In some patients, achieving a therapeutic serum clozapine concentration requires a high dose entailing a prolonged series of dose increases. This may be more common among smokers, and people with schizophrenia are more likely to smoke and to smoke more cigarettes per day than the population at large. One short cut to achieving a therapeutic level is adding fluvoxamine, a serotonin reuptake inhibitor used to treat anxiety and depression. Clozapine is converted by cytochrome enzyme 1A2 to the metabolite N-desmethylclozapine, known as norclozapine in clinical settings. Fluvoxamine inhibits this process which shifts the ratio of clozapine to norclozapine upward and prolongs the half life of clozapine. Fluvoxamine also inhibits CYP2C19 and in some people, CYP3A4 as well. The clinical effect is to permit a lower total dose of clozapine, and it may make once-daily dosing more tolerable. Furthermore, fluvoxamine can be used to treat concurrent anxiety and depression while maximizing clozapine serum levels. The evidence for the safety and benefits of these uses of fluvoxamine was reviewed in a recently published article.

The authors identified 24 case reports and series comprising 29 patients, and 9 prospective studies comprising 212 patients; 2 of these were randomized trials. Most patients had a primary diagnosis of schizophrenia, and the rationales for the various studies were diverse.

  • Increasing clozapine plasma level
  • Treating negative symptoms
  • Treating positive symptoms
  • Treating depressive symptoms
  • Treating obsessive-compulsive symptoms
  • Reducing metabolic adverse effects

The available evidence for most of these indications is mediocre or poor except for increasing plasma levels; according to the authors, fluvoxamine increases clozapine, norclozapine, and clozapine N-oxide plasma levels in a dose-dependent manner. The data among smokers is supportive but surprisingly limited. One point they raise is that the effects of changing the ratios of metabolites other than norclozapine is not understood. The evidence for reducing metabolic adverse effects is relatively good as it comes from a 12-week RCT, but long-term efficacy is unknown. As for treating depression or obsessive-compulsive symptoms, the authors conclude that it is safer to use an appropriate antidepressant without the pharmacokinetic complications of fluvoxamine given the risk of toxicity if clozapine levels rise abruptly.

Safety concerns addressed in studies include the risk of agranulocytosis and seizures for which there is no evidence of a protective or facilitative effect; the available evidence correlates increasing clozapine dose and not plasma level with risk of seizures. (2) The reports reviewed mention frequent occurrence of common adverse effects including sedation, sialorrhea with drooling, and constipation in fluvoxamine-treated patients. Clinicians and patients should be aware that prescribing fluvoxamine to enhance clozapine effects is not approved by Health Canada or the US Food and Drug Administration.


Polcwiartek C, Nielsen J. The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review. Psychopharmacology. Published online Dec 2, 2015. Abstract

Remington G, Agid O, Foussias G, et al. Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold? Psychopharmacology. 2013;225:505–518. Abstract

High IQ predicts suicide in Israeli men with schizophrenia

Previous research has correlated lower intellectual ability with suicide. Using population-based registries in Israel, Dr. Mark Weiser of Tel Aviv University and colleagues examined the correlation of IQ with subsequent suicide in men, all of whom have cognitive testing at age 17 by the national draft board. The Israeli hospital registry allows determination of diagnoses in anyone who has inpatient treatment. Causes of death were determined by examining the Israeli vital statistics registry; only unambiguous suicides were included. According to Weiser, this probably underestimated suicides as some proportion of deaths with undetermined cause were likely suicides.

Dr. Mark Weiser at the 2015 International Congress  on Schizophrenia Research, Colorado Springs

Dr. Mark Weiser at the 2015 International Congress on Schizophrenia Research, Colorado Springs, USA

The researchers began with 930,589 consecutively tested men from draft board records but excluded those that had developed psychosis within a year of testing, those hospitalized for non-psychotic illness, and those with missing data, which left a final sample of 596,607 men. Of these, 2881 had been hospitalized subsequently for schizophrenia, and 566,726 men were controls who had had no psychiatric hospitalizations. During the follow-up of 10 years, 319 men in the control group and 25 in the schizophrenia group died by suicide. In men with schizophrenia, those with an IQ one standard deviation or more above the mean had an odds ratio (OR) of suicide of 4.5 (p < 0.001) compared with the reference group of men without schizophrenia and with average IQ. Men with schizophrenia and intelligence one standard deviation below the mean had an OR of suicide of 1.8. Dr. Weis said that 60% of suicides in the schizophrenia group occurred within 6 months of hospital discharge.

Mark Weiser, Ori Kapara, Nomi Werbeloff, Abraham Reichenberg, Rinat Yoffe, Eyal Fruchter, Keren Ginat, Michael Davidson. A population based longitudinal study of suicide risk in male schizophrenia: proximity to first admission and the moderating effect of premorbid IQ. Symposium 2-7, 15th International Congress on Schizophrenia Research, Colorado Springs, Colorado. March 29-April 1, 2015.

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.

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)

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.