European Neuropsychopharmacology (v.23, #2)

Contents (OBC).

Testosterone in the brain: Neuroimaging findings and the potential role for neuropsychopharmacology by Peter Höfer; Rupert Lanzenberger; Siegfried Kasper (79-88).
Testosterone plays a substantial role in a number of physiological processes in the brain. It is able to modulate the expression of certain genes by binding to androgen receptors. Acting via neurotransmitter receptors, testosterone shows the potential to mediate a non-genomic so-called “neuroactive effect”. Various neurotransmitter systems are also influenced by the aromatized form of testosterone, estradiol. The following article summarizes the findings of preclinical and clinical neuroimaging studies including structural and functional magnetic resonance imaging (MRI/fMRI), voxel based morphometry (VBM), as well as pharmacological fMRI (phfMRI) and positron emission tomography (PET) regarding the effects of testosterone on the human brain. The impact of testosterone on the pathogenesis of psychiatric disorders and on sex-related prevalence differences have been supported by a wide range of clinical studies. An antidepressant effect of testosterone can be implicitly explained by its effects on the limbic system – especially amygdala, a major target in the treatment of depression – solidly demonstrated by a large body of neuroimaging findings.
Keywords: Testosterone; Brain; Neuroimaging; Sex differences; Androgen; PET; fMRI;

Alcohol consumption is a major risk factor for the burden of disease, and Alcohol Dependence (AD) is the most important disorder attributable to this behavior. The objective of this study was to quantify mortality associated with AD and the potential impact of treatment. For the EU countries, for the age group 15–64 years, mortality attributable to alcohol consumption in general, to heavy drinking, and to AD were estimated based on the latest data on exposure and mortality. Potential effects of AD treatment were modeled based on Cochrane and other systematic reviews of the effectiveness of the best known and most effective interventions. In the EU 88.9% of men and 82.1% of women aged 15–64 years were current drinkers; and 15.3% of men and 3.4% of women in this age group were heavy drinkers. AD affected 5.4% of men and 1.5% of women. The net burden caused by alcohol consumption was 1 in 7 deaths in men and 1 in 13 deaths in women. The majority of this burden was due to heavy drinking (77%), and 71% of this burden was due to AD. Increasing treatment coverage for the most effective treatments to 40% of all people with AD was estimated to reduce alcohol-attributable mortality by 13% for men and 9% for women (annually 10,000 male and 1700 female deaths avoided). Increasing treatment rates for AD was identified as an important issue for future public health strategies to reduce alcohol-attributable harm and to complement the current focus of alcohol policy.
Keywords: Alcohol consumption; Alcohol dependence; Treatment; Mortality; Europe;

Burden of psychiatric disorders in the pediatric population by Antonio Clavenna; Massimo Cartabia; Marco Sequi; Maria Antonella Costantino; Angela Bortolotti; Ida Fortino; Luca Merlino; Maurizio Bonati (98-106).
In order to estimate the burden of mental disorders in a representative Italian pediatric population, an epidemiological study was performed using three administrative databases: a drug prescription, a hospital discharge form, and an outpatient ambulatory visit database. The population target was 1,616,268 children and adolescents under 18 years living in the Lombardy Region, Italy. A youth was defined as a case if during 2008 he/she received at least one psychotropic drug prescription or was hospitalized for a psychiatric disorder (International Classification of Disease codes 290–319), or attended a child neuropsychiatric outpatient unit for a visit and/or a psychological intervention or rehabilitation at least once. Epileptic children were excluded.In all, 63,550 youths (39.3 per 1000; 95%CI 39.1–39.7‰) were identified as users of health care resources for a putative mental disorder. The prevalence was higher in boys than in girls (47.0‰ versus 31.3‰) and the highest value was recorded in children 8 years old (60.2‰).A total of 59,987 youths (37.1‰) attended a child and adolescent neuropsychiatry service at least once, 3605 (2.2‰) were admitted to hospital, and 2761 (1.7‰) received at least one psychotropic drug prescription, 57% of which did not attend a child neuropsychiatry service. In all, 14,741 youths (23.1% of users) had a disorder that required a high intensity of care (e.g. recurrent prescriptions for drugs and/or ambulatory care).The proportion of youths who received care for mental disorders in the Lombardy Region seems lower than in other countries. However, the fact that many children were prescribed psychotropic drugs without the supervision of a child psychiatrist is a reason for concern.
Keywords: Child; Adolescent; Mental disorders; Psychotropic drugs; Delivery of health care;

Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans by Matthias Hoch; Justin L. Hay; Petra Hoever; Marieke L. de Kam; Erik T. te Beek; Joop M.A. van Gerven; Jasper Dingemanse (107-117).
The orexin system plays a pivotal role in the regulation of the sleep/wake state. Almorexant is a selective, orally available dual orexin receptor antagonist. This study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between almorexant (200 mg p.o.) and alcohol (0.6 g/L i.v. ethanol clamp for 5 h) using various cognitive and psychomotor performance tests in healthy subjects (n=20; 10 males and 10 females) in a 4-way crossover study. No effect of almorexant on ethanol PK was observed. The effects of ethanol on the PK of almorexant were limited, its exposure (AUC) increased by 21%; the median difference in t max was 1.2 h; t 1/2 and C max of almorexant were unchanged. Almorexant showed decreases in adaptive tracking performance, saccadic peak velocity, and subjective alertness as assessed by visual analog scale (VAS) of Bond and Lader, but had no or small effects on smooth pursuit eye movements, body sway, VAS for alcohol intoxication, and a memory test. Almorexant administered together with ethanol showed additive effects for adaptive tracking performance, saccadic peak velocity, subjective alertness and, possibly, calmness, but not on body sway, smooth pursuit, VAS for alcohol intoxication, or memory testing. To conclude, administration of almorexant together with ethanol was associated with additive effects for some of the measured cognitive and psychomotor performance tests. No indications of synergistic effects of almorexant and ethanol for any measured variable were observed.
Keywords: Alcohol interaction; Ethanol; Almorexant; Orexin; Pharmacokinetics; Pharmacodynamics;

Time to all-cause treatment discontinuation of olanzapine compared to other antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis by Karla Soares-Weiser; Laura Béchard-Evans; Anthony Howard Lawson; John Davis; Haya Ascher-Svanum (118-125).
Objective: This comprehensive review and meta-analysis compared the effectiveness of olanzapine and other antipsychotics in schizophrenia treatment, defining effectiveness as time to all-cause medication discontinuation (primary) and as all-cause treatment discontinuation rates. This study examined randomized clinical trials (RCTs) and observational non-interventional studies. Experimental procedures: Schizophrenia studies that compared olanzapine with individual first- (FGAs) and/or second-generation antipsychotics (SGAs) were included in the meta-analyses. Hazard ratios (HR), risk ratios (RR), and their associated 95% confidence intervals were extracted for RCTs and observational studies. Sensitivity analyses assessed the impact of sources of funding, dose of olanzapine, and allocation concealment method on final results. Results: There were 60 RCTs (N=33,360) and 27 observational studies (N=202,591) included. On time to all-cause medication discontinuation, olanzapine was significantly better than aripiprazole, quetiapine, risperidone, ziprasidone and perphenazine for RCTs and better than amisulpride, risperidone, haloperidol, and perphenazine for observational studies. There were no significant differences between olanzapine and clozapine in RCTs or observational studies. All-cause discontinuation rates in RCTs were significantly lower for olanzapine compared to all comparators except amisulpride and clozapine. In observational studies, olanzapine was less effective than clozapine. Industry-sponsored studies favored olanzapine when compared to haloperidol and perphenazine; higher dose of olanzapine favored quetiapine and perphenazine when compared to olanzapine; method of allocation concealment did not generally affect the results. Conclusion: Using a global measure of medication effectiveness (time to all-cause medication discontinuation), olanzapine appears to be more effective – in both RCTs and observational studies – than most SGAs and FGAs, except for clozapine.
Keywords: Antipsychotics; Schizophrenia; Meta-analysis; Systematic review;

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis by Oswald J.N. Bloemen; Mariken B. de Koning; Tobias Gleich; Julia Meijer; Lieuwe de Haan; Don H. Linszen; Jan Booij; Thérèse A.M.J. van Amelsvoort (126-132).
Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([18F]–DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [123I]–IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.
Keywords: UHR; Schizophrenia; SPECT; Depletion; AMPT; Dopamine; Striatum;

Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters—A rat microdialysis and electrophysiology study by Alan L. Pehrson; Thomas Cremers; Cecile Bétry; Marieke G.C. van der Hart; Laerke Jørgensen; Mathias Madsen; Nasser Haddjeri; Bjarke Ebert; Connie Sanchez (133-145).
The monoaminergic network, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA) pathways, is highly interconnected and has a well-established role in mood disorders. Preclinical research suggests that 5-HT receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors as well as the 5-HT transporter (SERT), may have important roles in treating depression. This study evaluated the neuropharmacological profile of Lu AA21004, a novel multimodal antidepressant combining 5-HT3 and 5-HT7 receptor antagonism, 5-HT1B receptor partial agonism, 5-HT1A receptor agonism, and SERT inhibition in recombinant cell lines. Extracellular 5-HT, NE and DA levels were evaluated in the ventral hippocampus (vHC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute and subchronic treatment with Lu AA21004 or escitalopram. The acute effects of LuAA21004 on NE and DA neuronal firing were also evaluated in the locus coeruleus (LC) and ventral tegmental area (VTA), respectively. Acute Lu AA21004 dose-dependently increased 5-HT in the vHC, mPFC and NAc. Maximal 5-HT levels in the vHC were higher than those in the mPFC. Furthermore, mPFC 5-HT levels were increased at low SERT occupancy levels. In the vHC and mPFC, but not the NAc, high Lu AA21004 doses increased NE and DA levels. Lu AA21004 slightly decreased LC NE neuronal firing and had no effect on VTA DA firing. Results are discussed in context of occupancy at 5-HT3, 5-HT1B and 5-HT1A receptors and SERT. In conclusion, Lu AA21004, acting via two pharmacological modalities, 5-HT receptor modulation and SERT inhibition, results in a brain region-dependent increase of multiple neurotransmitter concentrations.
Keywords: Lu AA21004; Preclinical; Receptor occupancy; Neurotransmitters; Multimodal;

Operant behavior to obtain palatable food modifies neuronal plasticity in the brain reward circuit by Thomas Guegan; Laura Cutando; Eduard Ayuso; Emanuela Santini; Gilberto Fisone; Fatima Bosch; Albert Martinez; Emmanuel Valjent; Rafael Maldonado; Miquel Martin (146-159).
Palatability enhances food intake by hedonic mechanisms that prevail over caloric necessities. Different studies have demonstrated the role of endogenous cannabinoids in the mesocorticolimbic system in controlling food hedonic value and consumption. We hypothesize that the endogenous cannabinoid system could also be involved in the development of food-induced behavioral alterations, such as food-seeking and binge-eating, by a mechanism that requires neuroplastic changes in the brain reward pathway. For this purpose, we evaluated the role of the CB1 cannabinoid receptor (CB1-R) in the behavioral and neuroplastic changes induced by operant training for standard, highly caloric or highly palatable isocaloric food using different genetics, viral and pharmacological approaches. Neuroplasticity was evaluated by measuring changes in dendritic spine density in neurons previously labeled with the dye DiI. Only operant training to obtain highly palatable isocaloric food induced neuroplastic changes in neurons of the nucleus accumbens shell and prefrontal cortex that were associated to changes in food-seeking behavior. These behavioral and neuroplastic modifications induced by highly palatable isocaloric food were dependent on the activity of the CB1-R. Neuroplastic changes induced by highly palatable isocaloric food are similar to those produced by some drugs of abuse and may be crucial in the alteration of food-seeking behavior leading to overweight and obesity.
Keywords: CB1 cannabinoid receptor; Food-seeking; Mesocorticolimbic; Palatability; Structural plasticity;

Repeated administration of the indirect dopamine receptor agonist amphetamine (AMPH) produces robust locomotor sensitization and additional behavioral abnormalities. Accumulating evidence suggests that the developmental timing of drug exposure can critically influence this effect. The present study compared the consequences of withdrawal from repeated AMPH exposure in adolescence and adulthood on information processing and locomotor sensitization in C57BL/6 mice. Animals were injected daily with AMPH (1 or 2.5 mg/kg) or vehicle on 7 consecutive days starting either from postnatal day 35 to 42, or from postnatal day 70 to 77, following which they were given a 4 week withdrawal period before behavioral and pharmacological testing commenced. We found that withdrawal from the higher dose of AMPH (2.5 mg/kg/day) given either in adolescence or adulthood similarly disrupted selective associative learning as measured by the latent inhibition paradigm. None of the AMPH withdrawal groups displayed alterations in sensorimotor gating in the form of prepulse inhibition. Withdrawal from adult AMPH exposure at both doses induced marked locomotor sensitization, whereas adolescent pre-treatment with the higher (2.5 mg/kg/day) but not lower (1 mg/kg/day) dose of AMPH potentiated the locomotor-enhancing effects of acute AMPH re-challenge. Our study suggests that withdrawal from repeated AMPH exposure in adolescence and adulthood has similar consequences on selective associative learning, but the two manipulations differ with respect to their efficacy to induce long-term locomotor sensitization to the drug. The latter finding supports the hypothesis that the precise developmental timing determines, at least in part, the impact on long-term dopamine-associated sensitization processes.
Keywords: Amphetamine; Dopamine; Latent inhibition; Prepulse inhibition; Schizophrenia; Sensitization;