EUROPEAN NEUROLOGICAL JOURNAL REVIEW ARTICLE

Antidepressants for Migraine Prophylaxis

Christian Lampl and Christine Schweiger
Affiliation: Department of Neurology and Pain Medicine, Konventhospital Barmherzige Brüder Linz, Linz, Austria

A B S T R A C T

The objectives of this review are to provide a comprehensive critical analysis of published reports of randomized controlled trials of
antidepressants for reducing headache burden among adults with migraine, and to determine whether efficacy varies according to important
patient characteristics, such as coexisting depression. The mechanism whereby amitriptyline and other antidepressants produce their
analgesic effects is unknown, but the blockade of serotonin and norepinephrine re-uptake has been hypothesized to play a pivotal role.
Concerning amitriptyline, there is some evidence that this tricyclic antidepressant may be beneficial in the prophylaxis of migraine in some
patients. For selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), beneficial effects are
equivalent to those seen in the placebo group within 2 months of therapy. To conclude, there is limited evidence for a clinical superiority of
amitriptyline and SSRIs over other treatments with ß-blockers, anticonvulsants, or calcium channel blockers in preventing migraine.
Antidepressants in migraine should be considered if other first- or second-line drugs have not reduced the number of monthly attacks or if
concomitant depression exists. Therefore, antidepressants are second- or (even) third-line prophylactic agents in patients with migraine alone.

Keywords: Migraine, antidepressants, prophylactic treatment, SSRIs, SNRIs

Correspondence: Christian Lampl, Department of Neurology and Pain Medicine, Konventhospital Barmherzige Brüder Linz, Seilerstätte 2,
Linz, Austria. Tel: (43)-732-780-625320; Fax: (43)-732-780-625398; e-mail: christian.lampl@bblinz.at

INTRODUCTION confirmed in three large placebo-controlled studies [17–19].

Migraine is one of the most frequently observed neurolo-
gical problems at primary healthcare centers. Recurrent
migraines can be disabling, and the cost of missed workdays
and impaired performance associated with migraines exceeds
the direct costs of medical intervention.
In western countries, community-based studies of migraine
prevalence using standardized diagnostic criteria give 1-year
prevalence estimates of around 10–12% [1, 2], with the
highest rates reported in the age range 25–55 years; women
account for the majority of patients with migraine [3].
Notwithstanding appropriate management of acute
migraine, preventive therapy may reduce the frequency of
migraines by 50% or more, and patients should be evaluated
for initiation of preventive therapy. Factors that should
prompt consideration of preventive therapy include severe
impairment of quality of life, job duties, or school attendance,
frequency of attacks per month, non-response of migraine
attacks to acute drug treatment, or occurrence of frequent,
very long, or uncomfortable auras [4]. First-line agents for the
prophylaxis of migraine include the non-selective beta-
blocker propranolol [5, 6] and the beta-1-selective beta-
blocker metoprolol [7]. Bisoprolol is probably also effective,
but has only been examined in two studies [8, 9]. From the
group of ‘‘calcium antagonists’’, only flunarizine has been
confirmed as effective [10–12]. A dose of 5 mg is probably as
effective as 10 mg [13]. In several prospective studies, the
anticonvulsive valproic acid has been shown to be effective
[14–16]. Topiramate has migraine prophylactic properties
Except for bisoprolol, all the above-mentioned drugs are
recommended substances (drugs of first choice) for the
prophylactic treatment of migraine [4].
ANTIDEPRESSANTS—A CRITICAL APPROACH
TO THE MATTER
As the mechanisms underlying migraine headache are still
not fully understood, various types of medication have been
used for migraine prophylaxis so far. New research on
migraine pathophysiology has brought forward new concepts
for the prevention of migraine. The mechanism of action for
the alleviation of migraine headache pain is thought to be due
to the inhibition of reuptake of serotonin and norepinephrine
within the dorsal horn; however, other possible mechanisms
of action include alfa-adrenergic blockade, sodium channel
effects, and N-methyl-D-aspartic acid (NMDA) receptor
antagonism. Therefore, the drugs involved should converge
mainly on two targets: inhibition of cortical excitation and
restoration of nociceptive dysmodulation. The antiepileptics,
calcium channel blockers such as verapamil, and inhibitors of
cortical spreading depression are some examples of drugs
that reduce neuronal hyperexcitability. On the other hand,
modulators of the serotonergic and adrenergic systems and
cholinergic-enhancing drugs may restore descending noci-
ceptive inhibition and play a role in migraine prevention.
However, the administration of all other drugs, except beta-
blockers and anticonvulsants, is based more on empirical
data rather than on proven pathophysiological concepts.

