Rapid Transcranial Magnetic Stimulation (rTMS) and Normalisation of the
Dexamethasone Suppression Test (DST).
Short Title: Normalisation of DST with rTMS
Department of Psychological Medicine, Royal Hobart Hospital, Tasmania, Australia
Address correspondence and reprint requests to Prof. Saxby Pridmore, Department of
Psychological Medicine, Royal Hobart Hospital, Hobart, Tasmania, Australia.
Rapid Transcranial Magnetic Stimulation (rTMS) and Normalisation of the
Dexamethasone Suppression Test (DST).
Non-suppression of post dexamethasone cortisol is a feature of
endogenous/melancholic depression. Normalisation of the DST response is a feature of
remission and antidepressant treatment. Twelve consecutive depressed non-
suppressers were treated with rTMS. Six demonstrated normalisation and good
clinical improvement which was sustained for at least one month. Thus, rTMS has
some biological effects in common with other antidepressant treatments.
transcranial magnetic stimulation, dexamethasone suppression test
The dexamethasone suppression test 1 is the most studied state marker of depression.
2,3 Non-suppression is associated with endogenous/melancholic features 1,4 and
indicates a need for somatic intervention. 5 Non-suppression occurs when patients are
symptomatic and normalisation of response usually accompanies remission. 6-8 Failure
to normalise indicates a poor prognosis. 2,9
Recent animal 10 and clinical 8 studies suggest that normalisation of hypothalamic-
pituitary-adrenocortical function, as reflected in a return of DST suppression, is
integral to the pharmacological action of amitriptyline and not secondary to recovery.
Transcranial magnetic stimulation (TMS) was described by Barker et al
. in 1985.11
Machines capable of rapid stimulation (rTMS) have recently become available. A
strong current in an insulated electromagnet applied to the head produces a small eddy
current at about the junction of the grey and white matter. 12,13 Three blind trials 14-16
have demonstrated that rTMS can have an antidepressant effect.
Our group has been using rTMS for one year as a clinical option for individuals with
severe depression which has failed to respond to medication and for whom ECT is
being considered. We have prospectively collected comprehensive data. The aim of
this paper is to report the short term effects and the DST response to a course of
rTMS in depressed patients who are at baseline dexamethasone non-suppressers.
Consecutive patients with DSM-IV major depressive episode, which had failed to
respond to an trial of at least one antidepressant medication at maximum
recommended doses for one month and for whom the next treatment option was
electroconvulsive therapy were offered rTMS. Sex, age, diagnosis, ECT history and
current medication were recorded. Baseline Montgomery Asberg Depression Rating
Scale 17 (MADRS) Self-rating Depression Scale 18 (SDS) and DST were completed.
Dexamethasone 1 mg was given at 11 pm and blood was taken at 8 am and 4 pm the
following day - the threshold for suppression was defined as 138 nmol/litre (5
microg/dl) cortisol. This paper reports on the progress of all the non-suppressers who
were detected at baseline. For all patients, these assessments and the DST were
repeated on the day of completion of the course of treatment.
Patients remained in the care of their treating psychiatrist who referred them to the
author for rTMS. The treating psychiatrists were aware that systematic assessments
were being compiled but did not access them. Diagnosis was determined by the author
in collaboration with the treating psychiatrist. Ratings were performed by nursing
staff and registrars trained in the use of these psychological instruments. The raters
were not blind in so far as they were aware that a study was proceeding, but they
were not involved in the management of the patients they assessed and they were not
The patients were maintained on the least possible medication. With one exception, no
new medications were commenced in the month before the course of rTMS. The
exception was patient 4 who had been commenced on a very low dose of venlafaxine
two weeks earlier. These patients were followed up through their treating
psychiatrists for one month after the rTMS.
Treatment was with a Magstim Super Rapid stimulator with a double 70 mm coil.
One treatment session was given each day. Ten to 14 treatments were given over 12 to
16 days, depending on clinical response. A treatment sessions was 20, 5 second trains
of 10 Hz at 90-100 % of motor threshold, separated by 25 second rest periods,
applied to the left prefrontal cortex.
Twelve different patients were discovered to be dexamethasone non-suppressers at
baseline. One patient was treated four times, each time with marked reduction in
symptoms and normalisation of the DST response, however, to simplify these
results, only the findings relating to the first treatment are given. The age, sex
diagnosis, ECT history and current medication are presented in Table 1. The before
and after treatment MADRS, SDS and DST results are presented in Table 2.
The major finding was that six patients normalised during treatment. Five suppressed
at both morning and afternoon samples. The remaining individual escaped suppression
in the afternoon, but suppressed in the morning and had an overall reduction in post
dexamethasone cortisol of 56%. For these six patients the average MADRS moved
from 31 to 9 and the average SDS moved from 54 to 33. All achieved good clinical
improvement and in all cases this improvement was maintained for at least four weeks
Six patients did not normalise. Three initially showed some clinical improvement.
