German Journal of Psychiatry

ISSN 1433-1055

 

Update on psychotropic medication used concurrently with transcranial magnetic stimulation

Yvonne Turnier-Shea1, Marzena Rybak1, Phil Reid1, Saxby Pridmore1,2


1Department of Psychological Medicine, Royal Hobart Hospital

2Discipline of Psychiatry, University of Tasmania

Corresponding Author: Prof. S Pridmore, Department of Psychological Medicine, Royal Hobart Hospital, Hobart, Tasmania, Australia, 7000.

e-mail: s.pridmore@utas.edu.au

_________________________________________________________________

Abstract

Background. Rapid transcranial magnetic stimulation (rTMS) is a new technology which holds promise as a treatment in psychiatry. An electromagnet applied to the scalp is used to cause depolarisation of cortical cells. There has been concern that concurrent psychotropic medications, which lower seizure threshold, may increase the risk of seizure during rTMS treatment.

Objective. To examine the incidence of headache and seizure among patients concurrently treated with psychotropic medication and rTMS at our hospital.

Results. 82 patients received 986 treatments. 14 patients were receiving both an antidepressant and an antipsychotic medication. There were no seizures. 24% experienced headache on some occasion during treatment, and 10% took a mild analgesic for headache on some occasion during treatment.

Conclusion. While caution is still necessary, this study shows that it is possible to provide rTMS to patients receiving antidepressants and antipsychotic medications without causing seizure.

(German J Psychiatry 1999; 2: 46-59)

Key words: transcranial magnetic stimulation, seizures

Received: 16.9.99

Published: 15.10.99

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Introduction

Transcranial magnetic stimulation (TMS) is technique which employs electromagnetic principals to bridge the skull and provide electric currents in the superficial brain. An insulated coil is held on the scalp and a strong electric current passing through this coil produces an magnetic field which passes directly through the scalp and into the brain. With fluctuation in the magnetic field, a weak secondary electric current is produced at about the junction of the grey and white matter. The first single pulse machine was described by Barker et al in 1985. With engineering developments, rapid pulses (rTMS) machines are now commercially available.

This technology promises applications in psychiatry (George et al, 1999) but concern has been expressed that rTMS may trigger seizures. Caution has been expressed about using tricyclic antidepressants or neuropleptics concurrently with rTMS because of the potential of these medications to lower seizure threshold (Wassermann, 1998). A proven link between seizure and the concurrent use of psychotropic medication and rTMS could strongly inhibit the use of this new treatment.

Antidepressant effects of rTMS have been demonstrated in many open trials (George et al, 1995, Epstein et al, 1998; Fiensod et al, 1998) and three blind placebo controlled studies (Pascual-Leone et al, 1996, George et al, 1997, Padberg et al, 1998). Our group has demonstrated that rTMS can produce changes in facial expression of depressed individuals as measured by the Facial Measurement System (Katsikitis et al, 1999) and normalise the dexamethasone non-suppression in depressed individuals (Pridmore, 1999). Other potential applications include obsessive compulsive disorder (Greenburg et al, 1997) and posttraumatic stress disorder (Grisaru et al, 1998).

Recent preclinical reports include: 1) Fleischmann et al (1995) demonstrated that rTMS has similar behavioral effects as electroconvulsive shock (ECS) in behavioral models of depression in the rat, 2) Fleischmann et al (1996) demonstrated that rTMS can down regulate beta-adrenergic receptors in rat brain, 3) Fujiki and Steward (1997) demonstrated that rTMS can modify gene expression in the hippocampus of mice, 4) Ben-Shachar et al (1997) demonstrated that rTMS can produce the same changes in monoamines in rat brain as does ECS, and 5) Zyss et al (1997) confirmed some rodent behavioural effects and demonstrated that rTMS can reduce the activity of the cAMP system as does ECS.

The parameters which can be varied according to preference include: 1) the frequency of pulses, 2) the strength of the pulses, 3) the number of pulses in a train, 4) the intertrain interval (the number of seconds of rest between trains), 5) the number of trains in a treatment session, and 6) the number of treatment sessions administered in a course of treatment. Modern stimulators allow the provision of magnetic pulses from less than one, up to 50 Hz. The majority of centres use either 10 Hz, which was favoured by Prof. Alvaro Pascual-Leone (who is currently working at Harvard University) or 20 Hz which was favoured by Prof. Mark George (who is currently working at the Medical University of South Carolina). The strength of the pulse is quantified according to the motor threshold (MT) of the individual (even though treatment is usually applied not to the motor cortex, but to the prefrontal cortex). In the early stages, some centres used 80% MT, but more recently most centres have used 100-110 % MT. The number of pulses per train recommended by the guidelines (Pascual-Leone et al, 1993, Wassermann, 1998) depends on the selected frequency and strength of pulse. The intertrain interval is usually at least 20 seconds. The number of trains in a treatment session ranges from 5 to 30, the most commonly used being 20. The number of treatment sessions has ranged from 5 to 20, the most commonly used being 10.

