European Neuropsychopharmacology (v.27, #1)

Contents (OBC).

The association between premorbid cognitive ability and social functioning and suicide among young men: A historical-prospective cohort study by Mark Weiser; Daphna Fenchel; Nomi Werbeloff; Shira Goldberg; Eyal Fruchter; Abraham Reichenberg; Shimon Burshtein; Matthew Large; Michael Davidson; Gad Lubin (1-7).
Previous studies have found associations between low cognitive ability and later completed suicide. The aim of this study was to examine the association between cognitive ability and social functioning in adolescence, and later completed suicide in a large population-based longitudinal study. Data from the Israeli Draft Board Register for 634,655 Israeli male adolescents aged 16 and 17 was linked to a causes-of-death data registry, with a mean follow-up of 10.6 years for completed suicide. Our results show that in males without a psychiatric diagnosis, both low (adjusted HR=1.51, 95% CI: 1.19–1.92) and high (adjusted HR=1.36, 95% CI: 1.04–1.77) cognitive ability, and very poor (adjusted HR=2.30, 95% CI: 1.34–3.95) and poor (adjusted HR=1.64, 95% CI: 1.34–2.07) social functioning were associated with increased risk for later completed suicide; however positive predictive values were low (PPVs=0.09% and 0.10%, for low cognitive ability and very poor or poor social functioning, respectively). No association between cognitive ability or social functioning and risk for suicide was found in males with a psychiatric diagnosis. These data do not support the clinical utility of screening for such potential predictors.
Keywords: Suicide; Cognitive ability; Social functioning;

Adjunctive minocycline for schizophrenia: A meta-analysis of randomized controlled trials by Ying-Qiang Xiang; Wei Zheng; Shi-Bin Wang; Xin-Hu Yang; Dong-Bin Cai; Chee H. Ng; Gabor S. Ungvari; Deanna L. Kelly; Wei-Ying Xu; Yu-Tao Xiang (8-18).
This study aimed to conduct a meta-analysis of the efficacy and safety of adjunctive minocycline for schizophrenia. Randomized controlled trials (RCTs) comparing adjunctive minocycline with placebo in patients with schizophrenia were included in the meta-analysis. Two independent investigators extracted and synthesized data. Standard mean differences (SMDs), risk ratio (RR) ±95% confidence intervals (CIs) and the number-needed-to-harm (NNH) were calculated. Eight RCTs with 548 schizophrenia patient including 286 (52.2%) patients on minocycline (171.9±31.2 mg/day) and 262 (47.8%) on placebo completed 18.5±13.4 weeks of treatment. Meta-analyses of Positive and Negative Syndrome Scale (PANSS) (7 RCTs with 8 treatment arms)/Brief Psychiatric Rating Scale (BPRS) (1 RCT) total score [SMD: −0.64, (95%CI: −1.02, −0.27), P=0.0008; I 2=74%], positive, negative and general symptom scores [SMD: −0.69 to −0.22 (95%CI: −0.98, −0.03), P=0.02–0.00001; I 2=7–63%] revealed a significant superiority of adjunctive minocycline treatment over the placebo. There was no significant difference regarding neurocognitive function, discontinuation rate and adverse drug reactions between the two groups. This meta-analysis showed that adjunctive minocycline appears to be efficacious and safe for schizophrenia. Due to significant heterogeneity, future studies with a large sample size are needed to confirm these findings.
Keywords: Schizophrenia; Minocycline; Antipsychotic; Meta-analysis;

