Co-medication with disulfiram markedly increased serum clozapine levels: Two case reports.

BACKGROUND: Alcohol use disorder (AUD) is a significant co-morbidity in patients with schizophrenia. Clozapine offers some benefits in treating patients with refractory schizophrenia and AUD, but co-medicating with disulfiram is also common. PROCEDURES: We report two cases where co-medicating with disulfiram led to a significant increase in clozapine serum levels. FINDINGS: Clozapine serum levels decreased to one-third in Patient 1 when disulfiram was discontinued and started to increase again when disulfiram was reintroduced. Patient 2 developed toxic serum levels of clozapine during disulfiram treatment combined with heavy coffee drinking and symptoms reminiscent of neuroleptic malignant syndrome. CONCLUSIONS: Clozapine and disulfiram are both metabolized by cytochrome P450 CYP1A2 and clinically relevant interaction through this shared pathway is possible.

The role of alcohol use and adiposity in serum levels of IL-1RA in depressed patients.

BACKGROUND: The role of Interleukin-1 Receptor antagonist (IL-1Ra), an innate antagonist to pro-inflammatory cytokine IL-1, has attracted increasing attention due to its potential pathogenic and therapeutic implications in depression. However, the role of alcohol and adiposity in modulating IL-1Ra cytokine pathway in depressed patients has remainned unknown. The aim of this study was to follow the changes in IL-1Ra serum levels in depressed patients with or without simultaneous alcohol use disorder (AUD) and different degrees of adiposity during 6 months of follow-up. MATERIALS AND METHODS: A total of 242 patients with depression were followed for 6 months. At baseline 99 patients had simultaneous AUD. Levels of serum IL-1Ra and common mediators of inflammation (IL-6, hs-CRP) were measured. Clinical assessments included Body Mass Index (BMI), Montgomery-Asberg Depression Rating Scale (MADRS) and Alcohol Use Disorders Identification Test (AUDIT) scores. RESULTS: Significant reductions in clinical symptoms and IL-1Ra were observed during 6-month follow-up. In hierarchical linear regression analysis, the effect of MADRS score, age, gender, and smoking had a combined effect of 2.4% in the model. The effect of AUDIT score increased the effect to 4.2% of variance (p = 0.08), whereas adding BMI increased the effect to 18.5% (p <  0.001). CONCLUSION: Adiposity may influence the IL-1Ra anti-inflammatory response in depressed patients, whereas the effect of alcohol consumption in these patients seems insignificant. These findings should be considered in studies on the role of IL-1Ra in depression. TRIAL REGISTRATION: Ostrobothnia Depression Study in ClinicalTrials.gov , Identifier NCT02520271 .

Electroconvulsive therapy increases temporarily plasma vascular endothelial growth factor in patients with major depressive disorder.

OBJECTIVES: Vascular endothelial growth factor (VEGF) has been related to the etiology of major depressive disorder (MDD). The findings involving the effects of electroconvulsive therapy (ECT) on the VEGF levels have been conflicting. The aim was to examine the possible changes in the VEGF levels and their associations with clinical outcome in patients with MDD during ECT. METHODS: The study comprised 30 patients suffering from MDD. Their plasma VEGF levels were measured at baseline and 2 and 4 hr after the first, fifth, and last ECT session. The severity of depression was quantified by the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: The VEGF levels increased between the 2-hr and 4-hr measurements during the first (p = .003) and the fifth (p = .017) sessions. The baseline VEGF levels between individual ECT sessions remained unchanged during the ECT series. No correlations were found between the increased VEGF levels and the clinical outcome. CONCLUSIONS: Electroconvulsive therapy increased the VEGF levels repeatedly at the same time point in two different ECT sessions. These increases had no association with the response to ECT. Consequently, VEGF may act as a mediator in the mechanism of action of ECT.

Assessment of alcohol consumption in depression follow-up using self-reports and blood measures including inflammatory biomarkers.

