Showing papers by "Alasdair M. Barr published in 2016"

Antipsychotic Induced Dopamine Supersensitivity Psychosis: A Comprehensive Review

Abstract: Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes.

Factors affecting severity of positive and negative symptoms of psychosis in a polysubstance using population with psychostimulant dependence

Abstract: Approximately half of psychostimulant users experience psychotic symptoms, which include both positive and negative symptoms. Prior reports have exclusively used positive symptoms to characterize psychostimulant associated psychosis. Symptoms vary dramatically in severity, though most investigations categorize psychosis as a dichotomous occurrence. To explore the association between different substances of abuse and the severity of psychotic symptoms, we investigated 171 individuals meeting DSM-IV-TR criteria for psychostimulant (cocaine or methamphetamine) dependence in an observational cross-sectional study. Participants were predominantly male (72.5%), recruited from a socially disadvantaged neighborhood in Vancouver, Canada, with a mean age of 45.5(±8.8) years. Of the total sample, 85% were dependent on cocaine, and 28.1% were dependent on methamphetamine. Participants had a median total PANSS score of 63, ranging from 37 to 111. Demographic information, current substance use and early substance exposure were used to predict positive and negative psychotic symptom severity in linear regression models. Increased severity of positive psychotic symptoms was significantly related to greater methamphetamine and marijuana use in the past 28 days, and methadone-abstinence. Negative symptom severity was related to increased opioid use in the past 28 days. There was no overlap between predictors of positive and negative symptom severity.

Elevated clozapine plasma concentration secondary to a urinary tract infection: proposed mechanisms.

Abstract: A 59-year-old woman was admitted to a tertiary care refractory psychosis unit with a referral diagnosis of schizoaffective disorder. She was maintained on 400 mg of clozapine once daily as part of her pre-existing treatment for auditory hallucinations. The steady state plasma concentrations of clozapine and norclozapine were 2542 and 1465 nmol/L, respectively (metabolic ratio: 1.74). Seven weeks later, the plasma concentrations of clozapine and norclozapine increased to 3272 and 2025 nmol/L, respectively (metabolic ratio: 1.62), despite no changes in medications (including doses), smoking status, or adherence (based on previous clozapine levels). Although no adverse effects were observed in association with the elevated plasma concentrations, the daily dose was reduced to 200 mg as a precautionary measure. Upon investigation, a urinary tract infection (UTI) was diagnosed, for which nitrofurantoin and cotrimoxazole were initiated. After 1 week of antibiotic therapy, clozapine and norclozapine plasma concentrations decreased to 1406 and 639 nmol/L, respectively (metabolic ratio: 2.20). Similar increases in the plasma concentrations of clozapine and norclozapine have been described in other case reports involving concurrent UTIs.1–5 Adverse effects attributed to elevated plasma concentrations of clozapine include somnolence, confusion, disorientation, dizziness, aphasia and extrapyramidal symptoms.1–5 Apart from UTIs, this phenomenon has also been reported in association with other infectious processes and with tissue injury,1,6–9 sometimes without clozapine-associated adverse effects.10 The mechanism implicated in increasing plasma concentrations of clozapine and norclozapine is not believed to be related to the exposure to the pathogen or the damage to the tissue, but rather the effects of cytokines released in response to proinflammatory events, such as those mentioned above.11 Several cytokines involved in the acute inflammatory response have been identified as having an inhibitory effect on the expression of certain drug metabolizing enzymes. For instance, a downregulation of cytochrome P450 (CYP) 1A2 and CYP3A messenger RNA has been reported following the incubation of human hepatocytes with tumour necrosis factor, interleukin (IL)-1β, and IL-6. Furthermore, the activity of these enzymes were also reduced by the same cytokines.12 Since clozapine is primarily metabolized by CYP1A2, with contributions from CYP3A4,13 reductions in their expression and activity offer an explanation to the noted increase in its plasma concentration. However, this mechanism may not be in operation in our patient since the clozapine/norclozapine metabolic ratios did not increase from baseline to the time of UTI diagnosis. Typically, the ratio would increase to a value greater than 2:1 in response to inhibition of CYP1A2. Interestingly, there was a modest increase in the clozapine/norclozapine metabolic ratio after treatment for the UTI, which is consistent with the inhibitory effect of cotrimoxazole on CYP2C9, an enzyme involved in the demethylation of clozapine to norclozapine.14 A second mechanism that has been proposed to explain the UTI-associated elevations in the plasma concentrations of clozapine and norclozapine is related to an increase in α1-acid glycoprotein,10 an acute-phase protein whose synthesis is upregulated by cytokines such as IL-6.15 An increase in α1-acid glycoprotein will increase the binding capacity of both clozapine and norclozapine. The outcome will be an increase in the total (bound and unbound) plasma concentrations of clozapine and norclozapine; however, the unbound (free and active moiety) concentrations will remain unchanged. Since clinical laboratories report only total (bound and unbound) plasma concentrations, confirmation that the free levels have remained unchanged is not possible. The fact that the patient did not exhibit any clozapine-associated adverse effects supports the supposition that the free concentrations did not increase despite the increase in total concentration. Measuring plasma concentrations of α1-acid glycoprotein (if available) would have helped to confirm this proposed mechanism. UTI-associated increases in the plasma concentrations of clozapine and norclozapine are most readily explained by the actions of cytokines on drug metabolism and/or protein binding. Since we could not readily order plasma concentrations of unbound clozapine or α1-acid glycoprotein, confirmation of the underlying mechanism( s) was not possible. As such, clinicians should monitor for clozapine-associated adverse effects and adjust the dosage accordingly.

