Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol.

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Interest of Fluvoxamine as an Add-on to Clozapine in Children With Severe Psychiatric Disorder According to CYPs Polymorphisms: Experience From a Case Series

10.21203/rs.3.rs-143738/v1 ◽

2021 ◽

Author(s):

Camille BEREL ◽

Ulysse RIOT MOSSE ◽

Julien Wils ◽

Lauriane Cousin ◽

Laurent Imbert ◽

...

Keyword(s):

Side Effects ◽

Plasma Level ◽

Psychiatric Disorder ◽

Psychiatric Disorders ◽

Neurodevelopmental Disorders ◽

Case Series ◽

Clinical Effects ◽

A Minor ◽

Enzymatic Inhibitor ◽

Cyp Inhibitors

Abstract BackgroundDespite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine while isoforms 2C19, 2D6, 3A4 and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP’s polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and to a lesser extent of CYP3A4 and CYP2D6. Hence, in case of CYPs polymorphisms in youth, the use of fluvoxamine as add on to clozapine could help reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile, as it has already been described in adults.Case ReportWe report four pediatric cases with severe psychiatric disorders underlying our experience with CYPs polymorphism explorations and the use of fluvoxamine as add on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drugs interactions when fluvoxamine is considered. Hence, we propose a detailed step by step multidisciplinary protocol.ConlusionThe results pointed out the positive clinical effects of fluvoxamine as add-on to clozapine in youth with severe neurodevelopmental disorders but stresses the need for caution regarding drugs interactions.

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Sex hormones and mental health

Advances in Psychiatric Treatment ◽

10.1192/apt.5.2.126 ◽

1999 ◽

Vol 5 (2) ◽

pp. 126-134 ◽

Cited By ~ 2

Author(s):

Louise Golightly ◽

Allan Young

Keyword(s):

Mental Health ◽

Side Effects ◽

Psychiatric Disorder ◽

Psychiatric Disorders ◽

General Practitioners ◽

Sex Hormones ◽

Psychological Effects ◽

Psychiatric Side Effects ◽

The Relationship

Hormones are widely considered to cause powerful psychological effects and because of this psychiatrists may be asked to advise general practitioners, consultants in other specialities or patients about the relationship between hormones (including sex hormones) and psychiatric disorder. Sex hormones may be relevant to psychiatry in three ways:(a) Sex hormones may play a role in the pathophysiology of psychiatric disorders.(b) These agents may be utilised for treatment of psychiatric disorder.(c) Administration of sex hormones may cause psychiatric side-effects.

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High doses of carbamazepine for refractory partial epilepsy

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x1996000100007 ◽

1996 ◽

Vol 54 (1) ◽

pp. 42-46 ◽

Cited By ~ 1

Author(s):

Cristiana Borges Pereira ◽

Carlos Otto Heise ◽

Arthur Cukiert

Keyword(s):

Side Effects ◽

Plasma Level ◽

Plasma Levels ◽

Partial Epilepsy ◽

The Other ◽

Partial Seizures ◽

High Doses ◽

Higher Doses ◽

Refractory Partial Epilepsy

Forty-eight patients with partial seizures were analysed during treatment with 1200 mg/d or more of carbamazepine (CBZ). Thirty-three were on monotherapy and fifteen on polytherapy. The other drugs were kept unchanged in the patients on polytherapy. The dose of CBZ was increased if no control was observed and the patient had no side effects. The doses used ranged between 1200 and 1900 mg/day (1200 mg/day, n=18; 1300mg/day, n=1; 1400 mg/day, n=7; 1600 mg/day, n=9; 1700 mg/day, n=4; 1800 mg/day, n=8; 1900 mg/day, n=1). Anticonvulsant plasma levels were taken to confirm patient compliance. The average plasma level was 9.6 ug/mL. The period of follow up varied from 3 to 96 months (M=25.6). Seizure's control was observed in 7 (14.48%) patients taking 1200 mg/day and in 2 (4.16%) patients taking 1400 mg/day of CBZ. Thirty-nine patients did not show any control (81.21%). Ten patients (20.81%) had signs of intoxication. When patients have no improvement with 1400 mg/day, it is difficult to obtain any control despite the use of higher doses of CBZ, which frequently expose the patient to significant side effects.