AIMS: Alcohol consumption has been suggested a major role in the pathogenesis and prognosis of depression. However, reliable identification of hazardous drinking continues to be problematic. We compared the accuracy of different biomarkers and self-reports of alcohol consumption in the follow-up study of depression. METHODS: Data from 202 patients with major depressive disorder were obtained through self-reports, AUDIT and AUDIT-C questionnaires and biomarker analyses. The clinical assessments and measurements of biomarkers (GT, CDT, GT-CDT-combination, MCV, ALT, AST, hs-CRP, IL-6) were performed at baseline and after six months of treatment. Based on self-reported alcohol intake at baseline the patients were classified to three subgroups. RESULTS: About 27.2% of patients were categorized to high-risk drinkers, 26.3% low-risk drinkers and 46.5% abstainers. High-risk drinkers showed significantly higher mean values of GT, CDT, GT-CDT-combination and IL-6 than abstainers, diagnostic accuracy being highest with the combined marker of GT-CDT. The accuracy of AUDIT and AUDIT-C to detect high-risk drinking was also significant. During follow-up, the differences observed in the biomarkers at baseline disappeared together with recovery from depression. CONCLUSIONS: Our data suggest the combined use of GT-CDT and AUDIT questionnaires to improve the identification of drinking of patients with depression. This approach could be useful for improving treatment adherence and outcome in depressed patients.

Reversible psychiatric adverse effects related to deep brain stimulation of the anterior thalamus in patients with refractory epilepsy.

OBJECTIVE: Anterior nucleus of thalamus (ANT) deep brain stimulation (DBS) is becoming a more common treatment for drug-resistant epilepsy. Epilepsy and depression display a bidirectional association. Anterior nucleus of thalamus has connections to anterior cingulate cortex and orbitomedial prefrontal cortex, hence, a possible role in emotional and executive functions, and thus, ANT DBS might exert psychiatric adverse effects. Our aim was to evaluate previous and current psychiatric symptoms in patients with epilepsy undergoing ANT DBS surgery and assess the predictability of psychiatric adverse effects. Programming-related psychiatric adverse effects are also reported. METHOD: Twenty-two patients with ANT DBS for retractable epilepsy were examined, and a psychiatric evaluation of depressive and other psychiatric symptoms was performed with Montgomery and Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Symptom Checklist prior to surgery, concentrating on former and current psychiatric symptoms and medications. The follow-up visit was one year after surgery. RESULTS: At the group level, no changes on mood were observed during ANT DBS treatment. Two patients with former histories of depression experienced sudden depressive symptoms related to DBS programming settings; these were quickly alleviated after changing the stimulation parameters. In addition, two patients with no previous histories of psychosis gradually developed clear paranoid and anxiety symptoms that also relieved slowly after changing the programming settings. CONCLUSION: The majority of our ANT DBS patients did not experience psychiatric adverse effects. Certain DBS parameters might predispose to sudden depressive or slowly manifesting paranoid symptoms that are reversible via programming changes.

Low tumor necrosis factor-α levels predict symptom reduction during electroconvulsive therapy in major depressive disorder.

Objective: Changes in the tumor necrosis factor-α (TNFα) have been associated with major depressive disorder (MDD). Findings concerning the effects of electroconvulsive therapy (ECT) on the TNFα level have been contradictory. The aim was to examine the immediate and long-term changes in the TNFα level and their associations with symptom reduction in patients with MDD during ECT. Method: The study included 30 patients with MDD. Their TNFα levels were measured at baseline and 2 and 4 hr after the first, fifth and last ECT session. Depressive symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS). Results: The TNFα level decreased from baseline to the 2- and 4-hr measurements. There was a correlation between the first ECT session TNFα levels and the relative symptom reduction according to the MADRS score after the ECT series. Both the first (baseline) ECT and 4-hr TNFα levels were lower in responders than in nonresponders. Conclusion: ECT consistently induced a decrease in the TNFα level after each studied session. A low TNFα level at the first ECT appeared to predict a symptom reduction. These findings suggest that TNFα might have a role in the pathogenesis in MDD and in the mechanism of action of ECT.

The effects of adiposity and alcohol use disorder on adipokines and biomarkers of inflammation in depressed patients.

