic range and with seven of those ten having an
2
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Australasian Psychiatry
excellent or good sustained response. Laine et al. simi-
larly reported that the addition of paroxetine (2040 mg/
day) to the TCA nortriptyline resulted in therapeutic lev-
els being reached in four of five subjects who were ultra-
rapid metabolisers (and with many then reporting distinct
side effects),1 but without the authors reporting on the
clinical improvement rate. However, in my clinical prac-
tice this option has had a very low success rate.
In recent years I have been impressed by the potential of
the psychostimulants (i.e. methylphenidate, dexam-
phetamine) to augment a primary antidepressant drug
in those with melancholic depression. In one report,5
there was an impact of the psychostimulant on TCA lev-
els in one of two patients who were identified as rapid
metabolisers. One patient had a 0.54 serum level of nor-
triptyline (laboratory range being 0.190.57) when
receiving 250 mg/day of the TCA medication and
reported minimal side-effects. When methylphenidate
was introduced (1020 mg/day) and while the TCA was
maintained at the same dose his mood improved rap-
idly and he developed distinct TCA side-effects, and
with his serum TCA level having effectively doubled to
1.06. Subsequently, however, I have so tested three other
patients with a rapid metabolising profile and with none
having an increase in their base serum TCA level after
methylphenidate augmentation.
In conclusion, rapid and ultra-rapid metabolising status
should be considered in patients reporting failure to
respond to antidepressant medication and, especially
when they also fail to observe any drug side-effects.
While there are several options available for clinicians
this overview finishes with a cri de Coeur. In essence,
while the literature suggests several strategies, their
probability of success is, at least by my observations,
relatively low. It would be important if other clinicians
have found and could report alternative strategies to
those few options reported in small case studies.
Acknowledgement
Research assistance was provided by Georgia McClure.
Disclosure
The author reports no conflicts of interest. The author is responsible for the content and the
writing of the paper.
Funding
This work was supported by an NHMRC Program Grant (grant number 1037196).
References
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oxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline
pharmacokinetics and the debrisoquin test. Clin Pharmacol Ther 2001; 70: 327335.
2. Krause RP, Diaz P and McEachran A. Managing rapid metabolizers of antidepressants.
Depression Anxiety 1997; 4: 320327.
3. De Leon J, Armstrong SC and Cozza KL. Clinical guidelines for psychiatrists for the use of phar-
macogenetics testing for CYP450 2 D6 and CYP450 2C19. Psychosomatics 2006; 47: 7585.
4. Linder MW and Keck PE. Standards of laboratory practice: antidepressant drug monitor-
ing. Clin Chem 1998; 44: 10731084.
5. Parker G and Brotchie H. Do the old psychostimulant drugs have a role in managing
treatment-resistant depression? Acta Psychiatr Scand 2010; 121: 308314.