Reprinted from Journal of Obstetrics and
Gynaecology (1997) Vol.17, No.1, pp76-79. Reproduced by
permission.
Preliminary
Trial of Photo Stimulation for Premenstrual Syndrome
D.J.ANDERSON, N.J.LEGG and
DEBORAH A.RIDOUT
Department of Neurology and Medical Statistics Unit, Royal
Postgraduate Medical School, London UK
Summary
In an open study 17 women with confirmed, severe and long-standing
premenstrual syndrome used Photic Stimulation with a flickering
red light, every day for up to four menstrual cycles. At
the end of treatment prospectively recorded median luteal
symptom scores were reduced by 76% (95% confidence interval
54-93, P<0.001), with clinically and statistically significant
reductions for depression, anxiety, affective lability,
irritability, poor concentration, fatigue, food cravings,
bloating and breast pain. Twelve of the 17 patients (71%)
no longer had the premenstrual syndrome. One patient failed
to improve. One patient withdrew because of worsening premenstrual
depression, but Photic Stimulation was otherwise well tolerated.
The improvement is greater than that reported for relaxation
or in open studies of fluoxetine, and much more than historical
placebo rates. Photic Stimulation may be a useful treatment
for the premenstrual syndrome, and by its suggested action
on circadian rhythms may have wider therapeutic applications.
Introduction
Premenstrual syndrome (Reid and Yen, 1981; Mortola et al.
1990; Bancroft, 1993), also defined as premenstrual dysphoric
disorder (American Psychiatric Association, 1994), is a
common disorder of unknown aetiology. Patients have a range
of symptoms, physical, behavioural and psychological, which
vary in intensity over the course of the menstrual cycle,
disrupt normal functioning and are at their worst in the
week before the menses. Current treatments include fluoxetine
(prozac) which is better than placebo (Steiner et al. 1995),
progesterone, which is not (Freeman et al. 1995), and other
methods of altering the ovarian cycle, whose effects vary
(Bancroft, 1993). Relaxation therapy was an effective treatment
for severe cases in a controlled trial (Goodale et al. 1990).
Photic Stimulation can induce relaxation (Kroger and Schneider,
1959), and may therefore be of benefit. A portable variable
frequency Photic Stimulation device, used in a previous
study of migraine (Anderson, 1989), produced a significant
reduction in premenstrual symptoms over 6 months in one
subject who had obtained no relief from other measures.
The purpose of this study
was to quantify any beneficial effect of Photic Stimulation
with flickering red light in a group of premenstrual syndrome
patients, and to assess any effects on cycle length and
dysmenorrhoea.
Methods
The study was open and was designed to follow 20 patients
through a two-cycle baseline observation phase, a three-cycle
treatment phase and a final cycle off treatment. Patients
were self-referred following local and newspaper publicity
and were screened initially by a postal menstrual distress
questionnaire (Moos, 1968) and a covering letter explaining
the nature and demands of the study. Questionnaires (n=261)
were sent out and 82 were completed and returned. Patients
were selected on willingness to participate, provisional
confirmation of the diagnosis based on the menstrual distress
questionnaire and proximity to the study centre. Twenty
seven patients came for consultation, which included a full
clinical history and examination. They were asked to choose
their six most prominent and troublesome symptoms, including
at least one physical symptom. They could use their own
terms, for instance 'mood swings' or 'angry outbursts',
which were then assigned to the appropriate premenstrual
dysphoric category for analysis. In order to assess severity
of symptoms, they were supplied with diary cards, based
on the PMT-Cator (Magos and Studd, 1988), and similar to
an obstetric calendar, on which they could rate these 6
symptoms for up to 6 weeks. They were asked to record a
score from 0 (no symptom) to 9 (as bad as it could be) for
each symptom each day throughout the study. The luteal score
was the sum total of the scores for each of the six symptoms
for the 6 days prior to menses, and the follicular score
the sum of the score from days 5 to 10 inclusive of the
menstrual cycle. At each visit patients gave retrospective
ratings of their previous cycle including a score of 0 to
9 for severity of dysmenorrhoea and a menstrual distress
questionnaire.
During the baseline observation
phase three patients did not have cyclical changes of symptoms
and were excluded. Three others withdrew, one because of
pregnancy and two for personal reasons.
The 21 patients entering
the treatment phase satisfied all the criteria for premenstrual
dysphoric disorder (American Psychiatric Association, 1994)
and those of the National Institute of Mental Health (Bancroft,
1993) and Mortola et al. 1990 for premenstrual syndrome.