Their average MADRS and SDS showed moderate change. However, deterioration
soon followed and ECT was required within two weeks of completion of the course of
rTMS. These patients took a DST prior to ECT and all escaped suppression at both
the morning and afternoon samples. The other three patients who did not normalise
did not show clinical improvement. Their average MADRS and SDS showed little
change. On completion of the course of rTMS, but before discharge, a course of ECT
was administered. For this latter group of patients a DST prior to ECT was not
The numbers are small. On average, those who normalised were younger than those
who did not normalise (50 vs 64 years) and were less depressed, as determined by
lower baseline MADRS (31 vs 41) and SDS (54 vs 67). Also, those who normalised
had a lower average baseline post dexamethasone cortisol levels (272 vs 413 nmol/l)
Among the shortcoming is that this work was not fully blind. The MADRS was
scored by nurses and doctors who were aware that the patients were participating in
an rTMS study. The SDS was scored by the patient, but this could not have been
otherwise. The clinical decisions such as whether to discharge or commence ECT were
made by the treating psychiatrists and they may have been biased to please the
author, however, their primary responsibility was to their patients and these doctors
had to meet the consequences of any wrong decisions. The most important findings
emanate from the DST results and these were determined by technicians who had no
knowledge whatsoever of our clinical activities.
In six cases there was DST normalisation and good clinical improvement. Medication
was continued in five of these cases, however, it is unlikely that this was responsible
for the changes. In four cases the medication had been in place without success for one
month, and in the fifth case, in which medication had been more recently commenced,
There were no detectable side-effects of rTMS other than an occasional transient
headache. This is consistent with the findings of the double blind studies of Pascual-
Leone et al.
14 and George et al.
These patients all suffered severe mood disorder. One inclusion criterion was that the
current episode had failed to respond to an adequate trial of at least one
antidepressant. The majority had failed to respond to medication from two or more
different families. Ten of the had been hospitalised and received ECT for the treatment
of a previous major depressive episode. On the baseline MADRS and SDS scores all
at least reached the lower level of severe depression. Another inclusion criterion was
initial DST non-suppression. Thus, from a clinical 19,20 and biological 2,9 perspective,
clinical improvement in these patients in response to placebo was most unlikely.
Three non-suppressers showed some clinical improvement but relapsed within two
weeks and required ECT. This is entirely consistent with the findings that non-
suppression indicates a poor prognosis in spite of apparent clinical improvement. 2,9
Increasing age in both the presence 21 and absence 22 of depression has been associated
with increased hypothalamic-pituitary-adrenocortical dysregulation as reflected by the
DST. Common clinical experience is that depression in later life may prove less
responsive to treatment than depression of early adult life. These factors may have
been influential in the present study as the group which did not show normalisation of
the DST was on average older than the group which showed normalisation. There also
appeared to be a suggestion that those with higher baseline MADRS, SDS and post
dexamethasone cortisol level may be less responsive to rTMS. However, the numbers
are small and indicate only that an examination of the effect of age and severity of
depression, as revealed by baseline assessments, on the outcome of rTMS treatment
of depression may be justified. Very recent reports suggest that rTMS is less effective
in older as compared to younger patients 23 and in psychotic as compared to non-
While six patients achieved a favourable outcome during rTMS, six did not. It is
reasonable to expect that a greater yield of favourable outcomes can be achieved with,
as yet undetermined, optimum treatment parameters (frequency, train length, inter-
train interval, number of trains and intensity) and number of treatments. There is very
little information to guide the choice of parameters at the moment. Those we used are
very similar to those used by Pascual-Leone et al.
14 and dissimilar to those used by
George et al.
15 Our immediate plan is to continue to use these parameters, but to treat
people twice each day, morning and afternoon.
The important finding of this report is that rTMS resulted in the normalisation of the
DST response (accompanied by a good clinical improvement which persisted for at
least one month) of six patients with severe, medication resistant depression who had
not suppressed at baseline DST. This demonstrates that rTMS has some biological
effects in common with other antidepressants 8 and that this revolutionary technology
can have effects within and beyond the nervous system.
Thanks to the Hobart Clinic and Kevin Clamp for financial
1. Carroll B, Feinberg M, Greden J, Tarika J, Albala A, Haskett R, James N, Kronfol
Z, Lohr N, Steiner M, de Vigne J, Young E. A Specific Laboratory Test for the
Diagnosis of Melancholia. Arch. Gen. Psychiatry
2. American Psychiatric Association Task Force on Laboratory Tests in Psychiatry.
The dexamethasone suppression test: an overview of its current status in
psychiatry. Am. J. Psychiatry
3. Rush A, Giles D, Schlesser M, Orsulak P, Weissenburger J, Fulton C, Fairchild C
Roffwarg H. Dexamethasone response, thyrotropin-releasing hormone stimulation,
rapid eye movement latency, and subtypes of depression. Biol Psychiatry
4. Rush A, Weissenburger J. Melancholic symptom features and DSM-IV. Am. J.
5. Thase M, Dube S, Bowler K, Howland R, Myers J, Friedman E, Jarrett.
Hypothalamic-pituitary-adrenocortical activity and response to cognitive
behaviour therapy in undedicated, hospitalised depressed patients. Am. J.
