Journal of Psychopharmacology

Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor (D1R) signaling in the cortex, where D1Rs predominate, in patients with schizophrenia (SCZ), which may contribute to their cognitive deficits. Furthermore, studies in nonhuman primates (NHP) have suggested that intermittent administration of low doses of D1R agonists produce long-lasting reversals in cognitive deficits. The purpose of this trial was to test whether a similar design, involving subacute intermittent administration of low doses of a full, selective agonist at D1Rs, DAR-0100A, would improve cognitive deficits in SCZ.

We randomized 49 clinically stable individuals with SCZ to three weeks of intermittent treatment with 0.5 mg or 15 mg of DAR-0100A, or placebo (normal saline). Functional magnetic resonance imaging (fMRI) BOLD was used to evaluate the effects of drug administration on brain activity during a working memory (WM) task. Effects on cognition were also assessed using the MATRICS and the N-back task as primary endpoints. The CogState battery was used as a secondary endpoint.

There were no observed treatment effects on either the BOLD fMRI signal during WM tasks or the WM domains of the MATRICS. Moderate improvement was detected on the CogState battery and on the attention domain of the MATRICS.

These results suggest that low doses of D1 agonists that do not result in measureable occupancy of the D1R do not reliably improve cognition in SCZ, unlike the observations in NHP. As this drug is limited by its pharmacokinetic profile, better D1R agonists that can achieve adequate levels of D1R occupancy are needed to test the efficacy of this mechanism for cognitive enhancement in SCZ.

Antipsychotic polypharmacy (APP) is commonly used in schizophrenia despite a lack of robust evidence for efficacy, as well as evidence of increased rates of adverse drug reactions and mortality.

We sought to examine APP and the use of other adjunctive medications in patients with treatment-resistant schizophrenic disorders (ICD-10 diagnoses F20–F29) immediately prior to clozapine initiation, and to investigate clinical and sociodemographic factors associated with APP use in this setting.

Analysis of case notes from 310 patients receiving their first course of clozapine at the South London and Maudsley NHS Trust (SLaM) was undertaken using the Clinical Record Interactive Search (CRIS) case register. Medication taken immediately prior to clozapine initiation was recorded, and global clinical severity was assessed at time points throughout the year prior to medication assessment using the Clinical Global Impression – Severity scale (CGI-S). Logistic regression was used to investigate factors associated with APP.

The point prevalence of APP prior to clozapine initiation was 13.6% (n=42), with 32.6% of subjects prescribed adjuvant psychotropic medications. APP was associated with increasing number of adjuvant medications (odds ratio (OR) 1.97, 95% confidence interval (CI) 1.27–3.06), concurrent depot antipsychotic prescription (OR 2.64, CI 1.24–5.62), concurrent antidepressant prescription (OR 4.40, CI 1.82–10.63) and a CGI-S over the previous year within the two middle quartiles (Quartile 2 vs 1 OR 6.19, CI 1.81–21.10; Quartile 3 vs 1 OR 4.45, CI 1.29–15.37; Quartile 4 vs 1 OR 1.88, CI 0.45–7.13).

APP and augmentation of antipsychotics with antidepressants, mood stabilizers and benzodiazepines are being employed in treatment-resistant schizophrenia prior to clozapine. The conservative APP rate observed may have been influenced by an initiative within SLaM that reduced APP rates during the study window. Efforts to reduce the use of poorly evidenced prescribing should focus on adjuvant medications as well as APP.

Intra-individual variability in reaction time (IIV-RT) is common in individuals with attention-deficit/hyperactivity disorder (ADHD). It can be improved by stimulants. However, the effects of atomoxetine on IIV-RT are inconclusive. We aimed to investigate the effects of atomoxetine on IIV-RT, and directly compared its efficacy with methylphenidate in adults with ADHD.

An 8–10 week, open-label, head-to-head, randomized clinical trial was conducted in 52 drug-naïve adults with ADHD, who were randomly assigned to two treatment groups: immediate-release methylphenidate (n=26) thrice daily (10–20 mg per dose) and atomoxetine once daily (n=26) (0.5–1.2 mg/kg/day). IIV-RT, derived from the Conners’ continuous performance test (CCPT), was represented by the Gaussian (reaction time standard error, RTSE) and ex-Gaussian models (sigma and tau). Other neuropsychological functions, including response errors and mean of reaction time, were also measured. Participants received CCPT assessments at baseline and week 8-10 (60.4±6.3 days).

We found comparable improvements in performances of CCPT between the immediate-release methylphenidate- and atomoxetine-treated groups. Both medications significantly improved IIV-RT in terms of reducing tau values with comparable efficacy. In addition, both medications significantly improved inhibitory control by reducing commission errors.

Our results provide evidence to support that atomoxetine could improve IIV-RT and inhibitory control, of comparable efficacy with immediate-release methylphenidate, in drug-naïve adults with ADHD. Shared and unique mechanisms underpinning these medication effects on IIV-RT awaits further investigation.

Smoking cessation aids appear to be limited in their ability to prevent craving triggered by exposure to smoking-associated stimuli; however, the extent to which cue-induced cravings persist following denicotinized or nicotine-containing tobacco smoking is not known.

Thirty (17 male) ⩾12-hour abstinent dependent smokers completed two sessions during which they smoked a nicotine-containing or denicotinized cigarette. Instructions regarding the nicotine content of the cigarette varied across sessions, and all participants were exposed to a neutral cue followed by a smoking cue after cigarette consumption. Craving was assessed before and after cigarette consumption and cue exposure.

Reduced intentions to smoke were associated with both nicotine expectancy (p<0.05) and nicotine administration (p<0.01), while reduced withdrawal-related craving was uniquely associated with nicotine administration (p<0.05). Smoking-associated stimuli increased craving regardless of nicotine expectancy or administration (p-values<0.001).

While both nicotine pharmacology and expectancy appear to contribute to craving reduction associated with acute tobacco smoking, neither smoking-related nicotine administration nor expectation prevents increases in craving following exposure to smoking-associated stimuli. These findings suggest that cue-induced craving may be resistant to various pharmacological and psychological interventions.