Download Case series of perimenopausal women with insomnia treated with

Arch Womens Ment Health
DOI 10.1007/s00737-011-0205-7
CASE REPORT
Case series of perimenopausal women with insomnia treated
with mirtazapine followed by prolonged-release melatonin
add-on and monotherapy
Zipora Dolev
Received: 20 October 2010 / Accepted: 23 January 2011
# Springer-Verlag 2011
Abstract
Objectives The sedating antidepressant mirtazapine is used
off label for insomnia in perimenopausal women. Despite
its apparent efficacy, mirtazapine causes significant
increases in appetite and weight gain. Prolonged-release
melatonin (PRM) is approved for primary insomnia in
patients aged 55 years and older. A clinical experience with
PRM add-on to mirtazapine in facilitating mirtazapine
withdrawal while maintaining improved sleep quality and
abrogating weight gain in perimenopausal women with
insomnia is described.
Methods Eleven perimenopausal women (ages 45–52; FSH=
53±8; normal BMI, 22.9±0.6) with insomnia, who do not
suffer from depression as assessed by the Hamilton scale,
were treated with 15 mg mirtazapine (Remeron®) for 2–
4 weeks. PRM, 2 mg (Circadin®), was then added on, and
mirtazapine was tapered off for another 1–3 months. Prospective data on body weight and subjectively assessed sleep
quality and well-being (assessed by the Pittsburgh Sleep
Quality Index, PSQI, and Well-Being Index, WHO-5,
respectively) were collected before, during, and at the end of
the treatment.
Results Sleep quality ratings improved significantly (by
103% on average) during combined mirtazapine and PRM
intake and 180% during subsequent intake of PRM alone or
together with very low doses of mirtazapine (P<0.05 for
all). Well-being significantly improved by 83% during the
treatment. Seven of 11 women demonstrated weight gain
following mirtazapine intake, five of whom have started to
Z. Dolev (*)
Psychiatry Clinic,
20 Uri St.,
Herzelia, Israel
e-mail: [email protected]
reduce weight following mirtazapine withdrawal and PRM
intake. No adverse events were reported.
Conclusion Application of mirtazapine followed by PRM
add-on and monotherapy improves sleep in perimenopausal
women while evading mirtazapine-induced weight gain.
These results warrant further investigation of a larger
population in controlled clinical trials.
Keywords Melatonin . Mirtazapine . Insomnia .
Perimenopause . Body weight . Sleep
Introduction
For many women, sleep disturbances characterize the perimenopausal period (Kravitz et al. 2003; Krystal et al. 1998).
Despite concerns about risks and side effects, the most
common first-line treatment for menopausal sleep problems
is hormone replacement therapy (Polo-Kantola and Erkkola
2004). Other clinically explored alternatives include the use
of GABA-A receptor modulators, benzodiazepines (BZD)
(Soares 2005), or BZD-like sedatives such as zolpidem
(Dorsey et al. 2004) and, more recently, eszopiclone (Joffe
et al. 2010; Soares et al. 2006) which are associated with
cognitive and long-term safety issues.
In addition, the melatonin agonist ramelteon has
demonstrated amelioration of sleep disturbances in peri- and
postmenopausal women in an open-label trial (Dobkin et al.
2009).
Antidepressants are another class of drugs used off label
for the treatment of insomnia (reviewed in Wiegand 2008).
Specifically, mirtazapine, which primarily acts at -HT-2 and
presynaptic adrenergic alpha-2 receptors, was found to
improve sleep continuity while preserving (Winokur et al.
2003, 2000) or even enhancing deep sleep in depressed
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patients (Schmid et al. 2006), as well as in healthy patients
with obstructive sleep apnea (Carley et al. 2007).
In particular, low doses of mirtazapine have been shown
to successfully treat insomnia in a pilot study with women
demonstrating hot flushes and troubled sleep (Perez et al.
2004). However, mirtazapine has been found to blunt
hypothalamic–pituitary–adrenocortical activity, leading to
a decrease in cortisol in healthy individuals as well as in
depressed patients (Laakmann et al. 2004, 1999; Schmid et
al. 2006). In addition, the use of mirtazapine is associated
with a significant adverse increase in appetite and body
weight gain (Laimer et al. 2006) and thus needs to be
discontinued.
