European Neuropsychopharmacology (v.18, #3)

In recent years there has been increasing focus on the role of the drug transporter P-glycoprotein (P-gp) with regard to drug penetration into the brain. Studies using mice devoid of functional P-gp have revealed that P-gp at the blood–brain barrier (BBB) can exert a profound effect on the ability of some drugs to enter the brain, e.g. cardiovascular drugs (digoxin, quinidine), opioids (morphine, loperamide, methadone), HIV protease inhibitors, the new generation of antihistamines, and some antidepressants and antipsychotics. Among the latter group, risperidone is strongly influenced having about 10 times higher cerebral concentration in P-gp knock-out mice than in control mice. Taking into account that polytherapy is commonplace in psychiatry, theoretically there is a risk of drug–drug interactions with regard to P-gp at the BBB. Here we review the evidence for a role of P-gp with regard to psychoactive drugs from in vitro studies and experiments in knock-out mice devoid of functional P-gp. Moreover, the evidence for significant drug–drug interactions involving psychotropic drugs in rodents is considered. Clinical observations suggesting a role for P-gp in relation to drug–drug interactions at the BBB are sparse, and a definite conclusion awaits further studies. Also, the possible clinical relevance of P-gp genetic polymorphisms is questionable, and more investigations are needed on this subject.
Keywords: P-glycoprotein; Psychotropic drugs; Blood–brain barrier; Mdr1a/1b knock-out mice; Drug–drug interactions;

Antipsychotic prescription patterns in outpatient settings: 24-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study by Istvan Bitter; Tamas Treuer; Yulia Dyachkova; Ferenc Martenyi; Margaret McBride; Gabor S. Ungvari (170-180).
This report describes antipsychotic prescription patterns for outpatients with schizophrenia prescribed olanzapine (n  = 3222), clozapine (n  = 236), risperidone (n  = 1117), quetiapine (n  = 189) or haloperidol (n  = 256) monotherapy at study entry and treated in a naturalistic, clinical practice setting over 24 months. Predictive factors associated with remaining on monotherapy were also identified. Olanzapine patients had significantly greater odds of remaining on their initial monotherapy compared to other treatment groups, while clozapine or risperidone recipients were more likely to remain on monotherapy, compared to haloperidol patients. Switching antipsychotic medication was more common than addition of another antipsychotic agent, and the most common reason for modifying treatment was lack of effectiveness. The odds of modifying antipsychotic prescription due to intolerability were lower for patients treated with olanzapine, compared to patients treated with risperidone or haloperidol (p  ≤ .001). However, treatment modification due to patient request was significantly greater for olanzapine-treated patients, compared to risperidone-, quetiapine- or haloperidol-treated patients (p  ≤ .001).
Keywords: Antipsychotic agents; Schizophrenia; Prescription patterns; Drug; Treatment;

DHEAS repeated treatment improves cognitive and behavioral deficits after mild traumatic brain injury by A. Milman; O. Zohar; R. Maayan; R. Weizman; C.G. Pick (181-187).
Mild traumatic brain injury (mTBI) is characterized by diffused symptoms, which when combined are called “post-concussion syndrome”. Dehydroepiandrosterone sulfate (DHEAS) is a neuroactive neurosteroid. Previously, we have reported that closed head mTBI causes long lasting cognitive deficits and depressive-like behavior. In the present study we describe the effects of DHEAS on the behavior of mice that suffered closed head mTBI. Following the induction of mTBI, mice were treated once a week with DHEAS (s.c. 20 mg/kg) and their performance in the passive avoidance test and the forced swimming test (FST) were evaluated 7, 30, 60 and 90 days post-injury. The most important interactions were between injury and injection (passive avoidance; p  < 0.001 and FST; p  = 0.001), meaning that DHEAS has beneficial effects only when given to injured animals. Our results demonstrate that the long-term cognitive and behavioral effects induced by mTBI may be improved by a repeated weekly treatment with DHEAS.
Keywords: Cognitive deficits; Closed head trauma model; Depressive-like behavior; Mild traumatic brain injury (mTBI); Dehydroepiandrosterone sulfate (DHEAS);

