EBioMedicine 51 (2020) 102568 Contents lists available at ScienceDirect EBioMedicine journal homepage: www.elsevier.com/locate/ebiom Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial Iluminada Corripioa,b,c, Alexandra Rolda na,b, Salvador Sarro  c,d,e, Peter J. McKennac,d,*, Anna Alonso-Solís , Mireia Rabella , Anna Díaz , Dolors Puigdemonta,b,c, Víctor Pe a,b,c a,c a,b rez-Sola c,f,g,  Enric Alvareza,b,c valo , Pedro P. Padilla , Jesus M. Ruiz-Idiago , Rodrigo Rodríguezk, , Antonio Are d,h d,i d,j Joan Moletk, Edith Pomarol-Clotetc,d, Maria J. Portellaa,b,c a  Biomedica-Sant Pau (IIB-SANT PAU), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Psychiatry Department, Institut d'Investigacio b Department of Psychiatry and Forensic Medicine, Universitat Auto noma de Barcelona (UAB), Barcelona, Spain c n Biomedica en Red de Salud Mental (CIBERSAM), Madrid, Spain Centro de Investigacio d FIDMAG Germanes Hospitala ries Research Foundation, C/. Dr. Antoni Pujadas 38, 08830 Sant Boi de Llobregat, Barcelona, Spain e Psychiatry Department, Benito Menni CASM Hermanas Hospitalarias, Sant Boi de Llobregat, Spain f Psychiatry Department, Institut de Neuropsiquiatria i Addicions, Hospital del Mar, Barcelona, Spain g IMIM (Hospital del Mar Medical Research Institute), Universitat Auto noma de Barcelona (UAB), Barcelona, Spain h Psychiatry Department, Hospital Sagrat Cor Hermanas Hospitalarias, Barcelona, Spain i Psychiatry Department, Centro Neuropsiquia trico Nuestra Sen~ ora del Carmen Hermanas Hospitalarias, Zaragoza, Spain j Unitat Polivalent Barcelona Nord Hospital, Hospital Mare de Deu de la Merce Hermanas Hospitalarias, Barcelona, Spain k Neurosurgery Department, Hospital de la Santa Creu i Sant Pau, Universitat Auto noma de Barcelona (UAB), Barcelona, Spain A R T I C L E I N F O A B S T R A C T Article History: Background: Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% Received 11 November 2019 of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment Accepted 18 November 2019 resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to Available online xxx uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary out- come measure was PANSS total score, as assessed fortnightly. Methods: Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/ intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind cross- over phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed). Findings: One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improve- ment criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators’ knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively). Interpretation: These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects. © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) 1. Introduction * Corresponding author at: FIDMAG Germanes Hospitala ries Research Foundation, Schizophrenia is a severe and disabling mental disorder character- C/. Dr. Antoni Pujadas 38, 08830 Sant Boi de Llobregat, Barcelona, Spain. ized by positive, negative and cognitive symptoms, affecting around E-mail address: mckennapeter1@gmail.com (P.J. McKenna). 1% of the population worldwide [1]. It is estimated that around https://doi.org/10.1016/j.ebiom.2019.11.029 2352-3964/© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) 2 I. Corripio et al. / EBioMedicine 51 (2020) 102568 NCT01725334) aimed to use electrode placements in the NAcc or the Research in Context ventral tegmental area, with the aim of improving negative symp- toms; however, this trial was abandoned due to lack of recruitment. Evidence before this study A currently recruiting trial in Baltimore (Clinicaltrials.gov indentifier Poor response to antipsychotic drug treatment is a well-recognized NCT02361554), targets the substantia nigra pars reticulata; its ratio- problem in schizophrenia. Deep brain stimulation (DBS) has been nale is that local inhibitory effects will result in disinhibition of the used in treatment resistant major depression and obsessive-com- mediodorsal thalamic nucleus and lead to improvement in positive pulsive disorder, but trials are so far lacking in schizophrenia. Liter- and cognitive symptoms. ature review to confirm the absence of existing trials included (a) We report the outcome of the first completed trial of DBS in treat- searching PubMed using the terms deep brain stimulation and ment resistant schizophrenia. Because of the uncertainties concern- schizophrenia and checking the references of all relevant publica- ing electrode placement we decided to test the effectiveness of two tions; (b) checking ClinicalTrials.gov; and (c) personal communica- targets. One was in the ventral striatum, specifically the NAcc, and tion with the investigators of a currently recruiting American trial. the other was the subgenual ACC. Choice of these two sites was driven partly by the fact that both have been employed in obsessive- Added value of this study compulsive disorder and/or major depression, and partly because both sites can be considered to be in some sense characterized by This