TREATING ADDICTIONS WITH DEEP BRAIN STIMULATION IS PREMATURE BUT WELL-CONTROLLED CLINICAL TRIALS SHOULD BE PERFORMED

Authors

  • FLORENCE VORSPAN,

    1. Service de Psychiatrie, Hôpital Fernand Widal, AP-HP and Neuropsychopharmacologie des Addictions INSERM U70 – CNRS UMR8206 Pres-Sorbonne Paris Cité, Paris, France
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  • LUC MALLET,

    1. Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, INSERM UMR_S 975 – CNRS UMR 7225 Université Pierre et Marie Curie, Brain and Spine Institute, Paris, France
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  • JEAN-CHRISTOPHE CORVOL,

    1. Centre d'Investigation Clinique et Service de Pharmacologie, Hôpital Pitie-Salpêtrière, AP-HP, Paris, France
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  • ANTOINE PELISSOLO,

    1. Service de Psychiatrie, Hôpital Pitie-Salpêtrière, AP-HP et Centre Émotion CNRS USR 3246, Université Pierre et Marie Curie, Paris, France. E-mail: florence.vorspan@lrb.aphp.fr
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  • JEAN-PIERRE LÉPINE

    1. Service de Psychiatrie, Hôpital Fernand Widal, AP-HP and Neuropsychopharmacologie des Addictions INSERM U70 – CNRS UMR8206 Pres-Sorbonne Paris Cité, Paris, France
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Carter & Hall [1] are right when they say that the proposals to treat addiction with deep brain stimulation are premature, but we strongly disagree when they put on the same level the proposals to conduct clinical trials to assess the efficacy and safety of deep brain stimulation (DBS) in addicted patients. The authors propose minimal requirements for what could be the good practices of clinical trials with this technique. First, because the procedure has substantial risks, the trials should be aimed only at ‘severely debilitating forms of addiction that carries a high risk of morbidity or premature mortality’ and ‘that has not responded to adequate trials of effective treatment’. Secondly, ‘reasonable expectation’ of the treatment efficacy should be ascertained.

The procedure has substantial risks indeed. The risk of intracerebral haemorrhages is reported as between 0.2–5% and the risk of infection (of variable severity) between 1.8 and 15.2% in Parkinson disease, where the procedure has been performed for the last 15 years [2]. The risk of behavioural and emotional disturbances also has to be taken into account, the most serious ones being the risk of mania (1.9% in a meta-analysis of 921 patients with Parkinson disease [3]), psychosis or suicide. The ability of the team performing the surgery to modulate the stimulation parameters seems crucial in these aspects, as the hypomanic symptoms depend upon the location of the contact electrode and the parameters of the stimulation [4].

Conversely, all those risks have to be balanced with the spontaneous risk of mortality and morbidity (psychiatric disorders including suicide, infectious diseases, cardiovascular complications) in severely addicted patients. For overdoses only, the crude mortality rate is estimated to be around two per 100 person-years in a recent meta-analysis of studies in heroin addicts [5]. Cocaine has been associated with around 14% of drug-related deaths in the city of London [6], as well as with around 14% of drug-related deaths in newly released prisoners [7]. In high-risk patients, it would be ethical to test DBS in order to assess its benefice/risk balance.

Carter & Hall judge that the scientific rationale for the use of DBS in addiction is poor. They advocate for more pre-clinical research, saying that ‘pre-clinical evidence of likely benefice cannot be satisfied yet’. It is not the case when rodents are considered (see Rouaud et al. [8], who showed an efficacy of DBS of the subthalamus nucleus in two models of cocaine dependence). Of course, clinical reports of patients implanted for Parkinson disease who reported an improvement in one addiction or another are limited to a few; but how can it be different knowing that unstable psychiatric conditions including severe addictive behaviour are exclusion criteria in DBS programmes? Precise theoretical basis for the choice of stimulated targeted brain regions is poor in pre-clinical studies, because an animal brain cannot provide specific targets for the complex behaviour that constitutes drug dependence in humans. In this respect, the efficacy of DBS of the subthalamic nucleus in treating severely impaired obsessive–compulsive patients is particularly appealing. The short-term improvement was notable [−13 points on the Yale–Brown Obsessive Compulsive Scale (YBOCS)][9], although long-term data regarding improvement are still to be recorded. Severe addictions have both an obsessive and a compulsive dimension. Patients with relapsing addictions endorse the description of craving as composed of those two dimensions of obsessions and compulsions, and in the most severe patients this craving is refractory to pharmacological and psychotherapeutic treatment. This is why we also advocate that proper clinical trials should be performed. If it is not, the risk of spreading of DBS as a treatment before its efficacy and safety in addicted patients can be well-established exits. Fins et al. [10] also regret that the Food and Drug Administration's (FDA) humanitarian device exemption allows treating severe psychiatric disorders with DBS outside well-conducted clinical trials.

Finally, when dealing with the cost, the authors confound the cost of DBS trials and the costs of its generalization as a treatment of addiction. The costs estimated by the authors (US$50 000 plus maintenance of US$10 000 per year and per patient) have to be compared to the millions of dollars spent each year in the costs of clinical trials.

Therefore, although we discourage using DBS for the treatment of addiction in clinical practice, we advocate the idea that DBS stimulation effect should be assessed with the following conditions:

  • • clinical trials conducted with ethical rules and (as it is mandatory) properly registered as suggested by the authors to avoid publication bias;
  • • with the appropriate design, including double-blind periods and appropriate statistical power to achieve or rule out a proof of concept;
  • • be limited to severely impaired patients with life-threatening conditions who did not respond to at least two adequate trials of the most effective known treatment;
  • • excluding addictions where a pharmacological maintenance treatment with a proven efficacy exists (mainly smoking and heroin dependence), privileging treatment of severe cocaine or amphetamine dependence; and
  • • closely monitoring efficacy and safety.

Declarations of interest

None.

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