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Non-Pharmacological Biological Treatment Approaches to Difficult-To-Treat Depression

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Non-Pharmacological Biological Treatment Approaches to Difficult-To-Treat Depression Treatment resistance Clinical focus Non-pharmacological biological treatment approaches to difficult-to-treat depression t is well recognised that depression frequently does not Summary respond to standard pharmaceutical treatment and Ipsychotherapy techniques.1,2 Non-pharmacological • There has been substantial recent interest in novel biological treatments have a long history of use in difficult- brain stimulation treatments for difficult-to-treat to-treat psychiatric illnesses such as depression. With depression. increasing recognition of the frequency and impact of • Electroconvulsive therapy (ECT) is a well established, difficult-to-treat depression and a variety of technological effective treatment for severe depression. ECT’s developments, the past 10 years have seen a dramatic problematic side-effect profile and questions increase in interest in development of novel brain regarding optimal administration methods continue to stimulation techniques. Here, I provide an overview of the be investigated. characteristics and current status of development of non- • Magnetic seizure therapy, although very early in pharmacological biological treatments for depression (Box). development, shows promise, with potentially similar efficacy to ECT but fewer side effects. Electroconvulsive therapy • Vagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) are clinically Electroconvulsive therapy (ECT) is the most widely used and available in some countries. Limited research suggests effective non-pharmacological biological treatment for VNS has potentially long-lasting antidepressant effects depression and remains the most effective treatment for in a small group of patients. Considerable research difficult-to-treat depression. Its use is particularly indicated supports the efficacy of rTMS. Both techniques require when a rapid antidepressant response is required, such as in further study of optimal treatment parameters. highly suicidal patients. • Transcranial direct current stimulation may provide a low-cost antidepressant option if its efficacy is Although ECT has been in use for well over 50 years and is substantiated in larger samples. a commonly applied clinical tool, questions regarding • Deep brain stimulation is likely to remain reserved for optimal methods of administration remain. Cognitive side patients with the most severe and difficult-to-treat effects, especially anterograde and retrograde amnesia, depression, requiring further exploration of remain problematic, as does the substantial stigma administration methods and its role in depression associated with this treatment in the community. Over the therapy. past 10 years, slow progress has been made in refining ECT • New and innovative forms of brain stimulation, administration techniques, especially focused on trying to including low-intensity ultrasound, low-field magnetic achieve maximum therapeutic benefit with minimal stimulation and epidural stimulation of the cortical cognitive side effects. Studies have tended to confirm that surface, are in early stages of exploration and are yet right unilateral ECT at sufficient intensity has similar efficacy to move into the clinical domain. to bilateral treatment,5 although bilateral treatment may • Ongoing work is required to define which brain result in a more rapid clinical response. Bifrontal stimulation stimulation treatments are likely to be most useful, has not proven to be a substantial advance over other more and in which patient groups. Clinical service traditional approaches.5 Considerable focus has also been development of brain stimulation treatments will likely be inconsistent and variable. given to the use of ultra-brief pulse-width stimulation to try to minimise cognitive side effects. Similar efficacy has been reported in some studies,6,7 although response to ultra-brief neurones will result in changes in local cortical activity and treatment may take longer than standard approaches8 or be the stimulation of distal brain regions through the activation somewhat less than the response to bilateral treatment.9 ECT of projecting neurones. High-frequency rTMS (pulses can be life-saving, especially in urgent clinical situations, and applied at 5–20 Hz) is known to increase local cortical Paul B Fitzgerald remains a valuable tool for patients with severe depression excitability, and low-frequency stimulation (usually 1 Hz) MB BS, PhD, FRANZCP, 11 Professor of Psychiatry that does not respond to other therapies. has the opposite effect. In a therapeutic context, rTMS is usually provided in sessions lasting between 20 and 45 Repetitive transcranial magnetic stimulation minutes, 