All patients had a mean baseline luteal score above a severity
threshold of 65 (representing 20% of the maximum possible
score) (Freeman et al. 1995). No patient had history of
epilepsy or concurrent psychiatric disorder, or was taking
psychotropic drugs or hormones, including the oral contraceptive.
They were aged between 23 and 44 years (median 38 years),
had suffered from the syndrome for between 2 and 24 years
(median 10) and had a menstrual cycle of between 24 and
34 days (median 28). They had taken a median of three previous
treatments, without benefit.
Seventeen patients completed
at least two evaluable cycles on treatment. One patient
moved abroad, one was lost to follow up, and one withdrew
for personal reasons. One withdrew because of an increase
in premenstrual depression, and did not return for further
assessment.
Fourteen patients completed
the study by recording data for at least one more cycle
on treatment and one cycle off treatment. The other three
did not complete their diary cards for the third cycle and
withdrew, all for personal reasons related to their employment.
They did not stop treatment. Because of variations in cycle
length and changes to appointments nine patients were treated
for a fourth cycle.
Thus there were data from
17 patients for the two baseline cycles and the first two
treatment cycles, from 14 for the third treatment cycle,
from 9 for the fourth and from 14 for the follow up.
Photic
Stimulation Mask
The Photic Stimulation mask is a portable photic stimulator
delivering pulses of red light of wavelength 645nm to each
eye alternately, at a frequency of 0.5 to 50Hz and with
a luminance of 10 to 45 mcd. A control box, which controls
the control circuitry and battery is connected to miniature
light-emitting diodes mounted in a neoprene wrap-around
face. After the first cycle of treatment the median luteal
score fell from 196 (150-249) to 71 (41-136); P<0.001.
Improvement continued with a further fall to 25 (8-139)
by the fourth cycle, a reduction compared with the first
treated cycle (P<0.05). At this point no difference was
found between the median follicular and luteal scores. When
treatment was withdrawn the median luteal score rose very
little (see Figure 1).
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The median reduction
in luteal score for individual patients was 64% (54-93)
after one cycle of treatment, and 76% (54-93) at the
end of treatment.The three patients who withdrew after
treating two cycles had individual reductions in luteal
score of 82%, 91% and 53%, comparable with those in
patients who completed the trial.
After the first treated
cycle there were reductions in the individual luteal
symptom scores for depression, anxiety, affective lability,
irritability, difficulty concentrating, fatigue, change
in appetite, breast tenderness and bloating (P<0.05),
and possibly for social withdrawal (P=0.06). There was
insufficient data for separate analysis of the premenstrual
dysphoric disorder symptom categories 'hypersomnia and
insomnia' and 'being out of control'. In the last treated
cycle there was a suggestion of further improvement
in all symptoms except breast tenderness.
At the end of the treatment
cycle only one patient had a luteal score higher than
the baseline. Thirteen of the 17 patients had a reduction
of the luteal score of at least 50%, and 10 of these
had a reduction of at least 75%.Twelve of the 17 patients
no longer met the criteria for the premenstrual syndrome.
A substantial reduction
in retrospective menstrual distress questionnaire scores
of 74% (66-83) was seen after one cycle of treatment
compared with the baseline (P<0.001), with physical
symptoms responding similarly.
No differences were found
in the median cycle length, days menstruating, or menstrual
flow between baseline and treatment cycles. The median
dysmenorrhoea score was reduced from 5 (4-8) at the
baseline to 3 (2-4) at the end of treatment (P<0.01).
The duration of dysmenorrhoea was reduced from 36 hours
(24-48 hours) to 24 hours (2-24 hours); P<0.001.
Both severity and duration tended to return towards
pre-treatment levels on withdrawal of treatment.
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Figure 1. Total Luteal diary
card score (median and 95% confidence interval),
before, during and after treatment. F/U = follow
up. Changes from baseline at cycles 3 and 4 (P<0.001),
at cycles 5,6 and follow up (P<0.01), and between
cycles 3 and 6 (P<0.05). |
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Compliance
and treatment use
Patients used the Photic Stimulation mask for a median of
17 minutes a day (range 11-29 minutes a day), missing one
day per cycle (range 0-5) and using the mask between 21.00h
and 24.00h on 70% of occasions.
Discussion
Women with severe and chronic premenstrual syndrome obtained
considerable benefit from the use of Photic Stimulation with
flickering red light. Ninety-four percent of women responded
and the median decrease in prospectively recorded symptom
score was 76% (95% confidence interval, 54-93). There is no
previous report of variable frequency photic stimulation as
a treatment for the syndrome.