6. Carroll B. The hypothalamic-pituitary-adrenal axis in depression. In Davies B,
Carroll B, Mowbray R eds. Depressive illness: Some research studies.
Ill. Charles C Thaomas, 1972: 23-201.
7. Greden J, Gardner R, King D, Grunhaus L, Carroll B, Kronfol Z. Dexamethasone
suppression tests in antidepressant treatment of melancholia. Arch. Gen.
1983; 40: 493-500.
8. Heuser I, Schweiger U, Gotthardt U, Schmider J, Lammers C-H, Dettling M,
Yassouridis A, Holsboer F. Pituitary-adrenal-system regulation and
psychopathology during amitriptyline treatment in elderly depressed patients and
normal comparison subjects. Am. J. Psychiatry
9. Ribeiro S, Tandon R, Grunhaus L, Greden J. The DST as a predictor of outcome in
depression: a meta-analysis. Am. J. Psychiatry
10. Barden N, Reul J, Holsboer F. Do antidepressants stabilise mood thorough actions
on the hypothalamic-pituitary-adrenocortical system? Trends Neurosci
11. Barker A, Jalinous R, Freeston I. Non-invasive magnetic stimulation of human
motor cortex. Lancet
1985; 1: 1106-1107.
12. George M S, Wassermann E, Post R. Transcranial magnetic stimulation: a
neuropsychiatric tool for the 21st century. J. Neuropsychiatry Clin. Neurosci.
13. Kirkcaldie M, Pridmore S, Reid P. Electroconvulsive therapy (ECT) and
transcranial magnetic stimulation (TMS): the case of the skull. Convulsive Therapy
14. Pascual-Leone, A, Rubio, B., Pallardo, F Catala M. Beneficial effect of rapid-rate
transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in drug-
resistant depression. Lancet
15. George M S, Wassermann E, Kimbrell T, Little J, Williams W, Danielson A,
Greenberg B, Hallett M, Post R. Daily left prefrontal rTMS improves mood in
depression: a placebo-controlled crossover trial. Am. J. Psychiatry
16. Padberg F, Haag C, Zwanzger P, Thoma H, Kathmann N, Stubner S, Hampel H,
Moller H. Rapid and slow transcranial magnetic stimulation are equally effective in
medication-resistant depression: a placebo-controlled study. International Journal
1998, 1, Suppl. 1: S30.
17. Montgomery S, Asberg M. A new depression scale designed to be sensitive to
change. Br. J. Psychiatry
18. Zung W. A self-rating depression scale. Arch. Gen. Psychiatry
19. Fairchild C, Rush A, Vasavada N. Which depressions respond to placebo?
20. Zimmerman M, Spitzer R. Melancholia: from DSM-III to DSM-III-R. Am. J.
21. von Bardeleben U, Holsboer F. Effect of age upon the steroid response to human
CRH in depressed patients pre-treated with dexamethasone. Biol. Psychiatry
22. Heuser I, Gotthardt U, Schweiger U, Schmider J, Lammers C-H, Dettling M,
Holsboer F. Age-associated changes of pituitary-adrenocortical hormone regulation
in humans: importance of gender. Neurobiol. Aging
23. Figiel G, Epstein C, McDonald W, Amazon-Leece J, Figiel L, Saldivia a, Glover S.
The use of rapid rate transcranial magnetic stimulation (rTMS) in refractory
depressed patients. J Neuropsychiatry Clin Neurosci
1998; 10: 20-25.
24. Grunhaus L, Dannon P, Schreiber S. Effects of transcranial magnetic stimualtion on
sever depression. Similarities with ECT. Biol Psychiatry
1998; 43: 76S-77S.
AGE SEX DIAGNOSI
MEDICATION (DAILY TOTAL)
Table 1. The age, sex, diagnosis, ECT history (whether or not ECT has been received
in the past) and current medication of patients; listed in order of age. BP =bipolar disorder; MDD = major depressive disorder. Shading indicates thosewho did not normalise.
BEFORE AFTER BEFORE AFTER BEFORE
Table 2. The results of MADRS, SDS and DST conducted before and after a course of
rTMS. Patients listed in order of age. NA = not available. Shading indicatesthose who did not normalise. * = expressed in nmol/litre.
K E T O C O N A Z O L E I N A D V A N C E D P R O S T A T E C A N C E R 2006 , Edinburgh, Scotland: National 13 Taplin ME, Regan MM, Ko YJ et al . Cancer Institute, 2009. Available at: http:/22 Galsky MD, Simon K, Sonpavde G et al . Ketoconazole retains activity in patients Ferlay J, Parkin DM, Steliarova-Foucher
The medical management of motor neurone disease – a UK perspective of current practice The UK MND Interest group# Guidance on the management of motor neurone disease (MND), sometimes also known as amyotrophic lateral sclerosis (ALS), has previously appeared in documents including the Practice Parameter on the Care of the Patient with Amyotrophic Lateral Sclerosis  and the Pract