APA 2015 Round-up: What’s New About Agitation, Aggression and Violence

Editor: Leslie Citrome, MD, MPH

Clinical Professor of Psychiatry and Behavioral Sciences,

New York Medical College, Valhalla, NY

 

New on the Street: NBOMe Compounds

 

Oral presentations: The N-Bomb Strikes Again. A Case of Self-Injurious Behavior While Under the Influence of a Novel Psychedelic Drug. 

Chairs: Petros Levounis, M.D., Jennifer Hanner, M.D., M.P.H.

Speakers: Kristel Carrington, M.D., Erin Zerbo, M.D., Jennifer Hanner, M.D., M.P.H.

 

Why is this important?

  • These are relatively new drugs of abuse that can be associated with agitated behavior.
  • 25I-NBOMe is a highly potent, high-affinity agonist of the serotonin 2a (5HT2a) receptor.
  • Other hallucinogenic NBOMe drugs include 25C-NBOMe and 25BNBOMe.
  • See also Weaver MF, Hopper JA, Gunderson EW. Designer drugs 2015: assessment and management. Addict Sci Clin Pract. 2015 Mar 25;10(1):8.

 

Background

  • The goals of this session was to identify several classes of novel psychedelic drugs, including the NBOMe series; recognize the physiologic effects of NBOMe compounds in the body and identify the psychiatric sequelae of NBOMe intoxication; review the clinical management of potent psychedelic intoxication; and identify the public health concerns and legislative challenges related to research chemicals that are rapidly becoming drugs of abuse.

 

Methods

  • Individual presentations covering the above educational objectives.

 

Results

  • Underground production and trafficking of new psychoactive drugs has increased and include synthetic cannabinoids (e.g. "Spice"), cathinones ("bath salts"), and hallucinogens.
  • The NBOMe compounds (25B, 25C, 25I) are a relatively novel series of potent synthetic hallucinogen drugs that have recently emerged as popular designer drugs of abuse and can be purchased online in a number of countries.
  • Recreational use of NBOMe has been shown to carry significant risk of both physiologic and behavioral toxicity, including death.
  • The adverse effects include tachycardia, hypertension, agitation, auditory and visual hallucinations, aggression, hyperpyrexia, and metabolic disturbances.
  • As the NBOMe compounds cannot be detected on standard urine or blood screening toxicology tests, emergency medical clinicians are challenged to be aware of their potential role in cases evaluated in Emergency Departments.
  • A case example was given of a 24-year-old male with no past psychiatric history who presented with new onset psychosis and self-inflicted wounds to his head and neck in the context of 25I-NBOMe intoxication.

 

Conclusions

  • NBOMe compounds can cause psychosis and violence.
  • NBOMe compounds are easily available and can be purchased on the internet.
  • Some governments have enacted legislation controlling their possession, production, and sale.

 

Clinical Commentary

  • Clinicians trained in the era of wide abuse of PCP and crack cocaine may not be aware of a new array of substances of abuse that may be more easily obtainable than older illicit drugs.

 

Rapid Tranquilization: What Medications Are Used Today?

 

Poster presentation: Rapid Tranquillisation and Clinical Preferences: A Transatlantic Comparison

Lead Author: Pallavi S. Nadkarni, M.B.B.S., M.D. Co-Author(s): Sarah Penfold, MD., Dianne Groll, PhD

 

Why is this important?

  • With the current emphasis on least restrictive interventions to manage psychosis and agitated behavior, the idea of using rapid tranquilization appears to have fallen out of favor. Nonetheless, it may become necessary after other measures have failed.

 

Background

  • Aggression is the most common psychiatric emergency. It causes physical and psychological consequences to all and also accounts for staff absenteeism.
  • Management of dangerous behaviors poses a challenge to treatment teams.
  • Chemical restraint is a last-line resort after other methods have failed. Rapid tranquilization entails administering psychotropic drugs to control these behaviors.
  • The literature on this topic is sparse and varied.

 

Methods

  • Clinician preferences on rapid tranquilization in Kingston, Canada, were compared with results to an earlier survey from Leeds, UK.
  • The survey questionnaire was based on a clinical vignette and was electronically disseminated amongst 100 psychiatrists working in the department of psychiatry in Kingston, Canada.
  • Data was analyzed for the first and second drugs of choice, route of administration and estimated time to achieve a favorable outcome.

