Fluvoxamine

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.

References

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

Cognition in treatment resistance

Patients with treatment-resistant schizophrenia or schizoaffective disorder have the most severe form of the illness at least as determined by persistence of positive symptoms, but the other aspects, including negative and cognitive impairments, are typically not as well assessed clinically or in research. Most clinicians may assume that treatment-resistant patients, who often have profound functional deficits, have worse cognition than patients who respond to non-clozapine antipsychotics. This is an hypothesis that requires investigation, and a team from New Zealand have recently published such a study. They went further and also looked at the cognitive status of a group of clozapine-resistant (ultra-resistant) patients.

The 51 patients were recruited from outpatient and inpatient settings; 5 had schizoaffective disorder and the rest had schizophrenia. The control group comprised 22 healthy adults matched for age and sex. The mean age of the subjects was about 33 years. The researchers classified the patients into 3 groups based on treatment response: first-line antipsychotic responders (n=16), treatment-resistant but clozapine responders (n=20), and clozapine nonresponders (ultra-resistant; n=15). The latter group had a 8-week trial of monotherapy, and all ended up on at least 2 antipsychotics, most often clozapine and a another second-generation antipsychotic. Despite the designations, the 3 groups had no significant difference in PANSS total or subscale scores at the time of evaluation. The mean antipsychotic dose as measured in chlorpromazine equivalence was significantly greater in the clozapine-resistant group, but the mean duration of illness did not differ among groups. The control group had slightly greater mean educational attainment than the treatment-resistant group.

The cognitive assessments consisted of neuropsychologic tests covering the domains of the MATRICS Consensus Cognitive Battery developed by the U.S. National Institutes of Mental Health, considered the standard in psychosis cognitive evaluation. In this study, the testing was computerized and included such domains as executive function, social recognition, processing speed, and verbal and nonverbal learning and memory. The raw scores were converted to Z-scores normalized for age, sex and education.

The results showed that the patients overall had significant impairment in cognitive performance compared with healthy subjects, but the differences among the 3 patient groups were minimal. The treatment-resistant group, however, had a mean verbal fluency Z-score equal to that of the control group whereas the other patient groups had significantly worse performance in this domain, but subsequent analysis did not support a significant difference in verbal fluency performance in patient groups or controls. The researchers mention that pre-existing work has found that clozapine is associated with improvement in verbal fluency, an intriguing finding especially since in this study, verbal fluency was correlated with the negative-symptoms subscale of the PANSS in patients who responded to clozapine monotherapy.

The study is small, and the equivalent positive symptoms scores in the 3 patient groups raises questions about the distinctions based on treatment response, the findings tend to disconfirm the hypothesis that treatment resistance as defined by antipsychotic response necessarily indicates greater cognitive impairment.

Anderson VM, McIlwain ME, Kydd RR, Russell BR. Does cognitive impairment in treatment-resistant and ultra-treatment-resistant schizophrenia differ from that in treatment responders? Psychiatry Res. 2015; published online Oct 2015; http://dx.doi.org/10.1016/j.psychres.2015.10.036

Schizophrenia is not a progressive brain disease

DSC_0072 1 (2)Despite Emil Kraepelin’s early characterization of dementia praecox, the disorder or disorders that we now call schizophrenia are not characterized by dementia, or inevitable loss of cognitive ability and function. Dr. Robert B. Zipursky, Professor of Psychiatry and Behavioural Neurosciences at McMaster University in Hamilton, Ontario, said that psychiatrists may share Kraepelin’s impression of a malignant illness because of the clinician’s illusion, which arises from the biased sample of patients that psychiatrists treat, i.e. people with chronic, relapsing illness and multiple co-morbidities who come to hospitals (1). According to Professor Zipursky, who spoke at the 9th Annual Pacific Psychopharmacology Conference in Coquitlam, BC on September 18, 2015, available studies indicate that about 70% of people with first-episode psychosis will achieve remission within a year; he defined remission as having positive symptoms no greater that mild in severity and negative symptoms no greater than moderate in severity.