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European Neurological Journal
Because migraine is currently considered a neurovascular
disorder with a main central nervous system (CNS) compo-
nent, efforts now focus on attempting to prevent migraine
attacks by modulating neurotransmitter systems rather than
by changing intracranial vascular tone [20]. For this reason,
antidepressant drugs could be valuable treatment options for
migraine prophylaxis.
Lance and Curran [21], in 1964, as part of an exploratory
study, first showed that amitriptyline had a prophylactic effect
on tension-type headache in a group of 27 headache patients.
Over the past decade, subsequent studies have shown that
several classes of antidepressant are effective in preventing
chronic headache. As a result, such therapy has become an
accepted treatment for these patients [22, 23], although it is
not approved for that indication in the US or Europe.
However, the results of antidepressant studies for prophy-
lactic treatment in headache have to be viewed with caution.
In a published meta-analysis of 38 studies, the authors
concluded that the use of antidepressants in chronic headache
should be supported [24]. With regard to migraine, only six
studies used the 1988 International Headache Society (IHS)
criteria [25], whereas the recommendation of the 1962 Ad
Hoc Committee on Classification of Headaches [26] was used
in 11 studies. The remaining 23 studies used varying
definitions, and no two studies defined their outcome in
the same way. In such a meta-analysis, it is impossible to
differentiate whether the effects of antidepressant medica-
tions on migraine were independent of their effects on
depression. It is obvious that depressed patients experience
improvement in somatic complaints as their underlying
depression is successfully treated and, moreover, that patients
with depression have more headaches. In longitudinal
studies, evidence further supports a bidirectional relationship
between migraine and depression, with each disorder
increasing the risk of the other [27]. It obviously follows
that antidepressant drugs may have a benefit for chronic
headache patients.
The main questions to be raised are whether antidepressant
efficacy varies according to the specific headache diagnosis or
potentially important patient characteristics, such as coexist-
ing depression; whether antidepressants are as effective for
non-depressed patients; and whether they achieve a direct
analgesic effect in addition to treating concomitant depres-
sion.
In general, it must be stated that analysis of preventive
migraine therapy with antidepressants poses some methodo-
logical issues that need to be focused on: definition and
diagnostic criteria of migraine (trials before and after 1988);
quality of trials; definition of primary outcome parameters
(specific migraine score vs reduction of migraine frequency);
population of included patients (US patients vs European
comparisons between study populations); as well as informa-
tion on quality of life and comorbidity (e.g., depression and
anxiety).
Primarily, the diagnostic criteria of migraine should
conform to those of the IHS [28]. Concerning quality of
ENJ 2010; 000:(000). Month 2010
trials, the Clinical Trials Subcommittee of the IHS published
its first edition of the guidelines on controlled trials of
drugs for migraine in 1991. With the current trend for huge
multinational trials, there was a need for increased
awareness among clinical investigators of methodological
issues in clinical trials of drugs for migraine. Therefore, new
guidelines were developed to improve the quality of
controlled clinical trials in migraine, because only quality
trials can form the basis for international collaboration on
drug therapy [29].
Secondary, headache days with moderate or severe intensity,
migraine days, or frequency of migraine episodes should be
the primary efficacy measures. The evaluation of efficacy
should be based on a headache diary, which captures the key
assessment measures for each study.
To evaluate the total impact of headache and headache
therapies on the individual sufferer, outcomes research is
emerging as an important tool. Of increasing importance is
the impact of clinical measures on patient-perceived quality of
life, including comorbidity, work performance, and economic
cost. Health-related quality of life (HRQOL) represents the net
effect of an illness and its consequent therapy on a subject’s
perception of his or her ability to live a useful and fulfilling
life [30]. HRQOL can be measured with a variety of generic
and specific questionnaires such as the Migraine Disability
Assessment (MIDAS) questionnaire, which has been used in
