American Psychiatric Association 2017 Annual Meeting

American Psychiatric Association 2017

Dr Randall White was presenting a research poster at the American Psychiatric Association 2017 Annual Meeting in San Diego, CA.

Session: New Research Posters 1
Date: Monday, May 22
Time: 10:00 AM–12:00 PM
Poster Number: P5-020
Poster Hall: Exhibit Hall A, Ground Level, San Diego Convention Center

Dr White discussing the BCPP findings with Dr. John Kane, who did the first controlled trial of clozapine in North America.

ABSTRACT

Although clozapine is the standard for treatment-resistant psychosis, 40-60% of those treated with clozapine do not have an adequate response as measured by a 20% or greater reduction in the BPRS, PANSS or other assessments. This condition is known as clozapine resistance, ultra-resistance or refractory psychosis. At the publicly funded BC Psychosis Program, at UBC Hospital in Vancouver, Canada, we have developed criteria to identify clozapine resistance (CR) and an algorithmic approach to treatment based on available evidence. This involves assuring adequate clozapine treatment verified by dose and serum level, including addition of fluvoxamine when appropriate; offering ECT to CR patients, and/or antipsychotic augmentation preferably with sulpiride or aripiprazole. All patients admitted since program inception in February 2012 had failed at least 2 antipsychotic trials. A psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist evaluated each patient. All available summaries of previous psychiatric admissions were reviewed, and medical, pharmacological, social and behavioural histories were recorded.

All information is presented at a case conference and a DSM-IV or -5 multiaxial diagnosis reflects agreement among at least 2 psychiatrists and a psychologist. Symptom ratings included the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Psychopathology (GAPS), and the Clinical Global Impression-Severity and Improvement scales (CGI). Clozapine resistance is defined by an adequate trial, that is, at least 500 mg daily dose for ≥60 days; and continued symptoms manifested by PANSS with 2 positive scale items rated ≥ 4 (moderate) OR 1 item ≥ 6 (severe).

Of 114 patients with schizoaffective disorder or schizophrenia on clozapine at admission, 89 had received it for≥ 60 days; 23 were on at least 500 mg; and 20 met criteria for clozapine resistance (i.e., 17 men and 3 women). Of these, 17 had schizophrenia and 3 schizoaffective disorder; the mean age was 39.6 years. The mean PANSS scores at admission were Positive=28.3, Negative=26.2, General=50.0, Total=104.4; the mean CGI-S was 6.3. Of 16 patients with complete data, 8 were offered ECT and 3 accepted a course; the number of ECT treatments ranged 19-46. Of 19 patients discharged to date, 17 remained on clozapine with a mean dose of 463.2 mg; to obtain a therapeutic clozapine level, 6 received fluvoxamine, dose range 37.5-200 mg. Seven patients received adjunctive antipsychotics: 3 sulpiride, 2 aripiprazole, 4 first-generation agents. At discharge, the mean PANSS were Positive=20.8, Negative=22.1, General=40.0, Total=82.9; the mean CGI-S was 5.1.

Find full info on the American Psychiatric Association 2017 Annual Meeting here! 

Long-term benzodiazepine use is associated with increased mortality in people with schizophrenia

What I did before

When psychiatric patients are treated in an emergency department, they are often hypervigilant, manic, or otherwise in an excited, agitated state. The current standard of care to manage acute agitation in adults is using an antipsychotic medication and a benzodiazepine, often loxapine or haloperidol and lorazepam. For patients who have schizophrenia, antipsychotic medication alone often treats such symptoms in the longer term, yet many patients are discharged with a benzodiazepine prescription continue long-term benzodiazepine use possibly because the community clinician hopes to avoid triggering a relapse in discontinuing the medication. As a psychiatrist who has worked on acute and tertiary inpatient units, I have discharged patients on benzodiazepines with the expectation it would eventually be discontinued, but I have also seen many patients for whom it never was.

