European Neuropsychopharmacology (v.19, #1)

Contents (OBC).

BL-1020: A novel antipsychotic drug with GABAergic activity and low catalepsy, is efficacious in a rat model of schizophrenia by Yona Geffen; Abraham Nudelman; Irit Gil-Ad; Ada Rephaeli; Mei Huang; Kinneret Savitsky; Leah Klapper; Ilan Winkler; Herbert Y. Meltzer; Abraham Weizman (1-13).
Reduced brain γ-amino-butyric acid (GABA) participates in the pathogenesis of schizophrenia. GABA scarcely penetrates the brain. We evaluated the pharmacological properties of BL-1020, a novel GABA ester of perphenazine. Oral BL-1020 or perphenazine were assessed in acute and subchronic schizophrenia rat models. Catalepsy, serum prolactin, receptor binding profile and cortical (PFC), hippocampal (Hip) and dopamine (DA) levels were determined. Radioactive [14C] labeled BL-1020 was used for pharmacokinetics (PK). Acute and subchronic treatment with BL-1020 antagonized amphetamine-induced hyperactivity, with significantly lower catalepsy and sedation compared to equimolar perphenazine. At the same time, BL-1020 increased DA release in the PFC and Hip. BL-1020 and perphenazine stimulated prolactin secretion equally. BL-1020 displayed strong DA and serotonin (5HT) receptor inhibition (D2L K iz  = 0.066 nM, D2S K i  = 0.062 nM, 5-HT2A K i  = 0.21 nM). PK data revealed that BL-1020 penetrated the brain. Conclusions: The advantages of BL-1020 for treatment of schizophrenia stem from its being a DA/5HT antagonist and a GABAergic agsonist that releases cortical DA and antagonizes amphetamine-induced hyperactivity with reduced catalepsy and sedation
Keywords: Schizophrenia; Antipsychotics; GABA; Dopamine; Serotonin; Perphenazine;

Improvement of aggressive behavior and quality of life impairment following S-Adenosyl-Methionine (SAM-e) augmentation in schizophrenia by Rael D. Strous; Michael S. Ritsner; Shmuel Adler; Yael Ratner; Rachel Maayan; Moshe Kotler; Herbert Lachman; Abraham Weizman (14-22).
S-Adenosyl-Methionine (SAM-e), functions as a primary methyl group donor for several metabolic compounds. Since SAM-e is involved in several metabolic processes, its administration may have a role in the amelioration of several disorders. In addition, SAM-e increases catechol-O-methyltransferase (COMT) enzyme activity, which may ameliorate aggressive symptoms in certain patients. We have therefore investigated the efficacy of SAM-e in managing schizophrenia symptomatology in patients with the low activity COMT polymorphism. Eighteen patients with chronic schizophrenia were randomly assigned to receive either SAM-e (800 mg) or placebo for 8 weeks in double-blind fashion. Results indicated some reduction in aggressive behavior and improved quality of life following SAM-e administration. Female patients showed improvement of depressive symptoms. Clinical improvement did not correlate with serum SAM-e levels. Two patients receiving SAM-e exhibited some exacerbation of irritability. This preliminary pilot short-term study cautiously supports SAM-e as an adjunct in management of aggressive behavior and quality of life impairment in schizophrenia.
Keywords: S-Adenosyl-Methionine (SAM-e); Schizophrenia; COMT; Psychosis;

Though D3 receptor antagonists can enhance cognitive function, their sites of action remain unexplored. This issue was addressed employing a model of social recognition in rats, and the actions of D3 antagonists were compared to D1 agonists that likewise possess pro-cognitive properties. Infusion of the highly selective D3 antagonists, S33084 and SB277,011 (0.04–2.5 µg/side), into the frontal cortex (FCX) dose-dependently reversed the deficit in recognition induced by a delay. By contrast, the preferential D2 antagonist, L741,626 (0.63–5.0) had no effect. The action of S33084 was regionally specific inasmuch as its injection into the nucleus accumbens or striatum was ineffective. A similar increase of recognition was obtained upon injection of the D1 agonist, SKF81297 (0.04–0.63), into the FCX though it was also active (0.63) in the nucleus accumbens. These data suggest that D3 receptors modulating social recognition are localized in FCX, and underpin their pertinence as targets for antipsychotic agents.
Keywords: D3 receptor; D1 receptor; Social recognition; Frontal cortex; Nucleus accumbens; Striatum;

