Bruce R. Russell

Pharmacotherapy for treatment-resistant schizophrenia

Schizophrenia is a disabling mental illness with a lifetime prevalence of 0.7% worldwide and significant, often devastating, consequences on social and occupational functioning. A range of antipsychotic medications are available; however, suboptimal therapeutic response in terms of psychotic symptoms is common and affects up to one-third of people with schizophrenia. Negative symptoms are generally less amenable to treatment. Because of the consequences of inadequate symptom control, effective treatment strategies are required for people with treatment-resistant schizophrenia. Clozapine has been shown to be more effective than other antipsychotics in treatment-resistant populations in several studies; however, the occurrence of adverse effects, some of which are potentially life-threatening, are important limitations. In addition to those who are intolerant to clozapine, only 30% to 50% experience clinically significant symptom improvement. This review describes the recent evidence for treatment strategies for people not responding to nonclozapine antipsychotic agents and people not responding or only partially responding to clozapine.

Validation of an LC–MS Method for the Detection and Quantification of BZP and TFMPP and their Hydroxylated Metabolites in Human Plasma and its Application to the Pharmacokinetic Study of TFMPP in Humans*

Abstract:  An LC–MS method was developed for benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP), constituents of “party pills” or “legal herbal highs,” and their metabolites in human blood plasma. Compounds were resolved using a mixture of ammonium formate (pH 4.5, 0.01 M) and acetonitrile (flow rate of 1.0 mL/min) with a C18 column. Calibration curves were linear from 1 to 50 ng/mL (R2 > 0.99); the lower limit of quantification (LLOQ) was 5 ng/mL; the accuracy was >90%; the intra‐ and interday relative standard deviations (R.S.D) were <5% and <10%, respectively. Human plasma concentrations of TFMPP were measured in blood samples taken from healthy adults (n = 6) over 24 h following a 60‐mg oral dose of TFMPP: these peaked at 24.10 ng/mL (±1.8 ng/mL) (Cmax) after 90 min (Tmax). Plasma concentrations of 1‐(3‐trifluoromethyl‐4‐hydroxyphenyl) piperazine peaked at 20.2 ng/mL (±4.6 ng/mL) after 90 min. TFMPP had two disposition phases (t½ = 2.04 h (±0.19 h) and 5.95 h (±1.63 h). Apparent clearance (Cl/F) was 384 L/h (±45 L/h).

A Spiking Neural Network Methodology and System for Learning and Comparative Analysis of EEG Data From Healthy Versus Addiction Treated Versus Addiction Not Treated Subjects

This paper introduces a method utilizing spiking neural networks (SNN) for learning, classification, and comparative analysis of brain data. As a case study, the method was applied to electroencephalography (EEG) data collected during a GO/NOGO cognitive task performed by untreated opiate addicts, those undergoing methadone maintenance treatment (MMT) for opiate dependence and a healthy control group. Methods: the method is based on an SNN architecture called NeuCube, trained on spatiotemporal EEG data. Objective: NeuCube was used to classify EEG data across subject groups and across GO versus NOGO trials, but also facilitated a deeper comparative analysis of the dynamic brain processes. Results: This analysis results in a better understanding of human brain functioning across subject groups when performing a cognitive task. In terms of the EEG data classification, a NeuCube model obtained better results (the maximum obtained accuracy: 90.91%) when compared with traditional statistical and artificial intelligence methods (the maximum obtained accuracy: 50.55%). Significance: more importantly, new information about the effects of MMT on cognitive brain functions is revealed through the analysis of the SNN model connectivity and its dynamics. Conclusion: this paper presented a new method for EEG data modeling and revealed new knowledge on brain functions associated with mental activity which is different from the brain activity observed in a resting state of the same subjects.

The new psychoactive substances regime in New Zealand: A different approach to regulation

The New Zealand government has proposed a new psychoactive substances regime, which will place the onus onto manufacturers to prove that their products pose a low risk of harm, prior to receiving approval which allows the products to be legally manufactured and sold. This is an innovative and unique development in the regulation of emerging psychoactive substances, and offers an alternative response to prohibition. The details of the new regime and how it will operate are now emerging, and this offers an opportunity to critically explore some of the issues related to the proposed new regime and to speculate on some of the outcomes. This paper brings together a group of New Zealand based researchers from a range of disciplines with experience of ‘legal high’ research to discuss this innovative new regime.

