European Neuropsychopharmacology (v.19, #8)

Contents (OBC).

Cannabinoid ligands have wide ranging neural and behavioral effects; therefore, they are of substantial therapeutic interest. The levels of cannabinoids are tightly controlled in brain infusion and in vitro methodologies, although the studied dose-ranges are extremely wide (e.g. 0.4–470 nmol in brain infusion studies). The brain levels reached after systemic administration are virtually unknown. To investigate this issue, we injected intraperitoneally 3H-labeled WIN-55,212 and SR141716A (0.3, 1 and 3 mg/kg) and estimated their accumulation in the blood, adipose tissue and brain. Accumulation was dose-dependent. The largest amounts were found in the adipose tissue, while the levels seen in the blood and brain were approximately similar. The accumulation of SR141716A was markedly more pronounced than that of WIN-55,212 in all three tissues. The brain distribution of WIN-55,212 showed large regional differences. Such differences were significant but much smaller with SR141716A. The largest brain levels noticed after intraperitoneal injections did not exceed 2.5 nmol/g. This is larger than the brain level of the endocannabinoid anandamide but smaller than that of 2-arachidonoyl glycerol. Yet, the CB1 receptor affinity of WIN-55,212 and SR-141716A is two orders of magnitude larger than that of 2-arachidonoyl glycerol, suggesting that the exogenously administered compounds were functionally more active. Our findings also suggest that brain infusion and in vitro techniques employing considerably larger doses than 2.5 nmol should be dealt with caution. It appears that measuring brain levels after systemic injections increases our understanding of cannabinoid effects, and provides important clues for the comparison of results obtained with different methodologies.
Keywords: WIN-55,212; SR-141716A; Concentration; Brain; Levels; Mice;

Tolerability of outpatient antipsychotic treatment: 36-month results from the European Schizophrenia Outpatient Health Outcomes (SOHO) study by Diego Novick; Josep Maria Haro; Elena Perrin; David Suarez; João Marques Texeira (542-550).
SOHO is a 3-year, prospective, observational study of schizophrenia patients who started a new antipsychotic in 10 European countries. Cohorts of patients were defined according to the antipsychotic started at baseline: olanzapine, risperidone, quetiapine, amisulpride, clozapine, oral typical and depot typical antipsychotics. Tolerability in terms of rates of extrapyramidal symptoms (EPS), tardive dyskinesia (TD), anticholinergic use, loss of libido/impotence, amenorrhoea/galactorrhoea/gynaecomastia, and weight change was assessed in 4939 patients who started monotherapy. Logistic regression models related medication initiated at study entry to adverse events over follow-up, adjusting by baseline differences among treatment cohorts. Patients taking typical antipsychotics or risperidone were more likely to experience EPS and TD during follow-up than patients taking olanzapine. Patients taking olanzapine were less likely to have loss of libido/impotence during follow-up than patients in the risperidone, amisulpride, clozapine, oral typical and depot typical cohorts. Weight gain occurred in all groups, but was greater with olanzapine. In conclusion, antipsychotics have different tolerability profiles in terms of the adverse events we monitored. Results should be interpreted conservatively due to the observational study design.
Keywords: Tolerability; Atypical antipsychotic; Schizophrenia; Extrapyramidal side-effects; Weight;