A major concern has been the risk of accidental initiation of seizure. Wassermann (1998) collated seven cases of seizure believed to be initiated by rTMS which were known to June 1996. There have been no further reports to the time of writing.

Guidelines were developed using neurophysiological quantification of spreading of cortical excitability and after discharge, and clinical observations (Pascual-Leone et al., 1993; Wassermann, 1998). It is believed the danger of seizure increases with increases in the frequency and strength of pulses and with decreases with increases in the intertrain interval.

One of the patients who experienced a seizure (Wasserman, 1998) was being treated using parameters which were within the published guidelines. However, unknown to the researchers, she had been commenced on amitriptyline and haloperidol. This case, along with previous knowledge that psychotropic medication may lower seizure threshold, led to tricyclic antidepressants and neuroleptics being classified as relative contraindications to rTMS. Most of the atypical antipsychotics and the newer antidepressants are also said to lower seizure threshold.

Our group has been active in the field of rTMS since 1996. We have found, as Fink (1994) found with ECT, that most people who have failed drug treatment are still taking drugs when they present for assessment for treatment by other means. It is often impossible to cease the medication of severely mood disordered patients (Conca et al, 1996, Padberg et al, 1998; Belmaker and Grisaru, 1998). In our use of rTMS, our group has always remained within the stimulation parameter safety guidelines.

The objective of this paper was to review the occurrence of seizure and headache in the patient population who had concurrently received psychotropic medication and rTMS at our hospital.

 

Method

The records of all patients who had received rTMS were examined. Where psychotropic medication was used concurrently, details of stimulation parameters, side-effects, age, type and dose of medication were recorded. The details of the age of patients and medication dosage were collated according to the family of medication. Where patients were taking more than one medication, priority was given to the antidepressants.

 

Results

Concurrent psychotropic medication and rTMS treatment had been provided in 82 cases.

In all instances we aimed at treating at 100% MT. If this was uncomfortable we began at 85-90% and worked up to 100% during the first or second treatment session. Two treatment protocols were employed. Protocol 1 - for nine months we used 10 Hz pulses in trains of five seconds which where separated from each other by 20-30 second rest periods. Twenty trains were given each day (giving a daily total of 1000 stimulations) and patients were treated usually treated on 10 to 14 days (giving an average total number of stimulations of 12 000). Thirty one patients were treated according to this protocol and received 372 treatments. Protocol 2 - for over two years we used 20 Hz pulses in trains of two seconds separated by 20-30 second rest periods. Thirty trains were given each day (giving a daily total of 1200 stimulations) and patients were treated on 10 to 20 days (average 14 treatments, giving an average total number of stimulations of 16 800). Fifty one patients were treated according to this protocol and received 614 treatments. [In excess of 1.2 million pulses have been delivered.]

There were no seizures arising from the 986 treatments. In no patient did discomfort prevent the completion of a course of treatment. Twenty patients (24%) experienced a headache at sometime during treatment. Eight patients (10%) experienced a headache at some time during treatment for which they took an analgesic. In no patient did headaches continue after completion of the course of treatment. There were no other significant side effects.

Three patients were receiving anticonvulsants only, two were receiving nefazodone only, and two was receiving fluvoxamine only. These numbers were too small to justify further consideration. Twelve patients were concurrently treated with tricyclics antidepressants. Two were treated with a tricyclic and a medication from another antidepressant family, and three were treated with a combination of tricyclics and a phenothiazine. See Table 1 for details. Eleven patients were concurrently treated with moclobemide in therapeutic doses. Two were taking one other antidepressant and one was also taking clozapine. See Table 2 for details. Fourteen patients were concurrently treated with sertraline at therapeutic doses; one in combination with a phenothiazine. See Table 3 for details. Twelve patients were concurrently treated with fluoxetine at therapeutic doses. Four were also taking at least one phenothiazine. See Table 4 for details. Eight patients were concurrently treated with paroxetine in therapeutic doses. Two were also receiving a phenothiazine. See Table 5 for details. Sixteen patients were concurrently treated with venlafaxine in therapeutic doses. One was also taking a butyrophenone and two were taking a phenothiazine. See Table 6 for details. Eighteen patients were treated with an anitpsychotic medication. Four of these took only an antipsychotic or an antipsychotic plus lithium. Fourteen took an antipsychotic plus an antidepressant. They have been mentioned above. See Table 7 for details.

 

Table 1. Details of twelve patients concurrently treated with tricyclic antidepressant and rTMS.

Oral dose expressed in mg per day.