Extended-release methylphenidate for treatment of amphetamine/methamphetamine dependence: a randomized, double-blind, placebo-controlled trial

AIMS To assess the efficacy of methylphenidate as a substitution therapy for amphetamine/methamphetamine dependence in Finland and New Zealand. DESIGN Parallel-group, double-blind, randomized placebo-controlled trial. SETTING Out-patient care. PARTICIPANTS Amphetamine-/methamphetamine-dependent, aged 16-65 years. MEASUREMENTS The primary outcome measure was presence/absence of amphetamine/methamphetamine in urine samples collected twice weekly. Secondary measures included treatment adherence, alterations in craving scores and self-reported use. Primary analysis was by intention-to-treat (ITT). The study drug, methylphenidate (as Concerta(®) ), was up-titrated over 2 weeks to a maximum dose of 54 mg daily and continued for a further 20 weeks. Doses were given under daily supervision at the clinics. FINDINGS Seventy-nine participants were randomized (40 methylphenidate; 39 placebo); 76 received allocated treatment and 27 completed the trial. ITT analysis (n = 78) showed no statistically significant difference in the percentage of positive urines between the methylphenidate and placebo arms (odds ratio: 0.95, 95% confidence interval: 0.83-1.08). However, there was a significant difference (P < 0.05) between the active and placebo arms in retention, the placebo arm displaying a significantly lower retention from 6 weeks that persisted until the end of the trial. CONCLUSIONS The trial failed to replicate earlier findings suggesting that methylphenidate was superior to placebo. The low retention rate confounded the ability to draw firm conclusions about efficacy. The higher retention rate was observed in the methylphenidate arm. Any replication of this work would need to consider alternatives to the rigid clinic attendance criteria, and consider an increased dose.

Extensive Gray Matter Volume Reduction in Treatment-Resistant Schizophrenia

Background: Approximately one-third of people with schizophrenia are treatment-resistant and some do not achieve remission with clozapine, the gold-standard antipsychotic medication for treatment-resistant schizophrenia. This study compared global and regional brain volumes between treatment-respondent and treatment-resistant patients with schizophrenia, including a group of patients who were clozapine-resistant. Methods: T1-weighted brain MRIs were obtained on a 3T scanner in 20 controls and 52 people with schizophrenia who were selected based on their symptomatic responses to antipsychotic medication: 18 responded well to first-line atypical antipsychotics (FLR), 19 were treatment-resistant but responsive to clozapine monotherapy (TR), and 15 were ultra-treatment-resistant and did not respond to clozapine (UTR). Treatment groups were matched for disease duration and current psychopathology. SIENAX and FSL-VBM were used to investigate differences in the global brain, gray matter (GM), white matter, ventricular cerebrospinal fluid volumes, and regional GM volumes. Results: GM volume was significantly reduced in the TR and UTR groups compared with controls and the FLR group (p < 0.05). GM volume was significantly reduced in TR patients compared with FLRs in the superior, middle, and inferior temporal gyri, pre- and post-central gyri, middle and superior frontal gyri, right supramarginal gyrus, and right lateral occipital cortex. UTR patients showed reduced GM compared with FLRs in their right parietal operculum and left cerebellum. No significant volume differences were observed between TR and UTR groups. Conclusions: These differences are unlikely to be solely due to medication effects, and reduced GM volume in treatment-resistant schizophrenia may represent an accelerated disease course or a different underlying pathology.

Striatal Volume Increases in Active Methamphetamine-Dependent Individuals and Correlation with Cognitive Performance

The effect of methamphetamine (MA) dependence on the structure of the human brain has not been extensively studied, especially in active users. Previous studies reported cortical deficits and striatal gains in grey matter (GM) volume of abstinent MA abusers compared with control participants. This study aimed to investigate structural GM changes in the brains of 17 active MA-dependent participants compared with 20 control participants aged 18–46 years using voxel-based morphometry and region of interest volumetric analysis of structural magnetic resonance imaging data, and whether these changes might be associated with cognitive performance. Significant volume increases were observed in the right and left putamen and left nucleus accumbens of MA-dependent compared to control participants. The volumetric gain in the right putamen remained significant after Bonferroni correction, and was inversely correlated with the number of errors (standardised z-scores) on the Go/No-go task. MA-dependent participants exhibited cortical GM deficits in the left superior frontal and precentral gyri in comparison to control participants, although these findings did not survive correction for multiple comparisons. In conclusion, consistent with findings from previous studies of abstinent users, active chronic MA-dependent participants showed significant striatal enlargement which was associated with improved performance on the Go/No-go, a cognitive task of response inhibition and impulsivity. Striatal enlargement may reflect the involvement of neurotrophic effects, inflammation or microgliosis. However, since it was associated with improved cognitive function, it is likely to reflect a compensatory response to MA-induced neurotoxicity in the striatum, in order to maintain cognitive function. Follow-up studies are recommended to ascertain whether this effect continues to be present following abstinence. Several factors may have contributed to the lack of more substantial cortical and subcortical GM changes amongst MA-dependent participants, including variability in MA exposure variables and difference in abstinence status from previous studies.

