Application of transcranial magnetic stimulation in treatment of drug-resistant major depression?a report of two cases

HUMAN PSYCHOPHARMACOLOGY, VOL. 8,361-365

(1993)

CASE REPORT

Application of Transcranial Magnetic Stimulation in Treatment of Drug-Resistant Major DepressionA Report of Two Cases G. HOFLICH*', S. KASPER', A. HUFNAGEL', S. RUHRMANN' and H.-J. MOLLER' 'Department of Psychiatry, 0-53105 Bonn Sigmund Freudrtr. 25, Federal Republic of Germany. 'Department of Epileptology, University of Bonn. D-53105Bonn Sigmund F r d t r . 25, Federal Republic of Germany

We report the cases of two drug-resistant major depressed psychotic patients, who were treated with 10 sessions of transcranial magnetic stimulations (TMS) and afterwards with 10 sessions of electroconvulsive therapy (ECT) without changing the concomitant neuroleptic and antidepressive medication. TMS did not exert a therapeutic effect in one patient and only a slight one in the other. However, there was a clear beneficial effect for ECT in the patient not responding to TMS and a slight therapeutic effect in the other. In summary, there was no clear-cut evidence for effectiveness of TMS as a treatment for patients with psychotic, therapy resistant depression. However, since there was a slight therapeutic effect of TMS in one patient it seems worthwhile to explore its

therapeuticefficacy in a larger group of depressed patients. KEY

wow-Transcranial magnetic stimulation,electroconvulsive therapy, drug-resistantmajor depression.

INTRODUCTION

for muscular tension headaches and the induction of seizures using stimulation rates exceeding 1.0 Transcranial magnetic stimulation (TMS) of the Hz (Pascual-Leone et al., 1993). For psychiatry this human brain was introduced as a new investigamethod seems to be of particular interest since a tional and diagnostic method in neurology for dismood elevation has been found in healthy subjects orders of motor pathways (Barker et al., 1985, (Bickford et al., 1987). 1987). Recently, it has been shown that TMS is TMS does not induce a general seizure, Since able to activate epileptic foci and to facilitate epifeptifom afterdischarge after stimulation at the except in the rare cases of patients with a low seizvertex (Hufnagel et al., 1990). Furthermore, recent ure threshold, this would shed some light on the publications reported a variety of short-lived mechanism of action of antidepressant efficacy of effects of TMS on cerebral function, including electroconvulsive therapy (CET). For the latter changes in selection or conduct of skilled motor method the pivotal therapeutic role of the induced programms (Ammon and Gandevia, 1990; Cracco generalized seizure has been well established (e.g. et al., 1990) and suppression of visual perception Johnstone et al., 1980; Brandon et al., 1984; Gre(Amassian et al., 1989; Maccabee et al., 1991). gory et al., 1985), but possibly other mechanisms There are no side-effects as yet reported in the liter- may also play a substantial role which have not ature using TMS with stimulation rates c0.3 Hz been explored in detail. A possible therapeutic which currently is most commonly used in clinical effect of TMS may provide some insight into these practice, except the very rare possibility to induce mechanisms and include the clinical advantage of a seizure in patients with a low seizure threshold being without side-effects or risks, like the one of (Agnew and McCreery, 1987; Cracco, 1987). On anaesthesia. We therefore assessed the therapeutic the other hand there seems to be a higher potential efficacy of TMS in an open cross-over design with ECT in two patients with major depression who were classified as resistant to antidepressants. * Author to whom correspondenceshould be addressed. 0885-622U93/05036145~07.50 0 1993 by John Wiley & Sons, Ltd.

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ET AL.

