Clozapine-treated Patients Research Articles

Association between Serum Lipids and Antipsychotic Response in Schizophrenia.

Metabolic abnormalities are serious health problems in individuals with schizophrenia. Paradoxically, studies have noted an association where individuals who gained body weight or who have increased their serum lipids demonstrated a better antipsychotic response. As serum lipids serve as more specific physiological markers than body weight, the objective of this study was to review studies that examined the association between changes in serum lipids and changes in symptoms during antipsychotic treatment in individuals with schizophrenia. A Medline® literature search was performed. Fourteen studies were included and analyzed. Evidence suggests that increases in serum lipids may be associated with decreases in symptoms during antipsychotic treatment. This inverse association may be independent of confounding variables, such as weight gain, and may be most evident during treatment with clozapine. Also, according to recent randomized controlled tri-als, lipid-lowering agents do not appear to worsen symptoms although this needs to be further investigated in clozapine-treated patients. Future studies should investigate the association in question in a larger population and identify underlying mechanisms.

Reduction in N-Desmethylclozapine Level Is Determined by Daily Dose But Not Serum Concentration of Valproic Acid-Indications of a Presystemic Interaction Mechanism.

Valproic acid (VPA) is frequently used together with clozapine (CLZ) as mood-stabilizer or for the prevention of seizures in patients with psychotic disorders. VPA is known to reduce levels of the pharmacologically active CLZ-metabolite N-desmethylclozapine (N-DMC), but factors determining the degree of this interaction are unknown. Here, we investigated the relationship between VPA dose and serum concentration on N-DMC levels in a large patient population adjusting for sex, age, and smoking habits as covariates. A total of 763 patients with steady-state serum concentrations of CLZ and N-DMC concurrently using VPA (cases, n = 76) or no interacting drugs (controls, n = 687) were retrospectively included from a therapeutic drug monitoring service at Diakonhjemmet Hospital, Oslo, between March 2005 and December 2016. In addition to information about prescribed doses, age, sex, smoking habits, and use of other interacting drugs were obtained. The effects of VPA dose and serum concentration on dose-adjusted N-DMC levels were evaluated by univariate correlation and multivariate linear mixed-model analyses adjusting for covariates. The dose-adjusted N-DMC levels were approximately 38% lower in VPA users (cases) versus nonusers (controls) (P < 0.001). Within the VPA cases, a negatively correlation between VPA dose and dose-adjusted N-DMC levels was observed with an estimated reduction of 1.42% per 100-mg VPA dose (P = 0.033) after adjusting for sex, age, and smoking. By contrast, there was no correlation between VPA serum concentration and dose-adjusted N-DMC levels (P = 0.873). The study shows that VPA dose, not concentration, is of relevance for the degree of reduction in N-DMC level in clozapine-treated patients. Presystemic induction of UGT enzymes or efflux transporters might underlie the reduction in N-DMC level during concurrent use of VPA. Our findings indicate that a VPA daily dose of 1500 mg or higher provides a further 21% reduction in N-DMC concentration. This is likely a relevant change in the exposure of this active metabolite where low levels are associated with implications of CLZ therapy.

Clozapine and tardive dyskinesia in patients with schizophrenia: A systematic review.

It is commonly recommended that a switch to clozapine be implemented in the face of tardive dyskinesia, even if current treatment involves another "atypical" agent. However, reports do indicate clozapine carries a liability for tardive dyskinesia. This review sought to evaluate clozapine in relation to tardive dyskinesia in the context of available evidence. Medline, Embase, and PsycINFO databases were searched for studies published in English, using the keywords: clozapine AND tardive dyskinesia OR TD. References from major review articles were searched for additional relevant publications. Studies were included if they investigated: tardive dyskinesia in clozapine-treated patients diagnosed with schizophrenia spectrum disorders, and reported on two or more assessments of tardive dyskinesia severity measured by the Abnormal Involuntary Movement Scale; or clozapine's tardive dyskinesia liability. In total, 513 unique citations were identified and 29 reports met the inclusion criteria. Thirteen studies suggest clozapine reduces dyskinetic symptoms over time (n=905 clozapine-treated participants); however, the minimum required dose and effect of withdrawal requires further investigation. The majority of reports which address clozapine's liability for tardive dyskinesia are case studies (11 of 14 reports, 79%), and clozapine was only the first-line treatment in one of the remaining three studies reporting treatment-emergent dyskinetic symptoms with clozapine in 12% of patients. No significant between-drug differences were identified comparing clozapine's risk to other atypical antipsychotics. Research to date supports switching to clozapine for the purpose of reducing tardive dyskinesia risk and/or treating existing tardive dyskinesia, but prospective randomized controlled trials are necessary if we are to substantiate existing recommendations.