initial trial suggests that DBS might be beneficial in some neuronal overactivity in schizophrenia, and so potentially susceptible patients with treatment resistant schizophrenia. Of particular to the functional inhibitory effects of DBS. In the case of the NAcc note was the near-complete disappearance of positive symp- there is longstanding circumstantial evidence for a functional dopa- toms (delusions and hallucinations) in two patients with mine excess in the disorder [14], with current findings pointing to nucleus accumbens electrode placements. increased dopamine synthesis capacity in the striatum [15]. At a the- oretical level positive symptoms (in particular delusions and halluci- Implications of all the available evidence nations) have also been linked to ventral striatal overactivity via The apparent positive effects of DBS in schizophrenia in this Kapur’s [16] influential ‘aberrant salience’ proposal, of increased and trial need to be treated with caution given the small numbers inappropriate dopamine activity giving rise to abnormal reward pre- and mainly open label evaluation. It will also be important to diction error signals. Also relevant to the decision to employ a ventral determine whether and to what extent clinical improvement striatal electrode placement is the fact that this part of the basal gan- can be obtained without psychiatric adverse effects. glia receives major afferent input from the hippocampus, which has been considered to play a role in the pathophysiology of schizophre- nia and has been proposed as a target for DBS [11]. The choice of a subgenual ACC placement was based on the find- 20 30% of patients are resistant to conventional antipsychotic drug ing of failure of de-activation in the medial frontal cortex, described treatment [2], and less than half of such patients (40.1%, 95% confi- by ourselves [17] and others [18]. This failure is presumed to reflect dence interval 36.8% 43.4%) respond to the most effective of the sec- dysfunction in the so-called default mode network, a set of brain ond-generation or atypical antipsychotics, clozapine [3]. Other regions that are normally active at rest but which de-activate during psychopharmacological strategies, in particular the use of a range of performance of a wide range of attention-demanding tasks; the drugs with glutamatergic actions, have so far failed to fulfil their medial frontal cortex including the pregenual and subgenual por- promise, either for negative symptoms [4] or for all symptoms [5]. tions of the anterior cingulate cortex, but also more rostral regions Deep brain stimulation (DBS) is a well-established treatment for forms one of two prominent midline ‘nodes’ or ‘hubs’ of this network Parkinson’s disease and other movement disorders, whose use has [19]. On these grounds, the medial frontal cortex represents a more been extended in recent years to treatment resistant psychiatric ill- logical cortical target for the local inhibitory effects of DBS than the ness [6]. The technique involves high frequency stimulation of deep dorsolateral prefrontal cortex, which is also implicated in schizophre- brain areas through electrodes implanted under stereotactic surgery. nia but where the abnormality takes the form of hypofunction [20]. It is believed to work primarily by producing functional inhibition in In this paper we report clinical and functional outcomes from the the region around the electrode, but excitatory effects on local axons trial. Neuropsychological and functional imaging findings will be and more distant excitatory effects may also play a part [7]. It has reported in future communications. additionally been argued that the intervention may act in the longer term to correct pathological brain activity in brain networks with 2. Methods connections to the implantation site [8]. Importantly, unlike other forms of psychosurgery, DBS is reversible, i.e., the stimulation can be 2.1. Design turned off (and if necessary the electrodes explanted) without any permanent loss of function. The trial had a combined open (6+ month) and double-blind To date, DBS has been employed principally in treatment resistant crossover (24 weeks) design. The 24-week crossover phase length patients with two psychiatric disorders, obsessive-compulsive disor- was based on previous experience by one of the two groups of inves- der and major depression, with broadly encouraging results in both tigators with DBS for depression [21]. The aim was to recruit 8 cases [9,10]. The electrode placements most frequently employed patients who would be randomly assigned 1:1 to electrode place- have been in or around the nucleus accumbens (NAcc) in the former ments in either the NAcc or the subgenual ACC. This study is regis- disorder [9], and in this site and the subgenual anterior cingulate cor- tered with ClinicalTrials.gov (identifier NCT02377505). tex (subgenual ACC) in the latter [10]. The potential use of DBS in treatment resistant schizophrenia is currently a topic of considerable 2.2. Participants discussion [11,12], with