Hippocampal nAChRs mediate nicotine withdrawal-related learning deficits by Jennifer A. Davis; Thomas J. Gould (551-561).
Nicotine modulation of learning may contribute to its abuse liability. The role of hippocampal nicotinic acetylcholine receptors (nAChRs) in the effects of acute, chronic and withdrawal from chronic nicotine on learning was assessed via intrahippocampal drug infusion in mice. Acute dorsal hippocampal nicotine infusion enhanced contextual fear conditioning. Conversely, chronic intrahippocampal infusion of a matched dose had no effect, and withdrawal from chronic infusion impaired learning. Thus, hippocampal functional adaptation, evidenced by learning deficits during abstinence, occurs with the transition from acute to chronic nicotine exposure. To investigate which hippocampal nAChRs mediate these adaptations, C57BL/6, β2 nAChR subunit knockout (KO), and wildtype (WT) mice treated chronically with systemic nicotine received intrahippocampal dihydro-β-erythroidine (a high affinity nAChR antagonist). Intrahippocampal dihydro-β-erythroidine precipitated learning deficits in all but the KO mice. Therefore, the action of nicotine at hippocampal β2⁎ nAChRs mediates adaptations in hippocampal function that underlie withdrawal deficits in contextual fear conditioning.
Keywords: Nicotine;; Withdrawal;; Hippocampus;; Learning;; Nicotinic acetylcholine receptors;; Dihydro-β-erythroidine;; Addiction;; Cognition;

Immediate versus gradual suspension of previous treatments during switch to aripiprazole: Results of a randomized, open label study by Chi-Un Pae; Alessandro Serretti; Alberto Chiesa; Laura Mandelli; Changuk Lee; Chul Lee; Jungjin Kim; Diana De Ronchi; In-Ho Paik (562-570).
The aim of the present work was to investigate possible differences in terms of efficacy and tolerability between different switching options to aripiprazole. 77 subjects were randomly assigned to (1) administration of aripiprazole (10 mg) with simultaneous discontinuation of current antipsychotic; (2) administration of aripiprazole (10 mg) and tapering off current antipsychotic over 4 weeks with half dose after the first 2 weeks; (3) administration of aripiprazole (10 mg) and tapering off current antipsychotic over 6 weeks with half dose after the first 2 weeks. Efficacy assessments included CGI-S, CGI-I, BPRS and SANS. Safety assessments included SAS, BAS and AIMS. Severity of symptoms significantly decreased from baseline over the 12 weeks of treatment. Patients switched to aripiprazole with immediate discontinuation of the previous antipsychotic showed an increase of symptoms' severity at week 1. However, severity of side effects did not overall change significantly during the 12-weeks follow-up. Previous treatment's tapering off strategy for switching patients to aripiprazole could be preferable as compared to abrupt discontinuation, in order to prevent early worsening of symptoms and premature discontinuation of treatment, though this results has to be considered with caution given the limitations of the study.
Keywords: Switch; Anti-psychotics; Aripiprazole; Schizophrenia;

The specific glycine transporter 1 (GlyT1) inhibitor, SSR504734, is highly effective in enhancing N-methyl-d-aspartate receptor (NMDAR) function by elevating the availability of the NMDAR co-agonist, glycine, in the vicinity of NMDAR-containing glutamatergic synapses. According to the glutamatergic hypofunction hypothesis of schizophrenia, SSR504734 may therefore possess antipsychotic potential. Here, we evaluated the effects of SSR504734 in response to three psychomimetic drugs: phencyclidine, amphetamine, and apomorphine in male C57BL/6 mice. SSR504734 attenuated phencyclidine-induced (5 mg/kg, i.p.) hyperlocomotion, but potentiated the motor stimulant and motor depressant effects of amphetamine (2.5 mg/kg, i.p.) and apomorphine (0.75 mg/kg, s.c.), respectively. Hence, SSR504734 not only confers resistance to NMDAR blockade, but also enhances the locomotor response to dopaminergic stimulation. The latter finding adds to reports that SSR504734 may modulate dopamine-mediated behaviour by interference with normal glutamate-dopamine interaction. The specificity of this action of SSR504734 will be highly relevant to its potential application as an antipsychotic agent.
Keywords: Amphetamine;; Antipsychotic;; Dopamine;; Glycine;; NMDA;; Schizophrenia;