one trial [31] and proven useful.
AMITRIPTYLINE
The beneficial use of amitriptyline in migraine was reported
in the late 1960s by Friedman [32] and Mahloudji [33]. One of
the early clinical studies conducted by Gomersall and Stuart
in 1973 [34] showed efficacy of amitriptyline as a prophylactic
treatment for migraine in 26 patients. The number of attacks
was reduced by more than 50% in about half of the subjects,
and by more than 70% in a quarter of them. Total attacks
were reduced by 42%, which was statistically significant
(P,0.001).
In 1979, Couch and Hassanein [35] showed that 75 mg of
amitriptyline reduced a specific migraine score (reflecting
frequency, severity, and duration of attacks) by more than
50% in 55% of amitriptyline-treated patients, compared with
34% of placebo-treated patients. The therapeutic gain in that
particular study was 21%. However, data on migraine
frequency were not presented, and patients with comorbid
depression were not excluded.
Ten years later, Ziegler et al [36] presented the results of a
placebo-controlled trial comparing amitriptyline and propra-
nolol. They concluded that amitriptyline, as well as propra-
nolol, is effective in reducing a specific headache score and
that the positive results of amitriptyline are unrelated to
depression. All these early trials used loose criteria to define
migraine; they did not exclude patients with comorbid anxiety
and depression and were limited by their use of global clinical
ratings, rather than daily headache recordings, to assess
outcome.
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Rafieian-Kopaei et al [37] reported a significant reduction in
migraine frequency, duration, and intensity when using
amitriptyline. However, amitriptyline reduced the frequency
of migraine attacks during treatment; after discontinuation,
the rebound effect was higher than in the control group.
Two recently published studies compared amitriptyline with
topiramate. The first examined the prophylactic efficacy of
combined amitriptyline and topiramate in patients with 3–12
migraine episodes, compared with that of monotherapy with
each drug [38]. All treatments resulted in significant
improvement in all efficacy measures but, again, patients
with mild to moderate depression were not excluded.
The second study was performed by Dodick and colleagues
[39]. In that long-term, multicenter, randomized, double-
blind, double-dummy, parallel-group, non-inferiority study,
the primary efficacy outcome was the change from prospec-
tive baseline in the mean monthly number of migraine
episodes. The intent-to-treat population included 331 sub-
jects, and change from baseline in the mean monthly number
of migraine episodes did not differ significantly between the
topiramate and amitriptyline groups. The authors concluded
that topiramate was at least as effective as amitriptyline in
terms of reducing the rate of mean monthly migraine
episodes and all prespecified secondary efficacy endpoints.
Topiramate was associated with improvement in some
quality-of-life indicators compared with amitriptyline and
was associated with weight loss and improved weight
satisfaction.
We performed a trial to examine the prophylactic benefit of
two doses of amitriptyline extended release (ER) over a 6-
month observational period without a placebo arm in real-life
situations [40]. The study hypothesis was that amitriptyline is
effective in preventing migraine attacks and that 50 mg of ER
amitriptyline is more effective than 25 mg of ER amitriptyline.
Furthermore, we were interested in determining possible
predictive factors for therapeutic responsiveness. Change in
median number of migraine days from baseline to the end of
the intent-to-treat period of 6 months was adducted as a
primary efficacy measure. A statistically significant reduction
in median migraine days was found between baseline and
months 3 and 6. However, no significant difference in
treatment efficacy was observed between treatment with
amitriptyline ER 25 mg/day and with amitriptyline ER 50 mg/
day at any time period. In contrast to other similar studies, we
used the number of headache days as a primary efficacy
outcome instead of the recommended number of ‘‘attacks per
4 weeks’’, because we considered the number of headache
days to be a more robust and conservative parameter. When
looking at the secondary outcome measures, migraine days
were able to be reduced by >30% in 39% of the patients by
the end of the study. However, only 14% of the study patients
experienced a reduction of >50% in migraine headache days,
whereas none of the patients benefited by more than 70%.
This study shows that amitriptyline is probably not effective