Substantial and highly variable placebo response rates represent a major obstacle to antidepressant development in major depressive disorder (MDD). However, whether the likelihood of receiving active treatment or placebo, a proxy of the degree of expectation of improvement, may itself influence clinical trial outcome is unclear. The goal of this work was to examine whether the probability of receiving placebo influences clinical trial outcome antidepressant MDD trials. Medline/Pubmed publication databases were searched for randomized, double-blind, placebo-controlled trials of antidepressants for adults with MDD. 146 manuscripts involving 182 clinical trials were pooled (n = 36,385). Pooled response rates for drug and placebo were 53.8% and 37.3%. A meta-regression (random-effects) established that the probability of receiving placebo, year of publication, and baseline severity were independent predictors of the risk ratio of responding to antidepressants versus placebo. Specifically, a greater probability of receiving placebo, greater baseline severity and an earlier year of publication predicted greater antidepressant-placebo “efficacy separation”. Fixed versus flexible dose design, trial duration and population age did not influence clinical trial outcome.
Keywords: Antidepressant; Placebo; Major; Depressive; Disorder; Adults;

Antidepressants alleviate the impact of reinforcer downshift by Agnieszka Nikiforuk; Piotr Popik (41-48).
Depressive disorder is associated with problems of coping with life's difficulties, including episodes of frustration and disappointment, operationally defined as an unexpected reinforcer omission or a reduction of reinforcer magnitude. In a novel model aimed at detecting potential antidepressants, rats were trained in the operant task under progressive ratio schedule of reinforcement with the break point (BP, the value of the last completed response ratio) as a behavioral endpoint. In the main experiment, a 32% sucrose solution was initially used as the reinforcer. Once the stable responding was achieved, for the following 5 days animals were treated once daily with the experimental drugs, and were offered a 4% sucrose solution instead. In vehicle-treated controls, the reduction of sucrose concentration resulted in a decrease in responding from a BP of about 40 (totaling 166 responses) to a BP of about 9 (totaling 22 responses). Chlordiazepoxide (4 and 8 mg/kg), fluoxetine (3 mg/kg), citalopram (6 mg/kg) and cocaine (2.5 and 5 mg/kg) markedly inhibited this response decrement, while fluoxetine (6 mg/kg) augmented it. Neither desipramine (1–6 mg/kg) nor morphine (1–5 mg/kg) affected responding under the reduced sucrose concentration condition. In the control experiment, the rats have never been offered 32% sucrose solution but their responding was always maintained by 4% sucrose. Under these unchanged conditions, only cocaine (5 mg/kg) affected (increased) responding. The present results suggest that the antidepressants selectively inhibiting serotonin reuptake and a benzodiazepine anxiolytic but not psychostimulant cocaine may specifically protect animals from the effects of a reinforcer downshift.
Keywords: Antidepressants;; Depression;; Motivation;; Operant behavior;; Reinforcement schedule;; Sucrose;; Rat;

Neurosteroid blood levels in delinquent adolescent boys with conduct disorder by Pavel Golubchik; Tamar Mozes; Rachel Maayan; Abraham Weizman (49-52).
Accumulating data indicates that neurosteroids can modulate aggressive behavior. The aim of the present study was to examine neurosteroid blood levels in delinquent adolescent boys as compared to normal healthy controls. Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) and cortisol blood levels were measured in 16 delinquent adolescent (age 15.72 ± 0.95 years) with conduct disorder (CD) and 11 normal controls (16.82 ± 1.83 years). Severity of aggressive behavior was assessed by the Child Behavior Checklist (CBCL) and the Overt Aggression Scale (OAS). The delinquent adolescents tended to have higher DHEA-S levels than the normal control group (p  = 0.054). DHEA and cortisol levels did not differ between the two groups. The interaction between neurosteroids ( especial DHEA-S) and genetic, developmental and environmental factors in juvenile delinquency merits further investigation.
Keywords: Aggression; Cortisol; Dehydroepiandrosterone (DHEA); Dehydroepiandrosterone sulfate (DHEA-S); Juvenile delinquency; Neurosteroids;