What changed my practice

Then, in 2013 while at the 7th Annual Pacific Psychopharmacology Conference, I was introduced to research showing that people with schizophrenia on chronic benzodiazepine therapy have an increased risk for suicide and all-cause mortality. I kept these observations in the back of my mind and was further alarmed in 2016 when another article from the same researchers found high-dose benzodiazepine use, but not lesser doses, was associated with increased suicide and cardiovascular mortality.

What I do now

Based upon these studies, I find the evidence compelling that benzodiazepines are contraindicated for long-term use in people with schizophrenia. When appropriate, I continue to use lorazepam for acute agitation amongst other reasons, I also educate patients about the risk of long-term use, including dependence and cognitive impairment in addition to mortality.To raise awareness of this issue among my colleagues, I mention the rationale and include recommendations for tapering benzodiazepines in consultation reports and discharge summaries.

Find the full article here!

Riverview Refractory Psychosis Data Presented at International Psychiatry Congress

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View the poster in a PDF file here

Abstract

Treatment-resistant psychosis is a challenge to psychiatry and a substantial burden to health-care systems. The province of British Columbia in Canada has publicly funded, universal health care, and patients with treatment-resistant psychosis may receive care in a specialized residential program. Between 1993 and 2011, 663 patients were admitted to this program; this cohort contains one of the largest known series of patients with treatment-resistant schizoaffective disorder.

All patients were evaluated by a psychiatrist, social worker, pharmacist, nurse, general physician, and neuropsychologist. Records from previous hospital admissions were reviewed and all information was presented at a multidisciplinary conference. This resulted in a consensus DSM-III or -IV multiaxial diagnosis and a detailed treatment plan. Ratings of symptoms and functioning at admission and discharge included the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning Scale, the Social and Occupational Functioning Scale, and the Clinical Global Impression of Severity. A research psychologist compiled all data at the time of each patient’s hospitalization.

Patients who did not complete treatment or had a diagnosis other than schizophrenia (SZ), schizoaffective (SZA) or mood disorder (MD) were excluded; the following describes 551 included patients (SZ = 63%, SZA = 29%, MD = 8%). More than half were male (59%), and the mean duration of hospitalization was 30 weeks. The proportion receiving clozapine increased from 21% at admission to 61% at discharge. Those with a MD were less likely to receive clozapine than either SZ or SZA (SZ = 64%, SZA = 61%, MD = 41%). In each diagnostic group, both antipsychotic polypharmacy and the ratio of prescribed daily dose to defined daily dose (PDD/DDD) of antipsychotic medication decreased during hospital stay (polypharmacy: SZ: 52% to 16%, SZA: 52% to 14%, MD: 43% to 0%; PDD/DDD: SZ: 2.1 to 1.6, SZA: 2.1 to 1.4, MD: 1.6 to 1.1). The use of mood stabilizers declined in all groups, but antidepressant use declined only in SZ and SZA. Mean total PANSS score declined in all diagnostic groups, but most in MD, least in SZ, and intermediate in SZA.

In an intensive inpatient program for treatment-resistant psychosis, aggregate improvement occurred despite global reduction in medications while clozapine use nearly tripled. Lower total antipsychotic dose correlated with greater improvement at discharge.

ECT as augmentation for clozapine

In 1937, Cerletti conceived electroconvulsive therapy (ECT) as a treatment for schizophrenia, a safer way than injecting a drug to induce seizures, which by a still-unknown mechanism has an antipsychotic effect. For patients who are acutely suicidal or catatonic, ECT is often life-saving, but for chronic schizophrenia, it is overlooked as a treatment option perhaps because of lingering stigma. The combination of ECT and antipsychotics including clozapine is reported to be safe, but controlled trials of ECT are rare.

A team from New York has published the first single-blind trial of clozapine and ECT. Patients with DSM-IV schizophrenia who had failed to respond to 12 weeks of clozapine therapy despite adequate serum levels were randomly assigned to either continue clozapine alone or to a course of bilateral ECT under general anesthesia, 3 times weekly for 4 weeks, then twice weekly for 4 more weeks. The patients who continued clozapine but remained unwell after 8 weeks were given a course of ECT with the same parameters. In both treatment groups, the dose of clozapine on which the patient entered the study remained unchanged. Patients with significant depression or non-nicotine substance-use disorder were excluded.

