Interventional Psychiatry

Transcription

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2 Interventional Psychiatry ECT, TMS, and Ketamine December 4, 2018

3 Outline ECT: Address common questions from the referral process, to ethical/legal issues, Emergencies, Procedure, to treatment planning, medication modifications, and some case examples TMS: Dr. Jonathan Wilson. Comparison chart. Ketamine: continuation of Grand Rounds last week (use of IV Ketamine infusion in adolescent). Adults with treatment-resistant depression. Interventions not covered: VNS, DBS, and others. We do not have any relevant financial relationships with any commercial interests

4 ECT

5 Referrals and Indications for ECT Inpatient and outpatient providers. Inpatient from Oregon State Hospital, Unity, Providence, Cedar Hill. Outpatient psychiatrists and NPs Diagnoses: MDD, recurrent, severe, with or without psychotic features (>50% of cases). Elderly with failure to thrive, somatic delusions. Catatonia (from psychiatric conditions: bipolar disorder, 2/2 medical conditions, NOS). Recent case of Malignant Catatonia (emergent). Psychotic disorders (SZC, schizoaffective disorder) Others: Status Epilepticus (emergent)

6 Referral Process Call or Elizabeth Hurtado for ECT referral form, if you don t have it already. Fill out the referral form and or fax it back along with most recent H+P and progress notes. Eli will screen for insurance. (Kaiser has their own ECT at Kaiser Sunnyside. Providence has their own ECT at Providence Milwaukie. OHP is contracted with Providence. Exceptions are made for inpatients at Unity. We are contracted with OSH.) I will review the packet and give the okay for Eli to reach out to patient to schedule consult.

7 Emergencies and use of Emergent ECT Patients usually needing ICU level of care Malignant Catatonia: autonomic instability with increased HR, BP, Temperature, lab abnormalities (CK) Status Epilepticus: refractory of multiple AEDs, or recurrence of seizure when attempting to taper AEDs. ICU/medical team and psychiatry/ect team agree that patient is at imminent risk of death without intervention Care conference with family, although not able to consent legally on behalf of patient, are involved in the decision making.

8 Legal, ethical, and practical Severely ill patients who need ECT often lack capacity to consent Legal guardians cannot consent to ECT on patient s behalf unless they have been granted this special authority by a judge s order Involuntary ECT for committed patients Patients who are actively refusing may require restraints and IM meds Teams (Psychiatry, Anesthesia, Nursing), PACU environment, safety Impact on other patients

9 Procedure: PRE NPO past midnight Hold medications (BZD, mood stabilizers) as discussed the day before ECT Hold all medications the morning of ECT except for BP medications. Okay to take those with a sip of water the morning ECT. Take other meds afterwards. Check-in with a companion who takes patient to and from treatment. IV fluids, PRE meds for pain, nausea, anxiety/agitation if needed: Toradol, Zofran, Precedex

10 Procedure: PACU Anesthesia team Monitors: EEG, EKG, BP, pulse ox, end tidal CO2 Machine setting Pre-oxygenation Anesthetics: Brevital, Etomidate Paralytics: Succinylcholine, Rocuronium*. Reversal agent Fasciculation, bite blocks Stimulus

11 Procedure: POST Seizure monitoring: Motor, EEG Management of airway Emergence from anesthesia Post meds

12 Management of Adverse Effects Most common side effects: Headache, muscle soreness, nausea IV Toradol, IV Zofran, Tylenol Cardiac arrhythmia (A Fib), hypertension, tachycardia/bradycardia: continuous EKG, BP, pulse ox during treatment. IV agents: Esmolol, labetalol, glycopyrolate Prolonged seizures, status epilepticus: EEG monitoring, aborting seizures Post-ictal agitation/delirium: supportive/environmental management, BZD, Haldol.