 

Results

  • In Canada, 41% clinicians completed the questionnaire, compared to 54% in the UK.
  • In Canada, olanzapine (63%) was commoner than haloperidol (15%) and lorazepam (2%); 20% opted for other medications. In contrast, in the UK, lorazepam was chosen over olanzapine and haloperidol in that order, with only a minority opting for 'other'.
  • 68% preferred oral route to parenteral options with none opting for IV route in Canada; in contrast 78% in the UK chose the oral route with almost an equal numbers choosing for IM (12%) or IV (10%).
  • Dissolvable tablets were preferred in Canada (76%), three times more than in the UK.
  • Quick results within 60 minutes were expected in both surveys.
  • In Canada, 80% were willing to be persistent with the same drug in the event of the desired outcome not being achieved as opposed to only 33% in the UK.
  • A greater number of clinicians preferred patients to be calm but awake with rapid tranquilization as opposed to being sedated, which is in keeping with the guidelines (78% in Canada, 92% in the UK).
  • A high compliance with local guidelines was seen in both surveys.

 

Conclusions

  • Medication choice and route of administration can differ depending on locus of practice.
  • Several limitations are evident including closed questions that can limit responses, selection bias limiting generalization, and the possibility that respondents provided ideal responses that may not reflect actual practice.

 

Clinical Commentary

  • Uniform standards for the management of agitation are not universally adopted and can lead to suboptimal care.
  • Even when an evidence base is used to guide medication choices there is substantial variation in practice.
  • The reader is encouraged to review the guidelines espoused by the American Association for Emergency Psychiatry (AAEP) - Project BETA (Best practices in Evaluation and Treatment of Agitation) – which can be found in the February 2012 issue of the Western Journal of Emergency Medicine and available free on-line through PubMed.

 

Specific Anti-Hostility Effects of Antipsychotic Medications

 

Poster presentation: Cariprazine Reduces Agitation and Hostility Associated with Schizohprenia 

Lead Author: Leslie Citrome, M.D., M.P.H. Co-Author(s): Kaifeng Lu, Ph.D., Paul Ferguson, M.S., Istvan Laszlovszky, Pharm.D., Suresh Durgam, M.D.

 

Why is this important?

  • Agitated behavior can lead to aggression and violence.
  • These behaviors can lead to hospital admission, and if they persist, interfere with treatment and can delay discharge.

 

Background

  • Agitation is common in patients hospitalized with acute exacerbation of schizophrenia.
  • Patients experiencing severe agitation display excessive motor and verbal activity, are irritable and uncooperative, and frequently show aggressive or destructive behavior.
  • Effective control of agitation is an important goal of antipsychotic treatment.
  • Cariprazine is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. The efficacy and tolerability of cariprazine in patients with acute exacerbation of schizophrenia has been supported by 3 phase II/III studies (NCT00694707, NCT01104766, and NCT01104779).
  • Cariprazine is currently under review by the FDA and not commercially available at this time.

 

Methods

  • A pooled analysis evaluated the effects of cariprazine on agitation and hostility symptoms in patients with schizophrenia using data from 3 placebo-controlled trials.
  • Studies were similar in design and included 6 weeks of double-blind treatment; the primary efficacy measure in all studies was the Positive and Negative Syndrome Scale (PANSS).
  • Cariprazine dose groups were combined for analyses (dose range, 1.5 to 9 mg/day).
  • Post hoc assessments of agitation and hostility were conducted via mean change from baseline to Week 6 on: PANSS-Excited Component (PANSS-EC) (items: tension [G4], uncooperativeness [G8], poor impulse control [G14], excitement [P4], and hostility [P7]), PANSS hostility factor (items: G8, G14, P4, and P7), and the PANSS hostility item (P7).
  • To correct for potential confounder variables, the hostility item analysis was conducted both with and without adjustment for the following covariates: change in the sum of the PANSS items measuring the positive symptoms of schizophrenia (delusions, conceptual disorganization, hallucinatory behavior, grandiosity, suspiciousness/persecution, unusual thought content), and sedation (measured by the presence of sedation, somnolence, or hypersomnia adverse events).