A prolonged-release melatonin (PRM) formulation
(Circadin, 2 mg) is licensed in Europe and other countries
for the treatment of insomnia in patients aged 55 years and
older. This formulation, which essentially mimics the profile
of the endogenous production, improves sleep quality and
facilitates the initiation of sleep. It has no effect on appetite or
body weight gain and is not associated with amnesia,
hangover, withdrawal symptoms, or rebound effects when
discontinued (Lemoine et al. 2007; Luthringer et al. 2009;
Wade et al. 2008, 2010, 2011). Moreover, PRM was found
effective in facilitating BZD discontinuation (Garfinkel et al.
1999). It was therefore selected to help taper off mirtazapine
while maintaining good sleep quality in perimenopausal
women. The case series reported here describes 11 perimenopausal women with complaints of sleep disturbances and
no clinical signs of depression. Initially, all these women
were using different kinds of hypnotics or sedatives for long
periods of time. The efficiency of those drugs was poor, and
these women suffered from side effects.
As a first line of treatment, all women were put on a low
dose of mirtazapine (Remeron) in order to replace the
hypnotic drugs. Then, PRM (Circadin, 2 mg) was added on,
and mirtazapine was tapered off in an attempt to maintain
good sleep quality while preventing the weight gain
associated with mirtazapine.
Methods
Subjects Eleven women aged 45–52 in perimenopausal
stage as confirmed by FSH levels, with no clinical signs of
depression, were referred to the clinic because of sleep
problems. Ten of the 11 women were treated on a regular
basis with either BZD or BZD-like drugs as sleep aid for
several months to several years. All these women gave their
consent to use the data for the purpose of the current
publication.
Procedures At the first visit (visit 1), physical examination
and detailed psychological assessment were performed by a
qualified clinician in order to confirm the perimenopausal
state and insomnia and exclude patients with depression.
Patient-reported sleep-onset latency, sleep quality rating,
and well-being were also recorded. In addition, body
weight, height, and FSH levels were recorded. Patients
were instructed to discontinue all prior sleep medications
and start taking mirtazapine (7.5–15 mg) daily for a period
of 2–10 weeks.
Mirtazapine, initial dose, was selected for each patient
based on her history and adjusted, if needed, in order to
achieve good sleep, as reported subjectively. Patients with
longer history of sleep disturbances and subsequent longer
use of BZD or BZD-like treatment usually required higher
doses of mirtazapine. PRM (2 mg) add-on starting date was
based on each patient's report of attaining good sleep with
mirtazapine. Visit 2 was scheduled 1–5 weeks through
PRM add-on period and included recording of body weight
and sleep parameters.
Mirtazapine tapering off was begun within 0 to 5 weeks
thereafter, with a half dose of mirtazapine. Visit 3 took
place 13–20 weeks from the beginning of treatment and
included recording of body weight, patient-reported sense
of well-being, and sleep parameters.
Assessments Body weight was measured each visit. BMI
was calculated by weight/height2 as measured at visit 1.
Depression was assessed by the Hamilton rating scale at the
beginning of the treatment.
General sense of well-being was assessed by the WHO-5
questionnaire completed by the patients at visit 1, before
the beginning of treatment (baseline), and under PRM
treatment at visit 3.
Sleep quality, assessed by the Pittsburg Sleep Quality
Index (PSQI), and sleep-onset latency from PSQI question
2 were recorded each visit.
Statistics Sleep parameters and body weight at baseline,
visit 2, and visit 3 were compared by repeated-measure
ANOVA followed by paired post-hoc comparisons to
baseline values. Well-being at baseline and at the end of
treatment were compared using t test.
Results
Baseline characteristics
Nine of the 11 women had a normal BMI score (19.1–23.6),
while three had slightly higher than normal BMI of ≤25.7 at
baseline. The majority of women (9/11) showed no clinical
signs of depression as confirmed by a Hamilton scale score
of ≤7, and two women had a borderline score of 8 and 9.
Case series of perimenopausal women with insomnia
Patients were taking BZD and BZD-like drugs at indicated
doses for weeks to months prior to starting mirtazapine
treatment.
