Approaches to neuromodulation for schizophrenia.

Based on the success of deep brain stimulation (DBS) for treating movement disorders, there is growing interest in using DBS to treat schizophrenia (SZ). We review the unmet needs of patients with SZ and the scientific rationale behind the DBS targets proposed in the literature in order to guide future development of DBS to treat this vulnerable patient population. SZ remains a devastating disorder despite treatment. Relapse, untreated psychosis, intolerable side effects and the lack of effective treatment for negative and cognitive symptoms contribute to poor outcome. Novel therapeutic interventions are needed to treat SZ and DBS is emerging as a potential intervention. Convergent genetic, pharmacological and neuroimaging evidence implicating neuropathology associated with psychosis is consistent with SZ being a circuit disorder amenable to striatal modulation with DBS. Many of the DBS targets proposed in the literature may modulate striatal dysregulation. Additional targets are considered for treating tardive dyskinesia and negative and cognitive symptoms. A need is identified for the concurrent development of neurophysiological biomarkers relevant to SZ pathology in order to inform DBS targeting. Finally, we discuss the current clinical trials of DBS for SZ, and their ethical considerations. We conclude that patients with severe symptoms despite treatment must have the capacity to consent for a DBS clinical trial in which risks can be estimated, but benefit is not known. In addition, psychiatric populations should have access to the potential benefits of neurosurgical advances.

Long-term outcomes of deep brain stimulation for treatment-resistant schizophrenia: Exploring potential targets.

BACKGROUND: Schizophrenia is a complex and disabling disorder. Around 30% of patients have treatment-resistant schizophrenia (TRS). OBJECTIVE: This study summarizes the outcomes after three years follow-up of the first series of patients with TRS treated with deep brain stimulation (DBS) and discuss surgical, clinical and imaging analysis. METHODS: Eight patients with TRS treated with DBS in the nucleus accumbens (NAcc) or the subgenual cingulate gyrus (SCG) were included. Symptoms were rated with the PANSS scale and normalized using the illness density index (IDI). A reduction in IDI-PANSS of ≥25% compared to baseline was the criterion of good response. The volume of activated tissue was calculated to perform a connectomic analysis for each patient. An estimation of the tracts and cortical areas modulated was generated. RESULTS: Five women and three men were analyzed. After 3 years' follow-up, positive symptoms improved in 50% of the SCG group and 75% of the NAcc group (p = 0.06), and general symptoms improved in 25% and 50% respectively (p = 0.06). The SCG group showed activation of the cingulate bundle and modulation of orbitofrontal and frontomesial regions; in contrast, the NAcc group showed activation of the ventral tegmental area projections pathway and modulation of regions associated with the "default mode network" (precuneus) and Brodmann areas 19 and 20. CONCLUSIONS: These results showed a trend toward improvement for positive and general symptoms in patients with TRS treated with DBS. The connectomic analysis will help us understand the interaction of this treatment with the disease to pursue future trial designs.