Exercise-associated hippocampal plasticity and hippocampal microvascular plasticity in chronic refractory schizophrenia patients

RANDALL - WIN_20150331_130356Donna Jane-Mai Lang, Alexander Rauscher, Allen E Thornton, Kristina Gicas Geoff Smith, Vina Goghari, Olga Leonova, Randall F White, Fidel Vila-Rodriguez, Wayne Su, Barbara Humphries, Aaron Phillips, William Honer, Alexandra Talia Vertinsky, Darren E Warburton. Poster presented at 15th International Congress on Schizophrenia Research, Colorado Springs, Colorado. March 29-April 1, 2015.


Background: Hippocampal deficits are a commonly reported finding in chronic schizophrenia patients, and may contribute to severity of illness. Regular exercise is thought to remediate both hippocampal volume reductions and neurovascular flow to this region.

Methods: Seventeen chronic refractory schizophrenia patients were enrolled in a 12-week exercise intervention trial. Clinical assessments (PANSS, SOFAS, Hamilton Anxiety Scale (HAMAS), Calgary Depression Scale, Extrapyramidal Symptom Severity Scale), physical assessments (BMI, resting heart rate (RHR), blood pressure (BP), VO2 Max) and 3T MRI data (3D structural MRI, susceptibility weighted imaging) were ascertained at baseline and 12 weeks. Repeated measures ANOVAs with total (L+R) hippocampal and total hippocampal venule volumes expressed as ratios to total brain volume and total hippocampal volume respectively. Additional correlational models were applied.

Results: Patients had a significant increase in total hippocampal volume after 12 weeks of exercise (F(1, 33) = 6.8, p. = 0.019. Total hippocampal venule volume was not significantly increased after exercise (F(1, 33) = 0.17), although the overall increase in venule volume was 7-7.5%. A significant positive relationship between absolute change in total hippocampal volume and absolute change in hippocampal venule volume was observed (r = .52, p. = 0.04). Patients exhibited reduced symptom severity (p. = 0.0005), improved social and occupational functioning (p. = 0.0004), and a strong trend for reduced depression severity (p. = 0.06) at the end of the 12-week exercise intervention. Measures of BMI, RHR, BP and VO2 Max were not statistically different at 12 weeks, however exploratory investigations revealed a potential, but statistically nonsignificant relationship between improved VO2 Max capacity and reduced HAMAS score (r = -.44, p. = .067).

Conclusion: We observed exercise-associated hippocampal volume increases after 12 weeks of regular exercise in chronic refractory schizophrenia patients, as was previously reported by Pajonk et al, 2010. Moreover, these changes in hippocampal volume were correlated to changes in hippocampal venule volumes. These data support the hypothesis that regular exercise offers remediation in both hippocampal tissue volume and hippocampal microvascular volume in chronically treated refractory patients. Relationships to other clinical measures still remain to be clearly established.

Prenatal Tobacco Exposure and Schizophrenia


In utero exposure to tobacco, in other words having a mother who smoked during pregnancy, has been associated with several developmental disorders including attention deficit disorder and learning problems. Research from the Finnish Prenatal Study of Schizophrenia, a nationwide cohort of people with schizophrenia, suggests a link between this illness and in utero tobacco exposure. Dr. Alan Brown of Columbia University in New York described 997 Finnish patients with schizophrenia matched with same-sex and same-age controls whose mothers had blood samples taken during pregnancy. The American and Finnish research team examined serum cotinine, a metabolite of nicotine and a reliable biomarker for tobacco use, in the banked blood samples.
Among the affected offspring, 20.2% were born to women with serum cotinine greater than 50 ng/ml, considered a sign of high tobacco use, compared with 14.7% of controls; the odds ratio was 1.38 (95% CI, 1.05-1.82, p = 0.02), with adjustment for maternal age, parental psychiatric disorder, and birth province. When serum cotinine was analyzed as a continuous variable, the effect was weaker, with a final odds ratio of 1.06 (CI, 1.004-1.12; p = 0.035) when adjusted for the same factors along with a measure of maternal inflammation, C-reactive protein (CRP), which was also determined in banked serum.
The findings, while far from conclusive, suggest a dose-response which is one sign of plausibility. Furthermore, nicotine crosses the placenta and is associated with neurodevelopmental effects including cortical thinning and changes in the P1 auditory evoked response. The physiologic mechanisms of smoking may include reduced placental perfusion, increased carbon monoxide, oxidative stress, and the direct effects of nicotine on nicotinic acetylcholine receptors, which are important regulators of other neurotransmitters, and of neuron migration and cell survival.
A. Brown, H. Surcel, S. Niemela, S. Hinkka-Yli-Salomäki, I. W. McKeague, A. Sourander. Epidemiological Evidence for Inflammation and Nicotine Exposure as Prenatal Risk Factors for Schizophrenia. Symposium 1-2, 15th International Congress on Schizophrenia Research, Colorado Springs, Colorado. March 29-April 1, 2015.