The outcome measures, performed by masked raters at outset and weekly, were the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression-Severity scale (CGI). Patients also underwent a neuropsychologic battery at baseline and at treatment completion. Response was defined as a 40% or greater improvement in the psychotic subscale of the BPRS and a CGI of 3 (mildly ill) or less. The investigators note that these are stringent response criteria.

The ECT group comprised 20 patients of whom 17 completed the 8-week course; the clozapine-only group comprised 19 patients of whom 16 completed the trial. Ten of the patients receiving clozapine and ECT met response criteria whereas none of the clozapine-only patients did. In the crossover phase, 9 of 19, or 47% of the patients responded to the combined treatment.

The cognitive evaluations showed reduction in mean speed of processing in the ECT-treated group, whereas executive function and episodic memory showed inconsistent effects across patients. The collective global neurocognitive values did not change significantly in either group. As for other adverse effects, no patients had spontaneous seizures, but 2 ECT patients had transient confusion.

At the BC Psychosis Program, we frequently offer ECT to patients who have not had adequate response to other treatments. This study provides high-quality evidence that clozapine-resistant patients can benefit from this approach, and cognitive impairment, while not absent, is typically quite mild.

Petrides G, Malur C, Braga RJ et al. Electroconvulsive therapy augmentation in clozapine-resistant schizophrenia: A prospective, randomized study. Am J Psychiatry. Published online Aug 26, 2014. Abstract

Pharmacology research projects getting underway at BCPP

Dr. Ric Procyshyn, a UBC pharmacologist and researcher, is the principal investigator in two research projects underway at BC Psychosis Program. The goal is to recruit 50 patients for each study, and participants must give voluntary informed consent.

The first study, titled A Pilot Study to Determine if Pantoprazole Modifies Steady-State Plasma Concentrations of Orally Administered Psychotropic Medications, will look at the effects of proton pump inhibitors (PPIs) on the absorption and blood levels of psychiatric medications. People who smoke, are overweight, or take clozapine are prone to gastroesophageal reflux disease (GERD), hence many people with schizophrenia end up receiving PPIs. Patients at BC Psychosis Program with gastric reflux who would benefit from treatment, and who are taking valproic acid, lithium, or a second-generation antipsychotic, will receive the PPI pantoprazole for nine days. During this time, plasma concentrations of the medications as well as gastrin, a digestive hormone, will be obtained. If the medication benefits a patient, treatment can continue.

The second project is A Pilot Study to Determine How Frequency of Administration Modifies Steady-State Plasma Concentrations of Orally Administered Clozapine. Patients on clozapine often receive it once every 24 hours, usually at bedtime because of its sedating properties. However, clozapine has a short half-life and dissociates quickly from the dopamine D2 receptor, so it may work better with more frequent dosing. Patients already on clozapine will be assigned to receive it once or twice a day for 15 days during which plasma concentration of clozapine will be monitored along with effects on glucose, body weight, and symptoms of psychosis.

Case reports of sodium nitroprusside treatment of clozapine-resistant schizophrenia

In a randomized, controlled trial published in 2014, intravenous sodium nitroprusside was shown to be effective in further reducing positive and negative symptoms of schizophrenia in patients taking a number of antipsychotics including chlorpromazine, haloperidol, olanzapine, risperidone and quetiapine. The same researchers based in Brazil and Canada have published two case reports of patients on clozapine who safely received intravenous sodium nitroprusside (1). The patients, both men, were 22 and 33 years old, and they had persistent positive symptoms of psychosis despite receiving clozapine at adequate dose and duration. Serum clozapine levels were not reported.

The men received nitroprusside according to the same protocol published in JAMA Psychiatry: an infusion of 0.5 microgram per kilogram per minute for four hours. In both cases, the improvements in positive and negative symptoms as measured by the Positive and Negative Syndrome Scale became apparent within hours and lasted for days.