Proposing the Use of Partial AUC as an Adjunctive Measure in Establishing Bioequivalence Between Deltoid and Gluteal Administration of Long-Acting Injectable Antipsychotics.

Abstract: The maximum plasma concentration (Cmax) and the area under the plasma concentration–time curve (AUC) are commonly used to establish bioequivalence between two formulations of the same oral medication. Similarly, these pharmacokinetic parameters have also been used to establish bioequivalence between two sites of administration for the same injectable formulation. However, these conventional methods of establishing bioequivalence are of limited use when comparing modified-release formulations of a drug, particularly those with rates of absorption that are amenable to change with the site of injection. Inherent differences in the rate of absorption can result in clinically significant differences in early exposure and drug response. Here, we propose the use of the partial AUC (pAUC) as a measure of early exposure to aid in the assessment of bioequivalence between the gluteal and the deltoid site of administration for long-acting injectable antipsychotics.

Breakthrough symptoms after switching long-acting injectable paliperidone palmitate from the gluteal to the deltoid site of administration.

Abstract: A 34-year-old white man in whom schizophrenia was diagnosed at the age of 24 years was trialed over the course of illness on risperidone, olanzapine and aripiprazole. Although he responded well to these medications, he experienced relapses secondary to nonadherence. After discussing options to improve compliance and prevent relapse, he agreed to try long-acting injectable paliperidone palmitate. The initiation regimen consisted of 150 and 100 mg administered into the deltoid muscle on days 1 and 8, respectively, followed by 150 mg every 28 days into the gluteal muscle. On this regimen, the patient was free of positive symptoms. After 14 months, his maintenance dose was changed to the deltoid muscle (150 mg every 28 d). Four months later, the week before his next scheduled injection, he had breakthrough auditory hallucinations. As a consequence, the maintenance regimen was changed to 150 mg administered into the deltoid muscle every 3 weeks. The patient has been on this regimen for 9 months without any breakthrough symptoms. The breakthrough symptoms may have been due to differences in the rate and extent of drug absorption between the sites of injection. The rate of absorption from a depot into the vasculature is influenced by many factors. For example, formulations using different vehicles and salts of the active drug are used to control the rate of drug absorption. Injection technique also impacts bioavailability of drugs administered intramuscularly. Although intended to penetrate the striated muscle fibres, poor technique can result in the drug being deposited into the subcutaneous adipose tissue, resulting in a slower and more erratic rate of absorption. Physiologic factors also impact absorption and bioavailability of drugs administered intramuscularly. Compared with the gluteal muscle, the deltoid muscle has greater blood flow, allowing for a faster rate of drug absorption. Exercise that increases blood flow will also result in a faster rate of drug absorption. Finally, obesity to the point where the injection technique is compromised will reduce overall bioavailability. Taken together, all of these factors can lead to variability in the rate and extent of drug absorption. Site-dependent differences in the pharmacokinetics of paliperidone palmitate have been documented: In a randomized, single-dose, open-label, dose proportionality study of paliperidone palmitate (n = 201), the median maximum plasma concentration (dose normalized to 50 mg) was found to be higher (range 9%–65%) after deltoid injection than gluteal injection.1 Time to maximum (tmax) plasma concentration and half-life of paliperidone palmitate 150 mg were both shorter when administered into the deltoid muscle than the gluteal muscle (tmax: 14 v. 17 d, respectively; half-life: 40.6 v. 49.1 d, respectively). U.S. Food and Drug Administration drug submission review of a population pharmacokinetic study (using simulation scenarios with significant covariates)2 revealed that compared with deltoid injections, repeated administration in the gluteal muscle resulted in a delayed time to achieve steady state (about 4 wk longer).3 By definition, bioequivalence depends on rate and extent of drug absorption.4 If good injection technique is followed, then the site of administration will not affect the extent to which paliperidone palmitate reaches the systemic circulation. However, the rate of absorption of paliperidone is quicker when administered via the deltoid muscle. As such, administering paliperidone palmitate via the deltoid muscle versus the gluteal muscle may not be bioequivalent.5 Clinicians need to be vigilant when switching between administration sites using long-acting injectable paliperidone. Since the rate of absorption via deltoid administration is faster, it is possible that a therapeutic plasma concentration may not be maintained for the duration of the manufacturer’s recommended dosage interval of 4 weeks. In such cases, reducing the dosage interval to every 21 days may be appropriate; not every patient receiving paliperidone palmitate via the deltoid muscle needs to be on a 3-week regimen. The rate of absorption from the deltoid muscle is patient-specific and thus the dosing interval will reflect this.