much of the debate focusing on where to site the electrodes. Practical experience, in contrast, is virtually non-exis- Patients were recruited from the outpatient, inpatient and residen- tent. Plewnia et al. [13] reported beneficial effects of DBS on obses- tial facilities of two mental healthcare organizations in Barcelona: FID- sions and compulsions using an NAcc electrode placement in a MAG Germanes Hospitala ries and the Hospital de la Santa Creu i Sant patient with residual schizophrenia, but this patient had no psychotic Pau, plus referrals by other interested clinicians. Inclusion criteria were: symptoms. A trial in Toronto (Clinicaltrials.gov identifier age 18 55 years, having a diagnosis of schizophrenia according to I. Corripio et al. / EBioMedicine 51 (2020) 102568 3 DSM-IV criteria, having a five-year minimum duration of illness and was randomized to 12 weeks with the stimulation ‘on’ followed by showing evidence of treatment resistance. For treatment resistance the 12 weeks ‘off’ or vice-versa. In case of worsening, the patient could following were required: (a) presence of continuing positive symptoms be withdrawn from the study if necessary and the stimulation turned without remission for two years; (b) poor response to treatment with at on again (if it was currently switched off). Pharmacological treatment least two different antipsychotics, including at least one atypical anti- could not be modified throughout the study period, except for pre- psychotic (not including clozapine) given in adequate doses for a period scription of benzodiazepines or hypnotics if required. of at least 6 weeks; and (c) having been treated with clozapine with All patients gave written informed consent. The study was in line either no improvement at adequate dosage or poor tolerance. It was with the Declaration of Helsinki, and was approved by the hospital anticipated that most patients would also show negative symptoms, but ethical committee and the Spanish regulatory drug agency (Agencia presence of these was not an inclusion criteria. While not forming part Espan~ ola de Medicamentos y Productos Sanitarios). of current definitions of treatment resistance, we added a requirement that the patients had been treated with ECT at some point without sus- 2.3. Assessments tained improvement, unless this treatment was contra-indicated or not tolerated or had been refused. This was in the interests of focusing on In addition to PANSS total score, which was the primary outcome patients in whom all other potentially effective treatment options had measure, and its positive and negative subscales, assessments been tried [22]. included the Psychotic Symptom Rating Scales (PSYRATS) [24], the At the time of study entry the patients were required to have a Scale for the Assessment of Negative Symptoms (SANS) [25], the Cal- score of 4 (moderate) or greater on at least two of the Positive and gary Depression Scale for Schizophrenia (CDSS) [26] and the Global Negative Symptoms Scale (PANSS) items, delusions, hallucinatory Assessment of Functioning scale (GAF) [27]. Two social functioning behaviour, suspiciousness, unusual thought content, or alternatively scales were also used, the Personal and Social Performance (PSP) a score of 6 (severe) or greater on one symptom. They also had to Scale [28] and the Social Functioning Scale [29]. score 6 or greater (severely ill) on the Clinical Global Impression Symptomatic changes were evaluated every two weeks with the (CGI) scale and to have been on stable doses of treatment for at least PANSS until the end of the trial. The remaining clinical scales were two months. Women of childbearing age had to have a negative preg- administered at the main study points (i.e., baseline, immediately nancy test within 72 h pre-study and had to be using contraception. before the crossover phase and at termination). Adverse events were Exclusion criteria included: (a) contraindications to neurosurgery or assessed in detail monthly by the member of the trial team perform- DBS (e.g. pacemaker); (b) diagnosis of epilepsy or clozapine-induced ing the psychiatric and social evaluations. Following termination seizures currently requiring treatment with anticonvulsants; (c) pres- from the trial patients continued to be followed up by members of ence of suicidal or self-harming behaviour or ideation in the last two the trial team or their treating clinicians. years; (d) significant cognitive impairment, as defined by WAIS III IQ In the stabilization phase the assessors were blind to which elec- <70, or performance in the severely impaired range on memory or trode placement each patient had and to any changes in stimulation executive function tests on more detailed neuropsychological testing; parameters that were made. Both the patients and the clinicians (e) presence of significant cardiovascular and/or cerebrovascular disease were unaware of the patients’ stimulation status during the crossover (defined as history of cerebrovascular events, clinical symptoms of car- phase. Measures to assess the success of blinding were not employed. diac or vascular disease, ischaemic changes on ECG, uncontrolled hyper- tension); (f) if female, breastfeeding; (g) history of drug or alcohol abuse/dependency in the previous two years. 