VIENNA (FRONTLINE MEDICAL NEWS) – Even though deep brain stimulation has been used to treat obsessive-compulsive disorder in fewer than 300 patients worldwide, the therapy has had a huge impact on understanding of the disorder, Damiaan Denys, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.

Indeed, the efficacy of deep brain stimulation (DBS) in the most severe, treatment-refractory cases of OCD casts doubt upon the fundamental construct clinicians have relied upon for decades to comprehend OCD: Namely, that affected patients first experience obsessions, which induce anxiety, which then stimulates compulsions, and engaging in those compulsions brings relief and reward, and then the whole cycle starts over again.

That construct may not actually be true.

“Deep brain stimulation will force us to rethink OCD,” predicted Dr. Denys, professor and head of psychiatry at the University of Amsterdam.

What does DBS change, and is there a temporal order? It varies, the psychiatrist said.

“In some patients, anxiety is the first thing that changes. In others, it starts with obsessions. Compulsions do decrease, but it’s difficult. It takes some time, and often we need supplemental cognitive-behavioral therapy (CBT). What changes, mainly, in my experience, is not symptoms, but something outside of OCD: namely, mood. Deep brain stimulation has a huge impact on mood. That’s an interesting finding, because it suggests the possibility that you can change a psychiatric disorder by changing symptoms that are thought of as being outside the disorder,” Dr. Denys observed.

“Another interesting thing is that deep brain stimulation changes things that are not even within psychiatry. When we ask our patients what has been the most profound impact deep brain stimulation has had on their lives, all of them say, ‘It increases my self-confidence.’ And that’s not something that is included in our scales. We assess patients using the HAM-D [Hamilton Rating Scale for Depression] and Y-BOCS [Yale-Brown Obsessive Compulsive Scale] and other measures, but there are still some very important aspects we are not taking into account and that have a profound effect on symptoms. In this case, using deep brain stimulation, we improve self-confidence and thereby change a whole chain of symptoms,” he continued.

Among the 60 highly refractory OCD patients treated by DBS by Dr. Denys and his colleagues at the Amsterdam center over the past 15 years, 15% were cured as a result.

“I purposely use the word ‘cured,’ because they don’t have obsessive-compulsive symptoms, anymore, which is, of course, extraordinary,” Dr. Denys noted.

An additional 35% of patients had a good response, defined as 60%-80% improvement on the Y-BOCS. Ten percent of patients were partial responders, with a 20%-40% improvement on the Y-BOCS. And 15% were nonresponders.

Closed-loop system coming

DBS entails implantation of electrodes deep within the brain to interrupt dysfunctional brain signals in local areas and across neural networks. This dysfunctional brain activity is expressed as symptoms. To date, DBS has been used in what’s called an open-loop system: Patients report the symptoms they’re experiencing and the clinician then adjusts the electrode settings in order to quell those symptoms. This approach is about to change. The technology has improved vastly since the early days, when the electrodes had four contact points. Now they have 64 contact points, and are capable of sending and receiving electrical signals.

“The next step in deep brain stimulation will be a closed-loop system. We will remove the clinician and the patient, and attempt to use a device capable of recording what happens in the brain and then changing electrical activity in response to the recordings. Our purpose will be to block these brain signals in advance of obsessions and compulsions so patients don’t have these symptoms. It’s technically possible. It has been done in Parkinson’s, and I think it’s the next step in psychiatry,” Dr. Denys said.

Indeed, he and his coinvestigators are planning formal studies of closed-loop DBS. For him, the prospect raises three key questions: What are the neural correlates of OCD symptoms? What about the ethics of implanting a device in the brain which by itself results in different life experiences? And will closed-loop DBS have superior efficacy, compared with open-loop DBS?

“How is the mind rooted in the brain, and how is the brain expressed in the mind? It’s the most fascinating question; it’s why we all love psychiatry, and up until now, there are no answers,” he observed.

Significant progress already has been made on the neural correlates question. Dr. Denys and his colleagues have found that when OCD patients with deep brain electrodes engage in cleaning compulsions, their local field potentials in the striatal area show peaks of roughly 9 Hz in the alpha range and in the beta/low gamma range. These patterns may represent compulsive behavior and likely could be useful in steering a closed-loop system. Also, the Dutch investigators have found that 3- to 8-Hz theta oscillations in local field potentials in the striatal area may represent a neural signature for anxiety and/or obsessions.

Using a closed-loop system, he continued, investigators plan to test two quite different hypotheses about the fundamental nature of OCD. One is that obsessions, anxiety, compulsions, and relief are each separately related to different brain areas. The other hypothesis is that one central brain stimulus drives the chain of symptoms that characterize OCD, and that by identifying and blocking that primary signal, the whole pathologic process can be stopped.

Current status of procedure

While Dr. Denys focused on the near future of DBS for OCD, another speaker at the session, Sina Kohl, PhD, addressed DBS for OCD as it exists today, particularly the who, how, and where.

The “who” is the relatively rare patient with truly refractory OCD after multiple drug trials of agents in different antidepressant classes, one of which should be clomipramine, as well as a failed course of CBT provided by an expert in CBT for OCD, of which there are relatively few. In a study led by investigators at Brown University, Providence, R.I., only 2 of 325 patients with OCD were deemed truly refractory ( J Neuropsychiatry Clin Neurosci. 2014 Winter;26[1]:81-6 ). That sounds about right, according to Dr. Kohl, a psychologist at the University of Cologne, in Germany.

The “how” is to deliver DBS in conjunction with CBT. Response rates are higher at centers where that practice is routine, she added.

The “where” is an unsettled question. In Dr. Kohl’s meta-analysis of 25 published DBS studies, electrode placement in four different DBS target structures produced similar results: the nucleus accumbens, the anterior limb of the internal capsule, the ventral striatum, and the subthalamic nucleus. Stimulation of the inferior thalamic peduncle appeared to achieve better results, but this is a sketchy conclusion based upon two studies totaling just six patients ( BMC Psychiatry. 2014 Aug 2;14:214. doi: 10.1186/s12888-014-0214-y ).

Recently, Belgian investigators have reported particularly promising results – the best so far – for DBS targeting the bed nucleus of the stria terminalis ( Mol Psychiatry. 2016 Sep;21[9]:1272-80 ).

Bilateral DBS appears to be more effective than unilateral.

Dr. Kohl and her colleagues in Cologne recently completed a study of DBS in 20 patients. She noted that it took 5 years to collect these 20 patients, underscoring the high bar that’s appropriate for resort to DBS, even though the therapy is approved for OCD by both the Food and Drug Administration and European regulatory authorities. Forty percent of the patients were DBS responders, with a mean 30% improvement in Y-BOCS scores. That’s a lower responder rate than in Dr. Denys’s and some other series, which Dr. Kohl attributed to the fact that in Germany, postimplantation CBT is not yet routine.

Asked about DBS side effects, the speakers agreed that they’re transient and fall off after initial stimulation parameters are changed.

“The most consistent and impressive side effect is that initially after surgical implantation of the electrodes and stimulation of the nucleus accumbens, patients experience 3 or 4 days of hypomania, which then disappears,” Dr. Denys said. “It causes a kind of imprinting, because even a decade later, patients ask us, ‘Could you bring back that really nice feeling?’ It’s 3 days of love, peace, and hypomania. It’s a side effect, but people like it.”

Dr. Denys and Dr. Kohl reported no financial conflicts of interest regarding their presentations.


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