First-episode psychosis includes patients with various diagnoses including bipolar disorder, schizoaffective disorder, brief psychotic disorder as well as schizophrenia. Patients who achieve functional recovery, however, represent a smaller group, especially in those confirmed to have schizophrenia. In long-term outcome research, 20% or fewer of people with schizophrenia meet criteria for recovery defined as sustained remission of symptoms and success in social relations and competitive employment.
Some psychiatrists have concluded that this long-term functional impairment is due to progressive cognitive deterioration which may occur with untreated or chronic positive psychotic symptoms. A related hypothesis is the “neurotoxicity of psychosis” which posits that persisting psychosis leads to ongoing loss of cerebral tissue as manifested by enlarged ventricles and cortical atrophy on neuroimaging, accompanied by worsening deficits on neuropsychologic testing. Consequently, many clinicians working in first episode psychosis accept that the duration of untreated psychosis is an important determinant of long-term outcome.

While he acknowledged that deficits in grey matter volumes observed with MRI are more prominent in chronic patients, Dr. Zipursky asserted that many factors may contribute to this such as sampling bias; concurrent substance use including cannabis, tobacco and alcohol; lack of physical activity; and chronic antipsychotic therapy. The latter is controversial, but he cited a meta-analysis of longitudinal MRI studies in which change in grey matter volumes was correlated with antipsychotic exposure but not illness duration or severity (2). However, he emphasized that relieving suffering and improving function are the goals of treatment, not specifically increasing cerebral volume, which is affected by various factors mentioned before. Furthermore, Dr. Zipursky showed compelling evidence that following a first episode of schizophrenia, antipsychotic discontinuation is by far the most important cause of relapse.

Duration of untreated psychosis (DUP) has a small correlation with treatment outcome, likely accounting for less than 5% of the variance in clinical outcome measures, and questionable association with cognitive functioning and structural brain measures, according to Dr. Zipursky. He presented evidence that it is a risk marker for poor outcome in schizophrenia as opposed to a causative risk factor. “It’s not certain that it relates to improving outcomes, but it does relate to reducing suffering,” Zipursky said.
He concluded that to improve outcomes and promote functional recovery, antipsychotic medication is crucial but so are psychosocial interventions to manage substance use, educate families, provide adequate housing and income support when needed, and engage patients in vocational rehabilitation and supported employment.

References

Zipursky RB, Reilly TJ, Murray RM. The myth of schizophrenia as a progressive brain disease. Schizophr Bull. 2013;39:1363-1372. Full text

Fusar-Poli P, Smieskova R, Kempton MJ, Ho BC, Andreasen NC, Borgwardt S. Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev. 2013;37:1680-1691. Full text

Dr. Randall White at the 9th Annual Pacific Psychopharmacology Conference

Dr. Randall White is pleased to be attending the 9th Annual Pacific Psychopharmacology Conference this September where he will be Co-chairing the pre-conference and moderating many of the conference sessions. Join us to learn what’s new in evidence-based research on the pharmacotherapy of psychiatric illness.

This year’s conference theme is: Balancing Risks and Benefits to Improved Adherence

The pre-conference workshop title is: Strategies for Managing Mood and Anxiety Disorders in Primary Care at the workshop. The workshop will also cover the following topics in the format of brief presentations with cases:

  • Incorporating Measurement-Based Care for Mood Disorders into Clinical Practice
  • The BC Practice Support Program Adult Mental Health Module: Implications for Primary Care
  • Use of Antidepressants in Ambulatory Settings

Key speakers for the conference:

Martha Sajatovic, MD
Treatment Adherence in Bipolar Disorder
Dr. Martha Sajotovic, is a professor of Psychiatry and Neurology at Case Western Reserve University. She is also a director of the Geropsychiatry Program, and Neurological and Behavioral Outcomes Center, University Hospitals Case Medical Center, and a Willard Brown Chair in Neurological Outcomes Research, Cleveland. Her research focus is on treatment adherence in Bipolar Disorder and Improving Outcomes for People with Schizophrenia.

Robert Zipursky, MD, FRCPC
Improving Outcomes for People with Schizophrenia
Dr. Zipursky is a professor, Department of Psychiatry & Behavioural Neurosciences. ‘s research interests have been in investigating the biology of schizophrenia and its treatment using brain imaging techniques (CT, MRI, PET), the treatment of first episode psychosis, prevention of schizophrenia, and clinical outcomes from schizophrenia. He has served on the editorial boards of Schizophrenia Research and Schizophrenia Bulletin. He is a recipient of the John Cleghorn Memorial Award for Excellence and Leadership in Clinical Research from the Canadian Psychiatric Association and the Michael Smith Award from the Schizophrenia Society of Canada.If you are planning to attend, please introduce yourself to Randall! And if you’re coming from out of town, Be sure to ask for the “Annual Pacific Psychopharmacology Conference 2015” rate or quote booking ID #15906 at time of booking.