13 Management of Cognitive Side Effects Pre-treatment cognitive status and impact on cognition from depression Change to RUL Decrease electric dose Decrease frequency or stop ECT Reduce dose or stop psychotropics Compensatory skills: students and professionals

14 Use of Medications During ECT Course Antipsychotic medications: okay in combination with ECT, synergistic therapeutic effects Antidepressant medications: okay in combination of ECT, enhance antidepressant response or reduce risk of relapse when ECT is stopped Collaboration and communication with outpatient providers: value feedback from primary psychiatrist Ongoing psychotherapy during ECT: DBT, CBT, mindfulness based therapy. Exercise. Structured daily activities. Purposefulness and meaningful roles.

15 Medication Modifications Lithium: higher risk of for post-ictal delirium or post-ictal agitation. Risk diminishes with dose reduction or discontinuation. Some patient with severe, recurrent mood disorder cannot tolerate lithium taper, particularly in maintenance phase. Hold the dose or doses the day before. Benzodiazepines: reduces seizure duration in a dose-dependent fashion, interfere with maximal seizure expression. If clinically feasible, taper off prior to ECT course. If not, use shorter half-life agents (Ativan), hold as much as possible the day before.

16 Medication Modifications BZD: Catatonia (often >3 mg/day of Ativan), briefly reverse with BZD antagonist Flumazenil IV at the time of ECT treatment. Give back Versed or Ativan IV after seizure to avoid withdrawal effects. Use of Precedex IV pre-treatment for anxiety. IV or Intranasal. Anticonvulsants: Increase seizure threshold and interfere with seizure expression. Depakote, Carbamazepine, Lamictal, Gabapentin, Topamax Decrease dosage or taper off before course of ECT. If not possible to taper, hold one or two dose the day before ECT and morning of ECT.

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18 Negative and Positive Prognostic Factors Patients with borderline personality disorder (still can treat comorbid MDD, but discussion regarding risk vs benefit) Patients with chronic psychotic symptoms (Patients with acute onset of symptoms, shorter episode duration are more likely to respond then persistent, unremitting symptoms) Patients with chronic dysthymia (still treat major depression superimposed on dysthymic baseline) Better response in psychotic depression, catatonic symptoms Depression secondary to, or perpetuated by, psychosocial stressors, substance abuse

19 Management of Treatment Emergent Mania Treatment-Emergent Mania: small minority of patient with depression or in mixed state switch into hypomania or mania during the course of ECT. Patient with bipolar disorder are at higher risk Evaluate cognitive status (confusion, pronounce memory disturbance, disorientation) to distinguish from delirium (increase time btwn treatment, switch to RUL from BL). No established strategy for managing treatment emergent mania. ECT is treatment for mania: treating through manic symptoms, or wait and see if manic symptoms remit. Restart lithium or mood stabilizer or antipsychotics.

20 Medical Conditions associated with Substantial Risks No Absolute medical contraindication to ECT, it s all about balancing the risks vs benefits When ECT is associated with an increased likelihood of serious morbidity and mortality, decide to proceed if patient s psychiatric condition is grave and ECT is the safest treatment available. Careful evaluation of medical risk factors and modification in management to reduce level of risk Hemodynamic changes duration ECT: parasympathetic tone increase with stimulus: bradycardia, sinus pause. Then sympathetic surge: tachycardia and hypertension.

21 Medical Conditions associated with Substantial Risks Unstable or severe CV conditions: recent MI, unstable angina, poorly compensated CHF, severe valve disease Aneurysm and vascular malformation: rupture with increased BP Increased intracranial pressure: brain tumor, space-occupying cerebral lesions. Recent cerebral infarction Pulmonary conditions: severe COPD, asthma, pneumonia Pre-ECT anesthesia evaluation

22 TMS Dr. Jon Wilson

23 History of TMS Michael Faraday discovers principles of electromagnetic induction. Few attempts during 19 th century to study effects on brain due to limited technology Anthony Barker builds first electromagnetic stimulation device for human use first clinical trial published reporting results of TMS in treatment resistant depression Approved by FDA for treatment of major depression 2018 Approved by FDA for treatment of OCD