5 days a week, for 3–6 weeks. Monash Alfred MJAPsychiatry Open ISSN: 0025-729X 1 October 2012 1 4 48-51 In the initial studies, high-frequency rTMS was applied to Research©MJA Centre, Open 2012 www.mja.com.au the left dorsolateral prefrontal cortex (DLPFC), following Monash University Repetitive transcranial magnetic stimulation (rTMS) is a and Alfred Health, observation of this brain region as underactive in patients Clinical focus novel, non-convulsive brain stimulation technique that Melbourne, VIC. involves the repeated application of a time-variable with depression.12 Many sham-controlled studies, including paul.fitzgerald@ magnetic field to superficial areas of the cortex through a two large multisite trials, have investigated the efficacy of monash.edu stimulating coil held above the scalp.10 Magnetic fields this form of stimulation. Several meta-analyses have applied at sufficient intensity to the brain will induce summarised the results of these trials, with the more recent MJA Open 2012; 1 Suppl 4: 48–51 electrical activity in cortical neurones, including analyses showing clear positive antidepressant effects. For doi: 10.5694/mjao12.10509 depolarisation. Repeated stimulation of local groups of example, in a meta-analysis involving 30 trials and 1164 48 MJA Open 1 Suppl 4 · 1 October 2012 Clinical focus Treatment resistance patients, there was a highly significant effect of active stimulation to the left DLPFC is not the only effective treatment compared with placebo on the average reduction method for rTMS application. There is evidence for the in depression severity scores (P < 0.001).13 The included equivalent efficacy of low-frequency stimulation applied to trials involved a mixture of patients with treatment-resistant the right DLPFC and interest in the development of bilateral and non-treatment-resistant depression and produced methods of stimulation.16 Stimulation efficacy may be found effect sizes (typically moderate) similar to those seen with to improve with the use of better brain site targeting and antidepressant medication.13 Trials have also compared possibly with novel, more complex stimulation methods. rTMS with ECT, but substantial inequalities in the Research is also required to define the best methods of treatments provided in these studies (eg, the number of maintenance rTMS. treatment sessions) make interpretation of the results Generally speaking, rTMS treatment is safe and well problematic. Both of the two large multisite trials (one tolerated.17,18 There is a very low risk of incidental seizure independently sponsored and one industry sponsored) induction, and some patients find the procedure showed greater antidepressant effects of active rTMS uncomfortable, or it may produce a transient headache. compared with sham treatment.14,15 Remission rates Switch to mania in patients with bipolar disorder is also (usually defined as a reduction of rating scale scores below a possible. However, overall rates of treatment adherence are certain low cut-off) were similar to those seen in medication very high and no other major adverse consequences have trials with comparable patient populations. emerged, despite more than 15 years of clinical trials. rTMS The result of these trials has been the development of is likely to be a suitable approach for patients in whom one clinical rTMS programs in several countries, including the or more medication treatment trials have failed but who do United States, Canada, Germany and Australia. One rTMS not require a rapid antidepressant response that would device was licensed for depression treatment in the US in justify immediate ECT. 2008 and is now used in over 200 clinical services. The first publicly funded rTMS treatment program in Australia Magnetic seizure therapy commenced operation in Victoria in early 2012. Despite this clinical progression, substantial questions remain regarding Magnetic seizure therapy (MST) is a technique that the optimal methods for rTMS application. High-frequency combines both rTMS and ECT. During MST, a high- Characteristics of brain stimulation treatments for depression Repetitive Electroconvulsive transcranial Magnetic seizure Transcranial direct Vagus nerve Deep brain therapy magnetic stimulation therapy current stimulation stimulation stimulation Type of Convulsive Non-convulsive Convulsive Non-convulsive Surgical Surgical intervention Established Severe depression Difficult-to-treat Difficult-to-treat treatment Difficult-to-treat depression depression indications* (four failed depression Failure to tolerate other treatments medication trials Catatonia in US4) for depression Emergency treatment One failed of depression medication trial requiring urgent (United States3) clinical response Likely or Severe Difficult-to-treat Highly possible depression depression difficult-to-treat treatment depression indications†
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