Adjunctive fast repetitive transcranial magnetic stimulation in depression

The place of repetitive transcranial magnetic stimulation (rTMS)in the treatment of depression remains unclear. In this sham-controlledstudy we determined the efficacy and acceptability offast,left frontal rTMS given three times a week over 4–6 weeksto 29 patients with depression (79% treatment-resistant). Theprocedure was generally well tolerated and more effective thansham treatment (55 v.77% responding, P<0.05), with improvementmaintained to 12 weeks. This therapy could be a useful additionto available treatments but further research is needed to determinethe optimum treatment parameters.

INTRODUCTION

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INTRODUCTION

Approximately a third of people treated for depression failto respond to initial treatment and in 10–15% of casesthe disorder is refractory to multiple treatments (Anderson et al, 2000).The usefulness of repetitive transcranial magnetic stimulation(rTMS) is not clear because optimal treatment parameters are unknown and studies have been small, of short duration andhave used different methods (Loo & Mitchell, 2005). Weinvestigated the antidepressant efficacy of rTMS in a clinicallypractical protocol in patients with depression.

METHOD

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METHOD

We recruited out-patients aged over 17 years with a DSM–IVmajor depressive episode (American Psychiatric Association, 1994),diagnosed using the Mini International Neuropsychiatric Interview(Lecrubier et al, 1997), who were poorly responsive to –or choosing not to take – antidepressant drugs. Exclusioncriteria were safety considerations (e.g. suicidality, contraindicationsto TMS), organic brain disorder, non-affective psychosis orcurrent alcohol/drug misuse or dependence (by DSM–IVcriteria). The study was approved by the local research ethicscommittee and all participants gave written informed consent.

After determination of motor threshold, patients were randomised(sealed envelope) to active or sham treatment stratified bydegree of treatment resistance (fewer than two v. two or moreantidepressant trials equivalent to imipramine 150 mg). Treatmentwas thrice weekly for 4 weeks, extended for 2 more weeks inpartial responders. Medication at entry continued unchangedthrough the trial. Assessments were made before and 2, 4, 6and 12 weeks after the start of treatment with patients andassessors unaware of treatment allocation. Assessments werethe Mongomery–Åsberg Depression Rating Scale (MADRS;Montgomery & Åsberg, 1979), the Clinical Global ImpressionSeverity and Improvement scales (CGI–S, CGI–I; Guy, 1976), the Global Assessment of Functioning (GAF; American Psychiatric Association, 1994),and the self-rated Hospital Anxiety and Depression scale (HAD;Zigmond & Snaith, 1983). Adverse effects were determinedby open questions and a checklist.

Treatment using a Magstim Super Rapid (Magstim, Whitland, UK)was given using a figure-of-eight and matching sham coil. Afterdetermination of the motor threshold (the minimum setting tostimulate the right first abductor pollicis brevis muscle),treatment sessions consisted of 1000 stimulations at 10 Hzin 20 trains each separated by 30 s at 110% of motor thresholdover the left dorsolateral prefrontal cortex (5 cm anteriorto the motor threshold point).

The primary outcome measures were MADRS score and HAD depressionscores at treatment end-point given at least one post-baselineassessment (last observation carried forward; LOCF). Secondaryoutcome measures were other rating scale scores and responderstatus at treatment end-point (LOCF), scores at 12 weeks (LOCFand completers) and treatment withdrawal. Response was definedas a reduction of at least 50% in MADRS score plus a CGI–I rating of much or very much improved. Partial response at 4weeks was defined as 25–49% reduction in MADRS scorefrom baseline. Statistical analysis using SPSS for Windows,release 11.5, was by univariate analysis of variance covariedfor baseline values. Fisher’s exact test was used for categorical data and the exact proportion test for treatmentallocation guesses.

RESULTS

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RESULTS

Thirteen patients (7 women; mean age 48 years, s.d.=8) receivedactive treatment and 16 (9 women; mean age 46 years, s.d.=12)received sham treatment. There was no significant differencebetween groups in median duration of episode (active 14 months,range 3–60; sham 12 months, range 2–144); mediannumber of treatment trials (active 3, range 0–7; sham3, range 0–12); treatment resistance (active 85%; sham75%); electroconvulsive treatment in episode (active 31%; sham38%); and chronic ( $≥$ 2 years) episode (active 46%; sham 38%).All but 3 patients were taking antidepressants (active 92%;sham 88%); venlafaxine 34%; selective serotonin reuptake inhibitors24%; tricyclic antidepressants 14%; combinations were most oftenwith lithium (31%), an atypical antipsychotic (34%) or two antidepressants(17%). More patients in the active group were receiving venlafaxine(62 v. 13%; P<0.05), with a trend for the opposite for selectiveserotonin reuptake inhibitors (8 v. 38%, P<0.1).

Three patients in the active group partially responded at 4weeks and received a further 2 weeks’ treatment. Twenty-fivecases were evaluable for efficacy; at treatment end-point theactive group improved more than the sham group on primary outcomes(MADRS effect size 0.86, HAD depression effect size 0.92),GAF and in number of responders (Table 1). At 12 weeks significantbenefit to the active treatment group on self-rated HAD depression remained.

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Table 1 Effect of repetitive transcranial magnetic stimulation on efficacy outcome measures

Two patients per group withdrew before completing 2 weeks oftreatment (active: scalp pain, unrelated finger infection;sham: self-harm, treatment too stressful). Two patients inthe active group received 100% (reduced from 110%) motor thresholdstimulation owing to initial scalp discomfort, but overallthe treatment was well tolerated. Three participants did notreturn for assessment at 12 weeks. One patient in the activegroup was mildly hypomanic at 4 weeks. Four days after hislast treatment he had a series of epileptic seizures leadingto hospitalisation, but a primary cause was not identified.

Of 25 participants, 19 (76%, P<0.05) guessed their correct treatment allocation; 3 gave a reason related to the treatmentitself and 18 of 25 cited degree of improvement.

DISCUSSION

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DISCUSSION

In this small study, fast left frontal rTMS given three timesa week for 4–6 weeks was effective in mainly treatment-resistantdepression and tolerability was generally good. Hypomania followingrTMS has been reported before (Dolberg et al, 2001), is consistentwith rTMS having antidepressant properties and indicates theneed to screen for bipolarity. Seizures have occasionally occurredduring fast rTMS stimulation (Wassermann, 1998); however, delayedseizure provocation has not been described, is mechanistically implausible and rTMS causation in this case was thought veryunlikely.

Meta-analyses of the clinical efficacy of rTMS for depressionhave been conflicting (e.g Holtzheimer et al, 2001; Couturier, 2005).Variations in treatment methodology and patient factors makeinterpretation of the literature problematic (Loo & Mitchell, 2005). However, a number of recent studies of fast left frontal rTMSsupport the efficacy of higher dosages and a greater numberof treatments (e.g. Fitzgerald et al, 2006).

Our study is limited by its small number of participants, relativelybrief follow-up and uncontrolled concomitant medication. Nevertheless,taken together with other recent studies, our findings suggestthat fast left frontal rTMS warrants further evaluation asa clinically available treatment. A clinically feasible protocolof three treatments per week appears effective, provided thatsufficient stimulation strength and numbers of treatments are used.

ACKNOWLEDGMENTS

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ACKNOWLEDGMENTS

We are grateful for the help of Lewis Harpin and the WellcomeTrust Clinical Research Facility, Manchester for funding fromBolton, Salford and Trafford Mental Health Trust and the Universityof Modena, Italy.

REFERENCES

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