MATERIAL AND METHODS

Procedure of TMS

Patients

We used a commercially available stimulator (Magstim 200DJovametrix)with a 14-cm outer diameter, flat, round-shaped coil. The brief current within the coil induced a time varying magnetic field of a maximum strength of 1.5 Tesla (T) which according to physical rules induced a large electrical current within the brain. Series of magnetic pulses were applied to the central cortex at 0.75-1.50 T magnetic field strength. Stimulus intensities were set 5-30 per cent above threshold intensities to evoke motor responses at the abductor pollices brevis. The application of stimulus pulses was limited to a maximum rate 0.3 Hz because of the system’s need to recharge and a maximum of 25 stimuli in each series followed by a break of at least 1 min. In practical t e r n , the first 25 stimuli were applied at the vertex with a current direction stimulating predominantly the left hemisphere and vice versa the second 25 stimuli were applied with a current stimulating predominantly the right hemisphere. In this alternating protocol a total number of 250 stimuli/day were given at 9.30 a.m. f 30 min for two consecutive periods of five days (Monday to Friday, Saturday and Sunday no treatment, and again Monday to Friday). The maximal charge transferred by a single magnetic stimulus is estimated to be approximately 50pC. The amount of transferred energy of all 2500 stimuli is 125 mC, which is similar to that used in a single ECT session (100 mC-1 C) (Pippard and Ellam, 1981; Barker et al., 1987). Furthermore, it is known from clinical experience that a single session of ECT may have antidepressive efficacy. However, the two figures cannot be compared directly since their bio-physical mechanism is different.

The first patient was a 53-year-old woman with the second episode of a major depression, psychotic subtype (DSM-111-R: 296.34). The patient was considered to be refractory to antidepressant medication since the treatment with amitriptyline, fluvoxamine, maprotiline and doxepine in an adequate dosage partly in combination with promethazine, thioridazine, haloperidol, flupentixol, lorazepam, additive light therapy and sleep deprivation during a time period of more than four months was not successful.The patient was severely depressed and exhibited nihilistic ideas and the delusion of being responsible for her own disease. Moreover, the patient exhibited the symptoms of derealization, loss of energy, restlessnessand weakness and sometimes anxiety. During TMSECT, there was an unchanged medication of doxepine 200 mglday, flupentixoll5 mglday and thioridazine 50 mglday. The second patient was a 31-year-old woman with the fourth episode of a major depression, psychotic subtype (DSM-111-R: 296.34). The patient was considered to be refractory to antidepressant medication since the treatment with amitriptyline, fluvoxamine, maprotiline and doxepine partly in combination with thioridazine, promethazine, haloperidol, trifluperidol, flupentixol, lithium, biperiden and sleep deprivation for more than six months was not accompanied by clinical improvement. The patient was severely depressed and had delusions of guilt and no insight into her illness. Moreover the patient showed loss of energy and psychomotor activity, feeling of derealization, restlessness and weakness. During TMS/ECT, the administration of amitriptyline 250 mglday, flupentixol 20 mglday and thioridazine 125 mglday was kept unchanged. For both patients the physical and the apparative examinations including electrocardiogram (ECT), electroencephalogram (EEG), cranial computertomogram (CCT) were normal. Blood samples including thyroxine, triiodthyronine and thyreotropine revealed normal values. Both patients were right-handed. We first applied series of 10TMS sessions within two weeks to both patients followed by 10 ECT sessions within three weeks.

Procedure of ECT

For ECT we induced an anaesthesia by intravenous (i.v.) injection of methohexital(150-200 mg). Muscle relaxation was ensured by administration of i.v. injection of suxamethonium chloride (60-80 mg). Oxygen was administered before and after treatment. Convulsions were induced by a Siemens convulsator 2077 S with a peak current of 900 mA and a pulse frequency of 50 Hz. The duration of the stimulation was dependent on the seizure duration of the previous ECT sessions and ranged from 3 up to 9 s during the course of ECT. The treatments (10 for each patient) were given at 9.30 a.m. f 30 min with interval of 2-3 days. Both

TRANSCRANIAL MAGNETIC STIMULATION IN RESISTANT DEPRESSION

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HDRS Total Score

21

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16

-

11.

