Efficacy and Safety of Combo-stim Deep Brain Stimulation for Treatment-refractory Mental Disorders

This is a multi-center, single arm, prospective, open-label, extendable study for the efficacy and safety of combo-stim deep brain stimulation for treatment-refractory mental disorders (obsessive-compulsive disorder, schizophrenia, bipolar with depression, anorexia nervosa, gambling disorder and adult autism).

Total of 18 subjects from Shanghai Mental Health Center who fit inclusion and don't fit exclusion criteria are recruited to undergo neurosurgical implantation of combo-stim DBS in bilateral nucleus accumbens (NAcc) and anterior limb of internal capsule (ALIC) on a certain date, the DBS system will be turned on for stimulation and parameters adjusted 7-14 days after implantation, treatment purposes are evaluated after system has been turned on for 8-24 weeks. Primary efficacy is evaluated by change in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Positive and Negative Syndrome (PANSS), Montgomery-Asberg Depression Rating Scale (MADRS), Body Mass Index (BMI), Autism Behavior Checklist (AuBC) score and longest consecutive days without gambling within one month. Safety is evaluated by adverse events (AE) and device-related adverse events (ADE), serious adverse events (SAE) and serious device-related events (SADE), device deficiencies (DD) and device malfunction, physical examination and vital signs, laboratory examination, electrocardiogram (ECG), imaging examination, scale evaluation and early drop out ratio due to AE.

Eligibility Criteria:
Inclusion Criteria:

1. Treatment refractory obsessive-compulsive disorder:

   1. Aged 18\~65 when signing informed consent, outpatient or inpatient, male or female.
   2. Fits DSM-5 obsessive-compulsive disorder criteria.
   3. Fits treatment refractory obsessive-compulsive disorder criteria (both i and ii):

   i.Treated with at least 3 kinds of serotonin reuptake inhibitors (SSRIs) with at least 2 kinds of 2nd generation antipsychotic medication as enhancement, enough dosage and enough course of treatment, and still no effect or intolerant.

   ii.While using enough dosage of SSRIs, treated with more than 8\~12 times of Cognitive Behavior Therapy (CBT) or CBT-intolerant.

   d)Y-BOCS score ≥ 25 in screening period and baseline. e)CGI-S score ≥ 4 in screening period and baseline. f)Patient and guardian agree to DBS implant and sign informed consent after fully understood research aims, contents, anticipated treatments and risks.
2. Treatment refractory schizophrenia:

   1. Aged 18\~65 when signing informed consent, outpatient or inpatient, male or female.
   2. Fits DSM-5 schizophrenia criteria.
   3. Course of disorder ≥ 5 years.
   4. Fits treatment refractory schizophrenia criteria, one of the conditions below:

   i.Treated with more than 2 different anti-psychotic medications (clozapine excluded), enough dosage (equivalent dosage as chlorpromazine ≥ 600mg/day), enough course of treatment (≥ 12 weeks), no effect or intolerant.

   ii.Treated with enough dosage of clozapine (≥ 300mg/day or blood medication concentration ≥ 350ng/ml, enough course of treatment (≥ 12 weeks), no effect or intolerant.

   e)PANSS score ≥ 70 in screening period and baseline, and at least 1 item from 5 items (P1, P2, P3, P5, P6) of PANSS positive symptom scale ≥ 4; or at least 3 items from PANSS negative symptom scale (N1\~N7) ≥ 4, or at least 2 items ≥ 5.

   f)CGI-S ≥ 4 in screening period and baseline. g)GAF ≤ 60 in screening period and baseline. h)Patient and guardian agree to DBS implant and sign informed consent after fully understood research aims, contents, anticipated treatments and risks.
3. Treatment refractory bipolar with depression:

   1. Aged 18\~65 when signing informed consent, outpatient or inpatient, male or female.
   2. Fits DSM-5 bipolar I or bipolar II criteria, currently with depression episode.
   3. Course of disorder ≥ 2 years.
   4. Fits treatment refractory bipolar with depression criteria (treated with two different kinds of treatment below, enough dosage and enough course of treatment ≥ 8 weeks, and cannot acquire symptom cure for 8 consecutive weeks, either i or ii):

   i.Used at least two medications (alone) among Olanzapine (10-20mg/d) + Fluoxetine (20-60mg/d), Quetiapine (200-600mg/d), Lurasidone (40-160mg/d), Lamotrigine (200-400mg/d) ii.Used at least one medication above (alone), and used one of medication above with another medication among Lamotrigine (200-400mg/d), Valproate (1000-2000mg/d) and lithium salt (blood lithium reaches 0.8mmol/L).