Can e-cigarettes improve the well-being of people with mental health disorders?

Abstract This Viewpoint considers the merits of e-cigarettes as a harm-minimisation tool for clozapine-treated schizophrenia patients. It argues that e-cigarettes may be a gateway not to smoking tobacco, but rather to engagement in more desirable health attitudes amongst this particularly marginalised population group. In our opinion, this presents clinicians with valuable opportunities to engage their patients more effectively in healthcare strategies, beginning with but not limited to tobacco-free e-cigarettes.

A cross sectional study of impact and clinical risk factors of antipsychotic-induced OCD

A large proportion of schizophrenia patients treated with second generation antipsychotics will develop Obsessive Compulsive Disorder (OCD). However, there are few studies about the impact of this comorbidity and who is at higher risk. In this study of clozapine-treated patients, we aimed to determine the impact on outcome of clozapine-induced OCD, as well as the clinical and sociodemographic risk factors related to OCD-onset in clozapine patients. We had strict and novel inclusion criteria to minimise mis-identification of cases. The Obsessive-Compulsive Inventory-Revised (OCI-R) was used to divide 231 clozapine-treated patients into extreme cases of OCD (OCI ≥ 24 or checking subscale ≥6) versus non-OCD (OCI <15 and checking subscale <4). The Global Assessment of Functioning (GAF), short version of Warwick-Edinburgh Wellbeing scale and Clinical Global Impression for schizophrenia (CGI) scales were used to determine outcome. Socio-demographic information was used to identify the risk factors for OCD development. We found that schizophrenia patients with OCD symptoms had a significantly lower patient rated wellbeing scores (p < 0.001) only (no difference in clinician rated wellbeing scores), higher CGI positive (p < 0.01) and higher CGI depressive scores (p < 0.05). The only risk factors that reached significance level were higher treatment dose (p < 0.01) and younger paternal age at birth (p < 0.05). There is scope for future studies based on e.g. imaging and genetic studies to further investigate causality, and in improving clinician screening for OCD.

Switching to antipsychotic monotherapy vs. staying on antipsychotic polypharmacy in schizophrenia: A systematic review and meta-analysis

BackgroundWhile recent meta-analyses have reported the superiority of antipsychotic polypharmacy (APP) over antipsychotic monotherapy (APM) in schizophrenia, switching to APM can be beneficial in terms of side effects. To determine whether patients receiving APP should switch to APM or stay on APP, we conducted a systematic review and meta-analysis. MethodsRandomized controlled trials (RCTs) examining a switch from APP to APM vs. staying on APP were systematically selected from a previous meta-analysis comparing APP with APM in patients with schizophrenia. In addition, we conducted an updated systematic literature search using MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Data on study discontinuation, relapse, psychopathology, neurocognition, extrapyramidal symptoms, and body weight/body mass index (BMI) were extracted and synthesized. ResultsA total of 6 RCTs involving 341 patients were included. All studies examined a switch from 2 antipsychotic agents to a single agent. Clozapine-treated patients were included in 3 studies. There was a significant difference in study discontinuation due to all causes in favor of staying on APP (N = 6, n = 341, RR = 2.28, 95% CI = 1.50–3.46, P < 0.001). There were no significant differences in relapse, any psychopathology, neurocognition, extrapyramidal symptoms, or body weight/BMI between the 2 groups. The quality of evidence was low to very low. ConclusionsThe findings suggest that clinicians should closely monitor patient condition when switching to APM after receiving 2 antipsychotics. Given the low to very low overall quality of the evidence, the findings should be considered preliminary and inconclusive.

Association between electroencephalogram changes and plasma clozapine levels in clozapine-treated patients.

