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Duloxetine-mirtazapine combination in depressive illness: The case for

Limerick 'rocket fuel'

Article  in  Irish journal of psychological medicine · September 2006

DOI: 10.1017/S0790966700009782

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 Case report
Duloxetine-mirtazapine combination in
depressive illness: The case for Limerick
‘rocket fuel’
David Meagher, Noel Hannan, Maeve Leonard
Abstract
The use of complex psychopharmacological regimens is
increasingly advocated in more difficult to treat depressive
illness. The combination of venlafaxine with mirtazapine –
‘California rocket fuel’ is one such example involving an
SNRI combined with a NaSSA. We describe two cases that
highlight the potential usefulness of duloxetine used in
combination with mirtazapine that also emphasise the
danger of drug-induced hypomanic switching. This
combination may have a specific role for carefully selected
patients but caution is needed given the potential to induce
profound alterations in mental state.
Key words: Duloxetine; mirtazapine; antidepressant;
depression; hypomanic switch; combination; treatment;
adverse effects.
Introduction
Patients with depressive illness frequently do not achieve
an adequate response to their initial antidepressant treat-
ment. Clinical response (a reduction of at least 50% in
HAMD score) occurs in up to two-thirds but clinical remis-
sion (HAMD total score of seven or less) occurs in only one
third of cases.1-3 Dose escalation, switching antidepressant,
and combination or augmentation strategies are therefore
frequently needed. Complex psychopharmacology regimes
are increasingly recognised in more difficult to treat depres-
sive illness.4,5 Stahl6 highlighted the theoretical potential of the
‘heroic’ combination of venlafaxine and mirtazapine (so-called
‘California rocket fuel’) to boost monoamine neurotransmis-
sion by a combination of re-uptake inhibition and central
alpha-2 blockade. This combination is increasingly utilised in
clinical practice with evidence suggesting that it is more
effective than mirtazapine augmentation of SSRI’s7,8 has a
faster onset of action and shorter time to recovery than
mirtazapine augmentation of fluoxetine,8 and is generally well
tolerated.7-11 However, a significant number of patients cannot
tolerate this combination due to adverse effects and the
combination of an alternate SNRI with mirtazapine may be a
suitable option in such cases. We describe two cases involv-
*David Meagher, MD, MSc, DPM, MRCPsych, Noel Hannan,
MB, BCh, Maeve Leonard, MB, MRCPsych, Department of
Adult Psychiatry, Midwestern Regional Hospital, Limerick, Ireland.
*Correspondence
SUBMITTED: MARCH 21, 2006. ACCEPTED: JUNE 22, 2006.
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Ir J Psych Med 2006; 23(3): ??-??
ing the use of duloxetine with mirtazapine to treat depressive
illness that were characterised by markedly different
outcomes.
Case A
Mrs A, a 46 year old married lady was referred with a one
year history of persistent depression characterised by low
mood, anhedonia, middle insomnia, and generalised anxiety.
These difficulties occurred in the context of chronic low back
pain. She had no prior psychiatric history but family history
was positive for depression. At referral she had been receiv-
ing tramadol hydrochloride for low back pain as well as
venlafaxine for 16 weeks (12 weeks at 150mg/day and four
weeks at 225mg per day). Despite good compliance, depres-
sive symptoms continued to escalate culminating in suicidal
ideation.
Upon psychiatric review, in view of the prominent insomnia
and nausea, venlafaxine augmentation with mirtazapine 15mg
was preferred to continued monotherapy with venlafaxine at
higher dose. She experienced a partial response over the
following weeks until mirtazapine was further increased to
30mg whereupon depressive symptoms resolved. At subse-
quent reviews she complained of persistent nausea and
venlafaxine was gradually withdrawn and treatment continued
with mirtazapine 30mg as monotherapy. Soon after she expe-
rienced a depressive recurrence with marked suicidal
ideation. Duloxetine 60mg was added and over the ensuing
three weeks depressive symptoms settled. Nine months later
Mrs A remains well on a combination of duloxetine 60mg with
mirtazapine 30mg.
Case B
Mr B, a 46 year old single man had been treated with a
variety of antidepressant agents for recurrent depressive
disorder over the previous two decades. He had comorbid
alcoholism but no history of hypomania. There was no known
family history of bipolar illness. Mr B had previously experi-
enced a limited response to SSRI’s (fluoxetine, paroxetine)
and although responded well to dothiepen, experienced
excessive somnolence. A trial of venlafaxine was discontin-
ued due to an allergic rash. Duloxetine 60mg was
commenced but after six months he experienced break-
through depressive symptoms with marked insomnia in the
context of a number of significant life stressors. An increase
in duloxetine dose to 90mg had little impact and mirtazapine
15mg was added.
One week later the patient presented in an agitated state
with pressurised speech, racing thoughts, reduced sleep