   e)Upon medication treatment, electroconvulsive therapy ≥ 12 times, no effect or failed (such as intolerant).

   f)Fits severe symptom criteria: i.Depression episode ≥ 12 weeks in screening period. ii.MADRS score ≥ 26 in screening period and baseline. iii.GCI-BP score ≥ 4 in screening period and baseline. iv.YMRS score ≥ 12 in screening period and baseline. g)Patient and guardian agree to DBS implant and sign informed consent after fully understood research aims, contents, anticipated treatments and risks.
4. Treatment refractory anorexia nervosa:

   1. Aged 18\~65 when signing informed consent, outpatient or inpatient, male or female.
   2. Fits DSM-5 anorexia nervosa criteria, consider both restricting type and binge-eating/purging type.
   3. 10 ≤ BMI \< 16 in screening period and baseline.
   4. Fits treatment refractory anorexia nervosa criteria (both i, ii, iii and iv):

   i.Course of disorder ≥ 5 years, severe and sustained anorexia nervosa. ii.With ≥ 3 times repeated inpatient history and bad treatment effect (can't complete treatment or immediate relapse after treatment).

   iii.Through systemic nutrient treatment, medication (SSRIs and/or anti-psychotics), psychotherapies (such as reinforced CBT, FBT treatment), no effect or intolerant.

   iv.Worsened instability of clinical treatment, refuse treatment or bad reaction to reinforced treatment, last for more than 1 year, with more than 2 times of involuntary food intake.

   e)Patient and guardian agree to DBS implant and sign informed consent after fully understood research aims, contents, anticipated treatments and risks.
5. Gambling disorder:

   1. Aged 18\~65 when signing informed consent, outpatient or inpatient, male or female.
   2. Course of disorder ≥ 2 years.
   3. Diagnosed as gambling disorder based on DSM-5, fits medium or severe diagnostic standard (≥ 6 terms)
   4. Received systemic treatment (such as medication and social mental intervention) but still has iterative thoughts of impulse or gambling behaviors.
   5. Patient and guardian agree to DBS implant and sign informed consent after fully understood research aims, contents, anticipated treatments and risks.
6. Adult autism:

   1. Aged 18\~65 when signing informed consent, outpatient or inpatient, male or female.
   2. Fits DSM-5 autism spectrum disorder diagnostic standard, and there's severe, life-threatening iterative behaviors, and independently evaluated by two psychiatric doctors.
   3. AuBC score ≥ 62 in screening period and baseline.
   4. CGI-S score ≥ 4 in screening period and baseline.
   5. Course of disorder ≥ 10 years, received systemic behavior intervention or training ( such as critical reaction training, cognitive behavior intervention, language expression training, demonstration method, natural environment training, patriarch training, social skill training, intervention based on story tales, etc. ) but failed, or intolerant.
   6. Patient and guardian agree to DBS implant and sign informed consent after fully understood research aims, contents, anticipated treatments and risks.

Exclusion Criteria:

1. With mental disorders including physical mental disorders, paranoid personality disorder, delayed mental development etc.
2. Through clinical evaluation by investigators, there exists significant suicide behavior risk.
3. From screening period to baseline, patients who has significant improvement in evaluation scores:

   1. Obsessive compulsive disorder: Y-BOCS score decreased (or improved) ≥ 20%
   2. Schizophrenia: PANSS score decreased (or improved) ≥ 20%
   3. Bipolar with depression: MADRS score decreased (or improved) ≥ 20%
   4. Anorexia nervosa: BMI improved ≥ 20%
   5. Gambling: through evaluation by investigators, online gambling behavior is significantly improved
   6. Adult autism: AuBC score decreased (or improved) ≥ 20%.
4. With severe or unstable cardiovascular, inspiratory, liver, kidney, blood, endocrine, neural system or other system disorders.
5. Has neural system disorders including physical brain disorders, brain trauma, treatment-refractory seizure etc.
6. During screening period or baseline, abnormalities in patient's physical examination, laboratory examination, electrocardiogram examination, imaging examination have significant clinical meaning, and patients who are considered unfit by investigators.
7. Implanted artificial cochlea, pacemaker, similar single-side or double-side products or experienced other physical surgeries within half a year that are considered to have effect on this trial by investigators.
8. DBS implant surgery taboos present and is considered unfit by investigators.
9. Diagnosed as HIV positive.
10. Female in gestation, lactation, or blood HCG / urine gestation test positive. Or patients who can't take effective contraception actions during the trial. Or patients planning to birth or give birth after the trial begins for 3 months.
11. Currently involved or involved in other medication or medical device clinical trials 3 months before the screening period.
12. Other patients who are considered unfit by investigators.