Abstract
The antidepressant effect of rapid transcranial magnetic stimulation (rTMS) has been demonstrated in a double-blind, placebo-controlled trial by Pascual-Leone e t a l. [1]. They treated 17 patients s u ffering major depression with daily rTMS for 5 days and found a significant improvement in the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI) when active treatment was given over the left dorsolateral prefrontal cortex (LDLPFC). Areview of the recent literature by Kirkcaldie e t a l. [2] reveals rTMS to be well tolerated and apparently free of permanent side effects.
Method
Since November 1996, rTMS has been offered to consultant psychiatrists at the Royal Hobart Hospital as a treatment option for their inpatients suffering major depressive disorder (DSM-IV). The treatment of this patient was carried out prior to the Royal Australian and New Zealand College of Psychiatrist's position statement on TMS and was not part of an experiment. Both authors had studied TMS independently in Europe and were familiar with treatment and safety protocols. The patient was informed that rTMS was a novel treatment believed to have an antidepressant effect. She was fully informed of both common and rare side effects. Seizure production is a potential but rare side effect. We operated within published guidelines for safe clinical application [3].
Progress was monitored using the dexamethasone suppression test (DST) [4], CORE system [5], Montgomery A s b e rg Depression Rating Scale (MADRS) [6] and the Self-Rating Depression Scale (SDS) [7]. The DST protocol was dexamethasone 1 mg at 2300 h and serum cortisol levels taken at 0800 and 1600 h the following day. Threshold was set at 138 nmol/L (5 µg/dL) [4]. The CORE system [5] is a construct for rating psychomotor disturbance and a score of 8 or more is taken as indicating melancholia. Significant improvement in the MADRS and SDS was defined as a reduction of the presenting score by 50 and 25%, respectively.
A Magstim rapid machine was used with a 70 mm figure of eight coil producing a peak magnetic field of 2.0 T. The rTMS treatment regimen used was daily sessions of 20 trains at 10 Hz for 5 s to the LDLPFC with an intertrain interval of 25 s. Trains were given at 100% of motor threshold which is determined by stimulation of the motor cortex to produce movement of the first dorsal interosseous muscle. This was performed visually without electromyogram (EMG) [8]. A standard course is 10–14 sessions. Occasionally, treatment would be started at 90% to avoid excessive scalp discomfort and then worked up to 100%. The length of a rTMS course was determined by clinical improvement within a standard of 10–14 treatments. Treatments were given routinely on weekdays but also on weekends depending on the clinical condition of the patient and the availability of the authors.
Case history
Ms A. is a 36-year-old woman who suffered recurrent major depressive episodes. She reported suffering episodes of depressed mood for a decade before she first sought medical treatment. She commenced antidepressant therapy 2 years before her first course of rTMS. She had been admitted to our department on eight occasions and received one course of electroconvulsive therapy (ECT). The course consisted of eight bilateral treatments with moderate success. Headache and memory disturbance made repeated E C T compared with TMS unacceptable to the patient. Her pharmacotherapy included amitriptyline, phenelzine, fluoxetine and moclobemide at manufacturers recommended doses for in excess of 1 month.
Ms A. was found to have a pituitary prolactinoma when she was investigated for galactorhoea at the age of 33. At this time, thyroid function tests were normal, as were cortisol levels at 389 nmol/L (normal range == 1 3 8 − 6 9 0 nmol/L). Her endocrinologist prescribed bromocriptine; the galactorhoea ceased, serum prolactin returned to the normal range and the size of her tumour reduced on magnetic resonance imaging scanning. She was diagnosed and treated for this condition prior to being diagnosed with depression. She remains on 2.5 m g of bromocriptine with a prolactin level of 324 mu/L (normal range == 6 4 − 4 2 4 mu/L) and suffers no neurological symptoms.
Ms A. was treated for major depressive episode (DSM-IV) with rTMS on three occasions. She tolerated the treatment well and reported no side effects. On the first occasion, she had been relatively well for 3 months, but deteriorated over 3 weeks, reporting sleep disturbance with early morning wakening, anhedonia, and a depressed mood. She was admitted and commenced on venlafaxine 37.5 mg bd. After 2 weeks, with no change in symptomatology, she was referred by her treating consultant for rTMS. We continued venlafaxine at 37.5 mg bd to maintain the status quo and to reduce the possible withdrawal side effects. She had 13 treatments over 14 days. There was remission of her depressive symptoms. Venlafaxine may have contributed to her mood improvement, but this only occurred after the addition of rTMS. The before and after treatment DST, CORE, MADRS, and SDS results are presented in Table 1.
She remained well for 1 month and then represented with symptoms meeting the criteria of major depressive episode (DSM-IV). On this occasion, she was treated with rTMS as an outpatient. She received seven treatments over 9 days. There was remission of her depression. Assessment results are presented in Table 1.
Ms A. presented a third time, 5 weeks after completing the second course of rTMS. Again major depressive episode (DSM-IV) was diagnosed. She was treated as an outpatient and received 12 treatments over 16 days. There was remission of her depression. Pre- and post-treatment measurements are presented in Table 1.
On the last two occasions, antidepressant medication was ceased prior to rTMS. After the final course of rTMS venlafaxine was recommenced and maintained at a dose of 150 mg. The patient has returned to full-time employment and has suffered no relapse for over a year.
Discussion
A confounding factor in this case is the history of elevated serum prolactin and pituitary tumour. An association has been reported between elevated prolactin, pituitary tumour and depression [9, [10]]. Holroyd and Cohen [11] reported a case in which depressive symptoms could only be reduced after the prolactin level had been normalised. In the present case, it is impossible to be certain whether the prolactinoma and elevated prolactin were associated with the onset of depressive symptoms. However, during the period reported here, prolactin was within normal limits. While bromocriptine may produce psychosis and mania in less than 2% of patients [12] we could find no report of it producing a depressive disorder of the type exhibited by our patient.
The American Psychiatric Association Task Force on Laboratory Tests in Psychiatry [13] does not list prolactinoma or bromocriptine as being capable of interfering with the DST. It is conceivable that they may do so; however, if this was the case it would be reasonable to assume that the distortion would always be in the same direction.
Remission was not sustained beyond 5 weeks on the first two occasions in this patient. This was also observed by Pascual-Leone [1]. The limitations of TMS are hard to determine at present as optimal treatment protocols are still unknown. Recent work suggests continuing treatment to 4 weeks improves response rates [14]. Therefore, the limitations of this form of treatment in this patient may include treatment duration.
Assessment pre- and post-rapid transcranial magnetic stimulation course
Any causal relationship between DST and major depression is unknown. Depressive illness is associated with an abnormally high cortisol output. The DST is an indirect index of cortisol hypersecretion and a positive result is associated with more severe forms of depression. Transcranial magnetic stimulation can only stimulate superficial cortical regions directly; however, it is possible that activation of areas such as the prefrontal cortex may alter the function of more remote areas by their transneuronal connections.
This is a case of recurrent depression in an individual with a prolactinoma taking bromocriptine. On three occasions, the symptoms of major depressive episode (DSM-IV) and melancholia (CORE system) were removed through the application of rTMS. On each occasion, MADRS and CORE scores were reduced by greater than 50%, the SDS scores were reduced by greater than 25% and the DST status was converted from positive to negative.
Work by others [1] has indicated a role for rTMS in the treatment of depression. This is the first report of rTMS in the treatment of depression quantified as being of melancholic proportions. It is also the first report to demonstrate that rTMS is capable of converting DST status from positive to negative. It strengthens the position of rTMS as a treatment for depression.