This level of effect appears
at least equal to that reported for the most successful of
previous treatments. In a small open trial a gonadatrophin-releasing
hormone analogue, injected daily, abolished ovarian cyclicity,
and reduced prospectively recorded symptom scores by 76% (Mortola
et al. 1991). Fluoxetine, 20 mg daily, reduced symptom scores
by 55% in an open study (Rickels et al. 1990) and between
44% (Steiner et al. 1995) and 62 % (Wood et al. 1992) in placebo-controlled
studies.
An obvious question is whether
the effect of photic stimulation represents a placebo response,
and one can only observe that it is much larger than previously
reported placebo effects. A placebo response of up to 94%
is often quoted in premenstrual syndrome, but this refers
to one trial in which 33 of 35 women initially responded to
a placebo subcutaneous implant (Magos et al. 1986). Their
improvement measured by the mean reduction in daily symptom
scores, was only 20% which is within the 10% to 30% range
of placebo responses observed in other studies (Deeny et al.
1991; Wood et al. 1992; Freeman et al. 1995; Steiner et al.
1995). Patients are less likely to respond to placebo if they
have sought treatment for premenstrual syndrome before (Metcalf
and Hudson, 1985) or if the condition is long standing (Deeny
et al. 1991). By these criteria our current study group should
be poor placebo responders. Also placebo effects tend to wane
(Magos et al. 1986), and patients in placebo treated groups
tend to withdraw because of lack of response (Steiner et al.
1995), neither of which occurred in this study.
Two other possible mechanisms
for the response to photic stimulation are relaxation and
an effect on entrained rhythms in the brain.
Photic stimulation or flicker
has long been known to induce relaxation in normal subjects
(Kroger and Schneider, 1959), and also to evoke mood changes
(Walter and Walter, 1949). Patients described the mask as
relaxing, presumably because they found frequencies, which
evoked pleasant or neutral sensations. The two previous studies
of relaxation therapy are difficult to interpret because of
the way the data are presented. One showed a reduction in
symptom score of less than 20% in 12 patients (Morse et al.,
1991). In the other the reduction was 30% overall in 16 patients,
and 58% in the seven patients with undefined 'high severity'
premenstrual syndrome (Goodale et al., 1990). These reductions
are less than that found in the present study, suggesting
that photic stimulation may not act by relaxation alone.
An alternative mechanism is
an effect on entrained rhythms in the brain. In the syndrome
there is an abnormal relationship between the internal circadian
clock and the sleep-wake cycle, in the form of a phase advance
(Perry et al., 1990). Partial sleep deprivation has therefore
been tried as an experimental treatment, in a manner similar
to that used for major depressive disorders, and produced
an average reduction in premenstrual symptom score of 62%
(Perry et al., 1995). The mammalian circadian clock is intimately
connected with the visual system (Stain Malmgren, 1993), and
in humans it can certainly be phase-shifted by normal indoor
illumination (Boivin et al., 1996). Flicker can cause a distorted
sense of time (Walter and Walter, 1949), implying a direct,
though temporary, effect upon internal clocks. Photic stimulation
may perhaps reset the circadian clock, restoring normal synchrony
between internal biological rhythms and external entraining
cues. Such a mechanism could explain the improved sleep quality
which was spontaneously reported by some of our patients and
also the persistence of therapeutic response after the withdrawal
of treatment.
The optimum frequency and brightness
settings, if such exist, the optimum duration of use and time
of day of use, and the relative merits of alternate eye or
synchronous flicker were not addressed in this study. The
two patients with the poorest response, were the only ones
to use the photic stimulation mask at extreme settings, one
at the dimmest illumination and the other at the highest frequency,
of 50 Hz.
This open study of photic stimulation
in a small group of patients with severe premenstrual syndrome
has shown a considerable therapeutic effect, but it has not
been tested against placebo. If these results are confirmed
the underlying mechanisms will be of considerable interest.
Photic stimulation appears to be a simple and safe treatment
and may have other applications.
Acknowledgements
We thank Professor D. F. Hawkins for critical review of the
study proposal. This study was supported by Migra Ltd. The
photic stimulation mask and its use are covered by US patent
5092669 and UK patent 2196442. [One author D.J.A is the inventor
of the photic stimulator described and has a financial interest
in Migra Ltd.]
References
- Altman D. G. (1991)
Practical Statistics for Medical Research. London, Chapman
and Hall
- American Psychiatric
Association (1994) Diagnostic and Statistical Manual of
Mental Disorders, 4th edition, pp. 715-718. Washington,
DC, American Psychiatric Association.
- Anderson D. J. (1989)
The treatment of migraine with variable frequency photo-stimulation.
Headache, 29, 154-155 .
