The goal of this clinical trial is to assess the efficacy and safety of hippocampus-targeted deep brain stimulation (DBS) in treatment-resistant schizophrenia. The main question it aims to answer are:

• whether patients with treatment-resistant schizophrenia can benefit from hippocampus-targeted DBS;
• what is the neural and electrophysiological mechanism underlying the treatment effect of hippocampus-targeted DBS.

The first phase of the study will consist of DBS surgery. Participants will receive electrodes implantation in bilateral ventral hippocampus. Continuous stimulation will be applied to optimize and individualize the stimulus parameters. This period is anticipated between 3 and 6 months.

The next phase will consist of the crossover study. Patients who respond to DBS will be randomly assigned to two groups, for a period of 3 months: on stimulation group and off stimulation group. Patients will then be crossed over to the other group for a further 3 months.

Participants will receive PET-CT, clinical assessment and cognitive tests at the main study points to evaluate treatment efficacy and patient tolerance, and to reveal the underlying mechanism of the treatment effect of DBS.

Inclusion Criteria:

• Male or female aged between 18 and 55 years.

• Having a diagnosis of schizophrenia according to DSM-IV criteria

• Having a chronic, recurrent course of disease with a five-year minimum duration

• Determined to be treatment-resistant as demonstrated by:

  1. Persistence of positive symptoms which have not responded to appropriate treatments for at least 2 years.
  2. Inadequate response from adequate trials of two different classes of antipsychotic drugs (not including clozapine), at least 8 weeks.
  3. Inadequate response from adequate trial of clozapine, at least 3 months, or unable to tolerate clozapine because of intolerable side effects.
  4. Presence of persistent positive symptom defined as i) requiring a score of 4 (moderate) or more on at least 2 of the next PANSS items: delusions, conceptual disorganization, hallucinatory behavior, suspiciousness and unusual thought content; or as ii) requiring a score of 6 (severe) or more on at least 1 of the above PANSS items.

• Maintaining stable pharmacological treatment for two months preceding screening visit.

• Informed consent

Exclusion Criteria:

• Neurological disease
• Severe physical illness
• Contraindications to neurosurgery, MRI or PET-CT;
• Substance abuse or dependence
• Mental retardation
• Female patients who are pregnant or breastfeeding
• Severe suicide risk and tendencies