European Neuropsychopharmacology (v.18, #2)

CYP2D6 metabolizer status and atomoxetine dosing in children and adolescents with ADHD by Paula T. Trzepacz; David W. Williams; Peter D. Feldman; Rebecca E. Wrishko; Jennifer W. Witcher; Jan K. Buitelaar (79-86).
To determine whether physicians can adequately titrate atomoxetine without knowing genotype status for hepatic cytochrome P450 2D6, we pooled data from two open-label studies of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder. Patients were assessed weekly up to 10 weeks and doses titrated for efficacy and tolerability at the discretion of investigators (max. 1.8 mg/kg/d). Mean dose was 0.1 mg/kg/d lower in poor metabolizer (PM) patients (n  = 87) than extensive metabolizers (EMs, n  = 1239). PMs demonstrated marginally better efficacy on the ADHDRS-IV-Parent:Inv and had comparable safety profiles, except for a 4.0-bpm greater increase in mean pulse rate and a 1.0-kg greater weight loss. Changes from baseline in Fridericia QTc did not differ between groups or correlate with dose in PMs. Results suggest genotyping is unnecessary during routine clinical management, because investigators were able to dose atomoxetine to comparable efficacy and safety levels in EMs and PMs without knowledge of genotype metabolizer status.
Keywords: ADHD; Atomoxetine; Attention-deficit hyperactivity disorder; Cytochrome P450 CYP2D6; Genotype;

Pre-training administration of tianeptine, but not propranolol, protects hippocampus-dependent memory from being impaired by predator stress by Adam M. Campbell; Collin R. Park; Phillip R. Zoladz; Carmen Muñoz; Monika Fleshner; David M. Diamond (87-98).
Extensive research has shown that the antidepressant tianeptine blocks the adverse effects of chronic stress on hippocampal functioning. The current series of experiments extended this area of investigation by examining the influence of tianeptine on acute stress-induced impairments of spatial (hippocampus-dependent) memory. Tianeptine (10 mg/kg, ip) administered to adult male rats before, but not after, water maze training blocked the amnestic effects of predator stress (occurring between training and retrieval) on memory. The protective effects of tianeptine on memory occurred in rats which had extensive pre-stress training, as well as in rats which had only a single day of training. Tianeptine blocked stress effects on memory without altering the stress-induced increase in corticosterone levels. Propranolol, a β-adrenergic receptor antagonist (5 and 10 mg/kg, ip), in contrast, did not block stress-induced amnesia. These findings indicate that treatment with tianeptine, unlike propanolol, provides an effective means with which to block the adverse effects of stress on cognitive functions of the hippocampus.
Keywords: Predator stress; Rat; Memory; Amnesia; Antidepressant; Animal model;

Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia by Jan-Willem Muntjewerff; Henkjan Gellekink; Martin den Heijer; Mechteld L.C. Hoogendoorn; René S. Kahn; Richard J. Sinke; Henk J. Blom (99-106).
Evidence is emerging for the association of aberrant homocysteine-methylation cycle and increased risk of schizophrenia.We examined the prevalence of the catechol-O-methyltransferase (COMT) 324G>A (Val108/158Met) and methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphisms in 252 patients with schizophrenia and 405 control subjects. All subjects were of Dutch ancestry.The COMT 324AA genotype was not associated with an increased risk of schizophrenia (odds ratio (OR) = 1.38 [95% CI: 0.88–2.16], P  = 0.162), and the MTHFR 677TT genotype showed a nearly significant increased risk for schizophrenia (OR = 1.65 [95% CI: 0.97–2.82], P  = 0.067). The odds ratio for schizophrenia associated with joint occurrence of the COMT 324AA and MTHFR 677TT genotype was 3.08 (95% CI: 1.08–8.76) (P  = 0.035). Increasing number of low enzyme activity alleles in the COMT and MTHFR genotype combinations were associated with an increased risk of schizophrenia (test for trend, P  = 0.017).Our findings do not support a major role for the COMT 324AA and MTHFR 677TT genotype alone, but the combination of both genotypes might increase schizophrenia susceptibility.
Keywords: Catechol-O-methyltransferase; Folate; Genetics; Homocysteine; Methylenetetrahydrofolate reductase; Schizophrenia;

