Intensive HF-rTMS treatment in refractory medication-resistant unipolar depressed patients

Abstract

Background

Major depression is a worldwide severe mental health problem. Unfortunately, not all depressed patients respond to pharmacotherapy or psychotherapy, even when adhering to treatment guidelines. Even though current guidelines do not in particular advocate repetitive Transcranial Magnetic Stimulation (rTMS) in refractory treatment resistant depression (TRD), using more intensive stimulation parameters might hold promise as a valuable alternative.

Objective

Consequently, in this randomized sham-controlled crossover study, we wanted to evaluate clinical outcome of intensive HF-rTMS treatment in TRD when applied to the left dorsolateral prefrontal cortex (DLPFC).

Methods

After a 2-week antidepressant washout, 20 unipolar TRD patients, at least stage III, received 20 sham-controlled high-frequency (HF)-rTMS sessions, in a crossover design. Five daily suprathreshold HF-rTMS sessions were spread over four successive days delivering in total 31,200 stimuli.

Results

Overall, the procedure resulted in immediate statistical significant decreases in depressive symptoms regardless of order/type of stimulation (real/sham), suggesting possible placebo responses. On the other hand, albeit only 35% (7/20) of the patients showed a 50% reduction of their initial Hamilton Depression rating score at the end of the two-week procedure, all these patients showed a prompt clinical response after real HF-rTMS treatment, not after sham. Furthermore, a shorter duration of the current depressive episode was a predictor for beneficial clinical outcome. Unresponsiveness to former ECT could be indicative for negative clinical outcome in these kinds of patients.

Limitations

Single center setup with relatively small sample size and no follow-up.

Conclusions

Our findings indicate that intensive HF-rTMS treatment might have the potential to result in fast clinical response when confronted with a refractory TRD patient.

Introduction

Major depression is a severe mental health problem affecting millions worldwide (Nemeroff, 2007a). Unfortunately, not all depressed patients respond to the available pharmacological treatment algorithms and refractory depression is not uncommon (Fava, 2003). Ten percent or even more are documented to be resistant to several psychopharmacological interventions, even when adhering to treatment guidelines (Fagiolini and Kupfer, 2003, Berlim and Turecki, 2007). Not surprisingly, it has been proposed that refractory treatment resistance could be a different type of depression (Nemeroff, 2007b). Furthermore, when challenged with clinical non-response, treatment options are limited (Shelton et al., 2010, Ward and Irazoqui, 2010).

Electroconvulsive therapy (ECT), a well-known and widely used neurostimulation technique frequently applied in major depression, is not only considered to be one of our most potent treatment modalities, yielding response rates ‘unchallenged’ to the classic treatment algorithms, the application has also the capacity to result in significant clinical responses within weeks. By using unilateral or bilateral bifrontal/bitemporal ECT, after 10 sessions performed two or three times a week or even less, in general 80–90% of the depressed patients clinically respond (Kennedy and Giacobbe, 2007). When including treatment resistant depressed patients (TRD), clinical success is reached in 50–70% (Rush and Siefert, 2009). Unfortunately, the multiple anesthetic procedures and the risk for cognitive impairments temper its use on a more general basis (McLoughlin et al., 2007, Holtzheimer et al., 2012, Minichino et al., 2012). Needless to say that optimized or alternative treatments are needed.

For nearly two decades now, repetitive transcranial magnetic stimulation (rTMS) has been available as a non-invasive clinical tool to treat patients suffering from major depression and is now an accepted, evidence-based treatment option by the American Psychiatric Association (APA), the Canadian Network for Mood and Anxiety Treatments (CANMAT), and the World Federation of Societies of Biological Psychiatry (WFSBP). Over these years, a series of stimulation studies examined several TMS parameters to improve clinical outcome in majorly depressed patients (Dell'osso et al., 2011, Galletly et al., 2012, Fitzgerald et al., 2012). Two interesting clinical directions have evolved over the years. First, as already proposed by Gershon et al. (2003) nearly 10 years ago, to increase outcome rates stimulation parameters have to ‘intensify’ by using suprathreshold intensities, delivering more pulses per session and importantly, apply these stimulation parameters over longer periods of time (O'Reardon et al., 2007, Fitzgerald and Daskalakis, 2011). Bilateral sequential rTMS (i.e. HF-rTMS applied to the left DLPFC and low frequency (LF)-rTMS delivered to its right counterpart) could be another avenue to increase response rates. However, to date such treatment protocols did not demonstrate superior efficacy compared to unilateral rTMS treatment paradigms (Fitzgerald et al., in press). It has become common practice that the earlier daily sessions spreads over 10 days have been replaced by daily sessions over 20 days (George and Post, 2011). Second, it has been stated that we should be more careful with our patient selection, including younger patients with a relatively short period of clinical depression and optimally with a limited history of treatment resistance (George and Post, 2011). Although low and/or high-frequency paradigms seem to yield similar efficacy rates, targeting the left dorsolateral prefrontal cortex (DLPFC) with high frequent stimulation has the strongest evidence to have beneficial outcome (Schutter, 2009, Fitzgerald and Daskalakis, 2012). However, it remains an important question whether TRD patients could benefit from specific intensive protocols.

From a clinical perspective it is highly interesting if we could apply intensified rTMS treatment algorithms to safely and effectively treat TRD patients without the cognitive complications of ECT. In an effort to increase response rates, some research groups already started to apply rTMS parameters spread over a shorter time period. In an open study, treating 14 mildly treatment resistant depressed patients, Holtzheimer et al. (2010) applied 15 left dorsolateral prefrontal high frequency (HF)-rTMS sessions as add-on to pharmacotherapy. In total 15,000 pulses were delivered, spread over two successive days, yielding immediate clinical response rates of 43%. Recently, we published a case study of an ECT resistant bipolar I patient with mixed episode where we successfully and safely applied an intensive high frequency HF-rTMS treatment paradigm delivering a double amount of pulses (31,200 pulses spread over 4 days, five sessions per day) on the left DLPFC, resulting in immediate clinical response (Zeeuws et al., 2011). These intensive stimulation parameters still fall under the open safety, tolerability, and effectiveness study from Hadley et al. (2011) where treatment resistant uni and bipolar patients were treated with 6800 stimuli per session (34,000 stimuli per week) as add-on therapy. In contrast to Holtzheimer et al. (2010) and Zeeuws et al. (2011), the total length of HF-rTMS treatment could vary in function of clinical response, resulting in treatment sessions over one to five weeks. A daily session was performed in a single run without intersession time intervals.

In the current sham-controlled HF-rTMS study, we wanted to investigate whether an intensive HF-rTMS treatment paradigm delivering a fixed amount of pulses with in total 31,200 stimuli in one week could be in particular beneficial in a group of well-defined refractory depressed unipolar TRD patients. To exclude placebo effects, patients were randomized to receive in the first week 20 real or sham HF-rTMS sessions (five sessions/day for 4 days) and in the second week of treatment the other condition. All patients were considered at least stage III treatment resistant as described by Rush et al. (2003): they had a minimum of two unsuccessful treatment trials with serotonin reuptake inhibitors/noradrenaline and/or serotonin reuptake inhibitors (SSRI/NSRI) and one failed clinical trial with a tricyclic antidepressant (TCA). With the exception of benzodiazepines all patients were psychotropic-free after a two-week washout period.

We hypothesized that in this sample of refractory treatment resistant depressed patients; the application of this intensive protocol would result in significant acute beneficial clinical outcomes.