- Bancroft J. (1993)
The premenstrual syndrome - a reappraisal of the concept
and the evidence. Psychological Medicine, Suppl 24, 1-47
- Boivin D. B., Duffy
J. F., Kronauer R. E. and Czeisler C. A. (1996) Dose-response
relationships for resetting of human circadian clock by
light. Nature, 379, 540-542.
- Deeny M., Hawthorn
R. and McKay Hart D. (1991) Low dose danzol in the treatment
of the premenstrual syndrome. Postgraduate Medical Journal,
67, 450-454.
- Freeman E. W., Rickels
K., Sondheimer S. J. and Polansky M. (1995) A double-blind
trial of oral progesterone, alprazolam, and placebo in treatment
of severe premenstrual syndrome. Journal of the American
Medical Association, 274, 51-57.
- Goodale I. L., Domar
A. D. and Benson H. (1990) Alleviation of premenstrual syndrome
symptoms with the relaxation response. Obstetrics and Gynecology,
75, 649-655.
- Kroger W. S. and Schneider
A. S. (1959) An electronic aid for hypnotic induction: a
preliminary report. Journal of Clinical and Experimental
Hypnosis, 7, 93-98.
- Magos A. L., Brincat
M. and Studd J. W. (1986) Treatment of the premenstrual
syndrome by subcutaneous estradiol implants and cyclical
oral norethisterone: placebo controlled study. British Medical
Journal, 292, 1629-1633,
- Magos A. L. and Studd
J. W. (1988) A simple method for the diagnosis of premenstrual
syndrome by use of a self-assessment disk. American Journal
of Obstetrics and Gynecology, 158, 1024-1028.
- Metclaf M. G. and
Hudson S. M. (1985) The premenstrual syndrome: selection
of women for treatment trials. Journal of Psychosomatic
Research 29, 631-638.
- Moos R. H. (1986)
The development of a menstrual distress questionnaire. Psychosomatic
Medicine, 30, 853-867.
- Morse C. A., Dennerstein
L., Farrell E. and Varnavides K. (1991) A comparison of
hormone therapy, coping skills training, and relaxation
for the relief of premenstrual syndrome. Journal of Behavioural
Medicine, 14, 469-489.
- Mortola J. F., Girton
L., Beck L. and Yen S. S. (1990) Diagnosis of premenstrual
syndrome by a simple, prospective and reliable instrument:
the calendar of premenstrual experiences. Obstetrics and
Gynecology, 76, 302-307.
- Mortola J. F., Girton
L. and Fischer U. (1991) Successful treatment of severe
premenstrual syndrome by combined use of gonadotropin-releasing
hormone agonist and estrogen/progestin [see comments]. Journal
of Clinical Endocrinology and Metabolism, 72, 252A-252F.
- Parry B. L., Berga
S. L., Kripke D. F., Klauber M. R., Laughlin G. A., Yen
S. S. and Gillin J. C. (1990) Altered waveform of plasma
nocturnal melatonin secretion in premenstrual depression.
Archives of General Psychiatry, 47, 1139-1146
- Parry B.L., Cover
H., Mostofi N., LeVeau B., Sependa P.A., Resnick A. and
Gillian J.C. (1995) Early versus late partial sleep deprivation
in patients with premenstrual dysphoric disorder and normal
comparison subjects. American Journal of Psychiatry, 152,
404-412.
- Reid R. L. and Yen
S. S. (1981) Premenstrual syndrome. American Journal of
Obstetrics and Gynecology, 139, 85-104.
- Rickels K., Freeman
E. W., Sondheimer S. J. and Albert J. (1990) Fluoxetine
in the treatment of premenstrual syndrome. Current Therapeutic
Research, 48, 161-166.
- Stain Malmgren, R.
(1993) Biological cycles. In: The Headaches, edited by J.
Olesen, P. Tfelt-Hansen and K. M. A. Welch, pp. 137-143.
New York, Raven Press.
- Steiner M., Steinberg
S., Stewart D., Carter D., Berger C., Reid R., Grover D.,
and Streiner D. (1995) Fluoxetine in the treatment of premenstrual
dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative
Study Group [see comments]. New England Journal of Medicine,
332, 1529-1534.
- Walter V. J. and Walter
W. G.(1949) The central effects of rhythmic sensory stimulation.
Electroencephalography and Clinical Neurophysiology, 1,
57-86.
- Wood S. H., Mortola
J. F., Chan Y. F., Moossazadeh F. and Yen S. S. (1992) Treatment
of premenstrual syndrome with fluoxetine: a double-blind,
placebo-controlled, crossover study. Obstetrics and Gynecology,
80, 339-344.
Correspondence to: Dr. D.
J. Anderson, Department of Neurology, Royal Postgraduate Medical
School, Du Cane Road, London W12 0NN, UK.
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