Patients with depression and alcohol use disorder frequently present with elevated markers of inflammation. Adipose tissue may function as a source for inflammation, yet the interplay between adiposity, alcohol use and depression has remained unknown. We examined 242 patients, referred to treatment for depressive symptoms, and followed for a period of 6 months. The assessments included screening for alcohol use and measurements of body mass index, serum adiponectin, leptin, resistin, progranulin, hs-CRP, IL-6 and MCP-1 at baseline and after 6 months of treatment. During follow-up, mean MADRS and AUDIT scores decreased significantly, whereas BMI increased. The changes in the levels of cytokines and adipokines were influenced by alcohol consumption and adiposity in a gender-dependent manner. The presence of AUD seemed to particularly influence the levels of cytokines. The levels of IL-6, hs-CRP, progranulin, and leptin differed between AUD and non-AUD groups at baseline, but no longer at 6 months. Baseline levels of leptin and resistin were higher in women and changes occurring in leptin, progranulin, and adiponectin were more notable in women. The data indicates significant gender-dependent interactions between depression, alcohol and mediators of inflammation, which should be considered in studies on the pathogenesis of depression and its comorbidities.

Histaminergic gene polymorphisms associated with sedation in clozapine-treated patients.

Sedation is a common adverse effect of clozapine treatment, which may be partly related to clozapine binding to histamine receptors in the central nervous system. The objective of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the histaminergic system are associated with sedation in clozapine-treated patients. The study population comprised 237 clozapine-treated, Finnish, Caucasian patients that were diagnosed with schizophrenia and 176 were genotyped using Illumina HumanCoreExome-12 BeadChip. Sedation levels were assessed using self-rating questions from the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS). The relationships between 55 different SNPs in the histaminergic system and adverse sedation effects were examined. SNPs were analyzed separately, and in groups, to formulate a genetic risk score (GRS). A permutation test was performed to avoid type I errors. Eight linked SNPs (r2 = 1) in the HNMT gene were also associated with sedation according to the GLM, adjusted for age, gender and BMI (false-discovery-rate-adjusted p = 0.013). An association on a trend level between a GRS of four different SNPs (recessive histamine N-methyltransferase HNMT rs2737385, additive histamine receptor H1 rs1552498, dominant HRH1 rs17034063 and recessive amine oxidase, copper containing 1 AOC1 rs6977381) and sedation was found (permuted p-value = 0.066) in a generalized linear model (GLM) incorporating age, gender and body mass index (BMI; adjusted R2 = 0.22). Polymorphisms in genes encoding histamine receptors or enzymes related to histamine metabolism may explain individual variation in sedative effects experienced during clozapine treatment.

Resistin as an inflammatory marker in patients with schizophrenia treated with clozapine.

BACKGROUND: Schizophrenia is associated with excess cardiovascular comorbidity and mortality related to lifestyle factors, such as lack of physical activity, poor diet, and smoking. The prevalence of metabolic syndrome is increased among patients with schizophrenia, with the highest rates among patients on clozapine treatment. Smoking, obesity, physical inactivity, airway inflammation and obstruction, and adipose tissue and inflammatory marker activation are related in systemic inflammation. Low-grade inflammation is also associated with schizophrenia. Adipokine resistin is a biomarker involving several acute and chronic inflammatory states. However, the inflammatory role of resistin is so far inconclusive and studies in schizophrenia are scanty. AIMS: The aim of the present study was to explore the role of serum resistin as an inflammatory marker in patients with schizophrenia on clozapine treatment. METHODS: Associations between serum levels of resistin and some other selected cytokines/adipokines (adiponectin, leptin, adipsin, IL-6, IL-1Ra, TNF-α, hs-CRP) and metabolic markers in 190 patients with schizophrenia on clozapine treatment were studied using a cross-sectional study design. RESULTS: Among male patients especially, smokers had higher levels of resistin than non-smokers, and among smokers resistin levels were associated with IL-1Ra and hs-CRP levels. In the whole patient group levels of resistin associated with levels of IL-1Ra, and among male patients with low HDL-cholesterol. CONCLUSIONS: Resistin is a biomarker of systemic inflammation associated with smoking among patients with schizophrenia on clozapine treatment. Resistin might have a role as a marker of cardiovascular comorbidity.

