European Neuropsychopharmacology (v.21, #6)

Contents (OBC).

Review of atypical antipsychotics in anxiety by Nienke C.C. Vulink; Martijn Figee; Damiaan Denys (429-449).
Atypical antipsychotics are increasingly used for treatment of anxiety disorders, either in mono- or combination therapy. This is the first review reporting on the use of atypical antipsychotics in monotherapy or augmentation in patients with primary anxiety disorders or anxiety (disorders) comorbid to schizophrenia, bipolar disorder (BPD) and major depressive disorder (MDD). We included 49 open-label trials, 32 randomized, placebo-controlled trials (RCTpls) and five randomized controlled trials without placebo arm with almost 6000 patients (open-label: 1710, randomized: 4145). An increasing number of RCTpls show promising results in 27–71% of patients with primary or comorbid anxiety disorders who were treated with monotherapy atypical antipsychotics or augmentation therapy. However, methodological flaws of included studies may limit conclusions of this review and larger placebo-controlled trials are warranted comparing standard treatment with monotherapy and augmentation therapy of atypical antipsychotics and placebo. In addition, higher dropout rates and side effects from treatment with atypical antipsychotics may limit the use of atypical antipsychotics in patients with anxiety disorders.
Keywords: Atypical antipsychotics; Anxiety disorders; Obsessive–compulsive disorder;

Sodium oxybate in maintaining alcohol abstinence in alcoholic patients with and without psychiatric comorbidity by Fabio Caputo; Sara Francini; Romeo Brambilla; Federica Vigna-Taglianti; Michela Stoppo; Arfedele Del Re; Lorenzo Leggio; Giovanni Addolorato; Giorgio Zoli; Mauro Bernardi (450-456).
Sodium oxybate (SMO) is a GABA-ergic drug currently used for the treatment of alcohol-dependence in some European countries. In particular, clinical studies have shown a role of SMO in promoting alcohol abstinence, as well as in relieving withdrawal symptoms. The aim of this study was to describe alcohol abstinence and the onset of craving for and abuse of SMO in alcohol-dependent subjects with and without psychiatric co-morbidity. Forty-eight patients were enrolled and classified into two groups: group A (20 alcoholics without any psychiatric co-morbidity) and group B (28 alcoholics with a psychiatric co-morbidity). All patients were treated with oral SMO (50 mg/kg of body weight t.i.d.) for 12 weeks. Alcohol abstinence as well as alcohol drinking during the 12 weeks of treatment did not differ between the two groups at the end of treatment (p = 0.9). In addition, a reduction of alcohol intake in both groups has been observed (p < 0.0001). On the other hand, craving for SMO was significantly more frequent in group B than group A (p = 0.001). Cases of SMO abuse were observed in almost 10% of group B patients. In conclusion, alcohol abstinence achieved through SMO administration does not differ in patients with and without psychiatric co-morbidity. However, alcoholics with co-morbid borderline disorders appear to be at high risk of developing craving for and abuse of the drug; therefore, SMO may not be indicated in these patients.
Keywords: Alcohol-dependence; Alcohol pharmacotherapy; Sodium oxybate; Psychiatric co-morbidity; Craving for and abuse of sodium oxybate;

Dysfunction of GABAergic transmission related to abnormal expression of GABAA receptor subunits in specific brain regions underlies some pathological anxiety states. Besides involvement of the benzodiazepine recognition site of GABAA receptor in the expression of anxiety-like behaviour, the roles of the β23 subunits are not well characterized. To address this issue, the experimental design of this study utilized the GABAergic compound etifoxine (with a preferential effectiveness after binding to a specific site at β23 subunits) tested in two inbred mouse strains: BALB/cByJ and C57BL/6J mice using three behavioural paradigms (light/dark box, elevated plus maze and restraint stress-induced small intestinal transit inhibition) and the t-butylbicyclophosphorothionate-induced convulsions model. Etifoxine plasma and brain levels and β23 mRNAs and protein expression levels in various brain regions were compared between the two strains. The two mouse strains differed markedly in basal anxiety level. Etifoxine exhibited more pronounced anxiolytic and anticonvulsant effects in the BALB/cByJ mice compared to the C57BL/6J mice. The etifoxine brain/plasma ratios of the two strains were not different. Beta2 subunit mRNA and protein expression levels were around 25 and 10% higher respectively in the anterodorsal nucleus of the thalamus and the CA3 field of hippocampus of BALB/cByJ mice compared to C57BL/6J mice. Beta3 subunit mRNA and protein expression levels did not differ between the two strains. Based on these results, it is suggested that overexpression of GABAA receptor β2 subunit in BALB/cByJ mice relative to C57BL/6j mice contributes to the dysfunction in GABAA transmission in regions of brain known to regulate responses to stress. The dysregulated GABAA function in BALB/cByJ mice may be corrected by the administration of etifoxine.
Keywords: Anxiety-related behaviour; Anticonvulsant; GABAA receptor Beta2/3 subunits; Papez circuit; Etifoxine; Mouse strains;

Social isolation rearing (SIR) in rats induces behavioral and glutamatergic changes akin to schizophrenia. We studied the effects of 8 weeks SIR on cortico-striatal redox and social and cognitive behaviors in rats. SIR increased superoxide dismutase activity, decreased oxidized:reduced glutathione ratio and increased lipid peroxidation in both brain regions, and induced deficits in prepulse inhibition and social and self-directed interactive behaviors. Both behavioral and cortico-striatal redox disturbances were corrected by clozapine (5 mg/kg/day × 11 days). Behavioral changes evoked by SIR are associated with cortico-striatal oxidative stress that is reversed by clozapine treatment, providing novel insight into the neurobiology and treatment of schizophrenia.
Keywords: Social isolation;; Prepulse inhibition;; Social interaction;; Clozapine;; Schizophrenia;; Animal model;; Oxidative stress;

Neurokinin-3 receptors (NK3-R) are localized in brain regions which have been implicated in processes governing learning and memory as well as emotionality. The effects of acute subcutaneous (s.c.) senktide (0.2 and 0.4 mg/kg), a NK3-R agonist, were tested in aged (23–25 month old) Wistar rats: (a) in an episodic-like memory test, using an object discrimination task (this is the first study to test for deficits in episodic-like memory in aged rats, since appropriate tests have only recently became available); (b) on parameters of anxiety in an open field test, (c) on indices of depression in the forced swimming test and (d) on the activity of cholinergic neurons of the basal forebrain, using in vivo microdialysis and HPLC. Neither the saline-, nor senktide-treated aged animals, exhibited episodic-like memory. However, the senktide-, but not the vehicle-treated group, exhibited object memory for spatial displacement, a component of episodic memory. Senktide injection also had anxiolytic- and antidepressant-like effects. Furthermore, the active doses of senktide on behavior increased ACh levels in the frontal cortex, amygdala and hippocampus, suggesting a relationship between its cholinergic and behavioral actions. The results indicate cholinergic modulation by the NK3-R in conjunction with a role in the processing of memory and emotional responses in the aged rat.
Keywords: Aging; Neurokinin; NK3 receptor agonist; Episodic-like memory; Open field; Forced swimming test; Anxiety; Antidepressant-like; In vivo microdialysis; Acetylcholine;