2.4. Surgical procedure Only patients who were able to fully understand the potential benefits and risks of treatment were considered for the trial. The con- Electrode implantation was in the white matter adjacent to the sent process was rigorous, and included discussions with both the Cg25 region (subgenual ACC) and in the NAcc. The DBS pulse-gener- patient and his/her family if appropriate. Patients were also required ating device was implanted abdominally. Prior to surgery, a Leksell G to have a caregiver or identified responsible person (i.e., family mem- stereotactic frame (Elekta Instruments, Atlanta, GA, USA) was fitted ber, social worker, case-worker, or nurse) who spent at least four to the patient’s head. Using the StealthStation 7 (Medtronic Inc., Min- hours/week with the patient and was able to provide advice and sup- neapolis, MN, USA) the CT scan with the stereotactic frame was fused port concerning the study procedures. A committee including the to the MRI image to calculate the surgical targets. The target subge- patient’s psychiatrist, an independent senior psychiatrist and a neu- nual ACC white matter was delimited as follows: in a midline T2 sag- rosurgeon further considered the feasibility of enrolling each patient ittal image the cingulate gyrus inferior to the genu of the corpus into the study. callosum was identified; next, a line was traced from this point of the The patients were randomly assigned 1:1 to one of the two elec- corpus callosum to the anterior commissure and the mid-point was trode placements using PROC PLAN of SAS (version 9). Randomization identified; an image was then taken of the T2 coronal section corre- was carried out by central allocation using computer generated ran- sponding to the plane of the mid-point and the definitive coordinates dom numbers: an independent statistician from another department were calculated for the transition area between the white and grey generated the list, assigned the target sequence and communicated it matter for BA 25. The NAcc target was determined measuring the dis- to one of the investigators in a sealed envelope. This investigator tances from the anterior commissure (AC) and the posterior commis- communicated the target to the neurosurgeons. A block randomiza- sure (PC) with the following coordinates: x = 6 8 mm lateral to tion method was used. A similar procedure was followed for the ran- midpoint, y = 1 3 mm anterior to the AC, Z = 4 mm inferior to the AC domization in the crossover phase (which also took into account the line (see Fig. 1 for location of the NAc and subgenual ACC electrode first randomization to ensure balanced allocation within the targets). implantations in subjects N5 and N7, respectively). In the operating After undergoing surgery to implant the electrodes, stimulation was room, with the patient under general anaesthesia, a burr hole was started within 48 72 h and lasted until the patient was clinically sta- drilled in front of the coronal suture and laterally at a variable dis- ble, with a minimum period of 6 months. If the patient achieved tance from the midline seeking to avoid the ventricles. DBS electro- symptomatic response (defined as an improvement  25% in PANSS des (Medtronic model 3387, Medtronic Inc., Minneapolis, MN, USA) total score, calculated using the formula: [PANSS baseline score were implanted bilaterally. Each of the four electrode contacts was PANSS post-scores] £ 100/ [PANSS baseline score-30] [23], which tested intraoperatively at maximal voltage (9.0 V). During the same was maintained in at least 50% of the subsequent PANSS ratings, he surgical procedure, a programmable internal pulse generator (Activa or she then entered the 24-week double-blind crossover phase, and PC, Medtronic Inc., Minneapolis, MN, USA) was implanted 4 I. Corripio et al. / EBioMedicine 51 (2020) 102568 Fig 1. Location of the deep brain stimulation leads in the (A) nucleus accumbens (NAcc) and in the (B) subgenual anterior cingulate cortex (subgenual ACC) in right and left hemi- spheres. The upper row of images corresponds to coronal and sagittal slices; the lower images correspond to axial section in 2D and 3D views. The 3D plane shows a volumetric reconstruction of both targets (bilateral NAcc in metallic blue; left subgenual ACC in purple, right subgenual ACC in blue. Images were generated using the SureTune software (Med- tronic Eindhoven Design centre, MEDC). I. Corripio et al. / EBioMedicine 51 (2020) 102568 5 subcutaneously in abdominal wall tissue. The procedure was carried electrodes. As a result the generator and electrodes were removed out under general anaesthesia. three months after surgery. Stimulation was started 48 72 h after surgery using unilateral left All but one of the seven remaining patients showed ultra-treat- stimulation, (contact