6-

ttttt

tlttt

1

t t t t 1

1

I

I

I

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Figure 1. Total scores of the HDRS before ?US and after the 6fth and tenth TMS session and before ECT and after the second, fifth, seventh and tenth ECX session in two patients who were classified to be resistant to antidepressant medication.

patients were treated with unilateral stimulus electrode placement (d’Elia) at the non-dominant hemisphere, the second patient was changed to biIateral stimulation after the sixth ECT because of lack of treatment response. Rating of depression

The depressive symptomatology was evaluated in both patients by the 21-item version of the Hamilton Depression Rating Scale (HDRS, 1967) before TMS, after the fifth and last TMS session and before the first and after the second, the fifth, the seventh and the tenth ECT session. The ratings were made blind to treatment condition.

RESULTS TMS and ECT were well tolerated by both patients. However, the second patient suffered from memory dysfunction after the ninth ECT for 6 days. The psychopathological changes during the TMS and ECT sessions are displayed in Figure 1 for both patients. After TMS, the first patient showed a decrease from 29 to 23 points of the HDRS total

score (21 per cent) when the first visit was compared to the last. After the subsequently administered ECT, there was an additional decrease from 23 to 16 points of the HDRS total score (nearly 31 per cent) when the first visit was compared to the last. The second patient showed no change in the HDRS after TMS, but during the one course of ECT, there was a rapid reduction from 32 to 14 points of the HDRS total score (nearly 56 per cent). DISCUSSION Our preliminary results, obtained in two major depressed psychotic patients, who were considered to be resistant to antidepressant medication indicate that TMS did not exert a therapeutic effect in one patient and only a slight one in the other. However, there was a clear beneficial effect for ECT in the patient not responding to TMS and a slight therapeutic effect in the other. Based on the existing knowledge in the literature and our own observations we conclude that a general seizure was necessary to induce the antidepressant response in one of our two patients. One of the difficultieswhen comparing ECT and TMS is that both methods

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are quite different according to their bio-physical mechanisms, stimulation intensities and fractionized applications. In addition, the total amount of energy transferred in all TMS sessions was lower than the energy applied in a single ECT session. Nevertheless, there was a slight beneficial effect of TMS in one patient. Although this observation may possibly be explainedwith spontaneous partial remission or delayed drug effect, it also may give a hint that TMS has antidepressiveproperties. This notion may be supported by the findings of Philip et al. (199 1). This group treated depressed patients during a wash-out period of psychotropic drugs with a slightly different technique compared to TMS, that of transcranial electrostimulation (TES), which also does not induce a general seizure. Comparing both methods, the main difference is that transcranial electrical energy is used for TES whereas TMS induces intracranial electrical current by magneto-electrical principle. After the course of TES there was a reduction of anxiety and an improvement of sleep disturbances which was interpreted by the authors that TES possibly improves mood disturbances. One of the short-comings of our observations in two patients is that we did not use a balanced order of treatment modalities. Since we were not sure that TMS works, but we had the hypothesis that ECT will work, we firstly started in both patients with TMS.It could therefore be that an ordering effect influenced our results. In summary, there was no clear-cut evidence for effectiveness of TMS as a treatment for patients with psychotic, therapy resistant depression. However, since there was a slight therapeutic effect in one patient and because this method is well tolerated by the patients, it seems worthwhile to study further diagnosticsubgroups of patients with aEective disorders, especially milder depressive syndromes, to explore its therapeutic efficacy. Moreover, the question whether drug treatment can be enhanced by TMS as it has been demonstrated for sleep deprivation (Kasper et al., 1991) warrants further research. REFERENCES Agnew, W. F. and McCreery, D. B. (1987). Consideration for safety in the use of extracranial stimulation for motor evoked potentials. Neurosurgery, 20, 143147. Amassian, V. E., Cracco, R. Q.,Maccabee, P. J., Cracco, J. B., Rudell, A. and Eberle, L., (1989). Suppression

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Pascual-Leone, A., Houser, C. M.,Reese, K., Shotland, L. I., Grafman, J., Sato, S., Valls-Sole', J., Brasil-Neto, J. P., Wassermann, E. M., Cohen, L. G. and Hallett, M. (1993). Safety of rapid-rate transcranial magnetic stimulation in normal volunteers. Electroencephalogruphy and Clinical Neurophysiology, 89,120-1 30. Pippard, J. and Ellam, L. (1981). Electroconvulsive Treat-

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