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.

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

Pimozide is ineffective for clozapine augmentation

Partial or non-response to clozapine is a challenging clinical situation. For these patients, who are considered refractory or ultra-resistant, we have limited options. Available evidence for augmenting clozapine is discouraging, but even negative trial results are valuable as a guide for what not to do. Exposing patients to ineffective treatments increases both costs and risk of adverse effects.

Pimozide, a potent D2 receptor antagonist, was found to be effective in a 1997 open-label clinical trial in partial clozapine responders. In a 2011 double-blind, placebo-controlled, 12-week trial in patients with partial or non-response to clozapine, pimozide at a mean dose of 6.5 mg daily was ineffective (1). A different U.S. group just published another randomized, double-blind, placebo-controlled trial of pimozide at 4 mg daily in patients with partial clozapine response (2). Using the BPRS, the Schedule for the Assessment of Negative Symptoms, and evaluations of verbal memory, working memory and executive function, the investigators found no significant differences between the groups at 12 weeks, although both showed improvement in the BPRS over time.

With two negative trials, it seems that pimozide as a clozapine augmentation agent can be put to rest. In fact, the entire strategy of adding first-generation D2 antagonists to clozapine for partial or non-repsonse is dubious.


1. Friedman JI, Lindenmayer JP, Alcantara F, et al. Pimozide augmentation of clozapine in patients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy. Neuropsychopharmacology. 2011;36:1289-1295. Full text

2. Gunduz-Bruce H, Oliver S, Gueorguieva R, et al. Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia. Schizophr Res. 2013;143:344-347. Abstract

Does lamotrigine augment clozapine?

Many of the patients referred to B.C psychosis Program are on clozapine or have received it in the past, and many have had a limited response. Clozapine-resistance is a big challenge for psychiatrists who manage chronic psychosis, and a recent quantitative review of clozapine augmentation strategies provides little guidance or solace. Stefan Leucht and colleagues examined randomized, masked, placebo-controlled studies

of at least two weeks duration in which another drug was added following at least four weeks of  clozapine therapy. Whenever possible, they used intention-to-treat data to calculate effect size.

The studies involved a range of medications including antidepressants, antipsychotics, glutamatergic agents, and antiepileptics. Lamotrigine is particularly of interest because Tiihonen’s group performed a meta-analysis in 2009 based on five studies that showed a significant effect for augmentation of clozapine. This group obtained unpublished data from studies that looked at lamotrigine added to a variety of antipsychotics, and intention-to-treat outcomes from the trial by Zocali, the largest study to date with 30 subjects on active therapy. Based on the 2009 meta-analysis, Goff commented that “the addition of lamotrigine in patients who remain symptomatic despite adequate clozapine treatment represents the most promising treatment option currently available.”

Although Tiihonen et al. found insignificant heterogeneity, Leucht et al. did find heterogeneity and concluded that the Zocali study was an outlier. They therefore excluded it from their final analysis. This is the crucial difference between the two meta-analyses and the reason for the sharply divergent conclusions. Four studies of lamotrigine augmentation are negative and one is positive. A closer look reveals that the Zocali trial was 24 weeks in duration, whereas the other trials were 10 to 14 weeks; could this be a crucial difference? Goff is still correct, and rather than throw lamotrigine overboard, we need a replication trial lasting 24 or 30 weeks. We know that the benefits of clozapine may take many months to be fully evident, so we should not expect that clozapine augmentation to be a quick affair.

As for other findings of the Leucht meta-analysis, sulpiride augmentation showed significant impact on both positive and negative symptoms, and citalopram showed significant impact on negative symptoms, but the findings are based on one trial each. A trial of an experimental glutamatergic agent showed a signal. This leaves us with few clear optins but some direction for further research.


Sommer IE, Begemann MJ, Temmerman A, Leucht S. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull. Mar 21 2011; Epub ahead of print; doi:10.1093/schbul/sbr004

Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: A systematic review and meta-analysis. Schizophr Res. 2009;109:10–14.

Goff DC. Review: lamotrigine may be an effective treatment for clozapine resistant schizophrenia. Evid Based Mental Health. 2009;12:111.

Zoccali R,Muscatello MR,Bruno A, Cambria R, et al. The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res. 2007;93:109–116.