Riverview Refractory Psychosis Data Presented at International Psychiatry Congress



View the poster in a PDF file here


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.

Could grey matter loss in the superior temporal gyrus contribute to treatment resistance?

The DSM 5 abandoned classifying schizophrenia by psychopathology subtype, but the heterogeneity of the disorder still requires explanation. A more pragmatic approach advocated by some researchers is classification according to treatment response: antipsychotic responsive, clozapine responsive, and clozapine non-responsive. Investigators are looking at the biologic correlates of these subtypes, and a group from New Zealand recently examined differences in brain volume. Using a 3-Tesla scanner, they obtained T1-weighted images of the brains of 18 antipsychotic responders, 19 clozapine responders (for whom other antipsychotics failed), 15 clozapine nonresponders, and 20 controls. All subjects were 18 to 45 years old, and patients with neurologic or active addictive disorders were excluded. The clozapine responsive and non-responsive patients had failed to respond to at least two trials of other antipsychotics, and the PANSS was used to assess symptoms.

The groups of patients did not differ by mean age, PANSS scores or illness duration. The groups had some differences in substance use history; the clozapine-resistant patients had more use of hallucinogens, and the antipsychotic responsive group had more use of cannabis, but the groups did not differ in stimulant use history.

Compared with controls, all patient groups had a reduction in whole-brain and white-matter volumes, and the clozapine-resistant group had a significant increase in ventricular volume. The treatment-resistant and clozapine-resistant patients had smaller grey matter volumes compared with controls and antipsychotic-responsive patients. In analysis using voxel-based morphometry, a technique to examine the volume of specific brain regions, the clozapine-resistant patients, compared with controls, showed bilateral grey matter reductions in the superior and middle temporal gyri, ventromedial prefrontal cortex, anterior cingulate gyrus, and postcentral gyrus. The left cerebellum and right occipital cortex also showed grey matter reduction. Compared with controls, the treatment-resistant group had a similar magnitude of grey matter volume reduction which especially affected the right perisylvian region.

Compared with the antipsychotic-responsive group, both clozapine-resistant and clozapine-responsive groups had reduction in grey matter volume with somewhat differing patterns. Only the clozapine-resistant patients had a relative reduction in the left cerebellum and left anterior cingulate gyrus. No differences were seen in comparing the clozapine-resistant and clozapine-responsive groups.

A controversy in the field of neuroimaging of schizophrenia is the role of antipsychotic exposure in cerebral volume loss; previous research has shown conflicting results. In this study, the clozapine-resistant group had a higher mean daily dose of antipsychotic compared with the other groups, but the researchers found no overall correlation between daily dose and grey matter volume. The study did not look at lifetime antipsychotic exposure.

The investigators highlight the finding of prominent volume reduction in the superior temporal gyrus in the clozapine-resistant group, which was seen in a number of prior studies including longitudinal investigations and in first-episode patients. This brain structure is crucial for auditory processing and language, which are highly implicated in schizophrenia; perhaps tissue loss in this region contributes to poor medication response. However, as the researchers state, in this kind of observational study we are unable to draw conclusions about cause and effect.

Anderson VM, Goldstein ME, Kydd RR, Russell BR. Extensive grey matter volume reduction in treatment-resistant schizophrenia. Int J Neuropsychopharmacol. Published online Feb 25, 2015. Abstract

Dimenhydrinate (Gravol) abuse worsens schizophrenia

We just published a report in the Journal of Clinical Psychopharmacology of a woman who abused dimenhydrinate for years. Only after she had sustained abstinence from this over-the-counter remedy for nausea did her psychosis respond well to treatment. Read the case report.

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.


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.


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)