Background: Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to 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 outcome 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 crossover 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 improvement 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.

These results are consistent with the assumption of hyperfunctioning dopaminergic cortico-subcortical circuits in schizophrenia, which might be related with an alteration of subcortical structures, such as the hippocampus, along the course of the disease. According with these results, hippocampus abnormalities may serve as a prognostic marker of clinical outcome in patients with a first-episode psychosis.

G), degree of fibrosis (F), previous treatments, basal viral load (BVL), treatment duration, viral load at 12 weeks post-treatment, adherence and adverse effects (AEs). Effectiveness was evaluated according to SVR12. Results Ninety-one patients (57.1% men) received treatment with DAAs, with a mean age of 55.6±10.4 years; 20 (22%) were coinfected with HIV, and 55 (60,4%) had BVL >800 000 UI/mL. The genotype distribution was: 29 (31.9%) G1a, 28 (30.8%) G1b, 1 (1.1%) G2, 15 (16.5%) G3 and 18 (19.8%) G4. Degree of fibrosis: 27 F0-F1, 16 F1, 10 F2, 15 F3, 2 F3-F4 and 14 F4; 7 (7.7%) patients were without data (WD). There were 75 (82.4%) naive patients; 6 had received treatment with DAAs (2 with two different lines). Treatment distribution was: 36 (39.6%) glecaprevir/pibrentasvir, 28 for 8 weeks and 8 for 12 weeks; 29 (31.9%) elbasvir/grazoprevir, 28 for 12 weeks and 1 for 16 weeks; 23 (25.3%) sofosbuvir/velpatasvir for 2 weeks, 2 with ribavirin; 1 (1.1%) ledipasvir/sofosbuvir for 8 weeks; 2 (2.2%) sofosbuvir/ velpatasvir/voxilaprevir for 12 weeks, both after relapse to two previous lines with DAAs. The response observed was: glecaprevir/pibrentasvir 32 SVR12, 3 WD and 1 treatment suspension because of the patient's poor clinical condition; elbasvir/grazoprevir 26 SVR12 and 3 WD; sofosbuvir/velpatasvir 17 SVR12, 3 WD, 1 died (sepsis) and 2 virological failure (VF) (both G3, 1 F3, 1 F4, 1 relapsed to DAAs); ledipasvir/sofosbuvir: 1 SRV12; sofosbuvir/velpatasvir/voxilaprevir 2 SRV12. Of the total evaluable responses (n=80), 78 (97.5%) SRV12 and 2 (2.5%) VF were observed. Conclusion and relevance Our data confirm the effectiveness of the new DAAs, with SVR12 >95%, and are consistent with clinical trials which show that patients with G3 have the worst SVR12 rates.