anode, case cathode), with the initial following ment resistant illness, according to Howes et al. [30]. In the remaining parameters: 2.5 V, 60 microseconds (ms) pulse width and 130 Hertz patient (N6) clozapine was not tolerated at doses higher than (Hz) of frequency; these were chosen based on prior experience by 100 mg/day (the dose she was taking at study entry). These seven our group (Sant Pau) with DBS in patients with major depression. patients’ baseline characteristics and electrode placement after first Two contacts with good levels of impedance were selected taking randomization are shown in Table 1. Three patients were implanted into account the position of the electrode within the selected area in the NAcc (N1, N5, N6) and 4 patients in the subgenual ACC (N2, N4, (e.g., patient N1 showed had a contact outside the NAcc and so this was N7, N8). All patients were receiving treatment with clozapine aug- not used). After a week bilateral stimulation was begun, again based on mented with different antipsychotics. Highest stimulation parame- previous clinical experience with DBS in psychiatric populations. ters achieved during the study period in each patient are shown in During the stabilization phase stimulation parameters were modi- supplementary Table S1. fied individually for each patient by an independent clinician depending on clinical state, and guided specifically by the presence 3.2. Stabilization phase and degree of positive symptoms. Patients were not informed about any changes. The sequence of changes to maximize the therapeutic The open stabilization phase lasted between 8 and 20 (average 13) effect was (1) increasing voltage up to 7.5 V, (2) increasing pulse months. Average scores over first eight months of treatment (the width or frequency up to 210 ms/Hz, and (3) changing active contacts period during which all patients remained in the stabilization phase), or mode. separated according to electrode placement, are shown in Fig. 2. Indi- vidual scores for the patients over the entire stabilization phase are 2.5. Data analysis shown in Supplementary Figs. S1 and S2. It is noteworthy that two of the three patients with NAcc placements showed a nearly full remis- Formal analysis of changes in PANSS and other ratings was con- sion (N1) and full remission apart from intermittent recurrences (N6) sidered to be of limited value due to the small sample size, and is also of positive symptoms (which took the form exclusively of delusions complicated by the fact that the endpoint criteria (i.e., progression to and hallucinations in both cases). One of these patients (N1) has been crossover phase or termination due to lack of effectiveness) reported previously [31]. depended on response to DBS. For completeness, however, statistical Given the limitations of applying statistical analysis to the data, models were fitted to the PANSS data (PANSS total, PANSS positive, detailed results are reported in the Supplementary material. Briefly, PANSS negative) for the sample as a whole (i.e., not separating by however, testing across the whole sample (N = 7) revealed a signifi- electrode placement), considering only the stabilization phase. Linear cant effect of DBS on PANSS total, positive symptoms and negative mixed models with repeated measures evaluated the effect of DBS by symptoms scores (all p<0.001), when the baseline (i.e., DBS off) was considering the PANSS scores in the visit previous to the surgical compared to all remaining time points in the stabilization phase (i.e., implant and all the subsequent assessments up till the end of the sta- DBS on) using a repeated measures linear mixed model. This result bilization phase. This model also tested the effect of time (evolution was replicated for PANSS total score and positive symptoms score, of PANSS scores across time, discounting the DBS off-on effect) but not negative symptoms score, when a simpler paired t-test was including also individual slopes and intercepts (i.e., the random performed, considering the baseline (DBS off) and last observation effects part of the model). Paired t-tests were additionally carried (DBS on) (PANSS total p = 0.007; PANSS positive p = 0.002; PANSS out, considering individual PANSS scores at the baseline visit and at negative p = 0.18). the last recorded visit in the stabilization phase. Statistical analyses were conducted with version 3.6.0 of the R software. 