24 What is Transcranial Magnetic Stimulation (TMS)? A procedure that uses magnetic fields to stimulate nerve cells in the brain

25 What types of magnets/coils are used? H1 coil- stimulates deeper into the brain and more brain volume with a wider pulse width, increased frequency, and shorter train duration Figure 8 coil- less depth, less brain volume stimulated, short pulse width, less frequency, longer train duration

26 FDA indications Non-psychotic unipolar depression, having failed at least one medication trial OCD Pain associated with migraine headaches

27 What is a typical course of TMS for MDD? Initial consultation to determine appropriateness for treatment Mapping session: goal is to determine motor threshold and appropriate location. Start by placing coil over primary motor cortex and stimulating with low intensity until a thumb twitch is elicited. Typically, the TMS device will help determine the % of the motor threshold, and the DLPFC is about 5 cm anterior to the motor strip. Treatment- typically 5-6x per week for 5-6 weeks, about 30 treatments. Treatments are typically minutes with trains, of magnetic pulses for short bursts with intervals in between Taper- typically 3 treatments for first week, then 2x weekly, then 1x weekly Maintenance- not as well researched, but some device companies do recommend it

28 TMS and Depression For major depression, the coil is placed, over the left dorsolateral prefrontal cortex (DLPFC), and high frequency repetitive TMS (rtms) is delivered to stimulate this region of the brain. Some studies have looked at low frequency stimulation of the right DLPFC Parameter Coil location Stimulus intensity Frequency Details Typically left DLPFC, less often right DLPFC % of motor threshold HF (>1-20 Hz); LF (<1 Hz) Depolarization of cortical neurons with rapid, repetitive TMS increases blood flow and metabolism to left DLPFC in attempt at neuromodulation Train duration Interval between trains 3-30s (HF); 5s-15min (LF) 20-60s (HF); s (LF)

29 TMS and Depression- Evidence Studies typically are monotherapy with sham control, augmentation with sham control, and as comparison vs ECT Authors N(studies) and n (patients Results Berlim et al N= 29, n=1371 Response OR =3.3 (P<0.0001); NNT=6 Remission OR-3.3 (P<0.0001); NNT=8 Liu et al N= 5, n=279 Response OR= 5.12 (P<0.0003) Conclusions Left HF TMS was superior to sham procedure Left HF TMS was superior to sham as augmentation in TRD Ren et al N=9, n=425 ECT was superior to rtms in terms of response and remission, most notably in the subset of those with psychotic depression

30 TMS and OCD First studies began in 1997, treating patients in multiple areas of the brain include L and R DLPFC and midoccipital cortex as a control. Most studies use a sham control group Studies have looked at multiple areas to target symptoms of OCD typically associated with the cortical-striatal-thalamic-cortical circuit or the increased metabolism of the anterior cingulate cortex DLPFC- majority of research Orbitofrontal cortex Supplementary Motor Area All studies show some immediate improvement but no long term efficacy

31 TMS for OCD gets FDA approval A 2017 sham controlled study utilizing the H1 coil showed significant improvement in OCD symptoms that were sustained after treatment 94 patients were randomized for 29 sham or active (rtms) treatments. Treatments were localized to the medial PFC and anterior cingulate cortices. Stimulus was delivered at 100% of the motor threshold at 20 Hz in 2 second trains with a 20 second interval. Total of 2000 pulses per treatment

32 TMS for OCD gets FDA approval After 6 weeks, YBOCS (Yale Brown Obsessive Compulsive Scale) decreased by 5.7 points in treatment arm vs 3 in sham arm (P=0.0157). There was a > 30% reduction of YBOCS in 38.10% vs 11.11% in the treatment and sham arm, respectively. At week 10, 4 weeks after treatment, YBOCS was still decreased by 6.2 points in treatment arm vs 3.8 points in sham arm (P=0.0459). August 17 th, 2018, FDA approves H1 coil only for treatment of OCD based off this study. Treatment course is similar to depression, with 5x per week treatment for 6 weeks.