Patients with very-late-onset schizoprhenia-like psychosis have higher mortality rates than elderly patients with earlier onset schizophrenia.

OBJECTIVE: In this register-based study of schizophrenia patients aged 65 years or above, mortality and causes of death diagnosed at age of 60+ (very-late-onset schizophrenia-like psychosis, VLOSLP) were studied in comparison with sex- and age-matched general Finnish population. Standardized Mortality Ratios (SMRs) of VLOSLP patients were also compared with those of earlier onset (below 60 years) schizophrenia patients, and hazard of death was calculated between these patient groups. METHODS: The data was obtained from Finnish nationwide registers and consisted of 918 VLOSLP patients and 6142 earlier onset patients who were at least 65 years on 1 January 1999. The register-based follow-up for mortality covered 10 years between 1999 and 2008. RESULTS: Overall SMR was 5.02 (4.61-5.46) in the group of VLOSLP patients and 2.93 (2.83-3.03) in the group of earlier onset patients. In men, SMRs were 8.31 (7.14-9.62; n = 179) and 2.91 (2.75-3.07, n = 1316) and in women 4.21 (3.78-4.66; n = 364) and 2.94 (2.82-3.07, n = 2055). In the VLOSLP group, SMRs were higher in most causes-of-death categories such as accidents, respiratory diseases, dementias, neoplasms and circulatory diseases. However, in direct comparison adjusted for several variables, the difference between these groups was minimal (Hazard Ratio, HR, 1.16 95%CI 1.05-1.27, p = 0.003). CONCLUSION: Patients with VLOSLP, especially men, are at even higher risk of death than schizophrenia patients with earlier onset. Physical comorbidities and accidents in the VLOSLP group mostly explained this result. Targeted clinical interventions with effective collaboration between psychiatry and primary and specialist-level somatic care are crucial to reduce their excess mortality

Smoking and weight among patients using clozapine.

BACKGROUND: Both obesity and smoking are common in schizophrenia patients taking clozapine, causing cardiovascular disease and premature deaths. METHODS: Two hundred and thirty-seven patients with schizophrenia or related psychoses treated with clozapine completed the Liverpool University Neuroleptic Assessment Scale (LUNSERS) and a questionnaire including current height, weight, changes therein and smoking status. AIMS: The aim of this study was to analyze weight and weight change in smoking and non-smoking patients taking clozapine. A possible interaction between obesity and smoking was explored. RESULTS: No association was found between weight change and smoking status during clozapine treatment. There was no significant difference in body mass index (BMI) between non-smokers and smokers. In the analysis of covariance (ANCOVA) with BMI as the dependent variable, the best fitting model comprised age, sex, intensity of sedation, and reported amount of smoking as explanatory variables (ηp(2)= 0.116; P = 0.029; power = 0.750). None of the explanatory proportions of any single factor was significant. CONCLUSIONS: Estimated according to reported weight gain and BMI, no difference was found between smoking and non-smoking clozapine-treated patients. Number of cigarettes smoked explained BMI if age and sex were taken into account. This result is in line with the findings of some general population studies, where heavy smoking has been associated with a greater risk of obesity.

Cytokine and adipokine alterations in patients with schizophrenia treated with clozapine.

Metabolic syndrome is associated with both schizophrenia and antipsychotic medication, especially clozapine, with alterations in inflammatory cytokines and adipokines. However, the data in this field is heterogeneous and the sample sizes of the patients are limited. In this study we assessed the serum levels of cytokines/adipokines IL-6, IL-1Ra, hs-CRP and adiponectin, and components of metabolic syndrome in 190 patients with treatment resistant schizophrenia treated with clozapine. Substantial metabolic comorbidity was found in this patient group; overweight/obesity, smoking, hypertriglyceridemia, low HDL-cholesterol, high HOMA-IR, low adiponectin levels, elevated hs-CRP levels and elevated IL-1Ra levels. Elevated IL-1Ra levels are associated with insulin resistance, obesity and hypertriglyceridemia. Low adiponectin levels were associated with hypertriglyceridemia, low HDL cholesterol and high glucose, and in male patients also with obesity and high IL-1Ra levels. After controlling for confounding factors age and smoking, levels of IL-1Ra and hs-CRP associated with obesity, and the levels of IL-6 associated with obesity in female patients. We conclude that there are partly gender dependent cytokine and adipokine alterations in patients with schizophrenia on clozapine treatment associated with metabolic comorbidity. The genetic background of these cytokine alterations needs to be further investigated.

Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression.

Antidepressive medication and electroconvulsive therapy (ECT) increase hippocampal neurogenesis by promoting expression of trophic factors, including brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The aims were to test for an association between the VEGF 2578 C/A polymorphism and major depressive disorder (MDD) in two patient populations compared to controls, and the association between this polymorphism and response to serotonin selective reuptake inhibitors (SSRI) and to ECT. The first patient sample consisted of 119 subjects with treatment resistant major depressive disorder who were treated with ECT and the second of 98 depressive patients treated with SSRI. Treatment response was assessed by the Montgomery and Asberg Depression Rating Scale (MADRS). Patients scoring <8 in post-treatment MADRS were considered remitters. There was a trend that CC genotype of VEGF 2578C/A polymorphism was more common in ECT-treated and SSRI-treated patients than in controls (31.1%, 25.5% and 18.7% respectively; p=0.056). The VEGF 2578 C/A polymorphism was associated with treatment resistant MDD. CC genotype was more common in ECT patients than in controls (31.1% and 18.7% respectively; p=0.015). The VEGF 2578 C/A polymorphism was not associated with treatment response to SSRI or to ECT. The finding suggests an association between VEGF 2578 C/A polymorphism and treatment resistant depression which is reported for the first time. Further studies with larger samples will be required to confirm the results.

Increase in plasma proinflammatory cytokines after electroconvulsive therapy in patients with depressive disorder.

OBJECTIVES: Electroconvulsive therapy (ECT) is regarded as an effective treatment of drug-resistant depression, but its mechanism of action is mostly unknown. We have previously reported that epileptic seizures result in cerebral production of cytokines, which are also reflected in the plasma. In this study, we tested whether ECT is associated with similar acute release of cytokines. METHODS: The plasma levels of cytokines interleukin (IL) 1beta, IL-1 receptor antagonist, and IL-6 were measured using enzyme-linked immunosorbent assay at several time points after ECT. The study included 9 patients who met the diagnostic criteria of major depression (mean age, 55 years; mean Montgomery-Asberg Depression Rating Scale score, 30). RESULTS: Our results demonstrate that cytokines IL-1beta and IL-6 are increased at 3- and 6-hour time points after ECT. IL-6 release also correlated to the stimulus dose used, suggesting neuronal depolarization as a mechanism of cytokine release. CONCLUSIONS: These results indicate that ECT is associated with rapid induction of inflammatory cytokines most likely in the central nervous system, which are also measurable in the peripheral blood.

Interaction of tumor necrosis alpha - G308A and epidermal growth factor gene polymorphisms in early-onset schizophrenia.

The study population comprised 94 Finnish patients with DSM-IV diagnosis of schizophrenia. The patients were placed into two subgroups according to medication response to conventional neuroleptics. The aim of the study was to examine the frequency of tumor necrosis factor -308 (G > A) polymorphism in these patients and their 98 control subjects who were age- and gender-matched blood donors. Associations between TNFalpha -308 polymorphism alone and between the interaction of TNFalpha and epidermal growth factor gene polymorphisms, and medication response and age at onset of schizophrenia were also studied. The frequencies of TNFalpha A-allele were 11.7 % in patients and 12.8% in controls. The difference was not significant (p = 0.75). TNFalpha -308 polymorphism was not associated with medication response. However, patients with EGF AA and TNFalpha AG/AA genotype had a lower age at onset of schizophrenia compared with the rest of the patients not having this combination (20.0 years, 3.3 vs. 30.2 years, 10.1 mean + SD; p < 0.001). The results support earlier findings according to which TNFalpha polymorphism is not associated with the incidence of schizophrenia. On the other hand, the role of cytokines in schizophrenia may involve genetic interactions predisposing early onset of illness.