3.3. Double-blind crossover phase 2.6. Role of the funding source Four patients (N1, N2, N4 and N6) met the symptomatic response The funder of the study had no role in study design, data collec- criteria, 2 with NAcc (N1 and N6) and 2 (N2 and N4) with subgenual tion, data analysis, data interpretation or writing of the report. The ACC placements (for percentages of improvement see Supplementary corresponding author had full access to all the data in the study and Table S2). Three of these patients entered the crossover phase. Patient had final responsibility for the decision to submit for publication. N1 (NAcc placement) entered in an ‘on’ phase. Six weeks after the stimulation was switched to ‘off’ a worsening in psychotic symptoms 3. Results became evident, which took the form mainly of a worsening of nega- tive symptoms [PANSS scores immediately before entering crossover 3.1. Patient characteristics and in the first switch-off visit where a worsening of symptoms was evident: total: 64 vs. 73, positive symptoms: 14 vs. 14, negative Slightly less than thirty patients were considered for the trial symptoms: 16 vs. 21]. This patient remained in the trial until the end (Sant Pau N = 14; FIDMAG N = 13 15, exact numbers not recorded). of the crossover phase. Patient N2 (subgenual ACC placement) began The most common reason for exclusion was a lack of perceived need in an ‘off’ phase. This was followed by a worsening of psychotic for treatment by the patient. Other reasons in individual cases symptoms within a few days [PANSS scores: total: 79 vs. 98, positive included failure to meet diagnostic criteria, ongoing substance abuse, symptoms: 17 vs. 23, negative symptoms: 18 vs. 24]. The patient was presence of comorbid psychiatric disorder (obsessive-compulsive admitted with suicidal ideation, the stimulation was switched back disorder and autistic spectrum disorder) and failure to meet severity on, and he was withdrawn from the study. Patient N4 (subgenual criteria. ACC placement) also began in an ‘off’ phase and also showed a wors- Eight patients were enrolled in the study. The first patient was ening of psychotic symptoms, in this case two weeks later [PANSS recruited on 28/11/2014 and the last on 20/04/2017. One patient scores: total: 47 vs. 93, positive symptoms: 16 vs. 25, negative symp- (N3) did not proceed to stimulation; he suffered a right internal cap- toms: 13 vs. 29. The stimulation was switched back on, and the sule haemorrhage immediately after surgery and subsequently patient was withdrawn from the study. Details of the three patients’ developed infection in the device which threatened to spread to the courses during the crossover phase are summarized in Fig. 3. 6 I. Corripio et al. / EBioMedicine 51 (2020) 102568 The fourth patient who met the symptomatic response criteria (N6, NAcc placement) achieved excellent remission of psychotic symptoms, Electrode Placement although these intermittently returned, requiring frequent alterations of Subgenual ACC Subgenual ACC Subgenual ACC Subgenual ACC stimulus parameters. After 10 months in total, at a time when she had been symptom free for several weeks, the stimulation was turned off unknown to the patient and the investigators. (What happened is NAcc NAcc NAcc NAcc unclear but possibilities include either that the off button had been acci- dentally touched when her stimulus parameters were checked during a clinic visit, or that the stimulator function was interrupted when she CGI passed through a security scanner at a tourist attraction the same day.) 6 6 6 6 6 6 6 6 Her symptoms (delusions and auditory hallucinations) returned within GAF 40 25 25 30 30 30 31 31 24 h and persisted until the switching off event was discovered a few days later. The patient reported subjective improvement 20 min after PANSS General the current was turned back on. The next day she was symptom free. The patient was given the option of formally entering the crossover phase, but declined. Two spontaneous disconnections also occurred in N5 (NAcc place- 46 54 27 39 49 36 37 33 ment) at the beginning of treatment. These lasted less than a week on both occasions and were not obviously associated with clinical PANSS Negative changes. 3.4. Secondary outcomes 24 28 28 23 29 12 21 32 Clinical Gobal Impression of severity of illness. Average PSYRATS and SANS scores from baseline to randomiza- PANSS Positive tion or termination for all 7 patients are shown in Table 2. Mirroring the pattern with the PANSS, reductions were evident on both scales. Depression scores also decreased. Improvements were also seen on the GAF and CGI. There was evidence of improvement on one of the 27 26 21 22 24 17 27 22 two social functioning scales used, the PSP (see Table 2), but not on PANSS Total the other, the SFS (see Supplementary Table S3). 3.5. Adverse events 108 102 97 76 84 65 85 87 DBS was generally well-tolerated in the 7 patients who proceeded Intolerance (confusion) to electrode activation. However, one patient with an NAcc place- ment (N1) developed akathisia after the stimulation was changed from unilateral to bilateral; this eventually responded when the stim- Non-response Non-response Global Assessment of Functioning scale; CGI ulation was changed back to unilateral, maintaining the reduced Refused Refused Refused Refused parameters. As noted, during the crossover phase this patient devel- ECT Yes oped worsening of negative symptoms from a previously mild level. This worsening has persisted, despite DBS being resumed and subse- quent alterations in the stimulation parameters. Antipsychotic treatment Patient N5 described an electrical sensation in his trunk and his head Paliperidone depot