33 Contraindications, Warnings, and Side Effects Most devices have contraindication of metallic objects near or in the head: aneurysm clips, skull plate, deep brain stimulator Special consideration for history of seizures, TBI, or eating disorders Warning of worsening of depression or suicidality should be issued prior to starting treatment There is a less than 0.1% risk of a seizure, but special consideration should be used in patients with a history of seizures or any potential alteration of the seizure threshold Most common side effects include application site pain/discomfort (50%), headache (30%), dizziness, muscle twitching, and tinnitus

34 Consideration for Concomitant Medications There are no contraindications or warnings for SSRIs or SNRIs Bupropion should be lowered to 300 mg or less Anticonvulsants should be kept consistent throughout treatment if possible Benzodiazepines should also be kept consistent throughout treatment if possible Stimulants and caffeine have not been linked to increased seizure risk with TMS

35 Comparison of TMS, ECT, and Ketamine ECT TMS Ketamine Induction Electric Magnetic None Site of Stimulation Diffuse Focal N/A Anesthesia Yes No No (sub-threshold anesthetic doses are used) Intended Population Common side effects Depression with psychotic feat., catatonia Memory loss, headache, nausea Unipolar depression without psychotic features, OCD Site discomfort, headache Treatment resistant depression Cardiovascular changes, dissociation, dizziness, headaches, mood swings, cystitis, cognitive changes Setting Operative suite/pacu Office based Operative suite/pacu

36 Areas of future study Currently being studied for myriad of psychiatric diagnoses include panic disorder, generalized anxiety disorder, post-traumatic stress disorder, and substance use disorder Theta burst stimulation- patterned bursts, of magnetic pulses, typically 50 Hz, that are given for shorter periods of time with shorter interburst intervals. Transcranial direct current stimulation- using electrical current rather than magnetic. TMS with more direct inhibition of the anterior cingulate cortex with deeper stimulation More simultaneous combination studies (psychotherapy, ketamine, other neuromodulation such as ECT)

37 Ketamine

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39 FROM LAST WEEK History of Ketamine Clinical indication (use as an antidepressant is off label) Mechanism of action Safety and Tolerability Adverse effects Clinical evidence for use Antidepressant effects Ketamine use in ECT

40 TREATMENT PROTOCOL Assessment and screening by psychiatrist and anesthesiologist Referral process same as for ECT (MD, NP) Firm Dx, failed full or high doses of at least 3 antidepressants and/or augmentation strategies with good compliance, exhibit function impairment, suicide risk 40 min Infusion Low Stimulus environment Control noise and motion in the treatment room Preset protocol for treatment related hypertension and tachycardia When BP is 20% over baseline, stopping infusion, treat with IV BP medication if needed Mild, transient, peak at the end of a bag, turn off the drip

41 SIDE EFFECTS AND PRECAUTIONS Ketamine inhibits the reuptake of catecholamines, stimulating the sympathetic nervous system, resulting in cardiovascular symptoms Requires CV monitoring Serotonin reuptake inhibition in GI track is thought to underlie nausea and vomiting

42 TREATMENT PROTOCOL: EXCLUSIONS Challenges with patients with comorbid psychiatric disorders Personality disorders Dissociative disorders Somatic symptoms disorders Psychotic disorders Substance use disorders Contraindications Significant CV disease, Uncontrolled HTN, Increased ICP, Recent CVA, Liver failure, Thyrotoxicosis, Pregnancy, Active substance abuse, and Psychosis. Lacks capacity for informed consent

43 PRETREATMENT PHASE Pre-anesthesia evaluation: PE, labs, EKG within 30 days Resting BP within normal limits. Adequate control of HTN by PCP Pregnancy test for female of childbearing age Urine drug screen PHQ-9 Day of treatment NPO for 8 hours prior to treatment Cannot take BZD, Alcohol or narcotics for 12 hours prior to treatment and 24 hours after.