in a dose of up to 50 mg; the prophylactic effect seen in our
study did not reach beyond well-known placebo response
rates of 20–30%.
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Antidepressants for migraine prophylaxis
To conclude, there is some evidence that amitriptyline may
be beneficial in the prophylaxis of migraine in some patients.
Previous reports, exclusively from the US, have shown that
migraine patients may respond to amitriptyline used for
prophylactic therapy. Most of these studies had poor scientific
quality. Many of the trials considered in this review had
limited sample size (median of 50 randomized patients, with
a mean dropout rate of 20%), which leaves the findings
unclear for many outcome measures. Length of follow-up was
often too short (mean length, 12 weeks; recommended,
24 weeks), and the clinical outcomes measured (scales or
indices) often did not have a well-established rationale and
were not prespecified. The appropriateness of statistical
analyses was a frequent matter of concern, particularly in
light of multiple treatment comparisons, repeated measure-
ments over time, and questionable subgroup analyses.
In the past few years, the association between migraine and
depression has been described in both clinic- and commu-
nity-based populations. Many researchers maintain that
chronic migraine pain can induce a reactive depression that
becomes more evident the more chronic the pain is. To
explain a development from migraine to depression, it has
been hypothesized that unpredictable attacks of severe pain
might lead to anxiety and depression. In longitudinal studies,
the evidence supports a bidirectional relationship between
migraine and depression, with each disorder increasing the
risk of the other [27, 41]. In such cases amitriptyline may
provide more benefit than other drugs. However, this
approach is not successful in all migraine patients, and
finding a means of identifying patients who are likely to
respond to amitriptyline is a high-priority research goal.
In some cases, the benefits gained must be weighed against
the risks incurred. The most important adverse effects are
drowsiness and anticholinergic symptoms such as dry mouth,
constipation, and tachycardia. Weight gain occurs in many
patients together with elevated levels of leptin, insulin, and C
peptide [42], and can be a limiting factor leading to impaired
compliance and discontinuation. Occasionally, amitriptyline
may provoke glaucoma, PQ and QT interval prolongation on
electrocardiogram (ECG), as well as benign prostate hyper-
trophy, which should be excluded prior to treatment.
Amitriptyline is metabolized by cytochrome P450 (CYP)
isoenzymes, particularly CYP2D6, which is responsible for
multiple interactions (e.g., class Ia and IIIa antiarrhythmics,
warfarin, opiates, propranolol, diuretics, insulin). Therefore,
its use is further limited by age.
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs currently used in migraine comprise citalopram,
escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertra-
line. When compared with placebo, SSRIs did not show any
superiority in patients with migraine. When compared with
other active treatments, specifically tricyclic antidepressants,
SSRIs were not superior in migraine [43]. There is some
evidence that SSRIs are better tolerated than other active
treatments with respect to minor adverse events. This
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European Neurological Journal
tolerability has no impact on the total number of patients
withdrawing as a result of adverse effects [44]. Patients taking
tricyclic antidepressants for headache are as likely to continue
taking a tricyclic as patients treated with an SSRI are to
continue taking the SSRI. The issue of long-term treatment
(.3 months) with respect to efficacy and tolerability should
still be addressed, as in real-life conditions.
Fluoxetine is certainly the most extensively studied SSRI in
migraine prevention. A loss of habituation of visually evoked
potentials in migraine patients was normalized on fluoxetine
20 mg/day; in addition, migraine attack frequency diminished
significantly [45]. In a prospective study by Krymchantowski
et al [46] in patients with transformed migraine, amitriptyline
40 mg was found to be equally effective as a combination of
amitriptyline and fluoxetine, which argues against a strong
efficacy of fluoxetine. No significant effect of fluoxetine 20–
40 mg daily compared with placebo was found after 3 months
of intake on headache self-assessment scales, a proprietary
headache index, or number of severe headache days per week
[47]. Another double-blind, placebo-controlled study demon-
strated a significant improvement on a proprietary headache