The immediate early gene Arc is associated with behavioral resilience to stress exposure in an animal model of posttraumatic stress disorder by Nitsan Kozlovsky; Michael A. Matar; Zeev Kaplan; Moshe Kotler; Joseph Zohar; Hagit Cohen (107-116).
Mechanisms involved in adaptative and maladaptive changes in neural plasticity and synaptic efficacy in various brain areas are pivotal to understanding the physiology of the response to stress and the pathophysiology of posttraumatic stress disorder (PTSD). Activity-regulated cytoskeletal-associated protein (Arc) is an effector immediate early gene (IEG) which has direct effects on intracellular homeostatic functions. Increased expression of Arc has been associated with increased neuronal activity and with consolidation of long-term memory. It may thus play an important role in mediating experience-induced reorganization and/or development of synaptic connections. This study sought to characterize the pattern of expression of mRNA for the Arc gene in selected brain areas of test subjects classified according to their individual pattern of behavioral response to a stressor, correlated with circulating levels of corticosterone (as a physiological marker of stress response). The hippocampal CA1 and CA3 subregions of individuals whose behavior was minimally or partially disrupted in response to predator scent stress demonstrated significantly increased levels of mRNA for Arc, compared to unexposed controls. The group whose behavior was severely disrupted demonstrated no such upregulation. Consistent with the hypothesis that the Arc gene has a promoting effect on neuronal function and/or structural changes, the lack of Arc expression in the behaviorally and physiologically more severely affected individuals raises the possibility that Arc may be associated with resilience and/or recovery after stress exposure.
Keywords: Posttraumatic stress disorder; Animal model; Activity-regulated cytoskeletal-associated protein; Immediate early gene; Corticosterone; Synaptic efficacy; Neural plasticity;

Addition of memantine to antipsychotic treatment in schizophrenia inpatients with residual symptoms: A preliminary study by Amir Krivoy; Abraham Weizman; Lucian Laor; Nurit Hellinger; Zvi Zemishlany; Tsvi Fischel (117-121).
Schizophrenia is comprised of several debilitating symptoms. Antipsychotics offer an effective treatment for positive symptoms, while the negative signs and cognitive deficits are usually treatment-resistant. It was suggested that glutamate dysregulation may be involved in the neuropathology of schizophrenia, mainly through NMDA dysfunction. We hypothesized that addition of memantine, a weak non-selective NMDA receptor antagonist approved for dementia, to antipsychotics would improve the clinical status of un-remitted schizophrenia patients, notably the negative signs and cognitive deficits.Seven schizophrenia patients, were included in a six-week open-label study, with weekly increasing dosage (5, 10, 15, 20 mg) of memantine added to their on-going antipsychotic treatment.We found a significant improvement of the PANSS score (baseline 116.28 ± 21.9 vs. 97.86 ±24.48 after six weeks, t  = 5.98, p  < 0.001) with the most prominent improvement (21%) in negative signs sub-scale (baseline 40 ± 6.38 vs. 31.71 ± 7.76 after six weeks, t  = 5.87, p  < 0.001). Cognitive status, measured with the Neurobehavioral Cognitive Examination (NCSE) and Clock Drawing Test (CDT) showed no improvement.Memantine addition to antipsychotic treatment, in schizophrenia patients might improve their clinical status, primarily the negative signs, but not their cognitive deficits. Further research is needed to replicate these observations.
Keywords: Schizophrenia; Negative signs; Glutamate; Memantine; NMDA;

