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Focus on Rapid Antidepressant Treatments Cristina Cusin, MD Depression Clinical and Research Program Assistant Professor HMS

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Focus on Rapid Antidepressant Treatments Cristina Cusin, MD Depression Clinical and Research Program Assistant Professor HMS Rapid Treatments for Psychiatric Disorders: focus on rapid antidepressant treatments Cristina Cusin, MD Depression Clinical and Research Program Assistant Professor HMS www.mghcme.org Disclosures Cristina Cusin 2012-2017: – Speaking/CME/Consulting: Janssen, Takeda, Boehringer – Equity: None – Royalty/patent: PCT/US15/56192; 070919.00032 Acyliccucurbit[N]uril type molecular containers to treat intoxication and substance abuse www.mghcme.org Definition of rapid? • What does it mean “rapid”? • “Rapid” compared to what? • How do we compare with other specialties? (cardiology, anesthesia, neurology - stroke, pain, infectious disease) • If you had acute pain from kidney stone and the only ‘effective’ treatment was a drug with a chance of improvement of 45% in 6 weeks how would you feel? www.mghcme.org “Rapid treatments” at MGH in 1976 Rapid treatment of acute psychosis • 24 patients with acute functional psychoses (schizophrenia or mania) were treated with IM haloperidol in a three-hour period. • 5mg -> +10 mg Q30min vs 5mg-> +5mgQhr • There was almost complete remission of cardinal symptoms (thought disorder, hallucinations, and delusional activity) in this period for 11 patients. “Acute dystonia, easily reversed, was the only significant side effect” Anderson WH, American Journal Psychiatry, 1976, 133 (9) 1076-1078 www.mghcme.org Rapid for what problem? (Hint: Think emergency room setting) • Violent behavior • Psychosis • Intoxication/Overdose • Withdrawal • Drug reaction or interaction • Anxiety/Panic • Depression /Suicidality www.mghcme.org Rapid for what problem? - II • Route of administration of drugs (IV/IM) • Contain/restrain/stabilize • Administer something that solve the problem (i.e. naloxone for opiate OD) or stabilize (IV benzodiazepine for alcohol withdrawal) • We have “treatments” for conditions with known etiology • Do we have treatments for conditions of unknown etiology? www.mghcme.org How do we treat acute psychiatric problems? • Etiology not known • Acute onset or worsening • Old (cheap) drugs vs new expensive drugs ($$) • What treatment is more efficacious? • Do we have guidelines? www.mghcme.org When rapid treatment is a BAD idea • Hyponatremia: • Hyperglycemic crisis • Patient delirious and agitated www.mghcme.org Rapid “treatment” of agitation? • Still need to rule out organic causes of delirium/agitation/psychotic symptoms (check lytes, CBT, toxins, PE, stroke, etc) • What is the best pharmacologic treatment for non-organic psychosis? • comparative effectiveness are very hard to conduct www.mghcme.org Rapid tranquillization for agitated patients in emergency psychiatric rooms: a randomized trial of midazolam versus haloperidol plus promethazine. • 301 aggressive patients randomized to receive IM midazolam (15 mg) or IM haloperidol (10 mg) + promethazine (50 mg). • At 20’ were tranquil or asleep 89% of patients given midazolam vs 67% of those given haloperidol plus promethazine. • By 40 minutes, midazolam still had a statistically and clinically significant 13% relative advantage. • After 1 hour, about 90% of both groups were tranquil or asleep. TREC collaborative group BMJ 2003 Sep 27; 327(7417): 708–713. www.mghcme.org Rapid tranquillization of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomized trial of intramuscular lorazepam v. haloperidol plus promethazine. • 200 patients randomized to receive IM lorazepam (4 mg) or IM haloperidol (10 mg) + promethazine (25-50 mg mix). • 4 h later, equal numbers in both groups were tranquil or asleep. • 76% given the haloperidol-promethazine were asleep compared with 45% of those on lorazepam (RR=2.29,95% CI 1.59-3.39; NNT=3.2,95% CI 2.3-5.4). The haloperidol- promethazine mix produced a faster onset of tranquillization/sedation and more clinical improvement over the first 2 h. • Neither intervention differed significantly in the need for additional intervention or physical restraints, numbers absconding, or adverse effects Alexander et al. Br J Psychiatry 2004 Jul;185:63-9.. www.mghcme.org A practical clinical trial comparing haloperidol, risperidone, and olanzapine for the acute treatment of first-episode nonaffective psychosis. • 172 patients, practical clinical trial, haloperidol (N = 56), risperidone (N = 61), and olanzapine (N = 55). Mean modal daily doses were 5.4 mg/day for haloperidol, 4 mg/day for risperidone, and 15.3 mg/day for olanzapine; 98.3% of subjects were drug naive at baseline. • All 3 treatments showed similar effectiveness in reducing the severity of general, negative, and positive sx after 6 weeks. No statistical differences among groups. • extrapyramidal symptoms and concomitant anticholinergic medication use was greater with haloperidol than olanzapine or risperidone. • Olanzapine-treated patients had significantly more weight gain vs haloperidol and risperidone groups. Crespo-Facorro B, et al. J Clin Psychiatry. 