index [48], but the withdrawal rate was high, the overall
number in each group was low [n58], and the results were
not corrected for multiple testing.
In conclusion, current data on the use of SSRIs in migraine
prevention favor the use of fluoxetine. However, it should be
considered that these studies are partly inconsistent and
lacking in numbers of patients. The Cochrane review [44]
mentioned revealed that beneficial effects from SSRIs are
equivalent to those seen in the placebo group within 2 months
of therapy.
SEROTONIN NORADRENALIN
(NOREPINEPHRINE) REUPTAKE INHIBITORS
(SNRIS)
Duloxetine and venlafaxine have been promoted as being
especially useful in migraine and depression. In migraine, a
retrospective analysis of 65 migraine patients receiving 30–
60 mg daily for at least 2 months revealed a significant
reduction in attacks per month. Interestingly, those patients
with comorbid depression did not benefit significantly in a
subgroup analysis, whereas those with a comorbid anxiety
disorder experienced greater benefit than did all 65 migraine
patients together [49].
For venlafaxine, four studies were published, but the
reported positive results are limited by an open-label
procedure [50], the retrospective design, the fact that
concomitant migraine prophylactics were allowed, or that
the majority of patients had simultaneous tension-type
headache [51]. In the only randomized, double-blind, cross-
over trial, patients with migraine with and without aura
received either amitriptyline or venlafaxine extended release.
The number of attacks per month as well as the duration and
intensity of the attacks decreased significantly with both
drugs [52]. However, the small number of patients in each
group limits the impact of this outcome.
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CONCLUSIONS
In older placebo-controlled trials, positive results could be
shown for amitriptyline in the prophylactic treatment of
migraine. The results of a study comparing amitriptyline with
propranolol suggest that propranolol is more effective in
patients with a single migraine type, whereas amitriptyline is
more beneficial for patients with mixed migraine and tension
features. Compared with topiramate, amitriptyline was at
least as effective in terms of reducing the rate of mean
monthly migraine episodes. However, topiramate was asso-
ciated with improvement in some quality-of-life indicators
compared with amitriptyline and was associated with fewer
side-effects.
SSRIs did not show any superiority in patients with
migraine, when compared with placebo. When compared
with other active treatments, specifically tricyclic antidepres-
sants, SSRIs were not superior in migraine prophylaxis.
Furthermore, there is limited evidence for a clinical super-
iority of amitriptyline and SSRIs over other treatments with
beta-blockers, anticonvulsants, or calcium channel blockers
in preventing migraine.
Therefore, antidepressants in migraine should be discussed
with the patient if other drugs (beta-blockers, flunarizine,
valproate, and topiramate) have not reduced the number of
monthly attacks, are limited because of their several
important side-effects, or if concomitant depression (or other
psychiatric disease) exists. Antidepressants should be con-
sidered as second- (amitriptyline) or third-line (SSRIs, SNRIs)
prophylactic agents in patients with migraine alone. Our
cautious recommendations for the use of antidepressants
reflect the current lack of data on most substances. Future
studies should adopt a higher standard in terms of design and
reporting by using the International Headache Society
diagnostic criteria to classify patient pain in chronic forms
of either migraine and/or tension-type headache. According
to the Task Force of the International Headache Society
Clinical Trials Subcommittee, migraine headache days with
moderate or severe intensity, migraine days, or frequency of
migraine episodes should be the primary efficacy measures
[29]. Another heterogeneity is the fact that some of the
presented studies examined migraine preventive efficacy only
in those patients without concomitant depression, whereas
others allowed concurrent depression. Today, some guide-
lines adopt a rather strict approach recommending only
antidepressants for migraine prophylaxis [3], whereas others,
such as the US Academy of Neurology, recommend those
drugs, albeit stressing the low quality of evidence in the
corresponding drugs [53].
Disclosure: Christian Lampl received personal compensation from
Glaxo, Pfizer Austria, Mundipharma, Grünenthal, Bayer-Shering, Biogen
Idec and Astra Zeneca. Christine Schweiger has nothing to disclose.
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