that occurred occasionally and depended on certain body movements. Ziprasidone 160 Aripiprazole 45 Aripiprazole 20 Paliperidone 3 Olanzapine 10 Clozapine 350 Clozapine 500 Clozapine 600 Clozapine 800 Clozapine 400 Clozapine 100 Clozapine 450 Clozapine 500 Risperidone 6 Examination, including neuroimaging, did not reveal evidence of device Haloperidol 5 100/month Pimozide 10 malfunction (e.g., damaged electrodes or wire connections to the inter- Patients’ baseline characteristics and electrode placement at baseline. (mg/d) nal pulse generator). Changing of the stimulation from unipolar to bipo- lar mode was followed by a resolution of the symptom. After trial end, after 11 months of stimulation in total, patient N6 Illness duration (years) developed behavioural changes compatible with hypomania. Imme- Positive and Negative Symptoms Scale; GAF diately prior to this she had taken a unilateral decision to stop taking antipsychotic medication. Stimulation parameters were initially low- ered with a certain amount of improvement. However, six weeks later she was admitted in a mixed affective state, which responded to treatment with antipsychotics. Since then the patient’s clinical state 24 23 11 10 21 35 has been characterized by mood instability with fluctuations on a 9 8 daily basis, impulsive behaviour and at times suicidal ideation. These Age 46 34 37 53 43 35 38 54 symptoms initially proved difficult to control with mood stabilizers and changes to her DBS parameters, although her mood fluctuations Sex improved after re-instatement of antipsychotic medication (aripipra- M M M M F F F F zole). Currently she is free of prolonged periods of mood disturbance, although she continues to experience spells of depression lasting Patient ID hours or days. Her psychotic symptoms (referential delusions accom- Table 1 PANSS N1 N2 N3 N4 N5 N6 N7 N8 panied by auditory hallucinations) have remained in remission most of the time, though they are prone to re-appear for periods of 12 36 h, often when she is under stress. I. Corripio et al. / EBioMedicine 51 (2020) 102568 7 Fig 2. Symptomatic changes in the 7 DBS treated patients over the first 8 months of the stabilization phase. 3.6. Post-operative course in the patient who did not receive DBS (patient N6). As noted in the Introduction, the NAcc and the ventral striatum of which it forms part is a plausible target for the local func- After suffering a right-sided peri‑operative haemorrhage, patient tional inhibitory effects of DBS, as it is strongly suspected of being a N3 initially showed confusion which lasted four days. After this set- site of functional overactivity in schizophrenia, specifically increased tled he was noted to show improvement in his previously severe dopaminergic activity. Nevertheless, it should be noted that func- active psychotic symptoms. This improvement remained evident for tional imaging studies in schizophrenia have uniformly found that over seven months, but hallucinations and referential delusions ulti- ventral striatal activation in response to reward predictive stimuli is mately re-appeared, although less severely than before the opera- reduced rather than increased as the salience theory predicts [32]. tion. On this basis it is unclear why a functional inhibition produced by Six months after being withdrawn from the trial, the patient DBS would have an ameliorative effect on positive symptoms. Possi- showed no neurological signs, though he had experienced seizures ble explanations for this inconsistency might be in terms of the local which were controlled with anticonvulsant medication. He shows a or more distant excitatory effects of DBS [7], or possibly in terms of lesion in the anterior right internal capsule. modulatory effects on the mesolimbic and mesocortical components of the mesotelencephalic dopamine projection [11]. 4. Discussion In the patients with electrode placements in the subgenual ACC, improvement appeared less marked and, in the two who went on to To our knowledge, this is the first study reporting the effective- meet improvement criteria, was more gradual (see individual graphs ness and safety of DBS in patients with treatment resistant schizo- in Supplementary Fig. S2). Why this should be so is unclear. However, phrenia, all but one of whom were also resistant to clozapine. as noted by Veerakumar and Berton [8], while the motor effects of Although the sample size was small and the variability in treatment DBS in neurological disorders are immediate, the response in psychi- response makes it difficult to generalize, there were indications of atric disorders such as major depression is typically of the order of improvement, with the NAcc appearing to be the more promising of weeks to months, suggesting that longer-term effects on brain net- the two placements employed. Caution is necessary before accepting works of which the implantation site forms part may be relevant. improvement observed under open conditions at face value. How- As noted in the Introduction, our choice of sites for electrode