The expression of plasticity-related genes in an acute model of stress is modulated by chronic desipramine in a time-dependent manner within medial prefrontal cortex by Nicoletta Nava; Giulia Treccani; Heidi Kaastrup Müller; Maurizio Popoli; Gregers Wegener; Betina Elfving (19-28).
It is well established that stress plays a major role in the pathogenesis of neuropsychiatric diseases. Stress-induced alteration of synaptic plasticity has been hypothesized to underlie the morphological changes observed by neuroimaging in psychiatric patients in key regions such as hippocampus and prefrontal cortex (PFC). We have recently shown that a single acute stress exposure produces significant short-term alterations of structural plasticity within medial PFC. These alterations were partially prevented by previous treatment with chronic desipramine (DMI). In the present study we evaluated the effects of acute Foot-shock (FS)-stress and pre-treatment with the traditional antidepressant DMI on the gene expression of key regulators of synaptic plasticity and structure. Expression of Homer, Shank, Spinophilin, Densin-180, and the small RhoGTPase related gene Rac1 and downstream target genes, Limk1, Cofilin1 and Rock1 were investigated 1 day (1 d), 7 d and 14 d after FS-stress exposure. We found that DMI specifically increases the short-term expression of Spinophilin, as well as Homer and Shank family genes, and that both acute stress and DMI exert significant long-term effects on mRNA levels of genes involved in spine plasticity. These findings support the knowledge that acute FS stress and antidepressant treatment induce both rapid and sustained time-dependent alterations in structural components of synaptic plasticity in rodent medial PFC.
Keywords: Synaptic plasticity; Prefrontal cortex; Acute stress; Antidepressant; Real-time qPCR;

Significant treatment effect of add-on ketamine anesthesia in electroconvulsive therapy in depressive patients: A meta-analysis by Dian-Jeng Li; Fu-Chiang Wang; Che-Sheng Chu; Tien-Yu Chen; Chia-Hung Tang; Wei-Cheng Yang; Philip Chik-keung Chow; Ching-Kuan Wu; Ping-Tao Tseng; Pao-Yen Lin (29-41).
Add-on ketamine anesthesia in electroconvulsive therapy (ECT) has been studied in depressive patients in several clinical trials with inconclusive findings. Two most recent meta-analyses reported insignificant findings with regards to the treatment effect of add-on ketamine anesthesia in ECT in depressive patients. The aim of this study is to update the current evidence and investigate the role of add-on ketamine anesthesia in ECT in depressive patients via a systematic review and meta-analysis. We performed a thorough literature search of the PubMed and ScienceDirect databases, and extracted all relevant clinical variables to compare the antidepressive outcomes between add-on ketamine anesthesia and other anesthetics in ECT. Total 16 articles with 346 patients receiving add-on ketamine anesthesia in ECT and 329 controls were recruited. We found that the antidepressive treatment effect of add-on ketamine anesthesia in ECT in depressive patients was significantly higher than that of other anesthetics (p<0.001). This significance persisted in both short-term (1–2 weeks) and moderate-term (3–4 weeks) treatment courses (all p<0.05). However, the side effect profiles and recovery time profiles were significantly worse in add-on ketamine anesthesia group than in control group. Our meta-analysis highlights the significantly higher antidepressive treatment effect of add-on ketamine in depressive patients receiving ECT compared to other anesthetics. However, clinicians need to take undesirable side effects into consideration when using add-on ketamine anesthesia in ECT in depressive patients.
Keywords: Psychiatry; Depression; Treatment; NMDA;

Association of plasma calcium concentrations with alcohol craving: New data on potential pathways by Rilana Schuster; Anne Koopmann; Martin Grosshans; Iris Reinhard; Rainer Spanagel; Falk Kiefer (42-47).
Recently, calcium was suggested to be the active moiety of acamprosate. We examined plasma calcium concentrations in association with severity of alcohol dependence and its interaction with regulating pathways and alcohol craving in alcohol-dependent patients. 47 inpatient alcohol-dependent patients undergoing detoxification treatment underwent laboratory testing, including calcium, sodium, liver enzymes as well as serum concentrations of calcitonin, parathyroid hormone and vitamin D. The psychometric dimension of craving was analyzed with the Obsessive Compulsive Drinking Scale (OCDS). The severity of withdrawal was measured with the Alcohol Dependence Scale (ADS) and with the Alcohol Dependence Scale for high-risk sample (ADS-HR). The main findings of our investigation are: a) a negative correlation of plasma calcium concentrations with alcohol craving in different dimensions of the OCDS; b) a negative correlation of plasma calcium concentrations with breath alcohol concentration; c) lowered calcitonin concentration in the high-risk sample of alcoholics; d) lowered plasma vitamin D concentrations in all alcoholic subjects. Our study adds further support for lowered plasma calcium concentrations in patients with high alcohol intake and especially in patients with increased craving as a risk factor for relapse. Lowered calcitonin concentrations in the high-risk sample and lowered vitamin D concentrations may mediate these effects. Calcium supplementation could be a useful intervention for decreasing craving and relapse in alcohol-dependent subjects.
Keywords: Alcohol dependence; Calcitonin; Calcium; Craving; Parathyroid hormone; Vitamin D;

