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September 5, 2013 9:00 pm

Deep brain stimulation for treatment-resistant depression shows promising preliminary results

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This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

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Deep brain stimulation (DBS) is emerging as a viable option for treatment-resistant depression (TRD) but questions remain over which brain areas to target, as several areas appear to have some efficacy, experts told BioPharm Insight.

DBS directly stimulates brain regions through insertion of a device within the skull to target particular symptoms, and it is being pioneered for a range of CNS conditions.

Depression is characterized by sadness, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, feelings of tiredness and poor concentration, according to the World Health Organisation (WHO) website. The WHO website also noted that at least 350 million people live with depression worldwide and that it is the leading cause of disability.

Several academic groups worldwide are working with companies like Medtronic (NYSE:MDT), St. Jude Medical (NYSE:STJ), and Netherlands-based Sapiens Steering Brain Stimulation to investigate DBS as a potential treatment option for TRD.

Patients are considered to have TRD once they have not responded to available treatments including medication, psychotherapy or electroconvulsive therapy (ECT).

Around 10%-20% of patients diagnosed with major depressive disorder are treatment-resistant, said Dr Andres Lozano, professor, neurosurgery, and senior scientist, Division of Brain Imaging & Behaviour Systems, Neuroscience Toronto Western Research Institute, Canada. TRD patients who are eligible for DBS have tried pharmacological treatments, behavioural therapy, psychotherapy and ECT interventions and exhausted all possible treatment options, said Dr Volker Coenen, head, Stereotactic and Functional Neurosurgery, University Medical Center Freiburg, Germany. For these patients DBS is the last resort for what is a serious and potentially deadly disease, he said.

Several other noninvasive attempts at stimulating the brain, including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation are less efficacious than DBS, according to the experts, because they only offer superficial and nonspecific methods of stimulation.

Areas where DBS is showing potential

A variety of brain regions are being investigated with DBS by individual groups of researchers, with promising results, but with little consensus on the ideal brain area to target, several experts noted. There is limited published data from randomised controlled trials to date, making it difficult to evaluate DBS’ true potential, they added.

So far with DBS there does not seem to be an indication of any acute changes in patients, where they are immediately less depressed, but they are able to respond to events differently, said Dr Paul Holtzheimer, associate professor, Psychiatry and Surgery Director, Mood Disorders Service, Geisel School of Medicine at Dartmouth, New Hampshire. For example, such patients still feel bad when bad things happen, but they are then able to go back to feeling better rather than becoming stuck in a negative rut, he said.

However, Lozano noted some specific anecdotal effects that are seen soon after patients are fitted with a DBS device, where they report that “a black cloud is dissipating” and that the “world looks lighter” or that they feel like doing things. Holtzheimer noted that his group has also seen these acute effects.

Medtronic is running three clinical trials investigating various DBS devices for different TRD targets. The most advanced is a Phase III trial that is recruiting TRD patients already implanted with a DBS device to investigate on/off stimulation and reward motivation. St. Jude Medical also has three clinical trials. Among them is a futility analysis for a 200-patient Phase III DBS study called BROADEN, BioPharm Insight reported 30 July. TRD is listed as a potential indication for investigation on Sapiens Steering Brain Stimulation’s website.

Multiple possible targets for stimulation

More and more psychiatric symptoms are found to be caused by the connectivity between brain circuits rather than just the functions of a specific brain area, Lozano said. These networks are linked through pathways deeper in the brain than can be reached through targeting a single region near the surface of the skull, he added. This is why other approaches to stimulation such as TMS -- which can only access the cortical surface of the brain -- may be less effective, he noted.

Multiple brain areas are involved in depression and this is likely why there are multiple symptoms including emotional issues where mood is depressed, sleep disturbance, weight fluctuation, low self-esteem and anhedonia (the inability to enjoy usually pleasurable activities), Lozano said. Many of the regions are interconnected, and a deficiency in one area is transferred to another, he added. Through DBS it has been possible to identify the nodes where the issue lies and affect the region locally, which leads to remote changes, he said.

There is now evidence of the specific network of brain regions that are not functioning adequately, with several being viable targets for DBS, agreed Dr Helen Mayberg, professor, psychiatry, neurology and radiology, Emory University, Georgia.

DBS has shown efficacy when targeting different regions in the brain, and this may be explained by the very heterogeneous nature of depression symptoms, said Dr Bruno Millet, professor, adult psychiatry, Institute of Clinical Neuroscience Rennes, France. Sufferers may not have a specific localised brain lesion but rather a network of dysfunctional lesions, he said.

It is possible that targeting regions such as the Brodmann area 25 /subcallosal cingulate (SCC) white matter or nucleus accumbens (NAcc) and medial forebrain bundle may all be approaching a single network but from different angles, Coenen agreed. It is still too early to say whether there is a specific region that is most effective or to be confident enough to launch a large-scale pivotal trial investigating one of these targets, he added.

Mayberg, Lozano and Holtzheimer’s line of research has been focused on defining depression circuits using neuroimaging and targeting DBS at a specific brain region called the SCC. The three teams and additional groups have published several papers demonstrating six-month and long-term follow up efficacy data for this site as a target for TRD, Mayberg clarified.

Results suggest that at six months there is a significant improvement in depression symptoms as measured by the Hamilton Depression Rating Scale (HAM-D), she said at the British Association for Psychopharmacology in July in Harrogate, UK. This data represent six separate publications by four different teams on data for six months and longer outcome at this site.

Patients who respond don’t relapse unless the battery runs out, she noted.

The hypothesis is that by changing the activity at the SCC, it is possible to change the functional connectivity within the network of regions, said Holtzheimer. However, various other brain regions have shown promising results, he said, including the ventral striatum, nucleus accumbens (NAcc) and the medial forebrain bundle.

Preliminary data suggests DBS produces positive effects in reducing depression symptoms by targeting the NAcc, said Millet. The study targeted either the caudate or the NAcc, both of which are structures in the limbic system in patients with TRD, he noted. So far, he added, patients followed out to three months are showing improvements in their symptoms if DBS targeted the NAcc.

In collaboration with Dr Thomas Schlaepfer, University Hospital, Bonn, Germany, Coenen hypothesised that by targeting another single point in the brain called the medial forebrain bundle it is possible to influence the network that seems to broadly connect several brain regions thought to have a pathological role in depression.

Data published from a small pilot study shows that by placing an electrode in the medial forebrain bundle with low-voltage stimulation, it was possible to produce rapid and robust antidepressant effects in six of the seven patients treated (Schlaepfer TE. Biol Psychiatry. 2013;73(12):1204-12).

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