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).

Increasing prevalence of schizophrenia in Canada

The burden of schizophrenia for Canadian society is significant. In a review of incidence and prevalence studies published in peer-reviewed journals dating from 1953 through 2006, Dealberto estimated the one-year prevalence of schizophrenia in Canada at 2.5 to 5.6 per 1000. The investigator found that published incidence and prevalence rates have increased during the past 4 decades. Furthermore, the prevalence and incidence in Canada were greater than international median rates, with Canada’s estimated incidence rate situated between the 45th and 100th percentiles of international comparators.

Dealberto explained the relatively high prevalence of schizophrenia in Canada by three possible factors. First, many studies have found that immigrants have an increased incidence of schizophrenia in both the first and second generations. Canada has a high rate of immigration, about twice that of the United States; 20% of Canadians were born in another country. Second, schizophrenia is more common in countries at high latitude, although the cause of this effect is unknown. Third, urban populations have a greater prevalence of schizophrenia, and 80% of Canadians live in cities.

Population-based studies of the prevalence of treatment-resistant schizophrenia in Canada do not exist. Most reports indicate that treatment resistance occurs in about 30% of patients, hence based on Dealberto’s findings, the estimated one-year prevalence of treatment-resistant schizophrenia in Canada is 7.5 to 17 per 10,000.

Given these data, and assuming a continuation of current immigration policy in Canada, governments at federal and provincial levels must plan for and fund the health-care and social-service needs of a growing number of people with this disorder.

Reference

Dealberto MJ. Are the rates of schizophrenia unusually high in Canada? A comparison of Canadian and international data. Psychiatry Res. 2013;209(3):259-265. Abstract

Why the adolescent brain is sensitive to psychosis-inducing effects of cannabis

kaleidoscope, vision, cannabis to the brain

According to David A. Lewis, MD, who spoke at the American Psychiatric Association Institute on Psychiatric Services on October 31 in San Francisco, California, impairment in working memory is a key finding in schizophrenia, and this impairment is present before onset of psychosis, persists during the illness, and helps predict functional outcome. Furthermore, research in post-mortem brains and animal models shows that layer 3 of the dorsolateral prefrontal cortex is crucial to working memory.

In a lecture titled “Developmental trajectories in cortical circuits: Identifying sensitive periods for the emergence of schizophrenia,” Dr. Lewis, director of the Translational Neuroscience Program and chair of the department of psychiatry at the University of Pittsburgh, described research that has begun to explain why schizophrenia tends to strike people in late adolescence and early adulthood. A circuit consisting of pyramidal cells and inhibitory GABAergic cells, which is recorded electrophysiologically as the “gamma oscillation,” matures during childhood and early adolescence. In this complex process, which involves GABA, NMDA and cannabinoid receptors, some synapses are strengthened and others pruned. During this “sensitive period,” as Lewis called it, exposure to environmental insults can have a profound effect. One manifestation is that people with schizophrenia end up with 20% fewer dendritic spines, which are post-synaptic structures, on the pyramidal cells in cortical layer 3 than unaffected people.

Epidemiologic data consistently show that youth who use marijuana before 16 years of age double or triple their risk for developing schizophrenia. Tetrahydrocannabinol (THC), which binds to cannabinoid receptors on pyramidal and GABAergic neurons in the cortex, affects visual working memory in many people who use it. In an effort to mimic human teenagers’ regular use of marijuana, Dr. Lewis’ lab gave a group of young rhesus monkeys frequent doses of THC. Compared to non-exposed peers, monkeys who had a 6-month exposure to THC developed impairments in spatial working memory similar to enduring deficits exhibited by humans with schizophrenia. The researchers also looked at a second cognitive task that targets object working memory, which depends upon the ventral prefrontal cortex, an area of the brain that matures earlier. This function was unaffected by exposure to THC.

Dr. Lewis emphasized that timing is crucial and may help explain why certain exposures or traumas have major impact at one time in development and minor impact at another. The impact of treatments likewise may vary by developmental stage, and he said that those that aren’t targeted and timely may have unintended consequences.

(Photo: flickr.com/pt3rmin4t0r)

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

The refractory psychosis ward at Riverview Hospital between 1993 & 2010

Riverview Psychiatric Hospital Coquitlam BC

OBJECTIVES: Patients in British Columbia who have treatment-resistant psychosis may receive care in a publicly funded academic program where each patient undergoes a multidisciplinary diagnostic evaluation. We describe this assessment process and present findings on a series of patients including a large number with treatment-resistant schizoaffective (SZA) disorder.