Patient

Age

tricyclic

Additional Medication

1

57

doxepin 100

2

30

doxepin 200

3

61

trimipramine 150

4

32

prothiaden 200

5

52

amitriptyline 200

6

57

clomipramine 50

moclobemide 1200

7

50

imipramine 150

diazepam 10

8

25

doxepin 150

venlafaxine 150

9

40

doxepin 200

Li 1000

10

60

imipramine 100, doxepin 100

trifluoperazine 5

11

46

amitriptyline 200 mg

fluphenazine 10

12

54

imipramine 100, doxepin 100

thioridazine 100

Average

47

167

 

Table 2. Details of ten patients, and the location of one other, concurrently treated with moclobemide and rTMS.

Oral dose expressed in mg per day

Patient

Age

moclobemide

Additional Medication

1-5

30-62

300-900

nil

6

71

600

Li 1000, Na valproate 1500

7

45

1200

Na valproate 600

8

50

900

thyroxine sodium 0.1

9

46

300

fluoxetine 20

10

23

600

clozapine 300, Li 1000

Average

45

663

*11

* Patient 6 in Table 1 was taking moclobemide.

Table 3. Details of fourteen patients concurrently treated with sertraline and rTMS.

Oral dose expressed in mg per day

Patient

Age

sertraline

Additional Medication

1-12

32-58

100-250

nil

13

60

100

Li 1000

14

34

150

thioridazine 200, diazepam 5

Average

49

200

 

Table 4. Details of twelve patients concurrently treated with fluoxetine and rTMS.

Oral dose expressed in mg per day

Patient

Age

fluoxetine

Additional Medication

1-7

34-63

20-60

nil

8

51

60

thyroxine sodium 0.1

9

35

20

thioridazine 25

10

31

40

thioridazine 50, trifuloperazine 6

11

36

40

thioridazine 100, trifuloperazine 4

12

24

80

thioridazine 200, Na valproate 200

Average

38

40

Table 5. Details of eight patients concurrently treated with paroxetine and rTMS.

Oral dose expressed in mg per day

Patient

paroxetine

Additional Medication

1-5

29-54

20-60

nil

6

33

40

Li 2000, carbamazine 800

7

31

40

thioridazine 100

8

47

40

thioridazine 100

Average

46

35

Table 6. Details of fifteen patients, and the location of one other, concurrently treated with venlafaxine and rTMS.

Oral dose expressed in mg per day

Patient

Age

venlafaxine

Additional Medication

1-11

31-56

150-450

nil

12

56

150

Li 1000

13

74

75

haloperidol 5

14

67

150

thioridazine 250

15

26

300

chlorpromazine 100

Average

51

266

*16

* Patient 8 in Table 1 was taking venlafaxine.

 

 

 

Table 7. Details of four patients, and the location of fourteen others, concurrently treated with antipsychotic medication.

Oral dose expressed in mg per day.

Patient

Age

Antipsychotic

Additional Medication

1

26

risperidone 4

2

39

olanzapine 20

3

73

thioridazine 150

4

21

clozapine 300

Li 1000

Average

40

* 5-7

     

** 8

     

***9

     

**** 10-13

     

***** 14, 15

     

****** 16-18

     

* Patient 10 to 12 from Table 1. ** Patient 10 from Table 2. *** Patient 14 from Table 3. **** Patient 9 to 12 from Table 4. ***** Patient 7 and 8 from Table 5. ****** Patient 13 to 15 from Table 6.

 

Discussion

rTMS has been discussed as a possible replacement for electroconvulsive therapy, it can cause depolarisation of cortical cells with resultant movement of limbs, and its repeated nature is in some ways reminiscent of the photic stimuli which can produce seizure. Not surprisingly then, there has been great concern that rTMS may cause seizures. As mentioned, there have been seven seizures believed to be associated with rTMS, so there would appear to be some risk.

The risk must be small in depressed, non-epileptic patients as there are at least 14 centres studying rTMS in depression around the world and no reports of seizures have appeared in recent years. Only one seizure has been reported from workers using parameters within the guidelines (Wassermann, 1998). Unbeknown to the researcher, this patient had commenced amitriptyline and haloperidol. Such drugs lower the seizure threshold and caution in their concurrent use with rTMS is justified.

Caution is justified as predisposition epileptic seizure is rare. However, this study suggest that the concurrent use of tricyclics, moclobemide, sertraline, fluoxetine, paroxetine and venlafaxine with rTMS should not be prohibited. The same may also apply to the antipsychotics, but in this review of the number using the newer antipsychotics was small and the doses of the older antipsychotics were low. It is of interest that rTMS was used concurrently with clozapine 300 mg per day in two patients (which has been clearly demonstrated to lower seizure threshold).

rTMS is a technology of great potential for psychiatry. While further audits are necessary, and the present study involves relatively small numbers, these findings indicate that it is possible to use certain antidepressants concurrently with rTMS without initiating a seizure.

 

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