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760 Patients with Pre-existing Mental Illness Who Developed Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Lessons Learned at a Large Tertiary Burn Center and the Importance of Accurately Diagnosing Psychiatric Disorders

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa024.339 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

pp. S213-S214

Author(s):

Sarah L Laughon ◽

Michael Duplisea ◽

Carolyn Ziemer ◽

Lori Chrisco ◽

Felicia N Williams ◽

...

Keyword(s):

Bipolar Disorder ◽

Psychiatric Disorder ◽

Toxic Epidermal Necrolysis ◽

Psychiatric Disorders ◽

Skin Diseases ◽

Case Series ◽

Lessons Learned ◽

Stevens Johnson Syndrome ◽

Burn Center ◽

Johnson Syndrome

Abstract Introduction In recent years, burn centers are managing more patients with exfoliative skin disorders including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and SJS/TEN overlap. While it is well known that burn patients have higher rates of co-morbid psychiatric disorders than the general population, the incidence of pre-existing psychiatric disorders among patients who develop SJS, SJS/TEN overlap, and TEN is unknown. This study aimed to characterize a cohort of patients with pre-existing psychiatric disorders admitted to a tertiary burn center for treatment of SJS, SJS/TEN overlap, and TEN with specific focus on those who received the offending agent for a psychiatric indication. Methods A retrospective descriptive case series using an institutional burn center registry was performed. All patients admitted to a single verified burn center between January 1, 2009 and December 31, 2018 with biopsy-proven SJS, SJS/TEN overlap, or TEN and the presence of a co-morbid psychiatric disorder were identified. Demographic, hospital, and clinical information were extracted from the burn registry and verified through review of the electronic medical record. Results Among 168 patients with biopsy-proven SJS, SJS/TEN overlap, or TEN, 18% (30/168) had a pre-existing psychiatric disorder, with the offending agent being prescribed for a psychiatric indication in 30% (10/30) of patients. Lamotrigine was the offending agent in 80% of cases and prescribed 100% of the time for a psychiatric indication. Of those who received lamotrigine, patients were 100% female, 63% black, and had an average age of 38 years. The mean length of stay was 24 days and 88% received a psychiatric consultation. While 75% of patients were started on lamotrigine for a diagnosis of bipolar disorder, none of these patients met criteria for bipolar disorder. Conclusions Pre-existing psychiatric comorbidity is less common among patients that develop SJS, SJS/TEN overlap, and TEN than in burn-injured patients. For patients with pre-existing psychiatric disorders who develop these potentially fatal skin diseases from an offending agent that was prescribed for a psychiatric indication, early involvement of psychiatry colleagues is recommended to ensure proper psychiatric diagnosis and management moving forward. Applicability of Research to Practice This study highlights the importance of accurate assessment for and diagnosis of bipolar disorder prior to determining treatment approach. For the burn surgeon treating these patients, early involvement of psychiatric consultants is recommended and extremely important.

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Large Variations of Plasma Levels During Maintenance Treatment with Depot Neuroleptics

The British Journal of Psychiatry ◽

10.1192/bjp.169.5.618 ◽

1996 ◽

Vol 169 (5) ◽

pp. 618-621 ◽

Cited By ~ 15

Author(s):

Eva Tuninger ◽

Sten Levander

Keyword(s):

Side Effects ◽

Plasma Level ◽

Plasma Levels ◽

Clinical Effect ◽

Clinical Symptoms ◽

Repeated Measurements ◽

Neuroleptic Treatment ◽

Neuroleptic Medication ◽

Depot Neuroleptics ◽

Depot Neuroleptic

BackgroundStability of neuroleptic medication has been associated with optimal clinical effect and minimal side-effects. Depot administration is assumed to yield better stability.MethodThirty patients on depot neuroleptic treatment were followed during three years with repeated measurements of plasma level and concurrent ratings of clinical symptoms and side-effects.ResultsOf 120 blood samples 35 (29%) measurements were outside ± 2 s.d. measurement error (expected 5%). Perphenazine levels were more variable (46%) than haloperidol (25%) and flupenthixol (12.5%). No relationship was found between side-effect ratings and fluctuations of plasma levels.ConclusionDepot neuroleptic medication does not eliminate a clinically unwanted and sometimes marked variation in plasma level.