44 DOSING AND OTHER ROUTES 0.5 mg per kg IV infusion over 40 min Average 70 kg patient: 35 mg IV Actual body weight vs Ideal body weight Adjustments for BMI over 30 Oral bioavailability 16% IM bioavailability 95%

45 DISSOCIATIVE EXPERIENCE Floaty, out of body Sense of connection to something bigger Seeing myself as a seedling, bursting through the soil and growing Dissociation allowed for empathy for myself I don t like the trip, if I could have the effects without the trip, I would, from a patient with history of substance use disorder I was floating away to heaven, there were angels and harp music, I was scared that I may not come back

46 SIDE EFFECTS Dizziness Blurry Vision Nausea, vomiting Headache Dry mouth Palpitations Long term risks unknown Cystitis, Bladder ulceration as a club drug Cognitive issues

47 CAUTIONARY ADVICE POST TREATMENT Observed for an hour: stable VS, accompanying adult PHQ-9 Should not drive for 24 hours post treatment Must have a companion who can drive them home after treatment Should not sign legal documents for 24 hours post treatment Should not consume alcohol, use illicit drugs, or be in charge of minors for 24 hours post treatment

48 TREATMENT ISSUES AND PRECAUTIONS Setting expectation for the treatment Dissociation, feeling loss of control Having a discussion about alternatives Patients population who already failed multiple trials Prevent worsening hopelessness Follow up phone calls Importance of Therapy during treatment CBT, DBT, MBT

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50 HISTORY OF KETAMINE Use as anesthetic and analgesic Use as club drug Use as antidepressant (1990 s) 1970 s: used in Vietnam war Good for the battle field because it does not depress respiration or BP

51 STREET NAMES: SPECIAL K, KET, KIT KAT, VITAMIN K, DONKEY DUST

52 AS A CLUB DRUG DONKEY DUST

53 ONE GRAM OF KETAMINE IN SINGLE SHOT DISPENDER

54 KETAMINE CHEMICAL STRUCTURE S-Ketamine is more potent than R, higher binding affinity K rocked Kitty Kat on Etsy

55 KETAMINE STRUCTURE

56 MECHANISM OF ACTION NMDA Receptor antagonist, prevent glutamate from activing receptor Other NMDA receptor antagonists Memantine (NaMeDA for Alzheimer s disease, no antidepressant effect) Amantadine: used in Parkinson s disease as a Dopamine promoter, also used to treat and prevent Influenza A virus Dextromethorphan (DXM, Robitussin, used to treat cough, but abused for its sedative, dissociative, and stimulant properties at higher dose, Robotripping ) Phencyclidine (PCP): another drug abused for dissociative, hallucinogenic and euphoric properties

57 NMDA RECEPOR N-methyl-D-aspartate receptor Inotropic Glutamate Receptor, Ion channel Activated by glutamate and glycine, and allows positively charged ion to flow through the cell member Important in synaptic plasticity and memory functions

58 ANTIDEPRESSANT MECHANISM OF ACTION Ketamine blocks presynaptic NMDA receptor Tonic GABAergic inhibition of Glutamate release is blocked Results in increased Glutamate release Like taking your feet off the brakes

59 ANTIDEPRESSANT MECHANISM OF ACTION Leads to increased Glutamate transmission through the AMPA receptor AMPA receptors surface expression is upregulated Increases BDNF (Brain Derived Neurotrophic Factor) release Increased level of synaptogenesis

60 KETAMINE: OTHER MECHANISMS OF ACTION At least that s what we think how it works to produce its antidepressant effect Or could it be more complex It s a dirty drug, hits multiple types of receptors: A weak agonist at mu- and kappa-opioid receptor (analgesic effects, mood elevating like heroin) Inhibitor of reuptake of serotonin, dopamine (euphoric, antidepressant effects) and norepinephrine Dirty can be versatile Cholinergic (mach), Adrenergic, GABA