This retrospective observational study was performed to investigate electroencephalogram abnormalities in clozapine-treated patients with refractory schizophrenia or bipolar disorder. The electroencephalogram and plasma clozapine and norclozapine levels in 71 patients were measured on the same day. Fifty-nine patients (85.9%) had a diagnosis of schizophrenia, and 12 patients (14.1%) had a diagnosis of bipolar disorder. The mean daily clozapine dose was 242.9 ± 105.5 mg (range 25-500 mg), and the mean plasma clozapine and norclozapine levels were 429.4 ± 264.1 and 197.8 ± 132.6 ng/ml, respectively. Twenty-five patients (35.2%) were taking valproate in combination with clozapine. electroencephalogram abnormalities were found in 51 (71.8%) patients. No patient reported clinical seizures. Plasma clozapine level was significantly associated with electroencephalogram abnormalities and was identified as a significant predictor of electroencephalogram abnormalities in a logistic regression analysis. The plasma norclozapine levels of patients taking both clozapine and valproic acid were significantly lower than those of patients treated with clozapine alone. These results demonstrate that electroencephalogram abnormalities are closely correlated with plasma clozapine levels. Valproate reduced plasma norclozapine levels. Simultaneous monitoring of electroencephalogram and plasma clozapine levels was useful for adjusting clozapine doses, improving clinical efficacy, and preventing the side effects of clozapine treatment.

The prevalence of agranulocytosis and related death in clozapine-treated patients: a comprehensive meta-analysis of observational studies.

Clozapine treatment increases the risk of agranulocytosis, but findings on the epidemiology of agranulocytosis have been inconsistent. This meta-analysis examined the prevalence of agranulocytosis and related death in clozapine-treated patients. A literature search in the international (PubMed, PsycINFO, and EMBASE) and Chinese (WanFang, Chinese National Knowledge Infrastructure, and Sinomed) databases was conducted. Prevalence estimates of agranulocytosis and related death in clozapine-treated patients were synthesized with the Comprehensive Meta-Analysis program using the random-effects model. Thirty-six studies with 260 948 clozapine-treated patients published between 1984 and 2018 were included in the meta-analysis. The overall prevalence of agranulocytosis and death caused by agranulocytosis were 0.4% (95% CI 0.3-0.6%) and 0.05% (95% CI 0.03-0.09%), respectively. The prevalence of agranulocytosis was moderated by sample size, study quality, year of publication, and that of data collection. The prevalence of clozapine-associated agranulocytosis is low. Agranulocytosis-related death appears rare.

Long-term Use of Clozapine is Protective for Bone Density in Patients with Schizophrenia

Low bone mineral density (BMD) prevails among patients with schizophrenia. Antipsychotics use plays an important role in BMD. Previous cross-section study suggests that clozapine treatment may benefit BMD of women with schizophrenia. However, the effect of long-term clozapine therapy on BMD remains unknown. This prospective study compared clozapine and non-clozapine antipsychotics in long-term effects on BMD among both men and women with schizophrenia. Patients with schizophrenia and age-matched healthy individuals were enrolled from two centers. All patients, including clozapine receivers and non-clozapine antipsychotics recipients, kept clinically stable with unchanged antipsychotics and doses for at least 6 months at enrollment and during the follow-up period. BMD was examined by dual-energy X-ray absorptiometer upon enrollment and at 1- or 3-year follow-up. Thorough clinical and laboratory variables were measured too. The mean BMD of patients receiving clozapine was higher than that of the non-clozapine patients at both enrollment and follow-up. Overall, the patients in the clozapine group gained BMD, while those in the non-clozapine group lost BMD after 1–3 years (p = 0.015). There was no significant difference of BMD change between clozapine-treated patients and healthy controls. Factors associated with BMD change in the clozapine group included calcium level (B = −0.607, p = 0.021) and T3 level (B = −0.077, p = 0.007). This longitudinal study suggests that long-term clozapine treatment may protect BMD compared to prolactin-raising and non-clozapine prolactin-sparing antipsychotics among patients with schizophrenia. Future prospective studies are warranted to testify whether switching from non-clozapine antipsychotics to clozapine can rescue BMD.

SA107 - ELEVATED PERIPHERAL EXPRESSION OF NEUREGULIN-1 (NRG1) MRNA ISOFORMS IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA

Background Differential expression of Neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFα, EGFβ, pan-NRG1) in whole blood, and NRG1-β1 protein in serum of clozapine-treated schizophrenia patients (N=71) and healthy controls (N=57). In addition, using cultured Peripheral Blood Mononuclear Cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. Methods RT-PCR was used to measure gene expression level of different NRG1 isoforms in the whole blood of the schizophrenia patients and healthy controls in the clinical cohort as well as from the total RNA extracted from the In-Vitro clozapine exposure study. ELISA was used to measure NRG1-β1 protein level in serum in the clinical cohort and also in the total protein extracted from the in vitro clozapine exposure study. Results We found elevated levels of NRG1 mRNA, specifically the EGFα (P=0.0175), EGFβ (P=0.002) and typeI(Ig2) (P=0.023) containing transcripts, but lower NRG1-β1 serum protein levels (p=0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-β1 serum levels (p=0.050). Examination of clinical factors showed NRG1 EGFα (p=0.02) and EGFβ (p=0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Discussion Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest NRG1 transcription is up-regulated in those with schizophrenia and perhaps more specifically in treatment-resistant schizophrenia.