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Nortriptyline Plasma Levels and Subjective Side Effects*

The British Journal of Psychiatry ◽

10.1192/s0007125000282974 ◽

1978 ◽

Vol 132 (1) ◽

pp. 55-60 ◽

Cited By ~ 18

Author(s):

Vincent E. Ziegler ◽

John R. Taylor ◽

Richard D. Wetzel ◽

John T. Biggs

Keyword(s):

Side Effects ◽

Plasma Level ◽

Plasma Levels ◽

Tricyclic Antidepressants ◽

Dry Mouth ◽

Severity Of Depression ◽

The Common ◽

Pre Treatment ◽

The Individual ◽

Subjective Side

Nortriptyline plasma levels and the incidence and severity of the common subjective side effects of the tricyclic antidepressants were determined in 26 patients during six weeks of treatment with nortriptyline. The total corrected (treatment minus pre-treatment) score of the eight side effects most independent of the severity of depression correlated (0 · 60) with the nortriptyline plasma level. Increased perspiration (o · 59) and dry mouth (o · 54) were the individual corrected side effects which most consistently correlated with the plasma level. These subjective side effects may serve as clinically useful guides to dosage adjustments during treatment, though their value is limited by the magnitude of the correlations and the need to correct for their presence prior to treatment.

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Rapamycin Has Biological Activity in a Subset of Patients with Myelodysplastic Syndrome - Results of a Phase I/II Trial.

Blood ◽

10.1182/blood.v104.11.1449.1449 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1449-1449

Author(s):

Uwe Platzbecker ◽

Michael Haase ◽

Regina Herbst ◽

Anette Hanel ◽

Karsten Voigtmann ◽

...

Keyword(s):

Biological Activity ◽

Side Effects ◽

Plasma Level ◽

Myelodysplastic Syndrome ◽

Phase I ◽

Plasma Levels ◽

Immune Surveillance ◽

Therapeutic Benefit ◽

Significant Difference ◽

Median Plasma

Abstract The pathophysiology of myelodysplastic syndrome (MDS) involves disturbed regulation of angiogenesis, apoptosis, proliferation and differentiation as well as immune surveillance. There is increasing evidence that rapamycin (sirolimus) might affect these pathways positively thus possibly being of therapeutic benefit in patients with this disease. These data prompted us to perform a phase I/II study to evaluate the safety and efficacy of rapamycin in the treatment of patients with MDS. Nineteen patients (median age 72 years) diagnosed with MDS according to the WHO classification received rapamycin orally with a target blood concentration of 3–12 ng/ml. Rapamycin was administered for a median of 3.7 months (range 0.3–11). Three patients (1 x RAEB-2, 1 x RAEB-1, 1 x RCMD) showed either a major (1 x platelet, 1 x neutrophil) or a minor (1 x erythroid, 2 x platelet) hematological response according to the IWG criteria. There was no statistically significant difference in the rapamycin plasma levels between the three responders (median plasma level 3.62, range 1.63–4.39) and non-responders (median plasma level 4.22, range 2.81–7.4). Major side effects were hyperlipidemia (n=4), stomatitis (n=3), thrombocytopenia (n=2) and urinary tract infection (n=1). Study medication had to be stopped due to side effects in five patients (26 %), one of them being a responder to rapamycin. Plasma levels of rapamycin were not elevated in patients experiencing toxicity. Taken together these data demonstrate that rapamycin might have biological activity in patients with rather advanced MDS. New and possibly less toxic analogues of rapamycin are currently developed. They could be candidates for future trials in patients with MDS.