The goal of the present work was to conduct a meta-analysis comparing reboxetine and the selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder (MDD). Medline/Pubmed was searched for double-blind, randomized trials comparing these two agents for MDD. The makers of reboxetine (Pfizer Inc.) were also contacted to provide missing data and/or unpublished studies. 9 trials (n  = 2641) were combined using a random effects model. Response rates were comparable between the SSRI (63.9%) and reboxetine (59.2%)-treated groups (p  = 0.118). There was no significant difference in the degree of improvement in psychosocial functioning, as measured by the social adaptation self-evaluation scale, between the two groups. Overall discontinuation rates (25.1% versus 32.0%; p  = 0.015), and the rate of discontinuation due to intolerance (8.5% versus 12.6%; p  = 0.007) favored SSRI treatment. The rate of discontinuation due to lack of efficacy did not differ significantly between the two groups. SSRI-treated patients were more likely to experience nausea, hypersomnia, and fatigue. Reboxetine-treated patients were more likely to experience constipation, difficulty urinating, and insomnia. These results suggest that the NRI reboxetine and the SSRIs differ with respect to their side-effect profile and overall tolerability but not their efficacy in treating MDD.
Keywords: Reboxetine; SSRI; Major; Depressive; Disorder;

Neuroprotection by Imipramine against lipopolysaccharide-induced apoptosis in hippocampus-derived neural stem cells mediated by activation of BDNF and the MAPK pathway by Chi-Hsien Peng; Shih-Hwa Chiou; Shih-Jen Chen; Yueh-Ching Chou; Hung-Hai Ku; Cheng-Kuo Cheng; Chih-Ju Yen; Tung-Hu Tsai; Yuh-Lih Chang; Chun-Lan Kao (128-140).
Depression is accompanied by the activation of the inflammatory-response system, and increased production of proinflammatory cytokines may play a role in the pathophysiology of depressive disorders. Imipramine (IM), a tricyclic antidepressant drug, has recently been shown to promote neurogenesis and improve the survival rate of neurons in the hippocampus. However, whether IM elicits a neuroprotective or anti-inflammatory effect, or promotes the differentiation of neural stem cells (NSCs) remains to be elucidated. In this study, we cultured NSCs derived from the hippocampal tissues of adult rats as an in vitro model to evaluate the NSCs drug-modulation effects of IM. Our results showed that 3 µM IM treatment significantly increased the survival rate of NSCs, and up-regulated the mRNA and protein expression of brain-derived neurotrophic factor (BDNF) and Bcl-2 in Day-7 IM-treated NSCs. Similar to BDNF-treated effect, incubation of NSCs with 3 µM IM increased Bcl-2 protein levels and further prevented lipopolysaccharide (LPS)-induced apoptosis through the activation of the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) pathway. Inhibition of BDNF expression with small interfering RNA (siRNA), or blocking the MAPK pathway with U0126 further significantly decreased Bcl-2 protein levels and abrogated the neuroprotective effects of IM against LPS-induced apoptosis in NSCs. In addition, the percentages of serotonin and MAP-2-positive neuronal cells in the Day 7 culture of IM-treated NSCs were significantly increased. By using microdialysis with high performance liquid chromatography-electrochemical detection, the functional release of serotonin in the process of serotoninergic differentiation of IM-treated NSCs was concomitantly increasing and mediated by the activation of the BDNF/MAPK/ERK pathway/Bcl-2 cascades. In sum, the study results indicate that IM can increase the neuroprotective effects, suppress the LPS-induced inflammatory process, and promote serotoninergic differentiation in NSCs via the modulation of the BDNF/MAPK/ERK pathway/Bcl-2 cascades.
Keywords: Imipramine; Neural stem cells; BDNF; Neuroprotection; LPS; MAPK pathway;