Constipation, ileus and medication use during clozapine treatment in patients with schizophrenia in Iceland

Purpose of the article: Clozapine is the only evidence based treatment for treatment-resistant schizophrenia. Constipation is a well known side effect of clozapine treatment. The aims of this study are to describe the prevalence of constipation and ileus during clozapine treatment of patients with schizophrenia in Iceland and to assess the concomitant use of medication that can cause constipation, and laxatives used to treat constipation.Materials and methods: We identified 188 patients treated with clozapine by searching the electronic health records of Landspitali, the National University Hospital, during the study period 1.1.1998 – 21.11.2014. Cases of constipation and ileus were identified using an electronic search with keywords related to ileus in the patients’ electronic health records. Detailed medication use was available for 154 patients that used clozapine for at least one year.Results: Four out of 188 patients were diagnosed with ileus that resulted in admission to hospital. Two of these required a permanent stoma as a consequence of their ileus. Laxatives were prescribed for 24 out of 154 patients (15.4%) while on clozapine. In total 40.9% of the patients either had laxatives prescribed or had constipation documented in the medical records. Apart from clozapine, other medications known to cause constipation were prescribed to 28 out of 154 patients (18.2%).Conclusions: Constipation is a common problem during clozapine treatment which can progress to full-blown ileus which can be fatal. Clinicians need to monitor signs of constipation during treatment with clozapine and respond to it with lifestyle advice and laxative treatment.

Control of seizures in a clozapine-treated schizophrenia patient, using valproate: a case report

ABSTRACTSchizophrenia is characterized by an adverse clinical course and poor psychosocial functioning, and causes problems in the social-cognitive sphere. Clozapine is a potent antipsychotic agent...

S41. SHORT- AND LONG-TERM OUTCOMES OF VITAMIN D SUPPLEMENTATION IN CLOZAPINE TREATED CHRONIC SCHIZOPHRENIA PATIENTS

BackgroundVitamin D deficiency is highly prevalent in patients with psychosis. While accumulating data suggests that vitamin D deficiency may be involved in the clinical and metabolic outcomes of schizophrenia, there are no vitamin D supplementation studies in this context. Objective: To assess the short- and long-term impact of vitamin D supplementation on psychiatric and metabolic status in chronic clozapine-treated schizophrenia patients.MethodsFollowing a first phase of eight-week, randomized, double blind, placebo-controlled clinical trial, in which schizophrenia patients who had been maintained on clozapine treatment for at least 18 weeks with total PANSS scores >70 and with low levels of vitamin D (<75 nmol/L) were recruited, a second phase, post-RCT, was performed. In the RCT patients were randomly allocated to either weekly oral drops of vitamin D (14,000 IU) or placebo and subsequently assessed at two-week intervals regarding psychosis severity, mood, cognition and metabolic status. In the post-RCt phase, all participants were assessed at 24 weeks’ time point, while being prescribed 800 IU vitamin D daily supplementation in an open-label design.ResultsTwenty-four patients were randomly assigned to vitamin D and the other 23 patients to the placebo arm. No between-group differences were found in baseline measures. After eight weeks, the vitamin D group had higher increase in vitamin D levels (31.4 vs -0.4 nM, p<0.0001). There was no significant effect of vitamin D on PANSS score, depression or metabolic parameters. The vitamin D group, however, showed a positive small effect on cognitive function (effect size=0.17). On the long-term follow up, 37 patients completed the 24-week assessment. Mean vitamin D levels did not change from baseline (57.56 nM to 57.28 nM) and no association was found between this change and the changes in psychiatric, metabolic and cognitive measures. The only significant inverse association was found between vitamin D levels and HDL (p=0.007).DiscussionThis is the first study to assess the outcomes of vitamin D as an adjunct to clozapine in chronic schizophrenia patients, in the short and long term. The increase in vitamin D levels on the short-term was associated with a small positive effect on cognition, without any effect on psychosis, mood or metabolic status. There were no significant effects of vitamin D supplementation on the assessed measures in the long-term either.