To measure suspected abuse of the tricyclic antidepressant amitriptyline among methadone maintenance treatment (MMT) patients in Israel, we studied cross-sectionally, all our 303 patients (February, 2007).Tricyclics presence was screened in one of the random urine samples routinely taken for tests of other drugs. ASI questionnaire, variables from patients' records.48 (15.8%) patients were positive for amitriptyline. Logistic regression (multivariate analyses) found that the extent of being amitriptyline-positive was higher in benzodiazepine (BDZ) abusers (OR = 11.6 95% CI 4.4–30.7), in subjects with positive antibody to hepatitis C (OR = 2.2, 95% CI 1.02–4.9) and in patients treated with high-dose methadone (> 150 mg/day) (OR = 2.4, 95% CI 1.2–4.9). Amitriptyline was found in 12 (7.5%) of the “privileged” group of patients (stabilized patients who, based on their long-standing cessation of any type of street-drugs abuse and prolonged normative behavior in treatment are granted “take home” methadone doses) who, by definition, should not be abusing anything.The high prevalence of amitriptyline abuse found in our patients, and its potential cardiac hazards when combined with BDZ abuse, emphasizes the importance of amitriptyline routine monitoring in order to decrease the potential risk associated with amitriptyline combined with methadone and BDZ, and to implement appropriate interventions.
Keywords: Tricyclic antidepressants; Amitriptyline; Methadone maintenance treatment (MMT); Benzodiazepines (BDZ); Monitoring;

Nitrous oxide-antinociception is mediated by opioid receptors and nitric oxide in the periaqueductal gray region of the midbrain by Dimitris E. Emmanouil; Andrea S. Dickens; Rick W. Heckert; Yusuke Ohgami; Eunhee Chung; Shujie Han; Raymond M. Quock (194-199).
Previous studies have shown that nitrous oxide (N2O)-induced antinociception is sensitive to antagonism by blockade of opioid receptors and also by inhibition of nitric oxide (NO) production. The present study was conducted to determine whether these occur within the same brain site. Mice were stereotaxically implanted with microinjection cannulae in the periaqueductal gray (PAG) area of the midbrain. In saline-pretreated mice, exposure to 70% N2O resulted in a concentration-dependent antinociceptive effect in the mouse abdominal constriction test. Pretreatment with an opioid antagonist in the PAG significantly antagonized the antinociceptive effect. Pretreatment with an inhibitor of NO production in the PAG also significantly antagonized the antinociceptive effect. These findings suggest that N2O acts in the PAG via an NO-dependent, opioid receptor-mediated mechanism to induce antinociception.
Keywords: Nitrous oxide; Antinociception; Periaqueductal gray; Opioid receptors; Nitric oxide;

In vitro and in vivo pharmacological profile of AS057278, a selective d-amino acid oxidase inhibitor with potential anti-psychotic properties by Tiziana Adage; Anne-Cécile Trillat; Anna Quattropani; Dominique Perrin; Laurent Cavarec; Jeffrey Shaw; Oxana Guerassimenko; Claudio Giachetti; Béatrice Gréco; Ilya Chumakov; Serge Halazy; Arthur Roach; Paola Zaratin (200-214).
Non-competitive N-methyl-d-aspartate (NMDA) blockers induce schizophrenic-like behavior in healthy volunteers and exacerbate symptomatology in schizophrenic patients. Hence, a compound able to enhance NMDA neurotransmission by increasing levels of d-serine, an endogenous full agonist at the glycine site of the NMDA receptors, could have anti-psychotic activity. One way to increase d-serine levels is the inhibition of d-amino acid oxidase (DAAO), the enzyme responsible for d-serine oxidation. Indeed AS057278, a potent in vitro (IC50  = 0.91 μM) and ex vivo (ED50  = 2.2–3.95 μM) DAAO inhibitor, was able to increase d-serine fraction in rat cortex and midbrain (10 mg/kg i.v.). AS057278 was able to normalize phencyclidine (PCP)-induced prepulse inhibition after acute (80 mg/kg) and chronic (20 mg/kg b.i.d.) oral administration in mice. Finally, AS057278 after oral chronic treatment (10 mg/kg b.i.d.) was able to normalize PCP-induced hyperlocomotion. These results suggest that AS057278 has the potential to anti-psychotic action toward both cognitive and positive symptoms of schizophrenia.
Keywords: d-amino acid oxidase inhibitor; d-serine; Hypoglutamatergy; Schizophrenia; Phencyclidine; Prepulse inhibition; Open field;