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Rifabutin Use in Staphylococcus Biofilm Infections: A Case Series

Antibiotics ◽

10.3390/antibiotics9060326 ◽

2020 ◽

Vol 9 (6) ◽

pp. 326 ◽

Cited By ~ 1

Author(s):

James B. Doub ◽

Emily L. Heil ◽

Afua Ntem-Mensah ◽

Renaldo Neeley ◽

Patrick R. Ching

Keyword(s):

Side Effects ◽

Adjuvant Therapy ◽

Drug Interactions ◽

Case Series ◽

Staphylococcal Infections ◽

Chronic Medications

This is a case series of 10 patients who had staphylococcal biofilm infections that were treated with adjuvant rifabutin therapy instead of rifampin therapy. In these cases, rifampin was contraindicated secondary to drug–drug interactions with the patients’ chronic medications. Rifabutin therapy was well tolerated with no side effects. As well, no patients had recurrence of their staphylococcal infections. This case series shows that rifabutin can be a beneficial adjuvant therapy in Staphylococcus biofilm infections when drug–drug interactions limit the use of rifampin.

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Food and drugs

Medicinski pregled ◽

10.2298/mpns0202005d ◽

2002 ◽

Vol 55 (1-2) ◽

pp. 5-12 ◽

Cited By ~ 1

Author(s):

Kornelija Djakovic-Svajcer

Keyword(s):

Plasma Level ◽

Drug Metabolism ◽

Drug Interactions ◽

Therapeutic Effect ◽

Significant Influence ◽

Plasma Concentrations ◽

Chemical Properties ◽

Therapeutic Index ◽

Food Composition ◽

Drug Bioavailability

Food can exert a significant influence on the effects of certain drugs. The interactions between food and drugs can be pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions most often take place on absorption and drug metabolism levels. Absorption can be either accelerated or delayed, increased or decreased, while drug metabolism can be either stimulated or inhibited. The factors which influence food-drug interactions are as follows: composition and physic-chemical properties of drugs, the interval between a meal and drug intake and food composition. Food consistency is of lesser influence on drug bioavailability than food composition (proteins, fats, carbohydrates, cereals). Important interactions can occur during application of drugs with low therapeutic index, whereby the plasma level significantly varies due to changes in resorption or metabolism (e.g. digoxin, theophyllin, cyclosporin) and drugs such as antibiotics, whose proper therapeutic effect requires precise plasma concentrations.

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Descriptors of Cytochrome Inhibitors and Useful Machine Learning Based Methods for the Design of Safer Drugs

Pharmaceuticals ◽

10.3390/ph14050472 ◽

2021 ◽

Vol 14 (5) ◽

pp. 472

Author(s):

Tyler C. Beck ◽

Kyle R. Beck ◽

Jordan Morningstar ◽

Menny M. Benjamin ◽

Russell A. Norris

Keyword(s):

United States ◽

Machine Learning ◽

Drug Interactions ◽

The United States ◽

Structural Features ◽

Physiochemical Properties ◽

Drug Dosing ◽

Therapeutic Outcomes ◽

Cyp Inhibition ◽

Cyp Inhibitors

Roughly 2.8% of annual hospitalizations are a result of adverse drug interactions in the United States, representing more than 245,000 hospitalizations. Drug–drug interactions commonly arise from major cytochrome P450 (CYP) inhibition. Various approaches are routinely employed in order to reduce the incidence of adverse interactions, such as altering drug dosing schemes and/or minimizing the number of drugs prescribed; however, often, a reduction in the number of medications cannot be achieved without impacting therapeutic outcomes. Nearly 80% of drugs fail in development due to pharmacokinetic issues, outlining the importance of examining cytochrome interactions during preclinical drug design. In this review, we examined the physiochemical and structural properties of small molecule inhibitors of CYPs 3A4, 2D6, 2C19, 2C9, and 1A2. Although CYP inhibitors tend to have distinct physiochemical properties and structural features, these descriptors alone are insufficient to predict major cytochrome inhibition probability and affinity. Machine learning based in silico approaches may be employed as a more robust and accurate way of predicting CYP inhibition. These various approaches are highlighted in the review.

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