METHOD: All patients admitted to the refractory psychosis ward at Riverview Hospital between 1993 and 2010 had failed to respond to at least two previous 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 was presented at a case conference and a DSM-IV multiaxial diagnosis reflected agreement between at least two psychiatrists and a psychologist. Symptom ratings included the Positive and Negative Syndrome Scale, the Global Assessment of Functioning, and the Clinical Global Impression-Severity scale.

FINDINGS: Of the 642 patients who were admitted, 92 did not complete treatment (died, were transfered or left against advice) or received a diagnosis other than schizophrenia (SZ), SZA or mood disorder (MD). Consensus diagnosis differed from referral diagnosis in 27% of cases. Of 378 patients referred with SZ, the consensus diagnosis was SZ in 78%, SZA in 15%, MD in 2%, and other in 5%. Of the 145 referred with SZA, the consensus diagnosis was SZA in 63%, SZ in 26%, MD in 3%, and other in 2%. Two thirds of the SZA group were bipolar type. People with confirmed MD or SZA tended to be older and had a longer illness duration, and were more likely to be female, noncaucasian, and married. Functioning and symptom severity in the preceding year and at admission were worse in SZ than SZA patients. PANSS positive scores were greater for SZ and SZA than MD, and PANSS negative scores were more severe in SZ than SZA or MD. Prior depressive episodes were very common in MD (98%) and SZA (89%), but 35% of SZ patients also had a previous depressive episode. Lifetime substance use disorder was found in 63% and recent substance abuse in 35% of patients, and these proportions did not differ across diagnoses. At admission, SZA patients were more likely than SZ patients to have been on a mood stabilizer, but the mean number of antipsychotics and total amount (defined daily dose) did not differ.

CONCLUSION: In a series of patients with treatment-resistant psychosis, the most common diagnosis was SZ, but 29% had SZA. SZA patients were frequently misdiagnosed in the community, and compared to SZ patients, tended to have better baseline functioning, lower symptom severity, were older, and had been ill longer.

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

On July 19th, 2014, Dr. Randall White was invited to speak at  The Western Washington Chapter of Physicians for a National Health Program’s Ninth Annual Public Meeting. This year’s theme was: “Health Care is a Human Right: Making it Real in Washington State.” As a physician who has practiced both in Canada and the US, Randall brings a unique perspective to the table. Dr. White is a known advocate for health care equality, and stresses that financial access to health care is a major source of inequality. He says “Inequality has greater effects on Health Care than the actions of doctors and caregivers. In Canada, Health Care is a human right.” He goes on to encourage his American colleagues to continue to strive for universal health care.

MicroRNA: a new frontier in schizophrenia?

A large consortium of researchers in Europe, North American and Australia performed a genome-wide association study (GWAS) of single-nucleotide polymorphisms, which are uncommon variants of genes, among people with schizophrenia in two stages. In the first stage, a discovery analysis of pre-existing GWAS cohorts, they included, 9,394 people with schizophrenia and 12,462 controls, all of European ancestry. In the second-stage independent replication, they used a sample of 8,442 cases and 21,397 controls. In the combined stage-1-and-2 dataset, five alleles had a significant and novel association with schizophrenia, whereas two alleles identified in previous research had significant association. The most robustly newly associated allele was rs1625579 on chromosome 1p21.3, in intron 3 of AK094607. This region codes for the primary transcript of MIR137, a microRNA involved in adult neurogenesis and neuronal maturation. Two previous studies cited in the present report found an association of this regulatory mechanism with schizophrenia. Moreover, four genes identified as possibly associated with schizophrenia in the present study are targets of MIR137.

Although the evidence is circumstantial, the researchers assert a possible pathophysiologic role for the MIR137 mechanism in schizophrenia. Linkage studies, an older approach to identify candidate genes, have identified schizophrenia-related genes such as DISC1, and studies of patients with copy-number variants such as 22q11 deletion syndrome have suggested additional genetic etiologies of psychosis. The heterogeneity of “the group of schizophrenias,” as Bleuler called this disorder (2), is being borne out in genetic research, and psychiatrists should pay attention. We can hope that such work will bear fruit in improved treatments for our patients.

References

1. The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011.18;43:969-976. Full text

2. Bleuler, Eugen. Dementia praecox or the group of schizophrenias. Leipzig, Germany; 1911.