Persistent tachycardia in clozapine treated patients: A 24-hour ambulatory electrocardiogram study

Tachycardia is associated with cardiovascular mortality. Tachycardia is also a known clozapine adverse effect. However, whether clozapine-associated tachycardia is persistent is not known. Thirty clozapine-treated patients with clinical tachycardia were investigated with 24-hour ambulatory electrocardiography (ECG). Baseline peripheral heart rate (HR) was 106.7±7.8. The ambulatory ECG 24-hour-HR was 98.7±9.7. Baseline HR and 24-hour-HR correlated strongly (r=0.74, p=0.000003). Daytime HR was 106.4±9.9 and nighttime HR 89.2±12.0. Low dose bisoprolol reduced HR significantly. The high 24-hour-HR indicates a persistent tachycardia. Tachycardia should not discourage from clozapine use but the findings indicate a need of guidelines for detection and treatment of clozapine-associated tachycardia.

Distinct risk factors for obsessive and compulsive symptoms in chronic schizophrenia.

Obsessive-compulsive disorder (OCD) is common in clozapine-treated patients although the actual prevalence, phenomenology and risk factors remain unclear. The aim of the present study was to address the three aforementioned questions. The electronic records of a large cohort of clozapine-medicated schizophrenia patients routinely screened for OCD were used. The Obsessive Compulsive Inventory Revised version (OCI-R) was available from 118 cases and a 21 points cut-off threshold for OCD was defined. OCD prevalence was 47%, higher in patients on poly-pharmacy than on monotherapy (64% vs 31%; p = 0.001). Two OCI-R factors had significantly higher scores and distinct risk factors: checking behaviour (mean = 5.1; SD = 3.6) correlated with length of clozapine treatment (r = 0.21; p = 0.026), and obsessing factor (mean = 4.8; SD = 3.6) correlated with psychosis severity (r = 0.59; p = 0.001). These factors along with total OCI-R, did not correlate with either clozapine dose or plasma levels, after correcting for psychosis severity. Screening for OCD in clozapine patients, and probably in those treated with structurally similar drugs with potent antiserotoninergic properties, should be widely adopted by clinicians. Further research is needed to understand the pathophysiology underlying repetitive behavior onset in clozapine-treated patients.

‘Doing Things Little by Little’: Smoking and Vaping While Being Pharmaceutically Treated for Schizophrenia

ABSTRACTThis paper explores the experiences of smoking and ‘vaping’ while being pharmaceutically treated for schizophrenia, as well as what the experiences of breathing smoke and vapour in and out can reveal about health ‘care’, toward the self and others. Drawing on ethnographic data collected over 2015–2016 in Australia and the UK, and particularly on patient experiences in the UK where electronic cigarettes had become an endorsed Nicotine Replacement Therapy, I argue that inhaling nicotine via e-cigarettes can, like tobacco cigarettes, be experienced in terms of temporal opportunities for self-reclamation and experiences of health. When patients opted to vape instead of smoke, their sense of self-reclamation allowed for shifted attention toward the movement and materiality of exhalations, and toward how second-hand vapour (compared to smoke) is socially received. Experiences of vaping were, however, contingent on the clinical endorsement of e-cigarettes and were inconsistent inside and outside of clinical spaces. Further consideration should be given to vaping as a harm minimisation tool in Western societies dealing with widening disparities in health. Ultimately, clozapine-treated schizophrenia patients continue to smoke or vape for reasons that speak to the desire to make ‘time’; to find connections to life rather than focusing on death.

Correction: Effects of Low Dose Metformin on Metabolic Traits in Clozapine-Treated Schizophrenia Patients: An Exploratory Twelve-Week Randomized, Double-Blind, Placebo-Controlled Study

[This corrects the article DOI: 10.1371/journal.pone.0168347.].

Prevalence and Factors Associated With Clozapine-Related Constipation: An Observational Study.