Olanzapine modulation of long- and short-range functional connectivity in the resting brain in a sample of patients with schizophrenia by Wenbin Guo; Feng Liu; Jindong Chen; Renrong Wu; Lehua Li; Zhikun Zhang; Jingping Zhao (48-58).
Treatment effects of antipsychotic drugs on cerebral function are seldom examined. Exploring functional connectivity (FC) in drug-free schizophrenia patients before and after antipsychotic treatment can improve the understanding of antipsychotic drug mechanisms. A total of 17 drug-free patients with recurrent schizophrenia and 24 healthy controls underwent resting-state functional magnetic resonance imaging scans. Long- and short-range FC strengths (FCS) were calculated for each participant. Compared with the controls, the patients at baseline exhibited increased long-range positive FCS (lpFCS) in the bilateral inferior parietal lobule (IPL) and decreased lpFCS in the brain regions of the default-mode network (DMN) regions and sensorimotor circuits of the brain. By contrast, increased short-range positive FCS was observed in the right IPL of the patients at baseline compared with the controls. After treatment with olanzapine, increased FC in the DMN and sensorimotor circuits of the brain was noted, whereas decreased FC was observed in the left superior temporal gyrus (STG). Moreover, the alterations of the FCS values and the reductions in symptom severity among the patients after treatment were correlated. The present study provides evidence that olanzapine normalizes the abnormalities of long- and short-range FCs in schizophrenia. FC reductions in the right IPL may be associated with early treatment response, whereas those in the left STG may be related to poor treatment outcome.
Keywords: Schizophrenia; Functional connectivity; Olanzapine; Anatomical distance; Default-mode network;

Modeling the development of panic disorder with interoceptive conditioning by Klara De Cort; Mathias Schroijen; Rene Hurlemann; Suzanne Claassen; Jojanneke Hoogenhout; Omer Van den Bergh; Liesbet Goossens; Ilse Van Diest; Koen Schruers (59-69).
Panic disorder is characterized by the paroxysmal occurrence and fear of bodily symptoms. In recent years it has been proposed that patients “learn” to fear cardiorespiratory sensations through interoceptive conditioning. This study sought to model the initial stage of this process in healthy volunteers (N=44) using mild cardiac sensations. An additional aim was to explore whether anxiety sensitivity – a known risk factor for panic disorder – modulates such interoceptive learning. Infusions of pentagastrin and saline were used to manipulate the presence versus absence of cardiac sensations, respectively, and served as conditioned stimuli in a differential interoceptive conditioning paradigm. Inhalation of 35% CO2-enriched air served as the panicogenic, unconditioned stimulus (UCS). In half of the participants (“prepared” condition), cardiac sensations caused by pentagastrin were followed by inhalation of CO2-enriched air (penta CS+), whereas the absence of such sensations (saline) was followed by room air (saline CS−). The reversed combination (“unprepared” condition) was used in the other half of the participants. Conditioning effects showed up for self-reported UCS-expectancy, but not for skin conductance and anxiety ratings. Only participants from the prepared group learned to expect the UCS, and differential learning was impaired with higher scores on anxiety sensitivity. Expectancy learning was more easily established towards the presence compared to the absence of cardiac sensations, whereas the reverse effect was observed for safety learning. Modeling impaired discriminatory learning and the moderating effect of anxiety sensitivity provides new insight in the development of panic disorder.
Keywords: Anxiety sensitivity; Panic disorder; Interoceptive conditioning; Preparedness; 35% CO2; Pentagastrin;

