Deep Brain Stimulation for Psychosis

Exclusion Criteria

• •1. Active alcohol or substance use disorder within 6 months, excluding nicotine; Urine drug test positive for illicit drugs;
• •2. Current substantial suicidal risk as defined by a plan or clear immediate intent for self-harm, or made a suicide attempt within the last year; or as identified as The Columbia Suicide Severity Rating Scale (C-SSRS),
• •3. Neurological/Medical condition that makes the participant, in the opinion of the surgeon, a poor surgical candidate (e.g., progressive neurodegenerative disorder, significant cardiopulmonary disorder, need for chronic anticoagulation);
• •4. Any history of seizure disorder, hemorrhagic stroke, or has high risk of seizure (history of congenital brain malformation, history of brain injury, neuro-developmental disorder, currently taking medication that is known to lower seizure threshold, or other factors that predispose seizures);
• •5. Any medical contraindication to surgery such as infection;
• •6. Coagulopathy: Bleeding propensity and/or one of the following: international normalised ratio (INR) \> 1.5; prolonged activated partial thromboplastin time (aPTT) ≥ 45 sec; platelet count \< 100×103 /uL;
• •7. Uncontrolled hypertension (systolic \> 140mmHg and/or diastolic \> 90 mmHg), demonstrated on each of three repeated measurements taken within one hour regardless of whether or not the participant is taking antihypertensive medications.
• •8. Patients with a heart-rate corrected QT interval (QTc) of \> 450 msec
• •9. Participation in another drug, device, or biological study within 90 days;
• •10. Current implanted stimulation devices including cardiac pacemakers, defibrillators, and neurostimulators including spinal cord stimulators and deep brain stimulators;
• •11. Need for Diathermy;
• •12. Chronic use of anticoagulant or anti-platelet agents that cannot be safely stopped for a sufficient duration (minimum 2.5 weeks) in the peri-operative period.
• •13. Any Psychiatric/Neurological/Medical condition that makes the participant, in the opinion of the Investigator, a poor candidate.
• •14. A female participant of childbearing potential who is not able or willing to use highly effective (those that when used alone or in combination, result in a low failure rate \[i.e., less than 1 percent per year\], when used consistently and correctly) methods of birth control throughout the duration of participation in the trial.
• •15. A female participant of childbearing potential who is not able or willing to provide a negative pregnancy blood test during the screening phase of the study and during several additional timepoints throughout study participation. Specifically, the investigators will require a pregnancy test on the day of ketamine (or placebo) administration to avoid the risk of administering ketamine to a pregnant patient.
• •16. A separate cardiac condition that, in the opinion of study physician would present an unacceptable risk of undergoing general anesthesia or ketamine administration.
• •17. Participants with poorly controlled hypertension or persistent tachycardia, at baseline, will be excluded.
• •18. Participants who are taking an anti-depressant medication.
• •19. Any known contraindications for ketamine and/or esketamine (Spravato):
• •1. Patients for whom a significant elevation of blood pressure would constitute a serious hazard, according to the opinion of the study PI.
• •2. Patients with known hypersensitivity to ketamine, esketamine, or to any of the excipients.
• •3. Patients with Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation.
• •4. Patients with a history of intracerebral hemorrhage.
• •5. Patients with resting heart rate over 90 or below 55 beats per minute (BPM)
• •6. Participants taking a medication with a known interaction with ketamine or esketamine (amphetamines, monoamine oxidase (MAO)-Is, aminophylline, theophylline, norepinephrine, epinephrine, vasopressin, dobutamine, ephedrine, ethanol, Ergometrine/Ergonovine). Patients taking benzodiazepines will not be excluded as this is recommended to prompt monitoring of patients in the information for esketamine. Dr. McDonagh will review such cases including for symptoms of sedation associated with their use and the dosage and duration of therapy for each. The investigators will exclude subjects who have any evidence of central nervous system (CNS) depression, such as decreased level of arousal or respiratory depression, thought to be linked with CNS depressants. The investigators will use the PRODIGY score to exclude any patient taking one of these medicines determined to be HIGH risk (score of 15 points or higher, https://www.apsf.org/wp-content/uploads/newsletters/online-only/202006/PRODIGY-Interactive-Risk-Assessment-Tool.pdf). The investigators note that ketamine has been used as an adjunct for sedation with benzodiazepines and opiates in the anesthesia environment, and the FDA's guidance on ketamine states: "KETALAR has been studied in over 12,000 operative and diagnostic procedures, involving over 10,000 patients from 105 separate studies. During the course of these studies KETALAR was administered as the sole agent, as induction for other general agents, or to supplement low-potency agents."
• •7. During the ketamine administration phase in the hospital, patients with a history of benzodiazepine (or other CNS depressant) usage will undergo more frequent documentation of respiratory rate and heart rate (every 10 minutes). All patients will undergo continuous pulse oximetry monitoring to initiate supportive measures if there is any evidence of respiratory depression. In any patient with a history of opiate or 3-quinuclidinyl benzilate (BZ) administration, the investigators will have both flumazenil and naloxone immediately available at the bedside for administration if there is any evidence of respiratory distress.
• •8. On the day of planned ketamine (or placebo) administration, Dr. McDonagh will review all medicines being administered to the patient to ensure there is no potential interaction. This will be documented on the Ketamine Administration Checklist included in appendix 6.
• •9. On the day of planned ketamine (or placebo) administration, subjects will undergo a urine drug screen to avoid the accidental administration of ketamine to a patient who tests positive for any agents that is contraindicated (such as psychostimulants or CNS depressants). This is now reflected in the ketamine administration checklist (appendix 6).