Electroconvulsive therapy in patients with depression and fibromyalgia.

The effect of electroconvulsive therapy (ECT) on depression and other symptoms of fibromyalgia was studied in a prospective 3-month trial in 13 patients with fibromyalgia and concomitant depression. All the patients met the DSM-IV diagnostic criteria for Major Depressive Disorder and fulfilled the American College of Rheumatology diagnostic criteria for fibromyalgia. The Montgomery and Asberg Depression Rating Scale (MADRS) and the clinical global impression scale (CGI) were used to assess the severity of depression and the clinical change of the patients. The fibromyalgia impact questionnaire (FIQ) was used to evaluate the severity of the fibromyalgia symptoms. The intensity of pain was evaluated using a 6-point scale (0=no pain, 5=very severe pain), and tender point palpation. All assessments were performed at baseline and at follow-up visits, which took place one week, one month and three months after ECT. There was a significant improvement in depression after ECT according to MADRS. Using CGI, six patients were much or very much improved, while four patients were minimally improved and three patients had no change. There was significant improvement in four out of ten FIQ item scores, "feel good", "fatigue", "anxiety" and "depression". No significant change was found in the FIQ item scores "physical function", "pain", "stiffness" and "morning tiredness" or number of tender points and self-reported pain. We conclude that ECT is a safe and effective treatment for depression in fibromyalgia patients, but has no effect on the pain or other physical symptoms of these patients.

Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics.

OBJECTIVE: In this study we attempted to show that the interaction between NOTCH4 and catechol-O-methyltransferase (COMT) polymorphism predicts the response to typical neuroleptics in schizophrenia. Our sample consisted of 94 Finnish patients with DSM-IV schizophrenia and 98 controls. METHODS: Several studies have connected COMT and NOTCH4 genes to schizophrenia. We have previously shown that COMT polymorphism is significantly associated with treatment response in schizophrenia. NOTCH4 SNP2 polymorphism has been associated with age of onset in schizophrenia, but there is also a trend that this polymorphism may predict response to typical neuroleptics. In the present sample, there is a strong gene-gene interaction between these genes (P = 0.003) and they have additive effect in treatment response. RESULTS: Patients carrying both NOTCH4 C/C genotype and COMT low/low genotype, had more than ten times higher risk of being a non-responder than responder to treatment with typical neuroleptics [OR = 10.25 (95% CI 2.21-47.53), P < 0.001]. This combination of genotypes is also more common in patients considered non-responders than in controls [OR = 3.00 (95% CI 1.33-6.76), P = 0.007]. CONCLUSION: Our results suggest that an interaction between COMT and NOTCH4 genotypes may predict the treatment response to typical neuroleptics in patients with schizophrenia.

NOTCH4 gene promoter polymorphism is associated with the age of onset in schizophrenia.

OBJECTIVES: The NOTCH4 gene has a promoter polymor-phism at position -25, which leads to the three genotypes TT, CT and CC. These have been suggested to present a novel independent genetic risk factor for schizophrenia. We conducted a prospective case-control study to explore the impact of NOTCH4 T-25C polymorphism on the factors associated with schizophrenia. METHOD: NOTCH4 gene promoter T-25C polymorphism was determined by polymerase chain reaction among 94 patients with schizophrenia and 94 healthy age-matched and sex-matched blood donors. RESULTS: The T allele was highly associated with an earlier age of onset in male patients of schizophrenia (Kaplan-Meier log-rank test P<0.0001). Moreover, the male patients carrying the T allele were born significantly more often in June-November compared with other months of the year [odds ratio=3.92 (95% confidence interval=1.025-15.018), P=0.046]. No association was determined, however, between the NOTCH4 gene polymorphism under study and schizophrenia. CONCLUSION: The NOTCH4 T-25C polymorphism has an important effect on the age of onset in schizophrenia and thus may be related to an early pathogenesis of schizophrenia in young patients. Alternatively, these findings may represent a significant genetic marker for managing subgroups and etiological clues in schizophrenia.