Effects of cross-sex hormones on cerebral activation during language and mental rotation: An fMRI study in transsexuals by I.E.C. Sommer; P.T. Cohen-Kettenis; T. van Raalten; A.J. vd Veer; L.E. Ramsey; L.J.G. Gooren; R.S. Kahn; N.F. Ramsey (215-221).
Androgens and estrogens affect the performance on certain cognitive tests, particularly those measuring verbal fluency and mental rotation. Their effects on cognition have frequently been attributed to changes in cerebral lateralization. This study tested the impact of a reversal of the sex steroid milieu on cerebral activation and lateralization during verbal and spatial tasks in transsexuals.fMRI scans were obtained from 6 female-to-male and 8 male-to-female transsexuals at baseline and after cross-sex steroid treatment. Activation was measured during language and mental rotation tasks. Language activation increased after sex steroid treatment in both groups (F(1,12) = 3.7, p  = 0.08), and total language activity was correlated to post-treatment estradiol levels (rho = 0.54, p  = 0.05). Lateralization was not affected by the reversal of sex steroid milieus (F(1,12) = 1.47, p  = 0.25). Activation during mental rotation did not increase during treatment (F(1,12) = 0.54, p  = 0.34), but post-treatment testosterone levels correlated to total activation during mental rotation (rho = 0.64, p  = 0.01). Findings suggest that sex steroids may influence cerebral activation, but lateralization remains stable.
Keywords: Cerebral lateralization; Sex steroids; fMRI; Gender identity disorder; Transsexualism; Testosterone;

Norchloro-fluoro-homoepibatidine (NCFHEB) — A promising radioligand for neuroimaging nicotinic acetylcholine receptors with PET by W. Deuther-Conrad; J.T. Patt; P.R. Lockman; D.D. Allen; M. Patt; A. Schildan; V. Ganapathy; J. Steinbach; O. Sabri; P. Brust (222-229).
Cholinergic neurotransmission depends on the integrity of nicotinic acetylcholine receptors (nAChRs), and impairment of both is characteristic for various neurodegenerative diseases. Visualization of specific receptor subtypes by positron emission tomography (PET) has potential to assist with diagnosis of such neurodegenerative diseases and with design of suitable therapeutic approaches. The goal of our study was to evaluate in vivo the potential of 18F-labelled (+)- and (−)-norchloro-fluoro-homoepibatidine ([18F]NCFHEB) in comparison to 2-[18F]F-A-85380 as PET tracers. In the brains of NMRI mice, highest levels of radioactivity were detected at 20 min post-injection of (+)-[18F]NCFHEB, (−)-[18F]NCFHEB, and 2-F-[18F]-A-85380 (7.45, 5.60, and 3.2% ID/g tissue, respectively). No marked pharmacological adverse effects were observed at 25 μg NCFHEB/kg. Uptake studies in RBE4 cells and in situ perfusion studies suggest an interaction of epibatidine and NCFHEB with the carrier-mediated choline transport at the blood-brain barrier. The data indicate that (+)- and (−)-[18F]NCFHEB have potential for further development as PET tracers.
Keywords: Positron emission tomography; Blood-brain barrier; Epibatidine; Stereoselectivity; Subtype specificity;

A detailed examination of cytokine abnormalities in Major Depressive Disorder by N.M. Simon; K. McNamara; C.W. Chow; R.S. Maser; G.I. Papakostas; M.H. Pollack; A.A. Nierenberg; M. Fava; K.K. Wong (230-233).
Recent technological advances offer an opportunity to further elucidate the complex cytokine network in Major Depressive Disorder (MDD). Twenty cytokines were simultaneously assessed in 49 individuals with MDD and 49 age and gender matched controls. Multiple pro-inflammatory and two anti-inflammatory cytokines were significantly elevated in the MDD sample, including an antidepressant naïve subset. These data support a generalized chronic inflammatory state in MDD, and implicate additional cytokines and chemokines previously linked to cardiovascular disease.
Keywords: Cytokines; Inflammation; Depression; Major Depressive Disorder; Stress; Cardiovascular;