requirement, elated mood, and a range of grandiose delu-
sional ideas regarding the health services. The patient was
admitted to hospital, antidepressant medications were
discontinued, and he was commenced on risperidone 4mg
per day. After a week the patient’s mental state settled with
a return to normothymia. A subsequent collateral history
revealed that the patient had been doubling the dose of
mirtazapine (ie. 30mg) as well as a previously unidentified
family history of bipolar disorder.
Discussion
These two cases highlight the potential effects of duloxe-
tine and mirtazapine used in combination in the treatment of
depressed mood. While the SNRI-NaSSA combination was
associated with a specific and substantial therapeutic
response in patient A, the initiation of combination treatment
was followed by a hypomanic switch in patient B.
The management of case A was somewhat atypical in that
venlafaxine was initiated without a prior trial of an SSRI.
Recent NICE guidelines5 advocate SSRI’s as first line in the
treatment of depressive illness but it is not uncommon for
specialist mental health practitioners (including general prac-
titioners with a particular interest in mental health) to proceed
directly to potent therapies in more severe cases. The inter-
pretation of case A is also complicated by the concomitant
use of tramadol for analgesia. This synthetic analogue of
codeine is an opioid receptor agonist and a weak inhibitor of
serotonin and noradrenaline re-uptake.12 Although the poten-
tial antidepressant effect of tramadol in humans remains
undemonstrated, it has been shown to produce antidepres-
sant-like effects on monoamine function in rats13 and has
been linked to serotonin syndrome when combined with
venlafaxine and mirtazapine.14 In patient A the use of tramadol
did not appear to greatly influence depressive symptoms
possibly due to the relatively low dose used and /or because
the degree of serotonin and noradrenaline re-uptake inhibi-
tion produced by tramadol is insufficient to achieve the
desired antidepressant synergy.
Where gastrointestinal or other side-effects limit the upper
dose of venlafaxine treatment, mirtazapine augmentation may
additionally boost monaminergic neurotransmission allowing
symptom resolution. Moreover, where insomnia is a particu-
lar problem, addition of mirtazapine may be preferable to
further escalation of venlafaxine dose and / or use of an alter-
nate hypnotic stategy. The temporal relationship between
treatment and symptom response described in patient A
suggests a specific response to SNRI-NaSSA combination
therapy, where neither agent class alone controlled depres-
sive symptoms.
Case A suggests that duloxetine is an effective alternative
to venlafaxine where combination therapy is required. The
limited work to date comparing these agents suggests simi-
lar efficacy and side-effect profiles.15 The role of duloxetine in
depressive illness that has not responded to SSRI’s remains
unclear, although preliminary work suggests that the
response rate is similar to that observed in studies of
venlafaxine with a clinical response noted in approximately
60% of patients.16-18 The relatively greater affinity of duloxe-
tine for the noradrenergic transporter molecule19 may confer
a particular suitability where lower SNRI dose is desired.
Equally, this property may be linked to the risk of inducing
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Ir J Psych Med 2006; 23(3): ??-??
hypomanic switch, noted in Case B. Such shifts in mental
state are incompletely understood but appear less common
with SSRI’s compared to agents with broader neurochemi-
cal actions and may represent a syndrome of noradrenergic
instability.20
Antidepressant-induced hypomanic switches are more
common in patients who have been exposed to multiple anti-
depressant trials and those with a family history of bipolar
disorder.21 Greater awareness of family histories can assist in
identifying patients that require more cautious use of potent
antidepressant interventions. Particular caution is necessary
when using potent antidepressant treatments in patients that
are younger,22 where the precise nature of mood disorder is
less clear, or in those with more treatment-resistant illness or
other markers of possible bipolar illness.23 In such cases the
use of semistructured interviews or screening instruments
can assist in the identification of bipolar spectrum illness24,25
and treatments with less risk of inducing hypomanic switch
(eg. lithium augmentation) may be preferred.
Conclusion
Taken together these cases point to a potential role for
duloxetine and mirtazapine in combination for the treatment
of more difficult depressive illness but also highlight the need
for careful consideration of the potential for serious adverse
effects. The use of therapeutic strategies that include a
broader range of neurochemical actions appears to be asso-
ciated with greater overall efficacy, more rapid onset of
action, and effectiveness in treating a broader range of
depressive symptoms26 but further systematic study is
needed to clarify the relative benefits and side-effect risk as
well as the identification of patients that are most likely to
benefit from such strategies.
Declaration of interest: None
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