A Tetra-Primer Amplification Refractory System Technique for the Cost-Effective and Novel Genotyping of Eight Single-Nucleotide Polymorphisms of the Catechol-O-Methyltransferase Gene

Abstract: Aims: Catechol-O-methyltransferase (COMT) is an enzyme involved in the degradation of catecholamine neurotransmitters. Due to its role in neurotransmitter flux, multiple COMT variants have been associated with the development of psychiatric disorders. Notably, select single-nucleotide polymorphisms (SNPs) of the COMT gene have been implicated in schizophrenia risk, severity, and treatment response. In recognition of the value of a streamlined genotyping method for COMT SNP detection, this study was designed to develop a simple and economical tetra-primer amplification refractory mutation system (T-ARMS) assay for the concurrent detection of eight COMT SNPs: rs4680, rs737865, rs165599, rs2075507, rs4633, rs4818, rs6269, and rs165774. Materials and Methods: T-ARMS is a genotyping method that uses polymerase chain reaction (PCR) to amplify a multiplex reaction consisting of two primer pairs. T-ARMS primers are customized to each SNP and designed to generate different-sized allele-specific amplicons. This ass...

The information in this column is not intended as a definitive treatment strategy but as a suggested approach for clinicians treating patients with similar histories. Individual cases may vary and should be evaluated carefully before treatment is provided. The patient described in this column is a composite with characteristics of several real patients. Psychopharmacology for the Clinician

Abstract: intramuscularly. Although intended to penetrate the striated muscle fibres, poor technique can result in the drug being deposited into the subcutaneous adipose tissue, resulting in a slower and more erratic rate of absorption. Physiologic factors also impact absorption and bioavailability of drugs administered intramuscularly. Compared with the gluteal muscle, the deltoid muscle has greater blood flow, allowing for a faster rate of drug absorption. Exercise that increases blood flow will also result in a faster rate of drug absorption. Finally, obesity to the point where the injection technique is compromised will reduce overall bioavailability. Taken together, all of these factors can lead to variability in the rate and extent of drug absorption. Site-dependent differences in the pharmacokinetics of paliperidone palmitate have been documented: • In a randomized, single-dose, openlabel, dose proportionality study of paliperidone palmitate (n = 201), the median maximum plasma concentration (dose normalized to 50 mg) was found to be higher (range 9%– 65%) after deltoid injection than gluteal injection. 1 Time to maximum

Response to the Letter to the Editor on "Paliperidone Palmitate Long-Acting Injectable Given Intramuscularly in the Deltoid Versus the Gluteal Muscle: Are They Therapeutically Equivalent?"

Abstract: 3-month formulations of paliperidone palmitate were developed by Janssen Research & Development, and the authors participated in the development programs. The company also provided a formal review of this letter before submission to the journal. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share thework provided it is properly cited. Thework cannot be changed in any way or used commercially without permission from the journal.