Pre-conference Workshop Information
September 17, 2015
Time: 1-4pm, lunch provided prior to course at 12:30pm
Cost: $119 for delegates, $69 for residents, apply a $25 discount if you register for the Sept. 18 conference as well

This workshop will be great for nurse practitioners, pharmacy/therapeutics, psychiatrists, registered nurses, residents and students.

Conference Details:
September 18, 2015
Executive Plaza Hotel and Conference Centre

Social Media:
Follow Dr. Randall White @BCPsychosis on Twitter, use #CPDpppc to follow the conference.

Refugees in Canada have a high incidence of psychosis

A recent article which I reviewed found evidence for an increasing incidence of schizophrenia in Canada. The researcher speculated that Canada’s high rate of immigration may contribute to this finding. Studies from other industrialized countries have found that immigrants, both in the first and second generation, have an elevated risk of developing schizophrenia, but evidence of this in Canada is lacking. A group from the Centre for Addictions and Mental Health in Toronto estimated the incidence of schizophrenia and schizoaffective disorder in Ontario, the most populous and immigrant-rich province of Canada, by examining hospital and billing records with the records maintained by Canadian immigration authorities.

The identified cohort was all Ontario residents who were age 14 to 40 years at the beginning of the 10-year period from 1999-2008. Because of the universal health-care system, all people who come to medical attention have their diagnosis recorded in a provincial data set. All those listed as an immigrants by the federal ministry of citizenship were classified as such whereas all those not listed were classified as non-immigrants. The investigators also noted which immigrants were admitted under refugee status, an indication of a more vulnerable and likely trauma-exposed group.

The rate of new-onset psychosis in the general population was 55.6 (95% CI 54.9–56.4) per 100 000 person-years and 51.7 (95% CI 49.2–54.4) per 100 000 person-years in first-generation immigrants; these rates are not significantly different. Among the immigrants classified as refugees, the rate was higher: 72.8 (95% CI 67.1– 78.9) per 100 000 person-years, but this is not significantly different from the other rates. Closer examination found that immigrants of various origins had differing rates; those from the Caribbean and Bermuda had significantly higher risk whereas those from northern and southern Europe and east Asia had significantly lower risk than the general population. Among refugees, those from east Africa and south Asia had significantly greater risk of psychosis than the general population.

The shortcomings of this kind of study are considerable, mainly the retrospective design and the reliance on administrative-level diagnostic data. Furthermore, the general population included second-generation immigrants who could not be identified by the study methods but who also probably have a higher risk of psychosis. Moreover, the researchers mention that refugees often have other mental illnesses such as posttraumatic stress disorder which may be misdiagnosed as psychosis. Despite these sources of bias, the findings support an emerging theoretical framework in which those immigrants most subject to discrimination, often because of their race, may be most vulnerable to onset of psychosis. Socioeconomic factors and trauma also likely play a role. Early intervention programs may increase their effectiveness by taking this into consideration. The findings also underline the significance of the federal role in health-care funding for refugees, a highly vulnerable population.

Anderson KK, Cheng J, Susser E, McKenzie KJ, Kurdyak P. Incidence of psychotic disorders among first-generation immigrants and refugees in Ontario. CMAJ. 2015;17:e279-e286. Article

Norclozapine, the metabolite of clozapine, may be more useful than you think

Although psychiatrists know that long-term disability in schizophrenia is related to negative and cognitive symptoms, our treatment goals often focus on positive symptoms. The unfortunate reason is that we lack good treatments for cognitive and behavioral deficits. Many antipsychotics have anticholinergic properties which we know can dull cognition or even cause delirium in sensitive patients, but we accept this risk in exchange for the benefit of eliminating psychosis.

Clozapine is highly anticholinergic but its metabolite, N-desmethylclozapine or norclozapine, has partial cholinergic agonist activity at muscarinic receptors. Although psychopharmacologists have suspected that this property of norclozapine may have cognitive benefits, most psychiatrists focus on optimizing clozapine serum level which is sometimes achieved by blocking clozapine metabolism with cytochrome enzyme inhibitors such as the antidepressant fluvoxamine. This increases the clozapine/norclozapine ratio; some evidence suggests this may reduce the metabolic burden of clozapine therapy (1). However, new evidence suggests that this may come at the price of worse cognitive performance, in particular working memory.