Glutamatergic Neurometabolites in Clozapine- Responsive and -Resistant Schizophrenia

Background: According to the current schizophrenia treatment guidelines, 3 levels of responsiveness to antipsychotic medication exist: those who respond to first-line antipsychotics, those with treatment-resistant schizophrenia who respond to clozapine, and those with clozapine-resistant or ultra-treatment resistant schizophrenia. Proton magnetic resonance spectroscopy studies indicate that antipsychotic medication decreases glutamate or total glutamate + glutamine in the brains of patients with schizophrenia and may represent a biomarker of treatment response; however, the 3 levels of treatment responsiveness have not been evaluated. Methods: Proton magnetic resonance spectroscopy spectra were acquired at 3 Tesla from patients taking a second generation non-clozapine antipsychotic (first-line responders), patients with treatment-resistant schizophrenia taking clozapine, patients with ultra-treatment resistant schizophrenia taking a combination of antipsychotics, and healthy comparison subjects. Results: Group differences in cerebrospinal fluid-corrected total glutamate + glutamine levels scaled to creatine were detected in the dorsolateral prefrontal cortex [df(3,48); F = 3.07, P = .04, partial η2 = 0.16] and the putamen [df(3,32); F = 2.93, P = .05, partial η2 = 0.22]. The first-line responder group had higher dorsolateral prefrontal cortex total glutamate + glutamine levels scaled to creatine than those with ultra-treatment resistant schizophrenia [mean difference = 0.25, standard error = 0.09, P = .04, family-wise error-corrected]. Those with treatment-resistant schizophrenia had higher total glutamate + glutamine levels scaled to creatine in the putamen than the first-line responders (mean difference = 0.31, standard error = 0.12, P = .05, family-wise error-corrected) and those with ultra-treatment-resistant schizophrenia (mean difference = 0.39, standard error = 0.12, P = .02, family-wise error-corrected). Conclusions: Total glutamate + glutamine levels scaled to creatine in the putamen may represent a marker of response to clozapine. Future studies should investigate glutamatergic anomalies prior to clozapine initiation and following successful treatment.

Neuropsychological performance of methadone-maintained opiate users

Methadone maintenance treatment (MMT) has been used to treat opiate dependence since the mid-1960s. Previous studies have investigated the effects of methadone on cognitive function however the findings have been inconsistent. Some report a complete absence of deficits while others report different types of cognitive impairment. Our research aimed to investigate the effects of MMT on cognitive function by comparing the performance of patients currently enrolled in MMT (n=32) with opiate-dependent subjects (n=17) and healthy control subjects (n=25) on a computerised neuropsychological test battery. Both the patients undertaking MMT and the opiate users showed less efficient interaction between visual searching and manually connecting digits and letters during the Switching of Attention Task than the healthy control subjects (F(2,64)=3.25, p=0.05), which indicates deficits in information processing. Nevertheless, the performance of the MMT group was similar to that of healthy control subjects in all other tasks, in contrast to the group of opiate users who performed poorly when compared to healthy control subjects during tests of attention (mean difference (MD)=2.8, 95% confidence interval (CI) (0.9–4.7), p=0.001) and executive function (MD=5.9, 95% CI (1.3–10.5), p=0.007). These findings suggest that cognitive function in patients undertaking MMT is improved compared to those dependent on illicit opiates.

Methadone maintenance treatment and cognitive function: a systematic review.

Methadone has been used as a pharmacotherapy for the treatment of opiate dependence since the mid-1960s. Many studies examining the benefits of methadone maintenance treatment (MMT) for opiate dependence have documented a significant reduction in both criminal behavior and the use of other opiates. Nevertheless, emerging evidence suggests that MMT may impair cognitive function. However, it is unclear as to the part methadone dose, duration of MMT or plasma level may play in any observed deficits. Given the large number of people enrolled in MMT world-wide and the potential for deficits in cognitive function, a systematic review of the research investigating the association between MMT and cognitive function seemed warranted. The following databases were searched with a combination of free-text and thesaurus terms (methadone AND cognition): MEDLINE In-Process, EMBASE, PsycINFO and EBM Reviews-Cochrane Central Register of Controlled Trials. Seventy-eight articles were retrieved of which 35 met the inclusion criteria. The majority of research suggests that MMT is associated with impaired cognitive function and that deficits extended across a range of domains. However, caution is required when interpreting these results due to the methodological limitations associated with many studies. Further research that includes a combination of psychological and physiological measures within well-controlled group comparison studies is required to more accurately assess which cognitive domains are affected.