ever, three of the four patients who showed significant improvement placements was guided by a combination of evidence from its use in worsened when the current was switched off under double-blind other psychiatric disorders and pathophysiological findings from conditions; the fourth patient also worsened abruptly when the patients with the disorder itself. Relevant findings from animal stud- device was accidentally switched off without her or her clinicians’ ies have also recently become available and may potentially provide knowledge. further insights into the mechanism of DBS in schizophrenia. Thus, Two out of the three patients with NAcc targeted DBS met the Bikovsky et al. [33] examined the effects of DBS in an animal model symptomatic improvement criterion. In these patients the improve- of schizophrenia in which pregnant females were administered a ment in their main symptoms, delusions and hallucinations, was viral mimic (polyinosinic-polycytidilic acid, poly I:C). The progeny of marked, taking the form of a near complete disappearance (patient mothers administered these or other similar agents have been found N1) and complete absence of these symptoms most of the time to show a variety of behavioural and neuropathological changes 8 I. Corripio et al. / EBioMedicine 51 (2020) 102568 Fig 3. Changes in PANSS total, positive and negative scores in the three patients who entered the crossover phase. reminiscent of schizophrenia, which only emerge in late adolescence the crossover phase that has since proved resistant to all interven- or early adulthood; they also show decreased prepulse inhibition and tions. The features of this state are consistent with negative schizo- disrupted latent inhibition. DBS administered in both the NAcc and phrenic symptoms, but apathy is also a recognized side-effect of DBS the medial prefrontal cortex to such rats in adulthood was found to in Parkinson’s disease [34]. The other patient (N6) developed mood reduce abnormalities in both prepulse inhibition and latent inhibi- instability that has so far lasted over a year, though with a gradually tion. improving course. Depression and mood elevation, which can some- DBS was physically well-tolerated in the seven patients who pro- times be prolonged, are also recognized complications of DBS for Par- ceeded to electrode activation. The only major physical adverse event kinson’s disease with a variety of different electrode placements [34]. was akathisia in one patient with a NAcc placement which appeared It may also be relevant that while this patient was given a diag- after stimulation was changed from unilateral to bilateral; this nosis of schizophrenia before trial entry, lifetime structured psy- improved when the stimulation was changed back to unilateral [31]. chiatric interview at that time revealed a previous one-month On the other hand, lasting psychiatric adverse effects were promi- episode when, after her antipsychotic medication was changed, nent in the two patients with NAcc placements whose positive symp- she developed erotomanic ideation and showed flight of ideas; toms improved. One (N1) developed an amotivational state during psychotic symptoms remained present during this period. It I. Corripio et al. / EBioMedicine 51 (2020) 102568 9 Table 2 Salud Carlos III and the European Regional Development Fund (FEDER) Changes in other scales from baseline to randomization or termination. “Investing in your future”: Miguel Servet research contracts (CPII16/ Mean score at baseline Mean score at 00018 to E.P.-C. and CPII16/00020 to M.J.P.) and Research Projects (§SD) randomization/ (PI12/00042 to E.A., PI12/00686 to S.S and PI18/00880 to P.J.M.). The termination (§SD) project was also supported by Ona Corporation (AMA DABLAM PSYRATS (sum of delu- 44.71§12.65 32.57§21.79 Research Project, IIBSP-AMA-2016-99). sion and hallucination subscales SANS (total score) 55.57§12.97 46.29§23.43 Acknowledgements CDSS 7.29§6.21 3.71§4.79 GAF 31.14§4.49 47.14§17.07 The trial was funded by the Instituto de Salud Carlos III (PI12/ CGI 6 § 0.0 4.14§1.68 Personal and Social Per- 30.83§8.49 42.67§25.91 00042 and PI12/00686). We thank Raymond Salvador for his statisti- formance Scale* cal analysis of the data. The authors are grateful to the patients who * Based on 6 patients, data missing at randomization/termination for 1 patient. consented to participate, and their caregivers, for their huge contri- For scores on the Social Functioning Scale see Supplementary Table S3. bution to making this project possible. PSYRATS Psychotic Symptom Rating Scales; SANS Scale for the Assessment of Negative Symptoms; CDSS Calgary Depression Scale for Schizophrenia; GAF Global Assessment of Functioning scale; CGI Clinical Global Impression of Supplementary materials Severity. Supplementary material associated with this article can be found seems possible, therefore that her diagnosis may actually be in the online version at doi:10.1016/j.ebiom.2019.11.029. schizoaffective disorder. 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