Dopaminergic and serotonergic activity in neostriatum and nucleus accumbens enhanced by intranasal administration of testosterone by M.A. de Souza Silva; C. Mattern; B. Topic; T.E. Buddenberg; J.P. Huston (53-63).
Testosterone was administered intranasally in anesthetized male rats, and its effects on the activity of dopaminergic and serotonergic neurons in the neostriatum and nucleus accumbens were assessed by means of microdialysis and HPLC. The treatment (0.5, 1.0 or 2.0 mg/kg of testosterone or vehicle, 10 µl volume) was applied in both nostrils, half (5 µl) into each. Subcutaneous injections of testosterone (2.0, 4.0 or 8.0 mg/kg) or vehicle were tested in other subjects. Samples were collected for 5 h. In the neostriatum, an increase of dopamine occurred after 2.0 mg/kg. Serotonin levels increased after 1.0 mg/kg dose. In the nucleus accumbens, dopamine and serotonin increased after 1.0 mg/kg and 2.0 mg/kg doses. Subcutaneous administration of 8.0 mg/kg testosterone increased dopamine and serotonin in the neostriatum only. We conclude that intranasal administration of testosterone is a more efficacious way for targeting the brain than the subcutaneous route, and may be considered as a means to activate central dopaminergic and serotonergic systems.
Keywords: Dopamine; Serotonin; Testosterone; Nucleus accumbens; Neostriatum; Intranasal; Microdialysis;

Interaction between SERTPR and stressful life events on response to antidepressant treatment by Laura Mandelli; Elena Marino; Adele Pirovano; Raffaella Calati; Raffaella Zanardi; Cristina Colombo; Alessandro Serretti (64-67).
A polymorphism within the serotonin transporter gene (SERTPR) has been repeatedly associated to mood disorders and response to SSRIs treatment. Recent evidence suggested that influence of genetic effect of SERTPR might be modulated by stress, particularly as regard the development of anxious–depressive symptoms. Nevertheless, there is no information about the role of stressors as potential modulator of SERTPR effects on depressive outcome during pharmacological treatment. In a sample of 159 mood disorder patients treated with fluvoxamine, we found stressors preceding the onset of the illness significantly influencing the genetic effect exerted by SERTPR on response after 6 weeks of treatment. This preliminary finding supports the idea of complex interaction between biological and environmental factors underlying the efficacy of biological treatments, other than liability for mood disorders. Nevertheless, many limitations characterize the present investigation and well-funded studies on larger samples are required.
Keywords: SERTPR; Response to SSRIs; Stressful life events; Gene x environment interaction;

The dopamine agonist apomorphine differentially affects cognitive performance in alcohol dependent patients and healthy controls by Arnt F.A. Schellekens; Armand W.A.A. van Oosterwijck; Bart Ellenbroek; Cor A.J. de Jong; Jan K. Buitelaar; Lex Cools; Robbert-Jan Verkes (68-73).
Reduced metabolic activity in frontal brain regions, and reduced striatal dopamine receptor densities have been shown in alcohol dependent patients. Little is known on functional changes in the fronto-striatal-thalamic dopaminergic neurocircuitry in these patients. The objective of this study was to assess sensitivity of prefrontal dopamine receptors in alcohol dependent patients.Male alcohol dependent patients (N  = 40) and healthy controls (N  = 39) performed an AX-continuous performance test before and after administration of the DA agonist apomorphine (0.005 mg/kg).At baseline alcohol dependent patients were slower and less accurate compared to healthy controls. After administration of apomorphine, performance improved in alcohol dependent patients and deteriorated in healthy controls.Reduced cognitive performance in alcohol dependent patients compared with healthy controls may indicate dopamine dysfunctioning at the prefrontal level. Improvement of cognitive performance in alcohol dependent patients after administration of apomorphine and deterioration in healthy controls provides evidence for an inverted U-shape relation between dopaminergic functioning and cognitive performance.
Keywords: Alcohol dependence; Dopamine; Cognition; Apomorphine;

Zolpidem-induced amnesia and somnambulism: Rare occurrences? by Jui-Hsiu Tsai; Pinchen Yang; Cheng-Chung Chen; Weilum Chung; Tze-Chun Tang; Shing-Yaw Wang; Jong-Kang Liu (74-76).
Zolpidem, a non-benzodiazepine hypnotic of the imidazopyridine class, is very effective in treating insomnia with previous claims of little adverse effects. However, zolpidem-induced somnambulism and amnesic sleep-related behavioral problems were begun to be reported in literature but no systemic investigation has been undertaken in non-Western cultures. In our current retrospective survey, 5.1% (13 out of 255) of Taiwanese patients reported change in sleep-related behavior as adverse effects. This serves as a reminder for clinicians to inquire regarding any unusual behavior of parasomniac activities when prescribing zolpidem.
Keywords: Zolpidem; Imidazopyridine; Somnambulism;