Following the findings of perceived poor sleep and of chronic pain among former heroin addicts, current methadone maintenance treatment (MMT) patients, and its possible relation to methadone dose, we studied these patients' objective sleep parameters. Former heroin addicts maintained on “Low” (n  = 19, < 80 mg/d) or “High” (n  = 25, > 150 mg/d) methadone doses, underwent one-night polysomnography (PSG). Patients filled Pittsburgh Sleep Quality Index (PSQI) and chronic pain questionnaires, and current drug abuse was assessed by urine tests.Of the 44 patients, 18 (40.9%) had chronic pain, while 24 (54.5%) abused BDZ. “High” vs. “Low” methadone dose groups had more years of opiate abuse and lower % of NREM (non rapid eye movement) deep sleep (stages 3–4) with no other differences between groups. Years of opiate abuse and NREM stages 3–4 inversely correlated (R  = − 0.34, p  = 0.03). Chronic vs. non-chronic pain patients had lower sleep efficiency and sleep time, and higher wake stage. BDZ abusers vs. no-BDZ abusers had shorter % of NREM stages 3–4, shorter REM % and longer % of NREM light sleep (stage 2). Perceived sleep (as assessed by the PSQI) was worse among the chronic pain group and among the BDZ abusers.Patients with chronic pain or BDZ abuse presented both perceived and objective poorer sleep, regardless of methadone dosage. Sleep evaluation and treatment should address these two prevalent conditions in order to improve MMT patients' quality of sleep (and of life) and overall treatment outcome.
Keywords: Polysomnography (PSG); Chronic pain; Methadone maintenance treatment; Opiate abuse; Benzodiazepine abuse;

Modulation of sickness behavior by sleep: The role of neurochemical and neuroinflammatory pathways in mice by Adriano Zager; Monica L. Andersen; Marcelo M.S. Lima; Angela B. Reksidler; Ricardo B. Machado; Sergio Tufik (589-602).
Activation of the immune system elicits several behavioral changes that are collectively called sickness behavior and consists in a strategy to overcome infection. Sleep deprivation can increase susceptibility to pathogens and to behavioral alterations. Thus, the present study aimed to determine how paradoxical sleep deprivation (PSD) affects the behavioral and neurochemical responses to lipopolysaccharide (LPS, potent activator of the immune response). Adult inbred mice were paradoxical sleep deprived (72 h), whereas the control group was kept in their home cages. Both groups received either an injection of saline or LPS (5, 10 or 20 µg/animal ip) before behavioral tasks and tissue collection. During the recovery sleep period, LPS provoked a strong inhibition of sleep rebound due to a suppression of paradoxical sleep. PSD increased the susceptibility of mice to LPS-induced immobility in the open field, which was capable of affecting the anxiety-like behavior also. These altered behavioral responses to LPS were accompanied by reduction in dopamine turnover within the striatum and increased expression of cyclooxygenase-2 in the cortex. The study provides some insights into how the sleep–wake cycle affects the expression of sickness behavior induced by LPS.
Keywords: Sickness behavior; Paradoxical sleep deprivation; Lipopolysaccharide; Locomotion; Dopamine; Cyclooxygenase-2;

Psychopharmacology for children: From off label use to registration by Tamar Wohlfarth; Luuk Kalverdijk; Carin Rademaker; Patricia Schothorst; Ruud Minderaa; Christine Gispen-de Wied (603-608).
Pharmacological treatment of children and adolescents is largely based on evidence from adults' studies. There is, however, growing awareness that this evidence cannot simply be extrapolated to children. The Dutch Medicines Evaluation Board (MEB) in collaboration with the Child and Adolescent section of the Dutch Association of Psychiatry and the National Expertise Centre Child and Adolescent Psychiatry have organised a workshop to discuss the kind of evidence that would be necessary and the methods involved. There was consensus about the need to demonstrate efficacy in targeted disorders as well as symptoms within specific disorders and about the need for separate evidence for children and for adolescents. In addition, too little is known about safety, especially long-term safety, as consequences of treatment. Main issues are effects on growth, cognitive, motor, emotional, and sexual development, metabolic symptoms, cardiotoxicity, and dependence. Specific methodological issues were discussed, such as the role of different informants and the high rate of comorbidity.
Keywords: Children; Adolescents; Psychopharmacology; Treatment; Pharmacokinetic; Pharmacodynamic;