Sedative effect of Clozapine is a function of 5-HT2A and environmental novelty by Radhika S. Joshi; Rolen Quadros; Michael Drumm; Rupasri Ain; Mitradas M. Panicker (70-81).
Antipsychotic drugs are the mainstay in the treatment of schizophrenia and bipolar disorder. However, antipsychotics often exhibit sedation or activity suppression among many other side effects, and the factors that influence them remain poorly understood. We now show, using a 5-HT2A knockout (Htr2a −/− ) mouse, that environmental circumstances can affect suppression of activity induced by the atypical antipsychotic- Clozapine. We observed that Htr2a −/− mice were more resistant to Clozapine-induced suppression of activity (CISA) and this behaviour was dependent on the environment being ‘novel’. In their ‘home’ environment, at identical doses the mice exhibited CISA. Interestingly, the effect of genotype and environmental novelty on CISA could not be extended to the other antipsychotics that were tested, i.e. Haloperidol and Risperidone. Haloperidol-induced activity suppression was independent of context and genotype. Whereas context affected Risperidone-induced activity suppression only in the Htr2a +/+ mice. Furthermore, we observed that caffeine, a stimulant, elicited resistance to CISA similar to that seen in the ‘novel’ context. Our study establishes a previously unknown interaction between the environmental context, 5-HT2A and CISA and emphasises the role of non-pharmacological factors such as environment on the effects of the drug, which seem antipsychotic-specific. Our findings should advance the understanding of the side effects of individual antipsychotics and the role of environment to overcome side effects such as sedation.
Keywords: 5-HT2A; Clozapine; Environmental novelty; Knockout;

The impact of second generation antipsychotics on insight in schizophrenia: Results from 14 randomized, placebo controlled trials by Taina Mattila; Maarten Koeter; Tamar Wohlfarth; Jitschak Storosum; Wim van den Brink; Eske Derks; Hubertus Leufkens; Damiaan Denys (82-86).
Despite the negative impact of lack of insight on the prognosis, general functioning and treatment adherence, the effect of antipsychotic medication on insight has been investigated only in small samples and uncontrolled studies. In this study we examine whether previously reported effects of antipsychotics on insight from uncontrolled studies can be confirmed in a database including 14 randomized, double-blind, placebo-controlled trials.The database contained placebo-controlled RCTs of five second-generation antipsychotics (SGAs: olanzapine, paliperidone, quetiapine, risperidone and sertindole) and included a total of 4243 patients with schizophrenia. Insight was assessed with item G12 of the Positive and Negative Syndrome Scale (PANSS) at baseline and at six weeks.Overall, SGA treatment resulted in a significantly larger improvement in insight than placebo (0.43 points versus 0.15 points; Hedge׳s g 0.23; p<0.001). However this difference in improvement in insight was largely explained by improvement in other symptoms. In the initial analysis, one of the compounds was significantly less effective in improving insight than the other SGAs, but this difference no longer persisted when improvement in other symptoms was taken into account. The effect of SGAs on improvement in insight was not moderated by geographic region, illness duration or drop-out.The present study showed that SGA treatment of patients with schizophrenia is associated with improved insight, but that this improvement is associated with SGA induced improvements in other symptoms, though the causal relationship may not be established.
Keywords: schizophrenia; antipsychotics; insight; individual patient data;

Inverse agonists – What do they mean for psychiatry? by David Nutt; Stephen Stahl; Pierre Blier; Filippo Drago; Joseph Zohar; Sue Wilson (87-90).
The nomenclature of drugs is a critical aspect of science, since it can direct research and optimize treatment choices. Traditionally drugs acting on CNS receptors have been classified as either agonists or antagonists. Recently a new class of ligand, the inverse agonist, has been identified in some receptor systems. Inverse agonists have opposite actions to those of agonists but the effects of both of these can be blocked by antagonists. Pimavanserin is a new 5-HT2A receptor acting drug that has been given market authorization for psychosis in Parkinson׳s disease. The FDA have termed it an inverse agonist, but this conclusion is based on in-vitro data. In this paper we discuss the evidence for such a claim being made for pimavanserin in the human brain and conclude that this is not currently sufficient. It is therefore premature to conclude that the actions of pimavanserin in humans are due to inverse agonism, and we are of the opinion that it should be called a 5-HT2A antagonist until better evidence emerges.
Keywords: Inverse agonist; Antagonist; Serotonin; 5-HT2A;

Early introduction of clozapine after neuroleptic malignant syndrome may prevent malignant catatonia: A case report by G. van Rooijen; M. Strypet; A. Maat; D.S Scheepens; M.S. Oudijn; K.E. Klopper; D. Denys (91-92).