The report does not mention cardiovascular parameters, but in a personal communication, the investigators said that at this dose, nitroprusside has little effect on blood pressure in normotensive people despite treatment with antipsychotics that can reduce blood pressure. The two patients did not receive further infusions because of concern about toxicity with repeated doses of nitrous prusside, which transiently produces small amounts cyanide; however, toxicity is rare with doses less than 5 micrograms per kilogram per minute. With infusions lasting more than 24 hours or in patients with renal insufficiency, accumulation of thiocyanate may occur, which can cause delirium (2). The risk of such toxic events appears to be minimal in low-dose nitroprusside treatment in appropriately selected patients.

This treatment has promise for clozapine-resistant schizophrenia, a severe disease with no well-established treatments except possibly electroconvulsive therapy (ECT). Randomized controlled trial in clozapine-resistant schizophrenia, also called ultra-resistant or super-refractory schizophrenia, are warranted.

References

1. Maia-de-Oliveira JP, Belmonte-de-Abreu P, Bressan RA, Cachoeira C, Baker GB, Dursun SM, Hallak JE. Sodium nitroprusside treatment of clozapine-refractory schizophrenia. J Clin Psychopharmacol. 2014;34:761-763.

2. Michel T, Hoffman BB. Treatment of myocardial ischemia and hypertension. In: Brunton L, Chabner B, Knollman B, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill Co., 2011 (online version).

66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco

66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco

Randall is pleased to be attending the 66th Annual American Psychiatric Association Institute on Psychiatric Services in San Francisco. He presented findings on 630 patients treated during 1993-2010 on the refractory psychosis ward at Riverview Hospital, British Columbia.

To view his abstract, click here.

Follow the conference on Twitter: #IPS2014

Brazil: The Use of Nitrous Prusside for Schizophrenia

nitrous prusside, schizophrenia, mental health

In 2013, Drs. Jaime Hallak, Joao Paulo Maia-de-Oliveira and associates in Ribeirao Preto, Brazil, published results from a randomized controlled trial of intravenous nitroprusside in schizophrenia. Two Canadian researchers from the University of Alberta collaborated on the trial. This study was the first to find that sodium nitroprusside, a treatment for hypertensive crises, has a rapid and prolonged effect on both positive and negative symptoms in patients with acute psychosis. The presumed mechanism is enhancement of nitric oxide in the central nervous system, which may modulate the NMDA receptor-cGMP pathway. In normotensive patients, nitroprusside has minimal effect on blood pressure, and cyanide accumulation is a theoretical concern but occurs only after 72 hours or more of continuous infusion. In treating schizophrenia, the infusion dose is 0.5 mg/kg/minute for four hours.

In the initial trial published in JAMA Psychiatry, Hallak’s team used the Brief Psychiatric Rating Scale and the negative subscale of the Positive and Negative Syndrome Scale (PANSS) as outcome measures. A significant effect on certain components occurred within the first two to three hours of treatment, and improvement endured for four weeks. All the patients were also receiving an antipsychotic other than clozapine.

I met with Jaime, Joao Paulo and their team at the University of Sao Paulo Hospital in Ribeirao Preto and was able to observe a treatment. When I first met the patient, whose infusion had begun 10 minutes before, she appeared anxious and tended to avoid eye contact. When I returned 90 minutes later, she was engaged in an art activity and was eager to show me what she had created. She smiled broadly and even tested her English vocabulary a little. The researchers said that they often see an improvement in the patients’ affect over the course of the infusion, and they are trying to find ways to measure this more objectively. Although data are still limited, the effect in treatment-resistant patients tends to be more delayed.