Despite being a very effective treatment for resistant schizophrenia and bipolar disorder, use of clozapine is limited by adverse effects. Constipation is a common but potentially life-threatening adverse effect of clozapine that is understudied. The objective was to study the prevalence and factors associated with constipation in those receiving clozapine compared with control subjects. Fifty patients in age group of 18 to 55 years receiving clozapine were compared with 50 patients in the same age group receiving medications other than clozapine. Presence of constipation was ascertained using the World Gastroenterology Organization Practice Guidelines definition. The severity of constipation was assessed using Constipation Assessment Scale and Bristol Stool Form Scale, and anticholinergic burden was assessed using Anticholinergic Burden Scale. Among clozapine-treated patients, 28 (56%) had constipation as compared with 11 (22%) in the control subjects (P < 0.001); the odds of developing constipation was 4.5 (95% confidence interval, 1.9-10.8). Kaplan-Meier survival analysis showed median time to onset of constipation in clozapine-treated patients was 60 days (SE, 13.1 days; 95% confidence interval, 34.3-85.7 days) and median dose of clozapine was 300 mg/d (interquartile range, 312 mg/d). Clozapine group had high Constipation Assessment Scale scores (P = 0.005, Cohen d = 1.17) and higher prevalence of types 1 and 2 Bristol stool types (Fisher exact P = 0.005, Cramer V = 0.59). Constipation was prevalent in more than half of patients receiving clozapine, which was severe and took longer time for recovery. Limitations include using a hospital-based sample and that dietary habits and lifestyle factors were not studied.

Clozapine and Gastrointestinal Hypomotility.

Gastrointestinal hypomotility (GIH) is an under-reported but highly prevalent and potentially dangerous side effect of clozapine. In a comprehensive meta-analysis of clozapine-treated patients, the prevalence of GIH was 32%. In general, GIH has consistently been reported to have a negative impact on quality of life, and there is no reason to believe this will be different in clozapine-treated patients with therapy-resistant schizophrenia. GIH is dangerous; in a comparative review of lethal side effects of clozapine, the mortality of agranulocytosis was 2.2-4.2% compared with 15.0-27.5% for GIH. The mortality rate in our review of all published case reports of ileus was 43.7%. (Co-)Prescription of anticholinergic drugs in patients treated with clozapine should be avoided as anticholinergics are associated with increased incidence and fatality of ileus. Prevention of GIH can best be obtained by frequent and targeted questioning by the mental healthcare providers of the patients' defecation pattern and this is therefore strongly recommended for timely detection and treatment of treatment-emergent GIH throughout clozapine treatment. Treatment approaches can be either preventive laxative prescription with every clozapine prescription in all clozapine-treated patients or targeted treatment of treatment-emergent GIH. First-line treatments of GIH are the osmotic laxative macrogol, stool softener docusate and bowel stimulant senna. As the occurrence of severe cases of GIH is not restricted to a certain treatment duration, alertness for and/or treatment of GIH is required for the whole duration of clozapine treatment.

Elevated peripheral expression of neuregulin-1 (NRG1) mRNA isoforms in clozapine-treated schizophrenia patients

Differential expression of neuregulin-1 (NRG1) mRNA isoforms and proteins has been reported in schizophrenia, primarily in post-mortem brain tissue. In this study, we examined 12 NRG1 SNPs, eight NRG1 mRNA isoforms (type I, type I(Ig2), type II, type III, type IV, EGFα, EGFβ, pan-NRG1) in whole blood, and NRG1-β1 protein in serum of clozapine-treated schizophrenia patients (N = 71) and healthy controls (N = 57). In addition, using cultured peripheral blood mononuclear cells (PBMC) from 15 healthy individuals, we examined the effect of clozapine on NRG1 mRNA isoform and protein expression. We found elevated levels of NRG1 mRNA, specifically the EGFα (P = 0.0175), EGFβ (P = 0.002) and type I(Ig2) (P = 0.023) containing transcripts, but lower NRG1-β1 serum protein levels (P = 0.019) in schizophrenia patients compared to healthy controls. However, adjusting for smoking status attenuated the difference in NRG1-β1 serum levels (P = 0.050). Examination of clinical factors showed NRG1 EGFα (P = 0.02) and EGFβ (P = 0.02) isoform expression was negatively correlated with age of onset. However, we found limited evidence that NRG1 mRNA isoform or protein expression was associated with current chlorpromazine equivalent dose or clozapine plasma levels, the latter corroborated by our PBMC clozapine exposure experiment. Our SNP analysis found no robust expression quantitative trait loci. Our results represent the first comprehensive investigation of NRG1 isoforms and protein expression in the blood of clozapine-treated schizophrenia patients and suggest levels of some NRG1 transcripts are upregulated in those with schizophrenia.