Up to 30% of patients with schizophrenia and 15% with bipolar disorder (BD) are considered treatment-resistant.1,2 Although some strategies have been described for resistant forms,3–5 there is a need of new therapeutic strategies.

Deep brain stimulation (DBS) is a neurosurgical procedure originally developed for treating neurological disorders that involves the implantation of electrodes into brain subcortical nuclei or white matter to deliver electrical stimulation.6 This high frequency stimulation produces functional inhibition in the brain tissue around the electrode, while local and distant excitatory effects may also play a role.6 DBS is adjustable and can be turned-off without any permanent loss of function.

Though DBS has been extended in recent years for treating resistant psychiatric disorders with broadly encouraging results,7,8 but very few trials have been carried out in schizophrenia and BD patients. The only completed trial in schizophrenia reported significant improvement stimulating the nucleus accumbens (NAcc, n=3) and the subgenual anterior cingulate cortex (SACC, n=4), showing NAcc more benefits.9 There is also little evidence of the effects of DBS in patients with BD, being only a minority of the patients included in studies of DBS in mood disorders.7

This manuscript contains a series of the first four clinical cases treated with DBS in Hospital Clínic de Barcelona for these conditions and followed-up for one year.

Participants main baseline clinical and treatment characteristics and electrode placement are shown in Table 1.

All participants were on maintenance ECT. N3 and N4 were on clozapine treatment, while N2 had to be withdrawn twice due to the presence of neutropenia. After 12-month follow-up, no significant psychopharmacological treatment changes were registered.

We present a case series of four patients with treatment-resistant schizophrenia and BD treated with DBS, included in a pilot, last-resource protocol. At the one-year follow-up we observed: (i) A notable and durable therapeutic response in two patients (N1 and N3), a clinically relevant relief in a third (N2) and a lack of a significant response in the last one (N4); (ii) Maintenance ECT could be discontinued in the three responders to DBS, while it was reintroduced in the non-responder participant, without any particular incidence of security; (iii) No surgery related complications or side effects appeared; (iv) No relevant changes in cognitive functioning; (v) Relevant differences between physical activity and sleep time among participants.

Available, limited literature points out to DBS effectiveness for certain serious mental disorders. In the only clinical trial reported so far of DBS in schizophrenia, 4/7 patients met the study symptomatic improvement criteria.9 Similarly, different meta-analysis show that DBS seems effective in reducing resistant depressive symptoms in samples including few BD patients.8,12

Individualizing both the location and the stimulation programming is a key aspect in DBS application. According to available literature, we decided to stimulate SACC in the patient with predominant affective symptoms (N1), while in the rest of participants, where psychotic symptoms predominated, it was decided to stimulate NAcc.8,9 The stimulation plan was designed based on our previous experience using for DBS in neurological diseases and other published protocols with psychiatric patients.9,13 There is initial evidence indicating individual variations in the clinical response to electrical dosing of DBS in depression,13 pointing that future modifications of the stimulation parameters or of the contact locations could improve initial poor clinical responses.

An innovation in the present study was the use of digital monitoring. Though digital tools proved useful only for passive capturing data, the combination of neuromodulation techniques and digital innovation may help to advance in the precision psychiatry paradigm.14

Some limitations should be considered. Firstly, the small sample size. Secondly, the cohort heterogeneity in terms of diagnosis and DBS targets. Thirdly, the relatively short duration of follow-up. Fourthly, studying last resort therapies could generate expectation bias. Finally, the lack of multiple comparisons analysis could limit the interpretation of the grouped findings.

The possibility of finding therapeutic alternatives, such as DBS, for the treatment of resistant forms of schizophrenia and BD raises great interest. This study, along with others, may open the door to a new therapy for these disorders, eventually helping to incorporate these treatments into the daily clinical practice.

MB collected the clinical data, managed and analyzed the clinical data and wrote the first version of the paper; JR & PR collected the neurosurgical data and wrote the first version of the paper; LM collected the neuropsychological data and wrote the first version of the paper; DHM collected the wearable and apps data and wrote the first version of the paper; all the authors contributed to the final version of the paper.

This project was totally funded by the Pons-Balmes family legacy donated to the Psychiatry Department at the Hospital Clínic de Barcelona.

MB has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of has received honoraria from talks and/or consultancy of Adamed, Angelini, Casen-Recordati, Exeltis, Ferrer, Janssen, Lundbeck, Neuraxpharm, Otsuka, Pfizer and Sanofi, and grants from Spanish Ministry of Health, Instituto de Salud Carlos III (PI20/01066).

JGB has received financial support for educational activities from Takeda, Lundbeck, and Janssen. JGB has served as a consultant or provided teaching materials to Janssen, Sanofi and Casen Recordati.

DHM received CME-related honoraria and participation on advisory boards from Abbott, Angelini, Janssen-Cilag and Ethypharm with no financial or other relationship relevant to the subject of this manuscript.

EP has received honoraria and/or research grants and/or financial support for the Basic and Translational Research Laboratory in Schizophrenia from the following entities and companies: Fondo de Investigación Sanitaria of the Spanish Ministry of Science and Innovation, the Catalan Pons Balmes Grant, Fundació la Marató de TV3 of Catalonia, Relats, Assegurances Santasusana, Fundació Vila-Saborit, Janssen-Cilag, Adamed, Rovi, Lundbeck-Otsuka, Angelini, Sanofi, Kern, Casen Recordati, Glaxo-Smith Kline, Ferrer, Takeda, Biogen, GWAP and Acadia.

JR has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of has received honoraria from talks and/or consultancy of Medtronic and Boston Scientific, with no financial or other relationship relevant to the subject of this manuscript.

EV has received grants and served as consultant, advisor, or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Boehringer-Ingelheim, Celon Pharma, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, Janssen, Lundbeck, Merck, Novartis, Orion Corporation, Organon, Otsuka, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work.

The rest of the authors report no biomedical financial interests or potential conflicts of interest.