 

Results

  • For change from baseline on the PANSS-EC, the least squares mean difference (95% confidence interval) (LSMD [95% CI]) at Week 6 was significantly greater for cariprazine versus placebo (-1.5 [-2.0, -0.9], P<.0001).
  • Improvement for cariprazine versus placebo on the PANSS hostility factor score was also significantly different (-1.2 [-1.6, -0.7], P<.0001).
  • Significantly greater improvement on the PANSS hostility item score was observed for cariprazine compared with placebo from Week 1 through Week 6.
  • After adjusting for changes in positive symptoms and for the presence of sedation, improvement in the PANSS hostility item score remained statistically significant in favor of cariprazine versus placebo from Week 1 through Week 6.
  • At Week 6, higher levels of baseline hostility were associated with greater improvement in the hostility item, with the greatest score decrease seen in cariprazine patients with baseline hostility ≥4.

 

Conclusions

  • In patients with schizophrenia, there was significant improvement in hostility symptoms for cariprazine versus placebo as shown by mean change from baseline on the PANSS-EC and PANSS hostility factor score.
  • Significantly greater improvement for cariprazine- versus placebo-treated patients was also seen on the PANSS hostility item with statistically significant mean differences seen as early as Week 1 and persisting through Week 6; improvement associated with cariprazine treatment appeared to be partially independent of improvement in PANSS positive symptoms and the effect of sedation.
  • Results suggest that cariprazine is associated with specific anti-hostility effects that are independent of a general antipsychotic effect, which may be helpful for treating symptoms of aggression and hostility in patients with acute exacerbation of schizophrenia.

 

Clinical Commentary

  • Many, but not all, antipsychotics have demonstrated a specific anti-hostility effect. These can differ from agent to agent, and from individual to individual.
  • Of particular interest is whether new antipsychotics that may have somewhat different mechanisms of action can also be helpful in managing patients with hostility associated with schizophrenia.
  • Additional information can be found in Citrome L, Volavka J. The psychopharmacology of violence: making sensible decisions. CNS Spectr. 2014 Oct;19(5):411-8.

 

An Inhaled Antipsychotic for Agitation – Real World Experiences

 

Poster presentation: Inhaled Loxapine for the Control of Agitation: Results from a Naturalistic Longitudinal Study. 

Lead Author: Pedro M. Sanchez Gomez, M.D. Co-Author(s): Edorta Elizagarate, M.D., Jesus Ezcurra, M.D., Ana B. Yoller, M.D., Juan Larumbe, M.D., Rafael Garcia, M.D., Blanca Revuelta, M.D., Esther Ibarrola, M.D., Natalia Ojeda, Ph.D., Javier Pena, Ph.D., Koldo Callado, M.D.

 

Why is this important?

  • Agitated behavior can lead to aggression and violence.
  • These behaviors can lead to hospital admission, and if they persist, interfere with treatment and can delay discharge.
  • Least-invasive techniques to manage agitation are desirable

 

Background

  • Psychomotor agitation can be defined as excessive motor activity associated with a feeling of inner tension.
  • In patients with schizophrenia or bipolar I disorder, agitation may escalate along a continuum of severity over time.
  • There are few therapeutic options to control and reduce the levels of agitation back to normal in individuals with schizophrenia or bipolar disorder: verbal de-escalation, oral medication and intramuscular medication.
  • Inhaled loxapine is a typical antipsychotic recently approved for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults. Efficacy was demonstrated in 2 phase 3 trials in acute agitation: one in schizophrenia and one in bipolar I disorder.

 

Methods

  • This was a prospective, repeated measures, naturalistic, open-label study to assess the efficacy of inhaled loxapine in a sample of 20 consecutive agitated patients with schizophrenia or bipolar disorder, admitted at a psychiatric hospital.
  • Efficacy was measured as change from baseline in the PANSS-EC and CGI-S scales score.
  • Response time was measure as the time needed to achieve a score of 1 or 2 on the CGI-I.
  • Patient and Nurses satisfaction measures were also taken.

 

Results

  • Reduced agitation, as reflected in PANSS-EC score, was evident 2 minutes after first dose in the majority of patients.
  • In addition, efficacy was evident for all assessment times in the 24 hours after the first dose.
  • Inhaled loxapine produced significant improvement of agitation in both scoring endpoints.

 

Conclusions

  • This study, conducted in a sample of consecutive "real-world", inpatients with schizophrenia or bipolar disorder demonstrated efficacy.
  • The authors noted a fast onset of action.

 

Clinical Commentary

  • Although clinical trials designed for regulatory purposes can provide information regarding efficacy and tolerability, anecdotal evidence from actual clinical practice is helpful in putting the double-blind study results into context.
  • Inhaled loxapine appears to be a useful choice and may be regarded as an alternative to intramuscular injection when rapid control of agitated behavior is needed.