Sleep quality
During the mirtazapine tapering-off period, all women
received PRM, 2 mg, daily. Two women received 7.5 mg
mirtazapine 2–3 times a week, four women received
3.75 mg 2–7 times a week, and six women discontinued
mirtazapine completely. Mirtazapine+PRM and PRM significantly improved sleep quality as measured by the PSQI
global score compared to baseline scores. Thus, PSQI
global score decreased (improved) from 17.45±1 (mean+
SEM) at baseline to 8.55±1 at visit 2 and to 6.00±0.7 at
visit 3 (Fig. 1a). Similarly, sleep latency as measured by
PSQI question 2 was reduced from 52.73±14.05 min at
baseline to 21.36±3.7 min at visit 2 and 18.64±2.87 at visit
3 (Fig. 1b).
Body weight
Body weight was significantly increased by 1.95 Kg on
average during the intake of mirtazapine between baseline
visit 1 and visit 2 (Fig. 2a), particularly in patients with
higher BMI values (Fig. 2b). The increase was attenuated or
reversed (a decrease of 0.9 Kg on average) with mirtazapine
tapering off and PRM add-on (Fig. 2a-b).
Fig. 2 Mean body weight change, (a) individual body weight, and
BMI values (b) during treatment. BL baseline, R+C mirtazapine and
PRM add-on; C PRM (mirtazapine, tapered off). Repeated measures
ANOVA, P<0.05; t test post-hoc comparisons, P<0.01 for both
Well-being
Patients reported that their quality of life improved
significantly with mirtazapine+PRM and PRM alone as
reflected in WHO-5 score increase from 12.45±0.8 (mean+
SEM) at baseline to 19.45±0.39 (of 24) at the end of the
treatment (t test; P<0.01).
Discussion
Fig. 1 Mirtazapine+PRM (R+C) and PRM (C) improve sleep quality
(a) and reduce sleep latency (b) in perimenopausal women. BL
baseline; P<0.05, repeated measures ANOVA; *P<0.01, t test
This case series demonstrates the utility of mirtazapine
followed by PRM add-on and monotherapy in improving
sleep quality and, subsequently, the quality of life in
perimenopausal women with insomnia. PRM use is also
helpful in evading mirtazapine-associated weight gain.
Upon arrival, most of the patients in this case series have
been treated with BZD and BZD-like drugs, which they
considered unsatisfactory for treating their sleep problem. In
all but one woman, mirtazapine facilitated the termination of a
long-term use of BZD or BZD-like drugs. An easy switch to
mirtazapine has been previously described for BZD as well as
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several other drugs such as amphetamines, cannabis, and
alcohol (Benyamina et al. 2008; Chandrasekaran 2008;
Kongsakon et al. 2005; Liappas et al. 2004). While BZD
and BZD-like drugs are known to affect sleep architecture,
specifically by reducing slow-wave sleep and rapid eye
movement (Dijk 2010; Hemmeter et al. 2000), mirtazapine
does not suppress deep sleep (Winokur et al. 2003, 2000).
The results further show that, following the initial period
with mirtazapine, patients could be easily switched to PRM,
while maintaining or further enhancing sleep quality and
initiation.
The sleep-promoting effects of PRM are not associated
with modification of sleep architecture (Luthringer et al.
2009). The switch was beneficial in the reversal of
mirtazapine-induced weight gain. Previous studies in
insomnia patients have shown that response to PRM
develops over days to weeks (Luthringer et al. 2009; Wade
et al. 2010, 2011).
Interestingly, mirtazapine treatment has been reported to
increase endogenous nocturnal melatonin in normal controls (Palazidou et al. 1989) and in depressed patients
(Schmid et al. 2006). It is therefore likely that the buildup
of response to PRM took place already under mirtazapine
due to the increase in endogenous melatonin with this drug
and eventually facilitated the switch to PRM monotherapy.
The question remains, however, whether the interim use of
mirtazapine is necessary for the treatment of insomnia in
the perimenopausal women.
In BZD and BZD-like drug users, as were most of the
patients reported here, PRM might potentially be helpful in
tapering off the BZD and BZD-like drugs. PRM has been
shown to enhance the hypnotic activity of GABA-A modulators (Otmani et al. 2008) and successfully facilitate BZD
discontinuation while improving sleep quality in chronic
BZD users (Dagan et al. 1997; Garfinkel et al. 1999). In such
a case, the untoward weight gain associated with mirtazapine
might be avoided. Whether the protocol used in our clinic or
PRM alone would also be useful in hypnotic drug naïve
perimenopausal women remains to be studied. These
observations warrant further investigation of a larger
population in a controlled clinical trial setting.
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