61 PATIENT EXPERIENCE AND PRECAUTIONS Therapeutic effects felt hours to 48 hours after infusion Duration: variable, up to one week after single IV Allows for rapid assessment of efficacy CV monitoring: HTN, tachycardia Difficulties obtaining a ride, can t use Uber As a club drug: Effects on cognition, especially after tolerance Dissociative response: Indicator for good clinical response

62 COCHRANE REVIEW 2015: LET S LOOK AT THE EVIDENCE Ketamine and other glutamate receptor modulators for depression in adults Authors from Oxford UK, Israel, Kyoto Japan Looked at multiple compounds including Namenda, we ll focus on Ketamine Goal: Assess Antidepressant efficacy of Glutamate modulators in Unipolar Depression Included studies from 1950 to Jan 2015 Selection Criteria: Single- or Double-Blind Randomized controlled trials

63 COCHRANE REVIEW 2015 Comparing Ketamine (Namenda and other glutamate modulators) to saline placebo to other psychoactive drugs (midazolam) to ECT in adults with unipolar major depression No data or very limited data on important issues Suicidality Cognition Quality of life Costs to Healthcare Services Drop out rate due to lack of efficacy

64 COCHRANE REVIEW 2015 Only IV Ketamine is better than placebo up to one week (at 24 hours, 72 hours, and one week post) Effects less certain at two weeks (only one trial) Ketamine caused more confusion and emotional blunting compared to placebo RCT: Ketamine vs Midazolam N=72 Higher number of responders on Ketamine at 24hrs, 72hrs, and one week Ketamine caused more side effects

65 COCHRANE REVIEW 2015 Ketamine vs ECT N=18 Ketamine more efficacious than ECT at 24 hours and 72 hours But not at one week or two weeks Ketamine is not an alternative to ECT (more later) Future directions: further RTCs needed Explore different routes of administration Longer follow-up Efficacy of repeated administration

66 COCHRANE REVIEW 2015: TAKE HOME Ketamine and other glutamate receptor modulators for depression in adults Authors Conclusion: We found limited evidence for ketamine s efficacy over placebo at time points up to one week the effects were less certain at two weeks post-treatment. No significant results were found for the remaining ten glutamate receptor modulators.

67 THE NEWPORT META-ANALYSIS American Journal of Psychiatry, October 2015 APA Council of Research Task Force on Novel Biomarkers and Treatment Ketamine and other NMDA Antagonists Early Clinical trials and possible Mechanisms in Depression Meta-analysis of placebo-controlled, double-blinded randomized controlled trials in treatment of depression 7 trials encompassing 147 Ketamine treated participants

68 THE NEWPORT META-ANALYSIS RESULTS Ketamine produced a rapid yet transient antidepressant effect at 24 hours Ketamine augmentation of ECT (5 trials, 89 treated participants) significantly reduced depressive symptoms following an initial treatment, but not at the conclusion of ECT course Fleeting therapeutic effect, potential for abuse and neurotoxicity Use in clinical setting warrants caution

69 THE NEWPORT META-ANALYSIS: DISCUSSION ON CLINICAL USE OF KETAMINE The available data does not support Ketamine infusion as an ECT alternative for acute treatment of depression Relapse rate approaches 50% in the 6 months following ECT Relapse rate ranges up to nearly 90% in the 4 weeks following serial Ketamine infusion Neurotoxicity Risk Factors Administration early in development during synaptogenesis High doses Extended exposure

70 THE NEWPORT META-ANALYSIS: DISCUSSION ON CLINICAL USE OF KETAMINE Safeguards against neurotoxic effects Low, subanesthetic doses Repeated administration could have different safety profile Additional Concerns Addictive and abuse potential Diversion of prescribed Ketamine for illicit use Slippery slope posed by off-label use Future Directions Elucidating mechanism of action Administration profile for sustained benefit Safety profile of repeated low dose admin