Further studies of nitrous prusside in Ribeiroa Preto are underway, including for treatment-resistant patients, some on clozapine, and on neurophysiologic effects as detected with fMRI and event-related potential. Because the benefits of the treatment begin to wane after four weeks, they are planning a controlled trial of weekly nitrous prusside infusions for four weeks followed by 60 days of observation.
Reference
Hallak JEC, Maia-de-Oliveira JP, Abroa J, et al. Rapid Improvement of Acute Schizophrenia Symptoms After Intravenous Sodium Nitroprusside: A Randomized, Double-blind, Placebo-Controlled Trial. JAMA Psychiatry. 2013;70:668-676. Abstract
Photo: Left to right: Dr. Jaime Hallak, Dr. Joao Paolo Maia-de-Oliveira, Juliana Almeida (audiologist), their patient and her mother

Health Care is a Human Right: Making it Real in Washington State

We are pleased to announce that Dr. Randall White has been invited to be the third speaker at The Western Washington Chapter of Physicians for a National Health Program’s Ninth Annual Public Meeting. This year’s theme is: “Health Care is a Human Right: Making it Real in Washington State”, and includes a promising keynote to be delivered by Kshama Sawant, PHD, Seattle City Council Member. Sawant champions the rights of the working poor and disenfranchised, and is most recently recognized for her work on the successful $15Now campaign, a grass-roots living wage campaign.

Another highlight will be Philip Caper, MD, who was a staff member on Senator Edward Kennedy’s US Senate Labor and Human Resources Subcommittee on Health, a PNHP national Board Member and active in Maine AllCare.

Randall will be contributing “Remarks from a Canadian / American Perspective.” He will mention how commercialized mental health care compromises quality, provides less service for the severely mentally ill, and has been implicated in known corruption in the U.S.

We hope you will join us!

Attending the event? Or following from home? Use hashtag #HCHR2014 and @BCPsychosis

Saturday, July 19th, at 7PM at
Kane Hall Room 120, on the University of Washington Campus
Admission is free and open to the public.
There is free parking beneath Kane Hall.

12-month trial of clozapine augmentation with aripiprazole or haloperidol

The latest trial for clozapine-resistant patients comes from Italy (1). The Clozapine Haloperidol Aripiprazole Trial (CHAT) is a multicentre, randomized, 12-month trial of patients with schizophrenia and persistent positive symptoms despite at least six months of clozapine therapy at a minimum dose of 400 mg. Outcome measures included the Brief Psychiatric Rating Scale and, for subjective rating of adverse effects, the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). The primary outcome was treatment discontinuation, “a pragmatic and reliable estimate of treatment efficacy and tolerability” according to the authors.

Based on a power calculation, the investigators intended to recruit 194 participants but randomized 106 patients, about 65% men and with a mean age of 41 years. In addition to clozapine, patients received either haloperidol or aripirpazole for 12-months. Baseline demographics and BPRS scores did not significantly differ between the groups. The dose of adjunctive antipsychotic was adjusted according to clinical response, and the patients could receive any necessary additional medications including mood stabilizers and antidepressants. Although the investigators did not report the mean dose of adjunctive antipsychotics in this publication, they reported in 2011 that at month 3, the mean aripiprazole dose was 11.8 mg and the mean haloperidol dose was 2.8 mg (2).

During the study, 19 aripirpazole and 15 haloperidol patients withdrew, which was not significantly different. At 6 months, the mean BPRS score in the aripirpazole group had decreased by 8.8, and in the haloperidol group, by 8.1; the improvement persisted at 12 months. By 3 months the mean LUNERS score decreased significantly in the aripirpazole group but not in the haloperidol group, which indicated that patients taking aripirpazole reported a decrease in adverse effects whereas those taking haloperidol did not.
Both aripirpazole and haloperidol showed effectiveness in augmenting clozapine, but aripirpazole was better tolerated by self-report. Despite this apparent preference for aripirpazole, the groups had a comparable rate of treatment discontinuation: about a third of patients dropped out, most during the first 6 months of augmentation. The findings of the study are limited by lack of statistical power and of a placebo arm. The researchers claim, however, that CHAT is the longest non-industry-sponsored RCT of treatment-resistant schizophrenia.

Reference

1. Cipriani A, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia. J Clin Psychopharmacol. 2013;33: 533-537. Abstract

2. Barbui C, Accordini S, Nose M, et al. Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care: a randomized, controlled trial. J Clin Psychopharmacol. 2011;31: 266-273. Abstract