A team of researchers at the Centre for Mental Health and Addictions in Toronto examined the hypothesis that a greater ratio of clozapine to norclozapine would correlate with worse cognitive performance as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MATRICS battery) (2).  They recruited 30 adults, mean age 38.6 years, on clozapine monotherapy for schizophrenia or schizoaffective disorder whose dose had been unchanged for at least 4 weeks. The subjects had blood taken for clozapine and norclozapine concentrations on the same day that they underwent PANSS rating and the MATRICS battery, which comprises 10 tests in 7 cognitive domains such as verbal learning, visual learning, working memory and processing speed.

In multiple regression analyses, the clozapine/norclozapine ratio was negatively correlated with performance on working memory but not with the other 6 cognitive domains. Working memory performance was not correlated with demographic variables or PANSS score, nor with either clozapine or norclozapine serum concentrations independently of each other.

The investigators suggest that the significance of the clozapine/norclozapine ratio reflects the opposing effects of the two molecules on muscarinic type 1 receptors, given that the cholinergic system is crucial for complex attentional processes as tested by working memory measures. They acknowledge that the MATRICS battery may not be sensitive enough to detect effects on other domains, and also that this is a cross-sectional study that cannot establish causation. Serial measurements in individuals as the clozapine/norclozapine ratio changes would be more conclusive.

References

1. Lu ML, Lane HY, Lin SK, Chen KP, Chang WH. Adjunctive fluvoxamine inhibits clozapine-related weight gain and metabolic disturbances. J Clin Psychiatry. 2004;65:766-771. Abstract

2. Rajji TK, Mulsant BH, Davies S, et al. Prediction of working memory performance in schizophrenia by plasma ratio of clozapine to N-desmethylclozapine. Am J Psychiatry. 2015;172:579-585. Abstract

Supersensitivity psychosis in treatment resistance

Guy Chouinard proposed the concept of dopamine supersensitivity psychosis (DSP) in 1978, a consequence of chronic antagonism of dopamine D-2 receptors which also is posited to cause tardive dyskinesia (1). The proposed mechanism is upregulation of D2 receptors in the basal ganglia, and tardive dyskinesia is itself considered one of the markers of the condition, also characterized by tolerance to increasing doses of antipsychotic. Supersensitivity psychosis patients may therefore represent a subtype of treatment resistance. In this study from Japan, the investigators examined this hypothesis in a group of patients with chronic psychosis (2).

The 147 patients enrolled had treatment-resistant schizophrenia or schizoaffective disorder as defined by failure of at least 2 antipsychotics at a dose equivalent to 600 mg chlorpromazine for 4 weeks. Although specifics of antipsychotic therapy were not provided, none of the patients was on clozapine. Their mean duration of illness was about 23 years. Supersensitivity was diagnosed if a patient met one of 3 criteria, which were adopted from Chouinard:

  • Antipsychotic tolerance indicated by relapse while on medication and failure to improve despite 20% or more increase in dosage
  • Rebound psychosis manifested by swift relapse with reduction or discontinuation of medication; the psychosis may involve new symptoms for a patient
  • Presence of tardive dyskinesia

The investigators found that 106 or 72.1% of the patients met at least one criterion for DSP; 56% had tolerance, 44% had tardive dyskinesia, and 42% had rebound psychosis. The patients were also classified by the presence or absence of deficit syndrome, defined by prominent negative symptoms assessed by standardized rating instruments. Of 55 patients judged to have deficit syndrome, the majority did not meet criteria for DSP; hence, DSP was significantly negatively associated with prominent deficit symptoms.

Although the researchers evaluated the present state of each subject, the main limitation of the study was reliance on chart reviews for the longitudinal course of patients’ illness. Furthermore, relapse of symptoms due to nonadherence could not be reliably distinguished from antipsychotic tolerance. The findings however suggest that supersensitivity psychosis may be an important contributor to treatment resistance, and that investigations using functional imaging and other techniques are warranted to validate the concept of DSP.

References Continue reading

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.

Abstract

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

WIN_20150329_101048

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.