Paroxetine with pindolol augmentation: A double-blind, randomized, placebo-controlled study in depressed in-patients by Christian Geretsegger; Waltraud Bitterlich; Renate Stelzig; Christoph Stuppaeck; Brigitta Bondy; Wolfgang Aichhorn (141-146).
Pindolol, a 5-HT1A autoreceptor antagonist, given in combination with selective serotonin reuptake inhibitors (SSRIs), may enhance and/or accelerate the therapeutic efficacy of SSRIs. Fifty patients, meeting ICD-10 criteria for major depressive disorder or bipolar depression, were enrolled in our randomized, placebo-controlled, double-blind trial. One group received paroxetine plus pindolol (2.5 mg t.i.d.), and the other group received paroxetine plus placebo. The proportion of patients with sustained response (≥ 50% reduction of baseline HAM-D 17 score maintained until the endpoint; p  = 0.252) and the proportion of patients with remission (HAM-D 17 ≤ 8 at last visit; p  = 0.769) did not differ significantly between the two treatment groups. However, a significantly greater proportion of patients who were not previously treated with antidepressants (n  = 15; p  = 0.041) and of patients with bipolar depression (n  = 11; p  = 0.015) had a sustained response in the paroxetine plus pindolol group compared to the paroxetine plus placebo group; furthermore there was a trend for first episode depressed patients to have a greater response in the paroxetine plus pindolol group (n  = 12; p  = 0.071). Summarizing, the entire study population showed no antidepressive benefit from pindolol augmentation. Nevertheless patients with bipolar depression irrespective of previous treatments and duration of illness, and unipolar patients not previously treated demonstrated a significant benefit from pindolol augmentation.
Keywords: Paroxetine; Pindolol; Augmentation; Depression; Bipolar disorder;

Effects of CDP-choline and the combination of CDP-choline and galantamine differ in an animal model of schizophrenia: Development of a selective α7 nicotinic acetylcholine receptor agonist strategy by Stephen I. Deutsch; Richard B. Rosse; Barbara L. Schwartz; Nina R. Schooler; Brooke L. Gaskins; Katrice D. Long; John Mastropaolo (147-151).
The regionally selective reduction of expression of the α7 nicotinic acetylcholine receptor (α7 nAChR) in schizophrenia underlies impaired sensory inhibition, a possible endophenotype of the disorder. This ligand-gated ion channel receptor has been proposed as a pharmacotherapeutic target in schizophrenia. The current study examined the effect of CDP-choline alone and the combination of CDP-choline and galantamine, administered acutely and once-daily for five consecutive days, in an animal model of NMDA receptor hypofunction that is relevant to schizophrenia. The results support the allosteric modulatory influence of galantamine on CDP-choline; however, individual doses of CDP-choline and galantamine must be carefully titrated in order to achieve optimal levels of α7 nAChR “agonism” that may be necessary for the desired therapeutic effect.
Keywords: α7 nicotinic acetylcholine receptor; CDP-choline; Galantamine; NMDA receptor; Schizophrenia;

Evidence that lithium protects against tardive dyskinesia: The Curaçao Extrapyramidal Syndromes study VI by Peter N. van Harten; Hans W. Hoek; Glenn E. Matroos; Jim van Os (152-155).
Lithium may have neuroprotective properties and therefore could affect the occurrence of tardive dyskinesia (TD). We conducted a nine-year follow-up study with one baseline and six follow-up assessments including all psychiatric inpatients in Curaçao (N  = 194). TD was measured with the Abnormal Involuntary Movement Rating Scale (AIMS). There were 758 follow-up observations in the 166 patients (mean age 54.4 yrs, SD 16.0) with at least one follow-up assessment. Most patients (74%) had schizophrenia. The mean baseline score of the AIMS was 4.1 (SD 4.7). Sixteen patients (9.6%) used lithium at baseline and eight patients started lithium during follow-up. Prevalent and incident lithium significantly reduced the severity of existing TD with respectively 2.3 and 2.9 point reduction on the AIMS (AIMS score range: 0–23) and a standardised effect size of 0.5 for prevalent TD and 0.6 for incident TD. In the restricted sample of those with a baseline score of zero on the AIMS, prevalent lithium significantly lowered the risk of new abnormal movements (standardised effect size of 0.7). In conclusion, the use of lithium was significantly negatively associated with both persistence and onset of TD. These results suggest a beneficial effect on TD of lithium in some patients using long-term antipsychotics.
Keywords: Tardive dyskinesia; Incidence; Course; Lithium; Neuroprotective; Follow-up study;