2006 Oct;67(10):1511-21. www.mghcme.org Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine • 43 severely agitated patients • randomly assigned to either daily haloperidol 15 mg, olanzapine 20 mg, or risperidone 2 to 6 mg over 5 days. • All drugs were effective for rapid tranquilization within 2 hours. Over 5 days, the course differed between agents (P < 0.001), but none was superior. • Dropouts occurred only in the risperidone and olanzapine groups. Walther et al, J Clin Psychopharmacol. 2014 Feb;34(1):124-8. www.mghcme.org Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses • 4 trials olanzapine IM vs. IM placebo (total n=769, 217 placebo). • olanzapine IM >placebo at 2 hours (4 RCTs, n=769, RR 0.49 CI 0.42 to 0.59, NNT 4 CI 3 to 5) and olanzapine IM was as acceptable as placebo. • olanzapine IM did not seem associated with extrapyramidal effects • 2 trials olanzapine IM vs haloperidol IM (total n=482, 166 allocated to haloperidol). No differences between olanzapine IM and haloperidol by 2 hours for the outcome of 'no important clinical response’ • 2 trials compared olanzapine IM with lorazepam IM (total n=355, 119 allocated to lorazepam). For the outcome of 'no important clinical response' , there was no difference at 2 hours • No studies reported outcomes related to hospital and service use, satisfaction with care or suicide, self-harm or harm to others. • No studies evaluated the oro-dispersable form of olanzapine. Belgamwar RB. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003729. www.mghcme.org Olanzapine IM or velotab for acutely disturbed/agitated people with suspected serious mental illnesses • “Data relevant to the effects of olanzapine IM are taken from some studies that may not be considered ethical in many places, all are funded by a company with a pecuniary interest in the result. These studies often poorly report outcomes that are difficult to interpret for routine care. Other important outcomes are not recorded at all.” Belgamwar RB. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003729. www.mghcme.org Review: Haloperidol for psychosis-induced aggression or agitation (rapid tranquillization) • 41 studies comparing haloperidol with other treatments. • Few studies reflect real world practice, most were small and carried considerable risk of bias. • Compared with placebo, more people in the haloperidol group were asleep at two hours (2 RCTs, n=220, RR 0.88, 95%CI 0.82 to 0.95, very low- quality evidence) and experienced dystonia (2 RCTs, n=207, RR 7.49, 95%CI 0.93 to 60.21, very low-quality evidence) • The haloperidol group required fewer injections than those in the aripiprazole group (2 RCTs, n=473, low-quality evidence). More people in the haloperidol group experienced dystonia (very low-quality evidence) • Four trials (n=207) compared haloperidol with lorazepam with no significant differences with regard to number of participants asleep at one hour (very low-quality of evidence) or those requiring additional injections (very low-quality of evidence). Ostinelli Cochrane Database Syst Rev. 2017 Jul 31;7:CD009377 www.mghcme.org Haloperidol for psychosis-induced aggression or agitation (rapid tranquillization) • Where additional drugs are available, sole use of haloperidol for extreme emergency is considered unethical. • Addition promethazine is supported by evidence from within randomized trials. • Use of an alternative antipsychotic drug is only partially supported by fragmented and poor-grade evidence. • Adding a benzodiazepine to haloperidol does not have strong evidence of benefit and carries risk of additional harm. • After six decades of use for emergency rapid tranquillization, this is still an area in need of good independent trials relevant to real-world practice Ostinelli Cochrane Database Syst Rev. 2017 Jul 31;7:CD009377 www.mghcme.org De-escalation techniques for psychosis-induced aggression or agitation • De-escalation is a psychosocial intervention for managing people with disturbed or aggressive behavior. • Of the 345 citations that were identified using the search strategies, we found only one reference to be potentially suitable for further inspection. However, after viewing the full text, it was excluded as it was not a randomized controlled trial. • Using de-escalation techniques for people with psychosis induced aggression or agitation appears to be accepted as good clinical practice but is not supported by evidence from randomized trials. It is unclear why it has
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